Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-02-01
2001-12-25
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S651000
Reexamination Certificate
active
06333358
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a medicine, and more particularly relates to a medicine having a high affinity for MDR.
BACKGROUND ART
Benzodiazepine (Bz) receptors are recently classified into 2 subtypes of central benzodiazepine receptor (CBR) located on GABA
A
receptor/ion channel complex and mitochondrial DBI (diazepam binding inhibitor, Neuropharmacol., 30, 1425-1433 (1991)) receptor (BDR) located on the central nervous system (glial cells) or adrenal glands (Clin. Neuropharmacol., 16, 401-417 (1993)).
MDR agonists act indirectly on GABA
A
/ion channel complex via endogenous neurosteroids and cause an anti-anxiety action. Accordingly, they have a possibility to be usable for diseases (obsessive disorders, panic disorders) on which the previous Bzs do not have a satisfactorily therapeutic effect, and to alleviate side-effects such as excessive sedation or psychic dependence caused by the Bzs. Furthermore, MDR ligands act indirectly on GABA
A
receptors, and therefore, have a possibility of use as therapeutical agents of sleeping disorders, epilepsy, dyskinesia accompanied by muscle rigidity, feeding disorders, circulation disorders, recognition and learning disability or drug dependence (Progress in Neurobiology, 38, 379-395, 1992, ibid., 49, 73-97, 1996; J. Neurochem., 58, 1589-1601; Neuropharmacol., 30, 1435-1440, 1991). In addition, MDR ligands have a possibility of use as therapeutic agents of cancer (Biochimica et Biophysica Acta, 1241, 453-470, 1995), lipid metabolism abnormality (Eur. J. Pharmacol., 294, 601-607, 1995), schizophrenia (Neuropharmacology, 35, 1075-1079, 1996), cerebral infarction (J. Neurosci., 15, 5263-5274, 1995), AIDS (Abstracts of the fifth international conference on AIDS, p. 458, 1989), Alzheimer's disease (Alzheimer Dis. Assoc. Disotd., 2, 331-336, 1988) or Huntington chorea (Brain Res., 248, 396-401, 1982).
Some phenoxyaniline derivatives are reported in WO9533715, JP 61040249 and JP 57208295. However, they have a hydrogen atom or an alkyl group as the substituent on the nitrogen atom of the aniline, but there are not reported the derivatives having a carbonyl group as the substituent. Furthermore, the use of the derivatives of the above-mentioned patent is anti-inflammatory agents based on the action to arakidonic acid series, anti-arteriosclerosis drugs based on an increase of PGI
2
production, or heat sensitive recording materials, but there is not described affinity for MDR and anti-anxiety based on affinity for MDR.
An object of the present invention is to provide pharmaceutical compounds which are effective on diseases on which the previous Bzs do not have a satisfactorily therapeutic effect, and have a high affinity for MDR, and therefore, have a therapeutic or preventive effect on the central diseases such as anxiety, related diseases thereto, depression, epilepsy, etc. without side-effects such as excessive sedation or psychic dependence caused by the Bzs. Furthermore, another object of the present invention is to provide therapeutic agents of sleeping disorders, dyskinesia accompanied by muscle rigidity, feeding disorders, circulation disorders, recognition and learning disability, drug dependence, cancer, lipid metabolism abnormality, schizophrenia, cerebral infarction, AIDS, Alzheimer's disease or Huntington chorea.
DISCLOSURE OF THE INVENTION
As a result of extensive researches about aryloxyaniline derivatives, the present inventors have found novel aryloxyaniline derivatives having a high affinity for MDR, thus the present invention has been accomplished.
The present invention is illustrated as follows: the present invention is directed to an aryloxyaniline derivative represented by Formula [I]:
wherein Ar
1
and Ar
2
are the same or different, and are each a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group or naphthyl group, R
1
is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, a substituted or unsubstituted phenyl group or group of the formula:
—NR
2
(R
3
) (wherein R
2
and R
3
are the same or different, and are each a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, or R
2
and R
3
taken together with the nitrogen atom to which they are attached form a 4 to 10 membered cyclic amino group), X
1
is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a phenoxy group, a halogen atom, a trifluoro methyl group, a carbamoyl group or an aminosulfonyl group, y
1
is a branched or unbranched alkylene group having 1 to 6 carbon atoms or a single bond; or a pharmaceutically acceptable salt thereof.
