U.S. patent application number 13/084374 was filed with the patent office on 2011-08-04 for substituted pyrrole derivatives and their use as hmg-co inhibitors.
This patent application is currently assigned to RANBAXY LABORATORIES LIMITED. Invention is credited to Ram Chander ARYAN, Anita CHUGH, Yatendra KUMAR, Vikram Krishna RAMANATHAN, Mohammad SALMAN, Jitendra SATTIGERI.
Application Number | 20110190296 13/084374 |
Document ID | / |
Family ID | 33489407 |
Filed Date | 2011-08-04 |
United States Patent
Application |
20110190296 |
Kind Code |
A1 |
SALMAN; Mohammad ; et
al. |
August 4, 2011 |
Substituted Pyrrole Derivatives and Their Use as HMG-CO
Inhibitors
Abstract
The present invention relates to substituted pyrrole
derivatives, which can be used as
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase
inhibitors. Compounds disclosed herein can function as cholesterol
lowering agents and can be used for the treatment of
cholesterol-related diseases and related symptoms. Processes for
the preparation of disclosed compounds are provided, as well as
pharmaceutical compositions containing the disclosed compounds, and
methods of treating cholesterol-related diseases and related
symptoms.
Inventors: |
SALMAN; Mohammad;
(Princeton, NJ) ; SATTIGERI; Jitendra; (Gurgaon,
IN) ; KUMAR; Yatendra; (Gurgaon, IN) ; ARYAN;
Ram Chander; (New Delhi, IN) ; RAMANATHAN; Vikram
Krishna; (Gurgaon, IN) ; CHUGH; Anita; (New
Delhi, IN) |
Assignee: |
RANBAXY LABORATORIES
LIMITED
New Delhi
IN
|
Family ID: |
33489407 |
Appl. No.: |
13/084374 |
Filed: |
April 11, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10558859 |
Aug 17, 2006 |
7923467 |
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PCT/IB2004/001761 |
May 28, 2004 |
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13084374 |
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10449418 |
May 30, 2003 |
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10558859 |
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Current U.S.
Class: |
514/235.5 ;
514/326; 514/422; 514/423; 544/141; 546/208; 548/517; 548/537 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 3/00 20180101; C07C 69/716 20130101; C07D 403/04 20130101;
C07D 405/06 20130101; A61K 31/40 20130101; A61P 25/28 20180101;
A61P 9/12 20180101; C07D 413/04 20130101; C07D 207/34 20130101;
A61P 9/10 20180101; A61P 3/06 20180101; A61P 9/00 20180101; A61P
3/10 20180101; C07D 405/14 20130101; A61P 19/10 20180101; C07C
69/738 20130101; C07D 401/12 20130101 |
Class at
Publication: |
514/235.5 ;
548/537; 514/423; 548/517; 514/422; 544/141; 546/208; 514/326 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 207/34 20060101 C07D207/34; A61K 31/40 20060101
A61K031/40; A61P 3/10 20060101 A61P003/10; A61P 3/06 20060101
A61P003/06; A61P 9/10 20060101 A61P009/10; A61P 9/12 20060101
A61P009/12; A61P 25/28 20060101 A61P025/28; C07D 405/12 20060101
C07D405/12; A61K 31/4025 20060101 A61K031/4025; C07D 413/06
20060101 C07D413/06; C07D 401/06 20060101 C07D401/06; A61K 31/454
20060101 A61K031/454 |
Claims
1. A compound of the structure of Formula Ib, ##STR00030## or a
pharmaceutically acceptable salt thereof, pharmaceutically
acceptable tautomer, racemate, pure enantiomer, diastereoisomer or
a lactone form or N-oxide thereof, wherein ##STR00031## R.sub.1 is
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl, or optionally
substituted phenyl (wherein the substituent(s) is/are selected from
halogens, C.sub.1-C.sub.6 alkyl, cyano and C.sub.1-C.sub.3
perfluoroalkyl); R.sub.2 is optionally substituted phenyl (wherein
the substituent(s) is/are selected from cyano, acetyl and
optionally substituted amino); R.sub.3 is optionally substituted
C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl (wherein the
substituent(s) is/are selected from halogens, hydroxyl,
C.sub.1-C.sub.3 alkoxy, and protected hydroxyl); R.sub.3 can also
be --NR.sub.6R.sub.7 wherein R.sub.6 and R.sub.7 are optionally
substituted C.sub.1-C.sub.6 alkyl (wherein the optional
substituent(s) is/are selected from halogens, hydroxyl,
C.sub.1-C.sub.3 alkoxy, and protected hydroxyl); R.sub.4 is
--COR.sub.10 (wherein R.sub.10 is selected from C.sub.1-C.sub.2
alkoxy, hydroxyl and --NR.sub.11R.sub.12 (wherein R.sub.11 and
R.sub.12 are independently selected from hydrogen, alkyl, aryl,
C.sub.3-C.sub.7 cycloalkyl, aralkyl and R.sub.11 and R.sub.12
together form 5-7 membered ring with one or more optional
heteroatom(s) wherein the heteroatom(s) is/are independently
selected from nitrogen, oxygen and sulphur); and R.sub.5 is
hydrogen, C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl,
optionally substituted aryl or aralkyl [wherein the substituents
are selected from halogens, cyano, optionally substituted
C.sub.1-C.sub.6 alkyl (wherein the substituents are independently
selected from hydroxyl, protected hydroxyl, and halogen(s)],
optionally substituted amino, acetyl, trifluoromethyl and
C.sub.1-C.sub.6 alkoxycarbonyl.
2. The compound of claim 1 wherein R1, R2, R3 and R5 are
4-fluorophenyl, phenyl, isopropyl and hydrogen, respectively.
3. The compound according to claim 1, wherein R1 is phenyl
substituted with one or more halogen.
4. The compound according to claim 3, wherein R1 is phenyl
substituted with one or more fluorine.
5. The compound according to claim 4, wherein R1 is
4-fluorophenyl.
6. The compound according to claim 1, wherein R2 and R5 are phenyl
and hydrogen, respectively.
7. The compound according to claim 1, wherein R3 is C1-C6
alkyl.
8. The compound according to claim 1, wherein R3 is isopropyl.
9. The compound according to claim 1, wherein R10 is hydroxyl.
10. A compound according to claim 1, wherein R3 is alkyl of from
one to six carbon atoms or cycloalkyl of from three to six carbon
atoms.
11. A compound of the chemical formula: ##STR00032## wherein
##STR00033## or a pharmaceutically acceptable salt thereof.
12. A compound, which is
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-carboxyphenyl)ami-
no) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid or a
pharmaceutically acceptable salt thereof.
13. A pharmaceutically acceptable salt of a compound of claim 1,
wherein the salt is selected from the group consisting of lithium,
sodium, potassium, calcium, magnesium, zinc, aluminium, amino acid,
ammonium, mono-alkyl ammonium, dialkyl ammonium, trialkyl ammonium
and N-methyl glucamine.
14. The pharmaceutically acceptable salt of claim 13, wherein the
salt is sodium salt.
15. The pharmaceutically acceptable salt of claim 13, wherein the
salt is potassium salt.
16. The pharmaceutically acceptable salt of claim 13, wherein the
salt is hemicalcium salt.
17. The pharmaceutically acceptable salt of claim 13, wherein the
salt is hemimagnesium salt.
18. The pharmaceutically acceptable salt of claim 13, wherein the
salt is hemizinc salt.
19. The pharmaceutically acceptable salt of claim 13, wherein the
salt is N-methyl glucamine salt.
20. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1 together with a
pharmaceutically acceptable carrier, excipient or diluent.
21. A method of treating diabetes or a disease selected from the
group consisting of arteriosclerosis, atherosclerosis,
hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia,
hypertriglyceridemia, hypertension, stroke, ischemia, peripheral
vascular disease, peripheral arterial disease, coronary heart
disease, myocardial infarction, cerebral infarction, myocardial
microvascular disease, dementia, Alzheimer's disease, angina and
restenosis in a mammal in need of such treatment comprising
administering a therapeutically-effective amount of a compound of
claim 1 to the mammal.
22. The method according to claim 21, wherein the disease is
hyperlipidemia.
23. The method according to claim 21, wherein the disease is
hypercholesterolemia.
24. The method according to claim 21, wherein the disease is
hyperlipoproteinemia.
25. The method according to claim 21, wherein the disease is
hypertriglyceridemia.
26. The method according to claim 21, wherein the disease is
hypertension.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to substituted pyrrole
derivatives, which can be used as
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase
inhibitors.
[0002] Compounds disclosed herein can function as cholesterol
lowering agents and can be used for the treatment of
cholesterol-related diseases and related symptoms. Processes for
the preparation of disclosed compounds are provided, as well as
pharmaceutical compositions containing the disclosed compounds, and
methods of treating cholesterol-related diseases and related
symptoms.
BACKGROUND OF THE INVENTION
[0003] Cardiovascular disease and its associated maladies,
dysfunctions and complications are a principal cause of disability
and the chief cause of death. One specific factor significantly
contributing to this pathophysiologic process is atherosclerosis,
which has been generally recognized as the leading health care
problem both with respect to mortality and health care costs.
[0004] Atherosclerosis is characterized by the deposition of fatty
substances, primarily cholesterol, resulting in plaque formation on
the inner surface of the arterial wall and degenerative change to
the arteries.
[0005] It is now well established that cardiovascular disorders
including myocardial infarction, coronary heart disease,
hypertension and hypotension, cerebrovascular disorders including
stroke, cerebral thrombosis and memory loss due to stroke;
peripheral vascular disease and intestinal infarction are caused by
blockage of arteries and arterioles by atherosclerotic plaque.
Atherosclerotic plaque formation is multi-factorial in its
production. Hypercholesterolemia, especially elevated levels of
low-density lipoprotein cholesterol (LDL), is an important risk
factor for atherosclerosis and arteriosclerosis and associated
diseases.
[0006] The HMG-CoA reductase inhibitors (statins) have been used in
reducing blood levels of LDL cholesterol. Cholesterol is produced
via the mevalonic acid pathway. Reducing the formation of mevalonic
acid, a precursor to cholesterol, leads to a corresponding decrease
in hepatic cholesterol biosynthesis with a reduction in the
cellular pool of cholesterol.
[0007] U.S. Pat. No. 4,681,893 assigned to Wamer-Lambert, discloses
certain trans-6-[2-(3-, or 4-carbaoxamido-substituted
pyrrole-1-yl)alkyl]-4-hydroxypyran-2-ones and the corresponding
ring-opened hydroxy acids derived therefrom, including
trans(.+-.)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrah-
ydro-4-hydroxy-6-oxo-2,1-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide,
which are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A
reductase (HMG-CoA), an important coenzyme catalyzing the
intracellular synthesis of cholesterol.
[0008] U.S. Pat. No. 5,273,995 assigned to Warner Lambert, relates
to the optically pure (R, R) form of the ring-opened acid of
trans-5-(4-fluorophenyl)-2-(1-methylethyl-N,4-diphenyl-1-[2-tetrahydro-4--
hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide that is
[R--(R*,
R*)]-2-(4-fluorophenyl)-.beta.,.delta.-dihydroxy-5-(1-methylethy-
l)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid,
pharmaceutically acceptable salts thereof, specifically its calcium
salt (Atorvastatin, Lipitor.RTM.), which is currently being used
for the treatment of hypercholesterolemia.
[0009] U.S. Pat. No. 5,385,929 discloses certain phenyl hydroxy
derivatives of the compounds disclosed in U.S. Pat. No. 5,273,995,
and that such phenyl hydroxy derivatives are also active as the
inhibitors of the biosynthesis of cholesterol.
SUMMARY OF THE INVENTION
[0010] The present invention relates to substituted pyrrole
derivatives, which can be used as
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase
inhibitors, and processes for the synthesis of these compounds.
These compounds show utility in inhibiting HMG-CoA reductase, among
the key rate limiting steps in the biosynthetic pathway of
cholesterol formation. Therefore, these compounds hold promise for
the treatment of hypercholesterolemia and hyperlipidemia
[0011] Pharmaceutically acceptable salts, pharmaceutically
acceptable solvates, tautomers, racemates, polymorphs, pure
enantiomers, diastereoisomers, metabolites, prodrugs or N-oxides of
these compounds having the same type of activity are also
provided.
[0012] Pharmaceutical composition containing the compounds, and
which may also contain pharmaceutically acceptable carriers or
diluents, which can be used for the treatment of
cholesterol-related disease or related symptoms thereof are also
provided.
[0013] Other aspects will be set forth in the accompanying
description which follows and in the part will be apparent from the
description or may be learnt by the practice of the invention.
[0014] In accordance with another aspect, there is provided a
method for treating a mammal suffering from cholesterol related
disease, diabetes and related disease, cerebrovascular disease or
cardiovascular disease, comprising administering to a mammal a
therapeutically effective amount of compounds disclosed herein.
[0015] The compounds of the present invention can be used for
treating arteriosclerosis, atherosclerosis, hypercholesterolemia,
hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia,
hypertension, stroke, ischemia, endothelium dysfunction, peripheral
vascular disease, peripheral arterial disease, coronary heart
disease, myocardial infarction, cerebral infarction, myocardial
microvascular disease, dementia, Alzheimer's disease, osteoporosis
and/or osteopenia, angina or resterosis.
