DAS GOUTAM (IN)
ATIGNAL SHANKARA RAO ARVIND (IN)
MAZUMDAR-SHAW KIRAN (IN)
GANESH SAMBASIVAM (IN)
DAS GOUTAM (IN)
ATIGNAL SHANKARA RAO ARVIND (IN)
MAZUMDAR-SHAW KIRAN (IN)
| US5273995A | 1993-12-28 |
| 1. | [R (R*, R*)]2 (4fluorophenyl)beta, deltadihydroxy5 (l methylethyl)3phenyl4[(phenylamino)carbonyl]1 H pyrrole1heptanoic acid iron salt. |
| 2. | A process for the preparation of a compound of claim 1 comprising of reacting an ironcompound with a salt of [R (R*, R*)]2 (4fluorophenyl)beta, deltadihydroxy5 ( (1<BR> methylethyl)3phenyl4[(phenylamino) carbonyl]lH pyrrole1heptanoic acid. |
| 3. | A process for the preparation of a compound of claim 1 comprising of reacting an iron compound with [R (R*, R*) ]2<BR> (4fluorophenyl)beta, deltadihydroxy5((1methylethyl)3<BR> phenyl4[(phenylamino) carbonyl]lHpyrrole1heptanoic acid free acid, the lactone, a salt or a derivative thereof. |
| 4. | The process of claim 23, wherein the iron compound is selected from a group comprising ferric nitrate, ferrous nitrate, ferric sulfate, ferrous sulfate, ferric ammonium sulfate or ferrous ammonium sulfate, ferrous chloride or any suitable iron source, or hydrates thereof. |
| 5. | A pharmaceutical composition for treating hypercholesterolemia comprising a hypocholesterolemic effective amount of a compound of claim 1 and a pharmaceutical acceptable carrier. |
| 6. | A method of inhibiting cholesterol synthesis in humans suffering from hypercholesterolemia comprising administering a compound of claim 1 in unit dosage form. |
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. <BR> <BR> <P>Trans- (+-)- 5- (4-fluorophenyl)- 2- (1-methylethyl)- N, 4-<BR> diphenyl-1- [2-tetrahydro- 4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl] - IH-pyrroie-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- (1-methylethyl-3-phenyl- 4 ((phenylamino) carbonyl)-1 H-pyrrolyl-1-heptanoic acid, its lactone
form and salts thereof. The salts specifically claimed here are monosodium, monopotassium, hemicalcium, N-methyl glucamine, 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-dimethylpropylamine, 3-(2- aminoethylamino)-propylamine, n-butylamine, secondary butylamine, tertiary butylamine, dibutylamine, tertiary amylamine, <BR> <BR> cyclopentylamine, cyclohexylamine, cycloheptylamine,<BR> dicyclohexylamine, N-methylcyclohexylamine, N, N'- diisopropylethylenediamine, N, N'-diethylenediamine, N-methyl-1, 3- propanediamine, N-methylethylenediamine, N, N, N', N'-tetramethyl- 1, 2-diaminoethane, N, N, N', N'-tetramethyl-1, 4-diaminobutane, N, N, N', N'-tetramethyl-1, 6-diaminohexane, 1, 2-dipiperidinethane, dipiperidinemethane, 2-amino-3, 3-dimethylbutane, N, N- dimethylcyclohexylamine, neopentylamine, adamantylamine, N, N- diethylcyclohexylamine, N-isopropylcyclohexylamine, N- methylcyclohexylamine, cyclobutylamine, norborylamine, n- butylamine, secondary butylamine, tertiary butylamine, dibutylamine, 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-((1-methylethyl)-3- phenyl-4-[(phenylamino) carbonyl]-tH-pyrrole-1-heptanoic acid, namely, [R- (R*, R*)]-2- (4-fluorophenyl)-beta, delta-dihydroxy-5- <BR> <BR> ((1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-tH-pyrrole- 1-heptanoic acid iron salt.
SUMMARY OF THE INVENTION Accordingly the present invention provides for a compound <BR> <BR> [R-(R*, R*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-((1-<BR> methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-lH-pyrrole-1- heptanoic acid iron salt.
The present invention also relates to a pharmaceutical composition, useful as a hypocholesterolemic agent, comprising an effective amount of [R- (R*, R*)]-2- (4-fluorophenyl)-beta, delta- dihydroxy-5-((l-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-tH-pyrrole-1-heptanoic acid iron salt and a pharmaceutically acceptable carrier.
Further, the present invention is also a method of treating mammals, including humans, suffering from hypercholesterolemia by administering to such 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. 1H NMR of the compound of formula I.
DETAILED DESCRIPTION OF THE INVENTION The most preferred embodiment of the present invention is <BR> <BR> [R- (R*, R*)]-2- (4-fluorophenyl)-beta, delta-dihydroxy-5- ( (l-<BR> methylethyl)-3-phenyl-4- [ (phenylamino) carbonyl]-lH-pyrrole-l- heptanoic acid iron salt.
The compound according to present invention inhibits biosynthesis of cholesterol.
The other embodiment of the invention is the process for preparation of [R- (R*,, R*)]- 2- (4-fl uorophenyl)-beta,, delta- dihydroxy-5-((1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid iron salt.
