Oxiranecarboxylic acids for the treatment of diabetes

Details Oxiranecarboxylic acids for the treatment of diabetes Oxiranecarboxylic acids for the treatment of diabetes

2002-06-18

2003-12-30

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06670481

ABSTRACT:

AREA OF APPLICATION OF THE INVENTION
The invention relates to novel arylalkyl- or aryloxylalkyl-substituted oxiranecarboxylic acids, to processes for their preparation, to their use and to medicaments comprising them.
PRIOR ART
EP 0 046 590 describes hypoglycaemically and hypoketonaemically active phen(alk)oxy-substituted oxiranecarboxylic acids and esters thereof of the general formula A:
in which
R
1
is a hydrogen atom, a halogen atom, a 1-4 C-lower alkyl group, a 1-4 C-lower alkoxy group, a nitro group or a trifluoromethyl group,
R
2
has one of the meanings of R
1
,
R
3
is a hydrogen atom or a 1-4 C-lower alkyl group,
Y is the grouping —O—(CH
2
)
m
—,
m is 0 or an integer from 1 to 4 and
n is an integer from 1 to 8,
where the sum of m and n is an integer from 2 to 8, and the salts of the carboxylic acids.
EP 0 231 367 B1 describes the use of the compounds of the general formula A for the prevention and/or treatment of disorders which are caused by an elevated concentration of cholesterol and/or triglyceride in the organism.
DE-A 4 340 879 A1 describes the use of the compounds of the general formula A in the prevention and/or treatment of cardiac insufficiency.
DE-A 3 032 668 describes, inter alia, non-aromatic cycloalkyl(alk)oxy-substituted oxiranecarboxylic acids.
EP 0 283 168 describes phenylalkyl- and phenoxyalkyloxiranecarboxylic acids and esters thereof having 1-2 fluorine substituents in the alkyl chain which are said to act as inhibitors of fatty acid oxidation with a low potential to cause damage to cardiac muscle function.
DESCRIPTION OF THE INVENTION
The invention provides novel arylalkyl- or aryloxyalkyl-substituted oxiranecarboxylic acids or pharmacologically acceptable salts thereof of the general formula I
in which
Ar is a substituted phenyl radical
R
1
is a hydrogen atom, a halogen atom or a 1-4 C-lower alkyl group,
R
2
is one of the groups
 or a fully or predominantly fluorine-substituted 1-3 C-alkoxy group,
R
3
is a hydrogen atom or a 1-4 C-lower alkyl group,
R
4
is a hydrogen atom, a 1-4 C-lower alkyl group, an optionally fully or predominantly fluorine-substituted 1-3 C-alkoxy group or a halogen atom,
R
5
is a 1-4 C-lower alkyl group,
Y is the grouping —O— or —CH
2
—,
n is an integer from 2 to 8 and
Het is a heterocyclic ring, which preferably has 5 members and is selected from the group consisting of thiophene, thiazole, isothiazole, pyrrole and, particularly preferably, pyrazole, and which may carry 1 or 2 identical or different substituents R
1
,
where the chain —(CH
2
)
n
— may optionally be interrupted by a —CH(CH
3
)— or —C(CH
3
)
2
— unit, and the salts of the corresponding carboxylic acids (R
3
=H).
The 1-4 C-lower alkyl radicals can be straight-chain or branched. Straight-chain alkyl radicals are, for example, the methyl, ethyl, n-propyl and the butyl radical, of which those having 1 to 2 carbon atoms are preferred. Branched alkyl radicals are, for example, the isopropyl, isobutyl and the sec-butyl radical, of which that having 3 carbon atoms is preferred. Suitable alkyl radicals of lower alkoxy groups are both straight-chain and branched lower alkyl groups. A preferred lower alkyl group is the methoxy group. Suitable alkyl radicals in acyl groups are both straight-chain and branched lower alkyl groups, of which the methyl group and the tert-butyl group are preferred.
Halogen atoms are fluorine, chlorine and bromine atoms, of which fluorine and, in particular, chlorine, are preferred.
In the substituted phenyl radicals Ar, the substituents R
1
and R
2
are preferably in the m- or p-position and R
1
is preferably a hydrogen atom.
Among the fully or predominantly fluorine-substituted 1-3—C-alkoxy groups, preference is given to the trifluoromethoxy, the 2,2,2-trifluoroethoxy, the 1,1,2,2-tetrafluoroethoxy group and in particular to the difluoromethoxy group.
