JP2000007568A - Neurotrophic factor-like medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine having a low mol.wt., capable of being safely administered, and useful for preventing and treating neurodegenerative diseases, cerebrovascular diseases, dysmnesia, and psychiatric disorders by compounding a specific compound (salt) as an active ingredient. SOLUTION: This neurotrophic factor-like medicine contains a compound (salt) of the formula [Ar is (substituted, condensed) phenyl; (n) is 1-10; R is H or a (substituted) hydrocarbon; Y is (substituted) amino or a (substituted) nitrogen-containing saturated heterocyclic group] for example, 3-[1-(phenylmethyl)-4-piperidinyl]-1-(2,3,4,5,-tetrahydro-1H-1-benzaze pin-8-y1)-1- propanone fumarete} as an active ingredient. The compound as such can be mixed with a carrier and subsequently orally (parenterally) administered in the preparation of tablets, liquid medicines, injections, suppositories, sustained release medicines, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a neurotrophic factor-like agent having excellent properties.

[0002]

2. Description of the Related Art Neurotrophic factor (N)
As TF, nerve growth factor (NG)
F), ciliary neurotrophic factor, insulin-like growth factor-
I, brain-derived neurotrophic
Factors (BDNF) and the like are known, and these proteins are deeply involved in the homeostasis of nerve cells in vivo, and (1) survival / maintenance action of nerve cells, (2) action of promoting synapse formation, (3) It is responsible for neuronal cell death protection and (4) long-term potentiation in the hippocampus. Also, NGF, B
DNF and the like are choline acetyltransferases (ChA
T) It is known that compounds that increase activity and increase ChAT activity have neuroprotective and neurotrophic factor-like effects [The Journal of Neuroscience, 16, 21.
Issue, 6665-6675, 1996, Neuroscience
science), 55, No. 3, 629-641, 1993]. Therefore, a drug having an action similar to that of a neurotrophic factor can provide (1) a neurodegenerative disease (eg, senile dementia,
Alzheimer's disease, Down's syndrome, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic lateral cord sclerosis (AL
S), diabetic neuropathy, etc.), (2) at the time of cerebrovascular disorder (eg, cerebral infarction, cerebral hemorrhage, cerebral circulatory insufficiency due to cerebral arteriosclerosis), at the time of head injury / spinal cord injury, at the aftereffect of encephalitis or at the time of cerebral palsy Nervous disorders, (3) memory disorders (eg, senile dementia,
(4) It is useful for prevention and / or treatment of (4) mental disorders (eg, depression, panic disorder, schizophrenia, etc.). As having a ChAT activity activating effect,
No. 169569, the formula

Embedded image [In the formula, J is (a) a substituted or unsubstituted group shown below;
A phenyl group, a pyridyl group, a pyrazyl group, a quinolyl group, a cyclohexyl group, a quinoxalyl group or a furyl group, (b) a monovalent or divalent group selected from the following groups in which the phenyl group may be substituted;
Indanonyl, indenyl, indenonyl, indandionyl, tetralonyl, benzperonyl,
Indanolyl, formula

Embedded image (C) a monovalent group derived from a cyclic amide compound, (d) a lower alkyl group, or (e) a compound represented by the formula R _1-
CH = CH- (wherein, R ₁ represents a hydrogen atom or a lower alkoxycarbonyl group).
B is the formula _{-CO- (C (R 2) H} ) n - group represented by (wherein, n represents an integer of 0 or 1 to 10 .R ₂ in the formula - (C (R ₂₎ H ) represents a hydrogen atom or a methyl group in such a manner that the alkylene group represented by _n − has no substituent or has one or more methyl groups.)
Means T means a nitrogen atom or a carbon atom. Q
Represents a nitrogen atom, a carbon atom or a group represented by the formula> N → O. K represents a hydrogen atom, a substituted or unsubstituted phenyl group, an arylalkyl group optionally substituted with a phenyl group, a cinnamyl group optionally substituted with a phenyl group, a lower alkyl group, a pyridylmethyl group, a cycloalkylalkyl group, an adamantane It means a methyl group, a furylmethyl group, a cycloalkyl group, a lower alkoxycarbonyl group or an acyl group. q represents an integer of 1 to 3. Where:
... means a single bond or a double bond. And the pharmacologically acceptable salts thereof. Japanese Patent Application Laid-Open No. 5-140149 discloses a cyclic amine derivative having a cholinesterase inhibitory action.

Embedded image [Wherein, X represents R ¹ -N <(R ¹ represents a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group which may have a substituent), an oxygen atom or sulfur Represents an atom, R
² represents a hydrogen atom or a hydrocarbon group which may have a substituent; ring A represents a benzene ring which may have a substituent; k is an integer of 0 to 3; And n represents an integer of 1 to 6. Or a salt thereof.

[0003]

Attempts have been made to use neurotrophic factors themselves for the treatment of neurodegenerative diseases, neuropathies, and memory disorders. However, due to the large protein, oral administration is difficult, and the ability to enter the brain is difficult. It has disadvantages such as bad. Therefore, development of a prophylactic / therapeutic agent for the above-mentioned diseases which can be safely administered with a small molecule has been desired.

[0004]

Means for Solving the Problems In view of the above-mentioned situation, the present inventors proceeded with a search for compounds having a neurotrophic factor-like action, and as a result of intensive studies, found that the formula

Embedded image [Wherein, Ar is a phenyl group which may have a substituent and may be condensed, n is an integer of 1 to 10, R is a hydrogen atom or a hydrocarbon group which may have a substituent. , And Y represent an amino group which may have a substituent or a nitrogen-containing saturated heterocyclic group which may have a substituent. Or a salt thereof [hereinafter may be abbreviated as compound (I). Has unexpectedly excellent properties for medicines such as neurotrophic factor-like action based on the chemical structure of its unique basic skeleton, regardless of the presence or absence or type of substituents. The present invention was completed based on this.

