U.S. patent application number 15/063891 was filed with the patent office on 2016-06-30 for hydroxyphenyl derivatives and biological applications thereof.
The applicant listed for this patent is FAB PHARMA. Invention is credited to Yannick BONVIN, Alexis DENIS, Vincent GERUSZ.
Application Number | 20160185724 15/063891 |
Document ID | / |
Family ID | 37007447 |
Filed Date | 2016-06-30 |
United States Patent
Application |
20160185724 |
Kind Code |
A1 |
DENIS; Alexis ; et
al. |
June 30, 2016 |
HYDROXYPHENYL DERIVATIVES AND BIOLOGICAL APPLICATIONS THEREOF
Abstract
The invention relates to hydroxyphenyl derivatives of formula
(I); and uses thereof as anti-bacterial and/or anti-parasitic
agents.
Inventors: |
DENIS; Alexis; (Paris,
FR) ; GERUSZ; Vincent; (Paris, FR) ; BONVIN;
Yannick; (Paris, FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
FAB PHARMA |
PARIS |
|
FR |
|
|
Family ID: |
37007447 |
Appl. No.: |
15/063891 |
Filed: |
March 8, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14228893 |
Mar 28, 2014 |
9309179 |
|
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15063891 |
|
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12226281 |
Oct 14, 2008 |
8722746 |
|
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PCT/IB2007/002127 |
Apr 16, 2007 |
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14228893 |
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Current U.S.
Class: |
514/335 ;
514/340; 514/341; 514/345; 514/348; 514/349; 546/261; 546/272.4;
546/272.7; 546/296; 546/297; 546/302 |
Current CPC
Class: |
C07C 43/23 20130101;
C07D 213/73 20130101; A61P 31/06 20180101; C07C 41/16 20130101;
C07C 43/275 20130101; C07C 209/08 20130101; C07D 213/69 20130101;
C07D 213/74 20130101; C07C 217/90 20130101; C07D 209/50 20130101;
C07C 41/26 20130101; C07C 41/26 20130101; A61P 31/04 20180101; C07C
251/54 20130101; C07D 213/76 20130101; A61P 33/06 20180101; C07C
49/84 20130101; C07C 205/38 20130101; C07D 295/16 20130101; C07D
401/12 20130101; C07C 43/295 20130101; C07C 45/673 20130101; C07D
295/092 20130101; A61P 31/00 20180101; C07D 213/75 20130101; C07C
41/26 20130101; C07D 213/68 20130101; C07C 43/295 20130101; C07C
309/73 20130101; C07C 49/84 20130101; C07C 43/275 20130101; C07C
43/23 20130101; C07C 49/84 20130101; C07C 45/71 20130101; C07C
45/673 20130101; C07C 45/71 20130101; A61P 43/00 20180101; C07C
209/14 20130101; C07C 41/16 20130101; C07D 213/643 20130101 |
International
Class: |
C07D 213/643 20060101
C07D213/643; C07D 401/12 20060101 C07D401/12; C07D 213/76 20060101
C07D213/76; C07D 213/73 20060101 C07D213/73; C07D 213/69 20060101
C07D213/69 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 14, 2006 |
EP |
06290611.0 |
Claims
1. Hydroxyphenyl derivatives of the invention of formula (I)
##STR00250## R1 is a 6 membered monocyclic nitrogenous heteroaryl
of formula ##STR00251## Z4, Z5, Z6, Z7 and Z8 are independently C
or N with a maximum of three N, R1 being possibly substituted by 1
to 3 R identical or different, R being selected from the group
comprising H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, 5 or 6 membered monocyclic heteroaryl or
aliphatic heterocycle containing 1 to 3 heteroatoms selected from
N, O and S, COOR.sub.a, COR.sub.a, CONR.sub.aR.sub.b, OCOR.sub.a,
CN, OR.sub.a, NR.sub.aR.sub.b, CR.sub.a.dbd.NOR.sub.b,
NR.sub.aCOR.sub.b, NR.sub.aCOOR.sub.b, OCONR.sub.aR.sub.b,
NR.sub.aCONR.sub.bR.sub.c, SR.sub.a, SO.sub.2R.sub.a,
SO.sub.2NR.sub.aR.sub.b, NR.sub.aSO.sub.2R.sub.b and
NR.sub.aC(S)NR.sub.bR.sub.c, all being possibly substituted by R',
or R is C.sub.1-C.sub.4fluoro-alkyl, or R is halogeno, R2 is
phenyl, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, C.sub.1-C.sub.4fluoro-alkyl,
C.sub.2-C.sub.4fluoro-alkenyl, OR.sub.a, SR.sub.a, all being
possibly substituted by 1 to 3 identical or different R', R.sub.a,
R.sub.b and R.sub.c, identical or different, are selected from the
group consisting of H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, phenyl, heteroaryl and aliphatic
heterocycle as defined above for R2, the heteroaryl and the
heterocycle being possibly formed with the carbon and nitrogen
atoms to which R.sub.a, R.sub.b and R.sub.c are linked, R' is
selected from the group comprising heteroaryl and aliphatic
heterocycle as defined above for R2, C.sub.1-C.sub.8 alkyl,
CH.sub.2CO.sub.2R'', CO.sub.2R'', COR'', CONR''R''', OCOR'', OR'',
NR''R''', NR''COR''', NR''COOR''', OCONR''R''', NR''CONR''R''',
NR''SO.sub.2R''', SO.sub.2R'', NR''SO.sub.2R''', halogen and CN,
R'' and R''', identical or different, are H, C.sub.1-C.sub.8 alkyl
or form together a 4 to 6 membered heterocycle with 1 to 3
heteroatoms selected from N, O and S, Y represents H or a labile
chemical group able to regenerate in vivo the free phenol selected
from the group consisting of C(O)R.sub.a, C(O)OR.sub.a,
C(O)NR.sub.a,R.sub.b, P(O)(OH).sub.2 and
COCHR.sub.aNR.sub.bR.sub.c, Z1 and Z3, identical or different, are
halogen or H, Z2 is fluor or H, provided that either Z2 is fluor
and all the other definitions are as defined above, or Z6 is a
carbon atom substituted by R as defined above, R being different
from H, alkyl, halogen, NH.sub.2, OH, CONH.sub.2 or fluoro alkyl
and all the other definitions are as defined above, or Z4 or Z5, or
Z7 or Z8 are carbon atoms substituted by NR.sub.aR.sub.b or
OR.sub.a, OR.sub.a being different from OH and all the other
definitions are as defined above, or Z5, or Z7, is a carbon atom
substituted by R, R being different from H and all the other
definitions are as defined above, or R2 is a
C.sub.1-C.sub.8alkyl-heteroaryl radical or a
C.sub.1-C.sub.8alkyl-OR.sub.a radical, OR.sub.a being different
from OH and all the other definitions are as defined above, and the
pharmaceutically acceptable organic and mineral salts, as well as
the racemic derivatives and each unique not racemic derivatives, in
case the derivatives of formula (I) have one or more chiral
centers, both the cis (Z) and trans (E) isomers, in cases the
derivatives of formula (I) have unsaturated carbon=carbon double
bonds, and any N-oxide form of the derivatives.
2. The derivatives according to claim 1, wherein R1 is a 6 membered
monocyclic heteroaryl with 1 or 3 nitrogen atoms selected from the
group consisting of pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl
and triazinyl.
3. The derivatives according to claim 1, wherein R1 is substituted
by 1 to 3 substituents selected from the group comprising F,
COR.sub.a, OR.sub.a, NR.sub.aR.sub.b, alkynyl, SO.sub.2R.sub.a,
NR.sub.aSO.sub.2R.sub.b, SO.sub.2NR.sub.aR.sub.b,
NR.sub.aCOOR.sub.b and CR.sub.a.dbd.NOR.sub.b.
4. The derivatives according to claim 1, wherein Z2 is fluor.
5. The derivatives according to claim 1, wherein Z6 is a carbon
atom substituted by R as defined in claim 1, R being different from
H, alkyl, halogen, NH.sub.2, OH, CONH.sub.2 or fluoro alkyl.
6. The derivatives according to claim 1, wherein Z4 or Z5, or Z7 or
Z8, are carbon atoms substituted by NR.sub.aR.sub.b or
OR.sub.a.
7. The derivatives according to claim 1, wherein, Z5 or Z7 is a
carbon atom substituted by R as defined in claim 1, R being
different from H.
8. The derivatives according to claim 1, wherein R2 is a
C.sub.1-C.sub.8alkyl-heteroaryl or
C.sub.1-C.sub.8alkyl-OR.sub.a.
9. The derivatives according to claim 1, wherein Y represents
H.
10. The derivatives according to claim 1, wherein Y represents a
labile chemical group selected from the group consisting of
C(O)R.sub.a, CO(O)R.sub.a, C(O)NR.sub.aR.sub.b, P(O)(OH).sub.2 and
COCHR.sub.aNR.sub.bR.sub.c.
11. A process for making a derivative according to claim 1,
comprising the steps of a) reacting with AR1, a phenol derivative
of formula (II) ##STR00252## wherein R1, R2, Z1, Z2 and Z3 are as
defined in claim 1, R3 represents an alkyl group, and A is a
reactive group capable of reacting with the OH group of (II), under
basic conditions, to give a derivative of formula (III)
##STR00253## b) reacting the derivative of formula (III) with a
Lewis acid to give the desired derivative of formula (I).
12. The process according to claim 11, wherein to obtain derivative
with R2 representing a functional group, the desired function is
introduced prior removal of R3.
13. A process for making a derivative according to claim 1,
comprising the steps of a) reacting the protected phenol derivative
of formula (II) with TosCl to give a derivative of formula (IV)
##STR00254## wherein R2, Z1, Z2 and Z3 are as defined in claim 1
and R3 represents an alkyl group b) reacting the derivative of
formula (IV) with a Lewis acid to give a derivative of formula (V)
##STR00255## c) treating the derivative of formula (V) under basic
or acidic conditions, to introduce R4, R4 being a protecting group
selected from the group consisting of benzyl, BOM, SEM, MOM, MEM,
TBDMS, THP and analogs, to obtain a derivative of formula (VI),
##STR00256## d) reacting said derivative of formula (VI) under
basic conditions or with Mg in an alcohol, to remove the Tos group,
to obtain a derivative of formula (VII) ##STR00257## e) reacting
the derivative of formula (VII) with AR1 to obtain a product of
formula (III') ##STR00258## wherein A is a reactive group capable
of reacting with the OH group of (VII) and R1 is as defined in
claim 1, f) deprotecting the phenol group to obtain the desired
derivative of formula (I) with Y representing H.
14. A process for making the derivatives according to claim 1
wherein Z2 is fluor, comprising the steps of a) reacting the
bromophenol of formula (VIII): ##STR00259## with AR1, in the
presence of a base to obtain the compound of formula (IX):
##STR00260## wherein R3 represents an alkyl group, A is a reactive
group capable of reacting with the OH group of (VII) and R1 is as
defined in claim 1, then reacting the compound of formula (IX) with
a palladium catalyst in the presence of a base and a boronic
reactant of formula R2B, R2 is as defined in claim 1 and B is a
boronic ester residue, to obtain a derivative of formula (X),
##STR00261## b) alternatively protecting the compound of formula
(VIII), with a benzyl group prior to reacting it with a palladium
catalyst in the presence of a base and a boronic reactant of
formula R2B, to obtain the benzylated derivative (XI), ##STR00262##
debenzylating it with palladium on charcoal and hydrogen to obtain
the free phenol of formula (XII) ##STR00263## and reacting (XII)
with AR1 to generate the derivative of formula (X) wherein A is a
reactive group capable of reacting with the OH group of (VII) and
R1 is as defined in claim 1, c) Dealkylalating the compound of
formula (X) by reacting the compound of formula (X) with a Lewis
acid to generate the derivative of formula (I).
15. A process according to claim 11, wherein a compound of formula
(III), (VI), (VII), (X) or (I) is obtained from a compound of
formula (XIII) ##STR00264## in which R5 is H, by hydrogenation with
palladium on charcoal to give the corresponding ethyl compound
derivative (XIV) ##STR00265##
16. A process according to claim 11, wherein a derivative of
formula (I) in which Y.dbd.H is converted into a compound in which
Y is C(O)R.sub.a, CO(O)R.sub.a, C(O)NR.sub.a, R.sub.b,
P(O)(OH).sub.2, and COCHR.sub.aNR.sub.bR.sub.c.
17. A pharmaceutical composition comprising, as active ingredient,
a therapeutically effective amount of a derivative of formula (I)
as defined in claim 1, in combination with a pharmaceutically
acceptable carrier.
18. The pharmaceutical composition of claim 17, which is formulated
to be administered under oral, injectable, parental routes, to a
patient.
19. A method for treating human or animal infections by microbial
pathogens comprising E. coli, S. aureus, M. tuberculosis, H. pylori
or Plasmodium falciparum, said method comprising administering to a
patient in need thereof an effective amount of a hydroxyphenyl
derivative as defined in claim 1.
Description
[0001] This application is a continuation of application Ser. No.
14/228,893 (allowed), filed Mar. 28, 2014 (published as US
2014-0213589 A1), which is a continuation of application Ser. No.
12/226,281 (issued as U.S. Pat. No. 8,722,746), filed Oct. 14, 2008
(published as US 2010-0041658 A1), which is a U.S. national phase
of International Application No. PCT/182007/002127, filed Apr. 16,
2007, which designated the U.S. and claims priority to EP
06290611.0, filed Apr. 14, 2006, the entire contents of each of
which are hereby incorporated by reference.
[0002] The invention relates to hydroxyphenyl derivatives and a
process for making the same. It also relates to the biological
applications thereof, particularly as anti-bacterial and/or
anti-parasites agents.
[0003] The invention more particularly relates to Triclosan
derivatives. Triclosan (TCL)
5-chloro-2-(2,4-dichloro-phenoxy)-phenol (A) is a broad-spectrum
biocide that has been in use for over 30 years, mainly as a
component of antimicrobial wash products in health-care settings,
of formula (A)
##STR00001##
[0004] More recently, Triclosan has found extensive use in consumer
products such as toothpaste, mouthwashes, deodorants, hand soaps,
and lotions. It is also incorporated in children's toys, cutting
boards, and the plastic film used to wrap meat products. Until
recently, it was thought that Triclosan, being a small hydrophobic
molecule, was absorbed via diffusion into the bacterial cell wall
and that unspecific disruption of the cell wall was the mechanism
by which Triclosan exhibited its antibacterial activity. However,
the first evidence that Triclosan inhibits fatty acid biosynthesis
came when a strain of E. coli resistant to Triclosan was isolated,
and the resistance was mapped to the fabI gene which codes for the
E. coli trans enoyl-acyl carrier protein reductase (ENR). Fatty
acid biosynthesis in bacteria is essential to the production of a
number of lipid-containing components including the cell membrane.
The bacterial fatty acid synthase system (FASII) utilizes discrete
monofunctional enzymes that operate in conjunction with acyl
carrier protein (ACP)-associated substrates. Mammalian fatty acid
synthase (FASI) differs from FASII in that lipid biosynthesis is
mediated by a single multifunctional enzyme-ACP complex. The
differences in prokaryote and eukaryote fatty acid biosynthesis
offer an attractive opportunity for selective FASII inhibition.
FabI is an enoyl-ACP reductase that catalyzes the ultimate and
rate-limiting step of the chain elongation process of FASII. The
reaction involves the conjugate reduction of an enoyl-ACP to the
corresponding acyl-ACP using the cofactor NAD(P)H as a hydride
source.
[0005] Subsequently, extensive biochemical and structural studies
have been performed to substantiate Triclosan as a specific E. coli
FabI inhibitor. Two ENR isoforms, FabK and FabL, have been
discovered in the gram-positive bacteria, Streptococcus pneumoniae
and Bacillus subtilis, respectively. FabK is resistant to
Triclosan, whereas FabL is reversibly inhibited by Triclosan.
Triclosan also directly inhibits the FabI from Staphylococcus
aureus, Haemophilus influenzae, the ENR from Mycobacterium
tuberculosis, InhA, and the ENR from Plasmodium falciparum, the
malarial parasite.
[0006] Since the discovery of FabI as the bacterial target of
Triclosan, several specific inhibitors not structurally related to
TCL have been reported, few of them displaying antibacterial
activities.
[0007] Some analogues of Triclosan itself have been described in
separate chemo-enzymatic studies of the Triclosan mode of action
against FabI. Especially, the antibacterial activity of several
2-hydroxydiphenyl ethers hexachlorophene and
2-hydroxydiphenylmethanes as well as 5-alkylated, -fluorinated or
-formylated derivatives have been determined. On the other hand,
before the discovery of the potent inhibition of FabI by TCL, some
modifications of the dichlorophenol part of TCL were also reported.
For instance broad spectrum, but non specific antibacterial and
antifungal derivatives were reported by introducing a pyridine
instead of a phenyl ring.
[0008] In contrast to TCL, which displays a broad spectrum biocidal
effect with no distinction between microorganisms, new TCL
derivatives that would target only the microorganisms which carry
the FabI enzyme such as S. aureus or E. coli would be selective
antibacterial or antiparasitic agents of interest with no
antibacterial effect or selective pressure against other bacterial
species.
[0009] The inventors have found that specific substitutions of
hydroxyphenyl derivatives having triclosan basic structure lead to
derivatives that surprisingly display a selective and narrow
spectrum of activity against relevant pathogens, particularly
bacteria or parasites.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1. Treatment by molecules of example 21 at 50 mg/kg
mean results of 4 experiments.
[0011] FIG. 2. Treatment by molecules of example 48 at 100 mg/kg
mean results of 4 experiments.
[0012] An object of the invention is then to provide new
substituted hydroxyphenyl derivatives which selectively inhibit the
growth of bacteria carrying Fab enzymes such as FabI, FabL, FabK,
InhA.
[0013] Another object of the invention is to provide a process for
the synthesis of said derivatives.
[0014] Still another object is to take advantage of the biological
properties of said molecules to provide means, i.e. pharmaceutical
compositions and methods, particularly useful for treating
microbial infections.
[0015] The hydroxyphenyl derivatives of the invention have formula
(A)
##STR00002##
wherein [0016] R1 is aryl, heterocycle, aliphatic heterocycle,
cycloalkyl, all having one or several cycles, alkyl, all
substituted or not by one or several R identical or different,
selected in the group comprising, H, alkyl, alkenyl, alkynyl, aryl,
heterocycle, aliphatic heterocycle, fluoro-alkyl, halogen, COOH,
CO.sub.2R.sub.a, COR.sub.a, CONR.sub.aR.sub.b, OCOR.sub.a, CN,
OR.sub.a, aryloxy NR.sub.aR.sub.b, CR.sub.a.dbd.NOR.sub.b,
NR.sub.a-aryl, NR.sub.aCOR.sub.b, NR.sub.aCOOR.sub.b,
OCONR.sub.aR.sub.b, NR.sub.aCONR.sub.bR.sub.c, SR.sub.a,
SO.sub.2R.sub.a, SO.sub.2NR.sub.aR.sub.b, NR.sub.aSO.sub.2R.sub.b,
NR.sub.aC(S)NR.sub.bR.sub.c, [0017] R2 is aryl, aryloxy,
heterocycle, aliphatic heterocycle, cycloalkyl, all having one or
several cycles, H, alkyl, alkenyl, alkynyl, halogen, fluoro-alkyl,
fluoro-alkenyl, OCF.sub.3, OCHF.sub.2, NR.sub.aR.sub.b,
CO.sub.2R.sub.a, COR.sub.a, OR.sub.a, CONR.sub.aR.sub.b,
CR.sub.a.dbd.NOR.sub.b, SR.sub.a, [0018] all being substituted or
not by one or several R, identical or different, being such as
above defined, [0019] R.sub.a, R.sub.b and R.sub.c, identical or
different, being H or as above defined with respect to R, [0020]
two adjacent R, or two adjacent R.sub.a and/or R.sub.b, and for
R.sub.c optionally forming together a cycle [0021] X.dbd.O or S
[0022] Y represents C(O)R, CO(O)R, C(S)R, C(S)OR, C(O)NR.sub.a,
R.sub.b, phosphate, P(O)(OR).sub.2, CH.sub.2OR, or any labile group
which may act as a prodrug to regenerate the free phenol, [0023]
Z1, Z2, Z3, identical or different, are halogen or H, and the
pharmaceutically acceptable salts, the organic and mineral salts,
as well as the racemic derivatives and each unique non racemic
derivatives, in case the derivatives of formula (A) have one or
more chiral centers, both the cis (Z) and trans (E) isomers in case
the derivatives of formula (A) have unsaturated carbon=carbon
double bonds, both forms of tautomers in cases the derivatives of
formula (A) may exist in tautomeric forms, provided that with
respect to formula (A), when R2 is H, C1 to C26 alkyl substituted
or not by OH, NH2, SH, halo or CO.sub.2H or OR, SR, NHR, COOR, COR,
CONHR, SO.sub.2NHR, R being H, C1 to C26 substituted or not by OH,
NH.sub.2, SH, halo or CO.sub.2H; Y.dbd.H; X.dbd.O; Z1, Z2 Z3 are H;
and R1 is a group of formula,
##STR00003##
[0023] if T1 and T5 are independently N or C--R, R being H, methyl,
ethyl, halo, then [0024] either [0025] T2 or T4 are different from
CH or N, [0026] or [0027] T3 is different from N or C--R, wherein R
represent H, methyl, ethyl, halo, nitro, hydroxy, amino, amido or a
methyl or an ethyl group substituted with halo, nitro, hydroxy,
amino, amido; if T2 and T4 are independently CH or N, then [0028]
either [0029] T1 or T5 are different from N or C--R, R being H, Me,
ethyl, halo, [0030] or [0031] T3 is different from N or C--R,
wherein R represent H, methyl, ethyl, halo, nitro, hydroxy, amino,
amido or a methyl or an ethyl group substituted with halo, nitro,
hydroxy, amino, amido; if T3 represent N or C--R, wherein R
represent H, methyl, ethyl, halo, nitro, hydroxy, amino, amido or a
methyl or an ethyl group substituted with halo, nitro, hydroxy,
amino, amido; then. [0032] either [0033] T1 or T5 are different
from N or C--R, R being H, Me, ethyl, halo, [0034] or [0035] T2 or
T4 are different from CH or N.
[0036] When R1 is an heterocycle and more specifically a pyridine,
the invention also includes the N-oxide form.
[0037] "Alkyl" as applied herein means an optionally substituted
alkyl group and preferably methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl,
neopentyl,hexyl and octyl.
[0038] "Alkoxy" and "thioalkyl" mean any O or S atom substituted by
a substituted or not alkyl group.
[0039] "Aryloxy", "thioaryl", "NH-aryl" mean any O, S, N
substituted by a substituted or not aryl, or heterocyclic
group.
[0040] "Aryl" (or "Ar") means phenyl or naphtyl optionally
substituted by R.
[0041] "Alkenyl" and "alkynyl" mean optionally substituted C.dbd.C
or C.ident.C groups.
[0042] "Halogen" or "halo" means F, Cl, Br, and I.
[0043] "Aliphatic heterocycle" or "heterocycle" indicates an
optionally substituted five or six membered monocyclic ring, or a
nine or ten-membered bicyclic ring containing one to three
heteroatoms chosen from the group of nitrogen, oxygen and sulfur,
which are stable and available by conventional chemical synthesis.
Illustrative heterocycles are for example selected in the group
comprising benzofuryl, benzimidazolyl, benzopyranyl, benzothienyl,
furyl, imidazolyl, indolinyl, morpholinyl, piperidinyl,
piperazinyl, pyrrolyl, pyrrolidinyl, tetrahydropyridinyl,
pyridinyl, thiazolyl, thienyl, quinolinyl, isoquinolinyl, and
tetra- and perhydro-quinolinyl and isoquinolinyl, pyrazinyl,
pyrazidinyl, triazinyl, purine, indolyl, indazolyl, pyrimidinyl,
pyridonyl, oxazolyl, tetrahydropyranyl, tetrahydrofuranyl.
[0044] The invention more particularly relates to hydroxyphenyl
derivatives having formula (I)
##STR00004##
wherein [0045] R1 is phenyl or a 6 membered monocyclic nitrogenous
heteroaryl of formula
##STR00005##
[0046] Z4, Z5, Z6, Z7 and Z8 independently are C or N with a
maximum of three N, R1 being possibly substituted by 1 to 3 R
identical or different, R being selected from the group comprising
H, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, 5 or 6 membered monocyclic heteroaryl or aliphatic
heterocycle containing 1 to 3 heteroatoms selected from N, O and S,
COOR.sub.a, COR.sub.a, CONR.sub.aR.sub.b, OCOR.sub.a, CN, OR.sub.a,
NR.sub.aR.sub.b, CR.sub.a.dbd.NOR.sub.b, NR.sub.aCOR.sub.b,
NR.sub.aCOOR.sub.b, OCONR.sub.aR.sub.b, NR.sub.aCONR.sub.bR.sub.c,
SR.sub.a, SO.sub.2R.sub.a, SO.sub.2NR.sub.aR.sub.b,
NR.sub.aSO.sub.2R.sub.b and NR.sub.aC(S)NR.sub.bR.sub.c, all being
possibly substituted by R', or R is C.sub.1-C.sub.4 fluoro-alkyl,
or R is fluor when R1 is phenyl, or R is halogeno when R1 is
nitrogenous heteroaryl, [0047] R2 is phenyl, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl , C.sub.2-C.sub.8 alkynyl, C.sub.1-C.sub.4
fluoro-alkyl, C.sub.2-C.sub.4 fluoro-alkenyl, OR.sub.a, SR.sub.a,
all being possibly substituted by 1 to 3 identical or different R',
[0048] R.sub.a, R.sub.b and R.sub.c, identical or different, are
selected from the group consisting of H, C.sub.1-C.sub.8 alkyl ,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, phenyl,
heteroaryl and aliphatic heterocycle as defined above for R2, the
heteroaryl and the heterocycle being possibly formed with the
carbon and nitrogen atoms to which R.sub.a, R.sub.b and R.sub.c are
linked, [0049] R' is selected from the group comprising heteroaryl
and aliphatic heterocycle as defined above for R2,
C.sub.1-C.sub.8alkyl, CH.sub.2CO.sub.2R'', CO.sub.2R'', COR'',
CONR''R''', OCOR'', OR'', NR''R''', NR''COR''', NR''COOR''',
OCONR''R''', NR''CONR''R''', NR''SO.sub.2R''', SO.sub.2R'',
NR''SO.sub.2R''', halogen and CN, R'' and R''', identical or
different, are H, C.sub.1-C.sub.8 alkyl or form together a 4 to 6
membered heterocycle with 1 to 3 heteroatoms selected from N, O and
S, [0050] Y represents H or a labile chemical group able to
regenerate in vivo the free phenol selected from the group
consisting of C(O)R.sub.a, C(O)OR.sub.a, C(O)NR.sub.a, R.sub.b,
P(O)(OH).sub.2, and COCHR.sub.aNR.sub.bR.sub.c, [0051] Z1 and Z3,
identical or different, are halogen or H, [0052] Z2 is fluor or H,
provided that [0053] either Z2 is fluor and all the other
definitions are as defined above, [0054] or Z6 is a carbon atom
substituted by R as defined above, R being different from H, alkyl,
halogen, NH.sub.2, OH, CONH.sub.2 or fluoro alkyl and all the other
definitions are as defined above, [0055] or Z4 or Z5, or Z7 or Z8
are carbon atoms substituted by NR.sub.aR.sub.b or OR.sub.a being
different from H and all the other definitions are as defined
above, [0056] or Z5, or Z7, is a carbon atom substituted by R, R
being different from H and all the other definitions are as defined
above, [0057] or R2 is a C.sub.1-C.sub.8 alkyl-heteroaryl radical
or a C.sub.1-C.sub.8 alkyl-OR.sub.a and all the other definitions
are as defined above, and the pharmaceutically acceptable organic
and mineral salts, as well as the racemic derivatives and each
unique non racemic derivatives, in case the derivatives of formula
(I) have one or more chiral centers, both the cis (Z) and trans (E)
isomers in cases the derivatives of formula (I) have unsaturated
carbon=carbon double bonds, and any N-oxide form of the
derivatives. [0058] In formula I: [0059] "C.sub.1-C.sub.8 alkyl" as
applied herein means linear, branched or cyclic hydrocarbon groups
having 1 to 8 carbon atoms preferably methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl,
isopentyl, neopentyl, hexyl, octyl, cyclopropyl
cyclobutyl-cyclopentyl, cyclohexyl; [0060] "C.sub.2-C.sub.8 alkenyl
and "C.sub.2-C.sub.8 alkynyl" as applied herein means linear,
branched or cyclic hydrocarbon groups of 2 to 8 carbon atoms,
having at least one double bond or one triple bond and preferably,
ethenyl, propenyl, butenyl, cyclohexenyl, ethynyl, propargyl,
butynyl; [0061] "C.sub.1-C.sub.4 fluoro alkyl and C.sub.2-C.sub.4
alkenyl" means a C.sub.1-C.sub.4 alkyl or C.sub.2-C.sub.4 alkenyl
group substituted by 1 to 7 fluorine atoms. [0062] "Halogen" means
F, Cl, Br, and I; [0063] "Heteroaryl" and "Aliphatic Heterocycle"
as applied herein means a 5-10 membered aromatic or non-aromatic
mono or bicyclic ring, containing at least one heteroatom selected
from N, O and S. Illustrative heterocycles are for example selected
in the group comprising benzofuryl, benzimidazolyl, benzopyranyl,
benzothienyl, furyl, imidazolyl, indolinyl, azetidinyl,
morpholinyl, piperidinyl, piperazinyl, oxazolidinyl, pyrrolyl,
pyrrolidinyl, pyrazolyl, tetrahydropyridinyl, pyridinyl, thiazolyl,
thienyl, quinolinyl, isoquinolinyl, and tetra- and
perhydro-quinolinyl and isoquinolinyl, pyrazinyl, pyrazidinyl,
triazinyl, triazolyl, tetrazolyl, indolyl, indazolyl, pyrimidinyl,
pyridonyl, oxazolyl, isoxazolyl, isothienyl, quinazolinyl,
oxadiazolyl, thiadiazolyl, phtalimidyl. [0064] "C.sub.1-C.sub.8
alkyl-heteroaryl" means a C.sub.1-C.sub.8 alkyl such as above
defined substituted with one heteroaryl group such as above
defined. [0065] "C.sub.1-C.sub.8 alkyl-OR.sub.a" means a
C.sub.1-C.sub.8 alkyl such as above defined substituted with one
OR.sub.a group such as above defined, OR.sub.a being different from
OH.
[0066] According to a first family, the invention particularly
relates to derivatives of formula (I) wherein R1 is a 6-membered
monocyclic heteroaryl group such as above defined. Preferably, the
nitrogeneous heteroaryl with one or 3 nitrogen atoms is selected in
the group comprising a pyridine, a pyrimidine, a pyridazine, a
pyrazine or a triazine.
[0067] In particularly preferred derivatives of said first family,
R1 is a substituted heteroaryl group such as above defined.
[0068] Advantageously, the nitrogeneous heteroaryl group is
substituted by one or several substituents selected in the group
comprising F, COR.sub.a, OR, NR.sub.aR.sub.b, alkynyl,
SO.sub.2R.sub.a, NR.sub.aSO.sub.2R.sub.b, SO.sub.2NR.sub.aR.sub.b,
NR.sub.aCOOR.sub.b and CR.sub.a.dbd.NOR.sub.b.
[0069] According to a second family, the invention particularly
relates to derivatives of formula (I) wherein R1 is a phenyl
group.
[0070] Particularly preferred derivatives of said second family are
substituted by one or several substituents selected in the group
comprising F, COR.sub.a, OR, NR.sub.aR.sub.b, alkynyl,
SO.sub.2R.sub.a, NR.sub.aSO.sub.2R.sub.b, SO.sub.2NR.sub.aR.sub.b,
NR.sub.aCOOR.sub.b and CR.sub.a.dbd.NOR.sub.b.
[0071] In a preferred embodiment, in the above defined derivatives
of said first and/or second family, Z2 is fluor. The fluorine atom
being advantageously positioned in para of the OH group of compound
of formula I when Y.dbd.H to prevent the in vitro or in vivo
oxidation of the phenolic compound into the corresponding
quinone.
[0072] According to another embodiment, Z6 is a carbon atom
substituted by R as defined above, R being different from H, alkyl,
halogen, NH.sub.2, OH, CONH.sub.2, or fluoro alkyl and all the
other definitions are as defined with respect to formula (I).
[0073] According to still another preferred embodiment, Z4 or Z5,
or Z7 or Z8, are carbon atoms substituted by NR.sub.aR.sub.b or
OR.sub.a, OR.sub.a being different from OH and all the other
definitions are as defined with respect to formula (I).
[0074] In a further embodiment, Z5 or Z7 is a carbon atom
substituted by R, R being different from H and all the other
definitions are as defined with respect to formula (I).
[0075] According to an other embodiment family, the invention
particularly relates to derivatives of formula (I) wherein, R2 is a
C.sub.1-C.sub.8alkyl-heteroaryl or a C.sub.1-C.sub.8alkyl-OR.sub.a,
OR.sub.a being different from OH.
[0076] In a more preferred embodiment, Y represents H.
[0077] Also included in this invention are compounds in which Y is
different from H, Y being a labile chemical group able to
regenerate in vivo the free phenol compounds of formula I with Y
being H such C(O)R.sub.a, C(O)OR.sub.a, C(O)NR.sub.a, C(O)NR.sub.a,
R.sub.b, P(O)(OH).sub.2, COCHR.sub.aNR.sub.bR.sub.c
[0078] It will be understood that the above defined embodiment can
be used in combination with any one of the other defined
embodiments.
[0079] The invention also relates to a process for making the above
defined derivatives.
[0080] In a first embodiment of the invention, said process
comprises the steps of [0081] a) reacting with AR1, a phenol
derivative of formula (II)
[0081] ##STR00006## [0082] wherein R1, R2 and Z1, Z2, Z3 are as
above defined, R3 represents an alkyl group, and A is a reactive
group such as an halogen or a nitro capable of reacting with the OH
group of (II) under basic conditions known to the one skilled in
the art to give a derivative of formula (III)
[0082] ##STR00007## [0083] b) reacting the protected phenol
derivative of formula (III) with any suitable Lewis acid for
example BBr.sub.3 or BCl3, under conditions to give the desired
derivatives of formula (I). To obtain derivatives wherein R2
represents a functional group, the desired function is introduced
prior removal of R3.
