Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-12-14
1998-06-16
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5462781, 548181, 548491, 548113, 544333, A61K 3144, C07D40112
Patent
active
057671338
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/IB9,400,117, which is now published as WO94/29290 on Dec. 22, 1994.
BACKGROUND OF THE INVENTION
The present invention relates to certain compounds of the formula (I) depicted below, having utility as hypoglycemic and antiobesity agents, methods for their use and pharmaceutical compositions containing them. The compounds of the present invention also possess utility for increasing lean meat deposition and/or improving the lean meat to fat ratio in edible animals, i.e. ungulate animals and poultry.
The disease diabetes mellitus is characterized by metabolic defects in production and utilization of carbohydrates which result in the failure to maintain appropriate blood sugar levels. The result of these defects is elevated blood glucose or hyperglycemia. Research in the treatment of diabetes has centered on attempts to normalize fasting and postprandial blood glucose levels. Current treatments include administration of exogenous insulin, oral administration of drugs and dietary therapies.
Two major forms of diabetes mellitus are recognized. Type I diabetes, or insulin-dependent diabetes, is the result of an absolute deficiency of insulin, the hormone which regulates carbohydrate utilization. Type II diabetes, or non-insulin dependent diabetes, often occurs with normal, or even elevated levels of insulin and appears to be the result of the inability of tissues to respond appropriately to insulin. Most of the Type II diabetics are also obese.
The compounds of the present invention and the pharmaceutically active salts thereof effectively lower blood glucose levels when administered orally to mammals with hyperglycemia or diabetes.
The compounds of the present invention also decrease weight gain when administered to mammals. The ability of these compounds to affect weight gain is due to activation of .beta.-adrenergic receptors which stimulate the metabolism of adipose tissue.
.beta.-Adrenergic receptors can be divided into .beta..sub.1, .beta..sub.2 and .beta..sub.3 -subtypes. Activation of .beta..sub.1 -receptors invokes increases in heart rate while activation of .beta..sub.2 -receptors induces relaxation of smooth muscle tissue which produces a drop in blood pressure and the onset of smooth muscle tremors. Activation of .beta..sub.3 -receptors stimulates lipolysis (the breakdown of adipose tissue triglycerides to glycerol and free fatty acids), and thereby promotes the loss of fat mass. Compounds that stimulate .beta..sub.3 -receptors will have anti-obesity activity. In addition, compounds which are .beta..sub.3 -adrenoceptor agonists have hypoglycemic or anti-diabetic activity, but the mechanism of this effect is unknown. A compound that selectively stimulates .beta..sub.3 -receptors, i.e., has little or no .beta..sub.1 or .beta..sub.2 -activity, will have the desired anti-diabetic and/or anti-obesity activity, but without the undesirable effects of increased heart rate (.beta..sub.1 -effect) or muscle tremor (.beta..sub.2 -effect). The use of .beta..sub.3 -adrenoceptor agonists as antidiabetic, hypoglycemic and antiobesity agents has been frustrated, however, by the lack of selectivity of these agents for .beta..sub.3 -adrenoceptors over the other two other adrenoceptors, .beta..sub.1, and .beta..sub.2. The compounds of the present invention are selective .beta..sub.3 adrenoceptor agonists.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula ##STR2## wherein R.sup.1 is phenyl, --(CH.sub.2).sub.n --O-phenyl, pyridyl, pyrimidyl or thiazolyl; wherein said phenyl and the phenyl moiety of said --(CH.sub.2).sub.n --O-phenyl may optionally be substituted with one or more substituents independently selected from hydrogen, (C.sub.1 -C.sub.6)alkyl optionally substituted with one or more halo atoms, hydroxy, (C.sub.1 -C.sub.6)alkoxy optionally substituted with one or more halo atoms, (C.sub.1 -C.sub.6)alkylthio, fluoro, chloro, bromo, iodo, nitro, amino, --NR.sup.7 R.sup.8 and cyano; and wherein each of the ring carbon atoms of said pyridyl, pyrimid
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Dow Robert L.
Wright Stephen W.
Aulakh Charandit S.
Benson Gregg C.
Ivy C. Warren
Pfizer Inc.
Richardson Peter C.
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