JP2001348332A - Soluble beta-amyloid precursor protein secretion accelerator - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a pharmaceutical composition or the like which shows potent soluble β-amyloid precursor protein secretion facilitative effect and inhibits the dysfunction or apoptosis of the cell, particularly neurocyte, through a secreted soluble β-amyloid precursor protein having neurotrophic factor-like effect. SOLUTION: The pharmaceutical composition including a compound, its salt or its prodrug having soluble β-amyloid precursor protein secretion facilitative effect and apoptosis inhibitory effect and the compound represented by the formula (I) [wherein, R1 and R2 show each H, a lower alkyl group or the like.; Ring A shows benzene ring which may be substituted.; X shows oxygen atom or the like.; and Y shows CH or N.], its salt or its prodrug are obtained and the method for using and producing them is provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to pharmaceuticals, particularly Alzheimer's disease, Parkinson's disease, Down's syndrome, amyotrophic lateral sclerosis, prion's disease (Creuzfeld-Jakob disease),
Soluble beta-amyloid precursor protein secretagogue and soluble beta-amyloid precursor, which are effective for treating neurodegenerative diseases such as Huntington's chorea and neuropathy (preferably diabetic neuropathy and the like) and neuronal disorders at the time of cerebrovascular disorder. The present invention relates to a pharmaceutical composition having both a protein secretion promoting action and an apoptosis inhibitory action.

[0002]

2. Description of the Related Art No drug has been developed which suppresses neuronal cell death in the neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease and stops the progress of the disease. Alzheimer's disease is a disease characterized by the formation of senile plaques and neurofibrillary tangles together with neuronal degeneration and loss. Senile plaque, the most characteristic brain pathology of this disease, is beta-amyloid protein (hereinafter abbreviated as Aβ), a metabolite of beta-amyloid precursor protein (hereinafter sometimes abbreviated as βAPP) ) Are extracellular deposits (Biochem. Biophys. Res. Commun.
122 , 1131 (1984); Proc. Natl. Acad. Sci. USA. 82 ,
4245 (1985); J. Neurochem. 46 , 1820 (1986); Neuron
6 , 487 (1991)). A consisting of 40 or 42 amino acids
β is toxic to nerve cells (Science 250 ,
279 (1990); Brain Res. 563 , 311 (1991); J. Neurosc.
i. 12 , 376 (1992)), causing neurofibrillary tangles (Proc.
Natl. Acad. Sci. USA. 90 , 7789-7793 (1993)). βAPP is not only metabolized to Aβ,
Aβ is metabolized so that it is not produced, and the metabolite soluble beta-amyloid precursor protein (soluble APP, sAPP
Is sometimes secreted extracellularly (Science 24
8 , 492 (1990); Science 248 , 1122 (1990)). It has been reported that sAPP acts as a neurotrophic factor, that is, promotes nerve fiber elongation and suppresses neuronal cell death, using primary cultured neurons or neuroblastoma PC12 cells (Neuron 9). , 129 (1992); Neuron 10 , 243 (199
3); Physiol. Rev. 77 , 1081 (1997)). Decreased levels of sAPP in the cerebrospinal fluid of Alzheimer's disease patients have also been reported (Lancet 340 , 453 (1992); Ann. Neurol. 3
2 , 215 (1992); Proc. Natl. Acad. Sci. USA 89 , 2551.
(1992); Alzheimer Disease and Associated Disorder
s 11 , 201 (1997)).
APP metabolism leans toward Aβ production instead of sAPP,
In other words, it is inferred that the increase and accumulation of Aβ, a cytotoxin, outside the cell, and the decrease of sAPP, a neurotrophic factor, play a very important role in the onset of disease. Therefore, compounds that increase sAPP production and secretion in nervous system tissues are sA
It is expected to be a preventive and therapeutic agent for various neurodegenerative diseases, as it reduces neuronal damage and suppresses neuronal death due to various causes through the action of PP neurotrophic factor. It is also possible to suppress the production of Aβ, in particular, is expected as a preventive and remedy for Alzheimer's disease (J. Biol. Chem. 268 , 22959 (1993); A
nn. New York Acad. Sci. 777 , 175 (1997)). actually,
Phorbol ester, an activator of protein kinase C (sometimes abbreviated as PKC), is a potent
It is known that it suppresses not only the sAPP secretion promoting action but also the production and secretion of Aβ (Proc. Natl. Acad. Sci. USA.
87 , 6003 (1990); Proc. Natl. Acad. Sci. USA. 90 , 9
195 (1993); J. Neurochem. 61 , 2326 (1993); J. Bio
l. Chem. 269 , 8376 (1994)). Therefore, measures to increase sAPP using various cells or brain tissue sections have been attempted. For example, besides the above phorbol ester, M1
Muscarinic receptor agonist (Science 258 , 30
4 (1992); Proc. Natl. Acad. Sci. USA. 89 , 10075 (1
992); J. Neurosci. 15 , 7442 (1995)), glutamate agonist (Proc. Natl. Acad. Sci. USA. 92 , 8083 (19
95), and serotonin agonists (J. Biol. Chem. 23 ,
4188 (1996), etc., have been reported to promote sAPP secretion, and each agonist activates PKC, tyrosine kinase, or phospholipase A2 (phospholipase A2) via each receptor. It is believed to be possible.

[0003]

SUMMARY OF THE INVENTION From such a viewpoint,
It has been expected to find a sAPP secretion promoter that can replace the above compounds.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies and found that a tetrahydro-4-quinolinamine derivative has a potent sAPP secretion promoting action and a nerve cell death inhibiting action. Further, the formula (I)

Embedded image Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may have a substituent, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and Ar ¹ and Ar ² are each a substituent A ring represents an optionally substituted benzene ring, X represents an oxygen atom, CR ³ R ⁴ or NR ⁵ (R ³ , R ⁴ , R ⁵ are the same or different and each represents a hydrogen atom or a lower alkyl group which may have a substituent.), And Y is CH
Or N. Unexpectedly has a soluble beta-amyloid precursor protein secretion promoting action, and these compounds have excellent apoptosis inhibitory action and neurological dysfunction improving action. Was found to have. That is, the present inventors have found a pharmaceutical composition having both a promoting action on secretion of soluble beta-amyloid precursor protein and an inhibitory action on apoptosis. Furthermore, the present inventors have proposed that the compound or the like, due to these actions, may cause neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, prion disease or neuropathy (preferably diabetic neuropathy or the like), cerebrovascular dementia, cerebrovascular disorder. The present inventors have also found that the present invention is useful as a prophylactic / therapeutic agent for neuronal disorders, and completed the present invention based on these findings.