[0084] Alternatively, the derivatives of formula (I) are
advantageously obtained from the protected phenols of formula (II)
by introducing a R4 group different from R3=alkyl which can be
smoothly remove in a non restrictive manner by hydrogenation,
acidic conditions or treatment with fluoride derivatives to
generate compound of formula (I) according to a process comprising:
[0085] a) reacting the protected phenol derivative of formula (II)
with TosCl under conditions to give a derivative of formula
(IV)
[0085] ##STR00008## [0086] b) reacting the derivative of formula
(IV) with any suitable Lewis acid such as BBr.sub.3, BCl.sub.3
under appropriate conditions to give a derivative of formula
(V)
[0086] ##STR00009## [0087] c) treating the derivative of formula
(V) under basic or acidic conditions, to introduce R4, R4 being a
protecting group different from a linear alkyl, such as benzyl,
BOM, SEM, MOM, MEM, TBDMS, THP or analogs, resulting in a
derivative of formula (VI),
[0087] ##STR00010## [0088] d) reacting said derivative of formula
(VI) under appropriate conditions, to obtain the removal of Tosyl
group, resulting in of a derivative of formula (VII)
[0088] ##STR00011## [0089] e) reacting the derivative of formula
(VII) thus obtained with AR1 such as above defined to obtain a
compound of formula (III')
[0089] ##STR00012## [0090] and [0091] f) deprotecting the phenol
group to obtain the desired derivative of formula (I) with Y
representing H, wherein R2 is functionalized if desired as above
mentioned, optionally from derivative of formula (VI).
[0092] According to a second embodiment, compounds of formula (I)
with Z2=F can be obtained according to the following synthetic
scheme 1 by a process comprising: [0093] a) reacting the
bromophenol of formula (VIII) first with AR1 such as above defined
and a base to generate a derivative of formula (IX); then reacting
derivatives of formula (IX) with a suitable palladium catalyst with
its ligands, choosen from the group, as non restrictive examples of
Pd(PPh.sub.3).sub.4 or Pd(dppf)Cl.sub.2.DCM, a suitable base such
as potassium carbonate or cesium carbonate and R2B, R2 being as
above defined and B being a boronic ester residue to obtain the
derivatives of formula (X):
##STR00013##
[0093] or alternatively, [0094] b) compound of formula (VIII) is
protected with a benzyl group prior to be reacted with a palladium
catalyst in the presence of a base and a boronic reactant of
formula R2B, such as defined above, to generate the benzylated
derivative (XI), debenzylation with palladium on charcoal and
hydrogen generates the free phenol (XII) which is then reacted with
AR1 according to step the process described above to generates
derivatives of formula (X)
[0094] ##STR00014## [0095] c) finally, compounds of formula (X) are
dealkylated using Boron tribromide to generate derivatives of
formula (I) according to scheme 3.
##STR00015##
[0096] According to a third embodiment, the invention also
comprises a process wherein a compound of formula (XIII),
corresponding to compounds of formula (III), (VI), (VII), (X) or
(I) in which R2 is vinyl and R5 is R3 or R4 as above defined or H,
is reduced by hydrogenation with palladium on charcoal (according
to scheme 4) to give the R2=ethyl compound derivative (XIV),
corresponding to compounds of formula (III), (VI), (VII), (X) or
(I) which can be further deprotected according to the above process
when R5=R3 or R4.
##STR00016##
[0097] According to a fourth embodiment, the process of the
invention for making a compound of formula (I) consists of
converting, derivatives of formula I in which Y.dbd.H
advantageously by methods known by one skilled of the art into a
compound in which Y is C(O)R.sub.a, CO(O)R, C(O)NR.sub.a, R.sub.b,
P(O)(OH).sub.2, and COCHR.sub.aNR.sub.bR.sub.c.
[0098] As illustrated by the examples given hereinafter, the above
disclosed phenol derivatives of the invention have valuable
biological properties.
[0099] They are particularly useful as antibacterial agents having
a selective spectrum of activity in vitro against standard
bacterial strains which are used to screen for activity against
pathogenic bacteria. Notably, the derivatives of the present
invention show a high activity against bacteria carrying Fab
enzymes such as FabI, FabL, FabK, InhA. Particularly against
Staphylococcus aureus including multiresistant strains, Escherichia
coli, Helicobacter pylori and also bacteria such as Mycobacterium
tuberculosis carrying homologous Fab enzymes such as InhA or other
organisms such as Plasmodium falciparum. Said derivatives are then
particularly suitable as active principle of drugs.
[0100] The invention thus also relates to compositions comprising a
phenol derivative of formula (I) such as above defined for use as
drug.
[0101] It also relates to pharmaceutical compositions comprising a
phenol derivative of formula (I) such as above defined in
combination with a pharmaceutically acceptable carrier.
[0102] Said pharmaceutical compositions are formulated to be
administered under oral, injectable, parental routes, with doses
appropriate for the patient to be treated.
[0103] The compositions of the invention may conveniently be
presented in unit dosage form and may be prepared by any methods
well known in the art of pharmacy. The amount of active ingredient
which can be combined with a carrier material to produce a single
dosage form will generally be that amount of the compound which
produces a therapeutic effect.
[0104] A suitable daily dose of the compounds of the invention will
be that amount of the compound that is the lowest dose effective to
produce a therapeutic effect. Generally, topical, intravenous and
subcutaneous doses of the compositions of this invention for a
patient, when used for the indicated effects, will range from about
0.0001 to about 100 mg per kilogram of body weight per day, given
in one or several doses administered separately at appropriate
intervals throughout the day, optionally, in unit dosage forms.
[0105] Said compositions are particularly useful to treat human or
animal infections by microbial pathogens such as E. coli, H. pylori
or S. aureus or M. tuberculosis and parasites such as Plasmodium
falciparum.
[0106] Said compositions are also useful in multitherapy, in
combination with other drugs, for example with antibiotics.
[0107] The invention also relates to a method of treatment of
microbial infections which comprises administering to a patient in
need thereof an efficient amount of a pharmaceutical composition
such as above defined.
[0108] Other characteristics and advantages of the invention are
given in the examples hereafter wherein it is referred to FIGS. 1
and 2, which represent, the protection of mice against the lethal
effect of bacterial multiplication.
SYNTHESIS OF EXAMPLE COMPOUNDS
[0109] Proton nuclear magnetic resonance (.sup.1H NMR) spectra were
recorded at either 300 or 400 MHz, and chemical shifts are reported
in parts per million (.delta.) downfield from the internal standard
tetramethylsilane (TMS). Abbreviations for NMR data are as follows:
s=singlet, d=doublet, t=triplet, q=quadruplet, qt=quintuplet,
se=sextuplet, m=multiplet, dd=doublet of doublets, dt=doublet of
triplets, br=broad. J indicates the NMR coupling constant measured
in Hertz. CDCl.sub.3 is deuteriochloroform, DMSO-d.sup.6 is
hexadeuteriodimethylsulfoxide, and CD.sub.3OD is
tetradeuteriomethanol. Mass spectra were obtained using either
electrospray (ESI) or atmospheric pressure photoionization (APPI)
techniques. Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254
thin layer plates were used for thin layer chromatography. Flash
chromatography was carried out on Flashsmartpack cartridge,
irregular silica 40-60 .mu.m or spherical silica 20-40 .mu.m
[0110] TLC refers to thin layer chromatography, MS refers to mass
spectra, HPLC refers to high pressure liquid chromatography, NMR
refers to nuclear magnetic resonance, APT refers to attached proton
test, HSQC refers to heteronuclear single quantum correlation,
NOESY refers to nuclear Overhauser enhancement spectroscopy.
[0111] Certain reagents and radical groups are abbreviated herein
are abbreviated herein. t-Bu refers to the tertiary butyl radical,
Boc refers to the t-butyloxycarbonyl radical, Ph refers to the
phenyl radical, Cbz refers to the benzyloxycarbonyl radical, Bn
refers to the benzyl radical, Me refers to methyl, Et refers to
ethyl, Ac refers to acetyl, Nph refers to 1- or 2-naphthyl and cHex
refers to cyclohexyl. DCC refers to dicyclohexylcarbodiimide, DMAP
refers to 4-dimethylaminopyridine, EDC refers to
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride, HOBt
refers to 1-hydroxybenzotriazole, THF refers to tetrahydrofuran,
DIEA refers to diisopropylethylamine, DEAD refers to diethyl
azodicarboxylate, PPh.sub.3 refers to triphenylphosphine, DIAD
refers to diisopropyl azodicarboxylate, DME refers to
dimethoxyethane, DMF refers to dimethylformamide, NBS refers to
N-bromosuccinimide, Pd/C refers to a palladium on carbon catalyst,
PPA refers to polyphosphoric acid, DPPA refers to
diphenylphosphoryl azide, BOP refers to
benzotriazol-1-yloxy-tris(dimethyl-amino)phosphonium
hexafluorophosphate, TEA refers to triethylamine, TFA refers to
trifluoroacetic acid,. PCC refers to pyridinium chlorochromate,
TBAF refers to tetrabutyl ammonium fluoride, Tos refers to Tosyl
and TosCl refers to tosyl Chloride, BOM refers to p-methoxybenzyl,
MOM refers to methoxy-methyl, MEM refers to methoxy-ethoxymethyl,
SEM refers to trimethyl-silyl-ethoxymethyl, THP refers to
tetrahydropyranyl, TSI refers to triethylsilyl, TBDMS refers to
tButyl-dimethyl-silyl, DCM refers to dichloromethane, CAN refers to
acetonitrile, Pet ether refers to petroleum ether.
Example 1
2-[(3-amino-6-chloropyridin-2-yl)oxy]-5-propylphenol
a) 2-chloro-6-(2-methoxy-4-propylphenoxy)pyridin-3-amine (A) and
6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine (B)
##STR00017##
[0113] To a suspension of K.sub.2CO.sub.3 (2.4 mmol; 331 mg) in
anhydrous DMF (1 mL) under argon, was added
2-methoxy-4-propylphenol (1 mmol; 0.16 ml) followed by
2.6-Dichloro-3-nitropyridine (1 mmol; 176 mg). The reaction mixture
was stirred at 40.degree. C. over 48H.
[0114] After quenching with NaOH (0.1N; 3 mL), the mixture was
extracted with ethyl acetate (3*3 mL). Combined organic phases were
dried over Na.sub.2SO.sub.4, concentrated in vacuo, to give a
yellow solid (480 mg; 1.49 mmol; 74%), used without further
purification. 240 mg of that solid (0.75 mmol) were dissolved in
THE (3 mL) under argon. Palladium on activated carbon (50 mg) was
added then the reaction was flushed twice with hydrogen, then left
to stir overnight. The reaction mixture was then filtered on
celite, and then rinsed with ethyl acetate (3*5 mL), to give a
mixture of regioisomers. After purification by preparative TLC
(dichloromethane), the regioisomers were isolated as light yellow
oils. (A: 40 mg, 0.14 mmol, B: 30 mg, 0.1 mmol, global yield:
32%)
[0115] A: .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.08 (d, 1H,
J=8.3 Hz); 6.97 (d, 1H, J=7.9 Hz); 6.76 (m, 2H); 6.59 (d, 1H, J=8.5
Hz); 2.59 (t, 2H, J=7.6 Hz,); 1.65 (se, 2H, J=7.4 Hz); 0.98 (t, 3H,
J=7.2 Hz).
[0116] B: .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.6 (d, 1H, J=7.9
Hz); 6.98 (d, 1H, J=7.9 Hz); 6.79 (m, 3H); 2.59 (t, 2H, J=7.6 Hz,);
1.67 (se, 2H, J=7.4 Hz); 0.97 (t, 3H, J=7.2 Hz).
b) 2-[(3-amino-6-chloropyridin-2-yl)oxy]-5-propylphenol
##STR00018##
[0118] To a solution of 6-chloro-2-(2-methoxy-4-propyl
phenoxy)pyridin-3-amine (0.1 mmol; 30 mg) under argon, in
dichloromethane (2 mL), cooled to -78.degree. C., was added
BBr.sub.3 (0.5 mmol; 0.5 mL) dropwise. The reaction mixture was
allowed to stir for 5 hr, with gradual warming to -20.degree. C. At
-20.degree. C., the reaction was hydrolysed with saturated
NH.sub.4Cl (4 mL), extracted with dichoromethane (3*10 mL).
Combined organic phases dried over Na.sub.2SO.sub.4, concentrated
in vacuo, to give the desired product as a light brown solid
without further purification (27 mg; 0.1 mmol; 97%).
[0119] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.06 (d, 1H, J=8.0
Hz); 6.99 (d, 1H, J=8.2 Hz); 6.89(m, 2H); 6.69 (d, 1H, J=8.1 Hz);
2.52 (t, 2H, J=7.7 Hz,); 1.64 (se, 2H, J=7.5 Hz); 0.93 (t, 3H,
J=7.4 Hz).
Example 2
2-[(5-amino-6-chloropyridin-2-yl)oxy]-5-propylphenol
##STR00019##
[0121] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 2-chloro-6-(2-methoxy-4-propylphenoxy)pyridin-3-amine (0.14
mmol; 40 mg) the title compound (30 mg; 0.11 mmol; 77%). was
prepared without any purification as a light brown solid.
[0122] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.13 (d, 1H, J=8.4
Hz), 6.94 (d, 1H, J=8.2 Hz); 6.88(s, 1H); 6.74 (d, 1H, J=8.4 Hz);
6.66 (d, 1H, J=8.2 Hz); 2.52 (t, 2H, J=7.6 Hz,), 1.63 (se, 2H,
J=7.5 Hz); 0.95 (t, 3H, J=7.3 Hz).
Example 3
5-ethyl-2-[(6-fluoropyridin-2-yl)oxy]phenol
a) 2-(4-ethyl-2-methoxyphenoxy)-6-fluoropyridine
##STR00020##
[0124] To a suspension of NaH (1.2 mmol; 50 mg) in anhydrous DMSO
(1 mL) under argon, was added 4-ethyl-2-methoxyphenol (1 mmol;
152.2 mg) followed by 2,6-difluoropyridine (1 mmol; 0.1 ml). The
reaction mixture was stirred at 120.degree. C. overnight. After
quenching with NaOH (0.1N; 3 mL), the mixture was extracted with
dichloromethane (3*5 mL). Combined organic phases were dried over
Na.sub.2SO.sub.4, concentrated in vacuo, to give the title compound
as a light yellow oil (250 mg; 1 mmol; 100%), used without further
purification.
[0125] MS(ES): m/e 248 (M+H).sup.+.
b) 5-ethyl-2-[(6-fluoropyridin-2-yl)oxy]phenol
##STR00021##
[0127] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 2-(4-ethyl-2-methoxyphenoxy)-6-fluoropyridine (250 mg, 1 mmol)
the title compound (80 mg, 34%) was prepared as a white solid after
purification by flash chromatography on silica gel (gradient
dichloromethane/methanol).
[0128] MS(ES): m/e 234 (M+H).sup.+
[0129] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.77 (q, 1H, J1=7.9
Hz, J2=8.0 Hz); 7.01 (d, 1H, J=8.2 Hz,); 6.92 (d, 1H, J=1.9 Hz);
6.75 (td, 2H, J1=8.2 Hz, J2=2.0 Hz); 6.64 (dd, 1H, J1=7.9 Hz,
J2=2.4 Hz); 2.62 (q, 2H, J1=7.6 Hz, J2=7.6 Hz); 1.23 (t, 3H, J=7.6
Hz).
[0130] Alternatively compound of example 3 can be synthesized
starting from 2-Benzyloxy-4-ethyl-phenol instead of
4-ethyl-2-methoxyphenol according to the following procedure:
c) 4-ethyl-2-hydroxyphenyl-4-methylbenzenesulfonate
##STR00022##
[0132] a') To a solution of 2-methoxy-4-ethylphenol (26.3 mmol; 4.0
g), NaI (5.25 mmol; 788 mg), and K.sub.2CO.sub.3 (28.9 mmol; 3.98
g), under argon, in acetonitrile (20 mL) was added tosyl chloride
(27.6 mmol; 5.24 g). The reaction mixture was stirred at 70.degree.
C. for 30 hr, then quenched with NaOH (0.1N; 50 mL), and extracted
with ethyl acetate (3*20 mL). Combined organic phases were washed
with saturated NaHCO.sub.3 sat. (50 mL) then water (50 mL), dried
over MgSO.sub.4 and concentrated in vacuo. The crude was
recrystallized in cyclohexane (10 mL) to yield a brown oil (5.53 g;
18.1 mmol; 68%) engaged without further purification in step
b'.
[0133] b') To a solution of 5 g of Toluene-4-sulfonic acid
4-ethyl-2-methoxy-phenyl ester (16.3 mmol), under argon, in
dichloromethane (15 mL), cooled to -78.degree. C., was added
BBr.sub.3 (35 mmol; 35 mL) dropwise. The reaction mixture was
allowed to stir for 6 hr, with gradual warming to -20.degree. C. At
-78.degree. C., the reaction was hydrolysed with saturated
NH.sub.4Cl (30 mL), extracted with dichoromethane (2*10 mL).
Combined organic phases were washed with 100 mL of saturated
NaHCO.sub.3, dried over Na.sub.2SO.sub.4, concentrated in vacuo,
the title compound (1.97 g; 41%) was obtained as a colourless oil,
after purification on silica gel (dichloromethane/cyclohexane:
gradient).
[0134] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.76 (d, 2H, J=8.1
Hz); 7.34 (d, 2H, J=7.9 Hz); 6.84 (s, 1H); 6.65 (d, 1H, J=8.4 Hz);
6.58 (d, 1H, J=6.8 Hz); 5.86 (sl, 1H); 2.56 (q, 2H, J=7.6 Hz); 2.46
(s, 3H); 1.18 (t, 3H, J=7.6 Hz).
d) 2-(benzyloxy)-4-ethylphenyl-4-methylbenzenesulfonate
##STR00023##
[0136] To a solution of
4-ethyl-2-hydroxyphenyl-4-methylbenzenesulfonate (5 mmol; 1.46 g)
under argon, in acetone (10 mL), were added K.sub.2CO.sub.3 (6
mmol; 0.83 g), NaI (1 mmol; 0.15 g), and benzylbromide (5.5 mmol;
0.65 mL). The reaction was stirred at 40.degree. C. for 5 hr. The
reaction mixture was concentrated then hydrolysed with NH.sub.4Cl
sat. (10 mL) and extracted with ethyl acetate (3*5 mL). Combined
organic phases were washed with saturated NaHCO.sub.3 (10 mL),
dried over Na.sub.2SO.sub.4, concentrated. The residue was purified
on silica gel (dichloromethane/cyclohexane: gradient) to yield the
title compound as a clear oil (1.68 g; 4.39 mmol; 87%).
[0137] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.69 (d, 2H, J=8.3
Hz); 7.34 (m, 5H); 7.11 (m, 3H); 6.74 (m, 2H); 4.87 (s, 2H); 2.59
(q, 2H, J=7.6 Hz); 2.37 (s, 3H); 1.19 (t, 3H, J=7.6 Hz).
e) 2-Benzyloxy-4-ethyl-phenol
##STR00024##
[0139] To a solution of
2-(benzyloxy)-4-ethylphenyl-4-methylbenzenesulfonate
methylbenzenesulfonate (0.26 mmol; 100 mg) under argon, in methanol
(2 mL), was added magnesium (2.61 mmol; 0.63 g). The reaction was
stirred at room temperature overnight. The reaction mixture was
hydrolysed with HCl 1N (3 mL) and extracted with ethyl acetate (3*5
mL). Combined organic phases were washed with saturated NaHCO.sub.3
(10 mL), dried over Na.sub.2SO.sub.4, concentrated. The residue was
purified with preparative TLC (dichloromethane/cyclohexane: 9/1) to
yield the title compound as a yellow oil (48 mg; 0.21 mmol;
80%).
[0140] MS (ES) m/e 229 (M+H).sup.+
[0141] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.43 (m, 5H); 6.90
(d, 1H, J=8.0 Hz); 6.82 (s, 1H); 6.75 (d, 1H, J=8.0 Hz); 5.55 (s,
1H); 5.12 (s, 2H); 2.61 (q, 2H, J=7.6 Hz); 1.25 (t, 3H, J=7.6
Hz).
f) 2-[2-(benzyloxy)-4-ethylphenoxy]-6-fluoropyridine
##STR00025##
[0143] To a suspension of K.sub.2CO.sub.3 (0.25 mmol; 35 mg) in
anhydrous acetonitrile (2 mL) under argon, was added
2-Benzyloxy-4-ethyl-phenol (48 mg; 0.21 mmol) followed by
2,6-difluoropyridine (100 .mu.L; 1.10 mmol). The reaction mixture
was stirred at 80.degree. C. overnight.
[0144] Concentrated under argon, washed with NH.sub.4Cl (0.1N; 3
mL), the mixture was extracted with ethyl acetate (3*3 mL).
Combined organic phases were washed with NaHCO.sub.3 dried over
MgSO.sub.4, concentrated in vacuo, to give the title product as a
light oil (28.5 mg; 42%), after purification by preparative TLC
(cyclohexane/ethyl acetate: 9/1).
[0145] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.70 (q, 1H, J=8.0
Hz); 7.27 (m, 3H); 7.17 (d, 2H, J=5.8 Hz); 7.11 (d, 1H, J=8.0 Hz);
6.90 (s, 1H); 6.86 (d, 1H, J=8.1 Hz); 6.73 (d, 1H, J=7.5 Hz); 6.56
(dd, 1H, J.sub.1=7.8 Hz, J.sub.2=2.4 Hz); 5.06 (s, 2H); 2.66 (q,
2H, J=7.6 Hz); 1.27 (t, 3H, J=7.6 Hz).
g) 5-ethyl-2-[(6-fluoropyridin-2-yl)oxy]phenol
##STR00026##
[0147] 2-[2-(benzyloxy)-4-ethylphenoxy]-6-fluoropyridine (28 mg;
0.09 mmol) was dissolved in ethanol (4 mL), under argon. Palladium
on charcoal (4 mg; 0.02 mmol) was added and the reaction was
flushed twice with hydrogen, then left to stir overnight at room
temperature. The reaction mixture was filtered on celite, then
rinsed with methanol (3*3 mL). Concentration yielded a white solid
(25 mg; 98%) of title compound.
[0148] MS (ES) m/e 234 (M+H).sup.+.
Example 4
2-[(6-fluoropyridin-2-yl)oxy]-5-{2-[(6-fluoropyridin-2-yl)oxy]ethyl}phenol
a)
2-fluoro-6-(4-{2-[(6-fluoropyridin-2-yl)oxy]ethyl}-2-methoxyphenoxy)pyr-
idine
##STR00027##
[0150] To a suspension of KOH (2 mmol; 112 mg) in anhydrous DMF (1
mL) under argon, was added 4-(2-hydroxyethyl)-2-methoxyphenol (1
mmol; 168 mg) followed by 2,6-Difluoropyridine (1 mmol; 0.1 ml).
The reaction mixture was stirred at 110.degree. C. for 20 h.
[0151] After quenching with NaOH (0.1N; 3 mL), the mixture was
extracted with ethyl acetate (3*5 mL). Combined organic phases were
dried over Na.sub.2SO.sub.4, concentrated in vacuo, to give a clear
oil (50 mg; 0.14 mmol; 28%), after purification by flash
chromatography on silica gel (gradient
cylohexane/dichloromethane).
[0152] MS(ES): m/e 359 (M+H).sup.+
b)
2-[(6-fluoropyridin-2-yl)oxy]-5-{2-[(6-fluoropyridin-2-yl)oxy]ethyl}phe-
nol
##STR00028##
[0154] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for
2-fluoro-6-(4-{2-[(6-fluoropyridin-2-yl)oxy]ethyl}-2-methoxyphenoxy)pyrid-
ine (50 mg, 0.14 mmol) the title compound (20 mg, 30%) was prepared
as a white solid after purification by preparative TLC
(dichloromethane/methanol--9/1).
[0155] MS(ES): m/e 234 (M+H).sup.+.
[0156] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.76 (q, 1H, J1=7.9
Hz, J2=8.0 Hz); 7.62 (q, 1H, J1=8.3 Hz, J2=7.99); 7.02 (m, 2H);
6.83 (dd, 1H, J1=8.2 Hz, J2=2.0 Hz); 6.76 (d, 1H, J1=7.8 Hz,); 6.65
(dd, 1H, J1=7.7 Hz, J2=1.8 Hz); 6.59 (dd, 1H, J1=8.0 Hz, J2=1.1
Hz); 6.45 (dd, 1H , J1=7.7 Hz, J2=2.1 Hz); 6.09 (s, 1H); 4.47 (t,
2H, J=6.9 Hz); 3.03 (t, 2H, J=6.9 Hz).
Example 5
2-[(6-fluoropyridin-2-yl)oxy]-5-propylphenol
a) 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine
##STR00029##
[0158] According to the procedure of example 4(a) except
substituting 4-(2-hydroxyethyl)-2-methoxyphenol for
2-methoxy-4-propylphenol (2.1 mmol; 0.34 mL) the title compound
(449 mg; 86%) was prepared as a white solid, after purification by
silica gel chromatography (gradient
cyclohexane/dichloromethane).
[0159] MS (ES) m/e 262 (M+H).sup.+
b) 2-[(6-fluoropyridin-2-yl)oxy]-5-propylphenol
##STR00030##
[0161] To a solution of
2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine (1.7 mmol; 449 mg)
under argon, in dichloromethane (1.5 mL), cooled to -78.degree. C.,
was added BBr.sub.3 (17 mmol; 1M in CH.sub.2Cl.sub.2; 17 mL). The
reaction mixture was allowed to stir overnight, with gradual
heating to room temperature. At -20.degree. C., the reaction was
hydrolysed with saturated NH.sub.4Cl (3 mL), extracted with ethyl
acetate (3*10 mL). Combined organic phases were dried over
MgSO.sub.4, concentrated in vacuo. The residue was chromatographed
on silica gel (gradient cyclohexane/dichloromethane) to give the
desired product as a white solid (160 mg; 0.65 mmol; 38%).
[0162] MS (ES) m/e 248 (M+H).sup.+
[0163] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 7.78 (q, 1H, J=8 Hz);
7.02 (d, 1H, J=8.4 Hz); 6.92 (d, 1H, J=2 Hz); 6.76 (ta, 2H, J=9.2
Hz); 6.65 (dd, 1H, J.sub.1=8 Hz, J.sub.2=2.4 Hz); 2.58 (t, 2H,
J=7.6 Hz); 1.67 (s, 2H, J=7.6 Hz); 0.98 (t, 3H, J=7.2 Hz).
[0164] Alternatively compound of example 5 can be synthesized
starting from the 2-(benzyloxy)-4-propylphenol instead of
-methoxy-4-propylphenol using the same protocol as example 3 step
f) and g).
Synthesis of 2-(benzyloxy)-4-propylphenol
a) 2-methoxy-4-propylphenyl 4-methylbenzenesulfonate
##STR00031##
[0166] To a solution of 2-methoxy-4-propylphenol (10.0 mmol; 1.6
mL), NaI (1.0 mmol; 150 mg), and K.sub.2CO.sub.3 (11.0 mmol; 1.52
g), under argon, in acetonitrile (20 mL) was added tosyl chloride
(10.5 mmol; 2.0 g). The reaction mixture was stirred at 70.degree.
C. for 36 hr, then quenched with NaOH (0.1N; 3 mL), and extracted
with ethyl acetate (2*10 mL). Combined organic phases were washed
with saturated NaHCO.sub.3 sat. (5 mL), dried over MgSO.sub.4,
concentrated in vacuo. The crude was chromatographed on silica gel
(gradient cyclohexane/dichloromethane) to yield the desired
compound as a clear oil (2.13 g; 6.6 mmol; 66%).
[0167] MS (ES) m/e 321 (M+H).sup.+
[0168] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 7.77 (d, 2H, J=8.2
Hz); 7.31 (d, 2H, J=8.0 Hz); 7.03 (d, 1H, J=8.2 Hz); 6.70 (m, 2H);
3.57 (s, 3H); 2.54 (t, 2H, J=7.7 Hz); 2.46 (s, 3H); 1.63 (se, 2H,
J=7.6 Hz); 0.95 (t, 3H, J=7.3 Hz).
b)2-hydroxy-4-propylphenyl 4-methylbenzenesulfonate
##STR00032##
[0170] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 2-methoxy-4-propylphenyl 4-methylbenzenesulfonate (64 mg, 0.2
mmol), the title compound (40 mg; 65%) was prepared as a clear oil,
after purification by silica gel chromatography (gradient
cyclohexane/dichloromethane).
[0171] MS (ES) m/e 305 (M-H).sup.-
[0172] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 7.80 (d, 2H, J=8.3
Hz); 7.37 (d, 2H, J=8.1 Hz); 6.85 (s, 1H); 6.71 (d, 1H, J=8.3 Hz);
6.60 (d, 1H, J=8.3 Hz); 6.11 (s, 1H); 2.53 (t, 2H, J=7.6 Hz); 2.50
(s, 3H); 1.63 (se, 2H, J=7.5 Hz); 0.95 (t, 3H, J=7.3 Hz).
c) 2-(benzyloxy)-4-propylphenyl 4-methylbenzenesulfonate
##STR00033##
[0174] To a solution of 2-hydroxy-4-propylphenyl
4-methylbenzenesulfonate (0.11 mmol; 33 mg) under argon, in acetone
(0.2 mL), were added K.sub.2CO.sub.3 (0.13 mmol; 18 mg), NaI (0.02
mmol; 3 mg), and benzylbromide (0.12 mmol; 0.015 mL). The reaction
was stirred at 40.degree. C. for 5 hr. The reaction mixture was
then hydrolysed with NH.sub.4Cl sat. (3 mL) and extracted with
ethyl acetate (3*5 mL). Combined organic phases were washed with
saturated NaHCO.sub.3 (3 mL), dried over MgSO.sub.4, concentrated.
The residue was purified by preparative TLC (dichloromethane) to
yield the title compound as a clear oil (28 mg; 0.07 mmol;
64%).
[0175] MS (ES) m/e 397 (M+H).sup.+
[0176] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 7.71 (d, 2H, J=8.1
Hz); 7.34 (m, 5H); 7.12 (d, 3H, J=8.3 Hz); 6.74 (s, 2H); 4.88 (s,
2H); 2.54 (t, 2H, J=7.6 Hz); 2.39 (s, 3H); 1.61 (se, 2H, J=7.4 Hz);
0.92 (t, 3H, J=7.3 Hz).
d) 2-(benzyloxy)-4-propylphenol
##STR00034##
[0178] To a solution of 2-(benzyloxy)-4-propylphenyl
4-methylbenzenesulfonate (0.07 mmol; 28 mg) under argon, in a
mixture of ethanol (0.2 mL) and water (0.1 mL), was added KOH (0.09
mmol; 5 mg). The reaction was refluxed for 1 hr, then hydrolysed
with NH.sub.4Cl sat. (3 mL), and extracted with ethyl acetate (3*5
mL). Combined organic phases were washed with saturated NaHCO.sub.3
(3 mL), dried over MgSO.sub.4, concentrated. The residue was
purified by preparative TLC (cyclohexane/dichloromethane) to yield
the title compound as a clear oil (16 mg; 0.06 mmol; 86%).
[0179] MS (ES) m/e 243 (M+H).sup.+
[0180] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 7.41 (m, 5H); 6.87
(d, 1H, J=8.0 Hz); 6.79 (s, 1H); 6.71 (d, 1H, J=8.0 Hz); 5.51 (s,
1H); 5.11 (s, 2H); 2.53 (t, 2H, J=7.6 Hz); 1.61 (se, 2H, J=7.5 Hz);
0.94 (t, 3H, J=7.3 Hz).
Example 6
2-[(6-chloropyridin-2-yl)oxy]-5-propylphenol
a) 2-chloro-6-(2-methoxy-4-propylphenoxy)pyridine
##STR00035##
[0182] According to the procedure of example 5(a) except
substituting 2,6-difluoropyridine for 2,6-dichlororopyridine (296
mg, 2 mmol), the title compound (450 mg; 81%) was prepared as a
clear oil, after purification by silica gel chromatography
(gradient cyclohexane/ethyl acetate).
[0183] MS (ES) m/e 278 (M+H).sup.+
b) 2-[(6-chloropyridin-2-yl)oxy]-5-propylphenol
##STR00036##
[0185] According to the procedure of example 5(b), except
substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for
2-chloro-6-(2-methoxy-4-propylphenoxy)pyridine (450 mg, 1.62 mmol),
the title compound (148 mg; 35%) was prepared as white solid after
purification by silica gel chromatography (gradient
cyclohexane/ethyl acetate).
[0186] MS (ES) m/e 264 (M+H).sup.+
[0187] NMR.sup.1H (CD.sub.3OD) .delta. (ppm): 7.70 (t, 1H, J=8.0
Hz); 7.06 (d, 1H, J=7.7 Hz); 6.93 (d, 1H, J=8.1 Hz); 6.78 (s, 1H);
6.69 (m, 2H); 2.53 (t, 2H, J=7.8 Hz); 1.65 (se, 2H, J=7.6 Hz); 0.95
(t, 3H, J=7.4 Hz).
Example 7
2-[(6-aminopyridin-2-yl)oxy]-5-propylphenol
a) 6-(2-methoxy-4-propylphenoxy)pyridin-2-amine
##STR00037##
[0189] According to the procedure of example 5(a) except
substituting 2,6-difluoropyridine for 2-amino-6-bromopyridine (173
mg, 1 mmol) the title compound (125 mg; 48%) was prepared as a
clear oil, after purification by silica gel chromatography
(gradient cyclohexane/dichloromethane).
