U.S. patent application number 11/772474 was filed with the patent office on 2007-10-18 for carboxylic derivatives.
Invention is credited to Lanna Li, Eva-Lotte Lindstedt Alstermark, Christina Olsson.
Application Number | 20070244198 11/772474 |
Document ID | / |
Family ID | 27636750 |
Filed Date | 2007-10-18 |
United States Patent
Application |
20070244198 |
Kind Code |
A1 |
Li; Lanna ; et al. |
October 18, 2007 |
Carboxylic Derivatives
Abstract
The present invention provides a compound of formula I processes
for preparing such compounds, their the utility in treating
clinical conditions including lipid disorders (dyslipidemias)
whether or not associated with insulin resistance, methods for
their therapeutic use and pharmaceutical compositions containing
them.
Inventors: |
Li; Lanna; (Molndal, SE)
; Lindstedt Alstermark; Eva-Lotte; (Molndal, SE) ;
Olsson; Christina; (Molndal, SE) |
Correspondence
Address: |
FISH & RICHARDSON PC
P.O. BOX 1022
MINNEAPOLIS
MN
55440-1022
US
|
Family ID: |
27636750 |
Appl. No.: |
11/772474 |
Filed: |
July 2, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11477168 |
Jun 28, 2006 |
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11772474 |
Jul 2, 2007 |
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10518777 |
Mar 3, 2005 |
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PCT/EP04/06597 |
Jun 17, 2004 |
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11477168 |
Jun 28, 2006 |
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Current U.S.
Class: |
514/617 ;
564/161 |
Current CPC
Class: |
A61P 25/28 20180101;
C07C 233/51 20130101; A61P 35/00 20180101; C07B 2200/07 20130101;
C07C 235/22 20130101; A61P 27/02 20180101; A61P 25/00 20180101;
C07D 295/135 20130101; C07C 2601/14 20170501; C07C 309/66 20130101;
A61P 43/00 20180101; A61P 29/00 20180101; A61P 5/50 20180101; C07C
2601/04 20170501; A61P 3/06 20180101; A61P 13/12 20180101; A61P
3/04 20180101; C07C 255/46 20130101; C07C 235/20 20130101; C07C
323/56 20130101; C07C 2601/08 20170501; C07D 295/185 20130101; A61P
15/08 20180101; A61P 9/04 20180101; C07D 209/14 20130101; C07C
323/41 20130101; A61P 3/00 20180101; A61P 9/12 20180101; C07C
233/11 20130101; A61P 3/08 20180101; A61P 3/10 20180101; A61P 9/00
20180101; C07C 235/24 20130101; A61P 25/16 20180101; A61P 9/10
20180101 |
Class at
Publication: |
514/617 ;
564/161 |
International
Class: |
A61K 31/167 20060101
A61K031/167; C07C 235/16 20060101 C07C235/16 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 18, 2003 |
GB |
0314079.5 |
Claims
1-18. (canceled)
19. A compound of formula I ##STR20## as well as optical isomers
and racemates thereof as well as pharmaceutically acceptable salts,
prodrugs, solvates and crystalline forms thereof, wherein A is
situated in the para position and represents ##STR21## R is
--OR.sup.a, wherein R.sup.a represents hydrogen; R.sup.1 is
--OR.sup.e, wherein R.sup.e is alkyl R.sup.2 is hydrogen; R.sup.3
and R.sup.4 are hydrogen T represents O; n represents 1; R.sup.5 is
hydrogen; R.sup.6 independently represent hydrogen,
C.sub.1-13alkyl, C.sub.2-10alkenyl or C.sub.2-10alkynyl each of
which is optionally substituted by one or more of the following
which may be the same or different: C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkenyl, aryl, heterocyclyl, heteroaryl,
C.sub.1-8alkoxy (optionally substituted by one or more fluoro),
C.sub.3-8cycloalkoxy, C.sub.3-8cycloalkenyloxy, aryloxy,
heterocyclyloxy, heteroaryloxy, C.sub.3-8cycloalkyl
C.sub.1-8alkoxy, aryl C.sub.1-8alkoxy, heterocyclyl C.sub.1-8
alkoxy or heteroaryl C.sub.1-8 alkoxy, fluorine or hydroxy and
wherein each of these substituents may optionally be substituted on
carbon with one or more substituents which may be the same or
different and selected from C.sub.1-8alkyl, C.sub.3-8cycloalkyl
(optionally substituted by C.sub.1-8alkyl, C.sub.1-8alkoxy
(optionally substituted by one or more fluoro), halogen, hydroxy,
nitro or cyano), aryl (optionally substituted by C.sub.1-8alkyl,
C.sub.1-8alkoxy (optionally substituted by one or more fluoro),
halogen, hydroxy, nitro or cyano), heterocyclyl (optionally
substituted by C.sub.1-6alkyl on any nitrogen), heteroaryl
(optionally substituted by C.sub.1-8alkyl, C.sub.1-8alkoxy
(optionally substituted by one or more fluoro), halogen, hydroxy,
nitro or cyano), C.sub.1-8alkoxy (optionally substituted by one or
more fluoro), C.sub.3-8cycloalkoxy, C.sub.3-8 cycloalkyl
C.sub.1-8alkoxy, aryloxy (optionally substituted by C.sub.1-8alkyl,
C.sub.1-8alkoxy (optionally substituted by one or more fluoro),
halogen, hydroxy, nitro or cyano), aryl C.sub.1-8alkoxy (wherein
the aryl part is optionally substituted by C.sub.1-8alkyl,
C.sub.1-8alkoxy (optionally substituted by one or more fluoro),
halogen, hydroxy, nitro or cyano), halogen, amino, nitro, hydroxy,
methylsulfonyl, methylsulfonyloxy, cyano or methylenedioxy, or
R.sup.5 and R.sup.6 independently represent C.sub.3-C.sub.8
cycloalkyl; C.sub.3-C.sub.8 cycloalkenyl; aryl; heterocyclyl; or
heteroaryl; wherein each of these groups is optionally substituted
by one or more of the following: C.sub.1-8alkyl, C.sub.1-8alkoxy
(optionally substituted by one or more fluoro), halogen, hydroxy,
nitro or cyano), aryl (optionally substituted by C.sub.1-8alkyl,
C.sub.1-8alkoxy (optionally substituted by one or more fluoro),
halogen, hydroxy, nitro or cyano; or R.sup.5 and R.sup.6 together
with the nitrogen atom to which they are attached form a single or
a fused heterocyclic system.
20. A compound according to claim 19; wherein, R.sup.6 represents;
C.sub.1-13alkyl, which is optionally substituted by aryl, and
wherein the aryl is optionally substituted on carbon with
C.sub.1-8alkoxy.
21. A compound according to claim 20, wherein, R.sup.6 represents
C.sub.1-13 alkyl, substituted by aryl, which in its turn is
substituted on carbon with C.sub.1-8 alkoxy.
22. A compound according to claim 19, wherein R.sup.5 is H.
23. A compound according to claim 19, wherein R.sup.5 is H; and
R.sup.6 represents; C.sub.1-13alkyl, which is optionally
substituted by aryl, and wherein the aryl is optionally substituted
on carbon with C.sub.1-8alkoxy.
24. A compound according to claim 19, wherein R.sup.5 is H; and
R.sup.6 represents C.sub.1-13 alkyl, substituted by aryl, which in
its turn is substituted on carbon with C.sub.1-8 alkoxy.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to certain novel
3-(amino-oxo(alkyl, alkyloxy and alkylthio)phenyl) propanoic and
propenoic acid derivatives, to processes for preparing such
compounds, to their the utility in treating clinical conditions
including lipid disorders (dyslipidemias) whether or not associated
with insulin resistance and other manifestations of the metabolic
syndrome, to methods for their therapeutic use and to
pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
[0002] The metabolic syndrome including type 2 diabetes mellitus,
refers to a cluster of manifestations including insulin resistance
with accompanying hyperinsulinaemia, possibly type 2 diabetes
mellitus, arterial hypertension, central (visceral) obesity,
dyslipidaemia observed as deranged lipoprotein levels typically
characterised by elevated VLDL (very low density lipoproteins),
small dense LDL particles and reduced HDL (high density
lipoprotein) concentrations and reduced fibrinolysis.
[0003] Recent epidemiological research has documented that
individuals with insulin resistance run a greatly increased risk of
cardiovascular morbidity and mortality, notably suffering from
myocardial infarction and stroke. In type 2 diabetes mellitus
atherosclerosis related conditions cause up to 80% of all
deaths.
[0004] In clinical medicine there is awareness of the need to
increase the insulin sensitivity in patients with the metabolic
syndrome and thus to correct the dyslipidaemia which is considered
to cause the accelerated progress of atherosclerosis. However,
currently this is not a universally accepted diagnosis with
well-defined pharmacotherapeutic indications.
[0005] The S-enantiomer of the compound of formula C below ##STR1##
2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic
acid, is disclosed in PCT Publication Number WO99/62872. This
compound is reported to be a modulator of peroxisome
proliferator-activated receptors (PPAR, for a review of the PPARs
see T. M. Willson et al, J Med Chem 2000, Vol 43, 527) and has
combined PPAR.alpha./PPAR.gamma. agonist activity (Structure, 2001,
Vol 9, 699, P. Cronet et al). This compound is effective in
treating conditions associated with insulin resistance.
[0006] Surprisingly a series of compounds has now been found which
are selective PPAR.alpha. modulators.
DESCRIPTION OF THE INVENTION
[0007] The present invention provides a compound of formula I
##STR2## as well as optical isomers and racemates thereof as well
as pharmaceutically acceptable salts, prodrugs, solvates and
crystalline forms thereof wherein A is situated in the ortho, meta
or para position and represents ##STR3## wherein R is hydrogen;
[0008] --OR.sup.a, wherein R.sup.a represents hydrogen, alkyl, aryl
or alkylaryl; [0009] --NR.sup.aR.sup.b, wherein R.sup.a and R.sup.b
are the same or different and R.sup.a is as defined above and
R.sup.b represents hydrogen, alkyl, aryl, alkylaryl, cyano, --OH,
--Oalkyl, --Oaryl, --Oalkylaryl, --COR.sup.c or --SO.sub.2R.sup.d,
wherein R.sup.c represents hydrogen, alkyl, aryl or alkylaryl and
R.sup.d represents alkyl, aryl or alkylaryl; R.sup.1 is alkyl,
aryl, alkenyl, alkynyl, or when A is ##STR4## R.sup.1 can also be
[0010] cyano; [0011] --OR.sup.e, wherein R.sup.e is alkyl, acyl,
aryl or alkylaryl; [0012] --O--[CH.sub.2].sub.m--OR.sup.f, wherein
R.sup.f represents hydrogen, alkyl, acyl, aryl or alkylaryl and m
represents an integer 1-8; [0013] --OCONR.sup.aR.sup.c, wherein
R.sup.a and R.sup.c are as defined above; [0014] --SR.sup.d,
wherein R.sup.d is as defined above; [0015]
--SO.sub.2NR.sup.aR.sup.f, wherein R.sup.f and R.sup.a are as
defined above; [0016] --SO.sub.2OR.sup.a, wherein R.sup.a is as
defined above; [0017] --COOR.sup.d, wherein R.sup.d is as defined
above; R.sup.2 is hydrogen, halogen, alkyl, aryl, or alkylaryl,
R.sup.3 and R.sup.4 are the same or different and each represents
hydrogen, alkyl, aryl, or alkylaryl; T represents O, S or a single
bond; n represents 1, 2, 3 or 4; R.sup.5 and R.sup.6 are
independently selected substituents, comprising C, H, N, O, S, Se,
P or halogen atoms, which give compounds of the General Formula I a
molecular weight <650; with a first proviso that when A is
CH.sub.2CH(OC.sub.2H.sub.5)COOC.sub.2H.sub.5 or
CH.sub.2CH(OC.sub.2H.sub.5)COOH; T is O; n is 1 and R.sup.5
represents a C.sub.2-4alkyl group then R.sup.6 does not represent a
group of formula ##STR5## wherein R.sup.x represents chloro,
trifluoromethyl or trifluoromethoxy, R.sup.y represents H or
fluoro; and a second proviso that when A is
CH.sub.2CH(OC.sub.2H.sub.5)COOC.sub.2H.sub.5 or
CH.sub.2CH(OC.sub.2H.sub.5)COOH; T is O; n is 1 and R.sup.5
represents hexyl or heptyl then R.sup.6 does not represent a group
of formula R.sup.z--(CH.sub.2).sub.n-- wherein R.sup.z represents
phenyl, 2,4-difluorophenyl or cyclohexyl, and n is 1 or 2; provided
that the compound of formula I is not: [0018]
(2S)-4-[2-[[2-[[(2,6-dichlorophenyl)methyl]thio]ethyl]amino]-2-oxoethoxy]-
-.alpha.-methoxy-benzenepropanoic acid; [0019]
(2S)-4-[2-[butyl(1-phenylethyl)amino]-2-oxoethoxy]-.alpha.-methoxy-benzen-
epropanoic acid; [0020]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[[2-(3-pyridinyl)ethyl]amino]ethoxy]-benz-
enepropanoic acid; [0021]
(2S)-.alpha.-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-.-
alpha.-phenoxy-benzenepropanoic acid; [0022]
(2S)-.alpha.-methoxy-4-[2-[(1-methyl-3-phenylpropyl)amino]-2-oxoethoxy]-b-
enzenepropanoic acid; [0023]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]--
benzenepropanoic acid; [0024]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[4-[4-(trifluoromethyl)phenyl]-1-piperazi-
nyl]ethoxy]-benzenepropanoic acid; [0025]
(2S)-4-[2-[[2-(4-bromophenyl)ethyl]amino]-2-oxoethoxy]-.alpha.-methoxy-be-
nzenepropanoic acid; [0026]
(2S)-4-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-2-oxoethoxy]-.-
alpha.-methoxy-benzenepropanoic acid; [0027]
(2S)-4-[2-[[2-[ethyl(3-methylphenyl)amino]ethyl]amino]-2-oxoethoxy]-.alph-
a.-methoxy-benzenepropanoic acid; [0028]
.alpha.-methoxy-.alpha.-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amin-
o]ethoxy]-benzenepropanoic acid; [0029]
(2S)-.alpha.-methoxy-4-[2-[(3-methylbutyl)amino]-2-oxoethoxy]-benzeneprop-
anoic acid; [0030]
(2S)-4-[2-[4-(diphenylmethyl)-1-piperazinyl]-2-oxoethoxy]-.alpha.-methoxy-
-benzenepropanoic acid; [0031]
(2S)-4-[2-(heptylamino)-2-oxoethoxy]-.alpha.-methoxy-.alpha.-methyl-benze-
nepropanoic acid; [0032]
4-[2-[4-(2-fluorophenyl)-1-piperazinyl]-2-oxoethoxy]-.alpha.-methoxy-,
benzenepropanoic acid; [0033]
(2S)-4-[2-[4-(4-chlorobenzoyl)-1-piperidinyl]-2-oxoethoxy]-.alpha.-methox-
y-, benzenepropanoic acid; [0034]
(2S)-4-[2-[ethyl[(3-methylphenyl)methyl]amino]-2-oxoethoxy]-.alpha.-metho-
xy-benzenepropanoic acid; [0035]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethoxy]-benzenepr-
opanoic acid; [0036]
(2S)-.alpha.-methoxy-4-[2-[(1-methylhexyl)amino]-2-oxoethoxy]-benzeneprop-
anoic acid; [0037]
(2S)-4-[2-[([1,1'-biphenyl]-4-ylmethyl)amino]-2-oxoethoxy]-.alpha.-methox-
y-benzenepropanoic acid; [0038]
3-[2-[[cis-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-.alpha.-me-
thoxy-benzenepropanoic acid; [0039]
(2S)-4-[2-[4-(3-chlorophenyl)-1-piperazinyl]-2-oxoethoxy]-.alpha.-methoxy-
-benzenepropanoic acid; [0040]
(2S)-.alpha.-methoxy-4-[2-[methyl[(1S)-1-phenylethyl]amino]-2-oxoethoxy]--
benzenepropanoic acid; [0041]
(2S)-.alpha.-methoxy-4-[2-[4-(4-methylphenyl)-1-piperazinyl]-2-oxoethoxy]-
-benzenepropanoic acid; [0042]
(2S)-.alpha.-methoxy-4-[2-[[3-(methylphenylamino)propyl]amino]-2-oxoethox-
y]-benzenepropanoic acid; [0043]
(2S)-4-[2-(cyclobutylamino)-2-oxoethoxy]-.alpha.-methoxy-benzenepropanoic
acid; [0044]
(2S)-.alpha.-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-.-
alpha.-[4-(trifluoromethoxy)phenoxy]-benzenepropanoic acid; [0045]
(2S)-4-[2-(heptylamino)-2-oxoethoxy]-.alpha.-methoxy-benzenepropanoic
acid; [0046]
(2S)-4-[2-[4-(4-fluorophenyl)-1-piperazinyl]-2-oxoethoxy]-.alpha.-methoxy-
-benzenepropanoic acid; [0047]
(2S)-.alpha.-methoxy-4-[2-[[(1S)-1-(1-naphthalenyl)ethyl]amino]-2-oxoetho-
xy]-benzenepropanoic acid; [0048]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[[(1R)-1-phenylethyl](phenylmethyl)amino]-
ethoxy]-benzenepropanoic acid; [0049]
(2S)-4-[2-[(3,3-diphenylpropyl)amino]-2-oxoethoxy]-.alpha.-methoxy-benzen-
epropanoic acid; [0050]
(2S)-4-[2-[[trans-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-.al-
pha.-methoxy-benzenepropanoic acid; [0051]
(2S)-.alpha.-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-.-
alpha.-phenoxy-, ethyl ester-benzenepropanoic acid; [0052]
(2S)-4-[2-[(2,2,3,3,4,4,4-heptafluorobutyl)amino]-2-oxoethoxy]-.alpha.-me-
thoxy-benzenepropanoic acid; [0053]
(2S)-4-[2-(3,4-dihydro-2(1H)-isoquinolinyl)-2-oxoethoxy]-.alpha.-methoxy--
benzenepropanoic acid; [0054]
(2S)-3-[2-[[2-(4-ethylphenyl)ethyl]amino]-2-oxoethoxy]-.alpha.-methoxy-be-
nzenepropanoic acid; [0055]
(2S)-.alpha.-methoxy-4-[2-[(1-naphthalenylmethyl)amino]-2-oxoethoxy]-benz-
enepropanoic acid; [0056]
(2S)-4-[2-[[(4-chlorophenyl)phenylmethyl]amino]-2-oxoethoxy]-.alpha.-meth-
oxy-benzenepropanoic acid; [0057]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[[2-(2-pyridinyl)ethyl]amino]ethoxy]-benz-
enepropanoic acid; [0058]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[[(1S)-1-phenylethyl]amino]ethoxy]-benzen-
epropanoic acid; [0059]
(2S)-4-[2-(cyclopentylamino)-2-oxoethoxy]-.alpha.-methoxy-benzenepropanoi-
c acid; [0060]
(2S)-4-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-.alp-
ha.-methoxy-benzenepropanoic acid; [0061]
4-[2-[cyclohexyl[2-(4-ethylphenyl)ethyl]amino]-2-oxoethoxy]-.alpha.-ethox-
y-benzenepropanoic acid; [0062]
(2S)-4-[2-[(1,3-benzodioxol-5-ylmethyl)amino]-2-oxoethoxy]-.alpha.-methox-
y-benzenepropanoic acid; [0063] D-Phenylalanine,
N-[[4-[(2S)-2-carboxy-2-methoxyethyl]phenoxy]acetyl]-,
.alpha.-methyl ester; [0064]
(2S)-4-[2-[4-[(4-fluorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-.alpha.-
-methoxy-benzenepropanoic acid; [0065]
.alpha.-methoxy-3-[2-oxo-2-[(4-phenoxyphenyl)amino]ethoxy]-benzenepropano-
ic acid; [0066]
(2S)-.alpha.-methoxy-4-[2-[(1-methylbutyl)amino]-2-oxoethoxy]-benzeneprop-
anoic acid; [0067]
(2S)-.alpha.-methoxy-4-[2-[methyl(1-naphthalenylmethyl)amino]-2-oxoethoxy-
]-benzenepropanoic acid; [0068]
(2S)-3-[2-[[trans-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-.al-
pha.-methoxy-benzenepropanoic acid; [0069]
(2S)-4-[2-[4-[(4-chlorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-.alpha.-
-methoxy-benzenepropanoic acid; [0070]
(2S)-4-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-oxoethoxy]-.alpha.-methox-
y-benzenepropanoic acid; [0071]
(2S)-4-[2-[ethyl[(2-fluorophenyl)methyl]amino]-2-oxoethoxy]-.alpha.-metho-
xy-benzenepropanoic acid; [0072]
(2S)-.alpha.-methoxy-4-[2-[[2-(4-methoxyphenoxy)ethyl]amino]-2-oxoethoxy]-
-benzenepropanoic acid; [0073]
(2S)-4-[2-[(1,3-dimethylbutyl)amino]-2-oxoethoxy]-.alpha.-methoxy-benzene-
propanoic acid; [0074]
(2S)-.alpha.-(4-fluorophenoxy)-.alpha.-methyl-4-[2-oxo-2-[[2-(4-phenoxyph-
enyl)ethyl]amino]ethoxy]-benzenepropanoic acid; [0075]
(2S)-4-[2-[(3,3-dimethylbutyl)amino]-2-oxoethoxy]-.alpha.-methoxy-benzene-
propanoic acid; [0076]
(2S)-4-[2-[4-(4-chlorophenyl)-3-methyl-1-piperazinyl]-2-oxoethoxy]-.alpha-
.-methoxy-benzenepropanoic acid; [0077]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[[(1R)-1-phenylethyl]amino]ethoxy]-benzen-
epropanoic acid; [0078]
(2S)-4-[2-[4-(4-acetylphenyl)-1-piperazinyl]-2-oxoethoxy]-.alpha.-methoxy-
-benzenepropanoic acid; [0079]
(2S)-4-[2-[(3-ethoxy-3-oxopropyl)(phenylmethyl)amino]-2-oxoethoxy]-.alpha-
.-methoxy-benzenepropanoic acid; [0080]
(2S)-4-[2-[[cis-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-.alph-
a.-methoxy-benzenepropanoic acid; [0081]
(2S)-.alpha.-ethyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-.a-
lpha.-phenoxy-benzenepropanoic acid; [0082]
(2S)-4-[2-(hexylamino)-2-oxoethoxy]-.alpha.-methoxy-benzenepropanoic
acid; [0083]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[(2-phenylethyl)(phenylmethyl)amino]ethox-
y]-benzenepropanoic acid; [0084] or [0085]
(2S)-4-[2-[ethyl[2-(4-methoxyphenyl)-1-methylethyl]amino]-2-oxoethoxy]-.a-
lpha.-methoxy-benzenepropanoic acid.
