WO2005014541A1

WO2005014541A1 - Novel antihypercholesterolemic compound

Info

Publication number: WO2005014541A1
Application number: PCT/IN2003/000270
Authority: WO
Inventors: Sambasivam Ganesh; Goutam Das
Original assignee: Biocon Limited
Priority date: 2003-08-12
Filing date: 2003-08-12
Publication date: 2005-02-17
Also published as: AU2003263581A1

Abstract

A compound, Tris{[R-(R *, R*]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole-1-heptanoic acid} bismuth salt, a process of its preparation, a composition containing the novel compound and a method of treatment comprising the novel compound is disclosed.

Description

TITLE OF THE INVENTION

NOVEL ANTIHYPERCHOLESTEROLEMIC COMPOUND FIELD OF THE INVENTION The instant invention relates to a novel compound Tris{[R-(R*,R*)]~2-(4- fluorophenyl)-beta, delta-dihydroxy-5-((l-methylethyl) -3-phenyl-4- [(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid} bismuth salt.

BACKGROUND OF THE INVENTION The conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate is a rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase. HMG CoA reductase inhibitor compounds of a class called statins inhibit the enzyme from catalyzing this conversion. As such, statins are collectively potent lipid lowering agents. Tr-ms-(+-)-5-(4-fluorophenyl)-2-(l-memylethyl)-N,4-diphenyl-l-[2- tetιahydro-4-hyc-roxy-6-oxo-2H-pyran-2-yl)ethylj-lH-pyrrole-3-carboxamides are among compounds of U.S. Pat. No. 4,681,893 which have usefulness as inhibitors of HMG CoA reductase responsible for cholesterol biosynthesis. The compounds therein generically include 4-hydroxypyran-2-ones and the corresponding ring-opened acids derived therefrom. US 5,273,995 claims (R-(R*R*))-2-(4-fluorophenyl)-beta, delta-dihydroxy-

5-(l-memylemyl-3-phenyl-4((phenyl-urιino)carbonyι)-lH-pyrrolyl-l-heptanoic acid, its lactone form and salts thereof. The salts specifically claimed here are monosodium, monopotassium, hemicalcium, N-methyl glucanoine, hemimagnesium and hemizinc. WO 2000017150 claims a salt of an HMG-CoA reductase inhibitor with an amine. Specifically the amine is selected from the group consisting of (+-)-l ,2- dimemylpropylamine, 3-(2-aminoethylanτj o)-propylamine, n-butylamine, secondary butylamine, tertiary butylamine, ώbutyl-imine, tertiary amylamine, cyclopentylamine, cyclohexylamtne, cyclohcptylamine, clicyclohexyl mine, N- memylcyclohexylanώie, N,N'-dMsopropylemylenecliamine, N,N'- diethylenediamine, N-methyl-l,3-propanediamine, N-merJiylethylenedia-mine, N,N-N',N^,-tetjcamethyl-l ,2-diaminoethane, N,N,N',N'-tete-ιmethyι-l ,4- diaminobutane, N,N,N',Nbtet-tam.e1-hyl-l,6-diaminohexane, 1,2-dipiperidinethane, dipiperidinemethane, 2-ammo-3,3-dimethylbutane, N,N- dimethylcyclohexylamine, neopentylamine, adamantylamine, N,N- diethylcyclohexylamine, N^Jisopropylcydohexyl-unine, N-methylcyclohexylamine, cyclobutykmine, norborylamine, n-butyl--mine, secondary butylamine, tertiary butylamine, dibutylamihe, tertiary amylamine, cyclohexylamine, dicyclohexylamine, N-methylcyclohexylamine and N,N'- diisopropylethylenediamine. Specifically the HMG-CoA reductase inhibitor is selected from the group consisting of mevastatin, pravastatin, lovastatin, simvastatin, fluvastatin and atorvastatin. It is known that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) exists as the 3R-stereoisomer. The 3R form of atorvastatin is the most active form. Atorvastatin calcium, disclosed in U.S. 5,273,995, which is incorporated herein by reference, is a selective, competitive inhibitor of HMG-Co A reductase. The instant invention related to a novel salt of [R-(R*-R*)]-2-(4- fluorophenyl)-beta, delta-dihydroxy-5-((l-methylethyl) -3-phenyl-4- [(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid, namely, Tris{[R-(R*,R*)]- 2-(4-fluorophenyl)-beta, delta-dihydroxy-5-((l -methylethyl) -3-phenyl-4- [(phenyla ino) carbonyl]-lH-pyrrole-l-heptanoic acid} bismuth salt. SUMMARY OF THE INVENTION Accordingly the present invention provides for a compound Tris {[R- (R*-R*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(( -methylethyl) -3-phenyl-4- [(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid} bismuth salt (FORMULA I).