[0190] MS (ES) m/e 259 (M+H).sup.+
b) 2-[(6-aminopyridin-2-yl)oxy]-5-propylphenol
##STR00038##
[0192] According to the procedure of example 5(b) except
substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for
6-(2-methoxy-4-propylphenoxy)pyridin-2-amine (125 mg, 0.48 mmol),
the title compound (5 mg; 4%) was prepared as a clear oil, after
preparative TLC (cyclohexane/dichloromethane).
[0193] MS (ES) m/e 245 (M+H).sup.+
[0194] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 7.45 (t, 1H, J=7.9
Hz); 7.02 (d, 1H, J=8.1 Hz); 6.90 (s, 1H); 6.70 (d, 1H, J=8.0 Hz);
6.27 (d, 1H, J=7.8 Hz); 6.22 (d, 1H, J=7.9 Hz); 4.45 (br, 2H); 2.55
(t, 2H, J=7.6 Hz); 1.66 (se, 2H, J=7.6 Hz); 0.97 (t, 3H, J=7.3
Hz).
Example 8
4-[(6-fluoropyridin-2-yl)oxy]-3-hydroxy benzaldehyde
a) 4-[(6-fluoropyridin-2-yl)oxy]-3-methoxybenzaldehyde
##STR00039##
[0196] According to the procedure of example 4(a), except
substituting 4-(2-hydroxyethyl)-2-methoxyphenol for
4-hydroxy-3-methoxybenzaldehyde (304 mg, 2 mmol) the title compound
(220 mg; 44%) was prepared as a white solid, after purification by
silica gel chromatography (gradient cyclohexane/ethyl acetate).
[0197] MS (ES) m/e 248 (M+H).sup.+
b) 4-[(6-fluoropyridin-2-yl)oxy]-3-hydroxybenzaldehyde
##STR00040##
[0199] According to the procedure of example 5(b) except
substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for
4-[(6-fluoropyridin-2-yl)oxy]-3-methoxybenzaldehyde (220 mg, 0.89
mmol), the title compound (10 mg; 7%) was prepared as a white
solid, after purification by preparative TLC (cyclohexane/ethyl
acetate).
[0200] MS (ES) m/e 234 (M+H).sup.+
[0201] NMR.sup.1H (CD.sub.3OD) .delta. (ppm): 9.95 (s, 1H); 7.88
(q, 1H, J.sub.1=8.0 Hz); 7.59 (d, 1H, J=2.0 Hz); 7.49 (dd, 1H,
J.sub.1=8.4 Hz, J.sub.2=2.0 Hz); 7.29 (da, 2H, J=8.0 Hz); 6.93 (d,
1H, J=7.6 Hz); 6.75 (dd, 1H, J.sub.1=8.0 Hz, J.sub.2=2.0 Hz).
Example 9
2-[(6-fluoropyridin-2-yl)oxy]-5-methylphenol
a) 2-fluoro-6-(2-methoxy-4-methylphenoxy)pyridine
##STR00041##
[0203] According to the procedure of example 4(a), except
substituting 4-(2-hydroxyethyl)-2-methoxyphenol for
2-methoxy-4-methylphenol (0.25 mL, 2 mmol) the title compound (457
mg; 97%) was prepared as a white solid, after purification by
silica gel chromatography (gradient
cyclohexane/dichloromethane).
[0204] MS (ES) m/e 234 (M+H).sup.+
b) 2-[(6-fluoropyridin-2-yl)oxy]-5-methylphenol
##STR00042##
[0206] According to the procedure of example 5(b) except
substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for
2-fluoro-6-(2-methoxy-4-methylphenoxy)pyridine (457 mg, 1.93 mmol),
the title compound (71 mg; 16%) was prepared as a white solid,
after washing with diethyl ether.
[0207] MS (ES) m/e 220 (M+H).sup.+
[0208] NMR.sup.1H (CD.sub.3OD) .delta. (ppm): 7.81 (q, 1H,
J.sub.1=8.0 Hz); 6.79 (m, 2H); 6.63 (m, 3H); 2.28 (s, 3H).
Example 10
4-[(6-fluoropyridin-2-yl) oxy]-4'-methylbiphenyl-3-ol
a) 2-(4-chloro-2-methoxyphenoxy)-6-fluoropyridine
##STR00043##
[0210] According to the procedure of example 4(a) except
substituting 4-(2-hydroxyethyl)-2-methoxyphenol for
2-methoxy-4-chlorophenol (0.24 mL, 2 mmol) the title compound (423
mg; 84%) was prepared as a white solid, after purification by
silica gel chromatography (gradient
cyclohexane/dichloromethane).
[0211] MS (ES) m/e 254 (M+H).sup.+
b) 2-fluoro-6-[(3-methoxy-4'-methylbiphenyl-4-yl)oxy]pyridine
##STR00044##
[0213] To a solution of
2-(4-chloro-2-methoxyphenoxy)-6-fluoropyridine (0.53 mmol; 135 mg)
and 4-methylphenylboronic acid (0.94 mmol; 127 mg) in a degased
DME/water mixture (1.5/0.5 mL), under argon were added
K.sub.2CO.sub.3 (2.0 mmol; 276 mg), then
tetrakis(triphenylphosphine)palladium (0.07 mmol; 47 mg). The
reaction was stirred at 105.degree. C. for 48 hr. After
concentration, the residue was purified by flash chromatography
(gradient cyclohexane/dichloromethane) to yield the desired product
along with remaining starting material (160 mg; 0.53 mmol; 100%
max).
[0214] MS (ES) m/e 310 (M+H).sup.+
c) 4-[(6-fluoropyridin-2-yl)oxy]-4'-methylbiphenyl-3-ol
##STR00045##
[0216] According to the procedure of example 5(b) except
substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for
2-fluoro-6-[(3-methoxy-4'-methyl-1,1'-biphenyl-4-yl)oxy]pyridine
(160 mg, 0.53 mmol), the title compound (37 mg; 24%) was prepared
as a white solid, after purification by preparative TLC
(dichloromethane).
[0217] MS (ES) m/e 296 (M+H).sup.+
[0218] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 7.81 (q, 1H, J=8.0
Hz); 7.50 (d, 2H, J=8.1 Hz); 7.32 (d, 1H, J=1.6 Hz); 7.27 (d, 2H,
J=8.0 Hz); 7.17 (m, 2H); 6.84 (d, 1H, J=8.0 Hz); 6.68 (dd, 1H,
J.sub.1=7.9 Hz, J.sub.2=2.2 Hz); 6.33 (sb, 1H); 2.42 (s, 3H).
Example 11
2-{[5-(4-bromobut-1-yn-1-yl)pyridin-2-yl]oxy}-5-propylphenol
a) 4-[6-(2-methoxy-4-propylphenoxy)pyridin-3-yl]but-3-yn-1-ol
##STR00046##
[0220] To a solution of
5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine (0.19 mmol; 60 mg)
under argon, in degased DME (1 mL) were added 3-butyn-1-ol (0.47
mmol; 33 mg), Pd/C (0.02 mmol; 42 mg), CuI (0.04 mmol; 7.6 mg),
K.sub.2CO.sub.3 (0.47 mmol; 64 mg), and triphenylphosphine (0.08
mmol; 21 mg). The reaction mixture was stirred at 80.degree. C.
overnight, then filtered on celite, washed with ether (3 mL) then
ethyl acetate (3 mL). Combined organic phases were washed with
saturated NH.sub.4Cl (3 mL), dried over MgSO.sub.4, concentrated.
The residue was purified by preparative TLC (dichloromethane/ethyl
acetate) to yield the desired compound as a clear oil (25 mg; 0.08
mmol; 42%).
[0221] MS (ES) m/e 312 (M+H).sup.+
[0222] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 8.21 (d, 1H, J=1.8
Hz); 7.67 (dd, 1H, J.sub.1=8.6 Hz, J.sub.2=2.3 Hz); 7.04 (d, 1H,
J=7.9 Hz); 6.82 (m, 3H); 3.81 (t, 2H, J=6.3 Hz); 3.75 (s, 3H); 2.68
(t, 2H, J=6.3 Hz); 2.60 (t, 2H, J=7.8 Hz); 2.07 (sb, 1H); 1.69 (se,
2H, J=7.6 Hz); 0.98 (t, 3H, J=7.4 Hz).
b) 2-{[5-(4-bromobut-1-yn-1-yl)pyridin-2-yl]oxy}-5-propylphenol
##STR00047##
[0224] According to the procedure of example 5(b) except
substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for
4-[6-(2-methoxy-4-propylphenoxy)pyridin-3-yl]but-3-yn-1-ol (25 mg,
0.08 mmol), the title compound (6 mg; 21%) was prepared as a clear
oil, after purification by preparative TLC (dichloromethane).
[0225] MS (ES) m/e 361 (M+H).sup.+
[0226] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 8.24 (s, 1H); 7.75
(d, 1H, J=8.5 Hz); 7.01 (d, 1H, J=8.2 Hz); 6.93 (m, 2H); 6.74 (d,
1H, J=8.1 Hz); 3.54 (t, 2H, J=7.2 Hz); 2.99 (t, 2H, J=7.2 Hz); 2.56
(t, 2H, J=7.8 Hz); 1.66 (se, 2H, J=7.6 Hz); 0.96 (t, 3H, J=7.4
Hz).
Example 12
2-{[5-(4-hydroxybut-1-yn-1-yl)pyridin-2-yl]oxy}-5-propylphenol
##STR00048##
[0228] The title compound (1 mg; 4%) was isolated from the example
11(b) as a white solid, after purification by preparative TLC
(dichloromethane).
[0229] MS (ES) m/e 298 (M+H).sup.+
[0230] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 8.25 (s, 1H); 7.75
(d, 1H, J=8.4 Hz); 7.02 (d, 1H, J=8.5 Hz); 6.93 (m, 2H); 6.74 (d,
1H, J=8.0 Hz); 3.84 (t, 2H, J=6.2 Hz); 2.71 (t, 2H, J=6.2 Hz); 2.56
(t, 2H, J=7.9 Hz); 1.66 (se, 2H, J=7.6 Hz); 0.96 (t, 3H, J=7.4
Hz).
Example 13
2-[(6-fluoropyridin-2-yl)oxy]-5-isobutylphenol
a) 2-(4-bromo-2-methoxyphenoxy)-6-fluoropyridine
##STR00049##
[0232] According to the procedure of example 4(a) except
substituting 4-(2-hydroxyethyl)-2-methoxyphenol for
2-methoxy-4-bromophenol (406 mg, 2 mmol) the title compound
compound (540 mg; 90%) was prepared as a clear oil, after
purification by silica gel chromatography (gradient
cyclohexane/dichloromethane).
[0233] MS (ES) m/e 299 (M+H).sup.+
[0234] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 7.79 (q, 1H, J=8.0
Hz); 7.16 (m, 2H); 7.06 (d, 1H, J=9.0 Hz); 6.80 (d, 1H, J=8.0 Hz);
6.62 (d, 1H, J=7.8 Hz); 3.81 (s, 3H).
b) 2-fluoro-6-(4-isobutyl-2-methoxyphenoxy)pyridine
##STR00050##
[0236] To a suspension of Pd(PPh.sub.3).sub.4 (0.025 mmol; 17 mg)
under argon, in anhydrous, degased dioxane (2 mL), sheltered from
light, were added 2-(4-bromo-2-methoxyphenoxy)-6-fluoropyridine
(0.51 mmol; 151 mg), then isobutyl zinc bromide (1.0 mmol; 2.0 mL).
The reaction was heated to 105.degree. C. for 24 hr. The mixture
was then hydrolysed with water (3 mL), extracted with ethyl acetate
(3*3 mL). Combined organic phases were dried over MgSO.sub.4,
concentrated under reduced pressure. The crude was then purified by
preparative chromatography (cyclohexane/dichloromethane) to yield
the desired product as a clear oil (28 mg; 0.10 mmol; 20%).
[0237] MS (ES) m/e 276 (M+H).sup.+
[0238] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 7.71 (q, 1H, J=8.0
Hz); 7.04 (d, 1H, J=7.9 Hz); 6.78 (m, 2H); 6.68 (d, 1H, J=7.3 Hz);
6.56 (d, 1H, J=7.8 Hz); 3.77 (s, 3H); 2.50 (d, 2H, J=7.2 Hz); 1.90
(se, 1H, J=6.7 Hz); 0.96 (d, 6H, J=6.6 Hz).
c) 2-[(6-fluoropyridin-2-yl)oxy]-5-isobutylphenol
##STR00051##
[0240] According to the procedure of example 5(b) except
substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for
2-fluoro-6-(4-isobutyl-2-methoxyphenoxy)pyridine (25 mg, 0.1 mmol),
the title compound (18 mg; 69%) was prepared as a clear oil,
without purification.
[0241] MS (ES) m/e 262 (M+H).sup.+
[0242] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 7.78 (q, 1H, J=8.0
Hz); 7.02 (d, 1H, J=8.2 Hz); 6.89 (s, 1H); 6.77 (d, 1H, J=8.0 Hz);
6.72 (d, 1H, J=8.2 Hz); 6.66 (d, 1H, J=7.9 Hz); 2.46 (d, 2H, J=7.2
Hz); 1.88 (se, 1H, J=6.7 Hz); 0.94 (d, 6H, J=6.6 Hz).
Example 14
2-[(6-fluoropyridin-2-yl)oxy]-5-(hydroxymethyl)phenol
a) {4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}methanol
##STR00052##
[0244] According to the procedure of example 4(a) except
substituting 4-(2-hydroxyethyl)-2-methoxyphenol for
4-(hydroxymethyl)-2-methoxyphenol (308 mg; 2 mmol) the title
compound (200 mg; 40%) was prepared as a clear oil, after
purification by silica gel chromatography (gradient
cyclohexane/ethyl acetate).
[0245] MS (ES) m/e 250 (M+H).sup.+
b) 2-[(6-fluoropyridin-2-yl)oxy]-5-(hydroxymethyl)phenol
##STR00053##
[0247] According to the procedure of example 5(b) except
substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for
{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}methanol (104 mg,
0.42 mmol), the title compound (98 mg; 98%) was prepared as a white
solid, after washing with diethyl ether.
[0248] MS (ES) m/e 236 (M+H).sup.+
[0249] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 7.81 (q, 1H, J=8.0
Hz); 7.11 (s, 1H); 7.08 (d, 1H, J=8.3 Hz); 6.95 (d, 1H, J=8.3 Hz);
6.83 (d, 1H, J=7.9 Hz); 6.68 (d, 1H, J=7.9 Hz); 4.46 (s, 2H).
Example 15
4-[(6-fluoropyridin-2-yl)oxy]-3-hydroxybenzyl acetate
##STR00054##
[0251] To a solution of
2-[(6-fluoropyridin-2-yl)oxy]-5-(hydroxymethyl)phenol (0.42 mmol;
104 mg) under argon, in anhydrous DMF (0.8 mL), were added
K.sub.2CO.sub.3 (0.5 mmol; 68 mg), DMAP (0.08 mmol; 12 mg), and
acetic anhydride (0.41 mmol; 0.04 mL). The reaction was stirred at
room temperature overnight. After dilution with ethyl acetate (4
mL), the organic phase was washed with saturated NaHCO.sub.3 (3*3
mL), dried (MgSO.sub.4), concentrated in vacuo, purified by
preparative TLC (dichloromethane) to yield the title compound as a
clear oil (3 mg; 0.01 mmol; 3%).
[0252] MS (ES) m/e 278 (M+H).sup.+
[0253] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 7.82 (q, 1H, J=8.0
Hz); 7.56 (m, 3H); 6.82 (d, 1H, J=6.9 Hz); 6.68 (dd, 1H,
J.sub.1=7.8 Hz, J.sub.2=2.6 Hz); 5.16 (s, 2H); 2.17 (s, 3H).
Example 16
2-(4-methoxyphenoxy)-5-propylphenol
a) 2-methoxy-1-(4-methoxyphenoxy)-4-propylbenzene
##STR00055##
[0255] A mixture containing 2-methoxy-4-propylphenol (0.625 mmol;
100 .mu.l), copper(II) acetate (0.625 mmol; 114 mg),
4-methoxyphenylboronic acid (1.25 mmol; 190 mg), triethylamine
(3.12 mmol; 0.43 ml), some crushed molecular sieves 4 .ANG. in
dichloromethane (3 ml) was stirred at rt under air for 24 h. The
residue is filtered with chloroform on Celite. The organic phase is
washed with saturated NH.sub.4Cl, saturated NaHCO.sub.3 and brine.
After drying (MgSO.sub.4), concentration and purification by
preparative TLC on silica gel (ethyl acetate/cyclohexane--20/80),
the title compound is collected as a colorless oil (70 mg; 0.26
mmol; 41%).
[0256] MS (ES) 273 [M+1].sup.+ and 295 [M+Na].sup.+
[0257] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 6.94 (d, 2H, J=9.1
Hz); 6.85 (d, 2H, J=9.1 Hz); 6.82 (s, 1H); 6.80 (d, 1H, J=8.1 Hz);
6.70 (d, 1H, J=8.2 Hz); 3.87 (s, 3H); 3.80 (s, 3H); 2.58 (t, 2H,
J=7.7 Hz); 1.67 (se, 2H, J=7.6 Hz); 0.98 (t, 3H, J=7.3 Hz).
b) 2-(4-methoxyphenoxy)-5-propylphenol
##STR00056##
[0259] According to the procedure of example 5(b) except
substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for
2-methoxy-1-(4-methoxyphenoxy)-4-propylbenzene (0.18 mmol; 50 mg)
and adding 4 equivalents (0.735 mmol; 735 .mu.l) of boron
tribromide, the title compound was prepared in 32% yield (0.06
mmol; 15 mg) after purification by preparative TLC on silica gel
(ethyl acetate/cyclohexane--20/80).
[0260] MS (ES) 257 [M-1].sup.-
[0261] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 6.99 (d, 2H, J=9.0
Hz); 6.89 (d, 2H, J=9.0 Hz); 6.87 (s, 1H); 6.72 (d, 1H, J=8.2 Hz);
6.63 (d, 1H, J=8.1 Hz); 5.57 (s br, 1H); 3.82 (s, 3H); 2.54 (t, 2H,
J=7.8 Hz); 1.64 (se, 2H, J=7.5 Hz); 0.96 (t, 3H, J=7.3 Hz). NOE
observed between .delta. 3.82 and 6.89 ppm.
Example 17
N-[3-(2-hydroxy-4-propylphenoxy)phenyl]acetamide
a) N-[3-(2-methoxy-4 propylphenoxy)phenyl]acetamide
##STR00057##
[0263] According to the procedure of example 16(a) except
substituting 4-methoxyphenylboronic acid for
3-acetamidophenylboronic acid (1.25 mmol; 224 mg) the title
compound was prepared in 10% yield (0.06 mmol; 18 mg) after
purification by preparative TLC on silica gel (ethyl
acetate/cyclohexane--70/30).
[0264] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 7.28-7.16 (m, 3H);
7.05 (s, 1H); 6.92 (d, 1H, J=8.0 Hz); 6.83 (s, 1H); 6.76 (d, 1H,
J=7.9 Hz); 6.68 (d, 1H, J=7.4 Hz); 3.82 (s, 3H); 2.60 (t, 2H, J=7.4
Hz); 2.15 (s, 3H); 1.68 (t, 3H, J=7.4 Hz).
b) N-[3-(2-hydroxy-4-propylphenoxy)phenyl]acetamide
##STR00058##
[0266] According to the procedure of example 5(b) except
substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for
N-[3-(2-methoxy-4-propylphenoxy)phenyl]acetamide (0.06 mmol; 17
mg), the title compound was prepared in 56% yield (0.03 mmol; 9 mg)
after purification by preparative TLC on silica gel (ethyl
acetate/cyclohexane--70/30).
[0267] MS (ES) 286 [M+1].sup.+ and 308 [M+Na].sup.+
[0268] NMR.sup.1H (DMSO) .delta. (ppm): 9.90 (s, 1H); 9.37 (s, 1H);
7.28-7.19 (m, 3H); 6.86 (d, 1H, J=8.1 Hz); 6.79 (s, 1H); 6.64 (d,
1H, J=8.1 Hz); 6.52 (d, 1H, J=7.9 Hz); 2.00 (s, 3H); 1.59 (se, 2H,
J=7.5 Hz); 0.92 (t, 3H, J=7.3 Hz).
Example 18
2-{[6-(butylamino)pyridin-2-yl]oxy}-5-ethylphenol
a) N-butyl-6-(4-ethyl-2-methoxyphenoxy)pyridin-2-amine
##STR00059##
[0270] To 2-(4-ethyl-2-methoxyphenoxy)-6-fluoropyridine (94 mg;
0.32 mmol), under argon, was added butylamine (0.5 mL). The
reaction was heated to 80.degree. C. for 18 hours. The mixture was
concentrated in vacuo. After quenching with saturated NaHCO.sub.3
(10 mL), extractions with dichloromethane (3*5 mL), the organic
phase was dried over NaSO.sub.4, and concentrated in vacuo to give
the title compound as a light brown oil used without further
purification (87 mg; 0.29 mmol; 89%).
[0271] MS (ES) m/e 301 (M+H).sup.+
b) 2-{[6-(butylamino)pyridin-2-yl]oxy}-5-ethylphenol
##STR00060##
[0273] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for N-butyl-6-(4-ethyl-2-methoxyphenoxy)pyridin-2-amine (87 mg;
0.29 mmol), the title compound(36 mg; 43%) was obtained as a light
brown oil, after purification by preparative TLC (cyclohexane/ethyl
acetate: 8/2)
[0274] MS (ES) m/e 287 (M+H).sup.+
[0275] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.41 (t, 1H, J=7.9
Hz); 7.01 (d, 1H, J=8.1 Hz); 6.91 (s, 1H); 6.69 (d, 1H, J=8.0 Hz);
6.17 (d, 1H, J=7.8 Hz); 6.06 (d, 1H, J=8.1 Hz); 4.56 (sl, 1H); 3.18
(t, 2H, J=7.0 Hz); 2.61 (q, 2H, J=7.5 Hz); 1.55 (qt, 2H, J=7.5 Hz);
1.39 (se, 2H, J=7.4 Hz); 1.23 (t, 3H, J=7.6 Hz); 0.93 (t, 3H, J=7.3
Hz).
Example 19
2-[(6-ethoxypyridin-2-yl)oxy]-5-ethylphenol
a) 2-ethoxy-6-(4-ethyl-2-methoxyphenoxy)pyridine
##STR00061##
[0277] To a solution of sodium (55 mg; 2.39 mmol), under argon, in
ethanol (2 mL), was added
2-(4-ethyl-2-methoxyphenoxy)-6-fluoropyridine (82 mg; 0.33 mmol).
The reaction was heated to 80.degree. C. for 16 hours then to
90.degree. C. for 26 hours. The mixture was concentrated in vacuo.
After quenching with saturated NaHCO.sub.3 (10 mL), extractions
with ethyl acetate (3*5 mL), the organic phase was dried over
NaSO.sub.4, and concentrated in vacuo to give the desired product
as a light brown oil used without further purification (82 mg; 0.30
mmol; 90%).
[0278] MS (ES) m/e 274 (M+H).sup.+
b) 2-[(6-ethoxypyridin-2-yl)oxy]-5-ethylphenol
##STR00062##
[0280] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 2-ethoxy-6-(4-ethyl-2-methoxyphenoxy)pyridine (82 mg; 0.30
mmol), the title compound (31 mg; 37%) was prepared as a light
brown oil, after purification by preparative TLC (cyclohexane/ethyl
acetate: 8/2).
[0281] MS (ES) m/e 260 (M+H).sup.+
[0282] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.56 (t, 1H, J=7.6
Hz); 7.01 (d, 1H, J=8.2 Hz); 6.91 (d, 1H, J=1.8 Hz); 6.70 (dd, 1H,
J.sub.1=1.9 Hz, J.sub.2=8.2 Hz); 6.46 (d, 1H, J=5.1 Hz); 6.43 (d,
1H, J=4.8 Hz); 4.22 (q, 2H, J=7.0 Hz); 2.61 (q, 2H, J=7.6 Hz); 1.33
(t, 3H, J=7.1 Hz); 1.23 (t, 3H, J=7.0 Hz).
Example 20
2-[4-amino-2-(trifluoromethyl)phenoxy]-5-ethyl phenol
a)
4-ethyl-2-methoxy-1-[4-nitro-2(trifluoromethyl)phenoxy]benzene
##STR00063##
[0284] To a suspension of K.sub.2CO.sub.3 (2 mmol; 276 mg) in
anhydrous acetonitrile (1 mL) under argon, was added
2-methoxy-4-ethylphenol (0.285 mL; 2 mmol) followed by
1-fluoro-4-nitro-2-(trifluoromethyl)benzene (418 mg; 2 mmol). The
reaction mixture was stirred at 80.degree. C. overnight.
Concentrated under argon, washed with NaOH (0.1N; 3 mL), the
mixture was extracted with ethyl acetate (2*3 mL). Combined organic
phases were dried over MgSO.sub.4, concentrated in vacuo, to give
the title product as a light brown oil (651 mg; 95%), used without
further purification.
[0285] MS (ES) m/e 342 (M+H).sup.+.
b) 4-(4-ethyl-2-methoxyphenoxy)-3-(trifluoromethyl)aniline
##STR00064##
[0287]
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene
(1.90 mmol; 651 mg) was dissolved in anhydrous THF (8 mL) under
argon. Palladium on charcoal (0.095 mmol; 20 mg) was added and the
reaction was flushed twice with hydrogen, then left to stir
overnight. The reaction mixture was filtered on celite, rinsed with
methanol (3*10 mL). Concentration yielded a light brown oil (579
mg; 98%) used without further purification.
[0288] MS (ES) m/e 312 (M+H).sup.+.
c) 2-[4-amino-2-(trifluoromethyl)phenoxy]-5-ethylphenol
##STR00065##
[0290] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 4-(4-ethyl-2-methoxyphenoxy)-3-(trifluoromethyl)aniline (54 mg;
0.170 mmol), the title compound (24 mg; 47%) was prepared as a
light brown solid, after purification by preparative TLC
(dichloromethane/methanol: 98/2).
[0291] MS (ES) m/e 298 (M+H).sup.+
[0292] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 6.95 (d, 1H, J=2.1
Hz); 6.88 (s, 1H); 6.81 (d, 1H, J=8.7 Hz); 6.75 (dd, 1H,
J.sub.1=2.2 Hz, J.sub.2=8.4 Hz); 6.70 (d, 1H, J=8.2 Hz); 6.64 (d,
1H, 8.0 Hz); 2.59 (q, 2H, J=7.6 Hz); 1.22 (t, 3H, 7.6 Hz).
Example 21
2-[(2-aminopyridin-3-yl)oxy]-5-ethylphenol
a1) 3-(4-ethyl-2-methoxyphenoxy)-2-nitropyridine
##STR00066##
[0294] According to the procedure of example 20(a), except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for
3-bromo-2-nitropyridine (2 mmol; 406 mg), the title compound (73
mg; 13%) was prepared after chromatography on silica gel (gradient
cyclohexane/ethyl acetate).
[0295] MS (ES) m/e 275 (M+H).sup.+
[0296] Alternatively 3-(4-ethyl-2-methoxyphenoxy)-2-nitropyridine
can be synthezized using the following procedure:
a2) 3-Fluoro-2-nitropyridine
##STR00067##
[0298] To a stirred solution of 3-Amino 2-nitro pyridine (2.5 g,
17.97 mmol) in dry ethanol (20 ml) was added 10 ml of
tetrafluoroboric acid (48% in water). The reaction mixture was
cooled to 0.degree. C. and isoamyl nitrite (2.6 g, 22.4 mmol) was
added dropwise at 0.degree. C. and stirred at 0.degree. C. for 1
hour. The reaction mixture was filtered, and the solid obtained was
washed with diethyl ether. The filtered solid was added to
preheated (150 mL) toluene with stirring and reaction mixture was
refluxed for 24 hours. The solvent was evaporated and the residue
taken in ethyl acetate (200 ml) and washed with water followed by
brine, dried over anhydrous sodium sulfate and concentrated under
reduced pressure to get the crude 3-fluoro-2-nitropyridine. This
was purified by column over silica gel using 10% ethyl acetate in
pet ether as eluant to get 1 g (39%) of the title compound as a
yellow solid.
[0299] .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.45 (d, J=4.24 Hz,
1H), 7.78-7.83 (m, 1H), 7.70-7.74 (m, 1H)
a3) 3-(4-ethyl-2-methoxyphenoxy)-2-nitropyridine
##STR00068##
[0301] To a stirred solution of 3-Fluoro 2-nitro pyridine (1.6 g,
0.01126 mol) in dry Acetonitrile (20 ml) was added
4-Ethyl-2-methoxy phenol (1.71 g, 11.3 mmol) in dry acetonitrile
(10 ml) followed by potassium hydroxide (0.696 g, 12.4 mmol). The
reaction mixture was heated to 80.degree. C. and maintained for 2
hours. The solvent was evaporated and taken in ethyl acetate (200
ml). The organic layer was washed with water followed by brine,
dried over anhydrous sodium sulfate and concentrated under reduced
pressure to give 2.6 g of crude product purified by column
chromatography (5% Ethyl acetate in Petroleum ether) to yield: 1.75
g (56%) of title compound.
b) 3-(4-ethyl-2-methoxyphenoxy)pyridin-2-amine
##STR00069##
[0303] To a stirred solution of
3-(4-ethyl-2-methoxyphenoxy)-2-nitropyridine (1.3 g, 4.7 mmol) in
methanol (30 ml) were added anhydrous Ferric chloride (66 mg) and
activated charcoal (66 mg). The resulting mixture was heated to
reflux and Hydrazine hydrate (80%) (2 mL, 39 mmol) was added
dropwise. The reaction was allowed to stir under reflux condition
for 5 hours, then filtered through celite. The filtrate was
concentrated under reduced pressure, taken in ethyl acetate (150
ml). The organic phase was washed with water followed by brine,
dried over anhydrous sodium sulfate and concentrated under reduced
pressure to give 1.11 g of the title compound, 100% yield.
c) 2-[(2-aminopyridin-3-yl)oxy]-5-ethylphenol
##STR00070##
[0305] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 3-(4-ethyl-2-methoxyphenoxy)pyridin-2-amine (63 mg; 0.26 mmol)
the title compound (13 mg; 22%) was obtained as a light brown oil,
after two purifications by preparative TLC
(dichloromethane/methanol: 9/1).
[0306] MS (ES) m/e 231 (M+H).sup.+
[0307] .sup.1H NMR (MeOD) .delta. (ppm): 7.61 (m, 1H); 6.84 (m,
3H); 6.70 (d, 1H, J=8.2 Hz); 6.55 (m, 1H); 2.60 (q, 2H, J=7.5 Hz);
1.23 (t, 3H, J=7.6 Hz)
Example 22
N-[5-(2-hydroxy-4-propylphenoxy)pyridin-2-yl]methanesulfonamide
a) 5-(2-methoxy-4-propylphenoxy)-2-nitropyridine
##STR00071##
[0309] According to the procedure of example 20(a), except
substituting 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for
5-bromo-2-nitropyridine (406 mg, 2 mmol), the title compound (220
mg; 38%) was prepared as a white solid, after chromatography on
silica gel (gradient cyclohexane/dichloromethane), along with
5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine (238 mg; 37%).
[0310] MS (ES) m/e 289 (M+H).sup.+
b) 5-(2-methoxy-4-propylphenoxy)pyridin-2-amine
##STR00072##
[0312] According to the procedure of example 20(b), except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for
5-(2-methoxy-4-propylphenoxy)-2-nitropyridine (144 mg; 0.5 mmol),
the title compound (130 mg; 100%) was prepared as a white solid,
without purification.
[0313] MS (ES) m/e 259 (M+H).sup.+
c) 2-[(6-aminopyridin-3-yl)oxy]-5-propylphenol
##STR00073##
[0315] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 2-[(6-aminopyridin-3-yl)oxy]-5-propylphenol (130 mg, 0.50
mmol), the title compound (112 mg, 92%) was prepared as a white
solid after washing with diethyl ether.
[0316] MS (ES) m/e 245 (M+H).sup.+
[0317] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.92 (s, 1H); 7.22
(d, 1H, J=8.8 Hz); 6.90 (s, 1H); 6.68 (q, 2H, J=9.3 Hz); 6.54 (d,
1H, J=8.8 Hz); 2.55 (t, 2H, J=7.7 Hz); 1.66 (se, 2H, J=7.4 Hz);
0.97 (t, 3H, J=7.3 Hz).
Example 23
N-[5-(2-hydroxy-4-propylphenoxy)pyridin-2-yl]methane
sulfonamide
a) 2-({6-[(methylsulfonyl)amino]pyridin-3-yl}oxy)-5-propyl phenyl
methanesulfonate
##STR00074##
[0319] To a solution of 2-[(6-aminopyridin-3-yl)oxy]-5-propylphenol
(0.12 mmol; 30 mg) under argon, in anhydrous dichloromethane (0.5
mL), cooled to -40.degree. C., were added pyridine (0.13 mmol; 0.01
mL) and MsCl (0.12 mmol; 0.01 mL). The reaction mixture was stirred
overnight while progressively heating to room temperature. After
quenching with NH.sub.4Cl (1 mL), extraction with ethyl acetate
(3*3 mL), combined organic phases were washed with water (3 mL),
dried over MgSO.sub.4, concentrated in vacuo. The crude was
purified by preparative TLC (dichloromethane/ethyl acetate) to
yield the title compound as a white solid (37 mg; 0.09 mmol;
77%).
[0320] MS (ES) m/e 401 (M+H).sup.+
[0321] .sup.1H NMR (acetone-d.sub.6) .delta. (ppm): 8.16 (s, 1H);
7.52 (d, 1H, J=8.7 Hz); 7.33 (s, 1H); 7.22 (t, 2H, J=8.5 Hz); 7.04
(d, 1H, J=7.7 Hz); 3.35 (s, 3H); 3.28 (s, 3H); 2.63 (m, 2H); 1.67
(m, 2H); 0.95 (m, 3H).
b) N-[5-(2-hydroxy-4-propylphenoxy)pyridin-2-yl]methane
sulfonamide
##STR00075##
[0323] To a solution of
2-({6-[(methylsulfonyl)amino]pyridin-3-yl}oxy)-5-propylphenyl
methanesulfonate (0.09 mmol; 30 mg), under argon, in water (0.5
mL), was added KOH (0.26 mmol; 15 mg). The reaction mixture was
refluxed for 4 hr. After quenching with NH.sub.4Cl (1 mL),
extraction with ethyl acetate (3*3 mL), combined organic phases
were washed with water (3 mL), dried over MgSO.sub.4, concentrated
in vacuo, to yield the title compound as a white solid (37 mg; 0.09
mmol; 77%).
