Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1986-12-29
1987-10-27
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514369, 546246, 546274, 548183, C07D41710, A61K 31425
Patent
active
047030526
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to certain compounds of the formula ##STR1## having utility as hypoglycemic agents, methods for their use and pharmaceutical compositions containing them.
BACKGROUND ART
In spite of the early discovery of insulin and its subsequent wide-spread use in the treatment of diabetes, and the later discovery and use of sulfonylureas (e.g. chlorpropamide, tolbutamide, acetohexamide, tolazamide) and biguanides (e.g. phenformin) as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory. The use of insulin, necessary in about 10% of diabetic patients in which synthetic hypoglycemic agents are not effective (Type I diabetes, insulin dependent diabetes mellitus), requires multiple daily, usually self, injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in the urine or in the blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type II diabetes) usually consists of a combination of diet, exercise, oral agents, e.g., sulfonylureas, and in more severe cases, insulin. However, the clinically available hypoglycemics are unfortunately fraught with other toxic manifestations which limit their use. In any event, where one of these agents may fail in an individual case, another may succeed. A continuing need for hypoglycemic agents, which may be less toxic or succeed where others fail, is clearly evident.
In addition to the hypoglycemic agents cited above, a variety of other compounds have been reported to possess this type of activity, as reviewed recently by Blank [Burger's Medicinal Chemistry, Fourth Edition, Part II, John Wiley and Sons, N.Y. (1979), pp. 1057-1080].
U.S. Pat. No. 4,342,771 discloses a class of oxazolidinedione hypoglycemic agents of the general formula ##STR2## where R.sup.a is H or certain acyl groups and R.sup.b is certain mono- or bicyclic heterocyclic groups.
European Patent Application No. 117,035 discloses a group of 5-phenylthiazolidine-2,4-dione hypoglycemic agents of the formula ##STR3## where R.sup.c is lower alkyl, X.sup.a is F, Cl or Br and Y.sup.a is H, Cl, lower alkyl or lower alkoxy.
U.S. Pat. No. 4,461,902 discloses certain 5-[(4-cyclohexylmethoxyphenyl)methyl]thiazolidine-2,4-dione hypoglycemic agents of the formula ##STR4## where R.sup.d is H or lower alkyl and Y.sup.b is an oxo or hydroxy group.
DISCLOSURE OF INVENTION
The present invention relates to compounds of the formula ##STR5## or a pharmaceutically acceptable cationic salt thereof, wherein the broken line is a bond or no bond, n is zero, 1, or 2; X is O, S, ##STR6## CH.sub.2, C.dbd.O, CHOH or NR.sub.5 where R.sub.5 is H, formyl, (C.sub.2 -C.sub.5)alkanoyl, benzyloxycarbonyl, CO(CH.sub.2).sub.x C.sub.6 H.sub.5 where x is an integer from 1 to 3, (C.sub.1 -C.sub.6)alkyl, said alkyl optionally substituted by HO, Cl, Br, OCH.sub.3, phenyl or COOR.sub.6 where R.sub.6 is (C.sub.1 -C.sub.4)alkyl; R is H, CH.sub.3 or C.sub.2 H.sub.5 ; when taken separately, R.sub.1 is H, (C.sub.5 -C.sub.7)cycloalkyl, (C.sub.6 -C.sub.8)methylsubstituted cycloalkyl, pyridyl, thienyl, furyl, naphthyl, p-biphenylyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, C.sub.6 H.sub.4 W.sub.2 or alk-W.sub.1 and alk is (C.sub.1 -C.sub.6)alkylene, ethylidene or isopropylidene; W.sub.1 is H, OH, (C.sub.1 -C.sub.4)alkoxy, (C.sub.1 -C.sub.4)thioalkyl, pyridyl, furyl, thienyl, tetrahydrofuryl, tetrahydrothienyl, naphthyl, (C.sub.5 -C.sub.7)cycloalkyl or C.sub.6 H.sub.4 W.sub.2 and W.sub.2 is H, OH, F, Cl, Br, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy or (C.sub.1 -C.sub.4)thioalkyl; R.sub.2 is H or CH.sub.3, R.sub.3 is H, (C.sub.1 -C.sub.6)alkyl, C.sub.6 H.sub.4 W.sub.2 or benzyl; and R.sub.4 is H;
when R.sub.1 and R.sub.2 are taken together they form (C.sub.4 - C.sub.6)alkylene and R.sub.3 and R.sub.4 are each H;
when R.sub.3 and R.sub.4 are taken together they form (C.
REFERENCES:
patent: 4461902 (1984-07-01), Kawamatsu
patent: 4572912 (1986-02-01), Yoshioka
Eggler James F.
Holland Gerald F.
Johnson Mickael R.
Volkmann Robert A.
Blackwood Robert K.
Frost Albert E.
Gerstl Robert
Pfizer Inc.
Richardson Peter C.
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