Peptide compounds for treatment of no-mediated diseases

Details Peptide compounds for treatment of no-mediated diseases Peptide compounds for treatment of no-mediated diseases

1997-05-30

1999-08-03

Ramsuer, Robert W.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

514333, A61K 3144, C07D40714

Patent

active

059327375

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to new peptide compounds and pharmaceutically acceptable salt thereof which are useful as a medicament.


BACKGROUND ART

Some peptide compounds have been known as described, for example, in EP 0 394 989 A2.


DISCLOSURE OF INVENTION

This invention relates to new peptide compounds.
One object of this invention is to provide the new and useful peptide compounds and pharmaceutically acceptable salts thereof which possess a strong inhibitory activity on the production of nitric oxide (NO).
Another object of this invention is to provide process for preparation of the peptide compounds and salts thereof.
A further object o this invention is to provide a pharmaceutical composition comprising said peptide compounds or a pharmaceutically acceptable salt thereof.
Still further object of this invention is to provide a use of said peptide compounds or a pharmaceutically acceptable salt thereof as a medicament for prophylactic and therapeutic treatment of NO-mediated diseases such as adult respiratory distress syndrome, cardiovascular ischemia, myocarditis, heart failure, synovitis, shock (e.g., septic shock, etc.), diabetes (e.g. insulin-dependent diabetes mellitus, etc.), diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, glomerulonephritis, peptic ulcer, inflammatory bowel disease (e.g., ulcerative colitis, chronic colitis, etc.), cerebral infarction, cerebral ischemia, migraine, rheumatoid arthritis, gout, neuritis, postherpetic neuralgia, osteoarthritis, osteoporosis, systemic lupus erythematosis, rejection by organ transplantation, asthma, metastasis, Alzheimer's disease, arthritis, CNS disorders, and the like in human being and animals.
The object peptide compounds of the present invention are novel and can be represented by the following general formula (I) ##STR2## wherein W is lower alkyl, aryl which may have suitable substituent(s), fluorenyl which may have suitable substituent(s), heteromonocyclic group which may have suitable substituent(s), or a group of the formula: ##STR3## di(lower)alkylamino, amino, protected amino, hydroxyamino or lower alkoxy, ##STR4## (in which Y is CH or N, Z is NH, O or S, and ##STR5## (in which M is CH or N, and J is CH or N)!, ##STR6## (in which V is O or S), or --SO.sub.2 --, T is hydrogen, aryl which may have suitable substituent(s), heterocyclic group, hydroxy, acyloxy, ar(lower)alkoxy, sulfooxy, mercapto, lower alkylthio, mono(or di or tri)ar(lower)alkylthio, acylthio, amino, protected amino, guanidino, acylguanidino or a group of the formula: ##STR7## (in which R.sup.2 is hydroxy, ar(lower)alkoxy, morpholinyl, piperazinyl which may have suitable substituents), piperidyl which may have suitable substituent(s), pyrrolidinyl, thiomorpholinyl, homopiperazinyl which may have suitable substituent(s), piperazinlo which may have suitable substituent(s), piperidyloxy which may have suitable substituent(s), or amino having one or two suitable substituent(s), form ##STR8## R.sup.3 is hydrogen, aryl which may have suitable substituent(s), hydroxy, protected hydroxy, cyclo(lower)alkyl, lower alkylthio, or heterocyclic group which may have suitable substituent(s), to form ##STR9## and R.sup.4 is carboxy, protected carboxy, heterocycliccarbonyl which may have suitable substituent(s), or a group of the formula: ##STR10## (in which R.sup.5 is hydrogen or lower alkyl, and R.sup.6 is hydrogen, aryl, ar(lower)alkyl which may have suitable substituent(s), have suitable substituent(s)), or to form ##STR11## (in which R.sup.10 is ar(lower)alkyl), with proviso that
The main object compound (I) of the present invention can be prepared by the following processes. ##STR12## Process (2) ##STR13## Process (3) ##STR14## Process (4) ##STR15## Process (5) ##STR16## wherein W, T, A.sup.1, A.sup.2, A.sup.3, V, R.sup.3, R.sup.4, R.sup.8 and R.sup.9 are each as defined above, and ##STR17## is morpholino, piperazino which may have suitable substituent(s), piperidino which may have suitable substituent s), pyrrolidino, thiomorpholino, homopiperazino which

REFERENCES:
D. Hagiwara et al, "3tudies on Neurokinin Antagonist, 3, Design and Structure-Activity Relationships or New Branched Tripeptides Nalpha, (Substituted L-aspartyl, L-ornithyl, or L-lysyl)-N-(phenylmethyl-L-phenylalaninamides as Substance P Antagonists", J. Med.Chem. vol. 36 1993, pp. 2266-2278 (XP002006315).
D. Hagiwara et al: "Studies on Neurokinin Antagonists. 4", (see Table 1), J. Med. Chem, vol. 37, Jun. 21, 1991, pp. 2090 99, (XP002006316).

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