[0324] MS (ES) m/e 323 (M+H).sup.+
[0325] .sup.1H NMR (acetone-d.sub.6) .delta. (ppm): 7.99 (d, 1H,
J=13.2 Hz); 7.31 (d, 1H, J=9.1 Hz); 7.16 (d, 1H, J=9.0 Hz); 6.94
(d, 1H, J=7.8 Hz); 6.89 (s, 1H); 6.73 (d, 1H, J=7.3 Hz); 3.24 (s,
3H); 2.80 (s, 3H); 2.54 (t, 2H, J=6.8 Hz); 1.64 (se, 2H, J=6.4 Hz);
0.95 (t, 3, J=6.3 Hz).
Example 24
2-[(6-ethoxypyridin-3-yl)oxy]-5-propylphenol
a) 5-(2-hydroxy-4-propylphenoxy)pyridin-2-ol
##STR00076##
[0327] To a solution of 2-[(6-aminopyridin-3-yl)oxy]-5-propylphenol
(0.20 mmol; 50 mg) under argon, in H.sub.2SO.sub.4 (35%; 0.2 mL),
cooled to 0.degree. C., was slowly added NaNO.sub.2 (0.26 mmol; 18
mg) in water (0.2 mL). After 30 min, CuSO.sub.4 (3 mmol; 477 mg) in
water (1 mL), then Cu.sub.2O (0.18 mmol; 26 mg) were added. After
30 min, the mixture was neutralised with NaHCO.sub.3 sat. (1 mL),
extracted with ethyl acetate (3*3 mL). Combined organic phases were
washed with water (3 mL), dried over MgSO.sub.4, concentrated in
vacuo. An analytical sample was obtained by preparative TLC to
yield the title compound as a white solid (5 mg; 0.02 mmol; ca
20%).
[0328] MS (ES) m/e 246 (M+H).sup.+
[0329] .sup.1H RMN (CD.sub.3OD) .delta. (ppm): 7.48 (dd, 1H,
J.sub.1=9.8 Hz, J.sub.2=3.2 Hz); 7.01 (d, 1H, J=3.1 Hz); 6.80 (d,
1H, J=8.2 Hz); 6.76 (d, 1H, J=1.9 Hz); 6.63 (dd, 1H, J.sub.1=8.1
Hz, J.sub.2=2.0 Hz); 6.54 (d, 1H, J=9.8 Hz); 2.48 (t, 2H, J=7.8
Hz); 1.60 (se, 2H, J=7.5 Hz); 0.91 (t, 3H, J=7.4 Hz).
b) 5-(2-ethoxy-4-propylphenoxy)-1-ethylpyridin-2(1H)-one
##STR00077##
[0331] To a solution of 5-(2-hydroxy-4-propylphenoxy)pyridin-2-ol
(0.08 mmol; 20 mg) under argon, in anhydrous DMF (0.5 mL) cooled to
0.degree. C., were added LiOH (0.09 mmol; 2 mg), then EtBr (0.09
mmol; 0.007 mL). After allowing the mixture to warm overnight up to
room temperature, the reaction was neutralised with NaHCO.sub.3 (1
mL), extracted with ethyl acetate (3*3 mL). Combined organic phases
were washed with water (3 mL), dried over MgSO.sub.4, concentrated
in vacuo to yield the title compound as a brown oil (14 mg; 0.05
mmol; 58%), used as such.
[0332] MS (ES) m/e 302 (M+H).sup.+
c) 2-[(6-ethoxypyridin-3-yl)oxy]-5-propylphenol
##STR00078##
[0334] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 5-(2-ethoxy-4-propylphenoxy)-1-ethylpyridin-2(1H)-one (14 mg;
0.05 mmol), the title compound (7 mg; 51%) was prepared as a white
solid, after purification by preparative TLC (dichloromethane/ethyl
acetate).
[0335] MS (ES) m/e 274 (M+H).sup.+
[0336] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.23 (d, 1H, J=6.8
Hz); 7.10 (s, 1H); 6.86 (s, 1H); 6.69 (d, 1H, J=8.0 Hz); 6.63 (d,
1H, J=8.0 Hz); 6.58 (d, 1H, J=9.8 Hz); 3.95 (q, 2H, J=7.1 Hz); 2.51
(t, 2H, J=7.7 Hz); 1.62 (se, 2H, J=7.8 Hz); 1.34 (t, 3H, J=7.2 Hz);
0.92 (t, 3H, J=7.3 Hz).
Example 25
2-[(4,6-difluoropyridin-2-yl)oxy]-5-propylphenol (25A) and
2-[(2,6-difluoropyridin-4-yl)oxy]-5-propylphenol (25B)
a) 2,4-difluoro-6-(2-methoxy-4-propylphenoxy)pyridine and
2,6-difluoro-4-(2-methoxy-4-propylphenoxy)pyridine
##STR00079##
[0338] According to the procedure of example 5(a) except
substituting 2,6-difluoropyridine for 2,4,6-trifluoropyridine (0.32
mL, 2 mmol), the title compounds (265 mg; 47%) were prepared
together as a clear oil, after purification by silica gel
chromatography (gradient cyclohexane/dichloromethane).
[0339] MS (ES) m/e 280 (M+H).sup.+
b) 2-[(4,6-difluoropyridin-2-yl)oxy]-5-propylphenol (25A) and
2-[(2,6-difluoropyridin-4-yl)oxy]-5-propylphenol (25B)
##STR00080##
[0341] According to the procedure of example 5(b), except
substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for
2,4-difluoro-6-(2-methoxy-4-propylphenoxy)pyridine and
2,6-difluoro-4-(2-methoxy-4-propylphenoxy)pyridine (67 mg, 0.24
mmol), title compound A, as a white solid (11 mg; 17%), and title
compound B as a clear oil (22 mg; 35%) were prepared after
purification by preparative TLC (dichloromethane/ethyl
acetate).
[0342] A: MS (ES) m/e 266 (M+H).sup.+
[0343] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 7.01 (d, 1H, J=8.2
Hz); 6.92 (s, 1H); 6.77 (d, 1H, J=8.3 Hz); 6.49 (d, 1H, J=8.7 Hz);
6.41 (d, 1H, J=7.7 Hz); 5.72 (br, 1H); 2.57 (t, 2H, J=7.8 Hz); 1.67
(se, 2H, J=7.3 Hz); 0.97 (t, 3H, J=7.3 Hz).
[0344] B: MS (ES) m/e 266 (M+H).sup.+
[0345] NMR.sup.1H (CDCl.sub.3) .delta. (ppm): 6.97 (d, 1H, J=8.2
Hz); 6.92 (s, 1H); 6.80 (d, 1H, J=8.3 Hz); 6.36 (s, 2H); 5.37 (br,
1H); 2.58 (t, 2H, J=7.8 Hz); 1.68 (se, 2H, J=7.6 Hz); 0.97 (t, 3H,
J=7.4 Hz).
Example 26
2-[(6-fluoropyridin-2-yl)oxy]-5-(2,2,2-trifluoro-1-hydroxyethyl)phenol
a)
2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}ethano-
l
##STR00081##
[0347] To a solution of 4-[(6-fluoropyridin-2-yl)oxy]-3-methoxy
benzaldehyde (300 mg; 1.2 mmol) with trifluoro
methyltrimethylsilane (228 .mu.l; 1.46 mmol) in THF (3 ml) under
argon at 0.degree. C. was added a molar solution of TBAF in THF (10
.mu.l; 0.012 mmol). The reaction mixture was allowed to stir at rt
for 2 h and a molar aqueous solution of HCl was added dropwise (2.5
ml; 2.5 mmol). The reaction mixture was stirred for another 2 h.
water and diethylether were added. The aqueous phase was further
extracted (2.times.EtOAc). Combined organic phases were dried over
MgSO.sub.4, concentrated in vacuo to afford the title compound as a
white solid (333 mg; 1.05 mmol; 88%).
[0348] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.79 (q, 1H, J=8.0
Hz); 7.24-7.20 (m, 2H); 7.17-7.09 (m, 1H); 6.81 (d, 1H, J=8.0 Hz);
6.64 (d, 1H, J=7.8 Hz); 5.10 (m, 1H); 3.85 (s, 3H).
b) 2-[(6-fluoropyridin-2-yl)oxy]-5-(2,2,2-trifluoro-1-hydroxy
ethyl)phenol
##STR00082##
[0350] According to the procedure of example 5(b) except
substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine by
2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3
methoxyphenyl}ethanol (0.15 mmol; 50 mg) and adding 3.5 equivalents
(0.47 mmol; 470 .mu.l) of boron tribromide, the title compound was
prepared in 84% yield (0.13 mmol; 38 mg) after purification by
preparative TLC on silica gel (ethyl
acetate/cyclohexane--40/60).
[0351] MS (ES) 304 [M+1].sup.+
[0352] .sup.1H NMR (DMSO) .delta. (ppm): 9.79 (s, 1H); 7.97 (q, 1H,
J=8.3 Hz); 7.12 (s, 1H); 7.11 (d, 1H, J=8.1 Hz); 6.96 (d, 1H, J=9.1
Hz); 6.85 (d, 1H, J=8.0 Hz); 6.81 (d, 2H, J=5.4 Hz); 5.11 (qt,
1H).
Example 27
2-[(6-fluoropyridin-2-yl)oxy]-5-(2,2,2-trifluoroethyl)phenol
a) 2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxy
phenyl}ethyl 4-methylbenzenesulfonate
##STR00083##
[0354] To a solution of
2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}ethanol
(0.52 mmol; 165 mg), tosyl chloride (0.57 mmol; 109 mg) and DMAP
(0.01 mmol; 1.5 mg) under argon in dichloromethane (4 mL) at
0.degree. C. was added TEA (1.04 mmol; 145 .mu.l). The reaction
mixture was stirred at rt for 3 h, then washed with brine
(2.times.), dried over MgSO.sub.4, concentrated and purified by
preparative TLC on silica gel (ethyl acetate/cyclohexane--30/70) to
yield the title compound (101 mg; 0.21 mmol; 41%).
[0355] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.78 (q, 1H, J=8.6
Hz); 7.65 (d, 2H, J=8.2 Hz); 7.29 (d, 2H, J=8.6 Hz); 7.06 (d, 1H,
J=8.2 Hz); 6.92 (d, 1H, J=9.7 Hz); 6.86 (s, 1H); 6.77 (d, 1H, J=8.0
Hz); 6.63 (d, 1H, J=8.1 Hz); 5.69 (q, 1H, J=6.3 Hz); 3.67 (s, 3H);
2.40 (s, 3H).
b)2-fluoro-6-[2-methoxy-4-(2,2,2-trifluoroethyl)phenoxy]pyridine
##STR00084##
[0357] A solution of
2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}ethyl
4-methylbenzenesulfonate (0.2 mmol; 96 mg) in ethanol (3 ml)
containing a catalytic amount of Pd/C (10% wet; 0.014 mmol; 30 mg)
was stirred for 16 h at rt under 2.5 atm of hydrogen. Purification
by preparative TLC on silica gel (ethyl acetate/cyclohexane--30/70)
afforded the title compound (48 mg; 0.16 mmol; 80%).
[0358] MS (ES) 302 [M+1].sup.+
[0359] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.75 (q, 1H, J=7.9
Hz); 7.13 (d, 1H, J=8.5 Hz); 6.96-6.90 (m, 2H); 6.76 (d, 1H, J=7.3
Hz); 6.59 (d, 1H, J=7.9 Hz); 3.80 (s, 3H); 3.40 (q, 1H, J=10.9
Hz).
c) 2-[(6-fluoropyridin-2-yl)oxy]-5-(2,2,2-trifluoroethyl)phenol
##STR00085##
[0361] According to the procedure of example 5(b) except
substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine by
2-fluoro-6-[2-methoxy-4-(2,2,2-trifluoroethyl)phenoxy]pyridine
(0.14 mmol; 43 mg) and adding 3.5 equivalents (0.5 mmol; 500 .mu.l)
of boron tribromide, the title compound was prepared in 75% yield
(0.11 mmol; 30 mg) after purification by preparative TLC on silica
gel (ethyl acetate/cyclohexane--30/70).
[0362] MS (ES) 288 [M+].sup.+
[0363] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.84 (q, 1H, J=7.6
Hz); 7.12 (d, 1H, J=8.7 Hz); 7.05 (s, 1H); 6.89-6.82 (m, 2H); 6.71
(d, 1H, J=6.3 Hz); 6.02 (s br, 1H); 3.36 (q, 1H, J=10.3 Hz).
Example 28
2-[(6-fluoropyridin-2-yl)oxy]-5-(trifluorovinyl)phenol
a) 2-fluoro-6-[2-methoxy-4-(1,2,2,2
tetrafluoroethyl)phenoxy]pyridine
##STR00086##
[0365] To a solution of
2,2,2-trifluoro-1-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}ethanol
(0.22 mmol; 70 mg) under argon in dichloromethane (2 mL) at
-78.degree. C. was added dropwise DAST (0.22 mmol; 29 .mu.l). The
reaction mixture was let come back to rt for 2 h and quenched with
brine (3 ml). The aqueous phase was collected, neutralized with
sodium bicarbonate and extracted twice with chloroform. The organic
phases were combined, dried over MgSO.sub.4, concentrated and
purified by preparative TLC on silica gel (ethyl
acetate/cyclohexane--30/70) to yield the title compound (25 mg;
0.08 mmol; 37%).
[0366] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.78 (q, 1H, J=8.1
Hz); 7.22 (d, 1H, J=8.0 Hz); 7.10 (m, 2H); 6.80 (d, 1H, J=8.0 Hz);
6.62 (d, 1H, J=7.8 Hz); 5.62 (dq, 1H, J=37.8 and 6.2 Hz); 3.82 (s,
3H).
b) 2-fluoro-6-[2-methoxy-4-(trifluorovinyl)phenoxy]pyridine
##STR00087##
[0368] To a solution of
2-fluoro-6-[2-methoxy-4-(1,2,2,2-tetrafluoroethyl)phenoxy]pyridine
(0.078 mmol; 25 mg) under argon in THF (1 mL) at 0.degree. C. was
added dropwise a one molar solution of LiHMDS in THF (0.094 mmol;
94 .mu.l). The reaction mixture was let come back to rt for 16 h.
Concentration and purification by preparative TLC on silica gel
(ethyl acetate/cyclohexane--30/70) afforded the title compound (10
mg; 0.033 mmol; 43%).
[0369] 1.sub.H NMR (CDCl.sub.3) .delta. (ppm): 7.73 (q, 1H, J=7.9
Hz); 7.21 (d, 1H, J=8.1 Hz); 7.12 (d, 1H, J=9.9 Hz); 7.11 (s, 1H);
6.80 (d, 1H, J=7.9 Hz); 6.61 (d, 1H, J=7.7 Hz); 3.81 (s, 3H).
c) 2-[(6-fluoropyridin-2-yl)oxy]-5-(trifluorovinyl)phenol
##STR00088##
[0371] According to the procedure of example 5(b) except
substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine by
2-fluoro-6-[2-methoxy-4-(trifluorovinyl)phenoxy]pyridine (0.033
mmol; 10 mg) and adding 3.5 equivalents (0.117 mmol; 117 .mu.l) of
boron tribromide, the title compound was prepared in 64% yield
(0.021 mmol; 6 mg) after purification by preparative TLC on silica
gel (ethyl acetate/cyclohexane--30/70).
[0372] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.76 (q, 1H, J=8.0
Hz); 7.13 (d, 1H, J=1.9 Hz); 7.11 (d, 1H, J=8.6 Hz); 6.98 (d, 1H,
J=10.0 Hz); 6.80 (d, 1H, J=8.0 Hz); 6.63 (d, 1H, J=9.6 Hz); 6.00 (s
br, 1H).
Example 29
1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]ethanone
a) 1-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]ethanone
##STR00089##
[0374] According to the procedure of example 4(a) except
substituting 2,6-Difluoropyridine for
1-(3,4-difluorophenyl)ethanone (0.77 mmol; 0.97 ml), the title
compound was isolated as a light brown oil (244 mg; quantitative)
used without purification.
[0375] MS (ES) m/e 289 (M+H).sup.+
b) 1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]ethanone
##STR00090##
[0377] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 1-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]ethanone (244
mg; 0.70 mmol), an analytical sample of the title compound (11 mg;
5%) was prepared as a light brown oil, after purification by
preparative TLC (cyclohexane/ethyl acetate: 7/3).
[0378] MS (ES) m/e 275 (M+H).sup.+
[0379] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 9.38 (dd, 1H,
J.sub.1=2.0 Hz, J.sub.2=11.6 Hz); 7.65 (d, 1H, J=8.4 Hz); 6.95 (t,
2H, J=8.0 Hz); 6.85 (d, 1H, J=8.1 Hz); 6.72 (d, 1H, J=8.0 Hz); 5.59
(sl, 1H); 2.62 (q, 2H, J=7.6 Hz); 2.56 (s, 3H); 1.24 (t, 3H, J=7.5
Hz).
Example 30
(1E)-1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluoro
phenyl]ethanone-O-methyloxime
##STR00091##
[0381] To a solution of
1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]ethanone (46 mg;
0.17 mmol), under argon, in ethanol (1 mL), was added
O-methylhydroxylamine hydrochloride (14 mg; 0.17 mmol) and 0.05 mL
of triethylamine. The reaction was stirred to room temperature
overnight. The mixture was concentrated in vacuo to give the
desired product as light brown oil after purification by
preparative TLC (14.5 mg; 0.048 mmol; 28%).
[0382] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.53 (dd, 1H,
J.sub.1=1.9 Hz, J.sub.2=12.0 Hz); 7.33 (d, 1H, J=8.5 Hz); 6.99 (t,
1H, J=8.5 Hz); 6.90 (d, 1H, J=1.5 Hz); 6.75 (d, 1H, J=8.3 Hz); 6.66
(dd, 1H, J.sub.1=1.4 Hz, J.sub.2=8.2 Hz); 5.54 (s, 1H); 3.99 (s,
3H); 2.60 (q, 2H, J=7.6 Hz); 2.19 (s, 3H); 1.23 (t, 3H, J=7.6
Hz).
Example 31
2-[(6-fluoropyridin-2-yl)oxy]-5-(1H-imidazol-1-ylmethyl)phenol
a) 2-[4-(chloromethyl)-2-methoxyphenoxy]-6-fluoro pyridine
##STR00092##
[0384] To a solution of
{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}methanol (367 mg;
1.47 mmol), under argon, in dichloromethane (6 mL), cooled to
-40.degree. C., was added pyridine (131 .mu.L; 1.62 mmol) then
methanesulfonyl chloride (115 .mu.L; 1.47 mmol). The reaction
mixture was allowed to stir for 6 hr, with gradual warming to room
temperature. The mixture was cooled to -40.degree. C., pyridine (50
.mu.L; 0.62 mmol) and methanesulfonyl chloride (40 .mu.L; 0.51
mmol) were added. The reaction was stirred overnight, with gradual
warming to room temperature.
[0385] The reaction was hydrolysed with saturated NH.sub.4Cl (10
mL), extracted with ethyl acetate (2*5 mL). Combined organic phases
were dried over Na.sub.2SO.sub.4, concentrated in vacuo. The title
compound (185 mg; 47%) was obtained as a light oil, after
purification on silica gel (cyclohexane/ethyl acetate: 95/5).
[0386] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.75 (q, 1H, J=7.6
Hz); 7.10 (d, 1H, J=7.9 Hz); 7.04 (s, 1H); 7.00 (d, 1H, J=8.1 Hz);
6.74 (d, 1H, J=7.9 Hz); 6.57 (dd, 1H, J.sub.1=7.8 Hz, J.sub.2=1.8
Hz); 4.60 (s, 2H); 3.79 (s, 3H).
b)
2-fluoro-6-[4-(1H-imidazol-1-ylmethyl)-2-methoxyphenoxy]pyridine
##STR00093##
[0388] To a solution of imidazole (18 mg; 0.27 mmol) and NaH (12
mg; 0.30 mmol) in DMF (1 mL), under argon, was added a solution of
2-[4-(chloromethyl)-2-methoxyphenoxy]-6-fluoropyridine (65 mg; 0.24
mmol) in DMF (1 mL). The reaction mixture was allowed to stir
overnight, to 40.degree. C. After concentration, the reaction was
hydrolysed with saturated NH.sub.4Cl (1 mL), extracted with AcOEt
(2*1 mL). Combined organic phases were dried over Na.sub.2SO.sub.4,
concentrated in vacuo, the title compound (68 mg; 93%) was
obtained.
c)
2-[(6-fluoropyridin-2-yl)oxy]-5-(1H-imidazol-1-ylmethyl)phenol
##STR00094##
[0390] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 2-fluoro-6-[4-(1H-imidazol-1-ylmethyl)-2-methoxy
phenoxy]pyridine (68 mg; 0.23 mmol), the title compound (16 mg;
24%) was obtained as a white solid, after purification by
preparative TLC (dichloromethane/methanol: 9/1).
[0391] MS (ES) m/e 286 (M+H).sup.+
[0392] .sup.1H NMR (MeOD) .delta. (ppm): 7.93 (m, 2H); 7.28 (sl,
1H); 7.12 (m, 2H); 6.84 (m, 3H); 6.72 (dd, 1H, J.sub.1=7.8 Hz,
J.sub.2=2.0 Hz); 5.27 (s, 2H).
Example 32
2-[(6-fluoropyridin-2-yl)oxy]-5-(1H-1,2,4-triazol-1-ylmethyl)phenol
a)
2-fluoro-6-[2-methoxy-4-(1H-1,2,4-triazol-1-ylmethyl)phenoxy]pyridine
##STR00095##
[0394] To a solution of triazole (18 mg; 0.267 mmol) and NaH (10
mg; 0.25 mmol) in DMF (1 mL), under argon, was added a solution of
2-[4-(chloromethyl)-2-methoxyphenoxy]-6-fluoropyridine (65 mg;
0.243 mmol) in DMF (1 mL). The reaction mixture was allowed to stir
overnight at 40.degree. C. After concentration, the reaction was
hydrolysed with saturated NH.sub.4Cl (1 mL), extracted with AcOEt
(2*1 mL). Combined organic phases were dried over Na.sub.2SO.sub.4,
concentrated in vacuo, the title compound (72 mg; quantitative) was
obtained.
b)2-[(6-fluoropyridin-2-yl)oxy]-5-(1H-1,2,4-triazol-1-yl
methyl)phenol
##STR00096##
[0396] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
by
2-fluoro-6-[2-methoxy-4-(1H-1,2,4-triazol-1-ylmethyl)phenoxy]pyridine
(71 mg; 0.24 mmol), the title compound was prepared (37 mg; 54%)
after purification by preparative TLC on silica gel
(dichloromethane/methanol--9/1).
[0397] .sup.1H NMR (MeOD) .delta. (ppm): 8.75 (s, 1H); 8.08 (s,
1H); 7.74 (q, 1H, J=7.7 Hz); 6.95 (d, 1H, J=8.2 Hz); 6.82 (d, 1H,
J=1.8 Hz); 6.76 (dd, 1H, J.sub.1=8.1 Hz, J.sub.2=1.8 Hz); 6.64 (dd,
1H, J.sub.1=8.0 Hz, J.sub.2=1.0 Hz); 6.55 (dd, 1H, J.sub.1=7.8 Hz,
J.sub.2=2.2 Hz); 5.32 (s, 2H).
Example 33
5-ethyl-2-[(6-fluoropyridin-2-yl)oxy]phenyl acetate
##STR00097##
[0399] To a solution of 5-Ethyl-2-(6-fluoro-pyridin-2-yloxy)-phenol
(20 mg; 0.09 mmol), under argon, in dimethylformamide (2 mL),
cooled to 0.degree. C., was added triethylamine (36 .mu.L; 0.26
mmol) and acetic acid (10 .mu.L; 0.18 mmol). The reaction mixture
was allowed to stir overnight, with gradual warming to room
temperature. The reaction was concentrated, diluted with saturated
NaHCO.sub.3 (5 mL) and extracted with ethyl acetate (3*3 mL).
Combined organic phases were dried over Na.sub.2SO.sub.4,
concentrated in vacuo, the title compound (8 mg; 34%) was obtained
as clear oil, after purification on neutral alumina gel
(cyclohexane/ethyl acetate: 9/1).
[0400] .sup.1H RMN (CDCl.sub.3) (ppm): 7.73 (q, 1H, J=8.0 Hz); 7.11
(m, 2H); 6.72 (d, 1H, J=8.0 Hz); 6.60 (dd, 1H, J.sub.1=7.8 Hz,
J.sub.2=2.4 Hz); 2.67 (q, 2H, J=7.6 Hz); 2.11 (s, 3H); 1.26 (t, 3H,
J=7.6 Hz).
Example 34
2-(2-aminophenoxy)-5-ethylphenol
a) 4-ethyl-2-methoxy-1-(2-nitrophenoxy)benzene
##STR00098##
[0402] According to the procedure of example 21 (a3) except
substituting 3-Fluoro 2-nitro pyridine by 2-fluoronitrobenzene
(0.72 mmol; 102 mg), the title compound was prepared in
quantitative yield (205 mg) and used without further
purification.
[0403] MS (ES) m/e 274 (M+H).sup.+
b) 2-(4-ethyl-2-methoxyphenoxy)aniline
##STR00099##
[0405] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene by
4-ethyl-2-methoxy-1-(2-nitrophenoxy)benzene (0.66 mmol; 180 mg) and
THF by ethanol, the title compound was prepared in quantitative
yield (181 mg) and used without further purification.
[0406] MS (ES) m/e 244 (M+H).sup.+
c) 2-(2-aminophenoxy)-5-ethylphenol
##STR00100##
[0408] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
by 2-(4-ethyl-2-methoxyphenoxy)aniline (50 mg; 0.21 mmol), the
title compound was prepared in 42% yield (0.09 mmol; 20 mg) after
purification by preparative TLC on silica gel
(dichloromethane/methanol--40/60).
[0409] MS (ES) m/e 244 (M+H).sup.+
[0410] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 6.93 (t, 1H, J=7.4
Hz); 6.89-6.85 (m, 2H); 6.82-6.79 (m, 2H); 6.76-6.72 (m, 1H) 6.64
(dd, 1H, J.sub.1=8.1 Hz; J.sub.2=1.8 Hz); 2.58 (q, 2H, J=7.6 Hz);
1.22 (t, 3H, J=7.6 Hz).
Example 36
2-[(6-fluoropyridin-2-yl)oxy]-5-(methoxymethyl)phenol
a) 5-(chloromethyl)-2-[(6-fluoropyridin-2-yl)oxy]phenol
##STR00101##
[0412] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
by 2-[4-(chloromethyl)-2-methoxyphenoxy]-6-fluoro pyridine (205 mg;
0.77 mmol), the title compound (185 mg; 95%) was prepared as a
light brown solid without further purification.
[0413] MS (ES) m/e 254 (M+H).sup.+
[0414] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.81 (q, 1H, J=8.0
Hz); 7.11 (m, 2H); 6.95 (dd, 1H, J.sub.1=8.2 Hz, J.sub.2=1.9 Hz);
6.83 (d, 1H, J=8.0 Hz); 6.68 (dd, 1H, J.sub.1=7.9 Hz, J.sub.2=2.1
Hz); 4.55 (s, 2H).
b) 2-[(6-fluoropyridin-2-yl)oxy]-5-(methoxymethyl)phenol
##STR00102##
[0416] To a solution of
5-(chloromethyl)-2-[(6-fluoropyridin-2-yl)oxy]phenol (50 mg; 0.20
mmol), under argon, in methanol (1 mL) was added sodium methoxylate
(3.94 mmol; 22 mg) and sodium iodide (0.07 mmol; 10 mg). The
reaction mixture was allowed to stir at room temperature overnight.
The reaction was hydrolysed with saturated NH.sub.4Cl (5 mL),
extracted with ethyl acetate (3*2 mL), and washed with 5 mL of
saturated NaHCO.sub.3. Combined organic phases were dried over
Na.sub.2SO.sub.4, concentrated in vacuo, the title compound (49 mg;
100%) was prepared as a light yellow oil without further
purification.
[0417] MS (ES) m/e 250 (M+H).sup.+
[0418] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.77 (q, 1H, J=8.0
Hz); 7.07 (m, 2H); 6.89 (dd, 1H, J.sub.1=8.1 Hz, J.sub.2=1.3 Hz);
6.77 (d, 1H, J=7.8 Hz); 6.65 (dd, 1H, J.sub.1=7.8 Hz, J.sub.2=2.1
Hz); 4.42 (s, 2H); 3.40 (s, 3H).
Example 37
5-ethyl-2-{2-fluoro-4-[(4-hydroxybutyl)amino]phenoxy}phenol
a) 4-ethyl-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene
##STR00103##
[0420] According to the procedure of example 20(a) except
substituting 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for
3,4-difluoronitrobenzene (318 mg; 2.0 mmol), the title compound
(551 mg; 95%) was prepared as a yellow solid, used without further
purification.
[0421] MS (ES) m/e 292 (M+H).sup.+.
b) 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline and
4-{[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]amino}butan-1-ol
##STR00104##
[0423] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for
4-ethyl-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene (551 mg; 1.89
mmol), two compounds were obtained after purification on silica gel
(gradient: cyclohexane/ethyl acetate):
[0424] 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (202 mg; 40%)
MS (ES) m/e 262 (M+H).sup.+.
[0425]
4-{[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]amino}butan-1-ol
(30 mg; 5%) MS (ES) m/e 334 (M+H).sup.+.
c) 5-ethyl-2-{2-fluoro-4-[(4-hydroxybutyl)amino]phenoxy}phenol
##STR00105##
[0427] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for
4-{[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]amino}butan-1-ol
(30 mg; 0.009 mmol), the title compound (24 mg; 83%) was prepared
as a light brown solid, after purification by preparative TLC
(dichloromethane/methanol: 95/5).
[0428] MS (ES) m/e 320 (M+H).sup.+
[0429] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 6.90 (m, 2H); 6.60
(m, 2H); 6.42 (d, 1H, J=12.8 Hz); 6.33 (d, 1H, J=8.7 Hz); 3.71 (m,
2H); 3.12 (t, 2H, J=5.9 Hz); 2.56 (q, 2H, J=7.6 Hz); 1.70 (sl, 4H);
1.20 (t, 3H, J=7.6 Hz).
Example 38
2-{3-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-propyl}-isoindole-1,-
3-dione
a) 4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenol
##STR00106##
[0431] To a solution of
4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (215 mg; 0.82 mmol) in
H.sub.2SO.sub.4 35%, at 0.degree. C., was added a solution of
NaNO.sub.2 (69 mg; 1 mmol) in water (1 mL). The mixture was stirred
30 min. at 0.degree. C. A solution of copper(II) sulphate (1.85 g;
11.6 mmol) in 6 mL of water was added, followed by copper(I) oxide
(99 mg; 0.69 mmol). The reaction was stirred 45 min. at room
temperature, then hydrolysed with NaHCO.sub.3 sat (6 mL) and
NH.sub.4OH. The mixture was extracted with ethyl acetate (3*5 mL).
Combined organic phases were dried over Na.sub.2SO.sub.4,
concentrated in vacuo. The title compound (85 mg; 0.032 mmol; 39%)
was obtained as an oil, after purification by preparative TLC
(cyclohexane/ethyl acetate: 7/3).
[0432] MS (ES) m/e 285 (M+Na).sup.+
b)
2-{3-[4-(4-Ethyl-2-methoxy-phenoxy)-3-fluoro-phenoxy]-propyl}-isoindole-
-1,3-dione
##STR00107##
[0434] To a solution of 4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenol
(0.32 mmol; 85 mg) in dry acetone (3 mL), under argon, were added
potassium hydroxide (0.39 mmol; 54 mg), NaI (0.065 mmol; 10 mg) and
N-(3-bromopropyl)phtalimide (0.40 mmol; 107 mg). The reaction was
stirred 3 days at 50.degree. C. The mixture was concentrated in
vacuo, hydrolysed with NH.sub.4Cl sat. (5 mL) and extracted with
ethyl acetate (3*3 mL). Combined organic phases were dried over
Na.sub.2SO.sub.4, concentrated in vacuo. The title compound (75 mg;
0.17 mmol; 51%) was obtained as an oil, after purification by
preparative TLC (cyclohexane/ethyl acetate: 7/3).
[0435] MS (ES) m/e 285 (M+Na).sup.+
[0436] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.83 (dd, 2H,
J.sub.1=5.2 Hz; J.sub.2=3.0 Hz); 7.71 (dd, 2H, J.sub.1=5.2 Hz;
J.sub.2=2.9 Hz); 6.86 (t, 1H, J=9.1 Hz); 6.80 (s, 1H); 6.67 (s,
2H); 6.61 (dd, 1H, J.sub.1=12.1 Hz; J.sub.2=2.5 Hz); 6.50 (d, 1H,
J=8.9 Hz); 3.98 (t, 2H, J=5.9 Hz); 3.91-3.87 (m, 5H); 2.61 (q, 2H,
J=7.6 Hz); 2.20-2.16 (m, 2H); 1.23 (t, 3H, J=7.6 Hz).
c)
2-{3-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-propyl}-isoindole-
-1,3-dione
##STR00108##
[0438] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
by
2-{3-[4-(4-Ethyl-2-methoxy-phenoxy)-3-fluoro-phenoxy]-propyl}-isoindole-1-
,3-dione (64 mg; 0.14 mmol), the title compound was prepared in 83%
yield (0.12 mmol; 52 mg) after purification by preparative TLC on
silica gel (ethyl acetate/cyclohexane--30/70).