[0016] In accordance with one aspect, there is provided a compound
having the structure of Formula I,
##STR00001##
its pharmaceutically acceptable salts, pharmaceutically acceptable
solvates, prodrugs, metabolites, polymorphs, tautomers, racemates,
pure enantiomers, diastereoisomers or N-oxides wherein
##STR00002##
R.sub.1 can be C.sub.1-C.sub.6, C.sub.3-C.sub.6, or optionally
substituted phenyl (wherein up to three substituents are
independently selected from halogens, C.sub.1-C.sub.6 alkyl, cyano,
or C.sub.1-C.sub.3 perfluoroalkyl); R.sub.2 can be optionally
substituted phenyl (wherein up to three substituents are
independently selected from cyano, acetyl, or optionally
substituted amino, wherein up to two amino substituents are
independently selected from C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, acetyl, or sulfonamide); R.sub.3 can be optionally
substituted C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl
(wherein substituents are independently selected from halogens,
hydroxyl, C.sub.1-C.sub.3 alkoxy and protected hydroxyl); R.sub.3
can also be --NR.sub.8R.sub.9, wherein R.sub.8 and R.sub.9 are
optionally substituted C.sub.1-C.sub.6 alkyl (wherein the optional
substituent(s) is/are selected from halogens, hydroxy,
C.sub.1-C.sub.3 alkoxy and protected hydroxyl);
R.sub.4 can be
##STR00003##
[0017] wherein R.sub.5 and R.sub.6 are independently hydrogen,
C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl, optionally
substituted aryl or aralkyl, wherein the substituents are selected
from halogens, cyano, optionally substituted C.sub.1-C.sub.6 alkyl
(wherein up to two substituents are independently selected from
hydroxyl, protected hydroxyl, and halogen(s)), optionally
substituted amino (wherein up to two substituents are independently
selected from SO.sub.2R.sub.7, COR.sub.7, or CONHR.sub.7, wherein
R.sub.7 is C.sub.1-C.sub.6 alkyl or aryl), or acetyl,
trifluoromethyl, or C.sub.1-C.sub.6 alkoxycarbonyl, or R.sub.5 and
R.sub.6 together form a 5-7 membered ring with one or more optional
heteroatoms wherein the hetero atom(s) are independently selected
from nitrogen, oxygen and sulfur, or R.sub.4 can be an optionally
substituted mono-, bi- or tricyclic heterocycle having one or more
hetero atom(s) wherein said hereto atom(s) is/are independently
selected from oxygen, nitrogen and sulfur, and the optional
substituents are independently selected from halogens, hydroxy,
protected hydroxyl, C.sub.1-C.sub.3 alkoxy, cyano, C.sub.1-C.sub.3
perfluoroalkyl, C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6
cycloalkyl, aryl or optionally substituted aralkyl wherein the
substituents are independently selected from halogens, hydroxy,
protected hydroxyl, C.sub.1-C.sub.3 alkoxy, cyano, or
C.sub.1-C.sub.3 perfluoroalkyl, and the pharmaceutically acceptable
salts, tautomers, racemates, pure enantiomers or diastereoisomers,
and solvates of the compounds of Formula I, with the proviso that
R.sub.2 is phenyl only when (1) R.sub.5 or R.sub.6 is
C.sub.3-C.sub.6 cycloalkyl or phenyl substituted with acetyl,
alkyl, cycloalkyl, hydroxyalkyl, alkylsulfonamido, acetamido or (2)
when R.sub.5 and R.sub.6 together form a 5-7 membered ring with or
without one or more heteroatoms wherein the hetero atom(s) are
selected from nitrogen, oxygen and sulfur or (3) when R.sub.5 or
R.sub.6 is aralkyl optionally substituted with halogens, cyano,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 halogenated alkyl or (4)
when R.sub.4 is optionally substituted mono-, bi- or tricyclic
heterocycle having one or more hetero atom(s) (wherein the optional
substituents are independently selected from halogens, hydroxy,
protected hydroxyl, C.sub.1-C.sub.3 alkoxy, cyano, perfluoroalkyl
of one to three carbon atoms, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, aryl, or optionally substituted aralkyl
(wherein the aralkyl substituents are independently selected from
halogens, hydroxy, protected hydroxyl, C.sub.1-C.sub.3 alkoxy,
cyano, or C.sub.1-C.sub.3 perfluoroalkyl)).
[0018] In accordance with another aspect, there are provided
compounds having the structure of Formula Ib,
##STR00004##
their pharmaceutically acceptable salts, pharmaceutically
acceptable solvates, tautomers, racemates, polymorphs, pure
enantiomers, diastereoisomers, metabolites, prodrugs or N-oxides
wherein
##STR00005##
R.sub.1 can be C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl,
or optionally substituted phenyl (wherein the substituent(s) is/are
selected from halogens, C.sub.1-C.sub.6 alkyl, cyano and
C.sub.1-C.sub.3 perfluoroalkyl); R.sub.2 can be optionally
substituted phenyl (wherein the substituent(s) is/are selected from
cyano, acetyl and optionally substituted amino); R.sub.3 can be
optionally substituted C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6
cycloalkyl (wherein the substituent(s) is/are selected from
halogens, hydroxyl, C.sub.1-C.sub.3 alkoxy, and protected
hydroxyl); R.sub.3 can also be --NR.sub.6R.sub.7 wherein R.sub.6
and R.sub.7 are optionally substituted C.sub.1-C.sub.6 alkyl
(wherein the optional substituent(s) is/are selected from halogens,
hydroxyl, C.sub.1-C.sub.3 alkoxy, and protected hydroxyl); R.sub.4
can be acetyl, C.sub.1-C.sub.2 alkoxycarbonyl, optionally
substituted C.sub.1-C.sub.6 alkyl (wherein the substituent is
hydroxy or protected hydroxyl), NHR.sub.8 [wherein R.sub.8 is
selected from alkyl, aralkyl, SO.sub.2R.sub.9, COR.sub.9 or
CONHR.sub.9, CSNHR.sub.9 (wherein R.sub.9 is C.sub.1-C.sub.6 alkyl,
aryl or aralkyl)]; R.sub.4 can also be --COR.sub.10 (wherein
R.sub.10 is selected from hydroxyl and --NR.sub.11R.sub.12 (wherein
R.sub.11 and R.sub.12 are independently selected from hydrogen,
alkyl, aryl, C.sub.3-C.sub.7 cycloalkyl, heterocyclyl, aralkyl and
R.sub.11 and R.sub.12 together form 5-7 membered ring with one or
more optional heteroatom(s) wherein the heteroatom(s) is/are
independently selected from nitrogen, oxygen and sulphur); R.sub.5
can be hydrogen, C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6
cycloalkyl, optionally substituted aryl or aralkyl [wherein the
substituents are selected from halogens, cyano, optionally
substituted C.sub.1-C.sub.6 alkyl (wherein the substituents are
independently selected from hydroxyl, protected hydroxyl, and
halogen(s)], optionally substituted amino, acetyl, trifluoromethyl
and C.sub.1-C.sub.6 alkoxycarbonyl.
[0019] In one particular embodiment, there are provided compounds
of Formula Ib,
##STR00006##
their pharmaceutically acceptable salts, pharmaceutically
acceptable solvates, tautomers, racemates, polymorphs, pure
enantiomers, diastereoisomers, metabolites, prodrugs or N-oxides
wherein
##STR00007##
R.sub.1, R.sub.2, R.sub.3 and R.sub.5 are as defined earlier;
R.sub.4 can be NHR.sub.8 [wherein R.sub.8 is selected from aralkyl,
CONHR.sub.9 (wherein R.sub.9 is aralkyl); CSNHR.sub.9 (wherein
R.sub.9 is C.sub.1-C.sub.6 alkyl, aryl or aralkyl)]; --COR.sub.10
(wherein R.sub.10 is selected from hydroxyl and --NR.sub.11R.sub.12
(wherein R.sub.11 and R.sub.12 are independently selected from
hydrogen, alkyl, aryl, C.sub.3-C.sub.7 cycloalkyl, aralkyl and
R.sub.11 and R.sub.12 together form 5-7 membered ring with one or
more optional heteroatom(s) wherein the heteroatom(s) is/are
independently selected from nitrogen, oxygen and sulphur);
[0020] In yet another particular embodiment, there are provided
compounds of Formula Ib,
##STR00008##
their pharmaceutically acceptable salts, pharmaceutically
acceptable solvates, tautomers, racemates, polymorphs, pure
enantiomers, diastereoisomers, metabolites, prodrugs or N-oxides
wherein
##STR00009##
R.sub.1, R.sub.2, R.sub.3 and R.sub.5 can be 4-fluorophenyl,
phenyl, isopropyl and hydrogen, respectively; R.sub.4 can be
C.sub.1-C.sub.2 alkoxycarbonyl, optionally substituted
C.sub.1-C.sub.6 alkyl (wherein the substituent is hydroxy or
protected hydroxyl), NHR.sub.8 [wherein R.sub.8 is selected from
SO.sub.2R.sub.9, COR.sub.9 or CONHR.sub.9 (wherein R.sub.9 is
methyl or phenyl)]
[0021] In accordance with further aspect, there are provided
intermediates having the structure of Formula XIX,
##STR00010##
wherein R.sub.2 can be optionally substituted phenyl (wherein the
substituent(s) is/are selected from cyano, acetyl and optionally
substituted amino; R.sub.3 can be optionally substituted
C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl (wherein the
substituent(s) is/are selected from halogens, hydroxyl,
C.sub.1-C.sub.3 alkoxy, and protected hydroxyl); R.sub.3 can also
be --NR.sub.6R.sub.7 wherein R.sub.6 and R.sub.7 are optionally
substituted C.sub.1-C.sub.6 alkyl (wherein the optional
substituent(s) is/are selected from halogens, hydroxyl,
C.sub.1-C.sub.3 alkoxy, and protected hydroxyl). In accordance with
third aspect, there are provided intermediates having the structure
of Formula XX,
##STR00011##
wherein R.sub.1 can be C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, or optionally substituted phenyl (wherein the
substituent(s) is/are selected from halogens, C.sub.1-C.sub.6
alkyl, cyano and C.sub.1-C.sub.3 perfluoroalkyl); R.sub.2 can be
optionally substituted phenyl (wherein the substituent(s) is/are
selected from cyano, acetyl and optionally substituted amino;
R.sub.3 can be optionally substituted C.sub.1-C.sub.6 alkyl or
C.sub.3-C.sub.6 cycloalkyl (wherein the substituent(s) is/are
selected from halogens, hydroxyl, C.sub.1-C.sub.3 alkoxy, and
protected hydroxyl); R.sub.3 can also be --NR.sub.6R.sub.7 wherein
R.sub.6 and R.sub.7 are optionally substituted C.sub.1-C.sub.6
alkyl (wherein the optional substituent(s) is/are selected from
halogens, hydroxyl, C.sub.1-C.sub.3 alkoxy, and protected
hydroxyl). In accordance with fourth aspect, there are provided
intermediates having the structure of Formula XXI,
##STR00012##
wherein R.sub.1 can be C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, or optionally substituted phenyl (wherein the
substituent(s) is/are selected from halogens, C.sub.1-C.sub.6
alkyl, cyano and C.sub.1-C.sub.3 perfluoroalkyl); R.sub.2 can be
optionally substituted phenyl (wherein the substituent(s) is/are
selected from cyano, acetyl and optionally substituted amino;
R.sub.3 can be optionally substituted C.sub.1-C.sub.6 alkyl or
C.sub.3-C.sub.6 cycloalkyl (wherein the substituent(s) is/are
selected from halogens, hydroxyl, C.sub.1-C.sub.3 alkoxy, and
protected hydroxyl); R.sub.3 can also be --NR.sub.6R.sub.7 wherein
R.sub.6 and R.sub.7 are optionally substituted C.sub.1-C.sub.6
alkyl (wherein the optional substituent(s) is/are selected from
halogens, hydroxyl, C.sub.1-C.sub.3 alkoxy, and protected
hydroxyl). In accordance with fifth aspect, there are provided
intermediates having the structure of Formula XXII,
##STR00013##
wherein R.sub.1 can be C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
cycloalkyl, or optionally substituted phenyl (wherein the
substituent(s) is/are selected from halogens, C.sub.1-C.sub.6
alkyl, cyano and C.sub.1-C.sub.3 perfluoroalkyl); R.sub.2 can be
optionally substituted phenyl (wherein the substituent(s) is/are
selected from cyano, acetyl and optionally substituted amino;
R.sub.3 can be optionally substituted C.sub.1-C.sub.6 alkyl or
C.sub.3-C.sub.6 cycloalkyl (wherein the substituent(s) is/are
selected from halogens, hydroxyl, C.sub.1-C.sub.3 alkoxy, and
protected hydroxyl); R.sub.3 can also be --NR.sub.6R.sub.7 wherein
R.sub.6 and R.sub.7 are optionally substituted C.sub.1-C.sub.6
alkyl (wherein the optional substituent(s) is/are selected from
halogens, hydroxyl, C.sub.1-C.sub.3 alkoxy, and protected
hydroxyl).
[0022] As used herein the term "alkyl", unless otherwise defined,
refers to straight or branched chain hydrocarbon of from 1 to 10
carbon atom(s). Examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, isopropyl, butyl, octyl, and the like.
[0023] Alkyl may optionally be substituted with halogen, hydroxy,
protected hydroxyl, C.sub.1-C.sub.3 alkoxy, optionally substituted
amino and C.sub.1-C.sub.6 alkoxycarbonyl.
[0024] As used herein the term "optionally substituted amino",
unless otherwise defined, refers to NR.sub.14R.sub.15 wherein
R.sub.14 and R.sub.15 are independently selected from hydrogen,
alkyl, aryl, aralkyl, C.sub.3-C.sub.7 cycloalkyl, SO.sub.2R.sub.16,
COR.sub.16, CONHR.sub.16 and CSNHR.sub.16 (wherein R.sub.15 is
C.sub.1-C.sub.6 alkyl, aryl or aralkyl).
[0025] As used herein the term "protected hydroxyl" refers to a
hydroxy moiety protected by a group R.sub.17 wherein R.sub.17 is
selected from alkyl, cycloalkyl, aralkyl, aryl,
--(CH.sub.2).sub.nOR.sub.18 (wherein R.sub.18 is selected from
alkyl, cycloalkyl, aralkyl, aryl and n represents an integer from 1
to 6), COR.sub.19, CSR.sub.19, CONHR.sub.19 and CSNHR.sub.19
(wherein R.sub.19 is selected from alkyl, aryl, aralkyl and
heterocyclyl). Examples of protected hydroxyl include, but are not
limited to, --OCH.sub.3, --OC.sub.2H.sub.5, --O-n-propyl,
--O-1-propyl, --O-cyclopropyl, --O--CH.sub.2OCH.sub.3,
--O-cyclopentyl, --O-cyclohexyl, --O-benzyl, --O-chlorobenzyl,
--O-methoxybenzyl, --O-phenyl, --O-chlorophenyl, --O--COCH.sub.3,
--O--COC.sub.2H.sub.5, --O--CObenzyl, --O--COphenyl,
--O--COpyridinyl, --O--CONHphenyl, --O--CONHpyridinyl,
--O--CONH-octyl, --O--CSNHphenyl, and the like.
[0026] As used herein the term "aralkyl" refers to
(CH.sub.2).sub.naryl wherein n is an integer from 1 to 6.
[0027] As used herein the term "aryl", unless otherwise defined,
refers to an aromatic radical having 6 to 14 carbon atoms. Examples
of aryl include, but are not limited to, phenyl, napthyl, anthryl
and biphenyl, and the like.
[0028] As used herein the term "heterocyclyl" refers to
non-aromatic, aromatic or aromatic fused with non-aromatic ring
system having one or more heteroatom (s) in either the aromatic or
the non-aromatic part wherein the said hetero atom (s) is/are
selected from the group comprising of nitrogen, sulphur and oxygen
and the ring system includes mono, bi or tricyclic. Examples of
heterocycles include, but not limited to, benzoxazinyl,
benzthiazinyl, benzimidazolyl, benzofuranyl, carbazolyl, Indolyl,
indolinyl, oxazolyl, phenoxazinyl, pyridyl and phenothiazinyl, and
the like.
[0029] The said aryl or heterocyclyl may optionally be substituted
with one or more substituent(s) independently selected from
halogen, hydroxy, nitro, cyano, alkyl, aryl, alkoxy, thioalkyl,
cycloalkoxy, optionally substituted amino.
[0030] In accordance with yet another aspect, there are provided
processes for the preparation of the compounds described
herein.
