Indian Patents
Title of Invention

"SUBSTITUTED PYRROLE DERIVATIVES AND THEIR USE AS HMG-COA REDUCTASE 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.
Full Text Field of the Invention 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.
Background of the Invention
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.
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.
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.
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.
U. S. Patent No. 4,681,893 assigned to Warner-Lambert, discloses certain trans-6-[2-(3-,or 4-carbaoxamido-substituted pyrrole-l-yl)alkyI]-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-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-
yl)ethyl]-lH-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.
U. S. Patent 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-(l-methylethyl-N,4-diphenyl-l-[2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-lH-pyrrole-3-carboxamide that is [R-(R*, R*)]-2-(4-fluorophenyl)-P,8-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-1-heptanoic acid, pharmaceutically acceptable salts thereof, specifically its calcium salt (Atorvastatin, Lipitor®), which is currently being used for the treatment of hypercholesterolemia.
U. S. Patent No. 5,385,929 discloses certain phenyl hydroxy derivatives of the compounds disclosed in U. S. 5,273,995, and that such phenyl hydroxy derivatives are also active as the inhibitors of the biosynthesis of cholesterol.
Summary of the Invention
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
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.
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.
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.
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.
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.
In accordance with one aspect, there is provided a compound having the structure of Formula I,
its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, prodrugs, metabolites, polymorphs, tautomers, racemates, pure enantiomers, diastereoisomers or N-oxides wherein
OH
RI can be C1-C6, C3-C6, or optionally substituted phenyl (wherein up to three substituents are independently selected from halogens, C1-C6 alkyl, cyano, or C1-C3 perfluoroalkyl);
R2 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 C1-C6 alkyl, C3-C6 cycloalkyl, acetyl, or sulfonamide);
R3 can be optionally substituted C1-C6 alkyl or C3-C6 cycloalkyl (wherein substituents are independently selected from halogens, hydroxyl, C1-C3 alkoxy and protected hydroxyl);
R3 can also be -NR8R9, wherein R8 and R9 are optionally substituted C1-C6 alkyl (wherein the optional substituent(s) is/are selected from halogens, hydroxy, C1-C3 alkoxy and protected hydroxyl);
Rtcanbe
(Formula removed)

wherein R5 and R6 are independently hydrogen, C1-C6alkyl or C3-C6 cycloalkyl, optionally substituted aryl or aralkyl, wherein the substituents are selected from halogens, cyano, optionally substituted C1-C6 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 SO2R7, COR7, or CONHR7, wherein R7 is C1-C6 alkyl or aryl), or acetyl, trifluoromethyl, or C1-C6 alkoxycarbonyl, or R5 and R6 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 R4 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, C1-C3 alkoxy, cyano, C1-C3 perfluoroalkyl, C1-C6 alkyl or C3-C6 cycloalkyl, aryl or optionally substituted aralkyl wherein the substituents are independently selected from halogens, hydroxy, protected hydroxyl, C1-C3 alkoxy, cyano, or C1-C3 perfluoroalkyl,
and the pharmaceutically acceptable salts, tautomers, racemates, pure enantiomers or diastereoisomers, and solvates of the compounds of Formula I,
with the proviso that R2 is phenyl only when (1) R5 or R6 is C3-C6 cycloalkyl or phenyl substituted with acetyl, alkyl, cycloalkyl, hydroxyalkyl, alkylsulfonamido, acetamido or (2) when R5 and R6 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 R5 or R6 is aralkyl optionally substituted with halogens, cyano, C1-C6 alkyl, C1-C6 halogenated alkyl or (4) when R4 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, C1-C3 alkoxy, cyano, perfluoroalkyl of one to three carbon atoms, C1-C6 . alkyl, C3-C6 cycloalkyl, aryl, or optionally substituted aralkyl (wherein the aralkyl substituents are independently selected from halogens, hydroxy, protected hydroxyl, C1-C3 alkoxy, cyano, or C1-C3 perfluoroalkyl)).
In accordance with another aspect, there are provided compounds having the structure of Formula lb,
(Formula removed)

their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, tautomers, racemates, polymorphs, pure enantiomers, diastereoisomers, metabolites, prodrugs or N-oxides wherein
(Formula removed)


R1 can be C1-C6 alkyl, C3-C6 cycloalkyl, or optionally substituted phenyl (wherein the substituent(s) is/are selected from halogens, C1-C6 alkyl, cyano and C1-C3 perfluoroalkyl);
R2 can be optionally substituted phenyl (wherein the substituent(s) is/are selected from cyano, acetyl and optionally substituted amino);
R3 can be optionally substituted C1-C6 alkyl or C3-C6 cycloalkyl (wherein the substituent(s) is/are selected from halogens, hydroxyl, C1-C3 alkoxy, and protected hydroxyl); R3 can also be -NR6R7 wherein R6 and R7 are optionally substituted C1-C6 alkyl (wherein the optional substituent(s) is/are selected from halogens, hydroxyl, C1-C3 alkoxy, and protected hydroxyl);
R4 can be acetyl, C1-C2 alkoxycarbonyl, optionally substituted C1-C6 alkyl (wherein the substituent is hydroxy or protected hydroxyl), NHRg [wherein R8 is selected from alkyl, aralkyl, SO2R9, COR9 or CONHR9, CSNHR9 (wherein R9 is C1-C6 alkyl, aryl or aralkyl)]; R4 can also be -COR10 (wherein R10 is selected from hydroxyl and -NR11R12 (wherein R11 and R12 are independently selected from hydrogen, alkyl, aryl, C3-C7 cycloalkyl, heterocyclyl, aralkyl and Rn and R12 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);
R5 can be hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl, optionally substituted aryl or aralkyl [wherein the substituents are selected from halogens, cyano, optionally substituted C1-C6 alkyl (wherein the substituents are independently selected from hydroxyl, protected hydroxyl, and halogen(s)], optionally substituted amino, acetyl, trifluoromethyl and C1-C6 alkoxycarbonyl.
In one particular embodiment, there are provided compounds of Formula lb,
(Formula removed)


their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, tautomers, racemates, polymorphs, pure enantiomers, diastereoisomers, metabolites, prodrugs or N-oxides wherein
/"VTT
(Formula removed)


R1, R2, R3 and R5 are as defined earlier;
R4 can be NHRg [wherein R8 is selected from aralkyl, CONHR9 (wherein R9 is aralkyl); CSNHR9 (wherein R9 is C1-C6 alkyl, aryl or aralkyl)]; -COR10 (wherein R10 is selected from hydroxyl and -NR11R12 (wherein R11 and R12 are independently selected from hydrogen, alkyl, aryl, C3-C7 cycloalkyl, aralkyl and R11 and R12 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);
In yet another particular embodiment, there are provided compounds of Formula lb,
(Formula removed)


their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, tautomers, racemates, polymorphs, pure enantiomers, diastereoisomers, metabolites, prodrugs or N-oxides wherein
(Formula removed)

R1, R2, R3 and R5 can be 4-fluorophenyl, phenyl, isopropyl and hydrogen, respectively;
R4 can be C1-C2 alkoxycarbonyl, optionally substituted C1-C6 alkyl (wherein the substituent is hydroxy or protected hydroxyl), NHRg [wherein Rg is selected from SO2R9, COR9 or CONHR9 (wherein R9 is methyl or phenyl)]
In accordance with further aspect, there are provided intermediates having the structure of Formula XIX,
(Formula removed)

wherein
R2 can be optionally substituted phenyl (wherein the substituent(s) is/are selected from cyano, acetyl and optionally substituted amino);
R3 can be optionally substituted C1-C6 alkyl or C3-C6 cycloalkyl (wherein the substituent(s) is/are selected from halogens, hydroxyl, C1-C3 alkoxy, and protected hydroxyl); R3 can also be -NR6R7 wherein R6 and R7 are optionally substituted C1-C6 alkyl (wherein the optional substituent(s) is/are selected from halogens, hydroxyl, C1-C3 alkoxy, and protected hydroxyl).
In accordance with third aspect, there are provided intermediates having the structure of Formula XX,
(Formula removed)

wherein
R1 can be C1-C6 alkyl, C3-C6 cycloalkyl, or optionally substituted phenyl (wherein the substituent(s) is/are selected from halogens, C1-C6 alkyl, cyano and C1-C3 perfluoroalkyl);
R2 can be optionally substituted phenyl (wherein the substituent(s) is/are selected from cyano, acetyl and optionally substituted amino;
R3 can be optionally substituted C1-C6 alkyl or C3-C6 cycloalkyl (wherein the substituent(s) is/are selected from halogens, hydroxyl, C1-C3 alkoxy, and protected hydroxyl); R3 can also be NR6R7 wherein R6 and R7 are optionally substituted C1-C6 alkyl (wherein the optional substituent(s) is/are selected from halogens, hydroxyl, C1-C3 alkoxy, and protected hydroxyl).
In accordance with fourth aspect, there are provided intermediates having the structure of Formula XXI,
(Formula removed)

wherein
R1 can be C1-C6 alkyl, C3-C6 cycloalkyl, or optionally substituted phenyl (wherein the substituent(s) is/are selected from halogens, C1-C6 alkyl, cyano and C1-C3 perfluoroalkyl);
R2 can be optionally substituted phenyl (wherein the substituent(s) is/are selected from cyano, acetyl and optionally substituted amino;
R3 can be optionally substituted C1-C6 alkyl or C3-C6 cycloalkyl (wherein the substituent(s) is/are selected from halogens, hydroxyl, C1-C3 alkoxy, and protected hydroxyl); R3 can also be -NR6R7 wherein R6 and R7 are optionally substituted C1-C6 alkyl (wherein the optional substituent(s) is/are selected from halogens, hydroxyl, C1-C3 alkoxy, and protected hydroxyl).
In accordance with fifth aspect, there are provided intermediates having the structure of Formula XXII,
(Formula removed)

