Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1987-03-12
1990-06-12
Lee, Mary C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
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Patent
active
049333674
DESCRIPTION:
BRIEF SUMMARY
The subject of the present invention is new carboxylic acid derivatives of the general formula I ##STR1## wherein R.sub.1 is a substituted or unsubstituted aryl or aryloxy moiety, and, in the case where X represents the cyano group, an acylamino group or amino group, with 3-8 carbon atoms which has a chain length of at least 3 carbon atoms, R.sub.5, in which aryl group, the aryl moiety can be substituted, aryl or aralkyl moiety, be interrupted by O, S or NR.sub.6, and phenyl or benzyl moiety, nitriles, provided that, in the case phenyl moiety and methyl, must not be 4-phenylbutyl or 4-(4-methoxyphenyl)butyl, 4-phenylbutyl or 5-phenylpentyl, 3-(2-chlorophenyl)propyl or 5-(4-methoxyphenyl)pentyl.
Of the compounds of the general formula I only a few examples have been known heretofore, with the exception of the norvaline analogues (A=--(CH.sub.2).sub.3 -- and X=NR.sub.4 R.sub.5 and NHCOR.sub.3). The pharmacological action according to the invention has not yet been described in these cases: aromatic ring are described as reaction products (Pallaud et al., C.R. Acad. Sci., Ser. C 1971, 273, 711) (Julia et al., Bull. Soc. Chim. Fr. 1968, 3691; Chottard et al., Compt. Rend. 1964, 259, 2653) 3,562,330, as a precursor of antiarrhythmically active amines. Trost and Hung, J. Am. Chem. Soc. 1983, 105, 7757, as an intermediate. analogues, as well as 2-methyl-2-methylthio-6-(3-methoxyphenyl)hexanoic acid and 2-methyl-2-methylthio-7-(3,4-methylenedioxyphenyl)heptanoic acid are described by Trost et al., J. Org. Chem. 1978, 43, 4549, as intermediates for the production of enol thioethers.
Besides the already-mentioned norvaline analogues (A=--(CH.sub.2).sub.3 --), the following have also already been described as derivatives with an amino function: Pattabiraman et al., Biochem. J. 1972, 126, 645, by Kosui et al., Mem. Fac. Sci., Kyushu Univ., Ser. C 1981, 13, 89, and by Hashimoto et. al., Int. J. Pept. Protein Res. 1983, 21, 11. by Kosui et al., Bull. Chem. Soc. Jpn. 1982, 55, 918 and by Mihara et al., Int. J. Pept. Protein Res. 1984, 23, 447. 2-[(2,4-dinitrophenyl)amino]-7-phenylheptanoic acid by Kawai et al., Tetrahedron Lett. 1975, 2845 and Tetrahedron 1978, 34, 3435. Pharmazie 1983, 38, 22, with 4-cyanophenyl as aryl moiety, and by Vieweg and Wagner in Pharmazie 1983, 38, 818, with 4-methylphenyl and 1-naphthyl as aryl moieties. The two last-named substances are intermediates for the preparation of potential serine proteinase inhibitors. Chem. Soc. Perkin Trans. 1, 1973, 2789, and Kaye et al., DOS 2,060,443, and 2-acetyl-5-(2-chlorophenyl)pentanoic acid, by Amschler et al., Eur. Pat. Appl. 25,192. The latter serves for the preparation of antidiabetically active substances. However, no pharmacological action is attributed to the intermediate. Green, J. Chem. Soc., Perkin Trans. 1, 1974, 394, as a reaction product. et al., Tetrahedron 1969, 25, 4967, and 2-aminocarbonyl-5-phenylpentanoic acid by Gardner and Brandon, J. Org. Chem. 1957, 22, 1704, as reaction products.
The compounds of general formula I possess valuable pharmacological properties. They can be used for the treatment of diabetes, prediabetes, and especially for the treatment of diabetes of the aging.
The compounds of general formula I have no relationship to known antidiabetic compounds either structurally or in the nature of their action. They lower the blood sugar level by an increase of the peripheral glucose oxidation, their action depending upon an increase of the sensitivity of peripheral tissues towards insulin. In contradistinction to the biguanides, no increase of the blood lactate levels is observed. Therefore, the compounds of general formula I are also valuable for the treatment of nondiabetic illnesses in which insulin resistance is present, as for example adipositas and atherosclerosis.
It has furthermore been found that the antidiabetic effectiveness is not limited to the new compounds of the general formula I with the meanings given above for R.sub.1, R.sub.2, A and X, but also that already-known derivatives which are included by the genera
REFERENCES:
Pallaud et al., C. R. Acad. Sci. Ser. C 273:711-713 (1971).
Chottard et al., C. R. Acad. Sci. 259:2653-2657 (1964).
Pattabiraman et al., Biochem. J. 126:645-657 (1972).
Mihara et al., Int. J. Peptide Protein Res. 23:447-453 (1984).
Kawai et al., Tetrahedron 34:3435-3444 (1978).
Vieweg et al., Pharmazie 38:22-24, 818-820 (1983).
Ansell et al., J. Chem. Soc. Perkins Trans. 1:2789-2795 (1973).
Atkinson et al., J. Chem. Soc., Perkins Trans. 1:394-401 (1974).
Chottard et al., Tetrahedron 25:4967-4983 (1969).
Gardner et al., J. Org. Chem. 22:1704-1705 (1957).
Trost et al., J. Am. Chem. Soc. 1983, 105, 7757-7759.
Trost et al., J. Org. Chem., vol. 43, No. 23, 1978, pp. 4549-4551.
Kuhnle Hans-Frieder
Witte Ernst-Christian
Wolff Hans P.
Boehringer Mannheim GmbH
Lee Mary C.
Richter J.
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