[0086] According to another aspect the invention provides for a
compound of formula I ##STR6## as well as optical isomers and
racemates thereof as well as pharmaceutically acceptable salts,
prodrugs, solvates and crystalline forms thereof wherein A is
situated in the ortho, meta or para position and represents
##STR7## R is hydrogen; [0087] --OR.sup.a, wherein R.sup.a
represents hydrogen, alkyl, aryl or alkylaryl; [0088]
--NR.sup.aR.sup.b, wherein R.sup.a and R.sup.b are the same or
different and R.sup.a is as defined above and R.sup.b represents
hydrogen, alkyl, aryl, alkylaryl, cyano, --OH, --Oalkyl, --Oaryl,
--Oalkylaryl, --COR.sup.c or --SO.sub.2R.sup.d, wherein R.sup.c
represents hydrogen, alkyl, aryl or alkylaryl and R.sup.d
represents alkyl, aryl or alkylaryl; R.sup.1 is alkyl, aryl,
alkenyl, alkynyl, or when A is ##STR8## R.sup.1 can also be [0089]
cyano; [0090] --OR.sup.e, wherein R.sup.e is alkyl, acyl, aryl or
alkylaryl; [0091] --O--[CH.sub.2].sub.m--OR.sup.f, wherein R.sup.f
represents hydrogen, alkyl, acyl, aryl or alkylaryl and m
represents an integer 1-8; [0092] --OCONR.sup.aR.sup.c, wherein
R.sup.a and R.sup.c are as defined above; [0093] --SR.sup.d,
wherein R.sup.d is as defined above; [0094]
--SO.sub.2NR.sup.aR.sup.f, wherein R.sup.f and R.sup.a are as
defined above; [0095] --SO.sub.2OR.sup.a, wherein R.sup.a is as
defined above; [0096] --COOR.sup.d, wherein R.sup.d is as defined
above; R.sup.2 is hydrogen, halogen, alkyl, aryl, or alkylaryl,
R.sup.3 and R.sup.4 are the same or different and each represents
hydrogen, alkyl, aryl, or alkylaryl; T represents O, S or a single
bond; n represents 1, 2, 3 or 4; R.sup.5 and R.sup.6 are
independently selected substituents, comprising C, H, N, O, S, Se,
P or halogen atoms, which give compounds of the General Formula I a
molecular weight <650; with a first proviso that when A is
CH.sub.2CH(OC.sub.2H.sub.5)COOC.sub.2H.sub.5 or
CH.sub.2CH(OC.sub.2H.sub.5)COOH; T is O; n is 1 and R.sup.5
represents a C.sub.2-4alkyl group then R.sup.6 does not represent a
group of formula ##STR9## wherein R.sup.x represents chloro,
trifluoromethyl or trifluoromethoxy, R.sup.y represents H or
fluoro; and a second proviso that when A is
CH.sub.2CH(OC.sub.2H.sub.5)COOC.sub.2H.sub.5 or
CH.sub.2CH(OC.sub.2H.sub.5)COOH; T is O; n is 1 and R.sup.5
represents hexyl or heptyl then R.sup.6 does not represent a group
of formula R.sup.z--(CH.sub.2).sub.n-- wherein R.sup.z represents
phenyl, 2,4-difluorophenyl or cyclohexyl, and n is 1 or 2; provided
that the compound of formula I is not: [0097]
(2S)-4-[2-[[2-[[(2,6-dichlorophenyl)methyl]thio]ethyl]amino]-2-oxoethoxy]-
-.alpha.-methoxy-benzenepropanoic acid; [0098]
(2S)-4-[2-[butyl(1-phenylethyl)amino]-2-oxoethoxy]-.alpha.-methoxy-benzen-
epropanoic acid; [0099]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[[2-(3-pyridinyl)ethyl]amino]ethoxy]-benz-
enepropanoic acid; [0100]
(2S)-.alpha.-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-.-
alpha.-phenoxy-benzenepropanoic acid; [0101]
(2S)-.alpha.-methoxy-4-[2-[(1-methyl-3-phenylpropyl)amino]-2-oxoethoxy]-b-
enzenepropanoic acid; [0102]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]--
benzenepropanoic acid; [0103]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[4-[4-(trifluoromethyl)phenyl]-1-piperazi-
nyl]ethoxy]-benzenepropanoic acid; [0104]
(2S)-4-[2-[[2-(4-bromophenyl)ethyl]amino]-2-oxoethoxy]-.alpha.-methoxy-be-
nzenepropanoic acid; [0105]
(2S)-4-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]-2-oxoethoxy]-.-
alpha.-methoxy-benzenepropanoic acid; [0106]
(2S)-4-[2-[[2-[ethyl(3-methylphenyl)amino]ethyl]amino]-2-oxoethoxy]-.alph-
a.-methoxy-benzenepropanoic acid; [0107]
.alpha.-methoxy-.alpha.-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amin-
o]ethoxy]-benzenepropanoic acid; [0108]
(2S)-.alpha.-methoxy-4-[2-[(3-methylbutyl)amino]-2-oxoethoxy]-benzeneprop-
anoic acid; [0109]
(2S)-4-[2-[4-(diphenylmethyl)-1-piperazinyl]-2-oxoethoxy]-.alpha.-methoxy-
-benzenepropanoic acid; [0110]
(2S)-4-[2-(heptylamino)-2-oxoethoxy]-.alpha.-methoxy-.alpha.-methyl-benze-
nepropanoic acid; [0111]
4-[2-[4-(2-fluorophenyl)-1-piperazinyl]-2-oxoethoxy]-.alpha.-methoxy-,
benzenepropanoic acid; [0112]
(2S)-4-[2-[4-(4-chlorobenzoyl)-1-piperidinyl]-2-oxoethoxy]-.alpha.-methox-
y-, benzenepropanoic acid; [0113]
(2S)-4-[2-[ethyl[(3-methylphenyl)methyl]amino]-2-oxoethoxy]-.alpha.-metho-
xy-benzenepropanoic acid; [0114]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[(4-phenoxyphenyl)amino]ethoxy]-benzenepr-
opanoic acid; [0115]
(2S)-.alpha.-methoxy-4-[2-[(1-methylhexyl)amino]-2-oxoethoxy]-benzeneprop-
anoic acid; [0116]
(2S)-4-[2-[([1,1'-biphenyl]-4-ylmethyl)amino]-2-oxoethoxy]-.alpha.-methox-
y-benzenepropanoic acid; [0117]
3-[2-[[cis-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-.alpha.-me-
thoxy-benzenepropanoic acid; [0118]
(2S)-4-[2-[4-(3-chlorophenyl)-1-piperazinyl]-2-oxoethoxy]-.alpha.-methoxy-
-benzenepropanoic acid; [0119]
(2S)-.alpha.-methoxy-4-[2-[methyl[(1S)-1-phenylethyl]amino]-2-oxoethoxy]--
benzenepropanoic acid; [0120]
(2S)-.alpha.-methoxy-4-[2-[4-(4-methylphenyl)-1-piperazinyl]-2-oxoethoxy]-
-benzenepropanoic acid; [0121]
(2S)-.alpha.-methoxy-4-[2-[[3-(methylphenylamino)propyl]amino]-2-oxoethox-
y]-benzenepropanoic acid; [0122]
(2S)-4-[2-(cyclobutylamino)-2-oxoethoxy]-.alpha.-methoxy-benzenepropanoic
acid; [0123]
(2S)-.alpha.-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-.-
alpha.-[4-(trifluoromethoxy)phenoxy]-benzenepropanoic acid; [0124]
(2S)-4-[2-(heptylamino)-2-oxoethoxy]-.alpha.-methoxy-benzenepropanoic
acid; [0125]
(2S)-4-[2-[4-(4-fluorophenyl)-1-piperazinyl]-2-oxoethoxy]-.alpha.-methoxy-
-benzenepropanoic acid; [0126]
(2S)-.alpha.-methoxy-4-[2-[[(1S)-1-(1-naphthalenyl)ethyl]amino]-2-oxoetho-
xy]-benzenepropanoic acid; [0127]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[[(1R)-1-phenylethyl](phenylmethyl)amino]-
ethoxy]-benzenepropanoic acid; [0128]
(2S)-4-[2-[(3,3-diphenylpropyl)amino]-2-oxoethoxy]-.alpha.-methoxy-benzen-
epropanoic acid; [0129]
(2S)-4-[2-[[trans-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-.al-
pha.-methoxy-benzenepropanoic acid; [0130]
(2S)-.alpha.-methyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-.-
alpha.-phenoxy-, ethyl ester-benzenepropanoic acid; [0131]
(2S)-4-[2-[(2,2,3,3,4,4,4-heptafluorobutyl)amino]-2-oxoethoxy]-.alpha.-me-
thoxy-benzenepropanoic acid; [0132]
(2S)-4-[2-(3,4-dihydro-2(1H)-isoquinolinyl)-2-oxoethoxy]-.alpha.-methoxy--
benzenepropanoic acid; [0133]
(2S)-3-[2-[[2-(4-ethylphenyl)ethyl]amino]-2-oxoethoxy]-.alpha.-methoxy-be-
nzenepropanoic acid; [0134]
(2S)-.alpha.-methoxy-4-[2-[(1-naphthalenylmethyl)amino]-2-oxoethoxy]-benz-
enepropanoic acid; [0135]
(2S)-4-[2-[[(4-chlorophenyl)phenylmethyl]amino]-2-oxoethoxy]-.alpha.-meth-
oxy-benzenepropanoic acid; [0136]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[[2-(2-pyridinyl)ethyl]amino]ethoxy]-benz-
enepropanoic acid; [0137]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[[(1S)-1-phenylethyl]amino]ethoxy]-benzen-
epropanoic acid; [0138]
(2S)-4-[2-(cyclopentylamino)-2-oxoethoxy]-.alpha.-methoxy-benzenepropanoi-
c acid; [0139]
(2S)-4-[2-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-.alp-
ha.-methoxy-benzenepropanoic acid; [0140]
4-[2-[cyclohexyl[2-(4-ethylphenyl)ethyl]amino]-2-oxoethoxy]-.alpha.-ethox-
y-benzenepropanoic acid; [0141]
(2S)-4-[2-[(1,3-benzodioxol-5-ylmethyl)amino]-2-oxoethoxy]-.alpha.-methox-
y-benzenepropanoic acid; [0142] D-Phenylalanine,
N-[[4-[(2S)-2-carboxy-2-methoxyethyl]phenoxy]acetyl]-,
.alpha.-methyl ester; [0143]
(2S)-4-[2-[4-[(4-fluorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-.alpha.-
-methoxy-benzenepropanoic acid; [0144]
.alpha.-methoxy-3-[2-oxo-2-[(4-phenoxyphenyl)amino]ethoxy]-benzenepropano-
ic acid; [0145]
(2S)-.alpha.-methoxy-4-[2-[(1-methylbutyl)amino]-2-oxoethoxy]-benzeneprop-
anoic acid; [0146]
(2S)-.alpha.-methoxy-4-[2-[methyl(1-naphthalenylmethyl)amino]-2-oxoethoxy-
]-benzenepropanoic acid; [0147]
(2S)-3-[2-[[trans-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-.al-
pha.-methoxy-benzenepropanoic acid; [0148]
(2S)-4-[2-[4-[(4-chlorophenyl)methyl]-1-piperazinyl]-2-oxoethoxy]-.alpha.-
-methoxy-benzenepropanoic acid; [0149]
(2S)-4-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]-2-oxoethoxy]-.alpha.-methox-
y-benzenepropanoic acid; [0150]
(2S)-4-[2-[ethyl[(2-fluorophenyl)methyl]amino]-2-oxoethoxy]-.alpha.-metho-
xy-benzenepropanoic acid; [0151]
(2S)-.alpha.-methoxy-4-[2-[[2-(4-methoxyphenoxy)ethyl]amino]-2-oxoethoxy]-
-benzenepropanoic acid; [0152]
(2S)-4-[2-[(1,3-dimethylbutyl)amino]-2-oxoethoxy]-.alpha.-methoxy-benzene-
propanoic acid; [0153]
(2S)-.alpha.-(4-fluorophenoxy)-.alpha.-methyl-4-[2-oxo-2-[[2-(4-phenoxyph-
enyl)ethyl]amino]ethoxy]-benzenepropanoic acid; [0154]
(2S)-4-[2-[(3,3-dimethylbutyl)amino]-2-oxoethoxy]-.alpha.-methoxy-benzene-
propanoic acid; [0155]
(2S)-4-[2-[4-(4-chlorophenyl)-3-methyl-1-piperazinyl]-2-oxoethoxy]-.alpha-
.-methoxy-benzenepropanoic acid; [0156]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[[(1R)-1-phenylethyl]amino]ethoxy]-benzen-
epropanoic acid; [0157]
(2S)-4-[2-[4-(4-acetylphenyl)-1-piperazinyl]-2-oxoethoxy]-.alpha.-methoxy-
-benzenepropanoic acid; [0158]
(2S)-4-[2-[(3-ethoxy-3-oxopropyl)(phenylmethyl)amino]-2-oxoethoxy]-.alpha-
.-methoxy-benzenepropanoic acid; [0159]
(2S)-4-[2-[[cis-4-(1,1-dimethylethyl)cyclohexyl]amino]-2-oxoethoxy]-.alph-
a.-methoxy-benzenepropanoic acid; [0160]
(2S)-.alpha.-ethyl-4-[2-oxo-2-[[2-(4-phenoxyphenyl)ethyl]amino]ethoxy]-.a-
lpha.-phenoxy-benzenepropanoic acid; [0161]
(2S)-4-[2-(hexylamino)-2-oxoethoxy]-.alpha.-methoxy-benzenepropanoic
acid; [0162]
(2S)-.alpha.-methoxy-4-[2-oxo-2-[(2-phenylethyl)(phenylmethyl)amino]ethox-
y]-benzenepropanoic acid; [0163]
(2S)-4-[2-[ethyl[2-(4-methoxyphenyl)-1-methylethyl]amino]-2-oxoethoxy]-.a-
lpha.-methoxy-benzenepropanoic acid; [0164]
[[4-[2-oxo-2-[[phenyl[2-(1-piperidinyl)phenyl]methyl]amino]ethyl]phenyl]m-
ethyl]-, diethyl ester-propanedioic acid; [0165]
4-[2-(heptylamino)-2-oxoethyl]-.alpha.,.alpha.-dimethyl-, ethyl
ester-benzenepropanoic acid; [0166]
2-[[4-(2-amino-2-oxoethoxy)phenyl]methylene]-3-oxo-, methyl
ester-butanoic acid; [0167]
4-[2-[methyl(2-phenylethyl)amino]-2-oxoethyl]-.alpha.-phenyl-,ethyl
ester-benzenepropanoic acid; [0168]
4-[2-(heptylamino)-2-oxoethyl]-.alpha.,.alpha.-dimethyl-, ethyl
ester-benzenepropanoic acid; [0169]
4-[2-[[2-[[(1,1-dimethylethoxy)carbonyl]methylamino]-4-hydroxyphenyl]amin-
o]-2-oxoethoxy]-.alpha.-(methylthio)-, ethyl ester-benzenepropanoic
acid; [0170]
[[4-[2-oxo-2-[[phenyl[2-(1-piperidinyl)phenyl]methyl]aminoethyl]p-
henyl]methyl]-propanedioic acid; [0171]
N-[3-[4-[2-[methyl(2-phenylethyl)amino]-2-oxoethyl]phenyl]-1-oxo-2-phenyl-
propyl]-, methyl ester-glycine; [0172]
4-[2-[methyl(2-phenylethyl)amino]-2-oxoethyl]-.alpha.-phenyl-benzenepropa-
noic acid; [0173]
N-[3-[4-[2-[methyl(2-phenylethyl)amino]-2-oxoethyl]phenyl]-1-oxo-2-phenyl-
propyl]-glycine; [0174] or [0175]
4-[3-[methyl(2-phenylethyl)amino]-3-oxopropyl]-.alpha.-phenyl-benzenpropa-
noic acid.
[0176] Particularly R.sup.5 and R.sup.6 are independently selected
substituents, comprising C, H, N, O, S or halogen atoms, which give
compounds of the General Formula I a molecular weight <650.
Alternatively, R.sup.5 and R.sup.6 are independently selected
substituents, comprising C, N, O, S, Se, P or halogen atoms. 10.
According to one aspect of the invention, when either of R.sup.5
and R.sup.6 is hydrogen, the other is not an alkyl.
[0177] Particularly R.sup.5 and R.sup.6 independently represent
hydrogen, C.sub.1-13alkyl, C.sub.2-10alkenyl or C.sub.2-10alkynyl
each of which is optionally substituted by one or more of the
following which may be the same or different: C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkenyl, aryl, heterocyclyl, heteroaryl,
C.sub.1-8alkoxy (optionally substituted by one or more fluoro),
C.sub.3-8cycloalkoxy, C.sub.3-8cycloalkenyloxy, aryloxy,
heterocyclyloxy, heteroaryloxy, C.sub.3-8cycloalkyl
C.sub.1-8alkoxy, aryl C.sub.1-8alkoxy, heterocyclyl C.sub.1-8
alkoxy or heteroaryl C.sub.1-8 alkoxy, fluorine or hydroxy and
wherein each of these substituents may optionally be substituted on
carbon with one or more substituents which may be the same or
different and selected from C.sub.1-8alkyl, C.sub.3-8cycloalkyl
(optionally substituted by C.sub.1-8alkyl, C.sub.1-8alkoxy
(optionally substituted by one or more fluoro), halogen, hydroxy,
nitro or cyano), aryl (optionally substituted by C.sub.1-8alkyl,
C.sub.1-8alkoxy (optionally substituted by one or more fluoro),
halogen, hydroxy, nitro or cyano), heterocyclyl (optionally
substituted by C.sub.1-6alkyl on any nitrogen), heteroaryl
(optionally substituted by C.sub.1-8alkyl, C.sub.1-8alkoxy
(optionally substituted by one or more fluoro), halogen, hydroxy,
nitro or cyano), C.sub.1-8alkoxy (optionally substituted by one or
more fluoro), C.sub.3-8cycloalkoxy, C.sub.3-8 cycloalkyl
C.sub.1-8alkoxy, aryloxy (optionally substituted by C.sub.1-8alkyl,
C.sub.1-8alkoxy (optionally substituted by one or more fluoro),
halogen, hydroxy, nitro or cyano), aryl C.sub.1-8alkoxy (wherein
the aryl part is optionally substituted by C.sub.1-8alkyl,
C.sub.1-8alkoxy (optionally substituted by one or more fluoro),
halogen, hydroxy, nitro or cyano), halogen, amino, nitro, hydroxy,
methylsulfonyl, methylsulfonyloxy, cyano or methylenedioxy,
[0178] or R.sup.5 and R.sup.6 independently represent
C.sub.3-C.sub.8 cycloalkyl; C.sub.3-C.sub.8 cycloalkenyl; aryl;
heterocyclyl; or heteroaryl; wherein each of these groups is
optionally substituted by one or more of the following:
C.sub.1-8alkyl, C.sub.1-8alkoxy (optionally substituted by one or
more fluoro), halogen, hydroxy, nitro or cyano), aryl (optionally
substituted by C.sub.1-8alkyl, C.sub.1-8alkoxy (optionally
substituted by one or more fluoro), halogen, hydroxy, nitro or
cyano; or R.sup.5 and R.sup.6 together with the nitrogen atom to
which they are attached form a single or a fused heterocyclic
system.
[0179] Particularly A is CH.sub.2CH(OR.sup.t)COOR.sup.m wherein
R.sup.t represents C.sub.1-4alkyl and wherein R.sup.m represents H
or C.sub.1-4alkyl.
[0180] A preferred group of compounds is represented by formula Ia
##STR10## [0181] as well as optical isomers and racemates thereof
as well as pharmaceutically acceptable salts, prodrugs, solvates
and crystalline forms thereof wherein; T represents O or a single
bond; n=1 or 2; R.sup.5 and R.sup.6 are independently selected
C.sub.1-10alkyl (optionally substituted by one or more
C.sub.1-4alkoxy); C.sub.5-7cycloalkylC.sub.1-4alkyl (optionally
substituted cyano); benzyl or phenethyl (each of which is
optionally substituted by one or more of the following: halo;
C.sub.1-4alkyl; C.sub.1-4alkoxy; trifluoromethyl; trifluoromethoxy;
methylenedioxy; phenyl; benzyloxy; methanesulfonyloxy);
indolylmethyl; or thienylmethyl.
[0182] In preferred groups of compounds of formula I and formula
Ia, R.sup.5 represents C.sub.1-10alkyl (optionally substituted by
one or more C.sub.1-4alkoxy) and R.sup.6 represents benzyl
optionally substituted one or more of the following: halo;
C.sub.1-4alkyl; C.sub.1-4alkoxy; trifluoromethyl; trifluoromethoxy;
methylenedioxy; phenyl; benzyloxy or methanesulfonyloxy.
[0183] Alternatively n represents 2, 3 or 4.
[0184] In other preferred groups of compounds of formula I and Ia
R.sup.5 and R.sup.6 independently represent benzyl optionally
substituted one or more of the following: halo; C.sub.1-4alkyl;
C.sub.1-4alkoxy; trifluoromethyl; trifluoromethoxy; methylenedioxy;
phenyl; benzyloxy or methanesulfonyloxy.