That is, the present invention provides (1) a pharmaceutical composition containing a compound having a secretory promoting action of soluble beta-amyloid precursor protein and an inhibitory action on apoptosis, or a salt thereof, or a prodrug thereof;

Embedded image [In the formula, ring A represents a benzene ring which may have a substituent, and Y represents CH or N. Formula (b):

Embedded image [Wherein, Ar ² represents an aromatic group which may have a substituent. Or a partial structure represented by the formula (c):

Embedded image [In the formula, Ar ¹ represents an aromatic group which may have a substituent, and X represents an oxygen atom, CR ³ R ⁴ or NR ⁵ (R ³ ,
R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group which may have a substituent. )
And Y is as defined above. The pharmaceutical composition according to the above (1), comprising a compound having a partial structure represented by the formula: or a salt thereof or a prodrug thereof;

Embedded image Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may have a substituent, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and Ar ¹ and Ar ² are each a substituent A ring represents an optionally substituted benzene ring, X represents an oxygen atom, CR ³ R ⁴ or NR ⁵ (R ³ , R ⁴ , R ⁵ are the same or different and each represents a hydrogen atom or a lower alkyl group which may have a substituent.), And Y is CH
Or N. A soluble beta-amyloid precursor protein secretion promoter containing the compound represented by the formula (I) or a salt thereof or a prodrug thereof, (4) the agent according to the above (3), wherein R ¹ is a hydrogen atom, and (5) R ² The agent according to the above (3), which is a hydrogen atom or a lower alkyl group which may have a substituent, (6) the agent according to the above (3), wherein R ² is a hydrogen atom or a C _1-6 alkyl group, (7) The agent according to the above (3), wherein Ar ¹ is a phenyl group which may have a substituent or a quinolyl group which may have a substituent.
(8) the agent according to the above (3), wherein Ar ¹ is a phenyl group which may have a substituent; (9) Ar ¹ is a halogen atom, a C _1-3 alkylenedioxy group, agent according to (3) wherein optionally substituted in a C _1-6 alkoxy group optionally be also a C _1-6 alkyl group or halogenated a phenyl group, a (10) Ar ² is a substituted group (11) The agent according to the above (3), which is a monocyclic aromatic group which may have a phenyl group, a furyl group, a thienyl group or a pyridyl group, each of which Ar ² may have a substituent. Certain agents according to the above (3), (12) Ar
² is a halogen atom, C _1-3 alkylenedioxy group, phenyl which may be substituted respectively optionally halogenated C _1-6 alkyl group or a halogenated which may be C _1-6 alkoxy group (13) A agent according to the above (3), which is a group represented by the formula (3),
The agent according to the above (3), wherein the ring is an unsubstituted benzene ring,
(14) The agent according to the above (3), wherein X is NR ⁵ (R ⁵ has the same meaning as in the above (3)) and Y is CH.
5) R ¹ is a hydrogen atom, R ² is a methyl group, Ar
¹ is a phenyl group which may have a substituent, and Ar ²
Is a 3,4-dimethoxyphenyl group, A ring is an unsubstituted benzene ring, X is NR ⁵ (R ⁵ has the same meaning as in the above (3)), and Y is CH. ) Described agents,
(16) Formula (I)

Embedded image Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may have a substituent, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and Ar ¹ and Ar ² are each a substituent A ring represents an optionally substituted benzene ring, X represents an oxygen atom, CR ³ R ⁴ or NR ⁵ (R ³ , R ⁴ , R ⁵ are the same or different and each represents a hydrogen atom or a lower alkyl group which may have a substituent.), And Y is CH
Or N. An apoptosis inhibitor comprising a compound represented by the formula (I) or a salt thereof or a prodrug thereof:
(17) The agent according to the above (3) or (16), which is an agent for improving neurological dysfunction, (18) the agent according to the above (3) or (16), which is an agent for preventing or treating a neurodegenerative disease, (1)
9) The neurodegenerative disease is Alzheimer's disease, Parkinson's disease, prion disease or neuropathy (1).
8) The agent according to the above,

(20) Use of a compound having a soluble beta-amyloid precursor protein secretion promoting action and an apoptosis inhibitory action, or a salt thereof, or a prodrug thereof for the manufacture of a medicament having a neurological dysfunction improving effect;
(21) Use of a compound having soluble beta-amyloid precursor protein secretion promoting action and apoptosis inhibitory action or a salt thereof or a prodrug thereof for producing a prophylactic / therapeutic agent for a neurodegenerative disease, (22) Alzheimer's disease, Parkinson Use of a compound having a beta-amyloid precursor protein secretion promoting action and an apoptosis inhibitory action or a salt thereof or a prodrug thereof for the manufacture of a medicament having a preventive / therapeutic action for disease, prion disease or neuropathy; (23) soluble beta Formula (a) for producing a medicament having an amyloid precursor protein secretion promoting action and an apoptosis inhibitory action

Embedded image [In the formula, ring A represents a benzene ring which may have a substituent, and Y represents CH or N. Formula (b):

Embedded image [Wherein, Ar ² represents an aromatic group which may have a substituent. Or a partial structure represented by the formula (c):

Embedded image [In the formula, Ar ¹ represents an aromatic group which may have a substituent, and X represents an oxygen atom, CR ³ R ⁴ or NR ⁵ (R ³ ,
R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group which may have a substituent. )
And Y is as defined above. (24) use of a compound having a partial structure represented by the formula (I) or a salt thereof or a prodrug thereof; )

Embedded image Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may have a substituent, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and Ar ¹ and Ar ² are each a substituent A ring represents an optionally substituted benzene ring, X represents an oxygen atom, CR ³ R ⁴ or NR ⁵ (R ³ , R ⁴ , R ⁵ are the same or different and each represents a hydrogen atom or a lower alkyl group which may have a substituent.), And Y is CH
Or N. Use of a compound represented by the formula: or a salt thereof or a prodrug thereof;
A method for ameliorating neurological dysfunction, which comprises administering to a mammal a compound having an amyloid precursor protein secretion promoting action and an apoptosis inhibitory action or a salt thereof or a prodrug thereof, (26) a soluble beta-amyloid precursor protein secretion promoting action and A method for preventing or treating a neurodegenerative disease, which comprises administering a compound having an apoptosis-inhibiting activity or a salt thereof or a prodrug thereof to a mammal, (27) the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, prion disease or neuropathy (28) The method for prevention and treatment according to the above (26), wherein

