Somatostatin antagonists and agonists that act at the sst subtype 2 receptor

Abstract

Compounds according to the formula: 1 and pharmaceutically acceptable salts, solvates or hydrates thereof, wherein group Ar is optionally substituted (C.sub.6-C.sub.10)aryl or (C.sub.1-C.sub.9)heteroaryl; X is a direct link, --CH.sub.2 --, --SO.sub.2 --, --CO--, --CHR.sup.1-- where R.sup.1 is(C.sub.1-C.sub.6) alkyl, or --CR.sup.1'R.sup.1"-where both R.sup.1' and R.sup.1" are, independently, (C.sub.1-C.sub.6)alkyl; Y is N or CH; and Z and W are as herein defined, and pharmaceutical compositions thereof, and methods useful to facilitate secretion of growth hormone(GH) in mammals.

Description

FIELD OF THE INVENTION[0001] The present invention provides pharmaceutically active compounds that facilitate secretion of growth hormone (GH) by the anterior pituitary. Growth hormone (also known as somatotropin) acts indirectly to promote skeletal growth in children by stimulating the production of insulin like growth factor-1 from the liver. Growth hormone also stimulates the differentiation of fat cells and chondrocytes (cells that secrete collagen and proteoglycans to form cartilage). In adults, growth hormone is involved in the proper maintenence of connective and muscle tissues.[0002] Growth hormone deficiency may be congenital or acquired. Deficiency in children causes slow skeletal growth that, if not corrected, results in permanent short stature. In older adults, deficiency of growth hormone results in frailty. Additional adult symptoms of GH deficiency may include wrinkled skin and hypoglycemia.[0003] For veterinary application, upregulation of growth hormone is useful to...

AI Technical Summary

Benefits of technology

[0082] The subject invention also includes isotopically-labelled compounds, which are identical to those recited in Formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as .sup.2H .sup.3H, .sup.13C .sup.14C .sup.15N, .sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F, and .sup.36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as .sup.3H and .sup.14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., .sup.3H, and carbon-14, i.e., .sup.14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., .sup.2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of Formula (I) of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

[0088] In a further preferred example of the invention, there is provided a method for treating a non-human mammal to enhance the growth and performance thereof, comprising administering an effective amount of a pharmaceutical composition as aforementioned. Enhancement of growth and performance includes, for example, increased feed efficiency, improved milk yield or fertility, and increased leanness.

[0089] A highly preferred example of the invention provides a method whereinby secretion of growth hormone, gastrin, or glucagon can be increased on a sustained basis in a mammal, including a human, in need thereof, comprising adminstering a dose of a pharmaceutical composition as aforementioned. According to this example of the invention, physiologically adverse consequences of artificial fluctuations in the circulating (or locally needed) concentrations of these hormones can be avoided.

Problems solved by technology

Deficiency in children causes slow skeletal growth that, if not corrected, results in permanent short stature.

In older adults, deficiency of growth hormone results in frailty.

Although direct administration of growth hormone may be effective in certain therapeutic applications, it is difficult in practice.

Among other issues, since the half-life of growth hormone in the body is very short, direct administration leads to artificially increased levels in the concentration of circulating GH, which then rapidly drop off.

Sustained release, such as by a mechanical pump, has not been optimally set to practice.

However, such compounds are short peptides, a class of molecules not often suited for successful use as pharmaceuticals because of their typically short half life in the body.

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