Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-06-06
1998-12-29
Russel, Jeffrey E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 17, 514 18, 530322, 530329, 530330, A61K 3807, A61K 3808, A61K 3814, C07K 702
Patent
active
058542116
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a 35 U.S.C. 371 national application of PCT/DK94/00486 filed Dec. 22, 1994, which is incorporated herein by reference.
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 bio-availability. 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
p is 0 or 1;
A is imidazolyl-C.sub.1-6 -alkanoic acid, imidazolyl-C.sub.1-6 alkenoic acid, amino-C.sub.1-6 alkanoic acid or amino-C.sub.1-6 alkenoic acid or a L- or D- .alpha.-amino acid selected from the group consisting of H-His, H-Ala, H-D-Ala, H-(.beta.-alanine), H-Aib, sarcosine and Gly;
B is D-Trp, D-2Nal or D-Phe;
C is Ala, Ser or Gly;
D is Trp, Phe, .beta.-(2-Thienyl)-alanine, or N-aralkyl glycine;
E, when p is 1, is D-Phe, or, when p is 0, E is --NH--CH(CH.sub.2 --R.sup.3)--CO--R.sup.4 or --NH--CH(CH.sub.2 --R.sup.3)--CH.sub.2 --R.sup.4, wherein
R.sup.3 is phenyl,
and R.sup.4 is piperazino, morpholino, piperidino, --OH or --N(R.sup.5)R.sup.6, wherein each of R.sup.5 and R.sup.6 is independently hydrogen or lower allyl;
F, when p is 1, is --NH--CH(R.sup.10)--(CH.sub.2).sub.v --R.sup.7)--, wherein --N(R.sup.9)--R.sup.9, wherein each of R.sup.8 and R.sup.9 is independently hydrogen or lower alkyl, or the Amadori rearrangement product from an amino group and a hexapyranose or a hexapyranosyl-hexapyranose of formula ##STR1## and
R.sup.10 is --H, --COOH, --CO--R.sup.11, CH.sub.2 --R.sup.11 or --CH.sub.2 --OH, wherein R.sup.11 is piperazino, morpholino, piperidino or --N(R.sup.12)--R.sup.13, wherein each of R.sup.12 and R.sup.13 is independen
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Hansen Birgit Sehested
Johansen Nils Langeland
Lau Jesper
Lundt Behrend Friedrich
Madsen Kjeld
Agris, Esq. Cheryl H.
Novo Nordisk A S
Russel Jeffrey E.
Zelson Esq. Steve T.
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