US 4,857,546 AGranted

Novel HMG-CoA reductase inhibitors

AssigneeMerck & Co., Inc.

InventorsMark Duggan, George D. Hartman

Life of this patent

Estimating the term…

Abstract

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

Claims19

Dependent claims

A compound represented by the following structural formula (I):

##STR8## wherein:
R.sup.1 is selected from:
(1) C.sub.1-10 alkyl;
(2) substituted C.sub.1-10 alkyl in which one or more substituent(s) is selected from
(a) halogen,
(b) hydroxy,
(c) C.sub.1-10 alkoxy,
(d) C.sub.1-5 alkoxycarbonyl,
(e) C.sub.1-5 acyloxy,
(f) C.sub.3-8 cycloalkyl,
(g) phenyl,
(h) substituted phenyl in which the substituents are X and Y,
(i) C.sub.1-10 alkylS(O).sub.n in which n is 0 to 2,
(j) C.sub.3-8 cycloalkylS(O).sub.n,
(k) phenylS(O).sub.n,
(l) substituted phenylS(O).sub.n in which the substituents are X and Y, and
(m) oxo;
(3) C.sub.1-10 alkoxy;
(4) C.sub.2-10 alkenyl;
(5) C.sub.3-8 cycloalkyl;
(6) substituted C.sub.3.varies.8 cycloalkyl in which one substituent is selected from
(a) C.sub.1-10 alkyl
(b) substituted C.sub.1-10 alkyl in which the substituent is selected from
(i) halogen,
(ii) hydroxy,
(iii) C.sub.1-10 alkoxy,
(iv) C.sub.1-5 alkoxycarbonyl,
(v) C.sub.1-5 acyloxy,
(vi) phenyl,
(vii) substituted phenyl in which the substituents are X and Y,
(viii) C.sub.1-10 alkylS(O).sub.n,
(ix) C.sub.3-8 cycloalkylS(O).sub.n,
(x) phenylS(O).sub.n,
(xi) substituted phenylC(O).sub.n in which the substituents are X and Y, and
(xii) oxo,
(c) C.sub.1-10 alkylS(O).sub.n,
(d) C.sub.3-8 cycloalkylS(O).sub.n,
(e) phenylS(O).sub.n,
(f) substituted phenylS(O).sub.n in which the substituents are X and Y,
(g) halogen,
(h) hydroxy,
(i) C.sub.1-10 alkoxy,
(j) C.sub.1-5 alkoxycarbonyl,
(k) C.sub.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.sub.1-5 alkylamino;
(11) di(C.sub.1-5 alkyl)amino;
(12) phenylamino;
(13) substituted phenylamino in which the substituents are X and Y;
(14) phenyl C.sub.1-10 alkylamino;
(15) Substituted phenyl C.sub.1-10 alkylamino in which the substituents are X and Y;
and
(16) a member selected from
(a) C.sub.1-10 alkyl,
(b) phenyl, and
(c) substituted phenyl in which the substituents are X and Y;
R.sup.2 and R.sup.3 are independently selected from:
(1) hydrogen;
(2) C.sub.1-10 alkyl;
(3) substituted C.sub.1-10 alkyl in which one or more substituent(s) is selected from
(a) halogen,
(b) hydroxy,
(c) C.sub.1-10 alkoxy,
(d) C.sub.1-5 alkoxycarbonyl,
(e) C.sub.1-5 acyloxy,
(f) C.sub.3-8 cycloalkyl,
(g) phenyl,
(h) substituted phenyl in which the substituents are X and Y, and
(i) oxo;
(4) C.sub.1-10 acyl;
(5) substituted C.sub.1-10 acyl in which one or more substituent(s) is selected from
(a) halogen,
(b) hydroxy,
(c) C.sub.1-10 alkoxy,
(d) C.sub.1-5 alkoxycarbonyl,
(e) C.sub.1-5 acyloxy,
(f) C.sub.3-8 cycloalkyl,
(g) phenyl,
(h) substituted phenyl in which the substituents are X and Y, and
(i) oxo;
(6) phenylcarbonyl;
(7) substituted phenylcarbonyl in which the substituents are X and Y;
(8) C.sub.1-5 alkylaminocarbonyl;
(9) di(C.sub.1-5 alkyl)aminocarbonyl;
(10) phenylaminocarbonyl;
(10) substituted phenylaminocarbonyl in which the substituents are X and Y;
(11) phenyl C.sub.1-10 alkylaminocarbonyl;
(12) substituted phenyl C.sub.1-10 alkylaminocarbonyl in which the substituents are X and Y;
R.sup.4 is selected from:
trifluoromethyl, C.sub.1-3 alkyl, nitro, cyano or group selected from:
(1) R.sup.8 O (CH.sub.2) in which m is 0 to 3 and R.sup.8 and hydrogen, C.sub.1-3 alkyl or hydroxy-C.sub.2-3 alkyl;
(2) ##STR9## in which R.sup.9 is hydrogen, C.sub.1-3 alkyl, hydroxy-C.sub.2-3 alkyl, phenyl, naphthyl, amino-C.sub.1-3 alkyl, C.sub.1-3 alkylamino-C.sub.1-3 alkyl, di(C.sub.1-3 alkyl)amino-C.sub.1-3 alkyl hydroxy-C.sub.2-3 alkylamino-C.sub.1-3 alkyl or di(hydroxy-C.sub.2-3 alkyl) amino-C.sub.1-3 alkyl;
(3) ##STR10## in which R.sup.10 is hydrogen, C.sub.1-3 alkyl, hydroxy-C.sub.2-3 alkyl, C.sub.1-3 alkoxy-C.sub.1-3 alkyl, phenyl or naphthyl;
##STR11## in which R.sup.11 and R.sup.12 independently are hydrogen, C.sub.1-3 alkyl or, hydroxy-C.sub.2-3 alkyl
(5) R.sup.13 S(O).sub.n (CH.sub.2).sub.m in which R.sup.13 is hydrogen, C.sub.1-3 alkyl, amino, C.sub.1-3 alkylamino or di(C.sub.1-3 alkyl)amino;
and
a, b, c and d each represent single bonds or one of a, b, c and d represents a double bond or both a and c or b and d represent double bonds;
or a pharmaceutically acceptable salt thereof.

