Pyrimidine derivatives

Details Pyrimidine derivatives Pyrimidine derivatives

1999-11-05

2002-01-08

Cook, Rebecca (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06337334

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel pyrimidine derivatives and their salts, and to pharmaceuticals containing these compounds as active ingredients.
BACKGROUND ART
Endothelin, having potent vasoconstrictive effect, blood pressure elevating effect, and cell proliferation effect, is considered to be a substance that contributes to various diseases and disorders including heart diseases such as ischemic heart infarction, congestive heart failure, arrhythmia, and unstable angina; airway diseases such as asthma; hypertonia such as pulmonary hypertension, renal hypertension, and hypertension accompanying organ transplantation; circulatory diseases such as subarachnoid hemorrhage and post-PTCA reconstriction or vasospasm; kidney diseases such as acute and chronic renal failure; diabetes, hyperlipemia, and other diseases that are accompanied by vascular lesion, as well as arteriosclerosis; liver diseases such as alcohol-induced liver disorders; gastrointestinal disorders such as those of gastric mucosa; bone diseases; prostatic hypertrophy and urinary disorders; cancer; and skin diseases concurrent with proliferation of melanocytes [
Saishin
-
Igaku
(may be translated to “Medicine Up-to-date”), 94, 335-431 (1994),
Igaku
-
no
-
Ayumi
(may be translated to “Progress of Medicine”), 168, 675-692 (1994),
Igaku
-
no
-
Ayumi,
170, 357 (1994), Pharmac. Rev., 46, 325 (1994), and
Gendai
-
Iryo
(may be translated to “Modern Remedies”), 27, 1 (1995)].
It has come to be elucidated that a variety of actions of endothelin are triggered upon binding of endothelin to its receptors in organs of the body, and that the vasoconstriction caused by endothelin is induced by the mediation of at least two different receptors (ET
A
receptor and ET
B
receptor). Therefore, a compound that prevents endothelin from binding to these two receptors should be useful as a preventive and therapeutic agent for the above-mentioned diseases in which endothelin participates. Heretofore, a number of compounds have been reported as exhibiting endothelin antagonism [J. Med. Chem., 36, 2585 (1993), Nature, 365, 759 (1993), Circulation, 88, 1-316 (1994),
Saishin
-
Igaku,
94, 424-431 (1994), J. Med. Chem. 37, 1553 (1994), and Japanese Patent Application Laid-Open (kokai) No. 5-222003)].
However, there have not yet been found compounds that exhibit satisfactory endothelin antagonism.
Accordingly, the present invention is directed to the discovery of a compound that has potent endothelin antagonism, as well as to the provision of pharmaceuticals containing such a compound as the active ingredient.
DISCLOSURE OF THE INVENTION
Under the above circumstances, the present inventors carried out careful studies, and found that the pyrimidine derivatives represented by the following formula (1) and their salts exhibit excellent endothelin antagonism and thus are useful as medicines—particularly those for circulatory diseases. The present invention was accomplished based on this finding.
Accordingly, the present invention provides a pyrimidine derivative of the following formula (1) or a salt thereof:
[wherein R
1
represents a lower alkyl group; each of R
2
and R
3
, which are identical to or different from each other, represents a hydrogen atom, a lower alkyl group, or a lower alkoxyl group; each of R
4
and R
5
, which are identical to or different from each other, represents a hydrogen atom or a lower alkyl group; R
6
represents a lower alkyl group, —OR
7
, or —NR
8
R
9
; and n is a number between 0 and 3 inclusive (wherein R
7
represents a hydrogen atom, a lower alkyl group, a phenyl group which may have a substituent, or an aralkyl group which may have a substituent; and each of R
8
and R
9
, which are identical to or different from each other, represents a hydrogen atom, a hydroxyl group, a lower alkyl group which may have a substituent, a lower alkenyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, an amino group which may have a substituent, a heterocyclic group which may have a substituent, a heterocyclic-alkyl group which may have a substituent, or R
8
and R
9
may be linked to each other so as to form a 5- to 7-membered ring along with their adjacent nitrogen atom)].
The present invention also provides a medicine containing a pyrimidine derivative of formula (1) or a salt thereof.
The present invention also provides a pharmaceutical composition containing a pyrimidine derivative of formula (1) or a salt thereof and a pharmaceutically acceptable carrier.
The present invention also provides use as a medicine of a pyrimidine derivative of formula (1) or a salt thereof.
The present invention also provides a method for treating diseases induced by endothelin, wherein the method is characterized by administering an effective amount of a pyrimidine derivative of formula (1) or a salt thereof.


REFERENCES:
patent: 5883092 (1999-03-01), Hirata et al.
patent: 0 526 708 (1993-02-01), None
patent: 0 633 259 (1995-01-01), None
patent: 0 658 548 (1995-06-01), None
patent: 5-222003 (1993-08-01), None
patent: 97/09318 (1997-03-01), None
CA124:193131, Hopfgartner et al, J Mass Spectrom, 31 (1) 69-76, abstract, 1996.

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