FORMULA I The present invention also relates to a pharmaceutical composition, useful as a hypocholesterolemic agent, comprising a hypocholesterolemic effective l o amount of Tris { [R-(R*,R*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-((l - methylethyl) -3-phenyl-4-[(phenylaιnino) carbonyl]-lH-pyrrole-l~heptanoic acid} bismuth salt and a pharmaceutically acceptable carrier. Further, the present invention is also a method of treating mammals, including humans, suffering from hypercholesterolemia by aclministering to such 15 mammal a dosage form of the pharmaceutical composition described above. DESCRIPTION OF FIGURES FIGURE I. ¹³C NMR of the compound of formula I. FIGURE II. H NMR of the compound of formula I. DETAILED DESCRIPTION OF THE INVENTION 0 The most preferred embodiment of the present invention is Tris { [R- (R*,R*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-((l -methylethyl) -3-phenyl-4- [(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid} bismuth salt (FORMULA I).

FORMULA I The compound according to present invention of the formula I inhibit the biosynthesis of cholesterol. The other embodiment of the invention is the process for preparation of

Tris { [R-(R*,R*)]-2-(4-fluoroρhenyl)-beta, delta-dihydroxy-5-(( -methylethyl) -3- phenyl-4-[ henylamino) carbonyl]-lH-pyrrole-l-heptanoic acid} bismuth salt. The pharmaceutically acceptable salt of the invention is generally derived from the free acid, the lactone, a salt of R-(R*,R*)]-2-(4-fluorophenyl)-beta, delta-dmydroxy-5-((l-methylethyl) -3-phenyl-4-[(phenylamino) carbonyl]-lH- pyrrole-1-heptanoic acid or a derivative thereof. The pharmaceutically acceptable salt of the invention can be derived by dissolving a salt of [R-(TR*.R*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-((l- methylefhyl) -3-phenyl-4-[(phenylanώιo) carbonyl]-lH-pyrrole-l-heptanoic acid; in aqueous or aqueous alcohol solvent or other suitable solvents, extracting the free acid or lactone into water immiscible solvent, isolating the acid or lactone or mixture thereof by vaporizing the solvent; treating the residue with an alcohol, optionally containing base; optionally adjusting the pH; treating the solution with a bismuth compound and isolating the compound of formula I.

FORMULA I The pharmaceutically acceptable salt of the invention can be derived by dissolving an ester of [R-(R*.R*)]-2-(4-fluorophenyϊ)-beta- delta-dihydroxy-5-((l- methylethyl) -3-phenyl-4-[(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid; in aqueous or aqueous alcohol solvent or other suitable solvents, adjusting pH of the mixture; vaporizing of the solvents; optionally treating with a water immiscible solvent; optionally adjusting the pH; treating the solution with a bismuth compound and isolating the compound of formula I.

FORMULA I The pharmaceutically acceptable salt of the invention can be derived by dissolving a salt of [R-(R*,R*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-((l- methylefhyl) -3~phenyl-4-[(phenyl-ιmino) carbonylj-lH-pyrrole-l-heptanoic acid; in aqueous or aqueous alcohol solvent or other suitable solvents; optionally adjusting pH of the mixture; treating the solution with a bismuth compound and isolating the compound of formula I. The third embodiment of the present invention is the pharmaceutical composition prepared from the compound of the formula I.

