Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-28
2002-09-17
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S254060, C514S255030, C544S295000, C544S370000, C544S393000
Reexamination Certificate
active
06451800
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to phenylpiperazine derivatives and phenylpiperidine derivatives having integrin &agr;
v
&bgr;
3
antagonistic activity, and pharmaceuticals comprising the same.
2. Background Art
In recent years, cell adherent proteins have been enthusiastically studied to apply proteins or the like involved in the mechanism of the regulation of cell adhesion to pharmaceuticals. Regarding interaction between platelet membrane glycoprotein GP IIb/IIIa and fibrinogen which plays an important role in platelet aggregation, extensive studies have already been carried out in various countries of the world, with consideration of clinical tests. For example, ReoPro having platelet aggregation activity has been clinically used.
Integrin &agr;
v
&bgr;
3
which interacts with various extracellular matrix or cell adhesive proteins, has been proved to play an important role in the progress of arterial sclerosis, arterialization, and solid tumors. For this reason, regarding integrin &agr;
v
&bgr;
3
antagonist as well, animal experiments have been initiated with consideration of clinical tests in various countries. Attention has been drawn to this by chemical and biochemical researchers, as well as by medical care-related persons engaged in basic research (Journal of Cardiac Society of U.S.A., Circulation, I-668, 1997, DuPont-Merck).
Up to now, small molecules having integrin &agr;
v
&bgr;
3
antagonistic activity have been reported (WO 95/32710 (Merck), WO 96/37492 (DuPont-Merck), WO 97/01540 (SKB), WO 97/08145 (Searle & Co.), WO 97/23451 (Merck), WO 7/23480 DuPont-Merck), WO 97/24119(SKB), WO 97/33887 (DuPont-Merck), WO 97/36858 (Searle & Co.), WO 97/36859 (Searle & Co.), WO 97/36860 (Searle & Co.), WO 97/36861 (Searle & Co.), WO 97/36862 (Searle & Co.), and EP 0796855 (Hoechst).
SUMMARY OF THE INVENTION
The present inventors have found that a certain group of derivatives have potent integrin &agr;
v
&bgr;
3
antagonistic activity. The present inventors have also found that a certain group of derivatives have potent GP IIb/IIIa antagonistic activity and human platelet aggregation inhibitory activity.
Accordingly, an object of the present invention is to provide a compound having integrin &agr;
v
&bgr;
3
antagonistic activity, GP IIb/IIIa antagonistic activity, and/or human platelet aggregation inhibitory activity.
Another object of the present invention is to provide a therapeutic agent for integrin &agr;
v
&bgr;
3
-mediated diseases and an agent for inhibiting a platelet aggregation.
According to one aspect of the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof:
wherein
A represents a saturated or unsaturated five- to seven-membered heterocyclic group containing two nitrogen atoms, which is optionally substituted by C
1-6
alkyl or amino optionally substituted by C
1-6
alkyl, aralkyl, C
1-6
alkoxycarbonyl, or aralkyloxycarbonyl, or which is optionally condensed with other saturated or unsaturated five- to seven-membered carbocyclic ring or heterocyclic ring to form a bicyclic group, wherein the carbocyclic group and the heterocyclic group are optionally substituted by C
1-6
alkyl or amino optionally substituted by C
1-6
alkyl, aralkyl, C
1-6
alkoxycarbonyl, or aralkyloxycarbonyl,
or a group represented by formula
wherein
R
1
, R
2
, and R
3
, which may be the same or different, represent a hydrogen atom, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, aralkyl, or nitrile, or R
1
and R
2
may together form group —(CH
2
)
r
—, wherein r is 4 or 5, or group —(CH
2
)
2
—O—(CH
2
)
2
—, wherein C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, and aralkyl are optionally substituted by a halogen atom, C
1-6
alkoxy, amino, or hydroxyl;
X and Z, which may be the same or different, represent CH or N;
R
4
represents C
1-6
alkyl, C
1-6
alkoxy, a halogen atom, amino, nitro, hydroxyl, or an oxygen atom, wherein C
1-6
alkyl and C
1-6