Embedded image [In the formula, ring A represents a benzene ring which may have a substituent, and Y represents CH or N. Formula (b):

Embedded image [Wherein, Ar ² represents an aromatic group which may have a substituent. Or a partial structure represented by the formula (c):

Embedded image [In the formula, Ar ¹ represents an aromatic group which may have a substituent, and X represents an oxygen atom, CR ³ R ⁴ or NR ⁵ (R ³ ,
R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group which may have a substituent. )
And Y is as defined above. A method of promoting secretion of soluble beta-amyloid precursor protein and / or inhibiting apoptosis, which comprises administering a compound having a partial structure represented by the formula (I) or a salt thereof or a prodrug thereof to a mammal;

Embedded image Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may have a substituent, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and Ar ¹ and Ar ² are each a substituent A ring represents an optionally substituted benzene ring, X represents an oxygen atom, CR ³ R ⁴ or NR ⁵ (R ³ , R ⁴ , R ⁵ are the same or different and each represents a hydrogen atom or a lower alkyl group which may have a substituent.), And Y is CH
Or N. A method of promoting secretion of soluble beta-amyloid precursor protein and / or inhibiting apoptosis, which comprises administering a compound represented by the formula (I) or a salt thereof or a prodrug thereof to a mammal;
I)

Embedded image Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may have a substituent, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and Ar ¹ and Ar ² are each a substituent And the ring A represents a benzene ring which may have a substituent. Or a salt thereof or a prodrug thereof,
(31) R ¹ is a hydrogen atom, R ² is a methyl group,
Ar ¹ is a phenyl group which may have a substituent,
Wherein Ar ² is a 3,4-dimethoxyphenyl group, and ring A is an unsubstituted benzene ring, or a salt thereof or a prodrug thereof;
A pharmaceutical composition comprising the compound according to 0) or a salt thereof or a prodrug thereof, formula (33)

Embedded image Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may have a substituent, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and Ar ² has a substituent. And the ring A represents a benzene ring which may have a substituent. And a salt thereof represented by the formula: Ar ¹ OH [wherein, Ar ¹ represents an aromatic group which may have a substituent. Wherein the compound represented by the formula (II) or a salt thereof is subjected to a condensation reaction:

Embedded image [Wherein, R ¹ , R ² , Ar ¹ , Ar ² and ring A have the same meanings as described above. (34) a method for producing a compound represented by the formula (III):

Embedded image Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may be substituted, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and Ar ¹ is an aromatic group which may have a substituent. Group A, ring A represents an optionally substituted benzene ring, and ring B is an optionally halogenated C _1-6 alkoxy group, hydroxy group or C _1-3 alkylenedioxy group And X represents CR ³ R ⁴ or NR ⁵ (R ³ , R ⁴ and R ⁵ are the same or different, and each may be a hydrogen atom or a lower group which may have a substituent.) Y represents CH.
Or N (provided that X is NH, Y is CH and Ar ¹
Is an unsubstituted phenyl group). Or a salt thereof or a prodrug thereof, (3
5) R ¹ is a hydrogen atom the (34) The compound according or a salt thereof or a prodrug thereof, (36) R ² is a hydrogen atom or a substituted is also lower alkyl group described above (34 ) The compound according to the above (34) or a salt thereof or a prodrug thereof, wherein (37) Ar ¹ is a monocyclic aromatic group which may have a substituent, (38)
The compound according to the above (34), wherein Ar ¹ is a phenyl group which may have a substituent, or a salt thereof or a prodrug thereof; (39) the compound according to the above (34), wherein the A ring is an unsubstituted benzene ring. The compound or a salt thereof or a prodrug thereof, (40) the compound or a salt thereof according to the above (34), wherein X is NR ⁵ (R ⁵ has the same meaning as in the above (34)) and Y is CH, or a salt thereof. Prodrug, (4
1) R ¹ is a hydrogen atom, R ² is a methyl group, Ar
¹ is a phenyl group which may have a substituent, A ring is an unsubstituted benzene ring, X is NR ⁵ (R ⁵ has the same meaning as in the above (34)), and Y is CH (Provided that X is NH, Y is CH and Ar ¹ is an unsubstituted phenyl group) or the compound or a salt thereof or a prodrug thereof according to the above (34);
4) A pharmaceutical composition comprising the compound according to the above or a salt thereof or a prodrug thereof;

Embedded image Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may be substituted, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and ring A is an optionally substituted benzene And ring B represents a benzene ring which may be substituted with an optionally halogenated C _1-6 alkoxy group, hydroxy group or C _1-3 alkylenedioxy group. A compound represented by the formula: Ar ¹ -NR ⁵ H wherein R ⁵ represents a hydrogen atom or a lower alkyl group which may have a substituent, and Ar ¹ represents a substituent An aromatic group which may be possessed (except when R ⁵ is H and Ar ¹ is an unsubstituted phenyl group). A compound represented by the formula: or a salt thereof,

Embedded image [Wherein, R ¹ , R ² , R ⁵ , ring A, ring B, and Ar ¹ have the same meanings as described above. A method for producing a compound represented by the formula: or a salt thereof, or a prodrug thereof;

Embedded image Wherein R ¹ and R ² are the same or different,
A hydrogen atom or a lower alkyl group which may be substituted, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring with an adjacent carbon atom, and Ar ¹ is an aromatic group which may have a substituent; A group represents a ring, A ring represents a benzene ring which may have a substituent, and B ring represents an optionally halogenated C _1-6 alkoxy group, hydroxy group or C _1-3 alkylenedioxy group. Represents a benzene ring which may be substituted. ] Or a salt thereof, a compound represented by the formula: R ⁵ Z wherein R ⁵ represents a hydrogen atom or a lower alkyl group which may have a substituent, and Z represents a reactive substituent. . Wherein the compound represented by the formula (I) or a salt thereof is reacted:

Embedded image [Wherein, R ¹ , R ² , R ⁵ , ring A, ring B, and Ar ¹ have the same meanings as described above (except when R ⁵ is H and Ar ¹ is an unsubstituted phenyl group) ). A method for producing a compound represented by the formula (I) or a salt thereof or a prodrug thereof;
5) Formula

Embedded image Wherein R ¹ and R ² are the same or different,
Represents hydrogen atom or optionally substituted lower alkyl group, R ¹ and R ² for 4 to together with the carbon atom bonded to the adjacent form a 7-membered ring, Ar ¹ is aromatic may have a substituent A represents a benzene ring which may have a substituent, and X represents CR ³ R ⁴ or NR ⁵ (R ³ ,
R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group which may have a substituent. )
Y represents CH or N (provided that X is NH,
Except when Y is CH and Ar ¹ is an unsubstituted phenyl group). A compound represented by the formula:

