U.S. patent application number 12/906002 was filed with the patent office on 2011-02-10 for organic compounds.
Invention is credited to Daniel Kaspar Baeschlin, Garry Fenton, Kenji Namoto, Nils Ostermann, Richard Sedrani, Finton Sirockin.
Application Number | 20110034462 12/906002 |
Document ID | / |
Family ID | 38188290 |
Filed Date | 2011-02-10 |
United States Patent
Application |
20110034462 |
Kind Code |
A1 |
Baeschlin; Daniel Kaspar ;
et al. |
February 10, 2011 |
ORGANIC COMPOUNDS
Abstract
The present invention relates to compounds of the formula; and
their use in therapy. ##STR00001##
Inventors: |
Baeschlin; Daniel Kaspar;
(Arlesheim, CH) ; Fenton; Garry; (Harlow, GB)
; Namoto; Kenji; (Basel, CH) ; Ostermann;
Nils; (Binzen, DE) ; Sedrani; Richard; (Basel,
CH) ; Sirockin; Finton; (St. Louis, FR) |
Correspondence
Address: |
NOVARTIS VACCINES AND DIAGNOSTICS INC.
INTELLECTUAL PROPERTY- X100B, P.O. BOX 8097
Emeryville
CA
94662-8097
US
|
Family ID: |
38188290 |
Appl. No.: |
12/906002 |
Filed: |
October 15, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12296792 |
Oct 10, 2008 |
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PCT/EP2007/003185 |
Apr 10, 2007 |
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12906002 |
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Current U.S.
Class: |
514/235.2 ;
514/299 |
Current CPC
Class: |
C07D 211/26 20130101;
A61P 43/00 20180101; A61P 3/06 20180101; A61P 5/50 20180101; A61P
13/08 20180101; A61P 19/10 20180101; A61P 15/08 20180101; A61P
19/00 20180101; A61P 35/04 20180101; A61P 1/04 20180101; A61P 19/02
20180101; C07D 211/96 20130101; A61P 13/12 20180101; A61P 9/00
20180101; A61P 31/00 20180101; A61P 1/00 20180101; A61P 9/04
20180101; A61P 27/02 20180101; A61P 5/26 20180101; A61P 25/00
20180101; A61P 37/04 20180101; A61P 5/32 20180101; A61P 1/18
20180101; A61P 3/04 20180101; A61P 7/02 20180101; A61P 1/02
20180101; A61P 3/10 20180101; A61P 25/28 20180101; C07D 471/08
20130101; A61P 9/10 20180101; A61P 5/28 20180101; A61P 3/00
20180101; A61P 9/12 20180101; A61P 5/00 20180101; A61P 5/30
20180101; A61P 37/06 20180101 |
Class at
Publication: |
514/235.2 ;
514/299 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; A61K 31/439 20060101 A61K031/439; A61P 35/04 20060101
A61P035/04; A61P 3/10 20060101 A61P003/10; A61P 3/04 20060101
A61P003/04; A61P 19/02 20060101 A61P019/02 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 11, 2006 |
GB |
0607309.2 |
Oct 17, 2006 |
EP |
06122445.7 |
Claims
1.-59. (canceled)
60. A method of treating or preventing a disease or condition in a
patient, which comprises administering to a patient in need thereof
a therapeutically effective amount of a compound of Formula (I):
##STR00124## wherein the asterisk * designates a chiral centre of
(R) or (S) configuration; V is absent or is ethylene; W is --C(O)--
or --S(O).sub.1--; X is a linker having 1 to 12 in-chain atoms and
comprising one or more linkages selected from --O--, --C(O)--,
--S(O).sub.1--, --N(R.sup.9)-- and hydrocarbylene, optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11; Y is a linker selected
from --O--, --N(R.sup.9)--, --C(O)--, --C(O)O--,
--C(O)N(R.sup.9)--, --S(O).sub.1-- and S(O).sub.1N(R.sup.9)--;
R.sup.1 is selected from hydrogen; --N(R.sup.9)(R.sup.10);
hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.11;
hydrocarbyloxy optionally substituted with 1, 2, 3, 4 or 5
R.sup.11; and --(CH.sub.2).sub.k-heterocyclyl optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11; or, when Y is
--N(R.sup.9)--, R.sup.1 and R.sup.9 taken together with the
nitrogen atom to which they are attached may form a heterocycle,
wherein said heterocycle is bound to X via said nitrogen atom and
is optionally substituted with 1, 2, 3, 4 or 5 R.sup.11; R.sup.2
and R.sup.3 are each independently selected from R.sup.8,
--OR.sup.8, --C(O)R.sup.8, --C(O)OR.sup.8 and --S(O).sub.1R.sup.9;
R.sup.4 and R.sup.5 are each independently selected from hydrogen,
hydroxy, halogen and C.sub.1-6 alkyl optionally substituted with 1,
2, 3, 4 or 5 R.sup.11; R.sup.6 is aryl or heteroaryl, either of
which is optionally-substituted with 1, 2, 3, 4 or 5 R.sup.11;
R.sup.8 is selected from hydrogen; hydrocarbyl optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11; and
--(CH.sub.2).sub.k-heterocyclyl optionally substituted with 1, 2,
3, 4 or 5 R.sup.11; R.sup.9 and R.sup.10 are each independently
selected from R.sup.8, --OR.sup.8, --C(O)R.sup.8, --C(O)OR.sup.8
and --S(P).sub.1R.sup.8; or R.sup.9 and R.sup.10 taken together
with a nitrogen atom to which they are attached form heterocyclyl
optionally substituted with 1, 2, 3, 4 or 5 R.sup.11; each R.sup.11
is independently selected from R.sup.12; hydrocarbyl optionally
substituted with 1, 2, 3, 4 or 5 R.sup.12; and
--(CH.sub.2).sub.k-heterocyclyl optionally substituted with 1, 2,
3, 4 or 5 R.sup.12; R.sup.12 is independently selected from
halogen, trifluoromethyl, cyano, nitro, oxo, .dbd.NR.sup.13,
--OR.sup.13, --C(O)R.sup.13, --C(O)N(R.sup.13)R.sup.14,
--C(O)OR.sup.13, --OC(O)R.sup.13, --S(O).sub.1R.sup.13,
--S(O).sub.1N(R.sup.13)R.sup.14, --N(R.sup.13)R.sup.14,
--N(R.sup.13)N(R.sup.13)R.sup.14, --N(R.sup.13)C(O)R.sup.14 and
--N(R.sup.13)S(O).sub.1R.sup.13; R.sup.13 and R.sup.14 are each
independently hydrogen or selected from hydrocarbyl and
--(CH.sub.2).sub.k-heterocyclyl, either of which is optionally
substituted with 1, 2, 3, 4 or 5 substituents independently
selected from oxo, halogen, cyano, amino, hydroxy, C.sub.1-6 alkyl
and C.sub.1-6 alkoxy; k is 0, 1, 2, 3, 4, 5 or 6; and l is 0, 1 or
2; or a pharmaceutically acceptable salt or prodrug thereof;
thereby treating or preventing said disease or condition.
61. The method of claim 60, wherein the compound is of the Formula
(II): ##STR00125## or a pharmaceutically acceptable salt or prodrug
thereof.
62. The method of claim 60, wherein the compound is the Formula
(III): ##STR00126## or a pharmaceutically acceptable salt or
prodrug thereof.
63. The method of claim 60, wherein X is --X.sup.1-- and wherein
X.sup.1 is selected from --O--, --C(O)--, --S(O).sub.1--,
--N(R.sup.9)-- and hydrocarbylene optionally substituted with 1, 2,
3, 4 or 5 R.sup.11.
64. The method of claim 63, wherein the compound is of the Formula
(IV): ##STR00127## wherein X.sup.1 is --N(R.sup.9)-- or
hydrocarbylene optionally substituted with 1, 2, 3, 4 or 5
R.sup.11; or a pharmaceutically acceptable salt or prodrug
thereof.
65. The method of claim 60, wherein said disease or condition is
selected from non-insulin-dependent diabetes mellitus, arthritis,
obesity, allograft transplantation, calcitonin-osteoporosis, heart
failure, impaired glucose metabolism or impaired glucose tolerance,
neurodegenerative diseases, cardiovascular or renal diseases, and
neurodegenerative or cognitive disorders, hyperglycemia, insulin
resistance, lipid disorders, dyslipidemia, hyperlipidemia,
hypertriglyceridemia, hypercholesterolemia, low HDL levels, high
LDL levels, atherosclerosis, vascular restenosis, irritable bowel
syndrome, inflammatory bowel disease, pancreatitis, retinopathy,
nephropathy, neuropathy, syndrome X, ovarian hyperandrogenism
(polycystic ovarian syndrome), type 2 diabetes, growth hormone
deficiency, neutropenia, neuronal disorders, tumor metastasis,
benign prostatic hypertrophy, gingivitis, hypertension and
osteoporosis.
66. The method of claim 65, wherein said disease or condition is
Alzheimer's disease, Parkinson's disease, Crohn's disease or
ulcerative colitis.
67. The method of claim 65, wherein said disease or condition is
diabetic cardiomyopathy, left or right ventricular hypertrophy,
hypertrophic medial thickening in arteries and/or in large vessels,
mesenteric vasculature hypertrophy or mesanglial hypertrophy.
68. The method of claim 60, further comprising administering said
compound in combination with one or more additional therapeutic
agents selected from anti-diabetic agents, hypolipidemic agents,
anti-obesity or appetite-regulating agents, anti-hypertensive
agents, HDL-increasing agents, cholesterol absorption modulators,
Apo-A1 analogues and mimetics, thrombin inhibitors, aldosterone
inhibitors, inhibitors of platelet aggregation; estrogen,
testosterone, selective estrogen, receptor modulators, selective
androgen receptor modulators, chemotherapeutic agents, and
5-HT.sub.3 or 5-HT.sub.4 receptor modulators.
69. The method of claim 60, wherein the compound is selected from
the group consisting of: ##STR00128## ##STR00129## ##STR00130##
##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135##
##STR00136## ##STR00137## ##STR00138## ##STR00139## or a
pharmaceutically acceptable salt or prodrug thereof.
70. The method according to claim 60, wherein the compound is
selected from the group consisting of: ##STR00140## ##STR00141##
##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146##
##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151##
##STR00152## ##STR00153## ##STR00154## ##STR00155## ##STR00156##
##STR00157## ##STR00158## ##STR00159## ##STR00160## ##STR00161##
##STR00162## ##STR00163## ##STR00164## ##STR00165## ##STR00166##
##STR00167## ##STR00168## ##STR00169## ##STR00170## ##STR00171##
##STR00172## ##STR00173## ##STR00174## ##STR00175## ##STR00176##
##STR00177## ##STR00178## ##STR00179## ##STR00180## ##STR00181##
##STR00182## ##STR00183## ##STR00184## ##STR00185## ##STR00186##
##STR00187## ##STR00188## ##STR00189## ##STR00190## ##STR00191##
##STR00192## ##STR00193## ##STR00194## ##STR00195## ##STR00196##
##STR00197## ##STR00198## ##STR00199## ##STR00200## ##STR00201## or
a pharmaceutically acceptable salt or prodrug thereof.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to compounds and their use in
therapy.
BACKGROUND TO THE INVENTION
[0002] Dipeptidylpeptidase-IV (DPP-IV) is a serine protease which
cleaves N-terminal dipeptides from a peptide chain containing, in
general, a proline residue in the penultimate position. DPP-IV is
widely expressed in mammalian tissue as a type II integral membrane
protein. The protease is expressed on the surface of differentiated
epithelial cells of the intestine, liver, kidney proximal tubules,
prostate, corpus luteum, and on leukocyte subsets such as
lymphocytes and macrophages. A soluble form of the enzyme is found
in serum that has structure and function identical to the
membrane-bound form of the enzyme but lacks the hydrophobic
transmembrane domain.
[0003] DPP-IV has many physiologically relevant substrates
including chemokines (e.g. eotaxin and macrophage-derived
chemokine), neuropeptides (e.g. neuropeptide Y and substance P),
vasoactive peptides, and incretins (e.g. GLP-1 and GlP). GLP-1
(glucagon-like peptide-1) is a hormone produced in the L cells of
the distal small intestine in response to ingested nutrients. GLP-1
receptor binding on various tissues stimulates insulin gene
expression, biosynthesis and glucose-dependent insulin secretion,
inhibits glucagon secretion, promotes satiety, slows gastric
emptying and promotes growth of pancreatic beta cells.
[0004] Although the biological role of DPP-IV in mammalian systems
has not been completely established, it is believed to play an
important role in neuropeptide metabolism, T-cell activation,
attachment of cancer cells to the endothelium and the entry of HIV
into lymphoid cells. It has also been discovered that DPP-IV is
responsible for inactivating glucagon-like peptide-1 (GLP-1). Since
GLP-1 is a major stimulator of pancreatic insulin secretion and has
direct beneficial effects on glucose disposal, DPP-IV inhibition
appears to represent an attractive approach for treating, for
example, non-insulin-dependent diabetes mellitus (NIDDM).
[0005] DPP-IV has also been shown to play a part in the immune
response. Expressed by T-CD4+ lymphocytes, where it is synonymous
with the antigen CD26, DPP-IV plays an important part in the
mechanism of transplant rejection (Transplantation 1997, 63 (10),
1495-500). By allowing more selective suppression of the immune
response, inhibition of DPP-IV accordingly represents an extremely
promising approach in the prevention of transplant rejection in
transplant patients.
[0006] Inhibitors of DPP-IV are described inter alia in
WO-A-03/000180, WO-A-000181, WO-A-004498, WO-A-03/082817,
WO-A-04/032836, WO-A-04/007468, EP1679069 and WO-A-05/121089.
SUMMARY OF THE INVENTION
[0007] A first aspect of the invention is a compound of the Formula
(I):
##STR00002##
wherein [0008] the asterisk * designates a chiral centre of (R) or
(S) configuration; [0009] V is absent or is ethylene; [0010] W is
--C(O) or --S(O).sub.l--; [0011] X is a linker having 1 to 12 (e.g.
1 to 6) in-chain atoms and comprising one or more linkages selected
from --O--, --C(O)--, --S(O).sub.l, --N(R.sup.9)-- and
hydrocarbylene optionally substituted with 1, 2, 3, 4 or 5
R.sup.11; [0012] Y is a linker selected from --O--, --N(R.sup.9)--,
--C(O)--, --C(O)O--, --C(O)N(R.sup.9)--, --S(O).sub.l and
--S(O).sub.lN(R.sup.9); [0013] R.sup.1 is selected from hydrogen;
--N(R.sup.9)(R.sup.10); hydrocarbyl optionally substituted with 1,
2, 3, 4 or 5 R.sup.11; hydrocarbyloxy optionally substituted with
1, 2, 3, 4 or 5 R.sup.11; and --(CH.sub.2).sub.k-heterocyclyl
optionally substituted with 1, 2, 3, 4 or 5 R.sup.11; [0014] or,
when Y is --N(R.sup.9)--, R.sup.1 and R.sup.9 taken together with
the nitrogen atom to which they are attached may form a
heterocycle, wherein said heterocycle is bound to X via said
nitrogen atom and is optionally substituted with 1, 2, 3, 4 or 5
R.sup.11; [0015] R.sup.2 and R.sup.3 are each independently
selected from R.sup.8, --OR.sup.8, --C(O)R.sup.8, --C(O)OR.sup.8
and --S(O).sub.lR.sup.9; [0016] R.sup.4 and R.sup.5 are each
independently selected from hydrogen, hydroxy, halogen and
C.sub.1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5
R.sup.11; [0017] R.sup.6 is aryl or heteroaryl, either of which is
optionally substituted with 1, 2, 3, 4 or 5 R.sup.11; [0018]
R.sup.8 is selected from hydrogen; hydrocarbyl optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11; and
--(CH.sub.2).sub.k-heterocyclyl optionally substituted with 1, 2,
3, 4 or 5 R.sup.11; [0019] R.sup.9 and R.sup.10 are each
independently selected from R.sup.8, --OR.sup.8, --C(O)R.sup.8,
--C(O)OR.sup.8 and --S(O).sub.lR.sup.8; or R.sup.9 and R.sup.10
taken together with a nitrogen atom to which they are attached form
heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.11;
[0020] each R.sup.11 is independently selected from R.sup.12;
hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.12;
and --(CH.sub.2).sub.k-heterocyclyl optionally substituted with 1,
2, 3, 4 or 5 R.sup.12; [0021] R.sup.12 is independently selected
from halogen, trifluoromethyl, cyano, nitro, oxo, .dbd.NR.sup.13,
--OR.sup.13, --C(O)R.sup.13, --C(O)N(R.sup.13)R.sup.14,
--C(O)OR.sup.13, --OC(O)R.sup.13, --S(O).sub.lR.sup.13,
--S(O).sub.lN(R.sup.13)R.sup.14, --N(R.sup.13)R.sup.14,
--N(R.sup.13)N(R.sup.13)R.sup.14, --N(R.sup.13)C(O)R.sup.14 and
--N(R.sup.13)S(O).sub.lR.sup.13; [0022] R.sup.13 and R.sup.14 are
each independently hydrogen or selected from hydrocarbyl and
--(CH.sub.2).sub.k-heterocyclyl, either of which is optionally
substituted with 1, 2, 3, 4 or 5 substituents independently
selected from halogen, cyano, amino, hydroxy, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy; or [0023] R.sup.13 and R.sup.14 are each
independently hydrogen or selected from hydrocarbyl and
--(CH.sub.2).sub.k-heterocyclyl, either of which is optionally
substituted with 1, 2, 3, 4 or 5 substituents independently
selected from oxo, halogen, cyano, amino, hydroxy, C.sub.1-6 alkyl
and C.sub.1-6 alkoxy; [0024] k is 0, 1, 2, 3, 4, 5 or 6; and [0025]
l is 0, 1, or 2; or a pharmaceutically acceptable salt or prodrug
thereof.
[0026] In some embodiments, when X is C.sub.1-6 alkylene,
--O--C.sub.1-6 alkylene- or --N(R.sup.9)--C.sub.1-6 alkylene- and Y
is --O--, --S-- or --N(R.sup.9), said C.sub.1-6 alkylene linkage of
X is substituted with 1, 2, 3, 4 or 5 R.sup.11, wherein at least
one of said R.sup.11 is other than halogen or C.sub.1-6 alkyl.
[0027] A second aspect of the invention is a compound of the
invention for therapeutic use.
[0028] Another aspect of the invention is a pharmaceutical
formulation comprising a compound of the invention and, optionally,
a pharmaceutically acceptable diluent or carrier.
[0029] A further aspect of the invention is a product comprising a
compound of the invention and a therapeutic agent; as a combined
preparation for simultaneous, separate or sequential use in
therapy.
[0030] Another aspect of the invention is the use of a compound of
the invention for the manufacture of a medicament for the treatment
or prevention of a disease or condition selected from
non-insulin-dependent diabetes mellitus, arthritis, obesity,
allograft transplantation, calcitonin-osteoporosis, heart failure,
impaired glucose metabolism or impaired glucose tolerance,
neurodegenerative diseases, cardiovascular or renal diseases, and
neurodegenerative or cognitive disorders.
[0031] Another aspect of the invention is the use of a compound of
the invention for the manufacture of a medicament for producing a
sedative or anxiolytic effect, attenuating post-surgical catabolic
changes or hormonal responses to stress, reducing mortality and
morbidity after myocardial infarction, modulating hyperlipidemia or
associated conditions, or lowering VLDL, LDL or Lp(a) levels.
[0032] Another aspect of the invention is a method of treating or
preventing a disease or condition in a patient, which comprises
administering a therapeutically effective amount of a compound of
the invention.
[0033] The compounds of the invention can exist in different forms,
such as free acids, free bases, esters and other prodrugs, salts
and tautomers, for example, and the disclosure includes all variant
forms of the compounds.
[0034] The extent of protection includes counterfeit or fraudulent
products which contain or purport to contain a compound of the
invention irrespective of whether they do in fact contain such a
compound and irrespective of whether any such compound is contained
in a therapeutically effective amount.
[0035] Included in the scope of protection are packages which
include a description or instructions which indicate that the
package contains a species or pharmaceutical formulation of the
invention and a product which is or comprises, or purports to be or
comprise, such a formulation or species. Such packages may be, but
are not necessarily, counterfeit or fraudulent.
[0036] Features, integers, characteristics, compounds, chemical
moieties or groups described in conjunction with a particular
aspect, embodiment or example of the invention are to be understood
to be applicable to any other aspect, embodiment or example
described herein unless incompatible therewith.
DESCRIPTION OF VARIOUS EMBODIMENTS
Hydrocarbyl
[0037] The term "hydrocarbyl" as used herein includes reference to
a moiety consisting exclusively of hydrogen and carbon atoms; such
a moiety may comprise an aliphatic and/or an aromatic moiety. The
moiety may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19 or 20 carbon atoms. Examples of hydrocarbyl
groups include C.sub.1-6 alkyl (e.g. C.sub.1, C.sub.2, C.sub.3 or
C.sub.4 alkyl, for example methyl, ethyl, propyl, isopropyl,
n-butyl, sec-butyl or tert-butyl); C.sub.1-6 alkyl substituted by
aryl (e.g. benzyl) or by cycloalkyl (e.g cyclopropylmethyl);
cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl); aryl (e.g. phenyl, naphthyl or fluorenyl) and the
like. When hydrocarbyl is a cycloalkyl it can be attached to the
chemical moiety in the fom of a spiro substitution.
Alkyl
[0038] The terms "alkyl" and "C.sub.1-6 alkyl" as used herein
include reference to a straight or branched chain alkyl moiety
having 1, 2, 3, 4, 5 or 6 carbon atoms. This term includes
reference to groups such as methyl, ethyl, propyl (n-propyl or
isopropyl), butyl (n-butyl, sec-butyl or tert-butyl), pentyl, hexyl
and the like. In particular, alkyl may have 1, 2, 3 or 4 carbon
atoms.
Alkenyl
[0039] The terms "alkenyl" and "C.sub.2-6 alkenyl" as used herein
include reference to a straight or branched chain alkyl moiety
having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at
least one double bond, of either E or Z stereochemistry where
applicable. This term includes reference to groups such as ethenyl,
2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl,
2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl and 3-hexenyl and the
like.
Alkynyl
[0040] The terms "alkynyl" and "C.sub.2-6 alkynyl" as used herein
include reference to a straight or branched chain alkyl moiety
having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at
least one triple bond. This term includes reference to groups such
as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,
3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1-hexynyl, 2-hexynyl
and 3-hexynyl and the like.
Alkoxy
[0041] The terms "alkoxy" and "C.sub.1-6 alkoxy" as used herein
include reference to --O-alkyl, wherein alkyl is straight or
branched chain and comprises 1, 2, 3, 4, 5 or 6 carbon atoms. In
one class of embodiments, alkoxy has 1, 2, 3 or 4 carbon atoms.
This term includes reference to groups such as methoxy, ethoxy,
propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the
like.
Cycloalkyl
[0042] The term "cycloalkyl" as used herein includes reference to
an alicyclic moiety having 3, 4, 5, 6, 7 or 8 carbon atoms. The
group may be a bridged or polycyclic ring system. More often
cycloalkyl groups are monocyclic. This term includes reference to
groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
norbornyl, bicyclo[2.2.2]octyl and the like.
Aryl
[0043] The term "aryl" as used herein includes reference to an
aromatic ring system comprising 6, 7, 8, 9, 10, 11, 12, 13, 14, 15
or 16 ring carbon atoms. Aryl is often phenyl but may be a
polycyclic ring system, having two or more rings, at least one of
which is aromatic. This term includes reference to groups such as
phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the
like.
Carbocyclyl
[0044] The term "carbocyclyl" as used herein includes reference to
a saturated (e.g. cycloalkyl) or unsaturated (e.g. aryl) ring
moiety having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16
carbon ring atoms. In particular, carbocyclyl includes a 3- to
10-membered ring or ring system and, in particular, a 5- or
6-membered ring, which may be saturated or unsaturated. A
carbocyclic moiety is, for example, selected from cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, norbornyl,
bicyclo[2.2.2]octyl, phenyl, naphthyl, fluorenyl, azulenyl,
indenyl, anthryl and the like.
Heterocyclyl
[0045] The term "heterocyclyl" as used herein includes reference to
a saturated (e.g. heterocycloalkyl) or unsaturated (e.g.
heteroaryl) heterocyclic ring moiety having from 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which
is selected from nitrogen, oxygen, phosphorus, silicon and sulphur.
In particular, heterocyclyl includes a 3- to 10-membered ring or
ring system and more particularly a 5- or 6-membered ring, which
may be saturated or unsaturated. When the heterocyclyl is a
heterocycloalkyl it can be attached to the chemical moiety in the
fom of a spiro substitution.
[0046] A heterocyclic moiety is, for example, selected from
oxiranyl, azirinyl, 1,2-oxathiolanyl, imidazolyl, thienyl, furyl,
tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl,
isobenzofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl,
pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl,
benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl,
isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl,
pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl,
morpholinyl, thiomorpholinyl, especially thiomorpholino,
indolizinyl, 1,3-Dioxo-1,3-dihydro-isoindolyl, 3H-indolyl, indolyl,
benzimidazolyl, cumaryl, indazolyl, triazolyl, tetrazolyl, purinyl,
4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl,
tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl,
benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl,
phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl,
quinazolinyl, cinnolinyl, pteridinyl, carbazolyl,
.beta.-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,
phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl,
phenoxazinyl, chromenyl, isochromanyl, chromanyl,
3,4-dihydro-2H-isoquinolin-1-one, 3,4-dihydro-2H-isoquinolinyl, and
the like.
Heterocycloalkyl
[0047] The term "heterocycloalkyl" as used herein includes
reference to a saturated heterocyclic moiety having 3, 4, 5, 6 or 7
ring carbon atoms and 1, 2, 3, 4 or 5 ring heteroatoms selected
from nitrogen, oxygen, phosphorus and sulphur. The group may be a
polycyclic ring system but more often is monocyclic. This term
includes reference to groups such as azetidinyl, pyrrolidinyl,
tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl,
imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl, morpholinyl,
thiomorpholinyl, quinolizidinyl, tetrahydropyranyl,
tetrahydrofuranyl, 1,3-dihydro-isoindolyl
1,3-Dioxo-1,3-dihydro-isoindolyl, 3,4-dihydro-2H-isoquinolinyl,
3,4-dihydro-2H-isoquinolinyl-1-one and the like.
Heteroaryl
[0048] The term "heteroaryl" as used herein includes reference to
an aromatic heterocyclic ring system having 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15 or 16 ring atoms, at least one of which is selected
from nitrogen, oxygen and sulphur. The group may be a polycyclic
ring system, having two or more rings, at least one of which is
aromatic, but is more often monocyclic.
[0049] This term includes reference to groups such as pyridazinyl,
pyrimidinyl, furanyl, benzo[b]thiophenyl, thiophenyl, pyrrolyl,
imidazolyl, pyrrolidinyl, pyridinyl, benzo[b]furanyl, pyrazinyl,
purinyl, indolyl, benzimidazolyl, quinolinyl, phenothiazinyl,
triazinyl, phthalazinyl, 2H-chromenyl, oxazolyl, isoxazolyl,
thiazolyl, isoindolyl, indazolyl, purinyl, isoquinolinyl,
quinazolinyl, pteridinyl and the like.
Halogen
[0050] The term "halogen" as used herein includes reference to F,
Cl, Br or I. In a particular, halogen may be F or Cl, of which F is
more common.
Spiro
[0051] The term "spiro" as used herein includes 3- to 6-cycloalkyl
or 5- to 6-heterocycloalkyl groups which can optionally be
substituted by 1, 2, 3 or 4, R.sup.13. Non limitative examples of
spiro groups are;
##STR00003##
Substituted
[0052] The term "substituted" as used herein in reference to a
moiety means that one or more, especially up to 5, more especially
1, 2 or 3, of the hydrogen atoms in said moiety are replaced
independently of each other by the corresponding number of the
described substituents. The term "optionally substituted" as used
herein means substituted or unsubstituted.
[0053] It will, of course, be understood that substituents are only
at positions where they are chemically possible, the person skilled
in the art being able to decide (either experimentally or
theoretically) without inappropriate effort whether a particular
substitution is possible. For example, amino or hydroxy groups with
free hydrogen may be unstable if bound to carbon atoms with
unsaturated (e.g. olefinic) bonds. Additionally, it will of course
be understood that the substituents described herein may themselves
be substituted by any substituent, subject to the aforementioned
restriction to appropriate substitutions as recognised by the
skilled man.
Pharmaceutically Acceptable
[0054] The term "pharmaceutically acceptable" as used herein
includes reference to those compounds, materials, compositions,
and/or dosage forms which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of human
beings or animals without excessive toxicity, irritation, allergic
response, or other problem or complication, commensurate with a
reasonable benefit/risk ratio. This term includes acceptability for
both human and veterinary purposes.
Independently
[0055] Where two or more moieties are described as being "each
independently" selected from a list of atoms or groups, this means
that the moieties may be the same or different. The identity of
each moiety is therefore independent of the identities of the one
or more other moieties.
Compounds
[0056] The invention provides compounds of the Formula (I):
##STR00004##
wherein [0057] the asterisk * designates a chiral centre of (R) or
(S) configuration; and [0058] V, W, X, Y, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are as defined herein; [0059]
or a pharmaceutically acceptable salt or prodrug thereof.
[0060] As indicated above, the stereochemical configuration of the
chiral centre indicated by * (i.e. the carbon atom to which the
group --N(R.sup.2)(R.sup.3) is attached) may be (R) or (S). Of
particular mention are compounds of the invention in which the
stereochemical configuration at said carbon atom is (R), i.e.
compounds of the following Formula:
##STR00005## [0061] or a pharmaceutically acceptable salt or
prodrug thereof.
[0062] A compound of the invention may be in the form of a racemate
or in a substantially pure form (e.g. a form having a purity of
greater than 80% purity, in particular greater than 90%, 95% or
99%) of a single enantiomer or diastereomer. Thus, one embodiment
of the invention is a substantially pure form of a compound of
Formula (I, (R)).
[0063] Embodiments of the invention are described below. It will be
appreciated that the features specified in each embodiment may be
combined with other specified features, to provide further
embodiments.
V
[0064] V is absent or is ethylene. The invention therefore includes
compounds of the following Formulae:
##STR00006## [0065] or, in each case, a pharmaceutically acceptable
salt or prodrug thereof.
[0066] Where V is ethylene (i.e. compounds of Formula (III)), the
relative orientation of the ethylene bridge and the hydrogen atom
located p- to the nitrogen atom of the piperidine ring is often
exo, as illustrated below:
##STR00007##
[0067] The term "exo" in this context means that the ethylene
bridge and the hydrogen atom shown in the Formula above are on the
same side of the piperidine ring.
[0068] The present invention also concerns the herein described
compounds and claims wherein the bridged piperidine ring is in the
configuration exo as described in the above paragraph.
--W--X--Y-
[0069] In Formula (I), W is --C(O)-- or --S(O).sub.l--; X is a
linker having 1 to 12 (e.g. 1 to 6) in-chain atoms and comprising
one or more linkages selected from --O--, --C(O)--, --S(O).sub.l--,
--N(R.sup.9)-- and hydrocarbylene optionally substituted with 1, 2,
3, 4 or 5 R.sup.11; and Y is a linker selected from --O--,
--N(R.sup.9), --C(O), --C(O)O--, --C(O)N(R.sup.9), --S(O).sub.l--
and --S(O).sub.lN(R.sup.9).
W is usually --C(O)-- or --S(O).sub.2--.
[0070] Where X comprises one or more hydrocarbylene linkages, the
or each linkage may be aliphatic and/or carbocyclic (e.g.
cycloalkylene). Of particular mention are aliphatic, e.g.
alkylenic, hydrocarbylene linkages. Aliphatic linkages are usually
C.sub.1-6 aliphatic linkages, examples including C.sub.1-6 alkylene
linkages. Carbocyclylene is usually C.sub.3-7 carbocyclylene,
including cycloalkylene (e.g. C.sub.3-6 cycloalkylene, especially
cyclopropylene). In the case of carbocyclylene-containing linkages,
at least one (usually 1, 2, 3 or 4, especially 1 or 2 but in other
cases 3 or 4) of the in-ring atoms forms or is included in the
linkage. A hydrocarbylene linkage is often aliphatic, in particular
C.sub.1-6 alkylene. In one class of compounds, X comprises a
hydrocarbylene linkage which is directly bonded to W. In another
class of compounds, X comprises an arylene (e.g. phenylene) linkage
which is optionally substituted with 1, 2, 3, 4 or 5 R.sup.11. In
certain compounds, said arylene linkage is directly bonded in W. Of
particular mention are compounds comprising a phenylene linkage
optionally substituted with 1, 2, 3, 4 or 5 R.sup.11, wherein said
phenylene linkage is directly bonded to W.
[0071] X may comprise at least one linkage selected from
--N(R.sup.9), and aliphatic or cyclic hydrocarbylene (e.g.
C.sub.1-6 alkylene or cycloalkylene), either of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11. In particular, X may
comprise at least one linker selected from --N(R.sup.9)-- and
C.sub.1-6 alkylene (e.g. C.sub.1, C.sub.2 or C.sub.3 alkylene)
optionally substituted with 1, 2, 3, 4 or 5 R.sup.11. When X
comprises --N(R.sup.9), R.sup.9 is usually hydrogen or selected
from C.sub.1-6 alkyl (e.g. C.sub.1, C.sub.2, C.sub.3 or C.sub.4
alkyl), --(CH.sub.2).sub.k-carbocyclyl and
--(CH.sub.2).sub.k-heterocyclyl, any of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11.
[0072] Of mention are compounds in which X is a linker having 1 to
12 (e.g. 1 to 6) in-chain atoms and comprising one or more linkages
selected from --O--, --C(O)--, --S(O).sub.r, --N(R.sup.9) and
C.sub.1-6 aliphatic (e.g. C.sub.1-6 alkylene) optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11;
[0073] In one embodiment, X is selected from one of the following
linkers: [0074] --X.sup.1--; [0075] --X.sup.1--X.sup.2--; [0076]
--X.sup.1--X.sup.2--X.sup.3--, [0077]
--X.sup.1--X.sup.2--X.sup.3--X.sup.4; [0078]
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--; [0079]
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--; [0080]
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--;
and [0081]
--X.sup.1--X.sup.2--X.sup.3--X.sup.4--X.sup.5--X.sup.6--X.sup.7--X-
.sup.8--; wherein X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5,
X.sup.6, X.sup.7 and X.sup.8 are each independently selected from
--O--, --C(O)--, --S(O).sub.l, --N(R.sup.9)-- and hydrocarbylene
(e.g. C.sub.1-6 alkylene) optionally substituted with 1, 2, 3, 4 or
5 R.sup.11. More usually, X is --X.sup.1-- or
--X.sup.1--X.sup.2--.
