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Novel HMG-CoA reductase inhibitors

Assignee: Merck and Co Inc
•
Filing: 1988-01-07
•
Granted: 1989-09-12
•
Expires: 2008-01-07
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Abstract

Abstract Novel 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors are useful as antihypercholesterolemic agents and are represented by the following general structural formulae (I) and (II): ##STR1##

Inventors

  • 👤 William F. Hoffman
  • 👤 Robert L. Smith
  • 👤 Ta J. Lee

Bibliographic Details

Application Number —
Jurisdiction US
Data Source google_patents
Last Synchronized 2026-11-09 01:20
CPC Classifications
C; C07; C07D; C07D309/00; C07D309/16; C07D309/28; C07D309/30; A; A61; A61P; A61P3/00; A61P3/06

Claims Analysis

Total Claims: 11
Claim 1
Independent Claim 573 words
A compound represented by the following structural formula (I): ##STR8## wherein: R 1 is selected from: (1) C 1-10 alkyl; (2) substituted C 1-10 alkyl in which one or more substituent(s) is selected from (a) halogen, (b) hydroxy, (c) C 1-10 alkoxy, (d) C 1-5 alkoxycarbonyl, (e) C 1-5 acyloxy, (f) C 3-8 cycloalkyl, (g) phenyl, (h) substituted phenyl in which the substituents are X and Y, (i) C 1-10 alkylS(0)n in which n is 0 to 2, (j) C 3-8 cycloalkylS(0) n , (k) phenylS(0) n , (l) substituted phenylS(0) n in which the substituents are X and Y, and (m) oxo; (3) C 1-10 alkoxy; (4) C 2-10 alkenyl; (5) C 3-8 cycloalkyl; (6) substituted C 3-8 cycloalkyl in which one substituent is selected from (a) C 1-10 alkyl (b) substituted C 1-10 alkyl in which the substituent is selected from (i) halogen, (ii) hydroxy, (iii) C 1-10 alkoxy, (iv) C 1-5 alkoxycarbonyl, (v) C 1-5 acyloxy, (vi) phenyl, (vii) substituted phenyl in which the substituents are X and Y (viii) C 1-10 alkylS(0) n , (ix) C 3-8 cycloalkylS(0) n , (x) phenylS(0) n , (xi) substituted phenylS(O) n in which the substituents are X and Y, and (xii) oxo, (c) C 1-10 alkylS(0) n , (d) C 3-8 cycloalkylS(0) n , (e) phenylS(0) n , (f) substituted phenylS(0) n in which the substituents are X and Y, (g) halogen, (h) hydroxy, (i) C 1-10 alkoxy, (j) C 1-5 alkoxycarbonyl, (k) C 1-5 acyloxy, (l) phenyl, and (m) substituted phenyl in which the substituents are X and Y; (7) phenyl; (8) substituted phenyl in which the substituents are X and Y; (9) amino; (10) C 1-5 alkylamino; (11) di(C 1-5 alkyl)amino; (12) phenylamino; (13) substituted phenylamino in which the substituents are X and Y; (14) phenyl C 1-10 alkylamino; (15) substituted phenyl C 1-10 alkylamino in which the substituents are X and Y; (16) R 6 S in which R 6 is selected from (a) C 1-10 alkyl, (b) phenyl, and (c) substituted phenyl in which the substituents are X and Y; R 2 and R 3 are independently selected from: (1) C 1-10 alkyl; and (2) substituted C 1-10 alkyl in which one or more substituent(s) is selected from (a) halogen, (b) hydroxy, (c) C 1-10 alkoxy, (d) C 1-5 alkoxycarbonyl, (e) C 1-5 acyloxy, (f) C 3-8 cycloalkyl, (g) phenyl, or (3) together with the carbon atom to which they are attached form a C 3-8 carbocyclic ring; X and Y independently are hydrogen, halogen, trifluoromethyl, C 1-3 alkyl, nitro, cyano or group selected from: (1) R 8 O(CH 2 ) m in which m is 0 to 3 and R 8 is hydrogen, C 1-3 alkyl or hydrogen, C 2-3 alkyl; (2) ##STR9## in which R 9 is hydrogen, C 1-3 alkyl, hydroxy-C 2- alkyl, phenyl, naphthyl, amino C 1-3 alkyl, C 1-3 alkylamino-C 1-3 alkyl, di(C 1-3 alkyl)amino-C 1- alkyl, hydroxy C 2-3 alkylamino-C 1- alkyl or di(hydroxy C 2- alkyl) amino-C 1- alkyl; (3) ##STR10## in which R 10 is hydrogen, C 1- alkyl, hydroxy-C 2-3 alkyl, C 1-3 alkoxy-C 1-3 alkyl, phenyl or naphthyl; (4) ##STR11## in which R 11 and R 12 independently are hydrogen, C 1-3 alkyl, hydroxy C 2-3 alkyl; (5) R 13 S(0) n (CH 2 )m in which R 13 is hydrogen, C 1-3 alkyl, amino, C 1-3 alkylamino or di(C 1-3 alkyl)amino; or a pharmaceutically acceptable salt thereof.