Embedded image [In the formula, ring B represents a benzene ring which may be substituted with an optionally halogenated C _1-6 alkoxy group, hydroxy group or C _1-3 alkylenedioxy group. Wherein the compound represented by the formula (III) or a salt thereof is reacted:

Embedded image [Wherein R ¹ , R ² , Ar ¹ , X, Y, ring A and ring B have the same meanings as described above. A method for producing a compound represented by the formula: or a salt thereof or a prodrug thereof;

Embedded image Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may be substituted, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and ring A is an optionally substituted benzene And ring B represents a benzene ring which may be substituted with an optionally halogenated C _1-6 alkoxy group, hydroxy group or C _1-3 alkylenedioxy group. And a salt thereof represented by the formula: Ar ¹ CR ³ R ⁴ Z wherein Ar ¹ represents an aromatic group which may have a substituent, and R ³ and R ⁴ are the same as each other. Or differently, it represents a hydrogen atom or a lower alkyl group which may have a substituent, and Z represents a reactive substituent. Wherein the compound represented by the formula (I) or a salt thereof is reacted:

Embedded image [Wherein R ¹ , R ² , R ³ , R ⁴ , ring A, ring B, and Ar ¹
Is as defined above. Or a salt thereof or a prodrug thereof.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The pharmaceutical composition of the present invention contains a compound having a promoting action on secretion of soluble beta-amyloid precursor protein and an inhibitory action on apoptosis, a salt thereof, or a prodrug thereof. As the compound, a compound having a partial structure represented by the above formula (a), (b) or (c) is preferably used. In the partial structure represented by the above formula (c), examples of the “lower alkyl group” of the lower alkyl group which may have a substituent represented by R ³ , R ⁴ and R ⁵ include, for example, C _{1- 6} alkyl (eg,
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.). Preferred are methyl, ethyl and propyl. A hydrogen atom is preferably used as R ³ , R ⁴ and R ⁵ .

In the above formula, the “substituent” of the “optionally substituted lower alkyl group” represented by R ³ , R ⁴ and R ⁵ is, for example, a halogen atom (eg, fluorine, chlorine , Bromine, iodine, etc.), C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro, cyano, C _1-6 alkyl-C _6-10 aryl-C _2-6
Alkenyl (eg, methylphenylethenyl, etc.), optionally halogenated C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio , Hydroxy, optionally substituted C _6-10 aryloxy, C _6-10 aryl-C _7-16 aralkyloxy (eg, phenylbenzyloxy, etc.), amino, mono-C _1-6 alkylamino (Eg, methylamino, ethylamino, propylamino,
Isopropylamino, butylamino, etc.), di-C _1-6
Alkylamino (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), a 5- to 7-membered saturated cyclic amino which may have a substituent, acyl, acylamino, acyloxy and the like; Among them, halogen atom, C _1-3 alkylenedioxy, C _1-6 alkyl-C _6-10 aryl-C _2-6
Alkenyl, optionally halogenated C _1-6 alkoxy, hydroxy, optionally substituted C _6-10 aryloxy, acyl, acyloxy and the like are preferable.

The “lower alkyl group” of the “lower alkyl group optionally having substituent (s)” represented by R ³ , R ⁴ and R ⁵ is, for example, the above substituent can be substituted with a lower alkyl group. It may have 1 to 13, preferably 1 to 5 at the position, and when the number of substituents is 2 or more, each substituent may be the same or different.

The above-mentioned “C optionally having substituent (s)”_6-10A
Reeloxy_6-10As "aryloxy",
Examples include phenyloxy, naphthyloxy and the like.
It is. "C optionally having substituent (s)_6-10Aryloxy
Examples of the “substituent” of “C” include, for example, halogen
Atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C
_1-3Alkylenedioxy (eg, methylenedioxy, ethyl
Rangeoxy), nitro, cyano, halogenated
May be C_1-6Alkyl, even if halogenated
Good C_3-6Cycloalkyl, optionally halogenated
C_1-6Alkoxy, optionally halogenated C_1-6
Alkylthio, hydroxy, amino, mono-C_1-6Al
Killamino (eg, methylamino, ethylamino, propylamino
Amino, isopropylamino, butylamino, etc.),
Di-C_1-6Alkylamino (eg, dimethylamino, die
Tylamino, dipropylamino, dibutylamino, ethi
), Formyl, carboxy, carba
Moyl, optionally halogenated C_1-6Alkyl-
Carbonyl, C_1-6Alkoxy-carbonyl (eg, meth
Xoxycarbonyl, ethoxycarbonyl, propoxycal
Bonyl, tert-butoxycarbonyl, etc.), mono-
C_1-6Alkyl-carbamoyl (eg, methylcarbamoy)
, Ethylcarbamoyl, etc.), di-C_1-6Alkyl-
Carbamoyl (eg, dimethylcarbamoyl, diethylca
Rubamoyl, ethylmethylcarbamoyl, etc.), halogen
C which may be_1-6Alkylsulfonyl, phor
Milamino, optionally halogenated C_1-6Archi
Le-carboxamide, C_1-6Alkoxy-carboxami
(Eg, methoxycarboxamide, ethoxycarboxa
Mido, propoxycarboxamide, butoxycarboxa
Mid, etc.), C_1-6Alkylsulfonylamino (eg,
Tylsulfonylamino, ethylsulfonylamino
Etc.), C_1-6Alkyl-carbonyloxy (eg, aceto
Xy, propanoyloxy, etc.), C_1-6Alkoxy-
Carbonyloxy (eg, methoxycarbonyloxy, d
Toxylcarbonyloxy, propoxycarbonyloxy
, Butoxycarbonyloxy, etc.), mono-C_1-6A
Alkyl-carbamoyloxy (eg, methylcarbamoyl)
Oxy, ethylcarbamoyloxy, etc.), di-C_1-6
Alkyl-carbamoyloxy (eg, dimethylcarbamo)
Yloxy, diethylcarbamoyloxy, etc.)
One to five.