The pharmaceutical acceptable salt of the invention is generally derived from a salt of [R- (R*, R*)]-2- (4-fluorophenyl)- beta, delta-dihydroxy-5-((1-methylethyl)-3-phenyl-4- [(phenylamino) carbonyl]-lH-pyrrole-1-heptanoic acid, the free acid, the lactone or a derivative thereof.
The pharmaceutical acceptable salt of the invention can be derived by dissolving a salt of [R-(R*, R8)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-((1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-l H-pyrrole-1-heptanoic acid, in water or aqueous alcohol 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 or a water miscible solvent, optionally containing base; optionally adjusting the pH; treating the solution with an iron compound or a source of iron ion and isolating the compound of present invention.
The pharmaceutical acceptable salt of the invention can be derived by dissolving an ester of [R- (R*, R*)]-2- (4-fluorophenyl)- beta, delta-dihydroxy-5-((1-methylethyl)-3-phenyl-4- [ (phenylamino) carbonyl]-lH-pyrrole-1-heptanoic acid, in aqueous or aqueous alcohol solvent or other suitable solvents, adjusting pH of the mixture; vaporizing the solvents ; optionally treating with a water immiscible solvent ; optionally adjusting the pH; treating the solution with a iron compound and isolating the compound of present invention.
The pharmaceutical acceptable salt of the invention can be derived by dissolving a salt of [R- (R*, R*)]-2- (4-fluorophenyl)-beta, delta-dihydroxy-5-((1-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]-tH-pyrrole-1-heptanoic acid; in aqueous or aqueous alcoholic solvent or other suitable solvents ; optionally adjusting pH of the mixture; treating the solution with a iron compound and isolating the compound of present invention.
The third embodiment of the present invention is the pharmaceutical composition prepared from [R- (R*, R*)]- 2- (4- <BR> <BR> fluorophenyl)-beta, delta-dihydroxy-5- ( (l-methylethyl)-3-phenyl- 4- [ (phenylamino) carbonyl]-lH-pyrrole-1-heptanoic acid iron salt.
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 administered 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. Determinations of optimum dosages for a particular situation is within the skill of the art.
The cornpound present invention is in general equivalent for the activity of the utility as described herein.
The following examples illustrate the invention but does not limit it in any way.
EXAMPLES Example 1 To a suspension of calcium salt of [R- (R*, R*)]-2- (4- fluorophenyl)-beta, delta-dihydroxy-5- ( (l-methylethyl)-3-phenyl-4- [(phenylamino) carbonyl]-1H-pyrrole-l-heptanoic acid (5 g, 0.0043 mol) in water (100 ml), HCI (1.5 N) was added till pH was 3.0-4. 0 and extracted with ethyl acetate (3 x 50 ml). The combined organic layer was concentrated. The residue obtained was dissolved in acetone (5 ml) and a solution of sodium hydroxide (0.4 g, 0.01 mol) in water (100 mi) was added and stirred for 30 minutes. The reaction mixture was washed with methyl ter-butyl ether (25 mi) and warmed to 40-45°C. A solution of ferric nitrate. 9H2O (1. 73 g, 0.0043 mol) in water (10 mi) was added to the reaction mixture under stirring. The resulting mixture was further stirred at 40-45°C
for 1 hour and filtered to give iron salt of [R- (R*, R*)]-2- (4- fluorophenyl)-beta, delta-dihydroxy-5-((1-methylethyl)-3-phenyl-4-<BR> [ (phenylamino) carbonyl]-lH-pyrrole-1-heptanoic acid.
Example 2 A solution of sodium salt of [R- (R*, R*)]-2- (4-fluorophenyl)- beta, delta-dihydroxy-5-((1-methylethyl)-3-phenyl-4- [(phenylamino) carbonyl]-lH-pyrrole-1-heptanoic acid (5 g, 0.0086 mol) in water (100 ml) was washed with methyl tert-butyl ether (25 ml) and warmed to 40-45°C. A solution of ferrous sulfate. 7H20 (2.4 g, 0.0086 mol) in water (10 ml) was added to the reaction mixture under stirring. The resulting mixture was further stirred at 40-45°C for 1 hour and filtered to give iron salt of [R- (R*, R*)]-2- (4- <BR> <BR> fluorophenyl)-beta, delta-dihydroxy-5- ( (l-methylethyl)-3-phenyl-4- [(phenylamino) carbonyl]-1 H-pyrrole-1-heptanoic acid.
Example 3 A solution of sodium salt of [R- (R*, R*)]-2- (4-fluorophenyl)- beta, delta-dihydroxy-5-((1-methylethyl)-3-phenyl-4- [(phenylamino) carbonyl]-lH-pyrrole-1-heptanoic acid (100 g, 0.172 mol) in water (2 L) was washed with methyl ter-butyl ether (500 ml) and warmed to 40-45°C. A solution of ferrous chloride (10.8 g, 0.086 mol) in water (200 ml) was added to the reaction mixture under stirring. The resulting mixture was further stirred at 40-45°C for 2 hours and filtered to give iron salt of [R-(R*, R*)]-2- (4-fluorophenyl)-beta, delta-dihydroxy-5-((1-methylethyl)-3- phenyl-4- [ (phenylamino) carbonyl]-lH-pyrrole-l-heptanoic acid.