[0185] R.sup.3 and R.sup.4 may be the same or different and each
represents alkyl, aryl or alkylaryl. Alternatively R.sup.3 and
R.sup.4 are hydrogen.
[0186] In one aspect of the invention R.sup.2 is hydrogen or
fluorine.
[0187] A compound of formula VI: ##STR11## wherein R5, R6 and n is
as defined in any of the preceding claims and X is a leaving group,
such as a halide, OSO.sub.2CH.sub.3, OTosyl, ONosyl,
OSO.sub.2CF.sub.3, OC(O)OR, OP(O)(OR).sub.2 or OSO.sub.2OR,
particularly chloro or bromo. Formula VI is useful as an
intermediate in the process of manufacturing formula I.
[0188] The following definitions shall apply throughout the
specification and the appended claims with regard to the group
A.
[0189] Unless otherwise stated or indicated, the term "alkyl"
denotes a straight or branched, substituted or unsubstituted alkyl
group having from 1 to 6 carbon atoms or a cyclic alkyl having from
3 to 6 carbon atoms. The term "lower alkyl" denotes a straight or
branched, substituted or unsubstituted alkyl group having from 1 to
3 carbon atoms or a cyclic alkyl having 3 carbon atoms. Examples of
said alkyl and lower alkyl include methyl, ethyl, n-propyl,
isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and
branched-chain pentyl and hexyl as well as cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl.
[0190] Unless otherwise stated or indicated, the term "alkoxy"
denotes a group O-alkyl, wherein alkyl is as defined above.
[0191] Unless otherwise stated or indicated, the term "halogen"
shall mean fluorine, chlorine, bromine or iodine.
[0192] Unless otherwise stated or indicated, the term "aryl"
denotes a substituted or unsubstituted phenyl, furyl, thienyl or
pyridyl group, or a fused ring system of any of these groups, such
as naphthyl.
[0193] Unless otherwise stated or indicated, the term "substituted"
denotes an alkyl or an aryl group as defined above which is
substituted by one or more alkyl, alkoxy, halogen, amino, thiol,
nitro, hydroxy, acyl, aryl or cyano groups.
[0194] Unless otherwise stated or indicated, the term "alkylaryl"
denotes a ##STR12## wherein n is an integer 1 to 6 and R.sup.r and
R.sup.i are the same or different and each represents hydrogen or
an alkyl or aryl group as defined above.
[0195] Unless otherwise stated or indicated, the term "acyl"
denotes a group ##STR13## wherein R.sup.j is hydrogen, alkyl,
alkoxy, aryl and alkylaryl as defined above.
[0196] Unless otherwise stated or indicated, the terms "alkenyl"
and "alkynyl" denote a straight or branched, substituted or
unsubstituted unsaturated hydrocarbon group having one or more
double or triple bonds and having a maximum of 6 carbon atoms,
preferably 3 carbon atoms.
[0197] Unless otherwise stated or indicated the term "protective
group" (R.sup.p) denotes a protecting group as described in the
standard text "Protecting groups in Organic Synthesis", 2nd Edition
(1991) by Greene and Wuts. The protective group may also be a
polymer resin such as Wang resin or 2-chlorotrityl chloride
resin.
[0198] For the groups other than A the following definitions
apply.
[0199] "Cycloalkyl" means a non-aromatic monocyclic or multicyclic
ring system of from 3 carbon atoms up to 10 carbon atoms.
[0200] "Aryl" means an aromatic monocyclic or multicyclic ring
system of up to 14 carbon atoms.
[0201] "Heterocyclyl" means a non-aromatic monocyclic or
multicyclic ring system of up to 14 carbon atoms, containing at
least one heteroatom.
[0202] "Heteroaryl" means an aromatic monocyclic or multicyclic
ring system of up to 14 carbon atoms, containing at least one
heteroatom.
[0203] The term "prodrug" as used in this specification includes
derivatives of the carboxylic acid group which are converted in a
mammal, particularly a human, into the carboxylic acid group or a
salt or conjugate thereof. It should be understood that, whilst not
being bound by theory, it is believed that most of the activity
associated with the prodrugs arises from the activity of the
compound of formula I into which the prodrugs are converted.
Prodrugs can be prepared by routine methodology well within the
capabilities of someone skilled in the art. Various prodrugs of
carboxy are known in the art. For examples of such prodrug
derivatives, see:
a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and
Methods in Enzymology. 42: 309-396, edited by K. Widder, et al.
(Academic Press, 1985);
b) A Textbook of Drug Design and Development, edited by
Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and
Application of Prodrugs", by H. Bundgaard p. 113-191 (1991);
c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992);
d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285
(1988); and
e) N. Kakeya, et al., Chem Pharm Bull, 32:692 (1984).
[0204] The above documents a to e are herein incorporated by
reference.
[0205] In vivo cleavable esters are just one type of prodrug of the
parent molecule. An in vivo hydrolysable (or cleavable) ester of a
compound of the formula (I) that contains a carboxy group is, for
example, a pharmaceutically acceptable ester which is hydrolysed in
the human or animal body to produce the parent acid. Suitable
pharmaceutically acceptable esters for carboxy include
C.sub.1-6alkoxymethyl esters, for example, methoxymethyl;
C.sub.1-6alkanoyloxymethyl esters, for example, pivaloyloxymethyl;
phthalidyl esters; C.sub.3-8cycloalkoxycarbonyloxyC.sub.1-6alkyl
esters, for example, 1-cyclohexylcarbonyloxyethyl;
1,3-dioxolen-2-onylmethyl esters, for example,
5-methyl-1,3-dioxolen-2-onylmethyl; and
C.sub.1-6alkoxycarbonyloxyethyl esters, for example,
1-methoxycarbonyloxyethyl; and may be formed at any carboxy group
in the compounds of this invention.
[0206] Specific compounds of the invention are: [0207]
(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(octyl)amino]-2-oxoethoxy}phenyl)-2-eth-
oxypropanoic acid [0208]
(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-eth-
oxypropanoic acid [0209]
(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}pheny-
l)-2-ethoxypropanoic acid [0210]
(2S)-3-(4-{2-[Benzyl(methyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic
acid [0211]
(2S)-2-Ethoxy-3-[4-(2-{heptyl[(1-methylindol-2-yl)methyl]amino}-2-oxoetho-
xy)phenyl]propanoic acid [0212]
(2S)-3-(4-{2-[(2,3-Dimethoxybenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-e-
thoxypropanoic acid [0213]
(2S)-3-(4-{2-[Butyl(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-etho-
xypropanoic [0214]
(2S)-3-(4-{2-[(4-Chlorobenzyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}pheny-
l)-2-ethoxypropanoic acid [0215]
(2S)-3-(4-{2-[(Cyclohexylmethyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}ph-
enyl)-2-ethoxypropanoic acid [0216]
(2S)-2-Ethoxy-3-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)pro-
panoic acid [0217]
(2S)-3-(4-{2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phenyl)-2-et-
hoxypropanoic acid [0218]
(2S)-3-(4-{2-[bis(4-Chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropa-
noic acid [0219]
(2S)-3-(4-{2-[(4-tert-Butylbenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phen-
yl)-2-ethoxypropanoic acid [0220]
(2S)-3-[4-(2-{(4-Chlorobenzyl)[4-(trifluoromethyl)benzyl]amino}-2-oxoetho-
xy)phenyl]-2-ethoxypropanoic acid [0221]
(2S)-3-[4-(2-{bis[4-(Trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2--
ethoxypropanoic acid [0222]
(2S)-3-(4-{2-[Benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic
acid and [0223]
(2S)-3-(4-{2-[(4-tert-Butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-2-eth-
oxypropanoic acid [0224]
(2S)-3-(4-{2-[benzyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethox-
ypropanoic acid [0225]
(2S)-2-ethoxy-3-(4-{2-[(3-ethoxypropyl)(4-isopropylbenzyl)amino]-2-oxoeth-
oxy}phenyl)propanoic acid [0226]
(2S)-3-(4-{2-[butyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxy-
propanoic acid [0227]
(2S)-3-(4-{2-[(2-chlorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxy-
propanoic acid [0228]
(2S)-2-ethoxy-3-(4-{2-[heptyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl-
)propanoic acid [0229]
(2S)-3-(4-{2-[[(4-cyanocyclohexyl)methyl](4-isopropylbenzyl)amino]-2-oxoe-
thoxy}phenyl)-2-ethoxypropanoic acid [0230]
(2S)-2-ethoxy-3-(4-{2-[(4-isopropylbenzyl)(2-methoxybenzyl)amino]-2-oxoet-
hoxy}phenyl)propanoic acid [0231]
(2S)-3-(4-{2-[(2-chlorobenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)--
2-ethoxypropanoic acid [0232]
(2S)-3-(4-{2-[(4-chlorobenzyl)(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phe-
nyl)-2-ethoxypropanoic acid [0233]
(2S)-3-(4-{2-[(1,3-benzodioxol-5-ylmethyl)(4-ethoxybenzyl)amino]-2-oxoeth-
oxy}phenyl)-2-ethoxypropanoic acid [0234]
(2S)-3-(4-{2-[(1,3-benzodioxol-5-ylmethyl)(3-bromobenzyl)amino]-2-oxoetho-
xy}phenyl)-2-ethoxypropanoic acid [0235]
(2S)-3-[4-(2-1{(1,3-benzodioxol-5-ylmethyl)[3-(trifluoromethyl)benzyl]ami-
no}-2-oxoethoxy)phenyl]-2-ethoxypropanoic acid [0236]
(2S)-3-(4-{2-[(3,5-dimethoxybenzyl)(4-ethoxybenzyl)amino]-2-oxoethoxy}phe-
nyl)-2-ethoxypropanoic acid [0237]
(2S)-3-(4-{2-[(3-chloro-4-fluorobenzyl)(4-ethoxybenzyl)amino]-2-oxoethoxy-
}phenyl)-2-ethoxypropanoic acid [0238]
(2S)-2-ethoxy-3-(4-{2-[(4-ethoxybenzyl)(2-thienylmethyl)amino]-2-oxoethox-
y}phenyl)propanoic acid [0239]
(2S)-3-(4-{2-[benzyl(isopropyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropano-
ic acid [0240]
(2S)-3-{4-[2-(dibenzylamino)-2-oxoethoxy]phenyl}-2-ethoxypropanoic
acid [0241]
(2S)-3-(4-{2-[bis(2-methoxyethyl)amino]-2-oxoethoxy}phenyl)-2-eth-
oxypropanoic acid [0242]
(2S)-2-ethoxy-3-[4-(2-{heptyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethox-
y)phenyl]propanoic acid [0243]
(2S)-2-ethoxy-3-[4-(2-{heptyl[4-(trifluoromethoxy)benzyl]amino}-2-oxoetho-
xy)phenyl]propanoic acid [0244]
(2S)-2-ethoxy-3-(4-{2-[(4-ethylbenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)p-
ropanoic acid [0245]
(2S)-3-(4-{2-[(4-tert-butylbenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-et-
hoxypropanoic acid [0246]
(2S)-2-ethoxy-3-(4-{2-[heptyl(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl)-
propanoic acid [0247]
(2S)-3-(4-{2-[benzyl(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic
acid [0248]
(2S)-2-ethoxy-3-(4-{2-[(4-fluorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-
propanoic acid [0249]
(2S)-3-(4-{2-[(4-chlorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxy-
propanoic acid [0250]
(2S)-3-(4-{2-[(4-bromobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxyp-
ropanoic acid [0251]
(2S)-3-(4-{2-[butyl(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxyprop-
anoic acid [0252]
(2S)-3-(4-{2-[butyl(4-tert-butylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethox-
ypropanoic acid [0253] (2S)-3-(4-{2-[butyl
(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
[0254]
(2S)-3-(4-{2-[benzyl(butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypro-
panoic acid [0255]
(2S)-3-(4-{2-[butyl(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypro-
panoic acid [0256]
(2S)-3-(4-{2-[(4-bromobenzyl)(butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypr-
opanoic acid [0257]
(2S)-3-(4-{2-[butyl(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethox-
ypropanoic acid [0258]
(2S)-3-[4-(2-{(4-chlorobenzyl)[4-(trifluoromethoxy)benzyl]amino}-2-oxoeth-
oxy)phenyl]-2-ethoxypropanoic acid [0259]
(2S)-3-(4-{2-[(4-chlorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-
-ethoxypropanoic acid [0260]
(2S)-3-(4-{2-[(4-chlorobenzyl)(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl-
)-2-ethoxypropanoic acid [0261]
(2S)-3-(4-{2-[benzyl(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypr-
opanoic acid [0262]
(2S)-3-(4-{2-[(4-chlorobenzyl)(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)--
2-ethoxypropanoic acid [0263]
(2S)-3-(4-{2-[(4-bromobenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-
-ethoxypropanoic acid [0264]
(2S)-3-(4-{2-[(4-chlorobenzyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phen-
yl)-2-ethoxypropanoic acid [0265]
(2S)-2-ethoxy-3-[4-(2-{(4-methylbenzyl)[4-(trifluoromethyl)benzyl]amino}--
2-oxoethoxy)phenyl]propanoic acid [0266]
(2S)-2-ethoxy-3-[4-(2-{(4-methylbenzyl)
[4-(trifluoromethoxy)benzyl]amino}-2-oxoethoxy)phenyl]propanoic
acid [0267]
(2S)-2-ethoxy-3-(4-{2-[(4-ethylbenzyl)(4-methylbenzyl)amino]-2-ox-
oethoxy}phenyl)propanoic acid [0268]
(2S)-3-(4-{2-[(4-tert-butylbenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phen-
yl)-2-ethoxypropanoic acid [0269]
(2S)-2-ethoxy-3-(4-{2-[(4-isobutylbenzyl)(4-methylbenzyl)amino]-2-oxoetho-
xy}phenyl)propanoic acid [0270]
(2S)-3-(4-{2-[benzyl(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypr-
opanoic acid [0271]
(2S)-2-ethoxy-3-(4-{2-[(4-fluorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy-
}phenyl)propanoic acid [0272]
(2S)-3-(4-{2-[(4-chlorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)--
2-ethoxypropanoic acid [0273]
(2S)-3-(4-{2-[(4-bromobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-
-ethoxypropanoic acid [0274]
(2S)-3-(4-{2-[(2,4-difluorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phen-
yl)-2-ethoxypropanoic acid and pharmaceutically acceptable salts
thereof.
[0275] In the present specification the expression
"pharmaceutically acceptable salts" is intended to define but is
not limited to salts with bases.
[0276] It will also be understood that certain compounds of the
present invention may exist in solvated as well as unsolvated
forms. It is to be understood that the present invention
encompasses all such solvated forms. Certain compounds of the
present invention may exist as tautomers. It is to be understood
that the present invention encompasses all such tautomers.
Methods of Preparation
[0277] The compounds of the invention may be prepared as outlined
below. However, the invention is not limited to these methods. The
compounds may also be prepared as described for structurally
related compounds in the prior art. The reactions can be carried
out according to standard procedures or as described in the
experimental section.
[0278] Compounds of formula I may be prepared by reacting a
compound of formula II ##STR14## wherein A is situated in the
ortho, meta or para position and represents ##STR15## wherein in
which R.sup.1, R.sup.2 R.sup.3 and R.sup.4 are as previously
defined and R represents --OR.sup.p, wherein R.sup.p is a
protecting group for a carboxylic hydroxy group as described in the
standard text "Protective Groups in Organic Synthesis", 2.sup.nd
Edition (1991) by Greene and Wuts, with a de-protecting agent. The
protecting group may also be a resin, such as Wang resin or
2-chlorotrityl chloride resin. Protecting groups may be removed in
accordance to techniques that are well known to those skilled in
the art. One such protecting group is where --OR.sup.p represents a
C.sub.1-6alkoxy group or an arylalkoxy group eg benzyloxy, such
that COR.sup.p represents an ester. Such esters can be reacted with
a de-protecting agent e.g. a hydrolysing agent, for example lithium
hydroxide in a mixture of THF and water, at a temperature in the
range of 0-100.degree. C. to give compounds of formula I.
[0279] Compounds of formula II may be prepared by reacting a
compound of formula III ##STR16## in which A, T and n are as
previously defined with a compound of formula IV ##STR17## in which
R.sup.5 and R.sup.6 are as previously defined in an inert solvent,
for example dichloromethane, in the presence of a coupling agent,
for example a carbodimide, eg
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or oxalyl chloride,
optionally in the presence of a base particularly diisopropylethyl
amine, and optionally in the presence of a catalyst, for example a
basic catalyst, eg 4-dimethylaminopyridine, at a temperature in the
range of -25.degree. C. to 150.degree. C.
[0280] Compounds of formulae III and IV may be prepared by methods
described in the Examples or by analogous methods known to those
skilled in the art.
[0281] Compounds of formula II may be prepared by reacting a
compound of formula V ##STR18## in which A is as previously defined
with a compound of formula VI ##STR19## in which R.sup.5 and
R.sup.6 are as previously defined and X represents a leaving group,
for example a halide, OSO.sub.2CH.sub.3, OTosyl, ONosyl,
OSO.sub.2CF.sub.3, OC(O)OR, OP(O)(OR).sub.2 or OSO.sub.2OR,
particularly chloro or bromo, in an inert solvent, for example
acetonitrile, methyl isobutylketone, N-methylpyrrolidone, toluene,
toluene/water, ethanol or isopropylacetate in the presence of a
base, for example potassium carbonate, sodium hydroxide or
triethylamine, at a temperature in the range of -25.degree. C. to
150.degree. C. Optionally a catalyst may be used for example iodide
or a quartenary ammonium salt, particularly sodium iodide or
tetra-n-butylammonium-iodide, -bromide, -acetate or
-hydrogensulphate.
[0282] Compounds of formulae V and VI may be prepared by methods
described in the Examples or by analogous methods known to those
skilled in the art.
[0283] Formulae VI can be: [0284]
2-chloro-N-(2,4-difluorobenzyl)-N-octylacetamide [0285]
2-chloro-N-(2,4-difluorobenzyl)-N-nonylacetamide [0286]
2-chloro-N-(2,4-difluorobenzyl)-N-(4-ethylbenzyl)acetamide [0287]
2-chloro-N-(2,4-difluorobenzyl)-N-methylacetamide [0288]
2-chloro-N-heptyl-N-[(1-methyl-1H-indol-2-yl)methyl]acetamide
[0289] 2-chloro-N-(2,3-dimethoxybenzyl)-N-heptylacetamide [0290]
N-butyl-2-chloro-N-(2,3-dimethoxybenzyl)acetamide [0291]
2-chloro-N-(4-chlorobenzyl)-N-(4-isopropylbenzyl)acetamide [0292]
2-chloro-N-(cyclohexylmethyl)-N-(2,4-difluorobenzyl)acetamide
[0293] 2-chloro-N-ethyl-N-(2-fluorobenzyl)acetamide [0294]
N-[4-(benzyloxy)benzyl]-N-butyl-2-chloroacetamide [0295]
2-chloro-N-hexyl-N-(2-phenylethyl)acetamide [0296]
2-chloro-N,N-bis(4-chlorobenzyl)acetamide [0297]
N-(4-tert-butylbenzyl)-2-chloro-N-(4-chlorobenzyl)acetamide [0298]
2-chloro-N-(4-chlorobenzyl)-N-[4-(trifluoromethyl)benzyl]acetamide
[0299] 2-chloro-N,N-bis[4-(trifluoromethyl)benzyl]acetamide [0300]
N-benzyl-2-chloro-N-ethylacetamide [0301]
N-(4-tert-butylbenzyl)-2-chloro-N-ethylacetamide [0302]
2-chloro-N-ethyl-N-[4-(trifluoromethyl)benzyl]acetamide [0303]
2-chloro-N-(4-cyclohexylbutyl)-N-(2,4-difluorobenzyl)acetamide
[0304]
N-(2-biphenyl-4-ylethyl)-2-chloro-N-(2,4-difluorobenzyl)acetamide
[0305] 2-chloro-N-(4-chlorobenzyl)-N-(2-methoxybenzyl)acetamide
[0306] 4-{[butyl(chloroacetyl)amino]methyl}phenyl
methanesulfonate
[0307] Compounds of formulae II, III, IV, V and VI are useful
intermediates in the preparation of compounds of formula I.
Compounds of formula II, III, V and VI are herein claimed as a
further aspect of the present invention. The S-enantiomers of
compounds of formula II, III and V are preferred. The compounds of
the invention may be isolated from their reaction mixtures using
conventional techniques.
[0308] Persons skilled in the art will appreciate that, in order to
obtain compounds of the invention in an alternative and in some
occasions, more convenient manner, the individual process steps
mentioned hereinbefore may be performed in different order, and/or
the individual reactions may be performed at different stage in the
overall route (i.e. chemical transformations may be performed upon
different intermediates to those associated hereinbefore with a
particular reaction).
[0309] The expression "inert solvent" refers to a solvent that does
not react with the starting materials, reagents, intermediates or
products in a manner that adversely affects the yield of the
desired product.
Pharmaceutical Preparations
[0310] The compounds of the invention will normally be administered
via the oral, parenteral, intravenous, intramuscular, subcutaneous
or in other injectable ways, buccal, rectal, vaginal, transdermal
and/or nasal route and/or via inhalation, in the form of
pharmaceutical preparations comprising the active ingredient either
as a free acid, or a pharmaceutical acceptable organic or inorganic
base addition salt, in a pharmaceutically acceptable dosage form.
Depending upon the disorder and patient to be treated and the route
of administration, the compositions may be administered at varying
doses.
[0311] Suitable daily doses of the compounds of the invention in
therapeutical treatment of humans are about 0.0001-100 mg/kg body
weight, preferably 0.001-10 mg/kg body weight.
[0312] Oral formulations are preferred particularly tablets or
capsules which may be formulated by methods known to those skilled
in the art to provide doses of the active compound in the range of
0.5 mg to 500 mg for example 1 mg, 3 mg, 5 mg, 10 mg, 25 mg, 50 mg,
100 mg and 250 mg.