[0031] In accordance with another aspect, there is provided a
method for treating a mammal suffering from cholesterol related
disease, diabetes and related disease, cerebrovascular disease or
cardiovascular disease, comprising administering to a mammal a
therapeutically effective amount of compounds disclosed herein.
[0032] The compounds of the present invention can be used for
treating arteriosclerosis, atherosclerosis, hypercholesterolemia,
hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia,
hypertension, stroke, ischemia, endothelium dysfunction, peripheral
vascular disease, peripheral arterial disease, coronary heart
disease, myocardial infarction, cerebral infarction, myocardial
microvascular disease, dementia, Alzheimer's disease, osteoporosis
and/or osteopenia, angina or resterosis.
DETAILED DESCRIPTION OF THE INVENTION
[0033] The compounds described herein may be prepared by techniques
well known in the art and familiar to the average synthetic organic
chemist. In addition, the compounds of the present invention may be
prepared by the following reaction sequences as depicted in Schemes
I, Ia, Ib, II, IIa, III, IIIa, and IV. Further compounds which can
be useful for treatment of these diseases, and methods for making
such compounds, are disclosed in copending U.S. patent application
Ser. No. 10/448,770 filed 30 May, 2003, entitled "Substituted
Pyrrole Derivatives," and PCT Application No. PCT/IB2004/______
filed ______ entitled "Substituted Pyrrole Derivatives," which
applications are incorporated herein in their entirety.
##STR00014##
Scheme I
[0034] The compound of Formula XII can be prepared according to
Scheme I. Accordingly, a compound of Formula II is reacted with a
compound of Formula III, wherein R.sub.3, R.sub.5 and R.sub.6 are
as defined earlier, to give a compound of Formula IV which on
reaction with a compound of Formula V (wherein R.sub.2 is as
defined earlier) gives a compound of Formula VI, which on treatment
with a compound of Formula VII (wherein R.sub.1 is as defined
earlier) yields a compound of Formula VIII, which on further
reaction with a compound of Formula IX gives a compound of Formula
X, which on hydrolysis gives a compound of Formula XI, which can
then be further converted to hemicalcium salt.
[0035] The reaction of a compound of Formula II with a compound of
Formula III to give a compound of Formula IV can be carried out in
a nonpolar solvent, such as xylene or toluene. The reaction of a
compound of Formula II with a compound of Formula III can be
carried out in the presence of an organic base, such as
triethylamine, pyridine or 1,2-ethylenediamine. The reaction of a
compound of Formula IV with an aldehyde of Formula V to give a
compound of Formula VI can be carried out in a nonpolar solvent
such as hexane, heptane, dichloromethane or toluene or mixture(s)
thereof. The reaction of a compound of Formula IV with an aldehyde
of Formula V can be carried out in the presence of an organic base
such as piperidine, pyridine or .beta.-alanine and an organic acid
such as glacial acetic acid or benzoic acid. The reaction of a
compound of Formula VI with an aldehyde of Formula VII to give a
compound of Formula VIII can be carried out in the presence of a
suitable catalyst, such as sodium cyanide,
3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazolium bromide or
3-benzyl-5-(2-hydroxyethyl)-4-methyl thiazolium chloride, in a
solvent free condition or in an alcoholic solvent, such as
methanol, ethanol, propanol or isopropanol. The reaction of a
compound of Formula VI with an aldehyde of Formula VII can be
carried out in the presence of an organic base, such as
triethylamine or pyridine.
[0036] The reaction of a compound of Formula VIII with a compound
of Formula IX to give a compound of Formula X can be carried out in
a nonpolar solvent, such as xylene, toluene hexane, heptane,
tetrahydrofuran, or a mixture thereof in a suitable ratio. The
reaction of a compound of Formula VIII with a compound of Formula
IX can be carried out in the presence of an organic acid, such as
pivalic acid or p-toluene sulfonic acid.
[0037] The conversion of a compound of Formula X to a compound of
Formula XI can be carried out in a two-step manner, involving an
initial acid-catalysed cleavage of ketal, followed by
base-catalysed hydrolysis of the tert-butyl ester. The acid can be
a mineral acid, such as hydrochloric acid. The cleavage of ketal
can be carried out by any other cleavage method known in the prior
art. The base can be an organic base, such as lithium hydroxide,
sodium hydroxide or potassium hydroxide.
[0038] The compound of Formula XI can be converted into its
corresponding hemi calcium salt by following procedures well-known
to a person ordinary skilled in the art. The hemi calcium salts of
compound of Formula XI can also be prepared from the corresponding
lactones form of Formula XI by following procedures well-known in
the art.
##STR00015##
Scheme Ia
[0039] The compound of Formula XVII can be prepared according to
Scheme Ia. Accordingly, a compound of Formula KM (that is, Formula
X wherein R.sub.5.dbd.H and
##STR00016##
prepared according to Scheme I) is hydrolyzed to give a compound of
Formula XIV which, on reduction, gives a compound of Formula XV,
which on hydrolysis gives a compound of Formula XVI, which can then
be further converted to hemi calcium salt.
[0040] The hydrolysis of a compound of Formula XIII to give a
compound of Formula XIV can be carried out in a polar solvent, such
as tetrahydrofuran, dioxane, methanol, ethanol or mixture(s)
thereof. The hydrolysis of a compound of Formula XIII can be
carried out in the presence of an inorganic base such as lithium
hydroxide, sodium hydroxide or potassium hydroxide.
[0041] The reduction of a compound of Formula XIV to give a
compound of Formula XV can be carried out in the presence of iodine
and a reducing agent, such as sodium borohydride or borane
dimethylsulphide in an organic solvent, such as tetrahydrofuran,
dioxane or diethylether.
[0042] The conversion of a compound of Formula XV to a compound of
Formula XVI is carried out in a two-step manner, involving an
initial acid-catalyzed cleavage of ketal, followed by
base-catalyzed hydrolysis of the tert-butyl ester. The acid can be
a mineral acid, such as hydrochloric acid. The cleavage of ketal
can be carried out by any other cleavage method known in the prior
art. The base can be an inorganic base, such as lithium hydroxide,
sodium hydroxide or potassium hydroxide.
[0043] The compound of Formula XVI can be converted into its
corresponding hemi calcium salt by following procedures well-known
to a person ordinary skilled in the art. The hemi calcium salts of
compound of Formula XVI can also be prepared from the corresponding
lactone form of Formula XVI by following procedures well-known in
the art.
##STR00017## ##STR00018##
Scheme Ib
[0044] The compound of Formula XIIb can be prepared according to
Scheme Ib. Accordingly, a compound of Formula II is reacted with a
compound of Formula IIIb, wherein R.sub.3, R.sub.4 and R.sub.5 are
as defined earlier, to give a compound of Formula IVb which on
reaction with a compound of Formula V (wherein R.sub.2 is as
defined earlier) gives a compound of Formula VIb, which on
treatment with a compound of Formula VII (wherein R.sub.1 is as
defined earlier) yields a compound of Formula VIIIb, which on
further reaction with a compound of Formula I.times.gives a
compound of Formula Xb, which on hydrolysis gives a compound of
Formula XIb, which can then be further converted to hemicalcium
salt.
[0045] The reaction of a compound of Formula II with a compound of
Formula IIIb to give a compound of Formula IVb can be carried out
in an aromatic solvent, such as xylene or toluene. The reaction of
a compound of Formula II with a compound of Formula IIIb can be
carried out in the presence of an organic base, such as
triethylamine, pyridine or 1,2-ethylenediamine.
[0046] The reaction of a compound of Formula IVb with an aldehyde
of Formula V to give a compound of Formula VIb can be carried out
in a hydrocarbon solvent, such as hexane, heptane, or halogenated
solvent, such as dichloromethane, or aromatic solvent, such as
toluene, or mixture thereof. The reaction of a compound of Formula
IVb with an aldehyde of Formula V can be carried out in the
presence of an organic base such as piperidine, pyridine or
.beta.-alanine and an organic acid such as glacial acetic acid or
benzoic acid.
[0047] The reaction of a compound of Formula VIb with an aldehyde
of Formula VII to give a compound of Formula VIM can be carried out
in the presence of a suitable catalyst, such as sodium cyanide,
3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazolium bromide or
3-benzyl-5-(2-hydroxyethyl)-4-methyl thiazolium chloride, in a
solvent free condition or in an alcoholic solvent, such as
methanol, ethanol, propanol or isopropanol or ethers, such as
dioxan or tetrahydrofuran. The reaction of a compound of Formula
VIb with an aldehyde of Formula VII can be carried out in the
presence of an organic base, such as triethylamine or pyridine.
[0048] The reaction of a compound of Formula YAM with a compound of
Formula IX to give a compound of Formula Xb can be carried out in a
solvent, such as xylene, toluene, hexane, heptane, tetrahydrofuran,
or a mixture thereof in a suitable ratio. The reaction of a
compound of Formula VIIIb with a compound of Formula IX can be
carried out in the presence of an organic acid, such as pivalic
acid or p-toluene sulfonic acid.
[0049] The conversion of a compound of Formula Xb to a compound of
Formula XIb can be carried out in a two-step manner, involving an
initial acid-catalysed cleavage of ketal, followed by
base-catalysed hydrolysis of the tert-butyl ester. The acid can be
a mineral acid, such as hydrochloric acid. The cleavage of ketal
can be carried out by any other cleavage method known in the prior
art. The base can be an inorganic base, such as lithium hydroxide,
sodium hydroxide or potassium hydroxide.
[0050] The compound of Formula XIb can be converted into its
corresponding hemi calcium salt by following procedures well-known
to a person ordinary skilled in the art. The hemi calcium salts of
compound of Formula XIb can also be prepared from the corresponding
lactones form of Formula XIb by following procedures well-known in
the art.
##STR00019##
Scheme II
[0051] The compound of Formula XII can also be prepared according
to Scheme II. Accordingly, a compound of Formula XVIII is reacted
with a compound of Formula V to give a compound of Formula XIX
(wherein R.sub.2 and R.sub.3 are as defined earlier in Scheme I)
which on reaction with a compound of Formula VII (wherein R.sub.1
is as defined earlier) gives a compound of Formula XX, which on
treatment with a compound of Formula IX yields a compound of
Formula XXI, which on debenzylation gives a compound of Formula
XXII, which on
[0052] (a) conversion to corresponding acid chloride followed by
reaction with an amine of Formula III (Path a) or
[0053] (b) reaction with an amine of Formula III in the presence of
a coupling agent (Path b), gives a compound of Formula X, which on
hydrolysis gives a compound of Formula XI, which can be further
converted to hemicalcium salt of Formula XI by following the
procedure well known in the art.
[0054] The reaction of a compound of Formula XVIII with an aldehyde
of Formula V to give a compound of Formula XIX can be carried out
in a nonpolar solvent, such as xylene, toluene, heptane, hexane or
dichloromethane or mixture thereof. The reaction of a compound of
Formula XVIII with a compound of Formula V can be carried out in
the presence of an organic base, such as triethylamine, pyridine,
piperidine or .beta.-alanine and an organic acid such as glacial
acetic acid or benzoic acid.
[0055] The reaction of a compound of Formula XIX with an aldehyde
of Formula VII to give a compound of Formula XX can be carried out
in a polar solvent, such as an alcoholic solvent, for example,
methanol, ethanol, propanol or isopropanol. The reaction of a
compound of Formula XIX with an aldehyde of Formula VII can be
carried out in the presence of an organic base, such as
triethylamine or pyridine. The reaction of a compound of Formula
XIX with an aldehyde of Formula VII to give a compound of Formula
XX can be carried out in the presence of a catalyst, such as sodium
cyanide, 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazolium bromide or
3-benzyl-5-(2-hydroxyethyl)-4-methyl thiazolium chloride.
[0056] The reaction of a compound of Formula XX with an amine of
Formula IX to give a compound of Formula XXI can be carried out in
the presence of an acid, such as pivalic acid and p-toluene
sulfonic acid in a nonpolar solvent such as hexane, heptane,
toluene or tetrahydrofuran.
[0057] The debenzylation of a compound of Formula XXI to give a
compound of Formula XXII can be carried out in the presence of a
catalyst, such as palladium on carbon and hydrogen, in a polar
solvent, such as methanol, ethanol, propanol or dioxane.
[0058] The conversion of compound of Formula XXII to its
corresponding acid chloride (Path a) can be carried out with any
suitable chlorinating agent, such as oxalyl chloride, in a nonpolar
solvent, such as benzene, dichloromethane, tetrahydrofuran, toluene
or xylene, followed by reaction with an amine of Formula III to
give a compound of Formula X, in a nonpolar solvent, such as
benzene, and in the presence of an organic base, such as
triethylamine or pyridine.
[0059] Reaction of compound of Formula XXII with an amine of
Formula III to give a compound of Formula X can be carried out in
the presence of a coupling agent (Path b), such as
O-benzotriazol-1-yl-N,N,N',N'-tetramethyl uronium
hexafluorophosphate (HBTU), bis(2-oxo-3-oxazolidinyl)phosphine
(BOP), 1,3-dicyclohexycarbodiimide (DCC),
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TBTU),
benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium
hexafluorophosphate (PyBOP) or carbonyldiimidazole (CDI) in a polar
solvent, such as dimethylformamide, and an organic base, such as
diisopropylethyl amine.
[0060] The conversion of a compound of Formula X to a compound of
Formula XI can be carried out in a two-step manner, involving an
initial acid-catalysed cleavage of ketal, followed by
base-catalysed hydrolysis of the tert-butyl ester. The acid can be
a mineral acid, such as hydrochloric acid. The cleavage of ketal
can be carried out by any other cleavage method known in the prior
art. The base can be an inorganic base, for example, lithium
hydroxide, sodium hydroxide or potassium hydroxide.
[0061] The compound of Formula XI can be converted into its
corresponding hemi calcium salt by following procedures well-known
to a person ordinary skilled in the art. The hemi calcium salts of
compound of Formula XI can also be prepared from the corresponding
lactone form of Formula XI by following procedures well-known in
the art.
##STR00020##
Scheme IIa
[0062] The compound of Formula XVIa can be prepared according to
Scheme IIa. Accordingly, a compound of Formula XIIIa (that is,
Formula Xa wherein R.sub.5=H and R.sub.4=--COOCH.sub.3, prepared
according to Scheme I) is hydrolyzed to give a compound of Formula
XIVa, which on further hydrolysis gives a compound of Formula XVa,
which can then be converted to disodium salt.
[0063] The conversion of compounds of Formula XIIIa to compounds of
Formula XVa can be carried out in a two-step manner, involving an
initial acid-catalyzed cleavage of ketal, followed by
base-catalyzed hydrolysis of the methyl and tert-butyl ester. The
acid can be a mineral acid, such as hydrochloric acid. The cleavage
of ketal can be carried out by any other cleavage method known in
the prior art. The base can be an inorganic base, such as lithium
hydroxide, sodium hydroxide or potassium hydroxide.