Suitable salts are salts with inorganic and organic bases. Pharmacologically unacceptable salts are converted, by methods known per se, into pharmacologically, i.e. biologically, acceptable salts, which are preferred from among the salts according to the invention. Suitable cations for use for salt formation are, in particular, the cations of the alkali metals, alkaline earth metals or noble metals; however, it is also possible to use the corresponding cations of organic nitrogen bases, such as amines, aminoalcohols, amino sugars, basic amino acids, etc.
Examples which may be mentioned are salts of lithium, sodium, potassium, magnesium, calcium, aluminium, ethylenediamine, dimethylamine, diethylamine, morpholine, piperidine, piperazine, N-lower alkyl piperazine (for example N-methylpiperazine), methycyclohexylamine, benzylamine, ethanolamine, diethanolamine, triethanolamine, tris-(hydroxymethyl)-aminomethane, 2-amino-2-methylpropanol, 2-amino-2-methyl-1,3-propanediol, glucamine, N-methylglucamine, glucosamine, N-methylglucosamine, lysine, ornithine, arginine, quinoline.
The arylalkyl- or aryloxyalkyloxiranecarboxylic acids of the general formula I according to the invention have a chiral centre. Accordingly, the invention includes both the racemates and the enantiomers and mixtures thereof. For racemate separation of the carboxylic acids, particular preference is given to using salts with optically active bases, such as cinchonidine or dehydroabietylamine.
The compounds according to the invention have useful pharmacological properties which make them. They have hypoglycaemic and lipid-lowering action and improve the efficacy of insulin in the treatment of insulin-resistant conditions, such as, for example, in the case of metabolic syndrome and, in particular, diabetes type 2.
They are superior to the known oxiranecarboxylic acids of the prior art in the following manner:
a) they are distinguished by a therapeutic index which is significantly better under certain conditions in the manner that the increases of liver enzymes (transaminases) which occur in individual type 2-diabetics occur to a considerably lesser extent, if at all,
b) they have superior action with respect to increasing the effect of insulin in insulin-resistant conditions,
c) they are metabolized more quickly and do not form any long-lasting metabolites.
Owing to their advantageous and superior efficacy, the compounds of the general formula I according to the invention and the pharmacologically acceptable salts are suitable for the treatment and prophylaxis of disorders which are caused by disturbances of glucose and lipid metabolism, in human and veterinary medicine.
They are employed, for example, for treating prediabetic conditions; for the treatment and prevention of the manifestation of diabetes type 2 and of all pathological conditions which are associated with pathological insulin resistance; for the treatment and prevention of the manifestation of all pathological conditions with pathologically elevated production of ketone bodies; for the treatment and prevention of the manifestation of all pathological conditions which are caused by elevated cholesterol and/or triglyceride concentrations in the blood (hyperlipidaemia, arteriosclerosis, coronary heart disease).
The invention also provides the compounds according to the invention for use in the treatment and prophylaxis of the disorders mentioned.
The invention furthermore provides medicaments comprising one or more arylalkyl- or aryloxyalkyloxiranecarboxylic acids of the general formula I
in which
Ar is a substituted phenyl radical
 a 1- or 2-naphthyl radical which is substituted by a radical R
4
or is a heterocyclic radical Het,
R
1
is a hydrogen atom, a halogen atom or a 1-4 C-lower alkyl group,
R
2
is one of the groups
 or a fully or predominantly fluorine-substituted 1-3 C-alkoxy group,
R
3
is a hydrogen atom or a 1-4 C-lower alkyl group,
R
4
is a hydrogen atom, a 1-4 C-lower alkyl group, an optionally fully or predominantly fluorine-substituted 1-3 C-alkoxy group or a halogen atom,
R
5
is a 1-4 C-lower alkyl group,
Y is the grouping —O— or —CH
2
—,
n is an integer from 2 to 8 and
Het is a heterocyclic ring, which preferab

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