[0439] MS (ES) m/e 436 (M+H).sup.+
[0440] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.84 (dd, 2H,
J.sub.1=5.4 Hz; J.sub.2=3.1 Hz); 7.71 (dd, 2H, J.sub.1=5.4 Hz;
J.sub.2=3.0 Hz); 6.94 (t, 1H, J=9.0 Hz); 6.86 (s, 1H); 6.63-6.60
(m, 2H); 6.54-6.50 (m,1H); 3.98 (t, 2H, J=5.9 Hz); 3.90 (t, 2H,
J=6.8 Hz); 2.56 (q, 2H, J=7.6 Hz); 2.17 (qt, 2H, J=6.2 Hz); 1.20
(t, 3H, J=7.6 Hz).
Example 39
2-[4-(3-aminopropoxy)-2-fluorophenoxy]-5-ethyl phenol
##STR00109##
[0442] To a solution of
2-{3-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-propyl}-isoindole-1-
,3-dione (0.096 mmol; 42 mg) in methanol (2 mL), under argon, was
added hydrazine monohydrate (0.21 mmol; 10 .mu.L). The reaction was
heated to reflux for 1 h 30. After cooling to 0.degree. C., the
mixture was hydrolysed with HCl 1N and filtered. The filtrate was
basified with NaOH 0.1 N (pH=11) and extracted with chloroform (3*5
mL). Combined organic phases were dried over Na.sub.2SO.sub.4,
concentrated in vacuo. The title compound (13 mg; 0.04 mmol; 44%)
was obtained as yellow oil, after purification by preparative TLC
(dichloromethane/methanol/NH.sub.4OH: 90/10/1).
[0443] MS (ES) m/e 306 (M+H).sup.+
[0444] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 6.92 (t, 1H, J=9.1
Hz); 6.85 (s, 1H); 6.68 (dd, 1H, J.sub.1=12.1 Hz, J.sub.2=2.6 Hz);
6.63-6.56 (m, 3H); 3.90 (t, 2H, J=6.8 Hz); 3.86 (sl, 2H); 2.96(sl,
2H); 2.56 (q, 2H, J=7.6 Hz); 1.97 (qt, 2H, J=6.2 Hz); 1.19 (t, 3H,
J=7.6 Hz).
Example 40
[1-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenyl]-eth-(E)-ylideneaminooxy-
]-acetic acid ethyl ester
##STR00110##
[0446] According to the procedure of example 30 except substituting
O-methylhydroxylamine hydrochloride by (aminooxy)acetic acid
hydrochloride (0.21 mmol; 23 mg), the title compound was isolated
(43 mg; 65%) after purification by preparative (ethyl
acetate/cyclohexane/acetic acid--40/60/1).
[0447] MS (ES) m/e 376 (M+H).sup.+
[0448] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.51 (dd, 1H,
J.sub.1=12.0 Hz, J.sub.2=1.9 Hz); 7.32 (d, 1H, J=8.0 Hz); 6.96 (t,
1H, J=8.4 Hz); 6.89 (s, 1H); 6.75 (d, 1H, J=8.3 Hz); 6.66 (dd, 1H,
J.sub.1=8.2 Hz, J.sub.2=1.6 Hz); 4.72 (s, 2H); 4.24 (q, 2H, J=7.1
Hz); 2.60 (q, 2H, J=7.6 Hz); 2.27 (s, 3H); 1.29 (t, 3H, J=7.1 Hz);
1.22 (t, 3H, J=7.6 Hz).
Example 41
[({(1E)-1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]ethylidene}amino)ox-
y]acetic acid
##STR00111##
[0450] The title compound (11 mg; 18%) was isolated from the
example 40 as a white solid, after purification by preparative TLC
ethyl acetate/cyclohexane/acetic acid--40/60/1).
[0451] MS (ES) m/e 348 (M+H).sup.+
[0452] .sup.1H RMN (MeOD) .delta. (ppm): 7.52 (d, 1H, J=12.5 Hz);
7.33 (d, 1H, J=8.3 Hz); 6.83-6.80 (m, 2H); 6.77 (t, 1H, J=8.0 Hz);
6.68 (dd, 1H, J.sub.1=8.2 Hz, J.sub.2=1.8 Hz); 4.86 (sl, 2H); 2.59
(q, 2H, J=7.6 Hz); 2.26 (s, 3H); 1.23 (t, 3H, J=7.6 Hz).
Example 42
3-Morpholin-4-yl-propane-1-sulfonic acid
[4-(4-ethyl-2-hydroxy-phenoxy)-3-fluoro-phenyl]-amide
a)
3-chloro-N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]propane-1-sulfo-
namide
##STR00112##
[0454] To a solution of
4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (0.38 mmol; 100 mg) in
dry dichloromethane (1 mL), under argon, at 0.degree. C. were added
pyridine (0.46 mmol; 37 .mu.L) and 3-chloropropanesulfonyle
chloride (0.46 mmol; 56 .mu.L). The reaction was stirred overnight
at room temperature. The mixture was hydrolysed with NH.sub.4Cl
sat. (2 mL) and extracted with dichloromethane (3*1 mL). Combined
organic phases were dried over Na.sub.2SO.sub.4, concentrated in
vacuo. The title compound (200 mg; 0.38 mmol; quantitative) was
obtained as a brown oil, used without further purification.
[0455] MS (ES) m/e 306 (M+H).sup.+
b) 3-Morpholin-4-yl-propane-1-sulfonic
acid[4-(4-ethyl-2-methoxy-phenoxy)-3-fluoro-phenyl]-amide
##STR00113##
[0457] To a solution of
3-chloro-N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]propane-1-sulfona-
mide (0.38 mmol; 153 mg) in dry acetonitrile (2 mL), under argon,
was added morpholine (1.1 mmol; 100 .mu.L). The reaction was heated
at 50.degree. C. overnight. After cooling to room temperature, the
mixture was hydrolysed with 5 mL of water and extracted with
dichloromethane (3*2 mL). Combined organic phases were dried over
Na.sub.2SO.sub.4, concentrated in vacuo, the title compound (62 mg;
36%) was obtained after purification by preparative TLC on silica
gel (ethyl acetate/cyclohexane--40/60).
[0458] MS (ES) m/e 453 (M+H).sup.+
[0459] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.11 (dd, 1H,
J.sub.1=12.0 Hz, J.sub.2=2.1 Hz); 6.84-6.72 (m, 5H); 3.83 (s, 3H);
3.69 (m, 4H); 3.19 (t, 2H, J=7.1 Hz); 2.64 (q, 2H, J=7.6 Hz);
2.51-2.47 (m, 6H);2.04 (qt, 2H, J=6.8 Hz); 1.25 (t, 3H, J=7.6
Hz).
c) 3-Morpholin-4-yl-propane-1-sulfonic acid
[4-(4-ethyl-2-hydroxy-phenoxy)-3-fluoro-phenyl]-amide
##STR00114##
[0461] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
by
3-Morpholin-4-yl-propane-1-sulfonicacid[4-(4-ethyl-2-methoxy-phenoxy)-3-f-
luoro-phenyl]-amide (0.11 mmol; 50 mg), the title compound was
prepared in 60% yield (0.07 mmol; 29 mg) after purification by
preparative TLC (dichloromethane/methanol--95/5).
[0462] MS (ES) m/e 439 (M+H).sup.+
[0463] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.16 (dd, 1H,
J.sub.1=11.7 Hz, J.sub.2=2.3 Hz); 6.95-6.88 (m, 3H); 6.73 (d, 1H,
J=8.2 Hz); 6.65 (dd, 1H, J.sub.1=8.2 Hz, J.sub.2=1.9 Hz); 3.71 (t,
4H, J=4.2 Hz); 3.18 (t, 2H, J=7.0 Hz); 2.61-2.53(m, 8H); 2.06 (qt,
2H, J=6.8 Hz); 1.21 (t, 3H, J=7.6 Hz).
Example 43
2-[4-(1,1-Dioxo-isothiazolidin-2-yl)-2-fluoro-phenoxy]-5-ethyl-phenol
a)
2-[4-(4-Ethyl-2-methoxy-phenoxy)-3-fluoro-phenyl]-isothiazolidine
1,1-dioxide
##STR00115##
[0465] The title compound (44 mg; 31%) was isolated from the
example 42(b) as a white solid, after purification by preparative
TLC on silica gel (ethyl acetate/cyclohexane--40/60).
[0466] MS (ES) m/e 388 (M+Na).sup.+
[0467] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.11 (dd, 1H,
J.sub.1=12.0 Hz, J.sub.2=2.5 Hz); 6.94 (d, 1H, J=8.9 Hz); 6.87-6.80
(m, 3H); 6.72 (dd, 1H, J.sub.1=8.1 Hz, J.sub.2=1.3 Hz); 3.83 (s,
3H); 3.71 (t, 2H, J=6.6 Hz); 3.38 (t, 2H, J=7.4 Hz); 2.63 (q, 2H,
J=7.6 Hz); 2.51 (qt, 2H, J=7.6 Hz); 1.24 (t, 3H, J=7.6 Hz).
b)
2-[4-(1,1-Dioxo-isothiazolidin-2-yl)-2-fluoro-phenoxy]-5-ethyl-phenol
##STR00116##
[0469] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
by
2-[4-(4-Ethyl-2-methoxy-phenoxy)-3-fluoro-phenyl]-isothiazolidine
1,1-dioxide (0.10 mmol; 38 mg), the title compound was prepared in
76% yield (0.08 mmol; 28 mg) after purification by preparative TLC
on silica gel (dichloromethane/methanol--95/5).
[0470] MS (ES) m/e 374 (M+H).sup.+
[0471] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.11 (dd, 1H,
J.sub.1=12.0 Hz, J.sub.2=2.5 Hz); 7.03-6.96 (m, 2H); 6.88 (sl, 1H);
6.70 (d, 1H, J=8.2 Hz); 6.63 (dd, 1H, J.sub.1=8.2 Hz, J.sub.2=1.8
Hz); 3.73 (t, 2H, J=6.6 Hz); 3.39 (t, 2H, J=7.4 Hz); 2.61-2.50 (m,
4H); 1.21 (t, 3H, J=7.6 Hz).
Example 44
ethyl[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]carbamate
a) ethyl[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]carbamate
##STR00117##
[0473] 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (0.19 mmol; 50
mg) in 1 mL THF/NaHCO.sub.3 sat. (1/1), at 0.degree. C. were added
ethylchloroformate (0.38 mmol; 41 mg). The reaction was stirred
overnight at room temperature. The mixture was hydrolysed with
NH.sub.4Cl sat. (4 mL) and extracted with dichloromethane (3*2 mL).
Combined organic phases were dried over Na.sub.2SO.sub.4,
concentrated in vacuo. The title compound (36 mg; 56%) was obtained
as a brown oil, after purification by preparative TLC on silica gel
(ethyl acetate/cyclohexane--70/30).
[0474] MS (ES) m/e 334 (M+H).sup.+
b) ethyl[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]carbamate
##STR00118##
[0476] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
by ethyl[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]carbamate
(0.11 mmol; 35 mg), the title compound was prepared in 69% yield
(0.07 mmol; 23 mg) after purification by preparative TLC (ethyl
acetate/cyclohexane--70/30).
[0477] MS (ES) m/e 320 (M+H).sup.+
[0478] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.41 (d, 1H, J=12.0
Hz); 6.99-6.96 (m, 2H); 6.88 (sl, 1H); 6.67 (d, 1H, J=8.1 Hz); 6.62
(dd, 1H, J.sub.1=8.2 Hz, J.sub.2=1.8 Hz); 4.23 (q, 2H, J=7.1 Hz);
2.58 (q, 2H, J=7.6 Hz); 1.31 (t, 3H, J=7.1 Hz); 1.21 (t, 3H, J=7.6
Hz).
Example 45
5-ethyl-2-[4-(ethylamino)-2-fluorophenoxy]phenol
a) N-ethyl-4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline
##STR00119##
[0480] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for
4-ethyl-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene (1.16 g; 4.0
mmol) and tetrahydrofurane for ethanol (16 mL), two compounds were
obtained after purification on silica gel (gradient
cyclohexane/dichloromethane)4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline
(466 mg; 45%)
[0481] MS (ES) m/e 262 (M+H).sup.+
[0482] N-ethyl-4-(4-ethyl-2-methoxyphenox)-3-fluoroaniline (461 mg;
40%) MS (ES) m/e 290 (M+H).sup.+
b) 5-ethyl-2-[4-(ethylamino)-2-fluorophenoxy]phenol
##STR00120##
[0484] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for N-ethyl-4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (461 mg;
1.59 mmol), the title compound (270 mg; 62%) was prepared as a
light brown solid, after purification by chromatography on silica
gel (gradient dichloromethane/ethyl acetate).
[0485] MS (ES) m/e 276 (M+H).sup.+
[0486] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 6.93 (t, 1H, J=8.9
Hz); 6.87 (s, 1H); 6.62 (q, 2H, J=6.6 Hz); 6.46 (dd, 1H,
J.sub.1=12.7 Hz, J.sub.2=2.5 Hz); 6.37 (d, 1H, J=8.7 Hz); 3.15 (q,
2H, J=7.2 Hz); 2.59 (q, 2H, J=7.6 Hz); 1.30 (t, 3H, J=7.1 Hz); 1.21
(t, 3H, J=7.6 Hz).
Example 46
5-ethyl-2-[2-(methylamino)phenoxy]phenol
a) N-[2-(4-ethyl-2-methoxyphenoxy)phenyl]formamide
##STR00121##
[0488] To acetic anhydride (0.53 mmol; 51 .mu.L) under argon, at
0.degree. C., was added formic acid (0.66 mmol; 25 .mu.L). The
reaction was stirred 2 hours at 60.degree. C. After cooling to
0.degree. C., the mixture was diluted with 1 mL of dry THF,
followed by a solution of 2-(4-ethyl-2-methoxyphenoxy)aniline (0.21
mmol; 50 mg) in dry THF (1 mL). The reaction was stirred 2 hours at
room temperature. The mixture was concentrated in vacuo to give the
title compound (72 mg; quantitative) as a brown oil, used without
further purification.
[0489] MS (ES) m/e 272 (M+H).sup.+.
b) 2-(4-ethyl-2-methoxyphenoxy)-N-methylaniline
##STR00122##
[0491] To a solution of
N-[2-(4-ethyl-2-methoxyphenoxy)phenyl]formamide (0.21 mmol; 72 mg),
under argon, in dry THF was added at 0.degree. C., borane
dimethylsulfide complex (0.51 mmol, 49 .mu.L). The reaction was
stirred at reflux for 3 h 30. After cooling to 0.degree. C., the
mixture was diluted with 1 mL of dry methanol and stirred 1 hour.
HCl (4M in dioxane) was added at 0.degree. C. until pH 2, then the
mixture was refluxed 1 hour. After cooling to room temperature, the
reaction was diluted with 5 mL of methanol and concentrated in
vacuo. The crude was treated with 5 mL of NaOH (1N), until pH 12,
and extracted with ethyl acetate (3*2 mL). Combined organic phases
were dried over Na.sub.2SO.sub.4 and concentrated in vacuo to yield
the title compound (66 mg, quantitative) as a red oil used without
further purification.
[0492] MS (ES) m/e 258 (M+H).sup.+.
c) 5-ethyl-2-[2-(methylamino)phenoxy]phenol
##STR00123##
[0494] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
by 2-(4-ethyl-2-methoxyphenoxy)-N-methylaniline (0.26 mmol; 66 mg),
the title compound was prepared in 50% yield (0.13 mmol; 31 mg)
after purification by preparative TLC (ethyl
acetate/cyclohexane--70/30).
[0495] MS (ES) m/e 244 (M+H).sup.+
[0496] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.07 (t, 1H, J=6.6
Hz); 6.88 (s, 1H); 6.81-6.76 (m, 3H); 6.69-6.64 (m, 2H); 2.89 (s,
3H); 2.60 (q, 2H, J=7.6 Hz); 1.23 (t, 3H, J=7.6 Hz).
Example 47
5-ethyl-2-[4-(methylsulfonyl)phenoxy]phenol
a) 4-(4-ethyl-2-methoxyphenoxy)phenyl methyl sulfone
##STR00124##
[0498] To a suspension of Cu(OAc).sub.2 (3.0 mmol; 543 mg),
4-(methanesulphonyl)benzeneboronic acid (4.0 mmol; 800 mg) and
activated molecular sieves (800 mg) under air, in anhydrous
dichloromethane (5 mL), were added 2-methoxy-4-ethylphenol (2.0
mmol; 0.28 mL), anhydrous triethylamine (10 mmol; 1.4 mL), and
anhydrous pyridine (10 mmol; 0.8 mL). The reaction was stirred for
2 days at room temperature. The crude was filtered on silica gel,
washed with ethyl acetate, concentrated. The residue was then
purified by column chromatography (gradient
cyclohexane/dichloromethane) to yield the title compound as clear
oil (617 mg; 2.0 mmol; quantitative).
[0499] MS (ES) m/e 307 (M+H).sup.+
b) 5-ethyl-2-[4-(methylsulfonyl)phenoxy]phenol
##STR00125##
[0501] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 4-(4-ethyl-2-methoxyphenoxy)phenyl methyl sulfone (130 mg; 0.42
mmol), the title compound (94 mg; 76%) was prepared as a white
solid, after purification by preparative TLC (dichloromethane).
[0502] MS (ES) m/e 293 (M+H).sup.+
[0503] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.91 (d, 2H, J=8.8
Hz); 7.13 (d, 2H, J=8.9 Hz); 6.95 (s, 1H) 6.92 (d, 1H, J=8.2 Hz);
6.78 (d, 1H, J=8.2 Hz); 3.07 (s, 3H); 2.66 (q, 2H, J=7.6 Hz); 1.26
(t, 3H, J=7.6 Hz).
Example 48
5-Ethyl-2-[2-fluoro-4-(3-hydroxy-propylamino)-phenoxy]-phenol
a) 2-(benzyloxy)-4-ethyl-1-(2-fluoro-4-nitrophenoxy)benzene
##STR00126##
[0505] According to the procedure of example 20(a) except
substituting 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for
3,4-difluoronitrobenzene (30.5 g; 192 mmol), and
2-methoxy-4-ethylphenol for 2-(benzyloxy)-4-ethylphenol (33.6 g;
147 mmol) the title compound (58.1 g; 100%) was prepared as a brown
oil, used without further purification.
b) 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluoroaniline
##STR00127##
[0507] To a solution of 2-(benzyloxy)-4-ethyl-1-(2-fluoro-4-nitro
phenoxy)benzene (25 g; 68 mmol) in ether (86 mL), under argon
cooled to 0.degree. C., was added a suspension of tin dichloride
(153 g; 801 mmol) in HCl (50 mL; 2 mol). The mixture was allowed to
warm up to room temperature overnight, then a 10% NaOH solution was
added dropwise. The resulting mixture was extracted with ethyl
acetate (5*400 mL). Combined organic phases were washed with water
(400 mL) and brine, then dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified on silica gel (ethyl
acetate/cyclohexane 1:9) to yield the title compound as a light
brown solid (15.8 g; 68.8%)
[0508] MS (ES) m/e 338 (M+H).sup.+
c)
3-[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenylamino]-propan-1-ol
##STR00128##
[0510] 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluoroaniline (500 mg,
1.48 mmol), K.sub.2CO.sub.3 (1.23 g, 8.9 mmol) and
3-bromo-1-propanol (410 mg, 2.9 mmol) were taken in dry DMF (2 ml)
in a microwave vial and was subjected to microwave at 180.degree.
C. for 2 h. The reaction mixture was filtered over celite and the
residue washed thoroughly with ethyl acetate. The combined organic
fractions including the filtrate were washed with water, brine,
dried over Na.sub.2SO.sub.4 and concentrated. The crude obtained
was combined with earlier crude products obtained from a 100 mg and
200 mg batches and purified together by column chromatography over
silica gel using 40% ethylacetate in pet ether as eluant to get 400
mg (42.6%) of pure title compound.
d)
5-Ethyl-2-[2-fluoro-4-(3-hydroxy-propylamino)-phenoxy]-phenol
##STR00129##
[0512]
3-[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenylamino]-propan-1-o-
l (400 mg, 1.01 mmol) was taken in 15 ml of absolute ethanol, under
nitrogen. To this was added Pd(OH).sub.2, (20%, 50 mg) followed by
ammonium formate (200 mg, 3.1 mmol). The reaction mixture was
heated at 65.degree. C. and monitored by TLC. After complete
consumption of starting material (20 minutes), the heating was
stopped and mixture cooled to rt. The reaction mixture was filtered
through celite and the residue was washed with methanol. The
combined filtrate was concentrated to obtain 300 mg of crude
compound showing 70% by HPLC. The crude was purified by preparative
HPLC (Column: C18 Symmetry (300.times.19 mm), 7.mu., Mobile phase
A: 20 mM ammonium acetate, Mobile phase B: Acetonitrile) to get 140
mg (45.3%) of title compound.
Example 49
5-ethyl-2-(4-{[(E)-pyrrolidin-2-ylidenemethyl]sulfonyl}phenoxy)phenol
a)
(2E)-2-({[4-(4-ethyl-2-methoxyphenoxy)phenyl]sulfonyl}methylene)pyrroli-
dine
##STR00130##
[0514] To a solution of 4-(4-ethyl-2-methoxyphenoxy)phenyl methyl
sulfone (0.44 mmol; 136 mg), in anhydrous THF (1 mL), under argon,
cooled to 0.degree. C., was added sBuLi (1.2M in cyclohexane; 0.89
mmol; 0.74 mL). After stirring for 30 min, a solution of
1-BOC-2-Pyrrolidinone (0.44 mmol; 0.08 mL) in anhydrous THF (1 mL)
was slowly added. The reaction was stirred at 0.degree. C. for 30
min. then slowly warmed up to room temperature overnight. The
mixture was quenched with water and NH.sub.4Cl sat. (3 mL),
extracted with ethyl acetate (2*3 mL), to yield a light yellow oil
(164 mg), used without further purification.
[0515] MS (ES) m/e 374 (M+H).sup.+
b)
5-ethyl-2-(4-{[(E)-pyrrolidin-2-ylidenemethyl]sulfonyl}phenoxy)phenol
##STR00131##
[0517] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for
(2E)-2-({[4-(4-ethyl-2-methoxyphenoxy)phenyl]sulfonyl}methylene)pyrrolidi-
ne (164 mg; 0.44 mmol), the title compound (34 mg; 0.09 mmol; 22%)
was prepared as a clear oil, after purification by preparative TLC
(dichloromethane/ethyl acetate).
[0518] MS (ES) m/e 378 (M+H.sub.2O+H).sup.+
[0519] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.78 (d, 2H, J=8.8
Hz); 6.99 (d, 2H, J=8.8 Hz); 6.90 (s, 1H); 6.87 (d, 1H, J=8.3 Hz);
6.73 (d, 1H, J=8.0 Hz); 4.66 (s, 1H); 3.75 (t, 2H, J=1.8 Hz); 2.79
(q, 2H, J=6.7 Hz); 2.63 (t, 2H, J=7.6 Hz); 1.95 (qu, 2H, J=7.1 Hz);
1.24 (t, 3H, J=7.6 Hz).
Example 50
2-(2-amino-5-fluorophenoxy)-5-ethylphenol
a) 4-ethyl-1-(3-fluoro-4-nitrophenoxy)-2-methoxybenzene and
4-ethyl-1-(5-fluoro-2-nitrophenoxy)-2-methoxybenzene
##STR00132##
[0521] According to the procedure of example 20(a) except
substituting 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for
1,3-difluoro-4-nitrobenzene (110 .mu.L; 1 mmol), the title products
were obtained as a yellow solid (253 mg; 87%), after purification
by preparative TLC (cyclohexane/ethyl acetate: 9/1).
[0522] MS (ES) m/e 292 (M+H).sup.+.
b) 4-(4-ethyl-2-methoxyphenoxy)-2-fluoroaniline and
2-(4-ethyl-2-methoxyphenoxy)-4-fluoroaniline
##STR00133##
[0524] To a solution of
4-ethyl-1-(3-fluoro-4-nitrophenoxy)-2-methoxybenzene and
4-ethyl-1-(5-fluoro-2-nitrophenoxy)-2-methoxybenzene (100.5 mg,
0.69 mmol) in ethanol (5 mL) was added Tin(II)chloride dihydrate
(794 mg, 3.45 mmol). The reaction mixture was heated to reflux for
1 h 30. The reaction mixture was washed with water, solid sodium
hydrogenocarbonate and a NaOH solution (1 N). The mixture was
extracted with ethyl acetate. Combined organic phases were dried
over Na.sub.2SO.sub.4, concentrated in vacuo, to give the title
products as a light brown oil (51 mg; 28%), after purification by
preparative TLC (cyclohexane/ethyl acetate: 7/3).
[0525] MS (ES) m/e 262 (M+H).sup.+.
c) 2-(2-amino-5-fluorophenoxy)-5-ethylphenol
##STR00134##
[0527] According to the procedure of example 5(b), except
substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for a
mixture of 4-(4-ethyl-2-methoxyphenoxy)-2-fluoroaniline and
2-(4-ethyl-2-methoxyphenoxy)-4-fluoroaniline (50.9 mg, 0.19 mmol),
the title compound (8.9 mg; 19%) was obtained after purification by
preparative TLC (dichloromethane/ethyl acetate: 9/1).
[0528] MS (ES) m/e 248 (M+H).sup.+
[0529] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 6.90-6.87 (m, 2H);
6.80-6.67 (m, 3H); 6.59 (dd, 1H, J.sub.1=2.8 Hz; J.sub.2=9.6 Hz);
2.62 (q, 2H, J=7.6 Hz); 1.25 (t, 3H, J=7.6 Hz).
Example 51
N-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]-2,2,2-trifluoroethanesulfo-
namide
a)
N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]-2,2,2-trifluoroethanesu-
lfonamide
##STR00135##
[0531] According to the procedure of example 42(a) except
substituting 3-chloropropanesulfonyle chloride by
Trifluoroethanesulfonyl chloride (0.46 mmol; 84 mg), the title
compound was prepared (177 mg; quantitative yield) as a brown oil
used without further purification.
[0532] MS (ES) m/e 408 (M+H).sup.+
b)
N-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]-2,2,2-trifluoroethanesu-
lfonamide
##STR00136##
[0534] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
by
N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]-2,2,2-trifluoroethanesulf-
onamide (0.38 mmol; 156 mg), the title compound was prepared in 53%
yield (0.20 mmol; 80 mg) after purification by preparative TLC
(cyclohexane/ethyl acetate--7/3).
[0535] MS (ES) m/e 394 (M+H).sup.+
[0536] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.19 (dd, 1H,
J.sub.1=11.4 Hz, J.sub.2=2.4 Hz); 7.11 (sl, 1H); 7.01-6.93 (m, 2H);
6.90 (d, 1H, J=1.9 Hz); 6.77 (d, 1H, J=8.2 Hz); 6.69 (dd, 1H,
J.sub.1=8.2 Hz, J.sub.2=2.0 Hz); 3.83 (q, 2H, J=8.8 Hz); 2.60 (q,
2H, J=7.6 Hz); 1.24 (t, 3H, J=7.6 Hz).
Example 52
N-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]cyclopropane
sulfonamide
a) N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]cyclopropane
sulfonamide
##STR00137##
[0538] According to the procedure of example 42(a) except
substituting 3-chloropropanesulfonyle chloride by
cyclopropanesulfonyl chloride (0.46 mmol; 47 .mu.L), the title
compound was prepared (170 mg; quantitative yield) as a brown oil
used without further purification.
[0539] MS (ES) m/e 366 (M+H).sup.+
b) N-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]cyclopropane
sulfonamide
##STR00138##
[0541] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
by N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]cyclopropane
sulfonamide (0.38 mmol; 140 mg), the title compound was prepared in
94% yield (0.36 mmol; 126 mg) after purification by preparative TLC
(cyclohexane/ethyl acetate--7/3).
[0542] MS (ES) m/e 352 (M+H).sup.+
[0543] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.19 (d, 1H, J=11.8
Hz); 6.97 (m, 2H); 6.87 (m, 2H); 6.72 (d, 1H, J=8.3 Hz); 6.66 (dd,
1H, J.sub.1=8.3 Hz, J.sub.2=2.0 Hz); 2.59 (q, 2H, J=7.6 Hz); 2.51
(m, 1H); 1.24-1.17 (m, 5H); 1.03-0.98 (m; 2H)
Example 53
5-ethyl-2-{4-[(3-hydroxybutyl)sulfonyl]phenoxy}phenol
a) 4-{[4-(4-ethyl-2-methoxyphenoxy)phenyl]sulfonyl}butan-2-ol
##STR00139##
[0545] According to the procedure of example 49(a) except
substituting 1-BOC-2-Pyrrolidinone for propylene oxide (0.2 mL; 2.8
mmol), the title compound (200 mg; 0.56 mmol; 100%) was prepared as
a yellow oil, used without purification.
[0546] MS (ES) m/e 365 (M+H).sup.+
b) 5-ethyl-2-{4-[(3-hydroxybutyl)sulfonyl]phenoxy}phenol
##STR00140##
[0548] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 4-{[4-(4-ethyl-2-methoxyphenoxy)phenyl]sulfonyl}butan-2-ol (200
mg; 0.56 mmol), the title compound (11 mg; 0.03 mmol; 6%) was
prepared as a clear oil, after purification by preparative TLC
(dichloromethane/ethyl acetate).
[0549] MS (ES) m/e 351 (M+H).sup.+
[0550] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.81 (d, 2H, J=8.9
Hz); 7.08 (d, 2H, J=8.9 Hz); 6.90 (d, 2H, J=9.9 Hz); 6.75 (d, 1H,
J=8.2 Hz); 5.6 (sl, 1H); 3.90 (m, 1H); 3.21 (m, 2H); 2.63 (q, 2H,
J=7.6 Hz); 1.91 (m, 1H); 1.74 (m, 1H); 1.26 (t, 3H, J=7.6 Hz); 1.20
(d, 3H, J=6.2 Hz).
Example 54
2-(2-amino-5-methylphenoxy)-5-ethylphenol
a) 4-ethyl-2-methoxy-1-(5-methyl-2-nitrophenoxy)benzene
##STR00141##
[0552] According to the procedure of example 20(a) except
substituting 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for
2-fluoro-4-nitrotoluene (157 mg; 1 mmol), the title compound (258
mg; 90%) was prepared as a yellow oil after purification by
preparative TLC (cyclohexane/ethyl acetate: 7/3).
[0553] MS (ES) m/e 288 (M+H).sup.+.
b) 4-ethyl-2-methoxy-1-[(3-methyl-5-amino)phenoxy]benzene
##STR00142##
[0555] According to the procedure of example 50(b) except
substituting 4-(4-ethyl-2-methoxyphenoxy)-2-fluoroaniline and
2-(4-ethyl-2-methoxyphenoxy)-4-fluoroaniline for
4-ethyl-2-methoxy-1-[(5-methyl-2-nitro)phenoxy]benzene (257 mg,
0.90 mmol), the title compound was prepared as a brown oil (167 mg;
72%), after purification by preparative TLC (cyclohexane/ethyl
acetate: 7/3).
[0556] MS (ES) m/e 258 (M+H).sup.+.
c) 2-(2-amino-5-methylphenoxy)-5-ethylphenol
##STR00143##
[0558] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 2-(4-ethyl-2-methoxyphenoxy)-4-methylaniline (66.4 mg, 0.26
mmol), the title compound was prepared as a brown solid (4.9 mg;
8%), after purification by preparative TLC (cyclohexane/ethyl
acetate: 7/3).
[0559] MS (ES) m/e 244 (M+H).sup.+
[0560] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 6.89 (d, 1H, J=2
Hz); 6.83 (d, 1H, J=8 Hz); 6.79 (d, 1H, J=8 Hz); 6.75 (d, 1H, J=8
Hz); 6.68 (s, 1H); 6.66 (d, 1H, J=2 Hz); 2.61 (q, 2H, J=7.6 Hz);
2.21 (s, 3H); 1.24 (t, 3H, 1.24 Hz).
Example 55
2-(2-Fluoropyridin-3yloxy)-5-propylphenol
a) 3-(2-Methoxy-4-propylphenoxy)-2-nitropyridine
##STR00144##
[0562] According to the procedure of example 21 (a3) except
substituting 4-ethyl-2-methoxyphenol by 2-methoxy-4-propylphenol
(1.93 g, 11.61 mmol), the title compound was prepared in 86% yield
(2.6 g) after purification on silica gel (eluant ethyl acetate/pet
ether 15:85) as a pale yellow liquid.
[0563] .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.16 (d, J=4.4 Hz,
1H), 7.42 (dd, J=8.4 Hz, J=4.4 Hz, 1H), 7.23 (d, J=8.4 Hz 1H), 7.05
(d, J=7.8 Hz, 1H), 6.8-6.83 (m, 2H), 3.74 (s, 3H), 2.61 (t, J=7.4
Hz, 2H), 1.62-1.7 (m, 2H), 0.97 (t, J=7.4 Hz, 3H)
[0564] LC-MS m/z 289.1 (M+H).sup.+
b) 3-(2-Methoxy-4-propylphenoxy)-2-aminopyridine
##STR00145##
[0566] To a stirred solution of
3-(4-propyl-2-methoxyphenoxy)-2-nitropyridine (1.1 g, 3.8 mmol) in
methanol (15 ml) was added anhydrous Ferric chloride (55 mg, 5% by
wt) and activated charcoal (55 mg, 5% by wt). The resulting mixture
was heated to reflux and hydrazine hydrate (570 mg, 11.45 mmol) was
added dropwise. The reaction was allowed to stir under reflux
condition overnight, then filtered through celite. The filtrate was
concentrated under reduced pressure, taken in ethyl acetate (150
ml). The organic layer was washed with water followed by brine,
dried over, anhydrous sodium sulfate and concentrated under reduced
pressure. The residue was passed through silica column (eluant
ethylacetate/pet ether 1:3 to get 900 mg (91.3%) of title compound
as a pale yellow solid.