[0064] The compound of Formula XVa can be converted into its
corresponding disodium salt by following procedures well-known to a
person ordinary skilled in the art.
##STR00021##
Scheme III
[0065] The compound of Formula XXVII can be prepared according to
Scheme Amidoxime (prepared as per procedure described in J. Med.
Chem., 45:944 (2002) and J. Med. Chem., 29:2174 (1986)) of Formula
XXIII on coupling with a compound of Formula XXII (prepared
following the steps of Scheme II) gives a compound of Formula XXIV,
which on cyclisation in diglyme gives a compound of Formula XXV,
which on hydrolysis gives a compound of Formula XXVI, which can be
further converted to its hemi calcium salt.
[0066] The coupling of compound of Formula XXIII with a compound of
Formula XXII can be carried out in the presence of
N,N'-carbonyldiimidazole in an organic solvent, such as
tetrahydrofuran, dioxane or ether.
[0067] The cyclisation of compound of Formula XXIV can be carried
out in diglyme to give a compound of Formula XXV.
[0068] The conversion of a compound of Formula XXV to a compound of
Formula XXVI can be carried out in a two-step manner, involving an
initial acid-catalyzed cleavage of ketal, followed by
base-catalyzed hydrolysis of the tert-butyl ester. The acid can be
a mineral acid, such as hydrochloric acid. The cleavage of ketal
can be carried out by any other cleavage method known in the prior
art. The base can be an inorganic base, for example, lithium
hydroxide, sodium hydroxide or potassium hydroxide.
[0069] The compound of Formula XXVI can be converted into its
corresponding hemi calcium salt by following procedures well-known
to a person ordinary skilled in the art. The hemi calcium salts of
compound of Formula XXVI can also be prepared from the
corresponding lactone form of Formula XXVI by following procedures
well-known in the art.
##STR00022## ##STR00023##
Scheme IIIa
[0070] The compound of Formula XIIIa can also be prepared according
to Scheme IIIa. Accordingly, a compound of Formula XVIII is reacted
with a compound of Formula V to give a compound of Formula XIX
(wherein R.sub.2 and R.sub.3 are as defined earlier) which on
reaction with a compound of Formula VII (wherein R.sub.1 is as
defined earlier) gives a compound of Formula XX, which on treatment
with a compound of Formula IX yields a compound of Formula XXI,
which on debenzylation gives a compound of Formula XXII, which
on
[0071] (a) conversion to corresponding acid chloride followed by
reaction with an amine of Formula IIIa (Path a) or
[0072] (b) reaction with an amine of Formula IIIa in the presence
of a coupling agent (Path b) gives a compound of Formula Xa, which
on hydrolysis gives a compound of Formula XIa, which can be further
converted to hemi calcium salt of Formula XIa by following the
procedure well known in the art.
[0073] The reaction of a compound of Formula XVIII with an aldehyde
of Formula V to give a compound of Formula XIX can be carried out
in a hydrocarbon solvent, such as hexane or heptane, or halogenated
solvent, such as dichloromethane, or aromatic solvent, such as
toluene or xylene, or mixture thereof. The reaction of a compound
of Formula XVIII with a compound of Formula V can be carried out in
the presence of an organic base, such as triethylamine, pyridine,
piperidine or .beta.-alanine and an organic acid such as glacial
acetic acid or benzoic acid.
[0074] The reaction of a compound of Formula XIX with an aldehyde
of Formula VII to give a compound of Formula XX can be carried out
in a polar solvent, such as an alcoholic solvent, for example,
methanol, ethanol, propanol or isopropanol. The reaction of a
compound of Formula XIX with an aldehyde of Formula VII can be
carried out in the presence of an organic base, such as
triethylamine or pyridine. The reaction of a compound of Formula
XIX with an aldehyde of Formula VII to give a compound of Formula
XX can be carried out in the presence of a catalyst, such as sodium
cyanide, 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazolium bromide or
3-benzyl-5-(2-hydroxyethyl)-4-methyl thiazolium chloride.
[0075] The reaction of a compound of Formula XX with an amine of
Formula IX to give a compound of Formula XXI can be carried out in
the presence of an acid, such as pivalic acid and p-toluene
sulfonic acid in a hydrocarbon solvent, such as hexane or heptane,
or aromatic solvent, such as toluene, or ether, such as
tetrahydrofuran or mixture thereof.
[0076] The debenzylation of a compound of Formula XXI to give a
compound of Formula XXII can be carried out in the presence of a
catalyst, such as palladium on carbon and hydrogen, in a polar
solvent, such as alcoholic solvent, for example, methanol, ethanol
or propanol, or ether solvent, for example, dioxane.
[0077] The conversion of compound of Formula XXII to its
corresponding acid chloride (Path a) can be carried out with any
suitable chlorinating agent, such as oxalyl chloride or thionyl
chloride, in an aromatic solvent, such as benzene, toluene or
xylene, or halogenated solvent, such as dichloromethane, or ether,
such as tetrahydrofuran, followed by reaction with an amine of
Formula Ma to give a compound of Formula Xa, in an aromatic
solvent, such as benzene, and in the presence of an organic base,
such as triethylamine or pyridine.
[0078] Reaction of compound of Formula XXII with an amine of
Formula IIIa to give a compound of Formula Xa (path b) can be
carried out in the presence of a coupling agent, such as
O-benzotriazol-1-yl-N,N,N',N'-tetramethyl uronium
hexafluorophosphate (HBTU), bis(2-oxo-3-oxazolidinyl)phosphine
(BOP), 1,3-dicyclohexycarbodiimide (DCC),
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TBTU),
benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium
hexafluorophosphate (PyBOP) or carbonyldiimidazole (CDI) in a polar
solvent, such as dimethylformamide, and an organic base, such as
diisopropylethylamine.
[0079] The conversion of a compound of Formula Xa to a compound of
Formula XIa can be carried out in a two-step manner, involving an
initial acid-catalysed cleavage of ketal, followed by
base-catalysed hydrolysis of the tert-butyl ester. The acid can be
a mineral acid, such as hydrochloric acid. The cleavage of ketal
can be carried out by any other cleavage method known in the prior
art. The base can be an inorganic base, for example, lithium
hydroxide, sodium hydroxide or potassium hydroxide.
[0080] The compound of Formula XIa can be converted into its
corresponding hemi calcium salt by following procedures well-known
to a person ordinary skilled in the art.
[0081] The hemi calcium salts of compound of Formula XIa can also
be prepared from the corresponding lactones form of Formula XIa by
following procedures well-known in the art.
##STR00024##
Scheme IV
[0082] The compound of Formula XXXI can be prepared according to
Scheme IV. Accordingly, treating acid chloride of compound of
Formula XXII with ammonia affords a compound of Formula XXVIII,
which on condensation with N,N-dimethylbenzamide dimethylketal
followed by treatment with hydrazine hydrate gives a compound of
Formula XXIX, which on hydrolysis gives a compound of Formula XXX,
which can be further converted to its hemi calcium salt.
[0083] The reaction of compound of Formula XXII to give compound of
Formula XXVIII can be carried out in presence of a chlorinating
agent, such as oxalyl chloride or thionyl chloride followed by
reaction with ammonia.
[0084] The condensation of a compound of Formula XXVIII with
N,N-dimethylbenzamide dimethylacetal followed by treatment with
hydrazine hydrate affords compound of Formula XXIX.
[0085] The conversion of a compound of Formula XXIX to a compound
of Formula XXX can be carried out in a two-step manner, involving
an initial acid-catalyzed cleavage of ketal, followed by
base-catalyzed hydrolysis of the tert-butyl ester. The acid can be
a mineral acid, such as hydrochloric acid. The cleavage of ketal
can be carried out by any other cleavage, method known in the prior
art. The base can be an inorganic base, for example, lithium
hydroxide, sodium hydroxide or potassium hydroxide.
[0086] The compound of Formula XXX can be converted into its
corresponding hemi calcium salt by following procedures well-known
to a person ordinary skilled in the art. The calcium salts of
compound of Formula XXX can also be prepared from the corresponding
lactone form of Formula XXX by following procedures well-known in
the art.
[0087] In the above schemes, where specific reagents, such as
particular bases, reducing agents, solvents, etc., are mentioned,
it is to be understood that other bases, reducing agents, solvents,
etc., known to those skilled in the art may be used. Similarly, the
reaction temperature and duration may be adjusted according to the
desired needs.
[0088] An illustrative list of particular compounds disclosed
herein is given below (also shown in Table I): [0089]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(2-acetylphenylamin-
o) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound
No. 1) [0090]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(3-acetylphe-
nylaraino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 2) [0091]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-acetylphenylamin-
o) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound
No. 3) [0092]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(2,4-dimethy-
lphenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 4) [0093]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(cyclohexylamino)
carbonyl)]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.
5) [0094]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-trifluoro-
methylbenzylamino) carbonyl)]pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 6) [0095]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(morpholine-4-carbon-
yl)-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 7)
[0096]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(piperidine-1-carbon-
yl)-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 8)
[0097]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphe-
nylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 11) [0098]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-methanesulfonyla-
minophenyl amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 12) [0099]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-acetylaminopheny-
lamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 13) [0100]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-(4-cyanophenyl)-4-[(phenylami-
no) carbonyl)]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound
No. 14) [0101]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-carboxyphe-
nyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 1a), [0102]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-acetoxymethylphen-
yl)amino) carbonyl]pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 2a), [0103]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylthiocarbamo-
yl
oxymethylphenyl)amino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 3a), [0104]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-propionyloxymethy-
l phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 4a), [0105]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-octylcarbamoyloxy-
methyl phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 5a), [0106]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylacetoxymeth-
yl phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 6a), [0107]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylcarbamoyl
oxymethyl phenyl)amino)
carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.
7a), [0108]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-benzoyloxymethyl
phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 8a), [0109]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-isonicotinoyloxym-
ethyl phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 9a), [0110]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-pyridin-4-ylcarba-
moyl oxymethyl phenyl)amino)
carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.
10a), [0111]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylcarb-
amoyl phenyl)amino) carbonyl]pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 11a), [0112]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-cyclohexylcarbamo-
yl-phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 12a), [0113]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-methylcarbamoyl)--
phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 13a), [0114]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-benzylcarbamoyl)--
phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 14a), [0115]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(morpholine-4-car-
bonyl)-phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 15), [0116]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(piperidine-1-car-
bonyl)-phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 16), [0117]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-benzylamino
phenyl)amino) carbonyl]pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 17), [0118]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(1-hydroxyethyl)p-
henylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 18), [0119]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(2-hydroxyethyl)p-
henylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 19), [0120]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-hydroxypropyl
phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 20), [0121]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-methoxymethyl
phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 21), [0122]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-ethoxymethyl
phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 22), [0123]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-isopropoxymethyl
phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 23), [0124]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-propoxymethyl
phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 24), [0125]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-methoxymethoxyme-
thylphenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 25), [0126]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-cyclohexyloxymet-
hyl phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 26), [0127]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-cyclopentyloxyme-
thyl phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 27), [0128]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-benzyloxymethyl
phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 28) [0129]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-chlorobenzyloxym-
ethyl phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 29), [0130]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-methoxybenzyloxy-
methyl phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 30), [0131]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-phenoxymethylphe-
nylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 31), [0132]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-chlorophenoxymet-
hyl phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 32), [0133]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-acetylaminopheny-
lamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 33), [0134]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-benzoylamino
phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 34), [0135]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-benzenesulfonyla-
mino phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 36) [0136]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-phenyl-nreido)-
-phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 37), [0137]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-methyl-ureido)-
-phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 38), [0138]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-benzyll-ureido-
)-phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 39), [0139]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-benzyl-thioure-
ido)-phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 40), [0140]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-phenyl-thioure-
ido)-phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 41), [0141]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-methyl-thioure-
ido)-phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 42), and their pharmaceutically acceptable
salts, pharmaceutically acceptable solvates, tautomers, racemates,
polymorphs, pure enantiomers, diastereoisomers, metabolites,
prodrugs or N-oxides.
[0142] An illustrative list of compounds, which can be prepared by
following Schemes III and IV is given below (also shown in Table
I): [0143]
(3R,5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(3-phenyl-[1,-
2,4]oxadiazol-5-yl)-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 9) [0144]
(3R,5R)-7-[2-(4-Fluorophenyl0-5-isopropyl-3-phenyl-4-(5-phenyl-2H-[1,2,4]-
triazol-3-yl)-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound
No. 10)
[0145] In Tables I and Ia, R.sub.4 is the indicated structure,
unless otherwise noted.
TABLE-US-00001 TABLE I ##STR00025## C. No. R.sub.1 R.sub.2 R.sub.3
R.sub.4 R.sub.5 R.sub.6 1 4-Fluorophenyl Phenyl Isopropyl --
Hydrogen 2-Acetylphenyl 2 4-Fluorophenyl Phenyl Isopropyl --
Hydrogen 3-Acetylphenyl 3 4-Fluorophenyl Phenyl Isopropyl --
Hydrogen 4-Acetylphenyl 4 4-Fluorophenyl Phenyl Isopropyl --
Hydrogen 2,4-Dimethylphenyl 5 4-Fluorophenyl Phenyl Isopropyl --
Hydrogen Cyclohexyl 6 4-Fluorophenyl Phenyl Isopropyl -- Hydrogen
4-trifluoromethyl benzyl 7 4-Fluorophenyl Phenyl Isopropyl --
--(CH2).sub.2--O--(CH2).sub.2-- 8 4-Fluorophenyl Phenyl Isopropyl
-- --(CH2).sub.5-- 9* 4-Fluorophenyl Phenyl Isopropyl
1,2,4-Oxadiazinylphenyl -- 10* 4-Fluorophenyl Phenyl Isopropyl
1,2,4-Triazolylphenyl -- 11 4-Fluorophenyl Phenyl Isopropyl --
Hydrogen 4-(Hydroxymethyl)phenyl 12 4-Fluorophenyl Phenyl Isopropyl
-- Hydrogen 4-(Methylsulfonamido)-phenyl 13 4-Fluorophenyl Phenyl
Isopropyl -- Hydrogen 4-(Acetamido)phenyl 14 4-Fluorophenyl
4-cyanoPhenyl Isopropyl -- Hydrogen Phenyl ##STR00026##
##STR00027## *Hypothetical examples
TABLE-US-00002 TABLE Ia Formula I ##STR00028## Compound No. R.sub.4
.sub. 1a COOH .sub. 2a acetoxymethyl .sub. 3a
phenylthiocarbamoyloxymethyl .sub. 4a propionyloxymethyl .sub. 5a
octylcarbamoyloxymethyl .sub. 6a phenylacetoxymethyl .sub. 7a
phenylcarbamoyloxymethyl .sub. 8a benzoyloxymethyl .sub. 9a
isonicotinoyloxymethyl .sub. 10a pyridin-4-ylcarbamoyloxymethyl
.sub. 11a phenylcarbamoyl .sub. 12a cyclohexylcarbamoyl .sub. 13a
methylcarbamoyl .sub. 14a benzylcarbamoyl 15 morpholine-4-carbonyl
16 piperidine-1-carbonyl 17 benzylamino 18 (1-hydroxyethyl) 19
(2-hydroxyethyl) 20 (3-hydroxypropyl) 21 methoxymethyl 22
ethoxymethyl 23 isopropoxymethyl 24 propoxymethyl 25
methoxymethoxymethyl 26 cyclohexyloxymethyl 27 cyclopentyloxymethyl
28 benzyloxymethyl 29 4-chlorobenzyloxymethyl 30
4-methoxybenzyloxymethyl 31 phenoxymethyl 32 4-chlorophenoxymethyl
33 acetylamino 34 Benzoylamino 36 benzenesulfonylamino 37
3-phenyl-ureido 38 3-methyl-ureido 39 3-benzyl-ureido 40
3-benzyl-thioureido 41 3-phenyl-thioureido 42 3-methyl-thioureido
wherein ##STR00029## R.sub.1 = 4-fluorophenyl, R.sub.2 = phenyl,
R.sub.3 = isopropyl, R.sub.5 = hydrogen
[0146] The term "pharmaceutically acceptable" means approved by
regulatory agency of the federal or a state government or listed in
the U.S. Pharmacopeia or other generally recognized pharmacopeia
for use in animals, and more particularly in humans.
