U.S. patent application number 13/270208 was filed with the patent office on 2012-04-12 for azole derivatives and fused bicyclic azole derivatives as therapeutic agents.
This patent application is currently assigned to TransTech Pharma, Inc.. Invention is credited to Robert C. Andrews, Kwasi S. Avor, Xin Chen, Ramesh Gopalaswamy, Xiao-Chuan Guo, Suparna Gupta, Anitha Hari, David R. Jones, Adnan M.M. Mjalli, Ghassan Qabaja.
Application Number | 20120088778 13/270208 |
Document ID | / |
Family ID | 27805104 |
Filed Date | 2012-04-12 |
United States Patent
Application |
20120088778 |
Kind Code |
A1 |
Mjalli; Adnan M.M. ; et
al. |
April 12, 2012 |
AZOLE DERIVATIVES AND FUSED BICYCLIC AZOLE DERIVATIVES AS
THERAPEUTIC AGENTS
Abstract
This invention provides certain compounds, methods of their
preparation, pharmaceutical compositions comprising the compounds,
and their use in treating human or animal disorders. The compounds
of the invention are useful as modulators of the interaction
between the receptor for advanced glycated end products (RAGE) and
its ligands, such as advanced glycated end products (AGEs),
S100/calgranulin/EN-RAGE, .beta.-amyloid and amphoterin, and for
the management, treatment, control, or as an adjunct treatment for
diseases in humans caused by RAGE. Such diseases or disease states
include acute and chronic inflammation, the development of diabetic
late complications such as increased vascular permeability,
nephropathy, atherosclerosis, and retinopathy, the development of
Alzheimer's disease, erectile dysfunction, and tumor invasion and
metastasis.
Inventors: |
Mjalli; Adnan M.M.;
(Jamestown, NC) ; Andrews; Robert C.; (Jamestown,
NC) ; Gopalaswamy; Ramesh; (Jamestown, NC) ;
Hari; Anitha; (High Point, NC) ; Avor; Kwasi S.;
(High Point, NC) ; Qabaja; Ghassan; (High Point,
NC) ; Guo; Xiao-Chuan; (High Point, NC) ;
Gupta; Suparna; (Greensboro, NC) ; Jones; David
R.; (Asheboro, NC) ; Chen; Xin; (High Point,
NC) |
Assignee: |
TransTech Pharma, Inc.
High Point
NC
|
Family ID: |
27805104 |
Appl. No.: |
13/270208 |
Filed: |
October 10, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12799971 |
May 5, 2010 |
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13270208 |
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11511163 |
Aug 28, 2006 |
7714013 |
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12799971 |
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10382203 |
Mar 5, 2003 |
7361678 |
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11511163 |
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60361983 |
Mar 5, 2002 |
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Current U.S.
Class: |
514/253.09 ;
514/254.05; 514/310; 514/326; 514/333; 514/341; 514/378; 514/397;
514/399 |
Current CPC
Class: |
A61P 11/06 20180101;
A61P 9/00 20180101; C07D 403/12 20130101; C07D 453/02 20130101;
C07D 235/18 20130101; A61P 9/10 20180101; A61P 13/12 20180101; C07D
405/12 20130101; C07D 235/12 20130101; C07D 235/30 20130101; A61P
3/10 20180101; A61P 43/00 20180101; A61P 17/00 20180101; A61P 35/04
20180101; A61P 15/10 20180101; A61P 11/00 20180101; C07D 401/06
20130101; A61P 25/28 20180101; C07D 405/04 20130101; C07D 233/64
20130101; C07D 413/12 20130101; A61P 29/00 20180101; C07D 235/08
20130101; C07D 401/04 20130101; C07D 403/14 20130101; A61P 27/02
20180101; A61P 35/00 20180101; C07D 235/14 20130101; C07D 401/14
20130101; C07D 401/12 20130101 |
Class at
Publication: |
514/253.09 ;
514/326; 514/310; 514/399; 514/254.05; 514/397; 514/378; 514/341;
514/333 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 31/4725 20060101 A61K031/4725; A61P 27/02
20060101 A61P027/02; A61P 9/10 20060101 A61P009/10; A61K 31/4178
20060101 A61K031/4178; A61K 31/422 20060101 A61K031/422; A61K
31/4439 20060101 A61K031/4439; A61K 31/444 20060101 A61K031/444;
A61K 31/454 20060101 A61K031/454; A61K 31/4164 20060101
A61K031/4164 |
Claims
1.-7. (canceled)
8. A method for treating retinopathy in a subject having
retinopathy comprising administering to the subject a
therapeutically effective amount of a compound of Formula (Ib):
##STR00628## wherein R.sub.1 is -hydrogen, -alkyl, or -alkenyl,
R.sub.3 is -hydrogen or -alkyl, and R.sub.102 and R.sub.104 are
independently selected from the group consisting of: a) --H, b)
-alkyl, c) -aryl, d) -heteroaryl, e) -alkylene-heteroaryl-aryl, f)
-alkylene-aryl, g) -alkylene-W.sub.2--R.sub.18, h)
--Y.sub.4--NR.sub.23R.sub.24, i)
--Y.sub.4--NH--C(.dbd.NR.sub.25)NR.sub.23R.sub.24, j)
--Y.sub.4--C(.dbd.NR.sub.25)NR.sub.23R.sub.24, and k)
--Y.sub.4--Y.sub.5-A.sub.2; wherein W.sub.2 is --CH.sub.2--, --O--,
--N(H), --S--, SO.sub.2--, --CON(H)--, --NHC(O)--, --NHCON(H)--,
--NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--, --NHSO.sub.2NH--,
--O--S(O).sub.2--, --O--CO--, ##STR00629## wherein R.sub.19 and
R.sub.20 are independently selected from the group consisting of:
-hydrogen, -aryl, -alkyl, -alkylene-aryl, -alkoxy, and
-alkylene-O-aryl; R.sub.18 is -aryl, -alkyl, -alkylene-aryl,
-alkylene-heteroaryl, or -alkylene-O-aryl; Y.sub.5 is a direct
bond, --CH.sub.2--, --O--, --N(H), --S--, SO.sub.2--, --C(O)--,
--CON(H)--, --NHC(O)--, --NHCON(H)--, --NHSO.sub.2--,
--SO.sub.2N(H)--, --C(O)--O--, --NHSO.sub.2NH--, --O--CO--,
##STR00630## wherein R.sub.27 and R.sub.26 are independently
selected from the group consisting of -aryl, -alkyl,
-alkylene-aryl, -alkoxy, and -alkyl-O-aryl; Y.sub.4 is a)
-alkylene, b) -alkenylene, c) -alkynylene, d) -arylene, e)
-heteroarylene, f) -cycloalkylene, g) -heterocyclylene, h)
-alkylene-arylene, i) -alkylene-heteroarylene, j)
-alkylene-cycloalkylene, k) -alkylene-heterocyclylene, l)
-arylene-alkylene, m) -heteroarylene-alkylene, n)
-cycloalkylene-alkylene, o) -heterocyclylene-alkylene, p) --O--, q)
--S--, r) --S(O.sub.2)--, or s) --S(O)--; wherein said alkylene
groups may optionally contain one or more O, S, S(O), or SO.sub.2
atoms; A.sub.2 is a) heterocyclyl, fused arylheterocyclyl, or fused
heteroarylheterocyclyl, containing at least one basic nitrogen
atom, or b) -imidazolyl, R.sub.23, R.sub.24, and R.sub.25 are
independently selected from the group consisting of: -hydrogen,
-aryl, -heteroaryl, -alkylene-heteroaryl, -alkyl, -alkylene-aryl,
-alkylene-O-aryl, and -alkylene-O-heteroaryl; and R.sub.23 and
R.sub.24 may be taken together to form a five-membered ring having
the formula --(CH.sub.2).sub.s--X.sub.3--(CH.sub.2).sub.t-- bonded
to the nitrogen atom to which R.sub.23 and R.sub.24 are attached
wherein s and t are, independently, 1, 2, 3, or 4; X.sub.3 is a
direct bond, --CH.sub.2--, --O--, --S--, --S(O.sub.2)--, --C(O)--,
--CON(H)--, --NHC(O)--, --NHCON(H)--, --NHSO.sub.2--,
--SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--, --NHSO.sub.2NH--,
##STR00631## wherein R.sub.28 and R.sub.29 are independently
selected from the group consisting of: -hydrogen, -aryl,
-heteroaryl, -alkyl, -alkylene-aryl, and -alkylene-heteroaryl;
wherein the alkyl and/or aryl groups of R.sub.102 and R.sub.104 may
be optionally substituted 1-4 times with a substituent group
selected from the group consisting of: a) halogen, b) perhaloalkyl,
c) alkyl, d) cyano, e) alkyloxy, f) aryl, and g) aryloxy wherein
the ring or rings containing a heteroatom in the heteroaryl,
heterarylene, heterocyclyl, heterocyclene, fused arylheterocyclyl,
or fused heteroarylheterocyclyl groups in R.sub.102 or R.sub.104 or
in a substituent of R.sub.102 or R.sub.104 is a five-membered
nitrogen containing ring, or a pharmaceutically acceptable salt
thereof, and wherein a therapeutically effective amount comprises
sufficient compound to at least partially inhibit the binding of a
ligand to RAGE.
9. The method according to claim 8, wherein the compound is mixed
with a pharmaceutically acceptable carrier.
10. The method according to claim 8, wherein the compound is
administered parenterally, orally, topically, rectally or by
inhalation as a spray.
11. The method according to claim 8, wherein the compound comprises
a dosage ranging from 0.01 to 500 mg/kg/day.
12. The method according to claim 8, wherein the compound comprises
a dosage ranging from 0.01 to 200 mg/kg/day.
13. The method according to claim 8, wherein the compound comprises
a dosage ranging from 0.1 to 100 mg/kg/day.
14. The method according to claim 8, wherein the compound comprises
a dosage ranging from 5 to 500 mg/kg/day.
15. A method for treating retinopathy in a subject having
retinopathy comprising administering to the subject a
therapeutically effective amount of
[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl-
}-phenoxy)-propyl]-diethyl-amine or a pharmaceutically acceptable
salt thereof, and wherein a therapeutically effective amount
comprises sufficient
[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-
-propyl]-diethyl-amine or a pharmaceutically acceptable salt
thereof to at least partially inhibit the binding of a ligand to
RAGE.
16. The method according to claim 15, wherein the
[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-
-propyl]-diethyl-amine or a pharmaceutically acceptable salt
thereof is mixed with a pharmaceutically acceptable carrier.
17. The method according to claim 15, wherein the
[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-
-propyl]-diethyl-amine or a pharmaceutically acceptable salt
thereof is administered parenterally, orally, topically, rectally
or by inhalation as a spray.
18. The method according to claim 15, wherein the
[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-
-propyl]-diethyl-amine or a pharmaceutically acceptable salt
thereof comprises a dosage ranging from 0.01 to 500 mg/kg/day.
19. The method according to claim 15, wherein the
[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-
-propyl]-diethyl-amine or a pharmaceutically acceptable salt
thereof comprises a dosage ranging from 0.01 to 200 mg/kg/day.
20. The method according to claim 15, wherein the
[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-
-propyl]-diethyl-amine or a pharmaceutically acceptable salt
thereof comprises a dosage ranging from 0.01 to 100 mg/kg/day.
21. The method according to claim 15, wherein the
[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-
-propyl]-diethyl-amine or a pharmaceutically acceptable salt
thereof comprises a dosage ranging from 5 to 500 mg/kg/day.
22. The method according to claim 8, wherein the retinopathy is
diabetic retinopathy.
23. The method according to claim 15, wherein the retinopathy is
diabetic retinopathy.
Description
STATEMENT OF RELATED APPLICATION
[0001] This application is a continuation application of pending
U.S. patent application Ser. No. 12/799,971, filed May 5, 2010,
entitled "Azole Derivatives and Fused Bicyclic Azole Derivatives as
Therapeutic Agents" which is a divisional application of U.S.
patent application Ser. No. 11/511,163, filed Aug. 28, 2006,
entitled "Azole Derivatives and Fused Bicyclic Azole Derivatives as
Therapeutic Agents," now issued as U.S. Pat. No. 7,714,013, which
is a divisional application of U.S. patent application Ser. No.
10/382,203, filed Mar. 5, 2003, entitled "Azole Derivatives and
Fused Bicyclic Azole," now issued as U.S. Pat. No. 7,361,678, which
claims priority under 35 U.S.C. .sctn.119(e) from U.S. Provisional
Application No. 60/361,983, filed Mar. 5, 2002, entitled "Azole
Derivatives as Therapeutic Agents." and which are each incorporated
by reference in their entitieties herewith.
FIELD OF THE INVENTION
[0002] This invention relates to compounds which are modulators of
the receptor for advanced glycated end products (RAGE) and
interaction with its ligands such as advanced glycated end products
(AGEs), S100/calgranulin/EN-RAGE, .beta.-amyloid and amphoterin,
for the management, treatment, control, or as an adjunct treatment
of diseases caused by RAGE.
BACKGROUND OF THE INVENTION
[0003] Incubation of proteins or lipids with aldose sugars results
in nonenzymatic glycation and oxidation of amino groups on proteins
to form Amadori adducts. Over time, the adducts undergo additional
rearrangements, dehydrations, and cross-linking with other proteins
to form complexes known as Advanced Glycosylation End Products
(AGEs). Factors which promote formation of AGEs included delayed
protein turnover (e.g. as in amyloidoses), accumulation of
macromolecules having high lysine content, and high blood glucose
levels (e.g. as in diabetes) (Hori et al., J. Biol. Chem. 270:
25752-761, (1995)). AGEs have implicated in a variety of disorders
including complications associated with diabetes and normal
aging.
[0004] AGEs display specific and saturable binding to cell surface
receptors on endothelial cells of the microvasculature, monocytes
and macrophages, smooth muscle cells, mesengial cells, and neurons.
The Receptor for Advanced Glycated Endproducts (RAGE) is a member
of the immunoglobulin super family of cell surface molecules. The
extracellular (N-terminal) domain of RAGE includes three
immunoglobulin-type regions, one V (variable) type domain followed
by two C-type (constant) domains (Neeper et al., J. Biol. Chem.
267:14998-15004 (1992)). A single transmembrane spanning domain and
a short, highly charged cytosolic tail follow the extracellular
domain. The N-terminal, extracellular domain can be isolated by
proteolysis of RAGE to generate soluble RAGE (sRAGE) comprised of
the V and C domains.
[0005] RAGE is expressed in most tissues, and in particular, is
found in cortical neurons during embryogenesis (Hoh et al., J.
Biol. Chem. 270:25752-761 (1995)). Increased levels of RAGE are
also found in aging tissues (Schleicher at al., J. Clin. Invest. 99
(3): 457-468 (1997)), and the diabetic retina, vasculature and
kidney (Schmidt et al., Nature Med. 1:1002-1004 (1995)). Activation
of RAGE in different tissues and organs leads to a number of
pathophysiological consequences. RAGE has been implicated in a
variety of conditions including: acute and chronic inflammation
(Hofmann at al., Cell 97:889-901 (1999)), the development of
diabetic late complications such as increased vascular permeability
(Wautier et al., J. Clin. Invest 97:238-243 (1995)), nephropathy
(Teillet et al., J. Am. Soc. Nephrol. 11:1488-1497 (2000)),
atherosclerosis (Vlassara et. al., The Finnish Medical Society
DUODECIM, Ann. Med. 28:419-426 (1996)), and retinopathy (Hammes et
al., Diabetologia 42:603-607 (1999)). RAGE has also been implicated
in Alzheimer's disease (Yan at al., Nature 382: 685-691, (1996)),
erectile dysfunction, and in tumor invasion and metastasis (Taguchi
at al., Nature 405: 354-357, (2000)).
[0006] In addition to AGEs, other compounds can bind to, and
modulate RAGE. In normal development, RAGE interacts with
amphoterin, a polypeptide which mediates neurite outgrowth in
cultured embryonic neurons (Hori et at, 1995). RAGE has also been
shown to interact with EN-RAGE, a protein having substantial
similarity to calgranulin (Hofmann et al., Cell 97:889-901 (1999)).
RAGE has also been shown to interact with .beta.-amyloid (Yan et
al., Nature 389:589-595, (1997); Yan et al., Nature 382:685-691
(1996); Yan et al., Proc. Natl Acad. Sci., 94:5296-5301
(1997)).
[0007] Binding of ligands such as AGEs, S100/calgranulin/EN-RAGE,
.beta.-amyloid, CML (N.sup..epsilon.--Carboxymethyl lysine), and
amphoterin to RAGE has been shown to modify expression of a variety
of genes. For example, in many cell types interaction between RAGE
and its ligands generates oxidative stress, which thereby results
in activation of the free radical sensitive transcription factor
NF-.kappa.B, and the activation of NF-.kappa.B regulated genes,
such as the cytokines IL-1.beta., TNF-.alpha., and the like. In
addition, several other regulatory pathways, such as those
involving p21 ras, MAP kinases, ERK1 and ERK2, have been shown to
be activated by binding of AGEs and other ligands to RAGE. In fact,
transcription of RAGE itself is regulated at least in part by
NF-.kappa.B. Thus, an ascending, and often detrimental, spiral is
fueled by a positive feedback loop initiated by ligand binding.
Antagonizing binding of physiological ligands to RAGE, therefore,
is our target for down-regulation of the pathophysiological changes
brought about by excessive concentrations of AGEs and other ligands
for RAGE.
[0008] Thus, there is a need for the development of compounds that
antagonize binding of physiological ligands to the RAGE
receptor.
SUMMARY OF THE INVENTION
[0009] This invention provides substituted benzimidazole compounds.
Embodiments of the present invention provide compounds of Formula
(I) as depicted below, methods of their preparation, pharmaceutical
compositions comprising the compounds, and methods for their use in
treating human or animal disorders. Compounds of the invention are
useful as modulators of the interaction of the receptor for
advanced glycated end products (RAGE) with its ligands such as
advanced glycated end products (AGEs), S100/calgranulin/EN-RAGE,
.beta.-amyloid and amphoterin. The compounds are useful in a
variety of applications including the management, treatment,
control, and/or as an adjunct of diseases in humans caused by RAGE.
Such diseases or disease states include acute and chronic
inflammation, the development of diabetic late complications such
as increased vascular permeability, nephropathy, atherosclerosis,
and retinopathy, the development of Alzheimer's disease, erectile
dysfunction, and tumor invasion and metastasis.
DETAILED DESCRIPTION OF THE INVENTION
[0010] In a first aspect, the present invention provides certain
substituted azole compounds. Such compounds are useful in the
modulation, preferably in the inhibition, of the interaction of
RAGE with its physiological ligands, as will be discussed in more
detail below.
[0011] In a second aspect, the present invention provides compounds
of Formula (I):
##STR00001##
wherein [0012] R.sub.1 comprises -hydrogen, -aryl, -heteroaryl,
-cycloalkyl, -heterocyclyl, -alkyl, -alkenyl, -alkynyl,
-alkylene-aryl, -alkylene-heteroaryl, -alkylene-heterocyclyl,
-alkylene-cycloalkyl, -fused cycloalkylaryl, -fused
cycloalkylheteroaryl, -fused heterocyclylaryl, -fused
heterocyclylheteroaryl, -alkylene-fused cycloalkylaryl,
-alkylene-fused cycloalkylheteroaryl, -alkylene-fused
heterocyclylaryl, -alkylene-fused heterocyclylheteroaryl, or
-G.sub.1-G.sub.2-G.sub.3-R.sub.5 [0013] wherein [0014] G.sub.1 and
G.sub.3 independently comprise alkylene, alkenylene, alkynylene,
cycloalkylene, heterocyclylene, arylene, heteroarylene,
(aryl)alkylene, (heteroaryl)alkylene, (aryl)alkenylene,
(heteroaryl)alkenylene, or a direct bond; [0015] G.sub.2 comprises
--O--, --S--, --S(O)--, --N(R.sub.6)--, --S(O).sub.2--, --C(O)--,
--O--C(O)--, --C(O)--O--, --C(O)N(R.sub.6)--, --N(R.sub.6)C(O)--,
--S(O.sub.2)N(R.sub.6)--, N(R.sub.6)S(O.sub.2)--,
--O-alkylene-C(O)--, --(O)C-alkylene-O--, --O-alkylene-,
-alkylene-O--, alkylene, alkenylene, alkynylene, cycloalkylene,
heterocyclylene, arylene, heteroarylene, fused cycloalkylarylene,
fused cycloalkylheteroarylene, fused heterocyclylarylene, fused
heterocyclylheteroarylene, or a direct bond, wherein R.sub.6
comprises hydrogen, aryl, alkyl, -alkylene-aryl, alkoxy, or
-alkylene-O-aryl; and [0016] R.sub.5 comprises hydrogen, aryl,
heteroaryl, cycloalkyl, heterocyclyl, alkyl, alkenyl, alkynyl,
-alkylene-aryl, -alkylene-heteroaryl, -alkylene-heterocyclyl,
-alkylene-cycloalkyl, fused cycloalkylaryl, fused
cycloalkylheteroaryl, fused heterocyclylaryl, fused
heterocyclylheteroaryl, -alkylene-fused cycloalkylaryl,
-alkylene-fused cycloalkylheteroaryl, -alkylene-fused
heterocyclylaryl, or -alkylene-fused heterocyclylheteroaryl; [0017]
A.sub.1 comprises O, S, or --N(R.sub.2)--; [0018] wherein [0019]
R.sub.2 comprises [0020] a) --H; [0021] b) -aryl; [0022] c)
-heteroaryl; [0023] d) -cycloalkyl [0024] e) heterocyclyl; [0025]
f) -alkyl; [0026] g) -alkenyl; [0027] h) -alkynyl; [0028] i)
-alkylene-aryl, [0029] j) -alkylene-heteroaryl, [0030] k)
-alkylene-heterocyclyl, [0031] l) -alkylene-cycloalkyl; [0032]
m)-fused cycloalkylaryl, [0033] n)-fused cycloalkylheteroaryl,
[0034] o) -fused heterocyclylaryl, [0035] p) -fused
heterocyclylheteroaryl; [0036] q) -alkylene-fused cycloalkylaryl,
[0037] r) -alkylene-fused cycloalkylheteroaryl, [0038] s)
-alkylene-fused heterocyclylaryl, [0039] t) -alkylene-fused
heterocyclylheteroaryl; or [0040] u) a group of the formula
[0040] ##STR00002## [0041] wherein A.sub.3 comprises an aryl or
heteroaryl group; L.sub.1 and L.sub.2 independently comprise
alkylene or alkenylene; and L.sub.3 comprises a direct bond,
alkylene, --O--, --S--, --S(O.sub.2)--, --C(O)--, --CON(H)--,
--NHC(O)--, --NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--,
--C(O)--O--, --O--C(O)--, --NHSO.sub.2NH--,
[0041] ##STR00003## wherein R.sub.30, R.sub.31, and R.sub.32
independently comprise hydrogen, aryl, heteroaryl, alkyl,
alkylene-aryl, or -alkylene-heteroaryl; [0042] R.sub.3 and R.sub.4
independently comprise [0043] a) -hydrogen, [0044] b) -halogen,
[0045] c)-hydroxyl, [0046] d) -cyano, [0047] e) -carbamoyl, [0048]
f) -carboxyl, [0049] g) -aryl, [0050] h) -heteroaryl, [0051] i)
-cycloalkyl, [0052] j) -heterocyclyl, [0053] k) -alkyl, [0054] l)
-alkenyl, [0055] m) -alkynyl, [0056] n) -alkylene-aryl, [0057] o)
-alkylene-heteroaryl, [0058] p) -alkylene-heterocyclyl, [0059] q)
-alkylene-cycloalkyl, [0060] r) -fused cycloalkylaryl, [0061] s)
-fused cycloalkylheteroaryl, [0062] t) -fused heterocyclylaryl,
[0063] u) -fused heterocyclylheteroaryl, [0064] v) -alkylene-fused
cycloalkylaryl, [0065] w) -alkylene-fused cycloalkylheteroaryl,
[0066] x) -alkylene-fused heterocyclylaryl, [0067] y)
-alkylene-fused heterocyclylheteroaryl; [0068] z) --C(O)--O-alkyl;
[0069] a) --C(O)--O-alkylene-aryl; [0070] bb) --C(O)--NH-alkyl;
[0071] cc) --C(O)--NH-alkylene-aryl; [0072] dd) --SO.sub.2-alkyl;
[0073] ee) --SO.sub.2-alkylene-aryl; [0074] ff) --SO.sub.2-aryl;
[0075] gg) --SO.sub.2--NH-alkyl; [0076] hh) --SO.sub.2--NH--
alkylene-aryl; [0077] ii) --C(O)-alkyl; [0078] jj)
--C(O)-alkylene-aryl; [0079] kk) -G.sub.4-G.sub.5-G.sub.6-R.sub.7;
[0080] ll) --Y.sub.1-alkyl; [0081] mm) --Y.sub.1-aryl; [0082] nn)
--Y.sub.1-heteroaryl; [0083] oo) --Y.sub.1-alkylene-aryl; [0084]
pp) --Y.sub.1-alkylene-heteroaryl; [0085] qq)
--Y.sub.1-alkylene-NR.sub.9R.sub.10; or [0086] rr)
--Y.sub.1-alkylene-M-R.sub.11; [0087] wherein [0088] G.sub.4 and
G.sub.6 independently comprise alkylene, alkenylene, alkynylene,
cycloalkylene, heterocyclylene, arylene, heteroarylene,
(aryl)alkylene, (heteroaryl)alkylene, (aryl)alkenylene,
(heteroaryl)alkenylene, or a direct bond; [0089] G.sub.5 comprises
--O--, --S--, --N(R.sub.8)--, --S(O)--, --S(O).sub.2--, --C(O)--,
--O--C(O)--, --C(O)--O--, --C(O)N(R.sub.8)--, N(R.sub.8)C(O)--,
--S(O.sub.2)N(R.sub.8)--, N(R.sub.8)S(O.sub.2)--,
--O-alkylene-C(O)--, --(O)C-alkylene-O--, --O-alkylene-,
-alkylene-O--, alkylene, alkenylene, alkynylene, cycloalkylene,
heterocyclylene, arylene, heteroarylene, fused cycloalkylarylene,
fused cycloalkylheteroarylene, fused heterocyclylarylene, fused
heterocyclylheteroarylene, or a direct bond, wherein R.sub.g
comprises -hydrogen, -aryl, -alkyl, -alkylene-aryl, or
-alkylene-O-aryl; [0090] R.sub.7 comprises hydrogen, aryl,
heteroaryl, cycloalkyl, heterocyclyl, alkyl, alkenyl, alkynyl,
alkylene-aryl, -alkylene-heteroaryl, -alkylene-heterocyclyl,
-alkylene-cycloalkyl, fused cycloalkylaryl, fused
cycloalkylheteroaryl, fused heterocyclylaryl, fused
heterocyclylheteroaryl, alkylene-fused cycloalkylaryl,
-alkylene-fused cycloalkylheteroaryl, -alkylene-fused
heterocyclylaryl, or -alkylene-fused heterocyclylheteroaryl; [0091]
Y.sub.1 and W.sub.1 independently comprise --CH.sub.2--, --O--,
--N(H), --S--, SO.sub.2--, --CON(H)--, --NHC(O)--, --NHCON(H)--,
--NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--, --NHSO.sub.2NH--,
--O--CO--,
[0091] ##STR00004## [0092] wherein R.sub.12 and R.sub.13
independently comprise aryl, alkyl,-alkylene-aryl, alkoxy, or
-alkylene-O-aryl; and [0093] R.sub.9, R.sub.10, and R.sub.11
independently comprise aryl, heteroaryl, alkyl,
-alkylene-heteroaryl, or -alkylene-aryl; and R.sub.9 and R.sub.10
may be taken together to form a ring having the formula
--(CH.sub.2).sub.o--X.sub.1--(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.9 and R.sub.10 are attached, [0094]
wherein o and p are, independently, 1, 2, 3, or 4; and X.sub.1
comprises a direct bond, --CH.sub.2--, --O--, --S--,
--S(O.sub.2)--, --C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--,
--NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--,
--NHSO.sub.2NH--,
[0094] ##STR00005## wherein R.sub.14 and R.sub.15 independently
hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl, or
-alkylene-heteroaryl; wherein [0095] the aryl and/or alkyl group(s)
in R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13, R.sub.14,
and R.sub.15 may be optionally substituted 1-4 times with a
substituent group, wherein said substituent group(s) or the term
substituted refers to a group comprising: [0096] a) --H, [0097] b)
-halogen, [0098] c) -hydroxyl, [0099] d)-cyano, [0100]
e)-carbamoyl, [0101] f)-carboxyl, [0102] g) --Y.sub.2-alkyl; [0103]
h) --Y.sub.2-aryl; [0104] i) --Y.sub.2-heteroaryl; [0105] j)
--Y.sub.2-alkylene-heteroarylaryl; [0106] k)
--Y.sub.2-alkylene-aryl; [0107] l)
--Y.sub.2-alkylene-W.sub.2--R.sub.15; [0108] m)
--Y.sub.3--Y.sub.4--NR.sub.23R.sub.24, [0109] n)
--Y.sub.3--Y.sub.4--NH--C(.dbd.NR.sub.25)NR.sub.23R.sub.24, [0110]
o) --Y.sub.3--Y.sub.4--C(.dbd.NR.sub.25)NR.sub.23R.sub.24, or
[0111] p) --Y.sub.3--Y.sub.4--Y.sub.5-A.sub.2, [0112] wherein
[0113] Y.sub.2 and W.sub.2 independently comprise --CH.sub.2--,
--O--, --N(H), --S--, SO.sub.2--, --CON(H)--, --NHC(O)--,
--NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--,
--NHSO.sub.2NH--, --O--S(O).sub.2--, --O--CO--,
[0113] ##STR00006## wherein; R.sub.19 and R.sub.20 independently
comprise hydrogen, aryl, alkyl, -alkylene-aryl, alkoxy, or
-alkylene-O-aryl; and [0114] R.sub.18 comprises aryl, alkyl,
-alkylene-aryl, -alkylene-heteroaryl, and -alkylene-O-aryl; [0115]
Y.sub.3 and Y.sub.5 independently comprise a direct bond,
--CH.sub.2--, --O--, --N(H), --S--, SO.sub.2--, --C(O)--,
--CON(H)--, --NHC(O)--, --NHCON(H)--, --NHSO.sub.2--,
--SO.sub.2N(H)--, --C(O)--O--, --NHSO.sub.2NH--, --O--CO--,
[0115] ##STR00007## wherein R.sub.27 and R.sub.26 independently
comprise aryl, alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;
[0116] Y.sub.4 comprises a) -alkylene; b) -alkenylene; c)
-alkynylene; d) -arylene; e) -heteroarylene; f) -cycloalkylene; g)
-heterocyclylene; h) -alkylene-arylene; i) -alkylene-heteroarylene;
j) -alkylene-cycloalkylene; k) -alkylene-heterocyclylene; l)
-arylene-alkylene; m) -heteroarylene-alkylene; n)
-cycloalkylene-alkylene; o) -heterocyclylene-alkylene; p) --O--; q)
--S--; r) --S(O.sub.2)--; or s) --S(O)--; wherein said alkylene
groups may optionally contain one or more O, S, S(O), or SO.sub.2
atoms; [0117] A.sub.2 comprises a) heterocyclyl, fused
arylheterocyclyl, or fused heteroarylheterocyclyl, containing at
least one basic nitrogen atom, b)-imidazolyl, or c)-pyridyl; and
[0118] R.sub.23, R.sub.24, and R.sub.25 independently comprise
hydrogen, aryl, heteroaryl, -alkylene-heteroaryl, alkyl,
-alkylene-aryl, -alkylene-O-aryl, or -alkylene-O-heteroaryl; and
R.sub.23 and R.sub.24 may be taken together to form a ring having
the formula --(CH.sub.2).sub.s--X.sub.3--(CH.sub.2).sub.t-- bonded
to the nitrogen atom to which R.sub.23 and R.sub.24 are attached
wherein s and t are, independently, 1, 2, 3, or 4; X.sub.3
comprises a direct bond, --CH.sub.2--, --O--, --S--,
--S(O.sub.2)--, --C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--,
--NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--,
--NHSO.sub.2NH--,
[0118] ##STR00008## wherein R.sub.25 and R.sub.29 independently
comprise hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl, or
-alkylene-heteroaryl; wherein [0119] either [0120] at least one of
the groups R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are substituted
with at least one group of the formula
--Y.sub.3--Y.sub.4--NR.sub.23R.sub.24,
--Y.sub.3--Y.sub.4--NH--C(.dbd.NR.sub.25)NR.sub.23R.sub.24,
--Y.sub.3--Y.sub.4--C(.dbd.NR.sub.25)NR.sub.23R.sub.24, or
--Y.sub.3--Y.sub.4--Y.sub.5-A.sub.2, with the proviso that no more
than one of R.sub.23, R.sub.24, and R.sub.25 may comprise aryl or
heteroaryl; [0121] or [0122] R.sub.2 is a group of the formula
##STR00009##
[0122] and wherein [0123] one of R.sub.3 and R.sub.4, R.sub.3 and
R.sub.2, or R.sub.1 and R.sub.2 may be taken together to
constitute, together with the atoms to which they are bonded, an
aryl, heteroaryl, fused arylcycloalkyl, fused arylheterocyclyl,
fused heteroarylcycloalkyl, or fused heteroarylheterocyclyl ring
system, [0124] wherein [0125] said ring system or R.sub.1, R.sub.2,
R.sub.3, or R.sub.4 is substituted with at least one group of the
formula [0126] a) --Y.sub.5--Y.sub.6--NR.sub.33R.sub.34; [0127] b)
--Y.sub.5--Y.sub.6--NH--C(.dbd.NR.sub.35)NR.sub.33R.sub.34; [0128]
c) --Y.sub.5--Y.sub.6--C(.dbd.NR.sub.35)NR.sub.33R.sub.34; or
[0129] d) --Y.sub.5--Y.sub.6--Y.sub.7-A.sub.4; [0130] wherein
[0131] Y.sub.5 and Y.sub.7 independently comprise a direct bond,
--CH.sub.2--, --O--, --N(H), --S--, SO.sub.2--, --CON(H)--,
--NHC(O)--, --NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--,
--C(O)--O--, --NHSO.sub.2NH--, --O--CO--,
[0131] ##STR00010## wherein R.sub.36 and R.sub.37 independently
comprise aryl, alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;
[0132] Y.sub.6 comprises a) alkylene; b) alkenylene; c) alkynylene;
d) arylene; e) heteroarylene; f) cycloalkylene; g) heterocyclylene;
h) alkylene-arylene; i) alkylene-heteroarylene; j)
alkylene-cycloalkylene; k) alkylene-heterocyclylene; l)
arylene-alkylene; m) heteroarylene-alkylene; n)
cycloalkylene-alkylene; j) heterocyclylene-alkylene; p) --O--; q)
--S--; r) --S(O.sub.2)--; or s)--S(O)--; wherein said alkylene
groups may optionally contain one or more O, S, S(O), or SO.sub.2
atoms; [0133] A.sub.4 comprises a) heterocyclyl, fused
arylheterocyclyl, or fused heteroarylheterocyclyl, containing at
least one basic nitrogen atom, b) -imidazolyl, or c) -pyridyl; and
[0134] R.sub.33, R.sub.34 and R.sub.35 independently comprise
hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl, or
-alkylene-O-aryl; with the proviso that no two of R.sub.33,
R.sub.34 and R.sub.35 are aryl and/or heteroaryl; and R.sub.33 and
R.sub.34 may be taken together to form a ring having the formula
--(CH.sub.2)--X.sub.4--(CH.sub.2).sub.n-- bonded to the nitrogen
atom to which R.sub.33 and R.sub.34 are attached, wherein u and v
are, independently, 1, 2, 3, or 4; X.sub.4 comprises a direct bond,
--CH.sub.2--, --O--, --S--, --S(O.sub.2)--, --C(O)--, --CONCH)--,
--NHC(O)--, --NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--,
--C(O)--O--, --O--C(O)--, --NHSO.sub.2NH--,
[0134] ##STR00011## wherein R.sub.36 and R.sub.37 independently
comprise hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl, or
-alkylene-heteroaryl; and [0135] wherein said ring system is
optionally substituted with substituents comprising [0136] a) --H;
[0137] b) -halogen; [0138] c) -hydroxyl; [0139] d) -cyano; [0140]
e) -carbamoyl; [0141] f) -carboxyl; [0142] g) --Y.sub.8-alkyl;
[0143] h) --Y.sub.8-aryl; [0144] i) --Y.sub.8-heteroaryl; [0145] j)
--Y.sub.1-alkylene-aryl; [0146] k) --Y.sub.8-alkylene-heteroaryl;
[0147] l) --Y.sub.8-alkylene-NR.sub.38R.sub.39; or [0148] m)
--Y.sub.5-alkylene-W.sub.3--R.sub.40; [0149] wherein Y.sub.8 and
W.sub.3 independently comprise --CH.sub.2--, --O--, --N(H), --S--,
SO.sub.2--, --CON(H)--, --NHC(O)--, --NHCON(H)--, --NHSO.sub.2--,
--SO.sub.2N(H)--, --C(O)--O--, --NHSO.sub.2NH--, --O--CO--,
[0149] ##STR00012## wherein R.sub.41 and R.sub.42 independently
comprise aryl, alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl; and
R.sub.38, R.sub.39, and R.sub.40 independently comprise hydrogen,
aryl, alkyl, -alkylene-aryl, -alkylene-heteroaryl, and
-alkyene-O-aryl; and R.sub.38 and R.sub.39 may be taken together to
form a ring having the formula
--(CH.sub.2).sub.w--X.sub.7--(CH.sub.2).sub.x-- bonded to the
nitrogen atom to which R.sub.38 and R.sub.39 are attached wherein w
and x are, independently, 1, 2, 3, or 4; X.sub.7 comprises a direct
bond, --CH.sub.2--, --O--, --S--, --S(O.sub.2)--, --C(O)--,
--CON(H)--, --NHC(O)--, --NHCON(H)--, --NHSO.sub.2--,
--SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--, --NHSO.sub.2NH--,
##STR00013## wherein R.sub.43 and R.sub.44 independently comprise
hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl, or
-alkylene-heteroaryl; or a pharmaceutically acceptable salt
thereof.
[0150] In a preferred embodiment, the compound of Formula (I)
comprises a compound of the Formula (Ia)
##STR00014##
wherein [0151] R.sub.1 comprises -hydrogen, -aryl, -heteroaryl,
-cycloalkyl, -heterocyclyl, -alkyl, -alkylene-aryl,
-alkylene-heteroaryl, -alkylene-heterocyclyl, -alkylene-cycloalkyl,
or -G.sub.1-G.sub.2-G.sub.3-R.sub.5 [0152] wherein [0153] G.sub.1
and G.sub.3 independently comprise alkylene or a direct bond;
[0154] G.sub.2 comprises --O--, --CO.sub.2--, or a direct bond; and
[0155] R.sub.5 comprises hydrogen, aryl, heteroaryl, cycloalkyl,
heterocyclyl, alkyl, alkenyl, alkynyl, -alkylene-aryl,
-alkylene-heteroaryl, -alkylene-heterocyclyl, or
-alkylene-cycloalkyl. [0156] R.sub.2 comprises [0157] a) -hydrogen,
[0158] b) -aryl, [0159] c) -heteroaryl, [0160] d) -heterocyclyl,
[0161] e) -alkyl, [0162] f) -alkylene-aryl, [0163] g)
-alkylene-heteroaryl, [0164] h) -alkylene-heterocyclyl, [0165] i)
-fused cycloalkylaryl, [0166] j) -fused cycloalkylheteroaryl,
[0167] k) -fused heterocyclylaryl, [0168] l) -fused
heterocyclylheteroaryl; [0169] m) -alkylene-fused cycloalkylaryl,
[0170] n) -alkylene-fused cycloalkylheteroaryl, [0171] o)
-alkylene-fused heterocyclylaryl, [0172] p) -alkylene-fused
heterocyclylheteroaryl; or [0173] q) a group of the formula
[0173] ##STR00015## [0174] wherein [0175] A.sub.3 comprises an aryl
or heteroaryl group; [0176] L.sub.1 and L.sub.2 independently
comprise alkylene or alkenylene; [0177] L.sub.3 comprises a direct
bond, alkylene, --O--, --S--, --S(O.sub.2)--, --C(O)--, --CON(H)--,
--NHC(O)--, --NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--,
--C(O)--O--, --O--C(O)--, --NHSO.sub.2NH--,
[0177] ##STR00016## [0178] wherein R.sub.30, R.sub.31, and R.sub.32
independently comprise hydrogen, aryl, heteroaryl, alkyl,
alkylene-aryl, or -alkylene-heteroaryl; [0179] R.sub.3 and R.sub.4
independently comprise [0180] a) -hydrogen; [0181] b) -halogen,
[0182] c) -hydroxyl, [0183] d) -cyano, [0184] e) -carbamoyl, [0185]
f) -carboxyl; [0186] g) -aryl, [0187] h) -heteroaryl, [0188] i)
-cycloalkyl, [0189] j) -heterocyclyl, [0190] k) -alkyl, [0191] l)
-alkenyl, [0192] m) -alkynyl, [0193] n) -alkylene-aryl, [0194] o)
-alkylene-heteroaryl, [0195] p) -alkylene-heterocyclyl, [0196] q)
-alkylene-cycloalkyl, [0197] r) -fused cycloalkylaryl, [0198] s)
-fused cycloalkylheteroaryl, [0199] t) -fused heterocyclylaryl,
[0200] u) -fused heterocyclylheteroaryl, [0201] v) -alkylene-fused
cycloalkylaryl, [0202] w) -alkylene-fused cycloalkylheteroaryl,
[0203] x) -alkylene-fused heterocyclylaryl, [0204] y)
-alkylene-fused heterocyclylheteroaryl; [0205] z) --C(O)--O-alkyl;
[0206] a) --C(O)--O-alkylene-aryl; [0207] bb) --C(O)--NH-alkyl;
[0208] cc) --C(O)--NH-alkylene-aryl; [0209] dd) --SO.sub.2-alkyl;
[0210] ee) --SO.sub.2-alkylene-aryl; [0211] ff) SO.sub.2-aryl;
[0212] gg) --SO.sub.2--NH-alkyl; [0213] hh) --SO.sub.2--NH--
alkylene-aryl [0214] ii) --C(O)-alkyl; [0215] jj)
--C(O)-alkylene-aryl; [0216] kk) -G.sub.4-G.sub.5-G.sub.6-R.sub.7
[0217] ll) --Y.sub.1-alkyl; [0218] mm) --Y.sub.1-aryl; [0219] nn)
--Y.sub.1-heteroaryl; [0220] oo) --Y.sub.1-alkylene-aryl; [0221]
pp) --Y.sub.1-aralkylene-heteroaryl; [0222] qq)
--Y.sub.1-alkylene-NR.sub.9R.sub.10; and [0223] rr)
--Y.sub.1-alkylene-W.sub.1--R.sub.11; [0224] wherein [0225] G.sub.4
and O.sub.6 independently comprise alkylene, alkenylene,
alkynylene, cycloalkylene, heterocyclylene, arylene, heteroarylene,
(arylalkylene, (heteroary)alkylene, (aryl)alkenylene,
(heteroaryl)alkenylene, or a direct bond; [0226] G.sub.5 comprises
--O--, --S--, --N(R.sub.8)--, --S(O)--, --S(O).sub.2--, --C(O)--,
--C(O)N(R.sub.8)--, N(R.sub.8)C(O)--, --S(O.sub.2)N(R.sub.8)--,
N(R.sub.8)S(O.sub.2)--, --O-alkylene-C(O)--, --(O)C-alkylene-O--,
--O-alkylene-, alkylene-O--, alkylene, alkenylene, alkynylene,
cycloalkylene, heterocyclylene, arylene, heteroarylene, fused
cycloalkylaryl, fused cycloalkylheteroaryl, fused heterocyclylaryl,
fused heterocyclylheteroaryl, or a direct bond, wherein R.sub.8
comprises -hydrogen, -aryl, -alkyl, -alkylene-aryl, or
-alkylene-O-aryl; [0227] R.sub.7 comprises hydrogen; aryl,
heteroaryl, cycloalkyl, heterocyclyl, alkyl, alkenyl, alkynyl,
alkylene-aryl, -alkylene-heteroaryl, -alkylene-heterocyclyl,
-alkylene-cycloalkyl, fused cycloalkylaryl, fused
cycloalkylheteroaryl, fused heterocyclylaryl, fused
heterocyclylheteroaryl, alkylene-fused cycloalkylaryl,
-alkylene-fused cycloalkylheteroaryl, -alkylene-fused
heterocyclylaryl, or -alkylene-fused heterocyclylheteroaryl; [0228]
Y.sub.1 and W.sub.1 independently comprise --CH.sub.2--, --O--,
--N(H), --S--, SO.sub.2--, --CON(H)--, --NHC(O)--, --NHCON(H)--,
--NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--, --NHSO.sub.2NH--,
--O--CO--,
[0228] ##STR00017## [0229] wherein R.sub.12 and R.sub.13
independently comprise aryl, alkyl,-alkylene-aryl, alkoxy, or
-alkylene-O-aryl; [0230] R.sub.9, R.sub.10, and R.sub.11
independently comprise aryl, heteroaryl, alkyl,
-alkylene-heteroaryl, or -alkylene-aryl; and R.sub.9 and R.sub.10
may be taken together to form a ring having the formula
--(CH.sub.2).sub.o--X.sub.1--(CH.sub.2).sub.p-- bonded to the
nitrogen atom to which R.sub.9 and R.sub.10 are attached, [0231]
wherein o and p are, independently, 1, 2, 3, or 4; X.sub.1
comprises a direct bond, --CH.sub.2--, --O--, --S--,
--S(O.sub.2)--, --C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--,
--NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--,
--NHSO.sub.2NH--,
[0231] ##STR00018## [0232] with the proviso that R.sub.3 and
R.sub.4 can not both be hydrogen.
[0233] In one group of preferred embodiments of Formula (Ia),
R.sub.1 comprises a hydrogen, methyl, ethyl, propyl, butyl,
iso-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
3-butenyl, tert-butyl, 3-cyclohexyl-propyl, 3-phenoxy-propyl,
methoxymethyl, 4-fluoro-phenyl, 3-(4-chlorophenoxy)-propyl,
2,4,4-trimethyl-pentyl, 1-ethyl-propyl, 1-propyl-butyl,
benzyloxymethyl, 2-cyclopropy-ethyl, 2-phenyl-ethyl,
4-tert-butylphenoxymethyl, 4-tert-butylcyclohexyl,
4-butylcyclohexyl , 4-ethylcyclohexyl, 3-methoxycarbonyl-1-propyl,
or 2-(pyridin-3-yl)-ethyl group.
[0234] In another group of preferred embodiments of Formula (Ia),
R.sub.2 comprises a phenyl or 1,2,3,4-tetrahydroisoquinoline group,
wherein the phenyl group is substituted with at least one
substitutent comprising [0235] a) --Y.sub.2-alkyl; [0236] b)
--Y.sub.2-aryl; [0237] c) --Y.sub.2-heteroaryl; [0238] d)
--Y.sub.2-alkylene-heteroarylaryl; [0239] e)
--Y.sub.2-alkylene-aryl; --Y.sub.2-alkylene-W.sub.2--R.sub.18;
[0240] g) --Y.sub.3--Y.sub.4--NR.sub.23R.sub.24; [0241] h)
--Y.sub.3--Y.sub.4--NH--C(.dbd.NR.sub.25)NR.sub.23R.sub.24; [0242]
i) --Y.sub.3--Y.sub.4--C(.dbd.NR.sub.25)NR.sub.23R.sub.24; or
[0243] j) --Y.sub.3--Y.sub.4--Y.sub.5-A.sub.2; [0244] wherein
[0245] Y.sub.2 and W.sub.2 independently comprise --CH.sub.2-- or
--O--, and [0246] R.sub.18 comprises aryl, alkyl, -alkylene-aryl,
-alkylene-heteroaryl, or -alkylene-O-aryl; [0247] Y.sub.3 and
Y.sub.5 independently comprise a direct bond, --CH.sub.2--, --O--,
--N(H), --S--, SO.sub.2--, --C(O)--, --CON(H)--, --NHC(O)--,
--NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--, --NHSO.sub.2NH--,
--O--CO--,
[0247] ##STR00019## [0248] wherein R.sub.27 and R.sub.26
independently comprise aryl, alkyl, -alkylene-aryl, alkoxy, or
-alkyl-O-aryl; [0249] Y.sub.4 comprises [0250] a) -alkylene; [0251]
b) -alkenylene; [0252] c) -alkynylene; [0253] d) -arylene; [0254]
e) -heteroarylene; [0255] f) -cycloalkylene; [0256] g)
-heterocyclylene; [0257] h) -alkylene-arylene; [0258] i)
-alkylene-heteroarylene; [0259] j) -alkylene-cycloalkylene; [0260]
k) -alkylene-heterocyclylene; [0261] l) -arylene-alkylene; [0262]
m) -heteroarylene-alkylene; [0263] n) -cycloalkylene-alkylene;
[0264] t) -heterocyclylene-alkylene; [0265] u) --O--; [0266] v)
--S--; [0267] w) --S(O.sub.2)--; or [0268] x) --S(O)--; wherein
said alkylene groups may optionally contain one or more O, S, S(O),
or SO.sub.2 atoms; [0269] A.sub.2 comprises [0270] a) heterocyclyl,
fused arylheterocyclyl, or fused heteroarylheterocyclyl, containing
at least one basic nitrogen atom, [0271] b) -imidazolyl, or [0272]
c) -pyridyl; and [0273] R.sub.23, R.sub.24, and R.sub.25
independently comprise hydrogen, aryl, heteroaryl,
-alkylene-heteroaryl, alkyl, -alkylene-aryl, -alkylene-O-aryl, or
-alkylene-O-heteroaryl; and R.sub.23 and R.sub.24 may be taken
together to form a ring having the formula
--(CH.sub.2).sub.s--X.sub.3--(CH.sub.2).sub.t-- bonded to the
nitrogen atom to which R.sub.23 and R.sub.24 are attached [0274]
wherein s and t are, independently, 1, 2, 3, or 4; X.sub.3
comprises direct bond, --CH.sub.2--, --O--, --S--, --S(O.sub.2)--,
--C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--, --NHSO.sub.2--,
--SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--, --NHSO.sub.2NH--,
[0274] ##STR00020## wherein R.sub.28 and R.sub.29 independently
comprise hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl, or
-alkylene-heteroaryl.
[0275] In another group of preferred embodiments of compounds of
Formula (Ia), R.sub.2 comprises
4-[3-(N,N'-diethylamino)-propoxy]-phenyl,
4-[3-(N,N'-dimethylamino)-propoxy]-phenyl,
3-[3-(N,N'-diethylamino)-propoxy]-phenyl,
4-(3-fluoro-4-trifluoromethyl-phenoxy)-phenyl,
4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl,
4-(4-trifluoromethoxy-phenoxy)-phenyl,
4-(3,4-dichloro-phenoxy)-phenyl,
4-(3,5-bis-trifluoromethyl-phenoxy)-phenyl, 4-benzyloxy-phenyl,
4-(4-methyloxy-phenoxy)-phenyl,
4-(2-hexyl-4-chloro-phenoxy)-phenyl, 4-(4-phenyl-phenoxy)-phenyl,
4-(4-acetamido-phenoxy)-phenyl, 4-(4-methyl-phenoxy)-phenyl,
4-(4-fluoro-phenoxy)-phenyl, 4-(4-bromo-phenoxy)-phenyl,
4-(4-chloro-phenoxy)-phenyl, 4-(4-amino-phenoxy)-phenyl,
4-(3-ethyl-4-chloro-phenoxy)-phenyl,
4-[2-(N-ethylamino)-ethoxy]-phenyl,
4-[2,2'-dimethyl-3-(N,N'-dimethylamino)-propoxy]-phenyl,
1,2,3,4-tetrahydroisoquinolin-7-yl, 4-(4-benzamido-phenoxy)-phenyl,
4-(4-isonicotinamido-phenoxy)-phenyl,
4-[2-(N-methyl-N'-pyrid-4-yl)-ethoxy]-phenyl, 4-[3-(diethylmethyl
ammonium)-propoxy)]-phenyl, 4-(2,5-di-fluoro-benzyloxy)-phenyl,
4-(2,4-dichloro-phenoxy)-phenyl, 4-(naphthalen-2-yloxy)-phenyl,
4-(6-methoxy-naphthalen-2-yloxy)-phenyl,
4-(4-methoxy-naphthalen-2-yloxy)-phenyl,
4-(6-hydroxy-naphthalen-2-yloxy)-phenyl,
4-(dibenzofuran-2-yloxy)-phenyl,
4-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl,
4-[2-(piperazin-1-yl)-ethoxy]-phenyl, or
4-(4-tert-butyl-phenoxy)-phenyl.
[0276] In another group of preferred embodiments of Formula (Ia),
R.sub.3 comprises hydrogen; and R.sub.4 comprises a phenyl group,
wherein the phenyl group is substituted with at least one
substituent comprising [0277] a) --Y.sub.2-alkyl; [0278] b)
--Y.sub.2-aryl; [0279] c)--Y.sub.2-heteroaryl; [0280] d)
--Y.sub.2-alkylene-heteroarylaryl; [0281]
e)--Y.sub.2-alkylene-aryl; [0282] f)
--Y.sub.2-alkylene-W.sub.2--R.sub.18; [0283] g)
--Y.sub.3--Y.sub.4--NR.sub.23R.sub.24; [0284] h)
--Y.sub.3--Y.sub.4--NH--C(.dbd.NR.sub.25)NR.sub.23R.sub.24; [0285]
i) --Y.sub.3--Y.sub.4--C(.dbd.NR.sub.25)NR.sub.23R.sub.24; or
[0286] j) --Y.sub.3--Y.sub.4--Y.sub.5-A.sub.2; [0287] wherein
[0288] Y.sub.2 and W.sub.2 independently comprise --CH.sub.2-- or
--O--; [0289] R.sub.18 comprises aryl, alkyl, -alkylene-aryl,
-alkylene-heteroaryl, or -alkylene-O-aryl; [0290] Y.sub.3 and
Y.sub.5 independently comprise a direct bond, --CH.sub.2--, --O--,
--N(H), --S--, SO.sub.2--, --C(O)--, --CON(H)--, --NHC(O)--,
--NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--,
--NHSO.sub.2NH--, --O--CO--,
[0290] ##STR00021## [0291] wherein R.sub.27 and R.sub.26
independently comprise aryl, alkyl, -alkylene-aryl, alkoxy, or
-alkyl-O-aryl; [0292] Y.sub.4 comprises [0293] a) -alkylene; [0294]
b) -alkenylene; [0295] c) -alkynylene; [0296] d) -arylene; [0297]
e) -heteroarylene; [0298] f) -cycloalkylene; [0299] g)
-heterocyclylene; [0300] h) -alkylene-arylene; [0301] i)
-alkylene-heteroarylene; [0302] j) -alkylene-cycloalkylene; [0303]
k) -alkylene-heterocyclylene; [0304] l)-arylene-alkylene; [0305] m)
-heteroarylene-alkylene; [0306] n) -cycloalkylene-alkylene; [0307]
o) -heterocyclylene-alkylene; [0308] p) --O--; [0309] q) --S--;
[0310] r) --S(O.sub.2)--; or [0311] s) --S(O)--; wherein said
alkylene groups may optionally contain one or more O, S, S(O), or
SO.sub.2 atoms; [0312] A.sub.2 comprises [0313] a) heterocyclyl,
fused arylheterocyclyl, or fused heteroarylheterocyclyl, containing
at least one basic nitrogen atom, [0314] b) -imidazolyl, or [0315]
c) -pyridyl; [0316] R.sub.23, R.sub.24, and R.sub.25 independently
comprise hydrogen, aryl, heteroaryl, -alkylene-heteroaryl, alkyl,
-alkylene-aryl, -alkylene-O-aryl, or -alkylene-O-heteroaryl; and
R.sub.23 and R.sub.24 may be taken together to form a ring having
the formula --(CH.sub.2).sub.s--X.sub.3--(CH.sub.2).sub.t-- bonded
to the nitrogen atom to which R.sub.23 and R.sub.24 are attached
[0317] wherein s and t are, independently, 1, 2, 3, or 4; X.sub.3
comprises direct bond, --CH.sub.2--, --O--, --S--, --S(O.sub.2)--,
--C(O)--, CON(H)--, --NHC(O)--, --NHCON(H)--, --NHSO.sub.2--,
--SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--, --NHSO.sub.2NH--,
[0317] ##STR00022## wherein R.sub.28 and R.sub.29 independently
comprise hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl, or
-alkylene-heteroaryl.
[0318] In a more preferred group of compounds of Formula (Ia),
R.sub.3 comprises hydrogen and R.sub.4 comprises
4-{2-[(4-chlorophenyl)-ethoxy]}-phenyl,
4-[3-(N,N'-diethylamino)-propoxy]-phenyl,
4-(2-amino-ethoxy)-phenyl,
4-[2-(N-methyl-N'-pyridin-4-yl-amino)-ethoxy]-phenyl,
4-[2-(N-ethyl-N'-pyridin-4-yl-amino)-ethoxy]-phenyl,
4-[2-(N-pyridin-4-yl-amino)-ethoxy]-phenyl,
4-(4-amino-pyridin-3-yl-oxy)-phenyl,
4-[(pyridin-4-yl)-amino]-phenyl,
4-[2-(N,N'-bis-pyridin-2-ylmethyl-amino)-ethoxy]-phenyl,
4-[2-(guanidinyl)-ethoxy]-phenyl,
4-{2-[4-(pyridin-4-yl)-piperazin-1-yl]-2-oxo-ethoxy}-phenyl,
4-[2-(N-methyl-N'-3-methylpyridin-4-yl-amino)-ethoxy]-phenyl,
4-(4-hydroxy-pyrrolidin-2-ylmethyloxy)-phenyl,
4-(4-amino-3,5-dimethyl-pyrrolidin-2-ylmethyloxy)-phenyl,
dibenzofuran-2-yl, 4-[3-(piperazin-1-yl)-propoxy]-phenyl,
4-(piperazin-4-yloxy)-phenyl,
4-[5-(piperazin-1-yl)-pentoxy]-phenyl,
4-[3-(N,N'-dimethylamino)-propoxy]-phenyl,
4-(3-fluoro-4-trifluoromethyl-phenoxy)-phenyl,
4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl,
4-(4-phenyl-phenoxy)-phenyl, 4-(3-trifluoromethoxy-phenoxy)-phenyl,
4-(4-trifluoromethyl-benzyloxy)-phenyl,
4-(3,4-dichloro-phenoxy)-phenyl, 4-(2,4-dichloro-phenoxy)-phenyl,
4-(1-ethyl-piperidin-3-yloxy)-phenyl, 4-benzyloxy-phenyl,
4-[(1-ethyl-piperidin-3-yl)-methoxy]-phenyl,
4-(4-phenoxy-benzyloxy)-phenyl, 4-(4-benzyloxy-benzyloxy)-phenyl,
4-(2-benzenesulfonylmethyl-benzyloxy)-phenyl,
4-(3,4,5-trimethoxybenzoyloxy)-phenyl,
4-[2-(pyrrolidin-1-yl)-ethoxy]-phenyl,
442-(piperidin-1-yl)-ethoxy]-phenyl,
4-[2,2'-dimethyl-3-(N,N'-dimethylamino)-propoxy]-phenyl,
4-[2-(N,N'-diisopropylamino)-ethoxy]-phenyl,
4-(adamantan-1-ylmethoxy)-phenyl,
3-[(2,6-dichlorophenyl)-4-methyl-isoxazol-5-ylmethyloxy]-phenyl,
4-(4-bromo-benzyloxy)-phenyl, 4-(4-chlorophenoxy)-phenyl,
4-[4-{(1-ethyl-piperidin-4-yl)-methylamino}-phenoxy]-phenyl,
4-(3,3-diphenylpropoxy)-phenyl,
4-[3,3-Bis-(4-fluorophenyl)-propoxy]-phenyl,
4-[3,3-Bis-(4-chlorophenyl)-allyoxy]-phenyl,
4-(4-chlorophenoxy)-naphthalenyl,
4-[2-(biphenyl-4-yl)-acetamido]-phenyl,
4-(2-(9H-carbazole)-ethoxy]-phenyl, 4-[4-methoxyphenyoxy]-phenyl,
4-(4-tert-butyl-phenoxy)-phenyl, or
4-(naphthylen-2-ylmethoxy)-phenyl.
[0319] In another preferred embodiment, the compound Formula (I)
comprises the compound of Formula (Ib),
##STR00023##
wherein [0320] R.sub.1 comprises -hydrogen, -aryl, -heteroaryl,
-cycloalkyl, -heterocyclyl, -alkyl, -alkenyl, -alkylene-aryl,
-alkylene-heteroaryl, -alkylene-heterocyclyl, -alkylene-cycloalkyl,
-fused cycloalkylaryl, -fused cycloalkylheteroaryl, -fused
heterocyclylaryl, -fused heterocyclylheteroaryl, -alkylene-fused
cycloalkylaryl, -alkylene-fused cycloalkylheteroaryl,
-alkylene-fused heterocyclylaryl, -alkylene-fused
heterocyclylheteroaryl, or -G.sub.1-G.sub.2-G.sub.3-R.sub.5 [0321]
wherein [0322] G.sub.1 and G.sub.3 independently comprise alkylene,
alkenylene, alkynylene, cycloalkylene, heterocyclylene, arylene,
heteroarylene, (aryl)alkylene, (heteroaryl)alkylene,
(aryl)alkenylene, (heteroaryl)alkenylene, or a direct bond; [0323]
G.sub.2 comprises --O--, --S--, --S(O)--, --N(R.sub.6)--,
--S(O).sub.2--, --C(O)--, --CO.sub.2--, --C(O)N(R.sub.6)--,
N(R.sub.6)C(O)--, --S(O.sub.2)N(R.sub.6)--, N(R.sub.6)S(O.sub.2)--,
--O-alkylene-C(O)--, --(O)C-alkylene-O--, --O-alkylene-,
-alkylene-O--, alkylene, alkenylene, alkynylene, cycloalkylene,
heterocyclylene, arylene, heteroarylene, fused cycloalkylaryl,
fused cycloalkylheteroaryl, fused heterocyclylaryl, fused
heterocyclylheteroaryl, or a direct bond, wherein R.sub.6 comprises
hydrogen, aryl, alkyl, -alkylene-aryl, alkoxy, or -alkylene-O-aryl;
and [0324] R.sub.5 comprises hydrogen, aryl, heteroaryl,
cycloalkyl, heterocyclyl, alkyl, alkenyl, alkynyl, -alkylene-aryl,
-alkylene-heteroaryl, -alkylene-heterocyclyl, -alkylene-cycloalkyl,
fused cycloalkylaryl, fused cycloalkylheteroaryl, fused
heterocyclylaryl, fused heterocyclylheteroarylalkylene-fused
cycloalkylaryl, -alkylene-fused cycloalkylheteroaryl,
-alkylene-fused heterocyclylaryl, or -alkylene-fused
heterocyclylheteroaryl; [0325] R.sub.3 comprises hydrogen or an
alkyl group; and [0326] R.sub.102 and R.sub.104 independently
comprise [0327] a) --H; [0328] b) -alkyl; [0329] c) -aryl; [0330]
d) -heteroaryl; [0331] e) -alkylene-heteroarylaryl; [0332] f)
-alkylene-aryl; [0333] g) -alkylene-W.sub.2--R.sub.16; [0334] h)
--Y.sub.4--NR.sub.23R.sub.24; [0335] l)
--Y.sub.4--NH--C(.dbd.NR.sub.25)NR.sub.23R.sub.24; [0336] j)
--Y.sub.4--C(.dbd.NR.sub.25)NR.sub.23R.sub.24; or [0337] k)
--Y.sub.4--Y.sub.5-A.sub.2; [0338] wherein [0339] W.sub.2 comprises
--CH.sub.2--, --O--, --N(H), --S--, SO.sub.2--, --CON(H)--,
--NHC(O)--, --NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--,
--C(O)--O--, --NHSO.sub.2NH--, --O--S(O).sub.2--, --O--CO--,
[0339] ##STR00024## wherein R.sub.19 and R.sub.20 independently
comprise hydrogen, aryl, alkyl, -alkylene-aryl, alkoxy, or
-alkylene-O-aryl; and [0340] R.sub.18 comprises aryl, alkyl,
-alkylene-aryl, -alkylene-heteroaryl, and -alkylene-O-aryl; [0341]
Y.sub.5 comprises a direct bond, --CH.sub.2--, --O--, --N(H),
--S--, SO.sub.2--, --C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--,
--NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--, --NHSO.sub.2NH--,
--O--CO--,
[0341] ##STR00025## wherein R.sub.27 and R.sub.26 independently
comprise aryl, alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;
[0342] Y.sub.4 comprises a) -alkylene; b) -alkenylene; c)
-alkynylene; d) -arylene; e) -heteroarylene; f) -cycloalkylene; g)
-heterocyclylene; h) -alkylene-arylene; i) -alkylene-heteroarylene;
j) -alkylene-cycloalkylene; k) -alkylene-heterocyclylene; l)
-arylene-alkylene; m) -heteroarylene-alkylene; n)
-cycloalkylene-alkylene; o) -heterocyclylene-alkylene; p) --O--; q)
--S--; r) --S(O.sub.2)--; or s) --S(O)--; wherein said alkylene
groups may optionally contain one or more O, S, S(O), or SO.sub.2
atoms; [0343] A.sub.2 comprises a) heterocyclyl, fused
arylheterocyclyl, or fused heteroarylheterocyclyl, containing at
least one basic nitrogen atom, b) -imidazolyl, or c) -pyridyl;
[0344] R.sub.23, R.sub.24, and R.sub.25 independently comprise
hydrogen, aryl, heteroaryl, -alkylene-heteroaryl, alkyl,
-alkylene-aryl, -alkylene-O-aryl, or -alkylene-O-heteroaryl; and
R.sub.23 and R.sub.24 may be taken together to form a ring having
the formula --(CH.sub.2).sub.s--X.sub.3--(CH.sub.2).sub.r bonded to
the nitrogen atom to which R.sub.23 and R.sub.24 are attached
wherein s and t are, independently, 1, 2, 3, or 4; X.sub.3
comprises direct bond, --CH.sub.2--, --O--, --S--, --S(O.sub.2)--,
--C(O)--, --CON(H)--, --NHC(O)--, --NHCON(H)--, --NHSO.sub.2--,
--SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--, --NHSO.sub.2NH--,
[0344] ##STR00026## wherein R.sub.28 and R.sub.29 independently
comprise hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl, or
-alkylene-heteroaryl; [0345] wherein [0346] the alkyl and/or aryl
groups of R.sub.102 and R.sub.104 may be optionally substituted 1-4
times with a substituent group, wherein said substituent group(s)
or the term substituted refers to a group comprising: [0347] a)
halogen; [0348] b) perhaloalkyl; [0349] c) alkyl; [0350] d) cyano;
[0351] e) alkyloxy; [0352] f) aryl; or [0353] g) aryloxy.
[0354] In a group of preferred embodiments of the compound of
Formula (Ib), R.sub.1 comprises a hydrogen, methyl, ethyl, propyl,
butyl, iso-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
3-butenyl, tert-butyl, 3-cyclohexyl-propyl, 3-phenoxy-propyl,
methoxymethyl, 4-fluoro-phenyl, 3-(4-chlorophenoxy)-propyl,
2,4,4-trimethyl-pentyl, 1-ethyl-propyl, 1-propyl-butyl,
benzyloxymethyl, 2-cyclopropy-ethyl, 2-phenyl-ethyl,
4-tert-butylphenoxymethyl, 4-tert-butylcyclohexyl,
4-ethylcyclohexyl, 4-butylcyclohexyl, 3-methoxycarbonyl-1-propyl,
or 2-(pyridin-3-yl)-ethyl group, and R.sub.3 comprises
hydrogen.
[0355] In another group of preferred embodiments of the compound of
Formula (Ib), R.sub.102 and R.sub.104 independently comprise
2-(4-chlorophenyl)-ethyl, 3-(N,N'-diethylamino)-propyl,
2-amino-ethyl, 2-(N-methyl-N'-pyridin-4-yl-amino)-ethyl,
2-(N-ethyl-N'-pyridin-4-yl-amino)-ethyl,
2-(N-pyridin-4-yl-amino)-ethoxy, 4-(4-amino-pyridin-3-yl-oxy),
4-(pyridin-4-yl)-amino,
2-(N,N'-bis-pyridin-2-ylmethyl-amino)-ethyl, 2-(guanidinyl)-ethyl,
2-[4-(pyridin-4-yl)-piperazin-1-yl]-2-oxo-ethyl,
2-(N-methyl-N'-3-methylpyridin-4-yl-amino)-ethyl,
4-hydroxy-pyrrolidin-2-ylmethyl,
4-amino-3,5-dimethyl-pyrrolidin-2-ylmethyl, dibenzofuran-2-yl,
3-(piperazin-1-yl)-propyl, piperazin-4-yl,
5-(piperazin-1-yl)-pentyl, 3-(N,N'-dimethylamino)-propyl,
3-fluoro-4-trifluoromethyl-phenyl,
4-fluoro-3-trifluoromethyl-phenyl, 4-phenyl-phenyl,
3-trifluoromethoxy-phenyl, 4-trifluoromethyl-benzyl,
3,4-dichloro-phenyl, 2,4-dichloro-phenyl, 1-ethyl-piperidin-3-yl,
benzyl, (1-ethyl-piperidin-3-yl)-methyl, 4-phenoxy-benzyl,
4-benzyloxy-benzyl, 2-benzenesulfonylmethyl-benzyl,
3,4,5-trimethoxybenzyl, 2-(pyrrolidin-1-yl)-ethyl,
2-(piperidin-1-yl)-ethyl,
2,2'-dimethyl-3-(N,N'-dimethylamino)-propyl,
2-(N,N'-diisopropylamino)-ethyl,
3-(2,6-dichlorophenyl)-4-methyl-isoxazol-5-ylmethyl,
4-bromo-benzyl, 4-chlorophenyl,
4-{(1-ethyl-piperidin-4-yl)-methylamino}-phenyl,
3,3-diphenylpropyl, 3,3-Bis-(4-fluorophenyl)-propyl,
3,3-Bis-(4-chlorophenyl)-allyl, 4-(4-chlorophenoxy)-naphthalenyl,
4-[2-(biphenyl-4-yl)-acetamido]-phenyl, 2-(9H-carbazole)-ethyl,
4-methoxyphenyl, 4-tert-butyl-phenyl, or naphthylen-2-ylmethyl.
[0356] In another group of preferred embodiments of the compound of
Formula (Ib), R.sub.1 comprises -alkyl,
-alkylene-cycloalkylene-alkyl, -cycloalkyl, -heterocyclyl,
-alkylene-cycloalkyl, -alkylene-heteroaryl, -alkylene-heterocyclyl,
or -alkylene-heterocyclylene-alkyl; R.sub.3 comprises hydrogen;
R.sub.102 comprises -aryl or -alkylene-aryl substituted with at
least one of a halogen, a perhaloalkyl, or an alkoxy group; and
R.sub.104 comprises --Y.sub.4--NR.sub.23R.sub.24 or
--Y.sub.4--Y.sub.5-A.sub.2.
[0357] In another group of preferred embodiments of the compound of
Formula (Ib), R.sub.1 comprises -heterocyclyl,
heterocyclylene-heteroaryl, -alkylene-cycloalkyl,
-alkylene-heteroaryl, -alkylene-heterocyclyl, or
-alkylene-heterocyclylene-alkyl; R.sub.3 comprises hydrogen; and
R.sub.102 and R.sub.104 independently comprise -aryl or
-alkylene-aryl, wherein the alkyl or ary groups are optionally
substituted with at least one of a halogen, a perhaloalkyl, or an
alkoxy group, and wherein at least one of R.sub.102 and R.sub.104
comprise --Y.sub.4--NR.sub.23R.sub.24 or
--Y.sub.4--Y.sub.5-A.sub.2, wherein Y.sub.4 comprises alkylene.
[0358] In a preferred embodiment, the compound of Formula (I)
comprises a compound of the Formula (Ic)
##STR00027##
wherein [0359] R.sub.1 comprises -hydrogen, -aryl, -heteroaryl,
-cycloalkyl, -heterocyclyl, -alkyl, -alkenyl, -alkynyl,
-alkylene-aryl, -alkylene-heteroaryl, -alkylene-heterocyclyl,
-alkylene-cycloalkyl, -fused cycloalkylaryl, -fused
cycloalkylheteroaryl, -fused heterocyclylaryl, -fused
heterocyclylheteroaryl, -alkylene-fused cycloalkylaryl,
-alkylene-fused cycloalkylheteroaryl, -alkylene-fused
heterocyclylaryl, -alkylene-fused heterocyclylheteroaryl, or
-G.sub.1-G.sub.2-G.sub.3-R.sub.5 [0360] wherein [0361] G.sub.1 and
G.sub.3 independently comprise alkylene, alkenylene, alkynylene,
cycloalkylene, heterocyclylene, arylene, heteroarylene,
(aryl)alkylene, (heteroaryl)alkylene, (aryl)alkenylene,
(heteroaryl)alkenylene, or a direct bond; [0362] G.sub.2 comprises
--O--, --S--, --S(O)--, --N(R.sub.6)--, --S(O).sub.2--, --C(O)--,
--CO.sub.2--, --C(O)N(R.sub.6)--, N(R.sub.6)C(O)--,
--S(O.sub.2)N(R.sub.6)--, N(R.sub.6)S(O.sub.2)--,
--O-alkylene-C(O)--, --(O)C-alkylene-O--, --O-alkylene-,
-alkylene-O--, alkylene, alkenylene, alkynylene, cycloalkylene,
heterocyclylene, arylene, heteroarylene, fused cycloalkylaryl,
fused cycloalkylheteroaryl, fused heterocyclylaryl, fused
heterocyclylheteroaryl, or a direct bond, wherein R.sub.6 comprises
hydrogen, aryl, alkyl, -alkylene-aryl, alkoxy, or -alkylene-O-aryl;
and [0363] R.sub.6 comprises hydrogen, aryl, heteroaryl,
cycloalkyl, heterocyclyl, alkyl, alkenyl, alkynyl, -alkylene-aryl,
-alkylene-heteroaryl, -alkylene-heterocyclyl, -alkylene-cycloalkyl,
fused cycloalkylaryl, fused cycloalkylheteroaryl, fused
heterocyclylaryl, fused heterocyclylheteroaryl; -alkylene-fused
cycloalkylaryl, -alkylene-fused cycloalkylheteroaryl,
-alkylene-fused heterocyclylaryl, or -alkylene-fused
heterocyclylheteroaryl; [0364] R.sub.2 comprises [0365] a)
-hydrogen, [0366] b) -aryl, [0367] c) -heteroaryl, [0368] d)
-cycloalkyl, [0369] e) -heterocyclyl; [0370] f) -alkyl, [0371] g)
-alkenyl, [0372] h) -alkynyl, [0373] i) -alkylene-aryl, [0374] j)
-alkylene-heteroaryl, [0375] k) -alkylene-heterocyclyl, [0376] l)
-alkylene-cycloalkyl; [0377] m) fused cycloalkylaryl, [0378] n)
fused cycloalkylheteroaryl, [0379] o) fused heterocyclylaryl,
[0380] p) fused heterocyclylheteroaryl; [0381] q) -alkylene-fused
cycloalkylaryl, [0382] r) -alkylene-fused cycloalkylheteroaryl,
[0383] s) -alkylene-fused heterocyclylaryl, or [0384] t)
-alkylene-fused heterocyclylheteroaryl, [0385] R.sub.111,
R.sub.112, R.sub.113 and R.sub.114 independently comprise [0386] a)
-hydrogen, [0387] b) -halogen, [0388] c) -hydroxyl, [0389] d)
-cyano, [0390] e) -carbamoyl, [0391] f) -carboxyl, [0392] g)
--Y.sub.8-alkyl, [0393] h) --Y.sub.8-aryl, [0394] i)
--Y.sub.8-heteroaryl, [0395] j) --Y.sub.8-alkylene-aryl, [0396] k)
--Y.sub.8-alkylene-heteroaryl, [0397] l)
--Y.sub.8-alkylene-W.sub.3--R.sub.40, [0398] m)
--Y.sub.5--Y.sub.6--NR.sub.33R.sub.34, [0399] n)
--Y.sub.8--Y.sub.8--NH--C(.dbd.NR.sub.35)NR.sub.33R.sub.34, [0400]
o) --Y.sub.5--Y.sub.6--C(.dbd.NR.sub.35)NR.sub.33R.sub.34, or
[0401] l) --Y.sub.5--Y.sub.6--Y.sub.7-A.sub.4; [0402] wherein
[0403] Y.sub.5 and Y.sub.7 independently comprise a direct bond,
--CH.sub.2--, --O--, --N(H), --S--, SO.sub.2--, --CON(H)--,
--NHC(O)--, --NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--,
--C(O)--O--, --NHSO.sub.2NH--, --O--CO--,
[0403] ##STR00028## wherein R.sub.36 and R.sub.37 independently
comprise aryl, alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl;
[0404] Y.sub.6 comprises a) alkylene; b) alkenylene; c) alkynylene;
d) arylene; e) heteroarylene; f) cycloalkylene; g) heterocyclylene;
h) alkylene-arylene; i) alkylene-heteroarylene; j)
alkylene-cycloalkylene; k) alkylene-heterocyclylene; l)
arylene-alkylene; m) heteroarylene-alkylene; n)
cycloalkylene-alkylene; o) heterocyclylene-alkylene; p) --O--; q)
--S--; r) --S(O.sub.2)--; or s) --S(O)--; wherein said alkylene
groups may optionally contain one or more O, S, S(O), or SO.sub.2
atoms; [0405] A.sub.4 comprises a) heterocyclyl, fused
arylheterocyclyl, or fused heteroarylheterocyclyl, containing at
least one basic nitrogen atom, b) -imidazolyl, or c) -pyridyl;
[0406] R.sub.33, R.sub.34 and R.sub.35 independently comprise
hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl, or
-alkylene-O-aryl; and R.sub.33 and R.sub.34 may be taken together
to form a ring having the formula
--(CH.sub.2).sub.n--X.sub.4--(CH.sub.2).sub.v-- bonded to the
nitrogen atom to which R.sub.33 and R.sub.34 are attached, wherein
u and v are, independently, 1, 2, 3, or 4; X.sub.4 comprises a
direct bond, --CH.sub.2--, --O--, --S--, --S(O.sub.2)--, --C(O)--,
--CON(H)--, --NHC(O)--, --NHCON(H)--, --NHSO.sub.2--,
--SO.sub.2N(H)--, C(O)--O--, --O--C(O)--, --NHSO.sub.2NH--,
[0406] ##STR00029## wherein R.sub.36 and R.sub.37 independently
comprise hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl, or
-alkylene-heteroaryl; [0407] Y.sub.5 and W.sub.3 independently
comprise --CH.sub.2--, --O--, --N(H), --S--, SO.sub.2--,
--CON(H)--, --NHC(O)--, --NHCON(H)--, --NHSO.sub.2--,
--SO.sub.2N(H)--, --C(O)--O--, --NHSO.sub.2NH--, --O--CO--,
[0407] ##STR00030## wherein R.sub.41 and R.sub.42 independently
comprise aryl, alkyl, -alkylene-aryl, alkoxy, or -alkyl-O-aryl; and
[0408] R.sub.40 comprises hydrogen, aryl, alkyl, -alkylene-aryl,
-alkylene-heteroaryl, and -alkyene-O-aryl; [0409] wherein at least
one of R.sub.111, R.sub.112, R.sub.113, and R.sub.114 comprise a
group of the formula --Y.sub.5--Y.sub.6--NR.sub.33R.sub.34,
--Y.sub.5--Y.sub.6--NH--C(.dbd.NR.sub.35)NR.sub.33R.sub.34,
--Y.sub.5--Y.sub.6--C(.dbd.NR.sub.35)NR.sub.33R.sub.34, or
--Y.sub.5--Y.sub.6
[0410] In one group of preferred embodiments of the compound of
Formula (Ic), R.sub.2 comprises hydrogen or alkyl.
[0411] In another group of preferred embodiments of the compound of
Formula (Ic), R.sub.1 comprises a phenyl group substituted by one
or more substituents comprising [0412] a) --Y.sub.2-alkyl; [0413]
b) --Y.sub.2-aryl; [0414] c)--Y.sub.2-heteroaryl; [0415] d)
--Y.sub.2-alkylene-heteroarylaryl; [0416]
e)--Y.sub.2-alkylene-aryl; [0417] f)
--Y.sub.2-alkylene-W.sub.2--R.sub.18; [0418] g)
--Y.sub.3--Y.sub.4--NR.sub.23R.sub.24 [0419] h)
--Y.sub.3--Y.sub.4--NH--C(.dbd.NR.sub.25)NR.sub.23R.sub.24 [0420]
i) --Y.sub.3--Y.sub.4--C(.dbd.NR.sub.25)NR.sub.23R.sub.24 [0421] j)
--Y.sub.3--Y.sub.4--Y.sub.5-A.sub.2 [0422] wherein [0423] Y.sub.2
and W.sub.2 independently comprise --CH.sub.2--, --O--, and [0424]
R.sub.18 comprises aryl, alkyl, -alkylene-aryl,
-alkylene-heteroaryl, or -alkylene-O-aryl; [0425] Y.sub.3 and
Y.sub.5 independently comprise a direct bond, --CH.sub.2--, --O--,
--N(H), --S--, SO.sub.2--, --C(O)--, --CON(H)--, --NHC(O)--,
--NHCON(H)--, --NHSO.sub.2--, --SO.sub.2N(H)--, --C(O)--O--,
--NHSO.sub.2NH--, --O--CO--,
[0425] ##STR00031## [0426] wherein R.sub.27 and R.sub.26
independently comprise aryl, alkyl, -alkylene-aryl, alkoxy, or
-alkyl-O-aryl; [0427] Y.sub.4 comprises [0428] a) -alkylene; [0429]
b) -alkenylene; [0430] c) -alkynylene; [0431] d) -arylene; [0432]
e) -heteroarylene; [0433] f) -cycloalkylene; [0434] g)
-heterocyclylene; [0435] h) -alkylene-arylene; [0436] i)
-alkylene-heteroarylene; [0437] j) -alkylene-cycloalkylene; [0438]
k) -alkylene-heterocyclylene; [0439] l) -arylene-alkylene; [0440]
m) -heteroarylene-alkylene; [0441] n) -cycloalkylene-alkylene;
[0442] o) -heterocyclylene-alkylene; [0443] p) --O--; [0444] q)
--S--; [0445] r) --S(O.sub.2)--; or [0446] s) --S(O)--; wherein
said alkylene groups may optionally contain one or more O, S, S(O),
or SO.sub.2 atoms; [0447] A.sub.2 comprises [0448] a) heterocyclyl,
fused arylheterocyclyl, or fused heteroarylheterocyclyl, containing
at least one basic nitrogen atom, [0449] b) -imidazolyl, or [0450]
c) -pyridyl; [0451] R.sub.23, R.sub.24, and R.sub.25 independently
comprise hydrogen, aryl, heteroaryl, -alkylene-heteroaryl, alkyl,
-alkylene-aryl, -alkylene-O-aryl, or -alkylene-O-heteroaryl; and
R.sub.23 and R.sub.24 may be taken together to form a ring having
the formula --(CH.sub.2).sub.s--X.sub.3--(CH.sub.2).sub.t-- bonded
to the nitrogen atom to which R.sub.23 and R.sub.24 are attached
[0452] wherein s and t are, independently, 1, 2, 3, or 4; X.sub.3
comprises direct bond, --CH.sub.2--, --O--, --S--, --S(O.sub.2)--,
--C(O)--, --CONCH)--, --NHC(O)--, --NHCON(H)--, --NHSO.sub.2--,
--SO.sub.2N(H)--, --C(O)--O--, --O--C(O)--, --NHSO.sub.2NH--,
[0452] ##STR00032## wherein R.sub.28 and R.sub.29 independently
comprise hydrogen, aryl, heteroaryl, alkyl, -alkylene-aryl, or
-alkylene-heteroaryl.
[0453] In another group of preferred embodiments of the compound of
Formula (Ic), R.sub.1 comprises 2-methoxy-3,5-dimethyoxy-phenyl,
3-(4-tert-butyl-phenoxy)-phenyl,
4-[3-(N,N'-diethylamino)-propoxy]-phenyl,
4-[3-(N,N'-dimethylamino)-propoxy]phenyl,
4-[(pyrrolidin-1-yl)-ethoxy]-phenyl,
3-[(pyrrolidin-1-yl)-ethoxy]-phenyl,
2-[(pyrrolidin-1-yl)-ethoxy]phenyl, 3-(naphthalen-2-yloxy)-phenyl,
4-biphenyl, 3-(3,3-dimethylbutoxy)-phenyl, 3-(phenoxy)-phenyl,
3-(3,4-dichloro-phenoxy)-phenyl, 3-(3,5-dichloro-phenoxy)-phenyl,
4-tert-butyl-phenyl, 4-(dibutylamino)-phenyl,
4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl, 2-naphthyl, 2-benzofuranyl,
3-(3-trifluoromethyl-phenoxy)-phenyl, 4-chloro-phenyl,
2-benzhydryl, 4-isopropoxy-phenyl, 3-(4-tertbutyl-phenoxy)-phenyl,
4-[2-(4-chloro-phenyl)-ethoxy]-phenyl,
3-[2-(4-chloro-phenyl)-ethoxy]-phenyl,
2-{3-[2-(4-chloro-phenyl)-ethoxy]-phenyl)-ethyl,
2-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-ethyl, or
2-[3-(N,N-diethylamino)-propoxy)]-4-[2-(4-chloro-phenyl)-ethoxy]-phenyl.
[0454] In another group of preferred embodiments of the compound of
Formula (Ic), R.sub.1 comprises
4-[2-(4-chloro-phenyl)-ethoxy]-phenyl,
3-[2-(4-chloro-phenyl)-ethoxy]-phenyl,
2-{3-[2-(4-chloro-phenyl)-ethoxy]-phenyl]-ethyl,
2-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-ethyl, or
2-[3-(N,N-diethylamino)-propoxy)]-4-[2-(4-chloro-phenyl)-ethoxy]-phenyl.
[0455] In another group of preferred embodiments of the compound of
Formula (Ic), R.sub.111, R.sub.112 and R.sub.114 comprise hygrogen;
and R.sub.113 comprises --Y.sub.3--Y.sub.4--NR.sub.23R.sub.24, or
--Y.sub.3--Y.sub.4--Y.sub.5-A.sub.2.
[0456] In another group of preferred embodiments of the compound of
Formula (Ic), R.sub.1 comprises
4-[2-(4-chloro-phenyl)-ethoxy]-phenyl,
3-[2-(4-chloro-phenyl)-ethoxy]-phenyl,
2-{3-[2-(4-chloro-phenyl)-ethoxy]-phenyl]-ethyl,
2-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-ethyl, or
2-[3-(N,N-diethylamino)-propoxy)]-4-[2-(4-chloro-phenyl)-ethoxy]-phenyl;
R.sub.2 comprises alkyl; R.sub.112 and R.sub.114 comprise hygrogen;
and R.sub.111 and R.sub.113 comprise
--Y.sub.3--Y.sub.4--NR.sub.23R.sub.24, or
--Y.sub.3--Y.sub.4--Y.sub.5-A.sub.2.
[0457] In the compounds of Formula (I), the various functional
groups represented should be understood to have a point of
attachment at the functional group having the hyphen. In other
words, in the case of --C.sub.1-6 alkylaryl, it should be
understood that the point of attachment is the alkyl group; an
example would be benzyl. In the case of a group such as
--C(O)--NH--C.sub.1-6 alkylaryl, the point of attachment is the
carbonyl carbon.
[0458] Also included within the scope of the invention are the
individual enantiomers of the compounds represented by Formula (I)
above as well as any wholly or partially racemic mixtures thereof.
The present invention also covers the individual enantiomers of the
compounds represented by the Formula above as mixtures with
diastereoisomers thereof in which one or more stereocenters are
inverted.
[0459] Compounds of the present invention preferred for their high
biological activity are listed by name below in Table 1.