The “5- to 7-membered saturated cyclic amino” of the “5- to 7-membered saturated cyclic amino optionally having substituent (s)” includes, for example, morpholino, thiomorpholino,
Piperazin-1-yl, piperidino, pyrrolidin-1-
Yl, hexamethyleneimine-1-yl and the like. Examples of the “substituent” of the “optionally substituted 5- to 7-membered saturated cyclic amino” include C _1-6 alkyl, C _6-14 aryl _optionally substituted, substituted A C _7-19 aralkyl which may have a group, a 5- to 10-membered aromatic heterocyclic group which may have a substituent, a C _6-10 aryl-carbonyl which may have a substituent, Examples thereof include one to three optionally halogenated C _1-6 alkyl-carbonyl, and optionally halogenated C _1-6 alkylsulfonyl. The “C _6-14 aryl” of the “C _6-14 aryl optionally having substituent (s)” includes, for example, naphthyl such as phenyl, 1-naphthyl or 2-naphthyl, indenyl such as 2-indenyl, and 2 -Anthryl and the like. Preferred is phenyl and the like. "C optionally having substituent (s)
Examples of “C _7-19 aralkyl” of “ _7-19 aralkyl” include, for example, benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl , 4-phenylbutyl, 5-phenylpentyl and the like. Preferred is benzyl and the like. Examples of the “5- to 10-membered aromatic heterocyclic group” of the “5- to 10-membered aromatic heterocyclic group which may have a substituent” include, for example, 2
Pyridyl, such as-, 3- or 4-pyridyl, 1-, 2
Examples thereof include indolyl such as-or 3-indolyl, and thienyl such as 2- or 3-thienyl. Preferably, pyridyl such as 2-, 3- or 4-pyridyl and the like are used. The “C _6-10 aryl-carbonyl” of the “ _optionally substituted C _6-10 aryl-carbonyl” includes, for example, benzoyl, 1-naphthoyl, 2-naphthoyl and the like.

These “C optionally having substituent (s)”
_6-14 aryl "," _optionally substituted _C7-19 aralkyl "," _optionally substituted 5 to 10 aralkyl ".
Examples of the “substituent” that each of the “membered aromatic heterocyclic group” and “C _6-10 aryl-carbonyl _optionally substituted” may have include, for example, a halogen atom (eg,
Fluorine, chlorine, bromine, iodine, etc.), C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C
_1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio,
Hydroxy, amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino,
Isopropylamino, butylamino, etc.), di-C _1-6
Alkylamino (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), formyl, carboxy, carbamoyl,
An optionally halogenated C _1-6 alkyl - carbonyl, C _{1 -6} alkoxy - carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
tert- butoxycarbonyl, etc.), mono--C _1-6 alkyl - carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.), di -C _1-6 alkyl - carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.) Optionally halogenated C _1-6 alkylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide (eg,
Methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc., C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C
_1-6 alkyl-carbonyloxy (eg, acetoxy, propanoyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _6alkyl - carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.), di -C _1-6 alkyl -
And 1 to 5 carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.).

The "acyl", "acylamino" and "acyloxy" as the "substituent" of the "optionally substituted lower alkyl group" for R ³ , R ⁴ and R ⁵ "Is a formyl, carboxy, carbamoyl, optionally halogenated C
_1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), C _6-10 aryl-carbonyl optionally having substituent (s), C _6-10 aryloxy-carbonyl which may have a substituent, C _7-16 aralkyloxy-carbonyl which may have a substituent, 5- to 6-membered heterocyclic group which may have a substituent Ring carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl (eg,
Dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), which may have a substituent C _{6- 10} aryl - carbamoyl substituent may 5- to 6-membered heterocyclic ring-carbamoyl which may have a, halogenated C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl optionally having substituent (s), among others, optionally halogenated C _1-6 alkyl-carbonyl, C _1-6 Examples thereof include an alkoxy-carbonyl (eg, ethoxycarbonyl), an optionally substituted C _6-10 aryl-carbonyl, an optionally substituted C _6-10 arylsulfonyl, and the like.

The above "optionally substituted C"_6-10A
Reel-carbonyl "_6-10Aryl-carboni
As '', for example, benzoyl, 1-naphthoyl,
2-naphthoyl and the like. The above "having a substituent
May be C_6-10Aryloxy-carbonyl
"C _6-10“Aryloxy-carbonyl” includes, for example,
Examples include phenoxycarbonyl. The "place
C optionally having a substituent_7-16Aralkyloxy-cal
Bonil)_7-16Aralkyloxy-carbonyl "
For example, benzyloxycarbonyl, phenethyl
Loxycarbonyl and the like. The above "substituent
5 to 6-membered heterocyclic carbonyl which may be
As the "6-membered heterocyclic carbonyl", for example, nicotine
, Isonicotinoyl, 2-thenoyl or 3-tenoy
Or 2-furoil or 3-furoil
Which furoil, morpholinocarbonyl, piperidinocar
And bonyl, pyrrolidin-1-ylcarbonyl and the like.
It is. The above-mentioned “optionally substituted C_6-10Aryl
-Carbamoyl "_6-10Aryl-carbamoyl "
For example, phenylcarbamoyl, 1-naphthy
Rucarbamoyl, 2-naphthylcarbamoyl and the like.
Can be The above "5- to 6-membered heterocyclic group which may have a substituent"
“5- to 6-membered heterocyclic carbamoyl” of “cyclic carbamoyl”
For example, 2-pyridylcarbamoyl, 3-pyridyl
Jilcarbamoyl or 4-pyridylcarbamoyl, etc.
Pyridylcarbamoyl, 2-thienylcarbamoyl
Or thienylcarbamo such as 3-thienylcarbamoyl
And the like. The above "may have a substituent"
C_6-10Arylsulfonyl ”_6-10Arylsul
As “honyl”, for example, benzenesulfonyl, 1-
Naphthalenesulfonyl, 2-naphthalenesulfonyl, etc.
Is mentioned.

These "C _6-10 which may have a substituent"
Aryl-carbonyl "," optionally substituted _C6-10 aryloxy-carbonyl "," optionally substituted _C7-16 aralkyloxy-carbonyl ",
"Optionally substituted 5- to 6-membered heterocyclic carbonyl", "optionally substituted _C6-10 aryl-carbamoyl", "optionally substituted 5- Examples of the “substituent” of the “6-membered heterocyclic carbamoyl” and the “optionally substituted C _6-10 arylsulfonyl” include a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, halogenated _Optionally C _1-6 alkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di -C _1-6 alkylamino, formyl, carboxy, carbamoyl, optionally halogenated C _1-6 alkyl-carbonyl, C
_1-6 alkoxy-carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, optionally halogenated C _1-6 alkylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl - carboxamide, C _{1 -6} alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl 1 to 5, preferably 1 to 3 substituents selected from -carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy. Among them, a halogen atom, an optionally halogenated C _{1- 6} alkyl, optionally halogenated C
_1-6 alkoxy and the like are preferred.