That is, the present invention provides: (1) a neurotrophic factor-like agent comprising compound (I);

Embedded image [In the formula, ring A represents a benzene ring which may have a substituent, and ring B represents a heterocyclic ring which may have a substituent. (3) Ar is a group represented by the formula:

Embedded image [Wherein, X is an oxygen atom, a sulfur atom or a formula R ¹ -N <(R
¹ represents a hydrogen atom, a hydrocarbon group or an acyl group which may have a substituent), a ring A is a benzene ring which may have a substituent, and k is 0 to 3. Integer and m represent an integer of 1 to 8. And n is 1
R is a hydrogen atom, and Y is a group represented by the formula

Embedded image [In the formula, R ² represents a hydrogen atom or a hydrocarbon group which may have a substituent. (4) 3- [1- (phenylmethyl) -4-piperidinyl] -1- (2,3,4,5- Tetrahydro-1H-1
-Benzezepin-8-yl) -1-propanone fumarate according to the above (1), which is a neurotrophic factor-like agent; (5) The choline acetyltransferase activity activator according to the above (4). (6) The neurotrophic factor-like agent according to the above (1), which is a preventive and / or therapeutic agent for Parkinson's disease or amyotrophic lateral sclerosis.

In the above formula, the “substituent” of “phenyl which may have a substituent and may be condensed” represented by Ar is, for example, (i) halogenated Lower alkyl, (ii) halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), (iii) lower alkylenedioxy (eg, C _1-3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.), (Iv) nitro, (v) cyano, (vi) hydroxy, (vii) lower alkoxy optionally halogenated, (viii) cycloalkyl (for example, C _3-6 such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like) Cycloalkyl, etc.), (ix) optionally halogenated lower alkylthio, (x) amino, (xi) mono-lower alkylamino (eg, methylamino, ethyl Mono-C _1-6 alkylamino such as amino, propylamino, etc.), (xii) di-
Lower alkylamino (e.g., dimethylamino, di -C _1-6 alkylamino such as diethylamino, etc.), (xiii)
5- to 7-membered cyclic amino (for example, pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino which may have 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to one nitrogen atom) (Xiv) lower alkylcarbonylamino (eg, C _1-6 alkyl-carbonylamino such as acetylamino, propionylamino, butyrylamino, etc.), (xv) aminocarbonyloxy, (xv
i) mono-lower alkylaminocarbonyloxy (eg, mono-C _1-6 alkylamino-carbonyloxy such as methylaminocarbonyloxy, ethylaminocarbonyloxy, etc.), (xvii) di-lower alkylaminocarbonyloxy (eg, Di-C _1-6 alkylamino-carbonyloxy such as dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.), (xviii) lower alkylsulfonylamino (for example, C _1- such as methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, etc.) ₆ alkylsulfonylamino, etc.), (xi
x) lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
(C _1-6 alkoxy-carbonyl such as isobutoxycarbonyl), (xx) formyl, (xxi) carboxy, (xxi
i) lower alkylcarbonyl (eg, C _1-6 alkyl-carbonyl such as acetyl, propionyl, butyryl, etc.), (xxiii) cycloalkylcarbonyl (eg,
Cyclopropylcarbonyl, cyclobutylcarbonyl,
C _3-6 cycloalkyl-carbonyl such as cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), (xxiv)
Carbamoyl, thiocarbamoyl, (xxv) mono-lower alkylcarbamoyl (eg, methylcarbamoyl,
(Xxvi) di-lower alkylcarbamoyl (eg, mono-C _1-6 alkyl-carbamoyl such as ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl)
Di-carbodiyl such as diethylcarbamoyl and dibutylcarbamoyl
C _1-6 alkyl - carbamoyl, etc.), (xxvii) lower alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, C _1-6 alkylsulfonyl such as propylsulfonyl, etc.), (xxviii) cycloalkylsulfonyl (e.g., cyclopentylsulfonyl, C _3-6 cycloalkylsulfonyl such as cyclohexylsulfonyl, etc., (xxi
x) aryl (eg, C _6-14 aryl such as phenyl, naphthyl, anthryl, etc.), (xxx) aralkyl (eg, benzyl, phenethyl, diphenylmethyl, triphenylmethyl, naphthylmethyl, diphenylethyl, phenylpropyl, phenylbutyl) , phenyl pentyl, etc. C _7-19 aralkyl, etc.), (xxxi) aralkylcarbonyloxy (e.g. phenylmethyl alkylcarbonyloxy, phenyl ethyl carbonyloxy, diphenylmethyl carbonyloxy, C such as diphenyl ethylcarbonyloxy
_7-19 aralkyl-carbonyloxy, etc.), (xxxii) aryloxy (eg, C _6-14 aryloxy such as phenoxy, naphthyloxy, etc.), (xxxiii) aralkylcarbonyl (eg, phenylmethylcarbonyl, phenylethylcarbonyl, diphenyl) (C _7-19 aralkyl-carbonyl such as methylcarbonyl, diphenylethylcarbonyl, etc.), (xxxiv) aryloxycarbonyl (eg, C _6-14 aryloxy-carbonyl such as phenoxycarbonyl), (xxxv) aralkylcarbamoyl (eg, carbamoyl, etc.), (xxxvi) arylcarbamoyl (e.g., C _6-14 aryl phenylcarbamoyl, etc. - - C _7-19 aralkyl such as a phenyl methylcarbamoyl carbamoyl, etc.), (xxxvii) aralkylcarbonylamino (e.g., phenylmethyl mosquito C _7-19 aralkyl such as Boniruamino - carbonylamino like), (xxxv
iii) aralkylamino (e.g., C _7-19 aralkylamino such as phenylmethyl amino and the like), (xxxix) aralkylsulfonyl (e.g., C _7-19 aralkyl sulphonyl such as phenylmethylsulfonyl etc.), (xxxx) arylsulfonyl (e.g. Phenylsulfonyl, C _6-14 arylsulfonyl, etc.), (xxxxi) aralkylsulfinyl (eg, C _7-19 aralkylsulfinyl, such as benzylsulfinyl), (xxxxii) aralkylsulfonylamino (eg, C _{7 of} benzylsulfonylamino, etc.) _-19
Aralkylsulfonylamino), (xxxxiii) arylsulfonylamino (for example, C _6-14 arylsulfonylamino such as phenylsulfonylamino) and the like. The aryl, aralkyl, aralkylcarbonyloxy, aryloxy, aralkylcarbonyl,
Aryloxycarbonyl, aralkylcarbamoyl,
Arylcarbamoyl, aralkylcarbonylamino,
Aralkylamino, aralkylsulfonyl, arylsulfonyl, aralkylsulfinyl, aralkylsulfonylamino and arylsulfonylamino further include, for example, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, C _1-6 alkyl, etc.), lower alkoxy of hexyl (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, C _1-6 alkoxy such as tert- butoxy), halogen atom (e.g. , Chloro, bromo, iodo, etc.), hydroxy, benzyloxy, amino, mono-lower alkylamino (eg, mono-C _1-6 alkylamino such as methylamino, ethylamino, propylamino, etc.), di-lower alkylamino (For example, Arylamino, diethylamino and di -C _1-6 alkylamino, etc.), nitro, lower alkylcarbonyl (e.g., acetyl, propionyl, butyryl, etc. C _1-6 alkyl - carbonyl, etc.), and one to four selected from benzoyl It may have a substituent.