[0082] Of mention are compounds in which X.sup.1 is hydrocarbylene
(e.g. C.sub.1-6 alkylene, C.sub.2-6 alkenylene or carbocyclylene)
optionally substituted with 1, 2, 3, 4 or 5 R.sup.11. For example,
X.sup.1 may be C.sub.1-6 alkylene optionally substituted with 1, 2,
3, 4 or 5 R.sup.11. In particular, X.sup.1 may be methylene or
ethylene, either of which is optionally substituted with 1, 2, 3 or
4 substituents independently selected from halogen (e.g. fluorine
or chlorine), amino and hydroxy. Alternatively, X.sup.1 may be
arylene, e.g. phenylene, optionally substituted with 1, 2, 3, 4 or
5 R.sup.11.
[0083] Also of mention is a class of compounds in which X.sup.2 is
--N(R.sup.9)--, wherein R.sup.9 is usually hydrogen or selected
from C.sub.1-6 alkyl (e.g. C.sub.1, C.sub.2, C.sub.3 or C.sub.4
alkyl), --(CH.sub.2).sub.k-carbocyclyl and
--(CH.sub.2).sub.k-heterocyclyl, any of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11. In particular,
--N(R.sup.9)-- may be --NH-- or --N(CH.sub.3)--. In compounds where
X.sup.1 is arylene (e.g. phenylene), X.sup.2 is often C.sub.1-6
alkylene (e.g. C.sub.1 or C.sub.2 alkylene) optionally substituted
with 1, 2, 3, 4 or 5 R.sup.11.
[0084] Also included are compounds in which X.sup.1 is C.sub.1-6
alkylene substituted, e.g. at the 1- or 2-position relative to W
(which is typically carbonyl or sulphonyl), by at least one
R.sup.11. In this case, the at least one R.sup.11 is often selected
from halogen, trifluoromethyl, cyano, nitro, oxo, .dbd.NR.sup.13,
--OR.sup.13, --C(O)R.sup.13, --C(O)N(R.sup.13)R.sup.14,
--C(O)OR.sup.13, --OC(O)R.sup.13, --S(O)R.sup.13,
--S(O).sub.lN(R.sup.13)R.sup.14, --N(R.sup.13)R.sup.14,
--N(R.sup.13)N(R.sup.13)R.sup.14, --N(R.sup.13)C(O)R.sup.14,
--N(R.sup.13)S(O).sub.lR.sup.13, hydrocarbyl (which is other than
C.sub.1-6 alkyl, and is often --(CH.sub.2).sub.k-carbocyclyl)
optionally substituted with 1, 2, 3, 4 or 5 R.sup.12; and
--(CH.sub.2).sub.k-heterocyclyl optionally substituted with 1, 2,
3, 4 or 5 R.sup.12. In this case, R.sup.13 and R.sup.14 are often
each independently selected from hydrogen, C.sub.1-4 alkyl,
--(CH.sub.2).sub.k-carbocyclyl (e.g. phenyl, cyclopropyl or benzyl)
and, --(CH.sub.2).sub.k-heterocyclyl. Exemplary R.sup.11 moieties
include carbamate, phenyl, benzyl, --NH--C(O)--(C.sub.1-6 alkyl),
oxo, sulphonamido, urea, thiourea and acyl groups.
[0085] Also included are compounds in which X.sup.1 is an arylene
preferably selected from;
##STR00008##
[0086] In certain compounds, Y is --C(O), --C(O)O--,
--C(O)N(R.sup.9)--, --S(O), --S(O).sub.2-- or
--S(O).sub.lN(R.sup.9)--. In particular, Y is often --C(O)--,
--C(O)O--, --S(O)-- or --S(O).sub.2--.
[0087] In some embodiments, when X is C.sub.1-6 alkylene,
--O--C.sub.1-6 alkylene- or --N(R.sup.9)C.sub.1-6 alkylene-, Y is
--O--, --S-- or --N(R.sup.9)-- and R.sup.7 is hydrogen, said
C.sub.1-6 alkylene linkage of X is substituted with 1, 2, 3, 4 or 5
R.sup.11, wherein at least one of said R.sup.11 is other than
halogen or C.sub.1-6 alkyl. In this case, at least one R.sup.11,
e.g. the or each R.sup.11 is often independently selected from
trifluoromethyl, cyano, nitro, oxo, .dbd.NR.sup.13, --OR.sup.13,
--C(O)R.sup.13, --C(O)N(R.sup.13)R.sup.14, --C(O)OR.sup.13,
--OC(O)R.sup.13, --S(O).sub.lR.sup.13,
--S(O).sub.lN(R.sup.13)R.sup.14, --N(R.sup.13)R.sup.14,
--N(R.sup.13)N(R.sup.13)R.sup.14, --N(R.sup.13)C(O)R.sup.14,
--N(R.sup.13)S(O).sub.lR.sup.13, hydrocarbyl (which is other than
C.sub.1-6 alkyl, and is often --(CH.sub.2).sub.k-carbocyclyl)
optionally substituted with 1, 2, 3, 4 or 5 R.sup.12; and
--(CH.sub.2).sub.k-heterocyclyl optionally substituted with 1, 2,
3, 4 or 5 R.sup.12. In this case, R.sup.13 and R.sup.14 are often
each independently selected from hydrogen, C.sub.1-6 alkyl,
--(CH.sub.2).sub.k-carbocyclyl (e.g. phenyl, cyclopropyl or benzyl)
and, --(CH.sub.2).sub.k-heterocyclyl. Exemplary R.sup.11 moieties
include carbamate, sulphonamido, urea, thiourea and acyl groups.
Carbocyclyl and heterocyclyl may for example be 5, 6 or 7-membered
saturated or unsaturated rings, e.g. phenyl.
[0088] The linker --W--X--Y-- often comprises 3, 4 or 5, especially
4 or 5, in-chain atoms.
[0089] Of particular mention are compounds of the following
Formula:
##STR00009## [0090] wherein X.sup.1 is --N(R.sup.9)-- or
hydrocarbylene (e.g. C.sub.1-6 alkylene) optionally substituted
with 1, 2, 3, 4 or 5 R.sup.11; [0091] or a pharmaceutically
acceptable salt or prodrug thereof.
[0092] With regard to Formula (IV), Y is often --C(O), --C(O)O--,
--C(O)N(R.sup.9)--, --S(O)--, --S(O).sub.2-- or
--S(O).sub.lN(R.sup.9). In particular, Y is often --C(O)--,
--C(O)--, --S(O)-- or --S(O).sub.2--.
[0093] Examples of the linker --W--X.sup.1--Y-- are described in
the table below:
TABLE-US-00001 No. W X.sup.1 Y 1 --C(O)-- --N(R.sup.9)-- --C(O)-- 2
--C(O)-- C.sub.1-6 alkylene --C(O)-- 3 --C(O)-- --N(R.sup.9)--
--S(O).sub.2-- 4 --C(O)-- C.sub.1-6 alkylene --S(O).sub.2-- 5
--S(O).sub.1-- --N(R.sup.9)-- --C(O)-- 6 --S(O).sub.1-- C.sub.1-6
alkylene --C(O)-- 7 --S(O).sub.1-- C.sub.1-6 alkylene
--S(O).sub.2--
[0094] Further examples of the linker --W--X.sup.1--Y-- are
described in the table below:
TABLE-US-00002 No. W X.sup.1 Y 1 --C(O)-- C.sub.1-6 alkylene
--S(O).sub.2-- 2 --S(O).sub.1-- C.sub.1-6 alkylene --C(O)--
[0095] Further examples of the linker --W--X.sup.1--Y-- are
described in the table below:
TABLE-US-00003 No. W X.sup.1 Y 1 --C(O)-- C.sub.1-6 alkylene
--C(O)--N(R.sup.9)-- 2 --C(O)-- --CH.sub.2-- --C(O)--NH-- 3
--C(O)-- ##STR00010## --C(O)-- 4 --C(O)-- ##STR00011## --C(O)-- 5
--C(O)-- ##STR00012## --N(R.sup.9)-- 6 --C(O)-- ##STR00013##
--N(R.sup.9)-- 7 --C(O)-- arylene --C(O)-- 8 --C(O)-- C.sub.1-6
alkylene --C(O)-- 9 --C(O)-- arylene --N(R.sup.9)-- 10 --C(O)--
--CH.sub.2-- --C(O)-- 11 --C(O)-- --CH(CH.sub.3)-- --C(O)-- 12
--C(O)-- --C(CH.sub.3).sub.2-- --C(O)-- 13 --C(O)--
--CH.sub.2CH.sub.2-- --C(O)--
[0096] In one embodiment in the above compounds wherein Y is
--N(R.sup.9)--, R.sup.1 and R.sup.9 taken together form a 5- or
6-membered heterocyclyl optionally substituted by 1, 2, 3, 4 or 5
R.sup.11. The formed 5- or 6-membered heterocyclyl is for instance
1-methyl-imidazolidine-2,4-dione, imidazolidine-2,4-dione,
thiazoldine-2,4-dione, pyrrolidine-2,5-dione, isoindole-1,3-dione,
or pyrrolidinyl-2-oxo.
[0097] Further examples of the linker --W--X.sup.1--Y-- are
described in the table below:
TABLE-US-00004 No. W X.sup.1 Y 1 --C(O)-- --CH.sub.2--
--S(O).sub.2-- 2 --C(O)-- --CH(CH.sub.3)-- --S(O).sub.2-- 3
--C(O)-- --C(CH.sub.3).sub.2-- --S(O).sub.2-- 4 --C(O)--
--CH.sub.2CH.sub.2-- --S(O).sub.2-- 5 --S(O).sub.2-- --CH.sub.2--
--C(O)-- 6 --S(O).sub.2-- --CH(CH.sub.3)-- --C(O)-- 7
--S(O).sub.2-- --C(CH.sub.3).sub.2-- --C(O)-- 8 --S(O).sub.2--
--CH.sub.2CH.sub.2-- --C(O)--
[0098] Further examples of the linker --W--X.sup.1--Y-- are
described in the table below:
TABLE-US-00005 No. W X.sup.1 Y 1 --C(O)-- C.sub.1-6 alkylene
--C(O)-- 2 --S(O).sub.1-- C.sub.1-6 alkylene --S(O).sub.2--
[0099] Further examples of the linker --W--X.sup.1--Y-- are
described in the table below:
TABLE-US-00006 No. W X.sup.1 Y 1 --C(O)-- --CH.sub.2-- --C(O)-- 2
--C(O)-- --CH(CH.sub.3)-- --C(O)-- 3 --C(O)-- --C(CH.sub.3).sub.2--
--C(O)-- 4 --C(O)-- --CH.sub.2CH.sub.2-- --C(O)--
[0100] Also of particular mention are compounds of the above
Formula wherein X.sup.1 is carbocyclylene (e.g. cycloalkylene or
arylene) optionally substituted with 1, 2, 3, 4 or 5 R.sup.11; or a
pharmaceutically acceptable salt or prodrug thereof.
[0101] Further examples of the linker --W--X.sup.1--Y-- are
described in the table below:
TABLE-US-00007 No. W X.sup.1 Y 1 --C(O)-- cycloalkylene
--S(O).sub.2-- 2 --S(O).sub.1-- cycloalkylene --C(O)-- 3 --C(O)--
cycloalkylene --C(O)-- 4 --S(O).sub.1-- cycloalkylene
--S(O).sub.2--
[0102] Further examples of the linker --W--X.sup.1--Y-- are
described in the table below:
TABLE-US-00008 No. W X.sup.1 Y 1 --C(O)-- cyclopropylene
--S(O).sub.2-- 2 --S(O).sub.1-- cyclopropylene --C(O)-- 3 --C(O)--
cyclopropylene --C(O)-- 4 --S(O).sub.1-- cyclopropylene
--S(O).sub.2--
[0103] Further examples of the linker --W--X.sup.1--Y-- are
described in the table below:
TABLE-US-00009 No. W X.sup.1 Y 1 --C(O)-- arylene --S(O).sub.2-- 2
--S(O).sub.1-- arylene --C(O)-- 3 --C(O)-- arylene --C(O)-- 4
--S(O).sub.1-- arylene --S(O).sub.2--
[0104] Further examples of the linker --W--X.sup.1--Y-- are
described in the table below:
TABLE-US-00010 No. W X.sup.1 Y 1 --C(O)-- phenylene --S(O).sub.2--
2 --S(O).sub.1-- phenylene --C(O)-- 3 --C(O)-- phenylene --C(O)-- 4
--S(O).sub.1-- phenylene --S(O).sub.2--
[0105] Also of mention are compounds of the following Formula:
##STR00014## [0106] wherein one of X.sup.1 and X.sup.2 is
--N(R.sup.9)--; and the other is C.sub.1-6 alkylene optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11; [0107] or a
pharmaceutically acceptable salt or prodrug thereof.
[0108] With regard to Formula (V), Y is often --C(O)--, --C(O)O--,
--C(O)N(R.sup.9)--, --S(O)--, --S(O).sub.2-- or
--S(O).sub.lN(R.sup.9). In particular, Y is often --C(O)--,
--C(O)--, --S(O)-- or --S(O).sub.2--
[0109] Examples of the linker --W--X.sup.1--X.sup.2--Y-- are
described in the table below:
TABLE-US-00011 No. W X.sup.1 X.sup.2 Y 1 --C(O)-- C.sub.1-6
alkylene --O-- --C(O)-- 2 --C(O)-- C.sub.1-6 alkylene
--N(R.sup.9)-- --C(O)-- 3 --C(O)-- --O-- C.sub.1-6 alkylene
--C(O)-- 4 --C(O)-- --N(R.sup.9)-- C.sub.1-6 alkylene --C(O)-- 5
--C(O)-- C.sub.1-6 alkylene --N(R.sup.9)-- --S(O).sub.2-- 6
--C(O)-- --O-- C.sub.1-6 alkylene --S(O).sub.2-- 7 --C(O)--
--N(R.sup.9)-- C.sub.1-6 alkylene --S(O).sub.2-- 8 --S(O).sub.1--
C.sub.1-6 alkylene --O-- --C(O)-- 9 --S(O).sub.1-- C.sub.1-6
alkylene --N(R.sup.9)-- --C(O)-- 10 --S(O).sub.1-- --N(R.sup.9)--
C.sub.1-6 alkylene --C(O)-- 11 --S(O).sub.1-- C.sub.1-6 alkylene
--N(R.sup.9)-- --S(O).sub.2-- 12 --S(O).sub.1-- --N(R.sup.9)--
C.sub.1-6 alkylene --S(O).sub.2--
[0110] Examples of the linker --W--X.sup.1--X.sup.2--Y-- are
described in the table below:
TABLE-US-00012 1 --S(O).sub.l-- C.sub.1-6 alkylene --N(R.sup.9)--
--C(O)--O-- 2 --S(O).sub.l-- --CH.sub.2CH.sub.2-- --N(R.sup.9)--
--C(O)--O-- 3 --C(O)-- arylene --N(R.sup.9)-- --C(O)-- 4 --C(O)--
##STR00015## --N(R.sup.9)-- --C(O)-- 5 --C(O)-- ##STR00016##
--N(R.sup.9)-- --C(O)-- 6 --C(O)-- ##STR00017## C.sub.1-6 alkylene
--N(R.sup.9)-- 7 --C(O)-- ##STR00018## --CH.sub.2CH.sub.2--
--N(R.sup.9)--
[0111] Further examples of the linker --W--X.sup.1--X.sup.2--Y--
are described in the table below:
TABLE-US-00013 No. W X.sup.1 X.sup.2 Y 1 --C(O)-- C.sub.1-6
alkylene --N(R.sup.9)-- --C(O)-- 2 --C(O)-- C.sub.1-6 alkylene
--N(R.sup.9)-- --S(O).sub.2-- 3 --S(O).sub.2-- C.sub.1-6 alkylene
--N(R.sup.9)-- --C(O)-- 4 --S(O).sub.2-- C.sub.1-6 alkylene
--N(R.sup.9)-- --S(O).sub.2--
[0112] Further examples of the linker --W--X.sup.1--X.sup.2--Y--
are described in the table below:
TABLE-US-00014 No. W X.sup.1 X.sup.2 Y 1 --C(O)-- --CH.sub.2--
--N(R.sup.9)-- --C(O)-- 2 --C(O)-- --CH.sub.2-- --N(R.sup.9)--
--S(O).sub.2-- 3 --C(O)-- --CH(CH.sub.3)-- --N(R.sup.9)-- --C(O)--
4 --C(O)-- --CH(CH.sub.3)-- --N(R.sup.9)-- --S(O).sub.2-- 5
--C(O)-- --C(CH.sub.3).sub.2-- --N(R.sup.9)-- --C(O)-- 6 --C(O)--
--C(CH.sub.3).sub.2-- --N(R.sup.9)-- --S(O).sub.2-- 7 --C(O)--
--CH.sub.2CH.sub.2-- --N(R.sup.9)-- --C(O)-- 8 --C(O)--
--CH.sub.2CH.sub.2-- --N(R.sup.9)-- --S(O).sub.2-- 9 --S(O).sub.2--
--CH.sub.2-- --N(R.sup.9)-- --C(O)-- 10 --S(O).sub.2-- --CH.sub.2--
--N(R.sup.9)-- --S(O).sub.2-- 11 --S(O).sub.2-- --CH(CH.sub.3)--
--N(R.sup.9)-- --C(O)-- 12 --S(O).sub.2-- --CH(CH.sub.3)--
--N(R.sup.9)-- --S(O).sub.2-- 13 --S(O).sub.2--
--C(CH.sub.3).sub.2-- --N(R.sup.9)-- --C(O)-- 14 --S(O).sub.2--
--C(CH.sub.3).sub.2-- --N(R.sup.9)-- --S(O).sub.2-- 15
--S(O).sub.2-- --CH.sub.2CH.sub.2-- --N(R.sup.9)-- --C(O)-- 16
--S(O).sub.2-- --CH.sub.2CH.sub.2-- --N(R.sup.9)--
--S(O).sub.2--
[0113] A further example of the linker --W--X.sup.1--X.sup.2--Y--
is described in the table below:
TABLE-US-00015 No. W X.sup.1 X.sup.2 Y 1 --C(O)-- --CH(CH.sub.3)--
--NH-- --C(O)--
[0114] In each of the various tables above, R.sup.9 is usually
hydrogen or selected from C.sub.1-6 alkyl (e.g. C.sub.1, C.sub.2,
C.sub.3 or C.sub.4 alkyl), --(CH.sub.2).sub.k-carbocyclyl and
--(CH.sub.2).sub.k-heterocyclyl, any of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11. In particular,
--N(R.sup.9)-- may be --NH-- or --N(CH.sub.3)--.
[0115] Where C.sub.1-6 alkylene (e.g. --CH.sub.2--,
--CH(CH.sub.3)--, --C(CH.sub.3).sub.2-- or --CH.sub.2CH.sub.2--),
cycloalkylene (e.g. cyclopropylene) or arylene (e.g. phenylene) are
mentioned in the various tables, they may be substituted with 1, 2,
3, 4 or 5 R.sup.11, more usually being unsubstituted or substituted
by 1 or 2 substituents selected from hydroxy, amino, halogen (e.g.
fluorine or chlorine), C.sub.1-4 alkyl (e.g. C.sub.1, C.sub.2,
C.sub.3 or C.sub.4 alkyl) optionally substituted with 1, 2, 3, 4 or
5 R.sup.12, and arylene (e.g. phenylene) optionally substituted
with 1, 2, 3, 4 or 5 R.sup.12, where R.sup.12 is, for example,
--C(O)NH.sub.2. Also, where C.sub.1-6 alkylene is mentioned, it may
be exchanged for C.sub.3-6 carbocyclylene (e.g. cyclopropylene).
Where cyclopropylene is mentioned, it may be regarded as having 1
or 2 in-chain atoms, typically 1 in-chain atom.
R.sup.1
[0116] R.sup.1 is selected from hydrogen; --N(R.sup.9)(R.sup.10);
hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.11;
hydrocarbyloxy optionally substituted with 1, 2, 3, 4 or 5
R.sup.11; and --(CH.sub.2).sub.k-heterocyclyl optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11. Alternatively, when Y is
--N(R.sup.9)--, R.sup.1 and R.sup.9 taken together with the
nitrogen atom to which they are attached form a heterocycle,
wherein said heterocycle is bound to X via said nitrogen atom and
is optionally substituted with 1, 2, 3, 4 or 5 R.sup.11.
[0117] In one embodiment of the invention, R.sup.1 is
--N(R.sup.9)(R.sup.10). In this case, R.sup.9 and R.sup.10 are
usually each independently hydrogen or selected from C.sub.1-4
alkyl (e.g. C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl),
--(CH.sub.2).sub.k-carbocyclyl (e.g. --(CH.sub.2).sub.k-cycloalkyl
or --(CH.sub.2)-aryl) and (CH.sub.2-heterocyclyl, any of which is
optionally substituted with 1, 2, 3, 4 or 5 R.sup.11. For example,
R.sup.9 and R.sup.10 may be each independently hydrogen or
C.sub.1-4 alkyl (e.g methyl or ethyl) optionally substituted with
1, 2, 3, 4 or 5 R.sup.11. Of mention are compounds in which at
least one of R.sup.9 and R.sup.10 is C.sub.1-6 alkyl group
substituted with C.sub.1-4 alkoxy. In particular,
--N(R.sup.9)(R.sup.10) may be amino, methylamino, dimethylamino or
(methoxymethyl)methylamino.
[0118] In another embodiment of the invention, R.sup.1 is
hydrocarbyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.11.
In this case, R.sup.1 is often selected from C.sub.1-6 alkyl (e.g.
C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl) or
--(CH.sub.2).sub.k-carbocyclyl (e.g. --(CH.sub.2).sub.k-cycloalkyl
or --(CH.sub.2).sub.k-aryl), either of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11. In particular, R.sup.1
may be C.sub.1-6 alkyl (e.g. C.sub.1, C.sub.2, C.sub.3 or C.sub.4
alkyl), --(CH.sub.2).sub.k-cycloalkyl (e.g. cyclopropyl, cyclobutyl
or cyclopropylmethyl) or --(CH.sub.2).sub.k-aryl (e.g. phenyl or
benzyl), any of which is optionally substituted with 1, 2, 3, 4 or
5 R.sup.11. Of particular mention are methyl; methoxymethyl;
cyclopropyl optionally substituted with 1 or 2 R.sup.11; and phenyl
optionally substituted with 1, 2, 3, 4 or 5 R.sup.11.
[0119] In another embodiment of the invention, R.sup.1 is
hydrocarbyloxy optionally substituted with 1, 2, 3, 4 or 5
R.sup.11. In this case, R.sup.1 is often selected from C.sub.1-6
alkyl (e.g. C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl) or
--O--(CH.sub.2).sub.k-carbocyclyl (e.g.
--O--(CH.sub.2).sub.k-cycloalkyl or --O--(CH.sub.2).sub.k-aryl),
either of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.11. In particular, R.sup.1 may be C.sub.1-6 alkyl (e.g.
C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyloxy),
--O--(CH.sub.2).sub.k-cycloalkyl (e.g. cyclopropyloxy,
cyclobutyloxy or cyclopropylmethyloxy) or
--O--(CH.sub.2).sub.k-aryl (e.g. --O-phenyl or --O-benzyl), any of
which is optionally substituted with 1, 2, 3, 4 or 5 R.sup.11. Of
particular mention are methyl; methoxymethyl; cyclopropyl
optionally substituted with 1 or 2 R.sup.11; and phenyl optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11.
[0120] In a further embodiment, R.sup.1 is
--(CH.sub.2).sub.k-heterocyclyl optionally substituted with 1, 2,
3, 4 or 5 R.sup.11. Typically, k is 0, 1 or 2, more usually 0. The
heterocyclyl group may be heterocycloalkyl or heteroaryl, either of
which is optionally substituted with 1, 2, 3, 4 or 5 R.sup.11.
Exemplary heterocyclyl groups include oxiranyl, azirinyl,
1,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl,
pyranyl, imidazolyl, thiopyranyl, thianthrenyl, isobenzofuranyl,
benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl,
pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl,
pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl,
dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl,
piridinyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl,
thiomorpholinyl, especially thiomorpholino, indolizinyl,
isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, cumaryl,
indazolyl, triazolyl, tetrazolyl, purinyl, 4H-quinolizinyl,
isoquinolyl, quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl,
3,4-dihydro-2H-isoquinolin-1-one, 3,4-dihydro-2H-isoquinolinyl,
tetrehydropyranyl, 1,3-dihydro-isoindolyl,
1,3-Dioxo-1,3-dihydro-isoindolyl, 3,4-dihydro-2H-isoquinolinyl,
3,4-dihydro-2H-isoquinolinyl-1-one, decahydroquinolyl,
octahydroisoquinolyl, benzofuranyl, dibenzofuranyl,
benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl,
quinoxalyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl,
carbazolyl, .beta.-carbolinyl, phenanthridinyl, acridinyl,
perimidinyl, phenanthrolinyl, furazanyl, phenazinyl,
phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl and
chromanyl, any of which is optionally substituted with 1, 2, 3, 4
or 5 R.sup.11. Of particular mention are imidazolyl, oxazolyl,
morpholinyl, 1,4-benzodioxanyl, pyrimidyl, and pyrazinyl, any of
which is optionally substituted with 1, 2, 3, 4 or 5 R.sup.11. Also
of mention are 1,3-dioxo-isoindolyl, 2-oxo-pyrrolidinyl and
2,4-dioxo-thiazolidin-3-yl, any of which is optionally substituted
with 1, 2 or 3 R.sup.11.
[0121] In compounds in which Y is --C(O)--, R.sup.1 is often
C.sub.1-6 alkyl (e.g. C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl),
cycloalkyl (e.g. cyclopropyl), aryl (e.g. phenyl) or heterocyclyl
(e.g. imidazolyl, oxazolyl, morpholinyl, 1,4-benzodioxanyl or
pyrazinyl), any of which is optionally substituted with 1, 2, 3, 4
or 5 R.sup.11.
[0122] In compounds in which Y is --S(O).sub.2-- or
--S(O)N(R.sup.9)--, R.sup.1 is often hydrogen, C.sub.1-6 alkyl,
cycloalkyl (e.g. cyclopropyl or cyclopropylmethyl), aryl (e.g.
phenyl) or heterocyclyl (e.g. imidazolyl, oxazolyl, morpholinyl,
1,4-benzodioxanyl or pyrazinyl), any of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11. Alternatively, R.sup.1
may often be --N(R.sup.9)(R.sup.10), e.g. amino, C.sub.1-6
alkylamino or di(C.sub.1-6 alkyl)amino.
[0123] Of particular mention are compounds in which R.sup.1 is
morpholin-4-yl or cyclopropyl, either of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11.
[0124] In another embodiment, Y is --N(R.sup.9)--, and
--N(R.sup.9)R.sup.1 taken together form a nitrogen-containing
heterocycle optionally substituted with 1, 2, 3, 4 or 5 R.sup.11.
The heterocyclyl group may be heterocycloalkyl or heteroaryl,
either of which is optionally substituted with 1, 2, 3, 4 or 5
R.sup.11. Exemplary nitrogen-containing heterocyclyl groups include
azirinyl, imidazolyl, pyranyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl,
pyrrolidinyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl,
pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl,
isoxazolyl, pyridyl, pyrimidinyl, piperidyl, piperazinyl,
pyridazinyl, morpholinyl, thiomorpholinyl, piridinyl, indolizinyl,
isoindolyl, 3H-indolyl, indolyl, indazolyl, triazolyl, tetrazolyl,
purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,
tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl,
octahydroisoquinolyl, phthalazinyl, naphthyridinyl, quinoxalyl,
quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl,
.beta.-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,
phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl,
phenoxazinyl, 2,3-Dihydro-benzo[1,4]dioxine, Dihydro-benzodioxine,
tetrahydropyranyl, tetrahydrofuranyl,
1,3-Dioxo-1,3-dihydro-isoindolyl any of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11. Of mention are indolyl,
isoindolyl, pyrrolidinyl and thiazolidin-3-yl, any of which is
optionally substituted with 1, 2, 3, 4 or 5 R.sup.11. Of particular
mention are 1,3-dioxo-isoindolyl, 2-oxo-pyrrolidinyl and
2,4-dioxo-thiazolidin-3-yl, any of which is optionally substituted
with 1, 2 or 3 R.sup.11.
[0125] Where R.sup.1 is substituted with R.sup.11, the or each
R.sup.11 is often independently selected from halogen (e.g.
fluorine, chlorine or bromine), hydroxy, cyano, amino, --C(O)OH,
C.sub.1-6 alkyl, C.sub.1-6 alkoxy (e.g. C.sub.1, C.sub.2, C.sub.3
or C.sub.4 alkoxy), --C(O)--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6
alkyl, --S(O).sub.l--C.sub.1-6 alkyl, --NH(C.sub.1-6 alkyl), and
--N(C.sub.1-6 alkyl).sub.2, wherein any C.sub.1-6 alkyl group
present is optionally substituted with 1, 2, 3, 4 or 5 substituents
independently selected from halogen, cyano, amino, hydroxy and
C.sub.1-6 alkoxy.
[0126] Where R.sup.1 is substituted with R.sup.11, the or each
R.sup.11 is often independently selected from halogen (e.g.
fluorine, chlorine or bromine), hydroxy, cyano, amino, oxo,
--C(O)OH, --C(O)--NH.sub.2, --C(O)--NH--C.sub.1-6 alkyl, C.sub.1-6
alkyl, C.sub.1-6 alkoxy (e.g. C.sub.1, C.sub.2, C.sub.3 or C.sub.4
alkoxy), --O-aryl (e.g. --O-phenyl), --(CH.sub.2).sub.k-phenyl,
--(CH.sub.2).sub.k-heterocycyl, --(CH.sub.2).sub.k-cycloalkyl,
--C(O)-heterocycyl, --C(O)--C.sub.1-6 alkyl, --C(O)O--C.sub.1-6
alkyl, --S(O).sub.l--C.sub.1-6 alkyl, --NH(C.sub.1-6 alkyl),
--NH--C(O)--(C.sub.1-6 alkyl), 6- or 5-membered cycloaryl, a spiro
group (e.g. via a cyclopropyl) and --N(C.sub.1-6 alkyl).sub.2,
wherein any C.sub.1-6 alkyl group present is optionally substituted
with 1, 2, 3, 4 or 5 substituents independently selected from
halogen, cyano, amino, hydroxy and C.sub.1-6 alkoxy.
R.sup.2& R.sup.3
[0127] R.sup.2 and R.sup.3 are each independently selected from
R.sup.8, --OR.sup.8, --C(O)R.sup.8, --C(O)OR.sup.8 and
--S(O).sub.lR.sup.9.
[0128] In one embodiment of the invention, R.sup.2 and R.sup.3 are
each independently hydrogen; hydroxy; or selected from C.sub.1-6
alkyl, 6 alkoxy, --(CH.sub.2)-cycloalkyl,
--(CH.sub.2).sub.k-heterocycloalkyl, --(CH.sub.2).sub.k-aryl and
--(CH.sub.2).sub.k-heteroaryl, any of which is optionally
substituted with 1, 2, 3, 4, 5 or 6 R.sup.11.
[0129] In another embodiment, R.sup.2 is hydrogen; and R.sup.3 is
hydrogen, hydroxy, C.sub.1-4 alkyl, C.sub.1-6 alkoxy,
--(CH.sub.2).sub.k-cycloalkyl or --(CH.sub.2).sub.k-aryl, any of
which alkyl, alkoxy, cycloalkyl and aryl groups is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11, wherein the or each
R.sup.11 is, for example, hydroxy, halogen (for example, chlorine
or fluorine); C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl, for
example methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or
tert-butyl, any of which is optionally substituted with 1, 2, 3 or
4 halogen (e.g. fluorine or chlorine) atoms, an example being
trifluoromethyl; C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkoxy, for
example methoxy, ethoxy, propoxy, isopropoxy, butoxy or
tert-butoxy, any of which is optionally substituted with 1, 2, 3 or
4 halogen (e.g. fluorine or chlorine) atoms, and in particular
R.sup.3 is hydrogen, methyl, cyclopropylmethyl or benzyl.
[0130] In a further embodiment, R.sup.2 and R.sup.3 are each
hydrogen.
R.sup.4 & R.sup.5
[0131] R.sup.4 and R.sup.5 are each independently selected from
hydrogen, hydroxy, halogen and C.sub.1-6 alkyl optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11.
[0132] In one embodiment, R.sup.4 and R.sup.5 are each
independently hydrogen, hydroxy, halogen (for example, chlorine or
fluorine); or C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl, for
example methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or
tert-butyl, any of which is optionally substituted with 1, 2, 3 or
4 halogen (e.g. fluorine or chlorine) atoms, an example being
trifluoromethyl.
[0133] In another embodiment, R.sup.4 is hydrogen, hydroxy, halogen
(for example, chlorine or fluorine); or C.sub.1, C.sub.2, C.sub.3
or C.sub.4 alkyl, for example methyl, ethyl, propyl, isopropyl,
n-butyl, sec-butyl or tert-butyl, any of which is optionally
substituted with 1, 2, 3 or 4 halogen (e.g. fluorine or chlorine)
atoms, an example being trifluoromethyl; and R.sup.5 is typically
hydrogen.
[0134] In a further embodiment, R.sup.4 is hydrogen, hydroxy,
fluorine, chlorine or C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl;
and R.sup.5 is hydrogen.
[0135] In a further embodiment, R.sup.4 is hydrogen, hydroxy,
fluorine, chlorine or methyl; and R.sup.5 is hydrogen.
[0136] In a further embodiment, R.sup.4 and R.sup.5 are each
hydrogen.
R.sup.6
[0137] R.sup.6 is aryl or heteroaryl, either of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11.
