Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-06-05
2001-10-23
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S220000, C514S267000, C540S471000, C540S559000, C544S251000, C544S276000
Reexamination Certificate
active
06306847
ABSTRACT:
TECHNICAL FIELD
The present invention relates to condensed purine derivatives exhibiting adenosine A
3
receptor antagonising activity, and having an antiasthmatic action, a bronchodilator action, an antiallergic action, an anti-itching action, etc.
BACKGROUND ART
Adenosine binds to adenosine receptors at the cell surfaces to cause various biological response.
The four subtypes of adenosine receptors, including A
1
, A
2a
, A
2b
and A
3
are known to be present (Pharmacological Reviews, Vol. 46, No. 2, p143, 1994). It is indicated that adenosine A
3
receptors are highly represented in the human pulmonary tissue (Proc. Natl. Acad. Sci. USA, Vol. 90, p10365, 1993), and are related to acceleration of the release of various mediators from mast cells (J. Biol. Chem., Vol. 268, No. 23, p16887, 1993). It is also disclosed in WO 95/11681 that compounds antagonistic to A
3
receptors inhibit mast cell degranulation by adenosine and are 2288733A that compounds antagonistic to A
3
receptors inhibit the activation of eosinophil by adenosine and are expected as antiasthmatics. Namely, compounds antagonistic to adenosine A
3
receptors are expected as antiasthmatics. Allergic diseases such as pruritus are known to be caused by the release of mediators from mast cells due to various types of stimulation [Standard Dermatology, Vol. 4. p160 (Igakushoin), 1994]. Therefore, compounds antagonistic to A
3
receptors are also expected to inhibit the release of mediators from mast cells and exhibit an antiallergic action such as an antipruritic action or the like.
A paper ( J. Med. Chem., Vol. 23, p1188, 1980) discloses that as condensed purine compounds, compounds represented by formula (A) have a weak bronchodilator action. Also Japanese Unexamined Patent Publication No. 91-204880 discloses that compounds represented by formula (B) exhibit a diuretic action and a weak antiasthmatic action.
DISCLOSURE OF INVENTION
An object of the present invention is to provide novel condensed purine derivatives exhibiting adenosine A
3
receptor antagonising activity, and having an antiasthmatic action, a bronchodilator action, an antiallergic action, an antiitching action, etc.
The present invention relates to condensed purine compounds and pharmacologically acceptable salts thereof represented by the following formula (I):
(wherein R
1
represents substituted or unsubstituted aryl or a substituted or unsubstituted aromatic heterocyclic group; R
2
represents hydrogen, lower alkyl, alicyclic alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted aromatic heterocyclic group; R
3
represents hydrogen, lower alkyl, or substituted or unsubstituted aralkyl; X
1
and X
2
are the same or different and each represents hydrogen, lower alkyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted aryl; and n represents an integer of 0 to 3).
Hereinafter, compounds represented by formula (I) are referred to as “compounds (I)”. This applies to compounds represented by other formulas.
In the definition of each of the groups in formula (I), lower alkyl includes straight or branched groups having 1 to 9 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and the like. Alicyclic alkyl includes groups having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Aralkyl includes groups having 7 to 15 carbon atoms, such as benzyl, phenethyl, benzhydryl, naphthylmethyl, and the like. Aryl includes phenyl, naphthyl, indenyl, anthranyl, and the like. Aromatic heterocyclic groups include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, indolyl, indazolyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, purinyl, and the like.
Each of substituted aryl, aralkyl, and aromatic heterocyclic groups has 1 to 3 substituents which are the same or different, and which are selected from, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkinyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, hydroxy, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aralkyloxy, substituted or unsubstituted aryloxy, lower alkxoylcarbonyl, lower alkylthio, lower alkylsulfonyl, carboxy, carbamoyl, lower alkanoyl, aroyl, halogen, nitro, amino, mono- or di-lower alkylamine, cyano, trifluoromethyl, and the like. Of these substituents, lower alkyl and the lower alkyl moiety of each of lower alkoxy, lower alkoxycarbonyl, lower alkylthio, lower alkylsulfonyl, lower alkanoyl, and mono- or di-alkylamino are defined in the same way as defined above for lower alkyl. Aralkyl and the aralkyl moiety in the of aralkyloxy are defined in the same as defined above for aralkyl. Aryl and the aryl moiety in each of aryloxy and aroyl are defined in the same way as defined above for aryl.
Lower alkenyl includes straight or branched groups having 2 to 6 carbon atoms, such as vinyl, ally, 1-propenyl, methacryl, butenyl, crotyl, pentenyl, hexenyl, and the like.
Lower alkynyl includes straight or branched groups having 2 to 6 carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
Halogen includes fluorine, chlorine, bromine and iodine atoms. Each of substituted lower alkyl, substituted lower alkenyl, substituted lower alkynyl and substituted lower alkoxy has 1 to 3 are selected from which are the same or different and which are, for example, carboxy, sulfo, phospho, lower alkyl esters, aralkyl eaters or aryl esters thereof, hydroxy, halogen and the like. Each of the lower alkyl moiety of lower alkyl esters, the aralkyl moiety of aralkyl esters and the aryl moiety in aryl esters is defined in the same way as defined above. Halogen is defined as the same as the above. Each of substituted aralkyl, substituted aryl, substituted aralkyloxy and substituted aryloxy has 1 to 3 substituents which are the same or different, and are selected from lower alkyl, hydroxy, halogen and the like. Lower alkyl and halogen are defined as the same as the above.
As compounds (I), compounds having hydrogen as R
3
are preferable, and compounds having substituted or unsubstituted phenyl as R
1
are preferable. Where R
1
is substituted phenyl, compounds having 1 to 3 substituents in substituted phenyl as R
1
, which are the same or different and are selected from halogen, lower alkyl, lower alkoxy and substituted lower alkenyl, are preferred, and halogen is particularly prefered. As the substituent of substituted lower alkenyl, lower alkoxycarbonyl is prefered.
Pharmacologically acceptable salts of compounds (I) include pharmacologically acceptable metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, acid addition salts, and the like.
Pharmacologically acceptable metal salts of compounds (I) include alkali metal salts such as sodium salts, potassium salts, and the like; alkaline earth metal salts such as magnesium salts, calcium salts, and the like; aluminum salts; zinc salts; and the like. Pharmacologically acceptable ammonium salts include ammonium, tetramethylammonium, and the like. Pharmacologically acceptable organic amine addition salts include addition salts of morpholine, piperidine, and the like. Pharmacologically acceptable amino acid addition salts include addition salts of lysine, glycine, phenylalanine, and the like. Pharmacologically acceptable acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, phosphates, and the like; organic acid salts such as acetates, maleates, fumarates, tartrates, citrates, and the like.
The process for producing compounds (I) will be described below.
Process 1
Compounds (I) can be produced according to the following reaction steps:
(wher
Ichikawa Shunji
Ichimura Michio
Kosaka Nobuo
Nonaka Hiromi
Saki Mayumi
Antonelli Terry Stout & Kraus LLP
Berch Mark L.
Kyowa Hakko Kogyo Co. Ltd.
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