The above-mentioned "optionally halogenated lower alkyl" includes, for example, a lower alkyl optionally having 1 to 3 halogen atoms (for example, chloro, bromo, iodo and the like) (for example, methyl , Ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. C _1-6 alkyl) and the like. Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, Trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec- Butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl and the like. As the “optionally lower halogenated lower alkoxy”, for example, lower alkoxy optionally having 1 to 3 halogen atoms (for example, chloro, bromo, iodo and the like) (for example, methoxy, ethoxy, And C _1-6 alkoxy such as propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. Specific examples thereof include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2 , 2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,
4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like. Examples of the “optionally halogenated lower alkylthio” include, for example, lower alkylthio optionally having 1 to 3 halogen atoms (eg, chloro, bromo, iodo, etc.) (eg, methylthio, ethylthio, Propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, etc. C _1-6 alkylthio, etc.). Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, and isopropyl. Thio, butylthio, 4,4,4-trifluorobutylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio and the like.

Examples of the condensation of the “phenyl group” of the “phenyl group which may have a substituent and may be condensed” include (1) a monocyclic ring which may have a substituent When condensed with the formula heterocycle, (2) 2 which may have a substituent
Condensed with a cyclic heterocyclic ring, or condensed with two identical or different monocyclic rings (provided that at least one ring is a monocyclic heterocyclic ring), and (3) even if it has a substituent For example, the case of condensing with a good tricyclic heterocyclic ring may be mentioned. Specific examples of the case where the “phenyl group” is condensed with an optionally substituted heterocyclic ring include a compound represented by the formula

Embedded image [In the formula, ring A represents a benzene ring which may have a substituent, and ring B represents a heterocyclic ring which may have a substituent. And the like. As the “substituent” of the “optionally substituted benzene ring” represented by ring A,
The "substituent" of the above-mentioned "phenyl group which may have a substituent and may be condensed" is exemplified. "Heterocycle" of "heterocycle optionally having substituent (s)" for ring B
Is, for example, a 5- to 14-membered (monocyclic, bicyclic or tricyclic) heteroatom containing one or two or one to four heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom A ring, preferably (i) a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle, (ii) a 5- to 1-membered aromatic heterocycle.
And a zero-membered non-aromatic heterocyclic ring or (iii) a 7 to 10-membered heterocyclic bridged ring. Examples of the “5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle” include, for example, thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3 -B] thiophene, furan, phenoxathiin, pyrrole, imidazole, pyrazole, oxazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,
2,4-thiadiazole, 1,3,4-thiadiazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline , Carbazole, β-carboline, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, isoxazole, furazane, phenoxazine, aromatic heterocycle such as phthalimide,
Or a ring formed by condensing one or more (preferably one or two) of these rings with one or more (preferably one or two) aromatic rings (eg, benzene ring and the like). The above "5
Examples of the "10-membered non-aromatic heterocycle" include pyrrolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine,
Hexamethyleneimine, heptamethyleneimine, tetrahydrofuran, tetrahydrooxazepine and the like. Examples of the “7- to 10-membered bridged heterocyclic ring” include quinuclidine, 7-azabicyclo [2.2.1] heptane and the like. Of these, a 5- to 10-membered non-aromatic heterocyclic ring is preferred.

