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US File History 5273995 ERlAL NUMBER 07/660,976 02 THIS APPLN IS A CON OF 07/384,187 07/21/39 ABN **f FOREIGN/ ANTED 03/13/91 3/91 FILED SEPARATELY 07/384/187 07/21/89 548 **FOR€ FOREIGN/PCT APPLICATIONS********* VERIFIED --- FOREIGN FILING LICENSE GRANTED 08/10/89 Foreign priority claimed 35 USC 119 conditionsmet yes Xno AS JOAN THIERSTEIN a PATENT DEPARTMENT a WARNER-LAMBERT COMPANY 2 PLYMOUTH ROAD ANN ARBOR, MI 48105 LACTONE FORM AND SALTS THEREOF US. DEPT. of C0MM.-Pat. & TM Offlca - PTO-436L (rev. 10-78) PARTS Of APPLICATION FILED SEPARATELY NOTICE OF ALLOWANCE MAILED PREPARED FOR ISSUE CLAIMS ALLOWED Total Claims Print Claim Assistant Examiner Docket Clerk I ISSUE FEE DRAWING Sheets Drwg. Figs. Drwg. Print Fig. Primary Examiner ISSUE CLASSIFICATION ISSUE .- Class Subclass BATCH NUMBER Label Area WARNING: The information disclosed herein may be restricted. Unauthorized di prohibited by the United States Code Title 35, Sections 122,181 and 388. Possession outside the U.S. Patent mark Office Is restricted to aut and contractors only. Form PTO-436 (fev. 9/85 Entered or Counted CONTENTS 11- .I 3 -90 7. 9. 10. 11. 12" 13. 15. 16. 17. 18. 19. 20. 23. 25. 27. I 29. 31 SEARCHED Class Sub. Date Exmr. SEARCH NOTES Date Exrnr. 9 INTERFERENCE SEARCHED Date Exmr. INDEX OF CLAIMS i I I ! I ."I -- I SEARCHED Date Exmr. SEARCH NOTES I ... Date Exmr. 3-16 INTERFERENCE SEARCHED -- Class Sub. Date Exmr. Staple Issue Slip Here INDEX OF CLAIMS SYMBOLS Rejected Allowed (Through numeral) Canceled + Restricted N Non-elected I interference A Appeal Objected US005273995A United States Patent [19] [11] Patent Number: 5,273,995 . Roth [45] Date of Patent: Dec. 28, 1993 [54] [R-(R*R*)]-2-(4-FLOUROPHENYL)-B,-DIHY- [56] References Cited DROXY-5-(1-METHYLETHYL-3-PHENYl-4- U.S. PATENT DOCUMENTS (PHENYLAMINO) CARBONYL]- IH-PYRROLE-1-HEPTANOIC ACID, ITS 4,681,893 7/1987 Roth .................................... 514/223 LACTONE FORM AND SALTS THEREOF OTHER PUBLICATIONS [75] Inventor: Bruce D. Roth, Ann Arbor, Mich. J. Med. Chem. 1985,28,347-358-G. E. Stokker, et al. “3-Hydroxy-3-Methylglutaryl-Coenzyme a Reduc- tase ... ”. [73] Assignee: Warner-Lambert Company, Morris Tetrahedron Letters, vol. 28, No. 13, pp. 1385-1388, Plains, N.J. 1987 “Synthesis of an HMG-COA Reductase Inhibitor, [21] Appl. No.: 660,976 Primary Eraminer-Mary C. Lee Assistant Examiner-Jacqueline Haley [22] Filed: Feb. 26, 1991 Attorney, Agent, or Finn-Ronald A, Daignault [57] ABSTRACT Related Application Data US. [R-(R*,R*)]-2-(4-fluorophenyl)-B,dihydroxy-5-((1- [63] Continuation of Ser. No. 384,187, Jul. 21, 1989, aban- methylethyl)-3-phenyl-4-[p@hcnylamino)carbonyl]- 1H- doned. pyrrole-1-heptanoic acid or (2R-trans)-5-(4-fluoro- phenyl)-2-(l-mcthylcthyl-N,4-diphcnyl-1-[2-(tctrahy- [51] Int. Cl.5 ..................... A61K 31/40; C07D 405/06 dro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]- 1 H-pyrrole- [52] U.S. CI. .................................... 514/422; 514/423; 3-carboxamide; and pharmaceutically acceptable salts 548/517; 548/537 thereof. [58] Field of Search ................ 