[0138] In one embodiment of the invention, R.sup.6 is aryl, in
particular phenyl or naphthyl, either of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11. In embodiments, R.sup.6
is phenyl optionally substituted with 1, 2, 3, 4 or 5 R.sup.11,
wherein the or each R.sup.11 is, for example, hydroxy, halogen (for
example, chlorine or fluorine); C.sub.1, C.sub.2, C.sub.3 or
C.sub.4 alkyl, for example methyl, ethyl, propyl, isopropyl,
n-butyl, sec-butyl or tert-butyl, any of which is optionally
substituted with 1, 2, 3 or 4 halogen (e.g. fluorine or chlorine)
atoms, an example being trifluoromethyl; or C.sub.1, C.sub.2,
C.sub.3 or C.sub.4 alkoxy, for example methoxy, ethoxy, propoxy,
isopropoxy, butoxy, tert-butoxy, any of which is optionally
substituted with 1, 2, 3 or 4 halogen (e.g. fluorine or chlorine)
atoms. For example, R.sup.6 may be phenyl optionally substituted
with 1, 2, 3, 4 or 5 halogen (e.g. fluorine) atoms.
[0139] In a further embodiment, R.sup.6 is a group selected
from:
##STR00019##
[0140] In a further embodiment, R.sup.6 is
2,4,5-trifluorophenyl.
[0141] In another embodiment, R.sup.6 is heteroaryl (often
monocyclic), for example, thienyl or benzothiophenyl, and is
optionally substituted with 1, 2, 3, 4 or 5 R.sup.11, wherein the
or each R.sup.11 is, for example, hydroxy, halogen (for example,
chlorine or fluorine); C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl,
for example methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or
tert-butyl, any of which is optionally substituted with 1, 2, 3 or
4 halogen (e.g. fluorine or chlorine) atoms, an example being
trifluoromethyl; or C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkoxy,
for example methoxy, ethoxy, propoxy, isopropoxy, butoxy,
tert-butoxy, any of which is optionally substituted with 1, 2, 3 or
4 halogen (e.g. fluorine or chlorine) atoms.
R.sup.11
[0142] Each R.sup.11 is independently selected from R.sup.12;
hydrocarbyl (e.g. C.sub.1-6 alkyl or --(CH.sub.2).sub.k-aryl)
optionally substituted with 1, 2, 3, 4 or 5 R.sup.12; and
--(CH.sub.2).sub.k-heterocyclyl optionally substituted with 1, 2,
3, 4 or 5 R.sup.12; wherein R.sup.12 is independently selected from
halogen, trifluoromethyl, cyano, nitro, oxo, .dbd.NR.sup.13,
--OR.sup.13, --C(O)R.sup.13, --C(O)N(R.sup.13)R.sup.14,
--C(O)OR.sup.13, --OC(O)R.sup.13, --S(O).sub.lR.sup.13,
--S(O).sub.lN(R.sup.13)R.sup.14--N(R.sup.13)R.sup.4,
--N(R.sup.13)N(R.sup.13)R.sup.14, --N(R.sup.13)C(O)R.sup.14 and
--N(R.sup.13)S(O).sub.lR.sup.13; and R.sup.13 and R.sup.14 are each
independently hydrogen or selected from hydrocarbyl (e.g. C.sub.1-6
alkyl or --(CH.sub.2).sub.k-aryl, or --(CH.sub.2).sub.k-cycloalkyl)
and --(CH.sub.2).sub.k-heterocyclyl, either of which is optionally
substituted with 1, 2, 3, 4 or 5 substituents independently
selected from halogen, cyano, amino, hydroxy, C.sub.1-6 alkyl and
C.sub.1-6 alkoxy, or selected from oxo, halogen, cyano, amino,
hydroxy, C.sub.1-6 alkyl and C.sub.1-6 alkoxy.
[0143] Typically, each R.sup.11 is independently selected from
halogen (e.g. fluorine, chlorine or bromine), hydroxy, cyano,
amino, --C(O)OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy (e.g. C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkoxy), --C(O)--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-- alkyl, --S(O).sub.l--C.sub.1-6alkyl-NH(C.sub.1-6
alkyl) and --N(C.sub.1-6 alkyl).sub.2, wherein any C.sub.1-6 alkyl
group present is optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from halogen, cyano, amino,
hydroxy and C.sub.1-6 alkoxy.
[0144] Typically, each R.sup.11 is independently selected from
halogen (e.g. fluorine, chlorine or bromine), hydroxy, cyano,
amino, --C(O)OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxy (e.g. C.sub.1,
C.sub.2, C.sub.3 or C.sub.4 alkoxy), --C(O)--C.sub.1-6 alkyl,
--C(O)O--C.sub.1-6 alkyl, --S(O).sub.l--C.sub.1-6 alkyl,
--(CH.sub.2).sub.k-cycloalkyl, --(CH.sub.2).sub.k-aryl,
--(CH.sub.2).sub.k-heterocyclyl, --NH--(CH.sub.2).sub.k-aryl,
--NH--(CH.sub.2).sub.k-cycloalkyl,
--NH--C(O)--(CH.sub.2).sub.k-aryl,
--NH--C(O)--(CH.sub.2).sub.k-cycloalkyl, --N(C.sub.1-6
alkyl)-(CH.sub.2).sub.k-aryl, --N(C.sub.1-6
alkyl)(CH.sub.2).sub.k-cycloalkyl, --NH(C.sub.1-6 alkyl) and
--N(C.sub.1-6 alkyl).sub.2, wherein any C.sub.1-6 alkyl group or
aryryl or present is optionally substituted with 1, 2, 3, 4 or 5
substituents independently selected from halogen, cyano, amino,
hydroxy and C.sub.1-6 alkoxy.
[0145] For the avoidance of doubt, where a group is substituted
with more than one R.sup.11, each R.sup.11 is independently
selected from the range of substituents specified. The same applies
to compounds of the invention comprising more than one R.sup.11
substituent; each R.sup.11 is selected independently of any other
R.sup.11 substituent present in the compound. As previously
indicated, where R.sup.11 is halo, particularly fluoro, any number
of hydrogens may in principle be replaced.
[0146] A particular embodiment of the invention is a compound of
the following Formula:
##STR00020## [0147] or a pharmaceutically acceptable salt or
prodrug thereof.
[0148] The invention therefore includes compounds of the following
Formulae:
##STR00021## [0149] or, in each case, a pharmaceutically acceptable
salt or prodrug thereof.
[0150] Another embodiment of the invention is a compound of the
following Formula:
##STR00022## [0151] wherein X.sup.1 is selected from --O--,
--C(O)--, --S(O).sub.l--, --N(R.sup.9)-- and hydrocarbylene (e.g.
C.sub.1-6 alkylene) optionally substituted with 1, 2, 3, 4 or 5
R.sup.11; [0152] or a pharmaceutically acceptable salt or prodrug
thereof.
[0153] The invention therefore includes compounds of the following
Formulae:
##STR00023## [0154] or, in each case, a pharmaceutically acceptable
salt or prodrug thereof.
[0155] A further embodiment of the invention is a compound of the
following Formula:
##STR00024## [0156] wherein p is 0, 1, 2, 3, 4 or 5 or p is 0, 1, 2
or 3; [0157] or a pharmaceutically acceptable salt or prodrug
thereof.
[0158] The invention therefore includes compounds of the following
Formulae:
##STR00025## [0159] or, in each case, a pharmaceutically acceptable
salt or prodrug thereof.
[0160] With regard to Formulae (IX) to (XIV) and (XIVb), X.sup.1
may be defined as in Formula (IV), i.e. X.sup.1 is --N(R.sup.9)--
or hydrocarbylene (e.g. C.sub.1-6 alkylene) optionally substituted
with 1, 2, 3, 4 or 5 R.sup.11. Y is often --C(O), --C(O)O--,
--C(O)N(R.sup.9)--, --S(O)--, --S(O).sub.2-- or
--S(O).sub.lN(R.sup.9). In particular, Y is often --C(O)--,
--C(O)--, --S(O)-- or --S(O).sub.2--.
[0161] Of particular mention are compounds of any of Formulae (IX)
to (XIV) and (XIVb) in which --W--X.sup.1--Y-- is one of the
following linkers:
TABLE-US-00016 No. W X.sup.1 Y 1 --C(O)-- --N(R.sup.9)-- --C(O)-- 2
--C(O)-- C.sub.1-6 alkylene --C(O)-- 3 --C(O)-- --N(R.sup.9)--
--S(O).sub.2-- 4 --C(O)-- C.sub.1-6 alkylene --S(O).sub.2-- 5
--S(O).sub.1-- --N(R.sup.9)-- --C(O)-- 6 --S(O).sub.1-- C.sub.1-6
alkylene --C(O)-- 7 --S(O).sub.1-- C.sub.1-6 alkylene
--S(O).sub.2--
[0162] Also of mention are compounds of any of said Formulae in
which --W--X.sup.1--Y-- is one of the following linkers:
TABLE-US-00017 No. W X.sup.1 Y 1 --C(O)-- C.sub.1-6 alkylene
--S(O).sub.2-- 2 --S(O).sub.1-- C.sub.1-6 alkylene --C(O)--
[0163] Also of mention are compounds of any of said Formulae in
which --W--X.sup.1--Y-- is one of the following linkers:
TABLE-US-00018 No. W X.sup.1 Y 1 --C(O)-- C.sub.1-6 alkylene
--C(O)--N(R.sup.9)-- 2 --C(O)-- --CH.sub.2-- --C(O)--NH-- 3
--C(O)-- ##STR00026## --C(O)-- 4 --C(O)-- ##STR00027## --C(O)-- 5
--C(O)-- ##STR00028## --N(R.sup.9)-- 6 --C(O)-- ##STR00029##
--N(R.sup.9)-- 7 --C(O)-- arylene --C(O)-- 8 --C(O)-- C.sub.1-6
alkylene --C(O)-- 9 --C(O)-- arylene --N(R.sup.9)-- 10 --C(O)--
--CH.sub.2-- --C(O)-- 11 --C(O)-- --CH(CH.sub.3)-- --C(O)-- 12
--C(O)-- --C(CH.sub.3).sub.2-- --C(O)-- 13 --C(O)--
--CH.sub.2CH.sub.2-- --C(O)--
[0164] In one embodiment in the above compounds wherein Y is
--N(R.sup.9)--, R.sup.1 and R.sup.9 taken together form a 5- or
6-membered heterocyclyl optionally substituted by 1, 2, 3, 4 or 5
R.sup.11. The formed 5- or 6-membered heterocyclyl is for instance
1-methyl-imidazolidine-2,4-dione, imidazolidine-2,4-dione,
thiazoldine-2,4-dione, pyrrolidine-2,5-dione, isoindole-1,3-dione,
or pyrrolidinyl-2-oxo.
[0165] Also of mention are compounds of any of said Formulae in
which --W--X.sup.1--Y-- is one of the following linkers:
TABLE-US-00019 No. W X.sup.1 Y 1 --C(O)-- --CH.sub.2--
--S(O).sub.2-- 2 --C(O)-- --CH(CH.sub.3)-- --S(O).sub.2-- 3
--C(O)-- --C(CH.sub.3).sub.2-- --S(O).sub.2-- 4 --C(O)--
--CH.sub.2CH.sub.2-- --S(O).sub.2-- 5 --S(O).sub.2-- --CH.sub.2--
--C(O)-- 6 --S(O).sub.2-- --CH(CH.sub.3)-- --C(O)-- 7
--S(O).sub.2-- --C(CH.sub.3).sub.2-- --C(O)-- 8 --S(O).sub.2--
--CH.sub.2CH.sub.2-- --C(O)--
[0166] In the case of the table directly above, R.sup.1 is often a
6-membered heterocyclyl which may be unsubstituted or substituted
with 1, 2, 3, 4 or 5 R.sup.11. In the case of the table directly
above, in particular the first row thereof, R.sup.1 is often
morpholinyl (e.g. morpholin-4-yl) which may be unsubstituted or
substituted with 1, 2, 3, 4 or 5 R.sup.11.
[0167] Also of mention are compounds of any of said Formulae in
which --W--X.sup.1--Y-- is one of the following linkers:
TABLE-US-00020 No. W X.sup.1 Y 1 --C(O)-- C.sub.1-6 alkylene
--C(O)-- 2 --S(O).sub.1-- C.sub.1-6 alkylene --S(O).sub.2--
[0168] Also of mention are compounds of any of said Formulae in
which --W--X.sup.1--Y-- is one of the following linkers:
TABLE-US-00021 No. W X.sup.1 Y 1 --C(O)-- --CH.sub.2-- --C(O)-- 2
--C(O)-- --CH(CH.sub.3)-- --C(O)-- 3 --C(O)-- --C(CH.sub.3).sub.2--
--C(O)-- 4 --C(O)-- --CH.sub.2CH.sub.2-- --C(O)--
[0169] Also of particular mention are compounds of the above
Formula wherein X.sup.1 is carbocyclylene (e.g. cycloalkylene or
arylene) optionally substituted with 1, 2, 3, 4 or 5 R.sup.11; or a
pharmaceutically acceptable salt or prodrug thereof.
[0170] Also of mention are compounds of any of said Formulae in
which --W--X.sup.1--Y-- is one of the following linkers:
TABLE-US-00022 No. W X.sup.1 Y 1 --C(O)-- cycloalkylene
--S(O).sub.2-- 2 --S(O).sub.1-- cycloalkylene --C(O)-- 3 --C(O)--
cycloalkylene --C(O)-- 4 --S(O).sub.1-- cycloalkylene
--S(O).sub.2--
[0171] Also of mention are compounds of any of said Formulae in
which --W--X.sup.1--Y-- is one of the following linkers:
TABLE-US-00023 No. W X.sup.1 Y 1 --C(O)-- cyclopropylene
--S(O).sub.2-- 2 --S(O).sub.1-- cyclopropylene --C(O)-- 3 --C(O)--
cyclopropylene --C(O)-- 4 --S(O).sub.1-- cyclopropylene
--S(O).sub.2--
[0172] Also of mention are compounds of any of said Formulae in
which --W--X.sup.1--Y-- is one of the following linkers:
TABLE-US-00024 No. W X.sup.1 Y 1 --C(O)-- arylene --S(O).sub.2-- 2
--S(O).sub.1-- arylene --C(O)-- 3 --C(O)-- arylene --C(O)-- 4
--S(O).sub.1-- arylene --S(O).sub.2--
[0173] Also of mention are compounds of any of said Formulae in
which --W--X.sup.1--Y-- is one of the following linkers:
TABLE-US-00025 No. W X.sup.1 Y 1 --C(O)-- phenylene --S(O).sub.2--
2 --S(O).sub.1-- phenylene --C(O)-- 3 --C(O)-- phenylene --C(O)-- 4
--S(O).sub.1-- phenylene --S(O).sub.2--
[0174] A further embodiment of the invention is a compound of the
following Formula:
##STR00030## [0175] wherein X.sup.1 and X.sup.2 are each
independently selected from --O--, --C(O)--, --S(O).sub.r,
--N(R.sup.9) and C.sub.1-6 alkylene optionally substituted with 1,
2, 3, 4 or 5 R.sup.11; [0176] or a pharmaceutically acceptable salt
or prodrug thereof.
[0177] The invention therefore includes compounds of the following
Formulae:
##STR00031## [0178] or, in each case, a pharmaceutically acceptable
salt or prodrug thereof.
[0179] A further embodiment of the invention is a compound of the
following Formula:
##STR00032## [0180] wherein p is 0, 1, 2, 3, 4 or 5; [0181] or a
pharmaceutically acceptable salt or prodrug thereof.
[0182] The invention therefore includes compounds of the following
Formulae:
##STR00033## [0183] or, in each case, a pharmaceutically acceptable
salt or prodrug thereof.
[0184] With regard to Formulae (XV) to (XX) or (XXb), X.sup.1 and
X.sup.2 may be defined as in Formula (V), i.e. one of X.sup.1 and
X.sup.2 is --N(R.sup.9)--; and the other is C.sub.1-6 alkylene
optionally substituted with 1, 2, 3, 4 or 5 R.sup.11. Y is often
--C(O)--, --C(O)O--, --C(O)N(R.sup.9), --S(O)--, --S(O).sub.2-- or
--S(O).sub.lN(R.sup.9) In particular, Y is often --C(O)--,
--C(O)--, --S(O) or --S(O).sub.2--.
[0185] Of particular mention are compounds of any of Formulae (XV)
to (XX) in which --W--X.sup.1--X.sup.2--Y-- is one of the following
linkers:
TABLE-US-00026 No. W X.sup.1 X.sup.2 Y 1 --C(O)-- C.sub.1-6
alkylene --O-- --C(O)-- 2 --C(O)-- --O-- --N(R.sup.9)-- --C(O)-- 3
--C(O)-- C.sub.1-6 alkylene --N(R.sup.9)-- --C(O)-- 4 --C(O)--
--O-- C.sub.1-6 alkylene --C(O)-- 5 --C(O)-- --N(R.sup.9)--
C.sub.1-6 alkylene --C(O)-- 6 --C(O)-- C.sub.1-6 alkylene
--N(R.sup.9)-- --S(O).sub.2-- 7 --C(O)-- --O-- C.sub.1-6 alkylene
--S(O).sub.2-- 8 --C(O)-- --N(R.sup.9)-- C.sub.1-6 alkylene
--S(O).sub.2-- 9 --S(O).sub.1-- C.sub.1-6 alkylene --O-- --C(O)--
10 --S(O).sub.1-- C.sub.1-6 alkylene --N(R.sup.9)-- --C(O)-- 11
--S(O).sub.1-- --N(R.sup.9)-- C.sub.1-6 alkylene --C(O)-- 12
--S(O).sub.1-- C.sub.1-6 alkylene --N(R.sup.9)-- --S(O).sub.2-- 13
--S(O).sub.1-- --N(R.sup.9)-- C.sub.1-6 alkylene --S(O).sub.2--
[0186] Also of mention are compounds of any of said Formulae in
which --W--X.sup.1--X.sup.2--Y-- is one of the following
linkers:
TABLE-US-00027 1 --S(O).sub.l-- C.sub.1-6 alkylene --N(R.sup.9)--
--C(O)--O-- 2 --S(O).sub.l-- --CH.sub.2CH.sub.2-- --N(R.sup.9)--
--C(O)--O-- 3 --C(O)-- arylene --N(R.sup.9)-- --C(O)-- 4 --C(O)--
##STR00034## --N(R.sup.9)-- --C(O)-- 5 --C(O)-- ##STR00035##
--N(R.sup.9)-- --C(O)-- 6 --C(O)-- ##STR00036## C.sub.1-6 alkylene
--N(R.sup.9)-- 7 --C(O)-- ##STR00037## --CH.sub.2CH.sub.2--
--N(R.sup.9)--
[0187] Also of mention are compounds of any of said Formulae in
which --W--X.sup.1--X.sup.2--Y-- is one of the following
linkers:
TABLE-US-00028 No. W X.sup.1 X.sup.2 Y 1 --C(O)-- C.sub.1-6
alkylene --N(R.sup.9)-- --C(O)-- 2 --C(O)-- C.sub.1-6 alkylene
--N(R.sup.9)-- --S(O).sub.2-- 3 --S(O).sub.2-- C.sub.1-6 alkylene
--N(R.sup.9)-- --C(O)-- 4 --S(O).sub.2-- C.sub.1-6 alkylene
--N(R.sup.9)-- --S(O).sub.2--
[0188] Also of mention are compounds of any of said Formulae in
which --W--X.sup.1--X.sup.2--Y-- is one of the following
linkers:
TABLE-US-00029 No. W X.sup.1 X.sup.2 Y 1 --C(O)-- --CH.sub.2--
--N(R.sup.9)-- --C(O)-- 2 --C(O)-- --CH.sub.2-- --N(R.sup.9)--
--S(O).sub.2-- 3 --C(O)-- --CH(CH.sub.3)-- --N(R.sup.9)-- --C(O)--
4 --C(O)-- --CH(CH.sub.3)-- --N(R.sup.9)-- --S(O).sub.2-- 5
--C(O)-- --C(CH.sub.3).sub.2-- --N(R.sup.9)-- --C(O)-- 6 --C(O)--
--C(CH.sub.3).sub.2-- --N(R.sup.9)-- --S(O).sub.2-- 7 --C(O)--
--CH.sub.2CH.sub.2-- --N(R.sup.9)-- --C(O)-- 8 --C(O)--
--CH.sub.2CH.sub.2-- --N(R.sup.9)-- --S(O).sub.2-- 9 --S(O).sub.2--
--CH.sub.2-- --N(R.sup.9)-- --C(O)-- 10 --S(O).sub.2-- --CH.sub.2--
--N(R.sup.9)-- --S(O).sub.2-- 11 --S(O).sub.2-- --CH(CH.sub.3)--
--N(R.sup.9)-- --C(O)-- 12 --S(O).sub.2-- --CH(CH.sub.3)--
--N(R.sup.9)-- --S(O).sub.2-- 13 --S(O).sub.2--
--C(CH.sub.3).sub.2-- --N(R.sup.9)-- --C(O)-- 14 --S(O).sub.2--
--C(CH.sub.3).sub.2-- --N(R.sup.9)-- --S(O).sub.2-- 15
--S(O).sub.2-- --CH.sub.2CH.sub.2-- --N(R.sup.9)-- --C(O)-- 16
--S(O).sub.2-- --CH.sub.2CH.sub.2-- --N(R.sup.9)--
--S(O).sub.2--
[0189] A further example of the linker --W--X'--X.sup.2--Y-- is
described in the table below:
TABLE-US-00030 No. W X.sup.1 X.sup.2 Y 1 --C(O)-- --CH(CH.sub.3)--
--NH-- --C(O)--
[0190] In the case of the linker described in the table directly
above, R.sup.1 is especially cycloalkyl (e.g. cyclopropyl) and may
be unsubstituted or substituted with 1, 2, 3, 4 or 5 R.sup.11.
[0191] In each of the various tables above, R.sup.9 is usually
hydrogen or selected from Con alkyl (e.g. C.sub.1, C.sub.2, C.sub.3
or C.sub.4 alkyl), --(CH.sub.2)carbocyclyl and
--(CH.sub.2).sub.k-heterocyclyl, any of which is optionally
substituted with 1, 2, 3, 4 or 5 R.sup.11. In particular,
--N(R.sup.9)-- may be --NH-- or --N(CH.sub.3)--.
[0192] Where C.sub.1-6 alkylene (e.g. --CH.sub.2--,
--CH(CH.sub.3)--, --C(CH.sub.3).sub.2-- or --CH.sub.2CH.sub.2--),
cycloalkylene (e.g. cyclopropylene) or arylene (e.g. phenylene) are
mentioned in the various tables, they may be substituted with 1, 2,
3, 4 or 5 R.sup.11, more usually being unsubstituted or substituted
by 1 or 2 substituents selected from hydroxy, amino, halogen (e.g.
fluorine or chlorine), C.sub.1-6 alkyl (e.g. C.sub.1, C.sub.2,
C.sub.3 or C.sub.4 alkyl) optionally substituted with 1, 2, 3, 4 or
5 R.sup.12, and arylene (e.g. phenylene) optionally substituted
with 1, 2, 3, 4 or 5 R.sup.2, where R.sup.12 is, for example,
--C(O)NH.sub.2. Also, where C.sub.1-6 alkylene is mentioned, it may
be exchanged for C.sub.3-6 carbocyclylene (e.g. cyclopropylene).
Where cyclopropylene is mentioned, it may be regarded as having 1
or 2 in-chain atoms, typically 1 in-chain atom.
[0193] In one embodiment are the hereinabove described compounds
wherein X.sup.1 or X.sup.2 is an alkylene or arylene and wherein
X.sup.1 or X.sup.2 are is substituted by 1, 2, 3, 4 or 5 R.sup.11,
preferably 1 or 2 R.sup.11. Preferably the R.sup.11 substituents
are independently selected from a spiro group, C.sub.1-6 alky,
--O--C.sub.1-6 alky, --NH--C(O)--(C.sub.1-6 alky), phenyl, benzyl,
hydroxy, halogen, amino, wherein the alkyl group is optionally
substituted by amino, hydroxy, --C(O)N(C.sub.1-6 alky)(C.sub.1-4
alky), --C(O)--NH(C.sub.1-6 alky), --C(O)NH.sub.2, (C.sub.1-6
alky), or halogen.
[0194] In one embodiment in the above compounds wherein Y is
--N(R.sup.9)--, R.sup.1 and R.sup.9 taken together form a 5- or
6-membered heterocyclyl optionally substituted by 1, 2, 3, 4 or 5
R.sup.11. The formed 5- or 6-membered heterocyclyl is for instance
1-methyl-imidazolidine-2,4-dione, imidazolidine-2,4-dione,
thiazoldine-2,4-dione, pyrrolidine-2,5-dione or
pyrrolidinyl-2-oxo.
[0195] Examples of compounds of the invention include those shown
below. It will of course be appreciated that, where appropriate,
each compound may be in the form of the free compound, an acid or
base addition salt, or a prodrug. Where a nitrogen atom forming
only two bonds is shown, this generally represents NH.
##STR00038## ##STR00039## ##STR00040## ##STR00041## ##STR00042##
##STR00043## ##STR00044## ##STR00045## ##STR00046## ##STR00047##
##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052##
##STR00053## ##STR00054## ##STR00055## ##STR00056## ##STR00057##
##STR00058## ##STR00059## ##STR00060## ##STR00061## ##STR00062##
##STR00063## ##STR00064## ##STR00065## ##STR00066## ##STR00067##
##STR00068## ##STR00069## ##STR00070## ##STR00071## ##STR00072##
##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077##
##STR00078## ##STR00079## ##STR00080## ##STR00081##
[0196] Further compounds of the invention include:
##STR00082## ##STR00083## ##STR00084## ##STR00085##
##STR00086##
[0197] Compounds of the invention may be in the form of
pharmaceutically acceptable salts. The pharmaceutically acceptable
salts of the present disclosure can be synthesized from the parent
compound which contains a basic or acidic moiety by conventional
chemical methods. Generally, such salts can be prepared by reacting
the free acid or base forms of these compounds with a
stoichiometric amount of the appropriate base or acid in water or
in an organic solvent, or in a mixture of the two; generally,
nonaqueous media like ether, ethyl acetate, ethanol, isopropanol,
or acetonitrile are preferred. Lists of suitable salts are found in
Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing
Company, Easton, Pa., US, 1985, p. 1418, the disclosure of which is
hereby incorporated by reference; see also Stahl et al, Eds,
"Handbook of Pharmaceutical Salts Properties Selection and Use",
Verlag Helvetica Chimica Acta and Wiley-VCH, 2002.
[0198] The disclosure thus includes pharmaceutically-acceptable
salts of the disclosed compounds wherein the parent compound is
modified by making acid or base salts thereof, for example the
conventional non-toxic salts or the quaternary ammonium salts which
are formed, e.g. from inorganic or organic acids or bases. Examples
of such acid addition salts include acetate, adipate, alginate,
aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,
citrate, camphorate, camphorsulfonate, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, fumarate,
glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,
hexanoate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,
2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,
persulfate, 3-phenylpropionate, picrate, pivalate, propionate,
succinate, tartrate, thiocyanate, tosylate, and undecanoate. Base
salts include ammonium salts, alkali metal salts such as sodium and
potassium salts, alkaline earth metal salts such as calcium and
magnesium salts, salts with organic bases such as dicyclohexylamine
salts, N-methyl-D-glucamine, and salts with amino acids such as
arginine, lysine, and so forth. Also, the basic nitrogen-containing
groups may be quaternized with such agents as lower alkyl halides,
such as methyl, ethyl, propyl, and butyl chloride, bromides and
iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and
diamyl sulfates, long chain halides such as decyl, lauryl, myristyl
and stearyl chlorides, bromides and iodides, aralkyl halides like
benzyl and phenethyl bromides and others.
[0199] The invention includes prodrugs for the active
pharmaceutical species of the invention, for example in which one
or more functional groups are protected or derivatised but can be
converted in vivo to the functional group, as in the case of esters
of carboxylic acids convertible in vivo to the free acid, or in the
case of protected amines, to the free amino group. The term
"prodrug," as used herein, represents in particular compounds which
are rapidly transformed in vivo to the parent compound, for
example, by hydrolysis in blood. A thorough discussion is provided
in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems,
Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed.,
Bioreversible Carriers in Drug Design, American Pharmaceutical
Association and Pergamon Press, 1987; H Bundgaard, ed, Design of
Prodrugs, Elsevier, 1985; and Judkins, et al. Synthetic
Communications, 26(23), 4351-4367 (1996), each of which is
incorporated herein by reference.
[0200] Prodrugs therefore include drugs having a functional group
which has been transformed into a reversible derivative thereof.
Typically, such prodrugs are transformed to the active drug by
hydrolysis. As examples may be mentioned the following:
TABLE-US-00031 Functional Group Reversible derivative Carboxylic
acid Esters, including e.g. acyloxyalkyl esters, amides Alcohol
Esters, including e.g. sulfates and phosphates as well as
carboxylic acid esters Amine Amides, carbamates, imines, enamines,
Carbonyl Imines, oximes, acetals/ketals, enol esters, (aldehyde,
ketone) oxazolidines and thiazoxolidines
[0201] Prodrugs also include compounds convertible to the active
drug by an oxidative or reductive reaction. As examples may be
mentioned:
[0202] Oxidative Activation [0203] N- and O-dealkylation [0204]
Oxidative deamination [0205] N-oxidation [0206] Epoxidation
[0207] Reductive Activation [0208] Azo reduction [0209] Sulfoxide
reduction [0210] Disulfide reduction [0211] Bioreductive alkylation
[0212] Nitro reduction.
[0213] Also to be mentioned as metabolic activations of prodrugs
are nucleotide activation, phosphorylation activation and
decarboxylation activation. For additional information, see "The
Organic Chemistry of Drug Design and Drug Action", R B Silverman
(particularly Chapter 8, pages 497 to 546), incorporated herein by
reference.
[0214] The use of protecting groups is fully described in
`Protective Groups in Organic Chemistry`, edited by J W F McOmie,
Plenum Press (1973), and `Protective Groups in Organic Synthesis`,
2nd edition, T W Greene & P G M Wutz, Wiley-Interscience
(1991).
[0215] Thus, it will be appreciated by those skilled in the art
that, although protected derivatives of compounds of the disclosure
may not possess pharmacological activity as such, they may be
administered, for example parenterally or orally, and thereafter
metabolised in the body to form compounds of the invention which
are pharmacologically active. Such derivatives are therefore
examples of "prodrugs". All prodrugs of the described compounds are
included within the scope of the disclosure.
[0216] Some groups mentioned herein (especially those containing
heteroatoms and conjugated bonds) may exist in tautomeric forms and
all these tautomers are included in the scope of the disclosure.
More generally, many species may exist in equilibrium, as for
example in the case of organic acids and their counterpart anions;
a reference herein to a species accordingly includes reference to
all equilibrium forms thereof.
[0217] The compounds of the disclosure may also contain one or more
asymmetric carbon atoms and may therefore exhibit optical and/or
diastereoisomerism. All diastereoisomers may be separated using
conventional techniques, e.g. chromatography or fractional
crystallisation. The various stereoisomers may be isolated by
separation of a racemic or other mixture of the compounds using
conventional, e.g. fractional crystallisation or HPLC, techniques.
Alternatively the desired optical isomers may be made by reaction
of the appropriate optically active starting materials under
conditions which will not cause racemisation or epimerisation, or
by derivatisation, for example with a homochiral acid followed by
separation of the diastereomeric derivatives by conventional means
(e.g. HPLC, chromatography over silica). All stereoisomers are
included within the scope of the disclosure. Where a single
enantiomer or diasteromer is disclosed, the disclosure also covers
the other enantiomers or diastereomers, and also racemates; in this
regard, particular reference is made to the specific compounds
listed herein. As mentioned above, the stereochemical configuration
of the carbon atom to which the group --N(R.sup.2)(R.sup.3) is
attached may be (R) or (S), especially (R).
[0218] Geometric isomers may also exist in the compounds of the
present disclosure. The present disclosure contemplates the various
geometric isomers and mixtures thereof resulting from the
arrangement of substituents around a carbon-carbon double bond and
designates such isomers as of the Z or E configuration, wherein the
term "Z" represents substituents on the same side of the
carbon-carbon double bond and the term "E" represents substituents
on opposite sides of the carbon-carbon double bond.
[0219] The disclosure therefore includes all variant forms of the
defined compounds, for example any tautomer or any pharmaceutically
acceptable salt, ester, acid or other variant of the defined
compounds and their tautomers as well as substances which, upon
administration, are capable of providing directly or indirectly a
compound as defined above or providing a species which is capable
of existing in equilibrium with such a compound.
Synthesis
[0220] By way of illustration, a compound of the invention may be
prepared according to the following Schemes, in which Scheme 1
shows the synthesis of an intermediate in the form of a racemate;
Schemes 2 to 4 show synthesis of compounds of the invention in (S)
form, and Schemes 5 and 6 show synthesis of compounds in (R) form.
R.sup.x, R.sup.y and R.sup.z may each be any suitable group. For
example, R.sup.x and R.sup.y may be methyl and benzyl respectively,
while --N(R.sup.z).sub.2 may form a phthalimido group.
##STR00087##
##STR00088## ##STR00089##
##STR00090## ##STR00091##
##STR00092## ##STR00093##
##STR00094## ##STR00095##
##STR00096## ##STR00097##
[0221] It will be understood that the processes detailed above are
solely for the purpose of illustrating the invention and should not
be construed as limiting. A process utilising similar or analogous
reagents and/or conditions known to one skilled in the art may also
be used to obtain a compound of the invention.
[0222] Any mixtures of final products or intermediates obtained can
be separated on the basis of the physico-chemical differences of
the constituents, in a known manner, into the pure final products
or intermediates, for example by chromatography, distillation,
fractional crystallisation, or by the formation of a salt if
appropriate or possible under the circumstances.
Administration & Pharmaceutical Formulations
[0223] The compounds of the invention will normally be administered
orally, intravenously, subcutaneously, buccally, rectally,
dermally, nasally, tracheally, bronchially, by any other parenteral
route, as an oral or nasal spray or via inhalation. The compounds
may be administered in the form of pharmaceutical preparations
comprising prodrug or active compound either as a free compound or,
for example, a pharmaceutically acceptable non-toxic organic or
inorganic acid or base addition salt, in a pharmaceutically
acceptable dosage form. Depending upon the disorder and patient to
be treated and the route of administration, the compositions may be
administered at varying doses.
[0224] Typically, therefore, the pharmaceutical compounds of the
invention may be administered orally or parenterally
("parenterally" as used herein, refers to modes of administration
which include intravenous, intramuscular, intraperitoneal,
intrasternal, subcutaneous and intraarticular injection and
infusion) to a host to obtain an protease-inhibitory effect. In the
case of larger animals, such as humans, the compounds may be
administered alone or as compositions in combination with
pharmaceutically acceptable diluents, excipients or carriers.