The "substituent" of the "heterocyclic ring optionally having substituent (s)" represented by ring B includes, for example, (i) a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.), (ii) ) Nitro, (iii) cyano, (iv) oxo,
(V) hydroxy, (vi) lower alkyl (for example, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, etc.)
(Vii) lower alkoxy (eg, C _1-6 alkoxy such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, etc.); (viii) lower alkylthio (eg, C _1-6 alkylthio such as methylthio, ethylthio, propylthio, etc.) ), (Ix) amino, (x) mono-
Lower alkylamino (eg, mono-C _1-6 alkylamino such as methylamino, ethylamino, propylamino, etc.), (xi) di-lower alkylamino (eg, di-C _1-6 such as dimethylamino, diethylamino, etc.) Alkylamino, etc.), (xii) 5- to 7-membered cyclic amino (for example,
Pyrrolidino, piperidino, piperazino, morpholino which may have 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than one nitrogen atom;
5- to 7-membered cyclic amino such as thiomorpholino, etc.), (xi
ii) lower alkylcarbonylamino (for example, C such as acetylamino, propionylamino, butyrylamino, etc.)
_6alkyl - carbonylamino like), (xiv) lower alkylsulfonylamino (e.g., methylsulfonylamino, C _1-6 alkyl such as ethylsulfonylamino - sulfonylamino, etc.), (xv) lower alkoxycarbonyl (e.g., methoxy Carbonyl, ethoxycarbonyl,
Propoxycarbonyl C _1-6 alkoxy such as - carbonyl, etc.), (xvi) carboxy, (xvii) lower alkylcarbonyl (e.g., methylcarbonyl, ethylcarbonyl, C _1-6 alkyl, such as propyl carbonyl - carbonyl, etc.), (xviii ) Carbamoyl, (xix) mono-lower alkylcarbamoyl (eg, mono-C _1-6 alkyl-carbamoyl such as methylcarbamoyl, ethylcarbamoyl, etc.), (xx) di-lower alkylcarbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, etc.) carbamoyl, etc.), (xxi) lower alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, to 1 selected from C _1-6 alkylsulfonyl, etc.) such as propylsulfonyl 5 is used - di -C _1-6 alkyl Can be Among them, oxo, lower alkyl (for example, methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl and other C _1-6 alkyls) are preferred, and oxo is commonly used.

When the ring B has a nitrogen atom in the ring, for example, the ring B has the formula R ¹ -N <wherein R ¹ is a hydrogen atom,
It represents a hydrocarbon group or an acyl group which may have a substituent. ] May be included. The “hydrocarbon group” of the “hydrocarbon group which may have a substituent” represented by R ¹ represents a group obtained by removing one hydrogen atom from a hydrocarbon compound, and examples thereof include alkyl, Examples thereof include a chain or cyclic hydrocarbon group such as alkenyl, alkynyl, cycloalkyl, aryl, and aralkyl. Among them, a C _1-16 hydrocarbon group formed of a chain, a ring, or a combination thereof is preferable. Such "hydrocarbon group"
Examples include the following. (1) linear or branched lower alkyl (eg, methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl, sec- butyl, pentyl, C _1-6 alkyl such as hexyl, etc.); (2) linear or branched lower alkenyl (e.g., vinyl, allyl, iso (C _2-6 alkenyl such as propenyl, butenyl, isobutenyl, sec-butenyl, etc.); (3) linear or branched lower alkynyl (eg, C such as propargyl, ethynyl, butynyl, 1-hexynyl and the like)
_2-6 alkynyl, etc.); (4) cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, C _3-6 such as cyclohexyl
(5) a bridged cyclic saturated hydrocarbon group (for example, bicyclo [3.
2.1] Bridged cyclic C such as oct-2-yl, bicyclo [3.3.1] non-2-yl, adamantan-1-yl and the like
_8-14 saturated hydrocarbon group; (6) aryl (for example, phenyl, 1-naphthyl, 2
_-C6-14 aryl such as naphthyl, biphenylyl, 2-indenyl, 2-anthryl and the like, preferably phenyl and the like; (7) aralkyl (for example, phenyl- _C1-10 alkyl (for example, benzyl, phenylethyl, phenylpropyne) Le, phenylbutyl, phenylpentyl, phenylhexyl, etc.), naphthyl -C _1-6 alkyl (e.g., alpha-naphthylmethyl, etc.), C ₇ such as diphenyl -C _1-3 alkyl (e.g. diphenylmethyl, diphenylethyl, etc.) _-16
(8) arylalkenyl (for example, styryl, cinnamyl, 4-phenyl-2-butenyl, 4-phenyl-3)
-C _6-10 aryl-C _2-6 alkenyl such as butenyl); (9) arylalkynyl (eg, phenylethynyl, 3-phenyl-2-propynyl, 3-phenyl-1)
-C _6-10 aryl-C _2-6 alkynyl such as propynyl, etc.); (10) cycloalkyl-alkyl (eg, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cycloheptylmethyl, cyclopropylethyl, Cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclopropylpropyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylpropyl, cycloheptylpropyl, cyclopropylbutyl,
Cyclobutylbutyl, cyclopentylbutyl, cyclohexylbutyl, cycloheptylbutyl, cyclopropylpentyl, cyclobutylpentyl, cyclopentylpentyl, cyclohexylpentyl, cycloheptylpentyl, cyclopropylhexyl, cyclobutylhexyl,
(11) arylaryl (for example, C _3-7 cycloalkyl-C _1-6 alkyl such as cyclopentylhexyl and cyclohexylhexyl);
_6-10 aryl -C _6-10 aryl, etc.); (12) aryl - aryl - lower alkyl (e.g., biphenylylmethyl, biphenylyl ethyl, etc. C _6-10 aryl -C _6-10 aryl -C _1-6 alkyl etc). Preferred examples of the “hydrocarbon group” of the “hydrocarbon group which may have a substituent” represented by R ¹ include, for example, C _1-6 alkyl, C _3-8 cycloalkyl, C _7-16 Aralkyl and the like.

