Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1991-05-08
1993-09-14
Springer, David B.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548465, 548504, 548507, C07D40706, C07D20920, C07D20906, C07D20922, C07D
Patent
active
052450465
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention provides novel compounds. More particularly, the present invention provides novel .alpha.-amino-indole-3-acetic acids, tryptophans and their derivatives. The compounds are useful as anti-diabetic, anti-obesity and anti-atherosclerotic agents.
INFORMATION DISCLOSURE
.alpha.-Amino-indole-3-acetic acid, tryptophan and some of their derivatives are described in the literature. Thus, U.S. Pat. No. 3,074,942 discloses .alpha.-amino-indole-3-acetic acid and derivatives thereof that are described as being useful as anaesthetics, CNS depressants and as antagonists to serotonin, acetylcholine and histamine. Some of these same compounds are disclosed in U.S. Pat. No. 4,492,694, to Baker, J. W., Journal of Chemical Society, 458 (1940); Casnati et al, Gazz Chim. Ital., 93, 355 (1963); Dawes et al, Nature, 164, 705 (1949); Netherland published application 6,607,754; Armstrong et al, J. Biol. Chem., 232, 17 (1958).
U.S. Pat. No. 4,492,694 discloses acylated .alpha.-amino derivatives of .alpha.-amino-indole acetic acid.
U.S. Pat. No. 3,320,280, Netherland application 6,415,318, U.S. Pat. No. 3,316,260 and British patent 1,087,359 disclose .alpha.-(3-indolyl)lower aliphatic acid derivatives that contain a methyl substituent at the 2-position of the indole ring. Another feature of the compounds disclosed in U.S. Pat. No. 3,320,280 is the presence of an aromatic carboxylic acyl radical of less than three fused rings attached to the nitrogen atom of the indole ring.
U.S. Pat. No. 3,000,888 and Biekert et al, Ber., 97, 363 (1964) discloses an .alpha.-amino-indole-3-acetic acid derivative in which morpholino has been substituted for the .alpha.-amino group. It is described as being a therapeutic agent and an intermediate for preparing therapeutic agents.
German Offn. 2,345,775 and European patent application 7,615 published Feb. 6, 1980 discloses .alpha.-amino-indole-3-acetic acid derivatives having methyl and ethenyl substituents respectively, on .alpha.-carbon.
Yoneda, N., Chem. Pharm. Bull. 13, 1231 (1965), Kametani et al, J. Heterocycl. Chem., 5, 799 (1968), French patent 1,100,016 and Yamada et al, Chem. Pharm. Bull., 13, 88 (1965) disclose tryptophan derivatives in which one or both of the nitrogen atoms have been alkylated.
Preobrazhenskaya et al. Khim. Geterotsikl. Soedin, 7, 778 (1971) discloses tryptophan derivatives wherein the carboxylic acid group has been replaced by a hydroxyl, alkoxyl or benzyloxy group.
To applicants' knowledge, tryptophan is the only indole .alpha.-amino acid for which blood sugar altering effects have been reported.
Tryptophan reduced blood sugar levels in normal rats but not in rats with severe alloxan diabetes. Mirsky et al, Endocrinology, 59, 369 (1956) and Endocrinology, 6, 3180 (1957).
L-Tryptophan (2.5 mmoles/kg) administered i.p. to fasted rats blocked epinephrine-induced hyperglycemia 76%-89% and inhibited epinephrine-induced hyperglycemia to the same extent in both intact and diabetic rats indicatin that insulin was not involved in preventing the hyperglycemic response. Sanders et al, Pharmacology, 6, 155 (1971).
Fasting blood glucose levels were not affected by intragastric administration (120 mg/rat) of DL-tryptophan to female rats. The rise in blood glucose following glucose ingestion (1 g/rat) was decreased by DL-tryptophan as compared with rats receiving glucose only. Szigeti et al, Nahrung, 13, 171 (1969).
It was reported that tryptophan administered through the stomach does not produce hyperglycemia. Bedo et al, Egeszegtudomany, 13, 249 (1969).
Tryptophan facilitated deposition of glycogen, increased the liver weight, but decreased the pyruvate incorporation 7.5 times into liver glycogen. Lutkic et al, Bull. Sci., Cons., Acad. Sci. Arts RSF yougoslavie, Sect. A., 18, 8 (1973).
The oral administration of 10 g L-tryptophan to healthy human subjects induced a small but significant rise in blood sugar, a slight increase in blood insulin, a marked increase in plasma glucagon, and delayed increase in plasma growth hormone. This c
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Lin Chiu-Hong
Sih John C.
Tanis Steven P.
Youngdale Gilbert A.
Springer David B.
The Upjohn Company
Williams, Jr. Sidney B.
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