FORMULA I Likewise, the present invention relates to a method treatment of hypolipidemia using compound of formula I. The compound of the present invention utilized in the pharmaceutical method of this invention are administered to the patient at dosage levels of from 2 to 500 mg per day which for a normal human adult of approximately 75 kg is a dosage of from 0.1 to 8 mg/kg of body weight per day. The dosages may be preferably from 0.4 to 1.5 mg/kg per day. The dosage is preferably adr inistered as a unit dosage form. The unit dosage form for oral or parenteral use may be varied or adjusted from 10 to 500 mg, preferably from 20 to 100 mg according to the particular, application and the potency of the active ingredient. The compositions can, if desired, also contain other active therapeutic agents. Deterrriinations of optimum dosages for a particular situation is within the skill of the art. The compound of the formula I is in general equivalent for the activity of the utility as described herein. The following examples illustrate particular methods for preparing compounds in accordance with this invention. These examples are thus not to be read as limiting the scope of the invention. EXAMPLES Example 1: To a suspension of atorvastatin calcium (10 g, 0.0086 mol) in water (200 mL), aqueous HC1 (1.5 N) was added till pH of the mixture was 3.5-4.0 and the mixture was extracted with ethyl acetate~(2 x 250. mL). The combined extract was washed with brine and water and concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and a solution of sodium hydroxide (0.69 g, 0.017 mol) in water (200 mL) was added under stirring. The reaction mixture was extracted with methyl tert-butyl ether (75 mL) and pH of aqueous layer was adjusted to 7.5-8.0 by adding aqueous HC1 (1.0 N). After heating the aqueous layer to 45-50° C, a solution of bismuth nitrate pentahydrate (2.8 g, 0.0058 mol) in water (250 mL) was added under stirring. The reaction mixture was further stirred at 55-60° C for 1 hour and cooled to room temperature over a period of 4 hours. The precipitated product was filtered and dried. Yield: 8.0 g. Example 2: To a solution of tert- Butyl (6- {2-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl- 4-phenylcarbanιoyl-ρyrrol-l-yl]ethyl}-2,2-dinιethyl-[l,3]dioxan-4-yl)acetate (10 g, 0.015 mol) in methanol (180 ml,), aqueous HC1 (21 mL, IN) was added and stirred for 5 hours. Aqueous sodium hydroxide solution (15 mL, 10%) was added to the reation mixture and further stirred for 6 hours. The reaction mixture was evaporated to a residual volume of 30 mL and water (100 mL) followed by methyl tert-butyl ether (10 mL) were added. After separating the layers the aqueous layer was heated to 45-50° C and a solution of bismuth nitrate pentahydrate (3.0 g, 0.006 mol) in water (250 mL) was added under stirring. The reaction mixture was further stirred at 55-60° C for 1 hour and cooled to room temperature over a period of 4 hours. The precipitated product was filtered and dried. Yield: 5.0 g. Example 3: A solution of atorvastatin sodium (10 g, 0.017 mol) in water (200 mL) was heated 45-50° C and a solution of bismuth nitrate pentahydrate (4.0 g, 0.008 mol) in water (300 ml--) was added under stirring. The reaction mixture was further stirred at 55-60° C for 1 hour and cooled to room temperature over a period of 4 hours. The precipitated product was filtered and dried. Yield: 7.0 g. Example 4: To a suspension of atorvastatin ammonium (10 g, 0.017 mol) in water (200 mL), aqueous HCl (1.5 N) was added till pH of the mixture was 3.5-4.0 and the mixture was extracted with ethyl acetate (2 x 250 mL). The combined extract was washed with brine and water and concentrated under reduced pressure. The residue was dissolved in methanol (20 mL) and a solution of sodium hydroxide (0.9 g, 0.023 mol) in water (200 mL) was added under stirring. The reaction mixture was extracted with methyl tert-butyl ether (75 mL) and pH of aqueous layer was adjusted to 7.5-8.0 by adding aqueous HCl (1.0 N). After heating the aqueous layer to 45-50° C, a solution of bismuth nitrate pentahydrate (4.0 g, 0.008 mol) in water (250 mL) was added under stirring. The reaction mixture was further stirred at 55-60° C for 1 hour and cooled to room temperature over a period of 4 hours. The precipitated product was filtered and dried. Yield: 6.5 g.

Claims

We claim:

1. Tris{[R-(R ^!!',R^ϊ!') 2-(4-fluoroρhenyl)-beta, delta-dihydroxy-5-(l-methylethyl)- 3-phen) -4-[(phenyιanτώo)-carbonyιH acid} bismuth salt (formula I).

FORMULA I

2. A process for the preparation of a compound of claim 1 comprising of reacting bismuth salt!with atorvastatin.

3. A process for the; preparation of a compound of claim 1 comprising of reacting bismuth salt with atorvastatin free acid, the lactone, a salt or a derivative thereof.

4. The process of claim 2-3, wherein the bismuth salt is bismuth nitrate pentahydraye.

5. A pharmaceutical composition for treating hypercholesterolemia comprising a hypocholesterolemic effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

6. A method of irihibiting cholesterol synthesis in a human suffering from hypercholesterolemia comprising adnririistering a compound of claim 1 in unit dosage form.