514/422, 423; 548/517, 548/537 12 Claims, NO Drawings 5,273,995 1 2 [R*R*R*)]-2-(4-FLUOROPHENYL)-ß,§-DIHY- Ib DORXY-5-(1-METHYLETHYL-3-PHENYL-4- (PHENYLAMINO) CARBONYL]- 5 1H-PYRROLE-1-HEPTANOIC ACID, ITS LACTONE FORM AND SALTS THEREOF 07/384,187This is a filedcontinuation Jul. 21, 1989,of U.S. abandoned. application Ser. No. 10 BACKGROUND OF THE INVENTION Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4- diphenyl- 1-[2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- 15 H yl)ethyl]-1H-pyrrole-3-carboxamides are among apparently is required for inhibition of HMG-GoA re- pounds of U.S. Pat. No. 4,681,893 having usefulness ps ductase. This is reported by Lynch et al. in “Synthesis inhibitors of cholesterol biosynthesis. The compounds of an HMB-CoA Reductase Inhibitor; A diastereoselec- therein broadly include 4-hydroxypayran-2-ones the 20 tive Aldol Approach in Tetrahedron Letters, Vol. 28, No. 13, pp. 1385-1388 (1987) as the 4R, 6R configura- corresponding ring-opened acids derived therefrom. tion. It is now unexpectedly found that the enantiomer However, an ordinarily skilled artisan may not pre- having the R form of the ring-opened acid of tran-5-(4- dict the unexpected and surprising inhibition of choles- fluorophcny1)-2-(11-mthylethyl-N-4-diphenyl-1 -1-[2-tet- 25 terol biosynthesis Of present invention in view Of these disclosures. rahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1 H- pyrrole-3-carboxamide; that is [R-(R*,R*)]-2-(4-fluoro- SUMMARY OF THE INVENTION phenyl)-ß,§-dihydroxy-5-(1 -methylethyl)-3-phenyl-4- Accordingly the present invention provides for com- [(phenylamino)carbonyl]-1H-pyrrole- l-heptanoic acid, 30 pounds consisting of [R-R*,R*)]-2-(4-fluorophenyl)- ß,§-dihydroxy-5-(( 1methylethyl)-3-phenyl-4- provides inhibition Of biosynthesis Of [(phenylamino) carbonyl]-1H-pyrrole-1-heptanoic acid cholesterol. (compound of formula I), pharmaceutically acceptable It is known that 3-hydroxy-3-methyIglutaryl coen- salts thereof and (2R-trans)-5-(4-fluorophenyl)-2-(1- zyme A (HMG-CoA) exists as the 3R-sterioisomer. 35 methylethyl-N,4-diphenyl-1-[2-tetrhydro-4-hydroxy- 1H-pyrrole-3-carboxamide Additionally, as shown in the study of a series of 5-sub- 6-oxo-2H-pyran-2-yl)ethyl] (the lactone of the heptanoic acid or of stituted 3,5-dihydroxypentanoic acids by Stokker et al., formula II). in “3-Hydroxy-3-methylglutaryl-Coenzyme A Reduc- The present invention also relates to a pharmaceutical tase Inhibitors. 1. Structural Modification of 5-Sub- 40 composition, useful a hypocholesterolemic agent, stituted 3,5-Dihydroxypentanoic acids and Their Lac- comprising a hypocholesterolemic effective amount of [R-(R*,R*)]-2-(4-fluorophenyl)-ß,§-dihydroxy-5(1- tone Derivatives,” J. Med. Chem. 1985, 28, 347-358, methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-H- essentially all of the biological activity resided in the pyrrole-1-heptanoic acid, its pharmaeutically accept- trans diastereomer of (E)-6-[2-(2,4-dichlorophenyl)e- 45 able salts Of (2R-trans)-5-(4-fluorohenyl)-2-(1- thenyl’-3,4,5,6-tetrahydro-4-hydroxy-2H-pyranone methylethyl-N,4-diphenyl- 1-[2-(tetrahydro-4-hydroxy- 6-oxo-2H-pyran-2-yl)thyl] 1H-pyrrole-3-carboxamide having a positive rotation. Further, the absolute config- acid; and a pharmaceutically acceptable Fur- uration for the ß-hydroxy-§-lactone moiety common to ther, the present invention is also a method of treating mevinolin of the formula (la) 50 mammals, including humans, suffering from hypercho- lesterolemia by administering to such mammal a dosage form of the pharmaceutical composition described above. 