US 2003/0120086 A1 · New salts of HMG-CoA reductase inhibitors

Abstract

Lovastatin, pravastatin, simvastatin, mevastatin, atorvastatin, and derivatives and analogs thereof are known as HMG-CoA reductase inhibitors and are used as antihypercholesterolemic agents. The majority of them are produced by fermentation using microorganisms of different species identified as species belonging to Aspergillus, Monascus, Nocardia, Amycolatopsis, Mucor or Penicillium genus, some are obtained by treating the fermentation products using the methods of chemical synthesis or they are the products of total chemical synthesis. The present invention relates to the new amine salts of HMG-CoA reductase inhibitors, the preparation thereof, the preparation of pure HMG-CoA reductase inhibitors via amine salts thereof, use of the amine salts of HMG-CoA reductase inhibitors in the process for semisynthetic preparation of HMG-CoA reductase inhibitors, use of the amine salts of HMG-CoA reductase inhibitors in the process for biotechnological modification of HMG-CoA reductase inhibitors as well as the conversion of the amine salts of HMG-CoA reductase inhibitors into the pharmaceutically acceptable salts of the HMG-CoA reductase inhibitors and the conversion of the amine salts of HMG-CoA reductase inhibitors into the HMG-CoA reductase inhibitors in the lactone form.

A salt of a HMG-CoA reductase inhibitor with an amine, characterized in that said salt is an intermediate or a starting substance in a process for preparing the HMG-CoA reductase inhibitors and that said amine is selected from the group consisting of amines of the following formulae I and II:

a)
5
wherein:
a1) R1, R2, R3 and R4 independently denote:
a hydrogen atom;
a straight or a branched alkyl group having 1 to 8 carbon atoms;
a cycloalkyl group having 3 to 8 carbon atoms;
an arylalkyl group wherein the alkyl group is methyl or ethyl and the aryl group is phenyl, which is optionally substituted by an N-alkyl or N,N-dialkyl group wherein the alkyl group is alkyl having 1 to 4 carbon atoms;
an arylalkyl group which is optionally substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms;
a hydroxyalkyl group having 2 to 4 carbon atoms;
or
an aminoalkyl group having 2 to 4 carbon atoms, which are optionally substituted by an N-alkyl or N,N-dialkyl group wherein the alkyl group is alkyl having 1 to 4 carbon atoms;
X denotes a hydrogen atom, a hydroxyl group, a halogen or a methyl group;
m and n independently denote an integer from 0 to 5;
or
a2) NR1R2 or NR3R4 denote a heterocyclic ring having 3 to 7 methylene groups, wherein these groups are unsubstituted or one of these groups is substituted by an oxygen or a sulfur atom or an imine group;
and X, m and n are the same as defined above;
b)
6
wherein:
b1) R′1, R′2, and R′3 are the same or different and denote
hydrogen, alkyl, alkenyl, amino- or hydroxy- or alkoxy-substituted alkyl or alkenyl, or substituted amino-alkyl or alkenyl wherein the amino group is substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms and an esterified carboxyl having 1 to 4 carbon atoms, provided that R′1, R′2 and R′3 are not hydrogen at the same time;
or
b2) R′1,R′2, and optionally R′3 together with the nitrogen atom form a heterocyclic ring system including the nitrogen atom as a ring member, and optionally including an additional hetero atom, and if R′3 is not part of the ring system it is independently selected from hydrogen, alkyl, alkenyl, amino- or hydroxy- or alkoxy-substituted alkyl, or substituted amino-alkyl wherein the amino group is substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms and an esterified carboxyl having 1 to 4 carbon atoms;
or
b3) R′1 is a group of general formula III,
R′—(CHR′4)m— III
wherein m is zero or an integer from 1 to 5, R′ is an aliphatic hydrocarbon cyclic system having 3 to 8 carbon atoms in the ring, wherein R′ is optionally substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms and an esterified carboxyl having 1 to 4 carbon atoms;
R′4 is hydrogen, or alkyl, amino- or hydroxy- or alkoxy-substituted alkyl, or substituted amino-alkyl, wherein the amino group is substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms;
or a group of the same general formula as R′1 as defined herein above, R′2 and R′3 are the same as R′1 or hydrogen, alkyl, alkenyl, amino- or hydroxy- or alkoxy-substituted alkyl, or substituted amino-alkyl or alkenyl, wherein the amino group is substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms;
or
b4) R′1 is an optionally substituted aryl group of general formula IV,
7
wherein:
R′5 is hydrogen or one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms, and m is zero or an integer from 1 to 5, and R′2 and R′3 may be independently hydrogen, alkyl, amino- or hydroxy- or alkoxy-substituted alkyl, or substituted amino-alkyl, wherein the amino group is substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, an alkyl having 1 to 4 carbon atoms, an alkoxyl having 1 to 4 carbon atoms, an acyloxyl having 1 to 4 carbon atoms or an esterified carboxyl having 1 to 4 carbon atoms, or groups of the same general formula R′1;
provided that
when the HMG-CoA reductase inhibitor is lovastatin, the amine is not tetramethylamine or ethylenediamine;
when the HMG-CoA reductase inhibitor is tetrahydro-M-4 or tetrahydro-IsoM-4, the amine is not octylamine, 2-ethylhexylamine, benzylamine, a-methyl-benzylamine, phenethylamine, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylamine, N,N-diethylbenzylamine, N-ethyl-N-methylbenzylamine, tribenzylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexylamine, N-ethylcycloheptylamine, dicyclohexylamine, N,N-dimethycyclopentylamine, N,N-dimethylcyclohexylamine, N,N-diethylcycloheptylamine, pyrrolidine, N-methylpyrrolidine, piperidine, N-methylpiperidine or morpholine;
and
when the HMG-CoA reductase inhibitor is the octa-hydronaphthalene oxime derivative of ML-236A, ML-236B, MB-530A or MB-530B, the amine is not t-octylamine, dibenzylamine, dicyclohexylamine or morpholine;
wherein the HMG-CoA reductase inhibitor is selected from the group consisting of mevastatin, pravastatin, lovastatin, simvastatin, fluvastatin and atorvastatin;
and
wherein the amine is selected from the group consisting of (±)-1,2-dimethylpropylamine, 3-(2-aminoethylamino)-propyilamine, n-butylamine, secondary butylamine, tertiary butylamine, dibutylamine, tertiary amylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, 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-diethylcycohexylamine, N-isopropylcyclohexylamine, N-methylcyclohexylamine, cyclobutylamine and norborylamine.

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New salts of HMG-CoA reductase inhibitors

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New salts of HMG-CoA reductase inhibitors

Life of this patent

Abstract

Claims48