[0567] .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.74 (d, J=5.1 Hz,
1H), 6.9 (d, J=8 Hz, 1H), 6.8-6.83 (m, 2H), 6.76 (d, J=8.12 Hz,
1H), 6.56 (dd, J=7.8 Hz, J=5.2 Hz, 2H), 5.09 (bs, 2H), 3.82 (s,
3H), 2.59 (t, J=7.4 Hz, 2H), 1.60-1.66 (m, 2H), 0.97 (t, J=7.3 Hz,
3H)
[0568] LC-MS m/z 259.1 (M+H).sup.+
c) 2-(2-Aminopyridin-3-yloxy)-5-propylphenol
##STR00146##
[0570] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 3-(2-methoxy-4-propylphenoxy)pyridin-2-amine (0.9 g, 3.48
mmol), the title compound (0.52 g; 61%) was obtained.
[0571] .sup.1H NMR (DMSO-d6), .delta. (ppm): 9.4 (s, D2O
exchangeable, 1H), 7.59 (d, J=4.9 Hz, 1H), 6.83 (d, J=8.08 Hz, 1H),
6.77 (d, J=1.6 Hz, 1H), 6.66-6.61 (m, 2H), 6.43 (dd, J=7.6 Hz,
J=4.88 Hz, 1H), 5.82 (bs, D2O exchangeable, 2H), 2.46 (t, J=7.6 Hz,
2H), 1.58-1.52 (m, 2H), 0.88 (t, J=7.3 Hz, 3H)
[0572] LC-MS m/z 244.8 (M+H).sup.+
Example 56
N-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenyl]-4-morpholin-4-yl-4-oxo-b-
utyramide
a)
1-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]pyrrolidine-2,5-dione
##STR00147##
[0574] To 2-(4-aminophenoxy)-5-ethyl-4-fluorophenol (785 mg, 3
mmol) were added toluene (1.5 mL) and succinic anhydride (360.3 mg,
3.6 mmol). The reaction was left to stir for 3 days at 110.degree.
C. under argon, then concentrated, dissolved in dichloromethane,
washed with a saturated solution of NaHCO.sub.3 and a solution of
KOH (1 M) and extracted with dichloromethane. Combined organic
phases were dried over Na.sub.2SO.sub.4, concentrated in vacuo, to
give the title product as a white solid (624.3 mg; 61%), after
purification on silica gel (dichloromethane).
[0575] MS (ES) m/e 344 (M+H).sup.+
b)
N-[4-(4-Ethyl-2-methoxy-phenoxy)-3-fluoro-phenyl]-4-morpholin-4-yl-4-ox-
o-butyramide
##STR00148##
[0577] To
1-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]pyrrolidine-2,5-d-
ione (40.4 mg, 0.12 mmol) were added acetonitrile (120 .mu.L) and
morpholine (20 .mu.L, 0.24 mmol). The reaction mixture was stirred
at 30.degree. C. for 3 days under argon, then concentrated,
dissolved in ethyl acetate, washed with saturated NH.sub.4Cl and
extracted with ethyl acetate. Combined organic phases were dried
over Na.sub.2SO.sub.4, concentrated in vacuo, to give the title
product (45.1 mg; 87%) after purification by preparative TLC
(dichloromethane/methanol: 9/1).
[0578] MS (ES) m/e 431 (M+H).sup.+
c)
N-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenyl]-4-morpholin-4-yl-4-ox-
o-butyramide
##STR00149##
[0580] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for
N-[4-(4-Ethyl-2-methoxy-phenoxy)-3-fluoro-phenyl]-4-morpholin-4-yl-4-oxo--
butyramide (45 mg, 0.10 mmol), the title compound was prepared as a
white solid (29 mg; 69%), after purification by preparative TLC
(dichloromethane/methanol: 95/5).
[0581] MS (ES) m/e 417 (M+H).sup.+
[0582] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.64 (dd, 1H,
J.sub.1=2.4 Hz, J.sub.2=12.4 Hz); 7.10-7.07 (m, 1H); 6.97 (t, 1H,
J=8.8 Hz); 6.89 (d, 1H, J=1.6 Hz); 6.68 (d, 1H, J=8.0 Hz); 6.63
(dd, 1H, J.sub.1=2 Hz, J.sub.2=8.4 Hz), 3.73-3.66 (m, 8H),
2.76-2.73 (m, 4H), 2.60 (q, 2H, J=1.6 Hz), 1.23 (t, 3H, J=1.6
Hz).
Example 57
2-fluoro-6-[(3-fluoro-4-ethyl-6-hydroxy)phenoxy)]pyridine
a) 2-(4-bromo-5-fluoro-2-methoxyphenoxy)-6-fluoropyridine
##STR00150##
[0584] According to the procedure of example 20(a) except
substituting 2-methoxy-4-propylphenol for
4-bromo-5-fluoro-2-methoxyphenol (441 mg; 2 mmol), and
1-fluoro-4-nitro-2-(trifluoromethyl)benzene for
2,6-Difluoropyridine (0.18 mL; 2 mmol), the title compound was
prepared as a yellow oil (246 mg; 39%), after purification on
silica gel (cyclohexane/ethyl acetate: 95/5).
[0585] MS (ES) m/e 317 (M+H).sup.+.
b) 2-fluoro-6-(5-fluoro-2-methoxy-4-vinylphenoxy)pyridine
##STR00151##
[0587] To 2-(4-bromo-5-fluoro-2-methoxyphenoxy)-6-fluoropyridine
(227 mg, 0.71 mmol) were added
[1,1'-Bis(diphenylphosphino)ferrocene] dichloropalladium(II)
complex with dichloromethane (58.9 mg, 0.07 mmol) and potassium
carbonate (597 mg, 4.26 mmol). To the mixture were added
acetonitrile (4 mL), water (1.3 mL) and vinyl boronic acid pinacol
ester (180 .mu.L, 1.07 mmol). The reaction was flushed with argon,
and left to stir for 3 days at 60.degree. C. The reaction mixture
was then filtered on celite, rinsed with dichloromethane and
concentrated. After purification by preparative TLC
(cyclohexane/ethyl acetate: 70/30), the title product was isolated
as an orange oil (166 mg, 89%).
[0588] MS (ES) m/e 264 (M+H).sup.+.
c) 2-fluoro-6-[(3-fluoro-4-ethyl-6-methoxy)phenoxy)]pyridine
##STR00152##
[0590] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for
2-fluoro-6-[(3-fluoro-4-vinyl-6-methoxy)phenoxy)]pyridine (166 mg;
0.63 mmol) and tetrahydrofurane for ethanol (2 mL), the title
product was isolated (145.4 mg, 87%) after purification by
preparative TLC (cyclohexane/ethyl acetate: 80/20).
[0591] MS (ES) m/e 266 (M+H).sup.+.
d) 2-fluoro-6-[(3-fluoro-4-ethyl-6-hydroxy)phenoxy)]pyridine
##STR00153##
[0593] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 2-fluoro-6-[(3-fluoro-4-ethyl-6-methoxy)phenoxy)]pyridine (145
mg, 0.55 mmol), the title compound (120.5 mg; 87%) was prepared as
an oil, after purification by preparative TLC (cyclohexane/ethyl
acetate: 7/3).
[0594] MS (ES) m/e 252 (M+H).sup.+
[0595] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.83 (q, 1H, J=8
Hz); 6.92 (d, 1H, J=7.6 Hz); 6.84 (d, 2H, J=9.6 Hz); 6.70 (dd, 1H,
J=8 Hz); 2.65 (q, 2H, J=7.6 Hz); 1.26 (t, 3H, J=3.6 Hz).
Example 58
2-(4-{[2-(1,3-dioxolan-2-yl)ethyl]sulfonyl}phenoxy)-5-ethylphenol
a)
2-{2-[4-(4-Ethyl-2-methoxy-phenoxy)-benzenesulfonyl]-ethyl}-[1,3]dioxol-
ane
##STR00154##
[0597] According to the procedure of example 49(a) except
substituting 1-BOC-2-Pyrrolidinone for 2-Bromomethyl-1,3-dioxolane
(0.05 mL; 0.47 mmol), the title compound (152 mg; 0.39 mmol; 100%)
was prepared as a yellow oil, used without purification.
[0598] MS (ES) m/e 393 (M+H).sup.+
b)
2-(4-{[2-(1,3-dioxolan-2-yl)ethyl]sulfonyl}phenoxy)-5-ethylphenol
##STR00155##
[0600] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 2-{2-[4-(4-Ethyl-2-methoxy-phenoxy)-benzene
sulfonyl]-ethyl}-[1,3]dioxolane (152 mg; 0.39 mmol), the title
compound (3 mg; 0.02 mmol; 2%) was prepared as a clear oil, after
purification by preparative TLC (dichloromethane/ethyl
acetate).
[0601] MS (ES) m/e 379 (M+H).sup.+
[0602] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.86 (d, 2H, J=8.8
Hz); 7.12 (d, 2H, J=8.8 Hz); 6.95 (d, 1H, J=1.7 Hz); 6.92 (d, 1H,
J=8.2 Hz); 6.78 (d, 1H, J=8.2 Hz); 4.97 (t, 1H, J=3.9 Hz); 3.94 (m,
2H); 3.85 (m, 2H); 3.23 (m, 2H); 2.66 (q, 2H, J=7.6 Hz); 2.10 (m,
2H); 1.26 (t, 3H, J=7.6 Hz).
Example 59
(5R)-3-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluoro
phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one
a) [4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenyl]-carbamic acid
benzyl ester
##STR00156##
[0604] According to the procedure of example 44(a) except
substituting 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline for
4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluoroaniline (200 mg; 0.59
mmol) and ethylchloroformate by benzylchloroformate (150 .mu.L;
0.73 mmol), the title compound (300 mg; quantitative) was prepared
as a brown solid and used without further purification.
[0605] MS (ES) m/e 494 (M+Na).sup.+
b)
(5R)-3-[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenyl]-5-hydroxymethy-
l-oxazolidin-2-one
##STR00157##
[0607] To a solution of
[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenyl]-carbamic acid
benzyl ester (0.31 mmol; 145 mg), under argon, in dry THF cooled to
-78.degree. C., was added n-Butyl lithium 2.3M in THF (0.46 mmol;
200 .mu.L). the reaction mixture was stirred ten minutes and
(R)-glycidyl butyrate (0.34 mmol; 48 .mu.L) was added. The reaction
was stirred overnight with slow warming to room temperature. The
mixture was treated with saturated NH.sub.4Cl and extracted with
ethyl acetate. Combined organic phases were dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The title compound (70
mg; 52%) was obtained as . . . after purification by preparative
TLC (eluant: dichloromethane/methanol: 95/5).
[0608] MS (ES) m/e 438 (M+H).sup.+
c)
(5R)-3-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]-5-(hydroxylmethyl)-
-1,3-oxazolidin-2-one
##STR00158##
[0610] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for
(5R)-3-[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenyl]-5-hydroxymethyl--
oxazolidin-2-one (0.16 mmol; 70 mg), the title compound (0.12 mmol;
41 mg; 73%) was obtained as a white solid after purification by
preparative TLC (dichloromethane/methanol: 9/1).
[0611] MS (ES) m/e 438 (M+H).sup.+
[0612] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.55 (dd, 1H,
J.sub.1=12.6 Hz, J.sub.2=2.6 Hz); 7.10-7.07 (m, 1H); 6.98 (t, 1H,
J=8.9 Hz); 6.88 (d, 1H, J=1.6 Hz); 6.68 (d, 1H, J=6.7 Hz); 6.63
(dd, 1H, J.sub.1=8.3 Hz, J.sub.2=1.7 Hz); 4.74 (m, 1H); 4.02-3.96
(m, 3H); 3.75 (dd, 1H, J.sub.1=12.7 Hz, J.sub.2=3.7 Hz); 2.58 (q,
2H, J=7.6 Hz); 1.21 (t, 3H, J=7.6 Hz).
Example 60
5-Aminomethyl-3-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]oxazolidin-2--
one
a)
3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-5-hydroxymethyloxazol-
idin-2-one
##STR00159##
[0614] According to the procedure of example 59(b) except
substituting (R)-glycidyl butyrate for (R,S)-glycidyl butyrate
(0.43 mmol; 60 .mu.L), the title compound (240 mg; quantitative)
was prepared and used without further purification.
[0615] MS (ES) m/e 438 (M+Na).sup.+
b) Methanesulfonic acid
3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylme-
thyl ester
##STR00160##
[0617] To a solution of 3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluoro
phenyl]-5-hydroxymethyloxazolidin-2-one (240 mg, 0.54 mmol) in 5 ml
of dry dichloromethane and 0.16 ml (1.1 mmol) of triethylamine,
cooled to 0.degree. C., was added a solution of methanesulfonyl
chloride (0.06 ml, 0.76 mmol) in 0.5 ml of dichloromethane
dropwise. The reaction was allowed to warm to rt overnight. The
reaction mixture was diluted with 20 ml water, 20 ml of
dichloromethane were added and the layers separated. The aqueous
layer was extracted with dichloromethane and the combined
dichloromethane fraction was dried over anhydrous Na.sub.2SO.sub.4
and concentrated. The crude residue obtained was column purified
over silica gel using 20% ethyl acetate in petroleum ether as
eluant to get 120 mg, 42.8% of the title compound.
[0618] LC-MS m/z 516.1 (M+H).sup.+
c)
5-Azidomethyl-3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-oxazoli-
din-2-one
##STR00161##
[0620] To a solution of methanesulfonic acid
3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylme-
thyl ester (120 mg, 0.23 mmol) in 2 ml of dry DMF under nitrogen
was added sodium azide (57 mg, 0.88 mmol). The reaction mixture was
stirred at 75.degree. C. overnight. The reaction mixture was
diluted with 15 ml water and extracted with ethyl acetate. The
combined organic phase was washed with water, saturated brine
solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated in
vacuo to get 100 mg of the title compound which was used as such
for the next step.
d) 5-Aminomethyl-3-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluoro
phenyl]oxazolidin-2-one
##STR00162##
[0622] To a solution of
5-Azidomethyl-3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluoro
phenyl]-oxazolidin-2-one (100 mg, 0.16 mmol), in 15 ml of ethyl
acetate, under nitrogen, was added palladium (10% Pd/C, 10 mg) and
the mixture was stirred at rt under hydrogen overnight. The
reaction mixture was filtered through celite and the residue was
washed thoroughly with ethyl acetate. The combined filtrate was
concentrated and the obtained crude compound was column purified
over silica gel using a mixture of 5% methanol in chloroform as
eluant to obtain 70 mg 74.4% of the reduced product
5-Aminomethyl-3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-oxazolidi-
n-2-one.
[0623] Debenzylation of this 70 mg was achieved by repeating the
reaction using methanol as solvent, to obtain 30 mg, 54.1% of the
title compound.
[0624] .sup.1H NMR (CD.sub.3OD), .delta. (ppm): 7.64 (dd, J=13.12,
J=2.6 Hz, 1H), 7.17-7.14 (m, 1H), 6.87 (t, J=9 Hz, 1H), 6.8 (d,
J=1.96 Hz, 1H), 6.74 (d, J=8.16 Hz, 1H), 6.64 (dd, J=8.16 Hz,
J=1.88 Hz, 1H), 4.74-4.70 (m, 1H), 4.12 (t, J=8.96 Hz, 1H), 3.82
(dd, J=8.96 Hz, J=6.8 Hz, 1H), 2.99-2.92 (m, 2H), 2.57 (q, J=7.6
Hz, 2H), 1.22 (t, J=7.6 Hz, 3H)
[0625] LC-MS m/z 347.1 (M+H).sup.+
Example 61
N-{3-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluoro
phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide
##STR00163##
[0627] To a solution of
5-Aminomethyl-3-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]-oxazolidin--
2-one (10 mg, 0.028 mmol) in 2 ml of dry dichloromethane, cooled to
0.degree. C., was added acetic anhydride (3 mg, 0.028 mmol) taken
in 0.2 ml of dichloromethane. The reaction mixture was warmed to rt
and stirred for 5 minutes until reaction was complete on TLC. The
reaction mixture was diluted with 3 ml of water and the layers
separated. The aqueous layer was extracted with dichloromethane and
the combined organic fraction was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The crude residue obtained was
purified by preparative HPLC (Column: C18 Symmetry (300.times.19
mm), 7.mu., Mobile phase A: 20 mM ammonium acetate, Mobile phase B:
Acetonitrile) to get 6 mg, 55.2% of the title compound.
[0628] .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.58 (d, J=12.4,
1H), 7.09-7.02 (m, 2H), 6.9 (s, 1H), 6.71-6.64 (m, 2H), 6.15 (bs,
1H), 4.79 (bs, 1H), 4.04 (t, J=8.1 Hz, 1H), 3.80-3.62 (m, 3H), 2.57
(q, J=7.6 Hz, 2H), 2.25 (s, 3H), 1.22 (t, J=7.6 Hz, 3H)
[0629] LC-MS m/z 389.2 (M+H).sup.+
Example 62
2-(4-aminophenoxy)-5-ethyl-4-fluorophenol
a) 4-[(3-fluoro-4-bromo-6-methoxy)phenoxy)]nitrobenzene
##STR00164##
[0631] According to the procedure of example 20(a) except
substituting 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for
4-fluoronitrobenzene (210 .mu.L; 2 mmol) and
2-methoxy-4-ethylphenol for 4-bromo-5-fluoro-2-methoxyphenol (444
mg; 2 mmol), the title compound (527 mg; 77%) was prepared as a
light yellow solid after purification on silica gel
(cyclohexane/ethyl acetate: 95/5).
b) 4-[(3-fluoro-4-vinyl-6-methoxy)phenoxy)]nitrobenzene
##STR00165##
[0633] According to the procedure of example 57(b) except
substituting 2-(4-bromo-5-fluoro-2-methoxyphenoxy)-6-fluoro
pyridine for 4-[(3-fluoro-4-bromo-6-methoxy)phenoxy)]nitrobenzene
(200.3 mg, 0.58 mmol), the title product was isolated as an orange
oil (129.7 mg, 77%) after purification by preparative TLC
(cyclohexane/ethyl acetate: 70/30).
[0634] MS (ES) m/e 290 (M+H).sup.+.
c) 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)aniline
##STR00166##
[0636] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for
4-[(3-fluoro-4-vinyl-6-methoxy)phenoxy)]nitrobenzene (129 mg; 0.44
mmol) and tetrahydrofurane for ethanol (3 mL), the title compound
was isolated as an oil (45 mg, 39%) after purification by
preparative TLC (cyclohexane/ethyl acetate: 70/30).
[0637] MS (ES) m/e 262 (M+H).sup.+.
d) 2-(4-aminophenoxy)-5-ethyl-4-fluorophenol
##STR00167##
[0639] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)aniline (44 mg, 0.17
mmol), the title compound (7.9 mg; 19%) was prepared as a brown
powder, after purification by preparative TLC (cyclohexane/ethyl
acetate: 7/3).
[0640] MS (ES) m/e 248 (M+H).sup.+
[0641] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 6.89 (d, 2H, J=8.8
Hz); 6.84 (d, 1H, J=7.2 Hz); 6.70 (d, 2H, J=9.2 Hz); 6.55 (d, 1H,
J=10.4 Hz); 2.60 (q, 2H, J=7.6 Hz); 1.21 (t, 3H, J=7.6 Hz).
Example 63
2-(4-amino-2-fluorophenoxy)-5-[2-(3-thienyl)ethyl]phenol
a) 4-bromo-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene
##STR00168##
[0643] According to the procedure of example 21 (a3) except
substituting 4-Ethyl-2-methoxy phenol by 4-bromogualacol (2.51
mmol; 510 mg) and 3-Fluoro-2-nitropyridine by
3,4-difluoronitrobenzene (2.76 mmol; 305 .mu.L), the title compound
was prepared as a clear oil in quantitative yield (855 mg) and used
without further purification.
b) 4-(4-bromo-2-methoxyphenoxy)-3-fluoroaniline
##STR00169##
[0645] According to the procedure of example 50(b) except
substituting 4-ethyl-1-(3-fluoro-4-nitrophenoxy)-2-methoxy benzene
and 4-ethyl-1-(5-fluoro-2-nitrophenoxy)-2-methoxy benzene for
4-bromo-1-(2-fluoro-4-nitrophenoxy)-2-methoxy benzene (1.88 mmol;
644 mg), the title compound (87%, 512 mg) was obtained as a red
oil, and used without further purification.
[0646] MS (ES) m/e 312, 314 (M+H).sup.+
c) 2-(4-amino-2-fluorophenoxy)-5-bromophenol
##STR00170##
[0648] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 4-(4-bromo-2-methoxyphenoxy)-3-fluoroaniline (1.64 mmol; 512
mg), the desired compound was prepared as a dark solid in 72% yield
(350 mg) and used without further purification.
[0649] MS (ES) m/e 297, 299 (M+H.sup.+)
d) O,N,N-triBoc-2-(4-amino-2-fluorophenoxy)-5-bromophenol
##STR00171##
[0651] To a solution of 2-(4-amino-2-fluorophenoxy)-5-bromophenol
(0.62 mmol; 185 mg) in dry dichloromethane (3 mL), under argon,
were added to 0.degree. C. diisopropylethylamine (2.01 mmol; 350
.mu.L) and (Boc).sub.2O (2.01 mmol, 439 mg). The reaction was
stirred with a gradual warming to room temperature. The mixture was
treated with saturated NH.sub.4Cl and extracted with
dichloromethane. Combined organic layers were dried over
Na.sub.2SO.sub.4 and concentrated in vacuo to give a brown oil
(quantitative, 363 mg) used without further purification.
[0652] MS (ES) m/e 620, 622 (M+Na.sup.+)
e) O,N-diBoc-2-(4-amino-2-fluorophenoxy)-5-(3-thienyl
ethynyl)phenol
##STR00172##
[0654] According to the procedure of example 11(a) except
substituting 5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine by
O,N,N-triBoc-2-(4-amino-2-fluorophenoxy)-5-bromophenol (0.62 mmol;
363 mg) and 3-butyn-1-ol by 3-ethynylthiophene (1.55 mmol; 153
.mu.L), the title compound was obtained as a yellow solid (60%, 195
mg) after purification on silica gel (cyclohexane/ethyl acetate
gradient).
[0655] MS (ES) m/e 548 (M+Na).sup.+
f)
O,N-diBoc-2-(4-amino-2-fluorophenoxy)-5-[2-(3-thienyl)ethyl]phenol
and
O,N-diBoc-2-(4-amino-2-fluorophenoxy)-5-[(E)-2-(3-thienyl)vinyl]phenol
##STR00173##
[0657] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for
O,N,N-triBoc-2-(4-amino-2-fluorophenoxy)-5-bromophenol (0.37 mmol;
195 mg) and THF by ethanol, a mixture of title compounds (167 mg;
.apprxeq.80%) was obtained as a yellow oil, used without further
purification.
[0658] MS (ES) m/e 550, 552 (M+H).sup.+
g) 2-(4-amino-2-fluorophenoxy)-5-[2-(3-thienyl)ethyl]phenol and
2-(4-amino-2-fluorophenoxy)-5-[(E)-2-(3-thienyl)vinyl]phenol
##STR00174##
[0660] To a mixture of
O,N-diBoc-2-(4-amino-2-fluorophenoxy)-5-[2-(3-thienyl)ethyl]phenol
and
O,N-diBoc-2-(4-amino-2-fluorophenoxy)-5-[(E)-2-(3-thienyl)vinyl]phenol
(0.31 mmol; 162 mg) in dry THF (2 mL), cooled to 0.degree. C. under
argon, was added TFA (13 mmol, 1 mL). The reaction was stirred
overnight with gradual warming to rt. The mixture was treated with
saturated NaHCO.sub.3 and extracted with ethyl acetate. Combined
organic layers were dried and concentrated in vacuo, the title
mixture was obtained (44 mg, .apprxeq.43%) as a white solid after
purification on preparative TLC.
[0661] MS (ES) m/e 328, 330 (M+H).sup.+
h) 2-(4-amino-2-fluorophenoxy)-5-[2-(3-thienyl)ethyl]phenol
##STR00175##
[0663] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene by
a mixture of
2-(4-amino-2-fluorophenoxy)-5-[2-(3-thienyl)ethyl]phenol and
2-(4-amino-2-fluorophenoxy)-5-[(E)-2-(3-thienyl)vinyl]phenol (0.13
mmol; 44 mg), and THF by ethanol, the title compound was prepared
in 14% yield (0.02 mmol; 6 mg) as a brown oil after purification by
preparative TLC (cyclohexane/ethyl acetate--7/3).
[0664] MS (ES) m/e 330 (M+H).sup.+
[0665] .sup.1H RMN (MeOD) .delta. (ppm): 7.27 (dd, 1H, J.sub.1=4.9
Hz, J.sub.2=3.0 Hz); 6.98 (m, 1H); 6.93 (dd, 1H, J.sub.1=4.9 Hz,
J.sub.2=1.2 Hz); 6.79 (t, 1H, J=8.9 Hz); 6.73 (d, 1H, J=1.3 Hz);
6.57-6.52 (m, 3H); 6.46 (ddd, 1H, J.sub.1=8.6 Hz, J.sub.2=2.6 Hz,
J.sub.3=1.2 Hz); 2.91-2.87 (m, 2H); 2.82-2.78 (m, 2H).
Example 64
5-ethyl-2-[2-fluoro-4-(methylsulfonyl)phenoxy]phenol
a) 4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl methyl sulfone
##STR00176##
[0667] According to the procedure of example 20(a) except
substituting 1-fluoro-4-nitro-2-(trifluoromethyl)benzene for
1,2-difluoro-4-(methylsulphonyl)benzene (310 mg; 1.6 mmol), the
title compound (581 mg; 100%) was prepared as a light brown solid,
used without further purification.
[0668] MS (ES) m/e 325 (M+H).sup.+.
b) 5-ethyl-2-[2-fluoro-4-(methylsulfonyl)phenoxy]phenol
##STR00177##
[0670] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl methyl sulfone (63
mg; 0.19 mmol), the title compound (38 mg; 0.12%) was prepared as a
clear oil, after purification by preparative. TLC
(dichloromethane/ethyl acetate).
[0671] MS (ES) m/e 311 (M+H).sup.+
[0672] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.73 (dd, 1H,
J.sub.1=9.7 Hz, J.sub.2=2.1 Hz); 7.61 (d, 1H, J=8.6 Hz); 7.03 (t,
1H, J=8.5 Hz); 6.94 (s, 1H); 6.89 (d, 1H, J=8.2 Hz); 6.77 (dd, 1H,
J.sub.1=8.2 Hz; J.sub.2=2.0 Hz); 5.65 (sl, 1H); 3.07 (s, 3H); 2.64
(q, 2H, J=7.6 Hz); 1.25 (t, 3H, J=7.6 Hz).
Example 65
4-(4-ethyl-2-hydroxyphenoxy)-3-fluorobenzene sulfonamide
a) 4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzenesulfonyl
chloride
##STR00178##
[0674] NaNO.sub.2 (1.5 mmol; 103 mg) was slowly added to a solution
of 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (1.0 mmol; 261 mg)
in acetonitrile (8 mL), AcOH (0.8 mL), and conc. HCl (0.5 mL),
under argon at 0.degree. C., in the dark. After 30 min. stirring,
this solution was slowly added to a solution of H.sub.2SO.sub.3 (50
mmol; 4 mL), and NaCl (10 mmol; 580 mg) cooled to 0.degree. C.
CuCl.sub.2 (2 mmol; 268 mg) was slowly added. The reaction was
stirred with slow warming to room temperature for 3 hr, then heated
to 50.degree. C. for 30 min. Cooled to 0.degree. C., the mixture
was slowly hydrolysed with conc NH.sub.3, extracted with
dichloromethane (3*5 mL). Combined organic phases were dried over
Na.sub.2SO.sub.4, concentrated, to yield a brown oil (344 mg; 1.0
mmol; quantitative), used as such in the following reactions.
[0675] MS (ES) m/e 341 (M-Cl+MeOH)
b) 4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzenesulfonamide
##STR00179##
[0677] Conc. NH.sub.3 (5.0 mmol; 0.28 mL) was slowly added to a
solution of 4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzenesulfonyl
chloride (1.0 mmol; 344 mg) in THF (5 mL), under argon at 0.degree.
C. The reaction was stirred overnight with slow warming to room
temperature. Diluted with ethyl acetate (5 mL), the mixture was
washed with HCl (1N), and sat. NH.sub.4Cl. The organic phase was
dried over MgSO.sub.4, concentrated. The residue was purified by
chromatography (dichloromethane/ethyl acetate gradient) to yield
the title compound as an off-white solid (108 mg; 0.33 mmol;
33%).
[0678] MS (ES) m/e 326 (M+H).sup.+
c) 4-(4-ethyl-2-hydroxyphenoxy)-3-fluorobenzenesulfonamide
##STR00180##
[0680] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 4-(4-ethyl-2-hydroxyphenoxy)-3-fluorobenzene sulfonamide (108
mg; 0.33 mmol), the title compound (18 mg; 0.06 mmol; 18%) was
obtained as a white solid, after purification by preparative TLC
(dichloromethane/ethyl acetate).
[0681] MS (ES) m/e 311 (M+H).sup.+
[0682] .sup.1H RMN (MeOD) .delta. (ppm): 7.76 (dd, 1H, J.sub.1=10.5
Hz, J.sub.2=2.0 Hz); 7.61 (d, 1H, J=8.6 Hz); 6.96 (d, 1H, J=8.2
Hz); 6.90-6.86 (m, 2H); 6.77 (d, 1H, J=8.2 Hz); 2.66 (q, 2H, J=7.6
Hz); 1.29 (t, 3H, J=7.6 Hz).
Example 66
5-ethyl-2-{2-fluoro-4-[(pyridin-3-ylmethyl)amino]phenoxy}phenol
a) 4-(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-(pyridin-3-yl
methyl)aniline
##STR00181##
[0684] To 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline (261.2 mg, 1
mmol) were added methanol (4 mL) and nicotinaldehyde (120 .mu.L,
1.2 mmol). The reaction was stirred at 30.degree. C. for 17 h under
argon. To the reaction mixture was added NaBH.sub.4 (38 mg, 1
mmol). The reaction was stirred at 30.degree. C. for 4 h under
argon. The resulting mixture was concentrated in vacuo, dissolved
in dichloromethane, washed with a saturated solution of NH.sub.4Cl
and extracted with dichloromethane. Combined organic phases were
dried over Na.sub.2SO.sub.4, concentrated in vacuo, to give the
title product as a yellow oil (160.5 mg; 46%), after purification
by preparative TLC (cyclohexane/ethyl acetate: 7/3).
[0685] MS (ES) m/e 353 (M+H).sup.+
b)
5-ethyl-2-{2-fluoro-4-[(pyridin-3-ylmethyl)amino]phenoxy}phenol
##STR00182##
[0687] According to the procedure of example 5(b) except
substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for
4-(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-(pyridin-3-ylmethyl)aniline
(63.5 mg, 0.18 mmol), the title product as a brown solid (9.5 mg;
12%), after purification by preparative TLC
(dichloromethane/methanol: 9/1).
[0688] MS (ES) m/e 339 (M+H).sup.+
[0689] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 8.65 (s, 1H); 8.57
(d, 1H, J=4 Hz); 7.53 (d, 1H, J=8 Hz); 7.32 (m, 1H); 6.95 (t, 1H,
J=8 Hz); 6.87 (s, 1H); 6.62 (m, 2H); 6.45 (dd; 1H; J.sub.1=12.4 Hz,
J.sub.2=2.8 Hz); 6.37 (dd, 1H, J.sub.1=12 Hz, J.sub.2=4 Hz); 4.36
(s, 2H); 2.58 (q, 2H, 7.6 Hz); 1.22 (t, 3H, J=7.6 Hz).
Example 67
4-(4-ethyl-2-hydroxyphenoxy)-3-fluoro-N-(2-hydroxy
ethyl)benzenesulfonamide
a)
4-(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-(2-methoxyethyl)benzenesulfonam-
ide
##STR00183##
[0691] According to the procedure of example 65(b) except
substituting NH.sub.3 for 2-Methoxyethylamine (0.33 mL; 3.8 mmol),
the title compound (118 mg; 0.30 mmol; 32%) was obtained as a
yellow oil, after purification by chromatography
(cyclohexane/dichloromethane gradient).
[0692] MS (ES) m/e 384 (M+H).sup.+
b)
4-(4-ethyl-2-hydroxyphenoxy)-3-fluoro-N-(2-hydroxyethyl)benzenesulfonam-
ide
##STR00184##
[0694] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 4-(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-(2-methoxy
ethyl)benzenesulfonamide (116 mg; 0.30 mmol), the title compound
(45 mg; 0.13 mmol; 42%) was obtained as a clear oil, after
purification by preparative TLC (dichloromethane/ethyl
acetate).
[0695] MS (ES) m/e 356 (M+H).sup.+
[0696] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.63 (dd, 1H,
J.sub.1=10.0 Hz, J.sub.2=2.0 Hz); 7.50 (d, 1H, J=8.7 Hz); 6.94-6.87
(m, 3H); 6.73 (d, 1H, J=8.3 Hz); 5.64 (t, 1H, J=5.8 Hz); 3.64 (t,
2H, J=4.7 Hz); 3.05 (q, 2H, J=4.8 Hz); 2.61 (q, 2H, J=7.6 Hz); 1.24
(t, 3H, J=7.6 Hz).
Example 68
5-ethyl-2-{2-fluoro-4-[(1H-imidazol-2-ylmethyl)amino]phenoxy}phenol
a)
4-(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-(1H-imidazol-2-ylmethyl)aniline
##STR00185##
[0698] According to the procedure of example 66(a) except
substituting nicotinaldehyde for 1H-imidazole-2-carboxaldehyde (119
mg, 1.2 mmol), the title compound was prepared as a light yellow
solid (288.2 mg; 85%), after purification by preparative TLC
(dichloromethane/methanol: 9/1).
[0699] MS (ES) m/e 342 (M+H).sup.+
b)
5-ethyl-2-{2-fluoro-4-[(1H-imidazol-2-ylmethyl)amino]phenoxy}phenol
##STR00186##
[0701] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for
4-(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-(1H-imidazol-2-ylmethyl)aniline
(288 mg, 0.84 mmol), the title compound was prepared as a brown oil
(72.3 mg; 26%), after purification by preparative TLC
(dichloromethane/methanol: 9/1).
