Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1997-07-08
1999-10-19
Carr, Deborah D
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
514557, 514559, 514866, 534225, 534226, A01N 3700
Patent
active
059689820
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns 2,2-dichloroalkane-carboxylic acids, processes for their production and pharmaceutical agents containing these compounds.
The invention concerns 2,2-dichloroalkanecarboxylic acids of the general formula I ##STR2## in which A denotes an alkylene chain with 5-20 carbon atoms, chain with 1-10 carbon atoms, NR.sup.1, in which residue, a carbonyl, sulfonamide, sulfoxide or sulfonyl group, an E- or Z-vinylene or an acetylene group, a CR.sup.2 R.sup.3 group, in which a group NR.sup.4 R.sup.5, in which and group, a methyl, isopropyl or tert.-butyl residue; a C.sub.3 -C.sub.8 cycloalkyl residue which can be unsubstituted or be substituted by phenyl or C.sub.1 -C.sub.4 alkyl; a cyclohexenyl or cyclopentenyl residue, a phenyl ring which can be substituted by one or any combination of the following substituents: C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.4 alkylthio, C.sub.1 -C.sub.4 alkylsulfinyl, C.sub.1 -C.sub.4 alkylsulfonyl, trifluoromethyl, nitro, amino, hydroxy, cyano, mercapto, sulfonamino, acetylamino, carboxy, phenoxy, benzyloxy, phenyl, benzoyl, carboxy-C.sub.1 -C.sub.4 alkyl, methylenedioxy, ethylenedioxy, fluorine, chlorine, bromine, iodine, carboxymethoxy, carboxyethoxy, acetoxy, acetyl, propionyl, a NR.sup.6 R.sup.7 group, in which R.sup.6 denotes hydrogen, C.sub.1 -C.sub.4 alkyl or benzyl and R.sup.7 denotes hydrogen, C.sub.1 -C.sub.4 alkyl, benzyl, phenyl, or benzoyl whereby the respective aromatic ring is optionally unsubstituted, or can be substituted by one or any combination of the following substituents: halogen, hydroxy or C.sub.1 -C.sub.4 alkoxy; furthermore an .alpha.- or .beta.-naphthyl ring which can be substituted by methyl, hydroxy, methoxy, carboxy, methoxycarbonyl, ethoxycarbonyl, cyano, acetyl, chlorine or bromine or a tetrahydronaphthyl residue, which are hydrolyzed or metabolized in vivo to compounds of the general formula I. If chiral compounds are formed by substitution of the alkylene chain in I with the described residues, the substances in the R as well as S configuration are a subject matter of the invention C.sub.1 -C.sub.4 -alkyl residues denotes for branched or unbranched alkyl groups.
Compounds of formula I have valuable pharmacological properties. They normalize an increased glucose level without a concomitant risk of hypoglycaemia and are thus excellently suited for the therapy of diabetes mellitus.
Previous mechanisms of action of oral antidiabetics such as the generally used sulfonyl ureas are based on an increased release of insulin from the .beta.-cells of the pancreas, a mechanism which in the long term leads to the complete exhaustion of the endogenous production of insulin in diabetics. The modern view of the pathobiochemistry of adult-onset diabetes therefore emphasizes the need to treat the peripheral insulin resistance that is present in this case.
Compounds of formula I improve glucose utilization e.g in muscle, they decrease hyperinsulinaemia by increasing insulin sensitivity and thus comply exactly with the therapy concept.
Diabetics often suffer from a complete derangement of the entire metabolic condition characterized by hyperlipidaemia, increase in cholesterol, hypertension, adiposity and hyperinsulinaemia, a clinical picture which is denoted metabolic syndrome or syndrome X and leads to a very wide range of late complications. Apart from decreasing hyperinsulinaemia compounds of the general formula I additionally decrease triglycerides, cholesterol and fibrinogen and are thus excellently suitable for treating the metabolic syndrome.
Compounds of the general formula I in which W denotes a chlorine atom and A-B-A' denotes an alkylene chain --(CH.sub.2).sub.n -- have already been described with no information about a pharmacological effect. Thus the ethyl ester of 2,2,8-trichlorooctanoic acid (n=6) is described in Doklady Akad. Nauk S.S.S.R. 127, 1027 (1959). Izvest. Akad. Nauk S.S.S.R. 1960, 1215 describes the synthesis of 2,2,8-trichloro-octanoic acid (n=6), 2,2,6-trichlorohexanoic acid (n=4) and 2,2,6-tr
REFERENCES:
J. Med. Chem. 1989, 32, pp. 2072-2084; Jacob Bar-Tana, et al; Nov. 22, 1988.
Bull. Soc. Chim. Belg. vol. 97(7) 1988; pp. 525-533; De Buyck et al.
Ind. Eng. Chem. Res. 1992, 31, pp. 2425-2437; Paatero, et al.
Bull. Chem. Soc. Jpn., 67, pp. 1622-1626 (1994); M. Boni, et al.
Tetrahedran Lett, 1994, pp. 2961-2964: Bellesia et al.
Freund Peter
Pill Johannes
Voss Edgar
Carr Deborah D
Roche Diagnostics GmbH
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