Formula XXII
wherein
R1can be C1-C6 alkyl, C3-C6 cycloalkyl, or optionally substituted phenyl (wherein the substituent(s) is/are selected from halogens, C1-C6 alkyl, cyano and C1-C3 perfluoroalkyl);
R2 can be optionally substituted phenyl (wherein the substituent(s) is/are selected from cyano; acetyl and optionally substituted amino;
R3 can be optionally substituted C1-C6 alkyl or C3-C6 cycloalkyl (wherein the substituent(s) is/are selected from halogens, hydroxyl, C1-C3 alkoxy, and protected hydroxyl); R3 can also be -NR6R7 wherein R6and R7 are optionally substituted C1-C6 alkyl (wherein the optional substituent(s) is/are selected from halogens, hydroxyl, C1-C3 alkoxy, and protected hydroxyl).
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.
Alkyl may optionally be substituted with halogen, hydroxy, protected hydroxyl, C1-C3 alkoxy, optionally substituted amino and C1-C6 alkoxycarbonyl.
As used herein the term "optionally substituted amino", unless otherwise defined, refers to NR14R15 wherein R14 and R15 are independently selected from hydrogen, alkyl, aryl, aralkyl, C3-C7 cycloalkyl, SO2R16, COR16, CONHR1 and CSNHR16 (wherein R1 is C1- alkyl, aryl or aralkyl).
As used herein the term "protected hydroxyl" refers to a hydroxy moiety protected by a group Rn wherein R17 is selected from alkyl, cycloalkyl, aralkyl, aryl, -(CH2)nOR18(wherein R18
is selected from alkyl, cycloalkyl, aralkyl, aryl and n represents an integer from 1 to 6), COR19, CSR19, CONHR19 and CSNHR19 (wherein R19 is selected from alkyl, aryl, aralkyl and heterocyclyl). Examples of protected hydroxyl include, but are not limited to, -OCH3, -OC2H5, -O-n-propyl, -O-i-propyl, -O-cyclopropyl, -O-CH2OCH3, -O-cyclopentyl, -O-cyclohexyl, -O-benzyl, -O-chlorobenzyl, -O-methoxybenzyl, -O-phenyl, -O-chlorophenyl, -O-COCH3, -O-COC2H5, -O-CObenzyl, -O-COphenyl, -O-COpyridinyl, -O-CONHphenyl, -O-CONHpyridinyl, -O-CONH-octyl,-O-CSNHphenyl, and the like.
As used herein the term "aralkyl" refers to (CH2)„aryl wherein n is an integer from 1 to 6.
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.
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.
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.
In accordance with yet another aspect, there are provided processes for the preparation of the compounds described herein.
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.
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
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, la, lb,
II, IIaIII, III and IV.
(Formula removed)


SCHEME I
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 R3, R5 and R^ are
as defined earlier, to give a compound of Formula IV which on reaction with a compound of Formula V (wherein R2 is as defined earlier) gives a compound of Formula VI, which on treatment with a compound of Formula VII (wherein R1is 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.
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 (5-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.
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.
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.
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.
(Formula removed)


The compound of Formula XVII can be prepared according to Scheme la. Accordingly, a compound of Formula XIII (that is, Formula X wherein R5H and
(Formula removed)

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.
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.
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.
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.
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.
(Formula removed)

SCHEME lb
The compound of Formula Xllb can be prepared according to Scheme lb. Accordingly, a compound of Formula II is reacted with a compound of Formula IIIb, wherein R3, R4 and R5 are as defined earlier, to give a compound of Formula IVb which on reaction with a compound of Formula V (wherein R2 is as defined earlier) gives a compound of Formula VIb, which on treatment with a compound of Formula VII (wherein R1is as defined earlier) yields a compound of Formula Vlllb, which on further reaction with a compound of Formula IX gives a compound of Formula Xb, which on hydrolysis gives a compound of Formula Xlb, which can, then be further converted to hemicalcium salt.
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.
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 P-alanine and an organic acid such as glacial acetic acid or benzoic acid.
The reaction of a compound of Formula VIb with an aldehyde of Formula VII to give a compound of Formula Vlllb 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.
The reaction of a compound of Formula Vlllb 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 Vlllb 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.
The conversion of a compound of Formula Xb to a compound of Formula Xlb 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.
The compound of Formula Xlb 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 Xlb can also be prepared from the corresponding lactones form of Formula Xlb by following procedures well-known in the art.
(Formula removed)

SCHEME II
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 R2 and R3 are as defined earlier in Scheme I) which on reaction with a compound of Formula VII (wherein R1is 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
(a) conversion to corresponding acid chloride followed by reaction with an amine of Formula III (Path a) or
(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.
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 p-alanine and an organic acid such as glacial acetic
acid or benzoic acid.
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.
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.
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.
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.
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 0-benzotriazol-l-yl-N,N,N',N'-tetramethyl uronium hexafluorophosphate (HBTU), bis(2-oxo-3-oxazolidinyl)phosphine (BOP), 1,3-dicyclohexycarbodiimide (DCC), 2-(lH-benzotriazole-l-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.
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.
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.
(Formula removed)


SCHEME II
The compound of Formula XVIa can be prepared according to Scheme II Accordingly, a compound of Formula XII (that is, Formula Xa wherein R5H and R4 -COOCH3, prepared according to Scheme I) is hydrolyzed to give a compound of Formula XlVa, which on further hydrolysis gives a compound of Formula XVa, which can then be converted to disodium salt.
The conversion of compounds of Formula XIIIto 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.
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.
(Formula removed)

SCHEME III
The compound of Formula XXVII can be prepared according to Scheme III. 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.
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.
The cyclisation of compound of Formula XXIV can be carried out in diglyme to give a compound of Formula XXV.
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.
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.
(Formula removed)


SCHEME IIIa
The compound of Formula Xlla can also be prepared according to Scheme III Accordingly, a compound of Formula XVIII is reacted with a compound of Formula V to give a compound of Formula XIX (wherein R2 and R3 are as defined earlier) which on reaction with a compound of Formula VII (wherein R1is 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
(a) conversion to corresponding acid chloride followed by reaction with an amine of
Formula III(Path a) or
(b) reaction with an amine of Formula IIIin 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.
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 p-alanine and an organic acid such as glacial acetic acid or benzoic acid.
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.
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.
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.
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 Ilia 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.
Reaction of compound of Formula XXII with an amine of Formula Ilia to give a compound of Formula Xa (path b) can be carried out in the presence of a coupling agent, such as 0-benzotriazol-l-yl-N,N,N',N'-tetramethyl uroniurn hexafluorophosphate (HBTU), bis(2-oxo-3-
oxazolidinyl)phosphine (BOP), 1,3-dicyclohexycarbodiimide (DCC), 2-(lH-benzotriazole-l-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.
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.
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.
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.
(Formula removed)