[0313] According to a further aspect of the invention there is thus
provided a pharmaceutical formulation including any of the
compounds of the invention, or pharmaceutically acceptable
derivatives thereof, in admixture with pharmaceutically acceptable
adjuvants, diluents and/or carriers.
Pharmacological Properties
[0314] The present compounds of formula (I) are useful for the
prophylaxis and/or treatment of clinical conditions associated with
inherent or induced reduced sensitivity to insulin (insulin
resistance) and associated metabolic disorders (also known as
metabolic syndrome). These clinical conditions will include, but
will not be limited to, general obesity, abdominal obesity,
arterial hypertension, hyperinsulinaemia, hyperglycaemia, type 2
diabetes and the dyslipidaemia characteristically appearing with
insulin resistance. This dyslipidaemia, also known as the
atherogenic lipoprotein profile, is characterised by moderately
elevated non-esterified fatty acids, elevated very low density
lipoprotein (VLDL) triglyceride rich particles, high Apo B levels,
low high density lipoprotein (HDL) levels associated with low apoAI
particle levels and high Apo B levels in the presence of small,
dense, low density lipoproteins (LDL) particles, phenotype B.
[0315] The compounds of the present invention are expected to be
useful in treating patients with combined or mixed hyperlipidemias
or various degrees of hypertriglyceridemias and postprandial
dyslipidemia with or without other manifestations of the metabolic
syndrome.
[0316] Treatment with the present compounds is expected to lower
the cardiovascular morbidity and mortality associated with
atherosclerosis due to their antidyslipidaemic as well as
antiinflammatory properties. The cardiovascular disease conditions
include macro-angiopathies of various internal organs causing
myocardial infarction, congestive heart failure, cerebrovascular
disease and peripheral arterial insufficiency of the lower
extremities. Because of their insulin sensitizing effect the
compounds of formula I are also expected to prevent or delay the
development of type 2 diabetes from the metabolic syndrome and
diabetes of pregnancy. Therefore the development of long-term
complications associated with chronic hyperglycaemia in diabetes
mellitus such as the micro-angiopathies causing renal disease,
retinal damage and peripheral vascular disease of the lower limbs
are expected to be delayed. Furthermore the compounds may be useful
in treatment of various conditions outside the cardiovascular
system whether or not associated with insulin resistance, like
polycystic ovarian syndrome, obesity, cancer and states of
inflammatory disease including neurodegenerative disorders such as
mild cognitive impairment, Alzheimer's disease, Parkinson's disease
and multiple sclerosis.
[0317] The compounds of the present invention are expected to be
useful in controlling glucose levels in patients suffering from
type 2 diabetes.
[0318] The present invention provides a method of treating or
preventing dyslipidemias, the insulin resistance syndrome and/or
metabolic disorders (as defined above) comprising the
administration of a compound of formula I to a mammal (particularly
a human) in need thereof.
[0319] The present invention provides a method of treating or
preventing type 2 diabetes comprising the administration of an
effective amount of a compound of formula I to a mammal
(particularly a human) in need thereof.
[0320] In a further aspect the present invention provides the use
of a compound of formula I as a medicament.
[0321] In a further aspect the present invention provides the use
of a compound of formula I in the manufacture of a medicament for
the treatment of insulin resistance and/or metabolic disorders.
Combination Therapy
[0322] The compounds of the invention may be combined with another
therapeutic agent that is useful in the treatment of disorders
associated with the development and progress of atherosclerosis
such as hypertension, hyperlipidaemias, dyslipidaemias, diabetes
and obesity. The compounds of the invention may be combined with
another therapeutic agent that decreases the ratio of LDL:HDL or an
agent that causes a decrease in circulating levels of
LDL-cholesterol. In patients with diabetes mellitus the compounds
of the invention may also be combined with therapeutic agents used
to treat complications related to micro-angiopathies.
[0323] The compounds of the invention may be used alongside other
therapies for the treatment of metabolic syndrome or type 2
diabetes and its associated complications, these include biguanide
drugs, for example metformin, phenformin and buformin, insulin
(synthetic insulin analogues, amylin) and oral antihyperglycemics
(these are divided into prandial glucose regulators and
alpha-glucosidase inhibitors). An example of an alpha-glucosidase
inhibitor is acarbose or voglibose or miglitol. An example of a
prandial glucose regulator is repaglinide or nateglinide.
[0324] In another aspect of the invention, the compound of formula
I, or a pharmaceutically acceptable salt, solvate, solvate of such
a salt or a prodrug thereof, may be administered in association
with another PPAR modulating agent. PPAR modulating agents include
but are not limited to a PPAR alpha and/or gamma and/or delta
agonist, or pharmaceutically acceptable salts, solvates, solvates
of such salts or prodrugs thereof. Suitable PPAR alpha and/or gamma
agonists, pharmaceutically acceptable salts, solvates, solvates of
such salts or prodrugs thereof are well known in the art. These
include the compounds described in WO 01/12187, WO 01/12612, WO
99/62870, WO 99/62872, WO 99/62871, WO 98/57941, WO 01/40170, J Med
Chem, 1996, 39, 665, Expert Opinion on Therapeutic Patents, 10 (5),
623-634 (in particular the compounds described in the patent
applications listed on page 634) and J Med Chem, 2000, 43, 527
which are all incorporated herein by reference. Particularly a PPAR
alpha and/or gamma agonist refers to BMS 298585, clofibrate,
fenofibrate, bezafibrate, gemfibrozil and ciprofibrate; GW 9578,
pioglitazone, rosiglitazone, rivoglitazone, balaglitazone, KRP-297,
JTT-501, SB 213068, GW 1929, GW 7845, GW 0207, L-796449, L-165041
and GW 2433. Particularly a PPAR alpha and/or gamma agonist refers
to
(S)-2-ethoxy-3-[4-(2-{4-methanesulphonyloxy-phenyl}ethoxy)phenyl]propanoi-
c acid and pharmaceutically acceptable salts thereof.
[0325] In addition the combination of the invention may be used in
conjunction with a sulfonylurea for example: glimepiride,
glibenclamide (glyburide), gliclazide, glipizide, gliquidone,
chloropropamide, tolbutamide, acetohexamide, glycopyramide,
carbutamide, glibonuride, glisoxepid, glybuthiazole, glibuzole,
glyhexamide, glymidine, glypinamide, phenbutamide, tolcylamide and
tolazamide. Preferably the sulfonylurea is glimepiride or
glibenclamide (glyburide). More preferably the sulfonylurea is
glimepiride. Therefore the present invention includes
administration of a compound of the present invention in
conjunction with one, two or more existing therapies described in
this paragraph. The doses of the other existing therapies for the
treatment of type 2 diabetes and its associated complications will
be those known in the art and approved for use by regulatory bodies
for example the FDA and may be found in the Orange Book published
by the FDA. Alternatively smaller doses may be used as a result of
the benefits derived from the combination. The present invention
also includes a compound of the present invention in combination
with a cholesterol-lowering agent. The cholesterol-lowering agents
referred to in this application include but are not limited to
inhibitors of HMG-CoA reductase (3-hydroxy-3-methylglutaryl
coenzyme A reductase). Suitably the HMG-CoA reductase inhibitor is
a statin selected from the group consisting of atorvastatin,
bervastatin, cerivastatin, dalvastatin, fluvastatin, itavastatin,
lovastatin, mevastatin, nicostatin, nivastatin, pravastatin and
simvastatin, or a pharmaceutically acceptable salt, especially
sodium or calcium, or a solvate thereof, or a solvate of such a
salt. A particular statin is atorvastatin, or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof. A more particular statin is atorvastatin calcium salt. A
particularly preferred statin is, however, a compound with the
chemical name
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)-amino]-py-
rimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, [also known as
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[N-methyl-N-(methylsulfonyl)-amin-
o]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] or a
pharmaceutically acceptable salt or solvate thereof, or a solvate
of such a salt. The compound
(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl-(methylsulfonyl)-amino]-p-
yrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, and its
calcium and sodium salts are disclosed in European Patent
Application, Publication No. EP-A-0521471, and in Bioorganic and
Medicinal Chemistry, (1997), 5(2), 437-444. This latter statin is
now known under its generic name rosuvastatin.
[0326] In the present application, the term "cholesterol-lowering
agent" also includes chemical modifications of the HMG-CoA
reductase inhibitors, such as esters, prodrugs and metabolites,
whether active or inactive.
[0327] The present invention also includes a compound of the
present invention in combination with a bile acid sequestering
agent, for example colestipol or cholestyramine or cholestagel.
[0328] The present invention also includes a compound of the
present invention in combination with an inhibitor of the ileal
bile acid transport system (IBAT inhibitor).
[0329] Suitable compounds possessing IBAT inhibitory activity have
been described, see for instance the compounds described in WO
93/16055, WO 94/18183, WO 94/18184, WO 96/05188, WO 96/08484, WO
96/16051, WO 97/33882, WO 98/07449, WO 98/03818, WO 98/38182, WO
99/32478, WO 99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO
99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 00/62810, WO
01/68906, DE 19825804, WO 00/38725, WO 00/38726, WO 00/38727, WO
00/38728, WO 00/38729, WO 01/68906, WO 01/66533, WO 02/32428, WO
02/50051, EP 864 582, EP489423, EP549967, EP573848, EP624593,
EP624594, EP624595 and EP624596 and the contents of these patent
applications are incorporated herein by reference.
[0330] Particular classes of IBAT inhibitors suitable for use in
the present invention are benzothiepines, and the compounds
described in the claims, particularly claim 1, of WO 00/01687, WO
96/08484 and WO 97/33882 are incorporated herein by reference.
Other suitable classes of IBAT inhibitors are the
1,2-benzothiazepines, 1,4-benzothiazepines and
1,5-benzothiazepines. A further suitable class of IBAT inhibitors
is the 1,2,5-benzothiadiazepines.
[0331] One particular suitable compound possessing IBAT inhibitory
activity is
(3R,5R)-3-butyl-3-ethyl-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzo-
thiazepin-8-yl .beta.-D-glucopyranosiduronic acid (EP 864 582).
Other suitable IBAT inhibitors include one of: [0332]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(c-
arboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-ben-
zothiazepine; [0333]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N'-(carbox-
ymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,-
5-benzothiazepine; [0334]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N'-(2-
-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-ben-
zothiazepine; [0335]
1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1'-phenyl-1'-[N-
'-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-
-benzothiazepine; [0336]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N'-(2-sulp-
hoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,-
5-benzothiazepine; [0337]
1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N'-(2--
sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydr-
o-1,5-benzothiazepine; [0338]
1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N'-(2--
carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-ben-
zothiazepine; [0339]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N'-(2-carb-
oxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1-
,5-benzothiazepine; [0340]
1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N'-(5--
carboxypentyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-be-
nzothiazepine; [0341]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N'-(2-carb-
oxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzoth-
iazepine; [0342]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{.alpha.-[N'-(2-sulphoet-
hyl)carbamoyl]-2-fluorobenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-ben-
zothiazepine; [0343]
1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N'-(R)-
-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetr-
ahydro-1,5-benzothiazepine; [0344]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N'-(R)-(2--
hydroxy-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahyd-
ro-1,5-benzothiazepine; [0345]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-.alpha.-(N'-{(R)-1--
[N''-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]-2-hydroxyethyl}carbamoyl)ben-
zyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;
[0346]
1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{.alpha.-[N'-(carbox-
ymethyl)-carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzoth-
iazepine; [0347]
1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{1-[N'-((ethoxy)(met-
hyl)phosphoryl-methyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydr-
o-1,5-benzothiazepine; [0348]
1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-.alpha.-(N'-{2--
[(hydroxy)(methyl)phosphoryl]ethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,-
4,5-tetrahydro-1,5-benzothiazepine; [0349]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N'-(2-meth-
ylthio-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydr-
o-1,5-benzothiazepine; [0350]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-.alpha.-(N'-{2-[(me-
thyl)(ethyl)phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}--
2,3,4,5-tetrahydro-1, 5-benzothiazepine; [0351]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-.alpha.-(N'-{2-[(me-
thyl)(hydroxy)phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy-
}-2,3,4,5-tetrahydro-1, 5-benzothiazepine; [0352]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[(R)-N'-(2--
methylsulphinyl-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5--
tetrahydro-1,5-benzothiazepine; [0353]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-[N-{(R)-.alpha.-[N'-(2-sulphoe-
thyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-b-
enzothiazepine; [0354]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-((R)-1-c-
arboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3-
,4,5-tetrahydro-1, 2,5-benzothiadiazepine; [0355]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-((S)-1-c-
arboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,-
3,4,5-tetrahydro-1,2,5-benzothiadiazepine; [0356]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-((S)-1-c-
arboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-
-tetrahydro-1,2,5-benzothiadiazepine; [0357]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-((S)-1-c-
arboxybutyl)
carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-ben-
zothiadiazepine; [0358]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-((S)-1-c-
arboxypropyl)
carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiaz-
epine; [0359]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-((S)-1-c-
arboxyethyl)
carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiaz-
epine; [0360]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-((S)-1-c-
arboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetr-
ahydro-1,2,5-benzothiadiazepine; [0361]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-(2-sulph-
oethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2-
,5-benzothiadiazepine; [0362]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-((S)-1-c-
arboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydr-
o-1,2,5-benzothiadiazepine; [0363]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-((R)-1-c-
arboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrah-
ydro-1,2,5-benzothiadiazepine; [0364]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-{(S)-1-[-
N-((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoy-
lmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; [0365]
1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-((S)-1-c-
arboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydr-
o-1,2,5-benzothiadiazepine; [0366]
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-((S)-1-c-
arboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahyd-
ro-1,2,5-benzothiadiazepine; [0367]
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R/S)-.alpha.-{N-[1-(R)-
-2-(S)-1-hydroxy-1-(3,4-dihydroxyphenyl)prop-2-yl]carbamoyl}-4-hydroxybenz-
yl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;
[0368]
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-(2-(S)-3-
-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]-4-hydroxybenzyl}ca-
rbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine; and
[0369]
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-.alpha.-[N-(2-(S)-3-
-(R)-4-(R)-5-(R)-2,3,4,5,6-pentahydroxyhexyl)carbamoyl]benzyl}carbamoylmet-
hoxy)-2,3,4,5-tetrahydro-1, 2,5-benzothiadiazepine; or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof.
[0370] According to an additional further aspect of the present
invention there is provided a combination treatment comprising the
administration of an effective amount of a compound of the formula
I, or a pharmaceutically acceptable salt, solvate, solvate of such
a salt or a prodrug thereof, optionally together with a
pharmaceutically acceptable diluent or carrier, with the
simultaneous, sequential or separate administration one or more of
the following agents selected from:
a CETP (cholesteryl ester transfer protein) inhibitor, for example
those referenced and described in WO 00/38725 page 7 line 22-page
10, line 17 which are incorporated herein by reference;
a cholesterol absorption antagonist for example azetidinones such
as SCH 58235 and those described in U.S. Pat. No. 5,767,115 which
are incorporated herein by reference;
a MTP (microsomal transfer protein) inhibitor for example those
described in Science, 282, 751-54, 1998 which are incorporated
herein by reference;
a nicotinic acid derivative, including slow release and combination
products, for example, nicotinic acid (niacin), acipimox and
niceritrol;
a phytosterol compound for example stanols;
probucol;
an omega-3 fatty acid for example Omacor.TM.;
an anti-obesity compound for example orlistat (EP 129,748) and
sibutramine (GB 2,184,122 and U.S. Pat. No. 4,929,629);
[0371] an antihypertensive compound for example an angiotensin
converting enzyme (ACE) inhibitor, an angiotensin II receptor
antagonist, an andrenergic blocker, an alpha andrenergic blocker, a
beta andrenergic blocker for example metoprolol, a mixed alpha/beta
andrenergic blocker, an andrenergic stimulant, calcium channel
blocker, an AT-1 blocker, a saluretic, a diuretic or a
vasodilator;
a CB1 antagonist or inverse agonist for example as described in
WO01/70700 and EP 65635;
a Melanin concentrating hormone (MCH) antagonist;
a PDK inhibitor; or
modulators of nuclear receptors for example LXR, FXR, RXR, and
RORalpha;
or a pharmaceutically acceptable salt, solvate, solvate of such a
salt or a prodrug thereof, optionally together with a
pharmaceutically acceptable diluent or carrier to a warm-blooded
animal, such as man in need of such therapeutic treatment.
[0372] Particular ACE inhibitors or pharmaceutically acceptable
salts, solvates, solvate of such salts or a prodrugs thereof,
including active metabolites, which can be used in combination with
a compound of formula I include but are not limited to, the
following compounds: alacepril, alatriopril, altiopril calcium,
ancovenin, benazepril, benazepril hydrochloride, benazeprilat,
benzoylcaptopril, captopril, captopril-cysteine,
captopril-glutathione, ceranapril, ceranopril, ceronapril,
cilazapril, cilazaprilat, delapril, delapril-diacid, enalapril,
enalaprilat, enapril, epicaptopril, foroxymithine, fosfenopril,
fosenopril, fosenopril sodium, fosinopril, fosinopril sodium,
fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4, idrapril,
imidapril, indolapril, indolaprilat, libenzapril, lisinopril,
lyciumin A, lyciumin B, mixanpril, moexipril, moexiprilat,
moveltipril, muracein A, muracein B, muracein C, pentopril,
perindoprii, perindoprilat, pivalopril, pivopril, quinapril,
quinapril hydrochloride, quinaprilat, ramipril, ramiprilat,
spirapril, spirapril hydrochloride, spiraprilat, spiropril,
spiropril hydrochloride, temocapril, temocapril hydrochloride,
teprotide, trandolapril, trandolaprilat, utibapril, zabicipril,
zabiciprilat, zofenopril and zofenoprilat. Preferred ACE inhibitors
for use in the present invention are ramipril, ramiprilat,
lisinopril, enalapril and enalaprilat. More preferred ACE
inhibitors for uses in the present invention are ramipril and
ramiprilat.
[0373] Preferred angiotensin II antagonists, pharmaceutically
acceptable salts, solvates, solvate of such salts or a prodrugs
thereof for use in combination with a compound of formula I
include, but are not limited to, compounds: candesartan,
candesartan cilexetil, losartan, valsartan, irbesartan, tasosartan,
telmisartan and eprosartan. Particularly preferred angiotensin II
antagonists or pharmaceutically acceptable derivatives thereof for
use in the present invention are candesartan and candesartan
cilexetil.
[0374] Therefore in an additional feature of the invention, there
is provided a method for the treatment of type 2 diabetes and its
associated complications in a warm-blooded animal, such as man, in
need of such treatment which comprises administering to said animal
an effective amount of a compound of formula I, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof in simultaneous, sequential or separate
administration with an effective amount of one the other compounds
described in this combination section, or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof.
[0375] Therefore in an additional feature of the invention, there
is provided a method of treating hyperlipidemic conditions in a
warm-blooded animal, such as man, in need of such treatment which
comprises administering to said animal an effective amount of a
compound of formula I, or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof in
simultaneous, sequential or separate administration with an
effective amount of one the other compounds described in this
combination section or a pharmaceutically acceptable salt, solvate,
solvate of such a salt or a prodrug thereof.
[0376] According to a further aspect of the invention there is
provided a pharmaceutical composition which comprises a compound of
formula I, or a pharmaceutically acceptable salt, solvate, solvate
of such a salt or a prodrug thereof, and one of the other compounds
described in this combination section or a pharmaceutically
acceptable salt, solvate, solvate of such a salt or a prodrug
thereof, in association with a pharmaceutically acceptable diluent
or carrier.
[0377] According to a further aspect of the present invention there
is provided a kit comprising a compound of formula I, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, and one of the other compounds described in
this combination section or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof.
[0378] According to a further aspect of the present invention there
is provided a kit comprising:
a) a compound of formula I, or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof, in a first
unit dosage form;
b) one of the other compounds described in this combination section
or a pharmaceutically acceptable salt, solvate, solvate of such a
salt or a prodrug thereof; in a second unit dosage form; and
c) container means for containing said first and second dosage
forms.
[0379] According to a further aspect of the present invention there
is provided a kit comprising:
a) a compound of formula I, or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof, together with
a pharmaceutically acceptable diluent or carrier, in a first unit
dosage form;
b) one of the other compounds described in this combination section
or a pharmaceutically acceptable salt, solvate, solvate of such a
salt or a prodrug thereof, in a second unit dosage form; and
c) container means for containing said first and second dosage
forms.
[0380] According to another feature of the invention there is
provided the use of a compound of the formula I, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, and one of the other compounds described in
this combination section, or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof, in the
manufacture of a medicament for use in the treatment of metabolic
syndrome or type 2 diabetes and its associated complications in a
warm-blooded animal, such as man.
[0381] According to another feature of the invention there is
provided the use of a compound of the formula I, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, and one of the other compounds described in
this combination section, or a pharmaceutically acceptable salt,
solvate, solvate of such a salt or a prodrug thereof, in the
manufacture of a medicament for use in the treatment of
hyperlipidaemic conditions in a warm-blooded animal, such as
man.
[0382] According to a further aspect of the present invention there
is provided a combination treatment comprising the administration
of an effective amount of a compound of the formula I, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, optionally together with a pharmaceutically
acceptable diluent or carrier, with the simultaneous, sequential or
separate administration of an effective amount of one of the other
compounds described in this combination section, or a
pharmaceutically acceptable salt, solvate, solvate of such a salt
or a prodrug thereof, optionally together with a pharmaceutically
acceptable diluent or carrier to a warm-blooded animal, such as man
in need of such therapeutic treatment.
EXAMPLES
[0383] .sup.1H NMR and .sup.13C NMR measurements were performed on
a Varian Mercury 300 or Varian UNITY plus 400, 500 or 600
spectrometers, operating at .sup.1H frequencies of 300, 400, 500
and 600 MHz, respectively, and at .sup.13C frequencies of 75, 100,
125 and 150 MHz, respectively. Measurements were made on the delta
scale (6).
