Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-29
2002-07-23
Shah, Mukund J. (Department: 1611)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S242000, C514S252130, C514S252160, C514S252170, C544S179000, C544S182000, C544S234000, C544S235000, C544S250000, C544S254000, C544S257000, C544S264000, C544S284000, C544S344000, C544S349000, C544S353000, C544S359000
Reexamination Certificate
active
06423716
ABSTRACT:
TECHNICAL FIELD
The present invention relates to nitrogen-containing heterocyclic compounds or pharmaceutically acceptable salts thereof which have an activity of inhibiting phosphorylation of a platelet-derived growth factor (PDGF) receptor and are useful in treating cell proliferative diseases, such as arteriosclerosis, vascular re-obstruction disease, cancers, glomerulonephritis, and the like.
BACKGROUND ART
It is known that PDGF functions as an advancing factor upon cell proliferative diseases, such as arteriosclerosis, vascular re-obstruction after percutaneous transluminal coronary angioplasty or bypass angioplasty, cancers, glomerulonephritis, glomerulosclerosis, psoriasis, articular rheumatism, and the like [
Cell,
46: 155-169 (1986),
Science,
253: 1129-1132 (1991),
Nihon Rinsho,
50: 3038-3045 (1992),
Nephrol Dial Transplant,
10: 787-795 (1995),
Kidney International,
43 (Suppl. 39): 86-89 (1993),
Journal of Rheumatology,
21: 1507-1511 (1994),
Scandinavian Journal of Immunology,
27: 285-294 (1988), etc.].
Regarding nitrogen-containing heterocyclic compounds useful as medicaments, for example, N,N-dimethyl-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazine carboxamide is disclosed as a bronchodilator in South African Patent 67 06512 (1968). Also, pyrrolo[3,2-d]pyrimidine derivatives are disclosed in
Khimiko-Farmatsveticheskij Zhurnal,
16: 1338-1343 (1982) as antibacterial agents, quinoline derivatives having benzodiazepine receptor agonistic activity are disclosed in
Pharmacology Biochemistry and Behavior,
53: 87-97 (1996) and
European Journal of Medicinal Chemistry,
31: 417-425 (1996), and quinoline derivatives useful as anti-parasitic agents are disclosed in
Indian Journal of Chemistry,
26B: 550-555 (1987).
Also, regarding PDGF receptor phosphorylation inhibitors, bismono- and bicyclic aryl and heteroaryl compounds are disclosed in WO 92/20642, and quinoxaline derivatives in
Cancer Research,
54: 6106 (1994), pyrimidine derivatives in Japanese Published Unexamined Patent Application No. 87834/94, quinoline derivatives and quinazoline derivatives in WO 97/17329, pyrido[2,3-d]pyrimidine derivatives in
J. Med. Chem.,
40: 2296 (1997), etc. and selenium derivatives in
J. Med. Chem.,
40: 413 (1997).
Inhibitors of phosphorylation of epidermal growth factor (EGF) receptor family are disclosed, for example, in Japanese Published Unexamined Patent Application No. 208911/93, WO 96/09294, WO 96/31510 and WO 97/13771. Tricyclic system nitrogen-containing heterocyclic compounds disclosed in WO 95/19970 and pyridopyrimidine derivatives disclosed in
J. Med. Chem.,
39: 1823 (1996), for example, are known as compounds having the activity inhibiting phosphorylation of a receptor of EGF which is a tyrosine kinase. Also, as inhibitors of phosphorylation of an EGF receptor or EGF receptor family, pyrimidopyrimidine derivatives are disclosed in
J. Med. Chem.,
40: 1820 (1997), pyrrolo- and pyrazoloquinazoline derivatives are disclosed in
J. Med. Chem.,
40: 1519 (1997), and pyrrolopyrimidine derivatives are disclosed in WO 96/40142, WO 97/02266, WO 97/27199, EP 682027, etc. In addition, inhibitors of phosphorylation of EGF receptor family are disclosed in Japanese Published Unexamined Patent Application No. 208911/93, WO 96/09294, WO 96/31510, WO 97/13771, etc. All of these compounds are ring-fused pyrimidine derivatives and have a structure in which a simple amino group such as a substituted anilino group, an alkoxy group or the like are linked to the 4-position of the pyrimidine ring.