SCHEME IV
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.
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.
The condensation of a compound of Formula XXVIII with N, N-dimethylbenzamide dimethylacetal followed by treatment with hydrazine hydrate affords compound of Formula XXIX.
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.
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.
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.
An illustrative list of particular compounds disclosed herein is given below (also shown in Table I):
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(2-acetylphenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 1)
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(3-acetylphenylamino)carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 2)
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-acetylphenylamino)carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 3)
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(2,4-dimethylphenylamino)carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 4)
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(cyclohexylamino)carbonyl)]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 5)
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-trifluoromethylbenzylamino) carbonyl)]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 6)
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-(morpholine-4-carbonyl)-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 7)
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-(piperidine-l-carbonyl)-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 8)
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 11)
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-methanesulfonylaminophenyl amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 12)
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-acetylaminophenylamino)carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 13)
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-(4-cyanophenyl)-4-[(phenylamino)carbonyl)]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 14)
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-carboxyphenyl)amino)carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. la),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-acetoxymethylphenyl) amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 2a),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylthiocarbamoyl oxymethylphenyl)amino)carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 3a),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-propionyloxymethyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 4a),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-octylcarbamoyloxymethyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 5a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-phenylacetoxymethyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 6a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylcarbamoyl
oxymethyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No.
7a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-benzoyloxymethyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 8a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-isonicotinoyloxymethyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 9a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [4-pyridin-4-ylcarbamoyl
oxymethyl phenyl) amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No.
10a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-phenylcarbamoyl phenyl) amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 11a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-cyclohexylcarbamoyl-phenyl) amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 12a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-methylcarbamoyl)-phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 13a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-benzylcarbamoyl)-phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 14a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(morpholine-4-carbonyl)-phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 15),
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(piperidine-l -carbonyl)-phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 16),
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-benzylamino phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 17),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(l-hydroxyethyl)phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 18),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(2-hydroxyethyl) phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 19),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-hydroxypropyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 20),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-methoxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 21),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-ethoxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 22),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-isopropoxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 23),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-propoxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 24),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-
methoxymethoxymethylphenylamino) carbonyl]-pyrrol-1 -yl]-3,5-dihydroxy-heptanoic acid (Compound No. 25),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3 -phenyl -4- [(4-cyclohexyloxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 26),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-cyclopentyloxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 27),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3 -phenyl-4- [(4-benzyloxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 28)
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-chlorobenzyloxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 29),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3 -phenyl-4- [(4-methoxybenzyloxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 30),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-phenoxymethylphenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 31),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3 -phenyl -4- [(4-chlorophenoxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 32),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-acetylaminophenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 33),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-benzoylamino phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 34),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-benzenesulfonylamino phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 36)
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-phenyl-ureido)-phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 37),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-methyl-ureido)-phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 38),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-benzyll-ureido)-phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 39),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(3-benzyl-thioureido)-phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 40),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-phenyl-thioureido)-phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 41),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(3-methyl-thioureido)-phenylamino) carbonyl]-pyrrol-l-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.
An illustrative list of compounds, which can be prepared by following Schemes III and IV is given below (also shown in Table I):
(3R,5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(3-phenyl-[l,2,4]oxadiazol-5-yl)-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 9)
(3R,5R)-7-[2-(4-Fluorophenyl0-5-isopropyl-3-phenyl-4-(5-phenyl-2H-[l,2,4]triazol-3-yl)-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 10)
In Tables I and la, R4 is the indicated structure, unless otherwise noted.
(Table removed)