[0384] Unless otherwise stated, chemical shifts are given in ppm
with the solvent as internal standard.
[0385] Abbreviations [0386] DMSO dimethyl sulfoxide [0387] THF
tetrahydrofuran [0388] Pd/C palladium on charcoal [0389] DMAP
dimethylaminopyridine [0390] t triplet [0391] s singlet [0392] d
doublet [0393] q quartet [0394] m multiplet [0395] bs broad singlet
[0396] dm doublet of multiplet [0397] bt broad triplet [0398] dd
doublet of doublet
Example 1
(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(octyl)amino]-2-oxoethoxy}phenyl)-2-etho-
xypropanoic acid
(i) N-(2,4-Difluorobenzyl)octanamide
[0399] To a solution of 2,4-difluorobenzylamine (0.43 g, 3.0 mmol)
in methylene chloride (30 mL) were added octanoic acid (0.43 g, 3.0
mmol) and DMAP (0.37 g, 3.0 mmol) followed by
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60
g, 3.1 mmol) and the reaction mixture was stirred at room
temperature overnight. The resulting solution was diluted with
methylene chloride (100 mL) and the organic phase washed with 5%
HCl (3.times.75 mL), aqueous NaHCO.sub.3 (75 mL), and brine (75 mL)
and dried over anhydrous Na.sub.2SO.sub.4. Concentration in vacuo
afforded 0.78 g (96%) of an oil, which solidified upon
standing.
[0400] .sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 0.81-0.90 (m,
3H), 1.18-1.33 (m, 8H), 1.54-1.66 (m, 2H), 2.12-2.21 (m, 2H), 4.42
(d, 2H), 5.82 (bs, 1H), 6.73-6.87 (m, 2H), 7.32 (m, 1H).
(ii) N-(2,4-Difluorobenzyl)-N-octylamine hydrochloride
[0401] N-(2,4-Difluorobenzyl)octanamide (0.64 g, 2.4 mmol) was
dissolved in freshly distilled THF (20 mL) and cooled on an ice
bath under an argon atmosphere. Borane (3.0 mL of a 2 M solution of
the dimethylsulfide complex in diethyl ether) was added and the ice
bath was removed after 15 minutes. The reaction mixture was
refluxed for twenty hours and was then allowed to cool to room
temperature. The reaction was quenched by careful addition of 10%
HCl (1.2 mL) and the mixture was stirred overnight and then
concentrated in vacuo. Addition of ice cold THF (15 mL) afforded a
white precipitate, which was filtered off and dried in vacuo to
give 0.40 g (58%) of a white salt.
[0402] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 0.85-0.93 (m,
3H), 1.20-1.45 (m, 10H), 1.65-1.89 (m, 2H), 3.01-3.09 (m, 2H), 4.25
(s, 2H), 7.04-7.16 (m, 2H), 7.63 (m, 1H).
(iii) Ethyl
(2S)-3-(4-{2-[(2,4-difluorobenzyl)(octyl)amino]-2-oxoethoxy}phenyl)-2-eth-
oxypropanoate
[0403] To a solution of
{4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.120 g,
0.40 mmol) in methylene chloride (5.0 mL) were added
N-(2,4-difluorobenzyl)-N-octylamine hydrochloride (0.165 g, 0.57
mmol), DMAP (0.054 g, 0.45 mmol) and N,N-diisopropylethylamine
(0.078 mL, 0.45 mmol) followed by
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.085
g, 0.45 mmol) and the reaction mixture was stirred at room
temperature overnight. The resulting solution was diluted with
methylene chloride (50 mL) and the organic phase washed with 5% HCl
(3.times.25 mL), aqueous NaHCO.sub.3 (25 mL), and brine (25 mL),
dried over anhydrous Na.sub.2SO.sub.4, and concentrated in vacuo.
Purification on a prepacked column of silica gel (Isolute.RTM. SPE
Column, 5 g Si/25 mL) with methanol (0-1% gradient) in methylene
chloride as the eluent afforded 0.082 g (38%) of a colourless
oil.
[0404] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.80-0.90 (m,
3H), 1.14 (t, 3H), 1.17-1.30 (m, 13H), 1.42-1.64 (m, 2H), 2.86-3.00
(m, 2H), 3.20-3.40 (m, 3H), 3.59 (m, 1H), 3.95 (m, 1H), 4.15 (q,
2H), 4.59 (s, 2H), 4.69 and 4.70 (2s, 2H, rotamers), 6.71-6.88 (m,
4H), 7.07-7.18 and 7.20-7.31 (2m, 3H, rotamers).
(iv)
(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(octyl)amino]-2-oxoethoxy}phenyl)-2-
-ethoxypropanoic acid
[0405] To a solution of ethyl
(2S)-3-(4-{2-[(2,4-difluorobenzyl)(octyl)amino]-2-oxoethoxy}phenyl)-2-eth-
oxypropanoate (0.038 g, 0.071 mmol) in THF (3 mL) was added aqueous
0.10 M LiOH (2 mL) and the reaction mixture was stirred at room
temperature overnight. After acidification with 5% HCl, the mixture
was extracted with ethyl acetate (3.times.25 mL) and the combined
organic phase washed with brine (25 mL), dried over anhydrous
Na.sub.2SO.sub.4, and concentrated in vacuo to afford 0.035 g (98%)
of a colourless oil.
[0406] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.0.83-0.93 (m, 3H),
1.17 (t, 3H), 1.20-1.35 (m, 10H), 1.42-1.68 (m, 2H), 2.88-3.10 (m,
2H), 3.24-3.35 (m, 2H), 3.41 (m, 1H), 3.62 (m, 1H), 4.03 (m, 1H),
4.62 (s, 2H), 4.72 and 4.73 (2s, 2H, rotamers), 6.70-6.90 (m, 4H),
7.09-7.21 and 7.24-7.34 (2m, 3H, rotamers).
Example 2
(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-etho-
xypropanoic acid
(i) N-(2,4-Difluorobenzyl)nonanamide
[0407] To a solution of 2,4-difluorobenzylamine (0.47 g, 3.3 mmol)
in methylene chloride (30 mL) were added nonanoic acid (0.52 g, 3.3
mmol) and DMAP (0.40 g, 3.3 mmol) followed by
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.67
g, 3.5 mmol) and the reaction mixture was stirred at room
temperature overnight. The resulting solution was diluted with
methylene chloride (100 mL) and the organic phase washed with 5%
HCl (3.times.75 mL), aqueous NaHCO.sub.3 (75 mL), and brine (75 mL)
and dried over anhydrous Na.sub.2SO.sub.4. Concentration in vacuo
afforded 0.87 g (93%) of an oil, which solidified upon
standing.
[0408] .sup.1H NMR (600 MHz, CDCl.sub.3): .delta.0.80-0.86 (m, 3H),
1.16-1.28 (m, 10H), 1.53-1.62 (m, 2H), 2.11-2.17 (m, 2H), 4.37 (d,
2H), 6.12 (bs, 1H), 6.70-6.81 (m, 2H), 7.27 (m, 1H).
(ii) (N-(2,4-Difluorobenzyl)-N-nonylamine hydrochloride
[0409] N-(2,4-Difluorobenzyl)nonanamide (0.75 g, 2.6 mmol) was
dried once by azeotropic distillation with toluene, dissolved in
freshly distilled THF (23 mL), and cooled on an ice bath under an
argon atmosphere. Borane (3.3 mL of a 2 M solution of the
dimethylsulfide complex in diethyl ether) was added and the ice
bath was removed after 15 minutes. The reaction mixture was
refluxed for five hours and was then allowed to cool to room
temperature. The reaction was quenched by careful addition of 10%
HCl (1.3 mL) and the mixture was stirred for three hours and then
concentrated in vacuo. Addition of ice cold THF (15 mL) afforded a
white precipitate, which was filtered off and dried in vacuo to
give 0.69 g (85%) of a white salt.
[0410] .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 0.85-0.94 (m,
3H), 1.20-1.45 (m, 12H), 1.65-1.80 (m, 2H), 3.00-3.10 (m, 2H), 4.26
(s, 2H), 7.04-7.16 (m, 2H), 7.64 (m, 1H).
(iii) Ethyl
(2S)-3-(4-{2-[(2,4-difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-eth-
oxypropanoate
[0411] To a solution of
{4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.120 g,
0.40 mmol) in methylene chloride (5.0 mL) were added
(N-(2,4-difluorobenzyl)-N-nonylamine hydrochloride (0.173 g, 0.57
mmol), DMAP (0.058 g, 0.45 mmol), and N,N-diisopropylethylamine
(0.078 mL, 0.45 mmol) followed by
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.085
g, 0.45 mmol) and the reaction mixture was stirred at room
temperature overnight. The resulting solution was diluted with
methylene chloride (50 mL) and the organic phase washed with 5% HCl
(3.times.25 mL), aqueous NaHCO.sub.3 (25 mL), and brine (25 mL),
dried over anhydrous Na.sub.2SO.sub.4, and concentrated in vacuo.
Purification on a prepacked column of silica gel (Isolute.RTM. SPE
Column, 5 g Si/25 mL) with methanol (0-1% gradient) in methylene
chloride as the eluent afforded 0.117 g (53%) of a colourless
oil.
[0412] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.82-0.90 (m,
3H), 1.14 (t, 3H), 1.17-1.30 (m, 15H), 1.42-1.62 (m, 2H), 2.88-3.00
(m, 2H), 3.23-3.38 (m, 3H), 3.58 (m, 1H), 3.95 (m, 1H), 4.14 (q,
2H), 4.59 (s, 2H), 4.68 and 4.69 (2s, 2H, rotamers), 6.70-6.90 (m,
4H), 7.06-7.18 and 7.20-7.31 (2m, 3H, rotamers).
(iv)
(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-
-ethoxypropanoic acid
[0413] To a solution of ethyl
(2S)-3-(4-{2-[(2,4-difluorobenzyl)(nonyl)amino]-2-oxoethoxy}phenyl)-2-eth-
oxypropanoate (0.038 g, 0.070 mmol) in THF (3 mL) was added aqueous
0.10 M LiOH (2 mL) and the reaction mixture was stirred at room
temperature overnight. After acidification with 5% HCl, the mixture
was extracted with ethyl acetate (3.times.25 mL) and the combined
organic phase washed with brine (25 mL), dried over anhydrous
Na.sub.2SO.sub.4, and concentrated in vacuo to afford 0.034 g (94%)
of a colourless oil.
[0414] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.83-0.93 (m,
3H), 1.17 (t, 3H), 1.20-1.35 (m, 12H), 1.44-1.66 (m, 2H), 2.90-3.10
(m, 2H), 3.25-3.34 (m, 2H), 3.42 (m, 1H), 3.62 (m, 1H), 4.04 (m,
1H), 4.62 (s, 2H), 4.72 and 4.73 (2s, 2H, rotamers), 6.73-6.90 (m,
4H), 7.09-7.21 and 7.24-7.34 (2m, 3H, rotamers).
Example 3
(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl-
)-2-ethoxypropanoic acid
(i) N-(2,4-Difluorobenzyl)-4-ethylbenzamide
[0415] To a solution of 2,4-difluorobenzylamine (3.58 g, 25.0 mmol)
in methylene chloride (250 mL) were added 4-ethylbenzoic acid (3.94
g, 26.3 mmol) and DMAP (3.36 g, 27.5 mmol) followed by
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27
g, 27.5 mmol) and the reaction mixture was stirred at room
temperature overnight. The resulting solution washed with 5% HCl
(3.times.100 mL), saturated aqueous NaHCO.sub.3 (100 mL), and brine
(100 mL) and dried over Na.sub.2SO.sub.4. Concentration in vacuo
afforded 6.49 g (94%) of white solid.
[0416] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.24 (t, 3H),
2.69 (q, 2H), 4.64 (d, 2H), 6.45 (bs, 1H), 6.77-6.90 (m, 2H), 7.25
(d, 2H), 7.41 (m, 1H), 7.69 (d, 2H).
(ii) N-(2,4-Difluorobenzyl)-N-(4-ethylbenzyl)amine
[0417] N-(2,4-Difluorobenzyl)-4-ethylbenzamide (6.20 g, 22.5 mmol)
was dissolved in freshly distilled THF (220 mL) and cooled in an
ice bath under an argon atmosphere. Borane (28 mL of a 2 M solution
of the dimethylsulfide complex in diethyl ether) was added and the
ice bath was removed after 15 minutes. The reaction mixture was
refluxed overnight and was then allowed to cool to room
temperature. The reaction was quenched at 0.degree. C. by careful
addition of 10% HCl (11 mL) and the mixture was stirred at room
temperature for three hours and then concentrated in vacuo. The
residue was taken up in ethyl acetate (200 mL) and aqueous 2 M
K.sub.2CO.sub.3 (200 mL) and the phases were separated. The aqueous
phase was extracted with ethyl acetate (2.times.200 mL) and the
combined organic phase washed with brine (100 mL), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo to afford 5.56 g (94%)
of a yellow oil.
[0418] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.24 (t, 3H),
2.65 (q, 2H), 3.77 (s, 2H), 3.82 (s, 2H), 6.75-6.90 (m, 2H), 7.17
(d, 2H), 7.25 (d, 2H), 7.34 (m, 1H).
(iii) Ethyl
(2S)-3-(4-{2-[(2,4-difluorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}pheny-
l)-2-ethoxypropanoate
[0419] To a solution of
{4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0
mmol) and N-(2,4-difluorobenzyl)-N-(4-ethylbenzyl)amine (1.57 g,
6.0 mmol) in methylene chloride (50 mL) at 0.degree. C. were added
N,N-diisopropylethylamine (2.0 mL, 11.5 mmol) followed by
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was
stirred overnight and then concentrated in vacuo. The residue was
taken up in ethyl acetate (200 mL) and the organic phase washed
with 5% HCl (3.times.100 mL), saturated aqueous NaHCO.sub.3 (100
mL), and brine (100 mL), dried over Na.sub.2SO.sub.4, and
concentrated in vacuo. Purification on silica gel (240 g) with
methanol (0-4% gradient) in methylene chloride as the eluent and
collection of pure fractions afforded 1.18 g (44%) of a colourless
oil.
[0420] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.16 (t, 3H),
1.19-1.27 (m, 6H), 2.57-2.70 (m, 2H), 2.90-3.00 (m, 2H), 3.35 (m,
1H), 3.60 (m, 1H), 3.96 (m, 1H), 4.16 (q, 2H), 4.52, 4.54, 4.56 and
4.59 (4s, 4H, rotamers), 4.74 and 4.80 (2s, 2H, rotamers),
6.69-6.88 (m, 4H), 7.02-7.22 and 7.25-7.36 (2m, 7H, rotamers).
(iv)
(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}p-
henyl)-2-ethoxypropanoic acid
[0421] To a solution of ethyl
(2S)-3-(4-{2-[(2,4-difluorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}pheny-
l)-2-ethoxypropanoate (1.13 g, 2.1 mmol) in acetonitrile (100 mL)
was added aqueous 0.10 M LiOH (52 mL) and the solution was stirred
at room temperature overnight. After neutralisation with 5% HCl,
the solvent volume was reduced in vacuo and the remaining aqueous
phase was acidified with 5% HCl and extracted with ethyl acetate
(3.times.100 mL). The combined organic phase washed with brine (100
mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to
afford 1.01 g (94%) of a colourless oil.
[0422] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.16 (t, 3H),
1.19-1.28 (m, 3H), 2.56-2.71 (m, 2H), 2.95 (m, 1H), 3.05 (m, 1H),
3.41 (m, 1H), 3.61 (m, 1H), 4.02 (m, 1H), 4.52, 4.54, 4.55 and 4.59
(4s, 4H, rotamers), 4.75 and 4.81 (2s, 2H, rotamers), 6.70-6.88 (m,
4H), 7.04-7.22 and 7.25-7.35 (2m, 7H, rotamers), 8.04 (bs, 1H).
Example 4
(2S)-3-(4-{2-[Benzyl(methyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic
acid
(i) Ethyl
(2S)-3-(4-{2-[benzyl(methyl)amino]-2-oxoethoxy}phenyl)-2-ethoxyp-
ropanoate
[0423] To a solution of
{4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.320 g,
1.08 mmol) in methylene chloride (10 mL) were added
N-methylbenzylamine (0.145 g, 1.20 mmol) and
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (0.353 g, 1.10 mmol) and the reaction mixture was
stirred at room temperature for three days. The resulting solution
was diluted with methylene chloride (100 mL) and the organic phase
was washed with 5% HCl (3.times.50 mL), aqueous NaHCO.sub.3 (50 mL)
and brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, and
concentrated in vacuo. Purification on a prepacked column of silica
gel (Isolute.RTM. SPE Column, 10 g Si/70 mL) with methanol (0-1%
gradient) in methylene chloride as the eluent afforded 0.186 g
(43%) of a colourless oil.
[0424] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.10-1.24 (m,
6H), 2.88-2.99 (m, 2H), 2.91 and 2.95 (2s, 3H, rotamers), 3.33 (m,
1H), 3.58 (m, 1H), 3.95 (m, 1H), 4.08-4.20 (m, 2H), 4.57 and 4.59
(2s, 2H, rotamers), 4.69 and 4.70 (2s, 2H, rotamers), 6.77 and 6.87
(2d, 2H, rotamers), 7.07-7.38 (m, 7H).
(ii)
(2S)-3-(4-{2-[Benzyl(methyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropan-
oic acid
[0425] To a solution of ethyl
(2S)-3-(4-{2-[benzyl(methyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate
(0.155 g, 0.39 mmol) in THF (20 mL) was added aqeuous 0.10 M LiOH
(10 mL) and the reaction mixture was stirred overnight. After
acidification with 5% HCl, the mixture was extracted with ethyl
acetate (3.times.50 mL) and the combined organic phase washed with
brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, and
concentrated in vacuo to afford 0.139 g (97%) of a colourless
oil.
[0426] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.10-1.20 (m,
3H), 2.86-3.10 (m, 2H), 2.94 and 2.97 (2s, 3H, rotamers), 3.38 (m,
1H), 3.61 (m, 1H), 4.01 (m, 1H), 4.59 and 4.61 (2s, 2H, rotamers),
4.72 and 4.73 (2s, 2H, rotamers), 6.78 and 6.87 (2d, 2H, rotamers),
7.10-7.40 (m, 7H), 8.97 (bs, 1H).
Example 5
(2S)-2-Ethoxy-3-[4-(2-{heptyl[(1-methylindol-2-yl)methyl]amino}-2-oxoethox-
y)phenyl]propanoic acid
(i) N-heptyl-N-[(1-methylindol-2-yl)methyl]amine
[0427] To a solution of 1-methylindole-2-carbaldehyde (1.59 g, 10.0
mmol) and heptylamine (1.49 mL, 10.0 mmol) in ethanol (50 mL) were
added acetic acid (2.3 mL, 40 mmol) and sodium cyanoborohydride
(0.75 g, 12.0 mmol) and the reaction mixture was stirred at room
temperature overnight. Water (5 mL) was added and the mixture was
concentrated in vacuo. The residue was taken up in ethyl acetate
(75 mL) and aqueous 1 M KOH (75 mL) and the phases were separated.
The aqueous layer was extracted with ethyl acetate (2.times.75 mL)
and the combined organic phase washed with brine (75 mL), dried
over Na.sub.2SO.sub.4, and concentrated in vacuo. Purification on a
column of silica gel (130 g) with ethyl acetate (17-33% gradient)
in heptane as the eluent yielded 1.57 g (61%) of a yellow oil,
which solidified upon standing.
[0428] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.87-0.95 (m,
3H), 1.20-1.40 (m, 8H), 1.46-1.60 (m, 2H), 2.70 (t, 3H), 3.78 (s,
3H), 3.94 (s, 2H), 6.39 (s, 1H), 7.09 (m, 1H), 7.20 (m, 1H), 7.31
(d, 1H), 7.58 (d, 1H).
(ii) Ethyl
(2S)-2-ethoxy-3-[4-(2-{heptyl[(1-methylindol-2-yl)methyl]amino}-
-2-oxoethoxy)phenyl]propanoate
[0429] To a solution of
{4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.889 g,
3.00 mmol) and N-heptyl-N-[(1-methylindol-2-yl)methyl]amine (0.814
g, 3.15 mmol) in methylene chloride (30 mL) were added DMAP (0.403
g, 3.30 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (0.633 g, 3.30 mmol) and the reaction mixture was
stirred at room temperature for three days. The mixture was diluted
with methylene chloride (100 mL) and the organic phase washed with
2 M HCl (3.times.100 mL), saturated aqueous NaHCO.sub.3 (100 mL),
and brine (100 mL), dried over Na.sub.2SO.sub.4, and concentrated
in vacuo. Purification on a column of silica gel (100 g) with
methanol (0-5% gradient) in methylene chloride as the eluent
yielded 0.71 g (43%) of a pale yellow oil.
[0430] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.82-0.93 (m,
3H), 1.18 (t, 3H), 1.14-1.36 (m, 11H), 1.47-1.62 (m, 2H), 2.91-3.03
(m, 2H), 3.20-3.29 and 3.30-3.47 (2m, 3H, rotamers), 3.58 (s, 3H),
3.61 (m, 1H), 3.98 (m, 1H), 4.18 (q, 2H), 4.73 (s, 2H), 4.86 (s,
2H), 6.44 (s, 1H), 6.87 (d, 2H), 7.06-7.34 (m, 5H), 7.57 (d,
1H).
(iii)
(2S)-2-Ethoxy-3-[4-(2-{heptyl[(1-methylindol-2-yl)methyl]amino}-2-ox-
oethoxy)phenyl]propanoic acid
[0431] To a solution of ethyl
(2S)-2-ethoxy-3-[4-(2-{heptyl[(1-methylindol-2-yl)methyl]amino}-2-oxoetho-
xy)phenyl]propanoate (0.655 g, 1.22 mmol) in THF (60 mL) was added
aqueous 0.10 M LiOH (30 mL) and the reaction mixture was stirred at
room temperature overnight. After acidification with 2 M HCl, the
mixture was extracted with ethyl acetate (3.times.75 mL) and the
combined organic phase washed with brine (75 mL), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo to afford 0.61 g (95%)
of a pale yellow oil.