[0702] MS (ES) m/e 328 (M+H).sup.+
[0703] .sup.1H NMR (MeOD) .delta. (ppm): 7.04 (s, 2H); 6.87 (t, 1H,
J=8.8 Hz); 6.79 (d, 1H, J=1.2 Hz); 6.61-6.51 (m, 3H); 6.44 (dd, 1H,
J.sub.1=8.8 Hz, J.sub.2=2.0 Hz); 4.41 (s, 2H); 2.58 (q, 2H, 7.6
Hz); 1.24 (t, 3H, 7.6 Hz).
Example 69
N-{[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]sulfonyl}acetamide
a)
N-{[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]sulfonyl}acetamide
##STR00187##
[0705] To a solution of
4-(4-ethyl-2-hydroxyphenoxy)-3-fluorobenzenesulfonamide (0.28 mmol;
90 mg) in anhydrous dichloromethane (1 mL), under argon were added
EDAC (0.36 mmol; 69 mg), DMAP (0.31 mmol; 38 mg) and acetic acid
(0.36 mmol; 0.02 mL). The reaction was stirred overnight at room
temperature. Diluted with dichloromethane (3 mL), the mixture was
washed with HCl (1N; 3 mL). The organic phase was dried over
MgSO.sub.4, concentrated to yield the desired compound as a yellow
foam (90 mg; 0.25 mmol; 89%), used as such in the following
reaction.
[0706] MS (ES) m/e 368 (M+H).sup.+
b)
N-{[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]sulfonyl}acetamide
##STR00188##
[0708] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for
N-{[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]sulfonyl}acetamide
(90 mg; 0.25 mmol), the title compound (46 mg; 0.13 mmol; 52%) was
obtained as a clear oil, after purification by preparative TLC
(dichloromethane/ethyl acetate).
[0709] MS (ES) m/e 354 (M+H).sup.+
[0710] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.81 (dd, 1H,
J.sub.1=9.9 Hz, J.sub.2=2.0 Hz); 7.70 (d, 1H, J=8.7 Hz); 6.96-6.86
(m, 3H); 6.75 (d, 1H, J=8.2 Hz); 2.62 (q, 2H, J=7.6 Hz); 2.06 (s,
3H); 1.25 (t, 3H, J=7.6 Hz).
Example 70
N-{2-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-benzenesulfonylamino]-ethyl}--
acetamide
a) N-{2-[4-(4-Ethyl-2-methoxy-phenoxy)-3-fluoro-benzene
sulfonylamino]-ethyl}-acetamide
##STR00189##
[0712] N-Acetylethylenediamine (1.1 mmol; 0.10 mL) was slowly added
to a solution of
4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzenesulfonyl chloride (0.94
mmol; 325 mg) and TEA (2.8 mmol; 0.40 mL) in anhydrous THF (5 mL),
under argon at 0.degree. C. The reaction was stirred overnight with
progressive warming to room temperature. Concentrated, the mixture
was purified by chromatography (dichloromethane/methanol/ammonia
gradient) to yield the title compound as a yellow oil (142 mg; 0.35
mmol; 37%) used as such in the following reaction.
[0713] MS (ES) m/e 411 (M+H).sup.+
b) N-{2-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-benzene
sulfonylamino]-ethyl}-acetamide
##STR00190##
[0715] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for N-{2-[4-(4-Ethyl-2-methoxy-phenoxy)-3-fluoro-benzene
sulfonylamino]-ethyl}-acetamide (142 mg; 0.35 mmol), the title
compound (44 mg; 0.11 mmol; 32%) was obtained as a clear oil, after
purification by preparative TLC (dichloromethane/methanol).
[0716] MS (ES) m/e 397 (M+H).sup.+
[0717] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.58 (dd, 1H,
J.sub.1=10.0 Hz, J.sub.2=2.0 Hz); 7.44 (d, 1H, J=8.7 Hz); 6.91-6.88
(m, 2H); 6.84 (t, 1H, J=8.2 Hz); 6.74-6.68 (m, 2H); 6.10 (br, 1H);
3.23 (br, 2H); 2.98 (br, 2H); 2.59 (q, 2H, J=7.6 Hz); 1.88 (s, 3H);
1.24 (t, 3H, J=7.6 Hz).
Example 71
4-(4-ethyl-2-hydroxyphenoxy)-3-fluoro-N-propyl
benzenesulfonamide
a) 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorobenzenesulfonyl
chloride
##STR00191##
[0719] According to the procedure of example 65(a) except
substituting 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline for
4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluoroaniline (1.3 g; 3.8 mmol),
the title compound (1.51 g; 3.6 mmol; 95%) was obtained as a brown
oil used without purification in the following reaction.
[0720] MS (ES) m/e 417 (M-Cl+MeOH).sup.+
b)
4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-propyl-benzenesulfonamide
##STR00192##
[0722] According to the procedure of example 65(b) except
substituting 4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzene sulfonyl
chloride for 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorobenzene
sulfonyl chloride and NH.sub.3 for propylamine (1.7 mmol; 0.14 mL),
the title compound (140 mg; 0.32 mmol; 41%) was obtained as a brown
oil after purification on preparative TLC (dichloromethane).
[0723] MS (ES) m/e 444 (M+H).sup.+
c) 4-(4-ethyl-2-hydroxyphenoxy)-3-fluoro-N-propyl
benzenesulfonamide
##STR00193##
[0725] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for
4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-propyl-benzenesulfonamide
(140 mg; 0.32 mmol) and tetrahydrofurane for ethanol (3 mL), the
title compound (70 mg; 62%) was obtained as a clear oil, after
purification on preparative TLC (dichloromethane)
[0726] MS (ES) m/e 354 (M+H).sup.+
[0727] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.65 (dd, 1H,
J.sub.1=10.0 Hz, J.sub.2=2.1 Hz); 7.54 (d, 1H, J=9.5 Hz); 6.95 (t,
1H, J=8.5 Hz); 6.93 (d, 1H, J=1.9 Hz); 6.87 (d, 1H, J=8.2 Hz); 6.75
(d, 1H, J=8.2 Hz); 5.84 (br, 1H); 4.92 (t, 2H, J=6.1 Hz); 2.92 (q,
2H, J=6.5 Hz); 2.63 (q, 2H, J=7.6 Hz); 1.51 (se, 2H, J=7.2 Hz);
1.24 (t, 3H, J=7.6 Hz); 0.88 (t, 3H, J=7.5 Hz).
Example 72
N-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]-4-hydroxybutanamide
a)
N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]-4-hydroxybutanamide
##STR00194##
[0729] To
1-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]pyrrolidine-2,5-d-
ione (169.8 mg, 0.49 mmol) was added methanol (2 mL). The reaction
mixture was stirred for 1 h 30 at room temperature under argon.
Acetonitrile (2 mL) and NaBH.sub.4 (190.7 mg, 4.9 mmol) were added
to the reaction. The reaction mixture was stirred at 50.degree. C.
for 17 h. Then it was concentrated, dissolved in dichloromethane,
washed with a saturated solution of NH.sub.4Cl and extracted with
dichloromethane. Combined organic phases were dried over
Na.sub.2SO.sub.4, concentrated in vacuo, to give the title product
as a white solid used without further purification (169.5 mg;
100%).
[0730] MS (ES) m/e 348 (M+H).sup.+
[0731] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for
N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]-4-hydroxybutanamide
(47.9 mg, 0.14 mmol), the title compound was prepared as a
colorless oil (16.5 mg; 35%), after purification by preparative TLC
(dichloromethane/methanol: 9/1).
[0732] MS (ES) m/e 334 (M+H).sup.+
[0733] .sup.1H NMR (CD.sub.3OD) .delta. (ppm): 7.68 (dd, 1H,
J.sub.1=12.8 Hz, J.sub.2=2.4 Hz); 7.19 (m, 1H); 6.88 (m, 2H); 6.76
(d, 1H, J=8.0 Hz); 6.68 (dd, 1H, J.sub.1=8.4 Hz, J.sub.2=2.0 Hz);
3.68 (t, 2H, J=6.2 Hz); 2.62 (q, 2H, J=7.6 Hz), 2.51 (t, 2H, J=7.6
Hz), 1.96 (qt, 2H, J=6.8 Hz); 1.27 (t, 3H, 7.6 Hz).
Example 73
4-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-butyric acid
ethyl ester
a) 1-{4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenyl}ethanone
##STR00195##
[0735] According to the procedure of example 21 (a3) except
substituting 4-Ethyl-2-methoxy phenol by
2-(benzyloxy)-4-ethylphenol (1.3 g, 5.7 mmol) and
3-Fluoro-2-nitropyridine by 1-(3,4-difluorophenyl)ethanone (0.98 g,
6.27 mmol), the title compound was prepared as a clear oil in 96%
yield (2 g) and used without further purification.
[0736] LCMS m/z 365.0 (M+H)+
b) 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenyl acetate
##STR00196##
[0738] To a solution of
1-{4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenyl}ethanone (3
g,8.24 mmol) in dry dichloromethane (30 ml), was added PTSA (0.047
g, 0.247 mmol). The reaction mixture was cooled in an ice bath and
mCPBA (50% H2O) (2.84 g, 8.24 mmol) was added portionwise. The
resulting mixture was stirred at RT for 3 days, then concentrated
at 35-40 C. The residue was purified by column chromatography, (pet
ether:EtOAC). The resulting solid was dissolved in pet ether,
filtered then concentrated the yield the title compound (1.6 g;
51%)
[0739] LCMS m/z 379.2 (M-H)-
c) 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenol
##STR00197##
[0741] To a solution of
4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenyl acetate (1.6 g, 4.2
mmol) in MeOH:H.sub.2O (35 ml:35 ml), was added KOH (0.83 g, 14.8
mmol). The mixture was heated at 65.degree. C. for 4.5 hours,
concentrated in vacuo, then extracted with EtOAC (25 ml*2).
Combined organic phases were dried over Na.sub.2SO.sub.4 and
concentrated. The residue was purified by column chromatography,
(pet ether:EtOAC 95:5), to yield the title compound as a white
solid (630 mg; 44%)
[0742] LCMS m/z 336.9 (M-H)-
d) 4-[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenoxy]-butyric
acid ethyl ester
##STR00198##
[0744] To a solution of
4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorophenol (0.30 mmol; 100 mg)
in dry acetone (2 mL), under argon, were added potassium carbonate
(0.35 mmol; 49 mg), NaI (0.06 mmol; 9 mg) and ethyl bromobutyrate
(0.35 mmol; 51 .mu.L). The reaction was stirred 14 hours at
60.degree. C. Water (100 .mu.L) and tetrabutylammonium hydroxyde
(0.03 mmol; 8 mg) were added and the mixture was stirred 16 hours
at 60.degree. C. The reaction was hydrolysed with NH.sub.4Cl sat.
(5 mL) and extracted with ethyl acetate (3*3 mL). Combined organic
phases were dried over Na.sub.2SO.sub.4, concentrated in vacuo. The
title compound (100 mg; 0.22 mmol; 75%) was obtained as a yellow
oil, after purification by preparative TLC (cyclohexane/ethyl
acetate: 7/3).
[0745] MS (ES) m/e 475 (M+Na).sup.+
e) 4-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-butyric acid
ethyl ester
##STR00199##
[0747] According to the procedure of example 48(d) except
substituting
3-[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenylamino]-propan-1-ol
for 4-[4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-phenoxy]-butyric
acid ethyl ester (0.22 mmol; 100 mg) the title compound was
prepared as a clear oil (58 mg; 72%), after purification by
preparative TLC (Cyclohexane/Ethyl acetate: 7/3)
[0748] MS (ES) m/e 363 (M+H).sup.+
[0749] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.00 (t, 1H, J=9.1
Hz); 6.87 (s, 1H); 6.74 (dd, 1H, J.sub.1=12.1 Hz, J.sub.2=2.8 Hz);
6.64-6.59 (m, 3H); 4.15 (q, 2H, J=7.1 Hz); 3.98 (t, 2H, J=6.1 Hz);
2.57 (q, 2H, J=7.6 Hz); 2.51 (t, 2H, J=7.3 Hz); 2.11 (qt, 2H, J=7.0
Hz); 1.27 (t, 3H, J=7.1 Hz); 1.21 (t, 3H, J=7.6 Hz).
Example 74
4-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-butyric acid
##STR00200##
[0751] To a solution of ethyl ethyl
4-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-butyric acid
ethyl ester (0.16 mmol; 58 mg), in a THF/water mixture (1/1; 1 mL)
was added lithium hydroxide (0.64 mmol; 15 mg). The reaction was
heated 1 hour at 60.degree. C. After cooling to 0.degree. C., the
reaction was treated with concentrated HCl, and extracted with
ethyl acetate (3*2 mL). Combinated organic phases were dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. The title compound
(0.16 mmol; 54 mg; quantitative) was obtained as a clear oil, used
without purification.
[0752] MS (ES) m/e 335 (M+H).sup.+
[0753] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.00 (t, 1H, J=9.7
Hz); 6.87 (s, 1H); 6.74 (dd, 1H, J.sub.1=12.1 Hz, J.sub.2=2.8 Hz);
6.64-6.59 (m, 3H); 3.99 (t, 2H, J=6.0 Hz); 2.61-2.55 (m, 4H); 2.13
(qt, 2H, J=6.9 Hz); 1.23 (t, 3H, J=7.6 Hz).
Example 75
4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-N-(2-pyridin-2-yl-ethyl)-benzenesul-
fonamide
a)
4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-(2-pyridin-2-yl-ethyl)-benze-
ne sulfonamide
##STR00201##
[0755] According to the procedure of example 70(a) except
substituting N-Acetylethylenediamine for 2-(2-Aminoethyl)pyridine
(1.5 mmol; 0.18 mL), the title compound (150 mg; 0.30 mmol; 24%)
was obtained as a yellow oil after purification via chromatography
(gradient dichloromethane/ethyl acetate).
[0756] MS (ES) m/e 507 (M+H).sup.+
b)
4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-N-(2-pyridin-2-yl-ethyl)-benzene-
sulfonamide
##STR00202##
[0758] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for
4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-(2-pyridin-2-yl-ethyl)-benzene
sulfonamide (150 mg; 0.30 mmol) and tetrahydrofurane for ethanol (3
mL), the title compound (70 mg; 62%) was obtained as a clear oil,
after purification via preparative TLC (dichloromethane/ethyle
acetate).
[0759] MS (ES) m/e 417 (M+H).sup.+
[0760] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 8.41 (d, 1H, J=4.8
Hz); 7.62 (t, 1H, J=9.4 Hz); 7.53 (d, 1H, J=10.0 Hz); 7.45 (d, 1H,
J=8.7 Hz); 7.17-7.13 (m, 2H); 6.91-6.85 (m, 3H); 6.73 (d, 1H, J=8.2
Hz); 6.14 (br, 1H); 3.32 (t, 2H, J=5.8 Hz); 2.94 (t, 2H, J=6.3 Hz);
2.62 (q, 2H, J=7.6 Hz); 1.23 (t, 3H, J=7.6 Hz)
Example 76
4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-N-(3-imidazol-1-yl-propyl)-benzenes-
ulfonamide
a)
4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-(3-imidazol-1-yl-propyl)-ben-
zenesulfonamide
##STR00203##
[0762] According to the procedure of example 70(a) except
substituting N-Acetylethylenediamine for 1-(3-Aminopropyl)imidazole
(1.5 mmol; 0.18 mL), the title compound (160 mg; 0.31 mmol; 25%)
was obtained as a brown oil after purification by preparative TLC
(dichloromethane/methanol).
[0763] MS (ES) m/e 510 (M+H).sup.+
b)
4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-N-(3-imidazol-1-yl-propyl)-benze-
nesulfonamide
##STR00204##
[0765] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for
4-(2-Benzyloxy-4-ethyl-phenoxy)-3-fluoro-N-(3-imidazol-1-yl-propyl)-benze-
nesulfonamide (160 mg; 0.31 mmol) and tetrahydrofurane for ethanol
(3 mL), the title compound (55 mg; 42%) was obtained as a clear
oil, after purification via preparative TLC
(dichloromethane/methanol/triethylamine)
[0766] MS (ES) m/e 420 (M+H).sup.+
[0767] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.52 (d, 1H,
J.sub.1=10.0 Hz); 7.43 (d, 1H, J=8.7 Hz); 7.23 (s, 1H); 6.96-6.92
(m, 3H); 6.83-6.80 (m, 2H); 6.72 (d, 1H, J=8.2 Hz); 3.97 (t, 2H,
J=6.4 Hz); 2.81 (t, 2H, J=6.3 Hz); 2.61 (q, 2H, J=7.6 Hz); 1.94 (q,
2H, J=6.3 Hz); 1.23 (t, 3H, J=7.6 Hz)
Example 77
5-ethyl-2-(2-fluoro-4-[(1H-imidazol-4-ylmethyl)amino]phenoxy)phenol
a) 4(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-(1H-imidazol-4-yl
methyl)aniline
##STR00205##
[0769] According to the procedure of example 66(a) except
substituting nicotinaldehyde for 4(5)-imidazole carboxadehyde
(115.27 mg, 1.2 mmol), the title compound was prepared as a
colorless oil (300 mg; 88%), after purification by preparative TLC
(dichloromethane/methanol: 95/5+1% NH4+).
[0770] MS (ES) m/e 342 (M+H).sup.+
b)
5-ethyl-2-(2-fluoro-4-[(1H-imidazol-4-ylmethyl)amino]phenoxy)phenol
##STR00206##
[0772] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for
4(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-(1H-imidazol-4-ylmethyl)aniline
(300 mg, 0.87 mmol), the title compound (101 mg, 35%) was prepared
as a white solid, after purification by preparative TLC and washing
with diethyl ether (dichloromethane/methanol: 95/5+1% NH4+).
[0773] MS (ES) m/e 328 (M+H).sup.+
[0774] .sup.1H NMR (MeOD) .delta. (ppm): 7.62 (s, 1H), 6.97 (s,
1H), 6.79 (t, 1H, J=9.0 Hz), 6.71 (s, 1H), 6.51-6.50 (m, 3H), 6.42
(dd, 1H, J.sub.1=8.8 Hz, J.sub.2=3.8 Hz), 4.20 (s, 2H), 2.51 (q,
2H, J=7.6 Hz), 1.16 (t, 3H, J=7.6 Hz)
Example 78
2-[(6-fluoropyridin-2-yl)oxy]-5-[3-(1H-1,2,4-triazol-1-yl)propyl]phenol
a)
3-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}prop-2-yn-1-ol
##STR00207##
[0776] According to the procedure of example 11(a) except
substituting 5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine by
2-(4-bromo-2-methoxyphenoxy)-6-fluoropyridine (0.98 mmol; 300 mg)
and 3-butyn-1-ol by propargylic alcohol (2.50 mmol; 150 .mu.L), the
title compound was obtained as a yellow solid (71%, 191 mg) after
purification on silica gel (cyclohexane/ethyl acetate
gradient).
[0777] MS (ES) m/e 274 (M+H).sup.+
b)
3-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}prop-2-yn-ol
##STR00208##
[0779] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene by
3-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}prop-2-yn-1-ol
(0.33 mmol; 90 mg) and THF by absolute ethanol, the title compound
(quantitative, 102 mg) was obtained as a yellow oil, and used
without further purification.
[0780] MS (ES) m/e 339 (M+H).sup.+
c) 2-[4-(3-chloropropyl)-2-methoxyphenoxy]-6-fluoropyridine
##STR00209##
[0782] To a solution of
3-{4-[(6-fluoropyridin-2-yl)oxy]-3-methoxyphenyl}prop-2-yn-ol (0.37
mmol; 102 mg) in dry dichloromethane (2 mL), under argon, cooled to
-40.degree. C., was added triethylamine (0.41 mmol; 56 .mu.L) then
methanesulfonyl chloride (0.39 mmol; 30 .mu.L). The reaction
mixture was allowed to stir for 6 hr, with gradual warming to room
temperature. The reaction was hydrolysed with saturated NH.sub.4Cl,
extracted with ethyl acetate. Combined organic phases were dried
over Na.sub.2SO.sub.4, concentrated in vacuo. The title compound
(185 mg; 47%) was obtained as a light oil, after purification on
preparative TLC (cyclohexane/ethyl acetate: 7/3).
[0783] MS (ES) m/e 296(M+H).sup.+
d)
2-fluoro-6-{2-methoxy-4-[3-(1H-1,2,4-triazol-1-yl)propyl]phenoxy}pyridi-
ne
##STR00210##
[0785] To a solution of
2-[4-(3-chloropropyl)-2-methoxyphenoxy]-6-fluoropyridine (0.14
mmol) in a THF/DMF mixture (340 .mu.L/170 .mu.L), under argon, was
added NaI (0.14 mmol; 21 mg). The mixture was stirred 30 minutes at
50.degree. C., before addition of diisopropylethylamine (0.28 mmol,
36 mg) and 1,2,4-triazol (0.28 mmol; 19 mg). The reaction mixture
was allowed to stir overnight at 50.degree. C. After concentration,
the reaction was hydrolysed with saturated NH.sub.4Cl (1 mL),
extracted with AcOEt (2*1 mL). Combined organic phases were dried
over Na.sub.2SO.sub.4, concentrated in vacuo. The title compound
(15 mg; 33%) was obtained as a yellow oil after purification on
preparative TLC (dichloromethane/methanol: 9/1).
[0786] MS (ES) m/e 329 (M+H).sup.+
e)
2-[(6-fluoropyridin-2-yl)oxy]-5-[3-(1H-1,2,4-triazol-1-yl)propyl]phenol
##STR00211##
[0788] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for
2-fluoro-6-{2-methoxy-4-[3-(1H-1,2,4-triazol-1-yl)propyl]phenoxy}pyridine
(0.05 mmol; 15 mg), the desired compound was prepared in 41% yield
(6 mg) after purification by preparative TLC
(dichloromethane/methanol: 9/1).
[0789] MS (ES) m/e 315 (M+H.sup.+)
[0790] .sup.1H RMN (MeOD) .delta. (ppm): 8.48 (s, 1H); 8.02 (s,
1H); 7.85 (q, 1H, J=8.1 Hz); 6.96 (d, 1H, J=8.1 Hz); 6.79 (d, 1H,
J=1.9 Hz); 6.73-6.69 (m, 2H); 6.66 (dd, 1H, J.sub.1=7.9 Hz,
J.sub.2=2.2 Hz); 4.23 (t, 2H, J=7.0 Hz); 2.59 (t, 2H, J=7.6 Hz);
2.22 (qt, 2H, J=7.6 Hz).
Example 79
N-methanesulfonyl-N.sup.1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]pro-
pan-1,3-diamine
a)
N.sup.1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diami-
ne
##STR00212##
[0792] To 4-(2-benzyloxy-4-ethylphenoxy)-3-fluoroaniline (500 mg,
1.48 mmol) in 25 ml of ethanol was added 3-bromopropylphthalimide
(440 mg, 1.64 mmol). The mixture was refluxed for 2 days. The
reaction mixture was diluted with ethylacetate and washed with
water, saturated brine solution, dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The crude obtained was passed
through a silica gel column using 15% ethylacetate in petroleum
ether as eluant. The LCMS of the obtained mixture showed 53% mass
of the coupled product. This was taken in 25 ml of ethanol and
added 7 ml of hydrazine hydrate and refluxed overnight. Ethanol was
removed in vaccuo and added 20% KOH solution (20 ml) to the
residue. The aqueous fraction was then extracted with
dichlormethane and the combined dichloromethane fraction was dried
over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude product
obtained was purified by column chromatography using 5% methanol in
dichloromethane as eluant to obtain 110 mg (18.8% after 2 steps) of
the
N.sup.1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine-
.
[0793] LC-MS m/z 395.9 (M+H).sup.+
b)
N-Methanesulfonyl-N.sup.1-[4-(2-benzyloxy-4-ethylphenoxy)-3-fluoropheny-
l]propan-1,3-diamine
##STR00213##
[0795] To a solution of
N.sup.1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine
(90 mg, 0.23 mmol) in 5 ml of dry dichloromethane and 0.08 ml (0.57
mmol) of triethylamine, cooled to 0.degree. C., was added mesyl
chloride (26 mg, 0.23 mmol) taken in 0.5 ml of dichloromethane
dropwise. The reaction was quenched after 5 minutes as the reaction
was complete on TLC. The reaction mixture was diluted with water
and the layers separated. The aqueous layer was extracted with
dichloromethane and the combined dichloromethane fraction was
washed with water, dried over anhydrous Na.sub.2SO.sub.4 and
concentrated. The crude residue obtained was combined with the
crude obtained from an earlier 20 mg batch and column purified over
silica gel using 2% methanol in dichloromethane as eluant to get 90
mg, 68.3% of title compound.
[0796] LC-MS m/z 473.2 (M+H).sup.+
c)
N-methanesulfonyl-N.sup.1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]-
propan-1,3-diamine
##STR00214##
[0798] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for
N-Methanesulfonyl-N.sup.1-[4-(2-benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-
propan-1,3-diamine (90 mg, 0.19 mmol) and tetrahydrofurane for
methanol (15 mL), the title compound (50 mg, 68%) was obtained as a
brown liquid, after purification on silica gel
(dichloromethane/ethyl acetate: 8/2)
[0799] .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 6.93 (t, J=8.9 Hz,
1H), 6.87 (s, 1H), 6.66-6.57 (m, 3H), 6.49 (d, J=8.1 Hz, 1H), 4.78
(bs, 1H), 3.3-3.28 (m, 4H), 2.98 (s, 3H), 2.57 (q, J=7.5 Hz, 2H),
1.92 (m, 2H), 1.21 (t, J=7.5 Hz, 3H)
[0800] LC-MS m/z 383 (M+H).sup.+
Example 80
N-acetyl-N.sup.1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluoro
phenyl]propan-1,3-diamine
a)
N-acetyl-N.sup.1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan--
1,3-diamine
##STR00215##
[0802] To a solution of
N.sup.1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine
(60 mg, 0.15 mmol) in 10 ml of dry dichloromethane, cooled to
0.degree. C., was added acetic anhydride (20 mg, 0.19 mmol) taken
in 0.5 ml of dichloromethane dropwise. The reaction mixture was
warmed to rt and stirred for 1 h until reaction was complete on
TLC. The reaction mixture was diluted with water and the layers
separated. The aqueous layer was extracted with dichloromethane and
the combined dichloromethane fraction was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated. The crude residue obtained was
column purified over silica gel using 2% methanol in
dichloromethane as eluant to get 50 mg, 75.4% of title
compound.
[0803] LC-MS m/z 438.1 (M+H).sup.+
b)
N-acetyl-N.sup.1-[4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl]propan-1,-
3-diamine
##STR00216##
[0805] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for
N-acetyl-N.sup.1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,-
3-diamine (70 mg, 0.16 mmol) and tetrahydrofurane for methanol (15
mL), the title compound (50 mg, 91%) was obtained as a brown
liquid, after purification on silica gel (dichloromethane/ethyl
acetate: 5/5)
[0806] .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 6.93 (t, J=8.9 Hz,
1H), 6.86 (d, J=1.6 Hz, 1H), 6.64-6.58 (m, 2H), 6.46-6.42 (m, 1H),
6.36 (d, J=8.8 Hz, 1H), 5.64 (bs, 2H), 3.42-3.37 (m, 2H), 3.15 (t,
J=6.4 HZ, 2H), 2.57 (q, J=7.59 Hz, 2H), 2.06 (s, 3H), 1.80 (qt,
J=6.48 Hz, 2H), 1.21 (t, J=7.58 Hz, 3H)
[0807] LC-MS m/z 347.2 (M+H).sup.+
Example 81
5-Ethyl-2-[2-fluoro-4-(2-hydroxyethylamino)-phenoxy]phenol
a)
3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]oxazolidin-2-one
##STR00217##
[0809] A solution of
[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-carbamic
acid-benzyl ester (500 mg, 1.06 mmol) in 5 ml tetrahydrofuran under
nitrogen atmosphere was cooled to -78.degree. C. To this added 2.8M
n-butyl lithium (0.075 g, 1.16 mmol) dropwise and the stirring at
-78.degree. C. for 1 h. Condensed ethylene oxide (0.5 ml, 9.9 mmol)
was then added dropwise to the reaction mixture and warmed slowly
to rt. The reaction was stirred at rt overnight and then quenched
with saturated ammonium chloride solution. The aqueous phase was
extracted with dichloromethane and the combined organic phase was
dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude
obtained was purified by column chromatography on silica gel using
25% ethyl acetate in petroleum ether as eluant to obtain 350 mg,
81% of the title compound as a brown oil.
[0810] LC-MS m/z 407 (M+H).sup.+
b)
N-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-2-aminoethanol
##STR00218##
[0812] To a solution of
3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]oxazolidin-2-one
(350 mg, 0.85 mmol) in 5 ml of methanol was added barium hydroxide
(245 mg, 1.28 mmol) taken in 5 ml of water. The reaction mixture
was warmed to 65.degree. C. and stirred overnight (reaction was
complete on TLC). The reaction mixture concentrated in vacuo to
remove methanol, diluted with water and the aqueous layer was
extracted with ethyl acetate. The combined organic fraction was
washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and
concentrated to get 300 mg, 91.57% of the title compound as a brown
oil, used as such in the next step.
[0813] LC-MS m/z 382.3 (M+H).sup.+
c) 5-Ethyl-2-[2-fluoro-4-(2-hydroxyethylamino)-phenoxy]phenol
##STR00219##
[0815] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for
N-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-2-aminoethanol
(350 mg, 0.92 mmol) and tetrahydrofurane for methanol (25 mL), the
title compound (210 mg; 78%) was obtained as a yellow solid, after
purification on silica gel (ethylacetate and petroleum ether:
5/5)
[0816] .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 6.94 (t, J=8.9 Hz,
1H), 6.86 (d, J=1.2 Hz, 1H), 6.64-6.58 (m, 2H), 6.5 (dd, J=12.6 Hz,
J=2.6 Hz, 1H), 6.41 (dd, J=8.7 Hz, J=2.6 Hz, 1H), 3.87 (t, J=5.1
Hz, 2H), 3.28 (t, J=5.1 Hz, 2H), 2.57 (q, J=7.58 Hz, 2H), 1.21 (t,
J=7.58 Hz, 3H)
[0817] LC-MS m/z 292.3 (M+H).sup.+
Example 82
5-ethyl-2-[2-fluro-4-(propylamino)phenoxy]phenol
a) 4-(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-propylaniline
##STR00220##
[0819] According to the procedure of example 66(a) except
substituting nicotinaldehyde for propanaldehyde (28 .mu.l, 0.45
mmol), the title compound was prepared as a colorless oil (20 mg;
18%), after purification by preparative TLC (cyclohexane/ethyl
acetate: 80/20).
[0820] MS (ES) m/e 304 (M+H).sup.+
b) 5-ethyl-2-[2-fluro-4-(propylamino)phenoxy]phenol
##STR00221##
[0822] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 4-(4-ethyl-2-methoxyphenoxy)-3-fluoro-N-propylaniline (20 mg,
0.066 mmol), the title compound (9.4 mg, 53%) was prepared as a
white solid, after purification by preparative TLC
(cyclohexane/ethyl acetate: 80/20).
[0823] MS (ES) m/e 290 (M+H).sup.+
[0824] .sup.1H NMR (CDCl.sub.3) .delta. (ppm): 7.28 (s, 1H), 6.93
(t, 1H, J=8.8 Hz), 6.89 (d, 1H, J=1.6 Hz), 6.70-6.56 (m, 3H), 3.10
(t, 2H, J=7.5 Hz), 2.60 (q, 2H, J=7.6 Hz); 1.72 (se, 2H, J=7.3
Hz,), 1.22 (t, 3H, J=7.6 Hz), 1.02 (t, 3H, J=7.4 Hz)
Example 83
2-(4-amino-2-fluorophenoxy)-5-(2-pyridin-2-yl ethyl)phenol
a) 4-bromo-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene
##STR00222##
[0826] According to the procedure of example 21 (a3) except
substituting 4-Ethyl-2-methoxy phenol by 4-bromogualacol (2.51
mmol; 510 mg) and 3-Fluoro 2-nitro pyridine by
3,4-difluoronitrobenzene (2.76 mmol; 305 .mu.L), the title compound
was prepared as a clear oil in quantitative yield (855 mg) and used
without further purification.
b)
2-{[4-(2-fluoro-4-nitrophenoxy)-3-methoxyphenyl]ethynyl}pyridine
##STR00223##
[0828] According to the procedure of example 11(a) except
substituting 5-bromo-2-(2-methoxy-4-propylphenoxy)pyridine by
4-bromo-1-(2-fluoro-4-nitrophenoxy)-2-methoxybenzene (0.29 mmol;
100 mg) and 3-butyn-1-ol by 2-ethynylpyridine (0.73 mmol; 73
.mu.L), the title compound was prepared as a yellow solid (81%; 87
mg) after purification on preparative TLC (cyclohexane/ethyl
acetate: 7/3).
[0829] MS (ES) m/e 365 (M+H).sup.+
c) 3-fluoro-4-[2-methoxy-4-(2-pyridin-2-ylethyl)phenoxy]aniline
##STR00224##
[0831] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene by
2-{[4-(2-fluoro-4-nitrophenoxy)-3-methoxy phenyl]ethynyl}pyridine
(0.23 mmol; 84 mg) and THF by ethanol, the title compound was
obtained as a clear oil (68%, 53 mg) after purification on
preparative TLC (cyclohexane/ethyl acetate: 6/4).
[0832] MS (ES) m/e 339 (M+H).sup.+
d) 2-(4-amino-2-fluorophenoxy)-5-(2-pyridin-2-ylethyl)phenol
##STR00225##
[0834] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 3-fluoro-4-[2-methoxy-4-(2-pyridin-2-ylethyl)phenoxy]aniline
(0.16 mmol; 53 mg), the title compound was prepared as a clear oil
(45 mg; 15%) after purification by preparative TLC
(dichloromethane/methanol/ammonia: 95/5/1).