TABLE-US-00001 TABLE 1 Ex. Structure Name 1 ##STR00033##
1-butyl-2-(3-cyclohexylmethoxy-
phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazole 2
##STR00034## {3-[3-butyl-2-(3,5-di-tert-butyl-
2-methoxy-phenyl)-3H- benzimidazol-5-yloxy]-propyl}- diethyl-amine
3 ##STR00035## (2-{3-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-3H-
benzoimidazol-5-yloxy}-ethyl)- diisopropyl-amine 4 ##STR00036##
(3-{4-[1-butyl-6-(4-tert-butyl- phenoxy)-1H-benzimidazol-2-yl]-
phenoxy}-propyl)-diethyl-amine 5 ##STR00037##
1-butyl-6-(4-tert-butyl-phenoxy)- 2-[3-(2-pyrrolidin-1-yl-ethoxy)-
phenyl]-1H-benzimidazole 6 ##STR00038##
1-butyl-6-(4-tert-butyl-phenoxy)- 2-[2-(2-pyrrolidin-1-yl-ethoxy)-
phenyl]-1H-benzimidazole 7 ##STR00039## 1-butyl-2-[3-(naphthalen-2-
yloxy)-phenyl]-6-(2-piperazin- 1-yl-ethoxy)-1H-benzoimidazole 8
##STR00040## 2-biphenyl-4-yl-1-butyl-6-(2-
piperazin-1-yl-ethoxy)-1H- benzimidazole 9 ##STR00041##
1-butyl-6-(4-tert-butyl-phenoxy)- 2-[4-(2-pyrrolidin-1-yl-ethoxy)-
phenyl]-1H-benzimidazole 10 ##STR00042##
1-butyl-2-[3-(3,3-dimethyl- butoxy)-phenyl]-6-(2-piperazin-
1-yl-ethoxy)-1H-benzoimidazole 11 ##STR00043##
1-butyl-6-(4-fluoro-3- trifluoromethyl-phenoxy)-2-
[4-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-1H-benzimidazole 12
##STR00044## 1-butyl-2-(3-phenoxy-phenyl)-6-
(2-piperazin-1-yl-ethoxy)-1H- benzoimidazole 13 ##STR00045##
1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-(2-piperidin-
1-yl-ethoxy)-1H-benzimidazole 14 ##STR00046##
1-butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-6-(2-piperidin-
1-yl-ethoxy)-1H-benzimidazole 15 ##STR00047##
1-butyl-6-[2-(4-chloro-phenyl)- ethoxy]-2-[4-(2-pyrrolidin-1-yl-
ethoxy)-phenyl]-1H- benzimidazole 16 ##STR00048##
1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(2-
piperidin-1-yl-ethoxy)- 1H-benzimidazole 17 ##STR00049##
1-butyl-2-(4-tert-butyl-phenyl)-6- (2-piperazin-1-yl-ethoxy)-1H-
benzoimidazole 18 ##STR00050## dibutyl-{4-[1-butyl-6-(3-
diethylamino-propoxy)-1H- benzimidazol-2-yl]-phenyl}- amine 19
##STR00051## (2-{3-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-3H-
benzoimidazol-5-yloxy}-ethyl)- diisopropyl-amine 20 ##STR00052##
{3-[3-butyl-2-(4-tert-butyl- phenyl)-3H-benzimidazol-5-
yloxy]-propyl}-diethyl-amine 21 ##STR00053##
1-butyl-2-(3,5-di-tert-butyl-2- methoxy-phenyl)-6-(2-piperazin-
1-ylethoxy)-1H-benzoimidazole 22 ##STR00054##
{3-[3-butyl-2-(3-{4-[2-(4- methoxy-phenyl)-ethoxy]-
phenyl}-propyl)-3H- benzimidazol-5-yloxy]-propyl}- diethyl-amine 23
##STR00055## 1-butyl-2-naphthalen-2-yl-6-(2-
piperazin-1-yl-ethoxy)-1H- benzimidazole 24 ##STR00056##
(2-{3-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-3H-
benzoimidazol-5-yloxy}-ethyl)- dimethyl-amine 25 ##STR00057##
2-benzofuran-2-yl-1-butyl-6-(2- piperazin-1-yl-ethoxy)-1H-
benzimidazole 26 ##STR00058## 1-butyl-6-(2-piperazin-1-yl-
ethoxy)-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H- benzimidazole
27 ##STR00059## 2-benzhydryl-1-butyl-6-(2-
piperazin-1-yl-ethoxy)-1H- benzimidazole 28 ##STR00060##
1-Butyl-2-(4-chloro-phenyl)-6- (2-piperazin-1-yl-ethoxy)-1H-
benzoimidazole 29 ##STR00061## {3-[3-Butyl-2-(4-isopropoxy-
phenyl)-3H-benzoimidazol-5- yloxy]-propyl}-diethyl-amine 30
##STR00062## 1-Butyl-6-(2-piperazin-1-yl-
ethoxy)-2-[3-(4,4,4-trifluoro- butoxy)-phenyl]-1H- benzoimidazole
31 ##STR00063## {3-[3-Butyl-2-(2,4,4-trimethyl-
pentyl)-3H-benzoimidazol-5- yloxy]-propyl}-diethyl-amine 32
##STR00064## Diethyl-{2-[2-piperidin-3-yl-3-
(4-pyrrolidin-1-yl-butyl)-3H- benzoimidazol-5-yloxy]-ethyl}-amine
33 ##STR00065## Diethyl-{2-[2-piperidin-4-yl-3-
(4-pyrrolidin-1-yl-butyl)-3H- benzoimidazol-5-yloxy]-ethyl}-amine
34 ##STR00066## {3-[1-Butyl-6-(3-diethylamino-
propoxy)-2-piperidin-4-yl-1H- benzoimidazol-4-yloxy]-propyl)-
diethyl-amine 35 ##STR00067## {3-[3-butyl-2-[3-(4-tert-butyl-
phenoxy)-phenyl]-7-(2- pyrrolidin-1-yl-ethoxy)-3H-
benzimidazol-5-yloxy]-propyl}- diethyl-amine 36 ##STR00068##
1-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-
(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 37 ##STR00069##
1-butyl-2-[3-(3-tert-butyl- phenoxy)-phenyl]-6-(2-piperazin-
1-yl-ethoxy)-1H-benzoimidazole 38 ##STR00070##
2-[3-(biphenyl-4-yloxy)-phenyl]- 1-butyl-6-(2-piperazin-1-yl-
ethoxy)-1H-benzoimidazole 39 ##STR00071##
1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-
(2-piperazin-1-yl-ethoxy)-1H- benzimidazole 40 ##STR00072##
[3-(3-butyl-2-{3-[2-(4-chloro- phenyl)-ethoxy]-4-nitro-phenyl}-
3H-benzimidazol-5-yloxy)- propyl]-diethyl-amine 41 ##STR00073##
[2-(3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-3H-
benzimidazol-5-yloxy)-ethyl]- diethyl-amine 42 ##STR00074##
1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(piperidin-
4-ylmethoxy)-1H-benzoimidazole 43 ##STR00075##
1-butyl-2-{3-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-
(2-piperazin-1-yl-ethoxy)- 1H-benzoimidazole 44 ##STR00076##
{3-[3-butyl-2-(2-{4-[2-(4- chlorophenyl)-ethoxy]-phenyl}-
ethyl)-3H-benzimidazol-5- yloxy]-propyl}-diethyl-amine 45
##STR00077## 1-butyl-2-[3-(3,5-dichloro-
phenoxy)-phenyl]-6-(2-piperazin- 1-yl-ethoxy)-1H-benzimidazole 46
##STR00078## 1-butyl-6-[2-(4-butyl-piperazin-
1-yl)-ethoxy]-2-[3-(3- trifluoromethyl-phenoxy)-
phenyl]-1H-benzimidazole 47 ##STR00079## {3-[3-butyl-2-(2-{4-[2-(4-
chlorophenyl)-ethoxy]-phenyl}- ethyl)-3H-benzimidazol-5-yloxy]-
propyl}-diethyl-amine 48 ##STR00080## (3-{3-butyl-2-[3-(4-methoxy-
phenoxy)-phenyl]-3H- benzimidazol-5-yloxy}-propyl)- diethyl-amine
49 ##STR00081## {3-[2-{4-[2-(4-chloro-phenyl)-
ethoxy]-phenyl}-6-(2- diethylamino-ethoxy)-
benzimidazol-1-yl)-propyl}- diethyl-amine 50 ##STR00082##
[3-(1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-1H-
benzimidazol-4-yloxy)-propyl]- diethyl-amine 51 ##STR00083##
[3-(1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-1H-
benzimidazol-5-yl)-propyl]- diethyl-amine 52 ##STR00084##
1-butyl-2-[3-(2-isopropyl- phenoxy)-phenyl]-6-(2-piperazin-
1-yl-ethoxy)-1H-benzoimidazole 53 ##STR00085##
{3-[3-butyl-2-(2-{4-[3-(4- methoxy-phenyl)-propoxy]-
phenyl}-ethyl)-3H- benzimidazol-5-yloxy]-propyl}- diethyl-amine 54
##STR00086## {3-[3-butyl-2-(2-{4-[4-(4- methoxy-phenyl)-butoxy]-
phenyl}-ethyl)-3H- benzimidazol-5-yloxy]-propyl}- diethyl-amine 55
##STR00087## [3-(3-butyl-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-3-ethoxy- phenyl}-3H-benzimidazol-5-
yloxy)-propyl]-diethyl-amine 56 ##STR00088## (3-{3-butyl-2-[3-(3-
trifluoromethyl-phenoxy)- phenyl]-3H-benzimidazol-
5-yloxy}-propyl)-diethyl-amine 57 ##STR00089##
1-butyl-2-[3-(4-chloro-phenoxy)- phenyl]-6-(2-piperazin-1-yl-
ethoxy)-1H-benzoimidazole 58 ##STR00090##
1-butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-6-(2-piperazin-
1-yl-ethoxy)-1H-benzoimidazole 59 ##STR00091##
1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-
(piperidin-4-yloxy)-1H- benzoimidazole 60 ##STR00092##
3-(3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-3H-
benzoimidazol-5-yloxy)-1-aza- bicyclo[2.2.2]octane 61 ##STR00093##
1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-
(2,2,6,6,-tetramethyl-piperidin- 4-yloxy)-1H-benzoimidazole 62
##STR00094## 2-[3-(4-butoxy-phenoxy)-phenyl]-
1-butyl-6-(2-piperazin-1-yl- ethoxy)-1H-benzoimidazole 63
##STR00095## [3-(3-butyl-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-3H- benzimidazol-5-yloxy)-propyl]-
diethyl-amine 64 ##STR00096## {3-[2-{4-[2-(4-chloro-phenyl)-
ethoxy]-phenyl}-3-(3-methyl- butyl)-3H-benzimidazol-5-
yloxy]-propyl}-diethyl-amine 65 ##STR00097##
[3-(2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-3-hexyl-3H-
benzimidazol-5-yloxy)-propyl]- diethyl-amine 66 ##STR00098##
{3-[2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(2-
diethylamino-ethoxy)- benzimidazol-1-yl]-propyl}- dimethyl-amine 67
##STR00099## 1-butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-
phenyl]-6-(2-piperazin-1- ylethoxy)-1H-benzoimidazole 68
##STR00100## [3-(3-butyl-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-3H- benzimidazol-5-yloxy)-propyl]-
diethyl-amine 69 ##STR00101## {3-[2-(4-benzyloxy-3,5-dimethyl-
phenyl)-3-butyl-3H- benzimidazol-5-yloxy]-propyl}- diethyl-amine 70
##STR00102## {3-[3-butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-3H-
benzimidazol-5-yloxy]-propyl}- diethyl-amine 71 ##STR00103##
1-butyl-6-[2-(4-methyl-piperazin- 1-yl)-ethoxy]-2-[3-(3-
trifluoromethyl-phenoxy)- phenyl]-1H-benzimidazole 72 ##STR00104##
1-butyl-6-[2-(4-isopropyl- piperazin-1-yl)-ethoxy]-2-[3-(3-
trifluoromethyl-phenoxy)- phenyl]-1H-benzoimidazole 73 ##STR00105##
1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-(3-
piperazin-1-yl-propoxy)-1H- benzoimidazole 74 ##STR00106##
(3-{3-butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-3H-
benzimidazol-5-yloxy}-propyl)- diethyl-amine 75 ##STR00107##
1-butyl-2-[3-(3,4-dimethoxy- phenoxy)-phenyl]-6-(2-piperidin-
4-yloxy)-1H-benzoimidazole 76 ##STR00108## 1-butyl-2-[3-(4-chloro-
benzyloxy)-phenyl]-6-(2- piperazin-1-yl-ethoxy)-1H- benzoimidazole
77 ##STR00109## 1-butyl-2-[3-(3,5-dichloro-
phenoxy)-phenyl]-6-(2-piperazin- 1-yl-ethoxy)-1H-benzoimidazole 78
##STR00110## (3-{2-[2-(4-benzyloxy-phenyl)-
ethyl]-3-butyl-3H-benzimidazol- 5-yloxy}-propyl)-diethyl-amine 79
##STR00111## (3-{3-butyl-2-[2-(4-phenethyloxy-
phenyl)-ethyl]-3H-benzimidazol- 5-yloxy}-propyl)-diethyl-amine
80 ##STR00112## {3-[3-butyl-2-(2-{4-[2-(4-fluoro-
phenyl)-ethoxy]-phenyl}-ethyl)- 3H-benzimidazol-5-yloxy]-
propyl}-diethyl-amine 81 ##STR00113##
[3-(3-butyl-2-{2-[4-(4-chloro- benzyloxy)-phenyl]-ethyl}-3H-
benzimidazol-5-yloxy)-propyl]- diethyl-amine 82 ##STR00114##
(3-{3-butyl-2-[4-(4-fluoro- benzyloxy)-phenyl]-3H-
benzimidazol-5-yloxy}- propyl)-diethyl-amine 83 ##STR00115##
{3-[2-(3-benzyloxy-phenyl)-3- butyl-3H-benzimidazol-5-yloxy]-
propyl}-diethyl-amine 84 ##STR00116##
[3-(3-butyl-2-{4-chloro-3-[2-(4- chloro-phenyl)-ethoxy]-phenyl}-
3H-benzimidazol-5-yloxy)- propyl]-diethyl-amine 85 ##STR00117##
1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-(2-piperazin-
1-yl-ethoxy)-1H-benzimidazole 86 ##STR00118##
1-butyl-2-[4-(4-isopropyl- phenoxy)-phenyl]-6-(2-piperazin-
1-yl-ethoxy)-1H-benzoimidazole 87 ##STR00119##
1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-[3-(4-
methyl-piperazin-1-yl)-propoxy]- 1H-benzoimidazole 88 ##STR00120##
1-butyl-6-[2-(4-butyl-piperazin-1- yl)-ethoxy]-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-1H- benzoimidazole 89 ##STR00121##
1-butyl-2-[3-(3,4-dimethoxy- phenoxy)-phenyl]-6-(2-piperazin-
1-yl-ethoxy)-1H-benzoimidazole 90 ##STR00122##
1-butyl-2-[4-(4-tert-butyl-benzyl)- phenyl]-6-(2-piperazin-1-yl-
ethoxy)-1H-benzoimidazole 91 ##STR00123##
N-{4-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzimidazol-2-yl]-
2-[2-(4-chloro-phenyl)-ethoxy]- phenyl}-2,2-dimethyl- propioinamide
92 ##STR00124## (3-{3-butyl-2-[4-(4-fluoro-3-
trifluoromethyl-phenoxy)- phenyl]-3H-benzimidazol-5-
yloxy}-propyl)-diethyl-amine 93 ##STR00125##
1-butyl-2-[4-(naphthalen-2- yloxy)-phenyl]-6-(2-piperazin-1-
yl-ethoxy)-1H-benzoimidazole 94 ##STR00126##
1-butyl-2-[3-(4-fluoro-3- trifluoromethyl-phenoxy)-
phenyl]-6-(2-piperazin-1-yl- ethoxy)-1H-benzoimidazole 95
##STR00127## [3-(3-butyl-2-{4-[2-(4-methoxy-
phenyl)-ethoxy]-phenyl}-3H- benzimidazol-5-yloxy)-propyl]-
diethyl-amine 96 ##STR00128## 4-[1-butyl-6-(3-diethylamino-
propoxy)-1H-benzimidazol-2- yl]-2-[2-(4-chloro-phenyl)-
ethoxy]-phenylamine 97 ##STR00129##
1-{4-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzimidazol-2-
yl]-2-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-3-isopropyl-urea 98
##STR00130## {3-[2-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-6-(2-
dimethylamino-ethoxy)- benzimidazol-1-yl]-propyl}- dimethyl-amine
99 ##STR00131## 1-butyl-2-[3-(4-tert-butyl-
phenoxy)-phenyl]-6-[2-(4-methyl- piperazin-1-yl)-ethoxy]-1H-
benzimidazole 100 ##STR00132## 1-butyl-6-(4-cyclopentyl-
phenoxy)-2-[4-(4-methyl- piperazin-1-ylmethyl)-phenyl]-
1H-benzoimidazole 101 ##STR00133## {3-[2-(4-benzyloxy-phenyl)-3-
cyclopentylmethyl-3H- benzimidazol-5-yloxy]-propyl}- diethyl-amine
102 ##STR00134## 1-butyl-6-(4-butyl-phenoxy)-2-
{3,5-dimethyl-4-[2-(1-methyl- pyrrolidin-2-yl)-ethoxy]-phenyl}-
1H-benzoimidazole 103 ##STR00135## 1-butyl-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-6-(3- pyrrolidin-1-yl-propoxy)-1H-
benzoimidazole 104 ##STR00136## {3-[2-(4-benzyloxy-phenyl)-3-
isobutyl-3H-benzimidazol-5- yloxy]-propyl}-diethyl-amine 105
##STR00137## [3-(3-butyl-2-{3-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-3H- benzimidazol-5-yloxy)-propyl]-
diethyl-amine 106 ##STR00138## 1-butyl-6-(1-butyl-piperidin-4-
yloxy)-2-[3-(3,5-dichloro- phenoxy)-phenyl]-1H- benzoimidazole 107
##STR00139## 1-butyl-2-[3-(3,5-dichloro-
phenoxy)-phenyl]-6-(1-ethyl- piperidin-4-yloxy)-1H- benzoimidazole
108 ##STR00140## 1-butyl-6-(4-fluoro-3-
trifluoromethyl-phenoxy)-2-[4-(4- methyl-piperazin-1-ylmethyl)-
phenyl]-1H-benzoimidazole 109 ##STR00141##
diethyl-{3-[3-isobutyl-2-(2-{4-[2- (4-methoxy-phenyl)-ethoxy]-
phenyl}-ethyl)-3H-benzimidazol- 5-yloxy]-propyl}-amine 110
##STR00142## {3-[2-(2-{4-[2-(4-chlorophenyl)-
ethoxy]-phenyl}-ethyl)-3- isobutyl-3H-benzimidazol-5-
yloxy]-propyl}-diethyl-amine 111 ##STR00143##
1-butyl-6-(2-piperazin-1-yl- ethoxy)-2-[3-(3-trifluoromethyl-
phenoxy)-phenyl]-1H- benzimidazole 112 ##STR00144##
1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-(2-
pyrrolidin-1-yl-ethoxy)-1H- benzimidazole 113 ##STR00145##
1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-[2-(4-
methyl-piperazin-1-yl)-ethoxy]- 1H-benzimidazole 114 ##STR00146##
{3-[2-(4-benzyloxy-phenyl)-3- cyclopentyl-3H-benzimidazol-5-
yloxy)-propyl]-diethyl-amine 115 ##STR00147##
1-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-5-(4-
methyl-piperazin-1-ylmethyl)-1H- benzoimidazole 116 ##STR00148##
[2-(3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-3H-
benzimidazol-5-yloxy)-ethyl]- dimethyl-amine 117 ##STR00149##
[2-(3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-3H-
benzimidazol-5-yloxy)-ethyl]- diisopropyl-amine 118 ##STR00150##
1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-[2-(4-methyl-
piperazin-1-yl)-ethoxy]-1H- benzimidazole 119 ##STR00151##
(3-{1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-1H-
benzimidazol-4-yloxy}-propyl)- diethyl-amine 120 ##STR00152##
2-(3-butoxy-phenyl)-1-butyl-6- (2-piperazin-1-yl-ethoxy)-1H-
benzimidazole 121 ##STR00153## 1-butyl-2-[3-(4-methanesulfonyl-
benzyloxy)-phenyl]-6-(2- piperazin-1-yl-ethoxy)-1H- benzoimidazole
122 ##STR00154## 4'{3-[1-butyl-6-(2-piperazin-1-yl-
ethoxy)-1H-benzoimidazol-2-yl]- phenoxy}-biphenyl-4-carbonitrile
123 ##STR00155## {3-[2-(4-benzyloxy-phenyl)-3-
butyl-3H-benzimidazol-5-yloxy]- propyl}-diethyl-amine 124
##STR00156## 1-Butyl-2-[4-(3-chloro-phenoxy)-
phenyl]-6-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 125
##STR00157## 1-butyl-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-6-[2- (4-isopropyl-piperazin-1-yl)-
ethoxy]-1H-benzoimidazole 126 ##STR00158##
{3-[2-(3-benzyloxy-4-methoxy- phenyl)-3-butyl-3H-
benzimidazol-5-yloxy)- propyl]-diethyl-amine 127 ##STR00159##
(3-{3-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-3H-
benzimidazol-5-yloxy}-propyl)- diethyl-amine 128 ##STR00160##
{3-[3-butyl-2-(3-phenoxy- phenyl)-3H-benzimidazol-5-
yloxy]-propyl}-diethyl-amine 129 ##STR00161##
1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-[2-(4-ethyl-
piperazin-1-yl)-ethoxy]-1H- benzimidazole 130 ##STR00162##
1-butyl-2-[4-(2,3-di-methoxy- phenoxy)-phenyl]-6-(2-piperazin-
1-ylethoxy)-1H-benzoimidazole 131 ##STR00163##
[3-(3-butyl-2-{2-[4-(4-chloro- benzyloxy)-phenyl]-ethyl}-3H-
benzimidazol-5-yloxy)-propyl]- diethyl-amine 132 ##STR00164##
(3-{3-butyl-2-[3-(4-chloro- phenoxy)-phenyl]-3H-
benzimidazol-5-yloxy}-propyl)- diethyl-amine 133 ##STR00165##
{3-[2-(4-benzyloxy-phenyl)-3- isopropyl-3H-benzimidazol-5-
yloxy]-propyl}-diethyl-amine 134 ##STR00166## (2-{3-butyl-2-[3-(3-
trifluoromethyl-phenoxy)- phenyl]-3H-benzoimidazol-5-
yloxy}-ethyl)-diisopropyl-amine 135 ##STR00167##
1-butyl-6-[2-(4-ethyl-piperazin- 1-yl)-ethoxy]-2-[3-(3-
trifluoromethyl-phenoxy)- phenyl]-1H-benzimidazole 136 ##STR00168##
(3-[3-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-3H-
benzimidazol-5-yloxy]-propyl}- diethyl-amine 137 ##STR00169##
(3-{2-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-3H-
benzimidazol-5-yloxy}-ethyl)- cyclohexyl-methyl-amine 138
##STR00170## 1-butyl-6-[2-(4-propyl-piperazin-
1-yl)-ethoxy]-2-[3-(3- trifluoromethyl-phenoxy)-
phenyl]-1H-benzimidazole 139 ##STR00171##
1-butyl-6-(4-butyl-phenoxy)-2-[4- (4-methyl-piperazin-1-ylmethyl)-
phenyl]-1H-benzoimidazole 140 ##STR00172##
1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-(2-
morpholin-4-yl-ethoxy)-1H- benzimidazole 141 ##STR00173##
4-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzimidazol-2-yl]-
2-phenethyloxy-phenylamine 142 ##STR00174##
{2-[2-(4-benzyloxy-phenyl)-3- phenethyl-3H-benzimidazol-5-
yloxy]-ethyl}-diethyl-amine 143 ##STR00175##
{3-[3-butyl-2-(4-phenoxy- phenyl)-3H-benzimidazol-5-
yloxy]-propyl}-diethyl-amine 144 ##STR00176##
3-[4-(2-{3-butyl-2-[3-(3,4- dichloro-phenoxy)-phenyl]-3H-
benzimidazol-5-yloxy}-ethyl)- piperazin-1-yl]-propan-1-ol 145
##STR00177## 1-butyl-6-(2-pyrrolidin-1-yl-
ethoxy)-2-[3-(3-trifluoromethyl- phenoxy)-phenyl]-1H- benzimidazole
146 ##STR00178## (2-[2-[4-[2-(4-chloro-phenyl)-
ethoxy]-phenyl}-6-(2- diethylamino-ethoxy)-
benzimidazol-1-yl]-ethyl}- dimethyl-amine 147 ##STR00179##
1-butyl-6-(2-morpholin-4-yl- ethoxy)-2-[3-(3-trifluoromethyl-
phenoxy)-phenyl]-1H- benzimidazole 148 ##STR00180##
1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(1-methyl-
piperidin-4-yloxy)-1H- benzoimidazole 149 ##STR00181##
N'-[3-butyl-2-(2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-ethyl)-
3H-benzimidazol-5-yl]-N,N- diethyl-propane-1,3-diamine 150
##STR00182## 1-butyl-2-[3-(2,4-dichloro- phenoxy)-phenyl]-6-(2-
pyrrolidin-1-yl-ethoxy)-1H- benzimidazole 151 ##STR00183##
1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-(2-
morpholin-4-yl-ethoxy)-1H- benzimidazole 152 ##STR00184##
1-butyl-6-(2-piperazin-1-yl- ethoxy)-2-[4-(4-trifluoromethyl-
phenoxy)-phenyl]-1H- benzoimidazole 153 ##STR00185##
2-[4-(biphenyl-4-yloxy)-phenyl]- 1-butyl-6-(2-piperazin-1-yl-
ethoxy)-1H-benzoimidazole 154 ##STR00186##
1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(2-
morpholin-4-yl-ethoxy)-1H- benzimidazole 155 ##STR00187##
1-butyl-2-[3-(3,4-dimethoxy- phenoxy)-phenyl]-6-(2-piperazin-
1-yl-ethoxy)-1H-benzoimidazole
156 ##STR00188## 1-butyl-2-[3-(4-tert-butyl-
phenoxy)-phenyl]-5-(1H- imidazol-4-ylmethoxy)-1H- benzoimidazole
157 ##STR00189## {3-[2-(2-benzyloxy-phenyl)-3-
butyl-3H-benzimidazol-5-yloxy]- propyl}-diethyl-amine 158
##STR00190## {3-[1-Butyl-6-(3-diethylamino-
propoxy)-2-piperidin-4-yl-1H- benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 159 ##STR00191## (2-{2-[2-(4-Benzyloxy-phenyl)-
ethyl]-3-phenethyl-3H- benzoimidazol-5-yloxy}-ethyl)- diethyl-amine
160 ##STR00192## [3-(3-Butyl-2-{3-[4-(4-fluoro-
benzyloxy)-phenyl]-propyl}-3H- benzoimidazol-5-yloxy)-propyl]-
diethyl-amine 161 ##STR00193## [3-(4-Benzyloxy-phenyl)-propyl]-
[1-butyl-6-(3-diethylamino- propoxy)-1H-benzoimidazol-2- yl]-amine
162 ##STR00194## {3-[3-Butyl-2-(3-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-propyl)- 3H-benzoimidazol-5-yloxy]-
propyl}-diethyl-amine 163 ##STR00195## 1-Butyl-2-[3-(3,5-dichloro-
phenoxy)-phenyl]-6-(2-imidazol- 1-yl-ethoxy)-1H-benzoimidazole 164
##STR00196## 1-[4-(2-{3-Butyl-2-[3-(3- trifluoromethyl-phenoxy)-
phenyl]-3H-benzoimidazol-5- yloxy}-ethyl)-piperazin-1-yl]- ethanone
165 ##STR00197## N-[3-Butyl-2-(2-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-ethyl)- 3H-benzoimidazol-5-yl]-N-(3-
diethylamino-propyl)-N',N'- diethyl-propane-1,3-diamine 166
##STR00198## {3-[1-butyl-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-6-(3- diethylamino-propoxy)-1H-
benzimidazol-4-yl]-propyl}- diethyl-amine 167 ##STR00199##
{3-[1-Butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-(3-
diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 168 ##STR00200## {3-[2-(2-{4-[2-(4-chloro-phenyl)-
ethoxy]-phenyl}-ethyl)-6-(3- diethylamino-propoxy)-3H-
benzimidazol-4-yloxy]-propyl}- diethyl-amine 169 ##STR00201##
{3-[1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-
phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-
yloxy)-propyl}-diethyl-amine 170 ##STR00202##
(3-{1-Butyl-6-(3-diethylamino- propoxy)-2-[4-(4-fluoro-3-
trifluoromethyl-phenoxy)- phenyl]-1H-benzoimidazol-4-
yloxy}-propyl)-diethyl-amine 171 ##STR00203##
{3-[2-[3-(3,5-Dichloro-phenoxy)- phenyl]-6-(3-diethylamino-
propoxy)-1H-benzoimidazol-4- yloxy]-propyl}-diethyl-amine 172
##STR00204## 1-Butyl-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-4,6-bis- (2-pyrrolidin-1-yl-ethoxy)-1H-
benzoimidazole 173 ##STR00205## {3-[2-[3-(3,4-Dichloro-phenoxy)-
phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-
yloxy]-propyl}-diethyl-amine 174 ##STR00206##
(3-{6-(3-diethylamino-propoxy)- 2-[3-(3-trifluoromethyl-phenoxy)-
phenyl]-1H-benzimidazol-4- yloxy)-propyl)-diethyl-amine 175
##STR00207## {3-[1-Butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-6-(3-
diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 176 ##STR00208## {3-[2-[3-(4-Chloro-phenoxy)-
phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-
yloxy]-propyl}-diethyl-amine 177 ##STR00209##
{3-[1-Butyl-2-[3-(4-chloro- phenoxy)-phenyl]-6-(3-
diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 178 ##STR00210## {3-[1-Butyl-6-(3-diethylamino-
propoxy)-2-(3-p-tolyloxy- phenyl)-1H-benzoimidazol-4-
yloxy]-propyl}-diethyl-amine 179 ##STR00211##
{3-[1-Butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(3-
diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 180 ##STR00212## 1-Butyl-2-[3-(4-tert-butyl-
phenoxy)-phenyl]-4,6-bis-(2- pyrrolidin-1-yl-ethoxy)-1H-
benzoimidazole 181 ##STR00213## {3-[3-Butyl-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-7-(2- pyrrolidin-1-yl-ethoxy)-3H-
benzoimidazol-5-yloxy]-propyl}- diethyl-amine 182 ##STR00214##
(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(3-fluoro-
phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)- diethyl-amine
183 ##STR00215## {3-[2-{4-[2-(4-chloro-phenyl)-
ethoxy]-phenyl}-6-(3- diethylamino-propoxy)-1-
isopropyl-1H-benzimidazol-4- yloxy]-propyl}-diethyl-amine 184
##STR00216## {3-[1-Butyl-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-6-(2- pyrrolidin-1-yl-ethoxy)-1H-
benzoimidazol-4-yloxy]-propyl}- diethyl-amine 185 ##STR00217##
2-{4-[1-butyl-4,6-bis-(3- diethylamino-propoxy)-1H-
benzimidazol-2-yl-phenoxy}- benzoic acid methyl ester 186
##STR00218## {3-[2-[4-(biphenyl-4-yloxy)- phenyl]-1-butyl-6-(3-
diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 187 ##STR00219## {3-[2-[4-(3,5-Bis-trifluoromethyl-
phenoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-
benzoimidazol-4-yloxy]-propyl}- diethyl-amine 188 ##STR00220##
{3-[1-butyl-2-[4-(4-chloro- benzylsulfanyl)-phenyl]-6-(3-
diethylamino-propoxy)-1H- benzimidazol-4-yloxy]-propyl}-
diethyl-amine 189 ##STR00221## {3-[2-{4-[2-(4-chloro-phenyl)-
ethoxy]-phenyl}-6-(3- diethylamino-propoxy)-3H-
benzimidazol-4-yloxy]-propyl}- diethyl-amine 190 ##STR00222##
(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[3-(3-trifluoromethyl-
phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)- diethyl-amine
191 ##STR00223## [3-(1-butyl-6-(3-diethylamino-
propoxy)-2-{4-[2-(4-fluoro- phenyl)-ethoxy]-phenyl}-1H-
benzimidazol-4-yloxy}-propyl)- diethyl-amine 192 ##STR00224##
(3-{1-butyl-6-(3-diethylamino- propoxy)-2-{4-(3-trifluoromethyl-
phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)- diethyl-amine
193 ##STR00225## {3-[2-[3-(4-tert-Butyl-phenoxy)-
phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-
yloxy]-propyl}-diethyl-amine 194 ##STR00226##
(3-{1-Butyl-6-(3-diethylamino- propoxy)-2-[4-(4-fluoro-5-
trifluoromethyl-phenoxy)-2- trifluoromethyl-phenyl]-1H-
benzoimidazol-4-yloxy}-propyl)- diethyl-amine 195 ##STR00227##
{3-[1-Butyl-2-[4-chloro-2-(4- chloro-3-trifluoromethyl-
phenoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-
benzoimidazol-4-yloxy]-propyl}- diethyl-amine 196 ##STR00228##
2-[3-(4-Chloro-phenoxy)-phenyl]- 4,6-bis-(2-pyrrolidin-1-yl-
ethoxy)-1H-benzoimidazole 197 ##STR00229##
1-Butyl-2-[3-(4-chloro-phenoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-
yl-ethoxy)-1H-benzoimidazole 198 ##STR00230##
{3-[3-butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-
phenyl]-7-(2-pyrrolidin-1-yl- ethoxy)-3H-benzimidazol-5-
yloxy]-propyl}-diethyl-amine 199 ##STR00231##
{2-[1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-(2-
diisopropylamino-ethoxy)-1H- benzimidazol-4-yloxy]-ethyl}-
diethyl-amine 200 ##STR00232## {3-[2-[4-(3,5-Bis-trifluoromethyl-
phenoxy)-phenyl]-1-butyl-6-(3- diethylamino-propoxy)-1H-
benzoimidazol-4-yloxy]-propyl}- diethyl-amine 201 ##STR00233##
{3-[2-[4-(3,5-Bis-trifluoromethyl- phenoxy)-phenyl]-1-butyl-6-(3-
diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 202 ##STR00234## (3-{1-butyl-6-(3-diethylamino-
propoxy)-2-[4-(4-methoxy- phenoxy)-phenyl]-1H-
benzimidazol-4-yloxy}-propyl)- diethyl-amine 203 ##STR00235##
1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-
phenyl]-4,6-bis-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazole 204
##STR00236## 2-{4-[2-(4-Chloro-phenyl)- ethoxy]-phenyl}-4,6-bis-(2-
pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 205 ##STR00237##
1-Butyl-2-[4-(4-tert-butyl- phenoxy)-phenyl]-4,6-bis-(2-
pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 206 ##STR00238##
1-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-
phenyl]-4,6-bis-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazole 207
##STR00239## {3-[1-Butyl-2-[4-(3-chloro- phenoxy)-phenyl]-6-(3-
diethylamino-propoxy)- 1H-benzoimidazol-4-yloxy]-
propyl)-diethyl-amine 208 ##STR00240##
2-[5,7-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzimidazol-2-yl]-5-
[2-(4-chloro-phenyl)-ethoxy]- phenol 209 ##STR00241##
2-[3-(4-tert-butyl-phenoxy)- phenyl]-4,6-bis-(2-pyrrolodin-1-
yl-ethoxy)-1H-benzimidazole 210 ##STR00242##
(3-{6-(3-Diethylamino-propoxy)- 2-[2-(1,1-difluoro-ethyl)-4-(4-
fluoro-3-trifluoromethyl- phenoxy)-phenyl]-1H-
benzoimidazol-4-yloxy)-propyl)- diethyl-amine 211 ##STR00243##
{3-[1-Butyl-2-[4-(4-tert-butyl- phenoxy)-phenyl]-6-(3-
diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 212 ##STR00244## 2-[4-(4-tert-Butyl-phenoxy)-
phenyl]-4,6-bis-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazole 213
##STR00245## {3-[1-Butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-6-(2-
pyrrolidin-1-yl-ethoxy)-1H- benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 214 ##STR00246## [3-(3-butyl-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-6- diethylaminomethyl-3H-
benzimidazol-5-yloxy)-propyl]- diethyl-amine 215 ##STR00247##
(3-{6-(3-Diethylamino-propoxy)- 2-[4-(4-fluoro-3-trifluoromethyl-
phenoxy)-phenyl]-1H- benzoimidazol-4-yloxy}-propyl)- diethyl-amine
216 ##STR00248## (3-{1-butyl-6-(3-diethylamino-
propoxy)-2-[4-(4-trifluoromethyl- pyrimidin-2-ylsulfanyl)-phenyl]-
1H-benzoimidazol-4-yloxy}- propyl)-diethyl-amine 217 ##STR00249##
{3-[6-(3-Diethylamino-propoxy)- 2-(3-p-tolyloxy-phenyl)-1H-
benzoimidazol-4-yloxy]-propyl}- diethyl-amine 218 ##STR00250##
4-{3-[1-Butyl-4,6-bis-(3- diethylamino-propoxy)-1H-
benzoimidazol-2-yl]-phenoxy}- benzonitrile 219 ##STR00251##
[3-(3-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-7-
pyrrolidin-1-yl-3H- benzoimidazol-5-yloxy)-propyl]- diethyl-amine
220 ##STR00252## {3-[1-butyl-2-[4-(4-chloro-
phenylmethanesulfinyl)-phenyl]- 6-(3-diethylamino-propoxy)-1H-
benzimidazol-4-yloxy]-propyl}- diethyl-amine 221 ##STR00253##
(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(naphthalen-2-
yloxy)-phenyl]-1H- benzoimidazole-4-yloxy}- propyl)-diethyl-amine
222 ##STR00254## (3-{6-(3-diethylamino-propoxy)-
2-[4-(3-trifluoromethyl-phenoxy)- phenyl]-1H-benzimidazol-4-
yloxy)-propyl)-diethyl-amine 223 ##STR00255##
(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[3-(4-methoxy-
phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)- diethyl-amine
224 ##STR00256## 2-[3-(3,4-Dichloro-phenoxy)-
phenyl]-4,6-bis-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazole 225
##STR00257## {3-[2-[4-(4-tert-Butyl-phenoxy)-
phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-
yloxy]-propyl}-diethyl-amine
226 ##STR00258## {3-[3-butyl-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-7-[2- (tetrahydro-furan-2-yl)-ethoxy]-
3H-benzimidazol-5-yloxy}- propyl)-diethyl-amine 227 ##STR00259##
1-Butyl-2-[4-(3-chloro-phenoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-
yl-ethoxy)-1H-benzoimidazole 228 ##STR00260##
[3-(7-Butoxy-3-butyl-2-{4-[2-(4- chloro-phenyl)-ethoxy]-phenyl}-
3H-benzoimidazol-5-yloxy)- propyl]-diethyl-amine 229 ##STR00261##
4-{3-[4,6-Bis-(3-diethylamino- propoxy)-1H-benzoimidazol-2-
yl]-phenoxy}-benzonitrile 230 ##STR00262##
2-[3-(3,5-Dichloro-phenoxy)- phenyl]-4,6-bis-(2-pyrrolidin-1-
yl-ethoxy)-1H-benzoimidazole 231 ##STR00263##
{3-[1-butyl-2-(2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-ethyl)-
6-(3-diethylamino-propoxy)-1H- benzimidazol-4-yloxy]-propyl}-
diethyl-amine 232 ##STR00264## {3-[1-butyl-6-(3-diethylamino-
propoxy)-2-(3-phenoxy-phenyl)- 1H-benzimidazol-4-yloxy]-
propyl}-diethyl-amine 233 ##STR00265##
{3-[1-Butyl-2-[2-(4-chloro-3- trifluoromethyl-phenoxy)-
phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-
yloxy]-propyl}-diethyl-amine 234 ##STR00266##
2-[4-(4-Chloro-3-trifluoromethyl- phenoxy)-phenyl]-4,6-bis-(2-
pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 235 ##STR00267##
{3-[1-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-
phenyl]-6-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazol-4-
yloxy]-propyl}-diethyl-amine 236 ##STR00268##
[3-(3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-
methyl-3H-benzimidazol-5- yloxy)-propyl]-diethyl-amine 237
##STR00269## {3-[1-butyl-6-(3-diethylamino-
propoxy)-2-(4-phenoxy-phenyl)- 1H-benzimidazol-4-yloxy]-
propyl}-diethyl-amine 238 ##STR00270## 5-[4,6-bis-(3-diethylamino-
propoxy)-1H-benzoimidazlo- 2-yl]-2-[2-(4-chloro-phenyl)-
ethoxy]-phenol 239 ##STR00271## [3-(6-Butoxy-1-butyl-2-{4-[2-(4-
chloro-phenyl)-ethoxy]-phenyl}- 1H-benzoimidazol-4-yloxy)-
propyl]-diethyl-amine 240 ##STR00272##
{3-[2-[4-Chloro-2-(4-chloro-3- trifluoromethyl-phenoxy)-
phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-
yloxy]-propyl}-diethyl-amine 241 ##STR00273##
1-butyl-4-(4-chloro-benzyloxy)-2- {4-[2-(4-chloro-phenyl)-ethoxy]-
phenyl}-6-(2-pyrrolidin-1-yl- ethoxy)-1H-benzimidazole 242
##STR00274## 4-{4-[1-butyl-4,6-bis-(3- diethylamino-propoxy)-1H-
benzimidazol-2-yl]-phenoxy}- benzonitrile 243 ##STR00275##
[3-(1-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-
fluoro-1H-benzoimidazol-4- yloxy)-propyl]-diethyl-amine 244
##STR00276## (3-{6-(3-diethylamino-propoxy)-
2-[3-(4-methoxy-phenoxy)- phenyl]-1H-benzimidazol-4-
yloxy}-propyl)-diethyl-amine 245 ##STR00277##
(3-{6-(3-diethylamino-propoxy)- 2-[4-(4-methoxy-phenoxy)-
phenyl]-1H-benzimidazol-4- yloxy}-propyl)-diethyl-amine 246
##STR00278## {3-[1-butyl-2-[4-(4-chloro-3-
fluoro-phenoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-
benzimidazol-4-yl]-propyl}- diethyl-amine 247 ##STR00279##
(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(quinolin-8-yloxy)-
phenyl]-1H-benzimidazol-4- yloxy]-propyl}-diethyl-amine 248
##STR00280## {3-[2-[2-(4-chloro-3- trifluoromethyl-phenoxy)-
phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-
yloxy]-propyl}-diethyl-amine 249 ##STR00281##
2-[{2-[1-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-(2-
morpholin-4-yl-ethoxy)-1H- benzoimidazol-4-yloxy]-ethyl}-
(2-chloro-ethyl)-amino]-ethanol 250 ##STR00282##
(3-{6-(3-Diethylamino-propoxy)- 2-[3-(4-fluoro-3-trifluoromethyl-
phenoxy)-phenyl]-1H- benzoimidazol-4-yloxy}-propyl)- diethyl-amine
251 ##STR00283## [3-(3-butyl-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-7- isopropoxy-3H-benzimidazol-5-
yloxy)-propyl]-diethyl-amine 252 ##STR00284##
[3-(1-Butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-
cyclopentylmethoxy-1H- benzoimidazol-4-yloxy)-propyl]-
diethyl-amine 253 ##STR00285## 1-Butyl-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-4,6-bis- (2-morpholin-4-yl-ethoxy)-1H-
benzoimidazole 254 ##STR00286## {3-[2-[4-[2-(4-Chloro-phenyl)-
ethoxy]-3-(3-diethylamino- propoxy)-phenyl]-6-(3-
diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 255 ##STR00287## {3-[2-[1-butyl-6-(4-tert-butyl-
phenoxy)-1H-benzimidazol-2-yl]- 5-(3-diethylamino-propoxy)-
phenoxy]-propyl}-diethyl-amine 256 ##STR00288##
(3-{2-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzimidazol-2-yl]-
5-[2-(4-chloro-phenyl)-ethoxy]- phenoxy}-propyl)-diethyl-amine 257
##STR00289## (3-{1-butyl-6-(4-tert-butyl-
phenoxy)-2-[4-(3-diethylamino- propoxy)-phenyl]-1H-
benzoimidazol-4-yloxy}-propyl)- diethyl-amine 258 ##STR00290##
2-{2,4-bis-[2-(1-methyl- pyrrolidin-2-yl)-ethoxy]-phenyl}-
1-butyl-6-(4-tert-butyl-phenoxy)- 1H-benzoimidazole 259
##STR00291## 2-[2,4-bis-(2-pyrrolidin-1-yl-
ethoxy)-phenyl]-1-butyl-6-(4- butyl-phenoxy)-1H- benzoimidazole 260
##STR00292## 1-butyl-2-[4-[2-(4-chloro-phenyl)-
ethoxy]-2-(2-pyrrolodin-1-yl- ethoxy)-phenyl]-6-(2-pyrrolodin-
1-yl-ethoxy)-1H-benzoimidazole 261 ##STR00293##
{3-[2-{1-butyl-6-[2-(4-chloro- phenyl)-ethoxy]-1H-
benzimidazol-2-yl]-5-(3- diethylamino-propoxy)-phenoxy]-
propyl}-diethyl-amine 262 ##STR00294## 2-{2,4-bis-[2-(1-methyl-
pyrrolidin-2-yl)-ethoxy]-phenyl}- 1-butyl-6-(4-butyl-phenoxy)-1H-
benzoimidazole 263 ##STR00295## {3-[2-[1-butyl-5-(4-tert-butyl-
phenoxy)-1H-benzimidazol-1-yl]- 5-(3-diethylamino-propoxy)-
phenoxy]-propyl}-diethyl-amine 264 ##STR00296##
1-Butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-4,6-bis-(2-
pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 265 ##STR00297##
2-[2,4-bis-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1-butyl-6-(4-
cyclopentyl-phenoxy)-1H- benzoimidazole 266 ##STR00298##
2-{2,4-bis-[2-(1-methyl- pyrrolidin-2-yl)-ethoxy]-phenyl}-
1-butyl-6-(4-cyclopentyl- phenoxy)-1H-benzoimidazole 267
##STR00299## {3-[2-[1-butyl-6-(4-iospropyl-
phenoxy)-1H-benzimidazol-2-yl]- 5-(3-diethylamino-propoxy)-
phenoxy]-propyl}-diethyl-amine 268 ##STR00300##
(2-{1-butyl-6-(2-dimethylamino- ethylsulfanyl)-2-[4-(4-fluoro-3-
trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-
1H-benzoimidazol-4-ylsulfanyl}- ethyl)-dimethyl-amine 269
##STR00301## 2-[2,4-bis-(2-pyrrolidin-1-yl-
ethoxy)-phenyl]-1-butyl-6-(4- tert-butyl-phenoxy)-1H- benzimidazole
270 ##STR00302## {3-[2-[1-butyl-6-(4-butyl-
phenoxy)-1H-benzimidazol-2-yl]- 5-(3-diethylamino-propoxy)-
phenoxy]-propyl}-diethyl-amine 271 ##STR00303##
{3-[2-[1-butyl-6-(4-fluoro-3- trifluoromethyl-phenoxy)-1H-
benzimidazol-2-yl]-5-(3- diethylamino-propoxy)-phenoxy]-
propyl}-diethyl-amine 272 ##STR00304##
2-[2,4-bis-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1-butyl-6-(4-
isopropyl-phenoxy)-1H- benzoimidazole 273 ##STR00305##
1-Butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-4,6-bis-(2-
pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 274 ##STR00306##
(3-{3-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2-
pyrrolidin-1-yl-ethoxy)-phenyl]- 3H-benzoimidazol-5-yloxy}-
propyl)-diethyl-amine 275 ##STR00307##
{3-[2-[1-butyl-6-(4-cyclopentyl- phenoxy)-1H-benzimidazol-2-yl]-
5-(3-diethylamino-propoxy)- phenoxy]-propyl}-diethyl-amine 276
##STR00308## {3-[2-[1-butyl-4-(4-tert-butyl-
phenoxy)-1H-benzimidazol-2-yl]- 5-(3-diethylamino-propoxy)-
phenoxy]-propyl}-diethyl-amine 277 ##STR00309##
2-{2,4-bis-[2-(1-methyl- pyrrolidin-2-yl)-ethoxy]-phenyl}-
1-butyl-6-(4-isopropyl-phenoxy)- 1H-benzoimidazole 278 ##STR00310##
(3-{5-[2-(4-chloro-phenyl)- ethoxy]-2-[6-(3-diethylamino-
propoxy)-1-isopropyl-1H- benzimidazol-2-yl]-phenoxy}-
propyl)-diethyl-amine 279 ##STR00311## 1-Butyl-2-[4-(4-fluoro-3-
trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-
6-(2-pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 280 ##STR00312##
1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-4,6-bis-
(1-methyl-piperidin-4-yloxy)-1H- benzimidazole 281 ##STR00313##
{3-[2-[6-(4-tert-butyl-phenoxy)- 1H-benzimidazol-2-yl]-5-(3-
diethylamino-propoxy)-phenoxy]- propyl}-diethyl-amine 282
##STR00314## 1-butyl-2-[3-(3,4-dichloro-
phenoxy)-phenyl]-4,6-bis-(1- methyl-pyrrolidin-2-ylmethoxy)-
1H-benzoimidazole 283 ##STR00315## (3-{3-butyl-2-[4-[2-(4-chloro-
phenyl)-ethoxy]-2-(2- diethylamino-ethoxy)-phenyl]-
3H-benzimidazol-5-yloxy}- propyl)-diethyl-amine 284 ##STR00316##
(3-{2-[1-Butyl-6-(2-imidazol-1- yl-ethoxy)-1H-benzoimidazol-2-
yl]-5-[2-(4-chloro-phenyl)- ethoxy]-phenoxy}-propyl)- diethyl-amine
285 ##STR00317## (3-{2-[1-Butyl-6-(2-pyrrolidin-1-
yl-ethoxy)-1H-benzoimidazol-2- yl]-5-[2-(4-chloro-phenyl)-
ethoxy]-phenoxy}-propyl)- diethyl-amine 286 ##STR00318##
{3-[2-(3,5-bis-benzyloxy-phenyl)- 3-butyl-3H-benzimidazol-5-
yloxy]-propyl}-diethyl-amine 287 ##STR00319##
4,6-bis-(2-azepan-1-yl-ethoxy)-1-
butyl-2-[3-(4-tert-butyl-phenoxy)- phenyl]-1H-benzoimidazole 288
##STR00320## 1-butyl-2-[3-(4-butyl-phenoxy)-
phenyl]-4,6-bis-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazole 289
##STR00321## 1-butyl-2-[3-(4-tert-butyl-
phenoxy)-phenyl]-4,6-bis-(1- methyl-pyrrolidin-2-ylmethoxy)-
1H-benzoimidazole 290 ##STR00322## (2-{1-butyl-6-(2-dimethylamino-
ethylsulfanyl)-2-[3-(3- trifluoromethyl-phenoxy)-
phenyl]-1H-benzoimidazole-4- ylsufanyl}-ethyl)-dimethyl-amine 291
##STR00323## (3-{1-butyl-6-(3-diethylamino-
propoxy)-2-[4-(4-isopropyl- phenoxy)-phenyl]-1H-
benzimidazol-4-yloxy}-propyl)- diethyl-amine
292 ##STR00324## 4,6-bis-(2-azepan-1-yl-ethoxy)-1-
butyl-2-[3-(3,5-dichlorophenoxy)- phenyl]-1H-benzoimidazole 293
##STR00325## 1-butyl-2-[3-(4-tert-butyl-
phenoxy)-phenyl]-4,6-bis-[2- (cyclohexyl-methyl-amino)-
ethoxy]-1H-benzoimidazole 294 ##STR00326##
{3-[1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-6-(2-imidazol-
1-yl-ethoxy)-1H-benzimidazol-4- yloxy]-propyl}-diethyl-amine 295
##STR00327## [3-(2-{3,4-bis-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-3-butyl- 3H-benzimidazol-5-yloxy)-
propyl]-diethyl-amine 296 ##STR00328## 1-butyl-4,6-bis-(1-methyl-
piperidin-4-yloxy)-2-[3-(3- trifluoromethyl-phenoxy)-
phenyl]-1H-benzoimidazole 297 ##STR00329##
4,6-bis-(2-azepan-1-yl-ethoxy)-1- butyl-2-[3-(3-trifluoromethyl-
phenoxy)-phenyl]-1H- benzoimidazole 298 ##STR00330##
1-butyl-2-[3-(3,4-dichloro- phenoxy)-phenyl]-4,6-bis-(1-
ethyl-pyrrolidin-2-ylmethoxy)- 1H-benzoimidazole 299 ##STR00331##
[3-(2-{2-benzyloxy-4-[2-(4- chloro-phenyl)-ethoxy]-phenyl}-
3-butyl-3H-benzimidazol-5- yloxy]-propyl}-diethyl-amine 300
##STR00332## {3-[2-[1-Butyl-6-(3-diethylamino-
propoxy)-1H-benzoimidazol-2- yl]-5-(4-fluoro-3-trifluoromethyl-
phenoxy)-phenoxy]-propyl}- diethyl-amine 301 ##STR00333##
{3-[2-[1-Butyl-6-(2-pyrrolidin-1- yl-ethoxy)-1H-benzoimidazol-2-
yl]-5-(4-fluoro-3-trifluoromethyl- phenoxy)-phenoxy]-propyl}-
diethyl-amine 302 ##STR00334## 1-butyl-2-[3-(3,4-dimethoxy-
phenoxy)-phenyl]-4,6-bis-(2- pyrrolidin-1-yl-ethoxy)-1H-
benzimidazole 303 ##STR00335## (2-{1-butyl-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-6-(2- dimethylamino-ethylsulfanyl)-
1H-benzoimidazol-4-ylsulfanyl}- ethyl)-dimethyl-amine 304
##STR00336## 1-butyl-2-[3-(4-tert-butyl-
phenoxy)-phenyl]-4,6-bis-(1- ethyl-pyrrolidin-3-yloxy)-1H-
benzoimidazole 305 ##STR00337## {3-[2-[3-(3,4-bis-benzyloxy-
phenyl)-3-butyl-3H- benzimidazol-5-yloxy]-propyl}- diethyl-amine
306 ##STR00338## (3-{5-[2-(4-chloro-phenyl)-
ethoxy]-2-[6-(3-diethylamino- propoxy)-1H-benzimidazol-2-yl]-
phenoxy}-propyl)-diethyl-amine 307 ##STR00339##
1-butyl-2-[4-(2-diethylamino- ethoxy)-phenyl]-4,6-bis-[2-
(methyl-phenyl-amino)-ethoxy]- 1H-benzimidazole 308 ##STR00340##
{3-[3-butyl-2-{4-[2-(4- chlorophenyl)-ethoxy]-phenyl}-
7-(pyridin-3-yloxy)-3H- benzimidazol-5-yloxy]-propyl}-
diethyl-amine 309 ##STR00341## {2-[1-butyl-2-[3-(3,4-dichloro-
phenoxy)-phenyl]-6-(2- diisopropylamino-ethoxy)-1H-
benzimidazol-4-yloxy]-ethyl}- diethyl-amine 310 ##STR00342##
{3-[3-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-7-
(pyridin-3-ylmethoxy)-3H- benzimidazol-5-yloxy]-propyl}-
diethyl-amine 311 ##STR00343## 2-[1-butyl-6-(3-diethylamino-
propoxy)-1H-benzoimidazlo-2- yl]-5-[2-(4-chloro-phenyl)-
ethoxy]-phenol 312 ##STR00344## {3-[3-butyl-2-[2-(4-chloro-
phenylsulfanyl)-phenyl]-7-(3- diethylamino-propoxy)-3H-
benzimidazol-4-yloxy}-propyl)- diethyl-amine 313 ##STR00345##
(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(4-fluoro-2-
methoxy-phenoxy)-phenyl]-1H- benzimidazol-4-yloxy}-propyl)-
diethyl-amine 314 ##STR00346## [3-(3-butyl-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-2-isopropoxy- phenyl}-3H-benzimidazol-5-
yloxy)-propyl]-diethyl-amine 315 ##STR00347##
{2-[1-butyl-6-(3-diethylamino- propoxy)-1H-benzoimidazlo-2-
yl]-5-[2-(4-chloro-phenyl)- ethoxy]-phenoxy}-acetic acid methyl
ester 316 ##STR00348## (3-{2-[1-butyl-6-(4-tert-butyl-
phenoxy)-1H-benzimidazol-2-yl]- 5-[2-(4-chloro-phenyl)-ethoxy]-
phenoxy}-propyl)-diethyl-amine 317 ##STR00349##
(3-{1-butyl-6-(3-diethylamino- propoxy)-2-[4-(2-isopropoxy-
phenoxy)-phenyl]-1H- benzoimidazol-4-yloxy}-propyl)- diethyl-amine
318 ##STR00350## (3-{1-butyl-6-(3-diethylamino-
propoxy)-2-[4-(2,3-dimethoxy- phenoxy)-phenyl]-1H-
benzimidazol-4-yloxy}-propyl)- diethyl-amine 319 ##STR00351##
(3-{3-Butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(2-pyrrolidin-
1-yl-ethoxy)-phenyl]-3H- benzoimidazol-5-yloxy}-propyl)-
diethyl-amine 320 ##STR00352## (2-{1-butyl-6-fluoro-2-[3-(3-
trifluoromethyl-phenoxy)- phenyl]-1H-benzoimidazole-4-
ylsufanyl}-ethyl)-dimethyl-amine 321 ##STR00353## Methanesulfonic
acid 5-[2-(4- chloro-phenyl)-ethoxy]-2-[6-(3-
diethylamino-propoxy)-1H- benzoimidazol-2-yl]-phenyl ester 322
##STR00354## 5-[2-(4-Chloro-phenyl)-ethoxy]-
2-[6-(3-diethylamino-propoxy)- 1H-benzoimidazol-2-yl]-phenol 323
##STR00355## {3-[1-butyl-6-(3-diethylamino-
propoxy)-2-(4-pyrrolidin-1-yl- phenyl)-1H-benzoimidazol-4-
yloxy]-propyl}-diethyl-amine 324 ##STR00356##
1-butyl-2-[3-(4-tert-butyl- phenoxy)-phenyl]-4,6-bis-(1-
methyl-piperidin-4-yloxy)-1H- benzimidazole 325 ##STR00357##
1-butyl-2-[3-(3,5-dichloro- phenoxy)-phenyl]-4,6-bis-(2-
imidazol-1-yl-ethoxy)-1H- benzoimidazole 326 ##STR00358##
[2-(1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-6-
fluoro-1H-benzoimidazol-4- ylsulfanyl)-ethyl]-dimethyl-amine 327
##STR00359## {3-[1-Butyl-2-[4-[2-(4-chloro-
phenyl)-ethoxy]-2-(2-(pyrrolidin- 1-yl-ethoxy)-phenyl]-6-(3-
diethylamino-propoxy)-1H- benzimidazol-4-yloxy]-propyl}-
diethyl-amine 328 ##STR00360## 1-Butyl-2-[4-(4-fluoro-3-
trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-
4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 329
##STR00361## 1-Butyl-2-[4-(4-chloro-3-
trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-
4,6-bis-(2-pyrrolidin-1-yl- ethoxy)-1H-benzoimidazole 330
##STR00362## (3-{2-[1-butyl-6-(3-diethylamino-
propoxy)-4-(2-pyrrolidin-1-yl- ethoxy)-1H-benzimidazol-2-yl]-
5-[2-(4-chloro-phenyl)-ethoxy]- phenoxy}-propyl)-diethyl-amine 331
##STR00363## (3-{2-[1-butyl-4,6-bis-(3- diethylamino-propoxy)-1H-
benzimidazol-2-yl]-5-[2-(4- chloro-phenyl)-ethoxy]-
phenoxy}-propyl)-diethyl-amine 332 ##STR00364##
(3-{2-[1-Butyl-4,6-bis-(2- pyrrolidin-1-yl-ethoxy)-1H-
benzoimidazol-2-yl]-5- [2-(4-chloro-phenyl)-ethoxy]-
phenoxy}-propyl)-diethyl-amine 333 ##STR00365##
(3-{1-Butyl-6-(3-diethylamino- propoxy)-2-[4-(4-fluoro-3-
trifluoromethyl-phenoxy)-2-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-
1H-benzoimidazol-4-yloxy}- propyl)-diethyl-amine 334 ##STR00366##
{3-[1-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2-
pyrrolidin-1-yl-ethoxy)-phenyl]- 6-(2-pyrrolidin-1-yl-ethoxy)-1H-
benzoimidazol-4-yloxy]-propyl}- diethyl-amine 335 ##STR00367##
{3-[2-[1-Butyl-6-(3-diethylamino- propoxy)-4-(2-pyrrolidin-1-yl-
ethoxy)-1H-benzoimidazol-2-yl]- 5-(4-fluoro-3-trifluoromethyl-
phenoxy)-phenoxy]-propyl}- diethyl-amine 336 ##STR00368##
(3-[2-[1-Butyl-4,6-bis-(2- pyrrolidin-1-yl-ethoxy)-1H-
benzoimidazol-2-yl]-5-(4-fluoro- 3-trifluoromethyl-phenoxy)-
phenoxy]-propyl}-diethyl-amine 337 ##STR00369##
{3-[3-butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(2-pyrrolidin-
1-yl-ethoxy)-phenyl]-7-(2- pyrrolidin-1-yl-ethoxy)-3H-
benzimidazol-5-yloxy]-propyl}- diethyl-amine 338 ##STR00370##
(3-{2-[1-Butyl-4-(3-diethylamino- propoxy)-6-(2-pyrrolidin-1-yl-
ethoxy)-1H-benzoimidazol-2-yl]- 5-[2-(4-chloro-phenyl)-ethoxy]-
phenoxy}-propyl)-diethyl-amine 339 ##STR00371##
{3-[1-butyl-2-[4-(3,4-dichloro- phenoxy)-2-(2-pyrrolidin-1-yl-
ethoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-
benzimidazol-4-yloxy]-propyl}- diethyl-amine 340 ##STR00372##
{3-[2-[2,4-bis-(3-diethylamino- propoxy)-phenyl]-1-butyl-6-(4-
tert-butyl-phenoxy)-1H- benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 341 ##STR00373## {3-[1-butyl-2-[4-[2-(4-chloro-
phenyl)-ethoxy]-2-(pyridin-2- ylmethoxy)-phenyl]-6-(3-
diethylamino-propoxy)-1H- benzimidazol-4-yl]-phenyl}- diethyl-amine
342 ##STR00374## {3-[2-[4-[2-(4-Chloro-phenyl)-
ethoxy]-2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-6-(3-
diethylamino-propoxy)-1H- benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 343 ##STR00375## 1-Butyl-2-[4-[2-(4-chloro-
phenyl)-ethoxy]-2-(2-pyrrolidin- 1-yl-ethoxy)-phenyl)-4,6-bis-(2-
pyrrolidin-1-yl-ethoxy)-1H- benzoimidazole 344 ##STR00376##
{3-[1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-2-(2-
pyrrolidin-1-yl-ethoxy)-phenyl]- 6-(3-diethylamino-propoxy)-1H-
benzoimidazol-4-yloxy]-propyl}- diethyl-amine 345 ##STR00377##
(3-{6-(3-Diethylamino-propoxy)- 2-[4-(4-fluoro-3-trifluoromethyl-
phenoxy)-2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1H-
benzoimidazol-4-yloxy}-propyl)- diethyl-amine 346 ##STR00378##
{3-[2-[1-Butyl-4-(3-diethylamino- propoxy)-6-(2-pyrrolidin-1-yl-
ethoxy)-1H-benzoimidazol-2-yl]- 5-(4-fluoro-3-trifluoromethyl-
phenoxy)-phenoxy]-propyl}- diethyl-amine 347 ##STR00379##
{3-[3-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2-
pyrrolidin-1-yl-ethoxy)-phenyl]- 7-(2-pyrrolidin-1-yl-ethoxy)-3H-
benzoimidazol-5-yloxy]-propyl}- diethyl-amine 348 ##STR00380##
{3-[1-butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(2-pyrrolidin-
1-yl-ethoxy)-phenyl]-6-(2- pyrrolidin-1-yl-ethoxy)-1H-
benzimidazol-4-yloxy]-propyl}- diethyl-amine 349 ##STR00381##
{3-[2-[1-butyl-4,6-bis-(2- pyrrolodin-1-yl-ethoxy)-1H-
benzimidazol-2-yl]-5-(4-fluoro- 3-trifluoromethyl-phenoxy)-
phenyl]-propyl}-diethyl-amine 350 ##STR00382##
{3-[1-butyl-2-{4-[2-(4-chloro- phenyl)-ethoxy]-3-
diethylaminomethyl-phenyl}-6- (3-diethylamino-propoxy)-1H-
benzimidazol-4-yloxy]-propyl}- diethyl-amine 351 ##STR00383##
{3-[2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(pyridin-2-ylmethoxy)-
phenyl]-6-(3-diethylamino- propoxy)-1H-benzimidazol-4-yl]-
propyl}-diethyl-amine 352 ##STR00384##
3-(7-Butoxy-3-butyl-2-{4-[2-(4- chloro-phenyl)-ethoxy]-2-
cyclopentylmethoxy-phenyl}-3H- benzoimidazol-5-yloxy)-propan- 1-ol
353 ##STR00385## 3-(7-Butoxy-2-{4-[2-(4-chloro- phenyl)-ethoxy]-2-
cyclopentylmethoxy-phenyl}-3H- benzoimidazol-5-yloxy)-propan- 1-ol
354 ##STR00386## (3-{1-Butyl-6-(3-diethylamino-
propoxy)-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-
(pyridin-2-ylmethoxy)-phenyl]- 1H-benzoimidazol-4-yloxy}-
propyl)-diethyl-amine 355 ##STR00387## {3-[2-[1-Butyl-4,6-bis-(3-
diethylamino-propoxy)-1H- benzoimidazol-2-yl]-5-(4-fluoro-
3-trifluoromethyl-phenoxy)- phenoxy]-propyl}-diethyl-amine 356
##STR00388## 2-(3,5-bis-benzyloxy-phenyl)-1-
butyl-4,6-bis-(2-pyrrolodin-1-yl- ethoxy)-1H-benzimidazole
357 ##STR00389## {3-[2-[1-butyl-4,6-bis-(3-
diethylamino-propoxy)-1H- benzimidazol-2-yl]-5-(4-fluoro-3-
trifluoromethyl-phenoxy)- phenyl]-propyl}-diethyl-amine 358
##STR00390## 1-butyl-2-[4-[2-(4-chloro-phenyl)-
ethoxy]-2-(2-pyrrol-1-yl-ethoxy)- phenyl]-4,6-bis-(2-pyrrolodin-1-
yl-ethoxy)-1H-benzoimidazole 359 ##STR00391##
{3-[2-{4-[2-(4-chloro-phenyl)- ethoxy]-2-(3-diethylamino-
propoxy)-phenyl}-6-(3- diethylamino-propoxy)-1H-
benzimidazol-4-yloxy]-propyl}- diethyl-amine 360 ##STR00392##
{3-[1-Butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(pyridin-3-
ylmethoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-
benzoimidazol-4-yloxy]-propyl}- diethyl-amine 361 ##STR00393##
(3-{3-Butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(3-
diethylamino-propoxy)-phenyl]- 7-isopropoxy-3H-benzoimidazol-
5-yloxy}-propyl)-diethyl-amine 362 ##STR00394##
{3-[1-Butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(pyridin-4-
ylmethoxy)-phenyl]-6-(3- diethylamino-propoxy)-
1H-benzoimidazol-4-yloxy]- propyl}-diethyl-amine 363 ##STR00395##
{3-[2-[4-[2-(4-Chloro-phenyl)- ethoxy]-2-(pyridin-4-ylmethoxy)-
phenyl]-6-(3-diethylamino- propoxy)-1H-benzoimidazol-4-
yloxy]-propyl}-diethyl-amine 364 ##STR00396##
1-Butyl-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-
(pyridin-2-ylmethoxy)-phenyl]- 4,6-bis-(2-pyrrolidin-1-yl-
ethoxy)-1H-benzoimidazole 365 cor- rect ##STR00397##
2-[4-[2-(4-chloro-phenyl)- ethoxy]-2-(2-pyrrolidin-1-yl-
ethoxy)-phenyl]-5,7-bis-(2- pyrrolidin-1-yl-ethoxy)-1H-
benzimidazole 366 ##STR00398## {3-[1-Butyl-2-{4-[2-(4-chloro-
phenyl)-ethoxy]-2-methoxy- phenyl}-6-(3-diethylamino-
propoxy)-1H-benzoimidazol-4- yloxy]-propyl}-diethyl-amine 367
##STR00399## {3-[2-{4-[2-(4-Chloro-phenyl)-
ethoxy]-2-methoxy-phenyl}-6- (3-diethylamino-propoxy)-1H-
benzoimidazol-4-yloxy]-propyl}- diethyl-amine 368 ##STR00400##
(3-{1-Butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(3-
diethylamino-propoxy)-phenyl]- 6-isopropoxy-1H-benzoimidazol-
4-yloxy)-propyl)-diethyl-amine 369 ##STR00401##
{3-[1-Butyl-2-[4-(4-chloro-3- methyl-phenoxy)-2-(pyridin-2-
ylmethoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-
benzoimidazol-4-yloxy]-propyl}- diethyl-amine 370 ##STR00402##
1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-2-
cyclopentylmethoxy-phenyl]-4,6- bis-(2-pyrrolidin-1-yl-ethoxy)-
1H-benzoimidazole 371 ##STR00403## (2-{1-butyl-6-(2-dimethylamino-
ethoxy)-2-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-2-(2-
pyrrolidin-1-yl-ethoxy)-phenyl]- 1H-benzoimidazole-4-yloxy}-
ethyl)-dimethyl-amine 372 ##STR00404## 2-[1-butyl-4,6-bis-(3-
diethylamino-propoxy)-1H- benzimidazol-2-yl]-5-[2-(4-
chloro-phenyl)-ethoxy]-phenol 373 ##STR00405##
1-Butyl-2-[4-(4-chloro-3-methyl- phenoxy)-2-(pyridin-2-
ylmethoxy)-phenyl]-4,6-bis-(2- pyrrolidin-1-yl-ethoxy)-1H-
benzoimidazole 374 ##STR00406## 2-[4-(4-Chloro-3-trifluoromethyl-
phenoxy)-2-cyclopentylmethoxy- phenyl]-4,6-bis-(2-pyrrolidin-1-
yl-ethoxy)-1H-benzoimidazole 375 ##STR00407##
2-[4-(4-Fluoro-3-trifluoromethyl- phenoxy)-2-(2-pyrrolidin-1-yl-
ethoxy)-phenyl]-4,6-bis-(2- pyrrolidin-1-yl-ethoxy)-1H-
benzoimidazole 376 ##STR00408## {3-[2-(3,5-bis-benzyloxy-phenyl)-
1-butyl-6-(3-diethylamino- propoxy)-1H-benzimidazol-4-
yloxy]-propyl}-diethyl-amine 377 ##STR00409##
(3-{1-butyl-6-(3-dimethylamino- propoxy)-2-[4-(3-fluoro-
phenoxy)-2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1H-
benzoimidazole-4-yloxy}- propyl)-diethyl-amine 378 ##STR00410##
{3-[2-{1-butyl-4-(4-chloro- benzyloxy)-6-(2-pyrrolidin-1-yl-
ethoxy)-1H-benzimidazol-2-yl]-5- [2-(4-chloro-phenyl)-ethoxy]-
phenoxy}-propyl)-diethyl-amine 379 ##STR00411##
{3-[2-{4-[2-(4-chloro-phenyl)- ethoxy]-2-(3-diethylamino-
propoxy)-phenyl]-6-(3- diethylamino-propoxy)-3H-
benzimidazol-4-yloxy]-propyl}- diethyl-amine 380 ##STR00412##
{3-[2-[4-(3,4-dichloro-phenoxy)- 2-(2-pyrrolidin-1-yl-ethoxy)-
phenyl]-6-(3-diethylamino- propoxy)-1H-benzimidazol-4-
yloxy]-propyl}-diethyl-amine 381 ##STR00413##
{3-[1-Butyl-2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-2-
cyclopentylmethoxy-phenyl]-6- (3-diethylamino-propoxy)-1H-
benzoimidazol-4-yloxy]-propyl}- diethyl-amine 382 ##STR00414##
{3-[2-[4-(4-chloro-3- trifluoromethyl-phenoxy)-2-
cyclopentylmethoxy-phenyl]-6- (3-diethylamino-propoxy)-1H-
benzoimidazol-4-yloxy]-propyl}- diethyl-amine 383 ##STR00415##
(3-{1-butyl-6-(4-tert-butyl- phenoxy)-2-[4-[2-(4-chloro-
phenyl)-ethoxy]-2-(3- diethylamino-propoxy)-phenyl]-
1H-benzimidazol-4-yloxy}- propyl)-diethyl-amine 384 ##STR00416##
2-{2,4-bis-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-1-butyl-4,6-bis-
(2-pyrrolidin-1-yl-ethoxy)-1H- benzimidazole 385 ##STR00417##
(2-{1-butyl-6-(2-dimethylamino- ethoxy)-2-[4-(3-fluoro-phenoxy)-
2-(2-pyrrolidin-1-yl-ethoxy)- phenyl]-1H-benzoimidazole-4-
yloxy)-ethyl)-dimethyl-amine 386 ##STR00418##
{3-[2-[4-(3,5-bis-trifluoromethyl- phenoxy)-2-(2-pyrrolidin-1-yl-
ethoxy)-phenyl]-1-butyl-6-(3- diethylamino-propoxy)-1H-
benzimidazol-4-yloxy]-propyl}- diethyl-amine 387 ##STR00419##
{3-[1-butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-2-(2-pyrrolidin-
1-yl-ethoxy)-phenyl]-6-(3- diethylamino-propoxy)-1H-
benzimidazol-4-yloxy]-propyl}- diethyl-amine 388 ##STR00420##
(3-{2-(1-Butyl-4,6-diisopropoxy- 1H-benzoimidazol-2-yl)-5-[2-(4-
chloro-phenyl)-ethoxy]- phenoxy}-propyl)-diethyl-amine 389
##STR00421## {3-[1-butyl-2-{3-[2-(4-chloro- phenyl)-ethoxy]-4-
diethylaminomethyl-phenyl}-6- (3-diethylamino-propoxy)-1H-
benzimidazol-4-yloxy]-propyl}- diethyl-amine 390 ##STR00422##
(3-{1-Butyl-6-(3-diethylamino- propoxy)-2-[4-fluoro-2-(2-
pyrrolidin-1-yl-ethoxy)-phenyl]- 1H-benzoimidazol-4-yloxy}-
propyl)-diethyl-amine 391 ##STR00423##
(2-{1-butyl-6-fluoro-2-[4-(4- fluoro-3-trifluoromethyl-
phenoxy)-2-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1H-
benzoimidazol-4-ylsulfanyl}- ethyl)-dimethyl-amine 392 ##STR00424##
{3-[1-Butyl-2-[4-[2-(4-chloro- phenyl)-ethoxy]-3-(3-
diethylamino-propoxy)-phenyl]- 6-(3-diethylamino-propoxy)-1H-
benzoimidazol-4-yloxy]-propyl}- diethyl-amine 393 ##STR00425##
(4-benzyloxy-benzyl)-[1-butyl-6- (3-diethylamino-propoxy)-1H-
benzimidazol-2-ylmethyl]-hexyl- amine 394 ##STR00426##
(4-benzyloxy-benzyl)-[1-butyl-6- (3-diethylamino-propoxy)-1H-
benzimidazol-2-ylmethyl]- isobutyl-amine 395 ##STR00427##
[3-(2-{[(4-benzyloxy-benzyl)- cyclopentylmethyl-amino]-
methyl}-3-butyl-3H- benzimidazol-5-yloxy)-propyl]- diethyl-amine
396 ##STR00428## N-(4-benzyloxy-benzyl)-N-[1-
butyl-6-(3-diethylamino- propoxy)-1H-benzimidazol-2-
ylmethyl]-benzamide 397 ##STR00429##
(3-{3-butyl-2-[(dibenzylamino)- methyl]-3H-benzimidazol-5-
yloxy)-propyl]-diethyl-amine 398 ##STR00430## (3-{2-[(4-benzyloxy-
benzylamino)-methyl]-3-butyl- 3H-benzimidazol-5-yloxy}-
propyl)-diethyl-amine 399 ##STR00431## N-(4-benzyloxy-benzyl)-N-[1-
butyl-6-(3-diethylamino- propoxy)-1H-benzimidazol-2-
ylmethyl]-methanesulfonamide 400 ##STR00432##
N-(4-benzyloxy-benzyl)-N-[1- butyl-6-(3-diethylamino-
propoxy)-1H-benzimidazol-2- ylmethyl]-acetamide 401 ##STR00433##
{3-[3-butyl-2-({4-[2-(4-chloro- phenyl)-ethoxy]-benzylamino}-
methyl)-3H-benzimidazol-5- yloxy)-propyl]-diethyl-amine 402
##STR00434## [3-(2-{[Bis-(4-benzyloxy-benzyl)-
amino]-methyl}-3-butyl-3H- benzoimidazol-5-yloxy)-propyl]-
diethyl-amine 403 ##STR00435## [3-(2-{[Benzyl-(4-benzyloxy-
benzyl)-amino]-methyl}-3-butyl- 3H-benzoimidazol-5-yloxy)-
propyl]-diethyl-amine 404 ##STR00436##
{3-[4-(2-butyl-4-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-
imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 405 ##STR00437##
{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-isobutyl-
imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 406 ##STR00438##
[3-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-1H-imidazol-
4-yl}-phenoxy)-propyl]-diethyl- amine 407 ##STR00439##
1-[4-(4-{2-butyl-1-[4-(4-fluoro- 3-trifluoromethyl-phenoxy)-
phenyl]-1H-imidazol-4-yl}- phenoxy)-butyl]-piperazine 408
##STR00440## 4-(4-{2-butyl-1-[4-(4-fluoro-
3-trifluoromethyl-phenoxy)- phenyl]-1H-imidazol-4-yl}-
phenoxy)-1-methyl-piperidine 409 ##STR00441##
1-[5-(4-{2-butyl-1-[4-(4-fluoro- 3-trifluoromethyl-phenoxy)-
phenyl]-1H-imidazol-4-yl}- phenoxy)-pentyl]-piperazine 410
##STR00442## {3-[4-(4-{4-[2-(4-chloro-phenyl)-
ethoxy]-phenyl}-imidazol-1-yl)- phenoxy]-propyl}-diethyl-amine 411
##STR00443## {3-[3-(4-{4-[2-(4-chloro-phenyl)-
ethoxy]-phenyl}-imidazol-1-yl)- phenoxy]-propyl}-diethyl-amine 412
##STR00444## [3-(4-{1-[4-(4-tert-butyl-
phenoxy)-phenyl]-1H-imidazol- 4-yl)-phenoxy)-propyl]-diethyl- amine
413 ##STR00445## [3-(4-{2-butyl-1-[4-(4-fluoro-3-
trifluoromethyl-phenoxy)- phenyl]-1H-imidazol-4-yl}-
phenoxy)-propyl]-diethyl-amine 414 ##STR00446##
diethyl-[3-(4-{1-[4-(4- trifluoromethoxy-phenoxy)-
phenyl]-1H-imidazol-4-yl}- phenoxy)-propyl]-amine 415 ##STR00447##
[3-(4-{2-butyl-1-[4-(3,4-dichloro- phenoxy)-phenyl]-1H-imidazol-4-
yl}-phenoxy)-propyl]-diethyl- amine 416 ##STR00448##
[3-(4-{2-cyclobutyl-1-[4-(4- fluoro-3-trifluoromethyl-
phenoxy)-phenyl}-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl- amine
417 ##STR00449## [3-(4-{2-cyclopentyl-1-[4-(4-
fluoro-3-trifluoromethyl- phenoxy)-phenyl]-1H-imidazol-
4-yl}-phenoxy)-propyl]-diethyl- amine 418 ##STR00450##
[3-(4-{2-cyclohexyl-1-[4-(4- fluoro-3-trifluoromethyl-
phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl- amine
419 ##STR00451## diethyl-[3-(4-{1-[4-(4-fluoro-3-
trifluoromethyl-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-
4-yl}-phenoxy)-propyl]-amine 420 ##STR00452##
[3-(4-{2-but-3-enyl-1-[4-(4- fluoro-3-trifluoromethyl-
phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl- amine
421 ##STR00453## [3-(4-{2-tert-butyl-1-[4-(4-fluoro-
3-trifluoromethyl-phenoxy)- phenyl]-1H-imidazol-4-yl}-
phenoxy)-propyl]-diethyl-amine 422 ##STR00454##
diethyl-[3-(4-{2-(4-fluoro- phenyl)-1-[4-(4-fluoro-3-
trifluoromethyl-phenoxy)- phenyl]-1H-imidazol-4-yl)-
phenoxy)-propyl]-amine 423 ##STR00455## [3-(4-{1-[4-(3,5-bis-
trifluoromethyl-phenoxy)- phenyl]-2-butyl-1H-imidazol-4-
yl}-phenoxy)-propyl]-diethyl- amine 424 ##STR00456##
(3-{4-[1-(4-benzyloxy-phenyl)-2- butyl-1H-imidazol-4-yl]-
phenoxy}-propyl)-diethyl-amine
425 ##STR00457## {3-[4-(2-tert-butyl-4-{4-[2-(4-
chloro-phenyl)-ethoxy]-phenyl}- imidazol-1-yl)-phenoxy]-propyl}-
diethyl-amine 426 ##STR00458## [3-(4-{2-butyl-1-[4-(3-fluoro-4-
trifluoromethyl-phenoxy)- phenyl]-1H-imidazol-4-yl}-
phenoxy)-propyl]-diethyl-amine 427 ##STR00459##
diethyl-[3-(4-{4-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-
phenyl]-imidazol-1-yl}-phenoxy)- propyl]-amine 428 ##STR00460##
(3-{4-[4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-(4-fluoro-
phenyl)-imidazol-1-yl]-phenoxy}- propyl)-diethyl-amine 429
##STR00461## {3-[4-(4-{4-[2-(4-chloro-phenyl)-
ethoxy]-phenyl}-2-cyclopropyl- imidazol-1-yl)-phenoxy]-propyl}-
diethyl-amine 430 ##STR00462## {3-[4-(4-{4-[2-(4-chloro-phenyl)-
ethoxy]-phenyl}-2-cyclopentyl- imidazol-1-yl)-phenoxy]-propyl}-
diethyl-amine 431 ##STR00463## [3-(4-{4-[4-(biphenyl-4-yloxy)-
phenyl]-imidazol-1-yl}-phenoxy)- propyl]-diethyl-amine 432
##STR00464## diethyl-[3-(4-{4-[4-(3- trifluoromethyl-phenoxy)-
phenyl]-imidazol-1-yl}-phenoxy)- propyl]-amine 433 ##STR00465##
[3-(4-{4-[4-(3,4-dichloro- phenoxy)-phenyl]-imidazol-1-yl}-
phenoxy)-propyl]-diethyl-amine 434 ##STR00466##
[3-(4-{2-butyl-1-[4-(4-methoxy- phenoxy)-phenyl]-1H-imidazol-4-
yl}-phenoxy)-propyl]-diethyl- amine 435 ##STR00467##
1-[2-(4-{2-butyl-1-[4-(3-fluoro-4- trifluoromethyl-phenoxy)-
phenyl]-1H-imidazol-4-yl}- phenoxy)-ethyl]-piperazine 436
##STR00468## {3-[4-(4-{4-[2-(4-chloro-phenyl)-
ethoxy]-phenyl}-imidazol-1-yl)- phenoxy]-propyl}-dimethyl- amine
437 ##STR00469## 4-{4-[2-(4-chloro-phenyl)-
ethoxy]-phenyl}-1-{4-[2-(1- methyl-pyrrolidin-2-yl)-ethoxy]-
phenyl}-1H-imidazole 438 ##STR00470## 1-{2-[4-(4-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}- imidazol-1-yl)-phenoxy]-ethyl}- piperazine
439 ##STR00471## [3-(4-{2-(3-cyclohexyl-propyl)-
1-[4-(4-fluoro-3-trifluoromethyl- phenoxy)-phenyl]-1H-imidazol-
4-yl}-phenoxy)-propyl]-diethyl- amine 440 ##STR00472##
diethyl-(3-{4-[1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-
phenyl]-2-(3-phenoxy-propyl)- 1H-imidazol-4-yl]-phenoxy}-
propyl)-amine 441 ##STR00473## {3-[4-(4-{4-[2-(4-chloro-phenyl)-
ethoxy]-phenyl}-2-methyl- imidazol-1-yl)-phenoxy]-propyl}-
diethyl-amine 442 ##STR00474## 3-(4-{2-butyl-1-[4-(4-fluoro-
3-trifluoromethyl-phenoxy)- phenyl]-1H-imidazol-4-yl}-
phenoxy)-1-ethyl-piperidine 443 ##STR00475##
diethyl-[3-(4-{1-[4-(4-fluoro- 3-trifluoromethyl-phenoxy)-
phenyl]-2-methyl-1H-imidazol- 4-yl}-phenoxy)-propyl]-amine 444
##STR00476## (3-{4-[4-(4-benzyloxy-phenyl)-2-
butyl-imidazol-1-yl]-phenoxy}- propyl)-diethyl-amine 445
##STR00477## [3-(4-{2-butyl-1-[4-(2,5-difluoro-
benzyloxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl-
amine 446 ##STR00478## 3-(S)-(4-{2-butyl-1-[4-(4-fluoro-
3-trifluoromethyl-phenoxy)- phenyl]-1H-imidazol-4-yl}-
phenoxymethyl)-1-ethyl- piperidine 447 ##STR00479##
(3-{4-[4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-(2,4,4-
trimethyl-pentyl)-imidazol-1-yl]- phenoxy}-propyl)-diethyl-amine
448 ##STR00480## 3-(R)-(4-{2-butyl-1-[4-(4-fluoro-
3-trifluoromethyl-phenoxy)- phenyl]-1H-imidazol-4-yl}-
phenoxymethyl)-1-ethyl- piperidine 449 ##STR00481##
[3-(4-{2-butyl-1-[4-(3-tert-butyl- phenoxy)-phenyl]-1H-imidazol-
4-yl}-phenoxy)-propyl]-diethyl- amine 450 ##STR00482##
{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-
methoxymethyl-imidazol-1-yl)- phenoxy]-propyl}-diethyl-amine 451
##STR00483## (3-{4-[4-{4-[2-(4-chloro-phenyl)-
ethoxy]-phenyl}-2-(1-ethyl- propyl)-imidazol-1-yl]-phenoxy}-
propyl)-diethyl-amine 452 ##STR00484##
(3-{4-[4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-(3-phenoxy-
propyl)-imidazol-1-yl]-phenoxy}- propyl)-diethyl-amine 453
##STR00485## (3-{4-[4-{4-[2-(4-chloro-phenyl)-
ethoxy]-phenyl}-2-(1-propyl- butyl)-imidazol-1-yl]-phenoxy}-
propyl)-diethyl-amine 454 ##STR00486## {3-[4-(2-(4-chloro-
phenoxymethyl)-4-{4-[2-(4- chloro-phenyl)-ethoxy]-phenyl}-
imidazol-1-yl)-phenoxy]-propyl}- diethyl-amine 455 ##STR00487##
{3-[4-(2-benzyloxymethyl-4-{4- [2-(4-chloro-phenyl)-ethoxy]-
phenyl}-imidazol-1-yl)-phenoxy]- propyl}-diethyl-amine 456
##STR00488## {3-[4-(4-{4-[2-(4-chloro-phenyl)-
ethoxy]-phenyl}-2-isobutyl-5- methyl-imidazol-1-yl)-phenoxy]-
propyl}-diethyl-amine 457 ##STR00489##
{3-[4-(4-{4-[2-(4-chloro-phenyl)- ethoxy]-phenyl}-2-isobutyl-5-
propyl-imidazol-1-yl)- phenoxy]-propyl}-diethyl-amine 458
##STR00490## {3-[4-(5-butyl-4-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}-2- isobutyl-imidazol-1-yl)-phenoxy]-
propyl}-diethyl-amine 459 ##STR00491## {4-{4-{2-(4-chloro-phenyl)-
ethoxy]-phenyl}-1-[4-(3- diethylamino-propoxy)-phenyl]-
1H-imidazol-2-yl}-MeOH 460 ##STR00492##
diethyl-[3-(4-{2-isobutyl-4-[4-(4- phenoxy-benzyloxy)-phenyl]-
imidazol-1-yl}-phenoxy)-propyl]- amine 461 ##STR00493##
[3-(4-{4-[4-(4-benzyloxy- benzyloxy)-phenyl]-2-isobutyl-
imidazol-1-yl}-phenoxy)- propyl]-diethyl-amine 462 ##STR00494##
[3-(4-{4-[4-(2- benzenesulfonylmethyl-
benzyloxy)-phenyl]-2-isobutyl- imidazol-1-yl}-phenoxy)-propyl]-
diethyl-amine 463 ##STR00495## diethyl-[3-(4-{2-isobutyl-4-[4-
(3,4,5-trimethoxy-benzyloxy)- phenyl]-imidazol-1-yl}-phenoxy)-
propyl]-amine 464 ##STR00496## [3-(4-{1-[4-(4-chloro-phenoxy)-
phenyl]-2-isobutyl-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl-
amine 465 ##STR00497## [3-(4-{1-[4-(4-chloro-phenoxy)-
phenyl]-2-(2-cyclopentyl-ethyl)- 1H-imidazol-4-yl}-phenoxy)-
propyl]-diethyl-amine 466 ##STR00498##
[3-(4-{1-[4-(4-chloro-phenoxy)- phenyl]-2-phenethyl-1H-
imidazol-4-yl}-phenoxy)-propyl]- diethyl-amine 467 ##STR00499##
[3-(4-{2-(4-tert-butyl- phenoxymethyl)-1-[4-(4-chloro-
phenoxy)-phenyl]-1H-imidazol- 4-yl]-phenoxy)-propyl]-diethyl- amine
468 ##STR00500## [3-(4-{2-butyl-1-[4-(2,4-dichloro-
phenoxy)-phenyl]-1H-imidazol-4- yl}-phenoxy)-propyl]-diethyl- amine
469 ##STR00501## [3-(4-{2-butyl-1-[4-(4-chloro-
phenoxy)-phenyl]-5-methyl-1H- imidazol-4-yl}-phenoxy)-propyl]-
diethyl-amine 470 ##STR00502## [3-(4-{2-butyl-1-[4-(4-chloro-
phenoxy)-phenyl]-5-propyl-1H- imidazol-4-yl}-phenoxy)-propyl]-
diethyl-amine 471 ##STR00503## [3-(4-{2,5-dibutyl-1-[4-(4-chloro-
phenoxy)-phenyl]-1H-imidazol-4- yl}-phenoxy)-propyl]-diethyl- amine
472 ##STR00504## [3-(4-{2-butyl-1-[4-(4-chloro-
phenoxy)-phenyl]-5-ethyl-1H- imidazol-4-yl}-phenoxy)-propyl]-
diethyl-amine 473 ##STR00505## 2-butyl-1-[4-(4-chloro-phenoxy)-
phenyl]-4-[4-(2-pyrrolidin-1-yl- ethoxy)-phenyl]-1H-imidazole 474
##STR00506## 1-[2-(4-{2-butyl-1-[4-(4-chloro-
phenoxy)-phenyl]-1H-imidazol-4- yl}-phenoxy)-ethyl]-piperidine 475
##STR00507## [3-(4-{2-butyl-1-[4-(4-chloro-
phenoxy)-phenyl]-1H-imidazol-4- yl}-phenoxy)-2,2-dimethyl-
propyl]-dimethyl-amine 476 ##STR00508##
[2-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-1H-imidazol-4-
yl}-phenoxy)-ethyl]-diisopropyl- amine 477 ##STR00509##
[3-(4-{4-[4-(adamantan-1- ylmethoxy)-phenyl]-2-isobutyl-
imidazol-1-yl}-phenoxy)-propyl]- diethyl-amine 478 ##STR00510##
{3-[4-(4-{4-[3-(2,6-dichloro- phenyl)-4-methyl-isoxazol-5-
ylmethyloxy]-phenyl}-2-isobutyl- imidazol-1-yl)-phenoxy]-propyl}-
diethyl-amine 479 ##STR00511## [3-(4-{4-[4-(4-bromo-benzyloxy)-
phenyl]-2-isobutyl-imidazol-1- yl}-phenoxy)-propyl]-diethyl- amine
480 ##STR00512## [3-(4-{2-butyl-1-[4-(6-methoxy-
naphthalen-2-yloxy)-phenyl]-1H- imidazol-4-yl}-phenoxy)-propyl]-
diethyl-amine 481 ##STR00513## [3-(4-{2-butyl-1-[4-(naphthalen-
2-yloxy)-phenyl]-1H-imidazol-4- yl}-phenoxy)-propyl]-diethyl- amine
482 ##STR00514## [3-(4-{2-butyl-1-[4-(4-methoxy-
naphthalen-1-yloxy)-phenyl]-1H- imidazol-4-yl}-phenoxy)-propyl]-
diethyl-amine 483 ##STR00515## [3-[4-[2-butyl-1-[4-(dibenzofuran-
2-yloxy)-phenyl]-1H-imidazol-4- yl}-phenoxy)-propyl]-diethyl- amine
484 ##STR00516## 6-(4-{2-butyl-4-[4-(3-
diethylamino-propoxy)-phenyl]- imidazol-1-yl]-phenoxy)-
naphthalen-2-ol 485 ##STR00517## [3-(4-{2-butyl-4-[4-(4-chloro-
phenoxy)-phenyl]-imidazol-1-yl}- phenoxy)-propyl]-diethyl-amine 486
##STR00518## [3-(4-{2-(4-tert-butyl- cyclohexyl)-1-[4-(4-chloro-
phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl- amine
487 ##STR00519## [3-{4-[1-[4-(4-chloro-phenoxy)-
phenyl]-2-(trans-4-ethyl- cyclohexyl)-1H-imidazol-4-yl]-
phenoxy}-propyl)-diethyl-amine 488 ##STR00520##
[4-(4-{2-butyl-1-[4-(4-chloro- phenoxy)-phenyl]-1H-imidazol-
4-yl}-phenoxy)-phenyl]-(1-ethyl- piperidin-4-ylmethyl)-amine 489
##STR00521## [4-{1-[4-(4-chloro-phenoxy)- phenyl]-4-[4-(3-
diethylaminopropoxy)-phenyl]- 1H-imidazol-2-yl}-butyric acid methyl
ester 490 ##STR00522## [3-(4-{2-butyl-1-[4-(4-chloro-2-
cyclohexyl-phenoxy)-phenyl]-1H- imidazol-4-yl}-phenoxy)-propyl]-
diethyl-amine 491 ##STR00523## [3-(4-{1-[4-(biphenyl-4-yloxy)-
phenyl]-2-butyl-1H-imidazol-4- yl}-phenoxy)-propyl]-diethyl- amine
492 ##STR00524## [3-(4-{1-[4-(4-bromo-phenoxy)-
phenyl]-2-butyl-1H-imidazol-4- yl}-phenoxy)-propyl]-diethyl- amine
493 ##STR00525## N-[4-(4-{2-butyl-4-[4-(3-
diethylamino-porpoxy)-phenyl]- imidazol-1-yl}-phenoxy)-
phenyl]-acetamide 494 ##STR00526## (3-{4-[2-butyl-1-(4-p-tolyloxy-
phenyl)-1H-imidazol-4-yl]- phenoxy}-propyl)-diethyl-amine 495
##STR00527## [3-(4-{2-butyl-1-[4-(4-fluoro-
phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl-
amine
496 ##STR00528## [3-(4-{2-butyl-1-[4-(4-chloro-3-
ethyl-phenoxy)-phenyl]-1H- imidazol-4-yl}-phenoxy)-propyl]-
diethyl-amine 497 ##STR00529## {2-[4-(2-butyl-4-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}- imidazol-1-yl)-phenoxy]-ethyl}-
ethyl-amine 498 ##STR00530## [3-(4-{5-butyl-4-[4-(3,3-diphenyl-
propoxy)-phenyl]-2-isobutyl-1H- imidazol-4-yl}-phenoxy)-2,2-
dimethyl-propyl]-dimethyl-amine 499 ##STR00531##
[3-(4-{4-[4-(3,3-diphenyl- propoxy)-phenyl]-2-isobutyl-
imidazol-1-yl}-phenoxy)-propyl]- diethyl-amine 500 ##STR00532##
7-{2-butyl-4-[4-(4-chloro- phenoxy)-naphthalen-1-yl]-
imidazol-1-yl}-1,2,3,4-tetrahydro- isoquinoline 501 ##STR00533##
2-biphenyl-4-yl-N-{4-[2-butyl-1- (1,2,3,4-tetrahydro-isoquinolin-7-
yl)-1H-imidazol-4-yl]-phenyl}- acetamide 502 ##STR00534##
7-{2-butyl-4-[4-(2,4-dichloro- phenoxy)-phenyl]-1-yl}-
1,2,3,4-tetrahydro-isoquinoline 503 ##STR00535##
7-(2-butyl-4-{4-[2-(4-chloro- phenyl)-ethoxy]-phenyl}-2-
isobutyl-imidazol-1-yl)-1,2,3,4- tetrahydro-isoquinoline 504
##STR00536## 7-[4-(4-benzyloxy-phenyl)-2-
butyl-imidazol-1-yl]-1,2,3,4- tetrahydro-isoquinoline hydrochloride
hydrochloride 505 ##STR00537## 9-(2-{4-[2-butyl-1-(1,2,3,4-
tetrahydro-isoquinolin-7-yl)-1H- imidazol-4-yl]-phenoxy}-ethyl-
9H-carbazole 506 ##STR00538## 7-{2-butyl-4-[4-(4-methoxy-
phenoxy)-phenyl]-imidazol-1-yl}- 1,2,3,4-tetrahydro-isoquinoline
507 ##STR00539## 7-(2-butyl-4-{4-[2-(4-tert-butyl-
phenyl)-ethoxy]-phenyl}- imidazol-1-yl)-1,2,3,4-tetrahydro-
isoquinoline hydrochloride 508 ##STR00540##
7-{2-butyl-4-[4-(naphthalen-2- ylmethoxy)-phenyl]-1-yl}-
1,2,3,4-tetrahydro-isoquinoline hydrochloride 509 ##STR00541##
7-{2-butyl-4-[4-(4- trifluoromethyl-phenoxy)-
phenyl]-imidazol-1-yl}-1,2,3,4- tetrahydro-isoquinoline
hydrochloride 510 ##STR00542## 7-(2-butyl-4-{4-[2-(4-chloro-
phenyl)-ethoxy]-phenyl}- imidazol-1-yl)-1,2,3,4-tetrahydro-
isoquinoline 511 ##STR00543## [3-(4-{2-(4-Butyl-cyclohexyl)-1-
[4-(4-chloro-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxy)-
propyl]-diethyl-amine 512 ##STR00544##
2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-
4-yl}-phenoxy)-ethylamine 513 ##STR00545##
[3-(4-{2-(trans-4-tert-Butyl- cyclohexyl)-1-[4-(4-chloro-
phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl- amine
514 ##STR00546## [3-(4-{2-(cis-4-tert-Butyl-
cyclohexyl)-1-[4-(4-chloro- phenoxy)-phenyl]-1H-imidazol-
4-yl}-phenoxy)-propyl]- diethyl-amine 515 ##STR00547##
[2-(4-{2-Butyl-1-[4-(4-fluoro-3- trifluoromethyl-phenoxy)-
phenyl]-1H-imidazol-4-yl}- phenoxy)-ethyl]-methyl-pyridin-
4-yl-amine 516 ##STR00548## [2-(4-{1-[4-(4-Fluoro-phenoxy)-
phenyl]-2-isobutyl-1H-imidazol- 4-yl}-phenoxy)-ethyl]-methyl-
pyridin-4-yl-amine 517 ##STR00549## [2-(4-{1-[4-(4-Fluoro-phenoxy)-
phenyl]-2-isobutyl-1H-imidazol- 4-yl}-phenoxy)-ethyl]-methyl-
(3-methyl-pyridin-4-yl)-amine 518 ##STR00550##
[2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-
4-yl}-phenoxy)-ethyl]-ethyl- pyridin-4-yl-amine 519 ##STR00551##
[2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-
4-yl}-phenoxy)-ethyl]-pyridin-4- yl-amine 520 ##STR00552##
[2-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-
4-yl}-phenoxy)-ethyl]-bis- pyridin-2-ylmethyl-amine 521
##STR00553## N-[2-(4-{1-[4-(4-Chloro-
phenoxy)-phenyl]-2-isobutyl-1H- imidazol-4-yl}-phenoxy)-ethyl]-
guanidine 522 ##STR00554## 2-(4-{1-[4-(4-Chloro-phenoxy)-
phenyl]-2-isobutyl-1H-imidazol- 4-yl}-phenoxy)-1-(4-pyridin-4-
yl-piperazin-1-yl)-ethanone 523 ##STR00555##
5-(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-
4-yl}-phenoxymethyl)-pyrrolidin- 3-ol 524 ##STR00556##
3-(4-{1-[4-(4-Fluoro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-
4-yl}-phenoxy)-pyridin-4-ylamine 525 ##STR00557##
(4-{1-[4-(4-Chloro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-
4-yl}-phenyl)-pyridin-4-yl-amine 526 ##STR00558##
2-(4-{1-[4-(4-Fluoro-phenoxy)- phenyl]-2-isobutyl-1H-imidazol-
4-yl}-phenoxymethyl)-3,5- dimethyl-pyridin-4-ylamine 527
##STR00559## 1-[2-(4-{1-[4-(4-Chloro-
phenoxy)-phenyl]-2-isobutyl-1H- imidazol-4-yl]-phenoxy)-ethyl]-
4-pyridin-4-yl-piperazine 528 ##STR00560## 4-(4-{2-Butyl-4-[4-(3-
diethylamino-propoxy)-phenyl]- imidazol-1-yl}-phenoxy)- phenylamine
529 ##STR00561## {3-[4-(2-Butyl-4-dibenzofuran-
2-yl-imidazol-1-yl)-phenoxy]- propyl}-diethyl-amine 530
##STR00562## N-[4-(4-{2-Butyl-4-[4-(3-
diethylamino-propoxy)-phenyl]- imidazol-1-yl}-phenoxy)-phenyl]-
benzamide 531 ##STR00563## N-[4-(4-{2-Butyl-4-[4-(3-
diethylamino-propoxy)-phenyl]- imidazol-1-yl}-phenoxy)-phenyl]-
isonicotinamide 532 ##STR00564## [2-(4-{1-[4-(4-Chloro-phenoxy)-
phenyl]-2-isobutyl-1H-imidazol- 4-yl}-phenoxy)-ethyl]-methyl-
pyridin-4-yl-amine 533 ##STR00565## N-(4-{1-[4-(4-Chloro-phenoxy)-
phenyl]-2-isobutyl-1H-imidazol- 4-yl}-phenyl)-2-dimethylamino-
acetamide 534 ##STR00566## {3-[4-(4-{4-[3,3-Bis-(4-chloro-
phenyl)-allyloxy]-phenyl}-2- isobutyl-imidazol-1-yl)-phenoxy]-
propyl}-diethyl-amine 535 ##STR00567##
{3-[4-(4-{4-[3,3-Bis-(4-fluoro- phenyl)-propoxy]-phenyl}-2-
isobutyl-imidazol-1-yl)-phenoxy]- propyl}-diethyl-amine 536
##STR00568## [2-(4-{4-[4-(4-Chloro-phenoxy)-
phenyl]-2-isobutyl-imidazol-1- yl}-phenoxy)-ethyl]-methyl-
pyridin-4-yl-amine 537 ##STR00569##
[3-(4-{4-{4-[2-(4-Chloro-phenyl)- ethoxy]-phenyl}-2-[2-(1-methyl-
pyridin-3-yl)-ethyl]-imidazol-1- yl}-phenoxy)-propyl]-
diethylmethyl ammonium iodide 538 ##STR00570##
[3-(4-{2-(N-BOC-piperidine-4- ylmethyl)-1-[4-(4-chloro-
phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl- amine
539 ##STR00571## [3-(4-{2-(Piperidine-4-ylmethyl)-
1-[4-(4-chloro-phenoxy)-phenyl]- 1H-imidazol-4-yl}-phenoxy)-
propyl]-diethyl-amine 540 ##STR00572##
[3-(4-{2-(N-ethyl-piperidine-4- ylmethyl)-1-[4-(4-chloro-
phenoxy)-phenyl]-1H-imidazol- 4-yl}-phenoxy)-propyl]-diethyl- amine
541 ##STR00573## [3-(4-{2-(piperidine-4-ylmethyl)-
4-[4-(4-chloro-phenoxy)-phenyl]- imidazol-1-yl}-phenoxy)-propyl]-
diethyl-amine 542 ##STR00574## [3-(4-{2-(N-ethylpiperidine-4-
ylmethyl)-4-[4-(4-chloro- phenoxy)-phenyl]-imidazol-1-yl}-
phenoxy)-propyl]-diethyl-amine 543 ##STR00575##
[3-(4-{2-(N-acetylpiperidine-4- yl)-4-[4-(4-chloro-phenoxy)-
phenyl]-imidazol-1-yl}-phenoxy)- propyl]-diethyl-amine 544
##STR00576## [3-(4-{2-(piperidine-4-yl)-4-[4-
(4-chloro-phenoxy)-phenyl]- imidazol-1-yl)-phenoxy)-propyl]-
diethyl-amine 545 ##STR00577## [3-(4-{2-(N-Benzylpiperidine-4-
yl)-4-[4-(4-chloro-phenoxy)- phenyl]-imidazol-1-yl}-phenoxy)-
propyl]-diethyl-amine 546 ##STR00578## [3-(4-{2-(N-(2-
Pyridylmethyl)piperidine-4-yl)-4- [4-(4-chloro-phenoxy)-phenyl]-
imidazol-1-yl}-phenoxy)-propyl]- diethyl-amine 547 ##STR00579##
[3-(4-{2-(N-(2- Imidazolylmethyl)piperidine-4-
yl)-4-[4-(4-chloro-phenoxy)- phenyl]-imidazol-1-yl}-phenoxy)-
propyl]-diethyl-amine 548 ##STR00580## [3-(4-{2-(N-(4-
biphenyl)methylpiperidine-4-yl)- 4-[4-(4-chloro-phenoxy)-phenyl]-
imidazol-1-yl}-phenoxy)-propyl]- diethyl-amine 549 ##STR00581##
[3-(4-{2-(N- Cyclohexylpiperidine-4-yl)-4-[4-
(4-chloro-phenoxy)-phenyl]- imidazol-1-yl}-phenoxy)-propyl]-
diethyl-amine 550 ##STR00582## [3-(4-{2-(N-(4-
Cyanobenzyl)piperidine-4-yl)-4- [4-(4-chloro-phenoxy)-phenyl]-
imidazol-1-yl}-phenoxy)-propyl]- diethyl-amine 551 ##STR00583##
[3-(4-{2-(N-Ethylpiperidine-4- yl)-4-[4-(4-chloro-phenoxy)-
phenyl]-imidazol-1-yl}-phenoxy)- propyl]-diethyl-amine
DEFINITIONS OF TERMS
[0460] As used herein, the term "lower" refers to a group having
between one and six carbons.
