Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-22
2003-04-08
Balasubramanian, Venkataraman (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S263000, C514S218000, C540S480000, C540S574000
Reexamination Certificate
active
06545000
ABSTRACT:
TECHNICAL FIELD
The present invention relates to [1,2,4]triazolo[1,5-c]pyrimidine derivatives 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 exhibit therapeutic and symptom-improving effects upon Alzheimer's disease, progressive supranuclear palsy, AIDS encephalopathy, propagative spongiform encephalopathy, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, multiple system atrophy, cerebral ischemia, attention deficit hyperactivity disorder, somnipathy, ischemic heart disease, intermittent claudication, diabetes, or the like.
On the other hand, [1,2,4]triazolo[1,5-c]pyrimidine derivatives are disclosed as compounds having diuretic activity in Japanese Published Unexamined Patent Application No. 13792/85, as compounds having antiasthmatic activity in Japanese Published Unexamined Patent Application No. 56983/85, and as compounds having bronchodilative 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 or pharmaceutically acceptable salts thereof 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 relates to a [1,2,4]triazolo[1,5-c]pyrimidine derivative represented by formula (I):
wherein R
1
represents substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic group; R
2
represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic group; na and nb are the same or different, and each represents an integer of 0 to 4; Q represents a hydrogen atom or 3,4-dimethoxybenzyl; R
6
represents a hydrogen atom, substituted or unsubstituted lower alkyl, halogen, or hydroxy; R
3
represents (i) hydroxy, (ii) hydroxy-lower alkyl, (iii) substituted or unsubstituted lower alkoxy, or (iv) a group selected from the group consisting of substituted or unsubstituted imidazo[1,2-a]pyridyl, substituted or unsubstituted imidazo[1,2-a]pyrazinyl, substituted or unsubstituted imidazo[1,2-a]pyrimidinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzo-2,1,3-thiadiazolyl, substituted or unsubstituted isoxazolyl, and substituted or unsubstituted 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazinyl; and when R
3
represents hydroxy, hydroxy-lower alkyl, or substituted or unsubstituted lower alkoxy, R
4
and R
5
are the same or different, and each represents a substituted or unsubstituted lower alkyl or substituted or unsubstituted aryl, or R
4
and R
5
form a substituted or unsubstituted saturated carbocycle together with the adjacent carbon atom, and when R
3
represents a group selected from the group consisting of substituted or unsubstituted imidazo[1,2-a]pyridyl, substituted or unsubstituted imidazo[1,2-a]pyrazinyl, substituted or unsubstituted imidazo[1,2-a]pyrimidinyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted benzo-2,1,3-thiadiazolyl, substituted or unsubstituted isoxazolyl, and substituted or unsubstituted 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazinyl, R
4
and R
5
are the same or different, and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, or substituted or unsubstituted aryl, or R
4
and R
5
form a substituted or unsubstituted saturated carbocycle together with the adjacent carbon atom; or a pharmaceutically acceptable salt thereof.
In other aspect, the present invention relates to a medicament comprising the [1,2,4]triazolo[1,5-c]pyrimidine derivative represented by formula (I) or a pharmaceutically acceptable salt thereof.
In still other aspect, the present invention relates to an adenosine A
2A
receptor antagonist or an agent for preventing or treating a disease induced by hyperactivity of an adenosine A
2A
receptor, comprising the [1,2,4]triazolo[1,5-c]pyrimidine derivative represented by formula (I) or a pharmaceutically acceptable salt thereof,
In still other aspect, the present invention relates to use of the [1,2,4]triazolo[1,5-c]pyrimidine derivative represented by formula (I) or a pharmaceutically acceptable salt thereof for the preparation of an agent for preventing or treating a disease induced by hyperactivity of an adenosine A
2A
receptors.
In further aspect, the present invention relates to a method for preventing or treating a disease induced by hyperactivity of an adenosine A
2A
receptor, comprising administering an effective amount of the [1,2,4]triazolo[1,5-c]pyrimidine derivative represented by formula (I) or a pharmaceutically acceptable salt thereof.
In the definition of each group in formula (I), examples of the alkyl moiety of the lower alkyl, lower alkoxy, and hydroxy-lower alkyl include linear or branched alkyl 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 halogen include fluorine, chlorine, bromine and iodine atoms. Examples of the aryl include phenyl, naphthyl, indenyl, anthryl, and the like. Examples of the aromatic heterocyclic group include furyl, thienyl, pyrrolyl, pyridyl, oxazolyl, thiazolyl, imidazolyl, pyrimidinyl, triazinyl, indolyl, quinolyl, purinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, and the like. Examples of the saturated carbocycle include those having 3 to 8 carbon atoms, such as cyclopropane, cyclobutane, cyclopentane, cyclohexyane cycloheptane, cyclooctane, and the like.
Examples of the substituent in the substituted lower alkyl, substituted lower alkoxy, and substituted saturated carbocycle include 1 to 3 substituents which are the same or different, such as hydroxy, carboxy, a saturated carbocyclic group, 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. The saturated carbocyclic group means a group formed by removing one hydrogen atom from the above-described saturated carbocycle. The lower alkyl moiety of the lower alkoxy, lower alkoxycarbonyl, lower alkyl-substituted aromatic heterocyclic group, hydroxy-substituted lower alkoxy, lower alkoxy-substituted lower alkoxy, lower alkanoyl, and aryl-substituted lower alkanoyl has the same meaning as the above-described lower alkyl. The aryl and the aryl moiety of the aryloxy, aralkyloxy, aryl-substituted lower alkanoyl, and aroyl have the same meanings as the above-described aryl. The aromatic heterocycli
Imma Hironori
Kanda Tomoyuki
Kuwana Yoshihisa
Osakada Naoto
Shimada Jun'ichi
Balasubramanian Venkataraman
Fitzpatrick ,Cella, Harper & Scinto
Kyowa Hakko Kogyo Co. Ltd.
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