Patent ID: 6583295
Filing Date: 2003-06-24
Classification: C07C,C07D

Abstract:
A salt of an 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; 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, one of these groups being optionally substituted by an oxygen or a sulfur atom or an imine group; and X, m and n are the same as defined above; wherein:b1) Râ€²1, Râ€²2, and Râ€²3 are the same or different and denote hydrogen, alkyl, alkenyl, amine 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 or an esterified carboxyl having 1 to 4 carbon atoms, provided that Râ€²1, Râ€²2 and Râ€²3 are not hydrogen at the same time; or b2) Râ€²1 and Râ€²2, and optionally Râ€²3, 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 Râ€²3 is not part of the ring system it is independently selected from hydrogen, alky, alkenyl, amino- or hydroxy or alkoxy-substituted alky, 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 b3) Râ€²1 is a group of general formula III, Râ€²â€”(CHRâ€²4)mâ€”â€ƒâ€ƒIII â€ƒwherein m is zero or an integer from 1 to 5, Râ€² is an aliphatic hydrocarbon cyclic system having 3 to 8 carbon atoms in the ring, 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, Râ€²4 is hydrogen, alkyl, amino- or hydroxy- or alkoxy-substituted alkyl, 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 a group of the same general formula as Râ€²1 as defined herein above; Râ€²2 and Râ€²3 are the same as Râ€²1 or 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 or an esterified carboxyl having 1 to 4 carbon atoms, or alkenyl; or b4) Râ€²1 is an optionally substituted aryl group of general formula IV: â€ƒwherein Râ€²5 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 Râ€²2 and Râ€²3 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 Râ€²1; provided that when the HMG-CoA reductase inhibitor is lovastatin, the amine is not tetramethylamine or ethylenedianine, when the HMG-CoA reductase inhibitor is tetrahydro-M4 or tetrahydro-IsoM-4, the amine is not octylamine, 2-ethylhexylamine, benzylamine, &agr;-methyl-benzylamine, phenethyline, dibenzylamine, N-methylbenzylamine, N,N-dimethylbenzylanine, N,N-diethylbenzylamine, N-ethyl-N-methylbenzylamine, tribenzylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, N-methylcyclopentylamine, N-ethylcyclohexylamine, N-ethylcycloheptylamine, dicyclohexylamine, N,N-dimethylcyclopentylamine, N,N-dimethylcyclohexylamine, N,N-diethylcyclobeptylamine, pyrrolidine, N-methylpyrrolidine, piperidine, N-methylpiperidine or morpholine; and when the HMG-CoA reductase inhibitor is the octahydronaphthalene oxime derivative of ML-236A, ML-236B, MB-530A or MB-530B, the amine is not t-octylamine, dibenzylamine, dicyclohexylamine or morpholine.