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.
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.
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.
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.
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.
The present invention also includes metabolites, which become active upon introduction into the biological system.
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.
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.
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.
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.
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.
In case of capsules, tablets, and pills, the dosage form may also comprise buffering agents.
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.
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.
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.
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.
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.
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.
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 lb
Step 1: Preparation of (3-ketoamide-l (Formula IV and IVb)
A mixture of δketoester (Formula II, 1 equiv.), amine (Formula III, 1 equiv) 1,2-ethylene diamine (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
1H NMR(CDC13):8 1.19 (d, J=6.9Hz, 6H), 2.61 (s, 3H), 2.75 (sep, J=6.9Hz, IH), 3.64 (s, 2H), 7.43 (t, J=7.8Hz, IH), 7.71 (d, J=7.8Hz, IH), 7.87 (d, J=8.1Hz, IH), 8.08 (s, IH), 9.44 (brs, IH); MS (positive ion mode): m/z 248 [M+l]; Yield: 49%
4-Methyl-3-oxo-pentanoic acid (4-acetylphenyl)-amide
1H NMR(CDC13):5 1.19 (d, J=6Hz, 6H), 2.58 (s, 3H), 2.75 (sep, J=6Hz, IH), 3.65 (s, 2H), 7.67 (d, J=6Hz, 2H), 7.95 (d, J=6Hz, 2H), 9.60 (s, IH), MS (positive ion mode): m/z 248 [M+l]; Yield 54%
4-Methyl~3-oxo-pentanoic acid (2,4-dimethylphenyl)-amide
1H NMR(CDC13):8 1.18 (d, J=6Hz, 6H), 2.29 (s, 6H), 2.73 (Sep, J=6Hz, IH), 3.64 (s, 2H), 7.00 (s, 2H), 7.76 (d, J=6Hz, IH), 9.11 (brs, IH); MS (positive ion mode): m/z 234 [M+l] Yield 72%
4-Methyl~3-oxo-pentanoic acid 4-trifluoromethylbenzyl amide
1H NMR(CDC13):6 1.14 (d, J=6Hz, 6H), 2.70 (sept, J=6Hz, IH), 3.53 (s, 2H), 4.53 (d, J=6Hz, 2H), 7.40 (d, J=6Hz, 2H), 7.59 (d, J=6Hz, 2H); MS (positive ion mode): m/z 287
4-Methyl-1 -piper idin-1 -yl-pentane-1,3-dione
1 NMR(CDC13, 300MH)4 (d, J=6Hz, 6H), 1.57-1.65 (m, 6H), 2.76 (brs, IH), 3.20-3.75 (m, 6H);
4-Methyl-3-oxo-pentanoic acid phenylamide
Step 2: Preparation of P-ketoamide-2 (Formula VI and VIb)
To P-ketoamide-1 (Formula IV, 1 equiv) in hexane was added to p-alanine (0.18 equiv), aldehyde (Formula V, 1.1 equiv) and glacial acetic acid (0.16 % w/w of P-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 P-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
lH NMR(CDC13):δ 1.1 (d, J=6.9Hz, 6H), 2.50-2.70 (m, 4H), 7.28-7.52 (m, 6H), 7.73 (d, J=7.2Hz, 1H), 7.93 (d, J=8.1Hz, 1H), 8.19 (d, J=9.9Hz, 2H), 9.23 (s, 1H); MS (positive ion mode): m/z 336 [M+l]; Yield: 13%
2-Benzylidine-4-methyl-3-oxo-pentanoic acid (3-acetylphenyl)-amide; Isomer-2
1HNMR(CDCl3)δ 1.24 (d, J=9Hz, 6H), 2.60 (s, 3H), 3.39 (sep, J=6Hz, 1H), 7.33-7.98 (m, 11H); MS (positive ion mode): m/z 336 [M+l]; Yield: 32%
2-Benzylidene-4-methyl-3-oxo-pentanoicacid (4-acetylphenyl)-amide
1H NMR(CDC13):8 1.23 (d, J=6.6Hz, 6H), 2.58 (s, 3H), 3.37 (Sep, J=6.6Hz, 1H), 7.27-7.42 (m, 3H), 7.49-7.73 (m,5H), 7.95 (d, J=8.7Hz, 2H); MS (positive ion mode ): m/z 336 [M+l], Yield 48%
2-Benzylidene-4-methyl-3-oxo-pentanoic acid (2,4-dimethylphenyl)-amide
1H NMR(CDC13):8 1.23 (d, J=6Hz, 6H), 1.99 (s, 1H), 2.29 (s, 1H), 3.38 (Sep,J=6Hz, 1H), 6.97 (s, 1H), 7.04 (d, J=6Hz, 1H), 7.30 (s, 1H), 7.35-7.45 (m, 3H), 7.53-7.72 (m, 7H) MS (positive ion mode): m/z 323 [M+l]; Yield 50%
2-Benzylidine-4-methyl-3-oxo-pentanoic acid 4-trifluoromethylbenzyl amide
1HNMR(CDCl3)300MHz):δ 1.19 (d, J=6.9Hz, 6H), 3.30 (sept, J=6.9Hz, 1H), 6.16 (brs, 1H), 7.26-7.60 (m, 1 OH)
2-Benzylidene-4-methyl-l-piperidin-l-yl-pentane-l,3-dione
1HNMR(DCl3):δ 00MHz):5 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++l)
2-(4-Cyanobenzylidene)-4-methyl-3-oxo-pentanoic acid phenylamide
1H NMR (CDC13):5 1.23 (d, J=6Hz, 6H), 3.34 (Sep, J=6Hz, 1H), 7.18 (t, J=6Hz, 1H), 7.36 (t, J=6Hz, 2H), 7.48 (d, J=6Hz, 2H), 7.57 (s, 1H), 7.65 (s, 4H), 7.81 (s, 1H); MS (positive ion mode): m/z 319 [M+l]; Yield: 67%
Step 3: Preparation of Diketone (Formula VIII and VlIIb)
p-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 N2 and the vial was capped immediately and was heated to 78°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 Vlllb can be prepared analogously. The following intermediates were prepared following above general procedure
2-[2-(Fluorophenyl)-2-oxo-l-phenyl-ethyl]-4-methyl-3-oxo-pentanoic acid (3-acetylphenyl)-amide
1H NMR(CDC13):5 1.15 (d, J=6Hz, 3H), 1.20 (d, J=6Hz, 3H), 2.58 (s, 3H), 2.99 (sep, J=6Hz, IH), 4.61 (d, J=12Hz, IH), 5.38 (d, J=12Hz, IH), 7.05 (t, J=9Hz, 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+l]; Yield: 55%
2-[2-(4-Fluorophenyl)-2-oxo-l -phenylethyl] -4-methyl-3-oxo-pentanoic acid (4-acetylphenyl)-amide
1HNMR(CDCl3).S 1.16 d, J=6.9Hz, 3H), 1.23 (d, J=6.9Hz, 3H), 2.55 (s, 3H), 2.99 (Sep, J=6.6Hz, IH), 4.56 (d, J=10.5Hz, IH), 5.35 (d, J=10.8Hz, IH), 7.04 (t, J=8.7Hz, 3H), 7.18-7.37 (brm, 6H), 7.48 (s, IH), 7.86 (d, J=8.4Hz, 2H), 7.87-8.03 (m, 2H); MS (positive ion mode): m/z 460 [M+l]; Yield 64%
2-[2-(4-Fluorophenyl)-2-oxo-l-phenylethyl]-4-methyl-3-oxo-pentanoic acid (2,4-dimethylphenyl)-amide
1H NMR(DMSO-d6):8 0.99 (d, J=6.6Hz, 3H), 1.19 (d, J=6.9Hz, 3H), 1.67 (s, 3H), 2.18 (s, 3H), 3.00 (Sep, J=6.9Hz, IH), 4.94 (d, J=l 1.1Hz, IH), 5.36 (d, s=10.8Hz, IH), 6.68 (d, J=8.1Hz, IH), 6.82-6.93 (m, 2H), 7.17-7.45 (m, 7H), 8.08-8.24 (m, 2H), 9.60 (brs, IH) MS (positive ion mode): m/z 446 [M+l]; Yield 66%
2-[2-(4-Fluorophenyl)-2-oxo-l-phenyl-ethyl]-4-methyl-3-oxo-pentanoicacid4-trifluoromethylbenzyl amide
1H NMR(CDC13,300MHz):5 1.10 (d, J=6.6Hz, 3H), 1.16 (d, J=7.2Hz, 3H), 2.88 (sept, J=6.9Hz, 1H0, 4.15 (dd, J=15 & 4.8Hz, IH), 4.40 (dd, J=15.9 & 6.6Hz, IH), 4.46 (d, J=ll.lHz, IH), 5.32 (d, J=10.8Hz, IH), 5.80 (brs, IH), 6.89 (d, J=7.8Hz, 2H), 6.97 (t, J=8.4Hz, H), 7.45 (d, J=7.5Hz, 2H), 7.94-7.98 (m, 2H); MS (positive ion mode): m/z 500 (M++l}
l-(4-Fluorophenyl)-5-methyl-2-pentyl-3-(piperidine-l-carbonyl-hexane-l,4-dione
1HNMRCCDCl3, 300MHz):5 1.05 (d, J=6.9Hz, 3H), 1.19 (d, J=7.1Hz, 4H), 1.45 (brs, 5H), 2.62 (sept, J=6.8Hz, IH), 2.95-3.15 (m, IH), 3.20-3.40 (m, 2H), 3.45-3.60 (m, IH), 4.99 (d, J=10.5Hz, IH), 5.34 (d, J=10.6Hz, IH), 7.03 (t, J=8.5Hz, 2H), 7.24 (brs, 5H), 7.97-8.07 (m, 2H); MS (positive ion mode): m/z 493 (M++1)
2-[l-(4-Cyanophenyl)-2-(4-fluorophenyl)-2-oxo-ethyl]-4-methyl-3-oxo-pentanoicacid phenylamide
MS (positive ion mode): m/z 443 [M+l]
Step 4: Preparation of Pyrrole (Formula X and Xb)
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-l-yl]-ethyl}-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester
1HNMR(CDCl3:δ 1.30 (s, 3H), 1.36 (s, 3H), 1.43 (s, 9H), 1.53 (d, J=6Hz, 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, IH), 4.00-4.22 (m, 2H), 6.85-7.05 (m, 3H), 7.10-7.51 (m, 10H), 7.58 (d, J=9Hz, IH); MS (positive ion mode): m/z 697 [M+l]; Yield: 23%
(6-{2-[3-(4-Acetylphenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-pyrrol-l-yl]-ethyl}-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester
1H NMR(CDC13):5 1.31 (s, 3H), 1.38 (s, 3H), 1.44 (s, 9H), 1.53 (d, J=9Hz, 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=6Hz, 2H), 7.06-7.26 (m, 10H), 7.81 (d, J=9Hz, zH); MS (positive ion mode): m/z 698 [M+l]; Yield: 14%
(6- {2-[3-(2,4-Dimethylphenylcarbamoyl) -5- (4-fluorophenyl) -2-isopropyl-4-phenyl-pyrrol-1 -ylj-ethyl}-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester
1H NMR(CDC13):8 1.30 (s, 3H), 1.36 (s, 3H), 1.43 (s, 9H), 1.52 (d, s=6Hz, 6H), 1.65-1.76 (m, 2H), 2.18-2.32 (m, 4H), 2.33-2.47 (m, IH), 3.48 (Sep, J=6Hz, IH), 3.63-3.90 (m, 2H), 4.0-4.25 m, 2H), 6.72 (s, IH), 6.81 (s, IH), 6.99 (t, S=6Hz, 3H), 7.07-7.25 (m, 7H), 7.88 (d, J=6Hz, IH); MS (positive ion mode): m/z 684 [M+l]; Yield 21%
(6-{2-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(4-trifluoromethylbenzylcarbamoyl)-pyrrol-l-yl]-ethyl}-2,2-dimethyl-[l,3]dioxan-4-yl) acetic acid tert-butyl ester
1H NMR(CDC13, 300MHZ):8 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, IH), 2.38 (dd, J=15.0 & 6.0Hz, IH), 9.36-3.50 (m, IH), 3.6-3.7 (m, IH), 3.71-3.85 (m, IH), 4.1-4.25 (m, 2H), 4.38 (d, J=6.0Hz, 2H), 7.02-7.16 (m, 12H), 7.41 (d, J=9.0Hz, 2H); MS (positive ion): m/z 737.4 [M+l]+
6-{2-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(piperidine-l-carbonyl)-pyrrol-l-yl]-ethyl}-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acidtert-butyl ester
1HNMR(CDC13, 300MHz):5 0.99-1.60 (m, 29H), 2.17-2.52 (m, 2H), 2.80-3.25 m, 3H), 3.35-3.50 (m, IH), 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++l)
(6-{2-[3-(4-cyanophenyl)-5-isopropyl-2-(4-fluorophenyl)-4-(phenylamino) carbonyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[l,3]dioxan-4-yl) acetic acid tert-butyl ester
1H NMR (CDC13):5 1.30 (s, 3H), 1.36 (s, 3H), 1.44 (s, 9H), 1.50 (d, J=6.9Hz, 6H), 1.67 (brs, 3H), 1.55-1.75 (brm, 3H), 2.20-2.40 (m, 2H), 3.38 (sep, J=6.6Hz, IH), 3.63-3.88 (m, 2H), 3.97-4.24 (m, 2H), 6.85 (s, IH), 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 Xlb
(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°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 IN 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).
(b) To an aqueous solution of sodium salt of acid (is prepared by adding 1 equivalent IN 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.
Compounds of Formula Xlb and Xllb 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-acetylphenylamino) carbonyl]-pyrrol-1-ylJ-3,5-dihydroxy-heptanoic acid
lH NMR(DMSO-d6):5 1.23 (brs, 2H), 1.38 (d, J=6Hz, 6H), 1.63 (brs, 2H), 1.90-2.15 (m, 2H), 3.52 (brs, IH), 3.76 (brs, 2H), 3.99 (brs, IH), 6.95-7.45 (m, 10H), 7.60 (d, J=7.5Hz, IH), 7.71 (d, J=7.5Hz, IH), 8.15 (s, IH), 9.98 (s, IH, D20 exchanged); MS (positive ion mode): m/z 601 [Acid+1]; Yield: 21.35; m.pt: 167.5-204°C
Hemi calcium salt of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-acetylphenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
1HNMR(DMSO-d6):5 1.24 (brs, 2H), 1.37 (d, 3=6Hz, 6H), 1.58 (brs, 2H), 1.88-1.99 (m, IH), 2.00-2.12 (m, IH), 3.53 (brs, IH), 3.73 (brs, 2H), 3.96 (brs, IH), 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, IH, D20 exchanged); MS (positive ion mode): m/z 601 [Acid+1]; Yield 23%; m.pt 188.9-216.5°C
Hemi calcium salt of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(2,4-dimethylphenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid
1HNMR(DMS0):8 1.29 (brs, 2H), 1.31-1.76 (m, 11H), 1.87-2.01 (dd, J=15 & 6Hz, 1H),2.02-2.15 (dd, J=15 & 3Hz, IH), 2.19 (s, 3H), 3.59 (brs, IH), 3.76 (brs, 2H), 3.95 (brs, IH), 6.85-6.95 (m, 2H), 7.05-7.33 (m, 10H), 8.78 (s, IH, D20 exchanged); MS (positive ion mode): m/z 587 [Acid+1]; Yield 45%; m.p 172.6-198.9°C
Hemi calcium salt of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-trifluoromethylbenzylamino) carbonyl)]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid
1H NMR(DMSO-d6 300MHz):5 1.15-1.24 (m, 2H), 1.31 (d, J=6Hz, 6H), 1.48-1.56 (m, 2H), 1.84 (dd, J=158, 7.8Hz, IH), 2.01 (dd, J=15 &4.2Hz, IH), 3.15-3.33 (m, IH), 3.42 (brs, IH), 3.50 (brs, IH), 3.68-3.73 (m, 2H), 3.80-4.02 (m, IH), 4.29 d, J=5.4Hz, IH), 6.99 (brs, 2H), 7.05 (brs, 3H), 7.12-7.23 (m, 6H), 7.50 (d, J=8.1Hz, 2H), 8.24 (t, J=5.4Hz, IH); 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-l-carbonyl)-pyrrol-l -yl]-3,5-dihydroxy-heptanoic acid
1HNMR(DMSO-d6, 300MHz, D2O exchanged):5 1.08-1.13 (m, 2H), 1.24 (brs, 7H), 1.27 (d, J=9Hz, 6H), 1.43 (brs, 2H), 2.02 (dd, J=15 & 6Hz, IH), 2.15-2.19 (m, IH), 2.88-2.95 (m, 2H), 3.12-3.24 m, 2H), 3.64-3.69 (m, 3H), 6.95 (d, J=6Hz, 2H), 7.05-7.15 (m, 5H), 7.25 (brs, 2H), 8.08 (s, IH).
Hemi calcium salt of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-(4-cyanophenyl)-4-[(phenylamino) carbonyl)]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
1H NMR (DMSO-d6):8 1.24 (brs, 2H), 1.37 (d, J=6Hz, 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, IH), 7.01 (t, J=6Hz, IH), 7.13-7.35 (m, 8H), 7.45-7.63 (m, 4H), 10.02 (s, IH, D20 exchanged); MS (positive ion mode): m/z 584 [Acid+1]; Yield: 87%; m.pt. 197.7-222.1°C
SCHEME la
Step 1: Preparation of compound of Formula XIV
Compound XIII (prepared following the appropriate steps of Scheme I to produce a compound of Formula X with appropriate substitution) was dissolved in tetrahydrofuran: methanol (1:2) mixture and IN lithium hydroxide (equiv) was added. The reaction mixture was stirred at 0 °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-{[l-[2-(6-tert-butoxycarbonylmethyl-2,2-dimethyl-[l,3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-lH-pyrrol-3-carbonyl]-amino}-benzoic acid
1HNMR(CDCl3):δ 1.03-1.11 (m, IH), 1.26 (s, 3H), 1.30 (s, 3H), 1.43 (s, 9H), 1.53 (d, J=7.2Hz, 3H), 1.65-1.69 (m, 2H), 2.23 (dd, J=15.6 & 6.3Hz, IH), 2.40 (dd, J=15.6 & 6.3Hz, IH), 3.63-3.71 (m, 2H), 3.75-3.8 (m, IH), 4.05-4.20 (m, 2H), 6.96-7.20 (m, 12H), 7.90 (d, J=8.4Hz, 2H); MS (positive ion mode): m/z 698 (M++l); Yield = 51%
Step 2: Preparation of compound of Formula XV
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 °C. A solution of iodine (1 equiv) in tetrahydrofuran was added slowly at 0 °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.
1HNMRCCDCl3, 300MHz):5 1.02=1.06 (m, IH), 1.26 (s, 3H), 1.33 (s, 3H), 1.43 (s, 9H), 1.55 (d, J=6Hz, 6H), 2.21 (dd, J=15 & 6Hz, IH), 2.38 (dd, J=15 & 6Hz, IH), 2.40-4.17 (m, 5H), 4.58 (s, 2H), 6.87-7.19 (m, 13H); MS (+ ve ion mode): m/z 685 (MM); Yield = 87%
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 °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. Yield: 2.16 g (73.72%)
Step 3: Preparation of hemi calcium salt of Formula XVI