[0835] MS (ES) m/e 325 (M+H).sup.+
[0836] .sup.1H RMN (MeOD) .delta. (ppm): 8.46 (d, 1H, J=4.5 Hz);
7.78 (dt, 1H, J.sub.1=7.7 Hz, J.sub.2=1.8 Hz); 7.31-7.28 (m, 2H);
6.79 (t, 1H, J=8.9 Hz); 6.71 (s, 1H); 6.56 (dd, 1H, J.sub.1=12.7
Hz, J.sub.2=2.6 Hz); 6.51 (s, 2H); 6.47 (ddd, 1H, J.sub.1=8.7 Hz,
J.sub.2=2.6 Hz, J.sub.3=1.2 Hz); 3.08-3.04 (m, 2H); 2.93-2.87 (m,
2H)
Example 84
2-(2-aminopyridin-3yloxy)-5-ethyl-4-fluorophenol
a) 3-(4-bromo-5-fluoro-2-methoxyphenoxy)-2-nitropyridine
##STR00226##
[0838] According to the procedure of example 21 (a3) except
substituting 4-ethyl-2-methoxyphenol by
4-bromo-5-fluoro-2-methoxyphenol (1.5 g, 5.7 mmol), the title
compound was prepared in 95% yield (1.85 g) after purification on
silica gel (eluant ethyl acetate/pet ether: 1/9) as a pale yellow
solid.
[0839] .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.25 (dd, J=4.48
Hz, J=1.28 Hz, 1H), 7.48 (dd, J=8.4 Hz, J=4.48 Hz, 1H), 7.28 (m,
1H), 7.18 (d, J=6.28 Hz, 1H), 7.01 (d, J=8.04 Hz, 1H), 3.76 (s,
3H), LC-MS m/z 343.5 (M+H).sup.+
b) 3-(5-fluoro-2-methoxy-4-vinylphenoxy)-2-nitropyridine
##STR00227##
[0841] According to the procedure of example 57(b) except
substituting 2-(4-bromo-5-fluoro-2-methoxyphenoxy)-6-fluoropyridine
by 3-(4-bromo-5-fluoro-2-methoxyphenoxy)-2-nitropyridine (1.7 g,
4.9 mmol), the title compound was obtained (1.1 g; 76%) after
purification on silica gel (eluant ethyl acetate/hexane: 15/85) as
a pale yellow solid.
[0842] .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.23 (dd, J=4.4 Hz,
J=0.8 Hz, 1H), 7.47 (dd, J=8.4 Hz, J=4.8 Hz, 1H), 7.3 (dd, J=8.4
Hz, J=0.8 Hz, 1H), 7.08 (d, J=6.8 Hz, 1H), 6.91 (d, J=10 Hz, 1H),
6.85 (dd, J=17.6 Hz, J=11.2 Hz, 1H), 5.81 (d, J=17.6 Hz, 2H), 5.43
(d, J=11.2 Hz, 3H), 3.78 (s, 3H), LC-MS m/z 290.9 (M+H).sup.+
c) 3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-2-aminopyridine
##STR00228##
[0844] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene by
3-(5-fluoro-2-methoxy-4-vinylphenoxy)-2-nitropyridine (3.7 mmol,
1.1 g) and THF by methanol, the title compound was prepared as a
white solid (800 mg; 80.5%) and used without further
purification.
[0845] .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.82 (dd, J=4.8 Hz,
J=1.2 Hz, 1H), 6.89 (dd, J=8 Hz, J=1.2 Hz, 1H), 6.8 (d, J=6.8 Hz,
1H), 6.67 (d, J=10 Hz, 1H), 6.57-6.6.6 (m, 1H); 4.76 (bs, 2H, D2O
exchangeable), 3.82 (s, 3H), 2.66 (q, J=7.6 Hz, 2H), 1.24 (t, J=7.6
Hz, 3H)
[0846] LC-MS m/z 263 (M+H).sup.+
d) 2-(2-Aminopyridin-3yloxy)-5-ethyl-4-fluorophenol
##STR00229##
[0848] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-2-aminopyridine (400 mg,
1.53 mmol), the title compound was prepared in 86% yield (325 mg)
as a white solid after washing with hexane.
[0849] .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.85 (dd, J=5.2 Hz,
J=1.2 Hz, 1H), 6.98 (d, J=8 Hz, J=1.2 Hz, 1H), 6.89 (d, J=7.6 Hz,
1H), 6.58-6.64 (m, 2H), 4.67 (bs, 2H, D2O exchangeable), 2.62 (q,
J=7.6 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H)
[0850] LC-MS m/z 249.1 (M+H).sup.+
Example 85
2-(4-acetyl-2-fluorophenoxy)-5-ethylphenylamino acetate
hydrochloride
a) tert-Butoxycarbonylamino-acetic acid
2-(4-acetyl-2-fluoro-phenoxy)-5-ethyl-phenyl ester
##STR00230##
[0852] To a solution of
1-{4-(4-ethyl-2-hydroxyphenoxy)-3-fluorophenyl}ethanone (0.37 mmol;
100 mg) in dry THF (2 mL) cooled to 0.degree. C. were added,
N-Boc-glycine (0.37 mmol; 64 mg),
benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluoro
phosphate (0.37 mmol; 190 mg) and triethylamine (1.09 mmol; 153
.mu.L). The reaction was stirred at 0.degree. C. for 3 hours and
overnight at room temperature. The mixture was concentrated,
treated with saturated NH.sub.4Cl and extracted with
dichloromethane. Combined organic phases were washed with water,
dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The title
compound (91 mg; 58%) was obtained as clear oil after purification
on preparative TLC (cyclohexane/ethyl acetate: 7/3).
[0853] MS (ES) m/e 454 (M+Na).sup.+
b) 2-(4-acetyl-2-fluorophenoxy)-5-ethylphenylaminoacetate
hydrochloride
##STR00231##
[0855] To a solution of tert-Butoxycarbonylamino-acetic acid
2-(4-acetyl-2-fluoro-phenoxy)-5-ethyl-phenyl ester (0.21 mmol; 91
mg) in dry dioxane (1 mL) cooled to 0.degree. C., was added
HCl/dioxane 4M (0.84 mmol; 211 .mu.L). The reaction was stirred
overnight at room temperature. A precipitate was formed. The
mixture was cooled to 0.degree. C., filtered and the solid was
washed with diethylether. This white solid was dried in vacuo to
give the title compound (8%; 7 mg).
[0856] .sup.1H RMN (MeOD) .delta. (ppm): 7.85 (dd, 1H, J.sub.1=11.5
Hz, J.sub.2=2.0 Hz); 7.78 (d, 1H, J=8.7 Hz); 7.23-7.20 (m, 2H);
7.06-7.02 (m, 2H); 4.06 (s, 2H); 2.70 (q, 2H, J=7.6 Hz); 2.57 (s,
3H); 1.27 (t, 3H, J=7.6 Hz).
Example 86
1-[4-(4-ethyl-2-hydroxyphenoxy)phenyl]-4-hydroxy butan-1-one
a) 4-fluoro-N-methoxy-N-methylbenzamide
##STR00232##
[0858] To a solution of N,O-dimethylhydroxylamine (1.51 mmol; 147
mg) in dry THF (3 mL), under argon, was added at -78.degree. C.
nbutyllithium 2.5M (3.02 mmol; 1.21 mL). The mixture was stirred
minutes at -78.degree. C., before addition of 4-fluorobenzoyl
chloride (1.26 mmol; 150 .mu.L). The reaction was stirred overnight
at room temperature, then treated with saturated NH.sub.4Cl and
extracted with ethyl acetate. Combined organic layers were washed
with water, dried over Na.sub.2SO.sub.4 and concentrated in vacuo,
to give the title compound (66%; 173 mg) as a yellow oil used
without further purification.
[0859] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.78 (m, 2H); 7.10
(t, 2H, J=8.7 Hz); 3.56 (s, 3H); 3.38 (s, 3H).
b) 3-(1,3-dioxan-2-yl)-1-(4-fluorophenyl)propan-1-one
##STR00233##
[0861] To a solution of 4-fluoro-N-methoxy-N-methylbenzamide (0.94
mmol; 173 mg) in anhydrous THF (2 mL), at -78.degree. C. under
argon, was added a solution of (1,3-dioxan-2-ylethyl)magnesium
bromide, 0.5M in THF (1.04 mmol; 2.1 mL). The reaction was stirred
16 hours at room temperature. The mixture was cooled to -78.degree.
C. and (1,3-dioxan-2-ylethyl)magnesium bromide, 0.5M in THF (2.00
mmol; 4 mL) was added again. The reaction was stirred overnight at
room temperature. The mixture was treated with saturated NH.sub.4Cl
and extracted with ethyl acetate. The organic layer was washed with
water, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The
title compound was prepared in quantitative yield, used without
further purification.
[0862] MS (ES) m/e 239 (M+H).sup.+
c)
1-[4-(4-ethyl-2-methoxyphenoxy)phenyl]-3-(1,3-dioxan-2-yl)-1-phenylprop-
an-1-one
##STR00234##
[0864] According to the procedure of example 21(a3) except
substituting 3-Fluoro 2-nitro pyridine by
3-(1,3-dioxan-2-yl)-1-(4-fluorophenyl)propan-1-one (0.94 mmol; 401
mg), the title compound was obtained (42%, 149 mg) as a yellow oil
after purification on preparative TLC (cyclohexane/ethyl acetate:
8/2).
[0865] MS (ES) m/e 371 (M+H).sup.+
d)
3-(1,3-dioxan-2-yl)-1-[4-(4-ethyl-2-hydroxyphenoxy)phenyl]propan-1-one
and 4-[4-(4-ethyl-2-hydroxyphenoxy)phenyl]-4-oxobutanal
##STR00235##
[0867] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for
1-[4-(4-ethyl-2-methoxyphenoxy)phenyl]-3-(1,3-dioxan-2-yl)-1-phenylpropan-
-1-one (0.25 mmol; 91 mg), the following compounds were obtained
after purification by preparative TLC (cyclohexane/ethyl acetate:
7/3):
[0868]
3-(1,3-dioxan-2-yl)-1-[4-(4-ethyl-2-hydroxyphenoxy)phenyl]propan-1--
one (11 mg; 13%) as a white solid
[0869] MS (ES) m/e 357 (M+H).sup.+
[0870] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.95 (d, 2H, J=8.9
Hz); 7.00 (d, 2H, J=8.9 Hz); 6.91 (d, 1H, J=1.9 Hz); 6.87 (d, 1H,
J=8.2 Hz); 6.73 (dd, 1H, J.sub.1=8.2 Hz, J.sub.2=1.9 Hz); 5.46 (sl,
1H); 4.66 (t, 1H, J=4.9 Hz); 4.09 (dd, 2H, J.sub.1=10.7 Hz,
J.sub.2=4.9 Hz); 3.76 (td, 2H, J.sub.1=12.1 Hz, J.sub.2=2.4 Hz);
3.05 (t, 2H, J=7.2 Hz); 2.63 (q, 2H, J=7.6 Hz); 2.06-2.01 (m, 3H);
1.33 (d, 1H, J=13.4 Hz); 1.22 (t, 3H, J=7.6 Hz).
[0871] 4-[4-(4-ethyl-2-hydroxyphenoxy)phenyl]-4-oxobutanal (12.5
mg; 17%) as a clear oil.
[0872] MS (ES) m/e 299(M+H.sup.+)
e) 1-[4-(4-ethyl-2-hydroxyphenoxy)phenyl]-4-hydroxybutan-1-one
##STR00236##
[0874] To a suspension of NaBH.sub.4 (0.052 mmol; 2 mg) in dry
methanol, under argon at -78.degree. C., (0.5 mL) was added
4-[4-(4-ethyl-2-hydroxyphenoxy)phenyl]-4-oxobutanal (0.040 mmol; 12
mg). The reaction was stirred 5 hours with gradual warming to
-5.degree. C., and treated with acetic acid. The mixture was
diluted with water and extracted with ethyl acetate. Combined
organic layers were dried over Na.sub.2SO.sub.4 and concentrated in
vacuo. The title compound was obtained as a clear oil (7.6 mg; 63%)
after purification on preparative TLC (cyclohexane/ethyl acetate:
5/5).
[0875] MS (ES) m/e 301(M+H.sup.+)
[0876] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.30 (d, 2H, J=8.5
Hz); 6.97 (d, 2H, J=8.6 Hz); 6.89 (d, 1H, 1.9 Hz); 6.80 (d, 1H,
J=8.2 Hz); 6.68 (dd, 1H, J.sub.1=8.1 Hz, J.sub.2=2.0 Hz); 4.70 (t,
1H, J=6.3 Hz); 3.69 (se, 2H, J=5.8 Hz); 2.61 (q, 2H, J=7.6 Hz);
1.85 (q, 2H, J=6.6 Hz); 1.68 (se, 2H, J=7.0 Hz); 1.23 (t, 3H, J=7.6
Hz).
Example 87
5-Ethyl-4-fluoro-2-(2-fluoropyridin-3yloxy)phenol
a) 5-Ethyl-4-fluoro-2-(2-fluoropyridin-3yloxy)phenol
##STR00237##
[0878] To a stirred solution of
2-(2-aminopyridin-3yloxy)-5-ethyl-4-fluorophenol (45 mg, 0.18 mmol)
in glacial acetic acid (2.5 ml) was added 0.36 ml of
tetrafluoroboric acid (48% in water). The reaction mixture was
cooled to 0.degree. C. and sodium nitrite (18 mg, 0.27 mmol) was
added at 0.degree. C. and stirred at 0.degree. C. for 1.5 hours
until reaction was complete on TLC. The reaction mixture was
quenched by adding ice and sodium bicarbonate solution and stirred
for 10 minutes before extracting the aqueous solution with
ethylacetate. The combined ethyl acetate fraction was washed with
saturated sodium bicarbonate solution, water, followed by brine,
dried over anhydrous sodium sulfate and concentrated in vacuo to
get the crude compound. The crude material was column purified over
silica gel using Petroleum ether/ethyl acetate 9:1 as eluant and
then further purified by preparative HPLC using 0.1% TFA in water
and acetonitrile as solvent system to get 8 mg (17.6%) of
5-Ethyl-4-fluoro-2-(2-fluoropyridin-3yloxy)phenol as a white
solid.
[0879] .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 8.01-8.98 (m, 1H),
7.43-7.39 (m, 1H), 7.17-7.20 (m, 1H), 6.91 (d, J=7.2 Hz, 1H), 6.57
(d, J=9.6 Hz, 1H), 5.35 (s, 1H, D2O exchangeable), 2.63 (q, J=7.5
Hz, 2H), 1.25 (t, J=7.5 Hz, 3H)
[0880] LC-MS m/z 252 (M+H)
[0881] Alternatively the title compound can be synthesized from
3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-2-aminopyridine of step c)
of example 84 according to following steps:
b) 3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-2-fluoropyridine
##STR00238##
[0883] To a stirred solution of
3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-2-aminopyridine (1.5 g, 5.7
mmol) in glacial acetic acid (10 ml) was added 12 ml of
tetrafluoroboric acid (48% in water). The reaction mixture was
cooled to 0.degree. C. and sodium nitrite (590 mg, 8.5 mmol) was
added at 0.degree. C. and stirred at 0.degree. C. for 45 minutes
until reaction was complete on TLC. Formation of 2 compounds was
observed on the TLC. The colourless reaction mixture turned pale
yellow and then to deep yellow during this time. The reaction
mixture was quenched by adding ice and sodium bicarbonate solution
and the aqueous solution was extracted with ethyl acetate. The
combined ethyl acetate fraction was washed with water, followed by
brine, dried over anhydrous sodium sulfate and concentrated in
vacuo to get the crude compound. The crude material was column
purified over silica gel using pet ether/ethyl acetate 9:1 as
eluant to obtain the first fraction yielding 610 mg, 40.39% of the
title compound 3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-2-fluoro
pyridine as a colourless liquid. The column was then eluted with
100% ethyl acetate to collect the second fraction that gave 620 mg,
41.3% of the
3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-pyridin-2-ol.
3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-2-fluoropyridine
[0884] .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.90-7.89 (m, 1H),
7.20 (t, J=8 Hz, 1H), 7.1-7.07 (m, 1H), 6.82 (d, J=6.96 Hz, 1H),
6.73 (d, J=9.68 Hz, 1H), 3.8 (s, 3H), 2.67 (q, J=7.53 Hz, 2H), 1.25
(t, J=7.58 Hz, 3H)
[0885] LC-MS m/z 266.2 (M+H).sup.+
3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-pyridin-2-ol
[0886] .sup.1H NMR (CDCl.sub.3), .delta. (ppm): 7.15 (d, J=6.44 Hz,
1H), 6.82-6.78 (m, 2H), 6.72 (d, J=7.2 Hz, 1H), 6.17 (t, J=7.2 Hz,
1H), 3.81 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz,
3H)
[0887] LC-MS m/z 264.1 (M+H).sup.+
c) 5-Ethyl-4-fluoro-2-(2-fluoropyridin-3yloxy)phenol
##STR00239##
[0889] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
by 3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-2-fluoro pyridine (610
mg, 2.3 mmol), the title compound was prepared in 81% yield (470
mg) as a white solid after washing with hexane.
Example 88
N-Ethyl-4-(4-ethyl-2-hydroxy-phenoxy)-3-fluoro benzene
sulfonamide
a) 4-(2-Benzyloxy-4-ethyl-phenoxy)-N-ethyl-3-fluoro-benzene
sulfonamide
##STR00240##
[0891] According to the procedure of example 70(a) except
substituting N-Acetylethylenediamine for ethylamine.HCl ((8.4 mmol;
700 mg), the title compound (402 mg; 0.94 mmol; 25%) was obtained
as a yellow oil, after purification on silica gel (gradient
cyclohexane/dichloromethane/ethyle acetate).
[0892] MS (ES) m/e 430 (M+H).sup.+
b) N-Ethyl-4-(4-ethyl-2-hydroxy-phenoxy)-3-fluoro benzene
sulfonamide
##STR00241##
[0894] According to the procedure of example 20(b) except
substituting
4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene for
4-(2-Benzyloxy-4-ethyl-phenoxy)-N-ethyl-3-fluoro-benzene
sulfonamide (402 mg; 0.94 mmol) and tetrahydrofurane for ethanol (4
mL), the title compound (140 mg; 44%) was obtained as a clear oil,
after purification on preparative TLC (dichloromethane).
[0895] MS (ES) m/e 340 (M+H).sup.+
[0896] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.63 (d, 1H, J=10.0
Hz); 7.53 (d, 1H, J=8.7 Hz); 6.95 (d, 1H, J=8.2 Hz); 6.92 (s, 1H);
6.87 (d, 1H, J=8.2 Hz); 6.74 (d, 1H, J=8.2 Hz); 6.03 (br, 1H); 5.01
(t, 1H, J=5.9 Hz); 3.00 (qt, 2H, J=7.0 Hz); 2.62 (q, 2H, J=7.6 Hz);
1.23 (t, 3H, J=7.6 Hz); 1.10 (t, 3H, J=7.3 Hz).
Example 89
5-[(3-fluoropyridin-4-yl)methyl]-2-[(6-fluoro
pyridin-2-yl)oxy]phenol
a)
[4-(tert-Butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-(3-fluoro-pyridin-
-4-yl)-methanol
##STR00242##
[0898] To a solution of 3-fluoropyridine (2.3 mmol; 220 mg), under
argon, in anhydrous THF (1 mL) cooled to -78.degree. C., was added
nBuLi (2.3 mmol; 1 mL). The reaction was stirred 1 hr at
-78.degree. C. then a solution of vanilline-OTBS (2.3 mmol; 600 mg)
in THF (1 mL) was added. The reaction was allowed to warm up to
room temperature overnight. Hydrolysed by NH.sub.4Cl sat. (3 mL),
the mixture was extracted with dichloromethane (3 mL) and ethyl
acetate (2*3 mL). Combined organic phases were dried over
MgSO.sub.4, concentrated to yield a light brown solid. Heating in
diethyl ether, then filtering afforded the title compound as a
white solid (125 mg; 0.34 mmol; 15%) used without further
purification.
[0899] MS (ES) m/e 364 (M+H).sup.+
b) 4-[(3-fluoropyridin-4-yl)methyl]-2-methoxyphenol
##STR00243##
[0901] Pd/C (0.02 mmol; 40 mg) was added to a solution of
[4-(tert-Butyl-dimethyl-silanyloxy)-3-methoxy-phenyl]-(3-fluoro-pyridin-4-
-yl)-methanol (0.19 mmol; 70 mg) in methanol (2 mL) and
H.sub.2SO.sub.4 (0.5 mL). The mixture was flushed twice with
hydrogen, and the reaction was stirred overnight at 35.degree. C.
The mixture was filtered on celite, washed with methanol. After
concentration, water was added (3 mL) and K.sub.2CO.sub.3 until pH
8. The aqueous phase was extracted with ethyl acetate (2*3 mL).
Combined organic phases were dried over MgSO.sub.4, concentrated to
yield the title compound as a white solid (32 mg; 0.14 mmol; 71%)
used as such.
[0902] MS (ES) m/e 234 (M+H).sup.+
c)2-fluoro-6-{4-[(3-fluoropyridin-4-yl)methyl]-2-methoxyphenoxy}pyridine
##STR00244##
[0904] According to the procedure of example 21(a3) except
substituting 4-Ethyl-2-methoxy phenol for
4-[(3-fluoropyridin-4-yl)methyl]-2-methoxyphenol (60 mg; 0.26
mmol), the title compound (85 mg; 100%) was prepared as a brown
oil, used without any purification.
[0905] MS (ES) m/e 329 (M+H).sup.+
d)
5-[(3-fluoropyridin-4-yl)methyl]-2-[(6-fluoropyridin-2-yl)oxy]phenol
##STR00245##
[0907] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for
2-fluoro-6-{4-[(3-fluoropyridin-4-yl)methyl]-2-methoxyphenoxy}pyridine
(85 mg; 0.26 mmol), the title compound (23 mg; 28%) was prepared as
a clear oil, after purification by preparative TLC
(dichloromethane/ethyl acetate).
[0908] MS (ES) m/e 315 (M+H).sup.+
[0909] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 8.37 (s, 1H); 8.27
(d, 1H, J=4.7 Hz); 7.76 (q, 1H, J=8.0 Hz); 7.12 (t, 1H, J=5.7 Hz);
7.06 (d, 1H, J=8.2 Hz); 6.83 (d, 1H, J=1.8 Hz); 6.79-6.75 (m, 2H);
6.62 (dd, 1H, J.sub.1=7.9 Hz, J.sub.2=2.1 Hz); 3.98 (s, 2H).
Example 90
3-(4-Ethyl-5-fluoro-2-hydroxyphenoxy)-pyridin-2-ol
##STR00246##
[0911] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 3-(4-Ethyl-5-fluoro-2-methoxy-phenoxy)-pyridin-2-ol (50 mg,
0.19 mmol), the title compound (25 mg; 53%) was prepared as a white
solid, after washing with hexane twice and with diethylether MS
(ES) m/e 315 (M+H).sup.+
[0912] .sup.1H NMR (CD.sub.3OD), .delta. (ppm): 7.18 (d, J=6.5 Hz,
1H), 6.96 (d, J=7.4 Hz, 1H), 6.81 (d, J=7.4 Hz, 1H), 6.74 (d,
J=10.1 Hz, 1H), 6.32 (t, J=6.98 Hz, 1H), 2.6 (q, J=7.5 Hz, 2H), 1.2
(t, J=7.5 Hz, 3H)
[0913] LC-MS m/z 250 (M+H).sup.+
Example 91
2-amino-N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]ethanesulfonamide
a) 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid
[4-(4-ethyl-2-methoxy-phenoxy)-3-fluoro-phenyl]-amide
##STR00247##
[0915] According to the procedure of example 42(a) except
substituting 3-chloropropanesulfonyle chloride by 2-phtalimido
ethanesulfonyl chloride (0.46 mmol; 125 mg), the title compound
(77%; 147 mg) was obtained as a white gum after purification on
preparative TLC (cyclohexane/ethyl acetate: 6/4).
[0916] MS (ES) m/e 499 (M+H).sup.+
b) 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid
[4-(4-ethyl-2-hydroxy-phenoxy)-3-fluoro-phenyl]-amide
##STR00248##
[0918] According to the procedure of example 1(b) except
substituting 6-chloro-2-(2-methoxy-4-propylphenoxy)pyridin-3-amine
for 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethane sulfonic acid
[4-(4-ethyl-2-methoxy-phenoxy)-3-fluoro-phenyl]-amide (0.30 mmol;
147 mg), the desired compound was prepared in 55% yield (79 mg)
after purification by preparative TLC (cyclohexane/ethyl acetate:
7/3).
[0919] MS (ES) m/e 485(M+H.sup.+)
[0920] .sup.1H RMN (CDCl.sub.3) .delta. (ppm): 7.86 (dd, 2H,
J.sub.1=5.5 Hz, J.sub.2=3.1 Hz); 7.75 (dd, 2H, J.sub.1=5.4 Hz,
J.sub.2=3.0 Hz); 7.43 (s, 1H); 7.23 (dd, 1H, J.sub.1=11.5 Hz,
J.sub.2=2.4 Hz); 7.01 (d, 1H, J=8.8 Hz); 6.93 (t, 1H, J=8.6 Hz);
6.88 (d, 1H, J=1.77 Hz); 6.71 (d, 1H, J=8.2 Hz); 6.65 (dd, 1H,
J.sub.1=8.3 Hz, J.sub.2=1.9 Hz); 5.82 (sl, 1H); 4.15 (t, 2H, J=6.3
Hz); 3.48 (t, 2H, J=6.2 Hz); 2.59 (q, 2H, J=7.6 Hz); 1.22 (t, 3H,
J=7.6 Hz).
c)
2-amino-N-[4-(4-ethyl-2-methoxyphenoxy)-3-fluorophenyl]ethanesulfonamid-
e
##STR00249##
[0922] According to the procedure of example 39 except substituting
2-{3-[4-(4-Ethyl-2-hydroxy-phenoxy)-3-fluoro-phenoxy]-propyl}-isoindole-1-
,3-dione by 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic
acid [4-(4-ethyl-2-hydroxy-phenoxy)-3-fluoro-phenyl]-amide (0.13
mmol; 64 mg), the title compound was obtained as a yellow oil (20%,
10 mg) after purification on preparative TLC
(dichloromethane/methanol/ammonia: 90/10/1).
[0923] MS (ES) m/e 355 (M+H).sup.+
[0924] .sup.1H RMN (MeOD) .delta. (ppm): 7.22 (dd, 1H, J.sub.1=12.3
Hz, J.sub.2=2.5 Hz); 6.99 (d, 1H, J=8.8 Hz); 6.84-6.79 (m, 2H);
6.74 (d, 1H, J=8.2 Hz); 6.64 (dd, 1H, J.sub.1=8.2 Hz, J.sub.2=1.9
Hz); 3.25 (t, 2H, J=6.7 Hz); 3.10 (t, 2H, J=6.5 Hz); 2.57 (q, 2H,
J=7.6 Hz); 1.21 (t, 3H, J=7.6 Hz).
FabI Inhibition:
[0925] The compounds of the present invention are useful inhibitors
of bacterial FabI enzyme.
[0926] Compound inhibitory activity of FabI enzyme is measured in
vitro by the IC50 determination using a fluorescent based
assay.
[0927] The protein FabI from E. coli is prepared and purified using
standard methods for recombinant protein expression after cloning
of the gene in a prokaryotic expression vector.
[0928] The biochemical activity of the FabI enzyme is assessed
using the following method.
[0929] The assay buffer "AB" contains 50 mM Hepes pH7.5, 100 .mu.M
Dithiothreitol, 0.006% Triton-X100. The following components are
added in a black polystyrene Costar plate up to a final volume of
55 .mu.L: 1.5 .mu.L DMSO, or inhibitor dissolved in DMSO and 53.5
.mu.L of a FabI/NADH/NAD+ mixture in AB. After 60 min of
pre-incubation at room temperature, the reaction is started by
addition of 5 .mu.L of Crotonoyl-CoA to a final volume of 60 .mu.L.
This reaction mixture is then composed of 40 nM FabI (produced in
house from E. coli, C-terminal 6-His tagged), 20 .mu.M NADH
(Biochemika), 10 .mu.M NAD+ (Biochemika), 50 .mu.M Crotonoyl-CoA
(Biochemika) and compound at defined concentration. Fluorescence
intensity of NADH (l.sub.ex=360 nm, l.sub.em=520 nm) is measured
immediately after Crotonoyl-CoA addition, and 2 hours later by a
Fluostar Optima (BMG). Enzyme activity is proportional to the
signal decrease from which inhibition percentages are derived. For
IC.sub.50 determinations, the inhibitor is tested at 6 to 10
different concentrations, and the related inhibitions are fitted to
a classical langmuir equilibrium model using XLFIT (IDBS).
[0930] In Vitro Inhibition of Recombinant E. coli FabI Enzyme by
Selected Compounds of Formula (I).
TABLE-US-00001 Examples IC.sub.50 (.mu.M) 5 0.97 16 0.51 21 0.069
25B 0.57 27 0.47 28 0.85 29 0.15 37 0.41 48 1 50 0.3 55 0.092 57
1.1 64 0.13 71 0.33 84 0.1 85 0.11 87 0.031
[0931] Antibacterial Activity
[0932] The compounds of the present invention are useful
antibacterial agents having a selective spectrum of activity in
vitro against standard bacterial strains which are used to screen
for activity against pathogenic bacteria. Notably the compounds of
the present invention show activity against Staphylococcus aureus
including multiresistant strains and Escherichia coli. The activity
is presented as Minimum Inhibitory Concentration (MIC) expressed in
.mu.g/ml.
[0933] Whole-cell antimicrobial activity was determined by broth
microdilution method in microtiterplates. The compound was tested
in serial 4-fold dilutions ranging from 0.06 to 64 mcg/mL. Test
organisms were selected from the following laboratory strains:
Staphylococcus aureus CIP 76.25, Staphylococcus aureus BAA39 MDR,
Staphylococcus aureus NEM 14157 PeniR, Staphylococcus aureus CIP
54.146, Escherichia coli CIP 76.24. Bacteria were tested in Tryptic
Soy (TS) or Mueller Hinton (MH) broth using an inoculum of 10.sup.4
to 10.sup.6 UFC/mL incubated at 37.degree. C. for 20 h.
[0934] The minimum inhibitory concentration (MIC) was determined as
the lowest concentration of compound at which no visible bacteria
growth is observed (90% inhibition of absorbance of at 600 nM.)
Representative Examples of MIC (.mu.g/ml)
TABLE-US-00002 [0935] Compound E. coli S. aureus S. aureus S.
aureus Example No CIP 76.24 CIP 76.25 BAA39MDR NEM14157 Triclosan
0.25 0.125 1 16 1 1 0.25 3 4 0.25 0.25 0.25 5 4 0.25 0.25 0.25 6 16
1 1 1 7 >16 2 16 4 0.25 0.25 0.25 21 0.25 0.25 0.25 0.25 27 4
0.25 0.25 0.25 25A 16 0.25 25B 4 0.062 0.062 0.062 29 1 0.062 0.062
0.062 32 16 4 34 1 0.25 0.25 0.25 35 1 0.25 37 4 0.062 0.25 0.25 38
4 0.062 0.25 1 39 16 1 1 1 47 16 0.25 48 4 0.062 52 16 1 55 1 0.25
57 4 0.25 62 4 0.25 64 1 0.25 0.062 0.062 65 1 0.25 66 16 0.25 67
16 0.25 70 16 0.25 71 4 <0.062 0.25 0.062 74 4 0.062 0.062 0.062
79 16 0.25 0.25 0.25 81 4 0.25 82 16 0.25 84 0.25 0.25 0.25 0.25 85
1 0.062 86 4 0.062 0.062 0.062 87 0.25 0.062 0.062 0.016
In Vitro Activities Against Resistant Strains of S. aureus
TABLE-US-00003 [0936] S. aureus S. aureus S. aureus S. aureus S.
aureus MIC S. aureus USA300 1651 1652 2012 2018 (.mu.g/ml) MRSA*
MRSA* LRSA* LRSA VISA VISA* Vancomycin 1 0.5 1 1 8 4 Example 21
0.12 0.5 0.12 0.5 0.12 0.25 Example 48 0.06 0.5 0.12 0.5 0.12 0.25
MRSA = Methicillin Resistant S. aureus; LRSA = Linezolid resistant
S. aureus; VISA = Vancomycin Resistant S. aureus;
[0937] In Vivo Antibacterial Activity of Compounds
[0938] An experimental model of infection by S. aureus was used to
assess the antibacterial activity of FabI inhibitors.
[0939] Briefly in vivo studies were performed using 5-6-week-old
female BALB/c@Rj mice as follows Groups of six mice are used for
each condition.
[0940] The virulent strain of Staphylococcus aureus CIP 54.146 is
grown to exponential phase in Tryptic soy (TS) broth culture. The
bacterial culture is diluted to obtain a bacterial suspension of
1.10.sup.8 UFC/ml. Then 200 .mu.l of the suspension is administered
by intraperitoneal injection to each mouse, this infecting dose has
been determined to be the LD90 (Lethal dose 90%). The inoculums
count was determined by plating 10-fold dilutions of the suspension
on TH agar plates immediately after inoculation.
[0941] Compounds to be assessed are dissolved and diluted in an
aqueous solution containing 15% cyclodextrin and 200 .mu.l of the
solution is injected sub cuteanously to each mice, just after the
infection.
[0942] For 48 hours post-infection, mice are monitored and survival
recorded at 18 h and 24 h postinfection. The negative control group
receives the 15% cyclodextrin solution alone and vancomycin at 10
mg/kg is used as the positive control.
[0943] All animal experiments were carried out in accordance with
institutional guidelines. Compound activity is measure by its
effect at a given dose on the percentage of surviving animal.
[0944] As shown in FIGS. 1 and 2 results obtained with compound
derivative of the formula are able to protect mice against the
lethal effect of bacterial multiplication.
[0945] Example of Pharmaceutical Composition:
[0946] An injectable preparation was prepared comprising 500 mg of
a compound of example 87 and sufficient quantity of aqueous sterile
excipient for preparing 10 to 50 ml of injectable solution.
[0947] Tablets have been prepared containing: [0948] 300 mg of
compound of example 21 [0949] Sufficient quantity of exipient for a
1 g tablet
[0950] Detail of the excipient, starch, talc, magnesium
stearate
* * * * *