As the "acylamino" as the "substituent" of the "optionally substituted lower alkyl group" represented by R ³ , R ⁴ and R ⁵ , for example, And an amino group substituted with 1 to 2 acyl groups as described in the "substituent group" of the "optionally substituted aromatic group", preferably formylamino, and optionally halogenated C _{1-. 6-} alkyl-carboxamide, optionally substituted C _6-10 aryl-carboxamide (eg, phenylcarboxamide, naphthylcarboxamide, etc.), C _1-6 alkoxy-carboxamide (eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide) and butoxy carboxamide), C _1-6 alkylsulfonylamino (e.g., methylsulfonylamino, Echirusu Honiruamino, etc.), and the like.

The “acyloxy” as the “substituent” of the “optionally substituted lower alkyl group” represented by R ³ , R ⁴ and R ⁵ includes, for example, the aforementioned “substituted include oxy substituted by one "acyl" described in detail in the "substituent" also aromatic group "it has been found preferably, C _1-6 alkyl - carbonyloxy (e.g., acetoxy, propanoyl Oxy), an optionally substituted C _6-10 aryl-carbonyloxy (eg, benzoyloxy, 1-naphthoyloxy, 2-
Naphthoyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyl) Oxy, ethylcarbamoyloxy, etc.), di-C _1-6 alkyl-
Carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), optionally substituted C _6-10 aryl-carbamoyloxy (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), nicotinoyloxy, etc. No.

A in the partial structure represented by the above formula (b)
r ² and A in the partial structure represented by the above formula (c)
"Aromatic group optionally having substituent (s)" for r ¹
Examples of the “aromatic group” include a monocyclic aromatic group, a ring-assembled aromatic group, a condensed aromatic group and the like. Said,
As the “monocyclic aromatic group”, for example, benzene ring, 5
Or a monovalent group formed by removing any one hydrogen atom from a 6-membered aromatic heterocycle. "5 or 6
As the "membered aromatic heterocycle", for example, a 5- or 6-membered aromatic heterocycle containing one or more (for example, 1 to 3) heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom in addition to a carbon atom, and the like. No. Specifically, thiophene,
Furan, pyrrole, imidazole, pyrazole, thiazole, oxazole, pyridine, pyrazine, pyrimidine, pyridazine and the like. `` Monocyclic aromatic group ''
Specific examples of phenyl, thienyl such as 2- or 3-thienyl, furyl such as 2- or 3-furyl,
Pyrrolyl such as 1-, 2- or 3-pyrrolyl, imidazolyl such as 2- or 4-imidazolyl, pyrazolyl such as 3- or 4-pyrazolyl, 2-, 4- or 5
Thiazolyl such as -thiazolyl, 2-, 4- or 5-
Oxazolyl such as oxazolyl, 2-, 3- or 4
Pyridyl such as -pyridyl; pyrazinyl such as 2-pyrazinyl; pyrimidinyl such as 2-, 4- or 5-pyrimidinyl; and pyridazinyl such as 3- or 4-pyridazinyl.

As the above-mentioned "ring-assembled aromatic group", two or more (preferably 2 or 3) aromatic rings are directly connected by a single bond, and the number of directly bonded rings is a ring system. And a group formed by removing one arbitrary hydrogen atom from an aromatic ring assembly one less than the number of the above. Examples of the “aromatic ring” include an aromatic hydrocarbon, an aromatic heterocycle, and the like.
As the “aromatic hydrocarbon”, for example, a monocyclic or condensed polycyclic (bicyclic or tricyclic) aromatic hydrocarbon having 6 to 14 carbon atoms (eg, benzene, naphthalene, indene,
Anthracene). Examples of the "aromatic heterocycle" include, for example, a 5- to 14-membered member having one or more (for example, 1 to 4) heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom, preferably a 5- to 10-membered atom. Membered aromatic heterocycle, and the like. Specifically, thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-
b] thiophene, furan, phenoxatiin, pyrrole, imidazole, pyrazole, oxazole, isoxazole, 1,2,4-oxadiazole or 1,
Oxadiazoles such as 3,4-oxadiazole,
Thiadiazoles such as 1,2,4-thiadiazole or 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,
Aromatic heterocycles such as phenazine, thiazole, isothiazole, phenothiazine, furazane, phenoxazine, phthalimide, or one or more (preferably one or two) of these rings (preferably one or two) (e.g., , A benzene ring, etc.). Examples of the aromatic ring aggregate in which these aromatic rings are directly connected by a single bond include, for example, two or three (preferably 5 or 10-membered (preferably 5- or 6-membered) aromatic heterocycles selected from a benzene ring, a naphthalene ring and a 5- to 6-membered (preferably 5- or 6-membered) aromatic heterocyclic ring. Are two). Preferred examples of the aromatic ring assembly include benzene, naphthalene, pyridine, pyrimidine, thiophene, furan, thiazole, isothiazole, oxazole, 1,2,4-oxadiazole and 1,3,4-oxadiazole. Oxadiazole, 1,2,4-thiadiazole or 1,
An aromatic ring assembly comprising two or three aromatic rings selected from thiadiazoles such as 3,4-thiadiazole, quinoline, isoquinoline, indole, benzothiophene, benzoxazole, benzothiazole and benzofuran. Specific examples include biphenylyl such as 2-, 3- or 4-biphenylyl, 3- (1-naphthyl)
-1,2,4-oxadiazol-5-yl or 3-
(2-naphthyl) -1,2,4-oxadiazole-5
-Naphthyl-substituted oxadiazolyl such as -yl;
-Benzofuranyl) -1,2,4-oxadiazole-
Benzofuranyl-substituted oxadiazolyl such as 5-yl,
Phenyl-substituted oxadiazolyl such as 3-phenyl-1,2,4-oxadiazol-5-yl or 5-phenyl-1,3,4-oxadiazol-2-yl;
Benzoxazolyl-substituted oxadiazolyl, such as (2-benzoxazolyl) -1,2,4-oxadiazol-2-yl, 3- (3-indolyl) -1,2,4-oxadiazole-2 -Yl or indolyl-substituted oxadiazolyl such as 3- (2-indolyl) -1,2,4-oxadiazol-2-yl; phenyl-substituted thiazolyl such as 4-phenylthiazol-2-yl;
Benzofuranyl-substituted thiazolyl such as (2-benzofuranyl) thiazol-2-yl, 4-phenyl-1,3-
Phenyl-substituted oxazolyl such as oxazol-5-yl or 5-phenyloxazol-2-yl, phenyl-substituted isothiazolyl such as 5-phenyl-isothiazol-4-yl, 4- (2-thienyl) phenyl or 4- (3- Thienyl-substituted phenyl such as thienyl) phenyl, 3- (3-pyridyl) phenyl or 4- (3-
Pyridyl-substituted phenyl such as pyridyl) phenyl, 6-
Phenyl-substituted pyridyls such as phenyl-3-pyridyl,
Examples include naphthyl-substituted phenyl such as 4- (2-naphthyl) phenyl, benzofuranyl-substituted phenyl such as 4- (2-benzofuranyl) phenyl, and terphenylyl such as 4,4′-terphenylyl.