[0432] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.0.80-0.93 (m, 3H),
1.13-1.34 (m, 11H), 1.46-1.62 (m, 2H), 2.97 and 3.10 (AB part of
ABX system, 2H), 3.19-3.29 and 3.38-3.55 (2m, 3H, rotamers), 3.58
(s, 3H), 3.59 (m, 1H), 4.07 (m, 1H), 4.73 (s, 2H), 4.86 (s, 2H),
6.43 (s, 1H), 6.88 (d, 2H), 7.05-7.33 (m, 5H), 7.56 (d, 1H).
Example 6
(2S)-3-(4-{2-[(2,3-Dimethoxybenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-et-
hoxypropanoic acid
(i) N-Heptyl-2,3-dimethoxybenzamide
[0433] To a solution of 2,3-dimethoxybenzoic acid (4.55 g, 25.0
mmol) in methylene chloride (250 mL) were added heptylamine (2.78
g, 27.5 mmol) and DMAP (3.36 g, 27.5 mmol) followed by
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27
g, 27.5 mmol) and the reaction mixture was stirred at room
temperature overnight. The resulting solution was washed with 5%
HCl (3.times.100 mL), saturated aqueous NaHCO.sub.3 (100 mL), and
brine (100 mL) and dried over MgSO.sub.4. Concentration in vacuo
afforded 6.81 g (98%) of a colourless oil.
[0434] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.82-0.91 (m,
3H), 1.20-1.43 (m, 8H), 1.53-1.66 (m, 2H), 3.40-3.48 (m, 2H), 3.87
(s, 3H), 3.88 (s, 3H), 7.02 (dd, 1H), 7.13 (t, 1H), 7.67 (dd, 1H),
7.93 (bs, 1H).
(ii) N-(2,3-Dimethoxybenzyl)-N-heptylamine
[0435] N-Heptyl-2,3-dimethoxybenzamide (6.47 g, 23.2 mmol) was
dissolved in freshly distilled THF (230 mL) and cooled in an ice
bath under an argon atmosphere. Borane (29 mL of a 2 M solution of
the dimethylsulfide complex in diethyl ether) was added and the ice
bath was removed after 15 minutes. The reaction mixture was
refluxed overnight and was then allowed to cool to room
temperature. The reaction was quenched by careful addition of 10%
HCl (11 mL) and the mixture was stirred for four hours and then
concentrated in vacuo. The residue was taken up in ethyl acetate
(300 mL) and washed with aqueous 2 M K.sub.2CO.sub.3 (3.times.100
mL) and brine (100 mL), dried over Na.sub.2SO.sub.4, and
concentrated in vacuo. Purification on silica gel (160 g) with
ethyl acetate (33-100% gradient) in heptane and finally 5% ethanol
in ethyl acetate as the eluent yielded 3.40 g (55%) of a light
yellow oil.
[0436] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.83-0.91 (m,
3H), 1.20-1.35 (m, 8H), 1.42-1.54 (m, 2H), 2.54-2.61 (m, 2H), 3.79
(s, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 6.83 (d, 1H), 6.88 (d, 1H),
7.01 (t, 1H).
(iii) Ethyl
(2S)-3-(4-{2-[(2,3-dimethoxybenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-e-
thoxypropanoate
[0437] To a solution of N-(2,3-dimethoxybenzyl)-N-heptylamine (1.46
g, 5.5 mmol) and {4-[(2S)-2, 3-diethoxy-3-oxopropyl]phenoxy}acetic
acid (1.48 g, 5.0 mmol) in methylene chloride (50 mL) at 0.degree.
C. were added N,N-diisopropylethylamine (2.0 mL, 11.5 mmol) and
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was
stirred at room temperature overnight and then concentrated in
vacuo. The residue was taken up in ethyl acetate (200 mL) and the
organic phase washed with saturated aqueous NaHCO.sub.3
(3.times.100 mL), 5% HCl (3.times.100 mL), and brine (100 mL),
dried over Na.sub.2SO.sub.4 and concentrated in vacuo. Purification
on silica gel (100 g) with methanol (0-2% gradient) in methylene
chloride as the eluent and collection of pure fractions yielded
1.57 g (58%) of a pale yellow oil.
[0438] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.82-0.90 (m,
3H), 1.11-1.30 (m, 14H), 1.46-1.64 (m, 2H), 2.89-2.98 (m, 2H),
3.20-3.28 and 3.28-3.40 (2m, 3H, rotamers), 3.59 (m, 1H), 3.81,
3.82, 3.85 and 3.87 (4s, 6H, rotamers), 3.95 (m, 1H), 4.11-4.20 (m,
2H), 4.59, 4.69, 4.70 and 4.72 (4s, 4H, rotamers), 6.69-6.91 (m,
4H), 6.95 and 7.02 (2t, 1H, rotamers), 7.11 and 7.16 (2d, 2H,
rotamers).
(iv)
(2S)-3-(4-{2-[(2,3-Dimethoxybenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-
-2-ethoxypropanoic acid
[0439] To a solution of ethyl
(2S)-3-(4-{2-[(2,3-dimethoxybenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-e-
thoxypropanoate (1.40 g, 2.55 mmol) in acetonitrile (100 mL) was
added aqueous 0.10 M LiOH (50 mL) and the reaction mixture was
stirred at room temperature overnight. The solvent volume was
reduced in vacuo and the remaining aqueous phase was acidified with
5% HCl and extracted with ethyl acetate (3.times.100 mL). The
combined organic phase washed with brine (75 mL), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo to afford 1.29 g (98%)
of a pale yellow oil.
[0440] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.81-0.91 (m,
3H), 1.13-1.32 (m, 11H), 1.46-1.64 (m, 2H), 2.94 (m, 1H), 3.07 (m,
1H), 3.25 and 3.34 (2m, 2H, rotamers), 3.44 (m, 1H), 3.59 (m, 1H),
3.82 (s, 3H), 3.86 and 3.88 (2s, 3H, rotamers), 4.03 (m, 1H), 4.60,
4.70, 4.72 and 4.74 (4s, 4H, rotamers), 6.70-6.92 (m, 4H), 6.96 and
7.03 (2t, 1H, rotamers), 7.12 and 7.17 (2d, 2H, rotamers).
Example 7
(2S)-3-(4-{2-[Butyl(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-ethox-
ypropanoic acid
(i) N-Butyl-2,3-dimethoxybenzamide
[0441] To a solution of 2,3-dimethoxybenzoic acid (4.55 g, 25.0
mmol) in methylene chloride (250 mL) were added butylamine (2.01 g,
27.5 mmol) and DMAP (3.36 g, 27.5 mmol) followed by
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27
g, 27.5 mmol) and the reaction mixture was stirred at room
temperature overnight. The resulting solution was washed with 5%
HCl (3.times.100 mL), saturated aqueous NaHCO.sub.3 (100 mL), and
brine (100 mL) and dried over MgSO.sub.4. Concentration in vacuo
afforded 5.59 g (94%) of a colourless oil.
[0442] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.94 (t, 3H),
1.35-1.47 (m, 2H), 1.53-1.63 (m, 2H), 3.40-3.48 (m, 2H), 3.86 (s,
3H), 3.87 (s, 3H), 7.00 (dd, 1H), 7.11 (t, 1H), 7.66 (dd, 1H), 7.92
(bs, 1H).
(ii) N-Butyl-N-(2,3-dimethoxybenzyl)amine
[0443] N-Butyl-2,3-dimethoxybenzamide (5.37 g, 22.6 mmol) was
dissolved in freshly distilled THF (230 mL) and cooled in an ice
bath under an argon atmosphere. Borane (28 mL of a 2 M solution of
the dimethylsulfide complex in diethyl ether) was added and the ice
bath was removed after 15 minutes. The reaction mixture was
refluxed overnight and was then allowed to cool to room
temperature. The reaction was quenched by careful addition of 10%
HCl (11 mL) and the mixture was stirred for four hours and then
concentrated in vacuo. The residue was taken up in ethyl acetate
(300 mL) and washed with aqueous 2 M K.sub.2CO.sub.3 (3.times.100
mL) and brine (100 mL), dried over Na.sub.2SO.sub.4, and
concentrated in vacuo. Purification on silica gel (160 g) with
ethyl acetate (33-100% gradient) in heptane and finally 5% ethanol
in ethyl acetate as the eluent yielded 2.74 g (54%) of a light
yellow oil.
[0444] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.89 (t, 3H),
1.26-1.40 (m, 2H), 1.42-1.53 (m, 2H), 2.56-2.63 (m, 2H), 3.79 (s,
2H), 3.85 (s, 3H), 3.86 (s, 3H), 6.83 (dd, 1H), 6.89 (dd, 1H), 7.01
(t, 1H).
(iii) Ethyl
(2S)-3-(4-{2-[butyl(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2-etho-
xypropanoate
[0445] To a solution of N-butyl-N-(2,3-dimethoxybenzyl)amine (1.23
g, 5.5 mmol) and {4-[(2S)-2, 3-diethoxy-3-oxopropyl]phenoxy}acetic
acid (1.48 g, 5.0 mmol) in methylene chloride (50 mL) at 0.degree.
C. were added N,N-diisopropylethylamine (2.0 mL, 11.5 mmol)
followed by O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was
stirred overnight and then concentrated in vacuo. The residue was
taken up in ethyl acetate (200 mL) and the organic phase washed
with saturated aqueous NaHCO.sub.3 (3.times.100 mL), 5% HCl
(3.times.100 mL), and brine (100 mL), dried over Na.sub.2SO.sub.4,
and concentrated in vacuo. Purification on silica gel (120 g) with
methanol (0-2% gradient) in methylene chloride as the eluent and
collection of pure fractions afforded 1.07 g (43%) of a pale yellow
oil.
[0446] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.84-0.94 (m,
3H), 1.12-1.19 (m, 3H), 1.19-1.35 (m, 5H), 1.46-1.64 (m, 2H),
2.88-3.00 (m, 2H), 3.21-3.29 and 3.29-3.40 (2m, 3H, rotamers), 3.59
(m, 1H), 3.82, 3.82, 3.86 and 3.88 (4s, 6H, rotamers), 3.96 (m,
1H), 4.11-4.21 (m, 2H), 4.60, 4.70, 4.71 and 4.73 (4s, 4H,
rotamers), 6.69-6.92 (m, 4H), 6.96 and 7.03 (2t, 1H, rotamers),
7.12 and 7.16 (2d, 2H, rotamers).
(iv)
(2S)-3-(4-{2-[Butyl(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phenyl)-2--
ethoxypropanoic acid
[0447] To a solution of ethyl
(2S)-3-(4-{2-[(2,3-dimethoxybenzyl)(butyl)amino]-2-oxoethoxy}phenyl)-2-et-
hoxypropanoate (1.02 g, 2.0 mmol) in acetonitrile (80 mL) was added
aqueous 0.10 M LiOH (40 mL) and the reaction mixture was stirred at
room temperature overnight. The solvent volume was reduced in vacuo
and the remaining aqueous phase was acidified with 5% HCl and
extracted with ethyl acetate (3.times.100 mL). The combined organic
phase washed with brine (75 mL), dried over Na.sub.2SO.sub.4, and
concentrated in vacuo to afford 0.96 g (98%) of a light yellow
oil.
[0448] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.84-0.94 (m,
3H), 1.12-1.20 (m, 3H), 1.20-1.36 (m, 2H), 1.45-1.64 (m, 2H), 2.94
(m, 1H), 3.06 (m, 1H), 3.26 and 3.35 (2m, 2H, rotamers), 3.43 (m,
1H), 3.59 (m, 1H), 3.82 and 3.82 (2s, 3H, rotamers), 3.86 and 3.88
(2s, 3H, rotamers), 4.03 (m, 1H), 4.60, 4.70, 4.72 and 4.74 (4s,
4H, rotamers), 6.70-6.92 (m, 4H), 6.96 and 7.03 (2t, 1H, rotamers),
7.12 and 7.17 (2d, 2H, rotamers).
Example 8
(2S)-3-(4-{2-[(4-Chlorobenzyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl-
)-2-ethoxypropanoic acid
(i) N-(4-Chlorobenzyl)-N-(4-isopropylbenzyl)amine
[0449] To a solution of 4-chlorobenzylamine (2.83 g, 20.0 mmol) and
4-isopropylbenzaldehyde (2.96 g, 20.0 mmol) in methanol (100 mL)
were added acetic acid (4.6 mL, 80 mmol) and sodium
cyanoborohydride (1.51 g, 24.0 mmol) and the solution was stirred
at room temperature for three days. Water (5 mL) was added and the
mixture was concentrated in vacuo. The residue was taken up in
ethyl acetate (100 mL) and aqueous 1 M KOH (100 mL) and the phases
were separated. The aqueous phase was extracted with ethyl acetate
(2.times.100 mL) and the combined organic phase washed with brine
(100 mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to
afford 5.80 g of crude product as a white semicrystalline oil. The
product was used in the subsequent reaction step without further
purification.
[0450] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.22 (d, 6H),
2.88 (sep, 1H), 3.84 (s, 4H), 5.72 (bs, 1H), 7.22 (d, 2H), 7.28 (d,
2H), 7.31 (bs, 4H).
(ii) Ethyl
(2S)-3-(4-{2-[(4-chlorobenzyl)(4-isopropylbenzyl)amino]-2-oxoet-
hoxy}phenyl)-2-ethoxypropanoate
[0451] To a solution of
N-(4-chlorobenzyl)-N-(4-isopropylbenzyl)amine (1.64 g, 6.0 mmol) in
methylene chloride (50 mL) at 0.degree. C. were added
{4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (1.48 g, 5.0
mmol) and N,N-diisopropylethylamine (2.0 mL, 11.5 mmol) followed by
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was
stirred overnight. The mixture was diluted with methylene chloride
(100 mL) and the organic phase washed with 2 M HCl (3.times.75 mL),
saturated aqueous NaHCO.sub.3 (2.times.75 mL, some emulsions), and
brine (75 mL), dried over Na.sub.2SO.sub.4, and concentrated in
vacuo. Twice repeated purification on silica gel with methanol
(0-5% gradient) in methylene chloride as the eluent and collection
of pure fractions afforded 1.28 g (46%) of a colourless oil.
[0452] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.16 (t, 3H),
1.19-1.28 (m, 9H), 2.82-3.02 (m, 3H), 3.35 (m, 1H), 3.61 (m, 1H),
3.97 (m, 1H), 4.17 (q, 2H), 4.49, 4.50, 4.52 and 4.54 (4s, 4H,
rotamers), 4.74 and 4.77 (2s, 2H, rotamers), 6.75-6.86 (m, 2H),
7.04-7.36 (m, 10H).
(iii)
(2S)-3-(4-{2-[(4-Chlorobenzyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}-
phenyl)-2-ethoxypropanoic acid
[0453] To a solution of ethyl
(2S)-3-(4-{2-[(4-chlorobenzyl)(4-isopropylbenzyl)amino]-2-oxoethoxy}pheny-
l)-2-ethoxypropanoate (1.15 g, 2.1 mmol) in acetonitrile (100 mL)
was added aqueous 0.10 M LiOH (52 mL) and the solution was stirred
at room temperature overnight. After neutralisation with 5% HCl,
the solvent volume was reduced in vacuo and the remaining aqueous
phase was acidified with 5% HCl and extracted with ethyl acetate
(3.times.100 mL). The combined organic phase washed with brine (75
mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to
afford 1.02 g (93%) of a colourless oil.
[0454] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.17 (t, 3H),
1.21-1.28 (m, 6H), 2.92 (m, 1H), 2.95 and 3.07 (AB part of ABX
system, 2H), 3.44 (m, 1H), 3.61 (m, 1H), 4.04 (m, 1H), 4.49, 4.50,
4.53 and 4.55 (4s, 4H, rotamers), 4.75 and 4.78 (2s, 2H, rotamers),
6.76-6.87 (m, 2H), 7.04-7.36 (m, 10H).
Example 9
(2S)-3-(4-{2-[(Cyclohexylmethyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phe-
nyl)-2-ethoxypropanoic acid
(i) N-(Cyclohexylmethyl)-N-(2,4-difluorobenzyl)amine
[0455] To a solution of 2,4-difluorobenzylamine (2.84 g, 20.0 mmol)
and cyclohexanecarbaldehyde (2.60 mL, 20.0 mmol) in methanol (100
mL) were added acetic acid (4.6 mL, 80 mmol) and sodium
cyanoborohydride (1.51 g, 24.0 mmol) and the solution was stirred
at room temperature for three days. Water (10 mL) was added and the
mixture was concentrated in vacuo. The residue was diluted with
aqueous 1 M KOH (125 mL) and ethyl acetate (100 mL) and the phases
were separated. The aqueous phase was extracted with ethyl acetate
(2.times.100 mL) and the combined organic phase was dried over
Na.sub.2SO.sub.4 and concentrated in vacuo. Purification on a
prepacked column of silica gel (Isolute.RTM. SPE Column, 50 g
Si/150 mL) with ethyl acetate (33-100% gradient) in heptane as the
eluent yielded 2.40 g (50%) of white solids.
[0456] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.90-1.04 (m,
2H), 1.07-1.34 (m, 3H), 1.61-1.85 (m, 6H), 2.72 (d, 2H), 4.19 (s,
2H), 6.90 (m, 1H), 6.97 (m, 1H), 7.0 (bs, 1H), 7.63 (m, 1H).
(ii) Ethyl
(2S)-3-(4-{2-[(cyclohexylmethyl)(2,4-difluorobenzyl)amino]-2-ox-
oethoxy}phenyl)-2-ethoxypropanoate
[0457] To a solution of
N-(cyclohexylmethyl)-N-(2,4-difluorobenzyl)amine (0.574 g, 2.00
mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid
(0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added
N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (0.674 g, 2.10 mmol) and the reaction mixture was
stirred at room temperature overnight. The mixture was diluted with
methylene chloride (100 mL) and the organic phase washed with 2 M
HCl (3.times.75 mL), saturated aqueous NaHCO.sub.3 (2.times.75 mL),
and brine (75 mL), dried over Na.sub.2SO.sub.4, and concentrated in
vacuo. Purification on a prepacked column of silica gel
(Isolute.RTM. SPE Column, 20 g/70 mL) with methanol (0-2% gradient)
in methylene chloride as the eluent yielded 0.59 g (57%) of a
colourless oil.
[0458] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.83-1.02 (m,
2H), 1.08-1.30 (m, 9H), 1.51-1.82 (m, 6H), 2.88-3.00 (m, 2H),
3.10-3.22 (m, 2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.96 (m, 1H), 4.16
(q, 2H), 4.63 (s, 2H), 4.70 and 4.71 (2s, 2H, rotamers), 6.72-6.90
(m, 4H), 7.05-7.18 and 7.18-7.29 (2m, 3H, rotamers).
(iii)
(2S)-3-(4-{2-[(Cyclohexylmethyl)(2,4-difluorobenzyl)amino]-2-oxoetho-
xy}phenyl)-2-ethoxypropanoic acid
[0459] To a solution of ethyl
(2S)-3-(4-{2-[(cyclohexylmethyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}ph-
enyl)-2-ethoxypropanoate (0.297 g, 0.57 mmol) in acetonitrile (28
mL) was added aqueous 0.10 M LiOH (14 mL) and the solution was
stirred at room temperature overnight. After neutralisation with 5%
HCl, the solvent volume was reduced in vacuo and the remaining
aqueous phase was acidified with 5% HCl and extracted with ethyl
acetate (3.times.100 mL). The combined organic phase washed with
brine (100 mL), dried over Na.sub.2SO.sub.4, and concentrated in
vacuo to afford 0.258 g (89%) of a colourless oil.
[0460] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.0.80-1.00 (m, 2H),
1.03-1.30 (m, 6H), 1.48-1.80 (m, 6H), 2.92 (m, 1H), 3.01 (m, 1H),
3.10-3.20 (m, 2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.99 (m, 1H), 4.62
(s, 2H), 4.72 (s, 2H), 6.70-6.88 (m, 4H), 7.05-7.19 and 7.19-7.29
(2m, 3H, rotamers).
Example 10
(2S)-2-Ethoxy-3-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)prop-
anoic acid
(i) Ethyl
(2S)-2-ethoxy-3-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}p-
henyl) propanoate
[0461] To a solution of N-ethyl-N-(2-fluorobenzyl)amine (0.843 g,
5.50 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic
acid (1.482 g, 5.00 mmol) in methylene chloride (50 mL) were added
N,N-diisopropylethylamine (2.00 mL, 11.5 mmol) and
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (1.93 g, 6.0 mmol) and the reaction mixture was
stirred at room temperature overnight. The resulting solution was
diluted with methylene chloride (50 mL) and the organic phase
washed with 2 M HCl (3.times.75 mL), saturated aqueous NaHCO.sub.3
(2.times.75 mL), and brine (75 mL), dried over Na.sub.2SO.sub.4,
and concentrated in vacuo. Purification on a prepacked column of
silica gel (Isolute.RTM. SPE Column, 70 g/150 mL) with methanol
(0-2% gradient) in methylene chloride as the eluent yielded 1.90 g
(88%) of a colourless oil.
[0462] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.04-1.26 (m,
9H), 2.89-2.98 (m, 2H), 3.27-3.44 (m, 3H), 3.59 (m, 1H), 3.95 (m,
1H), 4.10-4.20 (m, 2H), 4.64, 4.67, 4.70, and 4.72 (4s, 4H,
rotamers), 6.76 and 6.87 (2d, 2H, rotamers), 6.97-7.32 (m, 6H).
[0463] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 12.4, 13.9,
14.3, 15.1, 38.5, 41.0, 41.3 (d), 41.7, 44.3 (d), 60.9, 66.3, 67.6,
67.9, 80.4, 114.5, 114.6, 115.3 (d), 115.7 (d), 123.8 (d), 124.2
(d), 124.5 (m), 128.7, 128.7 129.1 (d), 129.5 (d), 130.3-130.6 (m),
130.5, 130.6, 156.8, 156.9, 160.9 (d), 161.1 (d), 168.0, 168.1,
172.6. (The number of peaks is larger than the number of carbon
atoms due to rotamers.)