[0225] Actual dosage levels of active ingredients in the
pharmaceutical compositions of this invention may be varied so as
to obtain an amount of the active compound(s) that is effective to
achieve the desired therapeutic response for a particular patient,
compositions, and mode of administration. The selected dosage level
will depend upon the activity of the particular compound, the route
of administration, the severity of the condition being treated and
the condition and prior medical history of the patient being
treated. However, it is within the skill of the art to start doses
of the compound at levels lower than required for to achieve the
desired therapeutic effect and to gradually increase the dosage
until the desired effect is achieved.
[0226] In the treatment, prevention, control, amelioration, or
reduction of risk of conditions which require inhibition of DPP-IV
enzyme activity, an appropriate dosage level will generally be
about 0.01 to 500 mg per kg patient body weight per day which can
be administered in single or multiple doses. Preferably, the dosage
level will be about 0.1 to about 250 mg/kg per day; more preferably
about 0.5 to about 100 mg/kg per day. A suitable dosage level may
be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per
day, or about 0.1 to 50 mg/kg per day. Within this range the dosage
may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral
administration, the compositions are preferably provided in the
form of tablets containing 1.0 to 1000 milligrams of the active
ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0,
75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0,
750.0, 800.0, 900.0 and 1000.0 milligrams of the active ingredient
for the symptomatic adjustment of the dosage to the patient to be
treated. The compounds may be administered on a regimen of 1 to 4
times per day, preferably once or twice per day. The dosage regimen
may be adjusted to provide the optimal therapeutic response.
[0227] According to a further aspect of the invention there is thus
provided a pharmaceutical composition including a compound of the
invention, in admixture with a pharmaceutically acceptable
adjuvant, diluent or carrier.
[0228] Pharmaceutical compositions of this invention for parenteral
injection suitably comprise pharmaceutically acceptable sterile
aqueous or nonaqueous solutions, dispersions, suspensions or
emulsions as well as sterile powders for reconstitution into
sterile injectable solutions or dispersions just prior to use.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents or vehicles include water, ethanol, polyols (such as
glycerol, propylene glycol, polyethylene glycol and the like), and
suitable mixtures thereof, vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate. Proper fluidity can
be maintained, for example, by the use of coating materials such as
lecithin, by the maintenance of the required particle size in the
case of dispersions and by the use of surfactants.
[0229] These compositions may also contain adjuvants such as
preservative, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol or phenol sorbic acid. It may
also be desirable to include isotonic agents such as sugars or
sodium chloride, for example. Prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents (for example aluminum monostearate and gelatin)
which delay absorption.
[0230] In some cases, in order to prolong the effect of the drug,
it is desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This may be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug then depends upon its rate of dissolution which, in turn, may
depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally administered drug form is
accomplished by dissolving or suspending the drug in an oil
vehicle.
[0231] Injectable depot forms are suitably made by forming
microencapsule matrices of the drug in biodegradable polymers, for
example polylactide-polyglycolide. Depending upon the ratio of drug
to polymer and the nature of the particular polymer employed, the
rate of drug release can be controlled. Examples of other
biodegradable polymers include poly(orthoesters) and
poly(anhydrides). Depot injectable formulations may also prepared
by entrapping the drug in liposomes or microemulsions which are
compatible with body tissues. The injectable formulations can be
sterilized, for example, by filtration through a
bacterial-retaining filter or by incorporating sterilizing agents
in the form of sterile solid compositions which can be dissolved or
dispersed in sterile water or other sterile injectable media just
prior to use.
[0232] Solid dosage forms for oral administration include capsules,
tablets, pills, powders and granules. In such solid dosage forms,
the active compound is typically mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or one or more: a) fillers or
extenders such as starches, lactose, sucrose, glucose, mannitol and
silicic acid; b) binders such as carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants
such as glycerol; d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates and sodium carbonate; e) solution retarding agents such
as paraffin; f) absorption accelerators such as quaternary ammonium
compounds; g) wetting agents such as cetyl alcohol and glycerol
monostearate; h) absorbents such as kaolin and bentonite clay and
i) lubricants such as talc, calcium stearate, magnesium stearate,
solid polyethylene glycols, sodium lauryl sulfate and mixtures
thereof. In the case of capsules, tablets and pills, the dosage
form may also comprise buffering agents. Solid compositions of a
similar type may also be employed as fillers in soft and
hard-filled gelatin capsules using such excipients as lactose or
milk sugar as well as high molecular weight polyethylene glycol,
for example.
[0233] Suitably, oral formulations contain a dissolution aid. The
dissolution aid is not limited as to its identity so long as it is
pharmaceutically acceptable. Examples include nonionic surface
active agents, such as sucrose fatty acid esters, glycerol fatty
acid esters, sorbitan fatty acid esters (e.g. sorbitan trioleate),
polyethylene glycol, polyoxyethylene hydrogenated castor oil,
polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl
ethers, methoxypolyoxyethylene alkyl ethers, polyoxyethylene
alkylphenyl ethers, polyethylene glycol fatty acid esters,
polyoxyethylene alkylamines, polyoxyethylene alkyl thioethers,
polyoxyethylene polyoxypropylene copolymers, polyoxyethylene
glycerol fatty acid esters, pentaerythritol fatty acid esters,
propylene glycol monofatty acid esters, polyoxyethylene propylene
glycol monofatty acid esters, polyoxyethylene sorbitol fatty acid
esters, fatty acid alkylolamides, and alkylamine oxides; bile acid
and salts thereof (e.g. chenodeoxycholic acid, cholic acid,
deoxycholic acid, dehydrocholic acid and salts thereof, and glycine
or taurine conjugate thereof); ionic surface active agents, such as
sodium laurylsulfate, fatty acid soaps, alkylsulfonates,
alkylphosphates, ether phosphates, fatty acid salts of basic amino
acids; triethanolamine soap, and alkyl quaternary ammonium salts;
and amphoteric surface active agents, such as betaines and
aminocarboxylic acid salts.
[0234] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and may also be of a composition such that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, and/or in delayed fashion.
Examples of embedding compositions include polymeric substances and
waxes.
[0235] The active compounds may also be in micro-encapsulated form,
if appropriate, with one or more of the above-mentioned
excipients.
[0236] The active compounds may be in finely divided form, for
example it may be micronised.
[0237] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid
dosage forms may contain inert diluents commonly used in the art
such as water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan and mixtures thereof.
Besides inert diluents, the oral compositions may also include
adjuvants such as wetting agents, emulsifying and suspending
agents, sweetening, flavoring and perfuming agents. Suspensions, in
addition to the active compounds, may contain suspending agents
such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol
and sorbitan esters, microcrystalline cellulose, aluminum
metahydroxide, bentonite, agar-agar, and tragacanth and mixtures
thereof.
[0238] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at room temperature but liquid at
body temperature and therefore melt in the rectum or vaginal cavity
and release the active compound.
[0239] Compounds of the present invention can also be administered
in the form of liposomes. As is known in the art, liposomes are
generally derived from phospholipids or other lipid substances.
Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals which are dispersed in an aqueous medium. Any non-toxic,
physiologically acceptable and metabolisable lipid capable of
forming liposomes can be used. The present compositions in liposome
form can contain, in addition to a compound of the present
invention, stabilisers, preservatives, excipients and the like. The
preferred lipids are the phospholipids and the phosphatidyl
cholines (lecithins), both natural and synthetic. Methods to form
liposomes are known in the art, for example, Prescott, Ed., Methods
in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976),
p 33 et seq.
[0240] Dosage forms for topical administration of a compound of
this invention include powders, sprays, ointments and inhalants.
The active compound is mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants which may be required. Ophthalmic
formulations, eye ointments, powders and solutions are also
contemplated as being within the scope of this invention.
[0241] Advantageously, the compounds of the invention may be orally
active, have rapid onset of activity and low toxicity.
[0242] The compounds of the invention may have the advantage that
they are more efficacious, less toxic, longer acting, have a
broader range of activity, more potent, produce fewer side effects,
more easily absorbed than, or have other useful pharmacological
properties over, compounds known in the prior art.
Combination Therapies
[0243] Compounds of the invention may be administered in
combination with one or more additional therapeutic agents.
Accordingly, the invention provides a pharmaceutical composition
comprising an additional agent. The invention also provides a
product comprising a compound of the invention and an agent; as a
combined preparation for simultaneous, separate or sequential use
in therapy.
[0244] In particular, a composition or product of the invention may
further comprise a therapeutic agent selected from anti-diabetic
agents, hypolipidemic agents, anti-obesity or appetite-regulating
agents, anti-hypertensive agents, HDL-increasing agents,
cholesterol absorption modulators, Apo-A1 analogues and mimetics,
thrombin inhibitors, aldosterone inhibitors, inhibitors of platelet
aggregation, estrogen, testosterone, selective estrogen receptor
modulators, selective androgen receptor modulators,
chemotherapeutic agents, and 5-HT.sub.3 or 5-HT.sub.4 receptor
modulators; or pharmaceutically acceptable salts or prodrugs
thereof.
[0245] Examples of anti-diabetic agents include insulin, insulin
derivatives and mimetics; insulin secretagogues, for example
sulfonylureas (e.g. glipizide, glyburide or amaryl); insulinotropic
sulfonylurea receptor ligands, for example meglitinides (e.g.
nateglinide or repaglinide); insulin sensitisers, for example
protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g. PTP-112);
GSK3 (glycogen synthase kinase-3) inhibitors, for example
SB-517955, SB-4195052, SB-216763, N,N-57-05441 or N,N-57-05445; RXR
ligands, for example GW-0791 or AGN-194204; sodium-dependent
glucose cotransporter inhibitors, for example T-1095; glycogen
phosphorylase A inhibitors, for example BAY R3401; biguanides, for
example metformin; alpha-glucosidase inhibitors, for example
acarbose; GLP-1 (glucagon like peptide-1), GLP-1 analogues and
mimetics, for example exendin-4; DPPIV (dipeptidyl peptidase IV)
inhibitors, for example DPP728, LAF237 (vildagliptin), MK-0431,
saxagliptin or GSK23A; AGE breakers; and thiazolidone derivatives,
for example glitazone, pioglitazone, rosiglitazone or
(R)-1-{4-[5-methyl-2-(4-trifluoromethyl-phenylyoxazol-4-ylmethoxy]-benzen-
esulfonyl}-2,3-dihydro-1H-indole-2-carboxylic acid (compound 4 of
Example I9 of WO 03/043985) or a non-glitazone type PPAR-agonist
(e.g. GI-262570); or pharmaceutically acceptable salts or prodrugs
thereof.
[0246] Examples of hypolipidemic agents include
3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase
inhibitors, for example lovastatin, pitavastatin, simvastatin,
pravastatin, cerivastatin, mevastatin, velostatin, fluvastatin,
dalvastatin, atorvastatin, rosuvastatin or rivastatin; squalene
synthase inhibitors; FXR (farnesoid X receptor) ligands; LXR (liver
X receptor) ligands; cholestyramine; fibrates; nicotinic acid; and
aspirin; or pharmaceutically acceptable salts or prodrugs
thereof.
[0247] Examples of anti-obesity/appetite-regulating agents include
phentermine, leptin, bromocriptine, dexamphetamine, amphetamine,
fenfluramine, dexfenfluramine, sibutramine, or list at,
dexfenfluramine, mazindol, phentermine, phendimetrazine,
diethylpropion, fluoxetine, bupropion, topiramate, diethylpropion,
benzphetamine, phenylpropanolamine or ecopipam, ephedrine,
pseudoephedrine and cannabinoid receptor antagonists; or
pharmaceutically acceptable salts or prodrugs thereof.
[0248] Examples of anti-hypertensive agents include loop diuretics,
for example ethacrynic acid, furosemide or torsemide; diuretics,
for example thiazide derivatives, chlorithiazide,
hydrochlorothiazide or amiloride; angiotensin converting enzyme
(ACE) inhibitors, for example benazepril, captopril, enalapril,
fosinopril, lisinopril, moexipril, perinodopril, quinapril,
ramipril or trandolapril; Na-K-ATPase membrane pump inhibitors, for
example digoxin; neutralendopeptidase (NEP) inhibitors, for example
thiorphan, terteo-thiorphan or SQ29072; ECE inhibitors, for example
SLV306; dual ACE/NEP inhibitors, for example omapatrilat,
sampatrilat or fasidotril; angiotensin II antagonists, for example
candesartan, eprosartan, irbesartan, losartan, telmisartan or
valsartan; renin inhibitors, for example aliskiren, terlakiren,
ditekiren, RO-66-1132 or RO-66-1168; b-adrenergic receptor
blockers, for example acebutolol, atenolol, betaxolol, bisoprolol,
metoprolol, nadolol, propranolol, sotalol or timolol; inotropic
agents, for example digoxin, dobutamine or milrinone; calcium
channel blockers, for example amlodipine, bepridil, diltiazem,
felodipine, nicardipine, nimodipine, nifedipine, nisoldipine or
verapamil; aldosterone receptor antagonists; and aldosterone
synthase inhibitors; or pharmaceutically acceptable salts or
prodrugs thereof.
[0249] Examples of cholesterol absorption modulators include
Zetia.RTM. and KT6-971, or pharmaceutically acceptable salts or
prodrugs thereof.
[0250] Examples of aldosterone inhibitors include anastrazole,
fadrazole and eplerenone, or pharmaceutically acceptable salts or
prodrugs thereof.
[0251] Examples of inhibitors of platelet aggregation include
aspirin or clopidogrel bisulfate, or pharmaceutically acceptable
salts or prodrugs thereof.
[0252] Examples of chemotherapeutic agents include compounds
decreasing the protein kinase activity, for example PDGF receptor
tyrosine kinase inhibitors (e.g. imatinib or
4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyr-
idin-3-yl-pyrimidin-2-ylamino)-benzamide), or pharmaceutically
acceptable salts or prodrugs thereof.
[0253] Examples of 5-HT.sub.3 or 5-HT.sub.4 receptor modulators
include tegaserod, tegaserod hydrogen maleate, cisapride or
cilansetron, or pharmaceutically acceptable salts or prodrugs
thereof.
[0254] The weight ratio of the compound of the present invention to
the further active ingredient(s) may be varied and will depend upon
the effective dose of each ingredient. Generally, an effective dose
of each will be used. Thus, for example, when a compound of the
present invention is combined with another agent, the weight ratio
of the compound of the present invention to the other agent will
generally range from about 1000:1 to about 1:1000, preferably about
200:1 to about 1:200.
[0255] Combinations of a compound of the present invention and
other active ingredients will generally also be within the
aforementioned range, but in each case, an effective dose of each
active ingredient should be used.
[0256] In such combinations the compound of the present invention
and other active agents may be administered separately or in
conjunction. In addition, the administration of one element may be
prior to, concurrent to, or subsequent to the administration of
other agent(s).
Use
[0257] Compounds of the invention may be useful in the therapy of a
variety of diseases and conditions.
[0258] In particular, compounds of the invention may be useful in
the treatment or prevention of a disease or condition selected from
non-insulin-dependent diabetes mellitus, arthritis, obesity,
allograft transplantation, osteoporosis, heart failure, impaired
glucose metabolism or impaired glucose tolerance, neurodegenerative
diseases (for example Alzheimer's disease or Parkinson disease),
cardiovascular or renal diseases (for example diabetic
cardiomyopathy, left or right ventricular hypertrophy, hypertrophic
medial thickening in arteries and/or in large vessels, mesenteric
vasculature hypertrophy or mesanglial hypertrophy),
neurodegenerative or cognitive disorders, hyperglycemia, insulin
resistance, lipid disorders, dyslipidemia, hyperlipidemia,
hypertriglyceridemia, hypercholesterolemia, low HDL levels, high
LDL levels, atherosclerosis, vascular restenosis, irritable bowel
syndrome, inflammatory bowel disease (e.g. Crohn's disease or
ulcerative colitis), pancreatitis, retinopathy, nephropathy,
neuropathy, syndrome X, ovarian hyperandrogenism (polycystic
ovarian syndrome), type 2 diabetes, growth hormone deficiency,
neutropenia, neuronal disorders, tumor metastasis, benign prostatic
hypertrophy, gingivitis, hypertension and osteoporosis.
[0259] The compounds may also be useful in producing a sedative or
anxiolytic effect, attenuating post-surgical catabolic changes or
hormonal responses to stress, reducing mortality and morbidity
after myocardial infarction, modulating hyperlipidemia or
associated conditions; and lowering VLDL, LDL or Lp(a) levels.
EXAMPLES
[0260] The following Examples illustrate the invention.
[0261] Terms used in the Examples:
[0262] ACN: acetonitrile
[0263] HPLC: high performance liquid chromatography
[0264] Cbz: carbobenzyloxy
Intermediates A1 & A2
[0265] Intermediates A1 and A2 are prepared according to Scheme
A:
##STR00098## ##STR00099##
A) 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid benzyl
ester
[0266] To tropinone (20 g, 142 mmol) in toluene (600 mL) are added
benzyl chloroformate (42.2 mL, 284 mmol) and K.sub.2CO.sub.3 (118
mg, 0.853 mmol) and the resulting solution is stirred at reflux
during 16 h. After evaporation of the solvent, the residue is
treated with dichloromethane/aqueous saturated NaHCO.sub.3, the
organic phase is dried, filtered and evaporated to give a yellow
oil.
[0267] MS: 260 [M+H].sup.+
[0268] TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.7.
B)
3-[1-Methoxy-methylidene]-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid benzyl ester
[0269] To methoxymethyltriphenyl phosphonium chloride (46.6 g, 133
mmol) in tetrahydrofuran (900 mL) is added dropwise at -40.degree.
C. sodium bis(trimethylsilyl) amide in tetrahydrofuran (2M, 67 mL,
130 mmol) then the resulting red solution is stirred at -40.degree.
C. during 1 h and at 0.degree. C. during 30 min. After cooling to
-40.degree. C., 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid
benzyl ester (27 g, 83 mmol) in tetrahydrofuran (100 mL) is added,
The resulting mixture is warmed to 0.degree. C. and stirred during
30 min. It is quenched with aqueous saturated NH.sub.4Cl, extracted
with dichloromethane and washed with aqueous saturated NaHCO.sub.3.
The organic phase is dried, filtered and evaporated to give a
residue, which is purified by flash chromatography on silica gel
(eluent: cyclohexane/ethyl acetate 100/0 to 7/3) to yield a yellow
oil.
[0270] MS: 288 [M+H].sup.+
[0271] TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.75.
C) 3-exo-Formyl-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid benzyl
ester
[0272] To
3-[1-methoxy-methylidene]-8-aza-bicyclo[3.2.1]octane-8-carboxyli- c
acid benzyl ester (13 g, 40.7 mmol) in acetone (450 mL) and water
(50 mL) is added 37% conc HCl in water (0.920 mL, 9.4 mmol). The
resulting mixture is stirred at 50.degree. C. during 24 h. After
evaporation of the solvent, the residue is treated with
dichloromethane/aqueous saturated NaHCO.sub.3, the organic phase is
dried, filtered and evaporated to give a residue, which is purified
by flash chromatography on silica gel (eluent: cyclohexane/ethyl
acetate 100/0 to 7/3) to yield a yellow oil.
[0273] MS: 274 [M+H].sup.+
[0274] TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.42.
D)
3-exo-{[(S)-2-Methyl-propane-2-sulfinylimino]-methyl}-8-aza-bicyclo[3.2-
.1]octane-8-carboxylic acid benzyl ester
[0275] (S)-2-methyl-2-propanesulfinamide (543 mg, 4.39 mmol),
pyridinium toluene-4-sulfonate (46 mg, 0.183 mmol) and MgSO.sub.4
(2.21 g, 18.3 mmol) are stirred in dichloroethane (15 mL) for 1 h,
before the addition of
3-exo-formyl-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid benzyl
ester (1 g, 3.66 mmol) in dichloroethane (5 mL). The resulting
mixture is stirred at 50.degree. C. during 16 h, it is filtered and
evaporated to give a residue, which is purified by flash
chromatography on silica gel (eluent: cyclohexane/ethyl acetate
100/0 to 50/50) to yield a yellow oil.
[0276] MS: 377 [M+H].sup.+
[0277] TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.37.
E)
3-exo-[(R)-1-((S-2-Methyl-propane-2-sulfonylamino)-2-(2,4,5-trifluoro-p-
henyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid benzyl
ester (Intermediate A1); and
3-exo-[(S)-1-((S)-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-ph-
enyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid benzyl
ester (Intermediate A2)
[0278] To stirred magnesium turnings (18 mg, 0.75 mmol) in diethyl
ether (0.5 mL) is added 2,4,5-trifluorobenzylbromide (112 mg, 0.499
mmol) in diethyl ether (0.5 mL). After stirring during 30 min at
rt, the resulting suspension is added at 0.degree. C. to a solution
of
3-exo-{[(S)-2-methyl-propane-2-sulfinylimino]-methyl}-8-aza-bicyclo[3.2.1-
]octane-8-carboxylic acid benzyl ester (179 mg, 0.333 mmol) in
dichloromethane (1 mL). The resulting mixture is stirred for 4 h at
rt, before it is quenched at 0.degree. C. with saturated aqueous
NH.sub.4Cl and extracted with dichloromethane. The organic phase is
dried, filtered and evaporated to give a residue, which is purified
by flash chromatography on silica gel (eluent: cyclohexane/ethyl
acetate).
[0279] Intermediate A1: MS: 523 [M+H].sup.+
[0280] TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.17
[0281] Intermediate A2: MS: 523 [M+H].sup.+
[0282] TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.12
Intermediates A'1 & A'2
[0283] Intermediates A'1 and A'2 are prepared according to Scheme
A':
##STR00100##
4-[(R)-1-((S)-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-phenyl-
)-ethyl]-piperidine-1-carboxylic acid benzyl ester (Intermediate
A1); and
4-[(S)-1-((S)-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-phenyl-
)-ethyl]-piperidine-1-carboxylic acid benzyl ester (Intermediate
A2)
[0284] The title compounds are prepared analogously as described in
Scheme A using 4-Formyl-piperidine-1-carboxylic acid benzyl ester
instead of 3-exo-formyl-8-aza-bicyclo[3.2.1]octane-8-carboxylic
acid benzyl ester
[0285] Intermediate A'1: MS: 497.1 [M+H].sup.+
[0286] TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.23
[0287] Intermediate A'2: MS: 497.1 [M+H].sup.+
[0288] TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.10
Example B1
N-(2-{3-exo-[(S)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]octane-8-sulfonyl}-ethyl)-acetamide
[0289] This compound is prepared according to Scheme B:
##STR00101## ##STR00102##
A)
3-exo-[(S)-1-((S)-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-
-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane
[0290] To
3-exo-[(S)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tri-
fluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid
benzyl ester (Intermediate A2; 300 mg, 0.574 mmol) in ethylacetate
(10 mL) is added 10% Pd/C (610 mg, 0.57 mmol). The resulting
mixture is stirred and put under H.sub.2-atmosphere. After 1 h of
stirring, the suspension is filtered through celite and evaporated
to give a residue, which is purified by preparative HPLC (Column
Interchrom C18 ODB 10 .mu.m 28.times.250, Gradient: 0-2.5 min 5%
ACN, 2.5-25.5 min 5-100% ACN, 25.5-30 min 100% CAN) to yield the
title compound.
[0291] MS: 389 [M+H]+
[0292] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.06 min.
B)
N-(2-{3-exo-[(S)-1-((S)-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trif-
luoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-phthali-
mide
[0293] To
3-exo-[(S)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tri-
fluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane (540 mg, 1.2 mmol)
in dichloromethane/1M NaOH (1/1, 5 mL) is added 2-phthalimidoethane
sulfonyl chloride (1.101 g, 3.59 mmol) then the resulting mixture
is stirred at 50.degree. C. during 16 h. It is extracted with
dichloromethane, the organic phase is dried and evaporated to give
a white solid.
[0294] MS: 626 [M+H]+
[0295] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.44 min.
C)
2-{3-exo-[(S)-1-((S)-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluo-
ro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethylamine
[0296] To
N-(2-{3-exo-[(S)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4-
,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)--
phthalimide (100 mg, 0.160 mmol) in ethanol (2 mL) is added
hydrazine monohydrate (0.396 mL, 8 mmol) and the resulting solution
is stirred at rt during 12 h. After extraction with dichloromethane
and aqueous saturated NaHCO.sub.3, the organic phase is dried and
evaporated to give a residue, which is purified by preparative HPLC
(Column Waters C18 ODB 5 .mu.m 19.times.50, Gradient: 0-2.5 min 5%
ACN, 2.5-12.5 min 5-100% ACN, 12.5-15 min 100% ACN) to yield a
white solid.
[0297] MS 496 [M+H]+
[0298] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.05 min.
D)
N-(2-{3-exo-[(S)-1-((S)-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trif-
luoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-acetami-
de
[0299] To
2-{3-exo-[(S)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5--
trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethylamine
(27 mg, 0.054 mmol) in acetic acid (1 mL) is added acetic anhydride
(7.86 .mu.L, 0.081 mmol) and the resulting solution is stirred at
rt during 3 h. After extraction with dichloromethane and aqueous
saturated NaHCO.sub.3, the organic phase is dried and evaporated to
give a colorless gum.
[0300] MS 538 [M+H]+
E)
N-(2-{3-exo-[(S)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]octane-8-sulfonyl}-ethyl)-acetamide
[0301] To
N-(2-{3-exo-[(S)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4-
,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)--
acetamide (29.3 mg, 0.545 mmol) in dioxane (3 mL) is added 4N HCl
in dioxane (2 mL). The resulting mixture is stirred at rt during 1
h. The solution is frozen and lyophilised to give a white
solid.
[0302] MS: 435 [M+H]+
[0303] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.95 min.
Example C1
N-(2-{3-exo-[(S)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-2-oxo-ethyl)-acetamide
[0304] This compound is prepared according to Scheme C:
##STR00103## ##STR00104##
A)
N-(2-{3-exo-[(S)-1-((S-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trif-
luoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-phthalimid-
e
[0305] To a solution of N-phthaloylglycine (291 mg, 1.41 mmol) in
acetonitrile (7 mL) is added
benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate
(805 mg, 1.54 mmol) and the resulting mixture is stirred at rt
during 1 h before addition of
3-exo-[(S)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-ph-
enyl)-ethyl]-8-aza-bicyclo[3.2.1]octane (500 mg, 1.29 mmol) and
triethylamine (720 .mu.L, 5.16 mmol) in acetonitrile (5 mL). The
resulting solution is stirred at rt during 16 h and is evaporated
before purification by preparative HPLC (Column Interchrom C18 ODB
10 .mu.m 28.times.250, Gradient: 0-2.5 min 5% ACN, 2.5-25.5 min
5-100% ACN, 25.5-30 min 100% ACN) to yield a yellow solid.
[0306] MS: 576 [M+H]+
B)
N-(2-{3-exo-[(S)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl}-2-oxo-ethyl)-acetamide
[0307] The title compound is prepared analogously as described in
example B1 using
N-(2-{3-exo-[(S)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4-
,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-pht-
halimide instead of
N-(2-{3-exo-[(S)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-triflu-
oro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-phthalimi-
de.
[0308] MS: 384 [M+H]
[0309] HPLC (Nucleosil 100-5 C18, 10 min method (0-1 min 10% ACN,
1-6 min 10-100% ACN, 6-8.5 min 100% ACN, 8.5-9 min 100-10% ACN,
9-10 min 10% ACN): 3.28 min.
Example C2
Cyclopropanesulfonic acid
(2-{3-exo-[(S)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0310] This compound is also prepared according to Scheme C.
A) Cyclopropanesulfonic acid
(2-{3-exo-[(S)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluor-
o-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0311] To a solution of
2-{3-exo-[(S)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-
-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethylamine (50
mg, 0.112 mmol) in dichloromethane (1 mL) are added triethylamine
(32 .mu.L, 0.224 mmol) and cyclopropanesulfonyl chloride (14 .mu.L,
0.134 mmol). The resulting solution is stirred at rt during 16 h
before evaporation and purification by preparative HPLC (Column
Waters C18 ODB 5 .mu.m 19.times.50, Gradient: 0-2.5 min 5% ACN,
2.5-12.5 min 5-100% ACN, 12.5-15 min 100% ACN) to yield a colorless
gum.
[0312] MS 550 [M+H]+
[0313] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.17 min.
B) Cyclopropanesulfonic acid
(2-{3-exo-[(S)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0314] To cyclopropanesulfonic acid
(2-{3-exo-[(S)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluor-
o-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-amide
(27 mg, 0.049 mmol) in dioxane (0.5 mL) is added 4N HCl in dioxane
(0.5 mL). The resulting mixture is stirred at rt during 1 h. The
solution is frozen and lyophilised to give a white solid before
purification by preparative HPLC (Column Waters C18 ODB 5 .mu.m
19.times.50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min 5-100% ACN,
12.5-15 min 100% ACN) to yield a colorless gum.
[0315] MS 446 [M+H]+
[0316] HPLC (Nucleosil 100-5 C18, 10 min method (0-1 min 10% ACN,
1-6 min 10-100% ACN, 6-8.5 min 100% ACN, 8.5-9 min 100-10% ACN,
9-10 min 10% ACN): 3.5 min.
Example D1
5-Methyl-pyrazine-2-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide
[0317] This compound is prepared according to Scheme D:
##STR00105## ##STR00106##
A)
3-exo-[(R)-1-((S)-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-
-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane
[0318] To
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tri-
fluoro-phenyl ethyl]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid
benzyl ester (Intermediate A1; 7.74 g, 14.8 mmol) in ethanol (200
mL) is added 10% Pd/C (16 g, 15 mmol), the resulting mixture is
stirred and put under H.sub.2-atmosphere. After 1 h of stirring,
the suspension is filtered through celite and evaporated to yield
the title compound.
[0319] MS: 389 [M+H]+
[0320] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.91 min.
B)
N-(2-{3-exo-[(R)-1-((S-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trifl-
uoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-phthalim-
ide
[0321] To
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tri-
fluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane (265 mg, 0.68
mmol) in dichloromethane/1M NaOH (1/1, 5 mL) is added
2-phthalimidoethane sulfonyl chloride (577 mg, 2.05 mmol) then the
resulting mixture is stirred at 50.degree. C. during 16 h. It is
extracted with dichloromethane, the organic phase is dried and
evaporated to give a white solid.
[0322] MS: 626 [M+H]+
[0323] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.25 min.
C)
2-{3-exo-[(R)-1-((S)-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluo-
ro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethylamine
[0324] To
N-(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4-
,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)--
phthalimide (256 mg, 0.409 mmol) in ethanol (3 mL) is added
hydrazine monohydrate (1.01 mL, 20.5 mmol) and the resulting
solution is stirred at rt during 12 h. After extraction with
dichloromethane and aqueous saturated NaHCO.sub.3, the organic
phase is dried and evaporated to yield a colorless oil.
[0325] MS: 496 [M+H]+
[0326] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.95 min.
D) 5-Methyl-pyrazine-2-carboxylic acid
(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluor-
o-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-amide
[0327] To 5-methylpyrazinecarboxylic acid (18.8 mg, 0.133 mmol) in
acetonitrile (2 mL) is added
benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate
(75.6 mg, 0.145 mmol) and the resulting mixture is stirred at rt
during 1 h. After this time,
2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-
-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethylamine
(60 mg, 0.121) and triethylamine (50.5 .mu.L, 0.363 mmol) in
acetonitrile are added and the solution is shaken at rt during 16
h. The solution is purified by preparative HPLC (Column Waters C18
ODB 5 .mu.m 19.times.50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min
5-100% ACN, 12.5-15 min 100% CAN) to yield a white solid.
[0328] MS: 616 [M+H]+
[0329] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.18 min.
E) 5-Methyl-pyrazine-2-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide
[0330] To 5-methyl-pyrazine-2-carboxylic acid
(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluor-
o-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-amide
(48.5 mg, 0.0788 mmol) in dioxane (3 mL) is added 4N HCl in dioxane
(1 mL). The resulting mixture is stirred at rt during 1 h before it
is purified by preparative HPLC (Column Waters C18 ODB 5 .mu.m
19.times.50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min 5-100% ACN,
12.5-15 min 100% CAN) to yield a white solid.
[0331] MS 513 [M+H]+
[0332] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.95 min.
Example D2
Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide
[0333] This compound is prepared according to Scheme D.
A) Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluor-
o-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-amide
[0334] To a solution of
2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-
-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethylamine
(40 mg, 0.078 mmol) in dichloroethane (2 mL) are added
triethylamine (32.7 .mu.L, 0.235 mmol), 4-dimethylaminopyridine
(0.95 mg, 0.007 mmol) and cyclopropanesulfonyl chloride (16.8
.mu.L, 0.157 mmol). The resulting solution is stirred at rt during
2 h before evaporation to yield the title compound.
[0335] MS: 600 [M+H]+
[0336] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 3.28 min.
B) Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}ethyl)-amide
[0337] To Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-((S-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-
-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-amide
(63 mg, 0.102 mmol) in dioxane (2 mL) is added 4N HCl in dioxane (3
mL). The resulting mixture is stirred at rt during 1 h. The
solution is frozen and lyophilised to give a white solid before
purification by preparative HPLC (Column Waters C18 ODB 5 .mu.m
19.times.50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min 5-100% ACN,
12.5-15 min 100% ACN) to yield title compound.
[0338] MS: 496 [M+H]+
[0339] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-5%
ACN, 5.55-6 min 5% ACN): 2.56 min.
Example D2a
Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-aza-bicyclo[3.2.-
1]octane-8-sulfonyl}-ethyl)-amide maleate
[0340] This compound is prepared according to Scheme Da:
##STR00107##
[0341] A solution of maleic acid in ethyl acetate (1 molequivalent;
0.1 M) is added to a solution of Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide freebase (20 mg) in ethyl
acetate (1 mL) under stirring. The obtained mixture is left to
precipitate for one hour before it is stirred overnight. The
resulting white suspension is filtered and the obtained solid is
dried to yield the title compound.
Example D2b
Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide toluene-4-sulfonate
[0342] This compound is prepared according to Scheme Db:
##STR00108##
[0343] A solution of toluene-4-sulfonic acid in ethyl acetate (1
molequivalent; 0.1 M) is added to a solution of
Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide freebase (50 mg) in ethyl
acetate (1 mL) under stirring. The obtained mixture is left to
precipitate for 2 hours before it is stirred overnight. The
resulting white suspension is filtered and the obtained solid is
dried to yield the title compound.