The “condensed aromatic group” includes, for example,
Fused polycyclic (preferably 2 to 4 cyclic, preferably 2
Or tricyclic) monovalent groups formed by removing any one hydrogen atom from an aromatic ring. Examples of the “condensed polycyclic aromatic ring” include a condensed polycyclic aromatic hydrocarbon, a condensed polycyclic aromatic heterocycle, and the like. As the “condensed polycyclic aromatic hydrocarbon”, for example, a condensed polycyclic (bi- or tri-cyclic) aromatic hydrocarbon having 9 to 14 carbon atoms (eg,
Naphthalene, indene, anthracene, etc.). Examples of the “condensed polycyclic aromatic heterocycle” include, for example, one or more (eg, 1 to 4) heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom other than a carbon atom.
And a 9 to 14 membered, preferably 9 or 10 membered fused polycyclic aromatic heterocycle. In particular,
Benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho [2,3-b] thiophene, isoquinoline, quinoline,
And aromatic heterocycles such as indole, quinoxaline, phenanthridine, phenothiazine, phenoxazine, and phthalimide. Specific examples of the “condensed aromatic group” include naphthyl such as 1-naphthyl or 2-naphthyl, quinolyl such as 2-quinolyl, 3-quinolyl or 4-quinolyl, benzofuranyl such as 2-benzofuranyl, 2-benzothiazolyl and the like. Benzothiazolyl, benzimidazolyl such as 2-benzimidazolyl, and indolyl such as 1-indolyl, 2-indolyl or 3-indolyl.

Among the above, the aromatic groups represented by Ar ¹ and Ar ² include, for example, (1) phenyl, 2
Thienyl such as-or 3-thenyl, 2- or 3-
Monocyclic aromatic groups such as furyl such as furyl, pyridyl such as 2-, 3- or 4-pyridyl; (2) 2-, 3-
Or biphenylyl such as 4-biphenylyl, 3- (1
Naphthyl-substituted oxadiazolyl, such as -naphthyl) -1,2,4-oxadiazol-5-yl or 3- (2-naphthyl) -1,2,4-oxadiazol-5-yl; Benzofuranyl-substituted oxadiazolyl such as benzofuranyl) -1,2,4-oxadiazol-5-yl; phenyl-substituted oxadiazolyl such as 3-phenyl-1,2,4-oxadiazol-5-yl;
Benzoxazolyl-substituted oxadiazolyl such as 3- (2-benzoxazolyl) -1,2,4-oxadiazol-2-yl, 3- (3-indolyl) -1,2,4
Indolyl-substituted oxadiazolyl such as -oxadiazol-2-yl or 3- (2-indolyl) -1,2,4-oxadiazol-2-yl, phenyl-substituted thiazolyl such as 4-phenylthiazol-2-yl, 4-
Benzofuranyl-substituted thiazolyl such as (2-benzofuranyl) thiazol-2-yl, 4-phenyl-1,3-
Phenyl-substituted oxazolyl such as oxazol-5-yl, thienyl-substituted phenyl such as 4- (2-thienyl) phenyl, pyridyl-substituted phenyl such as 4- (3-pyridyl) phenyl, naphthyl such as 4- (2-naphthyl) phenyl Ring-assembled aromatic groups such as substituted phenyl, terphenylyl such as 4,4′-terphenylyl, (3) 2-,
Preferred are condensed aromatic groups such as quinolyl such as 3- or 4-quinolyl and indolyl such as 1-, 2- or 3-indolyl. As the aromatic group represented by Ar ¹ , for example, quinolyl such as phenyl, 2-, 3- or 4-quinolyl is more preferable, and phenyl is particularly preferably used. Examples of the aromatic group represented by Ar ² include phenyl, thienyl such as 2- or 3-phenyl, furyl such as 2- or 3-furyl, 2-, 3-furyl, and the like.
Monocyclic aromatic groups such as pyridyl such as 3- or 4-pyridyl are more preferred.

In the present specification, the “optionally halogenated C _1-6 alkyl” includes, for example, 1 to 5,
Preferably one to three halogen atoms (eg, fluorine,
C _1-6 alkyl _optionally having chlorine, bromine, iodine, etc. (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
Butyl, pentyl, hexyl, etc.). Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,
2-bromoethyl, 2,2,2-trifluoroethyl,
Pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-
Trifluorobutyl, isobutyl, sec-butyl, t
tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl,
6,6,6-trifluorohexyl and the like.

In the present specification, the “C _3-6 cycloalkyl which may be halogenated” includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine , Iodine, etc.)
_3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) and the like. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dichlorocyclohexyl, 2,2,3,3-tetrafluorocyclopentyl, 4-chlorocyclohexyl, and the like.

In the present specification, “C _1-6 alkoxy which may be halogenated” includes, for example, 1 to 5
, Preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
_1-6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, pentyloxy, etc.) and the like. Specific examples 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.

In the present specification, the “optionally halogenated C _1-6 alkylthio” includes, for example, 1 to 5
, Preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
_1-6 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.) and the like. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like.

In the present specification, the “optionally halogenated C _1-6 alkyl-carbonyl” includes, for example, 1
C _1-6 alkyl-carbonyl (eg, acetyl, propanoyl, butanoyl, pentanoyl) which may have from 5 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) Hexanoyl). Specific examples include, for example, acetyl, monochloroacetyl, trifluoroacetyl,
Trichloroacetyl, propanoyl, butanoyl, pentanoyl, hexanoyl and the like.

In the present specification, the “optionally halogenated C _1-6 alkylsulfonyl” includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine , Iodine, etc.) and C _1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, etc.) and the like. . Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.

