Compounds with growth hormone releasing properties

Details Compounds with growth hormone releasing properties Compounds with growth hormone releasing properties

1995-06-06

1998-06-16

Russel, Jeffrey E.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 18, 514 19, 530329, 530330, 530331, 546265, 5462804, 5462811, 546337, 548454, 548455, 548465, 548496, 549 58, 549 59, 549 77, 562445, 562448, 562450, 564155, 564164, A61K 3805, A61K 3806, A61K 3807, A61K 3808

Patent

active

057670854

DESCRIPTION:

BRIEF SUMMARY
FIELD OF INVENTION

The present invention relates to novel peptide derivatives, compositions containing them, and their use for treating medical disorders resulting from a deficiency in growth hormone.


BACKGROUND OF THE INVENTION

Growth hormone is a hormone which stimulates growth of all tissues capable of growing. In addition, growth hormone is known to have a number of effects on metabolic processes, e.g., stimulation of protein synthesis and free fatty acid mobilization and to cause a switch in energy metabolism from carbohydrate to fatty acid metabolism. Deficiency in growth hormone can result in a number of severe medical disorders, e.g., dwarfism.
Growth hormone is released from the pituitary. The release is under tight control of a number of hormones and neurotransmitters either directly or indirectly. Growth hormone release can be stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin. In both cases the hormones are released from the hypothalamus but their action is mediated primarily via specific receptors located in the pituitary. Other compounds which stimulate the release of growth hormone from the pituitary have also been described. For example arginine, L-3,4-dihydroxyphenylalanine (L-Dopa), glucagon, vasopressin, PACAP (pituitary adenylyl cyclase activating peptide), muscarinic receptor agonists and a synthethic hexapeptide, GHRP (growth hormone releasing peptide) release endogenous growth hormone either by a direct effect on the pituitary or by affecting the release of GHRH and/or somatostatin from the hypothalamus.
In disorders or conditions where increased levels of growth hormone is desired, the protein nature of growth hormone makes anything but parenteral administration non-viable. Furthermore, other directly acting natural secretagogues, e.g., GHRH and PACAP, are longer polypeptides for which reason oral administration of them is not viable.
The use of shorter peptides for increasing the levels of growth hormone in mammals has previously been proposed, e.g. in EP 18 072, EP 83 864, WO 89/07110, WO 89/01711, WO 89/10933, WO 88/9780, WO 83/02272, WO 91/18016, WO 92/01711 and WO 93/04081.
The composition of growth hormone releasing peptides or peptide derivatives is important for their growth hormone releasing potency as well as their bioavailability. It is therefore the object of the present invention to provide peptides with growth hormone releasing properties which have improved properties relative to known peptides of this type.


SUMMARY OF THE INVENTION

Accordingly, the present invention relates to a compound of general formula I --CO--, wherein piperidino or N(R.sup.2)-- lower alkyl optionally substituted by one or more hydroxyl, pyridinyl or furanyl groups; and ##STR1## wherein each of R.sup.16 and R.sup.17 is independently hydrogen or lower alkyl; natural L-amino acids or their corresponding D-isomers, or non-natural amino acids such as 1,4-diaminobutyric acid, aminoisobutyric acid, 1,3-diaminopropionic acid, 4-aminophenylalanine, 3-pyridylalanine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1,2,3,4-tetrahydronorharman-3-carboxylic acid, N-methylanthranilic acid, anthranilic acid, N-benzylglycine, 3-aminomethylbenzoic acid, 3-amino-3-methyl butanoic acid, sarcosine, nipecotic acid or iso-nipecotic acid; and wherein, when both t and u are 1, the amide bond between G and H is optionally substituted by ##STR2## wherein Y is >C.dbd.O or ##STR3## and R.sup.18 is hydrogen, lower alkyl or lower aralkyl; C is a D-amino acid of formula --NH--CH((CH.sub.2).sub.w --R.sup.4)--CO--wherein w is 0, 1 or 2; and ##STR4## each of which is optionally substituted with halogen, lower alkyl, lower alkyloxy, lower alkylamino, amino or hydroxy; --R.sup.5)--CO--or, when p is 0, --CH((CH.sub.2).sub.m--R.sup.5)--CO--R.sup.6, wherein ##STR5## each of which is optionally substituted with halogen, alkyl, alkyloxy amino or hydroxy; and or--N(R.sup.7)--R.sup.8, wherein each of R.sup.7 and R.sup.8 is independently hydrogen or lower alkyl; piperidino, 1.sup.19 ##STR6## w

REFERENCES:
patent: 4223019 (1980-09-01), Momany
patent: 4223020 (1980-09-01), Momany
patent: 4228156 (1980-10-01), Momany
patent: 4410512 (1983-10-01), Bowers

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