(a) To a solution of XV in methanol and tetrahydrofuran (1:1) was added IN 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°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 IN hydrochloric acid. The organic phase was extracted into ethyl acetate, and concentrated. The residue was then purified on column (silica gel 100-200 mesh).
(b) To an aqueous solution of the sodium salt of the acid (prepared by adding 1 equivalent IN 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.
The following compound was prepared similarly.
Hemi calcium salt of(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid
1H NMR(DMSO-d6):5 1.22-1.62 (M, 11H), 1.98 (dd, J=15 & 8.1Hz, 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°C
Scheme Ha
Step I: Preparation of compound of Formula XVa
A compound of Formula XIIIa (1 equiv.) and a mixture of IN 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 ~lpH with IN 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)amino) carbonylj-pyrrol-1-yl]'-3,5-dihydroxy-heptanoic acid
Yield: 5g (84.6%)
Step II: Preparation of disodium salt of compound of Formula XVa
A compound of XVa (1 equiv.), tetrahydrofuran:methanol (1:1) and sodium hydroxide (IN, 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 4.5g (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)amino) carbonyl]-pyrrol-l -ylJ-3,5-dihydroxy-heptanoic acid
1HNMR(DMSO,300MHz):5 1.135-1.179 (m, 2H), 1.365 (d, J=6.3Hz, 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=6Hz, 2H), 7.70 (d, J=9Hz, 2H), 9.827 (s, 1H); MS (positive ion mode): m/z 603.13 (Acid+ +1); Yield : 4.5g (84.9%).
SCHEME II
Preparation of Compound of Formula XIX
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 IN 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
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°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
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
To a solution of a compound of Formula XXI (0.8g) 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
To a solution of a compound of Formula XXII (1 equiv) in benzene at 0°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°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°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-A cetylphenylcarbamoyl) -5- (4-fluorophenyl)-2-isopropyl-4-phenyl-pyrrol-1 -ylj-ethyl}-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester
1HNMR(CDCl3,300MHz):5 1.0-1.15 (m, 1H), 1.30 (s, 1H), 1.33 (s, 3H), 1.44 (s, 9H), 1.48 (d, J=6.0Hz, 6H), 2.23 (dd, J=15.0 & 6.0Hz, 1H), 2.35-2.5 (m, 4H), 3.35 (sept. J=6.0Hz, 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=9.0Hz, 1H), 7.69 (d, J=6.0Hz, 1H), 8.82 (d, J=9.0Hz, 1H), 11.02 (brs, 1H); MS (positive ion): m/z 697.500 [M+l]+; Yield= 59%
Preparation of compound of Formula X : path b
To a solution of a compound of Formula XXII (1.2 mmole) in dimethylformamide (2.5 ml) was added diisopropylethylamine (2.4 mmole) and 0-benzotriazol-l-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°C to 60°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-pyrrol-1 -yl]-ethyl} -2,2-dimethyl-[l, 3]dioxan-4-yl)-acetic acid tert-butyl ester
1HNMR(CDC13, 300 MHz):5 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, J=6.9Hz, 6H), 1.43-1.48 (m, 2H), 1.63 (brs, 3H), 2.25 (dd, J=15 & 6Hz, 1H), 2.35 (dd, J=15 & 6.9Hz, 1H), 3.35 (sept, J=6.9Hz, 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++1)
Preparation of hemi calcium salt of Formula XI
(a) To a solution of a compound of Formula X in methanol and tetrahydrofuran (1:1) was added IN hydrochloric acid (3 equiv) and the mixture stirred at ambient temperature. After the complete hydrolysis of ketal, the reaction mixture was cooled to 0°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 IN 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).
(b) To an aqueous solution of the sodium salt of the acid (prepared by adding 1 equivalent IN 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.
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
1H NMR(DMSO-d6, D20 exchanged, 300MHz):5 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, 9H); 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-acetylphenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid
1HNMR(DMSO-d6,300MHz):6 1.10-1.25 (m, 2H), 1.39 (d, J=6.0Hz, 6H), 1.5-1.7 (m, 2H), 1.77 (dd, J=150 & 6.0Hz, 1H), 1.97 (dd, J=15.0 & 3.0Hz, 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=9.0Hz, 1H), 7.87 (d, J=6.0Hz, 1H), 8.58 (d, 9.0Hz, 1H), 10.98 (s, 1H); MS (positive ion): m/z 601.300 [Acid+1 ]+; Yield= 28%; m. pt: 202.6-208.7°C.
Scheme Ilia
Preparation of Compound of Formula XIX
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 IN 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).
1H NMR(CDC13, 300MHz):5 1.02 (d, J=6.9Hz, 6H), 2.65 (sept, J=7.2Hz, IH), 5.26 (s, 2H), 7.25 (s, 2H), 7.25 (brs, 10H), 7.81 (s, IH).). isomer 2 : 1H NMR(CDC13, 300MHz): 8 1.02 (d, J = 6.9 Hz, 6H), 2.65 (sept, J = 6.9 Hz, IH), 5.27 (s, 2H), 7.36 (brs, 10H), 7.82 (s, 1H).MS (+ ve ion mode): m/z 309 (M++l); Yield: 70%
Preparation of compound of Formula XX
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°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.
1H NMR(CDC13, 300MHZ): (1:1 mixture of diastereomers)8 0.48 (d, J=6.9Hz, 3H), 0.91 (d, J=6.6Hz, 3H), 1.07 (d, J=6.6Hz, 3H), 1.21 (d,J=6.9Hz, 3H), 2.30 (sept, J=6.6Hz, IH), 2.82 (sept, 6.6Hz, IH), 4.76 (d, J=14Hz, IH), 4.77 (d, J=12.3Hz, IH), 5.33 (d, J=l 1.1Hz, IH), 5.35 (d, J=l 1.1Hz, IH), 7.02 (t, J=8.4Hz, 6H), 7.22-7.29 (m, 8H), 7.75-7.99 (m, 4H); MS (+ ve ion mode): m/z 433 (MM). Yield: 72%
Preparation of compound of Formula XXI
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.
1HNMR(CDCI3, 300MHz):6 0.99-1.08 (m, 2H), 1.25 (s, 3H), 1.34 (s), 1.43 (s, 9H), 1.96 (d, J=6Hz, 6H), 1.58-1.63 (m, 2H), 2.21 (dd, J=158.6Hz, IH), 2.37 (dd, J=15 & 9Hz, IH), 3.51 (sept, J=6Hz), 3.65 (brs, IH), 3.75-3.85 (m, IH), 4.00-4.25 (m, 2H), 5.03 (s, 2H), 6.83-7.25 (m, 14H). MS (+ ve ion mode): m/z 670 (M++l). yield 74%
Preparation of compound of Formula XXII
To a solution of a compound of Formula XXI (0.8g) 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.
1HNMRCCDCh, 300MHz):8 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=7.1Hz), 1.59-1.65 (m, 2H), 2.22 (dd, J=15.2 & 6.1Hz, 1H), 2.35 (dd, J=15.2 & 6.1Hz, 1H), 3.61-3.66 (m, 2H), 3.67-3.86 (m, 1H), 4.00-4.15 (m, 2H), 6.95 (t, J=9Hz, 2H), 7.06-7.15 (m, 7H) MS (+ ve ion mode): m/z 586 (M+1) Yield 76%
Preparation of compound of Formula Xa: path a
To a solution of a compound of Formula XXII (1 equiv) in benzene at 0°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°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°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
To a solution of a compound of Formula XXII (1.2 mmole) in dimethylformamide (2.5 ml) is added diisopropylethylamine (2.4 mmole) and 0-benzotriazol-l-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°C to 60°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
(a) To a solution of a compound of Formula Xa in methanol and tetrahydrofuran (1:1) is added IN 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°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 IN 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).
(b) To an aqueous solution of the sodium salt of the acid (is prepared by adding 1 equivalent IN sodium hydroxide solution) is added dropwise an aqueous solution (IM) 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 lb or Ilia or both.
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-acetoxymethylphenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 2a) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-
phenylthiocarbamoyloxymethylphenyl)amino)carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 3a) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-
propionyloxymethylphenyl)amino) carbonyl]-pyrrol-1 -yl]-3,5-dihydroxy-heptanoic acid (Compound No. 4a) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-octylcarbamoyloxymethyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 5a) and its hemicalcium salt,
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-phenylacetoxymethyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 6a) and its hemicalcium salt,
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-phenylcarbamoyloxymethyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 7a) and its hemicalcium salt,
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-benzoyloxymethyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 8a) and its hemicalcium salt,
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-isonicotinoyloxymethyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 9a) and its hemicalcium salt,
(3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [4-pyridin-4-ylcarbamoyloxymethyl phenyl) amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 10a) and its hemicalcium salt,
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-phenylcarbamoyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 11a) and its hemicalcium salt,
(3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-cyclohexylcarbamoyl-phenyl) amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 12a) and its hemicalcium salt,
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-methylcarbamoyl)-phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 13a) and its hemicalcium salt,
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-benzylcarbamoyl)-phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 14a) and its hemicalcium salt,
(3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(morpholine-4-carbonyl)-phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 15) and its hemicalcium salt,
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(piperidine-l -carbonyl)-phenyl)amino) carbonyl]-pyirol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 16) and its hemicalcium salt,
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-benzylamino phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 17) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(l -hydroxyethyl)phenylamino) carbonyl]-pyrrol-1 -yl]-3,5-dihydroxy-heptanoic acid (Compound No. 18) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(2-hydroxyethyl) phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 19) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-hydroxypropyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 20) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-methoxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 21) and its hemicalcium salt,
(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,
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-isopropoxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 23) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-propoxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 24) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-
methoxymethoxymethylphenylamino) carbonyl]-pyrrol-1 -yl]-3,5-dihydroxy-heptanoic acid (Compound No. 25) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-cyclohexyloxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 26) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-cyclopentyloxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 27) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-benzyloxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 28) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-chlorobenzyloxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 29) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-methoxybenzyloxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 30) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-phenoxymethylphenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 31) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-chlorophenoxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 32) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-acetylaminophenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 33) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-benzoylamino phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 34) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-benzenesulfonylamino phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 36) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(3-phenyl-ureido)-
phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 37) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-methyl-ureido)-phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 38) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-benzyll-ureido)-phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 39) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(3-benzyl-thioureido)-phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 40) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(3-phenyl-thioureido)-phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 41) and its hemicalcium salt,
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(3-methyl-thioureido)-phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 42) and its hemicalcium salt.
Pharmacological activity
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.
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).
HMG-CoA reductase is a rate-limiting enzyme in the cholesterol biosynthesis, catalyzing the following reaction.
[14C] HMG-CoA + 2NADPH +2H+ —► [14C] mevanolate + CoA +2NADP+ microsomes, utilizing 2.5 uM [14C] HMG-CoA as a substrate. The reaction is carried out in presence of 100 mM KH2P04, 20 raM G-6-P, 2.5 mM NADP, 10 mM EDTA, 5 mM DTT and 1.4 G-6-P dehydrogenase, at 37 °C for 15 minutes and quantitating [14C] mevalonate as an end product. For IC50 determination, the compounds dissolved in 1% dimethylsulfoxide are preincubated with liver microsomes at 37°C for 30 minutes.
The IC50 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)].
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.










