Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-09
2001-06-12
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S228200, C544S061000, C546S122000
Reexamination Certificate
active
06245779
ABSTRACT:
This application is the national phase of PCT/JP98/03045 filed on Jul. 7, 1998.
FIELD OF THE INVENTION
The present invention relates to novel naphthyridine derivatives.
BACKGROUND ART
Our research group focused on compounds having a naphthyridine skeleton and continued intensive research thereon to develop compounds having excellent pharmacological effects. As a result, we found novel compounds having anti-inflammatory activity, anti allergic activity, immune regulating activity, analgesic activity and the like (Japanese Unexamined Patent Publication No. 304775/1995).
The novel compounds have potent anti-inflammatory effects but their alagesic effects are not completely satisfactory.
An object of the invention is to provide novel naphthyridine derivatives having potent analgesic effects.
We synthesized compounds in which the substituents at 1-position of the naphthyridine ring varied and carried out pharmacological screening of the same. Consequently we found a group of novel compounds having highly potent analgesic activity as compared with conventional compounds, and accomplished the present invention.
DISCLOSURE OF THE INVENTION
The present invention provides a naphthyridine derivative represented by the formula (1)
wherein A represents lower alkylene;
R
1
represents hydrogen or an electron pair “-”;
R
2
represents pyridyl; naphthyl; biphenylyl; or phenyl optionally having 1 to 3 substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy and halogen-substituted lower alkoxy;
when R
1
is an electron pair “-”, R
3
represents a group
(wherein R
4
and R
5
are the same or different and each represent lower alkyl, oxoalkyl, phenyl-lower alkyl, hydroxy-lower alkyl, di(lower alkyl)phosphono-lower alkyl, N-lower alkyl-carbamoyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, cycloalkyl, lower alkanoyloxy-lower alkyl, N-lower alkanoylamino-lower alkyl, lower alkoxy-lower alkyl, benzoyloxy-lower alkyl optionally having 1 to 3 substituents selected from the group consisting of lower alkoxy and lower alkanoyloxy on the benzene ring, N,N-di(lower alkyl)carbamoyloxy-lower alkyl, benzyloxy-lower alkyl having 1 to 3 lower alkoxy groups on the benzene ring, N-benzoylamino-lower alkyl having 1 to 3 lower alkoxy groups on the benzene ring, N-phenylcarbamoyl-lower alkyl having 1 to 3 lower alkoxy groups on the benzene ring, diphenylacetoxy-lower alkyl, or phenyl optionally having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxyl, halogen and lower alkoxy; or
R
4
and R
5
taken together form a heterocyclic ring containing the sulfur atom to which they are attached, wherein the heterocyclic ring may be substituted by 2-furoyl, tri(lower alkoxy)benzoyl or oxo or by phenyl and hydroxyl);
when R
1
is hydrogen, R
3
is a group —S—R
6
(wherein R
6
is lower alkyl, oxcalkyl, phenyl-lower alkyl, hydroxy-lower alkyl, di(lower alkyl)phosphono-lower alkyl, N-lower alkylcarbamoyl-lower alkyl, lower alkoxycarbonyl-lower alkyl, cycloalkyl, lower alkanoyloxy-lower alkyl, N-lower alkanoylamino-lower alkyl, lower alkoxy-lower alkyl, benzoyloxy-lower alkyl optionally having 1 to 3 substituents selected from the group consisting of lower alkoxy and lower alkanoyloxy on the benzene ring, N,N-di(lower alkyl) carbamoyloxy-lower alkyl, benzyloxy-lower alkyl having 1 to 3 lower alkoxy groups on the benzene ring, N-benzoylamino-lower alkyl having 1 to 3 lower alkoxy groups on the benzene ring, N-phenylcarbamoyl-lower alkyl having 1 to 3 lower alkoxy groups on the benzene ring, diphenylacetoxy-lower alkyl, or phenyl optionally having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxyl, halogen and lower alkoxy); and
R
7
is hydrogen or lower alkyl.
The present invention also provides pharmaceutical compositions containing the above naphthyridine derivative and a pharmaceutically acceptable carrier.