(ii)
(2S)-2-Ethoxy-3-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl-
)propanoic acid
[0464] To a solution of ethyl
(2S)-2-ethoxy-3-(4-{2-[ethyl(2-fluorobenzyl)amino]-2-oxoethoxy}phenyl)pro-
panoate (0.980 g, 2.27 mmol) in acetonitrile (120 mL) was added
aqueous 0.10 M LiOH (57 mL) and the reaction mixture was stirred at
room temperature overnight. After neutralisation with 5% HCl, the
solvent volume was reduced in vacuo and the remaining aqueous phase
was acidified with 5% HCl and extracted with ethyl acetate
(3.times.100 mL). The combined organic phase washed brine (100 mL),
dried over Na.sub.2SO.sub.4, and concentrated in vacuo to afford
0.868 g (95%) of a pale yellow oil.
[0465] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.05-1.28 (m,
6H), 2.87-2.99 (m, 1H), 2.99-3.10 (m, 1H), 3.33-3.45 (m, 3H), 3.61
(m, 1H), 4.01 (m, 1H), 4.65, 4.68, 4.72, and 4.73 (4s, 4H,
rotamers), 6.77 and 6.87 (2d, 2H, rotamers), 6.96-7.33 (m, 6H),
9.04 (bs, 1H).
[0466] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 12.4, 13.9,
15.1, 38.0, 41.2, 41.4 (d), 41.7, 44.4 (d), 66.7, 67.4, 67.7, 79.8,
114.6, 114.7, 115.3 (d), 115.7 (d), 123.6 (d), 124.0 (d), 124.5
(m), 128.7, 129.2 (d), 129.6 (d), 130.0-130.8 (m), 130.6, 130.7,
156.8, 156.9, 160.9 (d), 161.1 (d), 168.4, 168.5, 175.6. (The
number of peaks is larger than the number of carbon atoms due to
rotamers.
Example 11
(2S)-3-(4-{2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phenyl)-2-eth-
oxypropanoic acid
(i) Ethyl
(2S)-3-(4-{2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phe-
nyl)-2-ethoxypropanoate
[0467] To a solution of N-[4-(benzyloxy)benzyl]-N-butylamine (3.59
g, 12.0 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic
acid (2.96 g, 10.0 mmol) in methylene chloride (100 mL) were added
N,N-diisopropylethylamine (4.00 mL, 23.0 mmol) and
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (3.85 g, 12.0 mmol) and the reaction mixture was
stirred at room temperature overnight. The resulting solution was
diluted with methylene chloride (100 mL) and the organic phase
washed with 5% HCl (3.times.75 mL), saturated aqueous NaHCO.sub.3
(2.times.75 mL), and brine (75 mL), dried over Na.sub.2SO.sub.4,
and concentrated in vacuo. Purification on a prepacked column of
silica gel (Isolute.RTM. SPE Column, 70 g/150 mL) with methanol
(0-1% gradient) in methylene chloride as the eluent and collection
of pure fractions yielded 1.80 g (33%) of a whitish oil.
[0468] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 0.80-0.95 (m,
3H), 1.12-1.20 (m, 3H), 1.20-1.35 (m, 5H), 1.44-1.61 (m, 2H),
2.88-3.02 (m, 2H), 3.19-3.28 and 3.29-3.41 (2m, 3H, rotamers), 3.60
(m, 1H), 3.97 (m, 1H), 4.16 (q, 2H), 4.54 and 4.55 (2s, 2H,
rotamers), 4.66 and 4.72 (2s, 2H, rotamers), 5.50 and 5.06 (2s, 2H,
rotamers), 6.76-7.00 (m, 4H), 7.07-7.21 (m, 4H), 7.28-7.47 (m,
5H).
(ii)
(2S)-3-(4-{2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phenyl)--
2-ethoxypropanoic acid
[0469] To a solution of ethyl
(2S)-3-(4-{2-[[4-(benzyloxy)benzyl](butyl)amino]-2-oxoethoxy}phenyl)-2-et-
hoxypropanoate (0.116 g, 0.21 mmol) in acetonitrile (10 mL) was
added aqueous 0.10 M LiOH (5 mL) and the reaction mixture was
stirred at room temperature overnight. The solvent volume was
reduced in vacuo and the remaining aqueous phase was diluted with
water and aqueous 1 M KOH and washed with diethyl ether (2.times.50
mL). The aqueous phase was acidified with 5% HCl and extracted with
ethyl acetate (3.times.50 mL). The combined organic phase washed
with brine (50 mL), dried over Na.sub.2SO.sub.4, and concentrated
in vacuo to afford 0.070 g (63%) of a colourless oil.
[0470] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.0.83-0.95 (m, 3H),
1.10-1.20 (m, 3H), 1.20-1.36 (m, 2H), 1.42-1.62 (m, 2H), 2.95 (m,
1H), 3.05 (m, 1H), 3.19-3.29 and 3.30-3.46 (2m, 3H, rotamers), 3.61
(m, 1H), 4.02 (m, 1H), 4.54 and 4.56 (2s, 2H, rotamers), 4.68 and
4.74 (2s, 2H, rotamers), 5.04 and 5.06 (2s, 2H, rotamers),
6.76-7.00 (m, 4H), 7.09-7.22 (m, 4H), 7.28-7.47 (m, 5H).
Example 12
(2S)-3-(4-{2-[bis(4-Chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropan-
oic acid
(i) Ethyl
(2S)-3-(4-{2-[bis(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-et-
hoxypropanoate
[0471] To a suspension of N,N-bis(4-chlorobenzyl)amine (0.958 g,
3.60 mmol) in methylene chloride (30 mL) were added
{4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.889 g,
3.00 mmol) and N,N-diisopropylethylamine (1.20 mL, 6.9 mmol)
followed by O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (1.01 g, 3.15 mmol) and the reaction mixture was
stirred at room temperature overnight. The resulting solution was
diluted with methylene chloride (220 mL) and the organic phase
washed with 2 M HCl (3.times.50 mL), saturated aqueous NaHCO.sub.3
(2.times.50 mL), and brine (50 mL), dried over Na.sub.2SO.sub.4,
and concentrated in vacuo. Purification on a prepacked column of
silica gel (Isolute.RTM. SPE Column, 50 g/150 mL) with methanol
(0-2% gradient) in methylene chloride as the eluent yielded 1.02 g
(62%) of an oil, which solidified upon standing to give white
solids.
[0472] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.17 (t, 3H),
1.23 (t, 3H), 2.90-3.00 (m, 2H), 3.36 (m, 1H), 3.61 (m, 1H), 3.97
(m, 1H), 4.17 (q, 2H), 4.50 (s, 2H), 4.76 (s, 4H), 6.80 (d, 2H),
7.03-7.11 (m, 4H), 7.15 (d, 2H), 7.21-7.35 (m, 4H).
[0473] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 14.4, 15.2,
38.5, 47.6, 49.2, 61.0, 66.3, 68.1, 80.3, 114.5, 128.5, 129.0,
129.3, 129.9, 130.7, 133.7, 133.9, 134.5, 135.0, 156.6, 168.7,
172.5.
(ii)
(2S)-3-(4-{2-[bis(4-Chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxyp-
ropanoic acid
[0474] To a solution of ethyl
(2S)-3-(4-{2-[bis(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropa-
noate (0.597 g, 1.10 mmol) in acetonitrile (54 mL) was added
aqueous 0.10 M LiOH (27 mL) and the reaction mixture was stirred at
room temperature overnight. The solvent volume was reduced in vacuo
and the remaining aqueous phase was diluted with water and aqueous
1 M KOH (to a total volume of 400 mL, pH.about.9) and washed with
diethyl ether (2.times.100 mL). (The extraction process was
complicated by the formation of emulsions.) The aqueous phase was
acidified with 2 M HCl and extracted with ethyl acetate (4.times.75
mL). The combined organic phase washed with brine (100 mL), dried
over Na.sub.2SO.sub.4, and concentrated in vacuo to afford 0.475 g
(84%) of a whitish oil.
[0475] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.19 (t, 3H),
2.97 and 3.08 (AB part of ABX system, 2H), 3.47 (m, 1H), 3.61 (m,
1H), 4.06 (m, 1H), 4.50 (s, 4H), 4.76 (s, 2H), 6.80 (d, 2H),
7.04-7.12 (m, 4H), 7.15 (d, 2H), 7.25 (d, 2H), 7.32 (d, 2H).
[0476] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 15.2, 37.7,
47.7, 49.3, 67.0, 68.0, 79.8, 114.7, 128.5, 129.0, 129.3, 129.9,
130.0, 130.9, 133.7, 133.9, 134.4, 135.0, 156.8, 168.8, 174.1.
Example 13
(2S)-3-(4-{2-[(4-tert-Butylbenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}-phen-
yl)-2-ethoxypropanoic acid
(i) N-(4-tert-Butylbenzyl)-N-(4-chlorobenzyl)amine
[0477] To a solution of 4-tert-butylbenzaldehyde (3.24 g, 20.0
mmol) and 4-chlorobenzylamine (2.43 mL, 20.0 mmol) in methanol (100
mL) were added acetic acid (4.6 mL, 80 mmol) and sodium
cyanoborohydride (1.51 g, 24.0 mmol) and the reaction mixture was
stirred at room temperature overnight. Water (10 mL) was added and
the mixture was concentrated in vacuo. The residue was taken up in
ethyl acetate (50 mL) and aqueous 1 M KOH (50 mL) and the phases
were separated. The aqueous phase was extracted with ethyl acetate
(2.times.50 mL) and the combined organic phase was dried over
Na.sub.2SO.sub.4, and concentrated in vacuo. Purification on a
prepacked column of silica gel (Isolute.RTM. SPE Column, 70 g/150
mL) with ethyl acetate (33-100% gradient) in heptane as the eluent
yielded 4.31 g (75%) of white solids.
[0478] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.28 (s, 9H),
3.90 (s, 2H), 3.92 (s, 2H), 6.15 (bs, 1H), 7.28-7.33 (m, 6H), 7.40
(d, 2H).
[0479] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 31.3, 34.8,
50.1, 50.8, 126.3, 129.0, 129.4, 129.5, 130.9, 131.2, 135.3,
152.6.
(ii) Ethyl
(2S)-3-(4-{2-[(4-tert-butylbenzyl)(4-chlorobenzyl)amino]-2-oxoe-
thoxy}phenyl)-2-ethoxypropanoate
[0480] To a solution of
{4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.889 g,
3.00 mmol) in methylene chloride (30 mL) were added
N-(4-tert-butylbenzyl)-N-(4-chlorobenzyl)amine (1.04 g, 3.60 mmol),
N,N-diisopropylethylamine (1.20 mL, 6.9 mmol) and
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (1.01 g, 3.15 mmol) and the reaction mixture was
stirred at room temperature overnight. The resulting solution was
diluted with methylene chloride (220 mL) and the organic phase
washed with 2 M HCl (3.times.50 mL), saturated aqueous NaHCO.sub.3
(2.times.50 mL), and brine (50 mL), dried over Na.sub.2SO.sub.4,
and concentrated in vacuo. Twice repeated purification on prepacked
columns of silica gel (Isolute.RTM. SPE Column, 50 g/150 mL) with
methanol (0-2% gradient) in methylene chloride as the eluent and
collection of pure fractions yielded 0.459 g (27%) of a whitish
oil.
[0481] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.16 (t, 3H),
1.23 (t, 3H), 1.31 and 1.33 (2s, 9H, rotamers), 2.88-3.02 (m, 2H),
3.35 (m, 1H), 3.61 (m, 1H), 3.97 (m, 1H), 4.17 (q, 2H), 4.49 and
4.50 (2s, 2H, rotamers), 4.53 and 4.55 (2s, 2H, rotamers), 4.74 and
4.77 (2s, 2H, rotamers), 6.76-6.86 (m, 2H), 7.09 (d, 4H), 7.14 (d,
2H), 7.24, 7.31, and 7.37 (3d, 4H, rotamers).
[0482] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 14.3, 15.2,
31.4, 34.7, 38.6, 47.8, 48.0, 49.1, 49.4, 60.9, 66.3, 67.7, 68.1,
80.4, 114.6, 114.6, 125.7, 126.0, 126.7, 128.3, 128.4, 128.8,
129.1, 129.9, 130.6, 130.6, 132.8, 133.4, 133.7, 134.8, 135.5,
150.8, 151.2, 156.7, 168.5, 168.6, 172.6. (The number of peaks is
larger than the number of carbon atoms due to rotamers.)
(iii)
(2S)-3-(4-{2-[(4-tert-Butylbenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy-
}phenyl)-2-ethoxypropanoic acid
[0483] To a solution of ethyl
(2S)-3-(4-{2-[(4-tert-butylbenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phen-
yl)-2-ethoxypropanoate (0.400 g, 0.71 mmol) in acetonitrile (36 mL)
was added aqueous 0.10 M LiOH (18 mL) and the reaction mixture was
stirred at room temperature overnight. After acidification with 2 M
HCl, the solvent volume was reduced in vacuo and the mixture was
extracted with ethyl acetate (3.times.75 mL). The combined organic
phase washed with brine (75 mL), dried over Na.sub.2SO.sub.4, and
concentrated in vacuo to afford 0.375 g (99%) of a whitish oil.
[0484] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.18 (t, 3H),
1.31 and 1.33 (2s, 9H, rotamers), 2.96 and 3.07 (AB part of ABX
system, 2H), 3.44 (m, 1H), 3.61 (m, 1H), 4.04 (m, 1H), 4.49 and
4.50 (2s, 2H, rotamers), 4.53 and 4.55 (2S, 2H, rotamers), 4.75 and
4.78 (2s, 2H, rotamers), 6.76-6.87 (m, 2H), 7.09 (d, 4H), 7.15 (d,
2H), 7.24, 7.31, and 7.37 (3d, 4H, rotamers).
[0485] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 15.2, 31.5,
34.7, 37.9, 47.8, 48.0, 49.1, 49.5, 67.0, 67.6, 68.0, 79.8, 114.7,
114.8, 125.7, 126.1, 126.8, 128.3, 128.4, 128.9, 129.2, 129.9,
130.0, 130.8, 132.7, 133.4, 133.5, 133.7, 134.8, 135.4, 150.8,
151.2, 156.9, 168.6, 168.8, 174.7. (The number of peaks is larger
than the number of carbon atoms due to rotamers.)
Example 14
(2S)-3-[4-(2-{(4-Chlorobenzyl)[4-(trifluoromethyl)benzyl]amino}-2-oxoethox-
y)phenyl]-2-ethoxypropanoic acid
(i) Ethyl
(2S)-3-[4-(2-{(4-chlorobenzyl)[4-(trifluoromethyl)benzyl]amino}--
2-oxoethoxy)phenyl]-2-ethoxypropanoate
[0486] To a suspension of
N-(4-chlorobenzyl)-N-[4-(trifluoromethyl)benzyl]amine (0.989 g,
3.30 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic
acid (0.889 g, 3.00 mmol) in methylene chloride (60 mL) were added
N,N-diisopropylethylamine (1.20 mL, 6.9 mmol) and
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (1.01 g, 3.1 mmol) and the reaction mixture was
stirred at room temperature overnight. The resulting solution was
diluted with methylene chloride (190 mL) and the organic phase
washed with 2 M HCl (3.times.50 mL), saturated aqueous NaHCO.sub.3
(2.times.50 mL), and brine (50 mL), dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. Twice repeated purification on prepacked
columns of silica gel (Isolute.RTM. SPE Column, 70 g/150 mL) with
methanol (0-2% gradient) in methylene chloride as the eluent
yielded 1.02 g (59%) of a colourless oil.
[0487] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.16 (t, 3H),
1.22 (t, 3H), 2.90-3.00 (m, 2H), 3.35 (m, 1H), 3.60 (m, 1H), 3.97
(m, 1H), 4.17 (q, 2H), 4.52 (s, 2H), 4.59 (s, 2H), 4.76 and 4.78
(2s, 2H, rotamers), 6.77 and 6.81 (2d, 2H, rotamers), 7.03-7.11 (m,
2H), 7.11-7.19 (m, 2H), 7.20-7.36 (m, 4H), 7.53 and 7.60 (2d, 2H
rotamers).
[0488] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 14.4, 15.2,
38.5, 47.8, 47.9, 49.5, 61.0, 66.3, 68.1, 68.2, 80.3, 114.5, 114.5,
125.7 (m), 126.0 (m), 127.4, 128.5, 128.6, 129.0, 129.3, 129.6
131.2 (m), 129.9, 130.8, 130.8, 133.8, 134.0, 134.3, 134.9, 140.2,
140.6, 156.5, 168.8, 172.5. (The number of peaks is larger than the
number of carbon atoms due to rotamers. Trifluorinated carbon not
reported)
[0489] (ii)
(2S)-3-[4-(2-{(4-Chlorobenzyl)[4-(trifluoromethyl)benzyl]amino}-2-oxoetho-
xy)phenyl]-2-ethoxypropanoic acid To a solution of ethyl
(2S)-3-[4-(2-{(4-chlorobenzyl)[4-(trifluoromethyl)benzyl]amino}-2-oxoetho-
xy)phenyl]-2-ethoxypropanoat (0.482 g, 0.83 mmol) in acetonitrile
(42 mL) was added aqueous 0.10 M LiOH (21 mL) and the solution was
stirred at room temperature overnight. After acidification with 2 M
HCl, the solvent volume was reduced in vacuo and the mixture was
extracted with ethyl acetate (3.times.75 mL). The combined organic
phase washed with brine (75 mL), dried over Na.sub.2SO.sub.4, and
concentrated in vacuo to afford 0.407 g (89%) of a colourless
oil.
[0490] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.18 (t, 3H),
2.97 and 3.07 (AB part of ABX system, 2H), 3.44 (m, 1H), 3.62 (m,
1H), 4.04 (m, 1H), 4.53 (s, 2H), 4.60 (s, 2H), 4.77 and 4.79 (2s,
2H, rotamers), 6.77 and 6.81 (2d, 2H, rotamers), 7.04-7.12 (m, 2H),
7.12-7.20 (m, 2H), 7.21-7.37 (m, 4H), 7.53 and 7.60 (2d, 2H,
rotamers).
[0491] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 15.2, 37.9,
47.9, 48.0, 49.6, 66.9, 68.0, 68.1, 79.7, 114.6, 114.6, 125.7 (m),
126.0 (m), 127.3, 128.5, 128.6, 129.0, 129.3, 129.9, 130.2, 130.9,
133.8, 134.0, 134.2, 134.8, 140.1, 140.5, 156.6, 169.0, 175.2. (The
number of peaks is larger than the number of carbon atoms due to
rotamers. Trifluorinated carbon and quarternary carbon a to the
trifluoromethyl group not reported.)
Example 15
(2S)-3-[4-(2-{bis[4-(Trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2-e-
thoxypropanoic acid
(i) Ethyl
(2S)-3-[4-(2-{bis[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)p-
henyl]-2-ethoxypropanoate
[0492] To a solution of N,N-bis[4-(trifluoromethyl)benzyl]amine
(0.733 g, 2.20 mmol) and
{4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.593 g,
2.00 mmol) in methylene chloride (20 mL) were added
N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (0.674 g, 2.10 mmol) and the reaction mixture was
stirred at room temperature for 4 h. The resulting solution was
diluted with methylene chloride (130 mL) and the organic phase
washed with 5% HCl (3.times.75 mL), saturated aqueous NaHCO.sub.3
(2.times.75 mL), and brine (75 mL), dried over Na.sub.2SO.sub.4,
and concentrated in vacuo. Purification on a prepacked column of
silica gel (Isolute.RTM. SPE Column, 70 g/150 mL) with methanol
(0-1% gradient) in methylene chloride as the eluent yielded 0.91 g
(74%) of a whitish oil.
[0493] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.15 (t, 3H),
1.22 (t, 3H), 2.90-3.00 (m, 1H), 3.35 (m, 1H), 3.60 (m, 1H), 3.96
(m, 1H), 4.16 (q, 2H), 4.61 (s, 2H), 4.63 (s, 2H), 4.79 (s, 2H),
6.78 (d, 2H), 7.15 (d, 2H), 7.26 (m, 2H), 7.53 (d, 2H), 7.60 (d,
2H).
[0494] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 14.3, 15.2,
38.5, 48.2, 49.8, 60.9, 66.3, 68.2, 80.3, 114.5, 125.8 (m), 126.1
(m), 127.4, 128.6, 130.1 (q), 130.8, 130.9, 140.1, 140.5, 156.5,
169.0, 172.5. (Trifluorinated Carbon not Reported.)
(ii)
(2S)-3-[4-(2-{bis[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl-
]-2-ethoxypropanoic acid
[0495] To a solution of ethyl
(2S)-3-[4-(2-{bis[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]-2--
ethoxypropanoate (0.662 g, 1.1 mmol) in acetonitrile (54 mL) was
added aqueous 0.10 M LiOH (27 mL) and the solution was stirred at
room temperature overnight. The solvent volume was reduced in vacuo
and the remaining aqueous phase was diluted with water and aqueous
0.10 M LiOH (to a total volume of 300 mL, pH.about.12) and washed
with diethyl ether (2.times.100 mL). (The extraction process was
complicated by the formation of emulsions.) The aqueous phase was
acidified with 2 M HCl and extracted with ethyl acetate
(3.times.100 mL). The combined organic phase washed with brine (100
mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to
afford 0.292 g (46%) of a colourless oil.
[0496] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.18 (t, 3H),
2.97 and 3.07 (AB part of ABX system, 2H), 3.46 (m, 1H), 3.62 (m,
1H), 4.05 (dd, 1H), 4.62 (s, 2H), 4.64 (s, 2H), 4.80 (s, 2H), 6.79
(d, 2H), 7.16 (d, 2H), 7.22-7.31 (m, 4H), 7.53 (d, 2H), 7.60 (d,
2H).