Example D3
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]octane-8-sulfonyl}-ethyl)-acetamide
[0344] This compound is prepared according to Scheme D:
A)
N-(2-{3-exo-[(R)-1-((S)-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trif-
luoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethylacetamide
[0345] To
2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5--
trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethylamine
(100 mg, 0.202 mmol) in acetic acid (2 mL) is added acetic
anhydride (29.1 .mu.L, 0.303 mmol) and the resulting solution is
stirred at rt during 3 h. After extraction with dichloromethane and
aqueous saturated NaHCO.sub.3, the organic phase is dried and
evaporated to give the title compound.
[0346] MS: 538 [M+H]+
B)
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]octane-8-sulfonyl}-ethyl)-acetamide
[0347] To
N-(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4-
,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)--
acetamide (108 mg, 0.199 mmol) in dioxane (2 mL) is added 4N HCl in
dioxane (3 mL). The resulting mixture is stirred at rt during 1 h.
The solution is frozen and lyophilised to give a white solid before
purification by preparative HPLC (Column Waters C18 ODB 5 .mu.m
19.times.50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min 5-100% ACN,
12.5-15 min 100% ACN) to yield the title compound.
[0348] MS: 434 [M+H]+
[0349] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.84 min.
Example D3a
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]octane-8-sulfonyl}-ethyl)-acetamide maleate
[0350] The title compound is prepared analogously as described in
example D2a using
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-az-
a-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)acetamide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}ethyl)-amide.
Example D3b
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]octane-8-sulfonyl}-ethyl)-acetamide toluene-4-sulfonate
[0351] The title compound is prepared analogously as described in
example D2b using
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-az-
a-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-acetamide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example D4
Dimethylsulfamic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide
[0352] The title compound is prepared analogously as described in
example D2 using dimethylsulfamoyl chloride instead of
cyclopropanesulfonyl chloride.
[0353] MS: 499 [M+H]
[0354] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 0.94 min.
Example D4a
Dimethylsulfamic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide maleate
[0355] The title compound is prepared analogously as described in
example D2a using Dimethylsulfamic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide instead of cyclopropanesulfonic
acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example D4b
Dimethylsulfamic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide toluene-4-sulfonate
[0356] The title compound is prepared analogously as described in
example D2b using Dimethylsulfamic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}ethyl)-amide instead of cyclopropanesulfonic
acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl)ethyl}-amide.
Example D5
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]octane-sulfonyl}-ethyl)-4-methoxy-benzenesulfonamide
[0357] The title compound is prepared analogously as described in
example D2 using 4-methoxyphenylsulfonyl chloride instead of
cyclopropanesulfonyl chloride.
[0358] MS: 562 [M+H]
[0359] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.0 min.
Example D5a
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]octane-8-sulfonyl}-ethyl)-4-methoxy-benzenesulfonamide
maleate
[0360] The title compound is prepared analogously as described in
example D2a using
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-az-
a-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-4-methoxy-benzenesulfonamide
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example D5b
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]octane-8-sulfonyl}-ethyl)-4-methoxy-benzenesulfonamide
toluene-4-sulfonate
[0361] The title compound is prepared analogously as described in
example D2b using
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-az-
a-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-4-methoxy-benzenesulfonamide
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example D6
Tetrahydropyran-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide
[0362] The title compound is prepared analogously as described in
example D1 using tetrahydro-2H-pyran-4-carboxylic acid instead of
5-methylpyrazinecarboxylic acid.
[0363] MS: 505 [M+H]
[0364] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.92 min.
Example D7
Morpholine-4-sulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide
[0365] The title compound is prepared analogously as described in
example D2 using 4-morpholinesulfonyl chloride instead of
cyclopropanesulfonyl chloride.
[0366] MS: 541 [M+H]
[0367] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.13 min.
Example D8
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide
A) 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid
(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluor-
o-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-amide
[0368] To a solution of
2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-
-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethylamine
(100 mg, 0.202 mmol) in dichloromethane/2N NaOH (2 mL, 1/1) are
2-phtalimidoethanesulfonyl chloride (167 mg, 0.605 mmol). The
resulting solution is stirred at 50.degree. C. during 2 h before
extraction and evaporation of organic phase to yield the crude
compound. It is purified by preparative HPLC (Column Waters C18 ODB
5 .mu.m 19.times.50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min
5-100% ACN, 12.5-15 min 100% ACN) to yield title compound.
[0369] MS: 734 [M+H]+
[0370] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.43 min.
B) 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}ethyl)-amide
[0371] To 2-(1,3-Dioxo-1,3-dihydroisoindol-2-yl)ethanesulfonic acid
(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluor-
o-phenyl-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-amide
(49 mg, 0.057 mmol) in dioxane (3 mL) is added 4N HCl in dioxane (3
mL). The resulting mixture is stirred at rt during 1 h. The
solution is frozen and lyophilised to give a white solid before
purification by preparative HPLC (Column Waters C18 ODB 5 .mu.m
19.times.50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min 5-100% ACN,
12.5-15 min 100% ACN) to yield title compound.
[0372] MS: 629 [M+H]+
[0373] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.22 min.
Example D9
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]octane-8-sulfonyl}-ethyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pro-
pionamide
[0374] The title compound is prepared analogously as described in
example D1 using 2-phtamilidoethanecarboxylic acid instead of
5-methylpyrazinecarboxylic acid.
[0375] MS: 593 [M+H]
[0376] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.8 min.
Example D10
(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2-
.1]octane-8-sulfonyl}-ethyl)-carbamic acid 2-methoxy-ethyl
ester
[0377] The title compound is prepared analogously as described in
example D8 using chloroformic acid 2-methoxyethylester instead of
2-phtalimidoethanesulfonyl chloride.
[0378] MS: 494 [M+H]
[0379] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.14 min.
Example D10a
(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2-
.1]octane-8-sulfonyl}-ethyl)-carbamic acid 2-methoxy-ethyl ester
maleate
[0380] The title compound is prepared analogously as described in
example D2a using (2-{3-exo
[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-
-8-sulfonyl}-ethyl)-carbamic acid 2-methoxy-ethyl ester instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example D10b
(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2-
.1]octane-4-sulfonyl}-ethyl)-carbamic acid 2-methoxy-ethyl ester
toluene-4-sulfonate
[0381] The title compound is prepared analogously as described in
example D2b using
(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza--
bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-carbamic acid
2-methoxy-ethyl ester instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example D11
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]octane-8-sulfonyl}-ethyl)-4-methoxy-benzamide
[0382] The title compound is prepared analogously as described in
example D1 using p-anisic acid instead of
5-methylpyrazinecarboxylic acid.
[0383] MS: 526 [M+H]
[0384] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.18 min.
Example D12
(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2-
.1]octane-8-sulfonyl}-ethyl)-carbamic acid
1,1-dioxo-benzothiophen-2-yl-methyl ester
[0385] The title compound is prepared analogously as described in
example D8 using 1,1-dioxobenzothiophen-2-yl-methylchloroformate
instead of 2-phtalimidoethanesulfonyl chloride.
[0386] MS: 614 [M+H]
[0387] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.21 min.
Example D13
(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2-
.1]octane-8-sulfonyl}-ethyl)-carbamic acid ethyl ester
[0388] The title compound is prepared analogously as described in
example D2 using ethylchloroformate instead of cyclopropanesulfonyl
chloride.
[0389] MS: 464 [M+H]
[0390] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.96 min.
Example D14
Pyrrolidine-1-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide
[0391] The title compound is prepared analogously as described in
example D2 using 1-pyrrolidinecarbonyl chloride instead of
cyclopropanesulfonyl chloride.
[0392] MS: 489 [M+H]
[0393] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.97 min.
Example D15
Morpholine-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide
[0394] The title compound is prepared analogously as described in
example D2 using 4-morpholinecarbonyl chloride instead of
cyclopropanesulfonyl chloride.
[0395] MS: 505 [M+H]
[0396] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.92 min.
Example D15a
Morpholine-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide maleate
[0397] The title compound is prepared analogously as described in
example D2a using morpholine-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}ethyl)-amide instead of cyclopropanesulfonic
acid (2-{3-exo
[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example D15b
Morpholine-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide toluene-4-sulfonate
[0398] The title compound is prepared analogously as described in
example D2b using morpholine-4-carboxylic acid
(2-{3-ex-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2-
.1]octane-8-sulfonyl}-ethyl)-amide instead of cyclopropanesulfonic
acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example D16
1-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]octane-8-sulfonyl}-ethyl)-3-(2-methoxy-ethyl)-urea
A) (S)-2-Methyl-propane-2-sulfinic acid
[(R)-1-(3-exo-8-{2-[3-(2-methoxy-ethyl)-ureido]-ethanesulfonyl}-8-aza-bic-
yclo[3.2.1]oct-3-yl)-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
[0399] To a solution of 2-methoxyethylamine (29.8 uL, 0.344 mmol)
in dimethyl formamide (2 mL) is added 1,1'-carbonyldiimidazole
(58.6 mg). After stirring at rt,
2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-
-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethylamine
(180 mg, 0.312 mmol) is added. The resulting solution is stirred at
80.degree. C. during 3 h before purification by preparative HPLC
(Column Waters C18 ODB 5 .mu.m 19.times.50, Gradient: 0-2.5 min 5%
ACN, 2.5-12.5 min 5-100% ACN, 12.5-15 min 100% ACN) to yield title
compound.
[0400] MS: 597 [M+H]+
[0401] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.32 min.
B)
1-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]octane-8-sulfonyl}-ethyl)-3-(2-methoxy-ethyl)-urea
[0402] To (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-(3-exo-8-{2-[3-(2-methoxy-ethyl)ureido]-ethanesulfonyl}-8-aza-bicy-
clo[3.2.1]oct-3-yl)-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide (143
mg, 0.206 mmol) in dioxane (3 mL) is added 4N HCl in dioxane (3
mL). The resulting mixture is stirred at rt during 1 h. The
solution is frozen and lyophilised to give a white solid before
purification by preparative HPLC (Column Waters C18 ODB 5 .mu.m
19.times.50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min 5-100% ACN,
12.5-15 min 100% ACN) to yield title compound.
[0403] MS: 493 [M+H]+
[0404] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.12 min.
Example D17
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid
(2-{4-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidine-1-sulfony-
l}-ethyl)-amide
[0405] The title compound is prepared analogously as described in
example D8 using (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
instead of
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-ph-
enyl)-ethyl]-8-aza-bicyclo[3.2.1]octane.
[0406] MS: 603 [M+H]
[0407] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.17 min.
Example D18
N-[2-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]octane-8-sulfonyl}-ethylsulfamoyl)-ethyl]-benzamide
A) 2-Amino-ethanesulfonic acid
(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluor-
o-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-amide
[0408] The title compound is prepared analogously as described in
example D1 using
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid
(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluor-
o-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-amide
instead of
N-(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-triflu-
oro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-phthalimi-
de.
[0409] MS: 603 [M+H]
[0410] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.22 min.
B)
N-[2-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bic-
yclo[3.2.1]octane-8-sulfonyl}-ethylsulfamoyl)-ethyl]-benzamide
[0411] The title compound is prepared analogously as described in
example D1 using 2-amino-ethanesulfonic acid
(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluor-
o-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-amide
instead of
2-{3-exo-[(R)-1-((S)-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-
-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethylamine
and benzoic acid instead of 5-methyl-pyrazine-2-carboxylic
acid.
[0412] MS: 601 [M+H]
[0413] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.16 min.
Example D19
Oxazole-5-carboxylic acid
[2-(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo-
[3.2.1]octane-8-sulfonyl}-ethylsulfamoyl)-ethyl]-amide
[0414] The title compound is prepared analogously as described in
example D1 using oxazole-5-carboxylic acid instead of
5-methylpyrazinecarboxylic acid.
[0415] MS: 488 [M+H]
[0416] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.17 min.
Example E1
Cyclopropanecarboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-4-yl}-2-oxo-ethyl)-amide
[0417] This compound is prepared according to Scheme E:
##STR00109## ##STR00110##
A) (S)-2-Methyl-propane-2-sulfinic acid
[(R)-1-{3-exo-8-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetyl]-8-aza-bi-
cyclo[3.2.1]oct-3-yl}-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
[0418] To a solution of N-phthaloylglycine (291 mg, 1.41 mmol) in
acetonitrile (7 mL) is added
benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate
(805 mg, 1.54 mmol) and the resulting mixture is stirred at rt
during 1 h before addition of
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-ph-
enyl)-ethyl]-8-aza-bicyclo[3.2.1]octane (500 mg, 1.29 mmol) and
triethylamine (720 .mu.L, 5.16 mmol) in acetonitrile (5 mL). The
resulting solution is stirred at rt during 16 h and is evaporated
before purification by preparative HPLC (Column Interchrom C18 ODB
10 .mu.m 28.times.250, Gradient: 0-2.5 min 5% ACN, 2.5-25.5 min
5-100% ACN, 25.5-30 min 100% ACN) to yield a yellow solid.
[0419] MS: 576 [M+H]+
[0420] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.22 min.
B) (S)-2-Methyl-propane-2-sulfinic acid
[(R)-1-[3-exo-8-(2-amino-acetyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-(2,4,5-t-
rifluoro-phenyl)-ethyl]-amide
[0421] To (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-{3-exo-8-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)acetyl]-8-aza-bic-
yclo[3.2.1]oct-3-yl}-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide (300
mg, 0.521 mmol) in ethanol (3.5 mL) is added hydrazine monohydrate
(1.3 mL, 26.05 mmol) and the resulting solution is stirred at rt
during 16 h. After extraction with dichloromethane and aqueous
saturated NaHCO.sub.3, the organic phase is dried and evaporated to
yield a white solid.
[0422] MS: 446 [M+H]+
[0423] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.96 min.
C) Cyclopropanecarboxylic acid
(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluor-
o-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0424] To a solution of (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-[3-exo-8-(2-amino-acetyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-(2,4,5-t-
rifluoro-phenyl)-ethyl]-amide (50 mg, 0.112 mmol) in
dichloromethane (1 mL) are added triethylamine (32 .mu.L, 0.224
mmol) and cyclopropanecarbonyl chloride (14 .mu.L, 0.134 mmol). The
resulting solution is stirred at rt during 2 h before evaporation
and purification by preparative HPLC (Column Waters C18 ODB 5 .mu.m
19.times.50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min 5-100% ACN,
12.5-15 min 100% ACN) to yield a white solid.
[0425] MS: 514 [M+H]+
[0426] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
2.87 min.
D) Cyclopropanecarboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0427] To cyclopropanecarboxylic acid
(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluor-
o-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-amide
(26.4 mg, 0.052 mmol) in dioxane (0.5 mL) is added 4N HCl in
dioxane (0.5 mL). The resulting mixture is stirred at rt during 1
h. The solution is frozen and lyophilised to give a white
solid.
[0428] MS: 410 [M+H]+
[0429] HPLC (Nucleosil 100-5 C18, 10 min method (0-1 min 10% ACN,
1-6 min 10-100% ACN, 6-8.5 min 100% ACN, 8.5-9 min 100-10% ACN,
9-10 min 10% ACN): 3.55 min.
Example E1a
Cyclopropanecarboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-4-yl}-2-oxo-ethyl)-amide maleate
[0430] The title compound is prepared analogously as described in
example D2a using Cyclopropanecarboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide instead of cyclopropanesulfonic
acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example E1b
Cyclopropanecarboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide toluene-4-sulfonate
[0431] The title compound is prepared analogously as described in
example D2b using Cyclopropanecarboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide instead of cyclopropanesulfonic
acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example E2
5-Methyl-pyrazine-2-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0432] This compound is also prepared according to Scheme E and
analogously to example D1 using
2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-
-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethylamine
instead of
2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino-2-(2,4,5-trifluoro--
phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethylamine.
[0433] MS: 462 [M+H]
[0434] HPLC (Nucleosil 100-5 C18, 10 min method (0-1 min 10% ACN,
1-6 min 10-100% ACN, 6-8.5 min 100% ACN, 8.5-9 min 100-10% ACN,
9-10 min 10% ACN): 3.59 min.
Example E3
Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0435] This compound is prepared analogously to example E1 using
cyclopropanesulfonyl chloride instead of cyclopropanecarbonyl
chloride.
[0436] MS: 446 [M+H]
[0437] HPLC (Nucleosil 100-5 C18, 10 min method (0-1 min 10% ACN,
14 min 10-100% ACN, 6-8.5 min 100% ACN, 8.5-9 min 100-10% ACN, 9-10
min 10% ACN): 3.56 min.
Example E3a
Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide maleate
[0438] The title compound is prepared analogously as described in
example D2a using cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide instead of cyclopropanesulfonic
acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example E3b
Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide toluene-4-sulfonate
[0439] The title compound is prepared analogously as described in
example D2b using cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide instead of cyclopropanesulfonic
acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example E4
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-2-oxo-ethyl)-acetamide
A)
N-(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trif-
luoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-acetamide
[0440] To
2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5--
trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethylamine
(50 mg, 0.112 mmol) in acetic acid (2 mL) is added acetic anhydride
(16 .mu.L, 0.168 mmol) and the resulting solution is stirred at rt
during 3 h. After extraction with dichloromethane and aqueous
saturated NaHCO.sub.3, the organic phase is dried and evaporated to
give a residue which is purified by preparative HPLC (Column
Interchrom C18 ODB 10 .mu.m 28.times.250, Gradient: 0-2.5 min 5%
ACN, 2.5-25.5 min 5-100% ACN, 25.5-30 min 100% ACN) to yield a
colorless gum.
[0441] MS: 488 [M+H]+
[0442] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.09 min.
B)
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl}-2-oxo-ethyl)-acetamide
[0443] To
N-(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4-
,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-ace-
tamide (38 mg, 0.078 mmol) in dioxane (0.5 mL) is added 4N HCl in
dioxane (0.5 mL). The resulting mixture is stirred at rt during 1
h. The solution is frozen and lyophilised to give a white solid
before purification by preparative HPLC (Column Waters C18 ODB 5
.mu.m 19.times.50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min 5-100%
ACN, 12.5-15 min 100% ACN) to yield a light yellow solid.
[0444] MS 384 [M+H]+
[0445] HPLC (Nucleosil 100-5 C18, 10 min method (0-1 min 10% ACN,
1-6 min 10-100% ACN, 6-8.5 min 100% ACN, 8.5-9 min 100-10% ACN,
9-10 min 10% ACN): 3.28 min.
Example E5
Morpholine-4-sulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0446] The title compound is prepared analogously as described in
example E1 using morpholinesulfonyl chloride instead of
cyclopropanecarbonyl chloride.
[0447] MS: 491 [M+H]
[0448] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.92 min.
Example E6
Morpholine-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0449] The title compound is prepared analogously as described in
example E1 using morpholinecarbonyl chloride instead of
cyclopropanecarbonyl chloride.
[0450] MS: 455 [M+H]
[0451] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.87 min.
Example E6a
Morpholine-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide maleate
[0452] The title compound is prepared analogously as described in
example D2a using morpholine-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl-ethyl]-8-aza-bicyclo[3.2-
.1]oct-8-yl}-2-oxo-ethyl)-amide instead of cyclopropanesulfonic
acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example E6b
Morpholine-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide toluene-4-sulfonate
[0453] The title compound is prepared analogously as described in
example D2b using morpholine-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide instead of cyclopropanesulfonic
acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}ethyl)-amide.
Example E7
1-Hydroxy-cyclopropanecarboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0454] The title compound is prepared analogously as described in
example E2 using 1-hydroxycyclopropane-1-carboxylic acid instead of
4-methylpyrazinecarboxylic acid.
[0455] MS: 426 [M+H]
[0456] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.87 min.
Example E8
Tetrahydropyran-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0457] The title compound is prepared analogously as described in
example E2 using tetrahydropyran-4-carboxylic acid instead of
4-methylpyrazinecarboxylic acid.
[0458] MS: 454 [M+H]
[0459] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.18 min.
Example E9
Cyclobutanecarboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0460] The title compound is prepared analogously as described in
example E2 using cyclobutanecarboxylic acid instead of
4-methylpyrazinecarboxylic acid.
[0461] MS: 424 [M+H]
[0462] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.22 min.
Example E10
3-Methyl-3H-imidazole-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0463] The title compound is prepared analogously as described in
example E2 using 3-methyl-3H-imidazole-4-carboxylic acid instead of
4-methylpyrazinecarboxylic acid.
[0464] MS: 449 [M-H]+
[0465] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.76 min.
Example E11
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-2-oxo-ethyl)-4-fluoro-benzamide
[0466] This compound is prepared analogously to example E1 using
4-fluorobenzoyl chloride instead of cyclopropanecarbonyl
chloride.
[0467] MS: 464 [M-H]+
[0468] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.13 min.
Example E11a
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-2-oxo-ethyl)-4-fluoro-benzamide maleate
[0469] The title compound is prepared analogously as described in
example D2a using N-(2-{3-exo
[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8--
yl}2-oxo-ethyl)-4-fluoro-benzamide instead of cyclopropanesulfonic
acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example E11b
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-2-oxo-ethyl)-4-fluoro-benzamide
toluene-4-sulfonate
[0470] The title compound is prepared analogously as described in
example D2b using
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-az-
a-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-4-fluoro-benzamide instead
of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}ethyl)-amide.
Example E12
3H-Imidazole-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0471] This compound is prepared analogously to example E2 using
N-boc-3H-imidazole-4-carboxylic acid instead of
4-methylpyrazinecarboxylic acid.
[0472] MS: 436 [M-H]+
[0473] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.81 min.
Example E13
Pyrazine-2-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0474] This compound is prepared analogously to example E2 using
pyrazine-2-carboxylic acid instead of 4-methylpyrazinecarboxylic
acid.
[0475] MS: 448 [M-H]+
[0476] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.2 min.
Example E14
4-Methyl-oxazole-5-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0477] This compound is prepared analogously to example E2 using
4-methyl-oxazole-5-carboxylic acid instead of
4-methylpyrazinecarboxylic acid.
[0478] MS: 451 [M-H]+
[0479] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.9 min.
Example E15
2-Amino-pyrimidine-5-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0480] This compound is prepared analogously to example E2 using
2-amino-pyrimidine-5-carboxylic acid instead of
4-methylpyrazinecarboxylic acid.
[0481] MS: 463 [M-H]+
[0482] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.11 min.
Example E16
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-2-oxo-ethyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetam-
ide
[0483] This compound is prepared analogously to example E2 using
N-phthaloylglycine instead of 4-methylpyrazinecarboxylic acid.
[0484] MS: 530 [M-H]+
[0485] HPLC (waters symmetry C18, 6 min method (0-3.5 min 5-95%
ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 5%
ACN): 2.87 min.
Example E17
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-2-oxo-ethyl)-4-fluoro-benzenesulfonamide
[0486] This compound is prepared analogously to example E1 using
4-fluorophenylsulfonyl chloride instead of cyclopropanecarbonyl
chloride.
[0487] MS: 500 [M-H]+
[0488] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.14 min.
Example E18
N-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-3-oxo-propyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propi-
onamide
A) (S)-2-Methyl-propane-2-sulfinic acid
[(R)-1-[3-exo-8-(3-amino-propionyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-(2,4,-
5-trifluoro-phenyl)-ethyl]-amide
[0489] This compound is prepared analogously to example E1 using
N-phthaloyl-beta-glycine instead of N-phthaloylglycine.
[0490] MS: 460 [M-H]+
[0491] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.17 min.
B)
N-(3-{3-exo-[(R-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo-
[3.2.1]oct-8-yl}-3-oxo-propyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pro-
pionamide
[0492] This compound is prepared analogously to example E2 using
N-phthaloyl-beta-glycine instead of 4-methylpyrazinecarboxylic
acid. MS: 557 [M-H]+
[0493] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.17 min.
Example E19
Cyclopropanesulfonic acid
(3-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-3-oxo-propyl)-amide
[0494] This compound is prepared analogously to example E3 using
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-[3-exo-8-(3-amino-propionyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-(2,4,-
5-trifluoro-phenyl)-ethyl]-amide instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-[3-exo-8-(2-amino-acetyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-(2,4,5-t-
rifluoro-phenyl)-ethyl]-amide.
[0495] MS: 460 [M-H]+
[0496] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.11 min.
Example E20
N-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-3-oxo-propyl)-acetamide
[0497] This compound is prepared analogously to example E4 using
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-[3-exo-8-(3-amino-propionyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-(2,4,-
5-trifluoro-phenyl)-ethyl]-amide instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-[3-exo-8-(2-amino-acetyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-(2,4,5-t-
rifluoro-phenyl)-ethyl]-amide. MS: 398 [M-H]+
[0498] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.07 min.
Example E20a
N-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-3-oxo-propyl)-acetamide maleate
[0499] The title compound is prepared analogously as described in
example D2a using
N-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-az-
a-bicyclo[3.2.1]oct-8-yl}-3-oxo-propyl)acetamide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example E20b
N-3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-3-oxo-propyl)-acetamide toluene-4-sulfonate
[0500] The title compound is prepared analogously as described in
example D2b using
N-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-az-
a-bicyclo[3.2.1]oct-8-yl}-3-oxo-propyl)-acetamide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example E21
N-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-3-oxo-propyl)-benzamide
[0501] This compound is prepared analogously to example E19 using
benzoylchloride instead of cyclopropanesulfonyl chloride.
[0502] MS: 460 [M-H]+
[0503] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.12 min.
Example E22
Cyclopropanecarboxylic acid
(2-{4-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-2-ox-
o-ethyl)-amide
[0504] The title compound is prepared analogously as described in
example E1 (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
instead of
3-exo-[(R1)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-p-
henyl)-ethyl]-8-aza-bicyclo[3.2.1]octane.
[0505] MS: 384 [M+H]
[0506] HPLC (YMC Pack ODS-AQ 3 .mu.m 2.1.times.50 mm, 6 min method
(0-3.5 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-20% ACN,
5.55-6 min 5% ACN): 2.6 min.
Example E23
N-(2-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-2-o-
xo-ethyl)-benzamide
[0507] This compound is prepared analogously to example E22 using
benzoylchloride instead of cyclopropanecarbonyl chloride.
[0508] MS: 420 [M+H]
[0509] HPLC (YMC Pack ODS-AQ 3 .mu.m 2.1.times.50 mm, 6 min method
(0-3.5 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-20% ACN,
5.55-6 min 5% ACN): 2.83 min.
Example E24
Cyclopropanecarboxylic acid
(2-{(1S,3S,5R)-3-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bic-
yclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-isopropyl-amide
A) (S)-2-Methyl-propane-2-sulfinic acid
[(R)-1-[(1S,5R)-8-(2-isopropylamino-acetyl)
bicyclo[3.2.1]oct-3-yl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
[0510] To (S)-2-Methyl-propane-2-sulfinic acid
[(R)-1-[(1S,5R)-8-(2-amino-acetyl)-bicyclo[3.2.1]oct-3-yl]-2-(2,4,5-trifl-
uoro-phenyl)-ethyl]-amide (150 mg, 0.33 mmol) in methanol (3 mL) is
added acetic acid until to have pH 5-5.5. After addition of acetone
(124 uL, 1.68 mmol), the reaction is stirred at rt during 1 h and
sodium cyanoborohydride (43 mg, 0.67 mmol) is added before stirring
at rt during 16 h. The reaction is quenched with ethylacetate and
an aqueous saturated NaHCO3 solution, the organic phase is dried
and evaporated to afford the crude compound before purification
onto a SCX-2 cartridge (5 g, DCM/MeOH 1:1, then 2N NH3 in MeOH) to
yield the title compound.
[0511] MS: 488 [M+H]
[0512] HPLC (Luna 3 microns C18(2) 30.times.4.6 mm, 6 min method,
0-0.5 min 5% ACN, 0.5-5.5 min 5-95% ACN, 5.5-6 min 5% ACN): 2.17
min.
B) Cyclopropanecarboxylic acid
(2-{(1S,3S,5R)-3-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bic-
yclo[3.2.1]oct-8-yl}-2-oxo-ethyl)isopropyl-amide
[0513] This compound is prepared analogously to example E1 using
(S)-2-Methyl-propane-2-sulfinic acid
[(R)-1-[(1S,5R)-8-(2-isopropylamino-acetyl)-bicyclo[3.2.1]oct-3-yl]-2-(2,-
4,5-trifluoro-phenyl)-ethyl]-amide instead of
(S)-2-Methyl-propane-2-sulfinic acid
[(R)-1-[3-exo-8-(2-amino-acetyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-(2,4,5-t-
rifluoro-phenyl)-ethyl]-amide. MS: 452 [M+H]
[0514] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 6.39 min.
Example E25
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-3-phenyl-propionamide
[0515] The title compound is prepared analogously as described in
example E2 using 3-Phenylpropionic acid instead of
4-methylpyrazinecarboxylic acid.
[0516] MS: 474 [M+H]
[0517] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 6.74 min.
Example E25a
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-3-phenyl-propionamide
maleate
[0518] The title compound is prepared analogously as described in
example D2a using
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethy-
l]-8-aza-bicyclo[3.2.1]-oct-8-yl}-2-oxo-ethyl)-3-phenyl-propionamide
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example E25b
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-3-phenyl-propionamide
toluene-4-sulfonate
[0519] The title compound is prepared analogously as described in
example D2b using
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethy-
l]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-3-phenyl-propionamide
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example E26
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-2-phenoxy-acetamide
[0520] The title compound is prepared analogously as described in
example E2 using 2-Phenoxyacetic acid instead of
4-methylpyrazinecarboxylic acid.
[0521] MS: 476 [M+H]
[0522] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 6.67 min.
Example E27
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-2-(3-methyl-isoxazol-5-yl)-acetamide
[0523] The title compound is prepared analogously as described in
example E2 using (3-Methyl-isoxazol-5-yl)-acetic acid instead of
4-methylpyrazinecarboxylic acid.
[0524] MS: 465 [M+H]
[0525] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 5.76 min.
Example E28
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-2-morpholin-4-yl-acetamide
[0526] The title compound is prepared analogously as described in
example E2 using Morpholin-4-yl-acetic acid instead of
4-methylpyrazinecarboxylic acid.
[0527] MS: 469 [M+H]
[0528] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 4.09 min.
Example E29
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-2-phenyl-acetamide
[0529] The title compound is prepared analogously as described in
example E2 using Phenylacetic acid instead of
4-methylpyrazinecarboxylic acid.
[0530] MS: 460 [M+H]
[0531] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 6.38 min.
Example E30
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-C-phenyl-methanesulfonamide
[0532] The title compound is prepared analogously as described in
example E1 using Phenylmethanesulfonyl chloride instead of
cyclopropanecarbonyl chloride.
[0533] MS: 496 [M+H]
[0534] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 6.76 min.
Example E30a
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-C-phenyl-methanesulfonamide
maleate
[0535] The title compound is prepared analogously as described in
example D2a using
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethy-
l]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-C-phenyl-methanesulfonamide
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example E30b
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-C-phenyl-methanesulfonamide
toluene-4-sulfonate
[0536] The title compound is prepared analogously as described in
example D2b using
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethy-
l]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-C-phenyl-methanesulfonamide
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example E31
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-2-[1,2,4]triazol-1-yl-isobutyramide
[0537] The title compound is prepared analogously as described in
example E2 using 2-Methyl-2-[1,2,4]triazol-1-yl-propionic acid
instead of 4-methylpyrazinecarboxylic acid.
[0538] MS: 479 [M+H]
[0539] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 5.53 min.
Example E32
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-2-(tetrahydro-pyran-4-yl)-acetamide
[0540] The title compound is prepared analogously as described in
example E2 using (Tetrahydro-pyran-4-yl)acetic acid instead of
4-methylpyrazinecarboxylic acid.
[0541] MS: 468 [M+H]
[0542] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95% CAN, 22-25 min 5% ACN): 5.56 min.
Example E33
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-2-methoxy-benzamide
[0543] The title compound is prepared analogously as described in
example E2 using 2-methoxybenzoic acid instead of
4-methylpyrazinecarboxylic acid.
[0544] MS: 476 [M+H]
[0545] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 6.62 min.
Example E34
2,3-Dihydro-benzo[1,4]dioxine-5-carboxylic acid
(2-{(1S,3S,5R)-3-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bic-
yclo[3.2.1]oct-8-yl})-2-oxo-ethyl)-amide
[0546] The title compound is prepared analogously as described in
example E2 using 2,3-Dihydro-benzo[1,4]dioxine-5-carboxylic acid
instead of 4-methylpyrazinecarboxylic acid.
[0547] MS: 504 [M+H]
[0548] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 6.43 min.
Example E35
Pyridazine-3-carboxylic acid
(2-{(1S,3S,5R)-3-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bic-
yclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0549] The title compound is prepared analogously as described in
example E2 using Pyridazine-3-carboxylic acid instead of
4-methylpyrazinecarboxylic acid.
[0550] MS: 448 [M+H]
[0551] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 5.56 min.
Example E36
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-2-(3H-imidazol-4-yl)-acetamide
[0552] The title compound is prepared analogously as described in
example E2 using (3H-Imidazol-4-yl)acetic acid instead of
4-methylpyrazinecarboxylic acid.
[0553] MS: 450 [M+H]
[0554] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 0.84-3.14 min.
Example E37
2-Phenyl-ethanesulfonic acid
(2-{(1S,3S,5R)-3-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bic-
yclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0555] The title compound is prepared analogously as described in
example E1 using Phenylethanesulfonyl chloride instead of
cyclopropanecarbonyl chloride.
[0556] MS: 510 [M+H]
[0557] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 6.35 min.
Example E38
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-4-methyl-benzenesulfonamide
[0558] The title compound is prepared analogously as described in
example E1 using toluenesulfonyl chloride instead of
cyclopropanecarbonyl chloride.
[0559] MS: 496 [M+H]
[0560] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 6.11 min.
Example E39
2,3-Dihydro-benzo[1,4]dioxine-6-sulfonic acid
(2-{(1S,3S,5R)-3-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bic-
yclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0561] The title compound is prepared analogously as described in
example E1 using 2,3-Dihydro-benzo[1,4]dioxine-6-sulfonyl chloride
instead of cyclopropanecarbonyl chloride.
[0562] MS: 540 [M+H]
[0563] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 955% CAN, 22-25 min 5% ACN): 5.87 min.
Example E40
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-2-methoxy-benzenesulfonamide
[0564] The title compound is prepared analogously as described in
example E1 using 2-Methoxybenzenesulfonyl chloride instead of
cyclopropanecarbonyl chloride.
[0565] MS: 512 [M+H]
[0566] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 5.74 min.