Claim 2
Dependent Claim 573 words
A compound represented by the following structural formula (I): ##STR8## wherein: R 1 is selected from: (1) C 1-10 alkyl; (2) substituted C 1-10 alkyl in which one or more substituent(s) is selected from (a) halogen, (b) hydroxy, (c) C 1-10 alkoxy, (d) C 1-5 alkoxycarbonyl, (e) C 1-5 acyloxy, (f) C 3-8 cycloalkyl, (g) phenyl, (h) substituted phenyl in which the substituents are X and Y, (i) C 1-10 alkylS(0)n in which n is 0 to 2, (j) C 3-8 cycloalkylS(0) n , (k) phenylS(0) n , (l) substituted phenylS(0) n in which the substituents are X and Y, and (m) oxo; (3) C 1-10 alkoxy; (4) C 2-10 alkenyl; (5) C 3-8 cycloalkyl; (6) substituted C 3-8 cycloalkyl in which one substituent is selected from (a) C 1-10 alkyl (b) substituted C 1-10 alkyl in which the substituent is selected from (i) halogen, (ii) hydroxy, (iii) C 1-10 alkoxy, (iv) C 1-5 alkoxycarbonyl, (v) C 1-5 acyloxy, (vi) phenyl, (vii) substituted phenyl in which the substituents are X and Y (viii) C 1-10 alkylS(0) n , (ix) C 3-8 cycloalkylS(0) n , (x) phenylS(0) n , (xi) substituted phenylS(O) n in which the substituents are X and Y, and (xii) oxo, (c) C 1-10 alkylS(0) n , (d) C 3-8 cycloalkylS(0) n , (e) phenylS(0) n , (f) substituted phenylS(0) n in which the substituents are X and Y, (g) halogen, (h) hydroxy, (i) C 1-10 alkoxy, (j) C 1-5 alkoxycarbonyl, (k) C 1-5 acyloxy, (l) phenyl, and (m) substituted phenyl in which the substituents are X and Y; (7) phenyl; (8) substituted phenyl in which the substituents are X and Y; (9) amino; (10) C 1-5 alkylamino; (11) di(C 1-5 alkyl)amino; (12) phenylamino; (13) substituted phenylamino in which the substituents are X and Y; (14) phenyl C 1-10 alkylamino; (15) substituted phenyl C 1-10 alkylamino in which the substituents are X and Y; (16) R 6 S in which R 6 is selected from (a) C 1-10 alkyl, (b) phenyl, and (c) substituted phenyl in which the substituents are X and Y; R 2 and R 3 are independently selected from: (1) C 1-10 alkyl; and (2) substituted C 1-10 alkyl in which one or more substituent(s) is selected from (a) halogen, (b) hydroxy, (c) C 1-10 alkoxy, (d) C 1-5 alkoxycarbonyl, (e) C 1-5 acyloxy, (f) C 3-8 cycloalkyl, (g) phenyl, or (3) together with the carbon atom to which they are attached form a C 3-8 carbocyclic ring; X and Y independently are hydrogen, halogen, trifluoromethyl, C 1-3 alkyl, nitro, cyano or group selected from: (1) R 8 O(CH 2 ) m in which m is 0 to 3 and R 8 is hydrogen, C 1-3 alkyl or hydrogen, C 2-3 alkyl; (2) ##STR9## in which R 9 is hydrogen, C 1-3 alkyl, hydroxy-C 2- alkyl, phenyl, naphthyl, amino C 1-3 alkyl, C 1-3 alkylamino-C 1-3 alkyl, di(C 1-3 alkyl)amino-C 1- alkyl, hydroxy C 2-3 alkylamino-C 1- alkyl or di(hydroxy C 2- alkyl) amino-C 1- alkyl; (3) ##STR10## in which R 10 is hydrogen, C 1- alkyl, hydroxy-C 2-3 alkyl, C 1-3 alkoxy-C 1-3 alkyl, phenyl or naphthyl; (4) ##STR11## in which R 11 and R 12 independently are hydrogen, C 1-3 alkyl, hydroxy C 2-3 alkyl; (5) R 13 S(0) n (CH 2 )m in which R 13 is hydrogen, C 1-3 alkyl, amino, C 1-3 alkylamino or di(C 1-3 alkyl)amino; or a pharmaceutically acceptable salt thereof.
Claim 3
Dependent Claim 190 words