[0147] The term "pharmaceutically acceptable salts" refer to a salt
prepared from pharmaceutically acceptable monovalent, divalent or
trivalent non-toxic metal or organic base. Examples of such metal
salts include, but are not limited to, lithium, sodium, potassium,
calcium, magnesium, zinc, aluminum, and the like. Examples of such
organic bases include, but are not limited to, amino acid, ammonia,
mono-alkyl ammonium, dialkyl ammonium, trialkyl ammonium and
N-methyl glucamine and the like. The free acid forms of compounds
of the present invention may be prepared from the salt forms, if
desired, by contacting the salt with dilute aqueous solution of an
acid such as hydrochloric acid. The base addition salts may differ
from the free acid forms of the compounds of this invention in such
physical characteristics as solubility and melting point.
[0148] The term "pharmaceutically acceptable solvates" refers to
solvates with water (i-e hydrates) or pharmaceutically acceptable
solvents, for example solvates with ethanol and the like. Such
solvates are also encompassed within the scope of the
disclosure.
[0149] Furthermore, some of the crystalline forms for compounds
described herein may exist as polymorphs and as such are intended
to be included in the scope of the disclosure.
[0150] The present invention also includes within its scope
prodrugs of these agents. In general, such prodrugs will be
functional derivatives of these compounds, which are readily
convertible in vivo into the required compound. Conventional
procedure for the selection and preparation of suitable prodrug
derivatives are described, for example, in "design of prodrugs",
ed. H Bundgaard and, Elsevier, 1985.
[0151] The present invention also includes metabolites, which
become active upon introduction into the biological system.
[0152] The compounds of the invention possess two chiral centers,
they may, therefore, exist as enantiomers and diastereomers. It is
to be understood that all such isomers and racemic mixtures
therefore are encompassed within the scope of the present
invention. Preferably, this invention contemplates compounds only
with 3R and 5R configuration.
[0153] The crystalline or amorphous forms of compounds disclosed
herein may exist as polymorphs and as such are intended to be
included in the present invention.
[0154] Pharmaceutical compositions comprising compounds disclosed
herein, their pharmaceutically acceptable salt, pharmaceutically
acceptable solvates, or polymorphs, and pharmaceutically acceptable
carrier or excipient are also disclosed herein.
[0155] The compositions provided herein, both those containing one
disclosed compound and those containing two or more compounds, may
be suitable for oral or parenteral administration. The compositions
may be formulated to provide immediate or sustained release of the
therapeutic compounds. The compounds described herein can be
administered alone but will generally be administered as an
admixture with a suitable pharmaceutically acceptable carrier. The
term "pharmaceutically acceptable carrier" is intended to include
non-toxic, inert solid, semi-solid, liquid filter, diluent,
encapsulating materials or formulation auxiliaries of any type.
[0156] Solid form preparations for oral administration may include
capsules, tablets, pills, powder, granules or suppositories. For
solid form preparations, the active compound is mixed with at least
one inert, pharmaceutically acceptable excipient or carrier, for
example, sodium citrate, dicalcium phosphate and/or a filler, an
extender, for example, starch, lactose, sucrose, glucose, mannitol
or silicic acid; binders, for example, carboxymethyl cellulose,
alginates, gelatins, polyvinylpyrroledinone, sucrose, or acacia;
disintegrating agents, for example, agar-agar, calcium carbonate,
potato starch, aliginic acid, certain silicates or sodium
carbonate; absorption accelerators, for example, quaternary
ammonium compounds; wetting agents, for example, cetyl alcohol,
glycerol, or mono stearate adsorbents, for example, Kaolin;
lubricants, for example, talc, calcium stearate, magnesium
stearate, solid polyethyleneglycol, or sodium lauryl sulphate, and
mixtures thereof.
[0157] In case of capsules, tablets, and pills, the dosage form may
also comprise buffering agents.
[0158] The solid preparation of tablets, capsules, pills, or
granules can be accomplished with coatings and/or shells, for
example, enteric coatings and other coatings well known in the
pharmaceutical formulating art.
[0159] Liquid form preparations for oral administration can include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. For liquid form preparations, the active
compound can be mixed with water or other solvent, solubilizing
agents and emulsifiers, for example, ethyl alcohol, isopropyl
alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl
benzoate, propylene glycol, 1,3-butylene glycol, dimethyl
formamide, oils (for example, cottonseed, ground corn, germ, live,
caster and sesamine oil), glycerol and fatty acid ester of sorbitan
and mixture thereof.
[0160] Besides inert diluents, the oral compositions can also
include adjuvants, for example, wetting agents, emulsifying agents,
suspending agents, sweetening agents, flavoring agents and
perfuming agents.
[0161] The formulations as described herein may be formulated so as
to provide quick, sustained, or delayed release of the active
compound after administration to the patient by employing
procedures well-known to the art. The term "patient" as used herein
refers to a human or non-human mammal, which is the object of
treatment, observation or experiment.
[0162] The pharmaceutical preparations can be in unit dosage forms,
and in such forms, the preparations are subdivided into unit doses
containing appropriate quantities of an active compound.
[0163] The amount of a compound disclosed herein that will be
effective in the treatment of a particular disorder or condition
can be determined by standard clinical techniques. In addition, in
vitro or in vivo assays may optionally be employed to help identify
optimal dosage ranges.
[0164] Examples set forth below demonstrate general synthetic
procedures for preparation of particular representative compounds.
The examples are provided to illustrate particular aspects of the
disclosure, and do not constrain the scope of the present invention
as defined by the claims.
EXAMPLES
General Procedure
Schemes I and Ib
Step 1: Preparation of .beta.-ketoamide-1 (Formula IV and IVb)
[0165] A mixture of .beta. ketoester (Formula II, 1 equiv.), amine
(Formula III, 1 equiv) 1,2-ethylenediamine (0.01 equiv) in xylene
was refluxed with the azeotropic removal of water. After the
completion of reaction, solvent was evaporated & the residue
purified on column (silica gel; 100-200 mesh). Compounds of Formula
IVb can be prepared analogously. The following intermediates were
prepared following above general procedure
4-Methyl-3-oxo-pentanoic acid (3-acetylphenyl)-amide
[0166] .sup.1H NMR (CDCl.sub.3): .delta. 1.19 (d, J=6.9 Hz, 6H),
2.61 (s, 3H), 2.75 (sep, J=6.9 Hz, 1H), 3.64 (s, 2H), 7.43 (t,
J=7.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H), 8.08
(s, 1H), 9.44 (brs, 1H); MS (positive ion mode): m/z 248 [M+1];
Yield: 49%
4-Methyl-3-oxo-pentanoic acid (4-acetylphenyl)-amide
[0167] .sup.1H NMR (CDCl.sub.3): .delta. 1.19 (d, J=6 Hz, 6H), 2.58
(s, 3H), 2.75 (sep, J=6 Hz, 1H), 3.65 (s, 2H), 7.67 (d, J=6 Hz,
2H), 7.95 (d, J=6 Hz, 2H), 9.60 (s, 1H), MS (positive ion mode):
m/z 248 [M+1]; Yield 54%
4-Methyl-3-oxo-pentanoic acid (2,4-dimethylphenyl)-amide
[0168] .sup.1H NMR (CDCl.sub.3): .delta. 1.18 (d, J=6 Hz, 6H), 2.29
(s, 6H), 2.73 (Sep, J=6 Hz, 1H), 3.64 (s, 2H), 7.00 (s, 2H), 7.76
(d, J=6 Hz, 1H), 9.11 (brs, 1H); MS (positive ion mode): m/z 234
[M+1] Yield 72%
4-Methyl-3-oxo-pentanoic acid 4-trifluoromethylbenzyl amide
[0169] .sup.1H NMR (CDCl.sub.3): .delta. 1.14 (d, J=6 Hz, 6H), 2.70
(sept, J=6 Hz, 1H), 3.53 (s, 2H), 4.53 (d, J=6 Hz, 2H), 7.40 (d,
f=6 Hz, 2H), 7.59 (d, J=6 Hz, 2H); MS (positive ion mode): m/z
287
4-Methyl-1-piperidin-1-yl-pentane-1,3-dione
[0170] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 1.14 (d, J=6 Hz,
6H), 1.57-1.65 (m, 6H), 2.76 (brs, 1H), 3.20-3.75 (m, 6H);
4-Methyl-3-oxo-pentanoic acid phenylamide
Step 2: Preparation of (3-ketoamide-2 (Formula VI and VIb)
[0171] To .beta.-ketoamide-1 (Formula IV, 1 equiv) in hexane was
added to .beta.-alanine (0.18 equiv), aldehyde (Formula V, 1.1
equiv) and glacial acetic acid (0.16% w/w of .beta.-ketoamide-1).
The resulting suspension was heated under reflux with the
azeotropic removal of water. The reaction mixture was cooled and
product was isolated by filtration. The product was purified by
washing the precipitate with hot hexane, water and dried in vacuo
to afford .beta.-ketoamide-2. Compounds of Formula VIb can be
prepared analogously. The following intermediates were prepared
following above general procedure
2-Benzylidine-4-methyl-3-oxo-pentanoic acid (3-acetylphenyl)-amide;
Isomer-1
[0172] .sup.1H NMR (CDCl.sub.3): .delta. 1.1 (d, J=6.9 Hz, 6H),
2.50-2.70 (m, 4H), 7.28-7.52 (m, 6H), 7.73 (d, J=7.2 Hz, 1H), 7.93
(d, J=8.1 Hz, 1H), 8.19 (d, J=9.9 Hz, 2H), 9.23 (s, 1H); MS
(positive ion mode): m/z 336 [M+1]; Yield: 13%
2-Benzylidine-4-methyl-3-oxo-pentanoic acid (3-acetylphenyl)-amide;
Isomer-2
[0173] .sup.1H NMR (CDCl.sub.3): .delta. 1.24 (d, J=9 Hz, 6H), 2.60
(s, 3H), 3.39 (sep, J=6 Hz, 1H), 7.33-7.98 (m, 11H); MS (positive
ion mode): m/z 336 [M+1]; Yield: 32%
2-Benzylidene-4-methyl-3-oxo-pentanoic acid
(4-acetylphenyl)-amide
[0174] .sup.1H NMR (CDCl.sub.3): .delta. 1.23 (d, J=6.6 Hz, 6H),
2.58 (s, 3H), 3.37 (Sep, J=6.6 Hz, 1H), 7.27-7.42 (m, 3H),
7.49-7.73 (m, 5H), 7.95 (d, f=8.7 Hz, 2H); MS (positive ion mode):
ink 336 [M+1]
[0175] Yield 48%
2-Benzylidene-4-methyl-3-oxo-pentanoic acid
(2,4-dimethylphenyl)-amide
[0176] .sup.1H NMR (CDCl.sub.3): .delta. 1.23 (d, J=6 Hz, 6H), 1.99
(s, 1H), 2.29 (s, 1H), 3.38 (Sep, J=6 Hz, 1H), 6.97 (s, 1H), 7.04
(d, J=6 Hz, 1H), 7.30 (s, 1H), 7.35-7.45 (m, 3H), 7.53-7.72 (m,
7H)
[0177] MS (positive ion mode): m/z 323 [M+1]; Yield 50%
2-Benzylidine-4-methyl-3-oxo-pentanoic acid 4-trifluoromethylbenzyl
amide
[0178] .sup.1H NMR (CDCl.sub.3,300 MHz): .delta. 1.19 (d, J=6.9 Hz,
6H), 3.30 (sept, J=6.9 Hz, 1H), 6.16 (brs, 1H), 7.26-7.60 (m,
10H)
2-Benzylidene-4-methyl-1-piperidin-1-yl-pentane-1,3-dione
[0179] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 0.88-0.97 (m,
2H), 1.15-1.35 (m, 8H), 1.43-1.62 (m, 4H), 3.13-3.30 (m, 3H), 3.61
(brs, 1H), 3.78 (brs, 1H), 7.38 (brs, 3H), 7.54 (brs, 3H); MS
(positive ion mode): m/z 286 (M.sup.++1)
2-(4-Cyanobenzylidene)-4-methyl-3-oxo-pentanoic acid
phenylamide
[0180] .sup.1H NMR (CDCl.sub.3): .delta. 1.23 (d, J=6 Hz, 6H), 3.34
(Sep, J=6 Hz, 1H), 7.18 (t, J=6 Hz, 1H), 7.36 (t, J=6 Hz, 2H), 7.48
(d, J=6 Hz, 2H), 7.57 (s, 1H), 7.65 (s, 4H), 7.81 (s, 11-1); MS
(positive ion mode): m/z 319 [M+1]; Yield: 67%
Step 3: Preparation of Diketone (Formula VIII and VIIIb)
[0181] .beta.-ketoamide-2 (Formula VI, 1 equiv), aldehyde (Formula
VII, 1.1 equiv), triethylamine (1 equiv) ethanol and
3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazolium bromide (0.2 equiv)
were placed in a vial. The contents were flushed with N.sub.2 and
the vial was capped immediately and was heated to 78.degree. C.