99 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/142,378Filed 7 Jan 1988
Granted: 15 Aug 1989
Term ends: Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07C 229/32
Having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton: the carbon skeleton being unsaturated and containing…
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
C07D 309/30
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…

Family

No related US applications are recorded in the indexed filing history.

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Abstract

A compound represented by the following structural formula (I):

##STR8## wherein:
R.sup.1 is selected from:
(1) C.sub.1-10 alkyl;
(2) substituted C.sub.1-10 alkyl in which one or more substituent(s) is selected from
(a) halogen,
(b) hydroxy,
(c) C.sub.1-10 alkoxy,
(d) C.sub.1-5 alkoxycarbonyl,
(e) C.sub.1-5 acyloxy,
(f) C.sub.3-8 cycloalkyl,
(g) phenyl,
(h) substituted phenyl in which the substituents are X and Y,
(i) C.sub.1-10 alkylS(O).sub.n in which n is 0 to 2,
(j) C.sub.3-8 cycloalkylS(O).sub.n,
(k) phenylS(O).sub.n,
(l) substituted phenylS(O).sub.n in which the substituents are X and Y, and
(m) oxo;
(3) C.sub.1-10 alkoxy;
(4) C.sub.2-10 alkenyl;
(5) C.sub.3-8 cycloalkyl;
(6) substituted C.sub.3.varies.8 cycloalkyl in which one substituent is selected from
(a) C.sub.1-10 alkyl
(b) substituted C.sub.1-10 alkyl in which the substituent is selected from
(i) halogen,
(ii) hydroxy,
(iii) C.sub.1-10 alkoxy,
(iv) C.sub.1-5 alkoxycarbonyl,
(v) C.sub.1-5 acyloxy,
(vi) phenyl,
(vii) substituted phenyl in which the substituents are X and Y,
(viii) C.sub.1-10 alkylS(O).sub.n,
(ix) C.sub.3-8 cycloalkylS(O).sub.n,
(x) phenylS(O).sub.n,
(xi) substituted phenylC(O).sub.n in which the substituents are X and Y, and
(xii) oxo,
(c) C.sub.1-10 alkylS(O).sub.n,
(d) C.sub.3-8 cycloalkylS(O).sub.n,
(e) phenylS(O).sub.n,
(f) substituted phenylS(O).sub.n in which the substituents are X and Y,
(g) halogen,
(h) hydroxy,
(i) C.sub.1-10 alkoxy,
(j) C.sub.1-5 alkoxycarbonyl,
(k) C.sub.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.sub.1-5 alkylamino;
(11) di(C.sub.1-5 alkyl)amino;
(12) phenylamino;
(13) substituted phenylamino in which the substituents are X and Y;
(14) phenyl C.sub.1-10 alkylamino;
(15) Substituted phenyl C.sub.1-10 alkylamino in which the substituents are X and Y;
and
(16) a member selected from
(a) C.sub.1-10 alkyl,
(b) phenyl, and
(c) substituted phenyl in which the substituents are X and Y;
R.sup.2 and R.sup.3 are independently selected from:
(1) hydrogen;
(2) C.sub.1-10 alkyl;