[0461] As used herein, the term "alkyl" refers to a straight or
branched chain hydrocarbon having from one to ten carbon atoms,
optionally substituted with substituents selected from the group
consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl,
silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,
cyano, halogen, or lower perfluoroalkyl, multiple degrees of
substitution being allowed. Such an "alkyl" group may containing
one or more O, S, S(O), or S(O).sub.2 atoms. Examples of "alkyl" as
used herein include, but are not limited to, methyl, n-butyl,
t-butyl, n-pentyl, isobutyl, and isopropyl, and the like.
[0462] As used herein, the term "alkylene" refers to a straight or
branched chain divalent hydrocarbon radical having from one to ten
carbon atoms, optionally substituted with substituents selected
from the group consisting of lower alkyl, lower alkoxy, lower
alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, silyloxy optionally substituted by alkoxy,
alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or
aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such an "alkylene" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms. Examples of
"alkylene" as used herein include, but are not limited to,
methylene, ethylene, and the like.
[0463] As used herein, the term "alkyline" refers to a straight or
branched chain trivalent hydrocarbon radical having from one to ten
carbon atoms, optionally substituted with substituents selected
from the group consisting of lower alkyl, lower alkoxy, lower
alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, silyloxy optionally substituted by alkoxy,
alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or
aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Examples of "alkyline" as
used herein include, but are not limited to, methine,
1,1,2-ethyline, and the like.
[0464] As used herein, the term "alkenyl" refers to a hydrocarbon
radical having from two to ten carbons and at least one
carbon-carbon double bond, optionally substituted with substituents
selected from the group consisting of lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, silyloxy optionally substituted by alkoxy,
alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or
aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such an "alkenyl" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms.
[0465] As used herein, the term "alkenylene" refers to a straight
or branched chain divalent hydrocarbon radical having from two to
ten carbon atoms and one or more carbon-carbon double bonds,
optionally substituted with substituents selected from the group
consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl,
silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,
cyano, halogen, or lower perfluoroalkyl, multiple degrees of
substitution being allowed. Such an "alkenylene" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms. Examples of
"alkenylene" as used herein include, but are not limited to,
ethene-1,2-diyl, propene-1,3-diyl, methylene-1,1-diyl, and the
like.
[0466] As used herein, the term "alkynyl" refers to a hydrocarbon
radical having from two to ten carbons and at least one
carbon-carbon triple bond, optionally substituted with substituents
selected from the group consisting of lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, silyloxy optionally substituted by alkoxy,
alkyl, or aryl, silyl optionally substituted by alkoxy, alkyl, or
aryl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such an "alkynyl" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms.
[0467] As used herein, the term "alkynylene" refers to a straight
or branched chain divalent hydrocarbon radical having from two to
ten carbon atoms and one or more carbon-carbon triple bonds,
optionally substituted with substituents selected from the group
consisting of lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, silyloxy optionally substituted by alkoxy, alkyl, or aryl,
silyl optionally substituted by alkoxy, alkyl, or aryl, nitro,
cyano, halogen, or lower perfluoroalkyl, multiple degrees of
substitution being allowed. Such an "alkynylene" group may
containing one or more O, S, S(O), or S(O).sub.2 atoms. Examples of
"alkynylene" as used herein include, but are not limited to,
ethyne-1,2-diyl, propyne-1,3-diyl, and the like.
[0468] As used herein, "cycloalkyl" refers to an alicyclic
hydrocarbon group optionally possessing one or more degrees of
unsaturation, having from three to twelve carbon atoms, optionally
substituted with substituents selected from the group consisting of
lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. "Cycloalkyl" includes by way
of example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, or cyclooctyl, and the like.
[0469] As used herein, the term "cycloalkylene" refers to an
non-aromatic alicyclic divalent hydrocarbon radical having from
three to twelve carbon atoms and optionally possessing one or more
degrees of unsaturation, optionally substituted with substituents
selected from the group consisting of lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen, or lower
perfluoroalkyl, multiple degrees of substitution being allowed.
Examples of "cycloalkylene" as used herein include, but are not
limited to, cyclopropyl-1,1-diyl, cyclopropyl-1,2-diyl,
cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl, cyclohexyl-1,4-diyl,
cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, and the like.
[0470] As used herein, the term "heterocyclic" or the term
"heterocyclyl" refers to a three to twelve-membered heterocyclic
ring optionally possessing one or more degrees of unsaturation,
containing one or more heteroatomic substitutions selected from S,
SO, SO.sub.2, O, or N, optionally substituted with substituents
selected from the group consisting of lower alkyl, lower alkoxy,
lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
carbamoyl optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, nitro, cyano, halogen, or lower
perfluoroalkyl, multiple degrees of substitution being allowed.
Such a ring may be optionally fused to one or more of another
"heterocyclic" ring(s) or cycloalkyl ring(s). Examples of
"heterocyclic" include, but are not limited to, tetrahydrofuran,
1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine,
piperazine, and the like.
[0471] As used herein, the term "heterocyclyl containing at least
one basic nitrogen atom" refers to a "heterocyclic" "heterocyclyl
group as defined above, wherein said heterocyclyl group contains at
least one nitrogen atom flanked by hydrogen, alkyl, alkylene, or
alkylyne groups, wherein said alkyl and/or alkylene groups are not
substituted by oxo. Examples of "heterocyclyl containing at least
one basic nitrogen atom" include, but are not limited to,
piperazine-2-yl, pyrrolidine-2-yl, azepine-4-yl,
##STR00584##
and the like.
[0472] As used herein, the term "heterocyclylene" refers to a three
to twelve-membered heterocyclic ring diradical optionally having
one or more degrees of unsaturation containing one or more
heteroatoms selected from S, SO, SO.sub.2, O, or N, optionally
substituted with substituents selected from the group consisting of
lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, nitro, cyano, halogen, or lower perfluoroalkyl, multiple
degrees of substitution being allowed. Such a ring may be
optionally fused to one or more benzene rings or to one or more of
another "heterocyclic" rings or cycloalkyl rings. Examples of
"heterocyclylene" include, but are not limited to,
tetrahydrofuran-2,5-diyl, morpholine-2,3-diyl, pyran-2,4-diyl,
1,4-dioxane-2,3-diyl, 1,3-dioxane-2,4-diyl, piperidine-2,4-diyl,
piperidine-1,4-diyl, pyrrolidine-1,3-diyl, morpholine-2,4-diyl,
piperazine-1,4-diyl, and the like.
[0473] As used herein, the term "aryl" refers to a benzene ring or
to an optionally substituted benzene ring system fused to one or
more optionally substituted benzene rings, optionally substituted
with substituents selected from the group consisting of lower
alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,
lower alkylsulfonyl, oxo, hydroxy optionally substituted by acyl,
mercapto, amino optionally substituted by alkyl, carboxy,
tetrazolyl, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, acyl, aroyl,
heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl,
silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl
optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano,
halogen, or lower perfluoroalkyl, multiple degrees of substitution
being allowed. Examples of aryl include, but are not limited to,
phenyl, 2-naphthyl, 1-naphthyl, 1-anthracenyl, and the like.
[0474] As used herein, the term "arylene" refers to a benzene ring
diradical or to a benzene ring system diradical fused to one or
more optionally substituted benzene rings, optionally substituted
with substituents selected from the group consisting of lower
alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,
lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally
substituted by alkyl, carboxy, tetrazolyl, carbamoyl optionally
substituted by alkyl, aminosulfonyl optionally substituted by
alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,
alkoxycarbonyl, silyloxy optionally substituted by alkoxy, alkyl,
or aryl, silyl optionally substituted by alkoxy, alkyl, or aryl,
nitro, cyano, halogen, or lower perfluoroalkyl, multiple degrees of
substitution being allowed. Examples of "arylene" include, but are
not limited to, benzene-1,4-diyl, naphthalene-1,8-diyl, and the
like.
[0475] As used herein, the term "heteroaryl" refers to a five- to
seven-membered aromatic ring, or to a polycyclic heterocyclic
aromatic ring, containing one or more nitrogen, oxygen, or sulfur
heteroatoms, where N-oxides and sulfur monoxides and sulfur
dioxides are permissible heteroaromatic substitutions, optionally
substituted with substituents selected from the group consisting of
lower alkyl, lower alkoxy, lower alkylsulfanyl, lower
alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, amino
optionally substituted by alkyl, carboxy, tetrazolyl, carbamoyl
optionally substituted by alkyl, aminosulfonyl optionally
substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,
heteroaroyloxy, alkoxycarbonyl, silyloxy optionally substituted by
alkoxy, alkyl, or aryl, silyl optionally substituted by alkoxy,
alkyl, or aryl, nitro, cyano, halogen, or lower perfluoroalkyl,
multiple degrees of substitution being allowed. For polycyclic
aromatic ring systems, one or more of the rings may contain one or
more heteroatoms. Examples of "heteroaryl" used herein are furan,
thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole,
thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole,
pyridine, pyridazine, pyrazine, pyrimidine, quinoline,
isoquinoline, quinazoline, benzofuran, benzothiophene, indole, and
indazole, and the like.
[0476] As used herein, the term "heteroarylene" refers to a five-
to seven-membered aromatic ring diradical, or to a polycyclic
heterocyclic aromatic ring diradical, containing one or more
nitrogen, oxygen, or sulfur heteroatoms, where N-oxides and sulfur
monoxides and sulfur dioxides are permissible heteroaromatic
substitutions, optionally substituted with substituents selected
from the group consisting of lower alkyl, lower alkoxy, lower
alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo,
hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,
tetrazolyl, carbamoyl optionally substituted by alkyl,
aminosulfonyl optionally substituted by alkyl, acyl, aroyl,
heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl,
silyloxy optionally substituted by alkoxy, alkyl, or aryl, silyl
optionally substituted by alkoxy, alkyl, or aryl, nitro, cyano,
halogen, or lower perfluoroalkyl, multiple degrees of substitution
being allowed. For polycyclic aromatic ring system diradicals, one
or more of the rings may contain one or more heteroatoms. Examples
of "heteroarylene" used herein are furan-2,5-diyl,
thiophene-2,4-diyl, 1,3,4-oxadiazole-2,5-diyl,
1,3,4-thiadiazole-2,5-diyl, 1,3-thiazole-2,4-diyl,
1,3-thiazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,3-diyl,
pyridine-2,5-diyl, pyrimidine-2,4-diyl, quinoline-2,3-diyl, and the
like.
[0477] As used herein, the term "fused cycloalkylaryl" refers to
one or more cycloalkyl groups fused to an aryl group, the aryl and
cycloalkyl groups having two atoms in common, and wherein the aryl
group is the point of substitution. Examples of "fused
cycloalkylaryl" used herein include 5-indanyl,
5,6,7,8-tetrahydro-2-naphthyl,
##STR00585##
and the like.
[0478] As used herein, the term "fused cycloalkylarylene" refers to
a fused cycloalkylaryl, wherein the aryl group is divalent.
Examples include
##STR00586##
and the like.
[0479] As used herein, the term "fused arylcycloalkyl" refers to
one or more aryl groups fused to a cycloalkyl group, the cycloalkyl
and aryl groups having two atoms in common, and wherein the
cycloalkyl group is the point of substitution. Examples of "fused
arylcycloalkyl" used herein include 1-indanyl, 2-indanyl,
9-fluorenyl, 1-(1,2,3,4-tetrahydronaphthyl),
##STR00587##
and the like.
[0480] As used herein, the term "fused arylcycloalkylene" refers to
a fused arylcycloalkyl, wherein the cycloalkyl group is divalent.
Examples include 9,1-fluorenylene,
##STR00588##
and the like.
[0481] As used herein, the term "fused heterocyclylaryl" refers to
one or more heterocyclyl groups fused to an aryl group, the aryl
and heterocyclyl groups having two atoms in common, and wherein the
aryl group is the point of substitution. Examples of "fused
heterocyclylaryl" used herein include
3,4-methylenedioxy-1-phenyl,
##STR00589##
and the like
[0482] As used herein, the term "fused heterocyclylarylene" refers
to a fused heterocyclylaryl, wherein the aryl group is divalent.
Examples include
##STR00590##
and the like.
[0483] As used herein, the term "fused arylheterocyclyl" refers to
one or more aryl groups fused to a heterocyclyl group, the
heterocyclyl and aryl groups having two atoms in common, and
wherein the heterocyclyl group is the point of substitution.
Examples of "fused arylheterocyclyl" used herein include
2-(1,3-benzodioxolyl),
##STR00591##
and the like.
[0484] As used herein, the term "fused arylheterocyclyl containing
at least one basic nitrogen atom" refers to a "fused
arylheterocyclyl" group as defined above, wherein said heterocyclyl
group contains at least one nitrogen atom flanked by hydrogen,
alkyl, alkylene, or alkylyne groups, wherein said alkyl and/or
alkylene groups are not substituted by oxo. Examples of "fused
arylheterocyclyl containing at least one basic nitrogen atom"
include, but are not limited to,
##STR00592##
and the like.
[0485] As used herein, the term "fused arylheterocyclylene" refers
to a fused arylheterocyclyl, wherein the heterocyclyl group is
divalent. Examples include
##STR00593##
and the like.
[0486] As used herein, the term "fused cycloalkylheteroaryl" refers
to one or more cycloalkyl groups fused to a heteroaryl group, the
heteroaryl and cycloalkyl groups having two atoms in common, and
wherein the heteroaryl group is the point of substitution. Examples
of "fused cycloalkylheteroaryl" used herein include
5-aza-6-indanyl,
##STR00594##
and the like.
[0487] As used herein, the term "fused cycloalkylheteroarylene"
refers to a fused cycloalkylheteroaryl, wherein the heteroaryl
group is divalent. Examples include
##STR00595##
and the like.
[0488] As used herein, the term "fused heteroarylcycloalkyl" refers
to one or more heteroaryl groups fused to a cycloalkyl group, the
cycloalkyl and heteroaryl groups having two atoms in common, and
wherein the cycloalkyl group is the point of substitution. Examples
of "fused heteroarylcycloalkyl" used herein include
5-aza-1-indanyl,
##STR00596##
and the like.
[0489] As used herein, the term "fused heteroarylcycloalkylene"
refers to a fused heteroarylcycloalkyl, wherein the cycloalkyl
group is divalent. Examples include
##STR00597##
and the like.
[0490] As used herein, the term "fused heterocyclylheteroaryl"
refers to one or more heterocyclyl groups fused to a heteroaryl
group, the heteroaryl and heterocyclyl groups having two atoms in
common, and wherein the heteroaryl group is the point of
substitution. Examples of "fused heterocyclylheteroaryl" used
herein include 1,2,3,4-tetrahydro-beta-carbolin-8-yl,
##STR00598##
and the like.
[0491] As used herein, the term "fused heterocyclylheteroarylene"
refers to a fused heterocyclylheteroaryl, wherein the heteroaryl
group is divalent. Examples include
##STR00599##
and the like.
[0492] As used herein, the term "fused heteroarylheterocyclyl"
refers to one or more heteroaryl groups fused to a heterocyclyl
group, the heterocyclyl and heteroaryl groups having two atoms in
common, and wherein the heterocyclyl group is the point of
substitution. Examples of "fused heteroarylheterocyclyl" used
herein include -5-aza-2,3-dihydrobenzofuran-2-yl,
##STR00600##
and the like.
[0493] As used herein, the term "fused heteroarylheterocyclyl
containing at least one basic nitrogen atom" refers to a "fused
heteroarylheterocyclyl" group as defined above, wherein said
heterocyclyl group contains at least one nitrogen atom flanked by
hydrogen, alkyl, alkylene, or alkylyne groups, wherein said alkyl
and/or alkylene groups are not substituted by oxo. Examples of
"fused heteroarylheterocyclyl containing at least one basic
nitrogen atom" include, but are not limited to,
##STR00601##
and the like.
[0494] As used herein, the term "fused heteroarylheterocyclylene"
refers to a fused heteroarylheterocyclyl, wherein the heterocyclyl
group is divalent. Examples include
##STR00602##
and the like.
[0495] As used herein, the term "acid isostere" refers to a
substituent group which will ionize at physiological pH to bear a
net negative charge. Examples of such "acid isosteres" include but
are not limited to heteroaryl groups such as but not limited to
isoxazol-3-ol-5-yl, 1H-tetrazole-5-yl, or 2H-tetrazole-5-yl. Such
acid isosteres include but are not limited to heterocyclyl groups
such as but not limited to imidazolidine-2,4-dione-5-yl,
imidazolidine-2,4-dione-1-yl, 1,3-thiazolidine-2,4-dione-5-yl, or
5-hydroxy-4H-pyran-4-on-2-yl.
[0496] As used herein, the term "direct bond", where part of a
structural variable specification, refers to the direct joining of
the substituents flanking (preceding and succeeding) the variable
taken as a "direct bond". Where two or more consecutive variables
are specified each as a "direct bond", those substituents flanking
(preceding and succeeding) those two or more consecutive specified
"direct bonds" are directly joined.
[0497] As used herein, the term "alkoxy" refers to the group
R.sub.aO--, where R.sub.a is alkyl.
[0498] As used herein, the term "alkenyloxy" refers to the group
R.sub.aO--, where R.sub.a is alkenyl.
[0499] As used herein, the term "alkynyloxy" refers to the group
R.sub.aO--, where R.sub.1 is alkynyl.
[0500] As used herein, the term "alkylsulfanyl" refers to the group
R.sub.aS--, where R.sub.1 is alkyl.
[0501] As used herein, the term "alkenylsulfanyl" refers to the
group R.sub.aS--, where R.sub.1 is alkenyl.
[0502] As used herein, the term "alkynylsulfanyl" refers to the
group R.sub.aS--, where R.sub.1 is alkynyl.
[0503] As used herein, the term "alkylsulfenyl" refers to the group
R.sub.aS(O)--, where R.sub.1 is alkyl.
[0504] As used herein, the term "alkenylsulfenyl" refers to the
group R.sub.aS(O)--, where R.sub.1 is alkenyl.
[0505] As used herein, the term "alkynylsulfenyl" refers to the
group R.sub.aS(O)--, where R.sub.a is alkynyl.
[0506] As used herein, the term "alkylsulfonyl" refers to the group
R.sub.aSO.sub.2--, where R.sub.1 is alkyl.
[0507] As used herein, the term "alkenylsulfonyl" refers to the
group R.sub.3SO.sub.2--, where R.sub.1 is alkenyl.
[0508] As used herein, the term "alkynylsulfonyl" refers to the
group R.sub.aSO.sub.2--, where R.sub.1 is alkynyl.
[0509] As used herein, the term "acyl" refers to the group
R.sub.aC(O)--, where R.sub.1 is alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, or heterocyclyl.
[0510] As used herein, the term "aroyl" refers to the group
R.sub.aC(O)--, where R.sub.1 is aryl.
[0511] As used herein, the term "heteroaroyl" refers to the group
R.sub.aC(O)--, where R.sub.1 is heteroaryl.
[0512] As used herein, the term "alkoxycarbonyl" refers to the
group R.sub.aOC(O)--, where R.sub.1 is alkyl.
[0513] As used herein, the term "acyloxy" refers to the group
R.sub.aC(O)O--, where R.sub.1 is alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, or heterocyclyl.
[0514] As used herein, the term "alkoxycarbonyl" refers to the
group R.sub.aOC(O)--, where R.sub.1 is alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkenyl, or heterocyclyl.
[0515] As used herein, the term "aryloxycarbonyl" refers to the
group R.sub.aOC(O)--, where R.sub.1 is aryl or heteroaryl.
[0516] As used herein, the term "aroyloxy" refers to the group
R.sub.aC(O)O--, where R.sub.a is aryl.
[0517] As used herein, the term "heteroaroyloxy" refers to the
group R.sub.aC(O)O--, where R.sub.a is heteroaryl.
[0518] As used herein, the term "optionally" means that the
subsequently described event(s) may or may not occur, and includes
both event(s) which occur and events that do not occur.
[0519] As used herein, the term "substituted" refers to
substitution with the named substituent or substituents, multiple
degrees of substitution being allowed unless otherwise stated.
[0520] As used herein, the terms "contain" or "containing" can
refer to in-line substitutions at any position along the above
defined alkyl, alkenyl, alkynyl or cycloalkyl substituents with one
or more of any of O, S, SO, SO.sub.2, N, or N-alkyl, including, for
example, --CH.sub.2--O--CH.sub.2--,
--CH.sub.2--SO.sub.2--CH.sub.2--, --CH.sub.2--NH--CH.sub.3 and so
forth.
[0521] Whenever the terms "alkyl" or "aryl" or either of their
prefix roots appear in a name of a substituent (e.g.
arylalkoxyaryloxy) they shall be interpreted as including those
limitations given above for "alkyl" and "aryl". Alkyl or cycloalkyl
substituents shall be recognized as being functionally equivalent
to those having one or more degrees of unsaturation. Designated
numbers of carbon atoms (e.g. C.sub.1-10) shall refer independently
to the number of carbon atoms in an alkyl, alkenyl or alkynyl or
cyclic alkyl moiety or to the alkyl portion of a larger substituent
in which the term "alkyl" appears as its prefix root.
[0522] As used herein, the term "oxo" shall refer to the
substituent .dbd.O.
[0523] As used herein, the term "halogen" or "halo" shall include
iodine, bromine, chlorine and fluorine.
[0524] As used herein, the term "mercapto" shall refer to the
substituent --SH.
[0525] As used herein, the term "carboxy" shall refer to the
substituent --COOH.
[0526] As used herein, the term "cyano" shall refer to the
substituent --CN.
[0527] As used herein, the term "aminosulfonyl" shall refer to the
substituent --SO.sub.2NH.sub.2.
[0528] As used herein, the term "carbamoyl" shall refer to the
substituent --C(O)NH.sub.2.
[0529] As used herein, the term "sulfanyl" shall refer to the
substituent --S--.
[0530] As used herein, the term "sulfenyl" shall refer to the
substituent --S(O)--.
[0531] As used herein, the term "sulfonyl" shall refer to the
substituent --S(O).sub.2--.
[0532] As used herein, the term "solvate" is a complex of variable
stoichiometry formed by a solute (in this invention, a compound of
Formula (I)) and a solvent. Such solvents for the purpose of the
invention may not interfere with the biological activity of the
solute. Solvents may be, by way of example, water, ethanol, or
acetic acid.
[0533] As used herein, the term "biohydrolyzable ester" is an ester
of a drug substance (in this invention, a compound of Formula (I))
which either a) does not interfere with the biological activity of
the parent substance but confers on that substance advantageous
properties in vivo such as duration of action, onset of action, and
the like, or b) is biologically inactive but is readily converted
in vivo by the subject to the biologically active principle. The
advantage is that, for example, the biohydrolyzable ester is orally
absorbed from the gut and is transformed to (I) in plasma. Many
examples of such are known in the art and include by way of example
lower alkyl esters (e.g., C.sub.1-C.sub.4), lower acyloxyalkyl
esters, lower alkoxyacyloxyalkyl esters, alkoxyacyloxy esters,
alkyl acylamino alkyl esters, and choline esters.
[0534] As used herein, the term "biohydrolyzable amide" is an amide
of a drug substance (in this invention, a compound of general
Formula (I)) which either a) does not interfere with the biological
activity of the parent substance but confers on that substance
advantageous properties in vivo such as duration of action, onset
of action, and the like, or b) is biologically inactive but is
readily converted in vivo by the subject to the biologically active
principle. The advantage is that, for example, the biohydrolyzable
amide is orally absorbed from the gut and is transformed to (I) in
plasma. Many examples of such are known in the art and include by
way of example lower alkyl amides, .alpha.-amino acid amides,
alkoxyacyl amides, and alkylaminoalkylcarbonyl amides.
[0535] As used herein, the term "prodrug" includes biohydrolyzable
amides and biohydrolyzable esters and also encompasses a) compounds
in which the biohydrolyzable functionality in such a prodrug is
encompassed in the compound of Formula (I): for example, the lactam
formed by a carboxylic group in R.sub.2 and an amine in R.sub.4,
and b) compounds which may be oxidized or reduced biologically at a
given functional group to yield drug substances of Formula (I).
Examples of these functional groups include, but are not limited
to, 1,4-dihydropyridine, N-alkylcarbonyl-1,4-dihydropyridine,
1,4-cyclohexadiene, tert-butyl, and the like.
[0536] The term "pharmacologically effective amount" or shall mean
that amount of a drug or pharmaceutical agent that will elicit the
biological or medical response of a tissue, animal or human that is
being sought by a researcher or clinician. This amount can be a
therapeutically effective amount. The term "therapeutically
effective amount" shall mean that amount of a drug or
pharmaceutical agent that will elicit the therapeutic response of
an animal or human that is being sought.
[0537] The term "treatment" or "treating" as used herein, refers to
the full spectrum of treatments for a given disorder from which the
patient is suffering, including alleviation of one, most of all
symptoms resulting from that disorder, to an outright cure for the
particular disorder or prevention of the onset of the disorder.
[0538] The present invention also provides a method for the
synthesis of compounds useful as intermediates in the preparation
of compounds of Formula (I) along with methods for the preparation
of compounds of Formula (I). Unless otherwise indicated, variables
refer to those for Formula (I).
[0539] An aldehyde (1) (Scheme 1) may be condensed with a diamine
compound (2) in a solvent such as ethanol at a temperature of from
25 to 100 degrees Celsuis, to obtain the product benzimidazole (3),
where the intermediate adduct undergoes spontaneous oxidation.
Alternately, the acid (1a) may be coupled with the diamine compound
(2) employing a reagent such as HBTU to afford (2a). The reaction
may also afford some of the compound where the carboxylic acid has
coupled to the secondary aniline nitrogen. Either product (2a) may
be cyclized to (3). One nonlimiting method is to heat (2a) in a
solvent such as acetic acid at a temperature of from 25 to 100
degrees Celsuis, to obtain the cyclized product (3). Ar.sub.1 is a
group such as but not limited to an optionally substituted aryl or
heteroaryl ring system.
##STR00603##
[0540] Where R.sub.52 is aryl, heteroaryl, or contains an aryl or
heteroaryl group possessing a phenolic substituent, or where
R.sub.52 possesses a free hydroxyl group, an aldehyde of formula
(4) (Scheme 2) may be treated with an optionally substituted alkyl
halide R.sub.51-LG.sub.1 and a base such as potassium carbonate, in
a solvent such as DMF, at a temperature of from 0 to 120.degree.
C., to afford (5). LG.sub.1 represents a nucleofugal group such as
iodide, bromide, methanesulfonate, or toluenesulfonate (Scheme 2).
Where R.sub.53 in (6) represents an aryl or heteroaryl ring system,
direct treatment of (6) in the presence of a base such as DIEA or
TEA with an aryl or heteroaryl phenol Ar.sub.2--OH provides (7),
where the Ar.sub.2--O-- substituent is bonded to the same atom as
the F in (6).
##STR00604##
[0541] In Scheme 3, an aldehyde (8) processing two free hydroxyl
groups , two free phenolic groups, of a combination of phenolic and
hydroxyl groups may be treated with two equivalents of an
alkylating agent R.sub.51-LG.sub.1, in the presence of a suitable
base such as potassium carbonate or DIEA, in a solvent such as DMF,
to afford (9). Alternately, where R.sub.53 is an aryl ring
posessing ortho and para hydroxyl groups relative to the aldehyde
group, treatment of (8) with one equivalent of base and an
alkylating agent R.sub.51-LG.sub.1 in the presence of a suitable
base such as DIEA of potassium carbonate, followed by treatment
with a second alkylating agent R.sub.54-LG.sub.2 in the presence of
base, affords (10). The ortho, para difluoro aldehyde (11), where
R.sub.53 is a heteroaryl or aryl ring, may be treated with an
alcohol R.sub.55--OH in the presence of base such as DIEA, followed
by treatment with a phenol Ar.sub.3--OH in the presence of a base
such as DIEA or potassium carbonate, to afford (12).
##STR00605##
[0542] Scheme 4 describes the synthesis of substituted
arylenediamines.
##STR00606##
[0543] In Scheme 4, an ortho-fluoro nitrophenol such as (13) may be
alkylated with an alkyl halide or other alkylating agent
R.sub.56-LG.sub.1, in the presence of an alkali metal carbonate as
base in a solvent such as DMF or acetonitrile. LG.sub.1 may
represent a nucleofugal group such as iodide, bromide,
methanesulfonate, and the like. In this transformation, R.sub.56 is
a group such as but not limited to alkyl. The intermediate may be
treated with an amine R.sub.2--NH.sub.2 in the presence or absence
of a tertiary amine base, in a solvent such as THF, at a
temperature of from 0.degree. C. to 100.degree. C., to afford (14).
Reduction of the nitro group in (14) may be accomplished by
treatment of (14) in acidic or neutral ethanol with stannous
chloride at a temperature of from 25.degree. C. to 100.degree. C.
to afford the aniline (15). Alternately, (14) may be reduced by
treatment of (14) with a noble metal catalyst such as palladium on
charcoal and a hydrogen source such as gaseous hydrogen or ammonium
formate, in a solvent such as ethanol, at a temperature of from
25.degree. C. to 80.degree. C., to afford (15). The
difluoronitroaromatic compound (16) may be employed in similar
manner, where in (16), one fluoro is ortho to the nitro group.
Treatment of (16) with the one equivalent of amine
R.sub.2--NH.sub.2 gives preferential substitution of the ortho
fluorine. The second fluorine in the intermediate may be
substituted by an alcohol R.sub.57--OH to afford (17). In this
instance, R.sub.57 may also be aryl. Reduction of the nitro group
in (17) as before with stannous chloride provides (18). Ar.sub.4
represents a group such as but not limited to aryl or
heteroaryl.
[0544] Scheme 5 describes synthesis of aryl diamines. The
2,4,6-trifluoronitroaromatic compound (19) may be treated with one
equivalent of an amine R.sub.2--NH.sub.2 to afford the product of
substitution at one ortho fluoro; excess R.sub.58--OH may then be
employed in the presence of a base such as potassium tert-butoxide
or sodium hydride to afford (20). Reduction of the nitro group as
for Scheme 4 affords the aniline (21). Similarly, a
3,5-difluorophenolic aromatic compound (22) may be nitrated under
strong nitrating conditions, e.g. fuming nitric acid, to afford the
ortho nitro phenol (23) along with the para nitrophenol (24). Each
individually may be processed by sequential phenol alkylation,
ortho fluoro displacement by R.sub.2--NH.sub.2, and para or ortho
fluorodisplacement by R.sub.58--OH, to afford (25) and (26) after
reduction, following chemistries in the preceding general
procedures. Ar.sub.5 represents a group such as but not limited to
aryl or heteroaryl.
##STR00607##
[0545] Scheme 6 describes the synthesis of mono and di alkoxy
-substituted aminoaryl and aminoheteroaryl compounds. A
fluoronitroaromatic (27), where F is preferably ortho or para to
the nitro, may be treated with an alcohol or phenol R.sub.60--OH
and a base such as potassium tert-butoxide or sodium hydride, to
afford the ipso adduct. Reduction of the nitro group to amino
following preceding methods affords (28). Similarly, displacement
of the fluoro groups in (29) with R.sub.60--OH followed by
reduction as before give (30). The nitro compound (31) may be
treated with a base and R.sub.61-LG.sub.1 to afford the alkylation
product, then treated with R.sub.60--OH and a base, then reduced as
above to give (32). Alternately, (33) may be processed similarly to
give (32). Ar.sub.6 represents a group such as but not limited to
aryl or heteroaryl.
##STR00608##
[0546] Scheme 7 describes a general synthesis of imidazoles. An
aniline containing a basic side chain (--O--R.sub.62) (40) may be
coupled with a bromoketone containing a non-basic side chain
(--O--R.sub.63) (41) to give the aminoketone (42), which may then
be treated with acetic acid, heat, an aldehyde R.sub.1--CHO, and
ammonium acetate to afford (43). Alternately, (42) may be treated
with an acid chloride R.sub.1--COCl to afford (44), which may
subsequently be treated with ammonium acetate, acetic acid and heat
to afford (43). Ar.sub.7 and Ar.sub.8 represent groups such as but
not limited to aryl or heteroaryl.
##STR00609##
[0547] Scheme 8 describes another general synthesis of imidazoles.
An aniline containing a non-basic side chain (45) may be coupled
with a bromoketone containing a basic side chain (46) to give the
aminoketone (47), which may then be treated with acetic acid, heat,
an aldehyde R.sub.1--CHO, and ammonium acetate to afford (48).
Alternately, (42) may be treated with an acid chloride
R.sub.1--COCl to afford (49), which may subsequently be treated
with ammonium acetate, acetic acid and heat to afford (43).
Ar.sub.7 and Ar.sub.8 represent groups such as but not limited to
aryl or heteroaryl.
##STR00610##
[0548] Scheme 9 describes another general synthesis of imidazoles.
An aniline containing a basic side chain (40) may be coupled with a
bromoketone (50) to give the aminoketone (51), which may then be
treated with an acid chloride R.sub.1--COCl to afford (52), which
may subsequently be treated with ammonium acetate, acetic acid and
heat to afford (53). The phenol is then alkylated with a alkylating
agent R.sub.63-LG.sub.5 to generate the desired imidazole (54).
R.sub.63 is a group such as but not limited to substituted alkyl,
and LG.sub.5 is a leaving group such as iodide or methanesulfonate.
Ar.sub.7 and Ar.sub.8 represent groups such as but not limited to
aryl or heteroaryl.
##STR00611##
[0549] Scheme 10 describes another general synthesis of imidazoles.
An aniline containing a hydrophobic side chain (40) may be coupled
with a bromoketone (55) to give the aminoketone (56), which may
then be treated with an acid chloride R.sub.1--COCl to afford (57),
which may subsequently be treated with ammonium acetate, acetic
acid and heat to afford (58). The phenol is then deprotected;
PG.sub.1 may be a group sych as but not limited to benzyl, which
may be removed with treatment with hydrogen over palladium on
carbon. The free phenolic group is subsequently alkylated with an
alkylating agent R.sub.63-LG.sub.5 to generate the desired
imidazole (59). R.sub.63 is a group such as but not limited to
substituted alkyl, and LG.sub.5 is a leaving group such as iodide
or methanesulfonate.
##STR00612##
[0550] Scheme 11 describes the synthesis of diones or bromoketones.
A aryl ketone (60) may be treated with base and an alkylating agent
R.sub.64-LG.sub.6 to generate the phenyl ether. R.sub.64 is a group
such as but not limited to substituted alkyl, and LG.sub.6 is a
leaving group such as iodide or methanesulfonate. The product may
be brominated with a reagent such as but not limited to
pyrrolidinium hydrotribromide, to (61) and the bromide may be
oxidized by treatment with DMSO to afford (62). (63) may be treated
with Ar.sub.10--OH and base, followed by bromination, to afford
(64). Oxidation as before gives the dione (65). Ar.sub.9 is a group
such as but not limited to aryl or heteroaryl.
##STR00613##
[0551] Scheme 12 describes the synthesis of imidazoles. (66) may be
treated with (67) and an aldehyde R.sub.1--CHO to afford (68).
Alternately, (66) may be coupled with the bromoketone (70) to give
the aminoketone (71), which may be treated with acetic acid, heat,
an aldehyde R.sub.1--CHO, and ammonium acetate to afford (68).
Ar.sub.11 and Ar.sub.12 are groups such as but not limited to aryl
or heteroaryl.
##STR00614##
[0552] Scheme 13 describes the synthesis of imidazoles. A dione
(72) may be treated with R.sub.1--CHO and ammonium acetate -acetic
acid to afford (74). Alternately, an amine R.sub.2--NH.sub.2 may be
used in place of ammonium acetate to give (75).
##STR00615##
[0553] Scheme 14 describes another synthesis of imidazoles. (76)
may be coupled with the bromoketone (77) to give the aminoketone
(78), which may be treated with acetic acid, heat, an aldehyde
R.sub.1--CHO, and ammonium acetate to afford (80). Alternately,
(78) may be treated with an acid chloride R.sub.1--COCl to afford
(79), which may subsequently be treated with ammonium acetate,
acetic acid and heat to afford (80). The group R.sub.68 may be an
amino protecting group, such as BOC, which may be removed by
treatment of (80) with TFA. The amine may be directly alkylated or
reductively alkylated by methods known in the art. For example,
treatment of the NH compound with acetaldehyde and sodium
cyanoborohydride in a solvent such as acetic acid affords (80)
where R.sub.68 is ethyl. Ar.sub.12 is a group such as but not
limited to aryl or heteroaryl.
##STR00616##
[0554] Scheme 15 describes the synthesis of imidazoles. A dione
(81) may be treated with R.sub.1--CHO and an amine (76) in acetic
acid, in the presence of ammonium acetate, at a temperature of from
50 to 140.degree. C., to afford (83). If the group R.sub.68 is an
amine protecting group, then said protecting group may be removed
and the nitrogen alkylated as described in Scheme 14.
##STR00617##
[0555] The term "amino protecting group" as used herein refers to
substituents of the amino group commonly employed to block or
protect the amino functionality while reacting other functional
groups on the compound. Examples of such amino-protecting groups
include the formyl group, the trityl group, the phthalimido group,
the trichloroacetyl group, the chloroacetyl, bromoacetyl and
iodoacetyl groups, urethane-type blocking groups such as
benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl,
2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl,
3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl,
2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,
3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
4-cyanobenzyloxy-carbonyl, 2-(4-xenyl)iso-propoxycarbonyl,
1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl,
2-phenylprop-2-yloxycarbonyl, 2-(p-toluoyl)prop-2-yloxycarbonyl,
cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl,
cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl,
2-methylcyclohexanyloxycarbonyl,
2-(4-toluylsulfonyl)ethoxycarbonyl,
2(methylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphino)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl
("FMOC"), t-butoxycarbonyl ("BOC"),
2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,
1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl,
5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,
cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl,
isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; the
benzoylmethylsulfonyl group, the 2-(nitro)phenylsulfenyl group, the
diphenylphosphine oxide group and like amino-protecting groups. The
species of amino-protecting group employed is not critical so long
as the derivatized amino group is stable to the condition of
subsequent reaction(s) on other positions of the compound of
Formula (I) and can be removed at the desired point without
disrupting the remainder of the molecule. Preferred
amino-protecting groups are the allyloxycarbonyl, the
t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and the trityl
groups. Similar amino-protecting groups used in the cephalosporin,
penicillin and peptide art are also embraced by the above terms.
Further examples of groups referred to by the above terms are
described by J. W. Barton, "Protective Groups In Organic
Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y.,
1973, and T. W. Greene, "Protective Groups in Organic Synthesis",
John Wiley and Sons, New York, N.Y., 1981. The related term
"protected amino" or "protected amino group" defines an amino group
substituted with an amino-protecting group discussed above.
[0556] The term "hydroxyl protecting group" as used herein refers
to substituents of the alcohol group commonly employed to block or
protect the alcohol functionality while reacting other functional
groups on the compound. Examples of such alcohol -protecting groups
include the 2-tetrahydropyranyl group, 2-ethoxyethyl group, the
trityl group, the trichloroacetyl group, urethane-type blocking
groups such as benzyloxycarbonyl, and the trialkylsilyl group,
examples of such being trimethylsilyl, tert-butyldimethylsilyl,
phenyldimethylsilyl, triiospropylsilyl and thexyldimethylsilyl. The
choice of alcohol-protecting group employed is not critical so long
as the derivatized alcohol group is stable to the condition of
subsequent reaction(s) on other positions of the compound of the
formulae and can be removed at the desired point without disrupting
the remainder of the molecule. Further examples of groups referred
to by the above terms are described by J. W. Barton, "Protective
Groups In Organic Chemistry", J. G. W. McOmie, Ed., Plenum Press,
New York, N.Y., 1973, and T. W. Greene, "Protective Groups in
Organic Synthesis", John Wiley and Sons, New York, N.Y., 1981. The
related term "protected hydroxyl" or "protected alcohol" defines a
hydroxyl group substituted with a hydroxyl-protecting group as
discussed above.
[0557] The term "carboxyl protecting group" as used herein refers
to substituents of the carboxyl group commonly employed to block or
protect the --OH functionality while reacting other functional
groups on the compound. Examples of such alcohol -protecting groups
include the 2-tetrahydropyranyl group, 2-ethoxyethyl group, the
trityl group, the allyl group, the trimethylsilylethoxymethyl
group, the 2,2,2-trichloroethyl group, the benzyl group, and the
trialkylsilyl group, examples of such being trimethylsilyl,
tert-butyldimethylsilyl, phenyldimethylsilyl, triiospropylsilyl and
thexyldimethylsilyl. The choice of carboxyl protecting group
employed is not critical so long as the derivatized alcohol group
is stable to the condition of subsequent reaction(s) on other
positions of the compound of the formulae and can be removed at the
desired point without disrupting the remainder of the molecule.
Further examples of groups referred to by the above terms are
described by J. W. Barton, "Protective Groups In Organic
Chemistry", J. G. W. McOmie, Ed., Plenum Press, New York, N.Y.,
1973, and T. W. Greene, "Protective Groups in Organic Synthesis",
John Wiley and Sons, New York, N.Y., 1981. The related term
"protected carboxyl" defines a carboxyl group substituted with a
carboxyl-protecting group as discussed above.
[0558] The general procedures used in the methods of the present
invention are described below.
Methods
[0559] LC-MS data is obtained using gradient elution on a Waters
600 controller equipped with a 2487 dual wavelength detector and a
Leap Technologies HTS PAL Autosampler using an YMC Combiscreen
ODS-A 50.times.4.6 mm column. A three minute gradient is run from
25% B (97.5% acetonitrile, 2.5% water, 0.05% TFA) and 75% A (97.5%
water, 2.5% acetonitrile, 0.05% TFA) to 100% B. The mass
spectrometer used is a Micromass ZMD instrument. All data is
obtained in the positive mode unless otherwise noted. .sup.1H NMR
and .sup.13C NMR data is obtained on a Varian 400 MHz
spectrometer.
[0560] Abbreviations used in the Examples are as follows:
APCI=atmospheric pressure chemical ionization
BOC=tert-butoxycarbonyl
BOP=(1-benzotriazolyloxy)tris(dimethylamino)phosphonium
hexafluorophosphate d=day DIAD=diisopropyl azodicarboxylate
DCC=dicyclohexylcarbodiimide DCM=dichloromethane
DIC=diisopropylcarbodiimide DIEA=diisopropylethylamine
DMA=N,N-dimethylacetamide
[0561] DMAP=dimethylaminopyridine DME=1,2 dimethoxyethane
DMF=N,N-dimethylformamide
[0562] DMPU=1,3-dimethypropylene urea DMSO=dimethylsulfoxide
Et=ethyl iPr=isopropyl Bn=benzyl Me=methyl tBu=tert-butyl Pr=propyl
Bu=butyl iBu=isobutyl
EDC=1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride
EDTA=ethylenediamine tetraacetic acid ELISA=enzyme-linked
immunosorbent assay ESI=electrospray ionization ether=diethyl ether
EtOAc=ethyl acetate FBS=fetal bovine serum g=gram h=hour
HBTU=O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate HMPA=hexamethylphosphoric triamide
HOBt=1-hydroxybenzotriazole Hz=hertz i.v.=intravenous kD=kiloDalton
L=liter LAH=lithium aluminum hydride LDA=lithium diisopropylamide
LPS=lipopolysaccharide M=molar m/z=mass to charge ratio
mbar=millibar MeOH=methanol mg=milligram min=minute mL=milliliter
mM=millimolar mmol=millimole mol=mole mp=melting point
[0563] MS=mass spectrometry
N=normal NMM=N-methylmorpholine, 4-methylmorpholine NMR=nuclear
magnetic resonance spectroscopy p.o.=per oral
PS-carbodiimide=N-cyclohexylcarbodiimide-N'-propyloxymethyl
polystyrene PBS=phosphate buffered saline solution PMA=phorbol
myristate acetate ppm=parts per million psi=pounds per square inch
R.sub.f=relative TLC mobility rt=room temperature s.c.=subcutaneous
SPA=scintillation proximity assay TEA=triethylamine
TFA=trifluoroacetic acid THF=tetrahydrofuran THP=tetrahydropyranyl
TLC=thin layer chromatography TMSBr=bromotrimethylsilane,
trimethylsilylbromide T.sub.r=retention time General synthesis of
Monoalkoxybenzaldehydes:
General Procedure A
[0564] To a stirred solution of a 2-, 3-, or 4-hydroxybenzaldehyde
(2 mmol) in DMF (6 mL) at rt solid K.sub.2CO.sub.3 (4 mmol) is
added. An alkyl halide or mesylate (prepared from the corresponding
alcohol and methanesulfonyl chloride) (2.2 mmol) is added to the
reaction mixture and heated to 80.degree. C. until the reaction is
complete as indicated by TLC or HPLC. After cooling to rt, the
reaction mixture is poured into EtOAc (20 ml) and washed with water
(2.times.10 ml) and brine (15 ml). The organic layer is dried over
magnesium sulfate and after removal of the drying agent, the
solvent is removed under high vacuum to afford the desired product.
The crude product may be used for further transformation without
any purification or after purifying using silica gel column
chromatography.
General Synthesis of Monoaryloxybenzaldehydes:
General Procedure B
[0565] To a stirred solution of a 2-, 3-, or 4-fluorobenzaldehyde
(2 mmol) in DMF (6 mL) at rt requisite phenol (2.2) is added
followed by solid K.sub.2CO.sub.3 (3 mmol). The reaction mixture is
heated to 100.degree. C. until the reaction is complete as
indicated by TLC or HPLC. After cooling to rt, the reaction mixture
is poured into EtOAc (20 ml) and washed with water (2.times.10 ml)
and brine (15 ml). The organic layer is dried over magnesium
sulfate and after removal of the drying agent, the solvent is
removed under high vacuum to afford the desired product. The crude
product may be used for further transformation without any
purification or after purifying using silica gel column
chromatography.
General Synthesis of Homosubstituted 2,4-dialkoxybenzaldehydes:
General Procedure C
[0566] To a stirred solution of 2,4-dihydroxybenzaldehyde (2 mmol)
in DMF (8 mL) at it solid Cs.sub.2CO.sub.3 (6 mmol) is added. An
alkyl halide or mesylate (prepared from the corresponding alcohol
and methanesulfonyl chloride, see General Procedure P2) (4.4 mmol)
is added to the reaction mixture and heated to 80.degree. C. until
the reaction is complete as indicated by TLC or HPLC. After cooling
to rt, the reaction mixture is poured into EtOAc (20 ml) and washed
with water (2.times.10 ml) and brine (15 ml). The organic layer is
dried over magnesium sulfate and after removal of the drying agent,
the solvent is removed under high vacuum to afford the desired
product. The crude product may be used for further transformation
without any purification or after purifying using silica gel column
chromatography.
General Synthesis of Heterosubstituted
2,4-dialkoxybenzaldehydes:
General Procedure D1
[0567] To a stirred solution of 2,4-dihydroxybenzaldehyde (2.2
mmol) in DMF (5 mL) at it solid KHCO.sub.3 (2.2 mmol) is added. An
alkyl halide or mesylate (prepared from the corresponding alcohol
and methanesulfonyl chloride, see General Procedure P2) (2.0 mmol)
is added to the reaction mixture and heated at 130.degree. C. for 4
h. After cooling to rt, the reaction mixture is treated with cold
H.sub.2O (15 mL), and extracted with EtOAc (2.times.10 mL). The
combined organic layers is washed with brine, and dried over sodium
sulfate. The crude product is purified by flash chromatography to
provide the 2-hydroxy-4-alkoxybenzaldehyde intermediate.
General Procedure D2
[0568] To a stirred solution of aforementioned
2-hydroxy-4-alkoxybenzaldehyde intermediate (2 mmol) in DMSO (5 mL)
at rt solid Cs.sub.2CO.sub.3 (3 mmol) is added. An alkyl halide or
mesylate (prepared from the corresponding alcohol and
methanesulfonyl chloride, see General Procedure P2) (3 mmol) is
added to the reaction mixture and heated to 90.degree. C. until the
reaction is complete as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture is treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.10 mL). The combined organic layers
is washed with H.sub.2O (10 mL) and brine (10 mL) and dried over
sodium sulfate. After removal of the drying agent, the solvent is
removed under high vacuum to afford the desired product. The crude
product may be used for further transformation without any
purification or after purifying using silica gel column
chromatography.
General Synthesis of 2-alkoxy-4-aryloxybenzaldehydes:
General Procedure E
[0569] A solution of 2,4-difluorobenzaldehyde (2 mmol) in DMF (2
mL) is added dropwise to a precooled (0.degree. C.) solution of
sodium alkoxide (2 mmol) in DMF (6 ml) [prepared by stirring a
mixture of sodium hydride (2 mmol), and the corresponding alcohol
(2 mmol) in DMF]. The resulting reaction mixture is warmed to it
and stirred for an additional 3 h. To the same reaction vessel,
solid potassium carbonate (2 mmol) and requisite phenol (2 mmol))
is introduced and the reaction mixture is heated at 90.degree. C.
in an oil bath for 24. After cooling to rt, the reaction mixture is
poured into EtOAc (20 ml) and washed with water (2.times.10 ml) and
brine (15 ml). The organic layer is dried over magnesium sulfate
and after removal of the drying agent, the solvent is removed under
high vacuum to afford the desired product. The crude product may be
used for further transformation without any purification or after
purifying using silica gel column chromatography.
General Synthesis of Monoalkoxy Ortho-Phenylenediamines:
Method A:
General Procedure F1
[0570] To a stirred solution of 3-fluoro-4-nitrophenol (4 mmol) in
DMF (6 mL) at it solid K.sub.2CO.sub.3 (8 mmol) is added. An alkyl
halide or mesylate (prepared from the corresponding alcohol and
methanesulfonyl chloride, see General Procedure P2) (4.4 mmol) is
added to the reaction mixture and heated to 80.degree. C. until the
reaction is complete as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture is poured into EtOAc (40 ml) and washed
with water (2.times.20 ml) and brine (30 ml). The organic layer is
dried over magnesium sulfate and after removal of the drying agent,
the solvent is removed under vacuum to afford the desired product.
The crude product may be used for further transformation without
any purification or after purifying using silica gel column
chromatography.
General Procedure F2
[0571] To a stirred solution of 2-fluoro-4-alkoxynitrobenzene (2
mmol) obtained above, TEA (4 mmol) in DMF (5 mL) is added dropwise
a solution of requisite alkylamine (2.2 mmol) in DMF (2 mL) at rt
within 15 min, and then stirred at it for 5 h. The reaction mixture
is treated with cold H.sub.2O (10 mL), and extracted with EtOAc
(2.times.15 mL), The combined organic layers is washed with
H.sub.2O (10 mL) and brine (10 mL) and dried over sodium sulfate.
After removal of the drying agent, the solvent is removed under
high vacuum to afford the desired 2-alkylamino-4-alkoxynitrobenzene
intermediate. The crude product may be used for further
transformation without any purification or after purifying using
silica gel column chromatography.
Method B:
General Procedure G1
[0572] To a stirred solution of 2,4-difluoronitrobenzene (2 mmol),
TEA (4 mmol) in DMF (5 mL) is added dropwise a solution of
requisite alkylamine (2.2 mmol) in DMF (2 mL) at it within 15 min,
and then stirred at it for 5 h. The reaction mixture is treated
with cold H.sub.2O (10 mL), and extracted with EtOAc (2.times.15
mL), The combined organic layers is washed with H.sub.2O (10 mL)
and brine (10 mL) and dried over sodium sulfate. After removal of
the drying agent, the solvent is removed under high vacuum to
afford the desired 2-alkylamino-4-fluoronitrobenzene. The crude
product may be used for further transformation without any
purification or after purifying using silica gel column
chromatography.
General Procedure G2
[0573] To a stirred solution of 2-alkylamino-4-fluoronitrobenzene
as obtained above (2.0 mmol) in anhydrous THF (4 mL), an alcohol
(2.4 mmol) is added followed by powdered KOBu.sup.t (2.4 mmol) in
one portion at rt and under the N.sub.2 stream. The reaction
mixture is then refluxed until the reaction is complete as
indicated by TLC or HPLC. After cooling to rt, the reaction mixture
is treated with cold H.sub.2O (15 mL), and extracted with EtOAc
(2.times.10 mL). The combined organic layers is washed with brine,
and dried over sodium sulfate. Evaporation of the solvent in vacuo
afforded 2-alkylamino-4-alkoxynitrobenzene intermediate. The crude
product may be used for further transformation without any
purification or after purifying using silica gel column
chromatography.
Reduction of Monoalkoxy Nitrobenzenes:
General Procedure H
[0574] The nitro intermediate (2 mmol) obtained above as in Method
A or B is dissolved in MeOH (10 mL) and hydrogenated in the
presence of 10% Pd/C (10 mg) until the reaction is complete as
indicated by TLC or HPLC. The reaction mixture is then filtered
through a celite pad to remove the catalyst. The solvent is removed
under high vacuum to afford the desired diamine, which is used
directly for further transformation without further
purification.
General Procedure I
[0575] To a stirred solution of afforded
2-alkylamino-4-alkoxynitrobenzene intermediate [as obtained in
(b)](2 mmol) in EtOH (20 mL), SnCl.sub.2.2H.sub.2O (8 mmol) is
added and the mixture is refluxed until the reaction is complete as
indicated by TLC or HPLC. After completion of the reduction, the
solvent is removed in vacuo, and the residue is treated with
saturated NaHCO.sub.3 to pH.about.8. The resulting yellow
suspension is extracted with DCM (2.times.20 mL), washed with
brine, and dried. The solvent is removed under high vacuum to
afford the desired diamine, which is used directly for further
transformation without further purification.
[0576] General synthesis of homo disubstituted dialkoxy
ortho-phenylenediamines:
General Procedure J1
[0577] To a stirred solution of 2,4,6-trifluoronitrobenzene (3.0
mmol) and triethylamine (6.0 mmol) in DMF (6 mL), a solution of
alkyl amine (3.0 mmol) in DMF (2 mL) is added dropwise at rt within
15 min, and then stirred at rt for 5 h. The reaction mixture is
treated with cold H.sub.2O (10 mL), and extracted with EtOAc
(2.times.15 mL), The combined organic layers is washed with
H.sub.2O (10 mL) and brine (10 mL) and dried over sodium sulfate.
After removal of the drying agent, the solvent is removed under
high vacuum to afford the desired
2-alkylamino-4,6-difluoronitrobenzene. The crude product may be
used for further transformation without any purification or after
purifying using silica gel column chromatography.
General Procedure J2
[0578] To a stirred solution of
2-alkylamino-4,6-difluoronitrobenzene as obtained above (2.0 mmol)
in anhydrous THF (4 mL), an alcohol (4.4 mmol) is added followed by
powdered KOBu.sup.t (4.4 mmol) in one portion at rt and under the
N.sub.2 stream. The reaction mixture is then refluxed until the
reaction is complete as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture is treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
is washed with brine, and dried over sodium sulfate. Evaporation of
the solvent in vacuo afforded 2-alkylamino-4,6-dialkoxynitrobenzene
intermediate. The crude product may be used for further
transformation without any purification or after purifying using
silica gel column chromatography.
[0579] The nitro intermediate (2 mmol) obtained may be reduces to
the amino compound employing general procedures H or I.
General Synthesis of Hetero Disubstituted Dialkoxy
Ortho-Phenylenediamines:
General Procedure J3
[0580] To a stirred solution of 3,5-difluorophenol (3 g; 17 mmol)
in dichloromethane (30 mL) at 0.degree. C., conc. HNO.sub.3 (2.5
mL) is added dropwise over 10 min. The reaction mixture is then
stirred at 0.degree. C. for 60 min at which the nitration is
complete as indicated by TLC. After the reaction is complete cold
H.sub.2O (30 mL) is added to the reaction flask and stirred. The
contents are then poured into a separatory funnel and the layers
removed. The aqueous layer is then extracted with EtOAc (2.times.30
mL) and the combined organic layers are dried over magnesium
sulfate. After removal of the drying agent, the solvent is removed
under vacuum to the crude product mixture is purified using silica
gel column chromatography to provide the nitrodifluorophenol.
General Procedure J4
[0581] To a stirred solution of 3,5-difluoro-4-nitrophenol (4 mmol)
in DMF (6 mL) at rt solid K.sub.2CO.sub.3 (8 mmol) is added. An
alkyl halide or mesylate (prepared from the corresponding alcohol
and methanesulfonyl chloride, see General Procedure P2) (4.4 mmol)
is added to the reaction mixture and heated to 80.degree. C. until
the reaction is complete as indicated by TLC or HPLC. After cooling
to rt, the reaction mixture is poured into EtOAc (40 ml) and washed
with water (2.times.20 ml) and brine (30 ml). The organic layer is
dried over magnesium sulfate and after removal of the drying agent,
the solvent is removed under vacuum to afford the desired product.
The crude product may be used for further transformation without
any purification or after purifying using silica gel column
chromatography.
General Procedure J5
[0582] To a stirred solution of 2,6-difluoro-4-alkoxynitrobenzene
obtained above (3.0 mmol) and triethylamine (6.0 mmol) in DMF (6
mL), a solution of alkyl amine (3.0 mmol) in DMF (2 mL) is added
dropwise at rt within 15 min, and then stirred at rt for 5 h. The
reaction mixture is treated with cold H.sub.2O (10 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
is washed with H2O (10 mL) and brine (10 mL) and dried over sodium
sulfate. After removal of the drying agent, the solvent is removed
under high vacuum to afford the desired
2-alkylamino-4-alkoxy-6-fluoronitrobenzene. The crude product may
be used for further transformation without any purification or
after purifying using silica gel column chromatography.
General Procedure J6
[0583] To a stirred solution of
2-alkylamino-4-alkoxy-6-fluoronitrobenzene as obtained above (2.0
mmol) in anhydrous THF (5 mL) at 0.degree. C., a 1M solution of an
alkoxide (2.2 mmol) in THF (may be generated by adding the
corresponding alcohol to a 1M solution of KOBU.sup.t in THF) is
added dropwise and under the N.sub.2 stream. The reaction mixture
is maintained at 0.degree. C. until the reaction is complete as
indicated by TLC or HPLC. The reaction mixture is then treated with
cold H.sub.2O (15 mL), and extracted with EtOAc (2.times.15 mL).
The combined organic layers is washed with brine, and dried over
sodium sulfate. Evaporation of the solvent in vacuo afforded the
desired hetero dialkoxy substituted nitro intermediate. The crude
product may be used for further transformation without any
purification or after purifying using silica gel column
chromatography.
General Procedure J7
[0584] The nitro intermediate (2 mmol) obtained above is dissolved
in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10
mg) until the reaction is complete as indicated by TLC or HPLC. The
reaction mixture is then filtered through a celite pad to remove
the catalyst. The solvent is removed under high vacuum to afford
the desired hetero disubstituted dialkoxy
ortho-phenylenediamine.
General Procedure for Synthesis of Benzimidazoles:
General Procedure K
[0585] A solution of an ortho phenylenediamine (2 mmol) and an
appropriate aryl aldehyde in ethanol is refluxed until the reaction
is complete as indicated by TLC or HPLC. The solvent is removed in
vacuo and the residue obtained is purified by silica gel column
chromatography to afford the desired 2-arylbenzimidazole.
General Procedure for Synthesis of Monoalkoxyanilines:
Method A:
General Procedure L1
[0586] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
alkoxide (2.2 mmol) in THF (may be generated by adding the
corresponding alcohol to a 1M solution of KOBu.sup.t in THF) is
added dropwise and under the N.sub.2 stream. The reaction mixture
is stirred at 0.degree. C. until completion, as indicated by TLC or
HPLC. The reaction mixture is then treated with cold H.sub.2O (15
mL), and extracted with EtOAc (2.times.15 mL). The combined organic
layers were washed with brine and dried over sodium sulfate.
Evaporation of the solvent in vacuuo afforded the desired
4-alkoxynitrobenzene. The crude product could be used directly for
further transformation without any purification, or after purifying
using silica gel column chromatography.
Method B:
General Procedure M1
[0587] To a stirred solution of 4-nitrophenol (2 mmol) in DMF (6
mL) at rt, solid potassium carbonate (4 mmol) is added. An alkyl
halide or mesylate (prepared from the corresponding alcohol and
methanesulfonyl chloride, see General Procedure P2) (2.2 mmol) is
then added to the reaction mixture and heated to 80.degree. C.
until completion, as indicated by TLC or HPLC. After cooling to rt,
the reaction mixture is then treated with cold H.sub.2O (15 mL),
and extracted with EtOAc (2.times.15 mL). The combined organic
layers were washed with brine and dried over sodium sulfate.
Evaporation of the solvent in vacuuo afforded the desired
4-alkoxynitrobenzene. The crude product could be used directly for
further transformation without any purification, or after purifying
using silica gel column chromatography.
General Procedure for Synthesis of Homo Disubstituted
Alkoxy-Anilines:
Method C
General Procedure N1
[0588] To a stirred solution of 2,4-difluoronitrobenzene (2.0 mmol)
in anhydrous THF (4 mL) at 0.degree. C., an alcohol (4.4 mmol) is
added followed by powdered potassium t-butoxide (4.4 mmol) in one
portion under a N.sub.2 stream. The reaction mixture is then warmed
to rt and heated under reflux until completion, as indicated by TLC
or HPLC. After cooling to rt, the reaction mixture is treated with
cold H.sub.2O (15 mL), and extracted with EtOAc (2.times.15 mL).
The combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of the solvent in vacuuo afforded the
2,4-dialkoxynitrobenzene. The crude product could then be used for
further transformation without any purification, or after purifying
using silica gel column chromatography.
General Procedure for Synthesis of Alkoxy-Anilines:
General Procedure O2
[0589] To a stirred solution of 4-alkoxy-2-fluoronitrobenzene
obtained above (2.0 mmol) in anhydrous THF (5 mL) at 0.degree. C.,
a 1M solution of an alkoxide (2.2 mmol) in THF (may be generated by
adding the corresponding alcohol to a 1M solution of potassium
t-butoxide in THF) is added dropwise and under a N.sub.2 stream.
The reaction mixture is maintained at 0.degree. C. until
completion, as indicated by TLC or HPLC. The reaction mixture is
then treated with cold H.sub.2O (15 mL), and extracted with EtOAc
(2.times.15 mL). The combined organic layers were washed with
brine, and dried over sodium sulfate. Evaporation of the solvent in
vacuuo afforded the desired hetero-substituted dilkoxynitrobenzene.
The crude product may be used for further transformation without
any purification or after purifying using silica gel column
chromatography.
Method E:
General Procedure P1
[0590] To a stirred solution of a 2-nitro-5-fluorophenol (2.0 mmol)
in anhydrous THF (4 mL) at 0.degree. C., an alcohol (2.2 mmol) is
added followed by powdered potassium t-butoxide (4.2 mmol) in one
portion under a N.sub.2 stream. The reaction mixture is then warmed
up to rt and heated under reflux until completion, as indicated by
TLC or HPLC. After cooling to rt, the crude reaction mixture is
treated with an alkyl halide or mesylate (2.2 mmol, prepared from
the corresponding alcohol and methanesulfonyl chloride) and heated
under reflux until completion, as indicated by TLC or HPLC. The
reaction mixture is then cooled to rt, treated with cold H.sub.2O
(15 mL), and extracted with EtOAc (2.times.15 mL). The combined
organic layers were washed with brine, and dried over sodium
sulfate. Evaporation of the solvent in vacuuo afforded the
hetero-substituted dilkoxynitrobenzene. The crude product may be
used for further transformation without any purification or after
purifying using silica gel column chromatography.
General Procedure P2
[0591] A primary or secondary alcohol (20 mmol, 1 eq) is dissolved
in DCM (25 mL), TEA (40 mmol, 2 eq) is added and the mixture is
cooled to 0.degree. C. To this mixture, methanesulfonyl chloride
(30 mmol, 1.5 eq) is added slowly with stirring and the reaction
mixture is stirred at 0.degree. C. for an hour and at rt for
another hour (until the reaction is complete by HPLC). The solvent
is removed and to this saturated aqueous sodium bicarbonate is
added. The product is extracted with EtOAc (3.times.) and washed
with sodium bicarbonate and water. The solvent is removed in vacuuo
to afford the product methanesulfonate.
General Procedure for Synthesis of Alkyl Phenones;
Method F:
General Procedure Q1
[0592] To a stirred solution of 4'-hydroxyacetophenone (1.2 mmol)
in DMF (10 mL) at rt, solid potassium carbonate (3.0 mmol) is
added. An alkyl halide or mesylate (prepared from the corresponding
alcohol and methanesulfonyl chloride, see General Procedure P2)
(1.0 mmol) is added to the reaction mixture and heated to
80.degree. C. until completion, as indicated by TLC or HPLC. After
cooling to rt, the reaction mixture is quenched by removing solvent
in vacuuo and treating the residue with saturated sodium
bicarbonate. The aqueous layer is poured into EtOAc (20 ml) and
washed with H.sub.2O (2.times.10 ml) and brine (15 ml). The organic
layer is dried over magnesium sulfate, and the solvent is removed
in vacuuo to afford the desired product. The crude alkylated
product may be used for further transformation without any
purification or after purifying using silica gel column
chromatography.
Method G:
General Procedure Q2
[0593] To a stirred solution of an alcohol (75 mmol) in DMSO (80
mL) at rt, solid cesium carbonate (150 mmol) is added.
4'-fluoro-alkylphenone (50 mmol) is added to the reaction mixture
and heated to 90.degree. C. until completion, as indicated by TLC
or HPLC. After cooling to rt, the reaction mixture is treated with
saturated sodium bicarbonate (150 ml). The aqueous layer is
extracted with diethyl ether (4.times.100 ml). The organic layer is
washed with H.sub.2O (2.times.10 ml) and brine (15 ml). The organic
layer is dried over magnesium sulfate, and the solvent is removed
in vacuuo to afford the desired alkoxy acetophenone. The crude
alkylated acetophenone may be used for further transformation
without any purification or after purifying using silica gel column
chromatography.
General Procedure for N-Aryl Imidazoles:
Method H:
General Procedure R1
[0594] To a stirred solution of alkoxyacetophenone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq.) is added. The reaction mixture is stirred under nitrogen
at 0.degree. C. for 1 h and is allowed to warm to ambient
temperature until completion, as indicated by TLC or HPLC. The
solvent is then removed in vacuuo and the crude
alpha-bromoacetophenone is used for further transformation.
General Procedure R2
[0595] To a stirred solution of an alkoxy aniline (1.2 eq., 2 mmol)
in anhydrous DMF (5 mL) diisopropylethylamine (3 eq. 6 mmol) is
added, followed by a slow addition of the alpha-bromoacetophenone
described above (1.6 mmol). The reaction mixture is stirred under
nitrogen at rt until completion, as indicated by TLC or HPLC. The
reaction mixture is then diluted with cold H.sub.2O and the product
is isolated in EtOAc. The combined organic layers were washed with
brine and dried over sodium sulfate. Evaporation of solvent in
vacuuo afforded the desired product. The crude alkylated aniline is
purified by chromatography (Silica gel). Pure product obtained from
2-4% MeOH/DCM (yield .about.50-60%).
General Procedure R3
[0596] To a stirred solution of alkylated aniline described above
(2 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (3 eq., 6
mmol) is added, followed by a slow addition of an acid chloride or
anhydride (3 eq., 6 mmol). The reaction mixture is stirred under
nitrogen at 0.degree. C. for 1 h and allowed to warm to ambient
temperature until completion, as indicated by TLC or HPLC. The
solvent is removed in vacuuo, and the crude amide is used for
further transformation.
General Procedure R4
[0597] To a stirred solution of the amide described above (2 mmol)
in AcOH (2 mL), ammonium acetate (excess, .about.20 eq.) is added.
The reaction mixture is stirred at 90.degree. C. overnight. The
reaction mixture is then cooled down and neutralized with saturated
sodium bicarbonate solution. Usual extractive work up with EtOAc
gave the product imidazole, which is purified by column
chromatography (Silica gel). Pure product is obtained from 4-6%
MeOH/DCM (yield 40-50%).
General Procedure S1
[0598] To a stirred solution of an alkoxy aniline (2 mmol) in DCM
(4 mL) at rt, TEA (2.5 mmol) is added followed by an acid chloride
or anhydride (2.5 mmol). The reaction mixture is stirred under
nitrogen at rt until completion, as indicated by TLC or HPLC. The
reaction mixture is treated with saturated aqueous sodium
bicarbonate solution (5 mL), then extracted with EtOAc (2.times.15
mL). The combined organic layers were washed with H.sub.2O
(2.times.15 mL) and brine, and dried over sodium sulfate.
Evaporation of the solvent in vacuuo afforded the anilide. The
crude product is used for further transformation.
General Procedure S2
[0599] To a stirred solution of the anilide (2 mmol) obtained as
above in anhydrous THF (4 mL) solid sodium hydride (60% dispersion
in oil; 2.2 mmol) is added in portions. After the addition, a
solution of a bromo-acetophenone (2.2 mmol) (prepared as described
earlier) in anhydrous THF (2 mL) is added to the reaction mixture.
The reaction is then allowed to proceed at rt or heated under
reflux as needed. Upon completion of the reaction, EtOAc (20 mL) is
added to the reaction mixture followed by H.sub.2O (10 mL). The
organic layer is washed with H.sub.2O (2.times.15 mL) and brine,
and dried over sodium sulfate. Evaporation of the solvent in vacuuo
afforded the N-alkylated anilide. The crude product may be used for
further transformation.
General Procedure S3
[0600] To a stirred solution of the N-alkylated anilide (1 mmol)
obtained as above in AcOH (3 mL), solid NH.sub.4OAc (20 mmol) is
added in one portion. The reaction mixture is then heated to
100.degree. C. overnight. The reaction mixture is cooled to rt, and
treated with saturated aqueous sodium bicarbonate solution while
stirring to until the pH is 7-8. The contents were extracted with
EtOAc (2.times.15 mL). The combined organic layers is washed with
H.sub.2O (2.times.15 mL) and brine, and dried over sodium sulfate.
Evaporation of the solvent in vacuuo afforded the desired N-aryl
imidazole. The crude product is purified using silica gel column
chromatography.
General Procedure T1
[0601] 4N hydrogen chloride in dioxane solution (4 mmol) is added
to a mixture of BOC -amino compound (1 mmol) in anhydrous DCM (5
mL), and the mixture is stirred at rt until complete. Evaporation
of the solvents in vacuo afforded deprotected amine
hydrochloride.
General Procedure T2
[0602] A benzyl alkyl ether, benzyl ester, or a benzyl phenyl ether
is dissolved in MeOH and hydrogenated in the presence of 10% Pd/C
catalyst until the reaction is complete. reaction mixture is then
filtered through a celite pad to remove the catalyst. Evaporation
of the solvent in vacuo afforded the alcohol, carboxylic acid, or
phenol, respectively.
General Procedure T3
[0603] A phenol (0.2 mmol) in anhydrous DMF (5 mL) is alkylated by
a bromide or a mesylate (0.3 mmol) at rt (for a bromide, 60% NaH as
base) or at 90.degree. C. (for a mesylate, K.sub.2CO.sub.3 as
base). The reaction is quenched by adding sat. NaHCO.sub.3. The
resulting mixture is extracted with EtOAc washed with brine and
dried. The crude product is purified by silica gel column
chromatography if desired.
Example 1
1-Butyl-2-(3-cyclohexylmethoxy-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H-benz-
imidazole
[0604] Hydroxy benzimidazole was formed employing
1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine
(synthesized via General Procedures G1 and G2 and H) (2.92 g; 10
mmol) and 3-hydroxybenzaldehyde (1.34 g, 11 mmol) in ethanol (20
mL) following the general procedure K. The crude product was
purified by silica gel column chromatography using 2% MeOH in DCM
(3.2 g).
[0605] MS m/z 396 (M+H).sup.+
[0606] A solution of above mentioned hydroxybenzimidazole compound
(39.4 mg, 0.1 mmol) in THF (2 ml) was added cyclohexylmethyl
bromide (19.5 mg, 0.11 mmol) and NaH (0.8 mg, 60% , 0.12 mmol) at
0.degree. C. The resulting reaction mixture was warmed to rt and
stirred for additional 12 h. The mixture was quenched with brine
and extracted into EtOAc (2.times.10 mL). Combined organic EtOAc
extracts were dried over sodium sulfate and concentrated to give
compound which was purified by silica gel column chromatography
using dichloromethane and 2% methanol in dichloromethane as eluent,
to give N--BOC compound, which was subjected to General Procedure
T1 affording
1-butyl-2-(3-cyclohexylmethoxy-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H-ben-
zimidazole as a hydrochloride salt, 36.8 mg.
[0607] MS m/z 491 (M+H).sup.+
Example 2
(3-(3-butyl-2-(3-,5-di-tert-butyl-2-methoxy-phenyl)-3H-benzimidazol-5-ylox-
y-propyl)-diethyl-amine
[0608] This compound was prepared according to the general
procedure K by refluxing a mixture of
3,5-di-t-butyl-5-methoxybenzaldehyde (100 mg) and
N.sup.2-Butyl-4-(3-diethylamino-propoxy)-benzene-1,2-diamine
(synthesized via General Procedures G1 and G2 and H) (50 mg) in
ethanol overnight. Ethanol was removed in vacuo and the residue was
purified by silica gel chromatography using 5% MeOH in DCM to give
(3-(3-butyl-2-(3-,5-di-tert-butyl-2-methoxy-phenyl)-3H-benzimidazol-5-ylo-
xy-propyl)-diethyl-amine (45.0 mg).
[0609] MS: m/z 522 (M+H).sup.+
Example 3
(2-(3-butyl-2-(3-(4-tert-butyl-phenoxy)-phenyl)-3H-benzimidazol-5-yloxy-et-
hyl)-diisopropyl-amine
[0610] A solution of
2-(n-butylamino)-4-(2-diisopropylaminoethoxy)aniline (synthesized
via General Procedures G1 and G2 and H) (61.4 mg, 0.2 mmol) and
(3-(4-tert-butyl-phenoxy)-benzaldehyde (synthesized via General
Procedure B) (56 mg, 0.22 mmol) in ethanol (2 mL) was condensed
following General Procedure K. The crude product was purified by
silica gel column chromatography using 10% MeOH in DCM with a
gradual increment of triethylamine (0.2 to 1.0%) as eluent to
afford
(2-(3-butyl-2-(3-(4-tert-butyl-phenoxy)-phenyl)-3H-benzimidazol-5-yloxy-e-
thyl)-diisopropyl-amine (54 mg).
[0611] MS m/z 542 (M+H)+
Example 4
(3-{-4-[1-butyl-6-(4-tert-butyl-phenoxy)-1H-benzimidazol-2-yl]-phenoxy}-pr-
opyl)-diethyl-amine
[0612] To a stirred solution of 4-hydroxybenzaldehyde (20 mmol) in
DMSO (80 mL) at rt, solid Cs.sub.2CO.sub.3 (50 mmol) was added. A
mesylate (prepared from 3-diethylamino-1-propanol and
methanesulfonyl chloride, General Procedure P2) (30 mmol) was added
to the reaction mixture and heated to 90.degree. C. until the
reaction was complete as indicated by LC-MS (10 h). After cooling
to rt, the reaction was quenched by cold H.sub.2O (100 mL), and the
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with brine (3.times.50 mL) and
dried (anhydrous Na.sub.2SO.sub.4). The solvent was removed in
vacuo, and the crude product was purified by silica gel column
chromatography, eluting with 10% MeOH in DCM+0.5% Et.sub.3N, giving
the desired 4-(3-diethylaminopropoxy)benzaldehyde.
[0613] A solution of 2-t-butylamino-4-(4-n-butylphenoxy)aniline
(synthesized via General Procedures G1 and G2 and H) (130 mg, 0.4
mmol) and 4-(3-diethylaminopropoxy)benzaldehyde obtained above (70
mg, 0.3 mmol) in MeOH (10 mL) was subjected to General Procedure K.
The solvent was removed in vacuo and the residue was purified by
silica gel column chromatography, eluting with 10% MeOH in DCM with
a gradual increment of Et.sub.3N (0.5 to 1%), affording the desired
benzimidazole (120 mg).
[0614] MS m/z 528 (M+H).sup.+
[0615] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.84 (t, 3H),
1.05 (t, 6H), 1.24 (m, 2H), 1.31 (s, 9H), 1.75 (m, 2H), 1.98 (m,
2H), 2.58 (q, 4H), 2.66 (t, 2H), 4.09 (t, 2H), 4.13 (t, 2H), 6.93
(d, 2H,), 7.00 (dd, 1H), 7.02 (d, 2H), 7.07 (d, 1H), 7.33 (d, 2H,),
7.62 (d, 2H), 7.72 (d, 1H) ppm.
Example 5
1-butyl-6-(4-tert-butyl-phenoxy)-2-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-
H-benzimidazole
[0616] To a stirred solution of 3-hydroxybenzaldehyde (20 mmol) in
DMSO (50 mL) at rt, solid Cs.sub.2CO.sub.3 (60 mmol) was added.
1-(2-chloroethyl)pyrrolidine hydrochloride (30 mmol) was added to
the reaction mixture and heated to 90.degree. C. for 9 h. After
cooling to rt, the reaction was quenched by cold H.sub.2O (50 mL),
and the resulting mixture was extracted with EtOAc (3.times.100
mL). The combined EtOAc extracts were washed with brine (3.times.50
mL) and dried (anhydrous Na.sub.2SO.sub.4). The solvent was removed
in vacuo to afford crude
3-(2-pyrrolidin-1-yl-ethoxy)benzaldehyde.
[0617] A solution of 2-t-butylamino-4-(4-n-butylphenoxy)aniline
(synthesized via General Procedures G1 and G2 and H) (130 mg, 0.4
mmol) and 3-(2-pyrrolidin-1-yl-ethoxy)benzaldehyde obtained above
(70 mg, .about.0.3 mmol) in MeOH (10 mL) was subjected to General
Procedure K. The solvent was removed in vacuo and the residue was
purified by silica gel column chromatography, eluting with 10% MeOH
in DCM with a gradual increment of Et.sub.3N (0.5 to 1%), to afford
the desired benzimidazole (100 mg).
[0618] MS m/z 512 (M+H).sup.+
[0619] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.0.83 (t, 3H), 1.22
(m, 2H), 1.29 (s, 9H), 1.74 (m, 2H), 1.87 (m, 4H), 2.78 (m, 4H),
3.03 (m, 2H), 4.16 (t, 2H), 4.25 (m, 2H), 6.94 (d, 2H), 7.01 (br d,
1H), 7.07 (m, 2H), 7.26 (m, 2H), 7.33 (d, 2H), 7.41 (t, 1H), 7.74
(d, 1H) ppm.
[0620] The following Examples were synthesized according to the
Methods employed for Examples 1-5;
TABLE-US-00002 Example Name 6
1-butyl-6-(4-tert-butyl-phenoxy)-2-[2-(2-pyrrolidin-1-yl-ethoxy)-
phenyl]-1H-benzimidazole 7
1-butyl-2-[3-(naphthalen-2-yloxy)-phenyl]-6-(2-piperazin-1-yl-
ethoxy)-1H-benzoimidazole 8
2-biphenyl-4-yl-1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H-
benzimidazole 9
1-butyl-6-(4-tert-butyl-phenoxy)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-
phenyl]-1H-benzimidazole 10
1-butyl-2-[3-(3,3-dimethyl-butoxy)-phenyl]-6-(2-piperazin-1-yl-
ethoxy)-1H-benzoimidazole 11
1-butyl-6-(4-fluoro-3-trifluoromethyl-phenoxy)-2-[4-(2-pyrrolidin-1-yl-
ethoxy)-phenyl]-1H-benzimidazole 12
1-butyl-2-(3-phenoxy-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H-
benzoimidazole 13
1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-piperidin-1-yl-
ethoxy)-1H-benzimidazole 14
1-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-6-(2-piperidin-1-yl-
ethoxy)-1H-benzimidazole 15
1-butyl-6-[2-(4-chloro-phenyl)-ethoxy]-2-[4-(2-pyrrolidin-1-yl-ethoxy)-
phenyl]-1H-benzimidazole 16
1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-piperidin-1-yl-
ethoxy)-1H-benzimidazole 17
1-butyl-2-(4-tert-butyl-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H-
benzoimidazole 18
dibutyl-{4-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-
yl]-phenyl}-amine 19
(2-{3-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-3H-benzoimidazol-5-
yloxy}-ethyl)-diisopropyl-amine 20
{3-[3-butyl-2-(4-tert-butyl-phenyl)-3H-benzimidazol-5-yloxy]-propyl}-
diethyl-amine 21
1-butyl-2-(3,5-di-tert-butyl-2-methoxy-phenyl)-6-(2-piperazin-1-
ylethoxy)-1H-benzoimidazole 22
{3-[3-butyl-2-(3-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-propyl)-
3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 23
1-butyl-2-naphthalen-2-yl-6-(2-piperazin-1-yl-ethoxy)-1H-
benzimidazole 24
(2-{3-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-3H-benzoimidazol-5-
yloxy}-ethyl)-dimethyl-amine 25
2-benzofuran-2-yl-1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H-
benzimidazole 26
1-butyl-6-(2-piperazin-1-yl-ethoxy)-2-[3-(3-trifluoromethyl-phenoxy)-
phenyl]-1H-benzimidazole 27
2-benzhydryl-1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H-benzimidazole
28 1-Butyl-2-(4-chloro-phenyl)-6-(2-piperazin-1-yl-ethoxy)-1H-
benzoimidazole 29
{3-[3-Butyl-2-(4-isopropoxy-phenyl)-3H-benzoimidazol-5-yloxy]-
propyl}-diethyl-amine 30
1-Butyl-6-(2-piperazin-1-yl-ethoxy)-2-[3-(4,4,4-trifluoro-butoxy)-
phenyl]-1H-benzoimidazole
Example 31
(2-(3-butyl-2-(2,4,4-trimethylpentyl)-3H-benzimidazol-5-yloxy-propyl)-diet-
hyl-amine
##STR00618##
[0622] A solution of
2-(n-butylamino)-4-(3-diethylaminopropoxy)aniline (synthesized via
General Procedures G1 and G2 and H) (58.6 mg, 0.2 mmol) and
3,5,5-trimethylhexanal (31.2 mg, 0.22 mmol) in ethanol (2 mL) was
subjected to General Procedure K. The crude product was purified by
silica gel column chromatography using 10% MeOH in DCM with a
gradual increment of triethylamine (0.2 to 1.0%) as eluent to
afford
(2-(3-butyl-2-(2,4,4-trimethylpentyl)-3H-benzimidazol-5-yloxy-propyl)-die-
thyl-amine (41.0 mg).
[0623] MS m/z 416 (M+H).sup.+
Example 32
1-[(5-pyrrolidin-1-yl)pentyl-6-(3-diethylaminopropoxy)-2-piperidin-3-yl-1H-
-benzimidazole
[0624] A solution of
1-(t-butyloxycarbonyl)piperidine-3-carboxaldehyde (235 mg; 1.1
mmol) and
2-[(5-pyrrolidin-1-yl)pentylamino]-4-(3-diethylaminopropoxy)-4-(2-diethyl-
aminoethoxy)aniline (synthesized via General Procedures G1 and G2
and H) (362 mg; 1 mmol) in ethanol (5 mL) was subjected to General
Procedure K. The crude product was purified by silica gel column
chromatography using 10% MeOH in DCM with a gradual increment of
triethylamine (0.2 to 1.0%) as eluent to afford 410 mg of
tert-butyl
3-{[1-(5-pyrrolidin-1-yl)pentyl]-6-(3-diethylaminopropoxy)-1H-benzimidazo-
l-2-yl}piperidine-1-carboxylate.
[0625] A solution of tert-butyl
3-{[1-(5-pyrrolidin-1-yl)pentyl]-6-(3-diethylaminopropoxy)-1H-benzimidazo-
l-2-yl}piperidine-1-carboxylate (271 mg; 0.5 mmol) in DCM (2 mL)
was subjected to General Procedure T1. The resulting mixture was
stirred for 4-5 h and the solvent was removed in vacuo. The residue
obtained was washed with ether twice and dried under vacuum to
afford
1-[(5-pyrrolidin-1-yl)pentyl-6-(3-diethylaminopropoxy)-2-piperidin-3-yl-1-
H-benzimidazole trihydrochloride (210 mg).
[0626] MS m/z 442 (M+H).sup.+
Example 33
1-[(5-pyrrolidin-1-yl)pentyl-6-(3-diethylaminopropoxy)-2-piperidin-4-yl-1H-
-benzimidazole
[0627] A solution of
1-(t-butyloxycarbonyl)piperidine-4-carboxaldehyde (235 mg; 1.1
mmol) and
2-[(5-pyrrolidin-1-yl)pentylamino]-4-(3-diethylaminopropoxy)-4-(2-diethyl-
aminoethoxy)aniline (362 mg; 1 mmol) in ethanol (5 mL) was
subjected to General Procedure K. The crude product was purified by
silica gel column chromatography using 10% MeOH in DCM with a
gradual increment of triethylamine (0.2 to 1.0%) as eluent to
afford 430 mg of tert-butyl
4-{[1-(5-pyrrolidin-1-yl)pentyl]-6-(3-diethylaminopropoxy)-1H-benzimidazo-
l-2-yl}piperidine-1-carboxylate.
[0628] A solution of tert-butyl
4-{[1-(5-pyrrolidin-1-yl)pentyl]-6-(3-diethylaminopropoxy)-1H-benzimidazo-
l-2-yl}piperidine-1-carboxylate (271 mg; 0.5 mmol) in DCM (2 mL)
was subjected to General Procedure T1. The resulting mixture was
stirred for 4-5 h and the solvent was removed in vacuo. The residue
obtained was washed with ether twice and dried under vacuum to
afford
1-[(5-pyrrolidin-1-yl)pentyl-6-(3-diethylaminopropoxy)-2-piperidin-4-yl-1-
H-benzimidazole trihydrochloride (220 mg).
[0629] MS m/z 442 (M+H).sup.+
Example 34
{1-butyl-[4,6-di(3-diethylaminopropoxy)]-2-piperidin-4-yl}-1H-benzimidazol-
e
[0630] A solution of
1-(t-butyloxycarbonyl)piperidine-4-carboxaldehyde (235 mg; 1.1
mmol) and 2-butylamino-4,6-di(3-diethylaminopropoxy)aniline
(synthesized via General Procedures J1 and J2 and I) (424 mg; 1
mmol) in ethanol (5 mL) was subjected to General Procedure K. The
crude product was purified by silica gel column chromatography
using 10% MeOH in DCM with a gradual increment of triethylamine
(0.2 to 1.0%) as eluent to afford 425 mg of tert-butyl
{4-[1-butyl-4,6-di(3-diethylaminopropoxy)-1H-benzimidazol-2-yl]}piperidin-
e-1-carboxylate.
[0631] A solution of tert-butyl
4-[1-butyl-4,6-di(3-diethylaminopropoxy)-1H-benzimidazol-2-yl]piperidine--
1-carboxylate (308 mg; 0.5 mmol) in DCM (2 mL) was subjected to
General Procedure T1. The resulting mixture was stirred for 4-5 h
and the solvent was removed in vacuo. The residue obtained was
washed with ether twice and dried under vacuum to afford
{1-butyl-[4,6-di(3-diethylaminopropoxy)]-2-piperidin-4-yl}-1H-benzimidazo-
le trihydrochloride (260 mg).
[0632] MS m/z 516 (M+H).sup.+
Example 35
(3-(3-butyl-2-(3-(4-tert-butyl-phenoxy)-phenyl)-7-(2-pyrrolidin-1-yl-ethox-
y)-3H-benzimidazol-5-yloxy-propyl)-diethyl-amine
[0633] Example 35 was formed employing
3-(4-t-butyl-phenoxy)benzaldehyde (synthesized via General
Procedure B) (50 mg; 0.20 mmol) and
2-butylamino-4-(3-diethylaminopropoxy)-6-(2-pyrrolidin-1-yl-ethoxy)anilin-
e (synthesized via General Procedures J3-J7) (39 mg; 0.20 mmol) in
ethanol (1 mL) according to General Procedure K. The crude product
was purified by silica gel column chromatography using 10% MeOH in
DCM with a gradual increment of triethylamine (0.2 to 1.0%) as
eluent to afford 40 mg of Example 243.
[0634] MS m/z 641 (M+H).sup.+
Example 36
1-butyl-2-{4-[2-(4-chlorophenyl)ethoxy]phenyl}-6-(2-pyrrolidin-1-yl-ethoxy-
)-1H-benzimidazole
##STR00619##
[0636] This compound was prepared according to the General
Procedure K by refluxing a mixture of
4-[2-(4-chloro-phenyl)-ethoxy]-bezaldehyde (synthesized via General
Procedure A) (100 mg) and
N.sup.2-Butyl-4-(2-pyrrolidin-1-ylethoxy)-benzene-1,2-diamine
(synthesized via General Procedures G1 and G2 and H) (50 mg) in
ethanol overnight. Ethanol was removed in vacuo and the residue was
purified by silica gel chromatography using 5% MeOH in DCM to give
pure
1-butyl-2-{4-[2-(4-chlorophenyl)ethoxy]-phenyl}-6-(2-pyrrolidin-1-yl-etho-
xy)-1H-benzimidazole (37.0 mg, 40%).
[0637] MS: m/z 518 (M+H).sup.+
Example 37
1-butyl-2-{3-[3-tert-butyl-phenoxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-
-benzimidazole
[0638] A mixture of
1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine
(synthesized via General Procedures G1 and G2 and H) (0.130 g,
0.512 mmol) and 3-(3-tert-butylphenoxy)benzaldehyde was subjected
to General Procedure K. Reaction was concentrated and purified on
silica gel chromatography using DCM-2% MeOH/DCM. The BOC-group was
removed employing General Procedure T1 to give
1-butyl-2-{3-[3-tert-butyl-phenoxy]-phenyl}-6-(2-piperazin-1-yl-e-
thoxy)-1H-benzimidazole (0.10 g).
[0639] MS (m/z): 527 (M+H).sup.+
Example 38
1-butyl-2-{3-[biphenyl-4-yloxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-ben-
zimidazole
[0640] A mixture of 3-bromobenzaldehyde (1.05 g) and
1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine (1.85
g) was subjected to General Procedure K. The ethanol was removed in
vacuo and the residue purified on silica gel using 1-2%
MeOH/DCM.
[0641] To a solution of the aryl bromide (0.07 mmol) in pyridine (1
mL) was added copper powder (0.14 mmol) followed by K.sub.2CO.sub.3
(0.35 mmol) and the respective substituted phenol (0.14 mmol). The
mixture was heated at 110.degree. C. overnight, then diluted with
water (2 mL) and extracted with EtOAc (3.times.2 mL). The combined
organic extract was dried over Na.sub.2SO.sub.4, filtered and
concentrated to an oil, which was purified by column chromatography
on silica gel. The pure product was obtained from 1-6% methanol/DCM
(yield 28-42%). The BOC-group was removed via General Procedure T1
to give
1-butyl-2-{3-[biphenyl-4-yloxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy)-1H-be-
nzimidazole.
[0642] MS (m/z): 547 (M+H).sup.+
Example 39
1-butyl-2-{4-[2-(4-chlorophenyl)ethoxy]-phenyl}-6-(2-piperazin-1-yl-ethoxy-
)-1H-benzimidazole
[0643] A mixture of 4-[2-(4-chloro-phenyl)-ethoxy]-benzaldehyde
(0.08 g) and
1-BOC-4-[2-(4-amino-3-butylamino-phenoxy)-ethyl]-piperazine (0.10
g) was subjected to General Procedure K. Ethanol was removed in
vacuo and the residue purified on silica gel with 1-2% MeOH/DCM.
The BOC-group was removed employing General Procedure T1 to give
1-butyl-2-{(4-[2-(4-chlorophenyl)ethoxy]-phenyl}-6-(2-piperazin-1-yl-etho-
xy)-1H-benzimidazole (0.081 g).