After the completion of reaction, contents were cooled and
triturated with ethyl acetate. The organic layer was washed with 6N
hydrochloric acid, water, dried over anhydrous sodium sulphate,
concentrated on rotary evaporator and residue was purified on a
chromatographic column (silica gel, 100-200 mesh). Compounds of
Formula VIIIb can be prepared analogously. The following
intermediates were prepared following above general procedure
2-[2-(Fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoic
acid (3-acetylphenyl)-amide
[0182] .sup.1H NMR (CDCl.sub.3): .delta. 1.15 (d, J=6 Hz, 3H), 1.20
(d, J=6 Hz, 3H), 2.58 (s, 3H), 2.99 (sep, J=6 Hz, 1H), 4.61 (d,
J=12 Hz, 1H), 5.38 (d, J=12 Hz, 1H), 7.05 (t, I=9 Hz, 2H),
7.15-7.44 (m, 6H), 7.54-7.72 (m, 4H), 7.94-8.05 (m, 2H); MS
(positive ion mode): m/z 460 [M+1]; Yield: 55%
2-[2-(4-Fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic
acid (4-acetylphenyl)-amide
[0183] .sup.1H NMR (CDCl.sub.3): .delta. 1.16 d, J=6.9 Hz, 3H),
1.23 (d, J=6.9 Hz, 3H), 2.55 (s, 3H), 2.99 (Sep, J=6.6 Hz, 1H),
4.56 (d, J=10.5 Hz, 1H), 5.35 (d, J=10.8 Hz, 1H), 7.04 (t, J=8.7
Hz, 3H), 7.18-7.37 (brm, 6H), 7.48 (s, 1H), 7.86 (d, J=8.4 Hz, 2H),
7.87-8.03 (m, 2H); MS (positive ion mode): m/z 460 [M+1]; Yield
64%
2-[2-(4-Fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic
acid (2,4-dimethylphenyl)-amide
[0184] .sup.1H NMR (DMSO-d.sub.6): .delta. 0.99 (d, J=6.6 Hz, 3H),
1.19 (d, J=6.9 Hz, 3H), 1.67 (s, 3H), 2.18 (s, 3H), 3.00 (Sep,
1=6.9 Hz, 1H), 4.94 (d, J=11.1 Hz, 1H), 5.36 (d, s=10.8 Hz, 1H),
6.68 (d, J=8.1 Hz, 1H), 6.82-6.93 (m, 2H), 7.17-7.45 (m, 7H),
8.08-8.24 (m, 2H), 9.60 (brs, 1H) MS (positive ion mode): m/z 446
[M+1]; Yield 66%
2-[2-(4-Fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoic
acid 4-trifluoromethylbenzyl amide
[0185] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 1.10 (d, J=6.6
Hz, 3H), 1.16 (d, J=7.2 Hz, 3H), 2.88 (sept, J=6.9 Hz, 1H0, 4.15
(dd, J=15 & 4.8 Hz, 1H), 4.40 (dd, J=15.9 & 6.6 Hz, 1H),
4.46 (d, J=11.1 Hz, 1H), 5.32 (d, J=10.8 Hz, 1H), 5.80 (brs, 1H),
6.89 (d, J=7.8 Hz, 2H), 6.97 (t, J=8.4 Hz, H), 7.45 (d, J=7.5 Hz,
2H), 7.94-7.98 (m, 2H); MS (positive ion mode): m/z 500
(M.sup.++1}
1-(4-Fluorophenyl)-5-methyl-2-pentyl-3-(piperidine-1-carbonyl-hexane-1,4-d-
ione
[0186] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 1.05 (d, J=6.9
Hz, 3H), 1.19 (d, J=7.1 Hz, 411), 1.45 (brs, 5H), 2.62 (sept, J=6.8
Hz, 1H), 2.95-3.15 (m, 1H), 3.20-3.40 (m, 2H), 3.45-3.60 (m, 1H),
4.99 (d, J=10.5 Hz, 1H), 5.34 (d, J=10.6 Hz, 1H), 7.03 (t, J=8.5
Hz, 2H), 7.24 (brs, 5H), 7.97-8.07 (m, 2H); MS (positive ion mode):
m/z 493 (M.sup.++1)
2-[1-(4-Cyanophenyl)-2-(4-fluorophenyl)-2-oxo-ethyl]-4-methyl-3-oxo-pentan-
oic acid phenylamide
[0187] MS (positive ion mode): m/z 443 [M+1]
Step 4: Preparation of Pyrrole (Formula X and Xb)
[0188] A mixture of diketone (Formula VIII, 1 equiv), amine
(Formula IX, 1.00, equiv) and pivalic acid (1.03 equiv) in
heptane:toluene:tetrahydrofuran (4:1:1) was refluxed and water was
removed using Dean Stark trap. After the completion of reaction,
solvents were removed and the residue was dissolved in ethyl
acetate. The organic layer was washed in saturated sodium
bicarbonate, water, dried over anhydrous sodium sulphate,
concentrated on rotary evaporator and the residue was purified on a
chromatographic column (silica gel, 100-200 mesh). Compounds of
Formula Xb can be prepared analogously. The following intermediates
were prepared following above general procedure
(6-{2-[3-(3-Acetylphenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-
-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid
tert-butyl ester
[0189] .sup.1H NMR (CDCl.sub.3): .delta. 1.30 (s, 3H), 1.36 (s,
3H), 1.43 (s, 9H), 1.53 (d, J=6 Hz, 6H), 1.67 (brs, 2H), 2.20-2.43
(m, 2H), 2.52 (s, 3H), 3.52-3.75 (m, 2H), 3.76-3.88 (m, 1H),
4.00-4.22 (m, 2H), 6.85-7.05 (m, 3H), 7.10-7.51 (m, 10H), 7.58 (d,
J=9 Hz, 1H); MS (positive ion mode): m/z 697 [M+1]; Yield: 23%
(6-{2-[3-(4-Acetylphenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-
-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid
tert-butyl ester
[0190] .sup.1H NMR (CDCl.sub.3): .delta. 1.31 (s, 3H), 1.38 (s,
3H), 1.44 (s, 9H), 1.53 (d, J=9 Hz, 6H), 1.66 (brs, 2H), 2.22-2.49
(m, 2H), 2.54 (s, 3H), 3.49-3.75 (m, 2H), 4.00-4.25 (m, 2H), 7.01
(t, J=6 Hz, 2H), 7.06-7.26 (m, 10H), 7.81 (d, J=9 Hz, zH); MS
(positive ion mode): m/z 698 [M+1]; Yield: 14%
(6-{2-[3-(2,4-Dimethylphenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-ph-
enyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid
tert-butyl ester
[0191] .sup.1H NMR (CDCl.sub.3): .delta. 1.30 (s, 3H), 1.36 (s,
3H), 1.43 (s, 9H), 1.52 (d, s=6 Hz, 6H), 1.65-1.76 (m, 2H),
118-2.32 (m, 4H), 2.33-2.47 (m, 1H), 3.48 (Sep, J=6 Hz, 1H),
3.63-3.90 (m, 2H), 4.0-4.25 m, 2H), 6.72 (s, 1H), 6.81 (s, 1H),
6.99 (t, S=6 Hz, 3H), 7.07-7.25 (m, 711), 7.88 (d, J=6 Hz, 1H); MS
(positive ion mode): m/z 684 [M+1]; Yield 21%
(6-{2-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(4-trifluoromethylbenzylc-
arbamoyl)-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)acetic
acid tert-butyl ester
[0192] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 0.8-1.2 (m, 2H),
1.29 (s, 3H), 1.35 (s, 3H), 1.43 (s, 9H), 1.63 (brs, 2H), 2.22-2.27
(m, 1H), 2.38 (dd, J=15.0 & 6.0 Hz, 1H), 9.36-3.50 (m, 1H),
3.6-3.7 (m, 1H), 3.71-3.85 (m, 1H), 4.1-4.25 (m, 2H), 4.38 (d,
J=6.0 Hz, 2H), 7.02-7.16 (m, 12H), 7.41 (d, J=9.0 Hz, 2H); MS
(positive ion): ink 737.4 [M+1].sup.+
6-{2-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(piperidine-1-carbonyl)-py-
rrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid
tert-butyl ester
[0193] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 0.99-1.60 (m,
29H), 2.17-2.52 (m, 2H), 2.80-3.25 m, 3H), 3.35-3.50 (m, 1H),
3.65-3.90 (m, 3H), 3.90-4.25 (m, 3H), 6.91-7.19 (m, 9H); MS
(positive ion mode): m/z 646 (M.sup.++1)
(6-{2-[3-(4-cyanophenyl)-5-isopropyl-2-(4-fluorophenyl)-4-(phenylamino)
carbonyl-pyrrol-1-yl]ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)acetic
acid tert-butyl ester
[0194] .sup.1H NMR (CDCl.sub.3): .delta. 1.30 (s, 3H), 1.36 (s,
3H), 1.44 (s, 9H), 1.50 (d, J=6.9 Hz, 6H), 1.67 (brs, 3H),
1.55-1.75 (brm, 3H), 2.20-2.40 (m, 2H), 3.38 (sep, J=6.6 Hz, 1H),
3.63-3.88 (m, 2H), 3.97-4.24 (m, 2H), 6.85 (s, 1H), 6.96-7.48 (m,
12H); MS (positive ion mode): m/z 680 [M+1]; Yield: 20%
Step 5: Preparation of hemi calcium salt of compound of Formula XI
and XIb
[0195] (a) To a solution of a compound of Formula X in methanol and
tetrahydrofuran (1:1) was added 1N hydrochloric acid (3 equiv) and
the mixture was stirred at ambient temperature. After the complete
hydrolysis of the ketal, the reaction mixture was cooled to
0.degree. C. and sodium hydroxide pellets (6 equiv) were added. The
reaction was then stirred at ambient temperature. At the end of
ester hydrolysis, solvents were removed and the residue was
dissolved in water; aqueous layer was washed with ether, and was
neutralized with 1N hydrochloric acid. The organic phase was
extracted into ethyl acetate, and concentrated. The residue was
then purified on a chromatographic column (silica gel 100-200
mesh).
[0196] (b) To an aqueous solution of sodium salt of acid (is
prepared by adding 1 equivalent 1N sodium hydroxide solution) was
added dropwise an aqueous solution (1M) of calcium acetate (0.55
equiv). White precipitate was obtained, which was filtered off,
washed with copious amount of water, and dried in vacuo.
[0197] Compounds of Formula XIb and XIIb can be formed analogously.
The following compounds were prepared following above general
procedure
Hemi calcium salt of
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(3-acetylphenylamin-
o) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
[0198] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.23 (brs, 2H), 1.38 (d,
J=6 Hz, 6H), 1.63 (brs, 2H), 1.90-2.15 (m, 2H), 3.52 (brs, 1H),
3.76 (brs, 2H), 3.99 (brs, 1H), 6.95-7.45 (m, 1011), 7.60 (d, J=7.5
Hz, 1H), 7.71 (d, J=7.5 Hz, 1H), 8.15 (s, 1H), 9.98 (s, 1H,
D.sub.2O exchanged); MS (positive ion mode): m/z 601 [Acid+1];
Yield: 21.35; m.pt: 167.5-204.degree. C.
Hemi calcium salt of
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-acetylphenylamin-
o) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
[0199] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.24 (brs, 2H), 1.37 (d,
J=6 Hz, 6H), 1.58 (brs, 2H), 1.88-1.99 (m, 1H), 2.00-2.12 (m, 1H),
3.53 (brs, 1H), 3.73 (brs, 2H), 3.96 (brs, 1H), 7.09 (brs, 5H),
7.14-7.37 (m, 4H), 7.66 (d, J=9 Hz, 2H), 7.85 (d, J=9 Hz, 2H),
10.21 (s, 1H, D.sub.2O exchanged); MS (positive ion mode): m/z 601
[Acid+1]; Yield 23%; m.pt 188.9-216.5.degree. C.
Hemi calcium salt of
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(2,4-dimethylphenyl-
amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
[0200] .sup.1H NMR (DMSO): .delta. 1.29 (brs, 2H), 1.31-1.76 (m,
11H), 1.87-2.01 (dd, J=15 & 6 Hz, 1H), 2.02-2.15 (dd, 3=15
& 3 Hz, 1H), 2.19 (s, 3H), 3.59 (brs, 1H), 3.76 (brs, 2H), 3.95
(brs, 1H), 6.85-6.95 (m, 2H), 7.05-7.33 (m, 10H), 8.78 (s, 1H,
D.sub.2O exchanged); MS (positive ion mode): m/z 587 [Acid+1];
Yield 45%; m.p 172.6-198.9.degree. C.
Hemi calcium salt of
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-trifluoromethylb-
enzylamino) carbonyl)]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid
[0201] .sup.1H NMR (DMSO-d.sub.6,300 MHz): .delta. 1.15-1.24 (m,
2H), 1.31 (d, J=6 Hz, 6H), 1.48-1.56 (m, 2H), 1.84 (dd, J=158, 7.8
Hz, 1H), 2.01 (dd, J=15 &4.2 Hz, 1H), 3.15-3.33 (m, 1H), 3.42
(brs, 1H), 3.50 (brs, 1H), 3.68-3.73 (m, 2H), 3.80-4.02 (m, 1H),
4.29 d, J=5.4 Hz, 1H), 6.99 (brs, 2H), 7.05 (brs, 3H), 7.12-7.23
(m, 6H), 7.50 (d, J=8.1 Hz, 2H), 8.24 (t, J=5.4 Hz, 1H); MS
(positive ion mode): m/z 641 (acid+1)
Hemi calcium salt of
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(piperidine-1-carbon-
yl)-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
[0202] .sup.1H NMR (DMSO-d.sub.6, 300 MHz, D.sub.2O exchanged):
.delta. 1.08-1.13 (m, 2H), 1.24 (brs, 7H), 1.27 (d, J=9 Hz, 6H),
1.43 (brs, 2H), 2.02 (dd, J=15 & 6 Hz, 1H), 2.15-2.19 (m, 1H),
2.88-2.95 (m, 2H), 3.12-3.24 m, 2H), 3.64-3.69 (m, 3H), 6.95 (d,
J=6 Hz, 2H), 7.05-7.15 (m, 5H), 7.25 (brs, 2H), 8.08 (s, 1H).
Hemi calcium salt of
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-(4-cyanophenyl)-4-[(phenylami-
no) carbonyl)]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
[0203] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.24 (brs, 2H), 1.37 (d,
J=6 Hz, 6H), 1.45-1.73 (m, 2H), 1.87-2.15 (m, 2H), 3.10-3.60 (m,
2H), 3.70-3.90 (brm, 2H), 3.91-4.08 (brm, 1H), 7.01 (t, J=6 Hz,
1H), 7.13-7.35 (m, 8H), 7.45-7.63 (m, 4H), 10.02 (s, 1H, D.sub.2O
exchanged); MS (positive ion mode): m/z 584 [Acid+1]; Yield: 87%;
m.pt. 197.7-222.1.degree. C.
Scheme Ia
Step 1: Preparation of Compound of Formula XIV
[0204] Compound XIII (prepared following the appropriate steps of
Scheme Ito produce a compound of Formula X with appropriate
substitution) was dissolved in tetrahydrofuran:methanol (1:2)
mixture and 1N lithium hydroxide (equiv) was added. The reaction
mixture was stirred at 0.degree. C. for 12 to 15 hours. After
completion of reaction, reaction mixture was acidified and the
solvent was evaporated under reduced pressure to get crude product.
