[1,2,4] triazolo [1,5-C] pyrimidine...

Details [1,2,4] triazolo [1,5-C] pyrimidine... [1,2,4] triazolo [1,5-C] pyrimidine...

1999-09-23

2001-04-24

Shah, Mukund J. (Department: 1611)

Organic compounds -- part of the class 532-570 series

Organic compounds

Pteroyl per se or having -c-, wherein x is chalcogen, bonded...

C544S262000

Reexamination Certificate

active

06222035

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel [1,2,4]triazolo[1,5-c]pyrimidine derivatives and pharmaceutically acceptable salts thereof which show adenosine A
2A
receptor antagonism and are useful for treating or preventing various diseases induced by hyperactivity of adenosine A
2A
receptors (for example, Parkinson's disease, senile dementia, or depression).
BACKGROUND ART
It is known that adenosine shows attenuation of the activity of neurotransmitters via an A
2A
receptor [
European Journal of Pharmacology
, 168: 285 (1989)]. Consequently, adenosine A
2A
receptor antagonists are expected as remedies or preventives for various diseases induced by hyperactivity of adenosine A
2A
receptors, such as a remedy for Parkinson's disease, an anti-dementia drug, a remedy for depression, and the like. Furthermore, the above antagonists are expected to show therapeutic and symptom-improving effects upon Alzheimer's disease, progressive supranuclear palsy, AIDS encephalopathy, propagative cavernous encephalopathy, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, multiple system atrophy, cerebral ischemia, somnipathy, ischemic heart disease, intermittent claudication, or the like.
On the other hand, [1,2,4]triazolo[1,5-c]-pyrimidine derivatives are disclosed as compounds having diuresis activity in Japanese Published Unexamined Patent Application No. 13792/85, as compounds having antiasthma activity in Japanese Published Unexamined Patent Application No. 56983/85, and as compounds having bronchodilation activity in Japanese Published Unexamined Patent Application No. 167592/84.
However, adenosine receptor antagonism of [1,2,4]triazolo[1,5-c]pyrimidine derivatives and their activity on the central nervous system are not known.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide [1,2,4]triazolo[1,5-c]pyrimidine derivatives which have adenosine A
2A
receptor antagonism and are useful for treating or preventing various diseases induced by hyperactivity of an adenosine A
2A
receptor (for example, Parkinson's disease, dementia, depression, or the like).
The present invention can provide [1,2,4]triazolo[1,5-c]pyrimidine derivatives represented by formula (I):
{wherein R
1
represents substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic ring;
R
2
represents hydrogen, halogen, lower alkyl, lower alkanoyl, aroyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic ring, CHR
4A
R
4B
(wherein R
4A
represents hydrogen, hydroxy, or aryl; and R
4B
represents hydroxy, substituted or unsubstituted aryloxy, lower alkyl, lower alkoxy, formyl, lower alkanoyl, halogen, lower alkylthio, formula (A
1
):
(wherein na represents an integer of 0 to 3; R
5A
represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic ring, lower alkoxycarbonyl, formyl, lower alkanoyl, aroyl, or substituted or unsubstituted aralkyl; and R
6A
represents hydrogen, lower alkyl, halogen, or hydroxy), formula (B
1
):
(wherein na and R
6A
have the same meanings as defined above; and X
A
represents methylene, oxygen, sulfur, sulfinyl, or sulfonyl), or NR
7A
R
8A
(wherein R
7A
and R
8A
are the same or different, and each represents hydrogen, lower alkyl, lower cycloalkyl, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic ring, substituted or unsubstituted aralkyl, aroyl, formyl, or lower alkanoyl)), formyl, carboxyl, lower alkoxycarbonyl, CONR
9A
R
9B
(wherein R
9A
represents hydrogen or lower alkyl; and R
9B
represents hydrogen, substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic ring, substituted or unsubstituted aralkyl, lower cycloalkyl, lower alkoxy, or lower alkyl), COA