[0644] MS (m/z): 533 (M+H).sup.+
[0645] The following Examples were synthesized according to the
Methods employed for Examples 35-39;
TABLE-US-00003 Example Name 40
[3-(3-butyl-2-{3-[2-(4-chloro-phenyl)-ethoxy]-4-nitro-phenyl}-3H-
benzimidazol-5-yloxy)-propyl]-diethyl-amine 41
[2-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-
benzimidazol-5-yloxy)-ethyl]-diethyl-amine 42
1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(piperidin-4-ylmethoxy)-
1H-benzoimidazole 43
1-butyl-2-{3-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-piperazin-1-yl-
ethoxy)-1H-benzoimidazole 44
{3-[3-butyl-2-(2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-ethyl)-3H-
benzimidazol-5-yloxy]-propyl}-diethyl-amine 45
1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-piperazin-1-yl-
ethoxy)-1H-benzimidazole 46
1-butyl-6-[2-(4-butyl-piperazin-1-yl)-ethoxy]-2-[3-(3-trifluoromethyl-
phenoxy)-phenyl]-1H-benzimidazole 47
{3-[3-butyl-2-(2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-ethyl)-3H-
benzimidazol-5-yloxy]-propyl}-diethyl-amine 48
(3-{3-butyl-2-[3-(4-methoxy-phenoxy)-phenyl]-3H-benzimidazol-5-
yloxy}-propyl)-diethyl-amine 49
{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-diethylamino-
ethoxy)-benzimidazol-1-yl]-propyl}-diethyl-amine 50
[3-(1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1H-
benzimidazol-4-yloxy)-propyl]-diethyl-amine 51
[3-(1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1H-
benzimidazol-5-yl)-propyl]-diethyl-amine 52
1-butyl-2-[3-(2-isopropyl-phenoxy)-phenyl]-6-(2-piperazin-1-yl-
ethoxy)-1H-benzoimidazole 53
{3-[3-butyl-2-(2-{4-[3-(4-methoxy-phenyl)-propoxy]-phenyl}-ethyl)-3H-
benzimidazol-5-yloxy]-propyl}-diethyl-amine 54
{3-[3-butyl-2-(2-{4-[4-(4-methoxy-phenyl)-butoxy]-phenyl}-ethyl)-3H-
benzimidazol-5-yloxy]-propyl}-diethyl-amine 55
[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-3-ethoxy-phenyl}-3H-
benzimidazol-5-yloxy)-propyl]-diethyl-amine 56
(3-{3-butyl-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-3H-benzimidazol-
5-yloxy}-propyl)-diethyl-amine 57
1-butyl-2-[3-(4-chloro-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-
1H-benzoimidazole 58
1-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-6-(2-piperazin-1-yl-
ethoxy)-1H-benzoimidazole 59
1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(piperidin-4-yloxy)-
- 1H-benzoimidazole 60
3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-
benzoimidazol-5-yloxy)-1-aza-bicyclo[2.2.2]octane 61
1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2,2,6,6,-
tetramethyl-piperidin-4-yioxy)-1H-benzoimidazole 62
2-[3-(4-butoxy-phenoxy)-phenyl]-1-butyl-6-(2-piperazin-1-yl-ethoxy)-
1H-benzoimidazole 63
[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-
benzimidazol-5-yloxy)-propyl]-diethyl-amine 64
{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3-(3-methyl-butyl)-3H-
benzimidazol-5-yloxy]-propyl}-diethyl-amine 65
[3-(2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3-hexyl-3H-
benzimidazol-5-yloxy)-propyl]-diethyl-amine 66
{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-diethylamino-
ethoxy)-benzimidazol-1-yl]-propyl}-dimethyl-amine 67
1-butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-6-(2-
piperazin-1-ylethoxy)-1H-benzoimidazole 68
[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-
benzimidazol-5-yloxy)-propyl]-diethyl-amine 69
{3-[2-(4-benzyloxy-3,5-dimethyl-phenyl)-3-butyl-3H-benzimidazol-5-
yloxy]-propyl}-diethyl-amine 70
{3-[3-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-3H-benzimidazol-5-
yloxy]-propyl}-diethyl-amine 71
1-butyl-6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-2-[3-(3-trifluoromethyl-
phenoxy)-phenyl]-1H-benzimidazole 72
1-butyl-6-[2-(4-isopropyl-piperazin-1-yl)-ethoxy]-2-[3-(3-
trifluoromethyl-phenoxy)-phenyl]-1H-benzoimidazole 73
1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(3-piperazin-1-yl-
propoxy)-1H-benzoimidazole 74
(3-{3-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-3H-benzimidazol-5-
yloxy}-propyl)-diethyl-amine 75
1-butyl-2-[3-(3,4-dimethoxy-phenoxy)-phenyl]-6-(2-piperidin-4-yloxy)-
1H-benzoimidazole 76
1-butyl-2-[3-(4-chloro-benzyloxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-
1H-benzoimidazole 77
1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-piperazin-1-yl-
ethoxy)-1H-benzoimidazole 78
(3-{2-[2-(4-benzyloxy-phenyl)-ethyl]-3-butyl-3H-benzimidazol-5-yloxy}-
propyl)-diethyl-amine 79
(3-{3-butyl-2-[2-(4-phenethyloxy-phenyl)-ethyl]-3H-benzimidazol-5-
yloxy}-propyl)-diethyl-amine 80
{3-[3-butyl-2-(2-{4-[2-(4-fluoro-phenyl)-ethoxy]-phenyl}-ethyl)-3H-
benzimidazol-5-yloxy]-propyl}-diethyl-amine 81
[3-(3-butyl-2-{2-[4-(4-chloro-benzyloxy)-phenyl]-ethyl}-3H-
benzimidazol-5-yloxy)-propyl]-diethyl-amine 82
(3-{3-butyl-2-[4-(4-fluoro-benzyloxy)-phenyl]-3H-benzimidazol-5-
yloxy}-propyl)-diethyl-amine 83
{3-[2-(3-benzyloxy-phenyl)-3-butyl-3H-benzimidazol-5-yloxy]-propyl}-
diethyl-amine 84
[3-(3-butyl-2-{4-chloro-3-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-
benzimidazol-5-yloxy)-propyl]-diethyl-amine 85
1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-
- 1H-benzimidazole 86
1-butyl-2-[4-(4-isopropyl-phenoxy)-phenyl]-6-(2-piperazin-1-yl-
ethoxy)-1H-benzoimidazole 87
1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-[3-(4-methyl-
piperazin-1-yl)-propoxy]-1H-benzoimidazole 88
1-butyl-6-[2-(4-butyl-piperazin-1-yl)-ethoxy]-2-{4-[2-(4-chloro-phenyl)-
- ethoxy]-phenyl}-1H-benzoimidazole 89
1-butyl-2-[3-(3,4-dimethoxy-phenoxy)-phenyl]-6-(2-piperazin-1-yl-
ethoxy)-1H-benzoimidazole 90
1-butyl-2-[4-(4-tert-butyl-benzyl)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-
1H-benzoimidazole 91
N-{4-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-2-[2-
(4-chloro-phenyl)-ethoxy]-phenyl}-2,2-dimethyl-propioinamide 92
(3-{3-butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-3H-
benzimidazol-5-yloxy}-propyl)-diethyl-amine 93
1-butyl-2-[4-(naphthalen-2-yloxy)-phenyl]-6-(2-piperazin-1-yl-ethoxy)-
1H-benzoimidazole 94
1-butyl-2-[3-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-6-(2-
piperazin-1-yl-ethoxy)-1H-benzoimidazole 95
[3-(3-butyl-2-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-3H-
benzimidazol-5-yloxy)-propyl]-diethyl-amine 96
4-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-2-[2-(4-
chloro-phenyl)-ethoxy]-phenylamine 97
1-{4-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-2-[2-
(4-chloro-phenyl)-ethoxy]-phenyl}-3-isopropyl-urea 98
{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-dimethylamino-
ethoxy)-benzimidazol-1-yl]-propyl}-dimethyl-amine 99
1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-[2-(4-methyl-piperazin-1-
yl)-ethoxy]-1H-benzimidazole 100
1-butyl-6-(4-cyclopentyl-phenoxy)-2-[4-(4-methyl-piperazin-1-
ylmethyl)-phenyl]-1H-benzoimidazole 101
{3-[2-(4-benzyloxy-phenyl)-3-cyclopentylmethyl-3H-benzimidazol-5-
yloxy]-propyl}-diethyl-amine 102
1-butyl-6-(4-butyl-phenoxy)-2-{3,5-dimethyl-4-[2-(1-methyl-pyrrolidin-
2-yl)-ethoxy]-phenyl}-1H-benzoimidazole 103
1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(3-pyrrolidin-1-yl-
- propoxy)-1H-benzoimidazole 104
{3-[2-(4-benzyloxy-phenyl)-3-isobutyl-3H-benzimidazol-5-yloxy]-
propyl}-diethyl-amine 105
[3-(3-butyl-2-{3-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-
benzimidazol-5-yloxy)-propyl]-diethyl-amine 106
1-butyl-6-(1-butyl-piperidin-4-yloxy)-2-[3-(3,5-dichloro-phenoxy)-
phenyl]-1H-benzoimidazole 107
1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(1-ethyl-piperidin-4-
yloxy)-1H-benzoimidazole 108
1-butyl-6-(4-fluoro-3-trifluoromethyl-phenoxy)-2-[4-(4-methyl-
piperazin-1-ylmethyl)-phenyl]-1H-benzoimidazole 109
diethyl-{3-[3-isobutyl-2-(2-{4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-
ethyl)-3H-benzimidazol-5-yloxy]-propyl}-amine 110
{3-[2-(2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-ethyl)-3-isobutyl-3H-
benzimidazol-5-yloxy]-propyl}-diethyl-amine 111
1-butyl-6-(2-piperazin-1-yl-ethoxy)-2-[3-(3-trifluoromethyl-phenoxy)-
phenyl]-1H-benzimidazole 112
1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethox-
y)- 1H-benzimidazole 113
1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-[2-(4-methyl-
piperazin-1-yl)-ethoxy]-1H-benzimidazole 114
{3-[2-(4-benzyloxy-phenyl)-3-cyclopentyl-3H-benzimidazol-5-yloxy)-
propyl]-diethyl-amine 115
1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-5-(4-methyl-
piperazin-1-ylmethyl)-1H-benzoimidazole 116
[2-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-
benzimidazol-5-yloxy)-ethyl]-dimethyl-amine 117
[2-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-
benzimidazol-5-yloxy)-ethyl]-diisopropyl-amine 118
1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-[2-(4-methyl-piperazin-
1-yl)-ethoxy]-1H-benzimidazole 119
(3-{1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-1H-benzimidazol-4-
yloxy}-propyl)-diethyl-amine 120
2-(3-butoxy-phenyl)-1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H-
benzimidazole 121
1-butyl-2-[3-(4-methanesulfonyl-benzyloxy)-phenyl]-6-(2-piperazin-1-
yl-ethoxy)-1H-benzoimidazole 122
4'{3-[1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-
phenoxy}-biphenyl-4-carbonitrile 123
{3-[2-(4-benzyloxy-phenyl)-3-butyl-3H-benzimidazol-5-yloxy]-propyl}-
diethyl-amine 124
1-Butyl-2-[4-(3-chloro-phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-
1H-benzoimidazole 125
1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-[2-(4-isopropyl-
piperazin-1-yl)-ethoxy]-1H-benzoimidazole 126
{3-[2-(3-benzyloxy-4-methoxy-phenyl)-3-butyl-3H-benzimidazol-5-
yloxy)-propyl]-diethyl-amine 127
(3-{3-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-3H-benzimidazol-5-
yloxy}-propyl)-diethyl-amine 128
{3-[3-butyl-2-(3-phenoxy-phenyl)-3H-benzimidazol-5-yloxy]-propyl}-
diethyl-amine 129
1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-[2-(4-ethyl-piperazin-1-
yl)-ethoxy]-1H-benzimidazole 130
1-butyl-2-[4-(2,3-di-methoxy-phenoxy)-phenyl]-6-(2-piperazin-1-
ylethoxy)-1H-benzoimidazole 131
[3-(3-butyl-2-{2-[4-(4-chloro-benzyloxy)-phenyl]-ethyl}-3H-
benzimidazol-5-yloxy)-propyl]-diethyl-amine 132
(3-{3-butyl-2-[3-(4-chloro-phenoxy)-phenyl]-3H-benzimidazol-5-yloxy}-
propyl)-diethyl-amine 133
{3-[2-(4-benzyloxy-phenyl)-3-isopropyl-3H-benzimidazol-5-yloxy]-
propyl}-diethyl-amine 134
(2-{3-butyl-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-3H-
benzoimidazol-5-yloxy}-ethyl)-diisopropyl-amine 135
1-butyl-6-[2-(4-ethyl-piperazin-1-yl)-ethoxy]-2-[3-(3-trifluoromethyl-
phenoxy)-phenyl]-1H-benzimidazole 136
{3-[3-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-3H-benzimidazol-5-
yloxy]-propyl}-diethyl-amine 137
(3-{2-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-3H-benzimidazol-5-
yloxy}-ethyl)-cyclohexyl-methyl-amine 138
1-butyl-6-[2-(4-propyl-piperazin-1-yl)-ethoxy]-2-[3-(3-trifluoromethyl-
- phenoxy)-phenyl]-1H-benzimidazole 139
1-butyl-6-(4-butyl-phenoxy)-2-[4-(4-methyl-piperazin-1-ylmethyl)-
phenyl]-1H-benzoimidazole 140
1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-morpholin-4-yl-
ethoxy)-1H-benzimidazole 141
4-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-2-
phenethyloxy-phenylamine 142
{2-[2-(4-benzyloxy-phenyl)-3-phenethyl-3H-benzimidazol-5-yloxy]-
ethyl}-diethyl-amine 143
{3-[3-butyl-2-(4-phenoxy-phenyl)-3H-benzimidazol-5-yloxy]-propyl}-
diethyl-amine 144
3-[4-(2-{3-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-3H-benzimidazol-
5-yloxy}-ethyl)-piperazin-1-yl]-propan-1-ol 145
1-butyl-6-(2-pyrrolidin-1-yl-ethoxy)-2-[3-(3-trifluoromethyl-phenoxy)-
phenyl]-1H-benzimidazole 146
{2-[2-[4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-diethylamino-
ethoxy)-benzimidazol-1-yl]-ethyl}-dimethyl-amine 147
1-butyl-6-(2-morpholin-4-yl-ethoxy)-2-[3-(3-trifluoromethyl-phenoxy)-
phenyl]-1H-benzimidazole 148
1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(1-methyl-piperidin-4-
yloxy)-1H-benzoimidazole 149
N'-[3-butyl-2-(2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-ethyl)-3H-
benzimidazol-5-yl]-N,N-diethyl-propane-1,3-diamine 150
1-butyl-2-[3-(2,4-dichloro-phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl-
ethoxy)-1H-benzimidazole 151
1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-morpholin-4-yl-
ethoxy)-1H-benzimidazole 152
1-butyl-6-(2-piperazin-1-yl-ethoxy)-2-[4-(4-trifluoromethyl-phenoxy)-
phenyl]-1H-benzoimidazole 153
2-[4-(biphenyl-4-yloxy)-phenyl]-1-butyl-6-(2-piperazin-1-yl-ethoxy)-1H-
- benzoimidazole 154
1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-morpholin-4-yl-
ethoxy)-1H-benzimidazole 155
1-butyl-2-[3-(3,4-dimethoxy-phenoxy)-phenyl]-6-(2-piperazin-1-yl-
ethoxy)-1H-benzoimidazole 156
1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-5-(1H-imidazol-4-
ylmethoxy)-1H-benzoimidazole 157
{3-[2-(2-benzyloxy-phenyl)-3-butyl-3H-benzimidazol-5-yloxy]-propyl}-
diethyl-amine 158
{3-[1-Butyl-6-(3-diethylamino-propoxy)-2-piperidin-4-yl-1H-
benzoimidazol-4-yloxy]-propyl}-diethyl-amine 159
(2-{2-[2-(4-Benzyloxy-phenyl)-ethyl]-3-phenethyl-3H-benzoimidazol-
5-yloxy}-ethyl)-diethyl-amine 160
[3-(3-Butyl-2-{3-[4-(4-fluoro-benzyloxy)-phenyl]-propyl}-3H-
benzoimidazol-5-yloxy)-propyl]-diethyl-amine 161
[3-(4-Benzyloxy-phenyl)-propyl]-[1-butyl-6-(3-diethylamino-propoxy)-
1H-benzoimidazol-2-yl]-amine 162
{3-[3-Butyl-2-(3-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-propyl)-3H-
benzoimidazol-5-yloxy]-propyl}-diethyl-amine 163
1-Butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-imidazol-1-yl-
ethoxy)-1H-benzoimidazole 164
1-[4-(2-{3-Butyl-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-3H-
benzoimidazol-5-yloxy}-ethyl)-piperazin-1-yl]-ethanone 165
N-[3-Butyl-2-(2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-ethyl)-3H-
benzoimidazol-5-yl]-N-(3-diethylamino-propyl)-N',N'-diethyl-propane-
1,3-diamine
Example 166
(3-(1-Butyl-2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-6-(3-diethylaminoprop-
oxy)-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine
[0646] This compound was prepared according to General Procedure K
by refluxing a mixture of
4-[2-(4-chloro-phenyl)-ethoxy]-bezaldehyde (300 mg) and
N.sup.1-Butyl-3,5-bis-(3-diethylamino-propoxy)-benzene-1,2-diamin-
e (synthesized via General Procedures J1 and J2 and I) (200 mg) in
ethanol overnight. Ethanol was removed in vacuo and the residue was
purified by silica gel chromatography using 5% MeOH in DCM to give
pure
(3-(1-Butyl-2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-6-(3-diethylaminopro-
poxy)-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine (100 mg).
[0647] MS: m/z 663 (M+H).sup.+
Example 167
{3-[1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(3-diethylaminopropoxy)--
1H-benzimidazole-4-yloxy]propyl}diethyl-amine
[0648]
{3-[1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(3-diethylaminopr-
opoxy)-1H-benzimidazole-4-yloxy]-propyl}diethyl-amine was formed
employing 3(4-t-butyl-phenoxy)benzaldehyde (127 mg; 0.50 mmol) and
2-butylamino-4,6-di(3-diethylaminopropoxy)aniline (synthesized via
General Procedures J1 and J2 and I) (1.6 mg; 0.25 mmol) in ethanol
(1 mL) following General Procedure K. The crude product was
purified by silica gel column chromatography using 10% MeOH in DCM
with a gradual increment of triethylamine (0.2 to 1.0%) as eluent
to afford 145 mg (76%) of
{3-[1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(3-diethylaminopropoxy)-
-1H-benzimidazole-4-yloxy]-propyl}diethyl-amine.
[0649] MS: m/z 657 (M+H).sup.+
Example 168
{3-[2-(2-[4-[2-(4-chloro-phenyl)-ethoxy])-phenyl]-ethyl)-6-(3-diethylamino-
propoxy)-3H-benzimidazole-4-yloxy]-propyl}diethyl-amine
##STR00620##
[0651] This compound was prepared according to the General
Procedure K by refluxing a mixture of
3-{4-[2-(4-chloro-phenyl)-ethoxy]-propionaldehyde (100 mg) and
3,5-Bis-(3-diethylamino-propxy)-benzene-1,2-diamine (synthesized
via General Procedures J1 and J2 and I) (50 mg) in ethanol
overnight. Ethanol was removed in vacuo and the residue was
purified by silica gel chromatography using 10% MeOH in DCM to give
{3-[2-(2-[4-[2-(4-chloro-phenyl)-ethoxy])-phenyl]-ethyl)-6-(3-diethylamin-
opropoxy)-3H-benzimidazole-4-yloxy]-propyl}diethyl-amine (30
mg).
[0652] MS: m/z 635 (M+H).sup.+
Example 169
(3-(1-Butyl-6-(3-diethylaminopropoxy)-2-[4-(4-chloro-3-trifluoromethyl-phe-
noxy)-phenyl]-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine
[0653] 4-(4-Chloro-3-trifluoromethyl)phenoxybenzaldehyde
(synthesized employing General Procedure B) (150 mg) and
2-butylamino-4,6-di(3-diethylaminopropoxy)aniline (synthesized via
General Procedures J1 and J2 and I) 106 mg; 0.25 mmol) in ethanol
(1 mL) were condensed employing General Procedure K. The crude
product was purified by silica gel column chromatography using 10%
MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%)
as eluent to afford 160 mg of
(3-(1-Butyl-6-(3-diethylaminopropoxy)-2-[4-(4-chloro-3-trifluoromet-
hyl-phenoxy)-phenyl]-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine.
[0654] MS: m/z 703 (M+H).sup.+
Example 170
(3-(1-Butyl-6-(3-diethylaminopropoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phe-
noxy)-phenyl]-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine
##STR00621##
[0656] A solution of
2-butylamino-4,6-di(3-diethylaminopropoxy)aniline (synthesized via
General Procedures J1 and J2 and I) (84.4 mg, 0.2 mmol) and
4-(4-fluoro-3-trifluoromethyl)phenoxybenzaldehyde (synthesized
employing General Procedure B) (62.5 mg, 0.2 mmol) in ethanol (2
mL) was heated to reflux following the General Procedure K. The
crude product was purified by silica gel column chromatography
using 10% MeOH in DCM with a gradual increment of triethylamine
(0.2 to 1.0%) as eluent to afford
3-(1-Butyl-6-(3-diethylaminopropoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phe-
noxy)-phenyl]-1H-benzimidazole-4-yloxy)-propyl)diethyl-amine (62
mg).
[0657] MS m/z 687 (M+H)
[0658] The following Examples were synthesized according to the
Methods employed for Examples 166-170;
TABLE-US-00004 Example Name 171
{3-[2-[3-(3,5-Dichloro-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-
1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 172
1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-4,6-bis-(2-pyrrolidi-
n- 1-yl-ethoxy)-1H-benzoimidazole 173
{3-[2-[3-(3,4-Dichloro-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-
1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 174
(3-{6-(3-diethylamino-propoxy)-2-[3-(3-trifluoromethyl-phenoxy)-
phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 175
{3-[1-Butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-6-(3-diethylamino-
propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 176
{3-[2-[3-(4-Chloro-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-
benzoimidazol-4-yloxy]-propyl}-diethyl-amine 177
{3-[1-Butyl-2-[3-(4-chloro-phenoxy)-phenyl]-6-(3-diethylamino-
propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 178
{3-[1-Butyl-6-(3-diethylamino-propoxy)-2-(3-p-tolyloxy-phenyl)-1H-
benzoimidazol-4-yloxy]-propyl}-diethyl-amine 179
{3-[1-Butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(3-diethylamino-
propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 180
1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-
- ethoxy)-1H-benzoimidazole 181
{3-[3-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-7-(2-pyrrolidin--
1- yl-ethoxy)-3H-benzoimidazol-5-yloxy]-propyl}-diethyl-amine 182
(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(3-fluoro-phenoxy)-
phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 183
{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(3-diethylamino-
propoxy)-1-isopropyl-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine
184
{3-[1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-pyrrolidin--
1- yl-ethoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 185
2-{4-[1-butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl-ph-
enoxy}- benzoic acid methyl ester 186
{3-[2-[4-(biphenyl-4-yloxy)-phenyl]-1-butyl-6-(3-diethylamino-propoxy)-
- 1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 187
{3-[2-[4-(3,5-Bis-trifluoromethyl-phenoxy)-phenyl]-6-(3-diethylamino-
propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 188
{3-[1-butyl-2-[4-(4-chloro-benzylsulfanyl)-phenyl]-6-(3-diethylamino-
propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 189
{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(3-diethylamino-
propoxy)-3H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 190
(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[3-(3-trifluoromethyl-
phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 191
[3-(1-butyl-6-(3-diethylamino-propoxy)-2-{4-[2-(4-fluoro-phenyl)-
ethoxy]-phenyl}-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 192
(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(3-trifluoromethyl-
phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 193
{3-[2-[3-(4-tert-Butyl-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-
1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 194
(3-{1-Butyl-6-(3-diethylamino-propoxy)-2-[4-(4-fluoro-3-trifluoromethy-
l- phenoxy)-2-trifluoromethyl-phenyl]-1H-benzoimidazol-4-yloxy}-
propyl)-diethyl-amine 195
{3-[1-Butyl-2-[4-chloro-2-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-
- 6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 196
2-[3-(4-Chloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-
benzoimidazole 197
1-Butyl-2-[3-(4-chloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-eth-
oxy)- 1H-benzoimidazole 198
{3-[3-butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-7-(2-
pyrrolidin-1-yl-ethoxy)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine
199
{2-[1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-diisopropylamino-
ethoxy)-1H-benzimidazol-4-yloxy]-ethyl}-diethyl-amine 200
{3-[2-[4-(3,5-Bis-trifluoromethyl-phenoxy)-phenyl]-1-butyl-6-(3-
diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-
amine 201
{3-[2-[4-(3,5-Bis-trifluoromethyl-phenoxy)-phenyl]-1-butyl-6-(3-
diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-
amine 202
(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(4-methoxy-phenoxy)-
phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 203
1-Butyl-2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-4,6-bis-(2-
pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 204
2-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-4,6-bis-(2-pyrrolidin-1-yl-
ethoxy)-1H-benzoimidazole 205
1-Butyl-2-[4-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-
- ethoxy)-1H-benzoimidazole 206
1-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-4,6-bis-(2-
pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 207
{3-[1-Butyl-2-[4-(3-chloro-phenoxy)-phenyl]-6-(3-diethylamino-
propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 208
2-[5,7-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazol-2-yl]-5-[2-(4-
chloro-phenyl)-ethoxy]-phenol 209
2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolodin-1-yl-ethoxy)-
- 1H-benzimidazole 210
(3-{6-(3-Diethylamino-propoxy)-2-[2-(1,1-difluoro-ethyl)-4-(4-fluoro-3-
-
trifluoromethyl-phenoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-
diethyl-amine 211
{3-[1-Butyl-2-[4-(4-tert-butyl-phenoxy)-phenyl]-6-(3-diethylamino-
propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 212
2-[4-(4-tert-Butyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-
- 1H-benzoimidazole 213
{3-[1-Butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-6-(2-pyrrolidin-1-yl-
ethoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 214
[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-
diethylaminomethyl-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine
215
(3-{6-(3-Diethylamino-propoxy)-2-[4-(4-fluoro-3-trifluoromethyl-
phenoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine
216 (3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(4-trifluoromethyl-
pyrimidin-2-ylsulfanyl)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-
diethyl-amine 217
{3-[6-(3-Diethylamino-propoxy)-2-(3-p-tolyloxy-phenyl)-1H-
benzoimidazol-4-yloxy]-propyl}-diethyl-amine 218
4-{3-[1-Butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzoimidazol-2-
yl]-phenoxy}-benzonitrile 219
[3-(3-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-7-pyrrolidin-1-y-
l- 3H-benzoimidazol-5-yloxy)-propyl]-diethyl-amine 220
{3-[1-butyl-2-[4-(4-chloro-phenylmethanesulfinyl)-phenyl]-6-(3-
diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-
amine 221
(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(naphthalen-2-yloxy)-
phenyl]-1H-benzoimidazole-4-yloxy}-propyl)-diethyl-amine 222
(3-{6-(3-diethylamino-propoxy)-2-[4-(3-trifluoromethyl-phenoxy)-
phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 223
(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[3-(4-methoxy-phenoxy)-
phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 224
2-[3-(3,4-Dichloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-
- 1H-benzoimidazole 225
{3-[2-[4-(4-tert-Butyl-phenoxy)-phenyl]-6-(3-diethylamino-propoxy)-
1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 226
{3-[3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-7-[2-(tetrahydro-
-
furan-2-yl)-ethoxy]-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine
227
1-Butyl-2-[4-(3-chloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-
ethoxy)-1H-benzoimidazole 228
[3-(7-Butoxy-3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3H-
benzoimidazol-5-yloxy)-propyl]-diethyl-amine 229
4-{3-[4,6-Bis-(3-diethylamino-propoxy)-1H-benzoimidazol-2-yl]-
phenoxy}-benzonitrile 230
2-[3-(3,5-Dichloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-
- 1H-benzoimidazole 231
{3-[1-butyl-2-(2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-ethyl)-6-(3-
diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-
amine 232
{3-[1-butyl-6-(3-diethylamino-propoxy)-2-(3-phenoxy-phenyl)-1H-
benzimidazol-4-yloxy]-propyl}-diethyl-amine 233
{3-[1-Butyl-2-[2-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-6-(3-
diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-
amine 234
2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-4,6-bis-(2-
pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 235
{3-[1-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-6-(2-
pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-
amine 236
[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-methyl-3H-
benzimidazol-5-yloxy)-propyl]-diethyl-amine 237
{3-[1-butyl-6-(3-diethylamino-propoxy)-2-(4-phenoxy-phenyl)-1H-
benzimidazol-4-yloxy]-propyl}-diethyl-amine 238
5-[4,6-bis-(3-diethylamino-propoxy)-1H-benzoimidazlo-2-yl]-2-[2-(4-
chloro-phenyl)-ethoxy]-phenol 239
[3-(6-Butoxy-1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1H-
benzoimidazol-4-yloxy)-propyl]-diethyl-amine 240
{3-[2-[4-Chloro-2-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-6-(3-
diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-
amine 241
1-butyl-4-(4-chloro-benzyloxy)-2-{4-[2-(4-chloro-phenyl)-ethoxy]-
phenyl}-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole 242
4-{4-[1-butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-
phenoxy}-benzonitrile 243
[3-(1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-fluoro-1H-
benzoimidazol-4-yloxy)-propyl]-diethyl-amine 244
(3-{6-(3-diethylamino-propoxy)-2-[3-(4-methoxy-phenoxy)-phenyl]-1H-
benzimidazol-4-yloxy}-propyl)-diethyl-amine 245
(3-{6-(3-diethylamino-propoxy)-2-[4-(4-methoxy-phenoxy)-phenyl]-1H-
benzimidazol-4-yloxy}-propyl)-diethyl-amine 246
{3-[1-butyl-2-[4-(4-chloro-3-fluoro-phenoxy)-phenyl]-6-(3-
diethylamino-propoxy)-1H-benzimidazol-4-yl]-propyl}-diethyl-amine
247
(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(quinolin-8-yloxy)-phenyl]-
- 1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 248
{3-[2-[2-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-6-(3-
diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-
amine 249
2-[{2-[1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-
morpholin-4-yl-ethoxy)-1H-benzoimidazol-4-yloxy]-ethyl}-(2-chloro-
ethyl)-amino]-ethanol 250
(3-{6-(3-Diethylamino-propoxy)-2-[3-(4-fluoro-3-trifluoromethyl-
phenoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine
251
[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-7-isopropoxy-3H-
benzimidazol-5-yloxy)-propyl]-diethyl-amine 252
[3-(1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-
cyclopentylmethoxy-1H-benzoimidazol-4-yloxy)-propyl]-diethyl-amine
253 1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-4,6-bis-(2-
morpholin-4-yl-ethoxy)-1H-benzoimidazole 254
{3-[2-[4-[2-(4-Chloro-phenyl)-ethoxy]-3-(3-diethylamino-propoxy)-
phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-
propyl}-diethyl-amine
Example 255
{3-[2-[1-butyl-6-(4-tert-butyl-phenoxy)-1H-benzimidazol-2-yl}-5-(3-diethyl-
amino-propoxy)-phenoxy]-propyl}-diethyl-amine
[0659] To a stirred solution of 2,4-dihydroxybenzaldehyde (10 mmol)
in DMSO (50 mL) at rt, solid Cs.sub.2CO.sub.3 (45 mmol) was added.
A mesylate (prepared from 3-diethylamino-1-propanol and
methanesulfonyl chloride, General Procedure P2) (25 mmol) was added
to the reaction mixture and heated to 90.degree. C. until the
reaction was complete as indicated by LC-MS (.about.10 h). After
cooling to rt, the reaction was quenched by cold H.sub.2O (100 mL),
and the resulting mixture was extracted with EtOAc (3.times.100
mL). The combined EtOAc extracts were washed with brine (3.times.50
mL) and dried (anhydrous Na.sub.2SO.sub.4). The solvent was removed
in vacuo to afford the desired
2,4-bis(3-diethylaminopropoxy)benzaldehyde which was used for
further transformation.
[0660] To a stirred solution of 2,4-difluoronitrobenzene (50 mmol),
Et.sub.3N (100 mmol) and DMF (80 mL) was added dropwise a solution
of n-butylamine (51 mmol) in DMF (20 mL) at rt, and the mixture was
stirred at rt for 5 h. The reaction was quenched by cold H.sub.2O
(100 mL), and the resulting mixture was extracted with EtOAc
(4.times.100 mL). The combined EtOAc extracts were washed with
brine (3.times.60 mL) and dried (anhydrous Na.sub.2SO.sub.4). The
solvent was removed in vacuo to afford the desired
2-n-butylamino-4-fluoronitrobenzene which was used for further
transformation.
[0661] A mixture of 2-n-butylamino-4-fluoronitrobenzene (10 mmol),
4-t-butylphenol (13 mmol), solid K.sub.2CO.sub.3 (30 mmol) and DMF
(30 mL) was heated with stirring at 90.degree. C. for 10 h. The
reaction was quenched by cold H.sub.2O (50 mL), and the resulting
mixture was extracted with EtOAc (3.times.100 mL). The combined
EtOAc extracts were washed with brine (2.times.50 mL) and dried
(anhydrous Na.sub.2SO.sub.4). The solvent was removed in vacuo, and
the crude products were purified by silica gel column
chromatography (eluting with 10% EtOAc in hexane), giving
2-n-butylamino-4-(4-t-butylphenoxy)nitrobenzene.
[0662] The nitro intermediate (2 mmol) obtained above was dissolved
in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50
mg) until completion as indicated by LC-MS (.about.4 h). The
reaction mixture was then filtered through a celite pad to remove
the catalyst. The MeOH solution containing
2-n-butylamino-4-(4-butylphenoxy)aniline was used directly for
further transformation.
[0663] A solution of 2-n-butylamino-4-(4-t-butylphenoxy)aniline
(130 mg, 0.4 mmol) and 2,4-bis(3-diethylaminopropoxy)benzaldehyde
obtained above (110 mg, 0.3 mmol) in MeOH (10 mL) was refluxed
until the reaction was complete. The solvent was removed in vacuo
and the residue was purified by silica gel column chromatography,
eluting with 10% MeOH in DCM with a gradual increment of Et.sub.3N
(0.5 to 1%), to afford the desired benzimidazole (100 mg).
[0664] MS m/z 657 (M+H).sup.+
[0665] .sup.1H NMR (400 MHz, CDCl.sub.3) of HCl salt of the
benzimidazole: .delta. 0.80 (t, 3H), 1.19 (m, 2H), 1.26 (t, 6H),
1.32 (s, 9H), 1.41 (t, 6H), 1.74 (m, 2H), 2.44 (m, 4H), 3.12-3.39
(m, 12H), 4.21 (t, 2H), 4.29 (m, 4H), 6.68 (br d, 1H), 6.79 (br s,
1H), 6.98 (d, 2H), 7.17 (d, 1H), 7.22 (dd, 1H), 7.35 (d, 1H), 7.40
(d, 2H), 8.06 (d, 1H), 11.4 (br, N.HCl), 11.9 (br, N.HCl) ppm.
Example 256
(3-{2-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-[2-(4-ch-
loro-phenyl)-ethoxy]-phenoxy}-propyl)-diethylamine
[0666] A solution of
2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde
(synthesized via General Procedures D1 and D2) (429 mg; 1.1 mmol)
and 2-(n-butylamino)-4-(3-diethylaminopropoxy)aniline (synthesized
via General Procedures G1 and G2 and I) (293 mg; 1 mmol) in ethanol
(5 mL) was heated to reflux following General Procedure K. The
crude product was purified by silica gel column chromatography
using 10% MeOH in DCM with a gradual increment of triethylamine
(0.2 to 1.0%) as eluent to afford of
(3-{2-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-[2-(4-c-
hloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethylamine (430 mg).
[0667] MS m/z 663 (M+H).sup.+
Example 257
(3-{1-butyl-6-(4-tert-butyl-phenoxy)-2-[4-(3-diethylamino-propoxy)-phenyl]-
-1H-benzimidazol-4-yloxy}propyl)-diethyl-amine
[0668] To a stirred solution of 4-hydroxybenzaldehyde (20 mmol) in
DMSO (80 mL) at rt, solid Cs.sub.2CO.sub.3 (50 mmol) was added. The
mesylate prepared from 3-diethylamino-1-propanol and
methanesulfonyl chloride, General Procedure P2 (30 mmol) was added
to the reaction mixture and heated to 90.degree. C. until the
reaction was complete. After cooling to rt, the reaction was
quenched by cold H.sub.2O (100 mL), and the resulting mixture was
extracted with EtOAc (3.times.100 mL). The combined EtOAc extracts
were washed with brine (3.times.50 mL) and dried (anhydrous
Na.sub.2SO.sub.4). The solvent was removed in vacuo, and the crude
product was purified by silica gel column chromatography (eluting
with 10% MeOH in DCM+0.5% Et.sub.3N) to afford
4-(3-diethylaminopropoxy)benzaldehyde.
[0669] To a stirred solution of
6-(3-diethylaminopropoxy)-2,4-difluoronitrobenzene (11 mmol) and
triethylamine (22 mmol) in DMF (20 mL), a solution of n-butylamine
(11 mmol) in DMF (8 mL) was added dropwise at rt, and the mixture
was stirred at rt for 10 h. The reaction was quenched by cold
H.sub.2O (50 mL), and the resulting mixture was extracted with
EtOAc (3.times.100 mL). The combined EtOAc extracts were washed
with brine (3.times.50 mL) and dried (anhydrous Na.sub.2SO.sub.4).
The solvent was removed in vacuo to afford the desired
2-n-butylamino-6-(3-diethylaminopropoxy)-4-fluoronitrobenzene which
was used for further transformation.
[0670] A mixture of
2-n-butylamino-6-(3-diethylaminopropoxy)-4-fluoronitrobenzene
obtained above (3 mmol), 4-t-butylphenol (4 mmol), solid
K.sub.2CO.sub.3 (9 mmol) and DMF (15 mL) was heated with stirring
at 90.degree. C. for 15 h. The reaction was quenched by cold
H.sub.2O (30 mL), and the resulting mixture was extracted with
EtOAc (3.times.100 mL). The combined EtOAc extracts were washed
with brine (2.times.50 mL) and dried (anhydrous Na.sub.2SO.sub.4).
The solvent was removed in vacuo, and the crude products were
purified by silica gel column chromatography (eluting with 10% MeOH
in DCM), giving
2-n-butylamino-4-(4-t-butylphenoxy)-6-(3-diethylaminopropoxy)nitrobenzene-
.
[0671] The nitro intermediate (1 mmol) obtained above was dissolved
in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (40
mg) until completion as indicated by LC-MS (.about.4 h). The
reaction mixture was then filtered to remove the catalyst. The MeOH
solution containing
2-n-butylamino-4-(4-t-butylphenoxy)-6-(3-diethylaminopropoxy)aniline
was used directly for further transformation.
[0672] A solution of
2-n-butylamino-4-(4-t-butylphenoxy)-6-(3-diethylaminopropoxy)-aniline
(90 mg, 0.2 mmol) and 4-(3-diethylaminopropoxy)benzaldehyde
obtained above (65 mg, 0.25 mmol) in MeOH (10 mL) was refluxed
until the reaction was complete as indicated by LC-MS (.about.10
h). The solvent was removed in vacuo and the residue was purified
by silica gel column chromatography, eluting with 10% MeOH in DCM
with a gradual increment of Et.sub.3N (0.5 to 1%), to afford the
desired benzimidazole (80 mg).
[0673] MS m/z 657 (M+H).sup.+
[0674] .sup.1H NMR (400 MHz, CDCl.sub.3) of HCl salt of the
benzimidazole: .delta. 0.80 (t, 3H), 1.21 (m, 2H), 1.31 (s, 9H),
1.40 (m, 12H), 1.74 (m, 2H), 2.39 (m, 2H), 2.52 (m, 2H), 3.17-3.27
(m, 12H), 3.80 (m, 2H), 4.18 (m, 4H), 6.60 (br s, 1H), 6.62 (br s,
1H), 6.95 (d, 2H), 7.14 (br, 2H), 7.39 (d, 1H), 7.80 (br, 2H),
11.17 (br, N.HCl), 11.83 (br, N.HCl) ppm.
Example 258
2-{2,4-bis-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-1-butyl-6-(4-tert-
-butyl-phenoxy)-1H-benzimidazole
[0675] A solution of 2-n-butylamino-4-(4-t-butylphenoxy)aniline
(synthesized via General Procedures J3-J7) (100 mg, 0.3 mmol) and
2,4-bis[2-(1-methyl-2-pyrrolidin-2-yl)-ethoxy]benzaldehyde
(synthesized via General Procedure C) (55 mg, 0.15 mmol) in MeOH
(10 mL) was subjected to General Procedure K. The solvent was
removed in vacuo and the residue was purified by silica gel column
chromatography, eluting with 10% MeOH in DCM with a gradual
increment of Et.sub.3N (0.5 to 1%), to afford the desired
benzimidazole (50 mg).
[0676] MS m/z 653 (M+H).sup.+
[0677] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.73 (t, 3H),
1.10-2.53 (m, 22H), 1.32 (s, 9H), 2.20 (s, 3H), 2.39 (s, 3H),
3.94-3.99 (m, 6H), 6.50 (m, 2H), 6.92 (d, 2H), 6.98 (m, 1H), 7.05
(d, 1H), 7.32 (d, 2H), 7.42 (d, 1H), 7.70 (d, 1H) ppm.
Example 259
2-[2,4-bis-(2-pyrrolidin-1-yl)-ethoxy]-phenyl}-1-butyl-6-(4-butyl-phenoxy)-
-1H-benzimidazole
[0678] A solution of 2-n-butylamino-4-(4-n-butylphenoxy)aniline
(synthesized via General Procedures G1 and G2 and I) (80 mg, 0.25
mmol) and 2,4-bis(2-pyrrolidin-1-yl-ethoxy)benzaldehyde
(synthesized via General Procedure C) (50 mg, 0.15 mmol) was
subjected to General procedure K. The solvent was removed in vacuo
and the residue was purified by silica gel column chromatography,
eluting with 10% MeOH in DCM with a gradual increment of Et.sub.3N
(0.5 to 1%), to afford the desired benzimidazole (80 mg).
[0679] MS m/z 625 (M+H).sup.+
[0680] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.0.73 (t, 3H), 0.92
(t, 3H), 1.10 (m, 2H), 1.35 (m, 2H), 1.55-1.60 (m, 4H), 1.64 (m,
4H), 1.83 (m, 4H), 2.39 (m, 4H), 2.58 (t, 2H), 2.65 (m, 4H), 2.73
(t, 2H), 2.93 (t, 2H), 3.96 (t, 2H), 4.07 (t, 2H), 4.16 (t, 2H),
6.60 (br s, 1H), 6.62 (dd, 1H), 6.92 (d, 2H), 6.96 (dd, 1H), 7.04
(d, 1H), 7.12 (d, 2H), 7.40 (d, 1H), 7.70 (d, 1H) ppm.
[0681] The following Examples were synthesized according to the
Methods employed for Examples 255-259;
TABLE-US-00005 Example Name 260
1-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolodin-1-yl-ethoxy)-
- phenyl]-6-(2-pyrrolodin-1-yl-ethoxy)-1H-benzoimidazole 261
{3-[2-{1-butyl-6-[2-(4-chloro-phenyl)-ethoxy]-1H-benzimidazol-2-yl]-5--
(3- diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 262
2-{2,4-bis-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-1-butyl-6-(4--
butyl- phenoxy)-1H-benzoimidazole 263
{3-[2-[1-butyl-5-(4-tert-butyl-phenoxy)-1H-benzimidazol-1-yl]-5-(3-
diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 264
1-Butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-
- ethoxy)-1H-benzoimidazole 265
2-[2,4-bis-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-butyl-6-(4-cyclopentyl-
- phenoxy)-1H-benzoimidazole 266
2-{2,4-bis-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-1-butyl-6-(4-
cyclopentyl-phenoxy)-1H-benzoimidazole 267
{3-[2-[1-butyl-6-(4-iospropyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3-
diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 268
(2-{1-butyl-6-(2-dimethylamino-ethylsulfanyl)-2-[4-(4-fluoro-3-
trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-
benzoimidazol-4-ylsulfanyl}-ethyl)-dimethyl-amine 269
2-[2,4-bis-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-butyl-6-(4-tert-butyl-
phenoxy)-1H-benzimidazole 270
{3-[2-[1-butyl-6-(4-butyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3-
diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 271
{3-[2-[1-butyl-6-(4-fluoro-3-trifluoromethyl-phenoxy)-1H-benzimidazol--
2- yl]-5-(3-diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine
272
2-[2,4-bis-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1-butyl-6-(4-isopropyl-
phenoxy)-1H-benzoimidazole 273
1-Butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-
- ethoxy)-1H-benzoimidazole 274
(3-{3-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin--
1-yl-
ethoxy)-phenyl]-3H-benzoimidazol-5-yloxy}-propyl)-diethyl-amine 275
{3-[2-[1-butyl-6-(4-cyclopentyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3-
diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 276
{3-[2-[1-butyl-4-(4-tert-butyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3-
diethylamino-propoxy)-phenoxy]-propyl}-diethyl-amine 277
2-{2,4-bis-[2-(1-methyl-pyrrolidin-2-yl)-ethoxy]-phenyl}-1-butyl-6-(4-
isopropyl-phenoxy)-1H-benzoimidazole 278
(3-{5-[2-(4-chloro-phenyl)-ethoxy]-2-[6-(3-diethylamino-propoxy)-1-
isopropyl-1H-benzimidazol-2-yl]-phenoxy}-propyl)-diethyl-amine 279
1-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-
- ethoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole
280
1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-4,6-bis-(1-methyl-
piperidin-4-yloxy)-1H-benzimidazole 281
{3-[2-[6-(4-tert-butyl-phenoxy)-1H-benzimidazol-2-yl]-5-(3-diethylamin-
o- propoxy)-phenoxy]-propyl}-diethyl-amine 282
1-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-4,6-bis-(1-methyl-pyrrolid-
in-2- ylmethoxy)-1H-benzoimidazole 283
(3-{3-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-diethylamino-ethoxy-
)- phenyl]-3H-benzimidazol-5-yloxy}-propyl)-diethyl-amine 284
(3-{2-[1-Butyl-6-(2-imidazol-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-[2--
(4- chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 285
(3-{2-[1-Butyl-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-[-
2-(4- chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 286
{3-[2-(3,5-bis-benzyloxy-phenyl)-3-butyl-3H-benzimidazol-5-yloxy]-
propyl}-diethyl-amine 287
4,6-bis-(2-azepan-1-yl-ethoxy)-1-butyl-2-[3-(4-tert-butyl-phenoxy)-
phenyl]-1H-benzoimidazole 288
1-butyl-2-[3-(4-butyl-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-etho-
xy)- 1H-benzoimidazole 289
1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(1-methyl-pyrrolid-
in-2- ylmethoxy)-1H-benzoimidazole 290
(2-{1-butyl-6-(2-dimethylamino-ethylsulfanyl)-2-[3-(3-trifluoromethyl-
phenoxy)-phenyl]-1H-benzoimidazole-4-ylsufanyl}-ethyl)-dimethyl-amine
291
(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(4-isopropyl-phenoxy)-
phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 292
4,6-bis-(2-azepan-1-yl-ethoxy)-1-butyl-2-[3-(3,5-dichlorophenoxy)-
phenyl]-1H-benzoimidazole 293
1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-[2-(cyclohexyl-met-
hyl- amino)-ethoxy]-1H-benzoimidazole 294
{3-[1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-6-(2-imidazol-1-yl-eth-
oxy)- 1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine 295
[3-(2-{3,4-bis-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3-butyl-3H-
benzimidazol-5-yloxy)-propyl]-diethyl-amine 296
1-butyl-4,6-bis-(1-methyl-piperidin-4-yloxy)-2-[3-(3-trifluoromethyl-
phenoxy)-phenyl]-1H-benzoimidazole 297
4,6-bis-(2-azepan-1-yl-ethoxy)-1-butyl-2-[3-(3-trifluoromethyl-phenoxy-
)- phenyl]-1H-benzoimidazole 298
1-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-4,6-bis-(1-ethyl-pyrrolidi-
n-2- ylmethoxy)-1H-benzoimidazole 299
[3-(2-{2-benzyloxy-4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-3-butyl-3H-
benzimidazol-5-yloxy]-propyl}-diethyl-amine 300
{3-[2-[1-Butyl-6-(3-diethylamino-propoxy)-1H-benzoimidazol-2-yl]-5-(4-
fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine
301
{3-[2-[1-Butyl-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-(-
4- fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine
302
1-butyl-2-[3-(3,4-dimethoxy-phenoxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-y-
l- ethoxy)-1H-benzimidazole 303
(2-{1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-(2-dimethylami-
no-
ethylsulfanyl)-1H-benzoimidazol-4-ylsulfanyl}-ethyl)-dimethyl-amine
304
1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(1-ethyl-pyrrolidi-
n-3- yloxy)-1H-benzoimidazole 305
{3-[2-[3-(3,4-bis-benzyloxy-phenyl)-3-butyl-3H-benzimidazol-5-yloxy]-
propyl}-diethyl-amine 306
(3-{5-[2-(4-chloro-phenyl)-ethoxy]-2-[6-(3-diethylamino-propoxy)-1H-
benzimidazol-2-yl]-phenoxy}-propyl)-diethyl-amine 307
1-butyl-2-[4-(2-diethylamino-ethoxy)-phenyl]-4,6-bis-[2-(methyl-phenyl-
- amino)-ethoxy]-1H-benzimidazole 308
{3-[3-butyl-2-{4-[2-(4-chlorophenyl)-ethoxy]-phenyl}-7-(pyridin-3-ylox-
y)- 3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 309
{2-[1-butyl-2-[3-(3,4-dichloro-phenoxy)-phenyl]-6-(2-diisopropylamino-
ethoxy)-1H-benzimidazol-4-yloxy]-ethyl}-diethyl-amine 310
{3-[3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-7-(pyridin-3-
ylmethoxy)-3H-benzimidazol-5-yloxy]-propyl}-diethyl-amine 311
2-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzoimidazlo-2-yl]-5-[2-(4-
chloro-phenyl)-ethoxy]-phenol 312
{3-[3-butyl-2-[2-(4-chloro-phenylsulfanyl)-phenyl]-7-(3-diethylamino-
propoxy)-3H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 313
(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(4-fluoro-2-methoxy-
phenoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 314
[3-(3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-isopropoxy-phenyl}-3H-
benzimidazol-5-yloxy)-propyl]-diethyl-amine 315
{2-[1-butyl-6-(3-diethylamino-propoxy)-1H-benzoimidazlo-2-yl]-5-[2-(4-
chloro-phenyl)-ethoxy]-phenoxy}-acetic acid methyl ester 316
(3-{2-[1-butyl-6-(4-tert-butyl-phenoxy)-1H-benzimidazol-2-yl]-5-[2-(4-
chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 317
(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(2-isopropoxy-phenoxy)-
phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine 318
(3-{1-butyl-6-(3-diethylamino-propoxy)-2-[4-(2,3-dimethoxy-phenoxy)-
phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-amine 319
(3-{3-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-eth-
oxy)- phenyl]-3H-benzoimidazol-5-yloxy}-propyl)-diethyl-amine 320
(2-{1-butyl-6-fluoro-2-[3-(3-trifluoromethyl-phenoxy)-phenyl]-1H-
benzoimidazole-4-ylsufanyl}-ethyl)-dimethyl-amine 321
Methanesulfonic acid
5-[2-(4-chloro-phenyl)-ethoxy]-2-[6-(3-diethylamino-
propoxy)-1H-benzoimidazol-2-yl]-phenyl ester 322
5-[2-(4-Chloro-phenyl)-ethoxy]-2-[6-(3-diethylamino-propoxy)-1H-
benzoimidazol-2-yl]-phenol 323
{3-[1-butyl-6-(3-diethylamino-propoxy)-2-(4-pyrrolidin-1-yl-phenyl)-1H-
- benzoimidazol-4-yloxy]-propyl}-diethyl-amine 324
1-butyl-2-[3-(4-tert-butyl-phenoxy)-phenyl]-4,6-bis-(1-methyl-piperidi-
n-4- yloxy)-1H-benzimidazole 325
1-butyl-2-[3-(3,5-dichloro-phenoxy)-phenyl]-4,6-bis-(2-imidazol-1-yl-
ethoxy)-1H-benzoimidazole 326
[2-(1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-6-fluoro-1H-
benzoimidazol-4-ylsulfanyl)-ethyl]-dimethyl-amine
Example 327
{3-[1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-(pyrrolidin-1-yl-ethoxy-
)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diet-
hyl-amine
[0682]
4-[2-(4-chloro-phenyl)-ethoxy]-[2-(2-pyrrolidin-1-yl-ethoxy]-benzal-
dehyde (synthesized via General Procedures D1 and D2) (0.030 g,
0.080 mM) and
N-butyl-3,5-bis(3-dimethylamino-propoxy)benzene-1,2-diamine (0.035
g, 0.080 mM) were subjected to General Procedure K. After removal
of ethanol, the residue was purified on silica gel using 10%
MeOH/DCM with 0.1-0.4% Et.sub.3N, yield 0.025 g.
[0683] LC/MS (m/z): 776 (M+H).sup.+
Example 328
1-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-eth-
oxy)-phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole
[0684] A solution of
2-butylamino-4,6-bis(2-pyrrolidinyl-1-ethoxy)aniline (synthesized
via General Procedures G1 and G2 and H) (78.4 mg, 0.2 mmol) and
2-pyrrolidin-1-yl-ethoxy-4-(4-fluoro-3-trifluoromethyl)phenoxybenzald-
ehyde (synthesized via General Procedure E) (91 mg, 0.22 mmol) was
subjected to General Procedure K. The crude product was purified by
silica gel column chromatography using 10% MeOH in DCM with a
gradual increment of triethylamine (0.2 to 1.0%) as eluent to
afford Example 328 (62 mg).
[0685] MS m/z 768 (M+H).sup.+.
Example 329
1-Butyl-2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-eth-
oxy)-phenyl]-
##STR00622##
[0686] 4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole
[0687] A solution of
2-butylamino-4,6-bis(2-pyrrolidinyl-1-ethoxy)aniline (synthesized
via General Procedures G1 and G2 and H) (78.4 mg, 0.2 mmol) and
2-pyrrolidin-1-yl-ethoxy-4-(4-chloro-3-trifluoromethyl)phenoxybenzald-
ehyde (synthesized via General Procedure E) (91 mg, 0.22 mmol) in
ethanol (2 mL) was subjected to General Procedure K. The crude
product was purified by silica gel column chromatography using 10%
MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%)
as eluent to afford Example 329 (62.5 mg)
[0688] MS m/z 784 (M+H).sup.+
Example 330
(3-{2-[1-butyl-6-(3-diethylamino-propoxy)-4-(2-pyrrolidin-1-yl-ethoxy)-1H--
benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-
-amine
[0689] A solution of
2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde
(synthesized via General Procedure E) (858; 2.2 mmol) and
2-(n-butylamino)-4-(N,N-diethylaminopropoxy)-6-(N-pyrrolidinoethoxy)anili-
ne (synthesized via General Procedures J3-J7) (816 mg; 2 mmol) in
ethanol (5 mL) was subjected to General Procedure K. The crude
product was purified by silica gel column chromatography using 10%
MeOH in DCM with a gradual increment of triethylamine (0.2 to 1.0%)
as eluent to afford 520 mg (34%) of Example 330.
[0690] MS m/z 776 (M+H).sup.+
Example 331
(3-{2-[1-butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-[2-
-(4-chloro-phenyl)-ethoxy]phenoxy}-propyl)-diethyl-amine
[0691] To a stirred solution of 2-(4-chlorophenyl)ethanol (20.0 mL,
148 mmol), TEA (31.0 mL, 222 mmol) in anhydrous DCM (100 mL) was
added dropwise MsCl (12.0 mL, 156 mmol) at 0.degree. C. within 8
min, and stirred at the same temperature for 2 h. The resulting
yellow suspension was diluted with DCM (200 mL), washed with cold
H.sub.2O and brine, and dried. Removal of the solvent afforded the
mesylate (33.0 g).
[0692] A mixture of the mesylate obtained as above (23.6 g, 100
mmol), 2,4-dihydroxybenzaldehyde (16.6 g, 120 mmol) and KHCO.sub.3
(12.0 g, 120 mmol) in anhydrous DMF (150 mL) was heated at
130.degree. C. for 4 h following the general procedure described
for disubstituted benzaldehydes. The crude products were purified
by flash chromatography (eluting with 10% EtOAc in hexanes), giving
4-(4-chlorophenyl)ethoxysalicylaldehyde (12.5 g) as a white
solid.
[0693] Methanesulfonyl chloride, General Procedure P2 (2.90 mL,
37.5 mmol) was added dropwise at 0.degree. C. to a stirred solution
of 3-diethylaminopropanol (5.75 mL, 38.8 mmol), TEA (7.0 mL, 50.0
mmol) in anhydrous DCM (25 mL), and the mixture was stirred at the
same temperature for 1 h, and at rt for an additional 1 h. After
the removal of the solvent in vacuo, the solid residue was mixed
with the aldehyde formed above (7.0 g, 25.0 mmol), Cs.sub.2CO.sub.3
(20.4 g, 62.5 mmol) and anhydrous DMSO (100 mL), and the whole
mixture was heated at 90.degree. C. for 6 h. following the general
procedure described for disubstituted benzaldehydes to obtain oily
2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde
(11.0 g, .about.100% yield), which solidified upon standing.
[0694] To a stirred solution of 2,4,6-trifluoronitrobenzene (5.31
g, 30 mmol), TEA (8.37 mL, 60 mmol) and DMF (50 mL) was added
dropwise a solution of n-butylamine (2.96 mL, 30 mmol) in DMF (20
mL) at rt following General Procedure G1 to obtain crude
2-butylamino-4,6-difluoronitrobenzene (9.0 g). This product was
mixed with 3-diethylaminopropanol (11.1 mL, 75 mmol) and anhydrous
THF (150 mL), and then powdered KOBu.sup.t (8.5 g, 75 mmol) was
added following General Procedure G2 to afford crude
2-butylamino-4,6-di(3-diethylaminopropoxy)nitrobenzene (15.5
g).
[0695] The nitro compound formed above (6.8 g, 15 mmol) dissolved
in MeOH (90 mL) was hydrogenated following general procedure H and
2-butylamino-4,6-di(3-diethylaminopropoxy)aniline obtained was used
directly for the next step.
[0696] Example 331 was formed employing phenylenediamine formed
above (848 mg; 2 mmol) and
2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde
(858; 2.2 mmol) in ethanol (5 mL) following the general procedure
K. The crude product was purified by silica gel column
chromatography using 10% MeOH in DCM with a gradual increment of
triethylamine (0.2 to 1.0%) to afford 400 mg of Example 331.
[0697] MS m/z 792 (M+H).sup.+
Example 332
(3-{2-[1-Butyl-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-
-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine
[0698] 2-butylamino-4,6-difluoronitrobenzene (9.0 g) was mixed with
1-pyrrolidineethanol (8.81 mL, 75 mmol) and anhydrous THF (150 mL),
and then powdered KOBu.sup.t (8.5 g, 75 mmol) was added following
general procedures G1 and G2 described for homo disubstituted
phenylenediamine to afford crude
2-butylamino-4,6-di(pyrrolidineethoxy)nitrobenzene (13.5 g).
[0699] The nitro compound formed above (6.3 g, 15 mmol) dissolved
in MeOH (90 mL) was hydrogenated following general procedure H and
2-butylamino-4,6-di(pyrrolidineethoxy)aniline obtained was used
directly for the next step.
[0700] Example 332 was formed employing phenylenediamine formed
above (784 mg; 2 mmol) and
2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde
(858; 2.2 mmol) in ethanol (5 mL) following the general procedure
K. The crude product was purified by silica gel column
chromatography using 10% MeOH in DCM with a gradual increment of
triethylamine (0.2 to 1.0%) as eluent to afford 380 mg of Example
332.
[0701] MS m/z 760 (M+H).sup.+
Example 333
(3-{1-Butyl-6-(3-diethylamino-propoxy)-2-[4-(4-fluoro-3-trifluoromethyl-ph-
enoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-prop-
yl)-diethyl-amine
[0702] A solution of 2,4-difluorobenzaldehyde (2.13 g, 15.0 mmol)
in DMF (10 ml) was added dropwise to a precooled (0.degree. C.)
solution of sodium 2-pyrrolidinoethoxide in DMF (50 ml), which was
made by stirring a mixture of sodium hydride (600 mg, 15.0 mmol,
60% in mineral oil) and N-(2-hydroxyethyl)pyrrolidine (1.72 g, 15.0
mmol). The resulting reaction mixture was warmed to rt and stirred
for additional 3 h. To the same reaction flask was introduced
potassium carbonate (2.10 g, 15.0 mmol) and
3-fluoro-4-trifluoromethylphenol (2.7 g, 15.0 mmol) and the
reaction mixture was heated at 90.degree. C. as described in the
General Procedure E for 2-alkoxy-4-aryloxybenzaldehydes. The crude
product was purified by silica gel column chromatography using
dichloromethane and 5% methanol in dichloromethane as eluent, to
give
2-(2-pyrrolidineethoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldehyde
(2 g) as a brown oil.
[0703] MS m/z 399 (M+H).sup.+
[0704] Example 333 was formed employing the aldehyde formed above
(873 mg; 2.2 mmol) and
2-butylamino-4,6-di(3-diethylaminopropoxy)aniline (848; 2.0 mmol)
following the general procedure K. The crude product was purified
by silica gel column chromatography using 10% MeOH in DCM with a
gradual increment of triethylamine (0.2 to 1.0%) as eluent to
afford 390 mg of Example 333.
[0705] MS m/z 800 (M+H).sup.+
Example 334
{3-[1-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-
-ethoxy)-phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-4-yloxy]-pr-
opyl}-diethyl-amine
[0706] MsCl (1.4 mL, 18.0 mmol) was added dropwise at 0.degree. C.
to a stirred solution of pyrrolidineehanol (1.90 mL, 16.0 mmol),
TEA (2.8 mL, 20.0 mmol) in anhydrous DCM (20 mL), and the mixture
was stirred at rt for 1 h. After the removal of the solvent in
vacuo, the solid residue was mixed with 3,5-difluoro-4-nitrophenol
(1.75 g; 10 mmol) and K2CO3 (5.5 g; 40 mmol) following General
Procedure F1. The product,
2,6-difluoro-4-(N-pyrrolidineethoxy)nitrobenzene (1.5 g) was used
directly.
[0707] To a stirred solution of
2,6-difluoro-4-(N-pyrrolidineethoxy)nitrobenzene obtained above
(1.4 g; 5.1 mmol) and triethylamine (1.4 mL; 10.0 mmol) in DMF (10
mL), a solution of n-butylamine (505 .mu.L; 5.1 mmol) in DMF (3 mL)
was added according to General Procedure G1. The crude product,
2-(n-butylamino)-4-(N-pyrrolidineethoxy)-6-fluoronitrobenzene. (1.5
g) was used for further transformation without any
purification.
[0708] A solution of 3-diethylaminopropanol (652 .mu.L; 4.4 mmol)
in anhydrous THF 4.4 mL was added with powdered KOBu.sup.t (493 mg;
4.4 mmol) and stirred at rt for 5 min. This solution was added
dropwise to a stirred solution of
2-(n-butylamino)-4-(N-pyrrolidineethoxy)-6-fluoronitrobenzene (1.32
g; 4.0 mmol) in anhydrous THF (10 mL) according to General
Procedure G2. The crude product,
2-(n-butylamino)-4-(N-pyrrolidineethoxy)-6-(N,N-diethylaminopropoxy)nitro-
benzene. (1.5 g) was used directly.
[0709] The nitro compound formed above (1.31 g, 4 mmol) dissolved
in MeOH (20 mL) was hydrogenated following general procedure H. The
product obtained (1.15 g) was used directly for the next step.
[0710] Example 334 was formed employing phenylenediamine formed
above (816 mg; 2 mmol) and
2-(2-pyrrolidineethoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldehyde
(873 mg; 2.2 mmol) in ethanol (5 mL) following general procedure K.
The crude product was purified by silica gel column chromatography
using 10% MeOH in DCM with a gradual increment of triethylamine
(0.2 to 1.0%) as eluent to afford 375 mg of Example 334.
[0711] MS m/z 784 (M+H).sup.+
Example 335
{3-[2-[1-Butyl-6-(3-diethylamino-propoxy)-4-(2-pyrrolidin-1-yl-ethoxy)-1H--
benzoimidazol-2-yl]-5-(4-fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl-
}-diethyl-amine
[0712] A solution of 2,4-difluorobenzaldehyde (2.13 g, 15.0 mmol)
in DMF (10 ml) was added dropwise to a precooled (0.degree. C.)
solution of sodium 3-diethylaminopropoxide in DMF (50 ml), which
was made by stirring a mixture of sodium hydride (600 mg, 15.0
mmol, 60% in mineral oil) and 3-diethylaminopropanol (1.97 g, 15.0
mmol). The resulting reaction mixture was warmed to rt and stirred
for additional 3 h. To the same reaction flask was introduced
potassium carbonate (2.10 g, 15.0 mmol) and
3-fluoro-4-trifluoromethylphenol (2.7 g, 15.0 mmol) and the
reaction mixture was heated at 90.degree. C. as described general
procedure E. The crude product was purified by silica gel column
chromatography using dichloromethane and 5% methanol in
dichloromethane as eluent, to give
2-(3-diethylaminopropoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldehy-
de (2.2 g).
[0713] Methanesulfonyl chloride (General Procedure P2) (1.55 mL,
20.0 mmol) was added dropwise at 0.degree. C. to a stirred solution
of 3-diethylaminopropanol (2.70 mL, 18.0 mmol), TEA (2.8 mL, 20.0
mmol) in anhydrous DCM (30 mL), and the mixture was stirred at rt
for 1 h. After the removal of the solvent in vacuo, the solid
residue was mixed with 3,5-difluoro-4-nitrophenol (2.65 g; 15 mmol)
and K.sub.2CO.sub.3 (6.9 g; 50 mmol) according to General Procedure
F1. The crude product,
2,6-difluoro-4-(3-diethylaminopropoxy)nitrobenzene (3.9 g) was used
for further transformation.
[0714] To a stirred solution of
2,6-difluoro-4-(3-diethylaminopropoxy)nitrobenzene obtained above
(1.9 g; 6.6 mmol) and triethylamine (1.4 mL; 10.0 mmol) in DMF (12
mL), a solution of n-butylamine (656 .mu.L; 6.6 mmol) in DMF (4 mL)
was added dropwise at rt within 15 min, and the rest was followed
as described in the general methods. The crude product,
2-(n-butylamino)-4-(3-diethylaminopropoxy)-6-fluoronitrobenzene
(2.0 g) was used for further transformation without any
purification.
[0715] A solution of 3-diethylaminopropanol (516 .quadrature.L; 4.4
mmol) in anhydrous THF 4.4 mL was added with powdered KOBu.sup.t
(493 mg; 4.4 mmol) and stirred at room temperature for 5 min. This
solution was added dropwise to a stirred solution of
2-(n-butylamino)-4-(3-diethylaminopropoxy)-6-fluoronitrobenzene
(1.37 g; 4.0 mmol) in anhydrous THF (10 mL) at 0.degree. C. under a
N.sub.2 stream. The reaction mixture was maintained at 0.degree. C.
for 1 h at which time the reaction was complete the rest was
followed as described in the general methods. The crude product,
2-(n-butylamino)-4-(3-diethylaminopropoxy)-6-(N-pyrrolidineethoxy)nitrobe-
nzene. (1.6 g) was used for further transformation without any
purification.
[0716] The nitro compound formed above (1.31 g, 4 mmol) dissolved
in MeOH (20 mL) was hydrogenated following the general procedure
and
2-(n-butylamino)-4-(N-pyrrolidineethoxy)-6-(N,N-diethylaminopropoxy)anili-
ne (1.15 g) obtained was used directly for the next step reaction
without further purification. Example 335 was formed employing
phenylenedimaine formed above (816 mg; 2 mmol) and
2-(3-diethylaminopropoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldehy-
de (910 mg; 2.2 mmol) in ethanol (5 mL) following the general
procedure. The crude product was purified by silica gel column
chromatography using 10% MeOH in DCM with a gradual increment of
triethylamine (0.2 to 1.0%) as eluent to afford 380 mg of Example
335.
[0717] MS m/z 800 (M+H).sup.+
Example 336
{3-[2-[1-Butyl-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazol-2-yl]-5-
-(4-fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine
[0718] A solution of 2,4-difluorobenzaldehyde (2.13 g, 15.0 mmol)
in DMF (10 ml) was added dropwise to a precooled (0.degree. C.)
solution of sodium 3-dimethylaminopropoxide in DMF (50 ml), which
was made by stirring a mixture of sodium hydride (600 mg, 15.0
mmol, 60% in mineral oil) and 3-dimethylaminopropanol (1.55 g, 15.0
mmol). The resulting reaction mixture was warmed to rt and stirred
for additional 3 h. To the same reaction flask was introduced
potassium carbonate (2.10 g, 15.0 mmol) and
3-fluoro-4-trifluoromethylphenol (2.7 g, 15.0 mmol) and the
reaction mixture was heated at 90.degree. C. as described in
General Procedure E for 2-alkoxy-4-aryloxybenzaldehydes. The crude
product was purified by silica gel column chromatography using
dichloromethane and 5% methanol in dichloromethane as eluent, to
give
2-(3-dimethylaminopropoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldeh-
yde (2.0 g).
[0719] Example 336 was formed employing the aldehyde formed above
(823 mg; 2.2 mmol) and
2-butylamino-4,6-di(pyrrolidineethoxy)aniline (784; 2.0 mmol) in
ethanol (5 mL) following General Procedure K. The crude product was
purified by silica gel column chromatography using 10% MeOH in DCM
with a gradual increment of triethylamine (0.2 to 1.0%) as eluent
to afford 380 mg of Example 336.
[0720] MS m/z 784 (M+H).sup.+
Example 337
{3-[3-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy-
)-phenyl]-7-(2-pyrrolidin-1-yl-ethoxy)-3H-benzimidazol-5-yloxy]-propyl}-di-
ethyl-amine
[0721] A solution of 2,4-difluorobenzaldehyde (2.13 g, 15.0 mmol)
in DMF (10 ml) was added dropwise to a precooled (0.degree. C.)
solution of sodium 3-dimethylaminopropoxide in DMF (50 ml), which
was made by stirring a mixture of sodium hydride (600 mg, 15.0
mmol, 60% in mineral oil) and 3-dimethylaminopropanol (1.55 g, 15.0
mmol). The resulting reaction mixture was warmed to rt and stirred
for additional 3 h. To the same reaction flask was introduced
potassium carbonate (2.10 g, 15.0 mmol) and
3-fluoro-4-trifluoromethylphenol (2.7 g, 15.0 mmol) and the
reaction mixture was heated at 90.degree. C. as described in
General Procedure E for 2-alkoxy-4-aryloxybenzaldehydes. The crude
product was purified by silica gel column chromatography using
dichloromethane and 5% methanol in dichloromethane as eluent, to
give
2-(3-dimethylaminopropoxy)-4-(3-fluoro-4-trifluoromethyl)phenoxybenzaldeh-
yde (2.0 g).
[0722] Example 337 was formed employing the aldehyde formed above
(823 mg; 2.2 mmol) and
2-butylamino-4,6-di(pyrrolidineethoxy)aniline (784; 2.0 mmol) in
ethanol (5 mL) following General Procedure K. The crude product was
purified by silica gel column chromatography using 10% MeOH in DCM
with a gradual increment of triethylamine (0.2 to 1.0%) as eluent
to afford 380 mg of Example 337.
[0723] MS m/z 759 (M+H).sup.+
Example 338
(3-{2-[1-Butyl-4-(3-diethylamino-propoxy)-6-(2-pyrrolidin-1-yl-ethoxy)-1H--
benzoimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-diethy-
l-amine
[0724]
2-(3-diethylaminopropoxy)-4-[2-(4-chlorophenyl)ethoxy]benzaldehyde
(858; 2.2 mmol) and
2-(n-butylamino)-4-(N-pyrrolidineethoxy)-6-(N,N-diethylaminopropoxy)anili-
ne (816 mg; 2 mmol) were condensed to form the benzimidazole
following General Procedure K. The crude product was purified by
silica gel column chromatography using 10% MeOH in DCM with a
gradual increment of triethylamine (0.2 to 1.0%) as eluent to
afford 390 mg of Example 338.
[0725] MS m/z 776 (M+H).sup.+
[0726] The following Examples were synthesized according to the
Methods employed for Examples 327-338;
TABLE-US-00006 Example Name 339
{3-[1-butyl-2-[4-(3,4-dichloro-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-
phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-
diethyl-amine 340
{3-[2-[2,4-bis-(3-diethylamino-propoxy)-phenyl]-1-butyl-6-(4-tert-buty-
l- phenoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine 341
{3-[1-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(pyridin-2-ylmethoxy)-
phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yl]-phenyl}-
diethyl-amine 342
{3-[2-[4-[2-(4-Chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phe-
nyl]-
6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-
amine 343
1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-
- phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 344
{3-[1-Butyl-2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin--
1-yl-
ethoxy)-phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-
propyl}-diethyl-amine 345
(3-{6-(3-Diethylamino-propoxy)-2-[4-(4-fluoro-3-trifluoromethyl-phenox-
y)-
2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-
diethyl-amine 346
{3-[2-[1-Butyl-4-(3-diethylamino-propoxy)-6-(2-pyrrolidin-1-yl-ethoxy)-
-1H-
benzoimidazol-2-yl]-5-(4-fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-
propyl}-diethyl-amine 347
{3-[3-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin--
1-yl-
ethoxy)-phenyl]-7-(2-pyrrolidin-1-yl-ethoxy)-3H-benzoimidazol-5-yloxy]-
propyl}-diethyl-amine 348
{3-[1-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-eth-
oxy)-
phenyl]-6-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazol-4-yloxy]-propyl}-
diethyl-amine 349
{3-[2-[1-butyl-4,6-bis-(2-pyrrolodin-1-yl-ethoxy)-1H-benzimidazol-2-yl-
]-5-
(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-propyl}-diethyl-amine
350
{3-[1-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-3-diethylaminomethyl-
phenyl}-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-
diethyl-amine 351
{3-[2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(pyridin-2-ylmethoxy)-phenyl]--
6-(3-
diethylamino-propoxy)-1H-benzimidazol-4-yl]-propyl}-diethyl-amine
352 3-(7-Butoxy-3-butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-
cyclopentylmethoxy-phenyl}-3H-benzoimidazol-5-yloxy)-propan-1-ol
353
3-(7-Butoxy-2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-cyclopentylmethoxy-
phenyl}-3H-benzoimidazol-5-yloxy)-propan-1-ol 354
(3-{1-Butyl-6-(3-diethylamino-propoxy)-2-[4-(4-fluoro-3-trifluoromethy-
l-
phenoxy)-2-(pyridin-2-ylmethoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-
propyl)-diethyl-amine 355
{3-[2-[1-Butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzoimidazol-2-yl]-
-5-
(4-fluoro-3-trifluoromethyl-phenoxy)-phenoxy]-propyl}-diethyl-amine
356
2-(3,5-bis-benzyloxy-phenyl)-1-butyl-4,6-bis-(2-pyrrolodin-1-yl-ethoxy-
)- 1H-benzimidazole 357
{3-[2-[1-butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]--
5-
(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-propyl}-diethyl-amine
358
1-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrol-1-yl-ethoxy)-phe-
nyl]- 4,6-bis-(2-pyrrolodin-1-yl-ethoxy)-1H-benzoimidazole 359
{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-(3-diethylamino-propoxy)-pheny-
l}-
6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-
amine 360
{3-[1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(pyridin-3-ylmethoxy)-
phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 361
(3-{3-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(3-diethylamino-propox-
y)-
phenyl]-7-isopropoxy-3H-benzoimidazol-5-yloxy}-propyl)-diethyl-amine
362
{3-[1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(pyridin-4-ylmethoxy)-
phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 363
{3-[2-[4-[2-(4-Chloro-phenyl)-ethoxy]-2-(pyridin-4-ylmethoxy)-phenyl]--
6-
(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-
amine 364
1-Butyl-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(pyridin-2-ylmetho-
xy)- phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole
365
2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-
-5,7- bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzimidazole 366
{3-[1-Butyl-2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-methoxy-phenyl}-6-(3-
diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine
367 {3-[2-{4-[2-(4-Chloro-phenyl)-ethoxy]-2-methoxy-phenyl}-6-(3-
diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-diethyl-amine
368
(3-{1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(3-diethylamino-propox-
y)-
phenyl]-6-isopropoxy-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine
369
{3-[1-Butyl-2-[4-(4-chloro-3-methyl-phenoxy)-2-(pyridin-2-ylmethoxy)-
phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 370
1-Butyl-2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-2-cyclopentylmethoxy-
- phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 371
(2-{1-butyl-6-(2-dimethylamino-ethoxy)-2-[4-(4-fluoro-3-trifluoromethy-
l-
phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazole-4-
yloxy}-ethyl)-dimethyl-amine 372
2-[1-butyl-4,6-bis-(3-diethylamino-propoxy)-1H-benzimidazol-2-yl]-5-[2-
-(4- chloro-phenyl)-ethoxy]-phenol 373
1-Butyl-2-[4-(4-chloro-3-methyl-phenoxy)-2-(pyridin-2-ylmethoxy)-pheny-
l]- 4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 374
2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-2-cyclopentylmethoxy-phenyl]-
- 4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 375
2-[4-(4-Fluoro-3-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-
- phenyl]-4,6-bis-(2-pyrrolidin-1-yl-ethoxy)-1H-benzoimidazole 376
{3-[2-(3,5-bis-benzyloxy-phenyl)-1-butyl-6-(3-diethylamino-propoxy)-1H-
- benzimidazol-4-yloxy]-propyl}-diethyl-amine 377
(3-{1-butyl-6-(3-dimethylamino-propoxy)-2-[4-(3-fluoro-phenoxy)-2-(2-
pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazole-4-yloxy}-propyl)-
diethyl-amine 378
{3-[2-{1-butyl-4-(4-chloro-benzyloxy)-6-(2-pyrrolidin-1-yl-ethoxy)-1H-
benzimidazol-2-yl]-5-[2-(4-chloro-phenyl)-ethoxy]-phenoxy}-propyl)-
diethyl-amine 379
{3-[2-{4-[2-(4-chloro-phenyl)-ethoxy]-2-(3-diethylamino-propoxy)-pheny-
l]-
6-(3-diethylamino-propoxy)-3H-benzimidazol-4-yloxy]-propyl}-diethyl-
amine 380
{3-[2-[4-(3,4-dichloro-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-
-(3-
diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-diethyl-amine
381 {3-[1-Butyl-2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-2-
cyclopentylmethoxy-phenyl]-6-(3-diethylamino-propoxy)-1H-
benzoimidazol-4-yloxy]-propyl}-diethyl-amine 382
{3-[2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-2-cyclopentylmethoxy-
phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-
diethyl-amine 383
(3-{1-butyl-6-(4-tert-butyl-phenoxy)-2-[4-[2-(4-chloro-phenyl)-ethoxy]-
-2-(3-
diethylamino-propoxy)-phenyl]-1H-benzimidazol-4-yloxy}-propyl)-diethyl-
amine 384
2-{2,4-bis-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1-butyl-4,6-bis-(2-
pyrrolidin-1-yl-ethoxy)-1H-benzimidazole 385
(2-{1-butyl-6-(2-dimethylamino-ethoxy)-2-[4-(3-fluoro-phenoxy)-2-(2-
pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazole-4-yloxy}-ethyl)-
dimethyl-amine 386
{3-[2-[4-(3,5-bis-trifluoromethyl-phenoxy)-2-(2-pyrrolidin-1-yl-ethoxy-
)-
phenyl]-1-butyl-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-
propyl}-diethyl-amine 387
{3-[1-butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-2-(2-pyrrolidin-1-yl-eth-
oxy)-
phenyl]-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-
diethyl-amine 388
(3-{2-(1-Butyl-4,6-diisopropoxy-1H-benzoimidazol-2-yl)-5-[2-(4-chloro-
phenyl)-ethoxy]-phenoxy}-propyl)-diethyl-amine 389
{3-[1-butyl-2-{3-[2-(4-chloro-phenyl)-ethoxy]-4-diethylaminomethyl-
phenyl}-6-(3-diethylamino-propoxy)-1H-benzimidazol-4-yloxy]-propyl}-
diethyl-amine 390
(3-{1-Butyl-6-(3-diethylamino-propoxy)-2-[4-fluoro-2-(2-pyrrolidin-1-y-
l- ethoxy)-phenyl]-1H-benzoimidazol-4-yloxy}-propyl)-diethyl-amine
391
(2-{1-butyl-6-fluoro-2-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-2-(2-
pyrrolidin-1-yl-ethoxy)-phenyl]-1H-benzoimidazol-4-ylsulfanyl}-ethyl)-
dimethyl-amine 392
{3-[1-Butyl-2-[4-[2-(4-chloro-phenyl)-ethoxy]-3-(3-diethylamino-propox-
y)-
phenyl]-6-(3-diethylamino-propoxy)-1H-benzoimidazol-4-yloxy]-propyl}-
diethyl-amine
Example 393
(4-benzyloxy-benzyl)-[1-butyl-6-(3-diethylaminopropoxy)-1-H-benzimidazol-2-
-ylmethyl]-hexyl-amine
##STR00623##
[0728] To 2-butylamino-4-(3-diethylaminopropoxy)aniline (3.44 g;
11.7 mmol) and BOC-glycine (2.46 g, 14.1 mmol) in DCM (20 mL) was
added DCC (2.90 g, 14.1 mmol) and the reaction mixture was stirred
for 4 h. The solid was removed by filtration and the filtrate was
concentrated to afford the desired product. The crude product was
used for further transformation without any purification.
[0729] To the product (11.7 mmol) obtained above in dioxane (7.5
mL) was added acetic acid (2.5 mL) and the reaction mixture was
heated at 80.degree. C. until the reaction was complete. Saturated
sodium bicarbonate was added and the mixture was extracted with
EtOAc. The combined organic layer was washed with water and brine,
dried over sodium sulfate. Evaporation of the solvent in vacuo
afforded desired
1-butyl-2-boc-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole.
The product obtained was treated with 4 N HCl in dioxane according
to General Procedure H to give
1-butyl-2-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole
hydrochloride.
[0730] To
1-butyl-2-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole
(1.0 mmol) in DCM (8 mL) were added Et.sub.3N (3.0 mmol) and
4-benzoxybenzaldehyde (1.0 mmol) and the mixture was stirred for 4
h, then NaBH(OAc).sub.3 (4.0 mmol) was added and stirred for
another 4 h, then sodium bicarbonate was added and the mixture was
extracted with EtOAc. The combined organic layer was washed with
brine, and dried over sodium sulfate. The crude product was
purified by silica gel column chromatography using DCM with a
gradual increment of MeOH (1% to 10%) as eluent to afford
1-butyl-2-(4-benzyloxy-benzyl)-aminomethyl-6-(3-diethylaminopropoxy)-1-H--
benzimidazole.
[0731] To
1-butyl-2-(4-benzyloxy-benzyl)-aminomethyl-6-(3-diethylaminoprop-
xy)-1-H-benzimidazole (16 mg, 0.03 mmol) in DCM (2 mL) were added
hexanal (8.3 mg, 0.083 mmol) and the mixture was stirred for 10
min, then NaBH(OAc).sub.3 (32 mg, 0.15 mmol) was added and stirred
for 3 h, then sodium bicarbonate was added and the mixture was
extracted with EtOAc (3.times.10 mL). The combined organic layer
was washed with brine, and dried over sodium sulfate. The crude
product was purified by silica gel column chromatography using DCM
with a gradual increment of MeOH (1% to 5%) as eluent to afford 14
mg of Example 393.
[0732] MS m/z 613 [M+H].sup.+
Example 394
(4-benzyloxy-benzyl)-[1-butyl-6-(3-diethylaminopropoxy)-1-H-benzimidazol-2-
-ylmethyl]-isobutyl-amine
##STR00624##
[0734] To
1-butyl-2-(4-benzyloxy-benzyl)-aminomethyl-6-(3-diethylaminoprop-
xy)-1-H-benzimidazole (16 mg, 0.03 mmol) in DCM (2 mL) were added
isbutrylaldehyde (8.6 mg, 0.10 mmol) and the mixture was stirred
for 10 min, then NaBH(OAc).sub.3 (32 mg, 0.15 mmol) was added and
stirred for 3 h, then sodium bicarbonate was added and the mixture
was extracted with EtOAc. The combined organic layer was washed
with brine, and dried over sodium sulfate. The crude product was
purified by silica gel column chromatography using DCM with a
gradual increment of MeOH (1% to 5%) as eluent to afford 12 mg of
Example 394.
[0735] MS m/z 585 [M+H].sup.+
Example 395
[3-(2-[(4-benzyloxy-benzyl)-cyclopentylmethyl-amino]-methyl}-3-butyl-3-H-b-
enzimidazol-5-yloxy)-propyl]-diethylamine
##STR00625##
[0737] To
1-butyl-2-(4-benzyloxy-benzyl)-aminomethyl-6-(3-diethylaminoprop-
xy)-1-H-benzimidazole (16 mg, 0.03 mmol) in DCM (2 mL) were added
cyclopentyl carboxaldehyde (11 mg, 0.10 mmol) and the mixture was
stirred for 10 min, then NaBH(OAc).sub.3 (32 mg, 0.15 mmol) was
added and stirred for 3 h, then sodium bicarbonate was added and
the mixture was extracted with EtOAc (3.times.10 mL). The combined
organic layer was washed with brine, and dried over sodium sulfate.
The crude product was purified by silica gel column chromatography
using DCM with a gradual increment of MeOH (1% to 5%) as eluent to
afford 8.0 mg of Example 395.
[0738] MS m/z 611 [M+H].sup.+
Example 396
[0739]
N-(4-benzyloxy-benzyl)-N-[1-butyl-6-(3-diethylaminopropoxy)-1-H-ben-
zimidazol-2-ylmethyl]-benzamide
##STR00626##
[0740] To
1-butyl-2-(4-benzyloxy-benzyl)-aminomethyl-6-(3-diethylaminoprop-
xy)-1-H-benzimidazole (32 mg, 0.06 mmol) in DCM (3 mL) were added
benzoyl chloride (34 mg, 0.24 mmol), TEA (24 mg, 0.24 mmol), DMAP
(catalytic amount) and the mixture was stirred for 12 h, then
sodium bicarbonate was added and the mixture was extracted with
EtOAc (3.times.10 mL). The combined organic layer was washed with
brine, and dried over sodium sulfate. The crude product was
purified by silica gel column chromatography using DCM with a
gradual increment of MeOH (0 to 1%) as eluent to afford 30 mg of
Example 396.
[0741] MS m/z 633 [M+H].sup.+
Example 397
(3-{3-butyl-2-[(dibenzylamino)-methyl]-3H-benzimidazol-5-yloxy)-propyl]-di-
ethyl-amine
##STR00627##
[0743] To
1-butyl-2-aminomethyl-6-(3-diethylaminopropxy)-1-H-benzimidazole
(15 mg, 0.034 mmol) in DCM (2 mL) were added Et.sub.3N (0.10 mmol)
and benzaldehyde (180 mg, 0.17 mmol) and the mixture was stirred
for 10 min, then NaBH(OAc).sub.3 (72 mg, 0.34 mmol) was added and
stirred for 3 h, then sodium bicarbonate was added and the mixture
was extracted with EtOAc. The combined organic layer was washed
with brine, and dried over sodium sulfate. The crude product was
purified by silica gel column chromatography using DCM with a
gradual increment of MeOH (1% to 2%) as eluent to afford 10 mg of
Example 397.
[0744] MS m/z 513 [M+H].sup.+
[0745] The following Examples were synthesized according to the
Methods employed for Examples 393-397;
TABLE-US-00007 Example Name 398
(3-{2-[(4-benzyloxy-benzylamino)-methyl]-3-butyl-3H-
benzimidazol-5-yloxy}-propyl)-diethyl-amine 399
N-(4-benzyloxy-benzyl)-N-[1-butyl-6-(3-diethylamino-
propoxy)-1H-benzimidazol-2-ylmethyl]-methanesulfonamide 400
N-(4-benzyloxy-benzyl)-N-[1-butyl-6-(3-diethylamino-
propoxy)-1H-benzimidazol-2-ylmethyl]-acetamide 401
{3-[3-butyl-2-({4-[2-(4-chloro-phenyl)-ethoxy]-benzylamino}-
methyl)-3H-benzimidazol-5-yloxy)-propyl]-diethyl-amine 402
[3-(2-{[Bis-(4-benzyloxy-benzyl)-amino]-methyl}-3-
butyl-3H-benzoimidazol-5-yloxy)-propyl]-diethyl-amine 403
[3-(2-{[Benzyl-(4-benzyloxy-benzyl)-amino]-methyl}-3-
butyl-3H-benzoimidazol-5-yloxy)-propyl]-diethyl-amine
Example 404
{3-[4-(2-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-ph-
enoxy]-propyl}-diethyl-amine
[0746] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
diethylaminopropoxide (2.2 mmol) in THF was added dropwise and
under a nitrogen stream, according to General Procedure L1. The
reaction mixture was stirred at 0.degree. C. for 1 h and allowed to
warm to rt until completion, as indicated by TLC or HPLC. The
reaction mixture was then treated with cold H.sub.2O and extracted
with EtOAc. The combined organic layers were washed with brine and
dried over sodium sulfate. Evaporation of the solvent in vacuuo
afforded the desired 4-alkoxynitrobenzene.
[0747] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg), according to General Procedure H.
The reaction mixture was then filtered to remove the catalyst. The
solvent was removed in vacuuo to afford the desired
4-alkoxyaniline, which was used directly for further transformation
without further purification.
[0748] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was
added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the
reaction mixture and heated to 80.degree. C. until completion,
according to General Procedure Q1. After cooling to rt, the
reaction mixture was quenched using cold water (20 ml) and the
product was isolated in EtOAc (2.times.20 ml). The combined organic
layers were washed with saturated sodium bicarbonate (2.times.10
ml), water (2.times.10 ml) and brine (15 ml). The organic layer was
dried over magnesium sulfate, and the solvent was removed in vacuuo
to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone.
[0749] To a stirred solution of the
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.2 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the residue
was treated with saturated sodium bicarbonate. The aqueous layer
was poured into EtOAc (20 ml) and the product was isolated in EtOAc
(2.times.20 ml). The combined organic layers were washed with
saturated sodium bicarbonate (2.times.10 ml), and brine (15 ml).
The organic layer was dried over magnesium sulfate, and the solvent
was removed in vacuuo to afford the desired product. The crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified
by chromatography (Silica gel).
[0750] To a stirred solution of the
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[0751] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-p-
henylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5
mL) at 0.degree. C., TEA (3 eq., 4.8 mmol) was added, followed by
slow addition of valeryl chloride (2 eq., 3.2 mmol), according to
General Procedure R3. The reaction mixture was stirred under
nitrogen at 0.degree. C. for 1 h and allowed to warm to rt until
completion, as indicated by TLC or HPLC. The reaction mixture was
then diluted with cold water and the product was isolated in DCM.
The solvent was removed in vacuuo, and the crude amide was used for
further transformation.
[0752] To a stirred solution of the amide described above (1.6
mmol) in acetic acid (4 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography on
silica gel (yield: 270 mg).
[0753] MS m/z 561 (M+H).sup.+:
[0754] .sup.1H NMR: .delta. 7.85 (s, 1H), 7.71 (d, 2H), 7.56 (d,
2H), 7.32 (m, 4H), 7.24 (d, 2H), 7.06 (d, 2H), 4.25 (t, 2H), 3.43
(t, 2H), 3.35 (m, 6H), 3.12 (t, 2H), 2.97 (t, 2H), 2.31 (m, 2H),
1.65 (m, 2H), 1.41 (t, 6H), 1.37 (m, 2H), 0.85 (t, 3H) ppm.
Example 405
{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]phenyl}-2-isobutyl-imidazol-1-yl)--
phenoxy]-propyl}-diethyl-amine
[0755] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
diethylaminopropoxide (2.2 mmol) in THF was added dropwise and
under a nitrogen stream, according to General Procedure L1. The
reaction mixture was stirred at 0.degree. C. until completion, as
indicated by TLC or HPLC. The reaction mixture was then treated
with cold H.sub.2O (15 mL), and extracted with EtOAc (2.times.15
mL). The combined organic layers were washed with brine and dried
over sodium sulfate. Evaporation of the solvent in vacuuo afforded
the desired 4-alkoxynitrobenzene. The crude product was used
directly for further transformation without any purification, or
after purifying using silica gel column chromatography.
[0756] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg) until completion as indicated by
TLC or HPLC, according to General Procedure H. The reaction mixture
was then filtered to remove the catalyst. The solvent was removed
in vacuuo to afford the desired 4-alkoxyaniline, which was used
directly for further transformation without further
purification.
[0757] To a stirred solution of 4'-hydroxyacetophenone (1.2 mmol)
in DMF (10 mL) at rt, solid potassium carbonate (3.0 mmol) was
added. 4-chlorophenethyl mesylate (1.0 mmol) was added to the
reaction mixture and heated to 80.degree. C. until completion
according to General Procedure Q1, as indicated by TLC or HPLC.
After cooling to rt, the reaction mixture was quenched by removing
solvent in vacuuo and treating the residue with saturated sodium
bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and
washed with H.sub.2O (2.times.10 ml) and brine (15 ml). The organic
layer was dried over magnesium sulfate, and the solvent was removed
in vacuuo to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated
acetophenone was used for further transformation without any
purification or after purifying using silica gel column
chromatography.
[0758] To a stirred solution of the
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq) was added, according to General Procedure R1. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and was
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The solvent was then removed in vacuuo and the crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[0759] To a stirred solution of the
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq, 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added, followed by a
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was isolated in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was purified by
chromatography (Silica gel). Pure product was obtained from 2-4%
MeOH/DCM.
[0760] To a stirred solution of
1-{-4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)--
phenylamino]-ethanone described above (2 mmol) in anhydrous DCM (5
mL) at 0.degree. C., TEA (3 eq, 6 mmol) was added, followed by a
slow addition of isovaleryl chloride (3 eq, 6 mmol), according to
General Procedure R3. The reaction mixture was stirred under
nitrogen at 0.degree. C. for 1 h and allowed to warm to rt until
completion, as indicated by TLC or HPLC. The solvent was removed in
vacuuo, and the crude amide was used for further
transformation.
[0761] To a stirred solution of the amide described above (2 mmol)
in acetic acid (2 mL), ammonium acetate (excess, .about.20 eq) was
added, according to General Procedure R4. The reaction mixture was
stirred at 90.degree. C. overnight. The reaction mixture was then
cooled down and neutralized with saturated sodium bicarbonate
solution. Usual extractive work up with EtOAc gave the product
imidazole, which was purified by column chromatography (Silica
gel). Pure product was obtained from 4-6% MeOH/DCM (Yield: 390
mg).
[0762] MS m/z 560 (M+H).sup.+
[0763] .sup.1H NMR: .delta. 7.86 (s, 1H), 7.65 (d, 2H), 7.59 (d,
2H), 7.31 (m, 4H), 7.23 (d, 2H), 7.13 (d, 2H), 4.51 (m, 2H), 3.42
(t, 2H), 3.31 (m, 6H), 3.05 (t, 2H), 2.87 (t, 2H), 2.31 (m, 2H),
1.95 (m, 1H), 1.49 (t, 6H), 0.86 (d, 6H) ppm.
Example 406
[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)--
propyl]-diethyl-amine
[0764] 3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM
(25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled
to 0.degree. C. To this mixture, methanesulfonyl chloride (30 mmol,
1.5 eq) was added slowly with stirring and the reaction mixture
stirred at 0.degree. C. for an hour and at rt for another hour
(until the reaction was complete by HPLC). The solvent was removed
and saturated aqueous sodium bicarbonate was added. The product was
extracted with EtOAc (3.times.) and washed with sodium bicarbonate
and water. The solvent was removed in vacuuo.
[0765] The mesylate from the previous step (20 mmol, 1 eq) was
dissolved in anhydrous DMF (25 mL), and 4-hydroxyacetophenone (20
mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added. The
mixture was heated under reflux at 85.degree. C. for 18 h (until
the reaction was complete by HPLC), after which it was cooled to
rt. Saturated aqueous sodium bicarbonate was added to the mixture,
which was then transferred to a separatory funnel. The product
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was extracted with
EtOAc and washed with sodium bicarbonate and water. The solvent was
removed in vacuuo and the product was purified by flash
chromatography (going by increasing gradient up to 10% MeOH in
DCM).
