Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Utility Patent
1998-06-01
2001-01-02
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S259500, C544S283000, C544S362000
Utility Patent
active
06169088
ABSTRACT:
TECHNICAL FIELD
The present invention relates to nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof which have inhibitory activity on phosphorylation of platelet-derived growth factor (PDGF) receptor and are useful for the treatment of cell-proliferative diseases such as arteriosclerosis, vascular reobstruction, cancer and glomerulosclerosis.
BACKGROUND ART
PDGF is known to act as an aggravating factor for cell-proliferative diseases such as arteriosclerosis, vascular reobstruction after percutaneous coronary angioplasty and bypass operation, cancer, glomerulonephritis, glomerulosclerosis, psoriasis and articular rheumatism [Cell, 46, 155-169 (1986); Science, 253, 1129-1132 (1991); Nippon Rinsho (Japanese J. of Clinical Medicine), 50, 3038-3045 (1992); Nephrol Dial Transplant, 10, 787-795 (1995); Kidney International, 43 (Suppl. 39), S86-S89 (1993); Journal of Rheumatology, 21, 1507-1511 (1994); Scandinavian Journal of Immunology, 27, 285-294 (1988), etc.].
As for quinazoline derivatives which are useful as drugs, N,N-dimethyl-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazine carboxamide is described as a bronchodilator in South African Patent No. 67 06512 (1968). Dimethoxyquinazoline derivatives are described as inhibitors of phosphorylation of epidermal growth factor (EGF) receptor in Japanese Published Unexamined Patent Application No. 208911/93 and WO 96/09294. Quinoline derivatives having benzodiazepine receptor agonist activity are described in Pharmacology Biochemistry and Behavior, 53, 87-97 (1996) and European Journal of Medicinal Chemistry, 31, 417-425 (1996), and quinoline derivatives which are useful as anti-parasite agents are described in Indian Journal of Chemistry, 26B, 550-555 (1987).
Inhibitors of phosphorylation of PDGF receptor so far known include bismono- and bicyclic aryl compounds and heteroaryl compounds (WO 92/20642), quinoxaline derivatives [Cancer Research, 54, 6106-6114 (1994)], pyrimidine derivatives (Japanese Published Unexamined Patent Application No. 87834/94) and dimethoxyquinoline derivatives [Abstracts of the 116th Annual Meeting of the Pharmaceutical Society of Japan (Kanazawa) (1996), 2, p. 275, 29(C2) 15-21.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide nitrogen-containing heterocyclic compounds and pharmaceutically acceptable salts thereof which inhibit phosphorylation of PDGF receptor to hinder abnormal cell growth and cell wandering and thus are useful for the prevention or treatment of cell-proliferative diseases such as arteriosclerosis, vascular reobstruction, cancer and glomerulosclerosis.
The present invention relates to nitrogen-containing heterocyclic compounds represented by general formula (I):
{wherein V represents an oxygen atom or a sulfur atom; W represents 1,4-piperazinediyl or 1,4-homopiperazinediyl in which carbons on the ring may be substituted by 1-4-alkyl groups which may be the same or different;
R
1
represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alicyclic alkyl group, a substituted or unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group;
R
2
represents a substituted alkyl group, a substituted or unsubstituted alicyclic alkyl group, a substituted or unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteroarylalkyl group, —COR
10
(wherein R
10
has the same significance as R
1
) or —SO
2
R
11
(wherein R
11
represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alicyclic alkyl group, a substituted or unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaryl group, or a substituted or unsubstituted heteroarylalkyl group);
R
3
, R
4
, R
5
and R
6
, which may be the same or different, each represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl group, a nitro group, a cyano group, —OR
12
[wherein R
12
has the same significance as R
10
, or represents —COR
13
(wherein R
13
has the same significance as R
10
) or —SO
2
R
14
(wherein R
14
has the same significance as R
11
)], —NR
15
R
16
{wherein R
15
has the same significance as R
10
, and R
16
has the same significance as R
10
, or represents —SO
2
R
17
(wherein R
17
has the same significance as R
11
) or
[wherein X
1
represents an oxygen atom or a sulfur atom; and R
18
has the same significance as R
10
, or represents —OR
19
(wherein R
19
has the same significance as R
11
) or —NR
20
R
21
(wherein R
20
has the same significance as R
10
and R
21
has the same significance as R
10
, or R
20
and R
21
are combined together with the adjoining nitrogen atom to represent a substituted or unsubstituted nitrogen-containing alicyclic heterocyclic group) ]; or R
15
and R
16
are combined together with the adjoining nitrogen atom to represent a substituted or unsubstituted nitrogen-containing heterocyclic group},
[wherein m represents an integer of 0-2; and when m is 0, R
22
has the same significance as R
10
; when m is 1, R
22
has the same significance as R
11
; and when m is 2, R
22
has the same significance as R
11
, or represents —OR
23
(wherein R
23
has the same significance as R
10
) or —NR
24
R
25
(wherein R
24
and R
25
, which may be the same or different, each has the same significance as R
10
, or R
24
and R
25
are combined together with the adjoining nitrogen atom to represent a substituted or unsubstituted nitrogen-containing alicyclic heterocyclic group)] or —COR
26
[wherein R
26
has the same significance as R
10
, or represents —OR
27
(wherein R
27
has the same significance as R
10
) or —NR
28
R
29
(wherein R
28
and R
29
, which may be the same or different, each has the same significance as R
10
, or R
28
and R
29
are combined together with the adjoining nitrogen atom to represent a substituted or unsubstituted nitrogen-containing alicyclic heterocyclic group)]; or any adjoining two of R
3
, R
4
, R
5
and R
6
are combined together to represent methylenedioxy or ethylenedioxy; or any adjoining two of R
3
, R
4
, R
5
and R
6
are combined together with the two adjoining carbon atoms to form a substituted or unsubstituted phenyl ring; or R
3
and R
4
, R
4
and R
5
, or R
5
and R
6
are combined together with the two adjoining carbon atoms to represent
[wherein A represents an oxygen atom, a sulfur atom or —NR
30
— (wherein R
30
has the same significance as R
10
); and Q
1
has the same significance as R
10
, or represents —NR
31
R
32
(wherein R
31
and R
32
, which may be the same or different, each has the same significance as R
10
, or R
31
and R
32
are combined together with the adjoining nitrogen atom to represent a substituted or unsubstituted nitrogen-containing alicyclic heterocyclic group) or —SR
33
(wherein R
33
has the same significance as R
10
)], or
(wherein R
34
and R
35
, which may be the same or different, each has the same significance as R
10
; and Q
2
represents an oxygen atom, a sulfur atom or ═N—CN), or
(wherein R
36
has the same significance as R
10
);
Z represents a nitrogen atom or C—R
7
[wherein R
7
has the same significance as R
10
, or represents a halogen atom, —OR
37
(wherein R
37
has the same significance as R
10
), —SR
38
(wherein R
38
has the same significance as R
10
) or
Fujiwara Shigeki
Ichimura Michio
Ide Shin-ichi
Irie Junko
Matsuno Kenji
Fitzpatrick ,Cella, Harper & Scinto
Kyowa Hakko Kogyo Co. Ltd.
Shah Mukund J.
Sripada Pavanaram K
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