alkoxy are optionally substituted by a halogen atom, C
1-6
alkoxy, amino, or hydroxyl;
R
5
represents C
1-6
alkyl, C
1-6
alkoxy, a halogen atom, amino, nitro, or hydroxyl, wherein C
1-6
alkyl and C
1-6
alkoxy are optionally substituted by a halogen atom, C
1-6
alkoxy, amino, or hydroxyl;
Q represents >C═O, >CH
2
, >CHR
10
, or >CHOR
10
wherein R
10
represents C
1-6
alkyl;
R
6
represents a hydrogen atom, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, or aralkyl, wherein C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, and aralkyl are optionally substituted by a halogen atom, C
1-6
alkoxy, amino, or hydroxyl;
R
7
represents a hydrogen atom, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, aralkyl, or amino, wherein C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, and aralkyl are optionally substituted by a halogen atom, C
1-6
alkoxy, amino, or hydroxyl, and amino is optionally substituted by C
1-6
alkyl, C
1-6
alkoxycarbonyl, benzenesulfonyl in which the phenyl portion is optionally substituted by C
1-6
alkyl, or aralkyloxycarbonyl;
R
8
represents a hydrogen atom, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, aralkyl, or amino, wherein C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, and aralkyl are optionally substituted by a halogen atom, C
1-6
alkoxy, amino, or hydroxyl, and the amino is optionally substituted by C
1-6
alkyl, C
1-6
alkoxycarbonyl, alkylsulfonyl, benzenesulfonyl in which the phenyl portion is optionally substituted by C
1-6
alkyl, phenyl optionally condensed with the phenyl portion, carboxyl, hydroxyl, nitro, amino, saturated or unsaturated five- to seven-membered carbocyclic group or heterocyclic group, C
1-6
alkylamino or a halogen atom, aralkyloxycarbonyl, or group —C(═O)—(CH
2
)
s
—C(═O)—NHR
11
wherein s is an integer of 0 to 4 and R
11
represents a hydrogen atom or hydroxyl;
R
9
represents a hydrogen atom or C
1-6
alkyl;
m is an integer of 0 to 5;
n is an integer of 0 to 4;
p is 2 or 3; and
q is 0 or 1.
The compounds according to the present invention are useful in the treatment of integrin &agr;
v
&bgr;
3
-mediated diseases. The compounds according to the present invention are also useful as an agent for inhibiting platelet aggregation.
DETAILED DESCRIPTION OF THE INVENTION
Compound
As used herein, the term “C
1-6
alkyl” and “C
1-6
alkoxy” as a group or a part of a group respectively mean straight chain, branched chain, or cyclic alkyl and alkoxy having 1 to 6, preferably 1 to 4 carbon atoms.
As used herein, the term “C
2-6
alkenyl” and “C
2-6
alkynyl” as a group or a part of a group respectively mean straight chain, branched chain, or cyclic alkenyl or alkynyl having 2 to 6, preferably 2 to 4 carbon atoms.
Examples of C
1-6
alkyl include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, cyclopentyl, n-hexyl, and cyclohexyl.
Examples of C
1-6
alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, and t-butoxy.
Examples of C
2-6
-alkenyl include allyl.
Examples of C
2-6
alkynyl include 2-propynyl and ethinyl.
Examples of saturated or unsaturated five- to seven-membered carbocyclic groups include phenyl.
As used herein, the term “saturated or unsaturated five- to seven-membered heterocyclic ring” means a five- to seven-membered heterocyclic ring containing at least one hetero-atom selected from oxygen, nitrogen, and sulfur atoms, preferably a five- to seven-membered heterocyclic ring containing one nitrogen atom, more preferably a five- or six-membered heterocyclic ring containing one nitrogen atom. The term “hetero-atom” used herein means an oxygen, nitrogen, or sulfur atom. Examples of saturated or unsaturated five- to seven-membered heterocyclic groups include pyrimidyl, 1,4,5,6-tetrahydropyrimidyl, imidazolyl, tetrahydro-[1,3]diazepinyl, and imidazolidinyl.
The saturated or unsaturated heterocyclic group may be condensed with another saturated or unsaturated heterocyclic ring to form a bicyclic ring. Such condensed cyclic groups include ben
Ajito Keiichi
Gomi Shuichi
Hachisu Mitsugu
Ishikawa Minoru
Katano Kiyoaki
Meiji Seika Kaisha Ltd.
Wenderoth Lind & Ponack LLP
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