[0766] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (5 mmol) in anhydrous
MeOH (10 mL) at 0.degree. C., pyrrolidone hydrotribromide (6 mmol,
1.2 eq) was added, according to General Procedure R1. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and was
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The solvent was then removed in vacuuo and the crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[0767] To a solution of 4-chlorophenoxy aniline (1 eq, 5 mmol) in
anhydrous DMF (10 mL), DIEA (3 eq 15 mmol) was added, followed by
addition of the
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (5 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at it until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was purified by chromatography
(Silica gel). Pure product obtained from 2-4% MeOH/DCM.
[0768] To a stirred solution of
2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-
-ethanone (2 mmol) in anhydrous DCM (8 mL) at 0.degree. C., TEA (3
eq, 6 mmol) was added, followed by a slow addition of valeryl
chloride (3 eq, 6 mmol). The reaction mixture was stirred under
nitrogen at 0.degree. C. for 1 h and allowed to warm to it until
completion as indicated by TLC or HPLC, according to General
Procedure R3. The solvent was removed in vacuuo, and the crude
amide was used for further transformation.
[0769] To a stirred solution of the amide described above (2 mmol)
in acetic acid (8 mL), ammonium acetate (20 eq) was added,
according to General Procedure R4. The reaction mixture was stirred
at 90.degree. C. overnight. The reaction mixture was then cooled to
rt and neutralized with saturated sodium bicarbonate solution.
Usual extractive work up with EtOAc gave the product imidazole,
which was purified by column chromatography on silica gel elution
with 4-6% MeOH/DCM) (yield 424 mg).
[0770] MS m/z 532 (M+H).sup.+:
[0771] .sup.1H NMR (CDCl.sub.3): .delta. 7.68 (d, 2H), 7.34 (d,
2H), 7.28 (d, 2H), 7.14 (s, 1H), 7.07 (d, 2H), 7.01 (d, 2H,), 6.89
(d, 2H) 4.04 (t, 2H), 2.64-2.78 (m, 8H), 1.99 (m, 2H), 1.64 (m,
2H), 1.30 (m, 2H), 1.09 (t, 6H), 0.83 (t, 3H) ppm.
Example 407
1-[4-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imid-
azol-4-yl}-phenoxy)-butyl]piperazine
[0772] To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol)
in anhydrous DCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium
bromide perbromide (1.1 eq.) was added. The reaction mixture was
stirred under nitrogen at rt until completion, as indicated by TLC.
The mixture was diluted with EtOAc (100 ml) and washed with
H.sub.2O (2.times.50 ml), brine (30 ml) and dried with magnesium
sulfate. The solvent was then removed in vacuuo to give a white
solid. The alpha-bromoacetophenone was used for further
transformation without further purification.
[0773] To a stirred solution of
4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in
anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow
addition of the alpha-bromoacetophenone described above (2 eq),
according to General Procedure R2. The reaction mixture was stirred
under nitrogen at it until completion, as indicated by TLC and
HPLC. The reaction mixture was then diluted with cold H.sub.2O and
the product was isolated in Et.sub.2O. The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of solvent in vacuuo afforded the desired product. The crude
alkylated aniline was purified by chromatography on silica gel
(elution with 5-20% EtOAc/Hexane).
[0774] To a stirred solution of alkylated aniline described above
(1.0 mmol) in anhydrous THF (20 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by slow addition of valeryl chloride (3
eq, 3.0 mmol). The reaction mixture was stirred under nitrogen at
0.degree. C. for 1 h and allowed to warm to ambient temperature
until completion as indicated by TLC and HPLC, according to General
Procedure R3. The solvent was removed in vacuuo, and the crude
amide was used for further transformation.
[0775] To a stirred solution of the amide described above (1.0
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography on
silica gel (elution with 5-15% EtOAc/Hexane). MS: m/z 562
(M+H).sup.+)
[0776] The benzyl imidazole from above was dissolved in MeOH (20
mL), and Pd/C (100 mg) was added and the heterogeneous mixture was
stirred overnight under hydrogen atmosphere using a balloon,
according to General Procedure H. The catalyst was removed by
filtration. The solvent was removed in vacuuo, and the crude phenol
(MS: m/z 472 (M+H).sup.+) was used directly.
[0777] To a stirred solution of the phenol (0.16 mmol) obtained
above in anhydrous DMF (5 mL) solid sodium hydride (60% dispersion
in oil; 1.0 mmol) was added in portions. After the addition, a
solution of 4-bromobutyl methanesulfonate (0.2 mmol) (prepared as
described earlier) in anhydrous THF (2 mL) was added to the
reaction mixture. The reaction was then allowed to proceed at rt.
Upon completion of the reaction, piperazine (5.0 eq) was added. The
mixture was stirred overnight. Et.sub.2O (30 mL) was added to the
reaction mixture followed by H.sub.2O (10 mL). The organic layer
was washed with H.sub.2O (2.times.15 mL) and brine, and dried over
sodium sulfate. The solvent was removed in vacuuo. Product was
purified by column chromatography on silica gel (elution with 5-10%
MeOH/DCM) (yield 54.0 mg)
[0778] MS m/z 612 (M+1-1).sup.+:
Example 408
4-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazo-
l-4-yl}-phenoxy)-1-methyl-piperidine
[0779] To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol)
in anhydrous DCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium
bromide perbromide (1.1 eq.) was added, according to General
Procedure R1. The reaction mixture was stirred under nitrogen at rt
until completion, as indicated by TLC. The mixture was diluted with
EtOAc (100 ml) and washed with H.sub.2O (2.times.50 ml), brine (30
ml) and dried with magnesium sulfate. The solvent was then removed
in vacuuo to give a white solid. The alpha-bromoacetophenone was
used for further transformation without further purification.
[0780] To a stirred solution of
4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in
anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow
addition of the alpha-bromoacetophenone described above (2 eq),
according to General Procedure R2. The reaction mixture was stirred
under nitrogen at rt until completion, as indicated by TLC and
HPLC. The reaction mixture was then diluted with cold H.sub.2O and
the product was isolated in Et.sub.2O. The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of solvent in vacuuo afforded the desired product. The crude
alkylated aniline was purified by chromatography on silica gel
(elution with 5-20% EtOAc/Hexane).
[0781] To a stirred solution of alkylated aniline described above
(1.0 mmol) in anhydrous THF (20 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by slow addition of valeryl chloride (3
eq, 3.0 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion. The solvent was removed in
vacuuo, and the crude amide was used for further
transformation.
[0782] To a stirred solution of the amide described above (1.0
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography on
silica gel (elution with 5-15% EtOAc/Hexane).
[0783] MS: m/z 562 (M+H).sup.+)
[0784] The above product was dissolved in MeOH (20 mL), and Pd/C
(100 mg) was added and the heterogeneous mixture was stirred
overnight under hydrogen atmosphere using a balloon, according to
General Procedure T2. The Pd/C was removed by filtration. The
solvent was removed in vacuuo, and the crude
4-(1-{-4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-
-4-yl)phenol (MS: m/z 472 (M+H).sup.+) was used directly.
[0785] A stirred solution of the
4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol--
4-yl)phenol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with
solid sodium hydride (60% dispersion in oil; 1.0 mmol), added in
portions. The mesylate of 1-methylpiperidin-4-ol (1.5-2.0 eq) was
then added to the reaction mixture, which was heated at 90.degree.
C. overnight, according to General Procedure T3. After cooling the
mix to rt, Et.sub.2O (30 mL) was added to the reaction mixture
followed by H.sub.2O (10 mL). The organic layer was washed with
H.sub.2O (2.times.15 mL) and brine, and dried over sodium sulfate.
The solvent was removed in vacuuo. Pure imidazole was obtained from
chromatography in 5-10% MeOH/DCM (yield 14 mg).
[0786] MS m/z value (M+H).sup.+: 569
[0787] .sup.1H NMR (CDCl.sub.3): .delta.7.70 (d, 2H), 7.20-7.35 (m,
5H), 7.14 (s, 1H), 7.08 (d, 2H), 6.92 (d, 2H), 4.4 (bs, 1H), 1.0
3.05 (m, 17H) ppm.
Example 409
1-[5-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imid-
azol-4-yl}-phenoxy)-pentyl]piperazine
[0788] To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol)
in anhydrous DCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium
bromide perbromide (1.1 eq.) was added. The reaction mixture was
stirred under nitrogen at rt until completion, as indicated by TLC.
The mixture was diluted with EtOAc (100 ml) and washed with
H.sub.2O (2.times.50 ml), brine (30 ml) and dried with magnesium
sulfate. The solvent was then removed in vacuuo to give a white
solid. The alpha-bromoacetophenone was used for further
transformation without further purification.
[0789] To a stirred solution of
4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in
anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow
addition of the alpha-bromoacetophenone described above (2 eq),
according to General Procedure R2. The reaction mixture was stirred
under nitrogen at rt until completion, as indicated by TLC and
HPLC. The reaction mixture was then diluted with cold H.sub.2O and
the product was isolated in Et.sub.2O. The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of solvent in vacuuo afforded the desired product. The crude
alkylated aniline was purified by chromatography (Silica gel). Pure
product was obtained from 5-20% EtOAc/Hexane.
[0790] To a stirred solution of alkylated aniline described above
(1.0 mmol) in anhydrous THF (20 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by slow addition of valeryl chloride (3
eq, 3.0 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to ambient temperature until completion, as
indicated by TLC and HPLC. The solvent was removed in vacuuo, and
the crude amide was used for further transformation.
[0791] To a stirred solution of the amide described above (1.0
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 5-15%
EtOAc/Hexane.
[0792] MS: m/z 562 (M+H).sup.+)
[0793] The above product was dissolved in MeOH (20 mL), and Pd/C
(100 mg) was added and the heterogeneous mixture was stirred
overnight under hydrogen atmosphere using a balloon, according to
General Procedure H. The Pd/C was removed by filtration. The
solvent was removed in vacuuo, and the crude phenol (MS: m/z 472
(M+H).sup.+) was used for further transformation.
[0794] To a stirred solution of the imidazole (0.16 mmol) obtained
above in anhydrous DMF (5 mL) solid sodium hydride (60% dispersion
in oil; 1.0 mmol) was added in portions. After the addition, a
solution of 5-bromopentyl methanesulfonate (0.2 mmol) anhydrous THF
(2 mL) was added to the reaction mixture. The reaction was then
allowed to proceed at rt. Upon completion of the reaction,
piperazine (100 mg) added. The mixture was stirred overnight.
Et.sub.2O (30 mL) was added to the reaction mixture followed by
H.sub.2O (10 mL). The organic layer was washed with H.sub.2O
(2.times.15 mL) and brine, and dried over sodium sulfate. The
solvent was removed in vacuuo. Pure product was obtained after
chromatography on silica gel (elution with 5-10% MeOH/DCM) (yield
36.0 mg).
[0795] MS m/z 626 (M+H).sup.+:
Example 410
{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-p-
ropyl}-diethyl-amine
[0796] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
diethylaminopropoxide (2.2 mmol) in THF was added dropwise and
under a nitrogen stream, according to General Procedure L1. The
reaction mixture was stirred at 0.degree. C. until completion, as
indicated by TLC or HPLC. The reaction mixture was then treated
with cold H.sub.2O (15 mL), and extracted with EtOAc (2.times.15
mL). The combined organic layers were washed with brine and dried
over sodium sulfate. Evaporation of the solvent in vacuuo afforded
the desired 4-alkoxynitrobenzene. The crude product was used
directly for further transformation without any purification, or
after purifying using silica gel column chromatography.
[0797] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg) until completion as indicated by
TLC or HPLC, according to General Procedure H. The reaction mixture
was then filtered to remove the catalyst. The solvent was removed
in vacuuo to afford the desired
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine, which was used
directly for further transformation without further
purification.
[0798] To a stirred solution of 4'-hydroxyacetophenone (1.2 mmol)
in DMF (10 mL) at rt, solid potassium carbonate (3.0 mmol) was
added. 4-chlorophenethyl mesylate (1.0 mmol) was added to the
reaction mixture and heated to 80.degree. C. until completion
according to General Procedure Q1, as indicated by TLC or HPLC.
After cooling to rt, the reaction mixture was quenched by removing
solvent in vacuuo and treating the residue with saturated sodium
bicarbonate. The aqueous layer was poured into EtOAc (20 ml) and
washed with H.sub.2O (2.times.10 ml) and brine (15 ml). The organic
layer was dried over magnesium sulfate, and the solvent was removed
in vacuuo to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated
acetophenone was used for further transformation.
[0799] To a stirred solution of the
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidinone
hydrotribromide (1.2 eq) was added, according to General Procedure
R1. The reaction mixture was stirred under nitrogen at 0.degree. C.
for 1 h and was allowed to warm to rt until completion, as
indicated by TLC or HPLC. The solvent was then removed in vacuuo
and the crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone
was used for further transformation.
[0800] To a stirred solution of the
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq, 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added, followed by a
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was isolated in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was purified by
chromatography (Silica gel). Pure product was obtained from 2-4%
MeOH/DCM.
[0801] The
1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino--
propoxy)-phenylamino]-ethanone obtained as above (1 mmol) was
dissolved in formic acid (2 mL) and treated with ammonium formate
(20 mmol). The resulting mixture was heated to 90.degree. C.
overnight. The reaction mixture was then cooled to rt and
neutralized with saturated sodium bicarbonate solution. Usual
extractive work up with EtOAc gave the product imidazole, which was
purified by column chromatography on silica gel (elution with 4-6%
MeOH/DCM) (yield 161 mg).
[0802] MS m/z 504 (M+H).sup.+:
[0803] .sup.1H NMR (CDCl.sub.3): .delta. 7.77 (s, 1H), 7.73 (d,
2H), 7.38 (s, 1H), 7.10-7.35 (m, 6H), 6.97 (d, 2H), 6.92 (d, 2H),
4.17 (t, 2H), 4.06 (broad t, 2H), 3.07 (t, 2H), 2.81 (broad q, 4H)
1.95-2.15 (broad m, 4H), 1.17 (t, 6H) ppm.
Example 411
{3-[3-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-p-
ropyl}-diethyl-amine
[0804] To a stirred solution of 3-nitrophenol (2 mmol) in DMF (6
mL) at rt, solid potassium carbonate (4 mmol) was added. A solution
of the mesylate of N,N-diethylaminopropanol (2.2 mmol) in DMF (2
mL) was then added to the reaction mixture and heated to 80.degree.
C. until completion, according to General Procedure Q1, as
indicated by TLC or HPLC. After cooling to rt, the reaction mixture
was then treated with cold H.sub.2O (15 mL), and extracted with
EtOAc (2.times.15 mL). The combined organic layers were washed with
brine and dried over sodium sulfate. Evaporation of the solvent in
vacuuo afforded the desired
N,N-diethyl-N-[3-(3-nitrophenoxy)propyl]amine. The crude product
was used directly for further transformation.
[0805] The N,N-diethyl-N-[3-(3-nitrophenoxy)propyl]amine (1 mmol)
was dissolved in MeOH (5 mL) and hydrogenated in the presence of
10% Pd/C (50 mg) until completion as indicated by TLC or HPLC,
according to General Procedure H. The reaction mixture was then
filtered to remove the catalyst. The solvent was removed in vacuuo
to afford the desired
N-[3-(3-aminophenoxy)propyl]-N,N-diethylamine, which was used
directly for further transformation without further
purification.
[0806] To a stirred solution of
N-[3-(3-aminophenoxy)propyl]-N,N-diethylamine (1 mmol) in anhydrous
DMF (3 mL), DIEA (3 mmol) was added followed by a slow addition of
1-bromo-4'-(4-chlorophenethoxy)acetophenone (0.8 mmol), according
to General Procedure R2. The reaction mixture was stirred under
nitrogen at rt until completion, as indicated by TLC or HPLC. The
reaction mixture was then diluted with cold H.sub.2O and the
product was isolated in EtOAc. The combined organic layers were
washed with brine and dried over sodium sulfate. Evaporation of
solvent in vacuuo afforded the desired product. The crude alkylated
aniline was purified by chromatography on silica gel (elution with
2-4% MeOH/DCM).
[0807] The
1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino--
propoxy)-phenylamino]-ethanone obtained as above (0.5 mmol) was
dissolved in formic acid (1 mL) and treated with ammonium formate
(10 mmol). The resulting mixture was heated to 90.degree. C.
overnight. The reaction mixture was then cooled down and
neutralized with saturated sodium bicarbonate solution. Usual
extractive work up with EtOAc gave the product imidazole, which was
purified by column chromatography on silica gel (elution with 4-6%
MeOH/DCM).
[0808] MS m/z value (M+H).sup.+: 504
[0809] .sup.1H NMR (CDCl.sub.3): .delta.7.89 (s, 1H), 7.74 (d, 2H),
7.47 (s, 1H), 7.30-7.10 (m, 7H), 6.92 (d, 2H) 6.85 (t, 1H)
4.10-4.20 (m, 4H), 3.00-3.20 (m, 6H), 2.31 (broad, 2H), 1.36 (t,
6H) ppm.
Example 412
[3-(4-{1-[4-(4-tert-butyl-phenoxy)-phenyl]-1H-imidazol-4-yl)-phenoxy)-prop-
yl]-diethyl-amine
[0810] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of potassium
4-tert-butyl-phenoxide (2.2 mmol) in THF (may be generated by
adding the corresponding alcohol to a 1M solution of KOBu.sup.t in
THF) was added dropwise and under a nitrogen stream, according to
General Procedure L1. The reaction mixture was stirred at 0.degree.
C. until completion, as indicated by TLC or HPLC. The solvent was
then removed in vacuo and the reaction mixture was treated with
cold H.sub.2O (15 mL), and extracted with EtOAc (2.times.15 mL).
The combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of the solvent in vacuuo afforded the
desired 4-alkoxynitrobenzene. The crude product was used directly
for further transformation.
[0811] The nitro intermediate (2 mmol) obtained above was dissolved
in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10
mg) until completion, as indicated by TLC or HPLC, according to
General Procedure H. The reaction mixture was then filtered. The
solvent was removed in vacuuo to afford the desired
4-alkoxyaniline, which was used directly for further transformation
without further purification.
[0812] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (10 mL) at rt, solid K.sub.2CO.sub.3 (8.0 mmol) was added.
The mesylate of N,N-diethylaminopropanol (prepared from the
corresponding alcohol and methanesulfonyl chloride, 2.0 mmol) was
added to the reaction mixture and heated to 80.degree. C. until
completion according to General Procedure Q1, as indicated by TLC
or HPLC. After cooling to rt, the reaction mixture was diluted with
H.sub.2O and the product was isolated in EtOAc. The combined
organic layers were washed with saturated sodium bicarbonate
(2.times.15 ml), water (2.times.15 ml) and brine (15 ml). The
organic layer was dried over magnesium sulfate, and the solvent was
removed in vacuuo to afford the desired product. The crude
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified using
silica gel column chromatography (elution with 2-3% MeOH/DCM).
[0813] To a stirred solution of the
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (1 mmol) described
above 48% HBr (3 eq, 3 mmol) in DMSO (4 mL) was added. The reaction
mixture was heated to 80.degree. C. until completion, as indicated
by TLC or HPLC. After cooling to rt, the reaction mixture was
neutralized with 2N sodium hydroxide solution and the product was
isolated in EtOAc. The combined organic layers were washed with
H.sub.2O (2.times.15 ml) and brine (15 ml). The organic layer was
dried over magnesium sulfate, and the solvent was removed in vacuuo
to afford the desired product. The crude ketoaldehyde was used for
further transformation.
[0814] To a stirred solution of the ketoaldehyde (1 mmol) in AcOH
(5 mL) 4-tert-butyl-phenoxy aniline (1.2 eq., 1.2 mmol),
formaldehyde (excess, .about.30 eq.) and ammonium acetate (excess,
.about.30 eq.) were added, according to General Procedure R4. The
reaction mixture was heated to 80.degree. C. until completion, as
indicated by TLC or HPLC. After cooling to rt, the reaction mixture
was neutralized with saturated sodium bicarbonate solution and the
product was isolated in EtOAc. Usual extractive work up gave the
desired product, which was purified by column chromatography on
silica gel (elution with 3-4% MeOH/DCM) (Yield 150 mg).
[0815] MS: m/z 498 (M+H).sup.+
[0816] .sup.1H NMR (CDCl.sub.3): .delta.7.64 (s, 1H), 7.39 (d, 2H),
7.12 (s, 1H), 7.06 (d, 2H) 7.02 (d, 2H) 6.97 (m, 2H) 6.79 (d, 2H),
3.98 (t, 2H), 2.66 (m, 6H), 2.02 (m, 2H), 1.31 (s, 9H), 1.08 (t,
6H) ppm.
Example 413
[3-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidaz-
ol-4-yl}-phenoxy)-propyl]-diethyl-amine
[0817] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
4-fluoro-3-trifluoromethyl-phenoxide (2.2 mmol) in THF (may be
generated by adding the corresponding alcohol to a 1M solution of
potassium t-butoxide in THF) was added dropwise and under a
nitrogen stream, according to General Procedure L1. The reaction
mixture was stirred at 0.degree. C. until completion, as indicated
by TLC or HPLC. The solvent was then removed in vacuuo and the
reaction mixture was treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of the solvent in vacuuo afforded the desired
1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude
product could be used directly for further transformation.
[0818] The 1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene
(2 mmol) obtained above was dissolved in MeOH (10 mL) and
hydrogenated in the presence of 10% Pd/C (10 mg) until completion,
as indicated by TLC or HPLC, according to General Procedure H. The
reaction mixture was then filtered. The solvent was removed in
vacuuo to afford the desired 4-alkoxyaniline, which was used
directly for further transformation without further
purification.
[0819] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (10 mL) at rt, solid potassium carbonate (8.0 mmol) was
added. The mesylate of N,N-diethylaminopropanol (prepared from the
corresponding alcohol and methanesulfonyl chloride) (2.0 mmol) was
added to the reaction mixture and heated to 80.degree. C. until
completion according to General Procedure Q1, as indicated by TLC
or HPLC. After cooling to rt, the reaction mixture was diluted with
water and the product was isolated in EtOAc. The combined organic
layers were washed with saturated sodium bicarbonate (2.times.15
ml), water (2.times.15 ml) and brine (15 ml). The organic layer was
dried over magnesium sulfate, and the solvent was removed in vacuuo
to afford the desired product. The crude
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified using
silica gel column chromatography. Pure product was obtained after
elution with 2-3% MeOH/DCM. (yield 50-60%)
[0820] To a stirred solution of the
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1
mmol) in anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone
hydrotribromide (1.2 eq, 1.2 mmol) was added, according to General
Procedure R1. The reaction mixture was stirred under nitrogen at
0.degree. C. for 1 h and was allowed to warm to rt until
completion, as indicated by TLC or HPLC. The solvent was then
removed in vacuuo and the residue was treated with saturated sodium
bicarbonate and the product was isolated in EtOAc. The combined
organic layers were washed with water (2.times.15 ml) and brine (15
ml). The organic layer was dried over magnesium sulfate, and the
solvent was removed in vacuuo to afford the desired product. The
crude 2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was
used for further transformation.
[0821] To a stirred solution of the
4-fluoro-3-trifluoromethyl-phenoxy aniline (1.2 eq., 1.2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 3 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.0 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[0822] To a stirred solution of alkylated aniline described above
(1.0 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (3 eq., 3
mmol) was added, followed by slow addition of valeryl chloride (2
eq., 2.0 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The reaction mixture was then diluted with water and the
product was isolated in DCM. The solvent was removed in vacuuo, and
the crude amide was used for further transformation.
[0823] To a stirred solution of the amide described above (1 mmol)
in acetic acid (2 mL), ammonium acetate (excess, .about.20 eq.) was
added, according to General Procedure R4. The reaction mixture was
stirred at 90.degree. C. overnight. The reaction mixture was then
cooled to rt and neutralized with saturated sodium bicarbonate
solution. Usual extractive work up with EtOAc gave the product
imidazole, which was purified by column chromatography (Silica
gel). Pure product was obtained after elution with 4-6% MeOH/DCM
(Yield 175 mg).
[0824] MS m/z 584 (M+H).sup.+
Example 414
[0825]
diethyl-[3-(4-{1-[4-(4-trifluoromethoxy-phenoxy)-phenyl]-1H-imidazo-
l-4-yl}-phenoxy)-propyl]amine
[0826] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of potassium
4-trifluoromethoxy-phenoxide (2.2 mmol) in THF (may be generated by
adding the corresponding alcohol to a 1M solution of KOBu.sup.t in
THF) was added dropwise under a nitrogen stream, according to
General Procedure L1. The reaction mixture was stirred at 0.degree.
C. until completion, as indicated by TLC or HPLC. The solvent was
then removed in vacuo and the reaction mixture was treated with
cold H.sub.2O (15 mL), and extracted with EtOAc (2.times.15 mL).
The combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of the solvent in vacuo afforded the
desired 4-alkoxynitrobenzene. The crude product was used directly
for further transformation.
[0827] The nitro intermediate (2 mmol) obtained above was dissolved
in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10
mg) until completion, as indicated by TLC or HPLC, according to
General Procedure H. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
the desired 4-alkoxyaniline, which was used directly for further
transformation without further purification.
[0828] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (10 mL) at rt, solid K.sub.2CO.sub.3 (8.0 mmol) was added.
The mesylate of N,N-diethylaminopropanol (prepared from the
corresponding alcohol and methanesulfonyl chloride, 2.0 mmol) was
added to the reaction mixture and heated to 80.degree. C. until
completion according to General Procedure Q1, as indicated by TLC
or HPLC. After cooling to rt, the reaction mixture was diluted with
H.sub.2O and the product was isolated in EtOAc. The combined
organic layers were washed with saturated sodium bicarbonate
(2.times.15 ml), H.sub.2O (2.times.15 ml) and brine (15 ml). The
organic layer was dried over magnesium sulfate, and the solvent was
removed in vacuuo to afford the desired product. The crude
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified using
silica gel column chromatography. Pure product was obtained with
2-3% MeOH/DCM.
[0829] To a stirred solution of the
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (1 mmol) described
above 48% HBr (3 eq, 3 mmol) in DMSO (4 mL) was added. The reaction
mixture was heated to 80.degree. C. until completion, as indicated
by TLC or HPLC. After cooling to rt, the reaction mixture was
neutralized with saturated sodium bicarbonate solution and the
product was isolated in EtOAc. The combined organic layers were
washed with water (2.times.15 ml) and brine (15 ml). The organic
layer was dried over magnesium sulfate, and the solvent was removed
in vacuuo to afford the desired product. The crude ketoaldehyde was
used for further transformation.
[0830] To a stirred solution of the ketoaldehyde (1 mmol) in AcOH
(5 mL), 4-trifluoromethoxy-phenoxy-aniline (1.2 eq., 1.2 mmol),
formaldehyde (excess, .about.30 eq.) and ammonium acetate (excess,
.about.30 eq.) were added, according to General Procedure R4. The
reaction mixture was heated to 80.degree. C. until completion, as
indicated by TLC or HPLC. After cooling to rt, the reaction mixture
was neutralized with saturated sodium bicarbonate solution and the
product was isolated in EtOAc. Usual extractive work up with EtOAc
gave the desired product, which was purified by column
chromatography on silica gel, elution with 3-4% MeOH/DCM) (Yield
130 mg).
[0831] MS: m/z 526 (M+H).sup.+
[0832] .sup.1H NMR (CDCl.sub.3): .delta.7.91 (s, 1H), 7.41 (d, 2H),
7.28 (d, 2H), 7.05 (d, 2H), 6.98 (m, 4H) 6.81 (d, 2H) 3.99 (t, 2H),
2.96 (m, 6H), 2.18 (m, 2H), 1.22 (t, 6H) ppm.
Example 415
[3-(4-{2-butyl-1-[4-(3,4-dichloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-pheno-
xy)-propyl]-diethyl-amine
[0833] 3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM
(25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled
to 0.degree. C. To this mixture, methanesulfonyl chloride (30 mmol,
1.5 eq) was added slowly with stirring and the reaction mixture was
stirred at 0.degree. C. for an hour and at it for another hour
(until the reaction was complete by HPLC). The solvent was removed
and saturated aqueous sodium bicarbonate was added. The product was
extracted with EtOAc (3.times.) and washed with sodium bicarbonate
and water. The solvent was removed in vacuuo.
[0834] The product from the previous step (20 mmol, 1 eq) was
dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone
(20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added.
The mixture was heated under reflux at 85.degree. C. for 18 h
(until the reaction was complete by HPLC), after which it was
cooled to rt. Saturated aqueous sodium bicarbonate was added to the
mixture, which was then transferred to a separatory funnel. The
product was extracted with EtOAc and washed with sodium bicarbonate
and water. The solvent was removed in vacuuo and the
1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by
flash chromatography (going by increasing gradient up to 10% MeOH
in DCM).
[0835] 3,4-Dichlorophenol (10 mmol) was dissolved in 15 ml of
anhydrous DMF and potassium carbonate (30 mmol) was added with
stirring at rt. 4-Fluoronitrobenzene (10 mmol) was added to this
mixture, which was then heated under reflux at 80.degree. C. for 18
h. The reaction was quenched with 30 ml of water and 30 ml of
sodium bicarbonate, extracted with EtOAc (3.times.50 ml) and washed
with sodium bicarbonate and water. The EtOAc layer was dried over
anhydrous sodium sulfate and filtered, after which the solvent was
removed in vacuuo.
[0836] The nitro intermediate (10 mmol) obtained above was
dissolved in EtOH (30 mL) and hydrogenated in the presence of 10%
Pd/C (10 mg) until completion as indicated by TLC or HPLC,
according to General Procedure H. The reaction mixture was then
filtered to remove the catalyst. The solvent was removed in vacuuo
to afford the desired 4-(3,4-dichlorophenoxy)aniline, which was
used directly for further transformation without further
purification.
[0837] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2 mmol) in anhydrous
MeOH (6 mL) at 0.degree. C., pyrrolidone hydrotribromide (2.4 mmol,
1.2 eq) was added, according to General Procedure R1. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and was
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The solvent was then removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[0838] To a solution of 4-(3,4-dichlorophenoxy) aniline (1 eq, 2
mmol) in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added,
followed by addition of the
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (2 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was purified by chromatography
(Silica gel). Pure product obtained from 2-4% MeOH/DCM.
[0839] To a stirred solution of alkylated aniline described above
(1 mmol) in anhydrous DCM (4 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by a slow addition of valeryl chloride (3
eq, 3 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[0840] To a stirred solution of the amide described above (1 mmol)
in acetic acid (4 mL), ammonium acetate (excess, .about.20 eq) was
added according to General Procedure R4. The reaction mixture was
stirred at 90.degree. C. overnight. The reaction mixture was then
cooled to rt and neutralized with saturated sodium bicarbonate
solution. Usual extractive work up with EtOAc gave the product
imidazole, which was purified by column chromatography on silica
gel (elution with 4-6% MeOH/DCM) (yield 170 mg).
[0841] MS m/z 567 (M+H).sup.+:
[0842] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.7 (d, 2H), 7.3
(m, 3H), 6.9-7.1 (m, 7H), 4.0 (t, 2H), 2.7 (m, 8H), 2.0 (m, 2H),
1.6 (m, 2H), 1.3 (m, 2H), 1.1 (t, 6H), 0.8 (t, 3H) ppm.
Example 416
[3-(4-{2-cyclobutyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-i-
midazol-4-yl}-phenoxy)-propyl]-diethyl-amine
[0843] To a stirred solution of 4-fluoronitrobenzene (20 mmol),
4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt,
solid potassium carbonate (60 mmol) was added and the reaction
mixture was heated to 90.degree. C. for 5 h (monitored by TLC),
according to General Procedure L1. After cooling to rt, the
reaction mixture was poured into cold H.sub.2O (60 mL). The
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with H.sub.2O (2.times.40 mL)
and brine (50 mL), and dried over anhydrous sodium sulfate. The
solvent was removed in vacuuo to afford the desired
1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude
product was used directly for further transformation without
further purification.
[0844] The nitro intermediate (2 mmol) obtained above was dissolved
in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50
mg) until completion as indicated by TLC or LC-MS, according to
General Procedure H. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline, which was used
directly for further transformation without purification (overall
yield: 95%).
[0845] To a stirred solution of ice-cold 3-diethylaminopropanol (63
mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL),
methanesulfonyl chloride (60 mmol) was added dropwise and the
reaction mixture was stirred for 2 h at 0.degree. C., followed by
additional 1 h at rt. After the removal of the solvents in vacuuo,
the crude mesylate was dissolved in DMF (100 mL).
4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)
were added, and the mixture was heated with stirring at 90.degree.
C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction
was quenched with cold H.sub.2O (100 mL), and the resulting mixture
was extracted with EtOAc (4.times.100 mL). The combined EtOAc
extracts were washed with brine (3.times.60 ml), and dried over
anhydrous sodium sulfate. The solvent was removed in vacuuo, and
the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was
purified by silica gel column chromatography eluting with 10% MeOH
in EtOAc+0.2% TEA (yield: 75%).
[0846] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10
mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added,
according to General Procedure R1. The reaction mixture was stirred
at rt for 1 h (monitored by LC-MS). The solvent was then removed in
vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly
used for further transformation.
[0847] To a stirred solution of
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline (4.8 mmol)
dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added
followed by a slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained
above (.about.4 mmol), according to General Procedure R2. The
reaction mixture was stirred at rt and under nitrogen until
completion (.about.5 h), as indicated by LC-MS. The reaction was
quenched with saturated sodium bicarbonate (50 mL), and the
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with brine (3.times.40 mL), and
dried over anhydrous sodium sulfate. The solvent was removed in
vacuuo, and the crude product was purified by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield:
64%).
[0848] To a stirred solution of the alkylated aniline described
above (0.2 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (1.2
mmol, 6 eq) was added followed by a slow addition of
cyclobutanecarbonyl chloride (0.6 mmol, 3 eq), according to General
Procedure R3. The reaction mixture was stirred under nitrogen at
0.degree. C. for 1 h and allowed to warm to rt until completion, as
indicated by LC-MS. The solvent was removed in vacuuo, and the
crude amide was used directly for further transformation.
[0849] To a stirred solution of the amide described above
(.about.0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess,
.about.30 eq) was added according to General Procedure R4. The
reaction mixture was stirred at 100.degree. C. for 2-5 h (as
monitored by LC-MS). The reaction mixture was then cooled to rt and
neutralized with saturated sodium bicarbonate. The resulting
mixture was extracted with EtOAc (3.times.50 mL). The combined
EtOAc extracts were washed with brine (3.times.20 mL), and dried
over anhydrous sodium sulfate. The solvent was removed in vacuuo,
and the pure product was obtained by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield 64
mg).
[0850] MS m/z 582 (M+H).sup.+:
[0851] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.1.05 (t, 6H),
1.90-2.20 (m, 6H), 2.56 (m, 2H), 2.58 (q, 4H), 2.66 (t, 2H), 3.44
(m, 1H), 4.02 (t, 2H), 6.91 (d, 2H), 7.05 (d, 2H), 7.14 (s, 1H),
7.22-7.26 (m, 3H), 7.31 (d, 2H), 7.72 (d, 2H) ppm.
Example 417
[3-(4-{2-cyclopentyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H--
imidazol-4-yl}-phenoxy)-propyl]diethyl-amine
[0852] To a stirred solution of 4-fluoronitrobenzene (20 mmol),
4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt,
solid potassium carbonate (60 mmol) was added, and the reaction
mixture was heated to 90.degree. C. for 5 h (monitored by TLC),
according to General Procedure L1. After cooling to rt, the
reaction mixture was poured into cold H.sub.2O (60 mL). The
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with H.sub.2O (2.times.40 mL)
and brine (50 mL), and dried over anhydrous sodium sulfate. The
solvent was removed in vacuuo to afford the desired
1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude
product was used directly for further transformation without
further purification.
[0853] The nitro intermediate (2 mmol) obtained above was dissolved
in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50
mg) until completion as indicated by TLC or LC-MS, according to
General Procedure H. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline, which was used
directly for further transformation without purification (overall
yield: 95%).
[0854] To a stirred solution of ice-cold 3-diethylaminopropanol (63
mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL) was
added dropwise methanesulfonyl chloride (60 mmol), and the reaction
mixture was stirred for 2 h at 0.degree. C. and followed by
additional 1 h at rt. After the removal of the solvents in vacuuo,
the crude mesylate was dissolved in DMF (100 mL).
4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)
were added, and the mixture was heated with stirring at 90.degree.
C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction
was quenched with cold H.sub.2O (100 mL), and the resulting mixture
was extracted with EtOAc (4.times.100 mL). The combined EtOAc
extracts were washed with brine (3.times.60 ml), and dried over
anhydrous sodium sulfate. The solvent was removed in vacuuo, and
the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was
purified by silica gel column chromatography eluting with 10% MeOH
in EtOAc+0.2% TEA (yield: 75%).
[0855] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10
mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added,
according to General Procedure R1. The reaction mixture was stirred
at rt for 1 h (monitored by LC-MS). The solvent was then removed in
vacuuo and the crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was directly
used for further transformation.
[0856] To a stirred solution of
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline (4.8 mmol)
dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added,
followed by a slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained
above (.about.4 mmol), according to General Procedure R2. The
reaction mixture was stirred at rt and under nitrogen until
completion (.about.5 h), as indicated by LC-MS. The reaction was
quenched with saturated sodium bicarbonate (50 mL), and the
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with brine (3.times.40 mL), and
dried over anhydrous sodium sulfate. The solvent was removed in
vacuuo, and the crude product was purified by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield:
64%).
[0857] To a stirred solution of the alkylated aniline described
above (0.2 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (1.2
mmol, 6 eq) was added, followed by a slow addition of
cyclopentanecarbonyl chloride (0.6 mmol, 3 eq), according to
General Procedure R3. The reaction mixture was stirred under
nitrogen at 0.degree. C. for 1 h and allowed to warm to rt until
completion, as indicated by LC-MS. The solvent was removed in
vacuuo, and the crude amide was used directly for further
transformation.
[0858] To a stirred solution of the amide described above
(.about.0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess,
.about.30 eq) was added, according to General Procedure R4. The
reaction mixture was stirred at 100.degree. C. for 2-5 h (as
monitored by LC-MS). The reaction mixture was then cooled down and
neutralized with saturated sodium bicarbonate. The resulting
mixture was extracted with EtOAc (3.times.50 mL). The combined
EtOAc extracts were washed with brine (3.times.20 mL), and dried
over anhydrous sodium sulfate. The solvent was removed in vacuuo,
and the pure product was obtained by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (overall
yield: 60-70%) (yield 77 mg).
[0859] MS m/z 596 (M+H).sup.+:
[0860] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.03-2.00 (m,
11H), 1.07 (t, 6H), 2.59 (q, 4H), 2.65 (t, 2H), 4.03 (t, 2H), 6.91
(d, 2H), 7.08 (d, 2H), 7.14 (s, 1H), 7.24-7.27 (m, 3H), 7.33 (d,
2H), 7.71 (d, 2H) ppm.
Example 418
[3-(4-{2-cyclohexyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-i-
midazol-4-yl}-phenoxy)-propyl]-diethyl-amine
[0861] To a stirred solution of 4-fluoronitrobenzene (20 mmol),
4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt,
solid potassium carbonate (60 mmol) was added, and the reaction
mixture was heated to 90.degree. C. for 5 h (monitored by TLC),
according to General Procedure L1. After cooling to rt, the
reaction mixture was poured into cold H.sub.2O (60 mL). The
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with H.sub.2O (2.times.40 mL)
and brine (50 mL), and dried over anhydrous sodium sulfate. The
solvent was removed in vacuuo to afford the desired
1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude
product was used directly for further transformation without
further purification.
[0862] The nitro intermediate (2 mmol) obtained above was dissolved
in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50
mg) until completion as indicated by TLC or LC-MS, according to
General Procedure H. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline, which was used
directly for further transformation without purification.
[0863] To a stirred solution of ice-cold 3-diethylaminopropanol (63
mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL) was
added dropwise methanesulfonyl chloride (60 mmol), and the reaction
mixture was stirred for 2 h at 0.degree. C. and followed by
additional 1 h at rt. After the removal of the solvents in vacuuo,
the crude mesylate was dissolved in DMF (100 mL).
4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)
were added, and the mixture was heated with stirring at 90.degree.
C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction
was quenched with cold H.sub.2O (100 mL), and the resulting mixture
was extracted with EtOAc (4.times.100 mL). The combined EtOAc
extracts were washed with brine (3.times.60 ml), and dried over
anhydrous sodium sulfate. The solvent was removed in vacuuo, and
the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was
purified by silica gel column chromatography eluting with 10% MeOH
in EtOAc+0.2% TEA.
[0864] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10
mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added,
according to General Procedure R1. The reaction mixture was stirred
at rt for 1 h (monitored by LC-MS). The solvent was then removed in
vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly
used for further transformation.
[0865] To a stirred solution of
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline (4.8 mmol)
dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added,
followed by a slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained
above (.about.4 mmol), according to General Procedure R2. The
reaction mixture was stirred at rt and under nitrogen until
completion (.about.5 h), as indicated by LC-MS. The reaction was
quenched with saturated sodium bicarbonate (50 mL), and the
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with brine (3.times.40 mL), and
dried over anhydrous sodium sulfate. The solvent was removed in
vacuuo, and the crude product was purified by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA.
[0866] To a stirred solution of the alkylated aniline described
above (0.2 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (1.2
mmol, 6 eq) was added, followed by a slow addition of
cyclohexanecarbonyl chloride (0.6 mmol, 3 eq), according to General
Procedure R3. The reaction mixture was stirred under nitrogen at
0.degree. C. for 1 h and allowed to warm to rt until completion, as
indicated by LC-MS. The solvent was removed in vacuuo, and the
crude amide was used directly for further transformation.
[0867] To a stirred solution of the amide described above
(.about.0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess,
.about.30 eq) was added, according to General Procedure R4. The
reaction mixture was stirred at 100.degree. C. for 2-5 h (as
monitored by LC-MS). The reaction mixture was then cooled down and
neutralized with saturated sodium bicarbonate. The resulting
mixture was extracted with EtOAc (3.times.50 mL). The combined
EtOAc extracts were washed with brine (3.times.20 mL), and dried
over anhydrous sodium sulfate. The solvent was removed in vacuuo,
and the pure product was obtained by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield 74
mg).
[0868] MS m/z 610 (M+H).sup.+:
[0869] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.1.02-2.00 (m,
13H), 1.06 (t, 6H), 2.60 (q, 4H), 2.67 (t, 2H), 4.02 (t, 2H), 6.90
(d, 2H), 7.07 (d, 2H), 7.09 (s, 1H), 7.22-7.26 (m, 3H), 7.30 (d,
2H,), 7.69 (d, 2H) ppm.
Example 419
diethyl-[3-(4-{1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-2-isobuty-
l-1H-imidazol-4-yl}-phenoxy)-propyl]-amine
[0870] To a stirred solution of 4-fluoronitrobenzene (20 mmol),
4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt,
solid potassium carbonate (60 mmol) was added, and the reaction
mixture was heated to 90.degree. C. for 5 h (monitored by TLC),
according to General Procedure L1. After cooling to rt, the
reaction mixture was poured into cold H.sub.2O (60 mL). The
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with H.sub.2O (2.times.40 mL)
and brine (50 mL), and dried over anhydrous sodium sulfate. The
solvent was removed in vacuuo to afford the desired
1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude
product was used directly for further transformation without
further purification.
[0871] The nitro intermediate (2 mmol) obtained above was dissolved
in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50
mg) until completion as indicated by TLC or LC-MS, according to
General Procedure H. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline, which was used
directly for further transformation without purification (overall
yield: 95%).
[0872] To a stirred solution of ice-cold 3-diethylaminopropanol (63
mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL) was
added dropwise methanesulfonyl chloride (60 mmol), and the reaction
mixture was stirred for 2 h at 0.degree. C. and followed by
additional 1 h at rt. After the removal of the solvents in vacuuo,
the crude mesylate was dissolved in DMF (100 mL).
4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)
were added, and the mixture was heated with stirring at 90.degree.
C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction
was quenched with cold H.sub.2O (100 mL), and the resulting mixture
was extracted with EtOAc (4.times.100 mL). The combined EtOAc
extracts were washed with brine (3.times.60 ml), and dried over
anhydrous sodium sulfate. The solvent was removed in vacuuo, and
the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was
purified by silica gel column chromatography eluting with 10% MeOH
in EtOAc+0.2% TEA.
[0873] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10
mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added,
according to General Procedure R1. The reaction mixture was stirred
at rt for 1 h (monitored by LC-MS). The solvent was then removed in
vacuuo and the crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was directly
used for further transformation.
[0874] To a stirred solution of
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline (4.8 mmol)
dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added,
followed by a slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained
above (.about.4 mmol), according to General Procedure R2. The
reaction mixture was stirred at rt and under nitrogen until
completion (.about.5 h), as indicated by LC-MS. The reaction was
quenched with saturated sodium bicarbonate (50 mL), and the
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with brine (3.times.40 mL), and
dried over anhydrous sodium sulfate. The solvent was removed in
vacuuo, and the crude product was purified by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA.
[0875] To a stirred solution of the alkylated aniline described
above (0.2 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (1.2
mmol, 6 eq) was added, followed by a slow addition of isovaleryl
chloride (0.6 mmol, 3 eq), according to General Procedure R3. The
reaction mixture was stirred under nitrogen at 0.degree. C. for 1 h
and allowed to warm to rt until completion, as indicated by LC-MS.
The solvent was removed in vacuuo, and the crude amide was used
directly for further transformation.
[0876] To a stirred solution of the amide described above
(.about.0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess,
.about.30 eq) was added, according to General Procedure R4. The
reaction mixture was stirred at 100.degree. C. for 2-5 h (as
monitored by LC-MS). The reaction mixture was then cooled down and
neutralized with saturated sodium bicarbonate. The resulting
mixture was extracted with EtOAc (3.times.50 mL). The combined
EtOAc extracts were washed with brine (3.times.20 mL), and dried
over anhydrous sodium sulfate. The solvent was removed in vacuuo,
and the pure product was obtained by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield 70
mg).
[0877] MS m/z 584 (M+H).sup.+:
[0878] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.0.86 (d, 6H) 1.07
(t, 6H), 1.97 (m, 2H), 2.04 (m, 1H), 2.55 (d, 2H), 2.61 (q, 4H),
2.69 (t, 2H), 4.03 (t, 2H), 6.90 (d, 2H), 7.07 (d, 2H), 7.14 (s,
1H), 7.22-7.25 (m, 3H), 7.30 (d, 2H), 7.70 (d, 2H) ppm.
Example 420
[3-(4-{2-but-3-enyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-i-
midazol-4-yl}-phenoxy)-propyl]-diethyl-amine
[0879] To a stirred solution of 4-fluoronitrobenzene (20 mmol),
4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt,
solid potassium carbonate (60 mmol) was added, and the reaction
mixture was heated to 90.degree. C. for 5 h (monitored by TLC),
according to General Procedure L1. After cooling to rt, the
reaction mixture was poured into cold H.sub.2O (60 mL). The
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with H.sub.2O (2.times.40 mL)
and brine (50 mL), and dried over anhydrous sodium sulfate. The
solvent was removed in vacuuo to afford the desired
1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude
product was used directly for further transformation without
further purification.
[0880] The nitro intermediate (2 mmol) obtained above was dissolved
in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50
mg) until completion as indicated by TLC or LC-MS, according to
General Procedure H. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline, which was used
directly for further transformation without purification (overall
yield: 95%).
[0881] To a stirred solution of ice-cold 3-diethylaminopropanol (63
mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL) was
added dropwise methanesulfonyl chloride (60 mmol), and the reaction
mixture was stirred for 2 h at 0.degree. C. and followed by
additional 1 h at rt. After the removal of the solvents in vacuuo,
the crude mesylate was dissolved in DMF (100 mL).
4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)
were added, and the mixture was heated with stirring at 90.degree.
C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction
was quenched with cold H.sub.2O (100 mL), and the resulting mixture
was extracted with EtOAc (4.times.100 mL). The combined EtOAc
extracts were washed with brine (3.times.60 ml), and dried over
anhydrous sodium sulfate. The solvent was removed in vacuuo, and
the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was
purified by silica gel column chromatography eluting with 10% MeOH
in EtOAc+0.2% TEA (yield: 75%).
[0882] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10
mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added,
according to General Procedure R1. The reaction mixture was stirred
at rt for 1 h (monitored by LC-MS). The solvent was then removed in
vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly
used for further transformation.
[0883] To a stirred solution of
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline (4.8 mmol)
dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added,
followed by a slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained
above (.about.4 mmol), according to General Procedure R2. The
reaction mixture was stirred at rt and under nitrogen until
completion (.about.5 h), as indicated by LC-MS. The reaction was
quenched with saturated sodium bicarbonate (50 mL), and the
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with brine (3.times.40 mL), and
dried over anhydrous sodium sulfate. The solvent was removed in
vacuuo, and the crude product was purified by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield:
64%).
[0884] To a stirred solution of the alkylated aniline described
above (0.2 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (1.2
mmol, 6 eq) was added, followed by a slow addition of pent-4-enoyl
chloride (0.6 mmol, 3 eq), according to General Procedure R3. The
reaction mixture was stirred under nitrogen at 0.degree. C. for 1 h
and allowed to warm to rt until completion, as indicated by LC-MS.
The solvent was removed in vacuuo, and the crude amide was used
directly for further transformation.
[0885] To a stirred solution of the amide described above
(.about.0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess,
.about.30 eq) was added, according to General Procedure R4. The
reaction mixture was stirred at 100.degree. C. for 2-5 h (as
monitored by LC-MS). The reaction mixture was then cooled down and
neutralized with saturated sodium bicarbonate. The resulting
mixture was extracted with EtOAc (3.times.50 mL). The combined
EtOAc extracts were washed with brine (3.times.20 mL), and dried
over anhydrous sodium sulfate. The solvent was removed in vacuuo,
and the pure product was obtained by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield 58
mg).
[0886] MS m/z 582+H).sup.+:
[0887] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.12 (t, 6H),
2.03 (m, 2H), 2.45 (t, 2H), 2.63 (t, 2H,), 2.73 (q, 4H), 2.77 (t,
2H), 4.04 (t, 2H), 4.94 (dd, 1H), 5.00 (dd, 1H), 5.79 (m, 1H), 6.90
(d, 2H), 7.07 (d, 2H), 7.15 (s, 1H), 7.24-7.25 (m, 3H), 7.32 (d,
2H, 7.70 (d, 2H) ppm.
Example 421
[3-(4-{2-tert-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-i-
midazol-4-yl}-phenoxy)-propyl]-diethyl-amine
[0888] To a stirred solution of 4-fluoronitrobenzene (20 mmol),
4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt,
solid potassium carbonate (60 mmol) was added, and the reaction
mixture was heated to 90.degree. C. for 5 h (monitored by TLC),
according to General Procedure L1. After cooling to rt, the
reaction mixture was poured into cold H.sub.2O (60 mL). The
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with H.sub.2O (2.times.40 mL)
and brine (50 mL), and dried over anhydrous sodium sulfate. The
solvent was removed in vacuuo to afford the desired
1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude
product was used directly for further transformation without
further purification.
[0889] The nitro intermediate (2 mmol) obtained above was dissolved
in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50
mg) until completion as indicated by TLC or LC-MS, according to
General Procedure H. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline, which was used
directly for further transformation without purification (overall
yield: 95%).
[0890] To a stirred solution of ice-cold 3-diethylaminopropanol (63
mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL) was
added dropwise methanesulfonyl chloride (60 mmol), and the reaction
mixture was stirred for 2 h at 0.degree. C. and followed by
additional 1 h at rt. After the removal of the solvents in vacuuo,
the crude mesylate was dissolved in DMF (100 mL).
4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)
were added, and the mixture was heated with stirring at 90.degree.
C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction
was quenched with cold H.sub.2O (100 mL), and the resulting mixture
was extracted with EtOAc (4.times.100 mL). The combined EtOAc
extracts were washed with brine (3.times.60 ml), and dried over
anhydrous sodium sulfate. The solvent was removed in vacuuo, and
the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was
purified by silica gel column chromatography eluting with 10% MeOH
in EtOAc+0.2% TEA.
[0891] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10
mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added,
according to General Procedure R1. The reaction mixture was stirred
at rt for 1 h (monitored by LC-MS). The solvent was then removed in
vacuuo and the crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was directly
used for further transformation.
[0892] To a stirred solution of
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline (4.8 mmol)
dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added,
followed by a slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained
above (.about.4 mmol), according to General Procedure R2. The
reaction mixture was stirred at rt and under nitrogen until
completion (.about.5 h), as indicated by LC-MS. The reaction was
quenched with saturated sodium bicarbonate (50 mL), and the
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with brine (3.times.40 mL), and
dried over anhydrous sodium sulfate. The solvent was removed in
vacuuo, and the crude product was purified by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA.
[0893] To a stirred solution of the alkylated aniline described
above (0.2 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (1.2
mmol, 6 eq) was added, followed by a slow addition of pivaloyl
chloride (0.6 mmol, 3 eq), according to General Procedure R3. The
reaction mixture was stirred under nitrogen at 0.degree. C. for 1 h
and allowed to warm to rt until completion, as indicated by LC-MS.
The solvent was removed in vacuuo, and the crude amide was used
directly for further transformation.
[0894] To a stirred solution of the amide described above
(.about.0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess,
.about.30 eq) was added, according to General Procedure R4. The
reaction mixture was stirred at 100.degree. C. for 2-5 h (as
monitored by LC-MS). The reaction mixture was then cooled down and
neutralized with saturated sodium bicarbonate. The resulting
mixture was extracted with EtOAc (3.times.50 mL). The combined
EtOAc extracts were washed with brine (3.times.20 mL), and dried
over anhydrous sodium sulfate. The solvent was removed in vacuuo,
and the pure product was obtained by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield 76
mg).
[0895] MS m/z 584 (M+H).sup.+
[0896] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.1.09 (t, 6H), 1.24
(s, 9H), 1.99 (m, 2H), 2.64 (q, 4H), 2.72 (t, 2H), 4.02 (t, 2H),
6.89 (d, 2H), 7.02 (s, 1H), 7.03 (d, 2H), 7.23-7.25 (m, 3H), 7.35
(d, 2H), 7.69 (d, 2H) ppm.
Example 422
diethyl-[3-(4-{2-(4-fluoro-phenyl)-1-[4-(4-fluoro-3-trifluoromethyl-phenox-
y)-phenyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-amine
[0897] To a stirred solution of 4-fluoronitrobenzene (20 mmol),
4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt,
solid potassium carbonate (60 mmol) was added, and the reaction
mixture was heated to 90.degree. C. for 5 h (monitored by TLC),
according to General Procedure L1. After cooling to rt, the
reaction mixture was poured into cold H.sub.2O (60 mL). The
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with H.sub.2O (2.times.40 mL)
and brine (50 mL), and dried over anhydrous sodium sulfate. The
solvent was removed in vacuuo to afford the desired
1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude
product was used directly for further transformation without
further purification.
[0898] The nitro intermediate (2 mmol) obtained above was dissolved
in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50
mg) until completion as indicated by TLC or LC-MS, according to
General Procedure H. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline, which was used
directly for further transformation without purification (overall
yield: 95%).
[0899] To a stirred solution of ice-cold 3-diethylaminopropanol (63
mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL) was
added dropwise methanesulfonyl chloride (60 mmol), and the reaction
mixture was stirred for 2 h at 0.degree. C. and followed by
additional 1 h at rt. After the removal of the solvents in vacuuo,
the crude mesylate was dissolved in DMF (100 mL).
4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)
were added, and the mixture was heated with stirring at 90.degree.
C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction
was quenched with cold H.sub.2O (100 mL), and the resulting mixture
was extracted with EtOAc (4.times.100 mL). The combined EtOAc
extracts were washed with brine (3.times.60 ml), and dried over
anhydrous sodium sulfate. The solvent was removed in vacuuo, and
the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was
purified by silica gel column chromatography eluting with 10% MeOH
in EtOAc+0.2% TEA (yield: 75%).
[0900] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10
mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added,
according to General Procedure R1. The reaction mixture was stirred
at rt for 1 h (monitored by LC-MS). The solvent was then removed in
vacuuo and the crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was directly
used for further transformation.
[0901] To a stirred solution of
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline (4.8 mmol)
dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added,
followed by a slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained
above (.about.4 mmol), according to General Procedure R2. The
reaction mixture was stirred at rt and under nitrogen until
completion (.about.5 h), as indicated by LC-MS. The reaction was
quenched with saturated sodium bicarbonate (50 mL), and the
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with brine (3.times.40 mL), and
dried over anhydrous sodium sulfate. The solvent was removed in
vacuuo, and the crude product was purified by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield:
64%).
[0902] To a stirred solution of the alkylated aniline described
above (0.2 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (1.2
mmol, 6 eq) was added, followed by a slow addition of
4-fluorobenzoyl chloride (0.6 mmol, 3 eq), according to General
Procedure R3. The reaction mixture was stirred under nitrogen at
0.degree. C. for 1 h and allowed to warm to rt until completion, as
indicated by LC-MS. The solvent was removed in vacuuo, and the
crude amide was used directly for further transformation.
[0903] To a stirred solution of the amide described above
(.about.0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess,
.about.30 eq) was added, according to General Procedure R4. The
reaction mixture was stirred at 100.degree. C. for 2-5 h (as
monitored by LC-MS). The reaction mixture was then cooled down and
neutralized with saturated sodium bicarbonate. The resulting
mixture was extracted with EtOAc (3.times.50 mL). The combined
EtOAc extracts were washed with brine (3.times.20 mL), and dried
over anhydrous sodium sulfate. The solvent was removed in vacuuo,
and the pure product was obtained by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (overall
yield: 60-70%) (yield 75 mg).
[0904] MS m/z 622 (M+H).sup.+:
[0905] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.1.11 (t, 6H), 2.01
(m, 2H), 2.67 (q, 4H), 2.75 (t, 2H), 4.05 (t, 2H), 6.93 (d, 2H),
6.98-7.26 (m, 7H), 7.01 (d, 2H), 7.33 (s, 1H), 7.43 (d, 2H), 7.44
(d, 1H), 7.78 (d, 2H) ppm.
Example 423
[3-(4-{1-[4-(3,5-bis-trifluoromethyl-phenoxy)-phenyl]-2-butyl-1H-imidazol--
4-yl}-phenoxy)-propyl]-diethyl-amine
[0906] 3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM
(25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled
to 0.degree. C. To this mixture, methanesulfonyl chloride (30 mmol,
1.5 eq) was added slowly with stirring and the reaction mixture was
stirred at 0.degree. C. for an hour and at rt for another hour
(until the reaction was complete by HPLC). The solvent was removed
and saturated aqueous sodium bicarbonate was added. The product was
extracted with EtOAc (3.times.) and washed with sodium bicarbonate
and water. The solvent was removed in vacuuo.
[0907] The mesylate from the previous step (20 mmol, 1 eq) was
dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone
(20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added.
The mixture was heated under reflux at 85.degree. C. for 18 h
(until the reaction was complete by HPLC), after which it was
cooled to rt. Saturated aqueous sodium bicarbonate was added to the
mixture, which was then transferred to a separatory funnel. The
product was extracted with EtOAc and washed with sodium bicarbonate
and water. The solvent was removed in vacuuo and the
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flash
chromatography (going by increasing gradient up to 10% MeOH in
DCM). The overall yield was 60%.
[0908] 3,5-bis-trifluoromethylphenol (10 mmol) was dissolved in 15
ml of anhydrous DMF and potassium carbonate (30 mmol) was added
with stirring at rt. 4-Fluoronitrobenzene (10 mmol) was added to
this mixture, which was then heated under reflux at 80.degree. C.
for 18 h. The reaction was quenched with 30 ml of water and 30 ml
of sodium bicarbonate, extracted with EtOAc (3.times.50 ml) and
washed with sodium bicarbonate and water. The EtOAc layer was dried
over anhydrous sodium sulfate and filtered, after which the solvent
was removed in vacuuo.
[0909] The nitro intermediate (10 mmol) obtained above was
dissolved in EtOH (30 mL) and hydrogenated in the presence of 10%
Pd/C (10 mg) until completion as indicated by TLC or HPLC,
according to General Procedure H. The reaction mixture was then
filtered to remove the catalyst. The solvent was removed in vacuuo
to afford the desired 4-(3,5-bis-trifluoromethyl)phenoxyaniline,
which was used directly for further transformation without further
purification (yield 80%).
[0910] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2 mmol) in anhydrous
MeOH (6 mL) at 0.degree. C., pyrrolidone hydrotribromide (1.2 eq)
was added, according to General Procedure R1. The reaction mixture
was stirred under nitrogen at 0.degree. C. for 1 h and was allowed
to warm to rt until completion, as indicated by TLC or HPLC. The
solvent was then removed in vacuuo and the crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[0911] To a solution of 4-(3,5-bis-trifluoromethyl)phenoxyaniline
(1 eq, 2 mmol) in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was
added, followed by addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (2 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Removal of solvent in vacuuo afforded the desired product.
The crude alkylated aniline was purified by chromatography (Silica
gel). Pure product obtained from 2-4% MeOH/DCM (yield 50%).
[0912] To a stirred solution of alkylated aniline described above
(1 mmol) in anhydrous DCM (4 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by a slow addition of valeryl chloride (3
eq, 3 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[0913] To a stirred solution of the amide described above (1 mmol)
in acetic acid (4 mL), ammonium acetate (20 eq) was added,
according to General Procedure R4. The reaction mixture was stirred
at 90.degree. C. overnight. The reaction mixture was then cooled to
rt and neutralized with saturated sodium bicarbonate solution.
Usual extractive work up with EtOAc gave the product imidazole,
which was purified by column chromatography (Silica gel). Pure
product was obtained from 4-6% MeOH/DCM (yield 139 mg).
[0914] MS m/z 635 (M+H).sup.+:
[0915] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.7 (d, 2H), 7.3
(m, 3H), 7.1 (m, 5H), 6.9 (d, 2H), 4.0 (t, 2H), 2.6-2.8 (m, 8H),
2.0 (m, 2H), 1.6 (m, 2H), 1.3 (m, 2H), 1.1 (t, 6H), 0.8 (t, 3H)
ppm.
Example 424
(3-{4-[1-(4-benzyloxy-phenyl)-2-butyl-1H-imidazol-4-yl]-phenoxy}propyl)-di-
ethyl-amine
[0916] 3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM
(25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled
to 0.degree. C. To this mixture, methanesulfonyl chloride (30 mmol,
1.5 eq) was added slowly with stirring and the reaction mixture was
stirred at 0.degree. C. for an hour and at rt for another hour
(until the reaction was complete by HPLC). The solvent was removed
and saturated aqueous sodium bicarbonate was added. The product was
extracted with EtOAc (3.times.) and washed with sodium bicarbonate
and water. The solvent was removed in vacuuo.
[0917] The mesylate from the previous step (20 mmol, 1 eq) was
dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone
(20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added.
The mixture was heated under reflux at 85.degree. C. for 18 h
(until the reaction was complete by HPLC), after which it was
cooled to rt. Saturated aqueous sodium bicarbonate was added to the
mixture, which was then transferred to a separatory funnel. The
product was extracted with EtOAc and washed with sodium bicarbonate
and water. The solvent was removed in vacuuo and the product was
purified by flash chromatography (going by increasing gradient up
to 10% MeOH in DCM). The overall yield was 60%.
[0918] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2 mmol) in anhydrous
MeOH (6 mL) at 0.degree. C., pyrrolidone hydrotribromide (1.2 eq)
was added, according to General Procedure R1. The reaction mixture
was stirred under nitrogen at 0.degree. C. for 1 h and was allowed
to warm to rt until completion, as indicated by TLC or HPLC. The
solvent was then removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[0919] To a solution of 4-benzyloxyaniline (1 eq, 2 mmol) in
anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by
addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (2 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was purified by chromatography
(Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield
56%).
[0920] To a stirred solution of alkylated aniline described above
(1 mmol) in anhydrous DCM (4 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by a slow addition of valeryl chloride (3
eq, 3 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[0921] To a stirred solution of the amide described above (1 mmol)
in acetic acid (4 mL), ammonium acetate (20 eq) was added,
according to General Procedure R4. The reaction mixture was stirred
at 90.degree. C. overnight. The reaction mixture was then cooled to
rt and neutralized with saturated sodium bicarbonate solution.
Usual extractive work up with EtOAc gave the product imidazole,
which was purified by column chromatography (Silica gel). Pure
product was obtained from 4-6% MeOH/DCM (yield 205 mg).
[0922] MS m/z 513 (M+H).sup.+;
[0923] .sup.1H NMR (CDCl.sub.3): .delta. 7.68 (d, 2H), 7.40 (m,
5H), 7.23 (d, 2H), 7.11 (s, 1H), 7.05 (d, 2H), 6.89 (d, 2H), 5.12
(s, 2H), 4.02 (t, 2H), 2.62-2.73 (m, 8H), 1.98 (m, 2H), 1.63 (m,
2H), 1.28 (m, 2H), 1.07 (t, 6H), 0.82 (t, 3H) ppm.
Example 425
{3-[4-(2-tert-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-y-
l)-phenoxy]-propyl}-diethyl-amine
[0924] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
diethylaminopropoxide (2.2 mmol) in THF was added dropwise and
under a nitrogen stream, according to General Procedure L1. The
reaction mixture was stirred at 0.degree. C. for 1 h and allowed to
warm to rt until completion, as indicated by TLC or HPLC. The
reaction mixture was then treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene.
The crude product was used directly for further transformation.
[0925] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg) until completion as indicated by
TLC or HPLC, according to General Procedure H. The reaction mixture
was then filtered to remove the catalyst. The solvent was removed
in vacuuo to afford the desired 4-alkoxyaniline, which was used
directly for further transformation without further
purification.
[0926] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was
added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the
reaction mixture and heated to 80.degree. C. until completion
according to General Procedure Q1, as indicated by TLC or HPLC.
After cooling to rt, the reaction mixture was quenched using cold
water (20 ml) and the product was isolated in EtOAc (2.times.20
ml). The combined organic layers were washed with saturated sodium
bicarbonate (2.times.10 ml), water (2.times.10 ml) and brine (15
ml). The organic layer was dried over magnesium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated
acetophenone was used for further transformation.
[0927] To a stirred solution of the
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.2 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the residue
was treated with saturated sodium bicarbonate. The aqueous layer
was poured into EtOAc (20 ml) and the product was isolated in EtOAc
(2.times.20 ml). The combined organic layers were washed with
saturated sodium bicarbonate (2.times.10 ml), and brine (15 ml).
The organic layer was dried over magnesium sulfate, and the solvent
was removed in vacuuo to afford the desired product. The crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified
by chromatography (Silica gel). Pure product was obtained from
20-30% EtOAc/hexane (yield .about.70-75%).
[0928] To a stirred solution of the
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[0929] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-p-
henylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5
mL) at 0.degree. C., TEA (3 eq., 4.8 mmol) was added, followed by
slow addition of pivaloyl chloride (2 eq., 3.2 mmol), according to
General Procedure R3. The reaction mixture was stirred under
nitrogen at 0.degree. C. for 1 h and allowed to warm to rt until
completion, as indicated by TLC or HPLC. The reaction mixture was
then diluted with cold water and the product was isolated in DCM.
The solvent was removed in vacuuo, and the crude amide was used for
further transformation.
[0930] To a stirred solution of the amide described above (1.6
mmol) in acetic acid (4 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield:
270 mg).
[0931] MS m/z 561 (M+H).sup.+:
[0932] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.7.69 (d, 2H),
7.23-7.25 (m, 6H), 6.98 (s, 1H), 6.84 (m 4H), 4.15 (t, 2H), 4.08
(t, 2H), 3.05 (t, 2H), 2.85 (m, 6H), 2.16 (s, 9H), 2.05 (m, 2H),
1.19 (t, 6H) ppm.
Example 426
[3-(4-{2-butyl-1-[4-(3-fluoro-4-trifluoromethyl-phenoxy)-phenyl]-1H-imidaz-
ol-4-yl}-phenoxy)-propyl]-diethyl-amine
[0933] To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol)
in anhydrous DCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium
bromide perbromide (1.1 eq.) was added. The reaction mixture was
stirred under nitrogen at rt until completion, as indicated by TLC.
The mixture was diluted with EtOAc (100 ml) and washed with
H.sub.2O (2.times.50 ml), brine (30 ml) and dried with magnesium
sulfate. The solvent was then removed in vacuuo to give a white
solid. The alpha-bromoacetophenone was used for further
transformation without further purification.
[0934] To a stirred solution of
4-(3-fluoro-4-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in
anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow
addition of the alpha-bromoacetophenone described above (2 eq),
according to General Procedure R2. The reaction mixture was stirred
under nitrogen at rt until completion, as indicated by TLC and
HPLC. The reaction mixture was then diluted with cold H.sub.2O and
the product was isolated in Et.sub.2O. The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of solvent in vacuuo afforded the desired product. The crude
alkylated aniline was purified by chromatography (Silica gel). Pure
product was obtained from 5-20% EtOAc/Hexane (yield
.about.50-60%).
[0935] To a stirred solution of alkylated aniline described above
(1.0 mmol) in anhydrous THF (20 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by slow addition of valeryl chloride (3
eq, 3.0 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to ambient temperature until completion, as
indicated by TLC and HPLC. The solvent was removed in vacuuo, and
the crude amide was used for further transformation.
[0936] To a stirred solution of the amide described above (1.0
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 5-15% EtOAc/Hexane
(yield 80%). (MS: m/z 562 (M+H).sup.+)
[0937] The above product was dissolved in MeOH (20 mL), and Pd/C
(100 mg) was added and the heterogeneous mixture was stirred
overnight under hydrogen atmosphere using a balloon, according to
General Procedure H. The Pd/C was removed by filtration. The
solvent was removed in vacuuo, and the crude phenol (MS: m/z 472
(M+H).sup.+) was used for further transformation.
[0938] To a stirred solution of the phenol (1.0 eq) obtained above
in anhydrous DMF (5.0 mL) solid sodium hydride (60% dispersion in
oil; 1.0 mmol) was added in portions. After the addition, the
requisite alkylhalide or the mesylate (prepared from the
corresponding alcohol and methanesulfonyl chloride) (1.5-2.0 eq)
was added to the reaction mixture. The reaction mixture was heated
at 90.degree. C. overnight. After cooling the mix to rt, Et.sub.2O
(30 mL) was added to the reaction mixture followed by H.sub.2O (10
mL). The organic layer was washed with H.sub.2O (2.times.15 mL) and
brine, and dried over sodium sulfate. The solvent was removed in
vacuuo. Pure product was obtained from 5-10% MeOH/DCM (yield 65.0
mg).
[0939] MS m/z 557 (M+H).sup.+:
[0940] .sup.1H NMR (CDCl.sub.3): .delta. 7.70 (d, 2H), 7.20-7.35
(m, 5H), 7.14 (s, 1H), 7.08 (d, 2H), 6.92 (d, 2H), 4.02 (t, 2H),
2.66 (t, 2H), 2.47 (t, 2H), 2.26 (s, 6H), 1.96 (m, 2H), 1.64 (m,
2H), 1.29 (m, 2H) 0.9 (t, 3H) ppm.
Example 427
diethyl-[3-(4-{4-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-imidazol--
1-yl}-phenoxy)-propyl]amine
[0941] To a stirred solution of
N-[3-(4-aminophenoxy)propyl]-N,N-diethylamine (1.2 eq, 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added, followed by a
slow addition of 2-bromo-1-(4-bromophenyl)ethanone (1.6 mmol),
according to General Procedure R2. The reaction mixture was stirred
under nitrogen at rt until completion, as indicated by TLC or HPLC.
The reaction mixture was then diluted with cold H.sub.2O and the
product was isolated in EtOAc. The combined organic layers were
washed with brine and dried over sodium sulfate. Evaporation of
solvent in vacuuo afforded the desired product. The crude alkylated
aniline was purified by chromatography (Silica gel). Pure product
was obtained from 2-4% MeOH/DCM (yield .about.50-60%).
[0942] To a stirred solution of
1-(4-bromophenyl)-2-({4-[3-(diethylamino)propoxy]phenyl}amino)ethanone
(2 mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield
40-50%).
[0943] To a solution of
N-(3-{4-[4-(4-bromophenyl)-1H-imidazol-1-yl]phenoxy}propyl)-N,N-diethylam-
ine (0.07 mmol) in pyridine (1 mL), copper powder was added (0.14
mmol), followed by potassium carbonate (0.35 mmol) and
4-fluoro-3-methylphenol (0.14 mmol). The mixture was heated at
110.degree. C. overnight, then diluted with H.sub.2O (2 mL) and
extracted with EtOAc (3.times.2 mL). The combined organic extract
was dried over sodium sulfate, filtered and concentrated to an oil,
which was purified by column chromatography (Silica gel). The pure
product was obtained from 1-6% MeOH/DCM.
[0944] MS m/z 528 (M+H).sup.+:
[0945] .sup.1H NMR (400 MHz, CDCl.sub.3): .about.7.86-7.78 (m, 3H),
7.54-7.44 (m, 2H), 7.38-7.34 (m, 2H), 7.28-7.24 (m, 1H), 7.20-7.16
(m, 2H), 7.06-6.80 (m, 3H), 4.10 (t, 2H), 2.80-2.60 (m, 6H),
2.10-2.00 (m, 2H), 1.30 (t, 3H), 1.10 (t, 3H) ppm.
Example 428
(3-{-4-[4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-(4-fluoro-phenyl)-imid-
azol-1-yl]-phenoxy}-propyl)-diethyl-amine
[0946] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
diethylaminopropoxide (2.2 mmol) in THF was added dropwise and
under a nitrogen stream, according to General Procedure L1. The
reaction mixture was stirred at 0.degree. C. for 1 h and allowed to
warm to rt until completion, as indicated by TLC or HPLC. The
reaction mixture was then treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene.
The crude product was used directly for further transformation.
[0947] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg) until completion as indicated by
TLC or HPLC, according to General Procedure H. The reaction mixture
was then filtered to remove the catalyst. The solvent was removed
in vacuuo to afford the desired 4-alkoxyaniline, which was used
directly for further transformation without further
purification.
[0948] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was
added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the
reaction mixture and heated to 80.degree. C. until completion
according to General Procedure Q1, as indicated by TLC or HPLC.
After cooling to rt, the reaction mixture was quenched using cold
water (20 ml) and the product was isolated in EtOAc (2.times.20
ml). The combined organic layers were washed with saturated sodium
bicarbonate (2.times.10 ml), water (2.times.10 ml) and brine (15
ml). The organic layer was dried over magnesium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated
acetophenone was used for further transformation.
[0949] To a stirred solution of the
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.2 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the residue
was treated with saturated sodium bicarbonate. The aqueous layer
was poured into EtOAc (20 ml) and the product was isolated in EtOAc
(2.times.20 ml). The combined organic layers were washed with
saturated sodium bicarbonate (2.times.10 ml), and brine (15 ml).
The organic layer was dried over magnesium sulfate, and the solvent
was removed in vacuuo to afford the desired product. The crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified
by chromatography (Silica gel). Pure product was obtained from
20-30% EtOAc/hexane (yield .about.70-75%).
[0950] To a stirred solution of the
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[0951] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-p-
henylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5
mL) at 0.degree. C., TEA (3 eq., 4.8 mmol) was added, followed by
slow addition of 4-fluorobenzoyl chloride (2 eq., 3.2 mmol),
according to General Procedure R3. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and allowed to warm to rt
until completion, as indicated by TLC or HPLC. The reaction mixture
was then diluted with cold water and the product was isolated in
DCM. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[0952] To a stirred solution of the amide described above (1.6
mmol) in acetic acid (4 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield:
334 mg).
[0953] MS m/z 598 (M+H).sup.+:
[0954] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.7.76 (d, 2H), 7.41
(m, 2H), 7.26 (m, 2H), 7.21 (d, 2H), 7.16 (d, 2H), 7.01 (m, 7H),
4.16 (t, 2H), 4.05 (t, 2H), 3.05 (t, 2H), 2.97 (m, 6H), 2.18 (m,
2H), 1.24 (t, 6H) ppm
Example 429
{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-cyclopropyl-imidazol-1--
yl)-phenoxy]-propyl}-diethyl-amine
[0955] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
diethylaminopropoxide (2.2 mmol) in THF was added dropwise and
under a nitrogen stream, according to General Procedure L1. The
reaction mixture was stirred at 0.degree. C. for 1 h and allowed to
warm to rt until completion, as indicated by TLC or HPLC. The
reaction mixture was then treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene.
The crude product was used directly for further transformation.
[0956] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg) until completion as indicated by
TLC or HPLC, according to General Procedure H. The reaction mixture
was then filtered to remove the catalyst. The solvent was removed
in vacuuo to afford the desired 4-alkoxyaniline, which was used
directly for further transformation without further
purification.
[0957] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was
added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the
reaction mixture and heated to 80.degree. C. until completion
according to General Procedure Q1, as indicated by TLC or HPLC.
After cooling to rt, the reaction mixture was quenched using cold
water (20 ml) and the product was isolated in EtOAc (2.times.20
ml). The combined organic layers were washed with saturated sodium
bicarbonate (2.times.10 ml), water (2.times.10 ml) and brine (15
ml). The organic layer was dried over magnesium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated
acetophenone was used for further transformation.
[0958] To a stirred solution of the
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.2 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the residue
was treated with saturated sodium bicarbonate. The aqueous layer
was poured into EtOAc (20 ml) and the product was isolated in EtOAc
(2.times.20 ml). The combined organic layers were washed with
saturated sodium bicarbonate (2.times.10 ml), and brine (15 ml).
The organic layer was dried over magnesium sulfate, and the solvent
was removed in vacuuo to afford the desired product. The crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified
by chromatography (Silica gel). Pure product was obtained from
20-30% EtOAc/hexane.
[0959] To a stirred solution of the
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[0960] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-p-
henylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5
mL) at 0.degree. C., TEA (3 eq., 4.8 mmol) was added, followed by
slow addition of cyclopropanecarbonyl chloride (2 eq., 3.2 mmol),
according to General Procedure R3. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and allowed to warm to rt
until completion, as indicated by TLC or HPLC. The reaction mixture
was then diluted with cold water and the product was isolated in
DCM. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[0961] To a stirred solution of the amide described above (1.6
mmol) in acetic acid (4 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield:
260 mg).
[0962] MS m/z 544 (M+H).sup.+:
[0963] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.7.65 (d, 2H), 7.31
(m, 4H), 7.21 (d, 2H), 7.18 (s, 1H), 6.98 (d, 2H), 6.88 (d 2H),
4.18 (t, 2H), 4.08 (t, 2H), 3.07 (t, 2H), 3.12 (m, 1H) 2.78 (m,
6H), 2.57 (m, 4H), 2.06 (m, 2H), 1.12 (t, 6H) ppm
Example 430
{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-cyclopentyl-imidazol-1--
yl)-phenoxy]-propyl}-diethyl-amine
[0964] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
diethylaminopropoxide (2.2 mmol) in THF was added dropwise and
under a nitrogen stream, according to General Procedure L1. The
reaction mixture was stirred at 0.degree. C. for 1 h and allowed to
warm to rt until completion, as indicated by TLC or HPLC. The
reaction mixture was then treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene.
The crude product was used directly for further transformation.
[0965] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg) until completion as indicated by
TLC or HPLC, according to General Procedure H. The reaction mixture
was then filtered to remove the catalyst. The solvent was removed
in vacuuo to afford the desired 4-alkoxyaniline, which was used
directly for further transformation without further
purification.
[0966] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was
added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the
reaction mixture and heated to 80.degree. C. until completion
according to General Procedure Q1, as indicated by TLC or HPLC.
After cooling to rt, the reaction mixture was quenched using cold
water (20 ml) and the product was isolated in EtOAc (2.times.20
ml). The combined organic layers were washed with saturated sodium
bicarbonate (2.times.10 ml), water (2.times.10 ml) and brine (15
ml). The organic layer was dried over magnesium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated
acetophenone was used for further transformation.
[0967] To a stirred solution of the
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.2 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the residue
was treated with saturated sodium bicarbonate. The aqueous layer
was poured into EtOAc (20 ml) and the product was isolated in EtOAc
(2.times.20 ml). The combined organic layers were washed with
saturated sodium bicarbonate (2.times.10 ml), and brine (15 ml).
The organic layer was dried over magnesium sulfate, and the solvent
was removed in vacuuo to afford the desired product. The crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was purified
by chromatography (Silica gel). Pure product was obtained from
20-30% EtOAc/hexane (yield .about.70-75%).
[0968] To a stirred solution of the
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[0969] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-p-
henylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5
mL) at 0.degree. C., TEA (3 eq., 4.8 mmol) was added, followed by
slow addition of cyclopentanecarbonyl chloride (2 eq., 3.2 mmol),
according to General Procedure R3. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and allowed to warm to rt
until completion, as indicated by TLC or HPLC. The reaction mixture
was then diluted with cold water and the product was isolated in
DCM. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[0970] To a stirred solution of the amide described above (1.6
mmol) in acetic acid (4 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield:
366 mg).
[0971] MS m/z 572 (M+H).sup.+:
Example 431
[3-(4-{4-[4-(biphenyl-4-yloxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-die-
thyl-amine
[0972] To a stirred solution of
N-[3-(4-aminophenoxy)propyl]-N,N-diethylamine (1.2 eq, 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added, followed by a
slow addition of the 2-bromo-1-(4-bromophenyl)ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was isolated in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was purified by
chromatography (Silica gel). Pure product was obtained from 2-4%
MeOH/DCM (yield .about.50-60%).
[0973] To a stirred solution of
1-(4-bromophenyl)-2-({4-[3-(diethylamino)propoxy]phenyl}amino)ethanone
(2 mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield
40-50%).
[0974] To a solution of the
N-(3-{4-[4-(4-bromophenyl)-1H-imidazol-1-yl]phenoxy}propyl)-N,N-diethylam-
ine (0.07 mmol) in pyridine (1 mL), copper powder was added (0.14
mmol), followed by potassium carbonate (0.35 mmol) and
1,1'-biphenyl-4-ol (0.14 mmol). The mixture was heated at
110.degree. C. overnight, then diluted with H.sub.2O (2 mL) and
extracted with EtOAc (3.times.2 mL). The combined organic extract
was dried over sodium sulfate, filtered and concentrated to an oil,
which was purified by column chromatography (Silica gel). The pure
product was obtained from 1-6% MeOH/DCM (yield 11 mg).
[0975] MS m/z 518 (M+H).sup.+:
[0976] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.83-7.79 (m,
3H), 7.59-7.57 (m, 4H), 7.45-7.43 (m, 4H), 7.42-7.34 (m, 4H), 7.11
(d, 2H), 7.05 (d, 3H), 4.10 (t, 2H), 2.80-2.60 (m, 6H), 2.00-2.10
(m, 2H), 1.30 (t, 3H), 1.10 (t, 3H) ppm.
Example 432
diethyl-[3-(4-{4-[4-(3-trifluoromethyl-phenoxy)-phenyl]-imidazol-1-yl}-phe-
noxy)-propyl]-amine
[0977] To a stirred solution of
N-[3-(4-aminophenoxy)propyl]-N,N-diethylamine (1.2 eq, 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added, followed by a
slow addition of 2-bromo-1-(4-bromophenyl)ethanone (1.6 mmol),
according to General Procedure R2. The reaction mixture was stirred
under nitrogen at rt until completion, as indicated by TLC or HPLC.
The reaction mixture was then diluted with cold H.sub.2O and the
product was isolated in EtOAc. The combined organic layers were
washed with brine and dried over sodium sulfate. Evaporation of
solvent in vacuuo afforded the desired product. The crude alkylated
aniline was purified by chromatography (Silica gel). Pure product
was obtained from 2-4% MeOH/DCM (yield .about.50-60%).
[0978] To a stirred solution of
1-(4-bromophenyl)-2-({-4-[3-(diethylamino)propoxy]phenyl}amino)ethanone
(2 mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield
40-50%).
[0979] To a solution of
N-(3-{4-[4-(4-bromophenyl)-1H-imidazol-1-yl]phenoxy}propyl)-N,N-diethylam-
ine (0.07 mmol) in pyridine (1 mL), copper powder was added (0.14
mmol), followed by potassium carbonate (0.35 mmol) and
3-(trifluoromethyl)phenol (0.14 mmol). The mixture was heated at
110.degree. C. overnight, then diluted with H.sub.2O (2 mL) and
extracted with EtOAc (3.times.2 mL). The combined organic extract
was dried over sodium sulfate, filtered and concentrated to an oil,
which was purified by column chromatography (Silica gel). The pure
product was obtained from 1-6% MeOH/DCM (yield 10 mg).
[0980] MS m/z 510 (M+H).sup.+:
Example 433
[3-(4-{4-[4-(3,4-dichloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-propyl]-
-diethyl-amine
[0981] To a stirred solution of
N-[3-(4-aminophenoxy)propyl]-N,N-diethylamine (1.2 eq, 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq 6 mmol) was added, followed by a
slow addition of 2-bromo-1-(4-bromophenyl)ethanone (1.6 mmol),
according to General Procedure R2. The reaction mixture was stirred
under nitrogen at rt until completion, as indicated by TLC or HPLC.
The reaction mixture was then diluted with cold H.sub.2O and the
product was isolated in EtOAc. The combined organic layers were
washed with brine and dried over sodium sulfate. Evaporation of
solvent in vacuuo afforded the desired product. The crude alkylated
aniline was purified by chromatography (Silica gel). Pure product
was obtained from 2-4% MeOH/DCM (yield .about.50-60%).
[0982] To a stirred solution of
1-(4-bromophenyl)-2-({4-[3-(diethylamino)propoxy]phenyl}amino)ethanone
(2 mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield
40-50%).
[0983] To a solution of
N-(3-{4-[4-(4-bromophenyl)-1H-imidazol-1-yl]phenoxy}propyl)-N,N-diethylam-
ine (0.07 mmol) in pyridine (1 mL), copper powder was added (0.14
mmol) followed by potassium carbonate (0.35 mmol), and
3,4-dichlorophenol (0.14 mmol). The mixture was heated at
110.degree. C. overnight, then diluted with H.sub.2O (2 mL) and
extracted with EtOAc (3.times.2 mL). The combined organic extract
was dried over sodium sulfate, filtered and concentrated to an oil,
which was purified by column chromatography (Silica gel). The pure
product was obtained from 1-6% MeOH/DCM (yield 15 mg).
[0984] MS m/z 510 (M+H).sup.+:
Example 434
[3-(4-{2-butyl-1-[4-(4-methoxy-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)-
-propyl]-diethyl-amine
[0985] 3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM
(25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled
to 0.degree. C. To this mixture, methanesulfonyl chloride (30 mmol,
1.5 eq) was added slowly with stirring and the reaction mixture was
stirred at 0.degree. C. for an hour and at rt for another hour
(until the reaction was complete by HPLC). The solvent was removed
and to this saturated aqueous sodium bicarbonate was added. The
product was extracted with EtOAc (3.times.) and washed with sodium
bicarbonate and water. The solvent was removed in vacuuo.
[0986] The mesylate from the previous step (20 mmol, 1 eq) was
dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone
(20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added.
The mixture was heated under reflux at 85.degree. C. for 18 h
(until the reaction was complete by HPLC), after which it was
cooled to rt. Saturated aqueous sodium bicarbonate was added to the
mixture, which was then transferred to a separatory funnel. The
product was extracted with EtOAc and washed with sodium bicarbonate
and water. The solvent was removed in vacuuo and the
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flash
chromatography (going by increasing gradient up to 10% MeOH in
DCM). The overall yield was 60%.
[0987] 4-Methoxyphenol (10 mmol) was dissolved in 15 ml of
anhydrous DMF and potassium carbonate (30 mmol) was added with
stirring at rt. 4-Fluoronitrobenzene (10 mmol) was added to this
mixture, which was then heated under reflux at 80.degree. C. for 18
h. The reaction was quenched with 30 ml of water and 30 ml of
sodium bicarbonate, extracted with EtOAc (3.times.50 ml) and washed
with sodium bicarbonate and water. The EtOAc layer was dried over
anhydrous sodium sulfate and filtered, after which the solvent was
removed in vacuuo.
[0988] The nitro intermediate (10 mmol) obtained above was
dissolved in EtOH (30 mL) and hydrogenated in the presence of 10%
Pd/C (10 mg) until completion as indicated by TLC or HPLC,
according to General Procedure H. The reaction mixture was then
filtered to remove the catalyst. The solvent was removed in vacuuo
to afford the desired 4-(4-methoxyphenoxy)aniline, which was used
directly for further transformation without further purification
(yield 80%).
[0989] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2 mmol) in anhydrous
MeOH (6 mL) at 0.degree. C., pyrrolidone hydrotribromide (1.2 eq)
was added, according to General Procedure R1. The reaction mixture
was stirred under nitrogen at 0.degree. C. for 1 h and was allowed
to warm to rt until completion, as indicated by TLC or HPLC. The
solvent was then removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[0990] To a solution of 4-(4-methoxyphenoxy) aniline (1 eq, 2 mmol)
in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by
addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (2 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was purified by chromatography
(Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield
52%).
[0991] To a stirred solution of alkylated aniline described above
(1 mmol) in anhydrous DCM (4 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by a slow addition of valeryl chloride (3
eq, 3 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[0992] To a stirred solution of the amide described above (1 mmol)
in acetic acid (4 mL), ammonium acetate (20 eq) was added,
according to General Procedure R4. The reaction mixture was stirred
at 90.degree. C. overnight. The reaction mixture was then cooled to
rt and neutralized with saturated sodium bicarbonate solution.
Usual extractive work up with EtOAc gave the product imidazole,
which was purified by column chromatography (Silica gel). Pure
product was obtained from 4-6% MeOH/DCM (yield 190 mg).
[0993] MS m/z 529 (M+H).sup.+:
[0994] .sup.1H NMR (CDCl.sub.3): .delta.7.7 (d, 2H), 7.2 (d, 2H),
7.16 (s, 1H), 6.8-7.1 (m, 8H), 4.0 (t, 2H), 3.8 (s, 3H), 2.8-3.0
(m, 8H), 2.6 (m, 2H), 2.2 (m, 2H), 1.6 (m, 2H), 1.2 (t, 6H), 0.8
(t, 3H) ppm.
Example 435
1-[2-(4-{2-butyl-1-[4-(3-fluoro-4-trifluoromethyl-phenoxy)-phenyl]-1H-imid-
azol-4-yl}-phenoxy)-ethyl]-piperazine
[0995] To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol)
in anhydrous DCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium
bromide perbromide (1.1 eq.) was added. The reaction mixture was
stirred under nitrogen at rt until completion, as indicated by TLC.
The mixture was diluted with EtOAc (100 ml) and washed with
H.sub.2O (2.times.50 ml), brine (30 ml) and dried with magnesium
sulfate. The solvent was then removed in vacuuo to give a white
solid. The alpha-bromoacetophenone was used for further
transformation without further purification.
[0996] To a stirred solution of
4-(3-fluoro-4-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in
anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow
addition of the alpha-bromoacetophenone described above (2 eq),
according to General Procedure R2. The reaction mixture was stirred
under nitrogen at rt until completion, as indicated by TLC and
HPLC. The reaction mixture was then diluted with cold H.sub.2O and
the product was isolated in Et.sub.2O. The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of solvent in vacuuo afforded the desired product. The crude
alkylated aniline was purified by chromatography (Silica gel). Pure
product was obtained from 5-20% EtOAc/Hexane (yield
.about.50-60%).
[0997] To a stirred solution of alkylated aniline described above
(1.0 mmol) in anhydrous THF (20 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by slow addition of valeryl chloride (3
eq, 3.0 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to ambient temperature until completion, as
indicated by TLC and HPLC. The solvent was removed in vacuuo, and
the crude amide was used for further transformation.
[0998] To a stirred solution of the amide described above (1.0
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 5-15% EtOAc/Hexane
(yield 80%).
[0999] (MS: m/z 562 (M+H).sup.+)
[1000] The Above Product was Dissolved in MeOH (20 mL), and Pd/C
(100 mg) was Added and the heterogeneous mixture was stirred
overnight under hydrogen atmosphere using a balloon, according to
General Procedure H. The Pd/C was removed by filtration. The
solvent was removed in vacuuo, and the crude phenol (MS: m/z 472
(M+H).sup.+) was used for further transformation.
[1001] To a stirred solution of the phenol (0.16 mmol) obtained
above in anhydrous DMF (5 mL) solid sodium hydride (60% dispersion
in oil; 1.0 mmol) was added in portions. After the addition,
4-(2-methanesulfonyloxy)-piperazine-1-carboxylic acid
tertbutylester (2.0 mmol) was added to the reaction mixture. The
reaction mixture was heated at 90.degree. C. overnight. After
cooling the mix to rt, Et.sub.2O (30 mL) was added to the reaction
mixture followed by H.sub.2O (10 mL). The organic layer was washed
with H.sub.2O (2.times.15 mL) and brine, and dried over sodium
sulfate. The solvent was removed in vacuuo. Pure product was
obtained from 5-10% MeOH/DCM (yield .about.45%).
[1002] This product was dissolved in DCM (10 mL) and HCl (4.0 M in
dioxane, 1.0 mL) was added and stirrings continued overnight until
reaction completed as indicated by HPLC. EtOAc (40 ml) added,
followed by sodium bicarbonate (sat, 15 mL). The organic layer was
washed with brine (10 mL) and dried with magnesium sulfate. The
solvent was removed in in vacuuo to give the title compound as
white solid (yield 37 mg).
[1003] MS m/z 584 (M+H).sup.+:
[1004] .sup.1H NMR (CDCl.sub.3): .delta.7.70 (d, 2H), 7.20-7.35 (m,
5H), 7.14 (s, 1H), 7.08 (d, 2H), 6.92 (d, 2H), 4.05 (t, 2H), 3.0
(m, 4H), 2.8 (t, 2H), 3.4 (m, 6H), 1.6 (m, 2H), 1.3 (m, 3H), 0.9
(t, 3H) ppm.
Example 436
{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-p-
ropyl}-dimethyl-amine
[1005] To a stirred solution of 4-aminophenol (4.8 mmol) in MeOH
(20 mL), 1-bromo-4'-(4-chlorophenethoxy)acetophenone (4 mmol) was
added at rt. The resulting mixture was then heated to reflux for 45
min. The reaction mixture was then cooled to rt and the solvent was
removed in vacuuo. The resulting solid was dissolved in EtOAc (30
mL), washed with H.sub.2O (2.times.20 mL) and brine (20 mL) and
dried over sodium sulfate. Evaporation of solvent in vacuuo
afforded the desired
1-(4-hydroxyphenyl)amino-4'-(4-chlorophenethoxy)acetophenone, which
was used for further transformation.
[1006] The aminoacetophenone obtained as above (3 mmol) was
dissolved in formic acid (3 mL) and added with ammonium formate (60
mmol). The resulting mixture was heated to 90.degree. C. overnight.
The reaction mixture was then cooled down and neutralized with
saturated sodium bicarbonate solution. Usual extractive work up
with EtOAc gave the product,
4-{4-[2-(4-chlorophenyl)ethoxy]phenyl}-1-[(4-hydroxy)phenyl]-1H--
imidazole, which was purified by column chromatography (Silica
gel). Pure product was obtained from 4-6% MeOH/DCM (yield
.about.50%).
[1007] To a solution of the product obtained above (0.5 mmol) in
anhydrous THF (2 mL), NaH (60% dispersion in oil; 1 mmol) was added
at 0.degree. C. The resulting mixture was added with a solution of
the mesylate of N,N-dimethylpropanol (0.6 mmol) in THF (1 mL). The
reaction mixture was then heated to 70.degree. C. overnight. Usual
extractive work up with EtOAc gave the product imidazole, which was
purified by column chromatography (Silica gel). Pure product was
obtained from 4-6% MeOH/DCM.
[1008] MS m/z 476 (M+H).sup.+:
[1009] .sup.1H NMR (CDCl.sub.3): .delta.7.76 (s, 1H), 7.73 (d, 2H),
7.38 (s, 1H), 7.31 (d, 2H), 7.25 (AB.sub.q, 4H), 6.99 (d, 2H), 6.92
(d, 2H,), 4.18 (t, 2H), 4.05 (t, 2H), 3.07 (t, 2H), 2.49 (t, 2H),
2.28 (s, 6H), 1.99 (q, 2H) ppm.