The "substituent" of the "hydrocarbon group which may have a substituent" for R ¹ includes, for example, (i)
Halogen atom (for example, fluoro, chloro, bromo, iodo and the like), (ii) nitro, (iii) cyano, (iv) oxo, (v) hydroxy, (vi) lower alkyl which may be halogenated (for example, A lower alkyl group optionally having 1 to 3 halogen atoms (eg, chloro, bromo, iodo, etc.) (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, etc.) C _1-6 alkyl etc.), specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl,
3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl,
Neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc.), (vi
i) lower alkoxy which may be halogenated (for example, lower alkoxy which may have 1 to 3 halogen atoms (for example, chloro, bromo, iodo and the like) (for example, methoxy, ethoxy, propyloxy, C _1-6 alkoxy such as isopropyloxy, butyloxy and the like), specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2
-Trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.), (viii) lower alkylthio which may be halogenated (for example, Lower alkylthio (eg, C _1-6 alkylthio such as methylthio, ethylthio, propylthio, etc.) which may have 1 to 3 halogen atoms (eg, chloro, bromo, iodo, etc.); (Ix) amino, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio, etc.) , (X) mono-lower alkyl Mino (e.g., methylamino, ethylamino, mono- -C such propylamino
_1-6 alkylamino, etc.), (xi) di-lower alkylamino (for example, dimethylamino, diethylamino, etc.
C _1-6 alkylamino, etc.), (xii) 5 to 7-membered cyclic amino (e.g., one nitrogen atom other than the nitrogen atom, and, 1 to heteroatoms selected from oxygen atom and sulfur atom have three 5- to 7-membered cyclic aminos such as pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino; and (xiii) lower alkylcarbonylamino (for example, C _1-6 alkyl-carbonylamino such as acetylamino, propionylamino, and butyrylamino). ), (Xiv) lower alkylsulfonylamino (eg, C _1-6 alkylsulfonylamino such as methylsulfonylamino, ethylsulfonylamino, etc.), (xv) lower alkoxycarbonyl (eg, methoxycarbonyl,
C _1-6 such as ethoxycarbonyl and propoxycarbonyl
Alkoxy-carbonyl, etc.), (xvi) carboxy, (x
vii) Lower alkylcarbonyl (for example, C such as methylcarbonyl, ethylcarbonyl, propylcarbonyl, etc.)
_1-6 alkyl - carbonyl, etc.), (xviii) carbamoyl, thiocarbamoyl, (xix) mono - lower alkylcarbamoyl (e.g., methylcarbamoyl, mono -C _1-6 alkyl ethylcarbamoyl etc. - carbamoyl, etc.), (xx) Di-lower alkylcarbamoyl (e.g.,
Di- such as dimethylcarbamoyl and diethylcarbamoyl
C _1-6 alkyl - carbamoyl, etc.), (xxi) lower alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, C _1-6 alkylsulfonyl such as propylsulfonyl, etc.), (xxii) lower alkoxycarbonyl - lower alkyl (e.g., Methoxycarbonylmethyl, ethoxycarbonylmethyl, tert-butoxycarbonylmethyl,
C _1-6 alkyl-carbonyl-C _1-6 alkyl such as methoxycarbonylethyl, methoxycarbonylmethyl, methoxycarbonyl (dimethyl) methyl, ethoxycarbonyl (dimethyl) methyl, tert-butoxycarbonyl (dimethyl) methyl, etc., (xxiii ) Carboxy-lower alkyl (eg, carboxy-C _1-6 alkyl such as carboxymethyl, carboxyethyl, carboxy (dimethyl) methyl, etc.), (xxiv) a heterocyclic group optionally having a substituent, (xxv) 1 to 5 (preferably 1 to 3) selected from sulfo and the like. The "heterocyclic group" of the "heterocyclic group optionally having substituent (s)" includes, for example, a monocyclic group having 1 to 6 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. "Heterocyclic ring optionally having substituent (s)" represented by ring B above includes a group formed by removing one hydrogen atom from a cyclic or polycyclic heterocyclic ring such as 2 to 4 cyclic rings. And a group formed by removing one hydrogen atom from the "heterocycle". Of these, a group formed by removing one hydrogen atom from a monocyclic heterocyclic ring or a bicyclic heterocyclic ring is preferable. As the “substituent” of the “heterocyclic group optionally having substituent (s)”, the “substituent” (i) of the “heterocyclic ring optionally having substituent (s)” represented by the ring B above To (xxiii) and (xxv), and 1 to 5. Examples of the “acyl group” represented by R ¹ include, for example, formyl, optionally halogenated C _1-6 alkyl-carbonyl (eg, acetyl, trifluoroacetyl, etc.) and 5- to 6-membered heterocyclic carbonyl (eg, , Pyridylcarbonyl, thienylcarbonyl, furylcarbonyl, etc.), C _1-4 alkyl and / or C _1-4 alkoxy which may be substituted with C _1-4 alkoxy.
_6-10 aryl-carbonyl (eg, benzoyl, methylbenzoyl, methoxybenzoyl, etc.), C _6-10 arylsulfonyl (eg, benzenesulfonyl, naphthylsulfonyl, etc.), 5- to 6-membered heterocyclic sulfonyl (eg, thienylsulfonyl, etc.) And the like. R ¹ is preferably a hydrogen atom.