In the present invention, the substituted phenyl group is a phenyl group substituted with one to three members selected from the group consisting of an alkyl group having 1 to 10 carbon atoms, an alkyl group having 1 to 10 carbon atoms substituted with halogen atoms; hydroxyl groups; alkanoyloxy groups having 1 to 10 carbon atoms; carboxyl groups or alkoxycarbonyl groups, an alkenyl group having 2 to 10 carbon atoms, an alkoxy group having 1 to 10 carbon atoms, an alkylthio group having 1 to 10 carbon atoms, a group of the formula: —O—Z—R
4
(wherein Z is a branched or unbranched alkylene group having 1 to 10 carbon atoms, and R
4
is an amino group, an amino group substituted with one or two of an alkyl group having 1 to 7 carbon atoms, a cyclic amino group having 2 to 7 carbon atoms, a hydroxyl group, a carboxyl group or an alkoxycarbonyl group), an alkanoyl group having 2 to 10 carbon atoms or a ketal form thereof, a formyl group or an acetal form thereof, a carboxyl group, an alkoxycarbonyl group having 2 to 10 carbon atoms, a carbamoyl group, a carbamoyl group substituted with one or two of an alkyl group having 1 to 10 carbon atoms on the nitrogen atom, an aminosulfonyl group, an aminosulfonyl group substituted with one or two of an alkyl group having 1 to 10 carbon atoms on the nitrogen atom, a halogen atom and a nitro group, and examples thereof are a 2-methylphenyl group, a 2-propylphenyl group, a 2-isopropylphenyl group, a 2-cyclopentylphenyl group, a 2-(1-hydroxyethyl)phenyl group, a 2-carboxymethylphenyl group, a 2-methoxycarbonyl phenyl group, a 2-vinylphenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 2-ethoxyphenyl group, a 2-hexyloxyphenyl group, a 2-isopropoxyphenyl group, a 2-cyclopentoxyphenyl group, a 2,5-dimethoxyphenyl group, a 2,4,6-trimethoxyphenyl group, a 4-methylthiophenyl group, a 2-isopropylthiophenyl group, a 4-cyclohexylthiophenyl group, a 2-(2-dimethylamino ethoxy)phenyl group, a 2-(2-hydroxyethoxy)phenyl group, a 2-carboxymethoxyphenyl group, a 2-methoxycarbonylmethoxyphenyl group, a 2-acetylphenyl group, a 2-(2-methyl-1,3-dioxolan-2-yl)phenyl group, a 2-formylphenyl group, a 2-(1,3-dioxolan-2-yl)phenyl group, a 2-carboxylphenyl group, a 2-(N-methylaminocarbonyl)phenyl group, a 2-(N,N-dimethylamino-carbonyl)phenyl group, a 2-aminocarbonylphenyl group, a 2-aminosulfonylphenyl group, a 4-aminosulfonylphenyl group, a 2-methylaminosulfonylphenyl group, a 2-dimethylamino-sulfonylphenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 2,4-difluorophenyl group, a 2-nitrophenyl group, a 2-aminophenyl group, a 2-pyrrolidinophenyl group and a 4-dimethylaminophenyl group. The substituted pyridyl group refers to a pyridyl group substituted with a straight or branched alkoxy group having 1 to 10 carbon atoms, and examples thereof are a 2-methoxy-3-pyridyl group, a 3-methoxy-2-pyridyl group and a 4-methoxy-3-pyridyl group. The alkyl group having 1 to 10 carbon atoms refers to a straight, branched or cyclic alkyl group, and examples thereof are a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a cyclobutyl group,
Chaki Shigeyuki
Harada Koichiro
Nagamine Masashi
Nakamura Toshio
Nakazato Atsuro
Lorusso & Loud
Patel Sudhaker B.
Shah Mukund J.
Taisho Pharmaceutical Co. Ltd.
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