The crude product was purified by column chromatography (silica
gel--100-200 mesh) using 50% ethyl acetate in hexane. The following
intermediates wee prepared in this fashion.
4-{[1-[2-(6-tert-butoxycarbonylmethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-ethyl-
]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-3-carbonyl]-amino}-ben-
zoic acid
[0205] .sup.1H NMR (CDCl.sub.3): .delta. 1.03-1.11 (m, 1H), 1.26
(s, 3H), 1.30 (s, 3H), 1.43 (s, 9H), 1.53 (d, J=7.2 Hz, 3H),
1.65-1.69 (m, 2H), 2.23 (dd, J=15.6 & 6.3 Hz, 1H), 2.40 (dd,
J=15.6 & 6.3 Hz, 1H), 3.63-3.71 (m, 2H), 3.75-3.8 (m, 1H),
4.05-4.20 (m, 2H), 6.96-7.20 (m, 12H), 7.90 (d, J=8.4 Hz, 2H); MS
(positive ion mode): m/z 698 (M.sup.++1); Yield=51%
Step 2: Preparation of Compound of Formula XV
[0206] Method A: Compound XIV (1 equiv) was dissolved in dry
tetrahydrofuran and sodium borohydride (2 equiv) was added slowly
in two to three fractions. The resulting suspension was stirred for
5 minutes at 0.degree. C. A solution of iodine (1 equiv) in
tetrahydrofuran was added slowly at 0.degree. C. and reaction
mixture was stirred for 24 to 30 hours at an ambient temperature.
At the end of reaction, solvent was evaporated to get crude
product. The crude product was purified by column chromatography
(silica gel, 100-200 mesh) using 25% ethyl acetate in hexane.
[0207] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 1.02=1.06 (m,
1H), 1.26 (s, 3H), 1.33 (s, 3H), 1.43 (s, 9H), 1.55 (d, J=6 Hz,
6H), 2.21 (dd, J=15 & 6 Hz, 1H), 2.38 (dd, J=15 & 6 Hz,
1H), 2.40-4.17 (m, 5H), 4.58 (s, 2H), 6.87-7.19 (m, 13H); MS (+ve
ion mode): m/z 685 (M.sup.++1); Yield=87%
[0208] Method B: A mixture of compound of Formula XIV (1 equiv.)
and tetrahydrofuran (4 mL, Dry) was placed in a 3 neck round bottom
flask equipped with a reflux condenser, nitrogen was purged. The
reaction mixture was heated at about 50.degree. C. and borane
dimethylsulphide (2 equiv.) was added dropwise over 1 hour. Water
(6 mL) was added to the reaction mixture, solvent was evaporated.
Solid residue was dissolved in ethyl acetate, washed with water and
the aqueous layer was extracted with ethyl acetate. The organic
layer was washed with brine, dried over anhydrous sodium sulphate,
concentrated. The crude product was purified by silica gel column
chromatography using ethyl acetate and hexane as eluant.
[0209] Yield: 2.16 g (73.72%)
Step 3: Preparation of Hemi Calcium Salt of Formula XVI
[0210] (a) To a solution of XV in methanol and tetrahydrofuran
(1:1) was added 1N hydrochloric acid (3 equiv) and the mixture
stirred at an ambient temperature. After the complete hydrolysis of
ketal, the reaction mixture was cooled to 0.degree. C. and sodium
hydroxide pellets (6 equiv) were added. The reaction was then
allowed to stir at ambient temperature. At the end of ester
hydrolysis, solvents were removed and the residue was dissolved in
water; the aqueous layer was washed with ether, and neutralized
with 1N hydrochldric acid. The organic phase was extracted into
ethyl acetate, and concentrated. The residue was then purified on
column (silica gel 100-200 mesh).
[0211] (b) To an aqueous solution of the sodium salt of the acid
(prepared by adding 1 equivalent 1N sodium hydroxide solution) was
added dropwise an aqueous solution (1M) of calcium acetate (0.55
equiv). White precipitate was obtained, which was filtered off and
washed with copious amount of water, and dried in vacuo.
[0212] The following compound was prepared similarly.
Hemi calcium salt of
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphe-
nylamino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
[0213] .sup.1H NMR (DMSO-d.sub.6): .delta. 1.22-1.62 (M, 11H), 1.98
(dd, J=15 & 8.1 Hz, 1H), 2.06-2.16 (m, 1H), 3.25-3.37 (m, 2H),
3.57 (brs, 2H), 3.80 (brs, 1H), 4.43 (s, 2H), 7.03-7.28 (m, 12H),
7.50 (d, J=6H, 2H), 9.80 (s, 1H); MS (positive ion mode): m/z 589
(Acid+1); Yield=-31%; m.p. 189-204.degree. C.
Scheme IIa
Step 1: Preparation of Compound of Formula XVa
[0214] A compound of Formula XIIIa (1 equiv.) and a mixture of 1N
hydrochloric acid:methanol:tetrahydrofuran (2:5:5) were stirred at
room temperature for about 7 hours. At the end of reaction, sodium
hydroxide pellets (7 equiv.) were added and the reaction mixture
was further stirred at room temperature for about 5 hours. Reaction
mixture was concentrated and the residue was dissolved in distilled
water and acidified to .about.1 pH with 1N hydrochloric acid. The
aqueous layer was extracted with ethyl acetate, washed with water,
brine and dried over anhydrous sodium sulphate. Organic layer was
concentrated and adsorbed over silica gel (5%
methanol-dichloromethane). The following compound was prepared by
following above procedures
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-carboxyphenyl)amin-
o) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
[0215] Yield: 5 g (84.6%)
Step II: Preparation of Disodium Salt of Compound of Formula
XVa
[0216] A compound of XVa (1 equiv.), tetrahydrofuran:methanol (1:1)
and sodium hydroxide (1N, 2 equiv.) solution were stirred at
ambient temperature for about 2 hours. Disodium salt of compound of
Formula XVa was isolated by evaporating solvent under reduced
pressure. The residue was washed with diethylether, dried in vacuo
to afford the pure compound in a yield of 4.5 g (84.9%). The
following compound was prepared by following above procedures.
Disodium salt of
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-carboxyphenyl)ami-
no) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
[0217] .sup.1H NMR (DMSO, 300 MHz): .delta. 1.135-1.179 (m, 2H),
1.365 (d, J=6.3 Hz, 6H), 1.752 (brs, 4H), 1.752-1.779 (m, 1H),
1.950-1.998 (m, 1H), 2.733 (s, 1H), 2.89 (s, 1H), 3.607-3.75 (m,
3H), 3.924-4.004 (m, 2H), 6.99-7.07 (m, 5H), 7.155-7.247 (m, 4H),
7.4 (d, J=6 Hz, 2H), 7.70 (d, J=9 Hz, 2H), 9.827 (s, 1H); MS
(positive ion mode): m/z 603.13 (Acid.sup.++1); Yield: 4.5 g
(84.9%).
Scheme II
Preparation of Compound of Formula XIX
[0218] To a solution of a compound of Formula XVIII (4.5 mmoles;
prepared according to procedure as described in Tet. Let., 43:1161
(2002) and J. Org. Chem., 50:438 (1985), in toluene (15 ml) was
added a compound of Formula V (4.9 mmoles), piperidine (0.02 ml)
and acetic acid (0.054 ml). The mixture was heated at reflux with
azeotropic removal of water for about 4 to 6 hours. The reaction
mixture was concentrated and the residue was extracted in
dichloromethane. The organic layer was washed with 1N hydrochloric
acid solution, sodium bicarbonate solution, brine, dried over
anhydrous sodium sulphate, and concentrated. The crude product was
purified on a chromatographic column (silica gel, 100-200 mesh, 2%
EtOAc-hexane).
Preparation of Compound of Formula XX
[0219] A compound of Formula XIX (6.49 mmoles), a compound of
Formula VII (7.14 mmoles), 3-ethyl-5-(2-hydroxyethyl)-4-methyl
thiazolium bromide (1.298 mmoles), triethylamine (6.49 mmoles), and
ethanol (0.6 ml) were placed in a 30 ml vial, flushed with argon
and the vial sealed properly. The reaction mixture was stirred at
70.degree. C. for about 12 to 15 hours. To the reaction mixture was
added ethyl acetate, the mixture was washed with water, 6N
hydrochloric acid, again with water and brine, dried over anhydrous
sodium sulphate, and concentrated to give crude product. The crude
product was purified on a chromatographic column (silica gel
100-200 mesh) using 7% ethyl acetate in hexane.
Preparation of Compound of Formula XXI
[0220] To a solution of Formula XX (4.62 mmoles) in heptane:
toluene:tetrahydrofuran (4:1:1) was added a compound of Formula IX
(6.99 mmoles) and pivalic acid (4.768 mmoles). The mixture was
refluxed with azeotropic removal of water for about 22 to 25 hours.
The reaction mixture was concentrated, ethyl acetate was added, the
reaction mixture was washed with sodium bicarbonate solution and
brine, dried over anhydrous sodium sulphate and concentrated to
give the crude product. The crude product was purified on column
(silica gel, 100-200 mesh) using 7% ethyl acetate in hexane.
Preparation of Compound of Formula XXII
[0221] To a solution of a compound of Formula XXI (0.8 g) in
methanol:dioxan (2:8) mixture was added 10% palladium carbon (50%
wet, 60% w/w). The resulting reaction mixture was hydrogenated at
40 psi for about 2.5 hours. After the reaction was over, the
reaction mixture was passed through celite and the resulting
solution was concentrated under vacuum to give the required
product, which was further used as such for next step.
Preparation of Compound of Formula X: Path a
[0222] To a solution of a compound of Formula XXII (1 equiv) in
benzene at 0.degree. C. under argon, oxalyl chloride (2.0 equiv)
was added dropwise. After the evolution of gas had ceased, the
reaction mixture was heated on oil bath at 70.degree. C. for 2
hours. The reaction mixture was evaporated to dryness. The residue
was dissolved in benzene (dry) and added at ambient temperature to
a solution of amine of formula III (1.1 equiv.) in benzene. The
reaction mixture was then heated to 70.degree. C. until completion
of reaction. Volatiles were removed in vacuo and the residue was
purified on a chromatographic column (silica gel, 100-200 mesh).
The following compound was prepared following above general
procedure
(6-{2-[3-(2-Acetylphenylearbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-
-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid
tert-butyl ester
[0223] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 1.0-1.15 (m, 1H),
1.30 (s, 1H), 1.33 (s, 3H), 1.44 (s, 9H), 1.48 (d, J=6.0 Hz, 6H),
2.23 (dd, J=15.0 & 6.0 Hz, 1H), 2.35-2.5 (m, 4H), 3.35 (sept.
J=6.0 Hz, 1H), 3.64-3.89 (m, 2H), 4.0-4.25 (m, 2H), 6.93-7.08 (m,
8H), 7.18-7.22 (m, 2H), 7.50 (d, J=9.0 Hz, 1H), 7.69 (d, J=6.0 Hz,
1H), 8.82 (d, J=9.0 Hz, 1H), 11.02 (brs, 1H); MS (positive ion):
m/z 697.500 [M+1].sup.+; Yield=59%
Preparation of Compound of Formula X: Path b
[0224] To a solution of a compound of Formula XXII (1.2 mmole) in
dimethylformamide (2.5 ml) was added diisopropylethylamine (2.4
mmole) and O-benzotriazol-1-yl-N,N,N',N'-tetramethyl uronium
hexafluorophosphate (HBTU) (1.2 mmoles). To the resulting clear
solution was then added cyclohexylamine (1.2 mmoles) in
dimethylformamide (0.5 ml). The reaction mixture was stirred at
50.degree. C. to 60.degree. C. overnight. To the reaction mixture
was added water and the mixture was extracted with dichloromethane,
the organic layer was washed with water, brine, dried over
anhydrous sodium sulphate and concentrated to get the crude
product. The crude product was purified by column chromatography
(silica gel, 100-200 mesh) using 10% ethyl acetate in hexane. The
following compound was prepared as per this protocol.
(6-{2-[3-Cyclohexylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-pyrr-
ol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid
tert-butyl ester
[0225] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 0.7-0.88 (m, 2H),
0.97-1.05 (m, 2H), 1.20-1.30 (m, 4H), 1.30-1.34 (s, 3H), 1.43 (s,
9H), 1.47 (d, f=6.9 Hz, 6H), 1.43-1.48 (m, 2H), 1.63 (brs, 31-1),
2.25 (dd, J=15 & 6 Hz, 1H), 2.35 (dd, J=15 & 6.9 Hz, 1H),
3.35 (sept, J=6.9 Hz, 1H), 3.69-3.81 (m, 3H), 3.85-4.15 (m, 1H),
4.15-4.25 (m, 1H), 6.91-6.99 (m, 3H), 7.07-7.15 (m, 6H); MS
(positive ion mode): m/z 661 (M.sup.++1)
Preparation of Hemi Calcium Salt of Formula XI
[0226] (a) To a solution of a compound of Formula X in methanol and
tetrahydrofuran (1:1) was added 1N hydrochloric acid (3 equiv) and
the mixture stirred at ambient temperature. After the complete
hydrolysis of ketal, the reaction mixture was cooled to 0.degree.
C. and sodium hydroxide pellets (6 equiv) were added. The reaction
was then stirred at ambient temperature. At the end of ester
hydrolysis, solvents were removed and the residue was dissolved in
water; the aqueous layer was washed with ether, and neutralized
with 1N hydrochloric acid. The organic phase was extracted into
ethyl acetate, and concentrated. The residue was then purified on a
chromatographic column (silica gel 100-200 mesh).
[0227] (b) To an aqueous solution of the sodium salt of the acid
(prepared by adding 1 equivalent 1N sodium hydroxide solution) was
added dropwise an aqueous solution (1M) of calcium acetate (0.55
equiv). White precipitate was obtained, which was filtered, washed
with copious amount of water, and dried in vacuo.
[0228] The following compounds were prepared following above
general procedure
Hemi calcium salt of
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(cyclohexylamino)
carbonyl)]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
[0229] .sup.1H NMR (DMSO-d.sub.6, D.sub.2O exchanged, 300 MHz):
.delta. 0.99 (brs, 2H), 1.2-1.35 (m, 5H), 1.35-1.50 (m, 7H), 1.55
(m, 4H), 1.90-2.1 (m, 1H), 2.10-2.20 (m, 1H), 3.17-3.20 (m, 1H),
3.51 (brs, 1H), 3.73 (brs, 1H), 7.02-7.36 (m, 91-1); MS (positive
ion mode): m/z 565 (acid+1).