Example 437
4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-1-{4-[2-(1-methyl-pyrrolidin-2-y-
l)-ethoxy]-phenyl}-1H-imidazole
[1010] To a stirred solution of 4-aminophenol (4.8 mmol) in MeOH
(20 mL), 1-bromo-4'-(4-chlorophenethoxy)acetophenone (4 mmol) was
added at rt. The resulting mixture was then heated to reflux for 45
min. The reaction mixture was then cooled to rt and the solvent was
removed in vacuuo. The resulting solid was dissolved in EtOAc (30
mL), washed with H.sub.2O (2.times.20 mL) and brine (20 mL) and
dried over sodium sulfate. Evaporation of solvent in vacuuo
afforded the desired
1-(4-hydroxyphenyl)amino-4'-(4-chlorophenethoxy)acetophenone, which
was used for further transformation.
[1011] The aminoacetophenone obtained as above (3 mmol) was
dissolved in formic acid (3 mL) and added with ammonium formate (60
mmol). The resulting mixture was heated to 90.degree. C. overnight.
The reaction mixture was then cooled down and neutralized with
saturated sodium bicarbonate solution. Usual extractive work up
with EtOAc gave the product,
4-{4-[2-(4-chlorophenyl)ethoxy]phenyl}-1-[(4-hydroxy)phenyl]-1H--
imidazole, which was purified by column chromatography (Silica
gel). Pure product was obtained from 4-6% MeOH/DCM (yield
.about.50%).
[1012] To a solution of the product obtained above (0.5 mmol) in
anhydrous THF (2 mL), NaH (60% dispersion in oil; 1 mmol) was added
at 0.degree. C. The resulting mixture was added with a solution of
the mesylate of 2-(N-methylpyrrolidin-2-yl)ethanol (0.6 mmol) in
THF (1 mL). The reaction mixture was then heated to 70.degree. C.
overnight. Usual extractive work up with EtOAc gave the product
imidazole, which was purified by column chromatography (Silica
gel). Pure product was by obtained by elution with 4-6% MeOH/DCM
(yield 125 mg).
[1013] MS m/z 503 (M+H).sup.+:
[1014] .sup.1H NMR (CDCl.sub.3): .delta.7.75 (s, 1H), 7.72 (d, 2H),
7.38 (s, 1H), 7.31 (d, 2H), 7.26 (AB.sub.q, 4H), 6.95 (d, 2H), 6.92
(d, 2H), 4.17 (t, 2H), 3.04 (t, 2H), 2.90-2.50 (m, 4H), 2.43 (s,
3H), 2.30-1.50 (m, 7H) ppm.
Example 438
1-{2-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-phenoxy]-
-ethyl}-piperazine
[1015] To a stirred solution of 4-aminophenol (4.8 mmol) in MeOH
(20 mL), 1-bromo-4'-(4-chlorophenethoxy)acetophenone (4 mmol) was
added at rt. The resulting mixture was then heated to reflux for 45
min. The reaction mixture was then cooled to rt and the solvent was
removed in vacuuo. The resulting solid was dissolved in EtOAc (30
mL), washed with H.sub.2O (2.times.20 mL) and brine (20 mL) and
dried over sodium sulfate. Evaporation of solvent in vacuuo
afforded the desired
1-(4-hydroxyphenyl)amino-4'-(4-chlorophenethoxy)acetophenone, which
was used for further transformation.
[1016] The aminoacetophenone obtained as above (3 mmol) was
dissolved in formic acid (3 mL) and added with ammonium formate (60
mmol). The resulting mixture was heated to 90.degree. C. overnight.
The reaction mixture was then cooled down and neutralized with
saturated sodium bicarbonate solution. Usual extractive work up
with EtOAc gave the product,
4-{4-[2-(4-chlorophenyl)ethoxy]phenyl}-1-[(4-hydroxy)phenyl]-1H--
imidazole, which was purified by column chromatography (Silica
gel). Pure product was obtained by elution with 4-6% MeOH/DCM
(yield .about.50%).
[1017] To a solution of the product obtained above (0.5 mmol) in
anhydrous THF (2 mL), NaH (60% dispersion in oil; 1 mmol) was added
at 0.degree. C. The resulting mixture was added with a solution of
the mesylate of 1-(t-butyloxycarbonyl)-2-(2-hydroxy)ethylpiperazine
(0.6 mmol) in THF (1 mL). The reaction mixture was then heated to
70.degree. C. overnight. Usual extractive work up with EtOAc gave
the product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained by elution with 4-6%
MeOH/DCM (yield .about.50%).
[1018] The product obtained above was treated with 4M HCl in
dioxane (1 mL) and the resulting mixture was stirred at rt for 4 h.
Evaporation of the solvent, repeated washing of the hydrochloride
salt thus obtained with diethyl ether and subsequent drying in
vacuuo afforded the desired product.
[1019] MS m/z 503 (M+H).sup.+:
[1020] .sup.1H NMR (CD.sub.3OD): .delta.9.47 (s, 1H), 8.28 (s, 1H),
7.76 (d, 2H), 7.72 (d, 2H), 7.33 (d, 2H), 7.29 (s, 4H), 7.06 (d,
2H), 4.58 (broad t, 2H), 4.22 (t, 2H), 3.83 (broad t, 4H), 3.74
(broad t, 6H), 3.06 (t, 2H) ppm.
Example 439
[3-(4-{2-(3-cyclohexyl-propyl)-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-p-
henyl]-1H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine
[1021] To a stirred solution of 4-fluoronitrobenzene (20 mmol),
4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt,
solid potassium carbonate (60 mmol) was added, and the reaction
mixture was heated to 90.degree. C. for 5 h (monitored by TLC),
according to General Procedure L1. After cooling to rt, the
reaction mixture was poured into cold H.sub.2O (60 mL). The
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with H.sub.2O (2.times.40 mL)
and brine (50 mL), and dried over anhydrous sodium sulfate. The
solvent was removed in vacuuo to afford the desired
1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude
product was used directly for further transformation without
further purification.
[1022] The nitro intermediate (2 mmol) obtained above was dissolved
in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50
mg) until completion as indicated by TLC or LC-MS, according to
General Procedure H. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline, which was used
directly for further transformation without purification (overall
yield: 95%).
[1023] To a stirred solution of ice-cold 3-diethylaminopropanol (63
mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL) was
added dropwise methanesulfonyl chloride (60 mmol), and the reaction
mixture was stirred for 2 h at 0.degree. C. and followed by
additional 1 h at rt. After the removal of the solvents in vacuuo,
the crude mesylate was dissolved in DMF (100 mL).
4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)
were added, and the mixture was heated with stirring at 90.degree.
C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction
was quenched with cold H.sub.2O (100 mL), and the resulting mixture
was extracted with EtOAc (4.times.100 mL). The combined EtOAc
extracts were washed with brine (3.times.60 ml), and dried over
anhydrous sodium sulfate. The solvent was removed in vacuuo, and
the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was
purified by silica gel column chromatography eluting with 10% MeOH
in EtOAc+0.2% TEA (yield: 75%).
[1024] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10
mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added,
according to General Procedure R1. The reaction mixture was stirred
at it for 1 h (monitored by LC-MS). The solvent was then removed in
vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly
used for further transformation.
[1025] To a stirred solution of
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline (4.8 mmol)
dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added,
followed by a slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained
above (.about.4 mmol), according to General Procedure R2. The
reaction mixture was stirred at it and under nitrogen until
completion (.about.5 h), as indicated by LC-MS. The reaction was
quenched with saturated sodium bicarbonate (50 mL), and the
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with brine (3.times.40 mL), and
dried over anhydrous sodium sulfate. The solvent was removed in
vacuuo, and the crude product was purified by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield:
64%).
[1026] To a stirred solution of the alkylated aniline described
above (0.2 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (1.2
mmol, 6 eq) was added, followed by a slow addition of
4-cyclohexylbutanoyl chloride (0.6 mmol, 3 eq), according to
General Procedure R3. The reaction mixture was stirred under
nitrogen at 0.degree. C. for 1 h and allowed to warm to rt until
completion, as indicated by LC-MS. The solvent was removed in
vacuuo, and the crude amide was used directly for further
transformation.
[1027] To a stirred solution of the amide described above
(.about.0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess,
.about.30 eq) was added, according to General Procedure R4. The
reaction mixture was stirred at 100.degree. C. for 2-5 h (as
monitored by LC-MS). The reaction mixture was then cooled down and
neutralized with saturated sodium bicarbonate. The resulting
mixture was extracted with EtOAc (3.times.50 mL). The combined
EtOAc extracts were washed with brine (3.times.20 mL), and dried
over anhydrous sodium sulfate. The solvent was removed in vacuuo,
and the pure product was obtained by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (overall
yield: 60-70%) (yield 78 mg).
[1028] MS m/z 652 (M+H).sup.+:
[1029] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.75-1.65 (m,
15H), 1.07 (t, 6H), 1.97 (m, 2H), 2.62 (q, 4H), 2.63-2.70 (m, 4H),
4.02 (t, 2H), 6.90 (d, 2H), 7.07 (d, 2H), 7.14 (s, 1H), 7.22 (br s,
1H), 7.23 (br d, 1H), 7.25 (d, 1H), 7.31 (d, 2H), 7.69 (d, 2H)
ppm.
Example 440
diethyl-(3-{4-[1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-2-(3-phen-
oxy-propyl)-1H-imidazol-4-yl]-phenoxy}-propyl)-amine
[1030] To a stirred solution of 4-fluoronitrobenzene (20 mmol),
4-fluoro-3-trifluoromethylphenol (22 mmol) in DMF (50 mL) at rt,
solid potassium carbonate (60 mmol) was added, and the reaction
mixture was heated to 90.degree. C. for 5 h (monitored by TLC),
according to General Procedure L1. After cooling to rt, the
reaction mixture was poured into cold H.sub.2O (60 mL). The
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with H.sub.2O (2.times.40 mL)
and brine (50 mL), and dried over anhydrous sodium sulfate. The
solvent was removed in vacuuo to afford the desired
1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude
product was used directly for further transformation without
further purification.
[1031] The nitro intermediate (2 mmol) obtained above was dissolved
in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (50
mg) until completion as indicated by TLC or LC-MS, according to
General Procedure H. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline, which was used
directly for further transformation without purification (overall
yield: 95%).
[1032] To a stirred solution of ice-cold 3-diethylaminopropanol (63
mmol) and TEA (80 mmol) dissolved in anhydrous DCM (50 mL) was
added dropwise methanesulfonyl chloride (60 mmol), and the reaction
mixture was stirred for 2 h at 0.degree. C. and followed by
additional 1 h at rt. After the removal of the solvents in vacuuo,
the crude mesylate was dissolved in DMF (100 mL).
4-Hydroxyacetophenone (40 mmol) and cesium carbonate (100 mmol)
were added, and the mixture was heated with stirring at 90.degree.
C. for 18 h (monitored by LC-MS). After cooling to rt, the reaction
was quenched with cold H.sub.2O (100 mL), and the resulting mixture
was extracted with EtOAc (4.times.100 mL). The combined EtOAc
extracts were washed with brine (3.times.60 ml), and dried over
anhydrous sodium sulfate. The solvent was removed in vacuuo, and
the crude 1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was
purified by silica gel column chromatography eluting with 10% MeOH
in EtOAc+0.2% TEA (yield: 75%).
[1033] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4 mmol) in MeOH (10
mL) at rt, pyrrolidone hydrotribromide (4.8 mmol) was added,
according to General Procedure R1. The reaction mixture was stirred
at rt for 1 h (monitored by LC-MS). The solvent was then removed in
vacuuo and the crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was directly
used for further transformation.
[1034] To a stirred solution of
4-(4'-fluoro-3'-trifluoromethyl-phenoxy)aniline (4.8 mmol)
dissolved in anhydrous DMF (10 mL), DIEA (12 mmol) was added,
followed by a slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone obtained
above (.about.4 mmol), according to General Procedure R2. The
reaction mixture was stirred at rt and under nitrogen until
completion (.about.5 h), as indicated by LC-MS. The reaction was
quenched with saturated sodium bicarbonate (50 mL), and the
resulting mixture was extracted with EtOAc (3.times.100 mL). The
combined EtOAc extracts were washed with brine (3.times.40 mL), and
dried over anhydrous sodium sulfate. The solvent was removed in
vacuuo, and the crude product was purified by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield:
64%).
[1035] To a stirred solution of the alkylated aniline described
above (0.2 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (1.2
mmol, 6 eq) was added, followed by a slow addition of
4-phenoxybutanoyl chloride (0.6 mmol, 3 eq), according to General
Procedure R3. The reaction mixture was stirred under nitrogen at
0.degree. C. for 1 h and allowed to warm to rt until completion, as
indicated by LC-MS. The solvent was removed in vacuuo, and the
crude amide was used directly for further transformation.
[1036] To a stirred solution of the amide described above
(.about.0.2 mmol) in acetic acid (2 mL), ammonium acetate (excess,
.about.30 eq) was added, according to General Procedure R4. The
reaction mixture was stirred at 100.degree. C. for 2-5 h (as
monitored by LC-MS). The reaction mixture was then cooled down and
neutralized with saturated sodium bicarbonate. The resulting
mixture was extracted with EtOAc (3.times.50 mL). The combined
EtOAc extracts were washed with brine (3.times.20 mL), and dried
over anhydrous sodium sulfate. The solvent was removed in vacuuo,
and the pure product was obtained by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA (yield 73
mg).
[1037] MS m/z 662 (M+H).sup.+:
[1038] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.1.06 (t, 6H), 1.97
(m, 2H), 2.24 (m, 2H), 2.60 (q, 4H), 2.67 (t, 2H), 2.88 (t, 2H),
3.99 (t, 2H), 4.03 (t, 2H), 6.80 (d, 2H), 6.90-7.25 (m, 8H), 7.01
(d, 2H), 7.15 (s, 1H), 7.28 (d, 1H), 7.70 (d, 2H) ppm.
Example 441
{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-methyl-imidazol-1-yl)-p-
henoxy]-propyl}-diethyl-amine
[1039] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
diethylaminopropoxide (2.2 mmol) in THF was added dropwise and
under a nitrogen stream, according to General Procedure L1. The
reaction mixture was stirred at 0.degree. C. for 1 h and allowed to
warm to rt until completion, as indicated by TLC or HPLC. The
reaction mixture was then treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene.
The crude product was used directly for further transformation.
[1040] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg) until completion as indicated by
TLC or HPLC, according to General Procedure H. The reaction mixture
was then filtered to remove the catalyst. The solvent was removed
in vacuuo to afford the desired 4-alkoxyaniline, which was used
directly for further transformation without further
purification.
[1041] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was
added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the
reaction mixture and heated to 80.degree. C. until completion
according to General Procedure Q1, as indicated by TLC or HPLC.
After cooling to rt, the reaction mixture was quenched using cold
water (20 ml) and the product was isolated in EtOAc (2.times.20
ml). The combined organic layers were washed with saturated sodium
bicarbonate (2.times.10 ml), water (2.times.10 ml) and brine (15
ml). The organic layer was dried over magnesium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated
acetophenone was used for further transformation.
[1042] To a stirred solution of the
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.2 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the residue
was treated with saturated sodium bicarbonate. The aqueous layer
was poured into EtOAc (20 ml) and the product was isolated in EtOAc
(2.times.20 ml). The combined organic layers were washed with
saturated sodium bicarbonate (2.times.10 ml), and brine (15 ml).
The organic layer was dried over magnesium sulfate, and the solvent
was removed in vacuuo to afford the desired product. The crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified
by chromatography (Silica gel). Pure product was obtained by
elution with 20-30% EtOAc/hexane (yield .about.70-75%).
[1043] To a stirred solution of the
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[1044] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-p-
henylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5
mL) at 0.degree. C., TEA (3 eq., 4.8 mmol) was added, followed by
slow addition of acetyl chloride (2 eq., 3.2 mmol), according to
General Procedure R3. The reaction mixture was stirred under
nitrogen at 0.degree. C. for 1 h and allowed to warm to rt until
completion, as indicated by TLC or HPLC. The reaction mixture was
then diluted with cold water and the product was isolated in DCM.
The solvent was removed in vacuuo, and the crude amide was used for
further transformation.
[1045] To a stirred solution of the amide described above (1.6
mmol) in acetic acid (4 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained by elution with 4-6%
MeOH/DCM (yield: 250 mg).
[1046] MS m/z 519 (M+H).sup.+:
[1047] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.7.67 (d, 2H), 7.22
(d, 2H), 7.21 (m, 5H), 6.96 (d, 2H), 6.84 (d, 2H), 4.17 (t, 2H),
4.07 (t, 2H), 3.06 (t, 2H), 2.78 (t, 2H), 2.74 (m, 4H), 2.36 (s,
3H), 2.06 (m, 2H), 1.13 (t, 6H) ppm
Example 442
3-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazo-
l-4-yl}-phenoxy)-1-ethyl-piperidine
[1048] To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol)
in anhydrous DCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium
bromide perbromide (1.1 eq.) was added, according to General
Procedure R1. The reaction mixture was stirred under nitrogen at rt
until completion, as indicated by TLC. The mixture was diluted with
EtOAc (100 ml) and washed with H.sub.2O (2.times.50 ml), brine (30
ml) and dried with magnesium sulfate. The solvent was then removed
in vacuuo to give a white solid. The
1-[4-(benzyloxy)phenyl]-2-bromoethanone was used for further
transformation without further purification.
[1049] To a stirred solution of
4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in
anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow
addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone described
above (2 eq), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC and HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was isolated in Et.sub.2O. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired alkylated aniline, which was purified by chromatography
(Silica gel). Pure product was obtained by elution with 5-20%
EtOAc/Hexane (yield .about.50-60%).
[1050] To a stirred solution of alkylated aniline described above
(1.0 mmol) in anhydrous THF (20 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by slow addition of valeryl chloride (3
eq, 3.0 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to ambient temperature until completion, as
indicated by TLC and HPLC. The solvent was removed in vacuuo, and
the crude amide was used for further transformation.
[1051] To a stirred solution of the amide described above (1.0
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained by elution with 5-15%
EtOAc/Hexane (yield 80%).
[1052] The above product was dissolved in MeOH (20 mL), and Pd/C
(100 mg) was added and the heterogeneous mixture was stirred
overnight under hydrogen atmosphere using a balloon, according to
General Procedure T2. The Pd/C was removed by filtration. The
solvent was removed in vacuuo, and the crude
4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol--
4-yl)phenol was used for further transformation.
[1053] A stirred solution of the
4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol--
4-yl)phenol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with
solid sodium hydride (60% dispersion in oil; 1.0 mmol) in portions.
The mesylate of 1-(methylamino)piperidin-3-ol was then added to the
reaction mixture, which was heated at 90.degree. C. overnight,
according to General Procedure T3. After cooling the mix to rt,
Et.sub.2O (30 mL) was added to the reaction mixture followed by
H.sub.2O (10 mL). The organic layer was washed with H.sub.2O
(2.times.15 mL) and brine, and dried over sodium sulfate. The
solvent was removed in vacuuo. Pure imidazole was obtained by
elution with chromatography in 5-10% MeOH/DCM (yield 52.0 mg).
[1054] MS m/z 583 (M+H).sup.+:
[1055] .sup.1H NMR (CDCl.sub.3): .delta. 7.7 (m, 2H), 7.3 (m, 3H),
7.24 (m, 2H), 7.13 (s, 1H), 7.07 (d, 2H, J=8.8 Hz), 6.94 (m, 2H),
0.9-4.4 (m, 23H) ppm.
Example 443
diethyl-[3-(4-{1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-2-methyl--
1H-imidazol-4-yl}-phenoxy)-propyl]-amine
[1056] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
4-fluoro-3-trifluoromethyl-phenoxide (2.2 mmol) in THF (may be
generated by adding the corresponding alcohol to a 1M solution of
potassium t-butoxide in THF) was added dropwise and under a
nitrogen stream, according to General Procedure L1. The reaction
mixture was stirred at 0.degree. C. until completion, as indicated
by TLC or HPLC. The solvent was then removed in vacuuo and the
reaction mixture was treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of the solvent in vacuuo afforded the desired
1-fluoro-4-(4-nitrophenoxy)-2-(trifluoromethyl)benzene. The crude
product could be used directly for further transformation.
[1057] The nitro intermediate (2 mmol) obtained above was dissolved
in MeOH (10 mL) and hydrogenated in the presence of 10% Pd/C (10
mg) until completion, as indicated by TLC or HPLC, according to
General Procedure H. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
the desired 4-[4-fluoro-3-(trifluoromethyl)phenoxy]aniline, which
was used directly for further transformation without further
purification.
[1058] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (10 mL) at rt, solid potassium carbonate (8.0 mmol) was
added. The mesylate of N,N-diethylaminopropanol (prepared from the
corresponding alcohol and methanesulfonyl chloride) (2.0 mmol) was
added to the reaction mixture and heated to 80.degree. C. until
completion according to General Procedure Q1, as indicated by TLC
or HPLC. After cooling to rt, the reaction mixture was diluted with
water and the product was isolated in EtOAc. The combined organic
layers were washed with saturated sodium bicarbonate (2.times.15
ml), water (2.times.15 ml) and brine (15 ml). The organic layer was
dried over magnesium sulfate, and the solvent was removed in vacuuo
to afford the desired
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated
product was purified using silica gel column chromatography. Pure
product was obtained with 2-3% MeOH/DCM. (yield 50-60%)
[1059] To a stirred solution of the
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described above (1
mmol) in anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone
hydrotribromide (1.2 eq., 1.2 mmol) was added, according to General
Procedure R1. The reaction mixture was stirred under nitrogen at
0.degree. C. for 1 h and was allowed to warm to rt until
completion, as indicated by TLC or HPLC. The solvent was then
removed in vacuuo, the residue was treated with saturated sodium
bicarbonate and the product was isolated in EtOAc. The combined
organic layers were washed with water (2.times.15 ml) and brine (15
ml). The organic layer was dried over magnesium sulfate, and the
solvent was removed in vacuuo to afford the desired product. The
crude 2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was
used for further transformation.
[1060] To a stirred solution of the
4-fluoro-3-trifluoromethyl-phenoxy aniline (1.2 eq., 1.2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 3 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.0 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[1061] To a stirred solution of alkylated aniline described above
(1.0 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (3 eq., 3.0
mmol) was added, followed by slow addition of acetyl chloride (2
eq., 2.0 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The reaction mixture was then diluted with water and the
product was isolated in DCM. The solvent was removed in vacuuo, and
the crude amide was purified using silica gel chromatography. Pure
product was obtained by elution with 3-4% MeOH/DCM (Yield
40-45%).
[1062] To a stirred solution of the amide described above (0.5
mmol) in acetic acid (1 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained by elution with 4-6%
MeOH/DCM (yield: 108 mg).
[1063] MS m/z 542 (M+H).sup.+:
[1064] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.7.69 (d, 2H), 7.33
(m, 5H), 7.18 (s, 1H), 7.09 (d, 2H), 6.91 (d, 2H) 4.03 (t, 2H),
2.63 (m, 6H), 2.41 (s, 3H), 2.01 (m, 2H), 1.08 (t, 6H) ppm
Example 444
(3-{4-[4-(4-benzyloxy-phenyl)-2-butyl-imidazol-1-yl]-phenoxy}-propyl)-diet-
hyl-amine
[1065] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
diethylaminopropoxide (2.2 mmol) in THF was added dropwise and
under a nitrogen stream, according to General Procedure L1. The
reaction mixture was stirred at 0.degree. C. for 1 h and allowed to
warm to rt until completion, as indicated by TLC or HPLC. The
reaction mixture was then treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene.
The crude product was used directly for further transformation.
[1066] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg) until completion as indicated by
TLC or HPLC, according to General Procedure H. The reaction mixture
was then filtered to remove the catalyst. The solvent was removed
in vacuuo to afford the desired 4-(N,N-diethylaminopropoxy)aniline,
which was used directly for further transformation without further
purification.
[1067] To a stirred solution of the 4'-benzyloxyacetophenone (2
mmol) in anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone
hydrotribromide (1.2 eq., 2.2 mmol) was added, according to General
Procedure R1. The reaction mixture was stirred under nitrogen at
0.degree. C. for 1 h and was allowed to warm to rt until
completion, as indicated by TLC or HPLC. The solvent was then
removed in vacuuo and the residue was treated with saturated sodium
bicarbonate. The aqueous layer was poured into EtOAc (20 mL) and
the product was isolated in EtOAc (2.times.20 mL). The combined
organic layers were washed with saturated sodium thiosulfate
(2.times.10 mL), water (2.times.10 mL) and brine (15 mL). The
organic layer was dried over magnesium sulfate, and the solvent was
removed in vacuuo to afford the desired product. The crude
alpha-bromoacetophenone was purified by chromatography (Silica
gel). Pure product was obtained by elution with 20-30% EtOAc/hexane
(yield .about.70-75%).
[1068] To a stirred solution of the
4-(N,N-diethylaminopropoxy)aniline (1.2 eq., 2 mmol) in anhydrous
DMF (5 mL) the alpha-bromoacetophenone (1.6 mmol) described above
was added slowly, according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[1069] To a stirred solution of alkylated aniline described above
(1.6 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (3 eq., 4.8
mmol) was added, followed by slow addition of valeryl chloride (2
eq., 3.2 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The reaction mixture was then diluted with cold water and the
product was isolated in DCM. The solvent was removed in vacuuo, and
the crude amide was used for further transformation.
[1070] To a stirred solution of the amide described above (1.6
mmol) in acetic acid (4 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained by elution with 4-6%
MeOH/DCM (yield 179 mg).
[1071] MS m/z 512 (M+H).sup.+:
[1072] .sup.1H NMR (CDCl.sub.3): .delta.7.69 (d, 2H), 7.15-7.50 (m,
8H), 7.09 (s, 1H), 6.96 (m, 3H), 5.05 (s, 2H), 4.12 (t, 2H), 3.21
(broad m, 2H), 3.15 (q, 4H), 2.64 (t, 2H) 2.38 (broad m, 2H), 1.60
(q, 2H) 1.41 (t, 6H) 1.20-1.35 (m, 2H), 0.81 (t, 6H) ppm.
Example 445
[3-(4-{2-butyl-1-[4-(2,5-difluoro-benzyloxy)-phenyl]-1H-imidazol-4-yl}-phe-
noxy)-propyl]-diethyl-amine
[1073] 3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM
(25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled
to 0.degree. C. To this mixture, methanesulfonyl chloride (30 mmol,
1.5 eq) was added slowly with stirring and the reaction mixture was
stirred at 0.degree. C. for an hour and at rt for another hour
(until the reaction was complete by HPLC). The solvent was removed
and saturated aqueous sodium bicarbonate was added. The product was
extracted with EtOAc (3.times.) and washed with sodium bicarbonate
and water. The solvent was removed in vacuuo.
[1074] The mesylate from the previous step (20 mmol, 1 eq) was
dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone
(20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added.
The mixture was heated under reflux at 85.degree. C. for 18 h
(until the reaction was complete by HPLC), after which it was
cooled to rt. Saturated aqueous sodium bicarbonate was added to the
mixture, which was then transferred to a separatory funnel. The
product was extracted with EtOAc and washed with sodium bicarbonate
and water. The solvent was removed in vacuuo and the product
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flash
chromatography (going by increasing gradient up to 10% MeOH in
DCM). The overall yield was 60%.
[1075] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (6 mL) at 0.degree. C., a 1M solution of a potassium
alkoxide (2.2 mmol) in THF (may be generated by adding the
2,5-difluorobenzyl alcohol to a 1M solution of KOBu.sup.t in THF)
was added dropwise and under a nitrogen stream, according to
General Procedure L1. The reaction mixture was stirred at 0.degree.
C. until completion, as indicated by TLC or HPLC. The reaction
mixture was then treated with cold H.sub.2O (15 mL), and extracted
with EtOAc (2.times.15 mL). The combined organic layers were washed
with brine and dried over sodium sulfate. Evaporation of the
solvent in vacuuo afforded the desired 4-alkoxynitrobenzene. The
crude product could be used directly for further transformation
without any purification, or after purifying using silica gel
column chromatography.
[1076] The nitro intermediate (2 mmol) obtained above was dissolved
in MeOH (6 mL) and hydrogenated in the presence of 10% Pd/C (10 mg)
until completion, as indicated by TLC or HPLC, according to General
Procedure H. The reaction mixture was then filtered to remove the
catalyst. The solvent was removed in vacuuo to afford
4-(2,5-difluoro-benzyloxy)aniline, which was used directly for
further transformation without further purification (yield
80%).
[1077] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2 mmol) in anhydrous
MeOH (6 mL) at 0.degree. C., pyrrolidone hydrotribromide (1.2 eq)
was added, according to General Procedure R1. The reaction mixture
was stirred under nitrogen at 0.degree. C. for 1 h and was allowed
to warm to rt until completion, as indicated by TLC or HPLC. The
solvent was then removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1078] To a solution of 4-(2,5-difluoro-benzyloxy)aniline (1 eq, 2
mmol) in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added,
followed by addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (2 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was purified by chromatography
(Silica gel). Pure product by elution with 2-4% MeOH/DCM (yield
50%).
[1079] To a stirred solution of alkylated aniline described above
(1 mmol) in anhydrous DCM (4 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by a slow addition of valeryl chloride (3
eq, 3 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[1080] To a stirred solution of the amide described above (1 mmol)
in acetic acid (4 mL), ammonium acetate (20 mmol, 20 eq) was added,
according to General Procedure R4. The reaction mixture was stirred
at 90.degree. C. overnight. The reaction mixture was then cooled to
rt and neutralized with saturated sodium bicarbonate solution.
Usual extractive work up with EtOAc gave the product imidazole,
which was purified by column chromatography (Silica gel). Pure
product was obtained by elution with 4-6% MeOH/DCM (yield 208
mg).
[1081] MS m/z 549 (M+H).sup.+:
[1082] .sup.1H NMR (CDCl.sub.3): .delta.7.68 (d, 2H), 7.24 (m, 5H),
7.13 (s, 1H), 7.06 (d, 2H), 6.89 (d, 2H), 5.17 (s, 2H), 4.02 (t,
2H), 2.62-2.78 (m, 8H), 1.98 (m, 2H), 1.60 (m, 2H), 1.27 (m, 2H),
1.11 (t, 6H), 0.82 (t, 3H) ppm.
Example 446
3-(S)-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imi-
dazol-4-yl}-phenoxymethyl)-1-ethyl-piperidine
[1083] To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol)
in anhydrous DCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium
bromide perbromide (1.1 eq.) was added. The reaction mixture was
stirred under nitrogen at rt until completion, as indicated by TLC.
The mixture was diluted with EtOAc (100 ml) and washed with
H.sub.2O (2.times.50 ml), brine (30 ml) and dried with magnesium
sulfate. The solvent was then removed in vacuuo to give a white
solid. The alpha-bromoacetophenone was used for further
transformation without further purification.
[1084] To a stirred solution of
4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in
anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow
addition of the alpha-bromoacetophenone described above (2 eq),
according to General Procedure R2. The reaction mixture was stirred
under nitrogen at rt until completion, as indicated by TLC and
HPLC. The reaction mixture was then diluted with cold H.sub.2O and
the product was isolated in Et.sub.2O. The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of solvent in vacuuo afforded the desired product. The crude
alkylated aniline was purified by chromatography (Silica gel). Pure
product was obtained by elution with 5-20% EtOAc/Hexane (yield
.about.50-60%).
[1085] To a stirred solution of alkylated aniline described above
(1.0 mmol) in anhydrous THF (20 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by slow addition of valeryl chloride (3
eq, 3.0 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to ambient temperature until completion, as
indicated by TLC and HPLC. The solvent was removed in vacuuo, and
the crude amide was used for further transformation.
[1086] To a stirred solution of the amide described above (1.0
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained by elution with 5-15
EtOAc/Hexane (yield 80%).
[1087] (MS: m/z 562 (M+H).sup.+)
[1088] The above product was dissolved in MeOH (20 mL), and Pd/C
(100 mg) was added and the heterogeneous mixture was stirred
overnight under hydrogen atmosphere using a balloon, according to
General Procedure T2. The Pd/C was removed by filtration. The
solvent was removed in vacuuo, and the crude
4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol--
4-yl)phenol (MS: m/z 472 (M+H).sup.+) was used for further
transformation.
[1089] A stirred solution of the
4-(1-{-4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-
-4-yl)phenol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with
solid sodium hydride (60% dispersion in oil; 1.0 mmol) in portions.
The mesylate of [(3S)-1-ethylpiperidin-3-yl]methanol (1.5-2.0 eq)
was added to the reaction mixture, which was heated at 90.degree.
C. overnight, according to General Procedure T3. After cooling the
mix to rt, Et.sub.2O (30 mL) was added to the reaction mixture
followed by H.sub.2O (10 mL). The organic layer was washed with
H.sub.2O (2.times.15 mL) and brine, and dried over sodium sulfate.
The solvent was removed in vacuuo. Pure imidazole was obtained by
elution with chromatography in 5-10% MeOH/DCM (yield 50.0 mg).
[1090] MS m/z 597 (M+H).sup.+:
[1091] .sup.1H NMR (CDCl.sub.3): .delta. 7.70 (d, 2H), 7.20-7.35
(m, 5H), 7.14 (s, 1H), 7.08 (d, 2H), 6.92 (d, 2H), 4.05 (m, 1H),
3.92 (m, 2H), 2.60 (m, 4H), 1.0-2.5 (m, 18H) ppm.
Example 447
(3-{4-[4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-(2,4,4-trimethyl-pentyl-
)-imidazol-1-yl]-phenoxy}-propyl)-diethyl-amine
[1092] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
diethylaminopropoxide (2.2 mmol) in THF was added dropwise and
under a nitrogen stream, according to General Procedure L1. The
reaction mixture was stirred at 0.degree. C. for 1 h and allowed to
warm to rt until completion, as indicated by TLC or HPLC. The
reaction mixture was then treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene.
The crude product was used directly for further transformation.
[1093] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg) until completion as indicated by
TLC or HPLC, according to General Procedure H. The reaction mixture
was then filtered to remove the catalyst. The solvent was removed
in vacuuo to afford the desired 4-alkoxyaniline, which was used
directly for further transformation without further
purification.
[1094] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was
added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the
reaction mixture and heated to 80.degree. C. until completion
according to General Procedure Q1, as indicated by TLC or HPLC.
After cooling to rt, the reaction mixture was quenched using cold
water (20 ml) and the product was isolated in EtOAc (2.times.20
ml). The combined organic layers were washed with saturated sodium
bicarbonate (2.times.10 ml), water (2.times.10 ml) and brine (15
ml). The organic layer was dried over magnesium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated
acetophenone was used for further transformation.
[1095] To a stirred solution of the
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.2 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the residue
was treated with saturated sodium bicarbonate. The aqueous layer
was poured into EtOAc (20 ml) and the product was isolated in EtOAc
(2.times.20 ml). The combined organic layers were washed with
saturated sodium bicarbonate (2.times.10 ml), and brine (15 ml).
The organic layer was dried over magnesium sulfate, and the solvent
was removed in vacuuo to afford the desired product. The crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was purified
by chromatography (Silica gel). Pure product was obtained by
elution with 20-30% EtOAc/hexane (yield .about.70-75%).
[1096] To a stirred solution of the
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[1097] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-p-
henylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5
mL) at 0.degree. C., TEA (3 eq., 4.8 mmol) was added, followed by
slow addition of 3,5,5-trimethyl hexanoyl chloride (2 eq., 3.2
mmol), according to General Procedure R3. The reaction mixture was
stirred under nitrogen at 0.degree. C. for 1 h and allowed to warm
to rt until completion, as indicated by TLC or HPLC. The reaction
mixture was then diluted with cold water and the product was
isolated in DCM. The solvent was removed in vacuuo, and the crude
amide was used for further transformation.
[1098] To a stirred solution of the amide described above (1.6
mmol) in acetic acid (4 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained by elution with 4-6%
MeOH/DCM (yield: 296 mg).
[1099] MS m/z value (M+H).sup.+: 617
[1100] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.7.69 (d, 2H), 7.22
(d, 2H), 7.21 (m, 5H), 6.96 (d, 2H), 6.88 (d, 2H), 4.18 (t, 2H),
4.07 (t, 2H), 3.09 (t, 2H), 2.88 (d, 2H), 2.79 (m, 6H), 2.05 (m,
3H), 1.11 (t, 6H), 0.97 (d, 2H), 0.87 (d, 3H), 0.78 (s, 9H) ppm
Example 448
3-(R)-(4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imi-
dazol-4-yl}-phenoxymethyl)-1-ethyl-piperidine
[1101] To a stirred solution of 4-benzyloxyacetophenone (7.0 mmol)
in anhydrous DCM (30.0 mL) and MeOH (5.0 mL) at rt, pyridinium
bromide perbromide (1.1 eq.) was added. The reaction mixture was
stirred under nitrogen at rt until completion, as indicated by TLC.
The mixture was diluted with EtOAc (100 ml) and washed with
H.sub.2O (2.times.50 ml), brine (30 ml) and dried with magnesium
sulfate. The solvent was then removed in vacuuo to give a white
solid. The alpha-bromoacetophenone was used for further
transformation without further purification.
[1102] To a stirred solution of
4-(4-fluoro-3-trifluoromethyl-phenoxy)-aniline (1.64 mmol) in
anhydrous DMF (30 mL) DIEA (3 eq) was added, followed by slow
addition of the alpha-bromoacetophenone described above (2 eq),
according to General Procedure R2. The reaction mixture was stirred
under nitrogen at rt until completion, as indicated by TLC and
HPLC. The reaction mixture was then diluted with cold H.sub.2O and
the product was isolated in Et.sub.2O. The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of solvent in vacuuo afforded the desired product. The crude
alkylated aniline was purified by chromatography (Silica gel). Pure
product was obtained by elution with 5-20% EtOAc/Hexane (yield
.about.50-60%).
[1103] To a stirred solution of alkylated aniline described above
(1.0 mmol) in anhydrous THF (20 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by slow addition of valeryl chloride (3
eq, 3.0 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to ambient temperature until completion, as
indicated by TLC and HPLC. The solvent was removed in vacuuo, and
the crude amide was used for further transformation.
[1104] To a stirred solution of the amide described above (1.0
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained by elution with 5-15%
EtOAc/Hexane (yield 80%). (MS: m/z 562 (M+H).sup.+)
[1105] The above product was dissolved in MeOH (20 mL), and Pd/C
(100 mg) was added and the heterogeneous mixture was stirred
overnight under hydrogen atmosphere using a balloon, according to
General Procedure T2. The Pd/C was removed by filtration. The
solvent was removed in vacuuo, and the crude
4-(1-{-4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol-
-4-yl)phenol (MS: m/z 472 (M+H).sup.+) was used for further
transformation.
[1106] A stirred solution of the
4-(1-{4-[4-fluoro-3-(trifluoromethyl)phenoxy]phenyl}-2-butyl-1H-imidazol--
4-yl)phenol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with
solid sodium hydride (60% dispersion in oil; 1.0 mmol) in portions.
The mesylate of [(3R)-1-ethylpiperidin-3-yl]methanol (1.5-2.0 eq)
was added to the reaction mixture, which was heated at 90.degree.
C. overnight, according to General Procedure T3. After cooling the
mix to rt, Et.sub.2O (30 mL) was added to the reaction mixture
followed by H.sub.2O (10 mL). The organic layer was washed with
H.sub.2O (2.times.15 mL) and brine, and dried over sodium sulfate.
The solvent was removed in vacuuo. Pure imidazole was obtained by
elution with chromatography in 5-10% MeOH/DCM (yield 50.0 mg).
[1107] MS m/z 597 (M+H).sup.+:
[1108] .sup.1H NMR (CDCl.sub.3): .delta. 7.70 (d, 2H), 7.20-7.35
(m, 5H), 7.14 (s, 1H), 7.08 (d, 2H,), 6.92 (d, 2H), 4.05 (m, 1H),
3.92 (m, 2H), 2.60 (m, 4H), 1.0-2.5 (m, 18H). ppm.
Example 449
[3-(4-{2-butyl-1-[4-(3-tert-butyl-phenoxy)-phenyl]1H-imidazol-4-yl}-phenox-
y)-propyl]-diethyl-amine
[1109] 3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM
(25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled
to 0.degree. C. To this mixture, methanesulfonyl chloride (30 mmol,
1.5 eq) was added slowly with stirring and the reaction mixture was
stirred at 0.degree. C. for an hour and at rt for another hour
(until the reaction was complete by HPLC). The solvent was removed
and saturated aqueous sodium bicarbonate was added. The product was
extracted with EtOAc (3.times.) and washed with sodium bicarbonate
and water. The solvent was removed in vacuuo.
[1110] The mesylate from the previous step (20 mmol, 1 eq) was
dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone
(20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added.
The mixture was heated under reflux at 85.degree. C. for 18 h
(until the reaction was complete by HPLC), after which it was
cooled to rt. Saturated aqueous sodium bicarbonate was added to the
mixture, which was then transferred to a separatory funnel. The
product was extracted with EtOAc and washed with sodium bicarbonate
and water. The solvent was removed in vacuuo and the product
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flash
chromatography (going by increasing gradient up to 10% MeOH in
DCM). The overall yield was 60%.
[1111] 4-Methoxyphenol (10 mmol) was dissolved in 15 ml of
anhydrous DMF and potassium carbonate (30 mmol) was added with
stirring at rt. 4-Fluoronitrobenzene (10 mmol) was added to this
mixture, which was then heated under reflux at 80.degree. C. for 18
h. The reaction was quenched with 30 ml of water and 30 ml of
sodium bicarbonate, extracted with EtOAc (3.times.50 ml) and washed
with sodium bicarbonate and water. The EtOAc layer was dried over
anhydrous sodium sulfate and filtered, after which the solvent was
removed in vacuuo.
[1112] The nitro intermediate (10 mmol) obtained above was
dissolved in EtOH (30 mL) and hydrogenated in the presence of 10%
Pd/C (10 mg) until completion as indicated by TLC or HPLC,
according to General Procedure H. The reaction mixture was then
filtered to remove the catalyst. The solvent was removed in vacuuo
to afford the desired 4-(3-tert-butyl-phenoxy)aniline, which was
used directly for further transformation without further
purification (yield 80%).
[1113] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2 mmol) in anhydrous
MeOH (6 mL) at 0.degree. C., pyrrolidone hydrotribromide (1.2 eq)
was added, according to General Procedure R1. The reaction mixture
was stirred under nitrogen at 0.degree. C. for 1 h and was allowed
to warm to rt until completion, as indicated by TLC or HPLC. The
solvent was then removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1114] To a solution of 4-(3-tert-butyl-phenoxy)aniline (1 eq, 2
mmol) in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added,
followed by addition of the
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (2 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was purified by chromatography
(Silica gel). Pure product by elution with 2-4% MeOH/DCM (yield
51%).
[1115] To a stirred solution of alkylated aniline described above
(1 mmol) in anhydrous DCM (4 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by a slow addition of valeryl chloride (3
eq, 3 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[1116] To a stirred solution of the amide described above (1 mmol)
in acetic acid (4 mL), ammonium acetate (20 eq) was added,
according to General Procedure R4. The reaction mixture was stirred
at 90.degree. C. overnight. The reaction mixture was then cooled to
rt and neutralized with saturated sodium bicarbonate solution.
Usual extractive work up with EtOAc gave the product imidazole,
which was purified by column chromatography (Silica gel). Pure
product was obtained by elution with 4-6% MeOH/DCM (yield 177
mg).
[1117] MS m/z 555 (M+H).sup.+:
[1118] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.7 (d, 2H), 7.3
(m, 4H), 7.1-7.2 (m, 5H), 6.9 (d, 2H), 4.0 (t, 2H), 2.8-3.0 (m,
8H), 2.0 (m, 2H), 1.6 (m, 2H), 1.4 (m, 2H), 1.2 (15H), 0.8 (t, 3H)
ppm
Example 450
{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-methoxymethyl-imidazol--
1-yl)-phenoxy]-propyl}-diethyl-amine
[1119] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
diethylaminopropoxide (2.2 mmol) in THF was added dropwise and
under a nitrogen stream, according to General Procedure L1. The
reaction mixture was stirred at 0.degree. C. for 1 h and allowed to
warm to rt until completion, as indicated by TLC or HPLC. The
reaction mixture was then treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene.
The crude product was used directly for further transformation.
[1120] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg) until completion as indicated by
TLC or HPLC, according to General Procedure H. The reaction mixture
was then filtered to remove the catalyst. The solvent was removed
in vacuuo to afford the desired 4-alkoxyaniline, which was used
directly for further transformation without further
purification.
[1121] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was
added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the
reaction mixture and heated to 80.degree. C. until completion
according to General Procedure Q1, as indicated by TLC or HPLC.
After cooling to rt, the reaction mixture was quenched using cold
water (20 ml) and the product was isolated in EtOAc (2.times.20
ml). The combined organic layers were washed with saturated sodium
bicarbonate (2.times.10 ml), water (2.times.10 ml) and brine (15
ml). The organic layer was dried over magnesium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated
acetophenone was used for further transformation.
[1122] To a stirred solution of the
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.2 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the residue
was treated with saturated sodium bicarbonate. The aqueous layer
was poured into EtOAc (20 ml) and the product was isolated in EtOAc
(2.times.20 ml). The combined organic layers were washed with
saturated sodium bicarbonate (2.times.10 ml), and brine (15 ml).
The organic layer was dried over magnesium sulfate, and the solvent
was removed in vacuuo to afford the desired product. The crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was purified
by chromatography (Silica gel). Pure product was obtained by
elution with 20-30% EtOAc/hexane (yield .about.70-75%).
[1123] To a stirred solution of the
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[1124] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-p-
henylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5
mL) at 0.degree. C., TEA (3 eq., 4.8 mmol) was added, followed by
slow addition of methoxy acetyl chloride (2 eq., 3.2 mmol),
according to General Procedure R3. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and allowed to warm to rt
until completion, as indicated by TLC or HPLC. The reaction mixture
was then diluted with cold water and the product was isolated in
DCM. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[1125] To a stirred solution of the amide described above (1.6
mmol) in acetic acid (4 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained by elution with 4-6%
MeOH/DCM (yield: 265 mg).
[1126] MS m/z 549 (M+H).sup.+:
[1127] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.7.72 (d, 2H), 7.37
(d, 2H), 7.48 (m, 5H), 6.98 (d, 2H), 6.85 (d, 2H), 4.41 (s, 2H),
4.18 (t, 2H), 4.07 (t, 2H), 3.45 (s, 3H), 3.06 (t, 2H), 2.86 (m,
6H), 2.08 (m, 2H), 1.17 (t, 6H) ppm
Example 451
(3-{4-[4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-(1-ethyl-propyl)-imidaz-
ol-1-yl]-phenoxy}-propyl)-diethyl-amine
[1128] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
diethylaminopropoxide (2.2 mmol) in THF was added dropwise and
under a nitrogen stream, according to General Procedure L1. The
reaction mixture was stirred at 0.degree. C. for 1 h and allowed to
warm to rt until completion, as indicated by TLC or HPLC. The
reaction mixture was then treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene.
The crude product was used directly for further transformation.
[1129] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg) until completion as indicated by
TLC or HPLC, according to General Procedure H. The reaction mixture
was then filtered to remove the catalyst. The solvent was removed
in vacuuo to afford the desired 4-alkoxyaniline, which was used
directly for further transformation without further
purification.
[1130] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was
added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the
reaction mixture and heated to 80.degree. C. until completion
according to General Procedure Q1, as indicated by TLC or HPLC.
After cooling to rt, the reaction mixture was quenched using cold
water (20 ml) and the product was isolated in EtOAc (2.times.20
ml). The combined organic layers were washed with saturated sodium
bicarbonate (2.times.10 ml), water (2.times.10 ml) and brine (15
ml). The organic layer was dried over magnesium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated
acetophenone was used for further transformation.
[1131] To a stirred solution of the
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.2 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the residue
was treated with saturated sodium bicarbonate. The aqueous layer
was poured into EtOAc (20 ml) and the product was isolated in EtOAc
(2.times.20 ml). The combined organic layers were washed with
saturated sodium bicarbonate (2.times.10 ml), and brine (15 ml).
The organic layer was dried over magnesium sulfate, and the solvent
was removed in vacuuo to afford the desired product. The crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified
by chromatography (Silica gel). Pure product was obtained by
elution with 20-30% EtOAc/hexane (yield .about.70-75%).
[1132] To a stirred solution of the
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[1133] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-p-
henylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5
mL) at 0.degree. C., TEA (3 eq., 4.8 mmol) was added, followed by
slow addition of 2-ethyl butyryl chloride (2 eq., 3.2 mmol),
according to General Procedure R3. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and allowed to warm to rt
until completion, as indicated by TLC or HPLC. The reaction mixture
was then diluted with cold water and the product was isolated in
DCM. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[1134] To a stirred solution of the amide described above (1.6
mmol) in acetic acid (4 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained by elution with 4-6%
MeOH/DCM (yield: 230 mg).
[1135] MS m/z 575 (M+H).sup.+:
[1136] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.7.71 (d, 2H), 7.27
(m, 6H), 7.06 (s, 1H), 6.95 (d, 2H), 6.87 (d, 2H), 4.09 (t, 2H),
4.02 (t, 2H), 3.07 (t, 2H), 2.72 (m, 6H), 2.49 (m, 1H), 2.06 (m,
2H), 1.82 (m, 2H), 1.68 (m, 2H), 1.08 (t, 6H), 0.96 (t, 3H), 0.88
(t, 3H) ppm
Example 452
(3-{4-[4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-(3-phenoxy-propyl)-imid-
azol-1-yl]-phenoxy}-propyl)-diethyl-amine
[1137] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg) until completion as indicated by
TLC or HPLC, according to General Procedure H. The reaction mixture
was then filtered to remove the catalyst. The solvent was removed
in vacuuo to afford the desired 4-alkoxyaniline, which was used
directly for further transformation without further
purification.
[1138] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was
added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the
reaction mixture and heated to 80.degree. C. until completion
according to General Procedure Q1, as indicated by TLC or HPLC.
After cooling to rt, the reaction mixture was quenched using cold
water (20 ml) and the product was isolated in EtOAc (2.times.20
ml). The combined organic layers were washed with saturated sodium
bicarbonate (2.times.10 ml), water (2.times.10 ml) and brine (15
ml). The organic layer was dried over magnesium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated
acetophenone was used for further transformation.
[1139] To a stirred solution of the
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.2 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the residue
was treated with saturated sodium bicarbonate. The aqueous layer
was poured into EtOAc (20 ml) and the product was isolated in EtOAc
(2.times.20 ml). The combined organic layers were washed with
saturated sodium bicarbonate (2.times.10 ml), and brine (15 ml).
The organic layer was dried over magnesium sulfate, and the solvent
was removed in vacuuo to afford the desired product. The crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified
by chromatography (Silica gel). Pure product was obtained by
elution with 20-30% EtOAc/hexane (yield .about.70-75%).
[1140] To a stirred solution of the
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[1141] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-p-
henylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5
mL) at 0.degree. C., TEA (3 eq., 4.8 mmol) was added, followed by
slow addition of 4-phenoxy butyryl chloride (2 eq., 3.2 mmol),
according to General Procedure R3. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and allowed to warm to rt
until completion, as indicated by TLC or HPLC. The reaction mixture
was then diluted with cold water and the product was isolated in
DCM. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[1142] To a stirred solution of the amide described above (1.6
mmol) in acetic acid (4 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained by elution with 4-6%
MeOH/DCM (yield: 250 mg).
[1143] MS m/z 638 (M+H).sup.+:
[1144] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.7.69 (d, 2H),
7.23-7.25 (m, 8H), 7.12 (s, 1H), 6.92 (m 5H), 6.81 (d, 2H), 4.18
(t, 2H), 4.09 (t, 2H), 3.95 (t, 2H), 3.07 (t, 2H), 2.85 (m, 8H),
2.22 (m, 2H), 2.05 (m, 2H), 1.20 (t, 6H) ppm
Example 453
(3-{4-[4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-(1-propyl-butyl)-imidaz-
ol-1-yl]-phenoxy}-propyl)-diethyl-amine
[1145] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
diethylaminopropoxide (2.2 mmol) in THF was added dropwise and
under a nitrogen stream, according to General Procedure L1. The
reaction mixture was stirred at 0.degree. C. for 1 h and allowed to
warm to rt until completion, as indicated by TLC or HPLC. The
reaction mixture was then treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene.
The crude product was used directly for further transformation.
[1146] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg) until completion as indicated by
TLC or HPLC, according to General Procedure H. The reaction mixture
was then filtered to remove the catalyst. The solvent was removed
in vacuuo to afford the desired 4-alkoxyaniline, which was used
directly for further transformation without further
purification.
[1147] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was
added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the
reaction mixture and heated to 80.degree. C. until completion
according to General Procedure Q1, as indicated by TLC or HPLC.
After cooling to rt, the reaction mixture was quenched using cold
water (20 ml) and the product was isolated in EtOAc (2.times.20
ml). The combined organic layers were washed with saturated sodium
bicarbonate (2.times.10 ml), water (2.times.10 ml) and brine (15
ml). The organic layer was dried over magnesium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated
acetophenone was used for further transformation.
[1148] To a stirred solution of the
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.2 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the residue
was treated with saturated sodium bicarbonate. The aqueous layer
was poured into EtOAc (20 ml) and the product was isolated in EtOAc
(2.times.20 ml). The combined organic layers were washed with
saturated sodium bicarbonate (2.times.10 ml), and brine (15 ml).
The organic layer was dried over magnesium sulfate, and the solvent
was removed in vacuuo to afford the desired product. The crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified
by chromatography (Silica gel). Pure product was obtained by
elution with 20-30% EtOAc/hexane (yield .about.70-75%).
[1149] To a stirred solution of the
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[1150] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-p-
henylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5
mL) at 0.degree. C., TEA (3 eq., 4.8 mmol) was added, followed by
slow addition of 2-N-propyl-N-valeryl chloride (2 eq., 3.2 mmol),
according to General Procedure R3. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and allowed to warm to rt
until completion, as indicated by TLC or HPLC. The reaction mixture
was then diluted with cold water and the product was isolated in
DCM. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[1151] To a stirred solution of the amide described above (1.6
mmol) in acetic acid (4 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained by elution with 4-6%
MeOH/DCM (yield: 288 mg).
[1152] MS m/z 602 (M+H).sup.+:
[1153] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.7.69 (d, 2H),
7.23-7.25 (m, 6H), 7.04 (s, 1H), 6.97 (d, 2H), 6.87 (d, 2H), 4.18
(t, 2H), 4.09 (t, 2H), 3.06 (t, 2H), 2.87 (m, 6H), 2.63 (m, 1H),
2.13 (m, 2H), 1.81 (m, 2H), 1.54 (m, 2H), 1.17 (t, 10H), 0.89 (t,
6H) ppm
Example 454
{3-[4-(2-(4-chloro-phenoxymethyl)-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl-
}-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine
[1154] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
diethylaminopropoxide (2.2 mmol) in THF was added dropwise and
under a nitrogen stream, according to General Procedure L1. The
reaction mixture was stirred at 0.degree. C. for 1 h and allowed to
warm to rt until completion, as indicated by TLC or HPLC. The
reaction mixture was then treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene.
The crude product was used directly for further transformation.
[1155] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg) until completion as indicated by
TLC or HPLC, according to General Procedure H. The reaction mixture
was then filtered to remove the catalyst. The solvent was removed
in vacuuo to afford the desired 4-alkoxyaniline, which was used
directly for further transformation without further
purification.
[1156] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was
added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the
reaction mixture and heated to 80.degree. C. until completion
according to General Procedure Q1, as indicated by TLC or HPLC.
After cooling to rt, the reaction mixture was quenched using cold
water (20 ml) and the product was isolated in EtOAc (2.times.20
ml). The combined organic layers were washed with saturated sodium
bicarbonate (2.times.10 ml), water (2.times.10 ml) and brine (15
ml). The organic layer was dried over magnesium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated
acetophenone was used for further transformation.
[1157] To a stirred solution of the
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.2 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the residue
was treated with saturated sodium bicarbonate. The aqueous layer
was poured into EtOAc (20 ml) and the product was isolated in EtOAc
(2.times.20 ml). The combined organic layers were washed with
saturated sodium bicarbonate (2.times.10 ml), and brine (15 ml).
The organic layer was dried over magnesium sulfate, and the solvent
was removed in vacuuo to afford the desired product. The crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified
by chromatography (Silica gel). Pure product was obtained by
elution with 20-30% EtOAc/hexane (yield .about.70-75%).
[1158] To a stirred solution of the
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[1159] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-p-
henylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5
mL) at 0.degree. C., TEA (3 eq., 4.8 mmol) was added, followed by
slow addition of 4-chlorophenoxy acetyl chloride (2 eq., 3.2 mmol),
according to General Procedure R3. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and allowed to warm to rt
until completion, as indicated by TLC or HPLC. The reaction mixture
was then diluted with cold water and the product was isolated in
DCM. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[1160] To a stirred solution of the amide described above (1.6
mmol) in acetic acid (4 mL), ammonium acetate (excess, -20 eq.) was
added, according to General Procedure R4. The reaction mixture was
stirred at 90.degree. C. overnight. The reaction mixture was then
cooled to rt and neutralized with saturated sodium bicarbonate
solution. Usual extractive work up with EtOAc gave the product
imidazole, which was purified by column chromatography (Silica
gel). Pure product was obtained by elution with 4-6% MeOH/DCM
(yield: 250 mg).
[1161] MS m/z 644 (M+H).sup.+:
[1162] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.7.72 (d, 2H), 7.36
(d, 2H), 7.23-7.25 (m, 4H), 7.23 (m, 4H), 6.91 (m, 5H), 4.95 (s,
2H), 4.17 (t, 2H), 4.05 (t, 2H), 3.07 (m, 8H), 2.21 (m, 2H), 1.27
(t, 6H) ppm
Example 455
{3-[4-(2-benzyloxymethyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazo-
l-1-yl)-phenoxy]-propyl}-diethyl-amine
[1163] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
diethylaminopropoxide (2.2 mmol) in THF was added dropwise and
under a nitrogen stream, according to General Procedure L1. The
reaction mixture was stirred at 0.degree. C. for 1 h and allowed to
warm to rt until completion, as indicated by TLC or HPLC. The
reaction mixture was then treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene.
The crude product was used directly for further transformation.
[1164] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg) until completion as indicated by
TLC or HPLC, according to General Procedure H. The reaction mixture
was then filtered to remove the catalyst. The solvent was removed
in vacuuo to afford the desired 4-alkoxyaniline, which was used
directly for further transformation without further
purification.
[1165] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was
added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the
reaction mixture and heated to 80.degree. C. until completion
according to General Procedure Q1, as indicated by TLC or HPLC.
After cooling to rt, the reaction mixture was quenched using cold
water (20 ml) and the product was isolated in EtOAc (2.times.20
ml). The combined organic layers were washed with saturated sodium
bicarbonate (2.times.10 ml), water (2.times.10 ml) and brine (15
ml). The organic layer was dried over magnesium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated
acetophenone was used for further transformation.
[1166] To a stirred solution of the
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.2 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the residue
was treated with saturated sodium bicarbonate. The aqueous layer
was poured into EtOAc (20 ml) and the product was isolated in EtOAc
(2.times.20 ml). The combined organic layers were washed with
saturated sodium bicarbonate (2.times.10 ml), and brine (15 ml).
The organic layer was dried over magnesium sulfate, and the solvent
was removed in vacuuo to afford the desired product. The crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified
by chromatography (Silica gel). Pure product was obtained by
elution with 20-30% EtOAc/hexane (yield .about.70-75%).
[1167] To a stirred solution of the
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[1168] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-p-
henylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5
mL) at 0.degree. C., TEA (3 eq., 4.8 mmol) was added, followed by
slow addition of benzyloxyacetyl chloride (2 eq., 3.2 mmol),
according to General Procedure R3. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and allowed to warm to it
until completion, as indicated by TLC or HPLC. The reaction mixture
was then diluted with cold water and the product was isolated in
DCM. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[1169] To a stirred solution of the amide described above (1.6
mmol) in acetic acid (4 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained by elution with 4-6%
MeOH/DCM (yield: 350 mg).
[1170] MS m/z 624 (M+H).sup.+:
[1171] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.7.71 (d, 2H), 7.68
(d, 2H), 7.31 (m, 7H), 7.25 (d, 2H), 7.21 (s, 1H), 6.94 (d, 2H),
6.89 (d, 2H), 4.58 (s, 2H), 4.49 (s, 2H), 4.15 (t, 2H), 4.08 (t,
2H), 3.11 (t, 2H), 2.89 (m, 6H), 2.18 (m, 2H), 1.35 (t, 6H) ppm
Example 456
{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-isobutyl-5-methyl-imida-
zol-1-yl)-phenoxy]-propyl}-diethyl-amine
[1172] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]phenyl}-propan-1-one (1.0 mmol) in
dioxane (10.0 mL) at rt, pyridinium bromide perbromide (1.1 eq) was
added. The reaction mixture was stirred under nitrogen at rt until
completion, as indicated by TLC. The mixture was diluted with EtOAc
(100 ml) and washed with H.sub.2O (2.times.50 ml), brine (30 ml)
and dried with magnesium sulfate. The solvent was then removed in
vacuuo to give a white solid. The alpha-bromoketone was used for
further transformation without further purification.
[1173] A solution of the above alpha-bromoketone (1.0 eq),
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq), and DIEA
(1.5 eq) in anhydrous DMF (10 mL) was stirred under nitrogen at rt
until completion, as indicated by HPLC. The reaction mixture was
then diluted with cold H.sub.2O and the product was isolated in
Et.sub.2O. The combined organic layers were washed with brine and
dried over sodium sulfate. The solvent was removed in vacuuo
afforded the desired product. The crude alkylated aniline was
purified by chromatography (Silica gel). Pure product was obtained
by elution with 2-7% MeOH/DCM (yield .about.55%).
[1174] To a stirred solution of alkylated aniline described above
(0.55 mmol) in anhydrous THF (5 mL) at 0.degree. C., TEA (3.0 mmol)
was added, followed by slow addition of isovaleryl chloride (5.0
mmol), according to General Procedure R3. The reaction mixture was
stirred under nitrogen at 0.degree. C. for 1 h and allowed to warm
to ambient temperature until completion, as indicated by HPLC. The
solvent was removed in vacuuo, and the crude amide was used for
further transformation.
[1175] To a stirred solution of the amide described above (0.55
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 100.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole (yield 190 mg).
[1176] MS m/z 574 (M+H).sup.+:
Example 457
{3-[4-(4-{4-[2-(4-chloro-phenyl)-ethoxy]phenyl}-2-isobutyl-5-propyl-imidaz-
ol-1-yl)-phenoxy]-propyl}-diethyl-amine
[1177] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]phenyl}-pentan-1-one (1.0 mmol) in
dioxane (10.0 mL) at rt , pyridinium bromide perbromide (1.1 eq.)
was added. The reaction mixture was stirred under nitrogen at it
until completion, as indicated by TLC. The mixture was diluted with
EtOAc (100 ml) and washed with H.sub.2O (2.times.50 ml), brine (30
ml) and dried with magnesium sulfate. The solvent was then removed
in vacuuo to give a white solid. The alpha-bromophenone was used
for further transformation.
[1178] A solution of the above alpha-bromophenone (1.0 eq),
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq), and DIEA
(1.5 eq) in anhydrous DMF (10 mL) was stirred under nitrogen at it
until completion, as indicated by HPLC. The reaction mixture was
then diluted with cold H.sub.2O and the product was isolated in
Et.sub.2O. The combined organic layers were washed with brine and
dried over sodium sulfate. The solvent was removed in vacuuo
afforded the desired product. The crude alkylated aniline was
purified by chromatography (Silica gel). Pure product was obtained
by elution with 2-5% MeOH/DCM (yield .about.50%).
[1179] To a stirred solution of alkylated aniline described above
(0.48 mmol) in anhydrous THF (5 mL) at 0.degree. C., DMAP (0.25 eq)
was added, followed by slow addition of isovaleryl chloride (5.0
mmol), according to General Procedure R3. The reaction mixture was
stirred under nitrogen at 0.degree. C. for 1 h and allowed to warm
to ambient temperature until completion, as indicated by HPLC. The
solvent was removed in vacuuo, and the crude amide was used for
further transformation.
[1180] To a stirred solution of the amide described above (0.48
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 100.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole (yield 180 mg).
[1181] MS m/z 602 (M+H).sup.+:
[1182] .sup.1H NMR (CDCl.sub.3): .delta.7.58 (d, 2H), 7.28 (d, 2H),
7.21 (d, 2H), 7.11 (d, 2H), 6.98 (d, 2H), 6.91 (d, 2H), 4.17 (t,
2H), 4.08 (t, 2H), 3.07 (t, 2H), 2.6 (t, 2H), 2.57 (q, 6H), 2.47
(t, 4H), 2.36 (d, 2H), 2.0 (m, 3H), 1.3 (m, 2H), 1.05 (t, 6H), 0.82
(d, 6H), 0.72 (t, 3, H) ppm.
Example 458
{3-[4-(5-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-isobutyl-imidaz-
ol-1-yl)-phenoxy]-propyl}-diethyl-amine
[1183] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]phenyl}-hexan-1-one (0.785 mmol)
in dioxane (10.0 mL) at rt, pyridinium bromide perbromide (1.1 eq)
was added. The reaction mixture was stirred under nitrogen at rt
until completion, as indicated by TLC. The mixture was diluted with
EtOAc (100 ml) and washed with H.sub.2O (2.times.50 ml), brine (30
ml) and dried with magnesium sulfate. The solvent was then removed
in vacuuo to give a white solid. The alpha-bromophenone was used
for further transformation.
[1184] A solution of the above alpha-bromophenone (1.0 eq),
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq), and DIEA
(1.5 eq) in anhydrous DMF (10 mL) was stirred under nitrogen at rt
for 24 hour. The reaction mixture was then diluted with cold
H.sub.2O and the product was isolated in Et.sub.2O. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was purified by chromatography
(Silica gel). Pure product was obtained by elution with 2-7%
MeOH/DCM (yield .about.47%).
[1185] To a stirred solution of alkylated aniline described above
(0.31 mmol) in anhydrous THF (5 mL) at 0.degree. C., DMAP (0.25 eq)
was added, followed by slow addition of isovaleryl chloride (5.0
mmol), according to General Procedure R3. The reaction mixture was
stirred under nitrogen at 0.degree. C. for 1 h and allowed to warm
to ambient temperature until completion, as indicated by HPLC. The
solvent was removed in vacuuo, and the crude amide was used for
further transformation.
[1186] To a stirred solution of the amide described above (0.31
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 100.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole (yield 108 mg).
[1187] MS m/z 616 (M+H).sup.+:
[1188] .sup.1H NMR (CDCl.sub.3): .delta.7.6 (d, 2H), 7.28 (d, 2H),
7.21 (d, 2H), 7.11 (d, 2H), 7.00 (d, 2H), 6.90 (d, 2H), 4.18 (t,
2H), 4.08 (t, 2H, 3.06 (t, 2H), 2.45-2.65 (m, 8H), 2.36 (d, 2H),
2.0 (m, 4H), 0.7-1.3 (m, 18H) ppm.
Example 459
{4-{4-{2-(4-chloro-phenyl)-ethoxy]-phenyl}-1-[4-(3-diethylamino-propoxy)-p-
henyl]-1H-imidazol-2-yl}-MeOH
[1189] To a stirred solution of 4-fluoronitrobenzene (2.0 mmol) in
anhydrous THF (5 mL) at 0.degree. C., a 1M solution of a potassium
diethylaminopropoxide (2.2 mmol) in THF was added dropwise and
under a nitrogen stream, according to General Procedure L1. The
reaction mixture was stirred at 0.degree. C. for 1 h and allowed to
warm to it until completion, as indicated by TLC or HPLC. The
reaction mixture was then treated with cold H.sub.2O (15 mL), and
extracted with EtOAc (2.times.15 mL). The combined organic layers
were washed with brine and dried over sodium sulfate. Evaporation
of the solvent in vacuuo afforded the desired 4-alkoxynitrobenzene.
The crude product was used directly for further transformation.
[1190] The N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (2 mmol)
obtained above was dissolved in MeOH (10 mL) and hydrogenated in
the presence of 10% Pd/C (10 mg) until completion as indicated by
TLC or HPLC, according to General Procedure H. The reaction mixture
was then filtered to remove the catalyst. The solvent was removed
in vacuuo to afford the desired 4-alkoxyaniline, which was used
directly for further transformation without further
purification.
[1191] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (5 mL) at rt, solid potassium carbonate (9.0 mmol) was
added. 4-chlorophenethyl mesylate (2.0 mmol) was added to the
reaction mixture and heated to 80.degree. C. until completion
according to General Procedure Q1, as indicated by TLC or HPLC.
After cooling to rt, the reaction mixture was quenched using cold
water (20 ml) and the product was isolated in EtOAc (2.times.20
ml). The combined organic layers were washed with saturated sodium
bicarbonate (2.times.10 ml), water (2.times.10 ml) and brine (15
ml). The organic layer was dried over magnesium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated
acetophenone was used for further transformation.
[1192] To a stirred solution of the
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.2 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to it until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the residue
was treated with saturated sodium bicarbonate. The aqueous layer
was poured into EtOAc (20 ml) and the product was isolated in EtOAc
(2.times.20 ml). The combined organic layers were washed with
saturated sodium bicarbonate (2.times.10 ml), and brine (15 ml).
The organic layer was dried over magnesium sulfate, and the solvent
was removed in vacuuo to afford the desired product. The crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was purified
by chromatography (Silica gel). Pure product was obtained by
elution with 20-30% EtOAc/hexane (yield .about.70-75%).
[1193] To a stirred solution of the
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.2 eq., 2 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (1.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[1194] To a stirred solution of
1-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-[4-(3-diethylamino-propoxy)-p-
henylamino]-ethanone described above (1.6 mmol) in anhydrous DCM (5
mL) at 0.degree. C., TEA (3 eq., 4.8 mmol) was added, followed by
slow addition of benzyloxyacetyl chloride (2 eq., 3.2 mmol),
according to General Procedure R3. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and allowed to warm to it
until completion, as indicated by TLC or HPLC. The reaction mixture
was then diluted with cold water and the product was isolated in
DCM. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[1195] To a stirred solution of the amide described above (1.6
mmol) in acetic acid (4 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to it and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained by elution with 4-6%
MeOH/DCM (yield 30-40%).
[1196] To a stirred solution of the pure imidazole (0.48 mmol)
described above 6N HCl was added and the reaction mixture was
refluxed overnight. The reaction mixture was then cooled to it and
neutralized with 3N sodium hydroxide solution. Usual extractive
work up with EtOAc gave the product imidazole, which was purified
by column chromatography (Silica gel). Pure product was obtained by
elution with 4-6% MeOH/DCM (yield: 130 mg).
[1197] MS m/z 534 (M+H).sup.+:
[1198] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.7.66 (d, 2H), 7.41
(d, 2H), 7.28 (d, 2H), 7.22 (m, 3H), 6.99 (d, 2H), 6.89 (d, 2H),
4.62 (s, 2H), 4.17 (t, 2H), 4.08 (t, 2H), 3.07 (t, 2H), 2.88 (m,
6H), 2.18 (m, 2H), 1.24 (t, 6H) ppm
Example 460
diethyl-[3-(4-{2-isobutyl-4-[4-(4-phenoxy-benzyloxy)-phenyl]-imidazol-1-yl-
}-phenoxy)-propyl]-amine
[1199] To a stirred solution of
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol)
in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow
addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol).
The reaction mixture was stirred under nitrogen at rt until
completion, as indicated by HPLC. The reaction mixture was then
diluted with cold H.sub.2O and the product was isolated in
Et.sub.2O. The combined organic layers were washed with brine and
dried over sodium sulfate. Evaporation of solvent in vacuuo
afforded the desired product. The crude alkylated aniline was
purified by chromatography (Silica gel). Pure product was obtained
by elution with 2-7% MeOH/DCM (yield .about.30%).
[1200] To a stirred solution of the alkylated aniline described
above (0.88 mmol) in anhydrous DCM (10 mL) at 0.degree. C., TEA
(3.0 mmol) was added, followed by slow addition of isovaleryl
chloride (5.0 eq), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to ambient temperature until completion, as
indicated by HPLC. The solvent was removed in vacuuo, and the crude
amide was used for further transformation.
[1201] To a stirred solution of the amide described above (0.88
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 100.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
cyclized product, (crude .about.80%) which was taken to the next
transformation without purification.
[1202] The above product was dissolved in MeOH (20 mL), Pd/C (100
mg) was added and the heterogeneous mixture was stirred overnight
under H.sub.2 atmosphere using a balloon, according to General
Procedure T2. The Pd/C was removed by filtration. The solvent was
removed in vacuuo, and the crude
4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-y-
l}-phenol was used for further transformation without
purification.
[1203] A stirred solution of the
4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phe-
nol (1.0 eq) obtained above in anhydrous DMF (5.0 mL) was treated
with solid sodium hydride (60% dispersion in oil; 1.0 mmol) in
portions. The mesylate of (4-phenoxyphenyl)methanol (1.1 eq) was
added to the reaction mixture, which was stirred at rt overnight,
according to General Procedure T3. Et.sub.2O (30 mL) was added to
the reaction mixture followed by H.sub.2O (10 mL). The organic
layer was washed with H.sub.2O (2.times.15 mL) and brine, and dried
over sodium sulfate. The solvent was removed in vacuuo. Pure
imidazole was obtained by elution with chromatography in 5-10%
MeOH/DCM (yield 70.0 mg).
[1204] MS m/z 604 (M+H).sup.+:
[1205] .sup.1H NMR (CDCl.sub.3): .delta. 7.70 (d, 2H) 6.9-7.4 (m,
16H), 5.0 (s, 2H), 4.1 (t, 2H), 3.0 (m, 6H), 2.52 (d), 2.26 (m,
2H), 2.01 (m, 1H), 1.31 (t, 6H), 0.84 (d, 6H) ppm.
Example 461
[3-(4-{4-[4-(4-benzyloxy-benzyloxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phen-
oxy)-propyl]-diethyl-amine
[1206] To a stirred solution of
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol)
in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow
addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol).
The reaction mixture was stirred under nitrogen at rt until
completion, as indicated by HPLC. The reaction mixture was then
diluted with cold H.sub.2O and the product was isolated in
Et.sub.2O. The combined organic layers were washed with brine and
dried over sodium sulfate. Evaporation of solvent in vacuuo
afforded the desired product. The crude alkylated aniline was
purified by chromatography (Silica gel). Pure product was obtained
by elution with 2-7% MeOH/DCM (yield .about.30%).
[1207] To a stirred solution of the alkylated aniline described
above (0.88 mmol) in anhydrous DCM (10 mL) at 0.degree. C., TEA
(3.0 mmol) was added, followed by slow addition of isovaleryl
chloride (5.0 eq), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to ambient temperature until completion, as
indicated by HPLC. The solvent was removed in vacuuo, and the crude
amide was used for further transformation.
[1208] To a stirred solution of the amide described above (0.88
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 100.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
cyclized product, (crude .about.80%) which was taken to the next
transformation without purification.
[1209] The above product was dissolved in MeOH (20 mL), Pd/C (100
mg) was added and the heterogeneous mixture was stirred overnight
under H.sub.2 atmosphere using a balloon, according to General
Procedure T2. The Pd/C was removed by filtration. The solvent was
removed in vacuuo, and the crude
4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-y-
l}-phenol was used for further transformation without
purification.
[1210] A stirred solution of
4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phe-
nol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid
sodium hydride (60% dispersion in oil; 1.0 mmol) in portions. The
mesylate of [4-(benzyloxy)phenyl]methanol (1.1 eq) was added to the
reaction mixture, and stirred at rt overnight, according to General
Procedure T3. Et.sub.2O (30 mL) was added to the reaction mixture
followed by H.sub.2O (10 mL). The organic layer was washed with
H.sub.2O (2.times.15 mL) and brine, and dried over sodium sulfate.
The solvent was removed in vacuuo. Pure imidazole was obtained from
chromatography with 5-10% MeOH/DCM (yield 70.0 mg).
[1211] MS m/z 618 (M+H).sup.+:
[1212] .sup.1H NMR (CDCl.sub.3): .delta.7.70 (d, 2H), 7.3-7.45 (m,
7H), 7.21 (d, 2H), 7.1 (s, 1H), 6.9 (m, 6H), 5.07 (s, 2H), 5.00 (s,
2H), 4.1 (t, 2H), 3.0 (m, 6H), 2.52 (d, 2H), 2.26 (m, 2H), 2.01 (m,
1H), 1.31 (t, 6H), 0.84 (d, 6H) ppm.
Example 462
[3-(4-{4-[4-(2-benzenesulfonylmethyl-benzyloxy)-phenyl]-2-isobutyl-imidazo-
l-1-yl}-phenoxy)-propyl]-diethyl-amine
[1213] To a stirred solution of
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol)
in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow
addition of 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol). The
reaction mixture was stirred under nitrogen at rt until completion,
as indicated by HPLC. The reaction mixture was then diluted with
cold H.sub.2O and the product was isolated in Et.sub.2O. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was purified by
chromatography (Silica gel). Pure product was obtained by elution
with 2-7% MeOH/DCM (yield .about.30%).
[1214] To a stirred solution of the alkylated aniline described
above (0.88 mmol) in anhydrous DCM (10 mL) at 0.degree. C., TEA
(3.0 mmol) was added, followed by slow addition of isovaleryl
chloride (5.0 eq), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to ambient temperature until completion, as
indicated by HPLC. The solvent was removed in vacuuo, and the crude
amide was used for further transformation.
[1215] To a stirred solution of the amide described above (0.88
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 100.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
cyclized product, (crude .about.80%) which was taken to the next
transformation without purification.
[1216] The above product was dissolved in MeOH (20 mL), Pd/C (100
mg) was added and the heterogeneous mixture was stirred overnight
under H.sub.2 atmosphere using a balloon, according to General
Procedure T2. The Pd/C was removed by filtration. The solvent was
removed in vacuuo, and the crude
4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-y-
l}-phenol was used for further transformation without
purification.
[1217] A stirred solution of
4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phe-
nol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid
sodium hydride (60% dispersion in oil; 1.0 mmol) in portions. The
mesylate of {2-[(phenylsulfonyl)methyl]phenyl}methanol (1.1 eq) was
added to the reaction mixture, and stirred at rt overnight,
according to General Procedure T3. Et.sub.2O (30 mL) was added to
the reaction mixture followed by H.sub.2O (10 mL). The organic
layer was washed with H.sub.2O (2.times.15 mL) and brine, and dried
over sodium sulfate. The solvent was removed in vacuuo. Pure
imidazole was obtained from chromatography with 5-10% MeOH/DCM
(yield 77 mg).
[1218] MS m/z 666 (M+H).sup.+:
[1219] .sup.1H NMR (CDCl.sub.3): .delta.7.6-7.73 (m, 6), 7.3-7.5
(m, 4H), 7.20 (d, 2H), 7.1 (m, 2H), 6.97 (d, 2H), 6.9 (d, 2H), 4.93
(s, 2H), 4.5 (s, 2H), 4.07 (t, 2H), 2.6 (t, 2H), 2.63 (q, 4H), 2.53
(d, 2H), 2.01 (m, 3H), 1.08 (t, 6H), 0.85 (d, 6H) ppm.
Example 463
diethyl-[3-(4-{2-isobutyl-4-[4-(3,4,5-trimethoxy-benzyloxy)-phenyl]-imidaz-
ol-1-yl}-phenoxy)-propyl]-amine
[1220] To a stirred solution of
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol)
in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow
addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol).
The reaction mixture was stirred under nitrogen at rt until
completion, as indicated by HPLC. The reaction mixture was then
diluted with cold H.sub.2O and the product was isolated in
Et.sub.2O. The combined organic layers were washed with brine and
dried over sodium sulfate. Evaporation of solvent in vacuuo
afforded the desired product. The crude alkylated aniline was
purified by chromatography (Silica gel). Pure product was obtained
from 2-7% MeOH/DCM (yield .about.30%).
[1221] To a stirred solution of the alkylated aniline described
above (0.88 mmol) in anhydrous DCM (10 mL) at 0.degree. C., TEA
(3.0 mmol) was added, followed by slow addition of isovaleryl
chloride (5.0 eq), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to ambient temperature until completion, as
indicated by HPLC. The solvent was removed in vacuuo, and the crude
amide was used for further transformation.
[1222] To a stirred solution of the amide described above (0.88
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 100.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
cyclized product, (crude .about.80%) which was taken to the next
transformation without purification.
[1223] The above product was dissolved in MeOH (20 mL), Pd/C (100
mg) was added and the heterogeneous mixture was stirred overnight
under H.sub.2 atmosphere using a balloon, according to General
Procedure T2. The Pd/C was removed by filtration. The solvent was
removed in vacuuo, and the crude
4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-y-
l}-phenol was used for further transformation without
purification.
[1224] A stirred solution of
4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phe-
nol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid
sodium hydride (60% dispersion in oil; 1.0 mmol) in portions. The
mesylate of (3,4,5-trimethoxyphenyl)methanol (1.1 eq) was added to
the reaction mixture, and stirred at rt overnight, according to
General Procedure T3. Et.sub.2O (30 mL) was added to the reaction
mixture followed by H.sub.2O (10 mL). The organic layer was washed
with H.sub.2O (2.times.15 mL) and brine, and dried over sodium
sulfate. The solvent was removed in vacuuo. Pure imidazole was
obtained from chromatography with 5-10% MeOH/DCM (yield 66 mg).
[1225] MS m/z 602 (M+H).sup.+:
[1226] .sup.1H NMR (CDCl.sub.3): .delta.7.71 (d, 2H), 7.21 (d, 2H),
6.97 (m, 4H), 6.66 (s, 1H), 5 (s, 2H), 4.1 (t, 2H), 3.86 (s, 6H),
3.82 (s, 3H), 3.0 (m, 6H), 2.51 (d, 2H), 2.25 (m, 2H), 2.01 (m,
1H), 1.3 (t, 6H), 0.84 (d, 6H) ppm.
Example 464
[3-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenox-
y)-propyl]-diethyl-amine
[1227] To a stirred solution of 4'-hydroxyacetophenone (91 mmol) in
DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added.
The mesylate prepared from 3-diethylamino-1-propanol and
methanesulfonyl chloride (76 mmol) was added to the reaction
mixture and heated to 80.degree. C. until completion according to
General Procedure Q1, as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture was quenched by treating the mixture with
saturated sodium bicarbonate. The aqueous layer was poured into
EtOAc (100 mL) and washed with H.sub.2O (2.times.50 mL) and brine
(50 mL). The organic layer was dried over sodium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated
product was used for further transformation after purifying using
silica gel column chromatography (1-4% MeOH/DCM).
[1228] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (5.2 mmol) in
anhydrous MeOH (10 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 6.2 mmol) was added slowly in small portions, according
to General Procedure R1. The reaction mixture was stirred under
nitrogen at 0.degree. C. for 1 h and was allowed to warm to rt
until completion, as indicated by TLC or HPLC. The solvent was then
removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1229] To a stirred solution of 4-amino-4'-chlorodiphenyl ether
(1.2 eq., 6.2 mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 16 mmol)
was added, followed by slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (5.2 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was extracted in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was purified by
chromatography (Silica gel). Pure product obtained from 2-4%
MeOH/DCM (yield .about.22%).
[1230] To a stirred solution of alkylated 4-amino-4'-chlorodiphenyl
ether described above (0.4 mmol) in anhydrous DCM (5 mL) at
0.degree. C., TEA (3 eq., 1.2 mmol) was added, followed by slow
addition of isovaleryl chloride (3 eq., 1.2 mmol), according to
General Procedure R3. The reaction mixture was stirred under
nitrogen at 0.degree. C. for 1 h and allowed to warm to rt until
completion, as indicated by TLC or HPLC. The solvent was removed in
vacuuo, and the crude amide was used for further
transformation.
[1231] To a stirred solution of the
2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-
-ethanone (0.4 mmol) obtained as above in acetic acid (3 mL), solid
ammonium acetate (8 mmol) was added in one portion, according to
General Procedure R4. The reaction mixture was then heated to
100.degree. C. overnight. The reaction mixture was cooled to rt,
and treated with saturated aqueous sodium bicarbonate solution
while stirring to until the pH was 7-8. The contents were extracted
with EtOAc (2.times.15 mL). The combined organic layers was washed
with H.sub.2O (2.times.15 mL) and brine, and dried over sodium
sulfate. Evaporation of the solvent in vacuuo afforded the desired
N-aryl imidazole. The crude product was purified using silica gel
column chromatography (2-5% MeOH/DCM) (yield 117 mg).
[1232] MS m/z 532 (M+H).sup.+:
[1233] .sup.1H NMR (CDCl.sub.3): .delta.7.63 (d, 2H), 7.28 (d, 2H),
7.21 (d, 2H), 7.06 (s, 1H), 7.01 (d, 2H), 6.98 (d, 2H), 6.83 (d,
2H), 3.99 (t, 2H), 2.79 (t, 2H), 2.72 (q, 4H), 2.49 (d, 2H),
2.30-1.90 (m, 3H), 1.10 (t, 6H), 0.80 (d, 6H) ppm.
Example 465
[3-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-(2-cyclopentyl-ethyl)-1H-imidazol-
-4-yl}-phenoxy)-propyl]-diethyl-amine
[1234] To a stirred solution of 4'-hydroxyacetophenone (91 mmol) in
DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added.
The mesylate prepared from 3-diethylamino-1-propanol and
methanesulfonyl chloride (76 mmol) was added to the reaction
mixture and heated to 80.degree. C. until completion according to
General Procedure Q1, as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture was quenched by treating the mixture with
saturated sodium bicarbonate. The aqueous layer was poured into
EtOAc (100 mL) and washed with H.sub.2O (2.times.50 mL) and brine
(50 mL). The organic layer was dried over sodium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated
product was used for further transformation after purifying using
silica gel column chromatography (1-4% MeOH/DCM).
[1235] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (5.2 mmol) in
anhydrous MeOH (10 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 6.2) was added slowly in small portions, according to
General Procedure R1. The reaction mixture was stirred under
nitrogen at 0.degree. C. for 1 h and was allowed to warm to rt
until completion, as indicated by TLC or HPLC. The solvent was then
removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1236] To a stirred solution of 4-amino-4'-chlorodiphenyl ether
(1.2 eq., 6.2 mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 16 mmol)
was added, followed by slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (5.2 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was extracted in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was purified by
chromatography (Silica gel). Pure product obtained from 2-4%
MeOH/DCM (yield .about.22%).
[1237] To a stirred solution of alkylated 4-amino-4'-chlorodiphenyl
ether described above (0.4 mmol) in anhydrous DCM (5 mL) at
0.degree. C., TEA (3 eq., 1.2 mmol) was added, followed by slow
addition of 3-cyclopentylpropionyl chloride (3 eq., 1.2 mmol),
according to General Procedure R3. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and allowed to warm to rt
until completion, as indicated by TLC or HPLC. The solvent was
removed in vacuuo, and the crude amide was used for further
transformation.
[1238] To a stirred solution of the
2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-
-ethanone (0.4 mmol) obtained as above in acetic acid (3 mL), solid
ammonium acetate (8 mmol) was added in one portion, according to
General Procedure R4. The reaction mixture was then heated to
100.degree. C. overnight. The reaction mixture was cooled to rt,
and treated with saturated aqueous sodium bicarbonate solution
while stirring to until the pH was 7-8. The contents were extracted
with EtOAc (2.times.15 mL). The combined organic layers was washed
with H.sub.2O (2.times.15 mL) and brine, and dried over sodium
sulfate. Evaporation of the solvent in vacuuo afforded the desired
N-aryl imidazole. The crude product was purified using silica gel
column chromatography (2-5% MeOH/DCM) (yield 180 mg).
[1239] MS m/z 572 (M+H).sup.+:
[1240] .sup.1H NMR (CDCl.sub.3): .delta.7.69 (d, 2H), 7.35 (d, 2H),
7.29 (d, 2H), 7.14 (s, 1H), 7.08 (d, 2H), 7.02 (d, 2H), 6.89 (d,
2H), 4.05 (t, 2H), 2.95 (t, 2H) 2.85 (q, 4H), 2.71-2.65 (m, 2H),
2.19-2.12 (m, 3H), 1.72-1.61 (m, 4H), 1.59-1.42 (m, 4H), 1.21 (t,
6H), 1.01 (m, 2H) ppm.
Example 466
[3-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-phenethyl-1H-imidazol-4-yl}-pheno-
xy)-propyl]-diethyl-amine
[1241] To a stirred solution of 4'-hydroxyacetophenone (91 mmol) in
DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added.
The mesylate prepared from 3-diethylamino-1-propanol and
methanesulfonyl chloride (76 mmol) was added to the reaction
mixture and heated to 80.degree. C. until completion according to
General Procedure Q1, as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture was quenched by treating the mixture with
saturated sodium bicarbonate. The aqueous layer was poured into
EtOAc (100 mL) and washed with H.sub.2O (2.times.50 mL) and brine
(50 mL). The organic layer was dried over sodium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated
product was used for further transformation after purifying using
silica gel column chromatography (1-4% MeOH/DCM).
[1242] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (5.2 mmol) in
anhydrous MeOH (10 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 6.2) was added slowly in small portions, according to
General Procedure R1. The reaction mixture was stirred under
nitrogen at 0.degree. C. for 1 h and was allowed to warm to rt
until completion, as indicated by TLC or HPLC. The solvent was then
removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1243] To a stirred solution of 4-amino-4'-chlorodiphenyl ether
(1.2 eq., 6.2 mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 16 mmol)
was added, followed by slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (5.2 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was extracted in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was purified by
chromatography (Silica gel). Pure product obtained from 2-4%
MeOH/DCM (yield .about.22%).
[1244] To a stirred solution of the alkylated 4-chloroalkoxy
aniline described above (0.4 mmol) in anhydrous DCM (5 mL) at
0.degree. C., TEA (3 eq., 1.2 mmol) was added, followed by slow
addition of hydrocinnamoyl chloride (3 eq., 1.2 mmol), according to
General Procedure R3. The reaction mixture was stirred under
nitrogen at 0.degree. C. for 1 h and allowed to warm to rt until
completion, as indicated by TLC or HPLC. The solvent was removed in
vacuuo, and the crude amide was used for further
transformation.
[1245] To a stirred solution of the
2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-
-ethanone (.about.0.4 mmol) obtained as above in acetic acid (3
mL), solid ammonium acetate (8 mmol) was added in one portion,
according to General Procedure R4. The reaction mixture was then
heated to 100.degree. C. overnight. The reaction mixture was cooled
to rt, and treated with saturated aqueous sodium bicarbonate
solution while stirring to until the pH was 7-8. The contents were
extracted with EtOAc (2.times.15 mL). The combined organic layers
was washed with H.sub.2O (2.times.15 mL) and brine, and dried over
sodium sulfate. Evaporation of the solvent in vacuuo afforded the
desired N-aryl imidazole. The crude product was purified using
silica gel column chromatography (2-4% MeOH/DCM) (yield 50 mg).
[1246] MS m/z 580 (M+H).sup.+:
[1247] .sup.1H NMR (CDCl.sub.3): .delta.8.41 (m, 2H), 7.92 (m, 2H),
7.62 (d, 2H, 7.33 (d, 2H), 7.25-7.21 (m, 2H), 7.13-7.08 (m, 1H),
7.04 (s, 1H), 6.98 (m, 2H), 6.92 (m, 2H), 6.75 (m, 2H), 4.05 (t,
2H), 3.31 (m, 2H), 3.26-3.05 (m, 6H), 2.35 (m, 2H), 1.40 (t, 6H),
1.21 (m, 2H) ppm.
Example 467
[3-(4-{2-(4-tert-butyl-phenoxymethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-i-
midazol-4-yl}-phenoxy)-propyl]-diethyl-amine
[1248] 3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM
(25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled
to 0.degree. C. To this mixture, methanesulfonyl chloride (30 mmol,
1.5 eq) was added slowly with stirring and the reaction mixture was
stirred at 0.degree. C. for an hour and at rt for another hour
(until the reaction was complete by HPLC). The solvent was removed
and to this saturated aqueous sodium bicarbonate was added. The
product was extracted with EtOAc (3.times.) and washed with sodium
bicarbonate and water. The solvent was removed in vacuuo.
[1249] The mesylate from the previous step (20 mmol, 1 eq) was
dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone
(20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added.
The mixture was heated under reflux at 85.degree. C. for 18 h
(until the reaction was complete by HPLC), after which it was
cooled to rt. Saturated aqueous sodium bicarbonate was added to the
mixture, which was then transferred to a separatory funnel. The
product was extracted with EtOAc and washed with sodium bicarbonate
and water. The solvent was removed in vacuuo and the product
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flash
chromatography (going by increasing gradient up to 10% MeOH in
DCM). The overall yield was 60%.
[1250] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (5 mmol) in anhydrous
MeOH (10 mL) at 0.degree. C., pyrrolidone hydrotribromide (1.2 eq)
was added, according to General Procedure R1. The reaction mixture
was stirred under nitrogen at 0.degree. C. for 1 h and was allowed
to warm to rt until completion, as indicated by TLC or HPLC. The
solvent was then removed in vacuuo and the crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1251] To a solution of 4-chlorophenoxy aniline (1 eq, 5 mmol) in
anhydrous DMF (10 mL), DIEA (3 eq 15 mmol) was added, followed by
addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (5 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was purified by chromatography
(Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield
52%).
[1252] To a solution of
2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-
-ethanone described above (2 mmol) in anhydrous DCM (5 mL),
PS-carbodimide (2 eq, 4 mmol) and 4-t-butylphenoxy-acetic acid (3
mmol) were added. The reaction mixture was shaken overnight and
next day filtered to give the desired amide. The crude amide was
used for further transformation.
[1253] To a stirred solution of the amide described above (2 mmol)
in acetic acid (8 mL), ammonium acetate (20 eq) was added,
according to General Procedure R4. The reaction mixture was stirred
at 90.degree. C. overnight. The reaction mixture was then cooled to
rt and neutralized with saturated sodium bicarbonate solution.
Usual extractive work up with EtOAc gave the product imidazole,
which was purified by column chromatography (Silica gel). Pure
product was obtained from 4-6% MeOH/DCM (yield 255 mg).
[1254] MS m/z 638 (M+H).sup.+:
[1255] .sup.1H NMR (CDCl.sub.3): .delta.7.72 (d, 2H), 7.44 (d, 2H),
7.28-7.35 (m, 5H), 6.8-7.1 (m, 8H), 5.01 (s, 2H), 4.06 (t, 2H),
3.13-3.24 (m, 6H), 2.28 (m, 2H), 1.23-1.38 (m, 15H) ppm.
Example 468
[3-(4-{2-butyl-1-[4-(2,4-dichloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-pheno-
xy)-propyl]-diethyl-amine
[1256] To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol)
in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added
followed by addition of 2,4-dichlorophenol (10 mmol) to the
reaction mixture and heating to 80.degree. C. until the reaction
was complete as indicated by TLC or HPLC. After cooling to rt, the
reaction mixture was poured into H.sub.2O (100 ml), extracted with
EtOAc (2.times.50 mL), washed with H.sub.2O (2.times.50 ml) and
brine (50 ml), and dried over sodium sulfate. The solvent was
removed in vacuuo to afford the desired
4-(2,4-dichloro-phenoxy)-1-nitrobenzene. The crude product was used
for further transformation.
[1257] The nitro intermediate (10 mmol) obtained above was
dissolved in MeOH (20 mL), and treated with SnCl.sub.2.2H.sub.2O
(50 mmol), according to General Procedure I. The reaction mixture
was heated under reflux until completion, as indicated by TLC or
HPLC. The solvent was removed in vacuuo and the residue was treated
with 4.0 N aqueous NaOH to pH .about.8. The residue was extracted
with EtOAc (2.times.50 mL), washed with 1.0 N aqueous NaOH (50 mL),
brine (50 mL) and dried over sodium sulfate. The solvent was
removed in vacuuo to afford the desired
4-(2,4-dichloro-phenoxy)aniline, which was used directly for
further transformation without further purification.