55 DETAILED DESCRIPTION OF THE INVENTION The pharmaceutically acceptable salts of the inven- tion are those generally derived by dissolving the free acid or the lactone; preferably the lactone, in aqueous or 60 aqueous alcohol solvent or other suitable solvents with an appropriate base and isolating the salt by evaporating the solution or by reacting the free acid or lactone; preferably the lactone and base in an organic solvent in which the salt separates directly or can be obtained by 65 concentration of the solution. H3C In practice, use of the salt form amounts to use of the acid or lactone form. Appropriate pharmaceutically and compactin of the formula (lb) acceptable salts within the scope of the invention are 5,273,995 3 4 those derived from bases such as sodium hydroxide, through a cationic exchange resin (+resin) and evap- potassium hydroxide, lithium hydroxide, calcium hy- orating the water. droxide, 11-deoxy-2-(methylamino)-D-glucitol, magne- The most preferred embodiment of the present inven- sium hydroxide, zinc hydroxide, aluminum hydroxide, tion is [R-(R*R*)]-2-(4-fluorophenyl-ß,§-dihydorxy-5- ferrous or ferric hydroxide, ammonium hydroxide or 5 (l-methylethyl)-3-phenyl-4((phenylamino)carbonyl]- organic amines such as N-methylglucamine, choline, IH-pyrrole- I-heptanoic acid, hemicalcium salt. arginine and the like. Preferably, the lithium, calcium, Generally, the compounds I and II of the present magnesium, aluminum and ferrous or ferric salts are invention can be prepared by (1) resolving the race- prepared from the sodium or potassium salt by adding mate, that is prepared by the process described in U.S. the appropriate reagent to a solution of the sodium or 10 Pat. No. 4,681,893 which is incorporated by reference potassium salt, i.e., addition of calcium chloride to a therefor, or (2) synthesizing the desired chiral form solution of the sodium or potassium salt of the com- beginning from starting materials which arc known or pound of the formula I will give the calcium salt readily prepared using processes analogous to those thereof. which are known. The free acid can be prepared by hydrolysis of the 15 Specifically, resolution of the racemate may be ac- lactone form of formula II or by passing the salt complished as shown in Scheme I (where Ph is phenyl) . as follows: Scheme 1 PhHN PhHN 0 0 Ph Step A trans racemate + R OH OH 0 PhHN 0 1) Separate 2) NaOH 3) reflux in toluene Ph CONHPh Ph CONHPh [R(R*R*) isomer [S(R*R*) isomer 5,273,995 5 6 The "trans racemate" of Scheme 1 means a mixture of 20 the following: -continued HO 25 30 Ph CONHPh I\ Ph CONHPb [R(R*R*)]isomer The conditions of the Step 1 and 2 of Scheme 1 are 35 generally in the Examples and 7 hereinafter. and as found 6 The chiral synthesis is shown in Scheme 2 (where Ph is phenyl) as follows: Scheme 2 5,273,995 7 a -continued Scheme 2 0- F 0 2.
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