(3) substituted C.sub.1-10 alkyl in which one or more substituent(s) is selected from
(a) halogen,
(b) hydroxy,
(c) C.sub.1-10 alkoxy,
(d) C.sub.1-5 alkoxycarbonyl,
(e) C.sub.1-5 acyloxy,
(f) C.sub.3-8 cycloalkyl,
(g) phenyl,
(h) substituted phenyl in which the substituents are X and Y, and
(i) oxo;
(4) C.sub.1-10 acyl;
(5) substituted C.sub.1-10 acyl in which one or more substituent(s) is selected from
(a) halogen,
(b) hydroxy,
(c) C.sub.1-10 alkoxy,
(d) C.sub.1-5 alkoxycarbonyl,
(e) C.sub.1-5 acyloxy,
(f) C.sub.3-8 cycloalkyl,
(g) phenyl,
(h) substituted phenyl in which the substituents are X and Y, and
(i) oxo;
(6) phenylcarbonyl;
(7) substituted phenylcarbonyl in which the substituents are X and Y;
(8) C.sub.1-5 alkylaminocarbonyl;
(9) di(C.sub.1-5 alkyl)aminocarbonyl;
(10) phenylaminocarbonyl;
(10) substituted phenylaminocarbonyl in which the substituents are X and Y;
(11) phenyl C.sub.1-10 alkylaminocarbonyl;
(12) substituted phenyl C.sub.1-10 alkylaminocarbonyl in which the substituents are X and Y;
R.sup.4 is selected from:
trifluoromethyl, C.sub.1-3 alkyl, nitro, cyano or group selected from:
(1) R.sup.8 O (CH.sub.2) in which m is 0 to 3 and R.sup.8 and hydrogen, C.sub.1-3 alkyl or hydroxy-C.sub.2-3 alkyl;
(2) ##STR9## in which R.sup.9 is hydrogen, C.sub.1-3 alkyl, hydroxy-C.sub.2-3 alkyl, phenyl, naphthyl, amino-C.sub.1-3 alkyl, C.sub.1-3 alkylamino-C.sub.1-3 alkyl, di(C.sub.1-3 alkyl)amino-C.sub.1-3 alkyl hydroxy-C.sub.2-3 alkylamino-C.sub.1-3 alkyl or di(hydroxy-C.sub.2-3 alkyl) amino-C.sub.1-3 alkyl;
(3) ##STR10## in which R.sup.10 is hydrogen, C.sub.1-3 alkyl, hydroxy-C.sub.2-3 alkyl, C.sub.1-3 alkoxy-C.sub.1-3 alkyl, phenyl or naphthyl;
##STR11## in which R.sup.11 and R.sup.12 independently are hydrogen, C.sub.1-3 alkyl or, hydroxy-C.sub.2-3 alkyl
(5) R.sup.13 S(O).sub.n (CH.sub.2).sub.m in which R.sup.13 is hydrogen, C.sub.1-3 alkyl, amino, C.sub.1-3 alkylamino or di(C.sub.1-3 alkyl)amino;
and
a, b, c and d each represent single bonds or one of a, b, c and d represents a double bond or both a and c or b and d represent double bonds;
or a pharmaceutically acceptable salt thereof.

99 more elements

Facts

Application

07/142,378Filed 7 Jan 1988

Granted

15 Aug 1989

Term ends

Not estimatedThe source records don’t support an estimate.

Classification8 codes

C07C 229/32
Having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton: the carbon skeleton being unsaturated and containing…
A61P 3/06
Drugs for disorders of the metabolism: antihyperlipidemics
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
C07D 309/30
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…