[1258] To a stirred solution of 4'-hydroxyacetophenone (91 mmol) in
DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added.
The mesylate prepared from 3-diethylamino-1-propanol and
methanesulfonyl chloride (76 mmol) was added to the reaction
mixture and heated to 80.degree. C. until completion according to
General Procedure Q1, as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture was quenched by treating the mixture with
saturated sodium bicarbonate. The aqueous layer was poured into
EtOAc (100 mL) and washed with H.sub.2O (2.times.50 mL) and brine
(50 mL). The organic layer was dried over sodium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated
product was used for further transformation after purifying using
silica gel column chromatography (1-4% MeOH/DCM).
[1259] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4.4 mmol) in
anhydrous MeOH (10 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 5.3 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1260] To a stirred solution of 4-(2,4-dichloro-phenoxy)aniline
described above (1.2 eq., 5.2 mmol) in anhydrous DMF (20 mL) DIEA
(3 eq. 15 mmol) was added, followed by slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (4.4 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was isolated in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was purified by
chromatography (Silica gel). Pure product obtained from 2-4%
MeOH/DCM (yield .about.5%).
[1261] To a stirred solution of alkylated
4-(2,4-dichloro-phenoxy)aniline described above (0.2 mmol) in
anhydrous DCM (5 mL) at 0.degree. C., TEA (3 eq., 0.6 mmol) was
added, followed by slow addition of valeryl chloride (3 eq., 0.6
mmol), according to General Procedure R3. The reaction mixture was
stirred under nitrogen at 0.degree. C. for 1 h and allowed to warm
to rt until completion, as indicated by TLC or HPLC. The solvent
was removed in vacuuo, and the crude amide was used for further
transformation.
[1262] To a stirred solution of the N-alkylated anilide (0.2 mmol)
obtained as above in acetic acid (3 mL), solid ammonium acetate (6
mmol) was added in one portion, according to General Procedure R4.
The reaction mixture was then heated to 100.degree. C. overnight.
The reaction mixture was cooled to rt, and treated with saturated
aqueous sodium bicarbonate solution while stirring to until the pH
was 7-8. The contents were extracted with EtOAc (2.times.15 mL).
The combined organic layers was washed with H.sub.2O (2.times.15
mL) and brine, and dried over sodium sulfate. Evaporation of the
solvent in vacuuo afforded the desired N-aryl imidazole. The crude
product was purified using silica gel column chromatography (2-5%
MeOH/DCM).
[1263] MS m/z 566 (M+H).sup.+:
[1264] .sup.1H NMR (CDCl.sub.3): .delta.7.96 (s, 1H), 7.87 (m, 2H),
7.64 (d, 2H), 7.42 (m, 2H), 7.30 (d, 2H), 7.15 (s, 1H), 6.94-6.84
(m, 2H), 4.12 (m, 2H), 3.71-3.42 (m, 6H), 3.14 (m, 2H), 2.29 (t,
2H), 1.59-1.50 (m, 2H), 1.41-1.32 (m, 2H), 1.31 (t, 6H), 0.85 (m,
3H) ppm.
Example 469
[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-5-methyl-1H-imidazol-4-yl}--
phenoxy)-propyl]-diethyl-amine
[1265] To a stirred solution of the
1-[4-(3-diethylamino-propoxy)-phenyl]-propane-1-one (1.08 mmol) in
anhydrous MeOH (15 mL), pyrrolidone hydrotribromide (1.6 eq.) was
added, according to General Procedure R1. The reaction mixture was
heated under reflux overnight. The solvent was then removed in
vacuuo and the crude alpha-bromophenone was used for further
transformation.
[1266] To a stirred solution of the above alpha-bromoketone (1.0
eq), 4-(4-chloro-phenoxy)-aniline (1.0 eq) in anhydrous DMF (10 mL)
DIEA (1.0 eq) was added. The reaction mixture was stirred under
nitrogen at 90.degree. C. until completion, as indicated by HPLC.
The reaction mixture was cooled to rt then diluted with Et.sub.2O
(100 mL) and washed with sodium bicarbonate (10%, 30 ml), H.sub.2O
(2.times.30 mL), brine (30 mL) and dried with magnesium sulfate.
Evaporation of solvent in vacuuo gave a crude oil. The crude
alkylated aniline was purified by chromatography (Silica gel). Pure
product was obtained from 2-7% MeOH/DCM (yield .about.20%).
[1267] To a stirred solution of alkylated aniline described above
(0.2 mmol) in anhydrous THF (10 mL) at 0.degree. C., DMAP (0.3 eq.)
was added, followed by slow addition of valeryl chloride (5.0 eq),
according to General Procedure R3. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and allowed to warm to
ambient temperature until completion, as indicated by HPLC. The
solvent was removed in vacuuo, and the crude amide was used for
further transformation.
[1268] To a stirred solution of the amide described above (0.2
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield
66 mg).
[1269] MS m/z 546 (M+H).sup.+:
[1270] .sup.1H NMR (CDCl.sub.3): .delta.7.59 (d, 2H), 7.35 (d, 2H),
7.19 (d, 2H), 7.08 (d, 2H), 7.03 (d, 2H), 6.93 (d, 2H), 4.02 (t,
2H), 2.51-2.64 (m, 8H), 2.13 (s, 3H), 1.94 (m, 2H), 1.58 (m, 2H),
1.27 (m, 2H), 1.04 (t, 6H), 0.82 (t, 3H) ppm.
Example 470
[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-5-propyl-1H-imidazol-4-yl}--
phenoxy)-propyl]-diethyl-amine
[1271] To a stirred solution of the
1-[4-(3-diethylamino-propoxy)-phenyl]-pentane-1-one (1.08 mmol) in
anhydrous MeOH (15 mL), pyrrolidone hydrotribromide (1.6 eq.) was
added, according to General Procedure R1. The reaction mixture was
heated under reflux overnight. The solvent was then removed in
vacuuo and the crude alpha-bromophenone was used for further
transformation.
[1272] To a stirred solution of the above alpha-bromoketone (1.0
eq), 4-(4-chloro-phenoxy)-aniline (1.0 eq) in anhydrous DMF (10 mL)
DIEA (1.0 eq) was added. The reaction mixture was stirred under
nitrogen at 90.degree. C. until completion, as indicated by HPLC.
The reaction mixture was cooled to rt then diluted with Et.sub.2O
(100 mL) and washed with sodium bicarbonate (10%, 30 ml), H.sub.2O
(2.times.30 mL), brine (30 mL) and dried with magnesium sulfate.
Evaporation of solvent in vacuuo gave a crude oil. The crude
alkylated aniline was purified by chromatography (Silica gel). Pure
product was obtained from 2-7% MeOH/DCM (yield .about.20%).
[1273] To a stirred solution of alkylated aniline described above
(0.2 mmol) in anhydrous THF (10 mL) at 0.degree. C., DMAP (0.3 eq.)
was added, followed by slow addition of valeryl chloride (5.0 eq),
according to General Procedure R3. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and allowed to warm to
ambient temperature until completion, as indicated by HPLC. The
solvent was removed in vacuuo, and the crude amide was used for
further transformation.
[1274] To a stirred solution of the amide described above (0.2
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield
73 mg).
[1275] MS m/z 574 (M+H).sup.+:
[1276] .sup.1H NMR (CDCl.sub.3): .delta. 7.50 (d, 2H), 7.34 (d,
2H), 7.20 (d, 2H), 7.07 (d, 2H), 7.02 (d, 2H), 6.87 (d, 2H), 4.07
(t, 2H), 3.1-3.2 (m, 6H), 2.40-2.6 (m, 4H), 2.2 (m, 2H), 1.2-1.4
(m, 12H), 0.79 (t, 3H), 0.72 (t, 3H) ppm.
Example 471
[3-(4-{2,5-dibutyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-pheno-
xy)-propyl]-diethyl-amine
[1277] To a stirred solution of the
1-[4-(3-diethylamino-propoxy)-phenyl]-hexanane-1-one (1.08 mmol) in
anhydrous MeOH (15 mL), pyrrolidone hydrotribromide (1.6 eq.) was
added, according to General Procedure R1. The reaction mixture was
heated under reflux overnight. The solvent was then removed in
vacuuo and the crude alpha-bromophenone was used for further
transformation.
[1278] To a stirred solution of the above alpha-bromoketone (1.0
eq), 4-(4-chloro-phenoxy)-aniline (1.0 eq) in anhydrous DMF (10 mL)
DIEA (1.0 eq) was added. The reaction mixture was stirred under
nitrogen at 90.degree. C. until completion, as indicated by HPLC.
The reaction mixture was cooled to rt then diluted with Et.sub.2O
(100 mL) and washed with sodium bicarbonate (10%, 30 ml), H.sub.2O
(2.times.30 mL), brine (30 mL) and dried with magnesium sulfate.
Evaporation of solvent in vacuuo gave a crude oil. The crude
alkylated aniline was purified by chromatography (Silica gel). Pure
product was obtained from 2-7% MeOH/DCM (yield .about.20%).
[1279] To a stirred solution of alkylated aniline described above
(0.2 mmol) in anhydrous THF (10 mL) at 0.degree. C., DMAP (0.3 eq.)
was added, followed by slow addition of valeryl chloride (5.0 eq),
according to General Procedure R3. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and allowed to warm to
ambient temperature until completion, as indicated by HPLC. The
solvent was removed in vacuuo, and the crude amide was used for
further transformation.
[1280] To a stirred solution of the amide described above (0.2
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield
67.0 mg).
[1281] MS m/z 588 (M+H).sup.+:
[1282] .sup.1H NMR (CDCl.sub.3): .delta. 7.54 (d, 2H), 7.36 (d,
2H), 7.24 (d, 2H), 7.09 (d, 2H), 7.03 (d, 2H), 6.90 (d, 2H), 4.07
(t, 2H), 3.2-3.3 (m, 6H), 2.45-2.6 (m, 4H), 2.2 (m, 2H), 1.1-1.6
(m, 14H), 0.8 (t, 3H), 0.70 (t, 3H) ppm.
Example 472
[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-5-ethyl-1H-imidazol-4-yl}-p-
henoxy)-propyl]-diethyl-amine
[1283] To a stirred solution of the
1-[4-(3-diethylamino-propoxy)-phenyl]-butane-1-one (1.08 mmol) in
anhydrous MeOH (15 mL), pyrrolidone hydrotribromide (1.6 eq.) was
added, according to General Procedure R1. The reaction mixture was
heated under reflux overnight. The solvent was then removed in
vacuuo and the crude alpha-bromophenone was used for further
transformation.
[1284] To a stirred solution of the above alpha-bromoketone (1.0
eq), 4-(4-chloro-phenoxy)-aniline (1.0 eq) in anhydrous DMF (10 mL)
DIEA (1.0 eq) was added. The reaction mixture was stirred under
nitrogen at 90.degree. C. until completion, as indicated by HPLC.
The reaction mixture was cooled to rt then diluted with Et.sub.2O
(100 mL) and washed with sodium bicarbonate (10%, 30 ml), H.sub.2O
(2.times.30 mL), brine (30 mL) and dried with magnesium sulfate.
Evaporation of solvent in vacuuo gave a crude oil. The crude
alkylated aniline was purified by chromatography (Silica gel). Pure
product was obtained from 2-7% MeOH/DCM (yield .about.20%).
[1285] To a stirred solution of alkylated aniline described above
(0.2 mmol) in anhydrous THF (10 mL) at 0.degree. C., DMAP (0.3 eq.)
was added, followed by slow addition of valeryl chloride (5.0 eq),
according to General Procedure R3. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and allowed to warm to
ambient temperature until completion, as indicated by HPLC. The
solvent was removed in vacuuo, and the crude amide was used for
further transformation.
[1286] To a stirred solution of the amide described above (0.2
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was by elution with 4-6% MeOH/DCM (yield
70 mg).
[1287] MS m/z 560 (M+H).sup.+:
[1288] .sup.1H NMR (CDCl.sub.3): .delta.7.58 (d, 2H), 7.36 (d, 2H),
7.22 (d, 2H), 7.09 (d, 2H), 7.04 (d, 2H), 6.93 (d, 2H), 4.03 (t,
2H), 2.56 (m, 10H), 1.94 (m, 2H), 1.59 (m, 2H), 1.27 (m, 2H), 1.03
(t, 6H,), 0.97 (t, 3H), 0.82 (t, 3H) ppm.
Example 473
2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-(2-pyrrolidin-1-yl-ethoxy)-ph-
enyl]-1H-imidazole
[1289] To a stirred solution of NaH (3 eq., 6.0 mmol) in DMF (10
mL) at rt, 4'-hydroxyacetophenone (2.2 mmol) was added. The
mesylate of 1-(2-hydroxyethyl)-pyrrolidine (prepared from the
corresponding alcohol and methanesulfonyl chloride) (2.0 mmol) was
added to the reaction mixture and heated to 80.degree. C. until
completion according to General Procedure Q1, as indicated by TLC
or HPLC. After cooling to rt, the reaction mixture was diluted with
cold water and the product was isolated in EtOAc. The combined
organic layers were washed with saturated sodium bicarbonate
(2.times.15 ml), water (2.times.15 ml) and brine (15 ml). The
organic layer was dried over magnesium sulfate, and the solvent was
removed in vacuuo to afford the desired product. The crude
alkylated product was purified using silica gel column
chromatography. Pure product was obtained with 2-3% MeOH/DCM.
(yield 50-60%)
[1290] To a stirred solution of the alkoxyacetophenone described
above (1 mmol) in anhydrous MeOH (5 mL) at 0.degree. C.,
pyrrolidone hydrotribromide (1.2 eq., 1.2 mmol) was added,
according to General Procedure R1. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and was allowed to warm to
rt until completion, as indicated by TLC or HPLC. The solvent was
then removed in vacuuo and the residue was treated with saturated
sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml)
and washed with water (2.times.15 ml) and brine (15 ml). The
organic layer was dried over magnesium sulfate, and the solvent was
removed in vacuuo to afford the desired product. The crude
alpha-bromoacetophenone was used for further transformation.
[1291] To a stirred solution of 4-chloro-phenoxy aniline (1.2 eq.,
1.2 mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 3.0 mmol) was added,
followed by slow addition of the alpha-bromoacetophenone described
above (1.0 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[1292] To a stirred solution of alkylated aniline described above
(1.0 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (3 eq., 3.0
mmol) was added, followed by slow addition of valeryl chloride (2
eq., 2.0 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The reaction mixture was then diluted with water and the
product was isolated in DCM. The solvent was removed in vacuuo, and
the crude amide was purified using silica gel chromatography. Pure
product was obtained from 3-4% MeOH/DCM (Yield 40-45%).
[1293] To a stirred solution of the amide described above (0.5
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield:
105 mg).
[1294] MS m/z 51.6 (M).sup.+:
[1295] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.7.69 (d, 2H), 7.34
(d, 2H), 7.29 (d, 2H), 7.09 (s, 1H), 7.05 (m, 4H), 6.95 (d, 2H),
4.19 (t, 2H), 3.05 (t, 2H), 2.84 (m, 4H), 2.77 (t, 2H), 1.89 (m,
4H), 1.65 (m, 2H), 1.34 (m, 2H), 0.85 (t, 3H) ppm
Example 474
1-[2-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy-
)-ethyl]-piperidine
[1296] To a stirred solution of NaH (3 eq., 6.0 mmol) in DMF (10
mL) at rt, 4'-hydroxyacetophenone (2.2 mmol) was added. The
mesylate of 1-(2-hydroxyethyl)-piperidine (prepared from the
corresponding alcohol and methanesulfonyl chloride) (2.0 mmol) was
added to the reaction mixture and heated to 80.degree. C. until
completion according to General Procedure Q1, as indicated by TLC
or HPLC. After cooling to rt, the reaction mixture was diluted with
cold water and the product was isolated in EtOAc. The combined
organic layers were washed with saturated sodium bicarbonate
(2.times.15 ml), water (2.times.15 ml) and brine (15 ml). The
organic layer was dried over magnesium sulfate, and the solvent was
removed in vacuuo to afford the desired product. The crude
alkylated product was purified using silica gel column
chromatography. Pure product was obtained with 2-3% MeOH/DCM.
(yield 50-60%)
[1297] To a stirred solution of the alkoxyacetophenone described
above (1 mmol) in anhydrous MeOH (5 mL) at 0.degree. C.,
pyrrolidone hydrotribromide (1.2 eq., 1.2 mmol) was added,
according to General Procedure R1. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and was allowed to warm to
rt until completion, as indicated by TLC or HPLC. The solvent was
then removed in vacuuo and the residue was treated with saturated
sodium bicarbonate. The aqueous layer was poured into EtOAc (20 ml)
and washed with water (2.times.15 ml) and brine (15 ml). The
organic layer was dried over magnesium sulfate, and the solvent was
removed in vacuuo to afford the desired product. The crude
alpha-bromoacetophenone was used for further transformation.
[1298] To a stirred solution of 4-chloro-phenoxy aniline (1.2 eq.,
1.2 mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 3.0 mmol) was added,
followed by slow addition of the alpha-bromoacetophenone described
above (1.0 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[1299] To a stirred solution of alkylated aniline described above
(1.0 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (3 eq., 3.0
mmol) was added, followed by slow addition of valeryl chloride (2
eq., 2.0 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The reaction mixture was then diluted with water and the
product was isolated in DCM. The solvent was removed in vacuuo, and
the crude amide was purified using silica gel chromatography. Pure
product was obtained from 3-4% MeOH/DCM (Yield 40-45%).
[1300] To a stirred solution of the amide described above (0.5
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield:
92 mg).
[1301] MS m/z 530 (M+H).sup.+:
[1302] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.7.49 (d, 2H), 7.34
(d, 2H), 7.15 (d, 2H), 6.97 (s, 1H), 6.93 (m, 4H), 6.84 (d, 2H),
4.18 (t, 2H), 3.33 (m, 4H), 2.81 (t, 2H), 2.68 (t, 2H), 1.67 (m,
2H), 1.55 (m, 2H), 1.37 (m, 2H), 1.02 (m, 4H) 0.65 (t, 3H) ppm
Example 475
[3-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)--
2,2-dimethyl-propyl]-dimethyl-amine
[1303] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (10 mL) at rt, solid potassium carbonate (8.0 mmol) was
added. The mesylate of 3-dimethylamino-2,2-dimethyl-1-propanol
(prepared from the corresponding alcohol and methanesulfonyl
chloride) (2.0 mmol) was added to the reaction mixture and heated
to 80.degree. C. until completion according to General Procedure
Q1, as indicated by TLC or HPLC. After cooling to rt, the reaction
mixture was diluted with water and the product was isolated in
EtOAc. The combined organic layers were washed with saturated
sodium bicarbonate (2.times.15 ml), water (2.times.15 ml) and brine
(15 ml). The organic layer was dried over magnesium sulfate, and
the solvent was removed in vacuuo to afford the desired product.
The crude alkylated product was purified using silica gel column
chromatography. Pure product was obtained with 2-3% MeOH/DCM.
(yield 50-60%)
[1304] To a stirred solution of the alkoxyacetophenone described
above (1 mmol) in anhydrous MeOH (5 mL) at 0.degree. C.,
pyrrolidone hydrotribromide (1.2 eq., 1.2 mmol) was added,
according to General Procedure R1. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and was allowed to warm to
rt until completion, as indicated by TLC or HPLC. The solvent was
then removed in vacuuo and the residue was treated with saturated
sodium bicarbonate and the product was isolated in EtOAc. The
combined organic layers were washed with water (2.times.15 ml) and
brine (15 ml). The organic layer was dried over magnesium sulfate,
and the solvent was removed in vacuuo to afford the desired
product. The crude alpha-bromoacetophenone was used for further
transformation.
[1305] To a stirred solution of 4-chloro-phenoxy aniline (1.2 eq.,
1.2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 3.0 mmol) was added,
followed by slow addition of the alpha-bromoacetophenone described
above (1.0 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[1306] To a stirred solution of alkylated aniline described above
(1.0 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (3 eq., 3.0
mmol) was added, followed by slow addition of valeryl chloride (2
eq., 2.0 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The reaction mixture was then diluted with water and the
product was isolated in DCM. The solvent was removed in vacuuo, and
the crude amide was purified using silica gel chromatography. Pure
product was obtained from 3-4% MeOH/DCM (Yield 40-50%).
[1307] To a stirred solution of the amide described above (0.5
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 4-6% MeOH/DCM (yield:
105 mg).
[1308] MS m/z 532 (M+H).sup.+:
[1309] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.7.69 (d, 2H), 7.34
(d, 2H), 7.29 (d, 2H), 7.09 (s, 1H), 7.06 (d, 2H), 7.02 (d, 2H),
6.93 (d, 2H), 3.75 (s, 2H), 2.68 (t, 2H), 2.42 (s, 2H), 2.35 (s,
6H), 1.65 (m, 2H), 1.29 (m, 2H), 1.05 (s, 6H), 0.85 (t, 3H) ppm
Example 476
[2-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)--
ethyl]-diisopropyl-amine
[1310] To a stirred solution of 4'-hydroxyacetophenone (2.2 mmol)
in DMF (10 mL) at rt, solid potassium carbonate (8.0 mmol) was
added. The mesylate of 2-(diisopropylamino)ethanol (prepared from
the corresponding alcohol and methanesulfonyl chloride) (2.0 mmol)
was added to the reaction mixture and heated to 80.degree. C. until
completion according to General Procedure Q1, as indicated by TLC
or HPLC. After cooling to rt, the reaction mixture was diluted with
water and the product was isolated in EtOAc. The combined organic
layers were washed with saturated sodium bicarbonate (2.times.15
ml), water (2.times.15 ml) and brine (15 ml). The organic layer was
dried over magnesium sulfate, and the solvent was removed in vacuuo
to afford the desired product. The crude alkylated product was
purified using silica gel column chromatography. Pure product was
obtained with 2-3% MeOH/DCM. (yield 50-60%)
[1311] To a stirred solution of the alkoxyacetophenone described
above (1 mmol) in anhydrous MeOH (5 mL) at 0.degree. C.,
pyrrolidone hydrotribromide (1.2 eq., 1.2 mmol) was added,
according to General Procedure R1. The reaction mixture was stirred
under nitrogen at 0.degree. C. for 1 h and was allowed to warm to
rt until completion, as indicated by TLC or HPLC. The solvent was
then removed in vacuuo and the residue was treated with saturated
sodium bicarbonate and the product was isolated in EtOAc. The
combined organic layers were washed with water (2.times.15 ml) and
brine (15 ml). The organic layer was dried over magnesium sulfate,
and the solvent was removed in vacuuo to afford the desired
product. The crude alpha-bromoacetophenone was used for further
transformation.
[1312] To a stirred solution of 4-chloro-phenoxy aniline (1.2 eq.,
1.2 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 3.0 mmol) was added,
followed by slow addition of the alpha-bromoacetophenone described
above (1.0 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[1313] To a stirred solution of alkylated aniline described above
(1.0 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (3 eq., 3.0
mmol) was added, followed by slow addition of valeryl chloride (2
eq., 2.0 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The reaction mixture was then diluted with water and the
product was isolated in DCM. The solvent was removed in vacuuo, and
the crude amide was purified using silica gel chromatography. Pure
product was obtained from 3-4% MeOH/DCM (Yield 40-50%).
[1314] To a stirred solution of the amide described above (0.5
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 90.degree. C. overnight. The reaction
mixture was then cooled to rt and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 4-6% MeOH/DCM.
[1315] MS m/z 546 (M+H).sup.+:
Example 477
[3-(4-{4-[4-(adamantan-1-ylmethoxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phen-
oxy)-propyl]-diethyl-amine
[1316] To a stirred solution of
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol)
in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow
addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol).
The reaction mixture was stirred under nitrogen at rt until
completion, as indicated by HPLC. The reaction mixture was then
diluted with cold H.sub.2O and the product was isolated in
Et.sub.2O. The combined organic layers were washed with brine and
dried over sodium sulfate. Evaporation of solvent in vacuuo
afforded the desired product. The crude alkylated aniline was
purified by chromatography (Silica gel). Pure product was obtained
from 2-7% MeOH/DCM (yield .about.30%).
[1317] To a stirred solution of the alkylated aniline described
above (0.88 mmol) in anhydrous DCM (10 mL) at 0.degree. C., TEA
(3.0 mmol) was added, followed by slow addition of isovaleryl
chloride (5.0 eq), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to ambient temperature until completion, as
indicated by HPLC. The solvent was removed in vacuuo, and the crude
amide was used for further transformation.
[1318] To a stirred solution of the amide described above (0.88
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 100.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
cyclized product, (crude .about.80%) which was taken to the next
transformation without purification.
[1319] The above product was dissolved in MeOH (20 mL), Pd/C (100
mg) was added and the heterogeneous mixture was stirred overnight
under H.sub.2 atmosphere using a balloon, according to General
Procedure T2. The Pd/C was removed by filtration. The solvent was
removed in vacuuo, and the crude
4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-y-
l}-phenol was used for further transformation without
purification.
[1320] A stirred solution of the
4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phe-
nol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid
sodium hydride (60% dispersion in oil; 1.0 mmol) in portions. After
the addition, the mesylate of 1-adamantylmethanol (1.1 eq) was
added to the reaction mixture, and stirred at rt overnight,
according to General Procedure T3. Et.sub.2O (30 mL) was added to
the reaction mixture followed by H.sub.2O (10 mL). The organic
layer was washed with H.sub.2O (2.times.15 mL) and brine, and dried
over sodium sulfate. The solvent was removed in vacuuo. Pure
imidazole was obtained from chromatography with 5-10% MeOH/DCM
(yield 60 mg).
[1321] MS m/z 570 (M+H).sup.+:
[1322] .sup.1H NMR (CDCl.sub.3): .delta.7.68 (d, 2H), 7.20 (d, 2H),
7.09 (s, 1H), 6.97 (d, 2H), 6.90 (d, 2H), 4.06 (t, 2H), 3.5 (s,
2H), 2.6 (t, 2H), 2.58 (q, 4H), 2.52 (d), 1.6-2.1 (m, 18H), 1.05
(t, 6H), 0.85 (d, 6H) ppm.
Example 478
{3-[4-(4-{4-[3-(2,6-dichloro-phenyl)-4-methyl-isoxazol-5-ylmethyloxy]-phen-
yl}-2-isobutyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-amine
[1323] To a stirred solution of
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol)
in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow
addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol).
The reaction mixture was stirred under nitrogen at rt until
completion, as indicated by HPLC. The reaction mixture was then
diluted with cold H.sub.2O and the product was isolated in
Et.sub.2O. The combined organic layers were washed with brine and
dried over sodium sulfate. Evaporation of solvent in vacuuo
afforded the desired product. The crude alkylated aniline was
purified by chromatography (Silica gel). Pure product was obtained
from 2-7% MeOH/DCM (yield -30%).
[1324] To a stirred solution of the alkylated aniline described
above (0.88 mmol) in anhydrous DCM (10 mL) at 0.degree. C., TEA
(3.0 mmol) was added, followed by slow addition of isovaleryl
chloride (5.0 eq), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to ambient temperature until completion, as
indicated by HPLC. The solvent was removed in vacuuo, and the crude
amide was used for further transformation.
[1325] To a stirred solution of the amide described above (0.88
mmol) in acetic acid (2 mL), ammonium acetate (excess, -20 eq.) was
added, according to General Procedure R4. The reaction mixture was
stirred at 100.degree. C. overnight. The reaction mixture was then
cooled down and neutralized with saturated sodium bicarbonate
solution. Usual extractive work up with EtOAc gave the cyclized
product, (crude .about.80%) which was taken to the next
transformation without purification.
[1326] The above product was dissolved in MeOH (20 mL), Pd/C (100
mg) was added and the heterogeneous mixture was stirred overnight
under H.sub.2 atmosphere using a balloon, according to General
Procedure T2. The Pd/C was removed by filtration. The solvent was
removed in vacuuo, and the crude
4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-y-
l}-phenol was used for further transformation without
purification.
[1327] To a stirred solution of the
4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phe-
nol (1.0 eq) obtained above in anhydrous DMF (5.0 mL) solid sodium
hydride (60% dispersion in oil; 1.0 mmol) was added in portions.
After the addition, the requisite alkylhalide or the mesylate
(prepared from the corresponding alcohol and methanesulfonyl
chloride) (1.1 eq) was added to the reaction mixture. The reaction
mixture was stirred at rt overnight. Et.sub.2O (30 mL) was added to
the reaction mixture followed by H.sub.2O (10 mL). The organic
layer was washed with H.sub.2O (2.times.15 mL) and brine, and dried
over sodium sulfate. The solvent was removed in vacuuo. Pure
product was obtained from 5-10% MeOH/DCM (yield 57 mg).
[1328] MS m/z 661 (M+H).sup.+:
[1329] .sup.1H NMR (CDCl.sub.3): .delta. 7.65 (d, 2H), 7.2-7.44 (m,
5H), 7.08 (s, 1H), 6.96 (d, 2H), 0.677 (d, 2H), 4.74 (s, 2H), 4.13
(t, 2H), 2.9-3.15 (m, 6H), 2.6 (s, 3H), 2.51 (d, 2H), 2.3 (m, 3H),
1.35 (t, 6H), 0.83 (t, 6H) ppm
Example 479
[3-(4-{4-[4-(4-bromo-benzyloxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)-
-propyl]-diethyl-amine
[1330] To a stirred solution of
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol)
in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow
addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol).
The reaction mixture was stirred under nitrogen at rt until
completion, as indicated by HPLC. The reaction mixture was then
diluted with cold H.sub.2O and the product was isolated in
Et.sub.2O. The combined organic layers were washed with brine and
dried over sodium sulfate. Evaporation of solvent in vacuuo
afforded the desired product. The crude alkylated aniline was
purified by chromatography (Silica gel). Pure product was obtained
from 2-7% MeOH/DCM (yield .about.30%).
[1331] To a stirred solution of the alkylated aniline described
above (0.88 mmol) in anhydrous DCM (10 mL) at 0.degree. C., TEA
(3.0 mmol) was added, followed by slow addition of isovaleryl
chloride (5.0 eq), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to ambient temperature until completion, as
indicated by HPLC. The solvent was removed in vacuuo, and the crude
amide was used for further transformation.
[1332] To a stirred solution of the amide described above (0.88
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 100.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
cyclized product, (crude .about.80%) which was taken to the next
transformation without purification.
[1333] The above product was dissolved in MeOH (20 mL), Pd/C (100
mg) was added and the heterogeneous mixture was stirred overnight
under H.sub.2 atmosphere using a balloon, according to General
Procedure T2. The Pd/C was removed by filtration. The solvent was
removed in vacuuo, and the crude
4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-y-
l}-phenol was used for further transformation without
purification.
[1334] A stirred solution of the
4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phe-
nol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid
sodium hydride (60% dispersion in oil; 1.0 mmol) in portions. The
mesylate of (4-bromophenyl)methanol (1.1 eq) was added to the
reaction mixture, and stirred at rt overnight, according to General
Procedure T3. Et.sub.2O (30 mL) was added to the reaction mixture
followed by H.sub.2O (10 mL). The organic layer was washed with
H.sub.2O (2.times.15 mL) and brine, and dried over sodium sulfate.
The solvent was removed in vacuuo. Pure imidazole was obtained from
chromatography with 5-10% MeOH/DCM (yield 95 mg).
[1335] MS m/z 591 (M+H).sup.+:
[1336] .sup.1H NMR (CDCl.sub.3): .delta.7.7 (d, 2H), 7.5 (d, 2H),
7.32 (d, 2H), 7.21 (d, 2H), 7.11 (s, 1H), 6.96 (m, 4H), 5.03 (s,
2H), 4.07 (t, 2H), 2.5-2.8 (m, 8H), 2.0 (m, 3H), 1.07 (t, 6H), 0.84
(d, 6H) ppm.
Example 480
[3-(4-{2-butyl-1-[4-(6-methoxy-naphthalen-2-yloxy)-phenyl]-1H-imidazol-4-y-
l}-phenoxy)-propyl]-diethyl-amine
[1337] To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol)
in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added
followed by addition of 6-methoxy-2-naphthol (10 mmol) to the
reaction mixture and heating to 80.degree. C. until the reaction
was complete as indicated by TLC or HPLC. After cooling to rt, the
reaction mixture was poured into H.sub.2O (100 mL), extracted with
EtOAc (2.times.50 mL), washed with H.sub.2O (2.times.50 mL) and
brine (50 mL), and dried over sodium sulfate. The solvent was
removed in vacuuo to afford the desired
4-(6-methoxy-naphthalen-2-yloxy)-1-nitrobenzene. The crude product
was used for further transformation.
[1338] The nitro intermediate (10 mmol) obtained above was
dissolved in EtOAc (50 mL) and hydrogenated in the presence of 10%
Pd/C (360 mg) until completion according to General Procedure H, as
indicated by TLC or HPLC. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
the desired 4-(6-methoxy-naphthalen-2-yloxy)aniline, which was used
directly for further transformation without further
purification.
[1339] To a stirred solution of 4'-hydroxyacetophenone (91 mmol) in
DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added.
The mesylate prepared from 3-diethylamino-1-propanol and
methanesulfonyl chloride (76 mmol) was added to the reaction
mixture and heated to 80.degree. C. until completion according to
General Procedure Q1, as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture was quenched by treating the mixture with
saturated sodium bicarbonate. The aqueous layer was poured into
EtOAc (100 mL) and washed with H.sub.2O (2.times.50 mL) and brine
(50 mL). The organic layer was dried over sodium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated
product was used for further transformation after purifying using
silica gel column chromatography (1-4% MeOH/DCM).
[1340] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4.6 mmol) in
anhydrous MeOH (10 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 5.5 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1341] To a stirred solution of an
4-(6-methoxy-naphthalen-2-yloxy)aniline (5 mmol) in anhydrous DMF
(20 mL) DIEA (15 mmol) was added, followed by slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (4.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was isolated in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was used for further
transformation without additional purification.
[1342] To a stirred solution of alkylated
4-(6-methoxy-naphthalen-2-yloxy)aniline described above (4.6 mmol)
in anhydrous DCM (10 mL) at 0.degree. C., TEA (3 eq., 15 mmol) was
added, followed by slow addition of valeryl chloride (3 eq., 15
mmol), according to General Procedure R3. The reaction mixture was
stirred under nitrogen at 0.degree. C. for 1 h and allowed to warm
to rt until completion, as indicated by TLC or HPLC. The solvent
was removed in vacuuo, and the crude amide was used for further
transformation.
[1343] To a stirred solution of the N-alkylated anilide (.about.4.6
mmol) obtained as above in acetic acid (10 mL), solid ammonium
acetate (92 mmol) was added in one portion, according to General
Procedure R4. The reaction mixture was then heated to 100.degree.
C. overnight. The reaction mixture was cooled to rt, and treated
with saturated aqueous sodium bicarbonate solution while stirring
to until the pH was 7-8. The contents were extracted with EtOAc
(2.times.40 mL). The combined organic layers was washed with
H.sub.2O (2.times.40 mL) and brine, and dried over sodium sulfate.
Evaporation of the solvent in vacuuo afforded the desired N-aryl
imidazole. The crude product was purified using silica gel column
chromatography (2-5% MeOH/DCM) (yield 500 mg).
[1344] MS m/z 578 (M+H).sup.+:
[1345] .sup.1H NMR (CDCl.sub.3): .delta.8.51 (d, 1H), 8.42 (m, 1H),
8.31 (d, 1H), 7.75 (m, 2H), 7.62 (m, 2H) 7.37 (s, 1H), 7.23 (m,
2H), 7.12 (m, 2H), 7.08 (s, 1H), 6.97-6.79 (m, 2H), 3.98 (t, 2H),
3.41 (s, 3H), 3.23-3.05 (m, 6H), 2.75 (m, 2H), 2.45 (m, 2H),
1.75-1.48 (m, 4H), 1.37 (t, 6H), 0.80 (m, 3H) ppm.
Example 481
[3-(4-{2-butyl-1-[4-(naphthalen-2-yloxy)-phenyl]-1H-imidazol-4-yl}-phenoxy-
)-propyl]-diethyl-amine
[1346] To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol)
in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added
followed by addition of 2-naphthol (10 mmol) to the reaction
mixture and heating to 80.degree. C. until the reaction was
complete as indicated by TLC or HPLC. After cooling to rt, the
reaction mixture was poured into H.sub.2O (100 mL), extracated with
EtOAc (2.times.50 mL), washed with H.sub.2O (2.times.50 mL) and
brine (50 mL), and dried over sodium sulfate. The solvent was
removed in vacuuo to afford the desired
4-(naphthalen-2-yloxy)-1-nitrobenzene. The crude product was used
for further transformation.
[1347] The nitro intermediate (10 mmol) obtained above was
dissolved in EtOH (50 mL) and hydrogenated in the presence of 10%
Pd/C (300 mg) until completion according to General Procedure H, as
indicated by TLC or HPLC. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
the desired 4-(naphthalen-2-yloxy)aniline, which was used directly
for further transformation without further purification.
[1348] To a stirred solution of 4'-hydroxyacetophenone (91 mmol) in
DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added.
The mesylate prepared from 3-diethylamino-1-propanol and
methanesulfonyl chloride (76 mmol) was added to the reaction
mixture and heated to 80.degree. C. until completion according to
General Procedure Q1, as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture was quenched by treating the mixture with
saturated sodium bicarbonate. The aqueous layer was poured into
EtOAc (100 mL) and washed with H.sub.2O (2.times.50 mL) and brine
(50 mL). The organic layer was dried over sodium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated
product was used for further transformation after purifying using
silica gel column chromatography (1-4% MeOH/DCM).
[1349] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4.6 mmol) in
anhydrous MeOH (10 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 5.5 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to it until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1350] To a stirred solution of 4-(naphthalen-2-yloxy)aniline (1.2
eq., 5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 15 mmol) was
added, followed by slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (4.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was isolated in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was used for further
transformation without additional purification.
[1351] To a stirred solution of alkylated
4-(naphthalen-2-yloxy)aniline described above (4.6 mmol) in
anhydrous DCM (5 mL) at 0.degree. C., TEA (3 eq., 15 mmol) was
added, followed by slow addition of valeryl chloride (3 eq., 15
mmol), according to General Procedure R3. The reaction mixture was
stirred under nitrogen at 0.degree. C. for 1 h and allowed to warm
to rt until completion, as indicated by TLC or HPLC. The solvent
was removed in vacuuo, and the crude amide was used for further
transformation.
[1352] To a stirred solution of the N-alkylated anilide (.about.4.6
mmol) obtained as above in acetic acid (10 mL), solid ammonium
acetate (92 mmol) was added in one portion, according to General
Procedure R4. The reaction mixture was then heated to 100.degree.
C. overnight. The reaction mixture was cooled to rt, and treated
with saturated aqueous sodium bicarbonate solution while stirring
to until the pH was 7-8. The contents were extracted with EtOAc
(2.times.50 mL). The combined organic layers was washed with
H.sub.2O (50 mL) and brine, and dried over sodium sulfate.
Evaporation of the solvent in vacuuo afforded the desired N-aryl
imidazole. The crude product was purified using silica gel column
chromatography (2-5% MeOH/DCM) (yield 170 mg).
[1353] MS m/z 548 (M+H).sup.+:
[1354] .sup.1H NMR (CDCl.sub.3): .delta.7.91 (t, 1H), 7.84 (t, 1H),
7.77 (m, 1H), 7.71 (m, 2H) 7.56-7.42 (m, 4H), 7.32 (m, 2H), 7.18
(s, 1H), 7.16-7.03 (m, 2H), 7.00-6.86 (m, 2H), 4.02 (t, 2H),
3.00-2.76 (m, 6H), 2.70 (m, 2H), 2.12 (m, 2H), 1.44-1.28 (m, 4H),
1.23 (t, 6H), 0.93 (m, 3H) ppm.
Example 482
2-butyl-4-[4-(4-ethyl-hexyloxy)-phenyl]-1-[4-(4-methoxy-naphthalen-1-yl-ox-
y)-phenyl]-1H-imidazole
[1355] To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol)
in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added
followed by addition of 4-methoxy-1-naphthol (10 mmol) to the
reaction mixture and heating to 80.degree. C. until the reaction
was complete as indicated by TLC or HPLC. After cooling to rt, the
reaction mixture was poured into H.sub.2O (100 mL), extracted with
EtOAc (2.times.50 mL), washed with H.sub.2O (2.times.50 mL) and
brine (50 mL), and dried over sodium sulfate. The solvent was
removed in vacuuo to afford the desired
4-(4-methoxynaphthalen-1-yloxy)-1-nitrobenzene. The crude product
was used for further transformation.
[1356] The nitro intermediate (10 mmol) obtained above was
dissolved in EtOAc (50 mL) and hydrogenated in the presence of 10%
Pd/C (360 mg) until completion according to General Procedure H, as
indicated by TLC or HPLC. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
the desired 4-(4-methoxy-naphthalen-1-yloxy)aniline, which was used
directly for further transformation without further
purification.
[1357] To a stirred solution of 4'-hydroxyacetophenone (91 mmol) in
DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added.
The mesylate prepared from 3-diethylamino-1-propanol and
methanesulfonyl chloride (76 mmol) was added to the reaction
mixture and heated to 80.degree. C. until completion according to
General Procedure Q1, as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture was quenched by treating the mixture with
saturated sodium bicarbonate. The aqueous layer was poured into
EtOAc (100 mL) and washed with H.sub.2O (2.times.50 mL) and brine
(50 mL). The organic layer was dried over sodium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated
product was used for further transformation after purifying using
silica gel column chromatography (1-4% MeOH/DCM).
[1358] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2.3 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.7 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1359] To a stirred solution of
4-(4-methoxy-naphthalen-1-yloxy)aniline (1.2 eq., 2.5 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (2.3 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was isolated in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was used for further
transformation.
[1360] To a stirred solution of alkylated
4-(4-methoxynaphthalen-1-yloxy)aniline described above (2.3 mmol)
in anhydrous DCM (5 mL) at 0.degree. C., TEA (3 eq., 7.5 mmol) was
added, followed by slow addition of valeryl chloride (3 eq., 7.5
mmol), according to General Procedure R3. The reaction mixture was
stirred under nitrogen at 0.degree. C. for 1 h and allowed to warm
to rt until completion, as indicated by TLC or HPLC. The solvent
was removed in vacuuo, and the crude amide was used for further
transformation.
[1361] To a stirred solution of the N-alkylated anilide (2.3 mmol)
obtained as above in acetic acid (5 mL), solid ammonium acetate (46
mmol) was added in one portion, according to General Procedure R4.
The reaction mixture was then heated to 100.degree. C. overnight.
The reaction mixture was cooled to rt, and treated with saturated
aqueous sodium bicarbonate solution while stirring to until the pH
was 7-8. The contents were extracted with EtOAc (2.times.30 mL).
The combined organic layers was washed with H.sub.2O (2.times.30
mL) and brine, and dried over sodium sulfate. Evaporation of the
solvent in vacuuo afforded the desired N-aryl imidazole. The crude
product was purified using silica gel column chromatography (2-5%
MeOH/DCM) (yield 213 mg).
[1362] MS m/z 578 (M+H).sup.+:
[1363] .sup.1H NMR (CDCl.sub.3): .delta.8.35 (dd, 1H), 7.60 (dd,
1H), 7.72 (m, 2H), 7.55 (m, 2H), 7.24 (s, 1H), 7.23 (m, 2H), 7.15
(t, 1H), 7.04 (m, 2H), 6.90 (m, 2H), 6.80 (d, 1H), 4.04 (s, 3H),
3.95 (t, 2H), 3.00-2.87 (m, 6H), 2.67 (t, 2H), 2.10 (m, 2H), 1.65
(m, 2H), 1.38 (m, 2H), 1.21 (t, 6H), 0.95 (m, 3H) ppm.
Example 483
[3-(4-{2-butyl-1-[4-(dibenzofuran-2-yloxy)-phenyl]-1H-imidazol-4-yl}-pheno-
xy)-propyl]-diethyl-amine
[1364] To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol)
in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added
followed by addition of 2-hydroxydibenzofuran (10 mmol) to the
reaction mixture and heating to 80.degree. C. until the reaction
was complete as indicated by TLC or HPLC. After cooling to rt, the
reaction mixture was poured into H.sub.2O (100 mL), extracted with
EtOAc (2.times.50 mL), washed with H.sub.2O (2.times.50 mL) and
brine (50 mL), and dried over sodium sulfate. The solvent was
removed in vacuuo to afford the desired
4-(dibenzofuran-2-yloxy)-1-nitrobenzene. The crude product was used
for further transformation.
[1365] The nitro intermediate (10 mmol) obtained above was
dissolved in EtOAc (50 mL) and hydrogenated in the presence of 10%
Pd/C (360 mg) until completion according to General Procedure H, as
indicated by TLC or HPLC. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
the desired 4-(dibenzofuran-2-yloxy)aniline, which was used
directly for further transformation without further
purification.
[1366] To a stirred solution of 4'-hydroxyacetophenone (91 mmol) in
DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added.
The mesylate prepared from 3-diethylamino-1-propanol and
methanesulfonyl chloride (76 mmol) was added to the reaction
mixture and heated to 80.degree. C. until completion according to
General Procedure Q1, as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture was quenched by treating the mixture with
saturated sodium bicarbonate. The aqueous layer was poured into
EtOAc (100 mL) and washed with H.sub.2O (2.times.50 mL) and brine
(50 mL). The organic layer was dried over sodium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated
product was used for further transformation after purifying using
silica gel column chromatography (1-4% MeOH/DCM).
[1367] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2.3 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq, 2.7 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1368] To a stirred solution of 4-(dibenzofuran-2-yloxy)aniline
(1.2 eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol)
was added, followed by slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (2.3 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was isolated in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was used for further
transformation.
[1369] To a stirred solution of alkylated
4-(dibenzofuran-2-yloxy)aniline described above (.about.2.3 mmol)
in anhydrous DCM (5 mL) at 0.degree. C., TEA (3 eq., 7.5 mmol) was
added, followed by slow addition of valeryl chloride (3 eq., 7.5
mmol), according to General Procedure R3. The reaction mixture was
stirred under nitrogen at 0.degree. C. for 1 h and allowed to warm
to rt until completion, as indicated by TLC or HPLC. The solvent
was removed in vacuuo, and the crude amide was used for further
transformation.
[1370] To a stirred solution of the N-alkylated anilide (2.3 mmol)
obtained as above in acetic acid (5 mL), solid ammonium acetate (46
mmol) was added in one portion, according to General Procedure R4.
The reaction mixture was then heated to 100.degree. C. overnight.
The reaction mixture was cooled to rt, and treated with saturated
aqueous sodium bicarbonate solution while stirring to until the pH
was 7-8. The contents were extracted with EtOAc (2.times.30 mL).
The combined organic layers was washed with H.sub.2O (2.times.30
mL) and brine, and dried over sodium sulfate. Evaporation of the
solvent in vacuuo afforded the desired N-aryl imidazole. The crude
product was purified using silica gel column chromatography (2-5%
MeOH/DCM) (yield 164 mg).
[1371] MS m/z 588 (M+H).sup.+:
[1372] .sup.1H NMR (CDCl.sub.3): .delta.7.92 (d, 1H), 7.71 (m, 2H),
7.62 (d, 2H), 7.51 (t, 1H), 7.37 (t, 1H), 7.32-7.26 (m, 3H), 7.23
(m, 2H), 7.16 (s, 1H), 7.13-7.09 (m, 1H), 6.91 (d, 2H), 4.08 (t,
2H), 2.97-2.75 (m, 6H), 2.69 (t, 2H), 2.19 (m, 2H), 1.69 (m, 2H),
1.39-1.25 (m, 2H), 1.29 (t, 6H), 0.89 (t, 3H) ppm.
Example 484
6-(4-{2-butyl-4-[4-(3-diethylamino-propoxy)-phenyl]-imidazol-1-yl}-phenoxy-
)-naphthalen-2-ol
[1373] To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol)
in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added
followed by addition of 6-methoxy-2-naphthol (10 mmol) to the
reaction mixture and heating to 80.degree. C. until the reaction
was complete as indicated by TLC or HPLC. After cooling to rt, the
reaction mixture was poured into H.sub.2O (100 mL), extracted with
EtOAc (2.times.50 mL), washed with H.sub.2O (2.times.50 mL) and
brine (50 mL), and dried over sodium sulfate. The solvent was
removed in vacuuo to afford the desired
4-(6-methoxy-2-naphthalen-2-yloxy)-1-nitrobenzene. The crude
product was used for further transformation.
[1374] The nitro intermediate (10 mmol) obtained above was
dissolved in EtOAc (50 mL) and hydrogenated in the presence of 10%
Pd/C (360 mg) until completion according to General Procedure H, as
indicated by TLC or HPLC. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
the desired 4-(6-methoxy-naphthalen-2-yloxy)aniline, which was used
directly for further transformation without additional
purification.
[1375] To a stirred solution of 4'-hydroxyacetophenone (91 mmol) in
DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added.
The mesylate prepared from 3-diethylamino-1-propanol and
methanesulfonyl chloride (76 mmol) was added to the reaction
mixture and heated to 80.degree. C. until completion according to
General Procedure Q1, as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture was quenched by treating the mixture with
saturated sodium bicarbonate. The aqueous layer was poured into
EtOAc (100 mL) and washed with H.sub.2O (2.times.50 mL) and brine
(50 mL). The organic layer was dried over sodium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated
product was used for further transformation after purifying using
silica gel column chromatography (1-4% MeOH/DCM).
[1376] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (4.6 mmol) in
anhydrous MeOH (10 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 5.2 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1377] To a stirred solution of an
4-(6-methoxy-naphthalen-2-yloxy)aniline (5 mmol) in anhydrous DMF
(20 mL) DIEA (15 mmol) was added, followed by slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (4.6 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was isolated in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was used for further
transformation without additional purification.
[1378] To a stirred solution of alkylated
4-(6-methoxy-2-naphthalenoxy)aniline described above (4.6 mmol) in
anhydrous DCM (10 mL) at 0.degree. C., TEA (3 eq., 15 mmol) was
added, followed by slow addition of valeryl chloride (3 eq., 15
mmol), according to General Procedure R3. The reaction mixture was
stirred under nitrogen at 0.degree. C. for 1 h and allowed to warm
to rt until completion, as indicated by TLC or HPLC. The solvent
was removed in vacuuo, and the crude amide was used for further
transformation.
[1379] To a stirred solution of the N-alkylated anilide (.about.4.6
mmol) obtained as above in acetic acid (10 mL), solid ammonium
acetate (92 mmol) was added in one portion, according to General
Procedure R4. The reaction mixture was then heated to 100.degree.
C. overnight. The reaction mixture was cooled to rt, and treated
with saturated aqueous sodium bicarbonate solution while stirring
to until the pH was 7-8. The contents were extracted with EtOAc
(2.times.40 mL). The combined organic layers was washed with
H.sub.2O (2.times.40 mL) and brine, and dried over sodium sulfate.
Evaporation of the solvent in vacuuo afforded the desired N-aryl
imidazole. The crude product was purified using silica gel column
chromatography (2-5% MeOH/DCM) (Yield: 19%).
[1380] The N-aryl imidazole (0.12 mmol) previously described was
dissolved in 5 mL of 48% aqueous HBr and heated to 90.degree. C.
for 36 h until the reaction was complete by HPLC. The reaction
mixture was cooled to rt and treated with ice-cold saturated
aqueous sodium bicarbonate solution until pH 8. The mixture was
extracted with EtOAc (2.times.15 mL). The combined organic layers
was washed with H.sub.2O (2.times.15 mL) and brine, and dried over
sodium sulfate. Evaporation of the solvent in vacuuo afforded the
demethylated N-aryl imidazole. The crude product was purified using
silica gel column chromatography (2-5% MeOH/DCM) (yield 20 mg).
[1381] MS m/z 564 (M+H).sup.+:
[1382] .sup.1H NMR (CDCl.sub.3): .delta.7.62 (d, 2H), 7.60 (s, 1H),
7.58-7.54 (m, 2H), 7.32 (d, 1H), 7.18 (s, 1H), 7.16 (d, 1H),
7.15-7.10 (m, 2H), 7.08 (s, 1H), 7.02 (d, 2H), 6.78 (d, 2H), 3.95
(t, 2H), 3.00-2.81 (m, 6H), 2.60 (t, 2H), 2.12 (m, 2H), 1.56 (m,
2H), 1.30 (t, 2H), 1.21 (t, 6H), 0.75 (t, 3H) ppm.
Example 485
[3-(4-{2-butyl-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}-phenoxy)-pro-
pyl]-diethyl-amine
[1383] A mixture of 4-fluoroacetophone (50 mmol), 4-chlorophenol
(75 mmol, 1.5 eq), cesium carbonate (150 mmol, 3 eq) and anhydrous
DMSO (80 mL) was heated with stirring at 90.degree. C. for 20 h
(monitored by TLC). After cooling to rt, the reaction mixture was
treated with cold H.sub.2O (150 mL), and the resulting mixture was
extracted with ether (4.times.100 mL). The combined organic layers
were washed with 2N NaOH (4.times.100 mL), H.sub.2O (2.times.100
mL) and brine (100 mL), and dried over anhydrous sodium sulfate.
The crude 1-[4-(4-chlorophenoxy)phenyl]ethanone was purified by
flash chromatography (eluting with 5-10% EtOAc in hexane) to give
4-(4'-chlorophenoxy)acetophone as an almost colorless solid (yield:
80%).
[1384] To a stirred solution of 4-fluoronitrobenzene (50 mmol) and
3-diethylaminoproanol (70 mmol) dissolved in anhydrous THF (50 mL)
at 0.degree. C. and under a nitrogen stream was added KOBu.sup.t
(70 mmol) in portions, and the reaction mixture was allowed to warm
to rt, and stirred overnight, according to General Procedure L1.
The reaction mixture was then treated with cold H.sub.2O (80 mL),
and extracted with EtOAc (3.times.100 mL). The combined organic
layers were washed with brine (2.times.60 mL) and dried over
anhydrous sodium sulfate. Evaporation of the solvent in vacuuo
afforded the desired N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine,
which was used for further transformation without further
purification (yield: .about.98%).
[1385] The crude N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine
(.about.33 mmol) was dissolved in MeOH (50 mL), and hydrogenated in
the presence of 10% Pd/C (0.8 g) until the reaction was complete as
indicated by LC-MS (.about.4 h), according to General Procedure H.
The reaction mixture was then filtered to remove the catalyst. The
solvent was removed under high vacuum to afford
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine which was used
directly for further transformation without further purification
(yield: .about.96%).
[1386] 1-[4-(4-chlorophenoxy)phenyl]ethanone (24 mmol) was
dissolved in 1,4-dioxane (100 mL), and pyridine hydrotribromide
(25.2 mmol, 1.05 eq) was added, according to General Procedure R1.
After being stirred at rt for 7 h (monitored by TLC), the reaction
was quenched with cold H.sub.2O (100 mL). The resulting mixture was
extracted with ether (4.times.100 mL). The combined ether extracts
were washed with brine (3.times.50 mL), and dried over anhydrous
sodium sulfate. The solvent was then removed in vacuuo and the
crude 2-bromo-1-[4-(4-chlorophenoxy)phenyl]ethanone was directly
used for further transformation.
[1387] To a stirred solution of ice-cold
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (22 mmol, 1.1 eq)
dissolved in DCM (40 mL) was added dropwise a solution of the
2-bromo-1-[4-(4-chlorophenoxy)phenyl]ethanone (20 mmol) dissolved
in DMF (30 mL), according to General Procedure R2. The mixture was
stirred at 0.degree. C. for 3 h, and then allowed to warm to rt,
continuing the stirring for additional 2 h (monitored by LC-MS).
The reaction mixture was treated with saturated sodium bicarbonate
(100 mL), and the resulting mixture was extracted with EtOAc
(4.times.100 mL). The combined EtOAc extracts were washed with
brine (3.times.50 mL), and dried over anhydrous sodium sulfate. The
solvent was removed in vacuuo, and the crude product was purified
by silica gel column chromatography eluting with 10% MeOH in
EtOAc+0.2% TEA (overall yield from
1-[4-(4-chlorophenoxy)phenyl]ethanone: 60%).
[1388] To a stirred solution of the alkylated aniline described
above (10 mmol) dissolved in anhydrous DCM (100 mL) at 0.degree.
C., TEA (40 mmol, 4 eq) was added, followed by a slow addition of
valeryl chloride (20 mmol, 2 eq), according to General Procedure
R3. The reaction mixture was stirred under nitrogen at 0.degree. C.
for 2 h and allowed to warm to rt until completion, as indicated by
LC-MS. The solvent was removed in vacuuo, and the crude amide was
used directly for further transformation.
[1389] The crude amide described above (.about.6 mmol) was
suspended in acetic acid (10 mL), and ammonium acetate (excess,
.about.30 eq) was added, according to General Procedure R4. The
reaction mixture was stirred at 90.degree. C. for 6 h (as monitored
by LC-MS). The reaction mixture was then cooled down and
neutralized with saturated sodium bicarbonate and solid sodium
carbonate. The resulting mixture was extracted with EtOAc
(4.times.100 mL). The combined EtOAc extracts were washed with
H.sub.2O (2.times.60 mL) and brine (2.times.60 and dried over
anhydrous sodium sulfate. The solvent was removed in vacuuo, and
the crude product was purified by silica gel column chromatography
eluting with 10% MeOH in EtOAc+0.2% TEA affording Example 485.
[1390] MS m/z 532 (M+H).sup.+:
[1391] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.0.83 (t, 3H), 1.04
(t, 6H), 1.28 (m, 2H), 1.63 (m, 2H), 1.96 (m, 2H), 2.56 (q, 4H),
2.61-2.65 (m, 4H), 4.06 (t, 2H), 6.93 (d, 2H), 6.98 (d, 2H), 7.00
(d, 2H), 7.16 (s, 1H), 7.22 (d, 2H), 7.26 (d, 2H), 7.76 (d, 2H)
ppm.
Example 486
[3-(4-{2-(4-tert-butyl-cyclohexyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imid-
azol-4-yl}-phenoxy)-propyl]-diethyl-amine
[1392] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (80 mmol) in MeOH
(200 mL) at rt, pyrrolidone hydrotribromide (96 mmol, 1.2 eq) was
added in portions at rt, according to General Procedure R1. The
reaction mixture was stirred at rt for 2 h (monitored by LC-MS).
The solvent was then removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly
used for further transformation.
[1393] The solution of the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone dissolved in
anhydrous DMF (180 mL) was chilled to 0.degree. C., and
4-(4'-chlorophenoxy)aniline (88 mmol, 1.1 eq) was added, followed
by slowly adding DIEA (240 mmol, 3 eq), according to General
Procedure R2. After being stirred at 0.degree. C. for 1 h and at rt
for additional 4 h, the reaction mixture was treated with saturated
sodium bicarbonate (250 mL). The resulting mixture was extracted
with EtOAc (4.times.200 mL). The combined EtOAc extracts were
washed with brine (3.times.100 mL), and dried over anhydrous sodium
sulfate. The solvent was removed in vacuuo, and the crude product
was purified by silica gel column chromatography eluting with 10%
MeOH in EtOAc+0.2% TEA.
[1394] Oxayl chloride (420 mmol, 3 eq) was added slowly to an
ice-cold solution of 4-t-butylcyclohexanecarboxylic acid (140 mmol)
dissolved in anhydrous DCM (80 mL), and the reaction mixture was
stirred at 0.degree. C. for 3 h and at rt for additional 3 h. The
solvent was removed in vacuuo, and the resulting acid chloride was
pumped under high vacuum for about 30 min, and used for next step
reaction without further purification.
[1395] To a stirred solution of the
2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-
-ethanone described above (35 mmol) dissolved in anhydrous DCM (200
mL) at 0.degree. C., TEA (140 mmol, 4 eq) was added, followed by a
slow addition of the freshly prepared acid chloride (70 mmol, 2
eq). The reaction mixture was stirred under nitrogen at 0.degree.
C. for 2 h and allowed to warm to rt until completion, as indicated
by LC-MS. The solvent was removed in vacuuo, and the crude amide
was used directly for further transformation.
[1396] The crude amide described above (.about.35 mmol) was
suspended in acetic acid (50 mL), and ammonium acetate (excess,
.about.30 eq) was added, according to General Procedure R4. The
reaction mixture was stirred at 100.degree. C. for 6 h (as
monitored by LC-MS). The reaction mixture was then cooled down and
neutralized with saturated sodium bicarbonate and solid sodium
carbonate. The resulting mixture was extracted with EtOAc
(4.times.200 mL). The combined EtOAc extracts were washed with
H.sub.2O (2.times.100 mL) and brine (2.times.100 mL), and dried
over anhydrous sodium sulfate. The solvent was removed in vacuuo,
and the crude product was purified by silica gel column
chromatography eluting with 10% MeOH in EtOAc+0.2% TEA affording
the title compound as cis/trans (1:2 ratio) mixture (yield 14.5
g).
[1397] LC: 1.06 min; MS: m/z 614 (M+H).sup.+
Example 487
[3-{-4-[1-[4-(4-chloro-phenoxy)-phenyl]-2-(4-ethyl-cyclohexyl)-1H-imidazol-
-4-yl]-phenoxy}-propyl)-diethyl-amine
[1398] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (80 mmol) in MeOH
(200 mL) at rt, pyrrolidone hydrotribromide (96 mmol, 1.2 eq) was
added in portions at rt, according to General Procedure R1. The
reaction mixture was stirred at rt for 2 h (monitored by LC-MS).
The solvent was then removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was directly
used for further transformation.
[1399] The solution of the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone dissolved in
anhydrous DMF (180 mL) was chilled to 0.degree. C., and
4-(4'-chlorophenoxy)aniline (88 mmol, 1.1 eq) was added, followed
by slowly adding DIEA (240 mmol, 3 eq), according to General
Procedure R2. After being stirred at 0.degree. C. for 1 h and at it
for additional 4 h, the reaction mixture was treated with saturated
sodium bicarbonate (250 mL). The resulting mixture was extracted
with EtOAc (4.times.200 mL). The combined EtOAc extracts were
washed with brine (3.times.100 mL), and dried over anhydrous sodium
sulfate. The solvent was removed in vacuuo, and the crude product
was purified by silica gel column chromatography eluting with 10%
MeOH in EtOAc+0.2% TEA (yield: 45%).
[1400] Oxayl chloride (3 mmol, 3 eq) was added slowly to an
ice-cold solution of trans-4-ethylcyclohexanecarboxylic acid (1
mmol) dissolved in anhydrous DCM (5 mL), and the reaction mixture
was stirred at 0.degree. C. for 2 h and at it for additional 1 h.
The solvent was removed in vacuuo, and the resulting acid chloride
was pumped under high vacuum for about 30 min, and used without
further purification.
[1401] To a stirred solution of the
2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-
-ethanone (0.3 mmol) described above dissolved in anhydrous DCM (10
mL) at 0.degree. C., TEA (1.2 mmol, 4 eq) was added, followed by
slow addition of the freshly prepared acid chloride (.about.1 mmol,
.about.3 eq). The reaction mixture was stirred under nitrogen at
0.degree. C. for 2 h and allowed to warm to rt until completion, as
indicated by LC-MS. The solvent was removed in vacuuo, and the
crude amide was used directly for further transformation.
[1402] To a stirred solution of the amide described above
(.about.0.3 mmol) in acetic acid (2 mL), ammonium acetate (excess,
.about.30 eq.) was added, according to General Procedure R4. The
reaction mixture was stirred at 100.degree. C. for 3 h (as
monitored by LC-MS). The reaction mixture was then cooled to rt and
neutralized with saturated sodium bicarbonate. The resulting
mixture was extracted with EtOAc (3.times.50 mL). The combined
EtOAc extracts were washed with brine (3.times.20 ml), and dried
over anhydrous sodium sulfate. The solvent was removed in vacuuo,
and the pure product was obtained by silica gel column
chromatography eluting with 10% MeOH/EtOAc+0.2% Et.sub.3N (yield
123 mg).
[1403] MS m/z 586 (M+H).sup.+:
[1404] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.0.85 (t, 3H), 1.06
(t, 6H), 1.16-1.82 (m, 12H), 1.96 (m, 2H), 2.61 (q, 4H), 2.68 (t,
21-1), 4.01 (t, 2H), 6.89 (d, 2H), 7.03 (d, 2H), 7.06 (d, 2H), 7.08
(s, 1H), 7.27 (d, 2H), 7.35 (d, 2H), 7.68 (d, 2H) ppm.
Example 488
[4-(4-{2-butyl-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)--
phenyl]-(1-ethyl-piperidin-4-ylmethyl)-amine
[1405] To a stirred solution of the
4'-(4-nitro-phenoxy)acetophenone (2 mmol) in anhydrous MeOH (5 mL)
at 0.degree. C., pyrrolidone hydrotribromide (1.2 eq., 2.2 mmol)
was added, according to General Procedure R1. The reaction mixture
was stirred under nitrogen at 0.degree. C. for 1 h and was allowed
to warm to rt until completion, as indicated by TLC or HPLC. The
solvent was then removed in vacuuo and the residue was treated with
saturated sodium bicarbonate. The aqueous layer was poured into
EtOAc (20 ml) and washed with water (2.times.15 ml) and brine (15
ml). The organic layer was dried over magnesium sulfate, and the
solvent was removed in vacuuo to afford the desired product. The
crude alpha-bromoacetophenone was used for further
transformation.
[1406] To a stirred solution of the 4-chloro-phenoxy aniline (1.2
eq., 2.2 mmol) in anhydrous DMF (10 mL) DIEA (3 eq. 6 mmol) was
added, followed by slow addition of the alpha-bromoacetophenone
described above (1.6 mmol), according to General Procedure R2. The
reaction mixture was stirred under nitrogen at rt until completion,
as indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was used for further
transformation.
[1407] To a stirred solution of alkylated aniline described above
(1.6 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (3 eq., 4.8
mmol) was added, followed by slow addition of valeryl chloride (2
eq., 3.2 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The reaction mixture was then diluted with water and the
product was isolated in DCM. The solvent was removed in vacuuo, and
the crude amide was used for further transformation.
[1408] To a stirred solution of the amide described above (1 mmol)
in acetic acid (2 mL), ammonium acetate (excess, .about.20 eq.) was
added, according to General Procedure R4. The reaction mixture was
stirred at 90.degree. C. overnight. The reaction mixture was then
cooled to rt and neutralized with saturated sodium bicarbonate
solution. Usual extractive work up with EtOAc gave the cyclized
imidazole, which was purified by column chromatography (Silica
gel). Pure product was obtained from 30-40% ethylacetate/hexane
(yield 50-55%).
[1409] The cyclized imidazole intermediate obtained above (0.5
mmol) obtained above was dissolved in MeOH (5 mL) and hydrogenated
in the presence of 10% Pd/C (10 mg) until completion as indicated
by TLC or HPLC, according to General Procedure H. The reaction
mixture was then filtered to remove the catalyst. The solvent was
removed in vacuuo to afford the desired reduced imidazole, which
was used directly for further transformation without further
purification.
[1410] To a stirred solution of N-Boc-4-piperidineacetic acid (1.2
eq., 0.6 mmol) in anhydrous DCM (2 mL) was added DCC-PS (1.5 eq.,
0.75 mmol). The solution was allowed to shake at rt for 20-30 min.
This was followed by addition of the reduced cyclized imidazole
described above (0.5 mmol). The reaction mixture was shaken
overnight at rt until completion, as indicated by TLC or HPLC. The
reaction mixture was then filtered and the product was isolated in
DCM. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[1411] To a stirred solution of the amide described above (0.5
mmol) in anhydrous THF (2 mL) at 0.degree. C., borane/THF (3 eq,
1.5 mmol) was added. The reaction mixture was stirred under
nitrogen at 0.degree. C. for 1 h and allowed to warm to rt until
completion, as indicated by TLC or HPLC. The reaction mixture was
then cooled to rt and the solvent was removed in vacuuo to give the
product imidazole, which was purified by column chromatography
(Silica gel). Pure product was obtained from 3-4% MeOH/DCM (yield
150 mg).
[1412] MS m/z 635 (M+H).sup.+:
[1413] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.01 (s, 1H),
7.84 (d, 2H), 7.65 (d, 2H), 7.59 (d, 2H), 7.44 (d, 2H), 7.22 (m,
6H), 7.12 (d, 2H), 3.65 (d, 2H), 3.45 (d, 2H), 3.03 (t, 2H), 3.18
(m, 2H), 2.98 (m, 4H), 2.15 (m, 2H), 1.71 (m, 3H), 1.39 (m, 5H),
0.85 (t, 3H) ppm
Example 489
[4-{1-[4-(4-chloro-phenoxy)-phenyl]-4-[4-(3-diethylaminopropoxy)-phenyl]-1-
H-imidazol-2-yl}-butyric acid methyl ester
[1414] As described in Example 406,
2-[4-(4-chlorophenoxy)-phenylamino]-1-[4-(3-diethylamino-propoxy)-phenyl]-
-ethanone (0.5 mmol) was dissolved in anhydrous DCM (10 mL) and
cooled to 0.degree. C. TEA (2 mmol, 4 eq) was added to the reaction
mixture, followed by slow addition of methyl
4-(chloroformyl)butyrate (1.5 mmol, 3 eq), according to General
Procedure R3. The reaction mixture was stirred under nitrogen at
0.degree. C. for 2 h and allowed to warm to rt until completion, as
indicated by LC-MS. The solvent was removed in vacuuo, and the
crude amide was used directly for further transformation.
[1415] To a stirred solution of the amide described above in acetic
acid (2 mL), ammonium acetate (excess, .about.30 eq) was added,
according to General Procedure R4. The reaction mixture was stirred
at 100.degree. C. for 3 h (as monitored by LC-MS). The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate. The resulting mixture was extracted with EtOAc
(3.times.50 mL). The combined EtOAc extracts were washed with brine
(3.times.20 mL), and dried over anhydrous sodium sulfate. The
solvent was removed in vacuuo, and the pure product was obtained by
silica gel column chromatography eluting with 10% MeOH in
EtOAc+0.2% TEA (yield: .about.70%) (yield 202 mg).
[1416] MS m/z 576 (M+H).sup.+:
[1417] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.1.04 (t, 6H), 1.94
(m, 2H), 2.02 (m, 2H), 2.39 (t, 2H), 2.56 (q, 4H), 2.63 (t, 2H),
2.72 (t, 2H), 3.59 (s, 3H), 4.02 (t, 2H), 6.91 (d, 2H), 7.03 (d,
2H), 7.07 (d, 2H), 7.14 (s, 1H), 7.29 (d, 2H), 7.35 (d, 2H), 7.68
(d, 2H) ppm.
Example 490
[3-(4-{2-butyl-1-[4-(4-chloro-2-cyclohexyl-phenoxy)-phenyl]-1H-imidazol-4--
yl}-phenoxy)-propyl]-diethyl-amine
[1418] To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol)
in DMF (10 mL) at rt, solid potassium carbonate (30 mmol) was added
followed by addition of 4-chloro-2-cyclohexylphenol (10 mmol) to
the reaction mixture and heating to 80.degree. C. until the
reaction was complete as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture was poured into EtOAc (80 ml), washed with
H.sub.2O (2.times.40 ml) and brine (60 mL), and dried over sodium
sulfate. The solvent was removed in vacuuo to afford the desired
4-(4-chloro-2-cyclohexylphenoxy)-1-nitrobenzene. The crude product
was used for further transformation.
[1419] The nitro intermediate (10 mmol) obtained above was
dissolved in MeOH (20 mL), and treated with SnCl.sub.2.2H.sub.2O
(50 mmol), according to General Procedure I. The reaction mixture
was heated under reflux until completion, as indicated by TLC or
HPLC. The solvent was removed in vacuuo and the residue was treated
with 4.0 N aqueous NaOH to pH .about.8. The residue was extracted
with EtOAc (2.times.50 mL), washed with 1.0 N aqueous NaOH, brine
and dried over sodium sulfate. The solvent was removed in vacuuo to
afford the desired 4-(4-chloro-2-cyclohexylphenoxy) aniline, which
was used directly for further transformation without further
purification.
[1420] To a stirred solution of 4'-hydroxyacetophenone (91 mmol) in
DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added.
The mesylate prepared from 3-diethylamino-1-propanol and
methanesulfonyl chloride (76 mmol) was added to the reaction
mixture and heated to 80.degree. C. until completion according to
General Procedure Q1, as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture was quenched by treating the mixture with
saturated sodium bicarbonate. The aqueous layer was poured into
EtOAc (100 mL) and washed with H.sub.2O (2.times.50 mL) and brine
(50 mL). The organic layer was dried over sodium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated
product was used for further transformation after purifying using
silica gel column chromatography (1-4% MeOH/DCM).
[1421] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2.4 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq, 2.9 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1422] To a stirred solution of 4-(4-chloro-2-cyclohexylphenoxy)
aniline (1.2 eq., 2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6
mmol) was added, followed by slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (2.4 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was isolated in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was purified by
chromatography (Silica gel). Pure product obtained from 2-4%
MeOH/DCM (yield .about.50-60%).
[1423] To a stirred solution of alkylated
4-(4-chloro-2-cyclohexylphenoxy) aniline described above (2.4 mmol)
in anhydrous DCM (5 mL) at 0.degree. C., TEA (3 eq., 7.5 mmol) was
added, followed by slow addition of valeryl chloride (3 eq., 7.5
mmol), according to General Procedure R3. The reaction mixture was
stirred under nitrogen at 0.degree. C. for 1 h and allowed to warm
to rt until completion, as indicated by TLC or HPLC. The solvent
was removed in vacuuo, and the crude amide was used for further
transformation.
[1424] To a stirred solution of the N-alkylated anilide (.about.2.4
mmol) obtained as above in acetic acid (5 mL), solid ammonium
acetate (46 mmol) was added in one portion, according to General
Procedure R4. The reaction mixture was then heated to 100.degree.
C. overnight. The reaction mixture was cooled to rt, and treated
with saturated aqueous sodium bicarbonate solution while stirring
to until the pH was 7-8. The contents were extracted with EtOAc
(2.times.30 mL). The combined organic layers was washed with
H.sub.2O (2.times.30 mL) and brine, and dried over sodium sulfate.
Evaporation of the solvent in vacuuo afforded the desired N-aryl
imidazole. The crude product was purified using silica gel column
chromatography (2-5% MeOH/DCM) (yield 118 mg).
[1425] MS m/z 614 (M+H).sup.+:
[1426] .sup.1H NMR (CDCl.sub.3) .delta.7.86 (d, 1H), 7.63 (d, 2H),
7.25 (d, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 6.94 (d, 2H), 6.81 (d,
2H), 6.80 (d, 1H, 6.8 Hz), 4.12 (m, 2H), 3.20 (m, 2H), 2.98-2.79
(m, 6H), 2.60 (t, 2H), 2.21-2.19 (m, 2H), 2.15-2.05 (m, 1H),
1.78-1.72 (m, 2H), 1.59-1.50 (m, 2H), 1.36-1.24 (m, 4H), 1.21 (t,
6H), 0.84 (m, 4H), 0.79 (m, 3H) ppm.
Example 491
[3-(4-{1-[4-(biphenyl-4-yloxy)-phenyl]-2-butyl-1H-imidazol-4-yl}-phenoxy)--
propyl]-diethyl-amine
[1427] To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol)
in DMF (20 mL) at room temperature, solid K.sub.2CO.sub.3 (30 mmol)
was added followed by addition of 4-hydroxybiphenyl (10 mmol) to
the reaction mixture and heating to 80.degree. C. until the
reaction was complete as indicated by TLC or HPLC. After cooling to
room temperature to room temperature, the reaction mixture was
poured into EtOAc (100 mL), washed with water (2.times.50 mL) and
brine (50 mL), and dried over sodium sulfate. The solvent was
removed in vacuo to afford the desired
4-(biphenyl-4-oxy)-1-nitrobenzene. The crude product was used for
further transformation.
[1428] The nitro intermediate (10 mmol) obtained above was
dissolved in EtOAc (40 mL) and hydrogenated in the presence of 10%
Pd/C (360 mg) until completion, as indicated by TLC or HPLC. The
reaction mixture was then filtered to remove the catalyst. The
solvent was removed in vacuo to afford the desired
4-(biphenyl-4-oxy)aniline, which was used directly for further
transformation without further purification.
[1429] To a stirred solution of 4'-hydroxyacetophenone (91 mmol) in
DMF (80 mL) at room temperature, solid K.sub.2CO.sub.3 (153 mmol)
was added. The mesylate of 3-diethylamino-1-propanol and
methanesulfonyl chloride (76 mmol) was added to the reaction
mixture and heated to 80.degree. C. until completion, as indicated
by TLC or HPLC. After cooling to room temperature, the reaction
mixture was quenched by treating the mixture with saturated sodium
bicarbonate. The aqueous layer was poured into EtOAc (100 mL) and
washed with water (2.times.50 mL) and brine (50 mL). The organic
layer was dried over sodium sulfate, and the solvent was removed in
vacuuo to afford the desired product. The crude alkylated product
was used for further transformation after purifying using silica
gel column chromatography (1-4% methanol/DCM).
[1430] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2.4 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.9 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1431] To a stirred solution of 4-(biphenyl-4-oxy)aniline (1.2 eq.,
2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 6 mmol) was added,
followed by slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (2.4 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was isolated in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was purified by
chromatography (Silica gel). Pure product obtained from 2-4%
MeOH/DCM (yield .about.13%).
[1432] To a stirred solution of alkylated 4-(biphenyl-4-oxy)aniline
described above (0.3 mmol) in anhydrous DCM (3 mL) at 0.degree. C.,
TEA (3 eq., 0.9 mmol) was added, followed by slow addition of
valeryl chloride (3 eq., 0.9 mmol), according to General Procedure
R3. The reaction mixture was stirred under nitrogen at 0.degree. C.
for 1 h and allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was removed in vacuuo, and the crude amide
was used for further transformation.
[1433] To a stirred solution of the N-alkylated anilide (.about.0.3
mmol) obtained as above in acetic acid (3 mL), solid ammonium
acetate (6 mmol) was added in one portion, according to General
Procedure R4. The reaction mixture was then heated to 100.degree.
C. overnight. The reaction mixture was cooled to rt, and treated
with saturated aqueous sodium bicarbonate solution while stirring
to until the pH was 7-8. The contents were extracted with EtOAc
(2.times.15 mL). The combined organic layers was washed with
H.sub.2O (2.times.15 mL) and brine, and dried over sodium sulfate.
Evaporation of the solvent in vacuuo afforded the desired N-aryl
imidazole. The crude product was purified using silica gel column
chromatography (2-5% MeOH/DCM).
[1434] MS m/z 574 (M+H).sup.+
[1435] .sup.1H NMR (CDCl.sub.3) .delta.7.86 (d, 1H), 7.63 (d, 2H),
7.25 (d, 2H), 7.18 (s, 1H), 7.08 (s, 1H), 6.94 (d, 2H), 6.81 (d,
2H), 6.80 (d, 1H), 4.12 (m, 2H), 3.20 (m, 2H), 2.98-2.79 (m, 6H),
2.60 (t, 2H), 2.21-2.19 (m, 2H), 2.15-2.05 (m, 1H), 1.78-1.72 (m,
2H), 1.59-1.50 (m, 2H), 1.36-1.24 (m, 4H), 1.21 (t, 6H), 0.84 (m,
4H), 0.79 (m, 3H) ppm
Example 492
[3-(4-{1-[4-(4-bromo-phenoxy)-phenyl]-2-butyl-1H-imidazol-4-yl}-phenoxy)-p-
ropyl]-diethyl-amine
[1436] To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol)
in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added
followed by addition of 4-bromophenol (10 mmol) to the reaction
mixture and heating to 80.degree. C. until the reaction was
complete as indicated by TLC or HPLC. After cooling to rt, the
reaction mixture was poured into EtOAc (100 mL), washed with
H.sub.2O (2.times.50 mL) and brine (50 mL), and dried over sodium
sulfate. The solvent was removed in vacuuo to afford the desired
4-bromophenoxy-1-nitrobenzene. The crude product was used for
further transformation.
[1437] The nitro intermediate (10 mmol) obtained above was
dissolved in EtOAc (50 mL) and hydrogenated in the presence of 10%
Pd/C (360 mg) until completion according to General Procedure H, as
indicated by TLC or HPLC. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
the desired 4-bromophenoxyaniline, which was used directly for
further transformation without additional purification.
[1438] To a stirred solution of 4'-hydroxyacetophenone (91 mmol) in
DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added.
The mesylate prepared from 3-diethylamino-1-propanol and
methanesulfonyl chloride (76 mmol) was added to the reaction
mixture and heated to 80.degree. C. until completion according to
General Procedure Q1, as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture was quenched by treating the mixture with
saturated sodium bicarbonate. The aqueous layer was poured into
EtOAc (100 mL) and washed with H.sub.2O (2.times.50 mL) and brine
(50 mL). The organic layer was dried over sodium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated
product was used for further transformation after purifying using
silica gel column chromatography (1-4% MeOH/DCM).
[1439] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2.4 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.9 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1440] To a stirred solution of 4-bromophenoxyaniline (1.2 eq., 2.5
mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added,
followed by slow addition of the
2-bromo-1-{(4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (2.4 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was isolated in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was purified by
chromatography (Silica gel). Pure product obtained from 2-4%
MeOH/DCM.
[1441] To a stirred solution of alkylated 4-bromophenoxyaniline
described above (0.45 mmol) in anhydrous DCM (5 mL) at 0.degree.
C., TEA (3 eq., 1.35 mmol) was added, followed by slow addition of
valeryl chloride (3 eq., 1.35 mmol), according to General Procedure
R3. The reaction mixture was stirred under nitrogen at 0.degree. C.
for 1 h and allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was removed in vacuuo, and the crude amide
was used for further transformation.
[1442] To a stirred solution of the N-alkylated anilide
(.about.0.45 mmol) obtained as above in acetic acid (3 mL), solid
ammonium acetate (9 mmol) was added in one portion, according to
General Procedure R4. The reaction mixture was then heated to
100.degree. C. overnight. The reaction mixture was cooled to rt,
and treated with saturated aqueous sodium bicarbonate solution
while stirring to until the pH was 7-8. The contents were extracted
with EtOAc (2.times.15 mL). The combined organic layers was washed
with H.sub.2O (2.times.15 mL) and brine, and dried over sodium
sulfate. Evaporation of the solvent in vacuuo afforded the desired
N-aryl imidazole. The crude product was purified using silica gel
column chromatography (2-5% MeOH/DCM) (yield 66 mg).
[1443] MS m/z 577 (M+H).sup.+:
[1444] .sup.1H NMR (CDCl.sub.3): .delta.7.63 (d, 2H), 7.43 (d, 2H),
7.23 (d, 2H), 7.08 (s, 1H), 7.02 (d, 2H), 6.90 (d, 2H), 6.83 (d,
2H) 4.05 (t, 2H), 2.92-2.72 (m, 6H), 2.60 (t, 2H), 2.05-2.15 (m,
2H), 1.60 (m, 2H), 1.33 (m, 2H), 1.20 (t, 6H), 0.80 (t, 3H) ppm
Example 493
N-[4-(4-{2-butyl-4-[4-(3-diethylamino-porpoxy)-phenyl]-imidazol-1-yl}-phen-
oxy)-phenyl]-acetamide
[1445] 3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM
(25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled
to 0.degree. C. To this mixture, methanesulfonyl chloride (30 mmol,
1.5 eq) was added slowly with stirring and the reaction mixture was
stirred at 0.degree. C. for 1 h and at rt for 1 h (until the
reaction was complete by HPLC). The solvent was removed and to this
saturated aqueous sodium bicarbonate was added. The product was
extracted with EtOAc (3.times.) and washed with sodium bicarbonate
and water. The solvent was removed in vacuuo.
[1446] The mesylate from the previous step (20 mmol, 1 eq) was
dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone
(20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added.
The mixture was heated under reflux at 85.degree. C. for 18 h
(until the reaction was complete by HPLC), after which it was
cooled to rt. Saturated aqueous sodium bicarbonate was added to the
mixture, which was then transferred to a separatory funnel. The
product was extracted with EtOAc and washed with sodium bicarbonate
and water. The solvent was removed in vacuuo and the product
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flash
chromatography (going by increasing gradient up to 10% MeOH in
DCM). The overall yield was 60%.
[1447] 4-Acetamidophenol (10 mmol) was dissolved in 15 ml of
anhydrous DMF and potassium carbonate (30 mmol) was added with
stirring at rt. 4-Fluoronitrobenzene (10 mmol) was added to this
mixture, which was then heated under reflux at 80.degree. C. for 18
h. The reaction was quenched with 30 ml of water and 30 ml of
sodium bicarbonate, extracted with EtOAc (3.times.50 ml) and washed
with sodium bicarbonate and water. EtOAc layer was dried over
anhydrous sodium sulfate and filtered, after which the solvent was
removed in vacuuo.
[1448] The nitro intermediate (10 mmol) obtained above was
dissolved in EtOH (30 mL) and hydrogenated in the presence of 10%
Pd/C (10 mg) until completion according to General Procedure H, as
indicated by TLC or HPLC. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
the desired 4-(3,4-dichlorophenoxy)aniline, which was used directly
for further transformation without further purification (yield
80%).
[1449] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2 mmol) in anhydrous
MeOH (6 mL) at 0.degree. C., pyrrolidone hydrotribromide (1.2 eq)
was added, according to General Procedure R1. The reaction mixture
was stirred under nitrogen at 0.degree. C. for 1 h and was allowed
to warm to rt until completion, as indicated by TLC or HPLC. The
solvent was then removed in vacuuo and the crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1450] To a solution of 4-(4-acetamidophenoxy) aniline (1 eq, 2
mmol) in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added,
followed by addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (2 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was purified by chromatography
(Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield
54%).
[1451] To a stirred solution of alkylated aniline described above
(1 mmol) in anhydrous DCM (4 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by a slow addition of valeryl chloride (3
eq, 3 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[1452] To a stirred solution of the amide described above (1 mmol)
in acetic acid (4 mL), ammonium acetate (20 eq) was added,
according to General Procedure R4. The reaction mixture was stirred
at 90.degree. C. overnight. The reaction mixture was then cooled to
rt and neutralized with saturated sodium bicarbonate solution.
Usual extractive work up with EtOAc gave the product imidazole,
which was purified by column chromatography (Silica gel). Pure
product was obtained from 4-6% MeOH/DCM (yield 210 mg).
[1453] MS m/z 555 (M+H).sup.+:
[1454] .sup.1H NMR: (CDCl.sub.3): .delta.7.68 (d, 2H), 7.51 (d,
2H), 7.25 (d, 2H), 7.13 (s, 1H), 6.88-7.00 (m, 6H), 4.02 (t, 2H),
2.62-2.70 (m, 8H), 2.20 (s, 3H), 2.16 (m, 2H), 1.97 (m, 2H), 1.16
(m, 2H), 1.05 (t, 6H), 0.83 (t, 3H) ppm
Example 494
(3-{4-[2-butyl-1-(4-p-tolyloxy-phenyl)-1H-imidazol-4-yl]-phenoxy}-propyl)--
diethyl-amine
[1455] 3-Diethylaminopropanol (20 mmol, 1 eq) was dissolved in DCM
(25 mL), TEA (40 mmol, 2 eq) was added and the mixture was cooled
to 0.degree. C. To this mixture, methanesulfonyl chloride (30 mmol,
1.5 eq) was added slowly with stirring and the reaction mixture was
stirred at 0.degree. C. for an hour and at rt for another hour
(until the reaction was complete by HPLC). The solvent was removed
and to this saturated aqueous sodium bicarbonate was added. The
product was extracted with EtOAc (3.times.) and washed with sodium
bicarbonate and water. The solvent was removed in vacuuo.
[1456] The mesylate from the previous step (20 mmol, 1 eq) was
dissolved in anhydrous DMF (25 mL) to which 4-hydroxyacetophenone
(20 mmol, 1 eq) and potassium carbonate (60 mmol, 3 eq) were added.
The mixture was heated under reflux at 85.degree. C. for 18 h
(until the reaction was complete by HPLC), after which it was
cooled to rt. Saturated aqueous sodium bicarbonate was added to the
mixture, which was then transferred to a separatory funnel. The
product was extracted with EtOAc and washed with sodium bicarbonate
and water. The solvent was removed in vacuuo and the product
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was purified by flash
chromatography (going by increasing gradient up to 10% MeOH in
DCM). The overall yield was 60%.
[1457] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2 mmol) in anhydrous
MeOH (6 mL) at 0.degree. C., pyrrolidone hydrotribromide (1.2 eq)
was added, according to General Procedure R1. The reaction mixture
was stirred under nitrogen at 0.degree. C. for 1 h and was allowed
to warm to rt until completion, as indicated by TLC or HPLC. The
solvent was then removed in vacuuo and the crude
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1458] To a solution of 4-tolyloxy aniline (1 eq, 2 mmol) in
anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added, followed by
addition of the
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (2 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was purified by chromatography
(Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield
56%).
[1459] To a stirred solution of alkylated aniline described above
(1 mmol) in anhydrous DCM (4 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by a slow addition of valeryl chloride (3
eq, 3 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[1460] To a stirred solution of the amide described above (1 mmol)
in acetic acid (4 mL), ammonium acetate (20 eq) was added,
according to General Procedure R4. The reaction mixture was stirred
at 90.degree. C. overnight. The reaction mixture was then cooled to
rt and neutralized with saturated sodium bicarbonate solution.
Usual extractive work up with EtOAc gave the product imidazole,
which was purified by column chromatography (Silica gel). Pure
product was obtained from 4-6% MeOH/DCM (yield 204 mg).
[1461] MS m/z 512 (M+H).sup.+:
[1462] .sup.1H NMR (CDCl.sub.3): .delta. 7.68 (d, 2H), 7.23 (d,
2H), 7.19 (d, 2H), 7.13 (s, 1H), 7.04 (d, 2H), 6.97 (d, 2H), 6.87
(d, 2H) 4.04 (t, 2H), 2.88-2.96 (m, 8H), 2.36 (s, 3H), 2.12 (m,
2H), 1.59 (m, 2H), 1.23 (m, 2H), 1.18 (t, 6H), 0.83 (t, 3H) ppm
Example 495
[3-(4-{2-butyl-1-[4-(4-fluoro-phenoxy)-phenyl]-1H-imidazol-4-yl}-phenoxy)--
propyl]-diethyl-amine
[1463] To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol)
in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added
followed by addition of 4-fluorophenol (10 mmol) to the reaction
mixture and heating to 80.degree. C. until the reaction was
complete as indicated by TLC or HPLC. After cooling to rt, the
reaction mixture was poured into EtOAc (100 mL), washed with
H.sub.2O (2.times.50 mL) and brine (50 mL), and dried over sodium
sulfate. The solvent was removed in vacuuo to afford the desired
4-fluorophenoxy-1-nitrobenzene. The crude product may be used for
further transformation.
[1464] The nitro intermediate (10 mmol) obtained above was
dissolved in EtOAc (30 mL) and hydrogenated in the presence of 10%
Pd/C (360 mg) until completion according to General Procedure H, as
indicated by TLC or HPLC. The reaction mixture was then filtered to
remove the catalyst. The solvent was removed in vacuuo to afford
the desired 4-fluorophenoxyaniline, which was used directly for
further transformation without additional purification.
[1465] To a stirred solution of 4'-hydroxyacetophenone (91 mmol) in
DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added.
The mesylate prepared from 3-diethylamino-1-propanol and
methanesulfonyl chloride (76 mmol) was added to the reaction
mixture and heated to 80.degree. C. until completion according to
General Procedure Q1, as indicated by TLC or HPLC. After cooling to
rt; the reaction mixture was quenched by treating the mixture with
saturated sodium bicarbonate. The aqueous layer was poured into
EtOAc (100 mL) and washed with H.sub.2O (2.times.50 mL) and brine
(50 mL). The organic layer was dried over sodium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated
product was used for further transformation after purifying using
silica gel column chromatography (1-4% MeOH/DCM).
[1466] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2.3 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.8 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1467] To a stirred solution of 4-fluorophenoxyaniline (1.2 eq.,
2.5 mmol) in anhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added,
followed by slow addition of the
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (2.3 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was isolated in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was purified by
chromatography (Silica gel). Pure product obtained from 2-4%
MeOH/DCM (yield .about.30%).
[1468] To a stirred solution of alkylated 4-fluorophenoxyaniline
described above (0.8 mmol) in anhydrous DCM (5 mL) at 0.degree. C.,
TEA (3 eq., 2.4 mmol) was added, followed by slow addition of
valeryl chloride (3 eq., 2.4 mmol), according to General Procedure
R3. The reaction mixture was stirred under nitrogen at 0.degree. C.
for 1 h and allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was removed in vacuuo, and the crude amide
was used for further transformation.
[1469] To a stirred solution of the N-alkylated anilide (.about.0.8
mmol) obtained as above in acetic acid (3 mL), solid ammonium
acetate (16 mmol) was added in one portion, according to General
Procedure R4. The reaction mixture was then heated to 100.degree.
C. overnight. The reaction mixture was cooled to rt, and treated
with saturated aqueous sodium bicarbonate solution while stirring
to until the pH was 7-8. The contents were extracted with EtOAc
(2.times.15 mL). The combined organic layers was washed with
H.sub.2O (2.times.15 mL) and brine, and dried over sodium sulfate.
Evaporation of the solvent in vacuuo afforded the desired N-aryl
imidazole. The crude product was purified using silica gel column
chromatography (2-5% MeOH/DCM) (yield 214 mg).
[1470] MS m/z 516 (M+H).sup.+:
[1471] .sup.1H NMR (CDCl.sub.3): .delta.7.88 (d, 2H), 7.46 (d, 2H),
7.23 (d, 2H), 7.31 (s, 1H), 7.22 (d, 2H), 7.09 (d, 2H), 7.06 (d,
2H) 4.22 (t, 2H), 3.16 (m, 2H), 3.21 (q, 4H), 2.84 (t, 2H),
2.39-2.19 (m, 2H), 1.83 (m, 2H), 1.50 (m, 2H), 1.35 (t, 6H), 1.03
(t, 3H) ppm
Example 496
[3-(4-{2-butyl-1-[4-(4-chloro-3-ethyl-phenoxy)-phenyl]-1H-imidazol-4-yl}-p-
henoxy)-propyl]-diethyl-amine
[1472] To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol)
in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added
followed by addition of 4-chloro-3-ethylphenol (10 mmol) to the
reaction mixture and heating to 80.degree. C. until the reaction
was complete as indicated by TLC or HPLC. After cooling to rt, the
reaction mixture was poured into EtOAc (100 mL), washed with
H.sub.2O (2.times.50 mL) and brine (50 mL), and dried over sodium
sulfate. The solvent was removed in vacuuo to afford the desired
4-(4-chloro-3-ethylphenoxy)-1-nitrobenzene. The crude product was
used for further transformation.
[1473] The nitro intermediate (10 mmol) obtained above was
dissolved in MeOH (20 mL), and treated with SnCl.sub.22H.sub.2O (50
mmol), according to General Procedure I. The reaction mixture was
heated under reflux until completion, as indicated by TLC or HPLC.
The solvent was removed in vacuuo and the residue was treated with
4.0 N aqueous NaOH to pH .about.8. The residue was extracted with
EtOAc (2.times.50 mL), washed with 1.0 N aqueous NaOH (50 mL),
brine and dried over sodium sulfate. The solvent was removed in
vacuuo to afford the desired 4-chloro-3-ethylphenoxyaniline, which
was used directly for further transformation without additional
purification.
[1474] To a stirred solution of 4'-hydroxyacetophenone (91 mmol) in
DMF (80 mL) at rt, solid potassium carbonate (153 mmol) was added.
The mesylate prepared from 3-diethylamino-1-propanol and
methanesulfonyl chloride (76 mmol) was added to the reaction
mixture and heated to 80.degree. C. until completion according to
General Procedure Q1, as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture was quenched by treating the mixture with
saturated sodium bicarbonate. The aqueous layer was poured into
EtOAc (100 mL) and washed with H.sub.2O (2.times.50 mL) and brine
(50 mL). The organic layer was dried over sodium sulfate, and the
solvent was removed in vacuuo to afford the desired
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone. The crude alkylated
product was used for further transformation after purifying using
silica gel column chromatography (1-4% MeOH/DCM).