Further, the present invention provides use of the above napthyridine derivative for relieving a patient's pain or use of the above naphthyridine derivative for preparing an analgesic composition.
The present invention also provides a method for relieving a pain in a patient in need of such pain relief, which comprises administering to the patient an effective amount of the naphthyridine derivative defined in claim
1
.
The present invention will be described below in detail.
Examples of the groups in the formula (1) are shown below.
The lower alkylene group includes straight- or branched-chain alkylene groups having 1 to 6 carbon atoms, such as methylene, ethylene, ethylidene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like.
The pyridyl group includes 2-pyridyl, 3-pyridyl and 4-pyridyl.
The naphthyl group includes 1-naphthyl and 2-naphthyl.
The biphenylyl group includes 2-biphenylyl, 3-biphenylyl and 4-biphenylyl.
The halogen atom includes fluorine, chlorine, bromine and iodine.
The lower alkyl group includes straight- or branched-chain alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like.
The lower alkoxy group includes straight- or branched-chain alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like.
The halogen-substituted lower alkoxy group includes perhalogeno-(C
1-6
alkoxy) groups having as substituents halogen atoms selected from the group consisting of fluorine, chlorine, bromine and iodine, particularly perfluoro-(C
1-6
alkoxy) groups. Specific examples are trifluoromethoxy, pentafluoroethoxy, heptafluoropropoxy, nonafluorobutoxy, undecafluoropentyloxy, tridecafluorohexyloxy and the like.
The phenyl group optionally having 1 to 3 substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy and halogen-substituted lower alkoxy includes phenyl groups optionally having 1 to 3 substituents selected from the group consisting of halogen, C
1-6
alkyl, C
1-6
alkoxy and the above perhalogeno-(C
1-6
alkoxy) Specific examples are phenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-fluorophenyl, 4-bromophenyl, 4-iodophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorcphenyl, 2,4,6-trichlorophenyl, 2,4-dibromophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-ethoxyphenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4-butoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2-chloro-4-methoxyphenyl, 4-chloro-2-methoxyphenyl, 3,5-dichloro-4-methoxyphenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 4-n-butylphenyl, 4-t-butylphenyl, 4-n-pentylphenyl, 4-n-hexylphenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,4,5-trimethylphenyl, 2,4,6-trimethylphenyl, 3,4,5-trimethylphenyl, 4-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 4-pentafluoroethoxyphenyl, 4-heptafluoropropoxyphenyl, 4-nonafluorobutoxyphenyl, 4-undecafluoropentyloxyphenyl, 4-tridecafluorohexyloxyphenyl, 2,3-bis(trifluoromethoxy)phenyl, 2,4-bis(trifluoromethoxy)phenyl, 2,5-bis(trifluoromethoxy)phenyl, 2,6-bis(trifluoromethoxy)phenyl, 3,4-bis(trifluoromethoxy)phenyl, 3,5-bis(trifluoromethoxy)phenyl, 2,3,4-tris(trifluoromethoxy)phenyl, 2,3,5-tris(trifluoromethoxy)phenyl, 2,4,5-tris(trifluoromethoxy)phenyl, 2,4,6-tris(trifluoromethoxy)phenyl, 3,4,5-tris(trifluoromethoxy)phenyl, 4-methoxy-3,5-dimethyphenyl, 4-trifluoromethoxy-3,5-dimethylphenyl, 3-chloro-4-methylphenyl, 3-chloro-4-trifluoromethoxyphenyl, 3,5-dimethoxy-4-trifluoromethoxyphenyl and the like.
The oxoalkyl group includes oxoalkyl groups having 3 to 8 carbon atoms, such as 2-oxopropyl, 2-oxobutyl, 3-oxobutyl, 2-oxopentyl, 3-oxopentyl, 4-oxopentyl, 5-oxohexyl, 6-oxoheptyl, 7-oxooctyl and the like.
The phenyl-lower alkyl group includes phenyl-C
1-6
alkyl groups, such as benzyl, 1-phenylethyl, 2-phen
Iwamoto Takeshi
Okamura Takashi
Shibutani Tadao
Shoji Yasuo
Yasuda Tsuneo
Huang Evelyn Mei
Otsuka Pharmaceutical Factory Inc.
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