Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-03
2004-04-27
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06727259
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a therapeutic agent for neurodegenerative disorders.
BACKGROUND OF THE INVENTION
Most of the compounds according to the present invention are known compounds, and their adenosine A
2
-receptor antagonism, anti-Parkinson's disease action, anti-depressive action, anti-asthmatic action, inhibitory action on bone absorption and action on central excitation are known [Japanese Published Examined Patent Application No. 26516/72, J. Med. Chem., 34, 1431 (1991), J. Med. Chem., 36, 1333 (1993), WO 92/06976, Japanese Published Unexamined Patent Application No. 211856/94, Japanese Published Unexamined Patent Application No. 239862/94, WO 95/23165, Japanese Published Unexamined Patent Application No. 16559/94 and WO 94/01114).
However, it is not known that said compounds have an inhibitory action on neurodegeneration.
DISCLOSURE OF THE INVENTION
The present invention relates to a therapeutic agent for neurodegenerative disorders, comprising, as an active ingredient, xanthine derivatives represented by formula (I):
wherein R
1
, R
2
and R
3
independently represent hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R
4
represents cycloalkyl, —(CH
2
)
n
—R
5
(wherein R
5
represents substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group, and n is an integer of 0 to 4), or the following group:
wherein Y
1
and Y
2
independently represent hydrogen, halogen or lower alkyl, and Z represents substituted or unsubstituted aryl, the following group:
wherein R
6
represents hydrogen, hydroxy, lower alkyl, lower alkoxy, halogen, nitro or amino, and m is an integer of 1 to 3, or a substituted or unsubstituted heterocyclic group; and X
1
and X
2
independently represent O or S, or pharmaceutically acceptable salts thereof.
As the active ingredient for the therapeutic agent for neurodegenerative disorders, preferred compounds are compounds of formula (I) wherein X
1
and X
2
are O, or pharmaceutically acceptable salts thereof; or compounds of formula (I) wherein R
4
is the following-group:
wherein Z has the same meaning as defined above, or pharmaceutically acceptable salts thereof, and specifically preferred compounds are compounds of formula (I) wherein X
1
and X
2
are O and R
4
is the group defined above, or pharmaceutically acceptable salts thereof.
Further, the present invention relates to a method of treating neurodegenerative disorders, which comprises administering an effective dose of a xanthine derivative represented by formula (I) or a pharmaceutically acceptable salt thereof.
Furthermore, the present invention relates to use of a xanthine derivative represented by formula (I) or a pharmaceutically acceptable salt thereof for manufacturing a pharmaceutical composition useful for treatment of neurodegenerative disorders.
Hereinafter, the compound represented by formula (I) is referred to as compound (I).
In the definition of compound (I), the lower alkyl and the lower alkyl moiety in the lower alkoxy mean a straight-chain or branched C
1
to C
6
alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl and hexyl; the lower alkenyl means a straight-chain or branched C
2
to C
6
alkenyl group such as vinyl, allyl, methacryl, crotyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 2-hexenyl and 5-hexenyl; the lower alkynyl means a straight-chain or branched C
2
to C
6
alkynyl group such as ethynyl, propargyl, 2-butynyl, 3-butynyl, 2-pentynyl, 4-pentynyl, 2-hexynyl, 5-hexynyl and 4-methyl-2-pentynyl; the aryl means phenyl or naphthyl; the cycloalkyl means a C
3
to C
8
cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; examples of the heterocyclic groups are furyl, thienyl, pyrrolyl, pyranyl, thiopyranyl, pyridyl, thiazolyl, imidazolyl, pyrimidyl, triazinyl, indolyl, quinolyl, purinyl and benzothiazolyl; and the halogen includes fluorine, chlorine, bromine and iodine. The substituted aryl and the substituted heterocyclic group have 1 to 3 independently-selected substituents such as lower alkyl, hydroxy, substituted or unsubstituted lower alkoxy, halogen, nitro, amino, lower alkylamino, di(lower alkyl)amino, trifluoromethyl, tri-fluoromethoxy, benzyloxy, phenyl, phenoxy, lower alkanoyl, lower alkanoyloxy, aroyloxy, aralkanoyloxy, carboxy, lower alkoxycarbonyl, lower alkylcarbamoyl, di(lower alkyl)-carbamoyl, sulfo, lower alkoxysulfonyl, lower alkylsulfamoyl and di(lower alkyl)sulfamoyl. The lower alkyl and the alkyl moiety of the lower alkoxy, lower alkylamino, di(lower alkyl)amino, lower alkanoyl, lower alkanoyloxy, lower alkoxycarbonyl, lower alkylcarbamoyl, di(lower alkyl)-carbamoyl, lower alkoxysulfonyl, lower alkylsulfamoyl and di(lower alkyl)sulfamoyl have the same meaning as the lower alkyl defined above. The halogen has the same meaning as the halogen defined above. Examples of the substituents for the substituted lower alkoxy are hydroxy, lower alkoxy, halogen, amino, azido, carboxy and lower alkoxycarbonyl. The alkyl moiety of the lower alkoxy and lower alkoxycarbonyl has the same meaning as the lower alkyl defined above, and the halogen has the same meaning as the halogen-defined above. The aroyl moiety of the aroyloxy includes benzoyl and naphthoyl. The aralkyl moiety of the aralkanoyloxy includes benzyl and phenethyl.
The pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts and amino acid addition salts.
The pharmaceutically acceptable acid addition salts of compound (I) include inorganic acid addition salts such as hydrochloride, sulfate and phosphate, and organic acid addition salts such as acetate, maleate, fumarate, tartrate, citrate and methanesulfonate; the pharmaceutically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt; the pharmaceutically acceptable ammonium salts include ammonium and tetramethylammonium; the pharmaceutically acceptable organic amine addition salts include salts with morpholine and piperidine; and the pharmaceutically acceptable amino acid addition salts include salts with lysine, glycine and phenylalanine.
Compound (I) including a novel compound can be produced by the methods disclosed in the above-mentioned publications or according to the methods. The desired compound in the process can be isolated and purified by purification methods conventionally used in synthetic organic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization and various kinds of chromatography.
In the case where a salt of compound (I) is desired and it is produced in the form of a desired salt, it may be subjected to purification as such. In the case where compound (I) is produced in the free form and its salt is desired, it is dissolved or suspended in a suitable solvent, and then an acid or a base may be added thereto to form the salt.
Compound (I) and pharmaceutically acceptable salts thereof may be in the form of adducts with water or various solvents, which can satisfactorily be used as the therapeutic agent of the present invention.
Some of compounds (I) have optical isomers, and all potential stereoisomers and mixtures thereof can satisfactorily be used as the therapeutic agent of the present invention.
Examples of compound (I) are shown in Table 1.
TABLE 1
Com-
pound
No.
1
2
3
4
Compound 1: (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (Japanese Published Unexamined Patent Application No. 211856/94)
Melting point: 190.4-191.3° C.
Elemental analysis: C
20
H
24
N
4
O
4
Calcd. (%): C 62.48, H 6.29, N 14.57
Found (%): C 62.52, H 6.53, N 14.56
IR(KBr) &ngr;max(cm
−1
): 1697, 1655, 1518
NMR(CDCl
3
, 270 MHz) &dgr;(ppm): 7.74(1H, d, J=15.5 Hz), 7.18(1H, dd, J=8.3, 1.9 Hz), 7.08(1H, d, J=1.9 Hz), 6.89(1H, d, J=8.3 Hz), 6.77(1H, d, J&equals
Ikeda Ken
Kurokawa Masako
Kuwana Yoshihisa
Shimada Jun'ichi
Suzuki Fumio
Antonelli Terry Stout & Kraus LLP
Kyowa Hakko Kogyo Co. Ltd.
Spivack Phyllis G.
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