[1475] To a stirred solution of
1-{4-[3-(diethylamino)propoxy]phenyl}ethanone (2.4 mmol) in
anhydrous MeOH (5 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq., 2.9 mmol) was added, according to General Procedure R1.
The reaction mixture was stirred under nitrogen at 0.degree. C. for
1 h and was allowed to warm to rt until completion, as indicated by
TLC or HPLC. The solvent was then removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1476] To a stirred solution of
4-(4-chloro-3-ethylphenoxy)-1-nitrobenzene (1.2 eq., 2.5 mmol) in
anhydrous DMF (5 mL) DIEA (3 eq. 7.5 mmol) was added, followed by
slow addition of the
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (2.4 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold H.sub.2O and the product was isolated in EtOAc. The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of solvent in vacuuo afforded the
desired product. The crude alkylated aniline was used for further
transformation.
[1477] To a stirred solution of alkylated
4-(4-chloro-3-ethylphenoxy)-1-nitrobenzene described above
(.about.2.4 mmol) in anhydrous DCM (5 mL) at 0.degree. C., TEA (3
eq., 7.5 mmol) was added, followed by slow addition of valeryl
chloride (3 eq., 7.5 mmol), according to General Procedure R3. The
reaction mixture was stirred under nitrogen at 0.degree. C. for 1 h
and allowed to warm to rt until completion, as indicated by TLC or
HPLC. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[1478] To a stirred solution of the N-alkylated anilide (.about.2.4
mmol) obtained as above in acetic acid (3 mL), solid ammonium
acetate (46 mmol) was added in one portion, according to General
Procedure R4. The reaction mixture was then heated to 100.degree.
C. overnight. The reaction mixture was cooled to rt, and treated
with saturated aqueous sodium bicarbonate solution while stirring
to until the pH was 7-8. The contents were extracted with EtOAc
(2.times.30 mL). The combined organic layers was washed with
H.sub.2O (2.times.30 mL) and brine, and dried over sodium sulfate.
Evaporation of the solvent in vacuuo afforded the desired N-aryl
imidazole. The crude product was purified using silica gel column
chromatography (2-5% MeOH/DCM) (yield 60 mg).
[1479] MS m/z 560 (M+H).sup.+:
[1480] .sup.1H NMR (CDCl.sub.3): .delta.8.30 (d, 1H), 7.64 (d, 2H),
7.28 (d, 2H), 7.21 (s, 1H), 7.18 (s, 1H), 7.03 (d, 2H), 6.90 (m,
1H), 6.83 (d, 2H) 4.22 (t, 2H), 2.85-2.75 (m, 2H), 2.89 (q, 4H),
2.61 (m, 2H), 2.24 (t, 2H), 2.14 (d, 3H), 2.09-1.98 (m, 2H), 1.58
(m, 2H), 1.28 (m, 2H), 1.25 (t, 6H), 0.93 (t, 3H) ppm.
Example 497
{2-[4-(2-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-ph-
enoxy]-ethyl}-ethyl-amine
[1481] To a stirred solution of 4'-hydroxyacetophenone (4 mmol) in
DMF (10 mL) at rt, solid potassium carbonate (12.0 mmol) was added.
4-chlorophenthoxy mesylate (prepwered from the 4-chlorophemethanol
and methanesulfonyl chloride) (4.4 mmol) was added to the reaction
mixture and heated to 80.degree. C. until completion according to
General Procedure Q1, as indicated by TLC or HPLC. After cooling to
rt, the reaction mixture was quenched with saturated sodium
bicarbonate. The aqueous layer was poured into EtOAc (30 ml) and
washed with water (2.times.15 ml) and brine (15 ml). The organic
layer was dried over magnesium sulfate, and the solvent was removed
in vacuuo to afford the desired
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone. The crude alkylated
product was purified by silica gel chromatography and the pure
product obtained from 10% EtOAc/hexanes (yield 70%).
[1482] To a stirred solution of 4-fluoronitrobenzene (4.0 mmol) in
anhydrous THF (12 mL) at 0.degree. C., a 1M solution of a potassium
alkoxide (4.4 mmol) in THF (may be generated by adding the
N-Boc,N-ethyl ethanolamine to a 1M solution of KOBu.sup.t in THF)
was added dropwise and under a nitrogen stream, according to
General Procedure L1. The reaction mixture was stirred at 0.degree.
C. until completion, as indicated by TLC or HPLC. The solvent was
removed and the reaction mixture was then treated with cold
H.sub.2O (15 mL), and extracted with EtOAc (2.times.15 mL). The
combined organic layers were washed with brine and dried over
sodium sulfate. Evaporation of the solvent in vacuuo afforded the
desired 4-alkoxynitrobenzene. The crude product could be used
directly for further transformation.
[1483] The nitro intermediate (2 mmol) obtained above was dissolved
in EtOH (8 mL) and hydrogenated in the presence of 10% Pd/C (10 mg)
until completion, according to General Procedure H, as indicated by
TLC or HPLC. The reaction mixture was then filtered to remove the
catalyst. The solvent was removed in vacuuo to afford
4-(N-Boc-N-ethylaminoethoxy)aniline, which was used directly for
further transformation without further purification (yield
80%).
[1484] To a stirred solution of
1-{4-[2-(4-chlorophenyl)ethoxy]phenyl}ethanone (2 mmol) in
anhydrous MeOH (6 mL) at 0.degree. C., pyrrolidone hydrotribromide
(1.2 eq) was added, according to General Procedure R1. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and was
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The solvent was then removed in vacuuo and the crude
2-bromo-1-{4-[3-(diethylamino)propoxy]phenyl}ethanone was used for
further transformation.
[1485] To a solution of 4-(N-Boc-N-ethylethoxy)aniline (1 eq, 2
mmol) in anhydrous DMF (6 mL), DIEA (3 eq 6 mmol) was added,
followed by addition of the
2-bromo-1-{-4-[3-(diethylamino)propoxy]phenyl}ethanone described
above (2 mmol), according to General Procedure R2. The reaction
mixture was stirred under nitrogen at rt until completion, as
indicated by TLC or HPLC. The reaction mixture was then diluted
with cold water and the product was isolated in EtOAc. The combined
organic layers were washed with brine and dried over sodium
sulfate. Evaporation of solvent in vacuuo afforded the desired
product. The crude alkylated aniline was purified by chromatography
(Silica gel). Pure product obtained from 2-4% MeOH/DCM (yield
52%).
[1486] To a stirred solution of alkylated aniline described above
(1 mmol) in anhydrous DCM (4 mL) at 0.degree. C., TEA (3 eq, 3
mmol) was added, followed by a slow addition of valeryl chloride (3
eq, 3 mmol), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to rt until completion, as indicated by TLC or
HPLC. The solvent was removed in vacuuo, and the crude amide was
used for further transformation.
[1487] To a stirred solution of the amide described above (1 mmol)
in acetic acid (4 mL), ammonium acetate (20 eq) was added,
according to General Procedure R4. The reaction mixture was stirred
at 90.degree. C. overnight. The reaction mixture was then cooled to
rt and neutralized with saturated sodium bicarbonate solution.
Usual extractive work up with EtOAc gave the product imidazole,
which was purified by column chromatography (Silica gel). Pure
product obtained from 4-6% MeOH/DCM was treated with HCl in dioxane
for 2 h to give the hydrochloride salt of
{2-[4-(2-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-p-
henoxy]-ethyl}-ethyl-amine (yield 177 mg).
[1488] MS m/z 518 (M+H).sup.+:
[1489] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 7.7 (d, 2H), 7.2
(m, 4H), 7.1 (m, 3H), 6.8-7.0 (m, 4H), 4.0-4.3 (m, 6H), 3.0-3.2 (m,
6H), 2.9 (m, 2H), 2.6 (m, 2H), 1.2 (t, 3H), 0.8 (t, 3H) ppm
Example 498
[3-(4-{5-butyl-4-[4-(3,3-diphenyl-propoxy)-phenyl]-2-isobutyl-1H-imidazol--
4-yl}-phenoxy)-2,2-dimethyl-propyl]-dimethyl-amine
[1490] To a stirred solution of ice-cold 4-hydroxy-n-hexanophenone
(18 mmol), 3,3-diphenyl-1-propanol (22.6 mmol, 1.25 eq),
triphenylphosphine (22.6 mmol, 1.25 eq) dissolved in anhydrous THF
(100 mL) was added dropwise diisopropyl azodicarboxylate (DIAD)
(22.6 mmol, 1.25 eq). The reaction mixture was stirred at 0.degree.
C. for 1 h, and then allowed to warm to rt, continuing the stirring
for additional 6 h (monitored by TLC). The solvent was removed in
vacuuo, and the crude product was purified by silica gel column
chromatography eluting with 10% EtOAc in hexane (yield: 100%).
[1491] The acetophone described as above (18 mmol) was dissolved in
1,4-dioxane (100 mL), and treated with pyridine hydrotribromide
(18.9 mmol, 1.05 eq), according to General Procedure R1. After
stirring at rt for 6 h (monitored by TLC), the reaction was
quenched with cold H.sub.2O (100 mL). The resulting mixture was
extracted with EtOAc (4.times.100 mL). The combined EtOAc extracts
were washed with brine (3.times.50 mL), and dried over anhydrous
sodium sulfate. The solvent was then removed in vacuuo and the
crude alpha-bromoacetophenone was directly used for further
transformation.
[1492] To a stirred solution of the crude alpha-bromoacetophenone
described as above (.about.12 mmol) and 4-benzyloxyaniline (12
mmol) dissolved in DMF (40 mL), DIEA (36 mmol, 3 eq) was added at
rt, and the mixture was stirred at the same temperature for 12 h,
according to General Procedure R2 (monitored by TLC and LC-MS). The
reaction mixture was treated with saturated sodium bicarbonate (100
mL), and the resulting mixture was extracted with EtOAc
(4.times.100 mL). The combined EtOAc extracts were washed with
brine (3.times.50 mL), and dried over anhydrous sodium sulfate. The
solvent was removed in vacuuo, and the crude product was purified
by silica gel column chromatography eluting with 10-15% EtOAc in
hexane (overall yield from the acetophone: .about.50%).
[1493] To a stirred solution of ice-cold the alkylated aniline (1.7
mmol) obtained above and DMAP (3.4 mmol, 2 eq) dissolved in
anhydrous DCM (200 mL), isovaleryl chloride (6.8 mmol, 4 eq) was
added, according to General Procedure R3. The reaction mixture was
stirred under nitrogen at 0.degree. C. for 3 h and allowed to warm
to rt until completion, as indicated by LC-MS. The solvent was
removed in vacuuo, and the crude amide was used directly for
further transformation.
[1494] The crude amide described above (.about.3.7 mmol) was
suspended in acetic acid (10 mL), and ammonium acetate (excess,
.about.30 eq) was added, according to General Procedure R4. The
reaction mixture was stirred at 120.degree. C. for 20 h (as
monitored by TLC and LC-MS). The reaction mixture was then cooled
to rt and neutralized with saturated sodium bicarbonate and solid
sodium carbonate. The resulting mixture was extracted with EtOAc
(4.times.100 mL). The combined EtOAc extracts were washed with
H.sub.2O (2.times.60 mL) and brine (2.times.60 mL), and dried over
anhydrous sodium sulfate. The solvent was removed in vacuuo, and
the crude product was purified by silica gel column chromatography
eluting with 10-20% EtOAc in hexane (overall yield from the
alkylated aniline: 62%).
[1495] The product (2.9 mmol) obtained above was dissolved in MeOH
(50 mL) and hydrogenated in the presence of 10% Pd/C (0.5 g) until
completion as indicated by LC-MS (.about.2 h), according to General
Procedure H. The reaction mixture was then filtered to remove the
catalyst. The solvent was removed in vacuuo to afford the desired
1-(4'-hydroxyphenyl) imidazole, which was used directly for further
transformation without purification (yield: 100%).
[1496] To a stirred solution of ice-cold
3-dimethylamino-2,2-dimethyl-1-propanol (1 mmol) and TEA (1.5 mmol)
dissolved in anhydrous DCM (8 mmol) was added dropwise
methanesulfonyl chloride (1.05 mmol), and the reaction mixture was
stirred for 2 h at 0.degree. C. and followed by additional 1 h at
rt. After the removal of the solvents in vacuuo, the crude mesylate
was dissolved in DMF (10 mL). 1-(4'-hydroxyphenyl) imidazole (0.5
mmol) obtained above and cesium carbonate (3 mmol) were added, and
the mixture was heated with stirring at 90.degree. C. for 3 h
(monitored by LC-MS). After cooling to rt, the reaction was
quenched with saturated sodium bicarbonate (20 mL), and the
resulting mixture was extracted with EtOAc (3.times.50 mL). The
combined EtOAc extracts were washed with brine (3.times.30 mL), and
dried over anhydrous sodium sulfate. The solvent was removed in
vacuuo, and the pure product was obtained by silica gel column
chromatography eluting with 5-10% MeOH in EtOAc (yield 252 mg).
[1497] MS m/z 672 (M+H).sup.+:
[1498] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.0.70 (t, 3H), 0.83
(d, 6H), 1.03 (s, 6H), 1.13 (m, 2H), 1.28 (m, 2H), 1.96 (m, 1H),
2.29 (s, 6H), 2.31 (s, 2H), 2.36 (d, 2H), 2.47-2.56 (m, 4H), 3.77
(s, 2H), 3.91 (t, 2H), 4.26 (t, 1H), 6.86 (d, 2H), 7.00 (d, 2H),
7.11 (d, 2H), 7.19-7.28 (m, 10H), 7.56 (d, 2H) ppm
Example 499
[3-(4-{4-[4-(3,3-diphenyl-propoxy)-phenyl]-2-isobutyl-imidazol-1-yl}-pheno-
xy)-propyl]-diethyl-amine
[1499] To a stirred solution of
N,N-diethyl-N-[3-(4-nitrophenoxy)propyl]amine (1.0 eq., 2.5 mmol)
in anhydrous DMF (20 mL) DIEA (3 eq) was added, followed by slow
addition of the 1-[4-(benzyloxy)phenyl]-2-bromoethanone (2.5 mmol).
The reaction mixture was stirred under nitrogen at rt until
completion, as indicated by HPLC. The reaction mixture was then
diluted with cold H.sub.2O and the product was isolated in
Et.sub.2O. The combined organic layers were washed with brine and
dried over sodium sulfate. Evaporation of solvent in vacuuo
afforded the desired product. The crude alkylated aniline was
purified by chromatography (Silica gel). Pure product was obtained
from 2-7% MeOH/DCM (yield .about.30%).
[1500] To a stirred solution of the alkylated aniline described
above (0.88 mmol) in anhydrous DCM (10 mL) at 0.degree. C., TEA
(3.0 mmol) was added, followed by slow addition of isovaleryl
chloride (5.0 eq), according to General Procedure R3. The reaction
mixture was stirred under nitrogen at 0.degree. C. for 1 h and
allowed to warm to ambient temperature until completion, as
indicated by HPLC. The solvent was removed in vacuuo, and the crude
amide was used for further transformation.
[1501] To a stirred solution of the amide described above (0.88
mmol) in acetic acid (2 mL), ammonium acetate (excess, .about.20
eq.) was added, according to General Procedure R4. The reaction
mixture was stirred at 100.degree. C. overnight. The reaction
mixture was then cooled down and neutralized with saturated sodium
bicarbonate solution. Usual extractive work up with EtOAc gave the
cyclized product, (crude .about.80%) which was taken to the next
transformation without purification.
[1502] The above product was dissolved in MeOH (20 mL), Pd/C (100
mg) was added and the heterogeneous mixture was stirred overnight
under H.sub.2 atmosphere using a balloon, according to General
Procedure T2. The Pd/C was removed by filtration. The solvent was
removed in vacuuo, and the crude
4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-y-
l}-phenol was used for further transformation without
purification.
[1503] A stirred solution of the
4-{1-[4-(3-diethylamino-propoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phe-
nol (1.0 eq) in anhydrous DMF (5.0 mL) was treated with solid
sodium hydride (60% dispersion in oil; 1.0 mmol) in portions. The
mesylate of 3,3-diphenylpropan-1-ol (1.1 eq) was added to the
reaction mixture, and stirred at it overnight, according to General
Procedure T3. Et.sub.2O (30 mL) was added to the reaction mixture
followed by H.sub.2O (10 mL). The organic layer was washed with
H.sub.2O (2.times.15 mL) and brine, and dried over sodium sulfate.
The solvent was removed in vacuuo. Pure imidazole was obtained from
chromatography with 5-10% MeOH/DCM (yield 73 mg).
[1504] MS m/z 616 (M+H).sup.+:
[1505] .sup.1H NMR (CDCl.sub.3): .delta.7.67 (d, 2H), 7.15-7.3, (m,
12H), 7.09 (s, 1H), 6.96 (d, 2H), 6.84 (d, 2H), 4.25 (t, 1H), 4.07
(t, 2H), 3.9 (t, 2H), 3.74 (t, 1H), 2.46-2.75 (m, 10H), 2.0 (m,
3H), 1.0 (t, 6H), 0.84 (d, 6H) ppm.
Example 500
7-{2-butyl-4-[4-(4-chloro-phenoxy)-naphthalen-1-yl]-imidazol-1-yl}-1,2,3,4-
-tetrahydro-isoquinoline hydrochloride
7-Nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (8.2 g, 42%
yield) was prepared by slightly modifying the published procedure
(J. Med. Chem., 1997, 40, 3997-4005).
[1506] Di-tert-butyl dicarbonate (7.5 g, 33.8 mmol) was added to a
solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride
(3.8 g, 16.9 mmol), Et.sub.3N (9.42 mL, 67.6 mmol) and DMAP (0.1 g)
dissolved in anhydrous THF (60 mL). After being stirred overnight
at rt, the reaction mixture was treated with saturated NaHCO.sub.3
(50 mL), and the resulting mixture was extracted with EtOAc
(3.times.100 mL). The combined organic layers were washed with
brine and dried (Na.sub.2SO.sub.4). The crude products were
purified by flash chromatography (eluting with 10-20% EtOAc in
hexanes) to give 2-BOC-7-nitro-1,2,3,4-tetrahydroisoquinoline (4.1
g).
[1507] The nitro compound obtained above (4.1 g, 14.7 mmol) was
dissolved in MeOH (80 mL) and hydrogenated in the presence of 10%
Pd/C (0.3 g), according to General Procedure H. Workup afforded
afforded 7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline (2-Boc-TIQ
aniline (3.6 g, 98% yield) as a light-brown solid.
[1508] 4'-(4-chlorophenoxy)-1'-acetonaphthone was prepared from
4'-fluoro-1'acetonaphthone and 4-chlorophenol following general
procedure Q2. 4'-(4-chlorophenoxy)-1'-acetonaphthone was brominated
following general procedure R1. The bromo ketone was condensed with
7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general
procedure R2. The aminoketone intermediate was treated with
n-pentanoyl chloride according to general procedure R3. The product
amide was then subjected to imidazole formation employing general
procedure R4. The BOC group of the product was removed employing
general procedure T1 to afford
7-{2-Butyl-4-[4-(4-chloro-phenoxy)-naphthalen-1-yl]-imidazol-1-yl}-1,2,3,-
4-tetrahydro-isoquinoline hydrochloride.
[1509] LC-MS (m/z): 508 (M+H).sup.+.
Example 501
2-biphenyl-4-yl-N-{-4-[2-butyl-1-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H--
imidazol-4-yl]-phenyl}-acetamide hydrochloride
[1510] 4-Nitrophenacyl bromide (5 mmol) was added to a stirred
mixture of 2-BOC-7-nitro-1,2,3,4-tetrahydroisoquinoline (5 mmol) in
DCM (20 mL) at rt, and the mixture was stirred at rt overnight. The
reaction mixture was treated with sat. NaHCO.sub.3 (30 mL), the
resulting mixture was extracted with EtOAc (200 mL), washed with
brine and dried. The crude product was purified by silica gel
column chromatography (eluting with 8% EtOAc in hexane to give the
amino ketone intermediate (0.33 g).
[1511] Following the general procedures R2, R3, and R4 as for
Example 500, the amino ketone intermediate (330 mg, 0.8 mmol) was
converted into a 4-nitrophenyl-substituted imidazole. The imidazole
was reduced by Pd-carbon catalytic hydrogenation following general
procedure H to the corresponding 4-aminophenyl imidazole.
[1512] PS-carbodiimide (1.27 mmol/g, 310 mg, 0.4 mmol) was added to
a mixture of the 4-aminophenyl imidazole obtained above (45 mg, 0.1
mmol) and biphenylacetic acid (43 mg, 0.2 mmol) in anhydrous DCM (6
mL), and the mixture was slowly shaken at rt overnight. The pure
product (25 mg, 40% yield) was obtained after silica gel column
chromatography (20% EtOAc in hexane).
2-Biphenyl-4-yl-N-{4-[2-butyl-1-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H--
imidazol-4-yl]-phenyl}-acetamide hydrochloride (20 mg) was obtained
by treating the product with 4N hydrogen chloride in dioxane
solution, following the General Procedure T1.
[1513] LC-MS (m/z): 541 (M+1).sup.+.
Example 502
7-{2-butyl-4-[4-(2,4-dichloro-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetr-
ahydro-isoquinoline hydrochloride
[1514] 1-[4-(2,4-Dichlorophenoxy)phenyl]ethan-1-one (282 mg, 1
mmol) was brominated by General Procedure R1. The bromo ketone was
condensed with 7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline
following general procedure R2. The aminoketone intermediate was
treated with n-pentanoyl chloride according to General Procedure
R3. The product amide was then subjected to imidazole formation
employing general procedure R4. The BOC group of the product was
removed employing general procedure T1 to afford
7-{2-butyl-4-[4-(2,4-dichloro-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tet-
rahydro-isoquinoline hydrochloride (150 mg).
[1515] LC-MS (m/z): 493 (M+1).sup.+.
Example 503
7-(2-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-2-isobutyl-imidazol-1-
-yl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride
[1516] 1-[4-(4-chlorophenylethoxy)]ethan-1-one (1 mmol) was
brominated by General Procedure R1. The bromo ketone was condensed
with 7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general
procedure R2. The aminoketone intermediate was treated with
n-pentanoyl chloride according to General Procedure R3. The product
amide was then subjected to imidazole formation employing general
procedure R4. The BOC group of the product was removed employing
general procedure T1 to afford
7-(2-Butyl-4-[(4-[2-(4-chloro-phenyl)-ethoxy]-phenyl]-2-isobutyl-imidazol-
-1-yl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride (145 mg).
[1517] LC-MS (m/z): 486 (M+H).sup.+.
Example 504
7-[4-(4-benzyloxy-phenyl)-2-butyl-imidazol-1-yl]-1,2,3,4-tetrahydro-isoqui-
noline hydrochloride
[1518] 4-benzyloxyacetophone was brominated by General Procedure
R1. The bromo ketone was condensed with
7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general
procedure R2. The aminoketone intermediate was treated with
n-pentanoyl chloride according to General Procedure R3. The product
amide was then subjected to imidazole formation employing general
procedure R4 to afford
7-[4-(4-Benzyloxy-phenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrahydro-
-isoquinoline. The BOC group of the product was removed employing
general procedure T1 to afford
7-[4-(4-Benzyloxy-phenyl)-2-butyl-imidazol-1-yl]-1,2,3,4-tetrahydro-isoqu-
inoline hydrochloride (170 mg).
[1519] LC-MS (m/z): 438 (M+1).sup.+.
Example 505
9-(2-{-4-[2-butyl-1-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H-imidazol-4-yl-
]-phenoxy}-ethyl-9H-carbazole hydrochloride
[1520]
7-[4-(4-Benzyloxy-phenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetr-
ahydro-isoquinoline was debenzylated according to General Procedure
T2 to afford
7-[4-(4-hydroxyphenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrah-
ydro-isoquinoline. The phenol was condensed with the mesylate of
9H-carbazole-9-ethanol following general procedure T3 to afford the
ethylcarbazole ether intermediate. This ethylcarbazole intermediate
was deprotected employing general procedure T1 to afford
9-(2-{-4-[2-butyl-1-(1,2,3,4-tetrahydro-isoquinolin-7-yl)-1H-imidazol-4-y-
l]-phenoxy}-ethyl-9H-carbazole hydrochloride (55 mg).
[1521] LC-MS (m/z): 541 (M+1).sup.+.
Example 506
7-{2-butyl-4-[4-(4-methoxy-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrahy-
dro-isoquinoline hydrochloride
[1522] 1-[4-(4-methoxyphenoxy)phenyl]ethan-1-one (1 mmol) was
brominated by General Procedure R1. The bromo ketone was condensed
with 7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general
procedure R2. The aminoketone intermediate was treated with
n-pentanoyl chloride according to General Procedure R3. The product
amide was then subjected to imidazole formation employing general
procedure R4. The BOC group of the product was removed employing
general procedure T1 to afford
7-{2-butyl-4-[4-(4-methoxy-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-tetrah-
ydro-isoquinoline hydrochloride (yield 135 mg)
[1523] LC-MS (m/z): 454 (M+1).sup.+.
Example 507
7-(2-butyl-4-{4-[2-(4-tert-butyl-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-1,-
2,3,4-tetrahydro-isoquinoline hydrochloride
[1524]
7-[4-(4-hydroxyphenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrahy-
dro-isoquinoline was condensed with the mesylate of
2-(4-t-butylphenyl)ethanol according to General Procedure T3 to
afford the phenyl ether intermediate, which was deprotected
according to general procedure T1 to afford
7-(2-butyl-4-{4-[2-(4-tert-butyl-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-1-
,2,3,4-tetrahydro-isoquinoline hydrochloride (35 mg).
[1525] LC-MS (m/z): 508 (M+1).sup.+.
Example 508
7-{2-butyl-4-[4-(naphthalen-2-ylmethoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-te-
trahydro-isoquinoline hydrochloride
[1526]
7-[4-(4-hydroxyphenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrahy-
dro-isoquinoline was condensed with 2-(bromomethyl)naphthalene
according to general procedure T3 to afford the phenyl ether
intermediate, which was deprotected according to general procedure
T1 to afford
7-{2-butyl-4-[4-(naphthalen-2-ylmethoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-t-
etrahydro-isoquinoline hydrochloride (32 mg).
[1527] LC-MS (m/z): 488 (M+1).sup.+.
Example 509
7-{2-butyl-4-[4-(4-trifluoromethyl-phenoxy)-phenyl]-imidazol-1-yl}-1,2,3,4-
-tetrahydro-isoquinoline hydrochloride
[1528]
7-[4-(4-hydroxyphenyl)-2-butyl-imidazol-1-yl]-2-Boc-1,2,3,4-tetrahy-
dro-isoquinoline was condensed with 4-trifluoromethylbenzyl bromide
according to general procedure T3 to afford the phenyl ether
intermediate, which was deprotected according to general procedure
T1 to afford
77-{2-butyl-4-[4-(4-trifluoromethyl-phenoxy)-phenyl]-imidazol-1-yl-
}-1,2,3,4-tetrahydro-isoquinoline hydrochloride (45 mg).
[1529] LC-MS (m/z): 506 (M+1).sup.+.
Example 510
7-(2-butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-1,2,3,-
4-tetrahydro-isoquinoline hydrochloride
[1530] 1-[4-(4-chlorophenylethoxy)]ethan-1-one (1 mmol) was
brominated by General Procedure R1. The bromo ketone was condensed
with 7-amino-2-Boc-1,2,3,4-tetrahydroisoquinoline following general
procedure R2. The aminoketone intermediate was treated with
n-pentanoyl chloride according to General Procedure R3. The product
amide was then subjected to imidazole formation employing general
procedure R4. The BOC group of the product was removed employing
general procedure T1 to afford
7-(2-Butyl-4-{4-[2-(4-chloro-phenyl)-ethoxy]-phenyl}-imidazol-1-yl)-1,2,3-
,4-tetrahydro-isoquinoline hydrochloride (170 mg).
[1531] LC-MS (m/z): 486 (M+1).sup.+.
Example 511
[3-(4-{2-(4-Butyl-cyclohexyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidazol--
4-yl}-phenoxy)-propyl]-diethyl-amine
[1532] Example 511 was synthesized by the method established for
Example 406, using 4-butylcyclohexanecarbonyl chloride in place of
valeryl chloride (yield 300 mg).
[1533] MS: m/z 614 (M+H).sup.+
Example 512
2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy-
)-ethylamine
[1534] Example 512 was synthesized by the method established for
Example 464, utilizing N--BOC-ethanolamine in phase of
3-dimethylamino-1-propanol to produce
2-(4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenox-
y)-ethylamino tert-butyl carbamate as an intermediate. This
intermediate was deprotected employing general procedure T1 to
afford Example 512 as the hydrochloride salt. (Yield: 115 mg).
[1535] MS: m/z 462 (M+H).sup.+
Example 513
[3-(4-{2-(trans-4-tert-Butyl-cyclohexyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1-
H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine
[1536] Example 513 was prepared by chromatographic purification on
silica gel of the compound of Example 486. 500 mg of Example 486
was separated by silica gel column chromatography, eluting with
5-10% MeOH in DCM, to give the cis-isomer (120 mg) followed by
trans-isomer Example 513 (200 mg).
[1537] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.82 (s, 9H),
1.08 (t, 6H), 1.50-2.50 (m, 12H), 2.66 (q, 4H), 2.73 (t, 2H), 4.02
(t, 2H), 6.89 (d, 2H), 7.04 (d, 2H), 7.07 (d, 2H), 7.08 (s, 1H),
7.27 (d, 2H), 7.36 (d, 2H), 7.69 (d, 2H) ppm
[1538] MS: m/z 614 (M+H).sup.+
Example 514
[3-(4-{2-(cis-4-tert-Butyl-cyclohexyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H--
imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine
[1539] Example 514 was prepared by chromatographic purification on
silica gel of the compound of Example 486. 500 mg of Example 486
was separated by silica gel column chromatography, eluting with
5-10% MeOH in DCM, to give the cis-isomer Example 514 (120 mg)
followed by trans-isomer (200 mg).
[1540] MS: m/z 614 (M+H).sup.+
Example 515
[2-(4-{2-Butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidaz-
ol-4-yl}-phenoxy)-ethyl]-methyl-pyridin-4-yl-amine
[1541] A mixture of 4-chloropyridine hydrochloride salt (15.0 g)
and 2-methylaminoethanol (30 mL) was refluxed for 48 hour. After
cooling to rt the crude mixture was added slowly to saturated
solution of sodium bicarbonate (150 mL). The product was extracted
with EtOAc (3.times.100 mL), the combined EtOAc was washed with
brine (50 mL), dried (Na.sub.2SO.sub.4) and removed in vacuo to
give the desired product 2-[methyl(pyridin-4-yl)amino]ethanol as
yellow solid (7.0 g).
[1542] 2-[methyl(pyridin-4-yl)amino]ethyl methanesulfonate was
prepared according to general procedure P2.
[1543]
4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imi-
dazole-4-yl}-phenol was prepared via a modification of the
procedure employed to synthesize
{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol.
[1544] Sodium hydride (50.0 mg, 60% dispersion in oil) was added to
a mixture of 100 mg of
4-{2-butyl-1-[4-(4-fluoro-3-trifluoromethyl-phenoxy)-phenyl]-1H-imidazole-
-4-yl}-phenol and 200 mg 2-[methyl(pyridin-4-yl)amino]ethyl
methanesulfonate in DMF (5 mL). After 24 h of stirring at rt, the
mixture was added to ether (50 mL) and the ether was washed with
water and dried (Na.sub.2SO.sub.4). The solvent was removed in
vacuo. Silica gel chromatography afforded 150 mg of Example
515.
[1545] MS: m/z 605 (M+H).sup.+
Example 516
[2-(4-{1-[4-(4-Fluoro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenox-
y)-ethyl]-methyl-pyridin-4-yl-amine
[1546]
4-{1-[4-(4-fluoro-phenoxy)-phenyl]-2-isobutyl-1H-imidazole-4-yl}phe-
nol was prepared in analogous fashion to
4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazole-4-yl}phenol.
Alkylation of the phenol proceeded as for Example 515 to afford
Example 516 (47 mg).
[1547] MS: m/z 537 (M+H).sup.+
[1548] .sup.1H NMR (CDCl.sub.3): .delta. 8.23 (d, 2H), 7.70 (d,
2H), 7.53 (d, 2H,), 7.24 (s, 1H), 7.12 (d, 2H), 7.07 (m, 2H), 7.04
(d, 2H), 6.87 (d, 2H), 6.58 (d, 2H) 4.17 (t, 2H), 3.81 (t, 2H),
3.11 (s, 3H), 2.54 (d, 2H), 2.06 (m, 1H), 0.87 (d, 6H) ppm
Example 517
[2-(4-{1-[4-(4-Fluoro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenox-
y)-ethyl]-methyl-(3-methyl-pyridin-4-yl)-amine
[1549] Example 517 was prepared in analogous fashion to Example
516, with the use of 3-methyl-4-chloropyridine in place of
4-chloropyridine. (Yield: 110 mg)
[1550] MS: m/z 551 (M+H).sup.+
Example 518
[2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenox-
y)-ethyl]-ethyl-pyridin-4-yl-amine
[1551] 2-[Ethyl(pyridin-4-yl)amino]ethanol was synthesized via an
analogous method as that employed for
2-[methyl(pyridin-4-yl)amino]ethanol.
[1552] 2-[Ethyl(pyridin-4-yl)amino]ethanol was converted to the
methanesulfonate via a modification of General Procedure P2.
[1553]
{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol
was synthesized by an analogous series of procedures as for Example
77.
[1554] Another procedure was below;
[1555] 4-Acetoxyacetophenone (10.7 g, 60 mmol) in dioxane (200 mL)
was treated with pyridinium hydrotribromide (21 g, 66 mmol, 1.1 eq)
added in portions at rt, according to General Procedure R1. The
reaction mixture was stirred at rt for 6 h. The reaction was
quenched by adding cold H.sub.2O (100 mL), and extracted with ether
(4.times.100 mL). The ethereal solution was washed with H.sub.2O
(100 mL) and dried (anhydrous Na.sub.2SO.sub.4). The solvent was
then removed in vacuo and the .alpha.-bromoacetophenone obtained
above was added to a stirred solution of
4-(4'-chlorophenoxy)aniline (13.2 g, 60 mmol, 1.1 eq) and anhydrous
DMF (100 mL) at rt, and the mixture was stirred at the same
temperature for 5 h (monitored by LC-MS). The reaction mixture was
treated with sat. NaHCO.sub.3 (100 mL), and the resulting mixture
was extracted with EtOAc (4.times.100 mL). The combined EtOAc
extracts were washed with H.sub.2O (2.times.100 mL) and brine
(2.times.100 mL), and dried (Na.sub.2SO.sub.4).
The solvent was removed in vacuo, and the alkylated aniline was
used for next step To a stirred solution of the c alkylated aniline
dissolved in anhydrous DCM (250 mL) at 0.degree. C., triethylamine
(15.2 mL, 180 mmol) was added, followed by slow addition of
isovaleryl chloride (14.7 mL, 120 mmol), according to General
Procedure R3. The reaction mixture was stirred under N.sub.2 at
0.degree. C. for 0.5 h and then at rt for another 2 h (or monitored
by LC-MS). The solvent was removed in vacuo, and the crude amide
was used directly for further transformation.
[1556] To a stirred suspension of the amide described above in AcOH
(30 mL), ammonium acetate (80 g) was added, according to General
Procedure R4. The reaction mixture was stirred at 100.degree. C.
for 2 h (as monitored by LC-MS). The reaction mixture was then
cooled down and neutralized with sat. NaHCO.sub.3 (100 mL) and
solid Na.sub.2CO.sub.3. The resulting mixture was extracted with
EtOAc (4.times.150 mL) and the organic phase was concentrated. The
light-yellow solid product was collected after filtration. The
filtrate was concentrated in vacuo to about 150 mL volume and after
standing at rt the solid product was collected and dried, overall
yield 11 g of
{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol.
[1557] Sodium hydride (50.0 mg, 60% dispersion in oil) was added to
mixture of 100 mg of
4-[1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazole-4-yl]phenol
and 180 mg of 2-[ethyl(pyridin-4-yl)amino]ethyl methanesulfonate in
DMF (5 mL). After 24 h of stirring at rt, the mixture was added to
ether (50 mL) and washed with water and dried (Na.sub.2SO.sub.4).
The solvent was removed in vacuo. Chromatography on silica gel
afforded Example 518 (36 mg).
[1558] MS: m/z 567 (M+H).sup.+
Example 519
[2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenox-
y)-ethyl]-pyridin-4-yl-amine
[1559]
2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}--
phenoxy)-ethylamine, the product of Example 512, was treated with
4-chloropyridine in DMF and was heated at 100.degree. C. Aqueous
workup and chromatography on silica gel afforded Example 519.
(Yield: 80 mg)
[1560] MS: m/z 539 (M+H).sup.+
Example 520
[2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenox-
y)-ethyl]-bis-pyridin-2-ylmethyl-amine
[1561] The methanesulfonate of N-Boc-glycinol was synthesized by
modifying the general procedure P2.
[1562]
{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol
(2 mmol) was added to a solution of Cs.sub.2CO.sub.3 (10 eq., 20
mmol) in anhydrous DMF (5 ml). This was followed by addition of the
mesylate obtained above and the reaction mixture was heated to
90.degree. C. for 2-3 h. The reaction mixture was then cooled to
rt, diluted with cold water and the product was extracted with DCM.
The organic layer was dried over anhydrous sodium sulfate and
concentrated in vacuo to give desired product, which was
BOC-deprotected according to general procedure T1. The HCl salt was
dissolved in water, neutralized with 4N NaOH solution and the crude
product was extracted with EtOAc. The organic layer was dried over
anhydrous sodium sulfate and concentrated in vacuo to give desired
product amine.
[1563] The crude product obtained above was taken in anhydrous DCM
(5 ml). 2-pyridylcarboxaldehyde (2.5 eq.) and Na(OAc).sub.3BH (2.5
eq.) was added to this solution and the reaction mixture was
stirred at it for 2-3 h. The product was concentrated in vacuo and
extracted with EtOAc and the organic layer was washed with
saturated sodium bicarbonate solution. The organic layer was dried
over anhydrous sodium sulfate and concentrated in vacuo to give
desired product, Example 520 (yield 96 mg).
[1564] MS: m/z 644 (M+H).sup.+
Example 521
N-[2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phen-
oxy)-ethyl]-guanidine
[1565]
2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}--
phenoxy)-ethylamine, the product of Example 512, was treated in
acetonitile with DIEA and N,N'-bis-BOC-1-guanylpyrazole. The
resulting mixture was then refluxed. The reaction mixture was then
cooled to rt and diluted with EtOAc. The mixture was washed with
water and brine and dried over anhydrous sodium sulfate. Solvent
was removed in vacuo and the residue obtained was purified by
silica gel column chromatography to afford the BOC-protected
guanadino intermediate. The BOC-protected guanadino intermediate
was treated with 4M HCl/dioxane to remove the BOC group as
described in general procedure T1, affording Example 521.
[1566] MS: m/z 504 (M+H).sup.+
Example 522
2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy-
)-1-(4-pyridin-4-yl-piperazin-1-O-ethanone
[1567] To a stirred solution of 4-pyridyl-piperazine (2 mmol) in
DCM (4 mL) at 0.degree. C., triethylamine (6.0 mmol) was added
followed by addition of 2-chloroacetyl chloride (4 mmol). The
reaction mixture was stirred under nitrogen at rt until completion,
as indicated by TLC or HPLC. The reaction mixture was treated with
saturated aqueous sodium bicarbonate solution (5 mL), then
extracted with EtOAc (2.times.15 mL). The combined organic layers
were washed with H.sub.2O (2.times.15 mL) and brine, and dried over
sodium sulfate. Evaporation of the solvent in vacuo afforded the
amide. The crude product was used for further transformation.
[1568] To the above amide (2 mmol) in DMF (5 ml) was added Cesium
carbonate (10 mmol, 5 eq), followed by the addition of
{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol
(1.5 mmol) and the reaction was heated to 90.degree. C. until
completion, as indicated by TLC or HPLC. After cooling to rt, the
reaction mixture was treated with saturated sodium bicarbonate (150
ml). The aqueous layer was extracted with EtOAc (4.times.100 ml).
The organic layer was washed with water (2.times.10 ml) and brine
(15 ml). The organic layer was dried over magnesium sulfate, and
the solvent was removed in vacuo to afford the desired imidazole
which was purified by was purified by chromatography over silica
gel to afford Example 522.
[1569] MS: m/z 622 (M+H).sup.+
Example 523
5-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy-
methyl)-pyrrolidin-3-ol
[1570] Sodium borohydride (227 mg, 6 mmol) was added at 0.degree.
C. to a stirred solution of
(2S,4R)--N--BOC-4-(t-butyldimethylsilyloxy)prolinaldehyde (522 mg,
1.58 mmol) in MeOH (10 mL), and the mixture was stirred at rt for 3
h. The reaction was quenched by adding sat. NaHCO.sub.3 (20 mL),
and the resulting mixture was extracted with EtOAc (3.times.50 mL).
The EtOAc extracts were washed with brine (2.times.50 mL), and
dried (Na.sub.2SO.sub.4). The solvent was removed in vacuo to give
(2S,4R)--N--BOC-4-(t-butyldimethylsilylhydroxy)prolinol (550
mg).
[1571] The alcohol obtained above was converted to the
methanesulfonate according to general procedure P2.
[1572]
4-{1-[4-Chlorophenoxy)phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol
described above (840 mg, 2 mmol) was added to a stirred mixture of
the mesylate obtained in the previous step, Cs.sub.2CO.sub.3 (1.95
g, 6 mmol) in anhydrous DMF (20 mL), and the mixture was heated
with stirring at 90.degree. C. for 15 h. The reaction was quenched
by adding sat. NaHCO.sub.3 and the resulting mixture was extracted
with EtOAc. The EtOAc extracts were washed with brine and dried
(Na.sub.2SO.sub.4). The solvent was removed in vacuo to give crude
alkylated product.
[1573] 2N hydrogen chloride in ethereal solution (2 mL) was added
to a stirred mixture of the alkylated imidazole obtained above (150
mg) in DCM (8 mL) at rt. After being stirred at rt for 4 h, the
reaction mixture was treated with sat. NaHCO.sub.3. The resulting
mixture was extracted with EtOAc. The EtOAc extracts were washed
with brine and dried (Na.sub.2SO.sub.4). The solvent was removed in
vacuo, and the residue was purified by silica gel column
chromatography to give
5-(4-{1-[4-(4-chlorophenoxy)phenyl]-2-isobutyl-1H-imidazol-4-yl}phenoxyme-
thyl)pyrrolidin-3-ol (50 mg).
[1574] LC-MS: m/z 518 (M+H).sup.+
[1575] 1H NMR (400 MHz, CDCl.sub.3): .delta. 0.84 (d, 6H),
1.25-3.20 (m, 6H), 2.53 (d, 2H), 4.05 (m, 3H), 4.50 (m, 1H), 6.91
(d, 2H), 7.01 (d, 2H), 7.05 (d, 2H), 7.10 (s, 1H), 7.24 (d, 2H),
7.34 (d, 2H), 7.66 (d, 2H) ppm.
Example 524
3-(4-{1-[4-(4-Fluoro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy-
)-pyridin-4-ylamine
[1576] To an ice-cold solution of 3-bromopyridine-N-oxide (4 mmol)
in concentrated H.sub.2SO.sub.4 (4 ml), concentrated HNO.sub.3 (0.5
ml) was added gradually. The reaction mixture was heated at
90.degree. C. for 48 h. The reaction mixture was then cooled to rt,
diluted with cold water and the product was extracted with EtOAc.
The organic layer was dried over anhydrous sodium sulfate and
concentrated in vacuo to give desired product,
3-bromo-4-nitropyridine N-oxide.
[1577]
{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol
(1.1 eq. 4.4 mmol) was added slowly to a solution of NaH (8 mmol)
in anhydrous DMF (6 ml) at 0.degree. C. This was followed by
addition of 3-bromo-4-nitropyridine-N-oxide (4 mmol) and the
reaction mixture was heated to 90.degree. C. for 2-3 h or until the
completion of reaction. The reaction mixture was then cooled to rt,
diluted with cold water and the product was extracted with DCM. The
organic layer was dried over anhydrous sodium sulfate and
concentrated in vacuo to give desired product, which was taken up
in acetic acid (4 ml). Powdered iron (2 eq., 8 mmol) was added and
the reaction was heated to 90.degree. C. for 2-3 h. The reaction
mixture was then cooled to rt, diluted with cold water and the
product was extracted with EtOAc. The organic layer was dried over
anhydrous sodium sulfate and concentrated in vacuo to give desired
product, Example 524. (Yield: 60 mg)
[1578] MS: m/z 495 (M+1).sup.+
Example 525
(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenyl)-p-
yridin-4-yl-amine
[1579]
[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-aniline
was synthesized by procedures analogous to those for the similar
4-(4-aminophenyl)1H-imidazole intermediate in the preparation of
Example 501.
[1580] A mixture of 200 mg of
4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazole-4-yl}aniline
(200 mg, 0.47 mmole), 4-chloropyridine hydrochloride (0.5 g, 3.2
mmole) and potassium carbonate (0.5 g, 3.6 mmole) were heated at
100.degree. C. in DMF (10 mL) for 24 h. After cooling to rt the
mixture was diluted with ether, washed with water) and dried
(Na.sub.2SO.sub.4). Silica gel chromatography of the crude material
afforded Example 525 (50 mg).
[1581] MS: m/z 495 (M+H).sup.+
Example 526
2-(4-{1-[4-(4-Fluoro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenoxy-
methyl)-3,5-dimethyl-pyridin-4-ylamine
[1582] (3,5-dimethyl-4-nitro-2-pyridyl)methyl mesylate was
synthesized by the general procedure P2.
[1583]
{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}phenol
(2 mmol) was added to a solution of Cs.sub.2CO.sub.3 (10 eq., 20
mmol) in anhydrous DMF (5 ml). This was followed by addition of the
mesylate obtained above and the reaction mixture was heated to
90.degree. C. for 2-3 h. The reaction mixture was then cooled to
rt, diluted with cold water and the product was extracted with DCM.
The organic layer was dried over anhydrous sodium sulfate and
concentrated in vacuo to give desired phenyl ether.
[1584] The crude product obtained above was taken in acetic acid (5
ml). Powdered iron (2 eq., 8 mmol) was added to the reaction
mixture and the reaction was heated to 90.degree. C. for 2-3 h or
until the completion of reaction. The reaction mixture was then
cooled to rt, diluted with cold water and the product was extracted
with EtOAc. The organic layer was dried over anhydrous sodium
sulfate and concentrated in vacuo to give desired product. Example
526. (Yield: 80 mg)
[1585] MS: m/z 537 (M+H).sup.+
Example 527
1-[2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phen-
oxy)-ethyl]-4-pyridin-4-yl-piperazine
[1586] The product of Example 522 was taken in 4 ml of THF to which
was added 5 eq. of BH3-THF solution and the reaction was heated to
reflux until the reaction was complete. The crude product was
purified by silica gel chromatography to afford Example 527.
[1587] MS: m/z 608 (M+H).sup.+
Example 528
4-(4-{2-Butyl-4-[4-(3-diethylamino-propoxy)-phenyl]-imidazol-1-yl}-phenoxy-
)-phenylamine
[1588] Example 528 was prepared by modifying the procedures
utilized in the synthesis of Example 493, with utilization of
4-tert-butoxycarbonylaminophenol in place of 4-acetamidophenol. The
BOC group was removed from the intermediate utilizing general
procedure T1 to afford the product, Example 528, as the HCl
salt.
[1589] MS: m/z 513 (M+H).sup.+
Example 529
{3-[4-(2-Butyl-4-dibenzofuran-2-yl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-
-amine
[1590] A solution of dibenzofuran (0.5 mmol) in anhydrous DCM was
cooled to 0.degree. C. AlCl.sub.3 (1.5 eq., 0.75 mmol) was added
followed by a slow addition of acetyl chloride (1.5 eq., 0.75
mmol). The reaction mixture was stirred at 0.degree. C. for 2-3 h
or until the completion of reaction. The product was extracted with
DCM and washed with saturated sodium bicarbonate solution. The
organic layer was dried over anhydrous sodium sulfate and
concentrated in vacuo to give dibenzofuran-2-ylethan-2-one.
[1591] Example 529 was prepared by modifying the procedures
utilized for the synthesis of Example 463, utilizing
dibenzofuran-2-ylethan-2-one as the aryl ketone starting material.
(Yield: 75 mg)
[1592] MS: m/z 496 (M+H).sup.+
Example 530
N-[4-(4-{2-Butyl-4-[4-(3-diethylamino-propoxy)-phenyl]-imidazol-1-yl}-phen-
oxy)-phenyl]-benzamide
[1593] Example 530 was prepared by modifying the procedures
utilized in the synthesis of Example 493, with utilization of
4-(tert-butoxycarbonylamino)phenol in place of 4-acetamidophenol.
The BOC group was removed from the intermediate utilizing general
procedure T1 to afford the product, Example 528, as the HCl salt.
The product was treated with benzoyl chloride and TEA in DCM to
afford, after aqueous workup and purification by silica gel
chromatography, Example 530.
[1594] MS: m/z 617 (M+H).sup.+
Example 531
N-[4-(4-{2-Butyl-4-[4-(3-diethylamino-propoxy)-phenyl]-imidazol-1-yl}-phen-
oxy)-phenyl]-isonicotinamide
[1595] Example 530 was prepared by modifying the procedures
utilized in the synthesis of Example 493, with utilization of
4-(tert-butoxycarbonylamino)phenol in place of 4-acetamidophenol.
The BOC group was removed from the intermediate utilizing general
procedure T1 to afford the product, Example 528, as the HCl salt.
The product was treated with 4-pyridylcarbonyl chloride and TEA in
DCM to afford, after aqueous workup and purification by silica gel
chromatography, Example 531.
[1596] MS: m/z 618 (M+H).sup.+
Example 532
[2-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenox-
y)-ethyl]-methyl-pyridin-4-yl-amine
[1597] A mixture of 4-chloropyridine hydrochloride salt (15.0 g)
and 2-methylaminoethanol (30 mL) was refluxed for 48 hour. After
cooling to rt the crude mixture was added slowly to saturated
solution of sodium bicarbonate (150 mL). The product was extracted
with EtOAc (3.times.100 mL), the combined EtOAc was washed with
brine (50 mL), dried (Na.sub.2SO.sub.4) and removed in vacuo to
give the desired product 2-[methyl(pyridin-4-yl)amino]ethanol as
yellow solid (7.0 g).
[1598] 2-[methyl(pyridin-4-yl)amino]ethyl methanesulfonate was
synthesized as described for Example 515.
[1599] Sodium hydride (50.0 mg, 60% dispersion in oil) was added to
mixture of 150 mg of
4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazole-4-yl}phenol
and 2-[methyl(pyridin-4-yl)amino]ethyl methanesulfonate (75 mg) in
DMF (5 mL). After 24 h of stirring at rt, the mixture was added to
ether (50 mL) and the organic phase was washed with water and dried
(Na.sub.2SO.sub.4). The solvent was removed in vacuo and the
product purified by silica gel chromatography to afford 80 mg of
Example 532.
[1600] MS: m/z 553 (M+H).sup.+
Example 533
N-(4-{1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-1H-imidazol-4-yl}-phenyl)-
-2-dimethylamino-acetamide
[1601]
1-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-4-(4-nitrophenyl)-1H-imi-
dazole was synthesized following the general procedures utilized in
example 501. The nitro group was reduced according to general
procedure H to afford
1-[4-(4-chloro-phenoxy)-phenyl]-2-isobutyl-4-(4-aminophenyl)-1H-
-imidazole, which was coupled with N,N-dimethylglycine using
PS-carbodiimide according to the procedure utilized in Example 502
to afford Example 533.
[1602] MS: m/z 503 (M+H).sup.+
Example 534
{3-[4-(4-{4-[3,3-Bis-(4-chloro-phenyl)-allyloxy]-phenyl}-2-isobutyl-imidaz-
ol-1-yl)-phenoxy]-propyl}-diethyl-amine
[1603] Example 534 was synthesized by modification of the
procedures utilized for the synthesis of example 459.
3,3(4-chlorophenyl)-2-propene-1-ol was converted to the
methanesulfonate and utilized in condensation with
4'-hydroxyacetophenone. Isovaleryl chloride was utilized in place
of benzyloxyacetyl chloride (yield 35 mg).
[1604] MS: m/z 682 (M+H).sup.+
Example 535
{3-[4-(4-{4-[3,3-Bis-(4-fluoro-phenyl)-propoxy]-phenyl}-2-isobutyl-imidazo-
l-1-yl)-phenoxy]-propyl}-diethyl-amine
[1605] The intermediate phenol
4-(4-hydroxyphenyl)-2-isobutyl-imidazol-1-yl)-phenoxy]-propyl}-diethyl-am-
ine utilized in the synthesis of Example 477 was condensed with the
methanesulfonate of 3,3(4-fluorophenyl)-1-propanol (synthesized
according to general procedure P2). The condensation was conducted
in accord with similar operation in the preparation of Example 477
to provide Example 535.
[1606] MS: m/z 652 (M+H).sup.+
Example 536
[2-(4-{4-[4-(4-Chloro-phenoxy)-phenyl]-2-isobutyl-imidazol-1-yl}-phenoxy)--
ethyl]-methyl-pyridin-4-yl-amine
[1607] 4-Fluoronitrobenzene was condensed with
2-[methyl(pyridin-4-yl)amino]ethanol according to general procedure
C and the nitro group was then reduced according to general
procedure H to afford the aniline intermediate. This aniline was
utilized in modification of the procedure for preparation of
Example 485 to afford Example 536.
[1608] MS: m/z 553 (M+H).sup.+
Example 537
[3-(4-{4-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-2-[2-(1-methyl-pyridin-3--
yl)-ethyl]-imidazol-1-yl}phenoxy)-propyl]-diethylmethyl aminonium
iodide
[1609]
{4-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-2-[2-(pyridin-3-yl)-ethy-
l]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine was synthesized
modifying the procedures utilized in the preparation of Example
485, where 3-(3-pyridyl)-propionyl chloride was utilized in place
of valeryl chloride. The product
{4-{4-[2-(4-Chloro-phenyl)-ethoxy]-phenyl}-2-[2-(pyridin-3-yl)-ethyl]-imi-
dazol-1-yl}-phenoxy)-propyl]-diethyl-amine was treated with excess
methyl iodide, concentrated in vacuo, and the solid collected to
afford the product, Example 537 (Yield: 37 mg)
[1610] MS: m/z 625 (M+H).sup.+
Example 538
[3-(4-{2-(N--BOC-piperidine-4-ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-
-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine
[1611] The procedure utilized for the preparation of Example 486
was modified, employing N--BOC-piperidine-4-acetic acid in place of
4-tert-butylcyclohexanecarboxylic acid, to afford 270 mg of Example
538.
[1612] MS: m/z 673 (M+H).sup.+
Example 539
[3-(4-{2-(Piperidine-4-ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-imidaz-
ol-4-yl}-phenoxy)-propyl]-diethyl-amine
[1613] The compound of Example 538 was deprotected according to
General Procedure T1 to afford 116 mg of Example 539 as the HCl
salt.
[1614] MS: m/z 573 (M+H).sup.+
Example 540
[3-(4-{2-(N-ethyl-piperidine-4-ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1-
H-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine
[1615]
[3-(4-{2-(Piperidine-4-ylmethyl)-1-[4-(4-chloro-phenoxy)-phenyl]-1H-
-imidazol-4-yl}-phenoxy)-propyl]-diethyl-amine (Example 539) (0.1
mmol) was treated in anhydrous DCM (2 ml) with acetaldehyde (1.2
eq.,) followed by addition of Na(OAc).sub.3BH (1.5 eq.). The
reaction mixture was stirred at it Crude product was extracted into
EtOAc and washed with saturated sodium bicarbonate solution. The
organic layer was dried over anhydrous sodium sulfate and
concentrated in vacuo to give desired product, which was purified
by column chromatography on silica gel to afford 49 mg of Example
540.
[1616] MS: m/z 601 (M+H).sup.+
Example 541
[3-(4-{2-(piperidine-4-ylmethyl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol--
1-yl}-phenoxy)-propyl]-diethyl-amine
[1617] The procedure of Example 485 was adapted, using
4-BOC-piperidine-1-acetic acid in place of valeryl chloride. The
resulting imidazole was deprotected using General Procedure T1 to
afford Example 541 (48 mg) as the HCl salt.
[1618] MS: m/z 602 (M+H).sup.+
Example 542
[3-(4-{2-(N-ethylpiperidine-4-ylmethyl)-4-[4-(4-chloro-phenoxy)-phenyl]-im-
idazol-1-yl}-phenoxy)-propyl]-diethyl-amine
[1619] The product of Example 541 was treated in anhydrous DCM (2
ml) with acetaldehyde (1.2 eq.,) followed by addition of
Na(OAc).sub.3BH (1.5 eq.). The reaction mixture was stirred at rt.
Crude product was extracted into EtOAc and washed with saturated
sodium bicarbonate solution. The organic layer was dried over
anhydrous sodium sulfate and concenterated in vacuo to give desired
product, which was purified by column chromatography on silica gel
to afford 50 mg of Example 542.
[1620] .sup.1H NMR: .delta. 7.68 (d, 2H), 7.23 (m, 6H), 7.16 (s,
1H), 6.95 (m, 2H), 6.88 (d, 2H), 4.17 (t, 2H), 4.06 (t, 2H), 3.06
(t, 2H), 2.91 (d, 2H), 2.81 (broad, 1H), 2.57 (m, 6H), 2.43 (m,
6H), 1.95-2.05 (m, 6H), 1.09 (t, 9H) ppm
[1621] MS: m/z 629 (M+H).sup.+
Example 543
[3-(4-{2-(N-acetylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazo-
l-1-yl}-phenoxy)-propyl]-diethyl-amine
[1622] The procedure of Example 485 was adapted, using
4-acetyl-piperidine-1-carbonyl chloride in place of valeryl
chloride, to afford Example 543 (40 mg).
[1623] MS: m/z 629 (M+H).sup.+
Example 544
[3-(4-{2-(piperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-1-yl}--
phenoxy)-propyl]-diethyl-amine
[1624] Example 543 (1 mmol, 125 mg) was taken in 6 N HCl (5 ml) and
the reaction was refluxed. The reaction mixture was then cooled to
rt, diluted with water and neutralized with 3N NaOH solution.
Product was extracted with EtOAc and the organic layer was dried
over anhydrous sodium sulfate, concentrated in vacuo to give crude
product, which was purified by column chromatography on silica gel
to afford 290 mg of Example 544.
[1625] MS: m/z 587 (M+H).sup.+
Example 545
[3-(4-{2-(N-Benzylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazo-
l-1-yl}-phenoxy)-propyl]-diethyl-amine
[1626] The product of Example 544 was treated in anhydrous DCM (2
ml) with benzaldehyde (1.2 eq.,) followed by addition of
Na(OAc).sub.3BH (1.5 eq.). The reaction mixture was stirred at rt.
Crude product was extracted into EtOAc and washed with saturated
sodium bicarbonate solution. The organic layer was dried over
anhydrous sodium sulfate and concentrated in vacuo to give desired
product, which was purified by column chromatography on silica gel
to afford 50 mg of Example 545.
[1627] .sup.1H NMR: .delta. 7.68 (d, 2H), 7.28 (d, 2H), 7.21-7.26
(m, 9H), 7.17 (s, 1H), 6.97 (d, 2H), 6.87 (d, 2H), 4.16 (t, 2H),
4.07 (t, 2H), 3.48 (s, 2H), 3.05 (t, 2H), 2.91 (broad, 1H), 2.74
(t, 2H), 2.66 (m, 8H), 2.05 (m, 6H), 1.11 (t, 6H) ppm
[1628] MS: m/z 677 (M+H).sup.+
Example 546
[3-(4-{2-(N-(2-Pyridylmethyl)piperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phen-
yl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine
[1629] The product of Example 544 was treated in anhydrous DCM (2
ml) with pyridine-2-carboxaldehyde (1.2 eq.,) followed by addition
of Na(OAc).sub.3BH (1.5 eq.). The reaction mixture was stirred at
rt. Crude product was extracted into EtOAc and washed with
saturated sodium bicarbonate solution. The organic layer was dried
over anhydrous sodium sulfate and concentrated in vacuo to give
desired product, which was purified by column chromatography on
silica gel to afford 40 mg of Example 546.
[1630] MS: m/z 678 (M+H).sup.+
Example 547
[3-(4-{2-(N-(2-Imidazolylmethyl)piperidine-4-yl)-4-[4-(4-chloro-phenoxy)-p-
henyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine
[1631] The product of Example 544 was treated in anhydrous DCM (2
ml) with imidazole-2-carboxaldehyde (1.2 eq.,) followed by addition
of Na(OAc).sub.3BH (1.5 eq.). The reaction mixture was stirred at
rt. Crude product was extracted into EtOAc and washed with
saturated sodium bicarbonate solution. The organic layer was dried
over anhydrous sodium sulfate and concentrated in vacuo to give
desired product, which was purified by column chromatography on
silica gel to afford 40 mg of Example 547.
[1632] .sup.1H NMR: .delta. 7.66 (d, 2H), 7.2-7.3 (m, 7H), 7.06 (s,
1H), 6.98 (m, 3H), 6.88 (d, 2H), 4.18 (t, 2H), 4.05 (t, 2H), 3.65
(s, 2H), 3.08 (t, 2H), 2.81 (broad, 1H), 2.75 (m, 2H), 2.55-2.65
(m, 8H), 1.95-2.08 (m, 6H), 1.09 (t, 6H) ppm
[1633] MS: m/z 667 (M+H).sup.+
Example 548
[3-(4-{2-(N-(4-biphenyl)methylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phe-
nyl]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine
[1634] The product of Example 544 was treated in anhydrous DCM (2
ml) with 4-biphenylcarboxaldehyde (1.2 eq.,) followed by addition
of Na(OAc).sub.3BH (1.5 eq.). The reaction mixture was stirred at
rt. Crude product was extracted into EtOAc and washed with
saturated sodium bicarbonate solution. The organic layer was dried
over anhydrous sodium sulfate and concentrated in vacuo to give
desired product, which was purified by column chromatography on
silica gel to afford 45 mg of Example 548.
[1635] .sup.1H NMR: .delta. 7.68 (d, 2H), 7.59 (d, 2H), 7.54 (d,
2H), 7.38-7.44 (m, 5H), 7.19-7.29 (m, 6H), 7.09 (s, 1H), 6.79 (d,
2H), 6.88 (d, 2H), 4.18 (t, 2H), 4.08 (t, 2H), 3.55 (s, 2H), 3.08
(t, 2H), 2.98 (broad, 1H), 2.65 (t, 2H), 2.58-2.65 (m, 8H),
1.98-2.09 (m, 6H), 1.12 (t, 6H) ppm.
[1636] MS: m/z 753 (M+H).sup.+
Example 549
[3-(4-{2-(N-Cyclohexylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imi-
dazol-1-yl}-phenoxy)-propyl]-diethyl-amine
[1637] The product of Example 544 was treated in anhydrous DCM (2
ml) with cyclopentanone (1.2 eq.,) followed by addition of
Na(OAc).sub.3BH (1.5 eq.). The reaction mixture was stirred at rt.
Crude product was extracted into EtOAc and washed with saturated
sodium bicarbonate solution. The organic layer was dried over
anhydrous sodium sulfate and concentrated in vacuo to give desired
product, which was purified by column chromatography on silica gel
to afford 52 mg of Example 549.
[1638] .sup.1H NMR: .delta. 7.68 (d, 2H), 7.38 (m, 3H), 7.21 (m,
3H), 7.08 (s, 1H), 6.98 (m, 2H), 6.88 (d, 2H), 4.18 (t, 2H), 4.08
(t, 2H), 3.08 (t, 2H), 2.67 (t, 2H), 2.51-2.55 (m, 8H), 1.99-2.08
(m, 6H), 1.91 (broad, 4H), 1.68 (broad 2H), 1.51 (broad 4H), 1.12
(t, 6H) ppm.
[1639] MS: m/z 655 (M+H).sup.+
Example 550
[3-(4-{2-(N-(4-Cyanobenzyl)piperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl-
]-imidazol-1-yl}-phenoxy)-propyl]-diethyl-amine
[1640] The product of Example 544 was treated in anhydrous DCM (2
ml) with 4-cyanobenzaldehyde (1.2 eq.,) followed by addition of
Na(OAc).sub.3BH (1.5 eq.). The reaction mixture was stirred at rt.
Crude product was extracted into EtOAc and washed with saturated
sodium bicarbonate solution. The organic layer was dried over
anhydrous sodium sulfate and concentrated in vacuo to give desired
product, which was purified by column chromatography on silica gel
to afford 70 mg of Example 550.
[1641] .sup.1H NMR: .delta. 7.69 (d, 2H), 7.59 (d, 2H), 7.44 (d,
2H), 7.2-7.3 (m, 6H), 7.09 (s, 1H), 6.99 (d, 2H), 6.88 (d, 2H),
4.18 (t, 2H), 4.09 (t, 2H), 3.55 (s, 2H), 3.08 (t, 2H), 2.85
(broad, 1H), 2.5-2.8 (m, 10H), 1.9-2.1 (m, 6H), 1.09 (t, 6H)
ppm.
[1642] MS: m/z 702 (M+H).sup.+
Example 551
[3-(4-{2-(N-Ethylpiperidine-4-yl)-4-[4-(4-chloro-phenoxy)-phenyl]-imidazol-
-1-yl}-phenoxy)-propyl]-diethyl-amine
[1643] The product of Example 544 was treated in anhydrous DCM (2
ml) with acetaldehyde (1.2 eq.,) followed by addition of
Na(OAc).sub.3BH (1.5 eq.). The reaction mixture was stirred at rt.
Crude product was extracted into EtOAc and washed with saturated
sodium bicarbonate solution. The organic layer was dried over
anhydrous sodium sulfate and concentrated in vacuo to give desired
product, which was purified by column chromatography on silica gel
to afford 50 mg of Example 551.
[1644] .sup.1H NMR: .delta. 7.68 (d, 2H), 7.23 (d, 2H), 7.22 (m,
4H), 7.16 (s, 1H), 6.95 (d, 2H), 6.88 (d, 2H), 4.17 (t, 2H), 4.05
(t, 2H), 3.05-3.07 (m, 7H), 2.51-2.61 (m, 6H), 2.39 (q, 2H),
1.89-2.09 (m, 6H), 1.12 (t, 9H) ppm.
[1645] MS: m/z 678 (M+H).sup.+
Biological Assay
[1646] The following assay method is utilized to identify compounds
of Formula (I) which are effective in binding with RAGE, and hence
useful as modulators, preferably antagonists of RAGE.
General Assay Procedure
[1647] S100b, .beta.-amyloid and CML (500 ng/100 .mu.L/well) in 100
mM sodium bicarbonate/sodium carbonate buffer (pH 9.8) is loaded
onto the wells of a NUNC Maxisorp flat bottom 96-well microtitre
plate. The plate is incubated at 4.degree. C. overnight. The wells
are aspirated and treated with 50 mM imidazole buffer saline (pH
7.2) (with 5 mM CaCl.sub.2/mgCl.sub.2) containing 1% bovine serum
albumin (BSA) (300 .mu.L/well) for 1 h at RT. The wells are
aspirated.
[1648] Test compounds are dissolved in nanopure water
(concentration: 10-100 .mu.M). DMSO may be used as co-solvent. 25
.mu.L of test compound solution in 4% DMSO is added, along with 75
.mu.L sRAGE (6.75 nM FAC) to each well and samples are incubated
for 1 h at 37.degree. C. The wells are washed 4 times with 155 mM
NaCl pH 7.2 buffer saline and are soaked 10 seconds between each
wash.
[1649] Non-radioactive detection is performed by adding:
[1650] 10 .mu.L Biotinylated goat F(ab')2 Anti-mouse IgG.
(8.0.times.10.sup.-4 mg/mL, FAC)
[1651] 5 .mu.L Alk-phos-Sterptavidin (3.times.10.sup.-3 mg/mL
FAC)
[1652] 0.42 .mu.L per 5 mL Monoclonal antibody for sRAGE (FAC
6.0.times.10.sup.-3 mg/mL) to 5 mL 50 mM imidazole buffer saline
(pH 7.2) containing 0.2% bovine serum albumin and 5 mM CaCl.sub.2.
The mixture is incubated for 30 minutes at RT. 100 .mu.L complex is
added to each well and incubation is allowed to proceed at rt for 1
h. Wells are washed 4 times with wash buffer and soaked 10 s
between each wash. 100 .mu.L1 mg/mL (pNPP) in 1 M diethanolamine
(pH adjusted to 9.8 with HCl) is added. Color is allowed to develop
in the dark for 30 min to 1 h at rt. The reaction is quenched with
10 .mu.L of stop solution (0.5 N NaOH in 50% ethanol) and the
absorbance is measured spectrophotometrically with a microplate
reader at 405 nm.
[1653] The Examples in Table 1 were tested according to the assay
method described above, employing S100b as the RAGE ligand, and
were found to possess IC.sub.50 in the assay of less than 10 .mu.M.
IC.sub.50 (.mu.M) of ELISA assay represents the concentration of
compound at which 50% signal has been inhibited.
[1654] The invention further provides pharmaceutical compositions
comprising the RAGE modulating compounds of the invention. The term
"pharmaceutical composition" is used herein to denote a composition
that may be administered to a mammalian host, e.g., orally,
topically, parenterally, by inhalation spray, or rectally, in unit
dosage formulations containing conventional non-toxic carriers,
diluents, adjuvants, vehicles and the like. The term "parenteral"
as used herein, includes subcutaneous injections, intravenous,
intramuscular, intracisternal injection, or by infusion
techniques.
[1655] The pharmaceutical compositions containing a compound of the
invention may be in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous, or oily suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
or syrups or elixirs. Compositions intended for oral use may be
prepared according to any known method, and such compositions may
contain one or more agents selected from the group consisting of
sweetening agents, flavoring agents, coloring agents, and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets may contain the active ingredient
in admixture with non-toxic pharmaceutically-acceptable excipients
which are suitable for the manufacture of tablets. These excipients
may be for example, inert diluents, such as calcium carbonate,
sodium carbonate, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example corn starch or
alginic acid; binding agents, for example, starch, gelatin or
acacia; and lubricating agents, for example magnesium stearate,
stearic acid or talc. The tablets may be uncoated or they may be
coated by known techniques to delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained
action over a longer period. For example, a time delay material
such as glyceryl monostearate or glyceryl distearate may be
employed. They may also be coated by the techniques described in
U.S. Pat. Nos. 4,356,108; 4,166,452; and 4,265,874, incorporated
herein by reference, to form osmotic therapeutic tablets for
controlled release.
[1656] Formulations for oral use may also be presented as hard
gelatin capsules where the active ingredient is mixed with an inert
solid diluent, for example, calcium carbonate, calcium phosphate or
kaolin, or a soft gelatin capsules wherein the active ingredient is
mixed with water or an oil medium, for example peanut oil, liquid
paraffin, or olive oil.
[1657] Aqueous suspensions may contain the active compounds in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose, sodium alginate,
polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide such as
lecithin, or condensation products of an alkylene oxide with fatty
acids, for example polyoxyethylene stearate, or condensation
products of ethylene oxide with long chain aliphatic alcohols, for
example, heptadecaethyl-eneoxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and a
hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more coloring agents, one or more flavoring agents, and one or
more sweetening agents, such as sucrose or saccharin.
[1658] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as a liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[1659] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
compound in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example,
sweetening, flavoring, and coloring agents may also be present.
[1660] The pharmaceutical compositions of the invention may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example, olive oil or arachis oil, or a mineral
oil, for example a liquid paraffin, or a mixture thereof. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate, and condensation products of said partial esters with
ethylene oxide, for example polyoxyethylene sorbitan monooleate.
The emulsions may also contain sweetening and flavoring agents.
[1661] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents. The pharmaceutical compositions may
be in the form of a sterile injectable aqueous or oleaginous
suspension. This suspension may be formulated according to the
known methods using suitable dispersing or wetting agents and
suspending agents described above. The sterile injectable
preparation may also be a sterile injectable solution or suspension
in a non-toxic parenterally-acceptable diluent or solvent, for
example as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are water, Ringer's
solution, and isotonic sodium chloride solution. In addition,
sterile, fixed oils are conveniently employed as solvent or
suspending medium. For this purpose, any bland fixed oil may be
employed using synthetic mono- or diglycerides. In addition, fatty
acids such as oleic acid find use in the preparation of
injectables.
[1662] The compositions may also be in the form of suppositories
for rectal administration of the compounds of the invention. These
compositions can be prepared by mixing the drug with a suitable
non-irritating excipient which is solid at ordinary temperatures
but liquid at the rectal temperature and will thus melt in the
rectum to release the drug. Such materials include cocoa butter and
polyethylene glycols, for example.
[1663] For topical use, creams, ointments, jellies, solutions or
suspensions, lotions, eye ointments and eye or ear drops,
impregnated dressings and aerosols etc., containing the compounds
of the invention are contemplated. These topical formulations may
contain appropriate conventional additives such as preservatives,
solvents to assist drug penetration and emollients in ointments and
creams. The formulations may also contain compatible conventional
carriers, such as cream or ointment bases and ethanol or oleyl
alcohol for lotions. Such carriers may be present as from about
0.1% up to about 99% of the formulation. More usually they will
form up to about 80% of the formulation. For the purpose of this
application, topical applications shall include mouth washes and
gargles.
[1664] The compounds of the present invention may also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles, and
multilamellar vesicles. Liposomes may be formed from a variety of
phospholipids, such as cholesterol, stearylamine, or
phosphatidylcholines.
[1665] The compounds of the present invention may also be coupled
with soluble polymers as targetable drug carriers. Such polymers
can include polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine
substituted with palmitoyl residues. Furthermore, the compounds of
the present invention may be coupled to a class of biodegradable
polymers useful in achieving controlled release of a drug, for
example, polylactic acid, polepsilon caprolactone, polyhydroxy
butyric acid, polyorthoesters, polyacetals, polydihydropyrans,
polycyanoacrylates and cross-linked or amphipathic block copolymers
of hydrogels. Also provided by the present invention are prodrugs
of the invention.
[1666] For administration by inhalation the compounds according to
the invention are conveniently delivered in the form of an aerosol
spray presentation from pressurized packs or a nebulizer, with the
use of a suitable propellant, e.g. dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane,
tetrafluoroethane, heptafluoropropane, carbon dioxide or other
suitable gas. In the case of a pressurized aerosol the dosage unit
may be determined by providing a valve to deliver a metered amount.
Capsules and cartridges of e.g. gelatin for use in an inhaler or
insufflator may be formulated containing a powder mix of a compound
of the invention and a suitable powder base such as lactose or
starch.
[1667] Pharmaceutically acceptable salts of the compounds of the
present invention, where a basic or acidic group is present in the
structure, are also included within the scope of the invention. The
term "pharmaceutically acceptable salts" refers to non-toxic salts
of the compounds of this invention which are generally prepared by
reacting the free base with a suitable organic or inorganic acid or
by reacting the acid with a suitable organic or inorganic base.
Representative salts include the following salts: Acetate,
Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate,
Borate, Bromide, Calcium Edetate, Camsylate, Carbonate, Chloride,
Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate,
Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate,
Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide,
Hydrocloride, Hydroxynaphthoate, Iodide, Isethionate, Lactate,
Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate,
Methylbromide, Methyliodide, Methylchloride, Methylnitrate,
Methylsulfate, Monopotassium Maleate, Mucate, Napsylate, Nitrate,
N-methylglucamine, Oxalate, Pamoate (Embonate), Palmitate,
Pantothenate, Phosphate/diphosphate, Polygalacturonate, Potassium,
Salicylate, Sodium, Stearate, Subacetate, Succinate, Tannate,
Tartrate, Teoclate, Tosylate, Triethiodide, Trimethylammonium and
Valerate. When an acidic substituent is present, such as --COOH,
there can be formed the ammonium, morpholinium, sodium, potassium,
barium, calcium salt, and the like, for use as the dosage form.
When a basic group is present, such as amino or a basic heteroaryl
radical, such as pyridyl, an acidic salt, such as hydrochloride,
hydrobromide, phosphate, sulfate, trifluoroacetate,
trichloroacetate, acetate, oxlate, maleate, pyruvate, malonate,
succinate, citrate, tartarate, fumarate, mandelate, benzoate,
cinnamate, methiodide, methbromide, methchloride, methanesulfonate,
ethanesulfonate, picrate and the like, and include acids related to
the pharmaceutically-acceptable salts listed in the Journal of
Pharmaceutical Science, 66, 2 (1977) p. 1-19.
[1668] Other salts which are not pharmaceutically acceptable may be
useful in the preparation of compounds of the invention and these
form a further aspect of the invention.
[1669] In addition, some of the compounds of the present invention
may form solvates with water or common organic solvents. Such
solvates are also encompassed within the scope of the
invention.
[1670] Thus, in a further embodiment, there is provided a
pharmaceutical composition comprising a compound of the present
invention, or a pharmaceutically acceptable salt, solvate, or
prodrug thereof, and one or more pharmaceutically acceptable
carriers, excipients, or diluents.
[1671] The compounds of the present invention selectively act as
modulators of RAGE binding to a single endogenous ligand, i.e.,
selective modulators of .beta.-amyloid-RAGE interaction, and
therefore are especially advantageous in treatment of Alzheimer's
disease and related dementias.
[1672] Further, the compounds of the present invention act as
modulators of RAGE interaction with two or more endogenous ligands
in preference to others. Such compounds are advantageous in
treatment of related or unrelated pathologies mediated by RAGE,
i.e., Alzheimer's disease and cancer.
[1673] Further, the compounds of the present invention act as
modulators of RAGE binding to each and every one of its ligands,
thereby preventing the generation of oxidative stress and
activation of NF-.kappa.B regulated genes, such as the cytokines
IL-1, and TNF-.alpha.. Thus, antagonizing the binding of
physiological ligands to RAGE prevent targeted pathophysiological
consequences and useful for management or treatment of diseases,
i.e., AGE-RAGE interaction leading to diabetic complications,
S100/EN-RAGE/calgranulin-RAGE interaction leading to inflammatory
diseases, 1'-amyloid-RAGE interaction leading to Alzheimer's
Disease, and amphoterin-RAGE interaction leading to cancer.
I. RAGE and the Complications of Diabetes
[1674] As noted above, the compounds of the present invention are
useful in the treatment of the complications of diabetes. It has
been shown that nonenzymatic glycoxidation of macromolecules
ultimately resulting in the formation of advanced glycation
endproducts (AGEs) is enhanced at sites of inflammation, in renal
failure, in the presence of hyperglycemia and other conditions
associated with systemic or local oxidant stress (Dyer, D., et al.,
J. Clin. Invest., 91:2463-2469 (1993); Reddy, S., et al., Biochem.,
34:10872-10878 (1995); Dyer, D., et al., J. Biol. Chem.,
266:11654-11660 (1991); Degenhardt, T., et al., Cell Mol. Biol.,
44:1139-1145 (1998)). Accumulation of AGEs in the vasculature can
occur focally, as in the joint amyloid composed of
AGE-.beta..sub.2-microglobulin found in patients with
dialysis-related amyloidosis (Miyata, T., et al., J. Clin. Invest.,
92:1243-1252 (1993); Miyata, T., et al., J. Clin. Invest.,
98:1088-1094 (1996)), or generally, as exemplified by the
vasculature and tissues of patients with diabetes (Schmidt, A-M.,
et al., Nature Med., 1:1002-1004 (1995)). The progressive
accumulation of AGEs over time in patients with diabetes suggests
that endogenous clearance mechanisms are not able to function
effectively at sites of AGE deposition. Such accumulated AGEs have
the capacity to alter cellular properties by a number of
mechanisms. Although RAGE is expressed at low levels in normal
tissues and vasculature, in an environment where the receptor's
ligands accumulate, it has been shown that RAGE becomes upregulated
(Li, J. et at, J. Biol. Chem., 272:16498-16506 (1997); Li, J., et
al., J. Biol. Chem., 273:30870-30878 (1998); Tanaka, N., et al., J.
Biol. Chem., 275:25781-25790 (2000)). RAGE expression is increased
in endothelium, smooth muscle cells and infiltrating mononuclear
phagocytes in diabetic vasculature. Also, studies in cell culture
have demonstrated that AGE-RAGE interaction caused changes in
cellular properties important in vascular homeostasis.
II. RAGE and Cellular Dysfunction in the Amyloidoses
[1675] Also as noted above, the compounds of the present invention
are useful in treating amyloidoses and Alzheimer's disease. RAGE
appears to be a cell surface receptor which binds s-sheet fibrillar
material regardless of the composition of the subunits
(amyloid-.beta. peptide, A.beta., amylin, serum amyloid A,
prion-derived peptide) (Yan, S.-D., et al., Nature, 382:685-691
(1996); Yan, S-D., et al., Nat. Med., 6:643-651 (2000)). Deposition
of amyloid has been shown to result in enhanced expression of RAGE.
For example, in the brains of patients with Alzheimer's disease
(AD), RAGE expression increases in neurons and glia (Yan, S.-D., et
al., Nature 382:685-691 (1996)). The consequences of interaction
with RAGE appear to be quite different on neurons versus microglia.
Whereas microglia become activated as a consequence of A.beta.-RAGE
interaction, as reflected by increased motility and expression of
cytokines, early RAGE-mediated neuronal activation is superceded by
cytotoxicity at later times. Further evidence of a role for RAGE in
cellular interactions of A.beta. concerns inhibition of AB-induced
cerebral vasoconstriction and transfer of the peptide across the
blood-brain barrier to brain parenchyma when the receptor was
blocked (Kumar, S., et al., Neurosci. Program, p 141-#275.19
(2000)). Inhibition of RAGE-amyloid interaction has been shown to
decrease expression of cellular RAGE and cell stress markers (as
well as NF-kB activation), and diminish amyloid deposition (Yan,
S-D., et al., Nat. Med., 6:643-651 (2000)) suggesting a role for
RAGE-amyloid interaction in both perturbation of cellular
properties in an environment enriched for amyloid (even at early
stages) as well as in amyloid accumulation.
III. RAGE and Propagation of the Immune/Inflammatory Response
[1676] As noted above, the compounds of the present invention are
useful in treating inflammation. For example, S100/calgranulins
have been shown to comprise a family of closely related
calcium-binding polypeptides characterized by two EF-hand regions
linked by a connecting peptide (Schafer, B. et al., TIBS,
21:134-140 (1996); Zimmer, D., et al., Brain Res. Bull., 37:417-429
(1995); Rammes, A., et al., J. Biol. Chem., 272:9496-9502 (1997);
Lugering, N., et al., Eur. J. Clin. Invest., 25:659-664 (1995)).
Although they lack signal peptides, it has long been known that
S100/calgranulins gain access to the extracellular space,
especially at sites of chronic immune/inflammatory responses, as in
cystic fibrosis and rheumatoid arthritis. RAGE is a receptor for
many members of the S100/calgranulin family, mediating their
proinflammatory effects on cells such as lymphocytes and
mononuclear phagocytes. Also, studies on delayed-type
hypersensitivity response, colitis in IL-10 null mice,
collagen-induced arthritis, and experimental autoimmune
encephalitis models suggest that RAGE-ligand interaction
(presumably with S100/calgranulins) has a proximal role in the
inflammatory cascade as implicated in the inflammatory diseases
such as but not limited to rheumatoid arthritis and multiple
sclerosis.
[1677] RAGE is also implicated in inflammatory diseases of the skin
such as but not limited to atopic dermatitis, eczema, and
psoriasis. Psoriasis in particular is characterized by inflamed
itchy lesions. Psoriasis may be accompanied by arthropathic
symptoms that are similar to those in seen in rheumatoid
arthritis.
[1678] There is considerable evidence that psoriasis is a polygenic
autoimmune disorder. Psoriatic lesions are rich in cytokines, in
particular IL-1 and IL-8, both potent proinflammatory mediators.
IL-8 in particular is a chemotactic factor for neutrophils;
neutrophils are also known to synthesize and secrete S100 proteins,
one of the ligands for RAGE which is implicated in propogation of
the immune and inflammatory response. Psoriasin (S100A7) a new
member of the S100 gene family, is a secreted protein isolated from
psoriatic skin. Semprini et. al. (Hum. Genet. 2002 October,
111(4-5), 310-3) have shown a linkage of psoriasis genetic
susceptibility to distinct overexpression of S100 proteins in skin.
Therefore, a modulator of RAGE would be expected to regulate the
immune response in psoriasis.
IV. RAGE and Amphoterin
[1679] As noted above, the compounds of the present invention are
useful in treating tumor and tumor metastasis. For example,
amphoterin is a high mobility group I nonhistone chromosomal DNA
binding protein (Rauvala, H., et al., J. Biol. Chem.,
262:16625-16635 (1987); Parkikinen, J., et al., J. Biol. Chem.
268:19726-19738 (1993)) which has been shown to interact with RAGE.
It has been shown that amphoterin promotes neurite outgrowth, as
well as serving as a surface for assembly of protease complexes in
the fibrinolytic system (also known to contribute to cell
mobility). In addition, a local tumor growth inhibitory effect of
blocking RAGE has been observed in a primary tumor model (C6
glioma), the Lewis lung metastasis model (Taguchi, A., et al.,
Nature 405:354-360 (2000)), and spontaneously arising papillomas in
mice expressing the v-Ha-ras transgene (Leder, A., et al., Proc.
Natl. Acad. Sci., 87:9178-9182 (1990)).
[1680] Amphoterin is a high mobility group I nonhistone chromosomal
DNA binding protein (Rauvala, H. and R. Pihlaskari. 1987. Isolation
and some characteristics of an adhesive factor of brain that
enhances neurite outgrowth in central neurons. J. Biol. Chem.
262:16625-16635. (Parkikinen, J., E. Raulo, J. Merenmies, R. Nolo,
E. Kajander, M. Baumann, and H. Rauvala. 1993. Amphoterin, the 30
kDa protein in a family of HIMG1-type polypeptides. J. Biol. Chem.
268:19 726-19738).
V. RAGE and Erectile Dysfunction
[1681] Relaxation of the smooth muscle cells in the cavernosal
arterioles and sinuses results in increased blood flow into the
penis, raising corpus cavernosum pressure to culminate in penile
erection. Nitric oxide is considered the principle stimulator of
cavernosal smooth muscle relaxation (See Wingard C J, Clinton W,
Branam H, Stopper V S, Lewis R W, Mills T M, Chitaley K. Antagonism
of Rho-kinase stimulates rat penile erection via a nitric
oxide-independent pathway. Nature Medicine 2001 January;
7(1):119-122). RAGE activation produces oxidants (See Yan, S-D.,
Schmidt A-M., Anderson, G., Zhang, J., Brett, J., Zou, Y-S.,
Pinsky, D., and Stern, D. Enhanced cellular oxidant stress by the
interaction of advanced glycation endproducts with their
receptors/binding proteins. J. Biol. Chem. 269:9889-9887, 1994.)
via an NADH oxidase-like enzyme, therefore suppressing the
circulation of nitric oxide. Potentially by inhibiting the
activation of RAGE signaling pathways by decreasing the
intracellular production of AGEs, generation of oxidants will be
attenuated. RAGE blockers may promote and facilitate penile
erection by blocking the access of ligands to RAGE.
[1682] The calcium-sensitizing Rho-kinase pathway may play a
synergistic role in cavernosal vasoconstriction to maintain penile
flaccidity. The antagonism of Rho-kinase results in increased
corpus cavernosum pressure, initiating the erectile response
independently of nitric oxide (Wingard et al.). One of the
signaling mechanisms activated by RAGE involves the Rho-kinase
family such as cdc42 and rac (See Huttunen H J, Fages C, Rauvala H.
Receptor for advanced glycation end products (RAGE)-mediated
neurite outgrowth and activation of NF-kappaB require the
cytoplasmic domain of the receptor but different downstream
signaling pathways. J Biol Chem 1999 Jul. 9; 274(28):19919-24).
Thus, inhibiting activation of Rho-kinases via suppression of RAGE
signaling pathways will enhance and stimulate penile erection
independently of nitric oxide.
VI. RAGE and Respiratory Diseases
[1683] Airway inflammation is important in the pathogenesis of
asthma. Such inflammation may give rise to significant
exacerbations and increases in asthma severity, as well as to be a
major factor in a decline in asthmatic status. In severe
exacerbations of asthma there is an intense, mechanistically
heterogeneous inflammatory response involving neutrophil and
eosinophil accumulation and activation. Neutrophils are a
significant source of S100 proteins, key ligands for RAGE
implicated in the propogation of the immune response and
inflammation. Therefore, modulators of RAGE would be expected to
possess therapeutic value in the treatment of asthma.
[1684] Further, the propogation step in the immune response in the
lung driven by S100-RAGE interaction would be expected to lead to
the activation and/or recruitment of inflammatory cells, such as
neutrophils, which in chronic obstructive pulmonary diseases such
as emphysema, are significant sources of damaging proteases.
Therefore, a RAGE modulator would be expected possess potential in
the treatment of chronic obstructive pulmonary diseases.
[1685] Thus, in a further aspect, the present invention provides a
method for the inhibition of the interaction of RAGE with
physiological ligands. In a preferred embodiment of this aspect,
the present invention provides a method for treating a disease
state selected from the group consisting of acute and chronic
inflammation including but not limited to skin inflammation such as
psoriasis and atopic dermatitis and lung inflammation including
asthma and chronic obstructive pulmonary disease, vascular
permeability, nephropathy, atherosclerosis, retinopathy,
Alzheimer's disease, erectile dysfunction, and tumor invasion
and/or metastasis, which comprises administering to a subject in
need thereof a compound of the present invention, preferably a
pharmacologically effective amount, more preferably a
therapeutically effective amount. In a preferred embodiment, at
least one compound of Formula (I) is utilized, either alone or in
combination with one or more known therapeutic agents. In a further
preferred embodiment, the present invention provides method of
prevention and/or treatment of RAGE mediated human diseases,
treatment comprising alleviation of one or more symptoms resulting
from that disorder, to an outright cure for that particular
disorder or prevention of the onset of the disorder, the method
comprising administration to a human in need thereof a
therapeutically effective amount of a compound of the present
invention, preferably a compound of Formula (I).
[1686] In this method, factors which will influence what
constitutes an effective amount will depend upon the size and
weight of the subject, the biodegradability of the therapeutic
agent, the activity of the therapeutic agent, as well as its
bioavailability. As used herein, the phrase "a subject in need
thereof" includes mammalian subjects, preferably humans, who either
suffer from one or more of the aforesaid diseases or disease states
or are at risk for such. Accordingly, in the context of the
therapeutic method of the invention, this method also is comprised
of a method for treating a mammalian subject prophylactically, or
prior to the onset of diagnosis such disease(s) or disease
state(s).
[1687] In a further aspect of the present invention, the RAGE
modulators of the invention are utilized in adjuvant therapeutic or
combination therapeutic treatments with other known therapeutic
agents.
[1688] The term "treatment" as used herein, refers to the full
spectrum of treatments for a given disorder from which the patient
is suffering, including alleviation of one, most of all symptoms
resulting from that disorder, to an outright cure for the
particular disorder or prevention of the onset of the disorder.
[1689] The following is a non-exhaustive listing of adjuvants and
additional therapeutic agents which may be utilized in combination
with the RAGE modulators of the present invention:
[1690] Pharmacologic classifications of anticancer agents: [1691]
1. Alkylating agents: Cyclophosphamide, nitrosoureas, carboplatin,
cisplatin, procarbazine [1692] 2. Antibiotics: Bleomycin,
Daunorubicin, Doxorubicin [1693] 3. Antimetabolites: Methotrexate,
Cytarabine, Fluorouracil [1694] 4. Plant alkaloids: Vinblastine,
Vincristine, Etoposide, Paclitaxel, [1695] 5. Hormones: Tamoxifen,
Octreotide acetate, Finasteride, Flutamide [1696] 6. Biologic
response modifiers: Interferons, Interleukins, Anti-tumor
antibodies
[1697] Pharmacologic classifications of treatment for Rheumatoid
Arthritis (Inflammation) [1698] 1. Analgesics: Aspirin [1699] 2.
NSAIDs (Nonsteroidal anti-inflammatory drugs): Ibuprofen, Naproxen,
Diclofenac [1700] 3. DMARDs (Disease-Modifying Antirheumatic
drugs): Methotrexate, gold preparations, hydroxychloroquine,
sulfasalazine [1701] 4. Biologic Response Modifiers, DMARDs:
Etanercept, Infliximab Glucocorticoids
[1702] Pharmacologic classifications of treatment for Diabetes
Mellitus [1703] 1. Sulfonylureas: Tolbutamide, Tolazamide,
Glyburide, Glipizide [1704] 2. Biguanides: Metformin [1705] 3.
Miscellaneous oral agents: Acarbose, Troglitazone [1706] 4.
Insulin
[1707] Pharmacologic classifications of treatment for Alzheimer's
Disease [1708] 1. Cholinesterase Inhibitor: Tacrine, Donepezil
[1709] 2. Antipsychotics: Haloperidol, Thioridazine [1710] 3.
Antidepressants: Desipramine, Fluoxetine, Trazodone, Paroxetine
[1711] 4. Anticonvulsants: Carbamazepine, Valproic acid
[1712] In a further preferred embodiment, the present invention
provides a method of treating RAGE mediated diseases, the method
comprising administering to a subject in need thereof, a
therapeutically effective amount of a compound of Formula (I) in
combination with therapeutic agents selected from the group
consisting of alkylating agents, antimetabolites, plant alkaloids,
antibiotics, hormones, biologic response modifiers, analgesics,
NSAIDs, DMARDs, glucocorticoids, sulfonylureas, biguanides,
insulin, cholinesterase inhibitors, antipsychotics,
antidepressants, and anticonvulsants. In a further preferred
embodiment, the present invention provides the pharmaceutical
composition of the invention as described above, further comprising
one or more therapeutic agents selected from the group consisting
of alkylating agents, antimetabolites, plant alkaloids,
antibiotics, hormones, biologic response modifiers, analgesics,
NSAIDs, DMARDs, glucocorticoids, sulfonylureas, biguanides,
insulin, cholinesterase inhibitors, antipsychotics,
antidepressants, and anticonvulsants.
[1713] Generally speaking, the compound of the present invention,
preferably Formula (I), is administered at a dosage level of from
about 0.01 to 500 mg/kg of the body weight of the subject being
treated systemically, with a preferred dosage range between 0.01
and 200 mg/kg, most preferably 0.1 to 100 mg/kg of body weight per
day. The amount of active ingredient that may be combined with the
carrier materials to produce a single dosage will vary depending
upon the host treated and the particular mode of administration.
For example, a formulation intended for oral administration to
humans may contain 1 mg to 2 grams of a compound of Formula (I)
with an appropriate and convenient amount of carrier material which
may vary from about 5 to 95 percent of the total composition. Also
a dosage form intended for topical administration to the skin may
be prepared at 0.1% to 99% compound to topical excipient ratio and
a dosage form intended for inhaled administration of 0.01 to 200 mg
of compound in a suitable carrier to deliver an inhaled dosage of
compound. Dosage unit forms of systemically delivered compound will
generally contain between from about 5 mg to about 500 mg of active
ingredient. This dosage has to be individualized by the clinician
based on the specific clinical condition of the subject being
treated. Thus, it will be understood that the specific dosage level
for any particular patient will depend upon a variety of factors
including the activity of the specific compound employed, the age,
body weight, general health, sex, diet, time of administration,
route of administration, rate of excretion, drug combination and
the severity of the particular disease undergoing therapy.
[1714] While the invention has been described and illustrated with
reference to certain preferred embodiments thereof, those skilled
in the art will appreciate that various changes, modifications and
substitutions can be made therein without departing from the spirit
and scope of the invention. For example, effective dosages other
than the preferred dosages as set forth herein may be applicable as
a consequence of variations in the responsiveness of the mammal
being treated for RAGE-mediated disease(s). Likewise, the specific
pharmacological responses observed may vary according to and
depending on the particular active compound selected or whether
there are present pharmaceutical carriers, as well as the type of
formulation and mode of administration employed, and such expected
variations or differences in the results are contemplated in
accordance with the objects and practices of the present
invention.
* * * * *