Nitrogen-containing heterocyclic compounds having...

Details Nitrogen-containing heterocyclic compounds having... Nitrogen-containing heterocyclic compounds having...

2000-11-03

2002-10-29

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S253130, C514S326000, C514S330000, C514S331000, C514S341000, C544S384000, C544S360000, C544S386000, C544S399000, C544S402000, C544S403000, C546S189000, C546S210000, C546S229000, C546S237000, C546S329000, C546S339000

Reexamination Certificate

active

06472397

ABSTRACT:

This application is a 371 of PCT/JP98/02641 filed Jun. 16, 1998.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to nitrogen-containing heterocyclic compounds which inhibit the aggregation of platelets, and pharmaceutical compositions comprising the compound as an effective ingredient, which are effective for the treatment and prophylaxis of thrombotic diseases.
2. Background Art
Diseases in the cardiovascular system have increased with the change of diet or the increase of the aged population, and about 50% of these diseases is regarded to be caused by thrombus.
Platelet as an ingredient of plasma participates largely in the production of thrombus in body. For the treatment and prophylaxis of thrombotic diseases, there have thus been used clinically pharmaceuticals which suppress the function of platelets and inhibit the aggregation of platelets, for example aspirin which suppresses cyclooxygenase and cyclopyridine which activates adenylcyclase.
Recently, the analysis of glycoproteins has been progressively analyzed. It has been elucidated that a membrane glycoprotein referred to as GPIIb/IIIa has a function as a receptor of fibrinogen. Thus, an antagonist of the membrane glycoprotein GPIIb/IIIa has been expected to be effective for the treatment and prophylaxis of the thrombotic diseases as a platelet aggregation inhibitor having a new reaction mechanism (Trends in Pharmacological Science, 13, 413, 1992). There has been known as the compounds having such antagonistic effects monoclonal antibody (Ann. New York Acad. Sci., 614, 193, 1991), tripeptide derivatives comprising arginine-glycine-aspartic acid (J. Med. Chem., 35, 2040, 1992), amidinophenyl derivatives (J. Med. Chem., 35, 4393, 1992; Japanese Patent Laid-Open Publication No.4-264068, Japanese Patent Laid-Open Publication No. 4-334351, EP 483667, EP 525629, EP 529858, EP 537980, WO 9307867, WO 9402472, and the like), tyrosine derivatives (J. Med. Chem., 35, 4640, 1992), piperidine derivatives (EP 512831, EP 540334, EP 578535, and the like).
On the other hand, there have been desired as therapeutic and prophylactic agents of thrombotic diseases a highly selective agent having no side effects such as hemorrhage and a highly active antagonist effective even on its oral administration.
SUMMARY OF THE INVENTION
The present inventors have now prepared novel nitrogen-containing heterocyclic compounds having extremely high oral absorbing capacity.
The compounds according to the present invention are the compounds represented by the following general formula (I), and pharmaceutically acceptable salts and solvates thereof.
wherein
A represents CH
2
or CO,
B represents a group —(CH
2
)
k
—, where k is an integer of 1-4, or —(CH
2
)
m
—CO—, where m is an integer of 0-3,
X and Y, which are different from each other, represent N or CH,
W represents an ester moiety which can be removed under the physiological condition,
Z represents the group (II) or (III)
 wherein
n is an integer of 1-3,
D represents the group —V—(CH
2
)
p
—COOR, where V represents —O— or a bond, p is an integer of 1-4, R represents a hydrogen atom, C
1-8
alkyl, which may be substituted by a halogen atom, C
3-8
cycloalkyl, benzyl, five- to eight-membered saturated cycloalkyl containing an oxygen or sulfur atom, 1,3-bis(C
1-6
alkoxy)propan-2-yl, 1,3-bis(C
1-6
alkylthio)propan-2-yl, C
1-6
alkyl-(OCH
2
CH
2
)
q
— where q is an integer of 1-3, C
1-6
alkyl-(SCH
2
CH
2
)
r
— where r is an integer of 1-3, R′R″NCO—(CH
2
)
s
— where s is an integer of 1-3, and R′ and R″ independently represent a hydrogen atom or C
1-6
alkyl, or an ester moiety which may be removed under a physiological condition,
R
1
represents a hydrogen atom or C
1-6
alkyl which may be substituted by carboxyl, lower alkoxyl, carbamoyl, or phenyl.
SPECIFIC DESCRIPTION OF THE INVENTION
Definition