3
(A
3
represents formula (A
3
):
(wherein nc, R
5C
, and R
6C
have the same meanings as the above-described na, R
5A
, and R
6A
, respectively)), or COB
3
(B
3
represents formula (B
3
):
(wherein nc, R
6C
, and X
C
have the same meanings as the above-described na, R
5A
, and X
A
, respectively));
R
3
represents hydrogen, halogen, XR
10
(wherein X represents O or S; and R
10
represents substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic ring, substituted or unsubstituted aralkyl, lower alkyl, or hydroxy-substituted lower alkyl), formula (A
2
):
(wherein nb, R
5B
, and R
6B
have the same meanings as the above-described na, R
5A
, and R
6A
, respectively), formula (B
2
):
(wherein nb, R
6B
, and X
B
have the same meanings as the above-described na, R
5A
, and X
A
, respectively), or NR
7B
R
8B
(wherein R
7B
and R
8B
have the same meanings as the above-described R
7A
and R
8A
, respectively), and
Q represents hydrogen or 3,4-dimethoxybenzyl}, or
pharmaceutically acceptable salts thereof.
In the definition of each group in formula (I), examples of the lower alkyl and the lower alkyl moiety of the lower alkoxy, lower alkanoyl, lower alkylthio, lower cloalkyl-substituted lower alkyl, hydrosxy-substituted lower alkyl, lower alkoxy-substituted lower alkyl, substituted or unsubstituted aromatic heterocyclic ring-substituted lower alkyl and lower alkoxycarbonyl include straight-or branched-chain groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl and the like. Examples of the lower cycloalkyl include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl and the like. Examples of the halogen include fluorine, chlorine, bromine and iodine atoms. Examples of the aryl moiety of the substituted or unsubstituted aryl, substituted or unsubstituted aryloxy and aroyl include phenyl, naphthyl, indenyl, anthryl and the like. Examples of the aromatic heterocyclic ring moiety of the substituted or unsubstituted aromatic heterocyclic ring include furyl, thienyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl, pyrimidyl, triazinyl, indolyl, quinolyl, purinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl and the like. Examples of the aralkyl moiety of the substituted or unsubstituted aralkyl include those having 7 to 15 carbon atoms, such as benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl and the like.
Examples of the substituent in the substituted lower alkyl include 1 to 3 substitutents which are the same or different, such as hydroxy, carboxyl, lower cycloalkyl, lower alkoxy, lower alkoxycarbonyl, aryl, aryloxy, aralkyloxy, an aromatic heterocyclic group, a lower alkyl-substituted aromatic heterocyclic group, hydroxy-substituted lower alkoxy, lower alkoxy-substituted lower alkoxy, lower alkanoyl, aryl-substituted lower alkanoyl, aroyl, formyl, halogen, trifluoromethyl, vinyl, styryl, phenylethynyl and the like. Also, the lower cycloalkyl, the lower alkoxy, the lower alkoxy of the lower alkoxycarbonyl, the aryl, the aryl of the aryloxy, the aralkyl of the aralkyloxy, the aromatic heterocyclic group, the lower alkyl of the lower alkanoyl, the aryl of the aroyl and the halogen have the same meanings as defined above.
Examples of the substituent of the aryl, aromatic heterocyclic ring and aralkyl include 1 to 3 substituents which are the same or different, such as lower alkyl, hydroxy, hydroxy-substituted lower alkyl, halogeno lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aryl, aryloxy, aralkyl, aralkyloxy, an aromatic heterocyclic ring, halogenoaryloxy, halogenoaralkyloxy, carboxy, carbamoyl, formyl, lower alkanoyl, aroyl, halogen, nitro, amino, cyano, trifluoromethyl, trifluoromethoxy, methylenedioxy, ethylenedioxy and the like. The lower alkyl and the lower alkyl moiety of the hydroxy lower alkyl, halogeno lower alkyl, lower alkoxy,

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