Hemi calcium salt of
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(2-acetylphenylamin-
o) carbonyl]pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
[0230] .sup.1H NMR (DMSO-d.sub.6,300 MHz): .delta. 1.10-1.25 (m,
2H), 139 (d, J=6.0 Hz, 6H), 1.5-1.7 (m, 2H), 1.77 (dd, J=150 &
6.0 Hz, 1H), 1.97 (dd, J=15.0 & 3.0 Hz, 1H), 2.38 (s, 3H),
6.94-7.01 (m, 5H), 7.08-7.20 (m, 3H), 7.29-7.34 (m, 2H), 7.56 (t,
J=9.0 Hz, 1H), 7.87 (d, J=6.0 Hz, 1H), 8.58 (d, 9.0 Hz, 1H), 10.98
(s, 1H); MS (positive ion): m/z 601.300 [Acid+1].sup.+; Yield=28%;
m. pt: 202.6-208.7.degree. C.
Scheme IIIa
Preparation of Compound of Formula XIX
[0231] To a solution of a compound of Formula XVIII (4.5 mmoles;
prepared according to procedure as described in Tet. Let., 43:1161
(2002) and J. Org. Chem., 50:438 (1985)) in toluene (15 ml) was
added a compound of Formula V (4.9 mmoles), piperidine (0.02 ml)
and acetic acid (0.054 ml). The mixture was heated at reflux with
azeotropic removal of water for about 4 to 6 hours. The reaction
mixture was concentrated and the residue was extracted in
dichloromethane. The organic layer was washed with 1N hydrochloric
acid solution, sodium bicarbonate solution, brine, dried over
anhydrous sodium sulphate, and was concentrated. The crude product
was purified on a chromatographic column (silica gel, 100-200 mesh,
2% EtOAc-hexane).
[0232] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 1.02 (d, J=6.9
Hz, 6H), 2.65 (sept, J=7.2 Hz, 1H), 5.26 (s, 2H), 7.25 (s, 2H),
7.25 (brs, 10H), 7.81 (s, 1H).). isomer 2: .sup.1H NMR (CDCl.sub.3,
300 MHz): .delta. 1.02 (d, J=6.9 Hz, 6H), 2.65 (sept, J=6.9 Hz,
1H), 5.27 (s, 2H), 7.36 (brs, 10H), 7.82 (s, 1H) MS (+ve ion mode):
ink 309 (M.sup.++1); Yield: 70%
Preparation of Compound of Formula XX
[0233] A compound of Formula XIX (6.49 mmoles), a compound of
Formula VII (7.14 mmoles), 3-ethyl-5-(2-hydroxyethyl)-4-methyl
thiazolium bromide (1.298 mmoles), triethylamine (6.49 mmoles), and
ethanol (0.6 ml) were placed in a 30 ml vial, the reaction was
flushed with argon and the vial was sealed properly. The reaction
mixture was stirred at 70.degree. C. for about 12 to 15 hours. To
the reaction mixture was added ethyl acetate, the mixture was
washed with water, 6N hydrochloric acid, again with water and
brine, was dried over anhydrous sodium sulphate, and was
concentrated to give crude product. The crude product was purified
on a chromatographic column (silica gel 100-200 mesh) using 7%
ethyl acetate in hexane.
[0234] .sup.1H NMR (CDCl.sub.3, 300 MHz): (1:1 mixture of
diastereomers) .delta. 0.48 (d, J=6.9 Hz, 3H), 0.91 (d, J=6.6 Hz,
3H), 1.07 (d, J=-6.6 Hz, 3H), 1.21 (d, J=6.9 Hz, 3H), 2.30 (sept,
J=6.6 Hz, 1H), 2.82 (sept, 6.6 Hz, 1H), 4.76 (d, J=14 Hz, 1H), 4.77
(d, J=12.3 Hz, 1H), 5.33 (d, J=11.1 Hz, 1H), 5.35 (d, J=11.1 Hz,
1H), 7.02 (t, J=8.4 Hz, 6H), 7.22-7.29 (m, 8H), 7.75-7.99 (m, 4H);
MS (+ve ion mode): m/z 433 (M.sup.++1). Yield: 72%
Preparation of Compound of Formula XXI
[0235] To a solution of Formula XX (4.62 mmoles) in
heptane:toluene:tetrahydrofuran (4:1:1) was added a compound of
Formula IX (6.99 mmoles) and pivalic acid (4.768 mmoles). The
mixture was refluxed with azeotropic removal of water for about 22
to 25 hours. The reaction mixture was concentrated, ethyl acetate
was added, and the reaction mixture was washed with sodium
bicarbonate solution and brine, was dried over anhydrous sodium
sulphate and was concentrated to give the crude product. The crude
product was purified on column (silica gel, 100-200 mesh) using 7%
ethyl acetate in hexane.
[0236] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 0.99-1.08 (m,
2H), 1.25 (s, 3H), 1.34 (s), 1.43 (s, 9H), 1.96 (d, J=6 Hz, 6H),
1.58-1.63 (m, 2H), 2.21 (dd, J=158.6 Hz, 1H), 2.37 (dd, J=15 &
9 Hz, 1H), 3.51 (sept, J=6 Hz), 3.65 (brs, 1H), 3.75-3.85 (m, 1H),
4.00-4.25 (m, 2H), 5.03 (s, 2H), 6.83-7.25 (m, 14H). MS (+ve ion
mode): m/z 670 (M.sup.++1). yield 74%
Preparation of Compound of Formula XXII
[0237] To a solution of a compound of Formula XXI (0.8 g) in
methanol:dioxan (2:8) mixture was added 10% palladium carbon (50%
wet, 60% w/w). The resulting reaction mixture was hydrogenated at
40 psi for about 2.5 hours. After the reaction was over, the
reaction mixture was passed through celite and the resulting
solution was concentrated under vacuum to give the required
product, which was further used as such for next step.
[0238] .sup.1H NMR (CDCl.sub.3, 300 MHz): .delta. 0.95-1.05 (m,
1H), 1.21-1.28 (m, 1H), 1.28 (s, 3H), 1.34 (s, 3H), 1.43 (s, 9H),
1.47 (d, J=7.1 Hz), 1.59-1.65 (m, 2H), 2.22 (dd, J=15.2 & 6.1
Hz, 1H), 2.35 (dd, J=15.2 & 6.1 Hz, 1H), 3.61-3.66 (m, 2H),
3.67-3.86 (m, 1H), 4.00-4.15 (m, 2H), 6.95 (t, I=9 Hz, 2H),
7.06-7.15 (m, 7H) MS (+ve ion mode): m/z 586 (M.sup.++1) Yield
76%
Preparation of Compound of Formula Xa: Path a
[0239] To a solution of a compound of Formula XXII (1 equiv) in
benzene at 0.degree. C. under argon, oxalyl chloride (2.0 equiv) is
added dropwise. After the evolution of gas ceases, the reaction
mixture is heated on oil bath at 70.degree. C. for 2 hours. The
reaction mixture is evaporated to dryness. The residue is dissolved
in benzene (dry) and is added at ambient temperature to a solution
of amine of Formula IIIa (1.1 equiv.) in presence of triethylamine,
in benzene. The reaction mixture is then heated to 70.degree. C.
until completion of reaction. Volatiles are removed in vacuo and
the residue is purified on a chromatographic column (silica gel,
100-200 mesh).
Preparation of Compound of Formula Xa: Path b
[0240] To a solution of a compound of Formula XXII (1.2 mmole) in
dimethylformamide (2.5 ml) is added diisopropylethylamine (2.4
mmole) and O-benzotriazol-1-yl-N,N,N',N'-tetramethyl uronium
hexafluorophosphate (HBTU) (1.2 mmoles). To the resulting clear
solution is then added cyclohexylamine (1.2 mmoles) in
dimethylformamide (0.5 ml). The reaction mixture is stirred at
50.degree. C. to 60.degree. C. overnight. To the reaction mixture
is added water and the mixture is extracted with dichloromethane,
the organic layer is washed with water, brine, is dried over
anhydrous sodium sulphate and is concentrated to get the crude
product. The crude product is purified by column chromatography
(silica gel, 100-200 mesh) using 10% ethyl acetate in hexane.
Preparation of Hemi Calcium Salt of Formula XIa
[0241] (a) To a solution of a compound of Formula Xa in methanol
and tetrahydrofuran (1:1) is added 1N hydrochloric acid (3 equiv)
and the mixture is stirred at ambient temperature. After the
complete hydrolysis of ketal, the reaction mixture is cooled to
0.degree. C. and sodium hydroxide pellets (6 equiv) are added. The
reaction is then stirred at ambient temperature. At the end of
ester hydrolysis, solvents are removed and the residue is dissolved
in water; the aqueous layer is washed with ether, and is
neutralized with 1N hydrochloric acid. The organics phase is
extracted into ethyl acetate, and concentrated. The residue is then
purified on a chromatographic column (silica gel 100-200 mesh).
[0242] (b) To an aqueous solution of the sodium salt of the acid
(is prepared by adding 1 equivalent 1N sodium hydroxide solution)
is added dropwise an aqueous solution (1M) of calcium acetate (0.55
equiv). White precipitate is obtained, which is filtered, is washed
with copious amount of water, and is dried in vacuo. The following
compounds can be prepared following scheme Ib or IIIa or both.
[0243]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-acetoxymethylphen-
yl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 2a) and its hemicalcium salt, [0244]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylthiocarbamo-
yloxyraethylphenyl)amino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 3a) and its hemicalcium salt, [0245]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-propionyloxymethy-
lphenyl)amino) carbonyl]pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 4a) and its hemicalcium salt, [0246]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-octylcarbamoyloxy-
methyl phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 5a) and its hemicalcium salt, [0247]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylacetoxymeth-
yl phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 6a) and its hemicalcium salt, [0248]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylcarbamoylox-
ymethyl phenyl)amino)
carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.
7a) and its hemicalcium salt, [0249]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-benzoyloxymethyl
phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 8a) and its hemicalcium salt, [0250]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-isonicotinoyloxym-
ethyl phenyl)amino) carbonyl]pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 9a) and its hemicalcium salt, [0251]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-pyridin-4-ylcarba-
moyloxymethyl phenyl)amino)
carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.
10a) and its hemicalcium salt, [0252]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylcarbamoyl
phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 11a) and its hemicalcium salt, [0253]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-cyclohexylcarbamo-
yl-phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 12a) and its hemicalcium salt, [0254]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-methylcarbamoyl)--
phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 13a) and its hemicalcium salt, [0255]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-benzylcarbamoyl)--
phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 14a) and its hemicalcium salt, [0256]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(morpholine-4-car-
bonyl)-phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 15) and its hemicalcium salt, [0257]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(piperidine-1-car-
bonyl)-phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 16) and its hemicalcium salt, [0258]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-benzylamino
phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 17) and its hemicalcium salt, [0259]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(1-hydroxyethyl)p-
henylamino) carbonyl]pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 18) and its hemicalcium salt, [0260]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(2-hydroxyethyl)p-
henylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 19) and its hemicalcium salt, [0261]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-hydroxypropyl
phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 20) and its hemicalcium salt, [0262]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-methoxymethyl
phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 21) and its hemicalcium salt, [0263]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-ethoxymethyl
phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 22) and its hemicalcium salt, [0264]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-isopropoxymethyl
phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 23) and its hemicalcium salt, [0265]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-propoxymethyl
phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 24) and its hemicalcium salt, [0266]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-methoxymethoxyme-
thylphenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 25) and its hemicalcium salt, [0267]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-cyclohexyloxymet-
hyl phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 26) and its hemicalcium salt, [0268]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-cyclopentyloxyme-
thyl phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 27) and its hemicalcium salt, [0269]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-benzyloxymethyl
phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 28) and its hemicalcium salt, [0270]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-chlorobenzyloxym-
ethyl phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 29) and its hemicalcium salt, [0271]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4
methoxybenzyloxymethyl phenylamino)
carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.
30) and its hemicalcium salt, [0272]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-phenoxymethylphe-
nylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 31) and its hemicalcium salt, [0273]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-chlorophenoxymet-
hyl phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 32) and its hemicalcium salt, [0274]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-acetylaminopheny-
lamino) carbonyl]pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 33) and its hemicalcium salt, [0275]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-benzoylamino
phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 34) and its hemicalcium salt, [0276]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-benzenesulfonyla-
mino phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 36) and its hemicalcium salt, [0277]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-phenyl-ureido)-
-phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 37) and its hemicalcium salt, [0278]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-methyl-ureido)-
-phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 38) and its hemicalcium salt, [0279]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-benzyll-ureido-
)-phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
(Compound No. 39) and its hemicalcium salt, [0280]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-benzyl-thioure-
ido)-phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 40) and its hemicalcium salt, [0281]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-phenyl-thioure-
ido)-phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 41) and its hemicalcium salt, [0282]
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-methyl-thioure-
ido)-phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic
acid (Compound No. 42) and its hemicalcium salt.
Pharmacological Activity
[0283] The compounds disclosed herein have activity as inhibitors
of 3-hydroxy-3-methyl-glutanyl coenzyme A (HMG-CoA) reductase, and
thus are useful in inhibiting cholesterol biosynthesis and/or in
lowering triglycerides.
[0284] The compounds described herein are screened in an in-vitro
HMG-CoA reductase enzyme assay as described by Kubo et al.,
Endocrinology 120:214 (1987) and Hellar et al., Biochem and
Biophys. Res. Comm. 50:859 (1973).
[0285] HMG-CoA reductase is a rate-limiting enzyme in the
cholesterol biosynthesis, catalyzing the following reaction.
[.sup.14C]HMG-CoA+2NADPH+2H.sup.+.fwdarw.[.sup.14C]mevanolate+CoA+2NADP.s-
up.+ microsomes, utilizing 2.5 .mu.M [.sup.14C]HMG-CoA as a
substrate. The reaction is carried out in presence of 100 mM
KH.sub.2PO.sub.4, 20 mM G-6-P, 2.5 mM NADP, 10 mM EDTA, 5 mM DTT
and 1.4 G-6-P dehydrogenase, at 37.degree. C. for 15 minutes and
quantitating [.sup.14C]mevalonate as an end product. For IC.sub.50
determination, the compounds dissolved in 1% dimethylsulfoxide are
preincubated with liver microsomes at 37.degree. C. for 30
minutes.
[0286] The IC.sub.50 for HMG-CoA reductase inhibition in rat liver
microsome ranged from 0.1 to 0.96 nM. The compounds disclosed
herein ranged from being equipotent to 4 fold more potent than
atorvastatin. Some of the compounds disclosed herein were potent
than atorvastatin in inhibiting cholesterol synthesis in vivo rat
model. Some of the compounds disclosed herein have intrinsic
clearance in human liver microsome significantly less than
atorvastatin and are not major substrate for CYP3A4 (cytochrome
p450 3A4). Some of the compounds exhibit potency and selectivity
greater than atorvastatin in inhibition of cholesterol synthesis in
rat primary hepatocytes over inhibition of cholesterol synthesis in
extra hepatic cells/cell lines [e.g. NRK-49F (Fibroblast) and L6
(Myoblast)].
[0287] While the present invention has been described in terms of
its specific embodiments, certain modifications and equivalents
will be apparent to those skilled in the art and are intended to be
included within the scope of the present invention.
* * * * *