[0497] .sup.13C NMR (100 MHz, CDCl.sub.3): .delta. 15.2, 37.8,
48.3, 49.9, 66.9, 68.1, 79.7, 114.6, 125.8 (m), 126.1 (m), 127.4,
128.6, 130.5 (q), 130.2, 130.9, 140.0, 140.4, 156.6, 169.1, 174.9.
(Trifluorinated carbon not reported.)
Example 16
(2S)-3-(4-{2-[Benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic
acid
(i) Ethyl
(2S)-3-(4-{2-[benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypr-
opanoate
[0498] To a solution of
{4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.296 g,
1.00 mmol) and N-benzyl-N-ethylamine (0.149 g, 1.10 mmol) in
methylene chloride (10 mL) were added N,N-diisopropylethylamine
(0.40 mL, 2.3 mmol) and
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (0.353 g, 1.10 mmol) and the reaction mixture was
stirred at room temperature for three days. The resulting solution
was diluted with methylene chloride (90 mL) and the organic phase
washed with 2 M HCl (3.times.50 mL), saturated aqueous NaHCO.sub.3
(2.times.50 mL), and brine (50 mL), dried over Na.sub.2SO.sub.4 and
concentrated in vacuo. Purification on a prepacked column of silica
gel (Isolute.RTM. SPE Column, 70 g/150 mL) with methanol (0-1%
gradient) in methylene chloride as the eluent and collection of
pure fractions yielded 0.129 g (31%) of a whitish oil.
[0499] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.06-1.32 (m,
9H), 2.87-3.02 (m, 2H), 3.26-3.48 (m, 3H), 3.60 (m, 1H), 3.96 (m,
1H), 4.10-4.21 (m, 2H), 4.61 and 4.62 (2s, 2H, rotamers), 4.66 and
4.74 (2s, 2H, rotamers), 6.78 and 6.89 (2d, 2H, rotamers),
7.08-7.40 (m, 7H).
(ii)
(2S)-3-(4-{2-[Benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropano-
ic acid
[0500] To a solution of ethyl
(2S)-3-(4-{2-[benzyl(ethyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate
(0.112 g, 0.27 mmol) in acetonitrile (14 mL) was added aqueous 0.10
M LiOH (7 mL) and the reaction mixture was stirred at room
temperature overnight. After neutralisation with 5% HCl, the
solvent volume was reduced in vacuo and the mixture was extracted
with ethyl acetate (3.times.50 mL). The combined organic phase
washed with brine (50 mL), dried over Na.sub.2SO.sub.4, and
concentrated in vacuo to afford 0.096 g (92%) of a colourless
oil.
[0501] .sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 1.05-1.21 (m,
6H), 2.85-3.10 (m, 2H), 3.28-3.48 (m, 3H), 3.61 (m, 1H), 4.01 (m,
1H), 4.61 and 4.62 (2s, 2H, rotamers), 4.67 and 4.75 (2s, 2H,
rotamers), 6.76 and 6.88 (2d, 2H, rotamers), 7.08-7.38 (m, 7H),
8.78 (bs, 1H).
Example 17
(2S)-3-(4-{2-[(4-tert-Butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-2-etho-
xypropanoic acid
(i) Ethyl
(2S)-3-(4-{2-[(4-tert-butylbenzyl)(ethyl)amino]-2-oxoethoxy}phen-
yl)-2-ethoxypropanoate
[0502] To a solution of N-(4-tert-butylbenzyl)-N-ethylamine (0.383
g, 2.00 mmol) and {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic
acid (0.593 g, 2.00 mmol) in methylene chloride (20 mL) were added
N,N-diisopropylethylamine (0.80 mL, 4.6 mmol) and
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (0.706 g, 2.20 mmol) and the reaction mixture was
stirred at room temperature overnight. The resulting solution was
diluted with methylene chloride (40 mL) and the organic phase
washed with 5% HCl (50 mL), saturated aqueous NaHCO.sub.3 (50 mL),
and brine (50 mL), dried over Na.sub.2SO.sub.4, and concentrated in
vacuo. Purification on a prepacked column of silica gel
(Isolute.RTM. SPE Column, 50 g/150 mL) with methylene
chloride/ethyl acetate 10:1 as the eluent yielded 0.54 g (58%) of a
colourless oil. .sup.1H NMR (500 MHz, CDCl.sub.3): .delta.
1.07-1.25 (m, 9H), 1.30 and 1.32 (2s, 9H, rotamers), 2.88-3.00 (m,
2H), 3.28-3.40 and 3.40-3.48 (2m, 3H, rotamers), 3.60 (m, 1H), 3.96
(m, 1H), 4.12-4.20 (m, 2H), 4.57 and 4.59 (2s, 2H, rotamers), 4.66
and 4.73 (2s, 2H, rotamers), 6.78 and 6.89 (2d, 2H, rotamers),
7.09-7.20 (m, 4H), 7.31 and 7.36 (2d, 2H, rotamers).
(ii)
(2S)-3-(4-{2-[(4-tert-Butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-2-
-ethoxypropanoic acid
[0503] To a solution of ethyl
(2S)-3-(4-{2-[(4-tert-butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)-2-eth-
oxypropanoate (0.520 g, 1.11 mmol) in THF (50 mL) was added aqueous
0.10 M LiOH (25 mL) and the solution was stirred at room
temperature overnight. After neutralisation with 5% HCl, the
solvent volume was reduced in vacuo and the remaining aqueous phase
was acidified with 5% HCl and extracted with ethyl acetate
(2.times.50 mL). The combined organic phase washed with brine (50
mL), dried over Na.sub.2SO.sub.4, and concentrated in vacuo to
afforded 0.42 g (86%) of a colourless oil.
[0504] .sup.1H NMR (500 MHz, CDCl.sub.3): .delta. 1.08-1.22 (m,
6H), 1.30 and 1.32 (2s, 9H, rotamers), 2.94 (m, 1H), 3.07 (m, 1H),
3.30-3.50 (m, 3H), 3.59 (m, 1H), 4.04 (m, 1H), 4.57 and 4.59 (2s,
2H, rotamers), 4.67 and 4.74 (2s, 2H, rotamers), 6.79 and 6.89 (2d,
2H, rotamers), 7.09-7.21 (m, 4H), 7.31 and 7.36 (2d, 2H,
rotamers).
[0505] The following examples were prepared in a similar
manner.
Example 18
[0506]
(2S)-3-(4-{2-[(4-Cyclohexylbutyl)(2,4-difluorobenzyl)amino]-2-ox-
oethoxy}phenyl)-2-ethoxypropanoic acid.
Example 19
[0506] [0507]
(2S)-3-(4-{2-[(2,4-Difluorobenzyl)(4-biphenylylethyl)amino]-2-oxoethoxy}p-
henyl)-2-ethoxypropanoic acid.
Example 20
[0507] [0508]
(2S)-3-(4-{3-[(2,4-Difluorobenzyl)(heptyl)amino]-3-oxopropyl}phenyl)-2-et-
hoxypropanoic acid.
Example 21
[0508] [0509]
(2S)-3-(4-{3-[(Cyclohexylmethyl)(hexyl)amino]-3-oxopropyl}phenyl)-2-ethox-
ypropanoic acid.
Example 22
[0509] [0510]
(2S)-3-[4-(2-{(4-Chlorobenzyl)[2-methoxybenzyl]amino}-2-oxoethoxy)phenyl]-
-2-ethoxypropanoic acid.
Example 23
[0510] [0511]
(2S)-3-(4-{2-[(butyl)(4-methanesulfonyloxybenzyl)amino]-2-oxoethoxy}pheny-
l)-2-ethoxypropanoic acid. were performed by plate chemistry.
[0512] The following compounds were prepared by one of the
following methods.
Method A
Reductive Amination
[0513] 1.0 ml of amine solutions was added to 0.8 ml of aldehyde
solutions and the resulting mixtures were stirred for 12 h in
sealed 4 ml glass vial.
[0514] Then ca. 300 mg of borohydride resin (Aldrich 2.5 mmol/g
loading) was manually added to the individual vials, and the
mixture was stirred for 8-12 h (no seal, H2-evolution; after 5 h
add additional 1.0 ml of MeOH).
[0515] The mixture was filtered through a filter plate and washed
once with 2.0 ml of MeOH. The filtrates were collected in 24-well
plates with 4 ml glass vials. Then the solvent was removed in
vacuo, using the HT-4 vacuum centrifuge (30.degree. C., 5 h,
vacramp).
[0516] To the residue was added polymer supported aldehyde resin
(Novabiochem 2.85 mmol/g loading; 80-100 mg), to remove the excess
of amine and 2 ml of dry THF. The resulting mixture was stirred at
rt for 6-8 h, filtered through a filter plate, washed once with 1.0
ml of THF and the filtrate was collected in 24-well plates with 4
ml glass vials. Then the solvent was removed in vacuo, using the
HT-4 vacuum centrifuge (30.degree. C., 5 h, vacramp).
Method B
Amide Formation {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic
acid
[0517] To the residues were added the acid chloride solution (2.0
ml) and PS-DIEA (Argonaut 3.83 mmol/g loading; 70-80 mg) and the
resulting mixture is stirred for 5-12 h.
[0518] The solutions were filtered through NH2-plates (Isolute; 500
mg) to remove any excess of acid chloride and washed with 1.0 ml
THF. The filtrates were collected in 24-well plates with 4 ml glass
vials.
[0519] If the formed amide does not contain a tertiary amino group,
the solutions are filtered through SCX-plates (Isolute; 1 g (SCX-2,
PRS & SCX-3 can be used as well)) to remove the excess of
secondary amine. The SCX columns are washed with 1.0 ml of THF. The
combined filtrates were collected in 24-well plates with 4 ml glass
vials.
[0520] If the formed amide does contain a tertiary amine group,
polymer supported isocyanate (Novabiochem 1.5 mmol/g; ca 100 mg)
was added and the mixture was stirred for additional 6 h at RT.
This is to remove any excess of secondary amine. Then the mixtures
were filtered through filter plates into 24-well plates with 4 ml
glass vials, followed by a wash of 1.0 ml THF. The filtrates were
collected in 24-well plates with 4 ml glass vials. The solvent was
removed in vacuum, using the HT-4 vacuum centrifuge (30.degree. C.,
5 h, vacramp).
Hydrolysis
[0521] The dry residues (esters) are dissolved in 1.2 ml of THF.
400 .mu.l of the solution is transferred to a preweighed blue well
plate. The daughter plate is analysed by LC-MS (purified by
preparative HPLC if needed) and the solvent is removed in vacuum,
using the HT-4 vacuum centrifuge (30.degree. C., 5 h, vacramp). The
dry compounds (daughter plate) are then quantified by automatic
weighing and submitted to screen.
[0522] The mother plate (containing esters dissolved in 0.8 ml THF)
is treated with 0.8 ml 0.175M LiOH (per vial) overnight.
[0523] If a compound contains a tertiary amine, the solution is
poured onto an SCX column (Isolute; 1 g (SCX-2, PRS & SCX-3 can
be used as well)) to catch the product. The SCX columns are washed
with 3.times.1.0 ml of THF/MeOH. Afterwards the product is eluted
with 4.0 ml of MeOH, saturated with ammonia.
[0524] If a compound does not contain a tertiary amine, the solvent
is removed in vacuum, using the HT-4 vacuum centrifuge (30.degree.
C., 12 h, vacramp). The dry compounds are dissolved with 1.0 ml
0.2M HCl, followed by addition of 2.0 ml of DCM. The mixtures are
vigorously shaken for 30 min. Phase separators (6 ml, Whatman) are
used to separate the DCM layer, which contains the product, from
the water phase. The compounds are collected in 24-well plates with
4 ml glass vials. The solvent is removed in vacuum, using the HT-4
vacuum centrifuge (30.degree. C., 5 h, vacramp).
[0525] The dry compounds are dissolved with 0.5 ml THF (or
appropriate solvent) and transferred to a preweighed blue-well
plate. This is repeated with 0.3 ml MeOH. The solvent is afterwards
removed in vacuum, using the HT-4 vacuum centrifuge (30.degree. C.,
5 h, vacramp). The plate is analysed by LC-MS (purified by
preparative HPLC if needed) and the dry compounds are then
quantified by automatic weighing and submitted to screen.
[0526] The following compounds were prepared by these methods:
[0527]
(2S)-3-(4-{2-[benzyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethox-
ypropanoic acid [0528]
(2S)-2-ethoxy-3-(4-{2-[(3-ethoxypropyl)(4-isopropylbenzyl)amino]-2-oxoeth-
oxy}phenyl)propanoic acid [0529]
(2S)-3-(4-{2-[butyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxy-
propanoic acid [0530]
(2S)-3-(4-{2-[(2-chlorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxy-
propanoic acid [0531]
(2S)-2-ethoxy-3-(4-{2-[heptyl(4-isopropylbenzyl)amino]-2-oxoethoxy}phenyl-
)propanoic acid [0532]
(2S)-3-(4-{2-[[(4-cyanocyclohexyl)methyl](4-isopropylbenzyl)amino]-2-oxoe-
thoxy}phenyl)-2-ethoxypropanoic acid [0533]
(2S)-2-ethoxy-3-(4-{2-[(4-isopropylbenzyl)(2-methoxybenzyl)amino]-2-oxoet-
hoxy}phenyl)propanoic acid [0534]
(2S)-3-(4-{2-[(2-chlorobenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)--
2-ethoxypropanoic acid [0535]
(2S)-3-(4-{2-[(4-chlorobenzyl)(2,3-dimethoxybenzyl)amino]-2-oxoethoxy}phe-
nyl)-2-ethoxypropanoic acid [0536]
(2S)-3-(4-{2-[(1,3-benzodioxol-5-ylmethyl)(4-ethoxybenzyl)amino]-2-oxoeth-
oxy}phenyl)-2-ethoxypropanoic acid [0537]
(2S)-3-(4-{2-[(1,3-benzodioxol-5-ylmethyl)(3-bromobenzyl)amino]-2-oxoetho-
xy}phenyl)-2-ethoxypropanoic acid [0538]
(2S)-3-[4-(2-{(1,3-benzodioxol-5-ylmethyl)[3-(trifluoromethyl)benzyl]amin-
o}-2-oxoethoxy)phenyl]-2-ethoxypropanoic acid [0539]
(2S)-3-(4-{2-[(3,5-dimethoxybenzyl)(4-ethoxybenzyl)amino]-2-oxoethoxy}phe-
nyl)-2-ethoxypropanoic acid [0540]
(2S)-3-(4-{2-[(3-chloro-4-fluorobenzyl)(4-ethoxybenzyl)amino]-2-oxoethoxy-
}phenyl)-2-ethoxypropanoic acid [0541]
(2S)-2-ethoxy-3-(4-{2-[(4-ethoxybenzyl)(2-thienylmethyl)amino]-2-oxoethox-
y}phenyl)propanoic acid [0542]
(2S)-3-(4-{2-[benzyl(isopropyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropano-
ic acid [0543]
(2S)-3-{4-[2-(dibenzylamino)-2-oxoethoxy]phenyl}-2-ethoxypropanoic
acid [0544]
(2S)-3-(4-{2-[bis(2-methoxyethyl)amino]-2-oxoethoxy}phenyl)-2-eth-
oxypropanoic acid [0545]
(2S)-2-ethoxy-3-[4-(2-{heptyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethox-
y)phenyl]propanoic acid [0546]
(2S)-2-ethoxy-3-[4-(2-{heptyl[4-(trifluoromethoxy)benzyl]amino}-2-oxoetho-
xy)phenyl]propanoic acid [0547]
(2S)-2-ethoxy-3-(4-{2-[(4-ethylbenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)p-
ropanoic acid [0548]
(2S)-3-(4-{2-[(4-tert-butylbenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-et-
hoxypropanoic acid [0549]
(2S)-2-ethoxy-3-(4-{2-[heptyl(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl)-
propanoic acid [0550]
(2S)-3-(4-{2-[benzyl(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic
acid [0551]
(2S)-2-ethoxy-3-(4-{2-[(4-fluorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-
propanoic acid [0552]
(2S)-3-(4-{2-[(4-chlorobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxy-
propanoic acid [0553]
(2S)-3-(4-{2-[(4-bromobenzyl)(heptyl)amino]-2-oxoethoxy}phenyl)-2-ethoxyp-
ropanoic acid [0554]
(2S)-3-(4-{2-[butyl(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxyprop-
anoic acid [0555]
(2S)-3-(4-{2-[butyl(4-tert-butylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethox-
ypropanoic acid [0556] (2S)-3-(4-{2-[butyl
(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoic acid
[0557]
(2S)-3-(4-{2-[benzyl(butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypro-
panoic acid [0558]
(2S)-3-(4-{2-[butyl(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypro-
panoic acid [0559]
(2S)-3-(4-{2-[(4-bromobenzyl)(butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypr-
opanoic acid [0560]
(2S)-3-(4-{2-[butyl(2,4-difluorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethox-
ypropanoic acid [0561]
(2S)-3-[4-(2-{(4-chlorobenzyl)[4-(trifluoromethoxy)benzyl]amino}-2-oxoeth-
oxy)phenyl]-2-ethoxypropanoic acid [0562]
(2S)-3-(4-{2-[(4-chlorobenzyl)(4-ethylbenzyl)amino]-2-oxoethoxy}phenyl)-2-
-ethoxypropanoic acid [0563]
(2S)-3-(4-{2-[(4-chlorobenzyl)(4-isobutylbenzyl)amino]-2-oxoethoxy}phenyl-
)-2-ethoxypropanoic acid [0564]
(2S)-3-(4-{2-[benzyl(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypr-
opanoic acid [0565]
(2S)-3-(4-{2-[(4-chlorobenzyl)(4-fluorobenzyl)amino]-2-oxoethoxy}phenyl)--
2-ethoxypropanoic acid [0566]
(2S)-3-(4-{2-[(4-bromobenzyl)(4-chlorobenzyl)amino]-2-oxoethoxy}phenyl)-2-
-ethoxypropanoic acid [0567]
(2S)-3-(4-{2-[(4-chlorobenzyl)(2,4-difluorobenzyl)amino]-2-oxoethoxy}phen-
yl)-2-ethoxypropanoic acid [0568]
(2S)-2-ethoxy-3-[4-(2-{(4-methylbenzyl)[4-(trifluoromethyl)benzyl]amino}--
2-oxoethoxy)phenyl]propanoic acid [0569]
(2S)-2-ethoxy-3-[4-(2-{(4-methylbenzyl)[4-(trifluoromethoxy)benzyl]amino}-
-2-oxoethoxy)phenyl]propanoic acid [0570]
(2S)-2-ethoxy-3-(4-{2-[(4-ethylbenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}-
phenyl)propanoic acid [0571]
(2S)-3-(4-{2-[(4-ten-butylbenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}pheny-
l)-2-ethoxypropanoic acid [0572]
(2S)-2-ethoxy-3-(4-{2-[(4-isobutylbenzyl)(4-methylbenzyl)amino]-2-oxoetho-
xy}phenyl)propanoic acid [0573]
(2S)-3-(4-{2-[benzyl(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypr-
opanoic acid [0574]
(2S)-2-ethoxy-3-(4-{2-[(4-fluorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy-
}phenyl)propanoic acid [0575]
(2S)-3-(4-{2-[(4-chlorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)--
2-ethoxypropanoic acid [0576]
(2S)-3-(4-{2-[(4-bromobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phenyl)-2-
-ethoxypropanoic acid and [0577]
(2S)-3-(4-{2-[(2,4-difluorobenzyl)(4-methylbenzyl)amino]-2-oxoethoxy}phen-
yl)-2-ethoxypropanoic acid. Biological Activity
[0578] The compounds of the invention were tested in the assays
described in WO 03/051821.
Assay Procedure
[0579] Stock solutions of compounds in DMSO were diluted in
appropriate concentration ranges in master plates. From master
plates, compounds were diluted in culture media to obtain test
compound solutions for final doses.
[0580] After adjustment of the amount of cell medium to 75 .mu.l in
each well, 50 .mu.l test compound solution was added. Transiently
transfected cells were exposed to compounds for about 24 hours
before the luciferase detection assay was performed. For luciferase
assays, 100 .mu.l of assay reagent was added manually to each well
and plates were left for approximately 20 minutes in order to allow
lysis of the cells. After lysis, luciferase activity was measured
in a 1420 Multiwell counter, Victor, from Wallach.
Reference Compounds
[0581] The TZD pioglitazone was used as reference substance for
activation of both human and murine PPAR.gamma..
5,8,11,14-Eicosatetrayonic acid (ETYA) was used as reference
substance for human PPAR.alpha..
Calculations and Analysis
[0582] For calculation of EC.sub.50 values, a concentration-effect
curve was established. Values used were derived from the average of
two or three independent measurements (after subtraction of the
background average value) and were expressed as the percentage of
the maximal activation obtained by the reference compound. Values
were plotted against the logarithm of the test compound
concentration. EC.sub.50 values were estimated by linear
intercalation between the data points and calculating the
concentration required to achieve 50% of the maximal activation
obtained by the reference compound.
[0583] The compounds of formula I have an EC.sub.50 of less than
0.1 .mu.mol/l for PPAR.alpha. and particular compounds have an
EC.sub.50 of less than 0.01 .mu.mol/l. Additionally in particular
compounds the ratio of the EC.sub.50 (PPAR.gamma.):EC.sub.50
(PPAR.alpha.) is greater than 150:1. It is believed that this ratio
is important with respect to the pharmacological activity of the
compounds and to their therapeutic profile. TABLE-US-00001 Example
no EC.sub.50 PPAR.alpha. (.mu.M) ratio EC.sub.50
(PPAR.gamma.):EC.sub.50 (PPARa) 12 0.003 >1000 13 0.008 >400
15 0.003 >900
[0584] In addition the compounds of the present invention exhibit
improved DMPK (Drug Metabolism and Pharmacokinetic) properties for
example they exhibit improved metabolic stability in vitro. The
compounds also have a promising toxicological profile.
* * * * *