On the other hand, in the compounds disclosed in the present invention, a structure, such as urea, thiourea, guanidine, amidine, or the like, is linked to a position corresponding to the 4-position of pyrimidine, via substituted or unsubstituted piperazine or homopiperazine, and such a structure is not known as to substances having the activity of inhibiting phosphorylation of EGF receptors and the like.
DISCLOSURE OF THE INVENTION
The present invention relates to a nitrogen-containing heterocyclic compound represented by formula (I):
wherein W represents 1,4-piperazinediyl or 1,4-homopiperazinediyl in which carbon atoms on the ring may be substituted with 1 to 4 alkyl groups which are the same or different;
U represents NR
1
R
2
(wherein 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; and R
2
represents a hydrogen atom, 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, CQR
1A
(wherein Q represents an oxygen atom or a sulfur atom; and R
1A
has the same meaning as R
1
described above), or SO
2
R
3
(wherein R
3
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)), OR
4
(wherein R
4
has the same meaning as R
3
described above), or SR
5
(wherein R
5
has the same meaning as R
3
described above);
V represents an oxygen atom, a sulfur atom, N—R
6
(wherein R
6
has the same meaning as R
1
described above or represents a cyano group, a hydroxyl group, a nitro group, a carbamoyl group, COOR
3A
(wherein R
3A
has the same meaning as R
3
described above), CQ
A
R
1B
(wherein Q
A
has the same meaning as Q described above, and R
1B
has the same meaning as R
1
described above), or SO
2
R
3B
(wherein R
3B
has the same meaning as R
3
described above)), or CR
7
R
8
(wherein R
7
and R
8
are the same or different and each represents a hydrogen atom, a cyano group, a nitro group, COOR
3C
(wherein R
3C
has the same meaning as R
3
described above), or SO
2
R
3D
(wherein R
3D
has the same meaning as R
3
described above)), with the proviso that, when R
1
is hydrogen, R
6
and R
2
may be exchanged, V may represent N—R
2
(wherein R
2
has the same meaning as defined above), and R
2
may represent R
6
(wherein R
6
has the same meaning as defined above), and when U is OR
4
or SR
5
, V represents N—R
6
or CR
7
R
8
,
at least one of X, Y and Z represents a nitrogen atom, and the others are the same or different, and each represents a nitrogen atom or C—R
A
<wherein R
A
has the same meaning as R
1
defined above, or represents a halogen atom, a cyano group, a nitro group, NR
9
R
10
{wherein R
9
and R
10
are the same or different, and each has the same meaning as R
1
described above, or represents SO
2
R
3E
(wherein R
3E
has the same meaning as R
3
described above) or CQ
B
R
11
(wherein Q
b
has the same meaning as Q described above; and R
11
has the same meaning as R
1
described above, or represents OR
3F
(wherein R
3F
has the same meaning as R
3
described above) or NR
1C
R
1D
(wherein R
1C
and R
1D
are the same or different, and each has the same meaning as R
1
described above, or R
1C
and R
1D
are combined to represent a substituted or unsubstituted nitrogen-containing heterocyclic group)), or R
9
and R
10
are combined to represent a substituted or unsubstituted nitrogen-containing heterocyclic group}, CQ
C
R
11A
(wherei
Ichimura Michio
Ide Shin-ichi
Matsuno Kenji
Nomoto Yuji
Oda Shoji
Fitzpatrick ,Cella, Harper & Scinto
Kyowa Hakko Kogyo Co. Ltd.
Shah Mukund J.
Truong Tamthom N.
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