Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-03-15
2001-02-27
Lambkin, Deborah C. (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S640000, C514S645000, C564S265000, C564S300000
Reexamination Certificate
active
06194461
ABSTRACT:
This application is the national phase under 35 U.S.C. §371 of prior PCT International Application No. PCT/JP97/03377 which has an International filing date of Sep. 22, 1997 which designated the United States of America.
TECHNICAL FIELD
The present invention relates to a nitrone derivative and a precursor thereof useful as a medicament. The nitrone derivative and a precursor thereof are useful as a medicament for treating neurodegenerative disorders such as retinal degenerative disorders and the like.
BACKGROUND ART
The nitrone derivatives such as phenyl-t-butylnitrone (PBN) have been used as spin-traps to detect free radicals by electron spin resonance (ESR). J. Org. Chem., 57, 2624(1992) describes the syntheses of various mono-substituted PBN derivatives and their effects as spin traps.
It has been reported that the nitrone derivatives such as PBN would be useful as medicaments for treating the diseases caused by active oxygen damages (e.g. ischemia, infection, inflammation, radiation damages, damages of central or peripheral nervous systems or peripheral organs caused by drug abuse, etc.) by acting as antioxidants (WO 91/5552; WO 92/22290; WO 95/17876; J. Biol. Chem., 271, 3097(1996)). However, these documents do not disclose that these compounds are effective for treating retinal degenerative disorders. It is also reported that free radicals such as active oxygen have some relation with retinal damages caused by light (A. M. Van Der Hagen, et al., J. Am. Optom. Assoc., 64, 871(1993)).
JP 54-2324 (A) discloses the syntheses of compounds useful as insecticides using N-t-butyl-4-chlorobenzylamine, N-t-butyl-2,4-dichlorobenzylamine and the like as synthetic intermediates.
DESCRIPTION OF THE INVENTION
The present invention is intended to provide a novel compound useful as a medicament for treating neurodegenerative disorders (e.g. neurodegenerative disorders induced by stroke, hypoglycemia, cardiac arrest, perinatal apparent death and the like; epilepsy; Huntington's chorea; Alzheimer's disease; diabetic neuropathy; retinal degenerative disorders and the like).
The present invention is also intended to provide a medicament for treating retinal degenerative disorders (e.g. retinitis pigmentosa, senile macular degeneration, diabetic retinopathy, glaucoma, traumatic retinodialysis, etc.)
The inventors of the present invention have intensively carried out research, and found that nitrone derivatives are useful as a medicament for treating neurodegenerative disorders such as retinal degenerative disorders and the like, and that the corresponding amine which would be converted to the nitrone derivative in human bodies, have similar effects. Thus, the present invention has been accomplished.
The present inventions are as follows:
[1] A medicament for treating retinal degenerative disorder comprising a compound represented by the figure 1 or a pharmaceutically acceptable salt thereof:
wherein Ar is optionally substituted phenyl or optionally substituted heteroaryl;
n is 0, 1 or 2;
W is —CH
2
NH— or —CH═N(O)—;
R
1
, R
2
and R
3
are independently optionally substituted alkyl, carboxyl or alkoxycarbonyl; any two groups of R
1
, R
2
and R
3
may be taken together with the carbon atom to form optionally substituted cycloalkane; all of R
1
, R
2
and R
3
may be taken together with the adjacent carbon atom to form optionally substituted bicycloalkane or optionally substituted tricycloalkane;
R
4
and R
5
are independently hydrogen atom or optionally substituted alkyl, and
[2] A compound represented by the figure 2 or a pharmaceutically acceptable salt thereof:
wherein n, W, R
1
, R
2
, R
3
, R
4
and R
5
are as defined above;
Ar
1
is optionally substituted 5-membered heteroaryl or a group represented by the Figure 3:
wherein R
6
is halogen atom, trifluoromethyl, cyano or nitro;
R
7
is hydrogen atom or a substitutent;
R
8
is a substituent;
provided that Ar
1
is not dichlorophenyl when W is —CH
2
NH—.
Heteroaryl includes, for example, 5- or 6-membered heteroaryl containing 1 to 3 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms, and the like. 5-Membered heteroaryl includes, for example, 5-membered heteroaryl containing 1 to 3 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms, and the like. Typical examples are 5-membered heteroaryl containing 1 or 2 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms such as pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, and the like. 6-Membered heteroaryl includes, for example, 6-membered heteroaryl containing 1 to 3 nitrogen atoms, and the like. Typical examples are pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.
Heterocyclic group includes heteroaryl, heterocycloalkyl and the like. Heterocycloalkyl includes, for example, 5- or 6-membered heterocycloalkyl containing 1 to 3 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms, and the like. 5-Membered heterocycloalkyl includes, for example, 5-membered heterocycloalkyl containing 1 to 3 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms, and the like. Typical example is 5-membered heterocycloalkyl containing 1 or 2 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms, such as pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dioxolanyl and the like. 6-Membered heterocycloalkyl includes, for example, 6-membered heterocycloalkyl containing 1 to 3 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms, and the like. Typical example is 6-membered heterocycloalkyl containing 1 or 2 atoms selected independently from nitrogen atoms, sulfur atoms and oxygen atoms, such as piperidyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl and the like.
The substituent of substituted phenyl and substituted heteroaryl includes, for example, halogen atom, cyano, nitro, alkyl, alkyl substituted by halogen atom(s), alkoxy, alkoxycarbonyl, carbamoyl, carbamoyl substituted by alkyl(s) and the like. Phenyl and heteroaryl may be substituted independently by one or more substituents. Typical examples are the electron-withdrawing groups such as halogen atom, cyano, nitro, trifluoromethyl and the like. Preferable is halogen atom, and most preferable is fluorine atom.
The number of substituents of substituted aryl may be 1, 2 or 3. Typical examples are 1 and 2, and preferable is 2. Typical positions of the substitution are 4th position and 2nd and 4th positions if the aryl is substituted by 2 substituents.
Alkyl includes straight or branched C
1
-C
6
alkyl. Typical examples are methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, pentyl, 1,2-dimethylpropyl, hexyl, 3-ethylbutyl and the like.
Alkoxy includes straight or branched C
1
-C
6
alkoxy. Typical examples are methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, pentyloxy, 1,2-dimethylpropoxy, hexyloxy, 3-ethylbutoxy and the like.
Alkoxyalkoxy is the alkoxy substituted by alkoxy.
Alkoxycarbonyl is the carbonyl substituted by alkoxy.
Halogen-substituted alkyl and halogen-substituted alkoxy are the alkyl and alkoxy substituted by one halogen atom or more. Typical examples are trifluoromethyl, trifluoromethoxy and the like.
Alkanoyl of alkanoyloxy and alkanoylamino includes, for example, straight or branched C
1
-C
6
alkanoyl. Typical examples are formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, 2-methylbutyryl, hexanoyl and the like.
Cycloalkyl includes, for example, C
3
-C
8
cycloalkyl. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
In the carbamoyl substituted by alkyl(s), the carbamoyl may be substituted independently by 1 or 2 alkyl(s).
Halogen atom includes, for example, fluorine atom, chlorine atom, bromine atom, iodine atom and the like. Typical examples are fluorine atom, chlorine atom and bromine atom, and preferable is flu
Fujibayashi Tatsuya
Ikeda Kazuhito
Masumoto Shuji
Nagata Ryu
Ogo Hiroki
Birch & Stewart Kolasch & Birch, LLP
Lambkin Deborah C.
Sumitomo Pharmaceuticals Co. Ltd.
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