Example E40a
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-2-methoxy-benzenesulfonamide
maleate
[0567] The title compound is prepared analogously as described in
example D2a using
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethy-
l]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-2-methoxy-benzenesulfonamide
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example E40b
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-2-methoxy-benzenesulfonamide
toluene-4-sulfonate
[0568] The title compound is prepared analogously as described in
example D2b using
N-(2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethy-
l]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-2-methoxy-benzenesulfonamide
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example E41
3,5-Dimethyl-isoxazole-4-sulfonic acid
(2-{(1S,3S,5R)-3-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bic-
yclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0569] The title compound is prepared analogously as described in
example E1 using 3,5-Dimethyl-isoxazole-4-sulfonyl chloride instead
of cyclopropanecarbonyl chloride.
[0570] MS: 501 [M+H]
[0571] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 5.55 min.
Example E42
1,3,5-Trimethyl-1H-pyrazole-4-sulfonic acid
(2-{(1S,3S,5R)-3-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bic-
yclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0572] The title compound is prepared analogously as described in
example E1 using 1,3,5-Trimethyl-1H-pyrazole-4-sulfonyl chloride
instead of cyclopropanecarbonyl chloride.
[0573] MS: 514 [M+H]
[0574] HPLC (Higgins Clipeus 5 microns C18(2) 100.times.3 mm, 25
min method, 0-1 min 5% ACN, 1-15 min 5-95% ACN, 15-20 95% CAN,
20-22 min 95-5% CAN, 22-25 min 5% ACN): 5.15 min.
Example F1
Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-methyl-amide
[0575] This compound is prepared according to Scheme F, in which
"Cbz" is carbobenzoxy:
##STR00111## ##STR00112##
A)
Methyl-(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,-
5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-carb-
amic acid benzyl ester
[0576] The title compound is prepared analogously as described in
example E1 using N-methyl-N-Cbz-glycine instead of
N-phthaloylglycine.
[0577] MS: 594 [M+H]
[0578] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.25 min.
B)
Methyl-2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5--
trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethylamine
[0579] To
methyl-(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-
-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl-
)-carbamic acid benzyl ester (340 mg, 0.573 mmol) in ethanol (5 mL)
is added palladium on charcoal (122 mg, 0.114 mmol) and the
resulting mixture is stirred at rt during 4 h under
H.sub.2-atmosphere. The suspension is filtered through celite and
the filtrate is evaporated to yield a grey solid.
[0580] MS: 460 [M+H]
[0581] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.97 min.
C) Cyclopropanesulfonic acid
methyl-(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-t-
rifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-amide
[0582] To a solution of
methyl-2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tr-
ifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethylamine
(100 mg, 0.217 mmol) in dichloromethane (2 mL) are added
triethylamine (91 .mu.L, 0.651 mmol) and cyclopropanesulfonyl
chloride (33 .mu.L, 0.326 mmol). The resulting solution is stirred
at rt during 3 h before evaporation and purification by preparative
HPLC (Column Waters C18 ODB 5 .mu.m 19.times.50, Gradient 0-2.5 min
5% ACN, 2.5-12.5 min 5-100% ACN, 12.5-15 min 100% ACN) to yield a
white solid.
[0583] MS: 564 [M+H]+
[0584] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.18 min.
D) Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-methyl-amide
[0585] To cyclopropanesulfonic acid
methyl-(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-t-
rifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-amide
(62 mg, 0.11 mmol) in dioxane (1 mL) is added 4N HCl in dioxane (1
mL). The resulting mixture is stirred at rt during 1 h. The
solution is frozen and lyophilised to give a white solid.
[0586] MS 460 [M+H]+
[0587] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.95 min.
Example F1a
Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-methyl-amide maleate
[0588] The title compound is prepared analogously as described in
example D2a using cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-methyl-amide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]octane-8-sulfonyl}-ethyl)-amide.
Example F1b
Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-methyl-amide toluene-4-sulfonate
[0589] The title compound is prepared analogously as described in
example D2b using cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-2-oxo-ethyl)-methyl-amide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]octane-8-sulfonyl}-ethyl)-amide.
Example F2
Cyclopropanesulfonic acid
((S)-2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl}-1-hydroxymethyl-2-oxo-ethyl)-amide
[0590] The title compound is prepared analogously as described in
example F1 using N-Cbz-serine(tBu)-OH instead of
N-methyl-N-Cbz-glycine.
[0591] MS: 476 [M+H]+
[0592] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.88 min.
Example F3
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-2-oxo-ethyl)-N-methyl-acetamide
[0593] The title compound is prepared analogously as described in
example E4 using (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-[3-exo-8-(2-methylamino-acetyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-(2-
,4,5-trifluoro-phenyl)-ethyl]-amide instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-[3-exo-8-(2-amino-acetyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-(2,4,5-t-
rifluoro-phenyl)-ethyl]-amide.
[0594] MS: 398 [M+H]+
[0595] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.86 min.
Example F3a
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-2-oxo-ethyl)-N-methyl-acetamide maleate
[0596] The title compound is prepared analogously as described in
example D2a using
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-az-
a-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-N-methyl-acetamide instead
of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example F3b
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-2-oxo-ethyl)-N-methyl-acetamide
toluene-4-sulfonate
[0597] The title compound is prepared analogously as described in
example D2b using
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-az-
a-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-N-methyl-acetamide instead
of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example F4
Cyclopropanecarboxylic acid
((S)-2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl}-1-hydroxymethyl-2-oxo-ethyl)-amide
[0598] The title compound is prepared analogously as described in
example F1 using cyclopropane carbonyl chloride instead of
cyclopropane sulfonyl chloride.
[0599] MS: 424 [M+H]+
[0600] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 2.74 min.
Example F5
Cyclopropanecarboxylic acid
((S)-2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-amide
[0601] The title compound is prepared analogously as described in
example F4 using N-Cbz-(S)-alanine instead of
N-methyl-N-Cbz-glycine.
[0602] MS: 460 [M+H]+
[0603] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 2.80 min.
Example F5a
Cyclopropanecarboxylic acid
((S)-2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-amide maleate
[0604] The title compound is prepared analogously as described in
example D2a using cyclopropanecarboxylic acid
((S)-2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-amide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}ethyl)-amide.
Example F5b
Cyclopropanecarboxylic acid
((S)-2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-amide
toluene-4-sulfonate
[0605] The title compound is prepared analogously as described in
example D2b using cyclopropanecarboxylic acid
((S)-2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethylyamide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example F6
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-2-oxo-ethyl)-4-fluoro-N-methyl-benzenesulfonamide
[0606] The title compound is prepared analogously as described in
example F1 using 4-fluorophenylsulfonyl chloride instead of
cyclopropane sulfonyl chloride.
[0607] MS: 514 [M+H]+
[0608] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 3.13 min.
Example F7
Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-1,1-dimethyl-2-oxo-ethyl)-amide
[0609] The title compound is prepared analogously as described in
example F4 using N-Cbz-methyl-alanine instead of
N-methyl-N-Cbz-glycine.
[0610] MS: 474 [M+H]+
[0611] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.93 min.
Example F7a
Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-1,1-dimethyl-2-oxo-ethyl)-amide maleate
[0612] The title compound is prepared analogously as described in
example D2a using cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-1,1-dimethyl-2-oxo-ethyl)-amide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example F7b
Cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-1,1-dimethyl-2-oxo-ethyl)-amide
toluene-4-sulfonate
[0613] The title compound is prepared analogously as described in
example D2b using cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-1,1-dimethyl-2-oxo-ethyl)-amide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example F8
N-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-3-oxo-propyl)-N-methyl-acetamide
[0614] The title compound is prepared analogously as described in
example F3 using (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-[3-exo-8-(3-methylamino-propionyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-
-(2,4,5-trifluoro-phenyl)-ethyl]-amide instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-[3-exo-8-(2-methylamino-acetyl)-8-aza-bicyclo[3.2.1]oct-3-yl]-2-(2-
,4,5-trifluoro-phenyl)-ethyl]-amide.
[0615] MS: 412 [M+H]+
[0616] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.09 min.
Example F9
Cyclopropanecarboxylic acid
((R)-2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl}-1-hydroxymethyl-2-oxo-ethyl)-amide
A)
(R)-2-Benzyloxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)propioni-
c acid methyl ester
[0617] To (R-2-Benzyloxycarbonylamino-3-hydroxy-propionic acid
methyl ester (1 g, 4 mmol) in dimethyl formamide are added
triethylamine (1.2 mL, 8 mmol), tert-butyldimethylsilyl chloride
(895 mg, 6 mmol) and 4-dimethylaminopyridine (50 mg, 0.4 mmol).
After stirring at rt during 16 h, the reaction is quenched with
water and aqueous 1N HCl and extracted with ethyl acetate. The
organic phase is dried and evaporated to give a residue, which is
purified by flash chromatography (Silica gel, ethyl
acetate/cyclohexane 1/9 to 1/4) to yield a light yellow gum.
[0618] MS: 368 [M+H]+
[0619] HPLC (waters symmetry C18, 6 min method (0-3.5 min 20-95%
ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-20% ACN, 5.55-6 min 20%
ACN): 4.63 min.
B)
(R)-2-Benzyloxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)-propion-
ic acid
[0620] To
(R)-2-Benzyloxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)--
propionic acid methyl ester (1.450 g, 3.95 mmol) in
tetrahydrofuran/water (2/1) is added lithium hydroxide (250 mg,
5.92 mmol). After stirred at rt during 16 h, the solution is
treated with ethyl acetate and the pH is decrease to 2 with aqueous
1N HCl. The organic phase is dried and evaporated to yield the
title compound.
[0621] MS: 354 [M+H]+
[0622] HPLC (waters symmetry C18, 6 min method (0-3.5 min 20-95%
ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-20% ACN, 5.55-6 min 20%
ACN): 4.25 min.
C) Cyclopropanecarboxylic acid
((R)-2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl}-1-hydroxymethyl-2-oxo-ethyl)-amide
[0623] The title compound is prepared analogously as described in
example F2 using
(R)-2-benzyloxycarbonylamino-3-(tert-butyl-dimethyl-silanyloxy)--
propionic acid using instead of N-Cbz-serine(tBu)-OH and
cyclopropylcarboxylic acid instead of cyclopropylsulfonyl
chloride.
[0624] MS: 440 [M+H]+
[0625] HPLC (waters symmetry C18, 6 min method (0-3.5 min 5-95%
ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 5%
ACN): 2.65 min.
Example F10
N--((S)-2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-a-
za-bicyclo[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-isobutyramide
[0626] The title compound is prepared analogously as described in
example F5 using isobutyroyl chloride instead of cyclopropane
carbonyl chloride.
[0627] MS: 426 [M+H]+
[0628] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.239 min.
Example F11
N--((R)-2-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-a-
za-bicyclo[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-isobutyramide
[0629] The title compound is prepared analogously as described in
example F10 using N-Cbz-(R)-alanine instead of
N-Cbz-(S)-alanine.
[0630] MS: 426 [M+H]+
[0631] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.236 min.
Example F12
Cyclopropanecarboxylic acid
((R)-2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-amide
[0632] The title compound is prepared analogously as described in
example F5 using N-Cbz-(R)-alanine instead of N-Cbz-(S)-alanine.
MS: 424 [M+H]+
[0633] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.224 min.
Example F12a
Cyclopropanecarboxylic acid
((R)-2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-amide maleate
[0634] The title compound is prepared analogously as described in
example D2a using cyclopropanecarboxylic acid
((R)-2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl}-methyl-2-oxo-ethyl)-amide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example F12b
Cyclopropanecarboxylic acid
((R)-2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-amide
toluene-4-sulfonate
[0635] The title compound is prepared analogously as described in
example D2b using cyclopropanecarboxylic acid
((R)-2-{3-exo-[(R)-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[-
3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-amide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example G1
N--((S)-2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicy-
clo[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-acetamide
[0636] This compound is prepared according to Scheme G:
##STR00113##
A)
N--((S)-1-Methyl-2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino-
)-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-et-
hyl)acetamide
[0637] The title compound is prepared analogously as described in
example E1 using N-acetyl-L-alanine instead of
N-phtaloylglycine.
[0638] MS: 502 [M+H]+
[0639] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.11 min.
B)
N--((S)-2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-b-
icyclo[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-acetamide
[0640] To
N--((S)-1-Methyl-2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfiny-
lamino)-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2--
oxo-ethyl)acetamide (60 mg, 0.120 mmol) in dioxane (1 mL) is added
4N HCl in dioxane (1 mL). The resulting mixture is stirred at rt
during 1 h. The solution is frozen and lyophilised to give a white
solid before purification by preparative HPLC (Column Waters C18
ODB 5 .mu.m 19.times.50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min
5-100% ACN, 12.5-15 min 100% ACN) to yield the title compound.
[0641] MS: 398 [M+H]+
[0642] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.91 min.
Example G1a
N--((S)-2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicy-
clo[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-acetamide maleate
[0643] The title compound is prepared analogously as described in
example D2a using
N--((S)-2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-
-8-aza-bicyclo[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-acetamide
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example G1 b
N--((S)-2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicy-
clo[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-acetamide
toluene-4-sulfonate
[0644] The title compound is prepared analogously as described in
example D2b using
N--((S)-2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-
-8-aza-bicyclo[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-acetamide
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example G2
N--((R)-2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicy-
clo[3.2.1]oct-8-yl}-1-methyl-2-oxo-ethyl)-acetamide
[0645] The title compound is prepared analogously as described in
example G1 using N-acetyl-D-alanine instead of
N-acetyl-L-alanine.
[0646] MS: 398 [M+H]+
[0647] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.88 min.
Example G3
N-(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-2-oxo-ethyl)-benzamide
[0648] The title compound is prepared analogously as described in
example G1 using N-benzoylglycine instead of
N-acetyl-L-alanine.
[0649] MS: 446 [M+H]+
[0650] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.94 min.
Example G4
(R)-1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[-
3.2.1]oct-8-yl}-2-hydroxy-2-phenyl-propan-1-one
[0651] The title compound is prepared analogously as described in
example G1 using (R)-2-hydroxy-2-phenyl-propionic acid instead of
N-acetyl-L-alanine. MS: 433 [M+H]+
[0652] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.00 min.
Example G5
N--((S)-5-Acetylamino-1-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-eth-
yl]-8-aza-bicyclo[3.2.1]octane-carbonyl}-pentyl)-acetamide
[0653] The title compound is prepared analogously as described in
example G1 using (S)-2,6-bis-acetylamino-hexanoic acid instead of
N-acetyl-L-alanine.
[0654] MS: 497 [M+H]+
[0655] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.10 min.
Example G6
((S)-2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo-
[3.2.1]oct-8-yl}-2-oxo-1-phenyl-ethyl)-carbamic acid ethyl
ester
[0656] The title compound is prepared analogously as described in
example G1 using (S)-ethoxycarbonylamino-phenyl-acetic acid instead
of N-acetyl-L-alanine. MS: 490 [M+H]+
[0657] HPLC (waters symmetry C18, 6 min method (0-3.5 min 5-95%
ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 5%
ACN): 3.14 min.
Example G7
((R)-2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo-
[3.2.1]oct-8-yl}-2-oxo-1-phenyl-ethyl)-carbamic acid ethyl
ester
[0658] The title compound is prepared analogously as described in
example G1 using (R) ethoxycarbonylamino-phenyl-acetic acid instead
of N-acetyl-L-alanine.
[0659] MS: 490 [M+H]+
[0660] HPLC (waters symmetry C18, 6 min method (0-3.5 min 5-95%
ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 5%
ACN): 3.14 min.
Example G8
(S)-1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[-
3.2.1]oct-8-yl}-2-methoxy-2-phenyl-ethanone
[0661] The title compound is prepared analogously as described in
example G1 using (S) methoxyphenyl-acetic acid instead of
N-acetyl-L-alanine.
[0662] MS: 433 [M+H]+
[0663] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.556 min 20% ACN): 2.49 min.
Example G9
(R)-1-{-3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo-
[3.2.1]oct-8-yl}-2-methoxy-2-phenyl-ethanone
[0664] The title compound is prepared analogously as described in
example G1 using (R)-methoxyphenyl-acetic acid instead of
N-acetyl-L-alanine. MS: 433 [M+H]+
[0665] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 2.47 min.
Example G10
N-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-3-oxo-propyl)-benzenesulfonamide
[0666] The title compound is prepared analogously as described in
example G1 using 3-Benzenesulfonylamino-propionic acid instead of
N-acetyl-L-alanine.
[0667] MS: 496 [M+H]+
[0668] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.17 min.
Example G10a
N-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-3-oxo-propyl)-benzenesulfonamide maleate
[0669] The title compound is prepared analogously as described in
example D2a using
N-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-az-
a-bicyclo[3.2.1]oct-8-yl}-3-oxo-propyl)-benzenesulfonamide instead
of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example G10b
N-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-3-oxo-propyl)-benzenesulfonamide
toluene-4-sulfonate
[0670] The title compound is prepared analogously as described in
example D2b using N-(3-{3-exo
[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8--
yl}-3-oxo-propyl)-benzenesulfonamide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}ethyl)-amide.
Example G11
2,3-Dihydro-benzo[1,4]dioxine-6-sulfonic acid
(3-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]oct-8-yl}-3-oxo-propyl)-amide
[0671] The title compound is prepared analogously as described in
example G1 using
3-(2,3-dihydro-benzo[1,4]dioxine-6-sulfonylaminoypropionic acid
instead of N-acetyl-L-alanine.
[0672] MS: 554 [M+H]+
[0673] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.18 min.
Example G12
1-(3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl)-3-(2,3-dihydro-benzo[1,4]dioxine-6-sulfonyl)-propan-1-one
[0674] The title compound is prepared analogously as described in
example G1 using
3-(2,3-dihydro-benzo[1,4]dioxine-6-sulfonyl)-propionic acid instead
of N-acetyl-L-alanine. MS: 539 [M+H]+
[0675] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.97 min.
Example G13
N-[4-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl}-3-oxo-propane-1-sulfonyl)-phenyl]-acetamide
[0676] The title compound is prepared analogously as described in
example G1 using 3-(4-acetylamino-benzenesulfonyl)-propionic acid
instead of N-acetyl-L-alanine.
[0677] MS: 574 [M+H]+
[0678] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.12 min.
Example G14
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-3-(4-fluoro-benzenesulfonyl)-propan-1-one
[0679] The title compound is prepared analogously as described in
example G1 using 3-(4-fluoro-benzenesulfonylypropionic acid instead
of N-acetyl-L-alanine. MS: 499 [M+H]+
[0680] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.28 min.
Example G15
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-3-(4-thiophen-2-yl-6-trifluoromethyl-pyrimidine-2-sulfonyl)-pr-
opan-1-one
[0681] The title compound is prepared analogously as described in
example G1 using
3-(4-thiophen-2-yl-6-trifluoromethyl-pyrimidine-2-sulfonylypropi-
onic acid instead of N-acetyl-L-alanine.
[0682] MS: 663 [M+H]+
[0683] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.21 min.
Example G16
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-3-phenylmethanesulfonyl-propan-1-one
[0684] The title compound is prepared analogously as described in
example G1 using 3-phenylmethanesulfonyl-propionic acid instead of
N-acetyl-L-alanine.
[0685] MS: 495 [M+H]+
[0686] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.18 min.
Example G17
2-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]octane-8-carbonyl}-benzyl)-isoindole-1,3-dione
[0687] The title compound is prepared analogously as described in
example G1 using
3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl-methylybenzoic acid instead
of N-acetyl-L-alanine.
[0688] MS: 548 [M+H]+
[0689] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.30 min.
Example G18
N-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]octane-8-carbonyl}-benzyl)-benzamide
[0690] The title compound is prepared analogously as described in
example E21 using (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-{3-exo-8-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoyl]-8-
-aza-bicyclo[3.2.1]oct-3-yl}-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
instead of (SY2-methyl-propane-2-sulfinic acid
[(R)-1-{3-exo-8-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionyl]-8-aza-
-bicyclo[3.2.1]oct-3-yl}-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[0691] MS: 522 [M+H]+
[0692] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.28 min.
Example G19
3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-N-benzyl-3-oxo-propionamide
[0693] The title compound is prepared analogously as described in
example G1 using N-benzyl-malonamic acid instead of
N-acetyl-L-alanine.
[0694] MS: 462 [M+H]+
[0695] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.25 min.
Example G20
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-3-morpholin-4-yl-propane-1,3-dione
[0696] The title compound is prepared analogously as described in
example G1 using N-morpholin-malonamic acid instead of
N-acetyl-L-alanine.
[0697] MS: 440 [M+H]+
[0698] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.16 min.
Example G21
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-phen-
ylmethanesulfonyl-propan-1-one
[0699] The title compound is prepared analogously as described in
example G16 using (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
instead of
3-exo-[(R)-1-((S-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-phe-
nyl)-ethyl]-8-aza-bicyclo[3.2.1]octane.
[0700] MS: 469 [M+H]+
[0701] HPLC (YMC Pack ODS-AQ 3 .mu.m 2.1.times.50 mm, 6 min method
(0-3.5 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-20% ACN,
5.55-6 min 5% ACN): 2.98 min.
Example G21a
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-phen-
ylmethanesulfonyl-propan-1-one maleate
[0702] The title compound is prepared analogously as described in
example D2a using
1-{4-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-
-yl}-3-phenylmethanesulfonyl-propan-1-one instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]octane-8-sulfonyl}-ethyl)-amide.
Example G21b
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-phen-
ylmethanesulfonyl-propan-1-one toluene-4-sulfonate
[0703] The title compound is prepared analogously as described in
example D2b using
1-{4-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-
-yl}-3-phenylmethanesulfonyl-propan-1-one instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]octane-8-sulfonyl}-ethyl)-amide.
Example G22
1-(4-[(R)-1-Amino-2-{2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-(4-f-
luoro-benzenesulfonyl)-propan-1-one
[0704] The title compound is prepared analogously as described in
example G14 using (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
instead of
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-ph-
enyl)-ethyl]-8-aza-bicyclo[3.2.1]octane.
[0705] MS: 473 [M+H]+HPLC(YMC Pack ODS-AQ 3 .mu.m 2.1.times.50 mm,
6 min method (0-3.5 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55
min 95-20% ACN, 5.55-6 min 5% ACN): 2.78 min.
Example G23
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-benz-
enesulfonyl-propan-1-one
[0706] The title compound is prepared analogously as described in
example G1 using (SY2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
instead of
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-ph-
enyl)-ethyl]-8-aza-bicyclo[3.2.1]octane and
3-benzenesulfonyl-propionic acid instead of N-acetyl-L-alanine.
[0707] MS: 455 [M+H]+
[0708] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.13 min.
Example G24
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-(2,3-
-dihydro-benzo[1,4]dioxine-6-sulfonyl)-propan-1-one
[0709] The title compound is prepared analogously as described in
example G12 using (SY2-methyl-propane-2-sulfinic acid
[(R)-1-pipenidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
instead of
3-exo-[(R)-1-((S-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-phe-
nyl)-ethyl]-8-aza-bicyclo[3.2.1]octane.
[0710] MS: 513 [M+H]+
[0711] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.15 min.
Example G25
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-2-meth-
anesulfonyl-ethanone
[0712] The title compound is prepared analogously as described in
example G22 using methanesulfonyl-acetic acid instead of
3-(4-fluoro-benzenesulfonyl)-propionic acid.
[0713] MS: 401 [M+H]+
[0714] HPLC (YMC Pack ODS-AQ 3 .mu.m 2.1.times.50 mm, 6 min method
(0-3.5 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-20% ACN,
5.55-6 min 5% ACN): 2.48 min.
Example G26
3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]octane-8-carbonyl}-N-methyl-benzamide
[0715] The title compound is prepared analogously as described in
example G1 using N-methyl-isophthalamic acid instead of
N-acetyl-L-alanine.
[0716] MS: 446 [M+H]+
[0717] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.17 min.
Example G26a
3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]octane-8-carbonyl}-N-methyl-benzamide maleate
[0718] The title compound is prepared analogously as described in
example D2a using
3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-b-
icyclo[3.2.1]octane-8-carbonyl}N-methyl-benzamide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]octane-8-sulfonyl}ethylyamide.
Example G26b
3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]octane-8-carbonyl}-N-methyl-benzamide toluene-4-sulfonate
[0719] The title compound is prepared analogously as described in
example D2b using 3-{3-exo
[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-
-8-carbonyl}-N-methyl-benzamide instead of cyclopropanesulfonic
acid
(2-(3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl)ethyl)-amide.
Example G27
{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]-
oct-8-yl}-[3-morpholine-4-carbonyl)-phenyl]-methanone
[0720] The title compound is prepared analogously as described in
example G1 using 3-(morpholine-4-carbonyl)-benzoic acid instead of
N-acetyl-L-alanine.
[0721] MS: 502 [M+H]+
[0722] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.19 min.
Example G28
1-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]octane-8-carbonyl}-benzyl)-pyrrolidin-2-one
[0723] The title compound is prepared analogously as described in
example G1 using 3-(2-oxo-pyrrolidin-1-ylmethyl)-benzoic acid
instead of N-acetyl-L-alanine.
[0724] MS: 486 [M+H]+
[0725] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.23 min.
Example G29
3-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]octane-4-carbonyl}-benzyl)-thiazolidine-2,4-dione
[0726] The title compound is prepared analogously as described in
example G1 using 3-(2,4-dioxo-thiazolidin-3-ylmethyl)-benzoic acid
instead of N-acetyl-L-alanine.
[0727] MS: 518 [M+H]+
[0728] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.25 min.
Example G30
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-(pro-
pane-2-sulfonyl)-propan-1-one
A) 3-Isopropylsulfanyl-propionic acid benzyl ester
[0729] To benzylacrylate (100 mg, 0.617 mmol) in ethanol (2 mL) are
added triethylamine (95 uL, 0.679 mmol) and 2-propanethiol (58 uL,
0.617 mmol). After stirring at rt during 2 h, the solvent is
evaporated to give a residue which is treated with dichloromethane
and water. The organic phase is dried and evaporated to afford a
colorless oil before purification by preparative HPLC (Column
Waters C18 ODB 5 .mu.m 19.times.50, Gradient: 0-2.5 min 5% ACN,
2.5-12.5 min 5-100% ACN, 12.5-15 min 100% ACN) to yield the tiUe
compound.
[0730] MS: 239 [M+H]+
[0731] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 3.97 min.
B) 3-(Propane-2-sulfonylypropionic acid benzyl ester
[0732] To 3-isopropylsulfonyl-propionic acid benzyl ester (46 mg,
0.193 mmol) in acetic acid (500 uL) is added an aqueous 30% H2O2
solution (82 uL). After stirring at 80.degree. C. during 2 h, the
mixture is quenched with saturated NaHCO3 solution and extracted
with dichloromethane. The organic phase is dried and evaporated to
give the title compound.
[0733] MS: 271 [M+H]+
[0734] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 2.92 min.
C) 3-(Propane-2-sulfonylypropionic acid
[0735] To 3-(propane-2-sulfonylypropionic acid benzyl ester (49.3
mg, 0.182 mmol) in methanol (1 mL) is added Pd/C (5 mg) and the
mixture is stirred at rt during 16 h under H2 atmosphere. The
resulting suspension is filtered through celite and the filtrate is
evaporated to yield the title compound.
D)
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-(-
propane-2-sulfonyl propan-1-one
[0736] The title compound is prepared analogously as described in
example G24 using 3-(propane-2-sulfonyl)propionic acid instead of
3-(2,3-dihydro-benzo[1,4]dioxine-6-sulfonylamino)-propionic
acid.
[0737] MS: 421 [M+H]+
[0738] HPLC (YMC Pack ODS-AQ 3 .mu.m 2.1.times.50 mm, 6 min method
(0-3.5 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-20% ACN,
5.55-6 min 5% ACN): 2.6 min.
Example G31
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-3-(4-trifluoromethyl-pyrimidine-2-ulfonyl)-propan-1-one
[0739] The title compound is prepared analogously as described in
example G30 using 4-trifluoromethyl-pyrimidine-2-thiol instead of
2-propanethiol and
3-exo[(R)-1-((S)-2-methyl-propane-2-sulfinylaminos-2-(2,4,5-trifluoro-
-phenyl)-ethyl]-8-aza-bicyco[3.2.1]octane instead of
(SY2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[0740] MS: 551 [M+H]+
[0741] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.25 min.
Example G32
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-3-benzenesulfonyl-propan-1-one
[0742] The title compound is prepared analogously as described in
example G1 using 3-benzenesulfonyl-propionic acid instead of
N-acetyl-L-alanine.
[0743] MS: 481 [M+H]+
[0744] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.2 min.
Example G33
1-{4-[1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-2-(propane-
-2-sulfonyl)-ethanone
A) Isopropylsulfanyl-acetic acid benzyl ester
[0745] To benzyl bromoacetate (100 mg, 0.437 mmol) in dimethyl
formamide (2 mL) is added triethylamine (67 uL, 0.481 mmol) and
2-propanethiol (41 uL, 0.437 mmol). After stirring at rt during 2
h, the solvent is evaporated, the residue is treated with
dichloromethane and water. The organic phase is dried and
evaporated to give a crude compound before purification by
preparative HPLC (Column Waters C18 ODB 5 .mu.m 19.times.50,
Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min 5-100% ACN, 12.5-15 min
100% ACN) to yield the title compound.
[0746] MS: 225 [M+H]+
[0747] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 3.84 min.
B)
1-{4-[1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-2-(prop-
ane-2-sulfonyl)-ethanone
[0748] The title compound is prepared analogously as described in
example G30 using isopropylsulfanyl-acetic acid benzyl ester
instead of 3-isopropylsulfanyl-propionic acid benzyl ester.
[0749] MS: 551 [M+H]+
[0750] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.25 min.
Example G34
Cyclopropanecarboxylic acid
((S)-1-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]octane-8-carbonyl}-3-carbamoyl-propyl)-amide
A) (S)-4-Carbamoyl-2-(cyclopropanecarbonyl-amino)-butyric acid
[0751] To (S)-2-Amino-4-carbamoyl-butyric acid (100 mg, 0.684 mmol)
in water (16 mL) are added Na2CO3 (218 mg, 2.052 mmol) and a
solution of cyclopropylcarboxylic acid (62.1 uL, 0.684 mmol) in
tetrahydrofuran (8 mL). After stirring at rt during 2 h, ethyl
acetate is added and the pH is decreased to 3 by addition of
aqueous 1N HCl. The aqueous phase is evaporated, the residue is
mixed with methanol and filtrated. The filtrate is evaporated to
yield the title compound.
[0752] MS: 237 [M+H]+
[0753] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 0.504 min.
B) Cyclopropanecarboxylic acid
((S)-1-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]octane-8-carbonyl}-3-carbamoyl-propylyamide
[0754] The title compound is prepared analogously as described in
example G1 using
(SH4-carbamoyl-2-(cyclopropanecarbonyl-amino)-butyric acid instead
of N-acetyl-L-alanine.
[0755] MS: 482 [M+H]+
[0756] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.13 min.
Example G35
N-[4-(3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}--
3-oxo-propane-1-sulfonyl)-phenyl]-acetamide
[0757] The title compound is prepared analogously as described in
example G21 using 3-(4-acetylaminobenzenesulfonylypropionic acid
instead of 3-phenylmethanesulfonyl-propionic acid.
[0758] MS: 512 [M+H]+
[0759] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.19 min.
Example G35a
N-[4-(3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}--
3-oxo-propane-1-sulfonyl)-phenyl]-acetamide maleate
[0760] The title compound is prepared analogously as described in
example D2a using
N-[4-(3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piper-
idin-1-yl}-3-oxo-propane-1-sulfonyl)-phenyl]-acetamide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}ethyl)-amide.
Example G35b
N-[4-(3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}--
3-oxo-propane-1-sulfonyl)-phenyl]-acetamide toluene-4-sulfonate
[0761] The title compound is prepared analogously as described in
example D2b using
N-[4-(3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piper-
idin-1-yl}-3-oxo-propane-1-sulfonyl)-phenyl]-acetamide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example G36
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-(tet-
rahydro-furan-2-ylmethanesulfonyl)-propan-1-one
A) 3-(2-Benzyloxycarbonyl-ethyldisulfanylypropionic acid benzyl
ester
[0762] To 3,3'-dithiodipropionic acid (1 g, 4.75 mmol) in DCM (6
mL) are added DIPEA (2.86 mL, 16.64 mmol), DMAP (76 mg, 0.618 mmol)
and benzyl bromide (1.42 mL, 11.89 mmol). After stirring at rt
during 16 h, the mixture is washed with water, brine, an aqueous 1N
HCl solution and an aqueous 10% NaHCO3 solution. The organic phase
is dried and evaporated to afford a orange oil before purification
by flash chromatography on silica (cyclohexane/ethyl acetate 1/0 to
8/2) to yield a yellow oil.
[0763] MS: 391 [M+H]+
[0764] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 4.206 min.
B) 3-Mercapto-propionic acid benzyl ester
[0765] A stirred solution of
3-(2-Benzyloxycarbonyl-ethyldisulfanyl)-propionic acid benzyl ester
(1.73 g, 4.353 mmol) in THF (15 mL) and water (1.5 mL) is
deoxygenated during 15 min using a stream of N2. After addition of
tributylphosphine (2.15 mL, 8.706 mmol), the mixture is stirred at
rt during 6 h and the solvent is evaporated. The aqueous phase is
treated with DCM and an aqueous 1N HCl solution, the aqueous phase
is extracted with DCM and the combined organic phases are dried and
evaporated to afford a yellow oil before purification by flash
chromatography on silica (cyclohexane/ethyl acetate 1/0 to 8/2) to
yield a yellow oil.
[0766] MS: 219 [M+Na]+
[0767] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 3.365 min.
C) 3-(Tetrahydro-furan-2-ylmethylsulfanyl)propionic acid benzyl
ester
[0768] To 3-Mercapto-propionic acid benzyl ester (200 mg, 1.019
mmol) are added tetrahydrofurfuryl bromide (505 mg, 3.057 mmol) and
sodium methoxide (55 mg, 1.019 mmol). After stirring at rt during 2
h, the mixture is quenched with ethyl acetate and water, the
organic phase is washed with water and brine, dried and evaporated
to afford a yellow oil before purification by preparative HPLC
(Column interchim C18 ODB 5 .mu.m 19.times.50, Gradient: 0-5 min
20% ACN, 5-15 min 20-100% ACN, 15-20 min 100% ACN) to yield a
colorless oil.
[0769] MS: 281 [M+H]+
[0770] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 3.522 min.