WE CLAIM:
1. A compound having the structure of Formula I,
(Formula Removed)
its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, tautomers,
racemates, pure enantiomers, prodrugs, metabolites, polymorphs, diastereoisomers or N-
oxides, wherein
(Formula Removed)
R1 is C1-C6, C3-C6, or optionally substituted phenyl (wherein up to three substituents are independently selected from halogens, C1-C6 alkyl, cyano, or C1-C3 perfluoroalkyl);
R2 is 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 C1-C6 alkyl, C3-C6 cycloalkyl, acetyl, or sulfonamide);
R3 is optionally substituted C1-C6 alkyl or C3-C6 cycloalkyl (wherein substituents are independently selected from halogens, hydroxyl, C1-C3 alkoxy and protected hydroxyl);
R3 is also -NR8R9, wherein R8 and R9 are optionally substituted C1-C6 alkyl (wherein the optional substituent(s) is/are selected from halogens, hydroxy, C1-C3 alkoxy and protected hydroxyl);
R4 is
(Formula Removed)
wherein R5 and R6 are independently hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl, optionally substituted aryl or aralkyl, wherein the substituents are selected from halogens, cyano, optionally substituted C1-C6 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 SO2R7, COR7, or CONHR7, wherein R7 is C1-C6 alkyl or aryl), or acetyl, trifluoromethyl, or C1-C6 alkoxycarbonyl, or R5 and R6 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 R4 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, C1-C3 alkoxy, cyano, C1-C3 perfluoroalkyl, C1-C6 alkyl or C3-C6 cycloalkyl, aryl or optionally substituted aralkyl wherein the substituents are independently selected from halogens, hydroxy, protected hydroxyl, C1-C3 alkoxy, cyano, or C1-C3 perfluoroalkyl,
and the pharmaceutically acceptable salts, tautomers, racemates, pure enantiomers or diastereoisomers, and solvates of the compounds of Formula I,
with the provisio that R2 is phenyl only when (1) R5 or R6 is C3-C6 cycloalkyl or phenyl substituted with acetyl, alkyl, cycloalkyl, hydroxyalkyl, alkylsulfonamido, acetamido or (2) when R5 and R6 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 R5 or R6 is aralkyl optionally substituted with halogens, cyano, C1-C6 alkyl, C1-C6 halogenated alkyl or (4) when R4 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, C1-C3 alkoxy, cyano, perfluoroalkyl of one to three carbon atoms, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, or optionally substituted aralkyl (wherein the aralkyl substituents are independently selected from halogens hydroxy, protected hydroxyl, C1-C3 alkoxy, cyano, or C1-C3 perfluoroalkyl)).
2. The compound according to claim 1, wherein:
R1 is phenyl substituted with one or more halogens;
R2 is phenyl or 4-cyanophenyl;
R3 is alkyl of from one to six carbon atoms or cycloalkyl of from three to six carbon atoms;
R4 is 1,2,4-oxadiazinyl phenyl or 1,2,4-triazolylphenyl;
R5 is hydrogen;
R6 is phenyl, phenyl substituted with 4-(methylsulfonamido), 4-(acetamido), acetyl, one or more alkyl of from one to six carbon atoms or hydroxylated alkyl of from one or six carbon atoms; R6 is cycloalkyl of from three to six carbon atoms or benzyl substituted with halogenated alkyl of from one to six carbon atoms;
further, R5 and R6 together form 5-7 membered ring with or without one or more heteroatoms wherein heteroatoms are selected from nitrogen, oxygen or sulphur.
3. A compound as claimed in claim 1, which is:
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(2-acetylphenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 1),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(3-acetylphenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 2),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-acetylphenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 3),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(2,4-dimethylphenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 4),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(cyclohexylamino)carbonyl)]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 5),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-trifluoromethylbenzylamino) carbonyl)]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 6),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-(morpholine-4-carbonyl)-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 7),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(piperidine-l-carbonyl)-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 8),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbonyl]-pyrrol-1 -yl]-3,5-dihydroxy-heptanoic acid (Compound No. 11),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-
methanesulfonylaminophenylamino)carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoicacid (Compound No. 12),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-acetylaminophenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 13),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-(4-cyanophenyl)-4-[(phenylamino) carbonyl)]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 14),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-carboxyphenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. la),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-acetoxymethylphenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 2a),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-
phenylthiocarbamoyloxymethylphenyl)amino)carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 3a),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-
propionyloxymethylphenyl)amino) carbonyl]-pyrrol-1 -yl]-3,5-dihydroxy-heptanoic acid (Compound No. 4a),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-octylcarbamoyloxymethyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 5a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-phenylacetoxymethyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 6a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-phenylcarbamoyloxymethyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 7a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-benzoyloxymethyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 8a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-isonicotinoyloxymethyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 9a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- [4-pyridin-4-ylcarbamoyloxymethyl phenyl) amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 10a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-phenylcarbamoyl phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 11a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-cyclohexylcarbamoyl-phenyl) amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 12a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-methylcarbamoyl)-phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 13a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-benzylcarbamoyl)-phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 14a),
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(morpholine-4-carbonyl)-phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 15),
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(piperidine-1 -carbonyl)-phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 16),
(3R, 5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-benzylamino phenyl)amino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 17),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(l-hydroxyethyl)phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 18),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(2-hydroxyethyl)phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 19),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(3-hydroxypropyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 20),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-methoxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 21),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-ethoxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 22),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-isopropoxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 23),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-propoxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 24),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-
methoxymethoxymethylphenylamino) carbonyl]-pyrrol-1 -yl]-3,5-dihydroxy-heptanoic acid (Compound No. 25),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-cyclohexyloxymethyl phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 26),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-cyclopentyloxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 27),
(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)
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-chlorobenzyloxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 29),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3 -phenyl-4- [(4-methoxybenzyloxymethyl phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 30),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-phenoxymethylphenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 31),
(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-chlorophenoxymethyl phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 32),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3 -phenyl-4- [(4-acetylaminophenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 33),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-benzoylamino phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 34),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[(4-benzenesulfonylamino phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 36)
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(3-phenyl-ureido)-phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 37),
(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),
(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),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(3-benzyl-thioureido)-phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 40),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(3-phenyl-thioureido)-phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 41),
(3R,5R)-7-[2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-[4-(3-methyl-thioureido)-phenylamino) carbonyl]-pyrrol-l-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 42),
and their lactone forms, pharmaceutically acceptable solvates, pharmaceutically acceptable
salts, tautomers, racemates, pure enantiomers, diastereoisomers, metabolites, prodrugs,
polymorphs, or N-oxides.
4. A medicament comprising pharmaceutically acceptable salt of a compound of claim 1, wherein the salt is selected from lithium, sodium, potassium, calcium, magnesium, zinc, aluminium, amino acid, ammonium, mono-alkyl ammonium, dialkyl ammonium, trialkyl ammonium or N-methyl glucamine.
5. The medicament comprising as claimed in claim 4, wherein the salt is hemicalcium salt.
6. The compound as claimed in any one of claims 1 to 5, for use as a anticholesterolemic agent and antihyperlipidemic agent.
7. The compound according to claim 6, for use as an anticholesterolemic agent and antihyperlipidemic agent, wherein in the disease is selected from arteriosclerosis, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, hypertension, stroke, ischemia, endothellium dysfunctions, 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 restenosis.
8. A process for the preparation of compound of Formula XIb as claimed
in claim 1,
(Formula Removed)
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, tautomers, racemates, polymorphs, pure enantiomers, diastereoisomers, metabolites, prodrugs or N-oxides wherein
R1 is C1-C6 alkyl, C3-C6 cycloalkyl, or optionally substituted phenyl (wherein the substituent(s) is/are selected from halogens, C1-C6 alkyl, cyano and C1-C3 perfluoroalkyl);
R2 is optionally substituted phenyl (wherein the substituent(s) is/are selected from cyano, acetyl and optionally substituted amino;
R3 is optionally substituted C1-C6 alkyl or C3-C6 cycloalkyl (wherein the substituent(s) is/are selected from halogens, hydroxyl, C1-C3 alkoxy, and protected hydroxyl); R3 is also -NR6R7 wherein R6 and R7 are optionally substituted C1-C6 alkyl (wherein the optional

