Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-11-26
1999-08-10
Ramsuer, Robert W.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546146, 514307, 514310, A61K 31475, C07D21706
Patent
active
059360895
DESCRIPTION:
BRIEF SUMMARY
This invention relates to dipeptide compounds which are growth hormone releasing peptide (GHRP) mimetics and are useful for the treatment and prevention of osteoporosis.
BACKGROUND OF THE INVENTION
Growth hormone, which is secreted from the pituitary, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic process of the body: energy.
A deficiency in growth hormone secretion can result in various medical disorders, such as dwarfism.
It is now widely recognized that most human growth deficiencies are due to hypothalamic defects that impair the release of pituitary growth hormone and are not the result of a primary deficit in the production of growth hormone by the pituitary. As a result, the development of synthetic growth hormone-releasing agents and the use of drugs acting through established neurotransmitter systems in the brain to stimulate growth hormone release are being considered as alternatives to highly expensive growth hormone replacement therapy for the restoration of normal serum growth hormone levels. Strobel and Thomas, Pharm. Rev. 46, No. 1, pg. 1-34 (1994).
Various ways are known to release growth hormone. For example, chemicals such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasopressin, and insulin induced hypoglycemia, as well as activities such as sleep and exercise, indirectly cause growth hormone to be released from the pituitary by acting in some fashion on the hypothalamus perhaps either to decrease somatostatin secretion or to increase the secretion of the known secretagogue growth hormone releasing factor (GRF) or an unknown endogenous growth hormone-releasing hormone or all of these.
In cases where increased levels of growth hormone were desired, the problem was generally solved by providing exogenous growth hormone or by administering an agent which stimulated growth hormone production and/or release. In either case the peptidyl nature of the compound necessitated that it be administered by injection. Initially the source of growth hormone was the extraction of the pituitary glands of cadavers. This resulted in a very expensive product and carried with it the risk that a disease associated with the source of the pituitary gland could be transmitted to the recipient of the growth hormone. Recently, recombinant growth hormone has become available which, while no longer carrying any risk of disease transmission, is still a very expensive product which must be given by injection or by a nasal spray.
Other compounds have been developed which stimulate the release of endogenous growth hormone such as analogous peptidyl compounds related to GRF or the peptides of U.S. Pat. No. 4,411,890. These peptides, while considerably smaller than growth hormones are still susceptible to various proteases. As with most peptides, their potential for oral bioavailability is low.
WO 94/13696 refers to certain spiropiperidines and homologs which promote release of growth hormone. Preferred compounds are of the general structure shown below. ##STR2##
WO 94/11012 refers to certain dipeptides that promote release of growth hormone. These dipeptides have the general structure ##STR3## where L is ##STR4##
The compounds of WO 94/11012 and WO 94/13696 are reported to be useful in the treatment of osteoporosis in combination with parathyroid hormone or a bisphosphonate.
SUMMARY OF THE INVENTION
This invention provides a compound of the formula: ##STR5## wherein Z is --COC*R.sup.1 R.sup.2c LCOANR.sup.4 R.sup.5 ;
W is hydrogen or in combination with X is a benzo fusion in which W and X are linked to form a phenyl ring optionally substituted with one to three substituents independently selected from R.sup.3a, T-R.sup.3b and R.sup.12 ;
Y is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.10 cycloalkyl or aryl-K-, phenyl-(C.sub.1 -C.sub.6 alkyl)-K- or thienyl-(C.sub.1 -C.sub.6 alkyl)-K-, each ring optionally substituted with one to three substituents selected from R.sup.3a, R.sup.3b
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Strobel and Thomas, Pharm. Rev., 46(1), 1-34 (1994).
Carpino Philip A.
Dasilva-Jardine Paul A.
Lefker Bruce A.
Ragan John A.
Ginsburg Paul H.
Pfizer Inc
Ramsuer Robert W.
Richardson Peter C.
Speer Raymond M.
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