D) 3-(Tetrahydro-furan-2-ylmethanesulfonylypropionic acid
[0771] The title compound is prepared analogously as described in
example G30 using 3-(Tetrahydro-furan-2-ylmethylsulfonylypropionic
acid benzyl ester instead of 3-isopropylsulfonyl-propionic acid
benzyl ester. MS: 245 [M+Na]+
E)
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}3-(t-
etrahydro-furan-2-ylmethanesulfonyl)-propan-1-one
[0772] The title compound is prepared analogously as described in
example G24 using 3-(Tetrahydro-furan-2-ylmethanesulfonylypropionic
acid instead of
3-(2,3-dihydro-benzo[1,4]dioxine-6-sulfonylamino)-propionic
acid.
[0773] MS: 463 [M+H]+
[0774] HPLC (YMC Pack ODS-AQ 3 .mu.m 2.1.times.50 mm, 6 min method
(0-3.5 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-20% ACN,
5.55-6 min 5% ACN): 2.469 min.
Example G37
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-cycl-
opentanesulfonyl-propan-1-one
[0775] The title compound is prepared analogously as described in
example G30 using cyclopentyl mercaptan instead of
2-propanethiol.
[0776] MS: 447 [M+H]+
[0777] HPLC (YMC Pack ODS-AQ 3 .mu.m 2.1.times.50 mm, 6 min method
(0-3.5 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-20% ACN,
5.55-6 min 5% ACN): 2.641 min.
Example G38
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-etha-
nesulfonyl-propan-1-one
[0778] The title compound is prepared analogously as described in
example G30 using ethanthiol instead of 2-propanethiol.
[0779] MS: 407 [M+H]+
[0780] HPLC (YMC Pack ODS-AQ 3 .mu.m 2.1.times.50 mm, 6 min method
(0-3.5 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-20% ACN,
5.55-6 min 5% ACN): 2.43 min.
Example G39
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-(2-m-
ethyl-propane-2-sulfonyl)-propan-1-one
[0781] The title compound is prepared analogously as described in
example G30 using terbutylthiol instead of 2-propanethiol.
[0782] MS: 435 [M+H]+
[0783] HPLC (YMC Pack ODS-AQ 3 .mu.m 2.1.times.50 mm, 6 min method
(0-3.5 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-20% ACN,
5.55-6 min 5% ACN): 2.63 min.
Example G40
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-(tet-
rahydro-pyran-2-ylmethanesulfonyl)-propan-1-one
[0784] The title compound is prepared analogously as described in
example G36 using 2-(Bromomethyl)tetrahydro-2H-pyran instead of
tetrahydrofurfuryl bromide.
[0785] MS: 477 [M+H]+
[0786] HPLC (YMC Pack ODS-AQ 3 .mu.m 2.1.times.50 mm, 6 min method
(0-3.5 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-20% ACN,
5.55-6 min 5% ACN): 2.585 min.
Example G41
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-(2-m-
ethoxy-ethanesulfonyl)-propan-1-one
[0787] The title compound is prepared analogously as described in
example G36 using 2-bromoethyl-methyl ether instead of
tetrahydrofurfuryl bromide.
[0788] MS: 437 [M+H]+
[0789] HPLC (YMC Pack ODS-AQ 3 .mu.m 2.1.times.50 mm, 6 min method
(0-3.5 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-20% ACN,
5.55-6 min 5% ACN): 2.295 min.
Example G41a
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-(2-m-
ethoxy-ethanesulfonyl)-propan-1-one maleate
[0790] The title compound is prepared analogously as described in
example D2a using
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-
-yl}-(2-methoxy-ethanesulfonyl)-propan-1-one instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example G41b
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-(2-m-
ethoxy-ethanesulfonyl)-propan-1-one toluene-4-sulfonate
[0791] The title compound is prepared analogously as described in
example D2b using
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-
-yl}-3-(2-methoxy-ethanesulfonyl)propan-1-one instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example G42
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-2-(2-m-
ethyl-propane-2-sulfonyl)-ethanone
[0792] The title compound is prepared analogously as described in
example G33 using terbutylthiol instead of 2-propanethiol.
[0793] MS: 421 [M+H]+
[0794] HPLC (YMC Pack ODS-AQ 3 .mu.m 2.1.times.50 mm, 6 min method
(0-3.5 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-20% ACN,
5.55-6 min 5% ACN): 2.56 min.
Example G43
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-2-cycl-
opentanesulfonyl-ethanone
[0795] The title compound is prepared analogously as described in
example G33 using cyclopentyl mercaptan instead of
2-propanethiol.
[0796] MS: 433 [M+H]+
[0797] HPLC (YMC Pack ODS-AQ 3 .mu.m 2.1.times.50 mm, 6 min method
(0-3.5 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-20% ACN,
5.55-6 min 5% ACN): 2.68 min.
Example G44
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-2-(2-methyl-propane-2-sulfonyl)-ethanone
[0798] The title compound is prepared analogously as described in
example G42 using 3-exo-[(R)
1-((S-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-phenyl)-ethyl]-
-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[0799] MS: 447 [M+H]+
[0800] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.659 min.
Example G45
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-2-cyclopentanesulfonyl-ethanone
[0801] The title compound is prepared analogously as described in
example G43 using
3-exo-[(R)-1-((S-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tri-
fluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[0802] MS: 459 [M+H]+
[0803] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.755 min.
Example G46
1-(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicycl-
o[3.2.1]oct-8-yl)-2-(propane-2-sulfonyl)-ethanone
[0804] The title compound is prepared analogously as described in
example G33 using
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tr-
ifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[0805] MS: 433 [M+H]+
[0806] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.601 min.
Example G47
N-[4-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-
-bicyclo[3.2.1]oct-8-yl}-3-oxo-propane-1-sulfonyl)-phenyl]-acetamide
[0807] The title compound is prepared analogously as described in
example G35 using
3-exo-[(R)-1-((S2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trif-
luoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[0808] MS: 574 [M+H]+
[0809] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.12 min.
Example G48
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-3-(3-methoxy-benzenesulfonyl)-propan-1-one
[0810] The title compound is prepared analogously as described in
example G44 using 3-methoxythiophenol instead of terbutylthiol.
[0811] MS: 511 [M+H]+
[0812] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.26 min.
Example G49
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-3-(toluene-3-sulfonyl)-propan-1-one
[0813] The title compound is prepared analogously as described in
example G44 using 3-thiocresol instead of terbutylthiol.
[0814] MS: 495 [M+H]+
[0815] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.27 min.
Example G50
1-((1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl)-3-(pyrimidine-2-sulfonyl)-propan-1-one
[0816] The title compound is prepared analogously as described in
example G44 using Pyrimidine-2-thiol instead of terbutylthiol.
[0817] MS: 483 [M+H]+
[0818] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.17 min.
Example G51
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-3q6-methyl-pyridine-2-sulfonyl)-propan-1-one
[0819] The title compound is prepared analogously as described in
example G44 using 6-Methyl-pyridine-2-thiol instead of
terbutylthiol.
[0820] MS: 498 [M+H]+
[0821] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.24 min.
Example G52
7-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-3-oxo-propane-1-sulfonyl)-3,4-dihydro-2H-isoquinolin-
-1-one
[0822] The title compound is prepared analogously as described in
example G44 using 7-Mercapto-3,4-dihydro-2H-isoquinolin-1-one
instead of terbutylthiol.
[0823] MS: 550 [M+H]+
[0824] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.20 min.
Example G53
3-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-3-oxo-propane-1-sulfonyl)-benzamide
[0825] The title compound is prepared analogously as described in
example G44 using 3-Mercapto-benzamide instead of
terbutylthiol.
[0826] MS: 525 [M+H]+
Example G53a
3-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-3-oxo-propane-1-sulfonyl)-benzamide
maleate
[0827] The title compound is prepared analogously as described in
example D2a using
3-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethy-
l]-8-aza-bicyclo[3.2.1]oct-8-yl}-3-oxo-propane-1-sulfonylybenzamide
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example G53b
3-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-oxo-propane-1-sulfonyl)-benzamide
toluene-4-sulfonate
[0828] The title compound is prepared analogously as described in
example D2b using
3-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethy-
l]-8-aza-bicyclo[3.2.1]oct-8-yl}-3-oxo-propane-1-sulfonyl)benzamide
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example G54
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-3-cyclopentanesulfonyl-propan-1-one
[0829] The title compound is prepared analogously as described in
example G37 using
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tr-
ifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[0830] MS: 473 [M+H]+
[0831] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.731 min.
Example G55
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-3-(tetrahydro-furan-2-ylmethanesulfonyl)-propan-1-one
[0832] The title compound is prepared analogously as described in
example G36 using
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tr-
ifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[0833] MS: 489 [M+H]+
[0834] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.565 min.
Example G56
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-3-(2-methyl-propane-2-sulfonyl)-propan-1-one
[0835] The title compound is prepared analogously as described in
example G39 using 3-exo-[(Ry
1-((S-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-phenyl)-ethyl]-
-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[0836] MS: 461 [M+H]+
[0837] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.700 min.
Example G57
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-3-ethanesulfonyl-propan-1-one
[0838] The title compound is prepared analogously as described in
example G38 using
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-td-
ifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(SY2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide. MS:
433 [M+H]+
[0839] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.572 min.
Example G58
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-3-(tetrahydro-pyran-2-ylmethanesulfonyl)-propan-1-one
[0840] The title compound is prepared analogously as described in
example G40 using
3-exo-[(R)-1-((S2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trif-
luoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[0841] MS: 503 [M+H]+
[0842] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.666 min.
Example G59
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-3-(2-methoxy-ethanesulfonyl)-propan-1-one
[0843] The title compound is prepared analogously as described in
example G41 using
3-exo-[(R)-1-((S-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tri-
fluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[0844] MS: 463 [M+H]+
[0845] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.435 min.
Example G60
3-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]octane-8-arbonyl}-benzyl)-1-methyl-imidazolidine-2,4-dione
A) 3-(3-Methyl-2,5-dioxo-imidazolidin-1-ylmethyl)benzoic acid
methyl ester
[0846] To methylhydantoine (50 mg, 0.438 mmol) in DMF (2 mL) is
added at 0.degree. C. sodium hydride (23 mg, 0.525 mmol). After
stirring at 0.degree. C. during 1 h, methyl
2-bromomethylphenylcarboxylate (121 mg, 0.525 mmol) is added and
the mixture is stirred at rt during 2 h before quenching with an
aqueous saturated NaHCO3 solution and DCM. The organic phase is
dried and evaporated to give a crude compound before purification
by preparative HPLC (Column Waters C18 ODB 5 .mu.m 19.times.50,
Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min 5-100% ACN, 12.5-15 min
100% ACN) to yield the title compound.
[0847] MS: 285 [M+Na]+
[0848] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.216 min.
B) 3-(3-Methyl-2,5-dioxo-imidazolidin-1-ylmethylybenzoic acid
[0849] To 3-(3-Methyl-2,5-dioxo-imidazolidin-1-ylmethyl)benzoic
acid methyl ester (100 mg, 0.381 mmol) in THF/water (2/1, 2 mL) is
added lithium hydroxyde monohydrate (24 mg, 0.572 mmol) and the
reaction is stirred at rt during 16 h before quenching with water
and ethylacetate. The separated aqueous phase is acidified to pH 2
with an aqueous 1N HCl solution, extracted with ethylacetate and
the organic phase is dried and evaporated to give the title
compound.
[0850] MS: 267 [M+H.sub.2O+H]+
[0851] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.25 min.
C)
3-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-
-bicyclo[3.2.1]octane-8-carbonyl}benzyl)-1-methyl-imidazolidine-2,4-dione
[0852] The title compound is prepared analogously as described in
example G17 using
3-(3-Methyl-2,5-dioxo-imidazolidin-1-ylmethyl)-benzoic acid instead
of 3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl-methylybenzoic acid.
[0853] MS: 515 [M+H]+
[0854] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 595% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-5%
ACN, 5.55-6 min 5% ACN): 2.91 min.
Example G61
3-(4-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]octane-8-carbonyl}-benzyl)-thiazolidine-2,4-dione
[0855] The title compound is prepared analogously as described in
example G1 using 4-(2,4-Dioxo-thiazolidin-3-ylmethyl)-benzoic acid
instead of N-acetyl-L-alanine.
[0856] MS: 518 [M+H]+
[0857] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.245 min.
Example G62
1-(4-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]octane-8-carbonyl}-benzyl)-pyrrolidine-2,5-dione
A) 2-Methyl-propane-2-sulfinic acid
[(R)-1-{(1S,3S,5R)-8-[3-(2,5-dioxo-pyrrolidin-1-ylmethyl)-benzoyl]-8-aza--
bicyclo[3.2.1]oct-3-yl}-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
[0858] To 2-Methyl-propane-2-sulfinic acid
[(R)-1-[(1S,3S,5R)-8-(3-aminomethyl-benzoyl)-8-aza-bicyclo[3.2.1]oct-3-yl-
]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide (228 mg, 0.437 mmol) in
toluene (10 ml) are added succinic anhydride (53 mg, 0.524 mmol)
and molecular sieves (200 mg). After stirring at 110.degree. C.
during 6 h, CDI (107 mg, 0.655 mmol) and triethylamine (183 uL,
1.311 mmol) are added and the mixture is stirred at 110.degree. C.
during 24 h. After filtration and evaporation of the solvent, the
residue is treated with DCM and an aqueous saturated NaHCO3
solution, the organic phase is dried and evaporated to give a crude
compound before purification by preparative HPLC (Column Waters C18
ODB 5 .mu.m 19.times.50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min
5-100% ACN, 12.5-15 min 100% ACN) to yield the title compound.
[0859] MS: 604 [M+H]+
[0860] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.370 min.
B)
1-(4-{(1S,3S,5R).sub.3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-
-aza-bicyclo[3.2.1]octane-8-carbonyl}-benzyl)-pyrrolidine-2,5-dione
[0861] The title compound is prepared analogously as described in
example G1 using (SY2-Methyl-propane-2-sulfinic acid
[(R)-1-{(1S,3S,5R)-8-[3-(2,5-dioxo-pyrrolidin-1-ylmethyl)benzoyl]-8-aza-b-
icyclo[3.2.1]oct-3-yl}-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
instead of
N--((S)-1-Methyl-2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-
-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl-
yacetamide.
[0862] MS: 500 [M+H]+
[0863] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.212 min.
Example G63
1-{(4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-[2--
(1,1-dioxo-1lambda*6*hiomorpholin
4-yl)-2-oxo-ethanesulfonyl]-propan-1-one
A) 3-Carboxymethylsulfanyl-propionic acid benzyl ester
[0864] The title compound is prepared analogously as described in
example G36 using Bromoacefic acid instead of tetrahydrofurfuryl
bromide.
[0865] MS: 255 [M+H]+
[0866] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 2.841 min.
B) 3-(2-Oxo-2-thiomorpholin-4-yl-ethylsulfanylypropionic acid
benzyl ester
[0867] To 3-Carboxymethylsulfanyl-propionic acid benzyl ester (763
mg, 3 mmol), HBTU (1.71 g, 4.5 mmol) and DIPEA (2.05 mL, 12 mmol)
in DCM (10 mL) is added thiomorpholine (283 uL, 3 mmol). After
stirring at rt during 2 h and evaporation of the solvent, the
residue is dissolved with ethylacetate and washed with an aqueous
1N HCl solution and an aqueous saturated NaHCO3 solution. The
organic phase is dried and evaporated to afford the title
compound.
[0868] MS: 340 [M+H]+
[0869] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 3.529 min.
C)
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-[-
2-(1,1-dioxo-1lambda*6*-thiomorpholin-4-yl)-2-oxo-ethanesulfonyl]-propan-1-
-one
[0870] The title compound is prepared analogously as described in
example G36 using
3-(2-Oxo-2-thiomorpholin-4-yl-ethylsulfanyl)-propionic acid benzyl
ester instead of 3-(Tetrahydro-furan-2-ylmethylsulfonyl)-propionic
acid benzyl ester.
[0871] MS: 554 [M+H]+
[0872] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.214 min.
Example G63a
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-[2-(-
1,1-dioxo-1
lambda*6*-thiomorpholin-4-yl)-2-oxo-ethanesulfonyl]-propan-1-one
maleate
[0873] The title compound is prepared analogously as described in
example D2a using
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-
-yl}-3-[2-(1,1-dioxo-1
lambda*6*-thiomorpholin-4-ylY2-oxo-ethanesulfonyl]-propan-1-one
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example G63b
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-[2-(-
1,1-dioxo-1lambda*6*-thomorpholin-4-yl)-2-oxo-ethanesulfonyl]-propan-1-one
toluene-4-sulfonate
[0874] The title compound is prepared analogously as described in
example D2b using
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-
-yl}-3-[2-(1,1-dioxo-1
lambda*6*-thiomorpholin-4-yl2-oxo-ethanesulfonyl]-propan-1-one
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example G64
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-(2-m-
orpholin-4-yl-2-oxo-ethanesulfonyl)-propan-1-one
[0875] The title compound is prepared analogously as described in
example G63 using morpholine instead of thiomorpholine.
[0876] MS: 506 [M+H]+
[0877] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.296 min.
Example G65
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-(tet-
rahydro-pyran-2-ylmethanesulfonyl)-propan-1-one
[0878] The title compound is prepared analogously as described in
example G58 using (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
instead of
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-ph-
enyl)-ethyl]-8-aza-bicyclo[3.2.1]octane.
[0879] MS: 477 [M+H]+
[0880] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.372 min.
Example G66
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-3-[2-(1,1-dioxo-1
lambda*6*-thiomorpholin-4-yl)-2-oxo-ethanesulfonyl]-propan-1-one
[0881] The title compound is prepared analogously as described in
example G63 using
3-exo-[(R)-1-((S)-2-methyl-propane-2-sufinylamino)-2-(2,4,5-tri-
fluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide. MS:
580 [M+H]+
[0882] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.352 min.
Example G67
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-3-(2-morpholin-4-yl-2-oxo-ethanesulfonyl)-propan-1-one
[0883] The title compound is prepared analogously as described in
example G64 using
3-exo-[(R)-1-((S2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trif-
luoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[0884] MS: 532 [M+H]+
[0885] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.379 min.
Example H1
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2-(morpholine-4-sulfonyl)-ethanone
[0886] This compound is prepared according to Scheme H:
##STR00114##
A) Chlorosulfonyl-acetic acid methyl ester
[0887] To chlorosulfonyl chloride (3.34 g, 17.9 mmol) in diethyl
ether (30 mL) is added at 0.degree. C. methanol (800 .mu.L, 19.7
mmol). The resulting mixture is stirred at 0.degree. C. during 1 h
and the solvent is evaporated to give the title compound.
B) (Morpholine-4-sulfonyl)acetic acid methyl ester
[0888] To chlorosulfonyl-acetic acid methyl ester (3.39 g, 19.6
mmol) in dichloromethane (50 mL) is added morpholine (8.6 mL, 98
mmol). The resulting mixture is stirred at rt during 2 h and the
solvent is evaporated to yield the title compound.
[0889] MS: 223 [M-H]+
C) (Morpholine-4-sulfonyl)-acetic acid
[0890] (Morpholine-4-sulfonyl)acetic acid methyl ester (0.5 g, 2.24
mmol) is dissolved in 0.66 N KOH aqueous ethanol solution (1/1, 150
mL) and the mixture is heated at reflux during 16 h. The solvent is
evaporated and residue is extracted with dichloromethane/methanol
4:1 to yield the title compound.
[0891] MS: 232 [M+Na]
D)
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-2-(morpholine-4-sulfonyl)-ethanone
[0892] The title compound is prepared analogously as described in
example G1 using (morpholine-4-sulfonylyacetic acid instead of
N-acetyl-L-alanine. MS: 476 [M+H]+
[0893] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.94 min.
Example H1a
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2-(morpholine-4-sulfonyl)-ethanone maleate
[0894] The title compound is prepared analogously as described in
example D2a using
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-b-
icyclo[3.2.1]oct-8-yl}-2-(morpholine-4-sulfonyl)-ethanone instead
of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}ethyl)-amide.
Example H1b
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2-(morpholine-4-sulfonyl)-ethanone
toluene-4-sulfonate
[0895] The title compound is prepared analogously as described in
example D2b using
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-b-
icyclo[3.2.1]oct-8-yl}-2-(morpholine-4-sulfonylyethanone instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example H2
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2-benzenesulfonyl-ethanone
[0896] The title compound is prepared analogously as described in
example H1 using phenylsulfonylacetic acid instead of
(Morpholine-4-sulfonylyacetic acid.
[0897] MS: 466 [M+H]+
[0898] HPLC (Nucleosil 100-5 C18, 10 min method (0-1 min 10% ACN,
1-6 min 10-100% ACN, 6-8.5 min 100% ACN, 8.5-9 min 100-10% ACN,
9-10 min 10% ACN): 3.88 min.
Example H3
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2-methanesulfonyl-ethanone
[0899] The title compound is prepared analogously as described in
example H1 using methanesulfonylacetic acid instead of
(Morpholine-4-sulfonylyacetic acid. MS: 405 [M+H]+
[0900] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
0.87 min.
Example H4
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2-(piperidine-1-sulfonyl)-ethanone
[0901] The title compound is prepared analogously as described in
example H1 using piperidine instead of morpholine.
[0902] MS: 474 [M+H]+
[0903] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.28 min.
Example H5
2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2-oxo-ethanesulfonic acid benzylamide
[0904] The tite compound is prepared analogously as described in
example Hi using benzylamine instead of morpholine.
[0905] MS: 496 [M+H]+
[0906] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.28 min.
Example H6
2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2-oxo-ethanesulfonic acid benzyl-methyl-amide
[0907] The title compound is prepared analogously as described in
example H1 using N-methylbenzylamine instead of morpholine.
[0908] MS: 510 [M+H]+
[0909] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.30 min.
Example H7
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2-methyl-2-(morpholine-4-sulfonyl)-propan-1-one
A) 2-Methyl-2-(morpholine-4-sulfonyl)-propionic acid methyl
ester
[0910] To a solution of (Morpholine-4-sulfonylyacetic acid methyl
ester (500 mg, 2.24 mmol) in tetrahydrofuran (10 mL) is added
potassium bis(trimethylsilyl) amide (1.18 g, 5.6 mmol). After
stirring at rt during 1 h, methyliodide (349 uL, 5.6 mmol) is added
and the resulting mixture is stirred at rt during 1 h and at
50.degree. C. during the weekend. The solution is purified by flash
chromatography on silica gel (eluent: cyclohexane/ethyl acetate
100/0 to 0/100) to yield a yellow solid.
[0911] MS: 252 [M+H].sup.+
B)
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-2-methyl-2-(morpholine-4-sulfonyl)-propan-1-one
[0912] The title compound is prepared analogously as described in
example Hi using 2-methyl-2-(morpholine-4-sulfonyl)-propionic acid
methyl ester instead of (Morpholine-4-sulfonyl)-acetic acid methyl
ester.
[0913] MS: 504 [M+H]+
[0914] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.26 min.
Example H8
2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2-oxo-ethanesulfonic acid
(2-methoxy-ethyl)-methyl-amide
[0915] The title compound is prepared analogously as described in
example Hi using N-methyl-2-methoxyethylamine instead of
morpholine.
[0916] MS: 478 [M+H]+
[0917] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.22 min.
Example H8a
2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2-oxo-ethanesulfonic acid
(2-methoxy-ethyl)-methyl-amide maleate
[0918] The title compound is prepared analogously as described in
example D2a using 2-{3-exo
[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8--
yl}-2-oxo-ethanesulfonic acid (2-methoxy-ethylymethyl-amide instead
of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example H8b
2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2-oxo-ethanesulfonic acid
(2-methoxy-ethyl)-methyl-amide toluene-4-sulfonate
[0919] The title compound is prepared analogously as described in
example D2b using 2-{3-exo
[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8--
yl}-2-oxo-ethanesulfonic acid (2-methoxy-ethyl)-methyl-amide
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl) -amide.
Example H9
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-2-(mor-
pholine-4-sulfonyl)-ethanone
[0920] The title compound is prepared analogously as described in
example H1 using (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
instead of
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-ph-
enyl)-ethyl]-8-aza-bicyclo[3.2.1]octane.
[0921] MS: 450 [M+H]+
[0922] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 2.70 min.
Example H10
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2-methyl-1-oxo-propane-2-sulfonic acid
(2-methoxy-ethyl)-methyl-amide
[0923] The title compound is prepared analogously as described in
example H7 using N-methyl-2-methoxyethylamine instead of
morpholine.
[0924] MS: 506 [M+H]+
[0925] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.29 min.
Example H11
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2-methyl-1-oxo-propane-2-sulfonic acid
benzyl-methyl-amide
[0926] The title compound is prepared analogously as described in
example H7 using N-methyl-benzylamine instead of morpholine.
[0927] MS: 538 [M+H]+
[0928] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.36 min.
Example H12
{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]-
oct-8-yl}-[1-(morpholine-4-sulfonyl)-cyclopropyl]-methanone
[0929] The ttle compound is prepared analogously as described in
example H7 using 1,2-dibromoethane instead of methyliodide.
[0930] MS: 502 [M+H]+
Example H13
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2-(1,3-dihydro-isoindole-2-sulfonyl)-ethanone
[0931] The title compound is prepared analogously as described in
example Hi using isoindoline instead of morpholine.
[0932] MS: 508 [M+H]+
[0933] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.26 min.
Example H14
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-2-(4,4-difluoro-piperidine-1-sulfonyl)-ethanone
[0934] The title compound is prepared analogously as described in
example H1 using 4,4-Difluoropiperidine instead of morpholine.
[0935] MS: 510 [M+H]+
[0936] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.23 min.
Example I1
N-(3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3-
.2.1]oct-8-yl}-3-oxo-propyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propi-
onamide
[0937] This compound is prepared according to Scheme I:
##STR00115## ##STR00116##
A) (S)-2-Methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
[0938] The title compound is prepared analogously as described in
example Bl using
4-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tc
ofluoro-phenyl)-ethyl]-piperidine-1-carboxylic acid benzyl ester
instead of
3-exo-[(S)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-
-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid benzyl
ester.
[0939] MS: 363 [M+H]+
[0940] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 2.45 min.
B)
(3-{4-[(R)-1-((S)-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro--
phenyl)-ethyl]-piperidin-1-yl}-3-oxo-propyl)-carbamic acid benzyl
ester
[0941] To a solution of Cbz-beta-alanine (339 mg, 1.52 mmol) in
dichloromethane (10 mL) are added
O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (785 mg,
2.07 mmol) and diisopropylethylamine (960 uL, 5.52 mmol) before
addition of (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide (500
mg, 1.379 mmol). The resulting solution is stirred at rt during 2 h
and washed with water and brine. The organic phase is dried and
evaporated before purification by preparative HPLC (Column
Interchrom C18 ODB 10 .mu.m 28.times.250, Gradient: 0-2.5 min 5%
ACN, 2.5-25.5 min 5-100% ACN, 25.5-30 min 100% ACN) to yield a
yellow solid.
[0942] MS: 568 [M+H]+
[0943] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.41 min.
C) (SY2-Methyl-propane-2-sulfinic acid
[(R)-1-[1-(3-amino-propionyl)piperidin-4-yl]-2-(2,4,5-trifluoro-phenyl)-e-
thyl]-amide
[0944] To
(3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tri-
fluoro-phenyl)-ethyl]-piperidin-1-yl}-oxo-propyl)-carbamic acid
benzyl ester (684 mg, 1.205 mmol) in methanol (10 mL) are added
ammonium formiate (379 mg, 6.025 mmol) and Pd/C (171 mg). After
stirring at rt during 72 h, the solution is filtered through celite
and evaporated to yield a yellow solid.
[0945] MS: 434 [M+H]+
[0946] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.17 min.
D)
3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-(3-{4-[(R)-1-((S)-2-methyl-pr-
opane-2-sulfinylamino)-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-
-oxo-propyl)-propionamide
[0947] To 2-methyl-propane-2-sulfinic acid
[(R)-1-[1-(3-amino-propionyl)-piperidin-4-yl]-2-(2,4,5-trifluoro-phenyl)--
ethyl]-amide (104 mg, 0.241 mmol) in dichloromethane (3 mL) are
added triethylamine (101 uL, 0.723), N,N-dimethylamidosulfonyl
chloride (28.5 uL, 0.265 mmol) and 4-dimethylaminopyridine (6 mg,
0.05 mmol). After stirring during 4 h at rt, the mixture is washed
with saturated NaHCO3 solution, the organic phase is dried and
evaporated to give a residue which is purified by preparative HPLC
(Column Interchrom C18 ODB 5 .mu.m 19.times.50, Gradient: 0-5 min
10% ACN, 5-15 min 10-90% ACN, 15-20 min 90% ACN) to yield a yellow
oil.
[0948] MS: [M+H]+ 541
[0949] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.309 min.
E)
N-(3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}--
3-oxo-propyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylypropionamide
[0950] To
3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-(3-{4-[(R)-1-((S)-2-me-
thyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin--
1-yl}-3-oxo-propyl)propionamide (22.3 mg, 0.041 mmol) is added 4N
HCl in dioxane (2 mL). The resulting mixture is stirred at rt
during 1 h before it is frozen, lyophilized and purified by
preparative HPLC (Column YMC ODS-AQ 20.times.50 5 uM, Gradient:
0-2.5 min 5% ACN, 2.5-12.5 min 5-100% ACN, 12.5-15 min 100% CAN) to
yield a white solid.
[0951] MS 437 [M+H]+
[0952] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.09 min.
Example I1a
N-(3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-o-
xo-propyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionamide
maleate
[0953] The title compound is prepared analogously as described in
example D2a using
N-(3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidi-
n-1-yl}-3-oxo-propyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionamide
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example I1b
N-(3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-o-
xo-propyl)-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionamide
toluene-4-sulfonate
[0954] The title compound is prepared analogously as described in
example D2b using N-(3-{4-[(R)
1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-oxo-propyl)-3-
-(1,3-dioxo-1,3-dihydro-isoindol-2-ylypropionamide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example I2
Cyclopropanesulfonic acid
(3-{4-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-ox-
o-propyl)-amide
[0955] The title compound is prepared analogously as described in
example I1 using cyclopropanesulfonyl chloride instead of
N,N-dimethylamidosulfonyl chloride.
[0956] MS: 434 [M+H]+
[0957] HPLC (Nucleosil C18 HD CC70, 6 min method (0-3.5 min 5-95%
ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 5%
ACN): 4.008 min.
Example I3
Ethylsulfonic acid
(3-{4-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-ox-
o-propyl)-amide
[0958] The title compound is prepared analogously as described in
example I1 using ethylsulfonyl chloride instead of
N,N-dimethylamidosulfonyl chloride.
[0959] MS: 422 [M+H]+
[0960] HPLC (Nucleosil C18 HD CC70, 6 min method (0-3.5 min 5-95%
ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 5%
ACN): 3.957 min.
Example I4
methylsulfonic acid
(3-{4-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-ox-
o-propyl)-amide
[0961] The title compound is prepared analogously as described in
example I1 using methylsulfonyl chloride instead of
N,N-dimethylamidosulfonyl chloride.
[0962] MS: 408 [M+H]+
[0963] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.58 min.
Example I5
N-(3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-o-
xo-propyl)-formamide
[0964] The title compound is prepared analogously as described in
example I1 using 3-formylamino-propionic acid instead of
Cbz-beta-alanine.
[0965] MS: 358 [M+H]+
[0966] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.45 min.
Example I6
A)
3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-(3-{4-[(R)-1-((S)-2-methyl-pr-
opane-2-sulfinylamino)-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}3--
oxo-propylypropionamide
[0967] To a solution of
3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid (83 mg,
0.381 mmol) in dichloromethane (2 mL) are added
O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (196 mg,
0.519 mmol) and diisopropylethylamine (237 uL, 1.384 mmol) before
addition of (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-[1-(3-amino-propionyl)piperidin-4-yl]-2-(2,4,5-trifluoro-phenyl)-e-
thyl]-amide (150 mg, 0.346 mmol). The resulting solution is stirred
at rt during 16 h and washed with aqueous 1N HCl and saturated
aqueous NaHCO3. The organic phase is dried and evaporated before
purification by preparative HPLC (Column Interchrom C18 ODB 10
.mu.m 50.times.28, Gradient: 0-10 min 5% ACN, 10-20 min 5-90% ACN,
20-25 min 90% ACN) to yield an orange solid.
[0968] MS: 635 [M+H]+
[0969] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 3.14 min.
B)
N-(3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}--
3-oxo-propylY3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylypropionamide
[0970] To
3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-N-(3-{4-[(R)-1-((S)-2-me-
thyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin--
1-yl}-3-oxo-propyl)-propionamide (137 mg, 0.216 mmol) is added 4N
HCl in dioxane (2 mL). The resulting mixture is stirred at rt
during 1 h before it is frozen, lyophilized and purified by
preparative HPLC (Column Interchrom C18 ODS-AQ 10 .mu.m
50.times.20, Gradient: 0-2.5 min 2% ACN, 2.5-12.5 min 2-90% ACN,
12.5-15 min 90% ACN) to yield a light yellow solid.
[0971] MS: 553 [M+H]+
[0972] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.87 min.
Example I7
N-(3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-o-
xo-propyl)-isobutyramide
[0973] The title compound is prepared analogously as described in
example I6 using isobutyric acid instead of
3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid.
[0974] MS: 400 [M+H]+
[0975] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.096 min.
Example I8
Cyclopropanecarboxylic acid
(3-{4-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-ox-
o-propyl)-amide
[0976] The title compound is prepared analogously as described in
example I6 using cyclopropanecarboxylic acid instead of
3-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylypropionic acid. MS: 398
[M+H]+
[0977] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 1.75 min.
Example I9
5-Oxo-pyrrolidine-2-carboxylic acid
(3-{4-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-ox-
o-propyl)-amide
[0978] The title compound is prepared analogously as described in
example I6 using 5-oxo-pyrrolidine-2-arboxylic acid instead of
3-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylypropionic acid. MS: 441
[M+H]+
[0979] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.40 min.
Example I9a
5-Oxo-pyrrolidine-2-carboxylic acid
(3-{4-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-ox-
o-propyl)-amide maleate
[0980] The title compound is prepared analogously as described in
example D2a using 5-Oxo-pyrrolidine-2-carboxylic acid
(3-{4-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}3-oxo-
-propyl)amide instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example I9b
5-Oxo-pyrrolidine-2-carboxylic acid
(3-{4-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-ox-
o-propyl)-amide toluene-4-sulfonate
[0981] The title compound is prepared analogously as described in
example D2b using 5-Oxo-pyrrolidine-2-carboxylic acid
(3-{4-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-ox-
o-propyl)-amide instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example I10
Pyridazine-4-carboxylic acid
(3-{4-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-ox-
o-propyl)-amide
[0982] The title compound is prepared analogously as described in
example I6 using pynidazine-4-carboxylic acid instead of
3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid.