substituent(s) is/are selected from halogens, hydroxyl, C1-C3 alkoxy, and protected hydroxyl);
R4 is acetyl, C1-C2 alkoxycarbonyl, optionally substituted C1-C6 alkyl (wherein the substituent is hydroxy or protected hydroxyl), NHR8 [wherein R8 is selected from alkyl, aralkyl, SO2R9, COR9 or CONHR9, CSNHR9 (wherein R9 is C1-C6 alkyl, aryl or aralkyl)]; R4 is also -COR10 (wherein R10 is selected from hydroxyl and -NR11R12 (wherein R11 and R12 are independently selected from hydrogen, alkyl, aryl, C3-C7 cycloalkyl, heterocyclyl, aralkyl and R11 and R12 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
R5 is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl, optionally substituted aryl or aralkyl [wherein the substituents are selected from halogens, cyano, optionally substituted C1-C6 alkyl (wherein the substituents are independently selected from hydroxyl, protected hydroxyl, and halogen(s)], optionally substituted amino, acetyl, trifluoromethyl and C1-C6 alkoxycarbonyl,
comprising:
reacting a compound of Formula II with a compound of Formula IIIb to give a compound of Formula IVb
(Formula Removed)
treating the compound of Formula IVb with an aldehyde of Formula V to give a compound of Formula VIb;
(Formula Removed)
treating the compound of Formula VIb with an aldehyde of Formula VII to give a
compound of Formula VIIIb;
(Formula Removed)
treating the compound of Formula VIIIb with a compound of Formula IX to give a compound of Formula Xb; and
(Formula Removed)
9. A process for the preparation of a compound of Formula XI as claimed in claim 1,
(Formula Removed)
its lactone forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, prodrugs, metabolites, polymorphs, tautomers, racemates, pure enantiomers, diastereoisomers or N-oxides wherein
R1 is C1-C6, C3-C6, or optionally substituted phenyl (wherein up to three substituents are independently selected from halogens, C1-C6 alkyl, cyano, or C1-C3 perfluoroalkyl);
R2 is 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 C1-C6 alkyl, C3-C6 cycloalkyl, acetyl, or sulfonamide);