A compound of claim 1 wherein: R 1 is selected from: (1) C 1-10 alkyl; (2) substituted C 1-10 alkyl in which one or more substituent(s) is selected from (a) halogen, (b) hydroxy, (c) C 1-10 alkoxy, (d) C 1-5 alkoxycarbonyl, (e) C 1-5 acyloxy, (f) C 3-8 cycloalkyl, (g) phenyl, (h) substituted phenyl in which the substitents are X and Y, and (i) oxo; (3) C 3-8 cycloalkyl; (4) substituted C3-8 cycloalkyl in which one substituent is selected from (a) C 1-10 alkyl, (b) substituted C 1-10 alkyl in which the substituent is selected from (i) halogen, (ii) hydroxy, (iii) C 1-10 alkoxy (iv) C 1-5 acyloxy, (v) C 1-5 alkoxycarbonyl, (vi) phenyl, (vii) substituted phenyl in which the substituents are X and Y, and (viii) oxo, (c) halogen, (d) hydroxy, (e) C 1-10 alkoxy, (f) C 1-5 alkoxycarbonyl, (g) C 1-5 acyloxy, (h) phenyl, (i) substituted phenyl in which the substituents are X and Y; (5) phenylamino; (6) substituted phenylamino in which the substituents are X and Y; (7) phenyl C 1-10 alkylamino; and (8) substituted phenyl C 1-10 alkylamino in which the substituents are X and Y.
Claim 4
Dependent Claim 33 words
A compound of claim 2 wherein: R 1 is selected from: (1) C 1-10 alkyl; (2) C 3-8 cycloalkyl; (3) phenylamino; and (4) substituted phenylamino in which the substituents are X and Y.
Claim 5
Dependent Claim 37 words
A compound of claim 3 wherein: R 2 and R 3 are independently selected from: (1) C 1-10 alkyl; and (2) together with the carbon atom to which they are attached form a C 3-8 carbocyclic ring.
Claim 6
Dependent Claim 9 words
A compound of claim 4 which is 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6,6-trimethyl-1,2,3,4,4a(S),5,6,7,8,8a (S)-decahydronaphthyl-1(S)]ethyl]-4(R)-hdroxy-3,4,5,6,-tetrahydro-2H-pyran-2-one.
Claim 7
Dependent Claim 10 words
A compound of claim 4 which is 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6,6dimethylene-1,2,3,4,4a (S),5,6,7,8,8a (S)-decahydronaphthyl-1(S)]ethyl-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one.
Claim 8
Dependent Claim 23 words
A hypocholesterolemic, hypolipidemic pharmaceutical composition comprising a pharmaceutically acceptable carrier and a nontoxic effective amount of a compound as defined in claim 1.
Claim 9
Dependent Claim 19 words
A composition of claim 7 in which the compound is selected from: (1) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6,6-trimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S)]ethyl]-4(R) -hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one; (2) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6,6-dimethylene-1,2,3,4,4a(S)5,6,7,8, 8a(S)-decahtdronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5 6-tetrahydro-2H-pyran-2-one.
Claim 10
Dependent Claim 28 words
A method of inhibiting cholesterol biosynthesis comprising the administration to a subject in need of such treatment a nontoxic therapeutically effective amount of a compound of claim 1.
Claim 11
Dependent Claim 16 words
A method of claim 9 in which the compound is selected from: (1) 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S)-methyl-6,6-dimethylene-1,2,3,4,4a(S)5,6,7,8, 8a(S)-decahtdronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5 6-tetrahydro-2H-pyran-2-one.

References Cited (Backward Citations)

US4351844A Cited
US4444784A Cited
US4450171A Cited
US4661483A Cited
EP0245003A2 Cited

USPTO Annuity & Maintenance Windows

Annuity Stage Window Opens Payment Deadline Surcharge Period Until Estimated Fee Status
3.5 Years (Year 4) 1992-09-11 1993-03-13 1993-09-12 $2000.00 Window Closed / Lapsed
7.5 Years (Year 8) 1996-09-11 1997-03-13 1997-09-12 $3760.00 Window Closed / Lapsed
11.5 Years (Year 12) 2000-09-11 2001-03-13 2001-09-12 $7700.00 Window Closed / Lapsed

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