The “phenyl group optionally having a substituent and optionally condensed” represented by Ar is preferably a group represented by the formula:

Embedded image [In the formula, k is an integer of 0 to 3, m is an integer of 1 to 8, X is an oxygen atom, a sulfur atom or a group represented by the formula R ¹ -N <(R ¹ has the same meaning as described above.) , A ring are as defined above. ] The group represented by this. Particularly preferably, the formula

Embedded image [Wherein, R ¹ has the same meaning as described above. ] The group represented by this. R ¹ is preferably a hydrogen atom.

N is preferably an integer of 1 to 6, more preferably 2 to 6, and particularly preferably 2. R represents a hydrogen atom or a hydrocarbon group which may have a substituent, and may be different in repeating n. Also,
R may be bonded to Ar or a substituent of Ar. Examples of the “optionally substituted hydrocarbon group” represented by R include the “optionally substituted hydrocarbon group” represented by the above R ¹ . R is preferably a hydrogen atom.

As the "amino group optionally having substituent (s)" for Y, for example,

Embedded image [Wherein, R ³ and R ⁴ each represent a hydrogen atom, a hydrocarbon group which may have a substituent, or an acyl group. And the like. Examples of the “optionally substituted hydrocarbon group” represented by R ³ or R ⁴ include the “optionally substituted hydrocarbon group” represented by R ¹ . Preferred examples include (1) a lower alkyl (preferably C _1-6 alkyl) optionally having 1 to 3 substituents selected from a halogen atom, lower alkoxy and hydroxy, (2) a halogen atom, Aralkyl optionally having 1 to 3 substituents selected from lower alkoxy and hydroxy (preferably C _7-16
Aralkyl) and the like. The “acyl group” represented by R ³ or R ⁴ includes the “acyl group” represented by R ¹ . Examples of the “nitrogen-containing saturated heterocyclic group” of the “optionally substituted nitrogen-containing saturated heterocyclic group” represented by Y include, besides a carbon atom and one nitrogen atom, for example, a nitrogen atom, an oxygen atom And a 5- to 9-membered nitrogen-containing saturated heterocyclic group which may contain 1 to 3 hetero atoms such as a sulfur atom. These nitrogen-containing saturated heterocyclic groups may be groups having a bond at a ring-forming nitrogen atom or groups having a bond at a ring-forming carbon atom. As a specific example, the expression

Embedded image And a nitrogen-containing saturated heterocyclic group represented by Particularly preferred

Embedded image And so on. Examples of the “substituent” of the “nitrogen-containing saturated heterocyclic group optionally having substituent (s)” include, for example, “hydrocarbon group optionally having substituent (s)” represented by R ¹ and the like. Or three. Y is preferably a formula

Embedded image [In the formula, R ² represents a hydrogen atom or a hydrocarbon group which may have a substituent. And the like. More preferably as Y, for example, the formula

Embedded image Wherein R ² is as defined above. And the like. The "optionally substituted hydrocarbon group" represented by R ^2, "optionally substituted hydrocarbon group" or the like represented by R ¹ can be mentioned. Preferably, a C _7-16 aralkyl which may have a substituent (eg, phenyl-C _1-10 alkyl (eg, benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl, etc.), naphthyl- C
_1-6 alkyl (for example, α-naphthylmethyl and the like), and C _7-16 aralkyl such as diphenyl-C _1-3 alkyl (for example, diphenylmethyl and diphenylethyl) and the like. Particularly preferred is benzyl.

In the compound (I), preferably, Ar is a compound of the formula

Embedded image [Wherein, X is an oxygen atom, a sulfur atom or a formula R ¹ -N <(R
¹ is the same as defined above), ring A is an optionally substituted benzene ring, k is an integer of 0 to 3, and m is an integer of 1 to 8. A group represented by the formula:
Is an integer of 1 to 6, R is a hydrogen atom, and Y is a formula

Embedded image Wherein R ² is as defined above. ] The group represented by this. Particularly preferably, 3- [1- (phenylmethyl)
-4-piperidinyl] -1- (2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl) -1-
It is propanone or a salt thereof.

Examples of the salt of compound (I) include salts with inorganic bases, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. No. Preferable examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferred examples of the salt with an organic base include, for example, trimethylamine,
Salts with triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like can be mentioned. Preferable examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine and the like. Preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be Of these, pharmaceutically acceptable salts are preferred. For example, compound (I)
When having an acidic functional group therein, an alkali metal salt (eg,
Sodium salt, potassium salt, etc.), alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt, etc.)
And inorganic salts such as hydrochloride, sulfate, phosphate, hydrobromide or the like when compound (I) has a basic functional group, or acetate. Maleate, fumarate, succinate, methanesulfonate,
Organic salts such as p-toluenesulfonate, citrate and tartrate are exemplified. Compound (I) may be a hydrate or an anhydrate.

Compound (I) can be produced by a known production method. For example, Japanese Unexamined Patent Publication No.
And JP-A-64-79151 (EP-A-02965).
60), JP-A-5-140149 (EP-A-048)
7071), JP-A-6-166676 (EP-A-0)
560235) and JP-A-6-206875 (EP-
A-0567090), JP-A-2-169569 (USP 4,895,841), JP-A-7-2068
No. 54 (EP-A-0607864), JP-A-7-30
No. 9835 (EP-A-0655451) or the like or a method analogous thereto. Compound (I) has an excellent neurotrophic factor-like action, neurotrophic factor activating action, and the like. Among the compounds (I), in particular, the compound represented by the formula