R3 is optionally substituted C1-C6 alkyl or C3-C6 cycloalkyl (wherein substituents are independently selected from halogens, hydroxyl, C1-C3 alkoxy and protected hydroxyl);
R3 is also -NR8R9, wherein R8 and R9 are optionally substituted C1-C6 alkyl (wherein the optional substituent(s) is/are selected from halogens, hydroxy, C1-C3 alkoxy and protected hydroxyl);
R4 is
(Formula Removed)
wherein R5 and R6 are independently hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl, optionally substituted aryl or aralkyl, wherein the substituents are selected from halogens, cyano, optionally substituted C1-C6 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 SO2R7, COR7, or CONHR7, wherein R7 is C1-C6 alkyl or aryl), or acetyl, trifluoromethyl, or C1-C6 alkoxycarbonyl, or R5 and R6 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 R4 is 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, C1-C3 alkoxy, cyano, C1-C3 perfluoroalkyl, C1-C6 alkyl or C3-C6 cycloalkyl, aryl or optionally substituted aralkyl wherein the substituents are independently selected from halogens, hydroxy, protected hydroxyl, C1-C3 alkoxy, cyano, or C1-C3 perfluoroalkyl,
and the pharmaceutically acceptable salts, tautomers, racemates, pure enantiomers or diastereoisomers, and solvates of the compounds of Formula I,
with the provisio that R2 is phenyl only when (1) R5 or R6 is C3-C6 cycloalkyl or phenyl substituted with acetyl, alkyl, cycloalkyl, hydroxyalkyl, alkylsulfonamido, acetamido or (2) when R5 and R6 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 R5 or R6 is aralkyl optionally substituted with halogens, cyano, C1-C6 alkyl, C1-C6 halogenated alkyl or (4) when R4 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, C1-C3 alkoxy, cyano, perfluoroalkyl of one to three carbon atoms, C1-C6alkyl, C3-C6 cycloalkyl, aryl, or optionally substituted aralkyl (wherein the aralkyl substituents are independently selected from halogens, hydroxy, protected hydroxyl, C1-C3 alkoxy, cyano, or C1-C3 perfluoroalkyl)),
comprising:
reacting a compound of Formula II with a compound of Formula III to give a compound of Formula IV;
(Formula Removed)
treating the compound of Formula IV with an aldehyde of Formula V to give a compound of Formula VI;
(Formula Removed)
treating the compound of Formula VI with an aldehyde of Formula VII to give a compound of Formula VIII;
(Formula Removed)
treating the compound of Formula VIII with a compound of Formula IX to give a
compoundof Formula X; and
(Formula Removed)
hydrolysing the compound of Formula X to give a compound of Formula XI.
10 A process for the preparation of compound of Formula XVI as claimed in claim 1,
(Formula Removed)
its lactone forms, pharmaceutically acceptable salt, pharmaceutically acceptable solvates, prodrugs, metabolites, polymorphs, tautomers, racemates, pure enantiomers, diastereoisomers or N-oxides wherein
R1 is C1-C6, C3-C6, or optionally substituted phenyl (wherein up to three substituents are independently selected from halogens, C1-C6 alkyl, cyano, or C1-C3 perfluoroalkyl);
R2 is 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 C1-C6 alkyl, C3-C6 cycloalkyl, acetyl, or sulfonamide);
R3 is optionally substituted C1-C6 alkyl or C3-C6 cycloalkyl (wherein substituents are independently selected from halogens, hydroxyl, C1-C3 alkoxy and protected hydroxyl);
R3 is also -NR8R.9, wherein R8 and R9 are optionally substituted C1-C6 alkyl (wherein the optional substituent(s) is/are selected from halogens, hydroxy, C1-C3 alkoxy and protected hydroxyl);
comprising: hydrolysing a compound of Formula XIII to give a compound of Formula XIV;
(Formula Removed)
reducing the compound of Formula XIV to give a compound of Formula XV; and
(Formula Removed)
hydrolysing the compound of Formula XV to give a compound of Formula XVI. 11. A process for the preparation of compound of Formula X as claimed in claim 1,
(Formula Removed)
its lactone forms, pharmaceutically acceptable salt, pharmaceutically acceptable solvates, prodrugs, metabolites, polymorphs, tautomers, racemates, pure enantiomers, diastereoisomers or N-oxides wherein
R1 is C1-C6, C3-C6, or optionally substituted phenyl (wherein up to three substituents are independently selected from halogens, C1-C6 alkyl, cyano, or C1-C3 perfluoroalkyl);
R2 is 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 C1-C6 alkyl, C3-C6 cycloalkyl, acetyl, or
sulfonamide);
R3 is optionally substituted C1-C6 alkyl or C3-C6 cycloalkyl (wherein substituents are independently selected from halogens, hydroxyl, C1-C3 alkoxy and protected hydroxyl);
R3 is also -NR8R9, wherein R8 and R9 are optionally substituted C1-C6 alkyl (wherein the optional substituent(s) is/are selected from halogens, hydroxy, C1-C3 alkoxy and protected hydroxyl);
(Formula Removed)
wherein R5 and R6 are independently hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl, optionally substituted aryl or aralkyl, wherein the substituents are selected from halogens, cyano, optionally substituted C1-C6 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 SO2R7, COR7, or CONHR7, wherein R7 is C1-C6 alkyl or aryl), or acetyl, trifluoromethyl, or C1-C6 alkoxycarbonyl, or R5 and R6 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 R4 is 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, C1-C3 alkoxy, cyano, C1-C3 perfluoroalkyl, C1-C6 alkyl or C3-C6 cycloalkyl, aryl or optionally substituted aralkyl wherein the substituents are independently selected from halogens, hydroxy, protected hydroxyl, C1-C3 alkoxy, cyano, or C1-C3 perfluoroalkyl,
and the pharmaceutically acceptable salts, tautomers, racemates, pure enantiomers or diastereoisomers, and solvates of the compounds of Formula I,
with the provisio that R2 is phenyl only when (1) R5 or R6 is C3-C6 cycloalkyl or phenyl substituted with acetyl, alkyl, cycloalkyl, hydroxyalkyl, alkylsulfonamido, acetamido or (2) when R5 and R6 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 R5 or R6 is aralkyl optionally substituted with halogens, cyano, C1-C6 alkyl, C1-C6 halogenated alkyl or (4) when R4 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, C1-C3 alkoxy, cyano, perfluoroalkyl of one to three carbon atoms, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, or optionally substituted aralkyl (wherein the aralkyl substituents are independently selected from halogens, hydroxy, protected hydroxyl, C1-C3 alkoxy, cyano, or C1-C3 perfluoroalkyl)),
comprising:
reacting a compound of Formula XVIII with a compound of Formula V to give a compound of Formula XIX;
(Formula Removed)
reacting the compound of Formula XIX with a compound of Formula VII to give a
compound of Formula XX;
(Formula Removed)
treating the compound of Formula XX with a compound of Formula IX to yield a
compound of Formula XXI;
(Formula Removed)
debenzylating the compound of Formula XXI to give a compound of Formula XXII;
(Formula Removed)
converting the compound of Formula XXII to the corresponding acid chloride; reacting the acid chloride form of the compound of Formula XXII with an amine of Formula III to give a compound of Formula X; and
(Formula Removed)
hydrolyzing the compound of Formula X to give a compound of Formula XI. 12. A process for the preparation of compound of Formula XIIb as claimed in claim 1,
(Formula Removed)
their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, tautomers, racemates, polymorphs, pure enantiomers, diastereoisomers, metabolites, prodrugs or N-oxides wherein R1, R2, R3, R4 and R5 are the same as defined in claim 13,
comprising:
treating the compound of Formula XIb with sodium hydroxide followed by calcium acetate
(Formula Removed)
to give compound of Formula XIIb.
13. A process for the preparation of compound of Formula XVIa as claimed in claim 1,
(Formula Removed)
its lactone forms, its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, tautomers, racemates, polymorphs, pure enantiomers, diastereoisomers, metabolites, prodrugs or N-oxides wherein,
R1 is C1-C6 alkyl, C3-C6 cycloalkyl, or optionally substituted phenyl (wherein up to three substituents are independently selected from halogens, C1-C6 alkyl, cyano and C1-C3 perfluoroalkyl);
R2 is 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 C1-C6 alkyl, C3-C6 cycloalkyl, acetyl, or sulfonamide); and
R3 is optionally substituted C1-C6 alkyl or C3-C6 cycloalkyl (wherein the substituents are selected from halogens, hydroxyl, C1-C3 alkoxy, and protected hydroxyl); or
R3 is -NR6R7 wherein R6 and R7 are optionally substituted C1-C6 alkyl (wherein the optional substituent(s) is/are selected from halogens, hydroxyl, C1-C3 alkoxy, and protected hydroxyl);
R4 is -COOCH3; and R5 is H
comprising:
treating the compound of Formula XVa with sodium hydroxide
(Formula Removed)
to give a compound of Formula XVIa. 14. A process for the preparation of a compound of Formula XII as claimed in claim 1,
(Formula Removed)
its lactone forms, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, prodrugs, metabolites, polymorphs, tautomers, racemates, pure enantiomers, diastereoisomers or N-oxides wherein R1, R2, R3, R4, R5 and R6 are the same as defined in claim 24,
comprising:
treating the compound of Formula XI (prepared as per claim 24) with sodium hydroxide followed by calcium acetate
(Formula Removed)
to give a compound of Formula XII.
15. A process for the preparation of compound of Formula XVII as claimed in claim 1
(Formula Removed)
its lactone forms, pharmaceutically acceptable salt, pharmaceutically acceptable solvates, tautomers, racemates, pure enantiomers, diastereoisomers or N-oxides wherein R1, R2 and R3 are the same as defined in claim 25,
comprising:
treating the compound of Formula XVI with sodium hydroxide followed by calcium acetate
(Formula Removed)
to give a compound of Formula XVII.
16. A process for the preparation of compound of Formula XII as claimed in claim 1
(Formula Removed)
its lactone forms, pharmaceutically acceptable salt, pharmaceutically acceptable solvates, prodrugs, metabolites, polymorphs, tautomers, racemates, pure enantiomers, diastereoisomers or N-oxides wherein R1, R2, R3 R4, R5 and R6 are the same as defined in claim 26,
comprising:
treating the compound of Formula XI (prepared as per claim 26) with sodium hydroxide followed by calcium acetate
(Formula Removed)
to give a compound of Formula XII.

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Patent Number 269085
Indian Patent Application Number 6150/DELNP/2005
PG Journal Number 40/2015
Publication Date 02-Oct-2015
Grant Date 30-Sep-2015
Date of Filing 30-Dec-2005
Name of Patentee RANBAXY LABORATORIES LIMITED
Applicant Address 12TH FLOOR, DEVIKA TOWER,6, NEHRU PLACE, NEW DELHI- 110019, INDIA
Inventors:
# Inventor's Name Inventor's Address
1 MOHANNAD SALMAN PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA GURGAON-122001, HARYANA, INDIA
2 JITENDRA SATTIGERI PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA GURGAON-122001, HARYANA, INDIA
3 YATENDRA KUMAR PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA GURGAON-122001, HARYANA, INDIA
4 RAM CHANDER ARYAN PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA GURGAON-122001, HARYANA, INDIA
5 VIKRAM KRISHNA RAMANATHAN PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA GURGAON-122001, HARYANA, INDIA
6 ANITA CHUGH PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA GURGAON-122001, HARYANA, INDIA
PCT International Classification Number C07D 207/34
PCT International Application Number PCT/IB2004/001761
PCT International Filing date 2004-05-28
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 PCT/IB2004/001761 2004-05-28 PCT