Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-13
2001-12-11
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S251000
Reexamination Certificate
active
06329382
ABSTRACT:
This application is the National Stage Application of PCT/JP 97/04878, filed Dec. 26, 1997, which claims priority to Japanese Applications 9-047197 and 9-047211 filed Feb. 14, 1997.
TECHNICAL FIELD
The present invention relates to a therapeutic and preventive medicament for respiratory diseases represented by asthma in particular, and to novel pyrrolopyrazolopyrimidine derivatives.
BACKGROUND ART
At present, bronchodilation by xanthine type bronchodilators typified by theophylline are mainly practiced for the prevention and treatment of respiratory diseases represented by asthma and the like. Besides, beta-receptor stimuli such as ephedrine hydrochloride have been only used symptomatolytically.
However, all the above drugs have great side effects and hence have offered a problem. However, there has been nothing for it but to administer these drugs because any excellent drug substitutable for these drugs has not been yet found.
On the other hand, 3-cyano-5-methylpyrrolo[3,2-e]pyrazolo[1,5-a]pyrimidines as compounds having a pyrrolo[3,2-e]pyrazolo[1,5-a]pyrimidine skeleton have been known to have excellent vasodilative effect and tracheobronchodilative effect (Japanese Patent Publication No. 88999/1994). However, these compounds have been difficult to separate their action on circulatory organs such as hypotensive effect and their action on tracheas (or bronchus) from each other. It has therefore been desired to develop a drug which selectively acts on tracheas (or bronchus).
It is therefore an object of the present invention to provide a medicine which scarcely exhibits side effects and has excellent prophylactic and therapeutic effects on respiratory diseases.
DISCLOSURE OF THE INVENTION
In view of the foregoing circumstances, the present inventors have carried out an extensive investigation by syntheses, screening and the like with a view toward seeking compounds useful in the prevention and treatment of respiratory diseases. As a result, it has been found that compounds represented by the general formula (1), which will be described subsequently, or salts thereof have excellent tracheobronchodilative effect and inhibitory effect on airway constriction, act only weakly on circulatory organs, and are hence useful as prophylactic and therapeutic medicines for respiratory diseases, thus leading to completion of the present invention.
According to the present invention, there is thus provided a therapeutic and preventive medicament for respiratory diseases, comprising, as an active ingredient, a pyrrolopyrazolo-pyrimidine derivative represented by the following general formula (1):
wherein R
1
represents a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms; and R
2
represents a hydrogen or halogen atom, a substituted alkyl group, an amino group which may be substituted, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, or an alkylcarbamoyl group, or a salt thereof.
According to the present invention, there is also provided a therpeutic and preventive medicament composition for respiratory diseases, comprising a compound represented by the general formula (1) or a salt thereof and a pharmaceutically acceptable carrier.
According to the present invention, there is further provided use of a compound represented by the general formula (1) or a salt thereof for a therapeutic and preventive medicament for respiratory diseases.
According to the present invention, there is still further provided a method for the treatment of a respiratory disease, which comprises the administration of an effective amount of a compound represented by the general formula (1) or a salt thereof.
Of the compounds represented by the general formula (1), compounds represented by the general formula (1A), which will be described subsequently, are novel compounds not found in literature.
According to the present invention, therefore, there are yet still further provided a pyrrolopyrazolopyrimidine derivative represented by the following general formula (1A):
wherein R
1A
represents a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms (but a tert-butyl group); and R
2A
represents a halogen atom, a substituted alkyl group, an amino group which may be substituted, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, or an alkylcarbamoyl group, or a salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
In the general formula (1), R
1
is a linear, branched or cyclic alkyl group having 1 to 10 carbon atoms. R
1A
is any one of those represented by R
1
but a tert-butyl group. Specific examples of R
1
include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, 1-ethylpropyl, tert-amyl, cyclopentyl, n-hexyl, cyclohexyl, n-heptyl and cycloheptyl groups. Of these, isopropyl, cyclopropyl, sec-butyl, tert-butyl, cyclobutyl, 1-ethylpropyl, tert-amyl, cyclopentyl and cyclohexyl groups are preferred as R
1
. Preferable examples of R
1A
include these groups other than the tert-butyl group.
Examples of the halogen atoms represented by R
2
and R
2A
include fluorine, chlorine and bromine atoms. Of these, fluorine and chlorine atoms are preferred.
Examples of the substituted alkyl group include alkoxyalkyl groups, aryloxyalkyl groups, aralkyloxyalkyl groups, mono- or di-alkyl-aminoalkyl groups, cyclic aminoalkyl groups, and hydroxyalkyl groups. Of these, C
1-10
-alkoxy-C
1-10
-alkyl groups, phenoxy-C
1-10
-alkyl groups, phenyl-C
1-4
-alkyloxy-C
1-10
-alkyl groups, mono- or di-C
1-10
-alkylamino-C
1-10
-alkyl groups, cyclic amino-C
1-10
-alkyl groups and hydroxy-C
1-10
-alkyl groups are preferred. Specific examples thereof include methoxymethyl, ethoxymethyl, benzyloxymethyl, phenoxymethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, morpholinomethyl, piperazinomethyl, 4-methylpiperazinomethyl and hydroxymethyl groups.
Examples of the amino group which may be substituted include an amino group, mono- or di-alkylamino groups, cyclic amino groups, alkylsulfonylamino groups which may be substituted by halogen atoms, arylsulfonylamino groups, alkylcarbonylamino groups, arylcarbonylamino groups, a ureido group which may be substituted, a thioureido group which may be substituted, and a hydrazino group which may be substituted. The halogen atoms as substituents include fluorine, chlorine, bromine and iodine atoms. Examples of the substituents on the ureido, thioureido and hydrazino groups include linear, branched or cyclic alkyl groups. Of these alkyl groups, those having 1 to 10 carbon atoms are preferred. Preferable examples of the amino groups which may be substituted include an amino group, mono- or di-C
1-10
-alkylamino groups, three- to six-membered cyclic amino groups, C
1-10
-alkylsulfonylamino groups, C
1-10
-halogenoalkylsulfonylamino groups, a benzenesulfonylamino group, C
1-10
-alkylcarbonylamino groups, C
6-10
-arylcarbonylamino groups, C
1-10
-alkylureido groups, C
1-10
-alkylthioureido groups, and C
1-10
-alkylhydrazino groups. Specific examples of the amino group which may be substituted include amino, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropylamino, cyclobutylamino, pyrrolidino, piperidino, morpholino, piperazino, methanesulfonylamino, trifluoromethanesulfonylamino, benzenesulfonylamino, acetylamino, benzoylamino, ureido, methylureido, thioureido, methylthioureido, hydrazino and methylhydrazino groups.
The alkoxycarbonyl group is preferably an alkoxycarbonyl group having 2 to 11 carbon atoms in total, and more preferably an alkoxycarbonyl group having 2 to 7 carbon atoms in total. Examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl and isopropyloxycarbonyl groups.
The alkylcarbamoyl group is preferably an alkylcarbamoyl group having 2 to 11 carbon atoms in total, and more preferably an alkylcarbamoyl group having 2 to 7 carbon atoms in total. Examples of the alkylcarbamoyl group include methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl, dimethylcarbamoyl and diethylcarbamoyl groups.
Of thes
Hiyama Naoki
Ichinomiya Satoshi
Kawazu Yukio
Namiki Takayuki
Sugio Mayumi
McKenzie Thomas
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Pola Chemical Industries Inc.
Shah Mukund J.
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