Embedded image Wherein each symbol is as defined above. Or a salt thereof, etc., also have an excellent ChAT activity activating action. Thus, Compound (I) is useful for, for example, neurotrophic factor-related (1) neurodegenerative diseases (eg, senile dementia, Alzheimer's disease, Down's syndrome, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic spinal cord lateral sclerosis) Disease, diabetic neuropathy, etc.), (2) at the time of cerebrovascular disorder (eg, cerebral infarction, cerebral hemorrhage, cerebral circulatory insufficiency due to cerebral arteriosclerosis), at the time of head injury / spinal cord injury, at the aftereffect of encephalitis or at the time of cerebral palsy Neuropathy, (3) memory impairment (eg, senile dementia, amnesia, etc.),
(4) It is useful for the prevention and / or treatment of mental illness (eg, depression, panic disorder, schizophrenia, etc.). Compound (I) is used for the prophylactic treatment of the above-mentioned diseases, for example, anti-parkinson drugs (for example, carbidopa + levodopa, pergolide, ropinirole, cabergoline, pramipexole,
Entacapron, lazabemide, etc.), drugs for treating amyotrophic spinal cord lateral sclerosis (eg, riluzole, mecamermine, gabapentin, etc.), antidepressants (eg, fluoxetine, sertraline, paroxetine, venlafaxine, nefazodone, reboxetine, imipramine hydrochloride, duloxetine) And schizophrenia remedies (eg, olanzapine, risperidone, quetiapine, iloperidone, etc.) and the like. Furthermore, since compound (I) has low toxicity, it is safe to prevent and / or prevent the above diseases in mammals (eg, humans, cows, horses, dogs, cats, monkeys, mice, rats, etc., particularly humans). Used for treatment. Compound (I) can be formulated according to a method known per se, and a pharmaceutical composition such as compound (I) can be prepared by mixing an appropriate amount of compound (I) as it is or a pharmacologically acceptable carrier in the formulation step. Tablets (including sugar-coated tablets, film-coated tablets), powders, granules, capsules (including soft capsules), solutions, injections, suppositories, sustained-release preparations, etc., orally or parenterally (eg, topically, Rectally, intravenously, etc.). In the preparation of the present invention, the content of compound (I) is about 0.1 to about 100% by weight of the whole preparation. The dose varies depending on the administration subject, administration route, disease, symptom and the like. For example, when administered as an oral preparation to an adult (body weight of about 60 kg) as a therapeutic agent for Parkinson's disease, the active ingredient (compound (compound ( I)) as about 0.1 to about 200 mg, preferably about 1 to about 100 mg, more preferably about 2 to about 5 mg.
0 mg, which can be administered once or several times a day.

The pharmacologically acceptable carrier used in the production of the preparation of the present invention includes various organic or inorganic carrier substances commonly used as preparation materials, such as excipients, lubricants and the like in solid preparations. Binders, disintegrants; solvents in liquid preparations, solubilizers, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can be used. Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. Disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate,
And sodium citrate. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone, carboxy Methylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
And hydrophilic polymers such as hydroxypropylcellulose. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like. Examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Antioxidants include, for example, sulfites,
Ascorbic acid and the like.

[0019]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in more detail with reference to the following examples and experimental examples. However, these examples are merely examples, and do not limit the present invention. May be changed without departing from the range.

EXAMPLES Example 1 3- [1- (phenylmethyl) -4-piperidinyl]-
Film tablet containing 1- (2,3,4,5-tetrahydro-1H-1-benzazepin-8-yl) -1-propanone fumarate (hereinafter abbreviated as compound A) Formulation:

[Table 1] Compound A (440 g), D-mannitol (407) in a fluidized bed granulation dryer (FD-5S, Powrex).
0 g) and corn starch (605 g) were uniformly mixed, and then hydroxypropyl cellulose (HP
An aqueous solution in which (CL) (165 g) was dissolved was sprayed and granulated, and then dried in a fluidized bed granulating dryer. The obtained granules were crushed with a 1.5 mmφ punching screen using a power mill to give sized powder. The obtained sized powder (4
704 g), corn starch (161.7 g)
And magnesium stearate (34.3 g)
The mixture was mixed with a tumbler mixer to give granules for tableting, and the granules were tabletted with a tableting machine at a weight of 100 mg using a 6.5 mmφ punch to give plain tablets. Hydroxypropyl methylcellulose 2910 (TC-5 (trade name) manufactured by Shin-Etsu Chemical Co., Ltd.) was dissolved and mixed with a liquid in which titanium oxide and yellow iron sesquioxide were dispersed in water. The obtained tablets were sprayed in a coating machine (DRC-500) to give about 42,000 film tablets containing 8 mg of Compound A per tablet.

Example 2 Compound A-containing film tablet Formulation:

[Table 2] According to Example 1, the weight was 200 mg using an 8 mmφ punch.
To give a film tablet containing 16 mg of Compound A per tablet.

