Peptide compounds, their preparation and uses

Details Peptide compounds, their preparation and uses Peptide compounds, their preparation and uses

1997-06-24

1999-03-30

Raymond, Richard L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 19, 530331, 5462774, 5462811, 5462841, 546335, 548495, 549 58, 560 16, 560 41, 562426, 562427, A61K 3806, A61K 3807, C07K 508

Patent

active

058889728

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP94/01042, filed Jun. 28, 1994.


TECHNICAL FIELD

The present invention relates to new compound and a pharmaceutically acceptable salt thereof.
More particularly, it relates to new peptide compound and a pharmaceutically acceptable salt thereof which have pharmacological activities such as endothelin antagonistic activity and the like, to processes for its preparation, to a pharmaceutical composition comprising the same, and to a method of using the same therapeutically in the treatment and the prevention of endothelin mediated diseases such as hypertension, and the like.
Pharmacological and structural evidence supports the existence of at least two endothelin receptor subtypes, i.e., ET.sub.A and ET.sub.B. ET.sub.A receptors are distributed predominantly in vascular smooth muscle, heart and intestine, whereas ET.sub.B receptors are found in cerebral cortex, lung and kidney. Recently, it is found that in addition to ET.sub.A receptors, vasoconstrictor ET.sub.B receptors are also present on vascular smooth muscle. ET.sub.A receptors have a higher affinity to ET-1 than ET-3 and sarafotoxin S6c, while ET.sub.B receptors show nearly the same affinity to all isoforms of ET and sarafotoxin peptides.
The compounds of this invention may have ET.sub.B antagonistic activity.
One object of the present invention is to provide new and useful peptide compound and a pharmaceutically acceptable salt thereof which have pharmacological activities such as endothelin, particularly ET.sub.B antagonistic activity and the like.
Another object of the present invention is to provide processes for the preparation of said peptide compound and a salt thereof.
A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said peptide compound or a pharmaceutically acceptable salt thereof.
Still further object of the present invention is to provide a method of using the same for the treatment and the prevention of endothelin, particularly ET.sub.B mediated diseases such as hypertension, and the like.


DISCLOSURE OF INVENTION

The object compound of the present invention can be represented by the following general formula (I). ##STR3## in which R.sup.4 is acyl, heterocyclic-(lower)alkyl, ##STR4## wherein R.sup.1 is hydrogen, lower alkyl, common amino-protective group or optional substituted ar(lower)alkyl, optionally substituted heterocyclic-(lower)alkyl, optionally substituted cyclo(lower)alkyl(lower)alkyl, common amino-protective group, amino(or protected amino)(lower)alkyl, optionally substituted heterocyclic-carbonyl or cyclo(lower)alkyl,
According to the present invention, the new peptide compound (I) and a salt thereof can be prepared by the processes as shown in the following schemes. ##STR5## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, A, Z and m are each as defined above, ar(C.sub.1 -C.sub.5)alkyl, optionally substituted heterocyclic(C.sub.1 -C.sub.5)alkyl, optionally substituted cyclo(lower)alkyl(C.sub.1 -C.sub.5)alkyl, or amino(or protected amino)(C.sub.1 -C.sub.5)alkyl,
Some of the starting compounds used in the above Processes are novel and can be prepared according to the following Methods and/or by the procedures described in the following Preparations or by a conventional manner. ##STR6## wherein R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, A, Z and m are each as defined above,
Suitable pharmaceutically acceptable salts of the object compound (I) may be a conventional non-toxic salt and include an acid addition salt such as an organic acid salt (e.g. acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g. hydrochloride, hydrobromide, hydriodide, sulfate, nitrate, phosphate, etc.), or a salt with a base such as an amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.), an alkali metal salt (e.g. sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesiu

REFERENCES:
patent: 4921855 (1990-05-01), Hemmi et al.
patent: 4963530 (1990-10-01), Hemmi et al.
patent: 5223489 (1993-06-01), Hemmi et al.
patent: 5284828 (1994-02-01), Hemmi et al.
patent: 5430022 (1995-07-01), Hemmi et al.
patent: 5491132 (1996-02-01), Hemmi et al.

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