[0983] MS: 436 [M+H]+
[0984] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.49 min.
Example K1
3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-N-cycl-
opropyl-3-xo-propionamide
[0985] This compound is prepared according to Scheme I:
##STR00117## ##STR00118##
A)
3-{4-[(R)-1-((S-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-p-
henyl)-ethyl]-piperidin-1-yl}-3-oxo-propionic acid benzyl ester
[0986] The title compound is prepared analogously as described in
example I1 using malonic acid monobenzyl ester instead of
Cbz-beta-alanine.
[0987] MS: 539 [M+H]+
[0988] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 3.44 min.
B)
3-{4-[(R)-1-((S-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-ph-
enyl)-ethyl]-piperidin-1-yl}-3-oxo-propionic acid
[0989] The title compound is prepared analogously as described in
example I1 using
3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trif-
luoro-phenyloethyl]-piperidin-1-yl}-3-oxo-propionic acid benzyl
ester instead of
(3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-ph-
enyl)-ethyl]-piperidin-1-yl}-3-oxo-propylycarbamic acid benzyl
ester.
[0990] MS: 449 [M+H]+
[0991] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.24 min.
C)
N-Cyclopropyl-3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4-
,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-oxo-propionamide
[0992] To a solution of
3-{4-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-phe-
nyl)-ethyl]-piperidin-1-yl}-3-oxo-propionic acid (45 mg, 0.0.1
mmol) in dichloromethane (2 mL) are added
O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (57 mg,
0.15 mmol) and diisopropylethylamine (69 uL, 0.4 mmol) before
addition of cyclopropylamine (8 uL, 0.11 mmol). The resulting
solution is stirred at rt during 3 h and washed with water and
brine. The organic phase is dried and evaporated before
purification by preparative HPLC (Column Interchrom C18 ODB 110
.mu.m 50.times.28, Gradient: 0-2 min 10% ACN, 2-12 min 10-100% ACN,
12-15 min 100% ACN) to yield a colorless oil.
[0993] MS: 488 [M+H]+
[0994] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.27 min.
D)
3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-N-c-
yclopropyl-3-oxo-propionamide
[0995] To
N-cyclopropyl-3-{4-[(R)-1-((S)-2-methylpropane-2-sulfinylamino)--
2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-oxo-propionamide
(40 mg, 0.082 mmol) is added 4N HCl in dioxane (2 mL). The
resulting mixture is stirred at rt during 1 h before it is frozen,
lyophilized and purified by preparative HPLC (Column nucleosil
C18HD 5 um 50.times.21, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min
5-100% ACN, 12.5-15 min 100% ACN) to yield a white solid.
[0996] MS: 384 [M+H]+
[0997] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.57 min.
Example K1a
3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-N-cycl-
opropyl-3-oxo-propionamide maleate
[0998] The title compound is prepared analogously as described in
example D2a using
3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-
-yl}-N-cyclopropyl-3-oxo-propionamide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example K1b
3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-N-cycl-
opropyl-3-oxo-propionamide toluene-4-sulfonate
[0999] The title compound is prepared analogously as described in
example D2b using
3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-
-yl}-N-cyclopropyl-3-oxo-propionamide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example K2
3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-N,N-di-
ethyl-3-oxo-propionamide
[1000] The title compound is prepared analogously as described in
example Kl using diethylamine instead of cyclopropylamine.
[1001] MS: 400 [M+H]+
[1002] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.75 min.
Example K3
3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-N--((R-
)-2-hydroxy-propyl)-3-oxo-propionamide
[1003] The title compound is prepared analogously as described in
example KI using (R)-1-Amino-propan-2-ol instead of
cyclopropylamine. MS: 402 [M+H]+
[1004] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.39 min.
Example K4
4-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-N,N-di-
methyl-4-oxo-butyramide
[1005] The title compound is prepared analogously as described in
example K1 using succinic acid monobenzyl ester instead malonic
acid monobenzyl ester and dimethylamine instead of
cyclopropylamine.
[1006] MS: 386 [M+H]+
[1007] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.260 min.
Example K5
4-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-N-4-hy-
droxy-cyclohexyl)-4-oxo-butyramide
[1008] The title compound is prepared analogously as described in
example K4 using 4-amino-cyclohexanol instead of dimethylamine.
[1009] MS: 456 [M+H]+
[1010] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.46 min.
Example K6
4-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-N-cycl-
opropyl-4-oxo-butyramide
[1011] The title compound is prepared analogously as described in
example K1 using succinic acid monobenzyl ester instead malonic
acid monobenzyl ester.
[1012] MS: 398 [M+H]+
[1013] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.56 min.
Example K7
3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-N-cyclopropyl-3-oxo-propionamide
[1014] The title compound is prepared analogously as described in
example K1 using
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tri-
fluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[1015] MS: 412 [M+H]+
[1016] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.56 min.
Example K8
3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-N-(4-tert-butyl-cyclohexyl)-3-oxo-propionamide
[1017] The title compound is prepared analogously as described in
example K7 using 4-terbutylcyclohexylamine instead of
cyclopropylamine.
[1018] MS: 508 [M+H]+
[1019] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 3.38 min.
Example K9
{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]-
oct-8-yl}-[1-(morpholine-4-carbonyl)-cyclopropyl]-methanone
A)
1-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluo-
ro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-carbonyl}-cyclopropanecarbo-
xylic acid benzyl ester
[1020] The title compound is prepared analogously as described in
example K7 using cyclopropane-1,1-dicarboxylic acid benzyl ester
instead of malonic acid monobenzyl ester.
[1021] MS: 591 [M+H]+
[1022] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.5 min.
B)
1-(3-exo-[(R)-1-((S)-2-Methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluo-
ro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-carbonyl)cyclopropanecarbox-
ylic acid
[1023] To
1-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5--
trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-carbonyl}-cyclopropa-
necarboxylic acid benzyl ester (50 mg, 0.085 mmol) in MeOH (0.425
mL) is adde an aqueous 1N LiOH solution (93.5 uL, 0.093 mmol).
[1024] After stirring at rt during 16 h, the pH is ajusted to 3
with aqueous 1N HCl, the mixture is extracted with chloroform and
the organic phase is dried and evaporated to give a crude compound
which is and purified by preparative HPLC HPLC (Column Waters ODB
19.times.50 5 uM, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min 5-100%
ACN, 12.5-15 min 100% ACN) to yield a white solid.
[1025] MS 501 [M+H]+
[1026] LCMS (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 3.3 min.
C)
{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2-
.1]oct-8-yl}-[1-(morpholine-4-carbonylcyclopropyl]-methanone
[1027] The title compound is prepared analogously as described in
example K7 using
1-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5--
trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-carbonyl}-cyclopropa-
necarboxylic acid instead of
3-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-
-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-3-oxo-propionic acid
and morpholine instead of cyclopropylamine.
[1028] MS: 466 [M+H]+
[1029] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.23 min.
Example K10
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]octane-8-carbonyl}-cyclopropanecarboxylic acid benzylamide
[1030] The title compound is prepared analogously as described in
example K9 using benzylamine instead of morpholine.
[1031] MS: 487 [M+H]+
[1032] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.17 min.
Example K10a
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]octane-8-carbonyl})-clopropanecarboxylic acid benzylamide
maleate
[1033] The title compound is prepared analogously as described in
example D2a using
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-b-
icyclo[3.2.1]octane-8-carbonyl}-cyclopropanecarboxylic acid
benzylamide instead of cyclopropanesulfonic acid
(2-(3-exo-[(R1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]octane-8-sulfonyl)ethyl{amide.
Example K10b
1-(3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]octane-8-carbonyl}-cyclopropanecarboxylic acid benzylamide
toluene-4-sulfonate
[1034] The title compound is prepared analogously as described in
example D2b using
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-b-
icyclo[3.2.1]octane-8-carbonyl}cyclopropanecarboxylic acid
benzylamide instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl) amide.
Example K11
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]octane-8-carbonyl}-cyclopropanecarboxylic acid
benzyl-methyl-amide
[1035] The title compound is prepared analogously as described in
example K9 using N-methylbenzylamine instead of morpholine.
[1036] MS: 500 [M+H]+
[1037] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.27 min.
Example K12
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]octane-8-carbonyl}-cyclopropanecarboxylic acid
(2-methoxy-ethyl)-methyl-amide
[1038] The title compound is prepared analogously as described in
example K9 using N-methyl-2-methoxyethylamine instead of
morpholine.
[1039] MS: 468 [M+H]+
[1040] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.22 min.
Example K13
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]octane-8-carbonyl}-cyclopropanecarboxylic acid dimethylamide
[1041] The title compound is prepared analogously as described in
example K9 using dimethylamine instead of morpholine.
[1042] MS: 424 [M+H]+
[1043] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.22 min.
Example K14
1-{3-exo-[(R)-1-((S)-2-Methylpropane-2-sulfinylamino)-2-(2,4,5-trifluoro-p-
henyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-carbonyl}-cyclopropanecarboxyli-
c acid amide
[1044] The title compound is prepared analogously as described in
example K9 using ammonium carbonate instead of morpholine.
[1045] MS: 396 [M+H]+
[1046] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.11 min.
Example K15
4-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-N-cycl-
opropyl-4-oxo-butyramide
[1047] The title compound is prepared analogously as described in
example K6 using
4-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5--
trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]oct-8-yl}-4-oxo-butyric
acid instead of
4-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-4-oxo-
-butyric acid.
[1048] MS: 424 [M+H]+
[1049] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.61 min.
Example K16
4-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-N-(4-tert-butyl-cyclohexyl)-4-oxo-butyramide
[1050] The title compound is prepared analogously as described in
example K15 using 4-tert-butylcyclohexylamine instead of
cyclopropylamine.
[1051] MS: 522 [M+H]+
[1052] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 3.36 min.
Example K17
4-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-N-benzyl-4-oxo-butyramide
[1053] The title compound is prepared analogously as described in
example K15 using benzylamine instead of cyclopropylamine.
[1054] MS: 473 [M+H]+
[1055] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.89 min.
Example K18
3-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-N-benzyl-2,2-dimethyl-3-oxo-propionamide
[1056] The title compound is prepared analogously as described in
example K7 using dimethyl-1,1-dicarboxylic acid benzyl ester
instead of cyclopropane-1,1-dicarboxylic acid benzyl ester and
benzyl amine instead of morpholine.
[1057] MS: 489 [M+H]+
[1058] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.29 min.
Example K19
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2,2-dimethyl-3-morpholin-4-yl-propane-1,3-dione
[1059] The title compound is prepared analogously as described in
example K18 using morpholine instead of benzylamine.
[1060] MS: 468 [M+H]+
[1061] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.22 min.
Example K20
{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-[1-(morp-
holine-4-carbonyl)-cyclopropyl]-methanone
[1062] The title compound is prepared analogously as described in
example K9 using (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
instead of
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinyiamino)-2-(2,4,5-trifluoro-ph-
enyl)-ethyl]-8-aza-bicyclo[3.2.1]octane.
[1063] MS: 440 [M+H]+
[1064] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.594 min.
Example K20a
{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-[1-(morp-
holine-4-carbonyl)-cyclopropyl]-methanone maleate
[1065] The title compound is prepared analogously as described in
example D2a using
{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-y-
l}-[1-(morpholine-4-carbonyl)-cyclopropyl]-methanone instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}ethylyamide.
Example K20b
{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-[1-(morp-
holine-4-carbonyl)-cyclopropyl]-methanone toluene-4-sulfonate
[1066] The title compound is prepared analogously as described in
example D2b using
{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-y-
l}-[1-(morpholine-4-carbonyl)-cyclopropyl]-methanone instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example K21
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidine-1-carbonyl}-
-cyclopropanecarboxylic acid benzyl-methyl-amide
[1067] The title compound is prepared analogously as described in
example K11 using (SY2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
instead of
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-ph-
enyl)-ethyl]-8-aza-bicyclo[3.2.1]octane.
[1068] MS: 474 [M+H]+
[1069] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 3.00 min.
Example K22
1-(4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidine-1-carbonyl)-
-cyclopropanecarboxylic acid benzylamide
[1070] The title compound is prepared analogously as described in
example K10 using (SY2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
instead of
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-ph-
enyl)-ethyl]-8-aza-bicyclo[3.2.1]octane.
[1071] MS: 457 [M+H]+
[1072] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.881 min.
Example K23
3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-N-(4-hydroxy-cyclohexyl)-3-oxo-propionamide
[1073] The title compound is prepared analogously as described in
example K7 using 4-Aminocyclohexanol instead of
cyclopropylamine.
[1074] MS: 468 [M+H]+
[1075] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.500 min.
Example K24
3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-N,N-dimethyl-3-oxo-propionamide
[1076] The title compound is prepared analogously as described in
example K7 using dimethylamine instead of cyclopropylamine.
[1077] MS: 398 [M+H]+
[1078] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.413 min.
Example K25
{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo-
[3.2.1]oct-8-yl}-(1-{(1S,3S,5R)-3-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)--
ethyl]-bicyclo[3.2.1]octane-8-carbonyl}-cyclopropyl)-methanone
[1079] The title compound is prepared analogously as described in
example K9 using
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tri-
fluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
morpholine.
[1080] MS: 663 [M+H]+
[1081] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 2.974 min.
Example K26
4-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-N,N-dimethyl-4-oxo-butyramide
[1082] The title compound is prepared analogously as described in
example K4 using
3-exo-[(R)-1-((S-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trif-
luoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[1083] MS: 412 [M+H]+
[1084] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.643 min.
Example K27
4-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]8-aza-bicycl-
o[3.2.1]oct-8-yl}-N-(4-hydroxy-cyclohexyl)-4-oxo-butyramide
[1085] The title compound is prepared analogously as described in
example K5 using
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tri-
fluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[1086] MS: 482 [M+H]+
[1087] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.559 min.
Example L1
Tetrahydropyran-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-methyl-amide
[1088] This compound is prepared according to Scheme L:
##STR00119## ##STR00120##
A)
Methyl-(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,-
5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-ethyl)-c-
arbamic acid benzyl ester
[1089] The title compound is prepared analogously as described in
example D1 using (2-chlorosulfonyl-ethylymethyl-carbamic acid
benzyl ester instead of 2-phthalimidoethane sulfonyl chloride.
[1090] MS: 644 [M+H]+
[1091] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.53 min.
P B) (S)-2-Methyl-propane-2-sulfinic acid
[(R)-1-[3-exo-8-(2-methylamino-ethanesulfonyl)-8-aza-bicyclo[3.2.1]oct-3--
yl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
[1092] To
methyl-(2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-
-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}-et-
hyl)-carbamic acid benzyl ester (530 mg, 0.799 mmol) in ethanol (20
mL) is added Pd/C (85 mg, 0.799 mmol). After stirring at rt during
2 h under H2 atmospher, the solution is filtered through celite and
evaporated to yield a yellow solid.
[1093] MS: 510 [M+H]+
C) Tetrahydropyran-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-methyl-amide
[1094] The title compound is prepared analogously as described in
example D6 using (SY2-methyl-propane-2-sulfinic acid
[(R)-1-[3-exo-8-(2-methylamino-ethanesulfonyl)-8-aza-bicyclo[3.2.1]oct-3--
yl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide instead of
2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-
-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}ethylamine.
[1095] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.13 min.
Example L1a
Tetrahydropyran-4-carboxylic acid
(2-(3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl)-ethyl)-methyl-amide maleate
[1096] The title compound is prepared analogously as described in
example D2a using tetrahydropyran-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-methyl-amide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]octane-8-sulfonyl}-ethyl)-amide.
Example L2b
Tetrahydropyran-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-methyl-amide toluene-4-sulfonate
[1097] The title compound is prepared analogously as described in
example D2b using tetrahydropyran-4-carboxylic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}ethyl)-methyl-amide instead of
cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]octane-8-sulfonyl}-ethyl)-amide.
Example L2
(2-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2-
.1]octane-8-sulfonyl}-ethyl)-methyl-carbamic acid ethyl ester
[1098] The title compound is prepared analogously as described in
example D13 using (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-[3-exo-8-(2-methylamino-ethanesulfonyl)-8-aza-bicyclo[3.2.1]oct-3--
yl]-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide instead of
2-{3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-
-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane-8-sulfonyl}ethylamine.
[1099] MS: 478 [M+H]+
[1100] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.21 min.
Example M1
1-{3-exo-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.-
1]oct-8-yl}-2-(morpholine-4-sulfonyl)-ethanone
[1101] This compound is prepared according to Scheme M:
##STR00121## ##STR00122##
A) Cyclohexylsulfanyl-acetic acid
[1102] To cyclohexylmercaptane (147 uL, 1.2 mmol) in DMF (1 mL) are
added bromoacetic acid (167 mg, 1.2 mmol) and DIPEA (616 uL, 3.6
mmol). The resulting mixture is stirred at rt during 2 h and used
such as in the next step.
B) (SY2-Methyl-propane-2-sulfinic acid
[(R)-1-[1-(2-cyclohexylsulfanyl-acetyl)piperidin-4-yl]-2-(2,4,5-trifluoro-
-phenyl)-ethyl]-amide
[1103] To (SY2-Methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide (200
mg, 0.552 mmol) in dichloromethane (1 mL) are added EDC (127 mg,
0.662 mmol), HOBt (97 mg, 0.718 mmol), DIPEA (283 uL, 1.656 mmol)
and cyclohexylsulfanyl-acetic acid in DMF (2 mL, 1.2 mmol). After
stirring at rt during 3 days, the mixture is washed with an aqueous
1N HCl solution, the organic phase is dried and evaporated to give
the title compound.
[1104] MS 519 [M+H]+
[1105] LCMS (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 20-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min
95-20% ACN, 5.55-6 min 20% ACN): 4.236 min.
C)
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-2-c-
yclohexylsulfanyl-ethanone
[1106] To (S)-2-Methyl-propane-2-sulfinic acid
[(R)-1-[1-(2-cyclohexylsulfanyl-acetyl)-piperidin-4-yl]-2-(2,4,5-trifluor-
o-phenyl)-ethyl]-amide (367 mg, 0.552 mmol) is added 4N HCl in
dioxane (2 mL). The resulting mixture is stirred at rt during 20
min. The solution is frozen and lyophilised to give a yellow oil
before purification by preparative HPLC HPLC (Column YMC ODS-AQ
20.times.50 5 uM, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min 5-100%
ACN, 12.5-15 min 100% ACN) to yield a colorless oil.
[1107] MS 415 [M+H]+
[1108] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.287 min.
D)
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl-2-cy-
clohexanesulfonyl-ethanone
[1109] To
1-(4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1--
yl}-2-cyclohexylsulfanyl-ethanone (84 mg, 0.203 mmol) in acetic
acid (465 uL) is added an aqueous 30% H2O2 solution (83 uL, 0.812
mmol). The resulting mixture is stirred at 80.degree. C. during 30
min. The solution is frozen and lyophilised to give a colorless
oil
[1110] MS: 447 [M+H]+
[1111] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.219 min.
Example M1a
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-2-cycl-
ohexanesulfonyl-ethanone maleate
[1112] The title compound is prepared analogously as described in
example D2a using
1-{4-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-
-yl}-2-cyclohexanesulfonyl-ethanone instead of cyclopropanesulfonic
acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example M1b
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-2-cycl-
ohexanesulfonyl-ethanone toluene-4-sulfonate
[1113] The title compound is prepared analogously as described in
example D2b using
1-{4-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-
-yl}-2-cyclohexanesulfonyl-ethanone instead of cyclopropanesulfonic
acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example M2
2-(3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-o-
xo-propane-1-sulfonyl)-N,N-diethyl-acetamide
A) 3-Diethylcarbamoylmethylsulfanyl-propionic acid
[1114] To 3-mercaptopropionic acid (200 mg, 1.884 mmol) in methanol
(3 mL) are added sodium methoxide (204 mg, 3.768 mmol) and
2-Bromo-N,N-diethyl-acetamide (402 mg, 2.070 mmol). After stirring
at 80.degree. C. during 4 h and evaporation of solvent, the residue
is treated with ethyl acetate and water, the pH is adjusted to 10
with an aqueous NaHCO3 solution and the aqueous phase is extrated
with ethyl acetate. After acidication of the aqueous phase to pH 2
with an aqueous 1N HCl solution, it is extracted with ethyl
acetate, then the organic phase is dried and evaporated to give the
title compound.
[1115] MS: 220 [M+H]+
[1116] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 0.9 min.
B)
2-(3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}--
3-oxo-propane-1-sulfonyl)-N,N-diethyl-acetamide
[1117] The title compound is prepared analogously as described in
example M1 using 3-Diethylcarbamoylmethylsulfanyl-propionic acid
instead of Cyclohexylsulfanyl-acetic acid.
[1118] MS: 492 [M+H]+
[1119] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.548 min.
Example M3
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-cycl-
opropylmethanesulfonyl-propan-1-one
[1120] The title compound is prepared analogously as described in
example M2 using Bromomethylcyclopropane instead of
2-Bromo-N,N-diethyl-acetamide.
[1121] MS: 433 [M+H]+
[1122] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.48 min.
Example M4
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-meth-
anesulfonyl-propan-1-one
[1123] The title compound is prepared analogously as described in
example Ml using 3-Methylthiopropionic acid instead of
Cyclohexylsulfanyl-acetic acid.
[1124] MS: 392 [M+H]+
Example M5
1-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-cycl-
ohexanesulfonyl-propan-1-one
[1125] The title compound is prepared analogously as described in
example Ml using 3-bromopropionic acid instead of bromoacetic
acid.
[1126] MS: 461 [M+H]+
[1127] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.221 min.
Example M6
7-(3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}-3-o-
xo-propane-1-sulfonyl)-3,4-dihydro-2H-isoquinolin-1-one
A) 1-Oxo-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride
[1128] To Chlorosulfonic acid (30 mL) is added
3,4-Dihydro-2H-isoquinolin-1-one (5 g, 34 mmol) at 0.degree. C.
After stirring at rt during 1 h, the mixture is heated at
50.degree. C. during 16 h, then it is poured carefully into an ice
bath and stirred at 0.degree. C. during 30 min. The precipitate is
filtered and dried in oven at 60.degree. C. to give the title
compound.
[1129] MS: 246 [M+H]+
B) 7-Mercapto-3,4-dihydro-2H-isoquinolin-1-one
[1130] To a zinc powder (2.79 g, 42.7 mmol) and
Dichlorodimethylsilane (5.15 mL, 42.7 mmol) in DCE (45 mL) is added
a solution of 1-Oxo-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl
chloride (3 g, 12.2 mmol) and 1,3-dimethylimidazolidin-2-one (3.96
mL, 36.6 mmol) in DCE (5 mL). After stirring at rt during 2 h, the
mixture is concentrated.
[1131] MS: 180 [M+H]+
C)
7-(3-{4-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-piperidin-1-yl}--
3-oxo-propane-1-sulfonyl)-3,4-dihydro-2H-isoquinolin-1-one
[1132] The title compound is prepared analogously as described in
example Ml using 7-Mercapto-3,4-dihydro-2H-isoquinolin-1-one
instead of cyclohexylmercaptane.
[1133] MS: 510 [M+H]+
[1134] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-5%
ACN, 5.55-6 min 5% ACN): 2.776 min.
Example M7
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-2-cyclohexanesulfonyl-ethanone
[1135] The title compound is prepared analogously as described in
example Ml using
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tri-
fluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(SY2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[1136] MS: 473 [M+H]+
[1137] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.239 min.
Example M8
2-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-3-oxo-propane-1-sulfonyl)-N,N-diethyl-acetamide
[1138] The title compound is prepared analogously as described in
example M2 using
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tri-
fluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[1139] MS: 518 [M+H]+
[1140] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.648 min.
Example M8a
2-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-3-oxo-propane-1-sulfonyl)-N,N-diethyl-acetamide
maleate
[1141] The title compound is prepared analogously as described in
example D2a using
2-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethy-
l]-8-aza-bicyclo[3.2.1]oct-8-yl}-3-oxo-propane-1-sulfonyl)-N,N-diethyl-ace-
tamide instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example M8b
2-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-yl}-3-oxo-propane-1-sulfonyl)-N,N-diethyl-acetamide
toluene-4-sulfonate
[1142] The title compound is prepared analogously as described in
example D2b using
2-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethy-
l]-8-aza-bicyclo[3.2.1]oct-8-yl}-3-oxo-propane-1-sulfonyl)-N,N-diethyl-ace-
tamide instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example M9
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-3-cyclopropylmethanesulfonyl-propan-1-one
[1143] The title compound is prepared analogously as described in
example M3 using
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tri-
fluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[1144] MS: 459 [M+H]+
[1145] HPLC (YMC, 6 min method (0-3 min 5-95% ACN, 3.5-5.5 min 95%
ACN, 5.5-5.55 min 95-5% ACN, 5.55-6 min 20% ACN): 2.573 min.
Example M10
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-3-cyclohexanesulfonyl-propan-1-one
[1146] The title compound is prepared analogously as described in
example M5 using
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tri-
fluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[1147] MS: 487 [M+H]+
[1148] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.241 min.
Example M11
1-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyc-
lo[3.2.1]oct-8-yl}-3-methanesulfonyl-propan-1-one
[1149] The title compound is prepared analogously as described in
example M4 using
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-tri-
fluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2.1]octane instead of
(S)-2-methyl-propane-2-sulfinic acid
[(R)-1-piperidin-4-yl-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
Example N1
2-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]8-aza-bic-
yclo[3.2.1]oct-8-ylmethyl}-benzyl)-isoindole-1,3-dione
[1150] This compound is prepared according to Scheme N:
##STR00123##
A) 2-(3-Hydroxymethyl-benzyl)isoindole-1,3-dione
[1151] To 3-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoic
acid (300 mg, 1.066 mmol) in DCM (1 mL9 are added at 0.degree. C.
triethylamine (164 uL, 1.173 mmol) and ethylchloroformate (112 uL,
1.173 mmol). After stirring at 0.degree. C. during 15 min and
filtration, the obtained solution is added at 0.degree. C. to NaBH4
(61 mg, 1.599 mmol) in water (400 uL) before stirring at 0.degree.
C. during 30 min and at rt during 2 h. The solution is acidified to
pH 3 with an aqueous 1N HCl solution, extracted with ethylacetate,
the organic phase is dried and evaporated to give a crude compound
before purification by flash chromatography on silica gel (eluent:
cyclohexane/ethyl acetate 9/1 to 1/1) to yield a colorless gum.
TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.15.
B) 3-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethylybenzaldehyde
[1152] To oxalylchloride (43 uL, 0.449 mmol) in DCM (400 uL) is
added at -78.degree. C. DMSO (43 uL, 0.598 mmol). After stirring at
-78.degree. C. during 15 min,
2-(3-Hydroxymethyl-benzyl)isoindole-1,3-dione (80 mg, 0.299 mmol)
in DCM (600 uL) is added and the mixture is stirred at -78.degree.
C. during 45 min before addition of triethylamine (210 uL, 1.495
mmol). After stirring at rt during 4 h, the reaction is quenched
with water, extracted with DCM, the organic phase is washed with an
aqueous 10% NaHSO4 solution and an aqueous saturated NaHCO3
solution. The organic phase is dried and evaporated to give a crude
compound before purification by flash chromatography on silica gel
(eluent: cyclohexane/ethyl acetate 9/1 to 2/1) to yield a colorless
gum.
[1153] MS: 266 [M+H]+
[1154] TLC, Rf (cyclohexane/ethyl acetate 1/1)=0.7.
C) (S)-2-Methyl-propane-2-sulfinic acid
[(R)-1-{(1S,3S,5R)-8-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethylybenzyl-
]-8-aza-bicyclo[3.2.1]oct-3-yl}-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
[1155] 3-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethylybenzaldehyde
(44 mg, 0.166 mmol) and
3-exo-[(R)-1-((S)-2-methyl-propane-2-sulfinylamino)-2-(2,4,5-trifluoro-ph-
enyl)-ethyl]-aza-bicyclo[3.2.1]octane (54 mg, 0.138 mmol) in DCE
(500 uL) are stirred at rt during 1 h before added of sodium
triacetoxyborohydride (74 mg, 0.345 mmol). The mixture is stirred
at rt during 16 h and the solvent is evaporated to give a crude
compound before purification by preparative HPLC (Column Waters C18
ODB 5 .mu.m 19.times.50, Gradient: 0-2.5 min 5% ACN, 2.5-12.5 min
5-100% ACN, 12.5-15 min 100% ACN) to yield the title compound.
[1156] MS: 638 [M+H]+
[1157] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.361 min.
D)
2-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-
-bicyclo[3.2.1]oct-8-ylmethyl}-benzyl)-isoindole-1,3-dione
[1158] The title compound is prepared analogously as described in
example G17 using S)-2-Methyl-propane-2-sulfinic acid
[(R)-1-{(1S,3S,5R)-8-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzy-
l]-8-aza-bicyclo[3.2.1]oct-3-yl}-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
instead of (SY2-Methyl-propane-2-sulfinic acid
[(R)-1-{(1S,3S,5R)-8-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzo-
yl]-8-aza-bicyclo[3.2.1]oct-3-yl}-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[1159] MS: 534 [M+H]+
[1160] HPLC (Zorbax SB C18, 2 min method (0-0.8 min 10-95% ACN,
0.8-1.5 min 95% ACN, 1.5-1.6 min 95-10% ACN, 1.6-2 min 10% ACN):
1.228 min.
Example N1a
2-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-ylmethyl}-benzyl)-isoindole-1,3-dione maleate
[1161] The title compound is prepared analogously as described in
example D2a using
2-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethy-
l]-8-aza-bicyclo[3.2.1]oct-8-ylmethyl}-benzyl)-isoindole-1,3-dione
instead of cyclopropanesulfonic acid
(2-{3-exo-[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.-
2.1]octane-8-sulfonyl}-ethyl)-amide.
Example N1b
2-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-ylmethyl}-benzyl)-isoindole-1,3-dione
toluene-4-sulfonate
[1162] The title compound is prepared analogously as described in
example D2b using
2-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethy-
l]-8-aza-bicyclo[3.2.1]oct-8-ylmethyl}-benzyl)-isoindole-1,3-dione
instead of cyclopropanesulfonic acid
(2-{3-exo[(R)-1-amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bicyclo[3.2-
.1]octane-8-sulfonyl}-ethyl)-amide.
Example N2
N-(3-{(1S,3S,5R)-3-[(R)-1-Amino-2-(2,4,5-trifluoro-phenyl)-ethyl]-8-aza-bi-
cyclo[3.2.1]oct-8-ylmethyl}-benzyl)-benzamide
[1163] The title compound is prepared analogously as described in
example G18 using (SY2-Methyl-propane-2-sulfinic acid
[(R)-1{(1S,3S,5R)-8-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzyl-
]-8-aza-bicyclo[3.2.1]oct-3-yl}-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide
instead of (S)-2-methyl-propane-2-sulfinic acid
[(R)-1-{3-exo-8-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoyl]-8-
-aza-bicyclo[3.2.1]oct-3-yl}-2-(2,4,5-trifluoro-phenyl)-ethyl]-amide.
[1164] MS: 508 [M+H]+
[1165] HPLC (Waters Symmetry C18 3.5 .mu.m 2.1.times.50 mm, 6 min
method (0-3 min 5-95% ACN, 3.5-5.5 min 95% ACN, 5.5-5.55 min 95-5%
ACN, 5.55-6 min 5% ACN): 2.863 min.
Example P
Activity Assay
[1166] Various compounds of the invention were tested for their
inhibitory activity to human DPP-IV.
Materials
[1167] Human DPP-IV consisting of amino acids 39 to 766 followed by
a C-terminal Streptavidin-tag was expressed using the baculovirus
system and purified to >80% purity. The enzyme was stored in 25
mM Tris buffer, pH 9.0, containing 300 mM NaCl at -80.degree. C.
The fluorogenic substrates H-Gly-Pro-AMC was purchased from Bachem
AG (Bubendorf, Switzerland). The substrate was kept as a 5 mM stock
solution in DMSO at -20.degree. C. All other chemicals were
purchased from Sigma (Buchs, Switzerland).
[1168] The assay buffer for the DPP-IV reaction was 25 mM Tris/HCl,
pH 7.5, containing 140 mM NaCl, 10 mM KCl and 0.05% (w/v)
CHAPS.
[1169] Compound and Liquid Handling
[1170] The test compounds were dissolved in 90% DMSO/10% H2O (v/v).
Serial dilutions of the compounds from 3 mM to 0.03 .mu.M in 90%
DMSO/10% H2O (v/v) followed by a 1:33.3 dilution in assay buffer
was done in 96-well polypropylene plates using a CyBio Dilus
8-channel pipeftor (CyBio AG, Jena, Germany) with tip change after
each pipetting step. The compound solutions as well as the
substrate and the enzyme solutions were transferred to the assay
plates (384-well black Cliniplate; cat. no. 95040020 Labsystems Oy,
Finland) by means of a CyBi-Well 96-channel pipeftor (CyBio AG,
Jena, Germany).
Kinetic Measurements
[1171] Enzyme kinetics were measured by mixing 10 .mu.l of a 3-fold
concentrated substrate solution in assay buffer (final substrate
concentration was 10 .mu.M) with 10 .mu.l of the corresponding
compound solution. The reactions were initiated by addition of 10
.mu.l of a 3-fold concentrated solution of the enzyme in assay
buffer. Final enzyme (active site) concentrations in the assay was
10 pM for DPP-IV. Fluorescence product (AMC) formation was
monitored for 1 hour at room temperature at 35 second intervals by
measuring the fluorescence emission at 500 nm using an exitation
wavelength of 350 nm in a TECAN Ultra fluorescence reader (TECAN,
Maennedorf, Switzerland). The fluorescence in each well was excited
by one flash per measurement. The Origin software package (Origin
7.5 Mircocal, Northampton, Mass., USA) was used to generate all
graphs and to perform the IC50 calculations.
Results
[1172] The inhibitory activities (IC50 values) of the compounds to
human DPP-IV were found to be 4.7 .mu.M or less and in many cases
0.01 .mu.M or less. In the case of exemplary compounds, their IC50
values were found to be between 4.7 and 0.0001 .mu.M or between 4.7
.mu.M and 0.0053 .mu.M.
Representative Examples
TABLE-US-00032 [1173] Examples hDPPIV IC50 (.mu.M) D1 0.0077 E7
0.0006 G4 0.01 H13 0.007
* * * * *