Experimental Example 1 (Method) Pharmacology of Neurotrophic Factors Annual Review of Pharmacology and Toxicology
otrophic factors, Ann. Rev. Pharmacol. Toxico
l.), Vol. 37, pp. 239-267, 1997. The hippocampus was excised from 1 to 2 day old SD rats, cells were isolated by trypsinization, and cultured in a serum-containing culture medium in a flask. The confluent astrocytes were detached by trypsin treatment, seeded in a 96-well plate at a density of 50,000 cells / well, treated with 10 μM cytosine arabinoside to stop growth, and used as a feeder. The basal forebrain, mainly the septum, was taken from the embryonic day 17 SD rat fetus, and the neurons were isolated by trypsin treatment and dispersed in a serum-free medium.
Plated on astrocyte feeders at a density of 75000 cells / well. A test substance was added in the presence or absence of 3 ng / ml of recombinant human NGF (rhNGF), respectively, and cultured for 7 days.
The cells were solubilized with 0.1% Triton X-100, and the ChAT activity was quantified by the Fonnam radioisotope method. (Results) 1) The results of the addition of the test substance alone in the absence of rhNGF are shown in FIG. Compound A is 10 to 1000 nM
Showed a clear ChAT activity increasing effect. On the other hand, tacrine and physostigmine, which are acetylcholinesterase inhibitors, did not show a ChAT activity increasing effect. 2) The result of the addition of the test substance in the presence of 3 ng / ml rhNGF is shown in FIG. Compound A exhibited a significant ChAT activity increasing effect at 10 to 1000 nM. On the other hand, tacrine and physostigmine which are acetylcholinesterase inhibitors are ChA
It did not show a T activity increasing effect. From these results, it can be seen that Compound A has a clear neurotrophic factor-like action and a neurotrophic factor activating action at a low concentration of 10 nM. Experimental Example 2 (Method) Using 9-week-old JcI: Wistar rats, Stroke, Pulsinelli et al., Volume 10, 267-
Four-vessel occlusion was performed for 10 minutes according to the method described on page 272, 1979. Compound A (10 mg / kg) was orally administered 1 hour before and 4 hours after the ischemic treatment, and once a day for 6 days from the next day. Rats 7 days after ischemic treatment (the day after the last administration)
Under pentobarbital anesthesia, the mice were sacrificed by refluxing physiological saline from the heart, and the extracted brain was immersed and fixed in FAM (formalin: acetic acid: methanol = 1: 1: 8). After trimming the fixed brain, it is embedded in paraffin,
A 6 μm thick frontal cut was made 3.8 to 4.3 mm behind the bregma. The sections were stained with hematoxylin and eosin, and then CA1 under a microscope.
The number of surviving cells in the 250 μm area was counted. The average value of the number of cells on the left and right is used as data for each individual, and the difference between groups is Stud
Tested using the entt-test. (Results) The results are shown in FIG. The number of cone cells in the sham operation group was about 30 cells / 250 μm. In contrast, 10
A remarkable decrease in the number of cells (mean -75.9%) was observed in the ischemic control group for four minutes (group administered with the four-vessel occlusion solvent) (P
<0.01). On the other hand, the number of surviving cells in the group administered with Compound A at 10 mg / kg was significantly higher than that in the control group (group administered with a four-vessel occlusion solvent) (P <0.05). The results show that Compound A has a protective effect against ischemia.

[0022]

The compound (I) is useful as a trophic factor-like agent and involves a neurotrophic factor. (1) Neurodegenerative diseases (eg, senile dementia, Alzheimer's disease, Down syndrome,
Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis, diabetic neuropathy, etc.),
(2) Cerebral vascular disorders (eg, cerebral infarction, cerebral hemorrhage, cerebral circulatory insufficiency associated with cerebral arteriosclerosis), head injury / spinal cord injury, encephalitis sequelae or cerebral palsy, (3) memory impairment (Eg, senile dementia, amnesia, etc.), (4) mental disorders (eg,
It is useful for prevention and / or treatment of depression, panic disorder, schizophrenia, etc.).

[Brief description of the drawings]

FIG. 1 is a graph showing the results of ChAT activity in the absence of NGF by adding compound A, tacrine and physostigmine alone. In the figure,-●-indicates compound A,-□-indicates tacrine, and-▲-indicates physostigmine.

FIG. 2: Ch by adding compound A, tacrine and physostigmine alone in the presence of 3 ng / ml of NGF
Graph showing the results of AT activity. In the figure,-●-indicates compound A,-□-indicates tacrine, and-▲-indicates physostigmine.

FIG. 3 is a graph showing the number of CA1 pyramidal cells in a group treated with 10 mg / kg of tetravascular occlusion compound A, a sham operation group, and a group administered with a tetravascular occlusion solvent.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 43/00 A61K 31/00 643D // C07D 401/06 C07D 401/06

Claims (6)

[Claims] (1) Formula (1) [Wherein, Ar is a phenyl group which may have a substituent and may be condensed, n is an integer of 1 to 10, R is a hydrogen atom or a hydrocarbon group which may have a substituent. , And Y represent an amino group which may have a substituent or a nitrogen-containing saturated heterocyclic group which may have a substituent. And a salt thereof. 2. Ar is a compound of the formula [In the formula, ring A represents a benzene ring which may have a substituent, and ring B represents a heterocyclic ring which may have a substituent. 3. The neurotrophic factor-like agent according to claim 1, which is a group represented by the formula: 3. Ar is a compound of the formula [Wherein, X is an oxygen atom, a sulfur atom or a formula R ¹ -N <(R
¹ represents a hydrogen atom, a hydrocarbon group or an acyl group which may have a substituent), a ring A is a benzene ring which may have a substituent, and k is 0 to 3. Integer and m represent an integer of 1 to 8. And n is 1
R is a hydrogen atom and Y is a formula [In the formula, R ² represents a hydrogen atom or a hydrocarbon group which may have a substituent. The neurotrophic factor-like agent according to claim 1, which is a group represented by the formula: 4. A compound of the formula: 3- [1- (phenylmethyl) -4-piperidinyl] -1- (2,3,4,5-tetrahydro-1
The neurotrophic factor-like agent according to claim 1, which comprises H-1-benzazepin-8-yl) -1-propanone fumarate. 5. The neurotrophic factor-like agent according to claim 4, which is a choline acetyltransferase activity activator. 6. The neurotrophic factor-like agent according to claim 1, which is a prophylactic or therapeutic agent for Parkinson's disease or amyotrophic lateral sclerosis.