In the present specification, alkyl, alkenyl and alkynyl groups may be either of straight chain or branched chain. The term “halogen atom” means herein fluorine, chlorine, bromine or iodine atoms. The term “aryl” means preferably phenyl, naphthyl or tolyl. Furthermore, the term “aralkyl” means preferably benzyl, phenylethyl (phenethyl), or methylbenzyl.
Compounds of the Formula (I)
In the formula (I), A represents CH
2
or CO. According to the preferred embodiment of the present invention, the compound of the formula (I) wherein A represents CO is preferred.
In the formula (I), B represents the group —(CH
2
)
k
—, wherein k is an integer of 1-4, preferably 1 or 2, or the group —(CH
2
)
m
—CO—, wherein m is an integer of 0-3, preferably 0, 1 or 2. According to the preferred embodiment of the present invention, B preferably represents the group —(CH
2
)
m
—CO—, more preferably the group —CH
2
—CO—.
In the formula (I), X and Y are different from each other and represent N or CH. According to the preferred embodiment of the present invention, X represents CH and Y represents N.
In the formula (I), W represents an ester moiety which can be removed under a physiological condition. The first example of the preferred ester moiety is the following group represented by the formula (a):
wherein R
2
and R
3
represent independently a hydrogen atom or C
1-6
alkyl (preferably C
1-4
alkyl), R
4
represents C
1-10
alkyl (preferably C
1-6
alkyl, more preferably C
1-4
alkyl), C
2-10
alkenyl (preferably C
2-6
alkenyl, more preferably C
2-4
alkenyl), C
2-5
alkynyl, aryl such as phenyl, naphthyl or tolyl, or C
3-8
cycloalkyl (preferably C
5-8
cycloalkyl). According to the preferred embodiment of the present invention, the compounds of the formula (I) having the group (a) where R
2
represents a hydrogen atom, R
3
represents a hydrogen atom or C
1-6
alkyl, and R
4
represents C
1-6
alkyl are preferred.
The second example of the preferred ester moiety is the following group represented by the formula (b):
wherein R
5
represents a hydrogen atom, C
1-6
alkyl (preferably C
1-4
alkyl), or C
6-8
aralkyl such as benzyl, phenylethyl (phenethyl) or methylbenzyl, R
6
and R
7
independently represent a hydrogen atom or C
1-6
alkyl (preferably C
1-4
alkyl). According to the preferred embodiment of the present invention, the compounds of the formula (I) having the group (b) where R
5
represents C
1-6
alkyl, and R
6
and R
7
represent a hydrogen atom are preferred.
The third example of the preferred ester moiety is the following group represented by the formula (c):
wherein R
8
, R
9
, R
10
and R
11
independently represent a hydrogen atom, C
1-6
alkyl or C
6-8
aralkyl, R
12
and R
13
independently represent a hydrogen atom or C
1-6
alkyl. According to the preferred embodiment of the present invention,in the group (c), R
8
, R
9
, R
10
and R
11
represent a hydrogen atom, R
12
and R
13
represent a hydrogen atom.
In the formula (I), Z represents the groups represented by the formula (II) or (III). In the groups (II) and (III), n is an integer of 1-3, preferably 1 or 2. This means that the number of the substituent D is 1-3, preferably 1 or 2. In addition, the substituent D is at the para or meta position to that of the substituent B.
In the group —V—(CH
2
)
p
—COOR in the group Z, V represents an oxygen atom or a bond. According to the preferred embodiment of the present invention, V is an oxygen atom. In the group, p is an integer of 1-4, preferably 1 or 2. In addition, R represents a hydrogen atom, C
1-8
alkyl which may be substituted by a halogen atom, C
3-8
cycloalkyl, benzyl, a five- to eight-membered saturated cycloalkyl group containing an oxygen or sulfur atom, preferably a five- to eight-membered saturated cycloalkyl group containing an oxygen atom, more preferably tetrahydropyranyl, 1,3-bis(C
1-6
alkoxy)propan-2-yl, (preferably 1,3-bis(C
1-4
alkoxy)propan-2-yl), 1,3-bis(C
1-6
alkylthio)propan-2-yl (preferably 1,3-bis-(C
1-4
alkylthio)propan-2-yl), C
1-6
alkyl-(OCH
2
CH
2
)
q
—, wherein q is an integer of 1-3, C
1-6
alkyl-(SCH
2
CH
2
)
r
— wherein r is an integer of 1-3, R′R″NCO—(CH
2
)
s
—, wherein s is an integer o

Affiliated with

Also associated with

Rating

Nitrogen-containing heterocyclic compounds having... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Nitrogen-containing heterocyclic compounds having..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Nitrogen-containing heterocyclic compounds having... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2944019