In the present specification, the “optionally halogenated C _1-6 alkyl-carboxamide” includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (eg, fluorine, chlorine, C _1-6 alkyl-carboxamide (eg, acetamide, etc.) which may have bromine, iodine, and the like. Specific examples include acetamide, trifluoroacetamide, propanamide, butanamide and the like.

In the above formula, Ar¹And Ar^TwoIndicated by
"Optionally substituted aromatic group", "substituted
Monocyclic aromatic group which may be substituted '', `` having a substituent
A phenyl group ", Ar¹With a substituent
May have a phenyl group or a substituent
A good quinolyl group ", Ar^TwoHaving a substituent represented by
Phenyl, furyl, thienyl or pi
A lysyl group "and a" substituted group represented by ring A
Examples of the “substituent” of the “good benzene ring” include, for example,
Logen atoms (eg, fluorine, chlorine, bromine, iodine, etc.),
C_1-3Alkylenedioxy (eg, methylenedioxy, d
Tylene dioxy), nitro, cyano, halogenated
C that may be_1-6Alkyl, C_6-10Aryloxy
-C_1-6Alkyl (eg, phenoxymethyl, etc.), C_1-6
Alkyl-C_6-10Aryl-C_2-6Alkenyl (eg,
Phenylphenylethenyl, etc.)
Good C _3-6Cycloalkyl, which may have a substituent
C_7-16Aralkyl, optionally halogenated C_1-6
Alkoxy, optionally halogenated C_1-6Archi
Luthio, hydroxy, optionally substituted C_6-10
Aryloxy, C_6-10Aryl-C_7-16Aralquilo
Xy (eg, phenylbenzyloxy), amino,
No-C_1-6Alkylamino (eg, methylamino, ethyl
Amino, propylamino, isopropylamino, butyl
Amino, etc.), di-C_1-6Alkylamino (eg, dimethi
Ruamino, diethylamino, dipropylamino, dibuti
Amino, ethylmethylamino, etc.)
5- to 7-membered saturated cyclic amino, acyl, acyl
Amino, acyloxy, etc., among which halo
Gen atom, C_1-3Alkylenedioxy, halogenated
May be C_1-6Alkyl, C _6-10Aryloxy-
C_1-6Alkyl, C_1-6Alkyl-C_6-10Aryl-C
_2-6Alkenyl, optionally substituted C_7-16Ara
Alkyl, optionally halogenated C_1-6Alkoki
C, hydroxy, optionally substituted C_6-10Ants
Preferred are hydroxy, acyl, acyloxy and the like.

The “aromatic group” of the “aromatic group optionally having substituent (s)” represented by Ar ¹ and Ar ² is, for example, one in which the above substituent is substituted at a position where the aromatic group can be substituted. It may have from 5 to 5, preferably 1 to 3, and when the number of substituents is 2 or more, each substituent may be the same or different. When the substituent is cyclic, the aromatic ring of the aromatic group and the substituent may be bonded by a spiro bond. The “benzene ring” of the “benzene ring optionally having substituent (s)” represented by ring A is, for example, the above-mentioned substituent is substituted at 1 to 4 at a substitutable position of an aromatic group.
And preferably one or two, and when the number of substituents is two or more, each substituent may be the same or different. When the substituent is cyclic, the benzene ring and the substituent may be bonded by a spiro bond.

The “C _7-16 aralkyl” of the “C _7-16 aralkyl _optionally having substituent (s)” includes, for example,
Benzyl, phenethyl, naphthylmethyl and the like. Examples of the “C _6-10 aryloxy” of the “C _6-10 aryloxy _optionally having substituent (s)” include, for example,
Examples include phenyloxy and naphthyloxy. These "C _7-16 aralkyl _optionally having substituent (s)",
Examples of the “substituent” of the “ _optionally substituted C _6-10 aryloxy” include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-3 alkylenedi Oxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C _1-6 alkyl, optionally halogenated C _3-6
Cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, Propylamino, isopropylamino, butylamino, etc.), di-C
_1-6 alkylamino (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), formyl, carboxy, carbamoyl, optionally halogenated C _1-6 alkyl-carbonyl, C _{1- 6} alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), mono-C
_1-6 alkyl - carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.), di -C _1-6 alkyl -
Carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), optionally halogenated C _1-6 alkylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl-carboxamide, C _{1 -6} alkoxy-carboxamide (eg, methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc.), C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C _1-6 alkyl-carbonyloxy (Eg, acetoxy, propanoyloxy, etc.), C _1-6 alkoxy-
Carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), di-C _{1 -6}
One to five alkyl-carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.) and the like can be mentioned.

The “5- to 7-membered saturated cyclic amino” of the “5- to 7-membered saturated cyclic amino optionally having substituent (s)” includes, for example, morpholino, thiomorpholino,
Piperazin-1-yl, piperidino, pyrrolidin-1-
Yl, hexamethyleneimine-1-yl and the like. Examples of the “substituent” of the “optionally substituted 5- to 7-membered saturated cyclic amino” include C _1-6 alkyl, C _6-14 aryl _optionally substituted, substituted A C _7-19 aralkyl which may have a group, a 5- to 10-membered aromatic heterocyclic group which may have a substituent, a C _6-10 aryl-carbonyl which may have a substituent, Examples thereof include one to three optionally halogenated C _1-6 alkyl-carbonyl, and optionally halogenated C _1-6 alkylsulfonyl. The “C _6-14 aryl” of the “C _6-14 aryl optionally having substituent (s)” includes, for example, naphthyl such as phenyl, 1-naphthyl or 2-naphthyl, indenyl such as 2-indenyl, and 2 -Anthryl and the like. Preferred is phenyl and the like. "C optionally having substituent (s)
Examples of “C _7-19 aralkyl” of “ _7-19 aralkyl” include, for example, benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl , 4-phenylbutyl, 5-phenylpentyl and the like. Preferred is benzyl and the like. Examples of the “5- to 10-membered aromatic heterocyclic group” of the “5- to 10-membered aromatic heterocyclic group which may have a substituent” include, for example, 2
Pyridyl, such as-, 3- or 4-pyridyl, 1-, 2
Examples thereof include indolyl such as-or 3-indolyl, and thienyl such as 2- or 3-thienyl. Preferably, pyridyl such as 2-, 3- or 4-pyridyl and the like are used. The “C _6-10 aryl-carbonyl” of the “ _optionally substituted C _6-10 aryl-carbonyl” includes, for example, benzoyl, 1-naphthoyl, 2-naphthoyl and the like.

These "C which may have a substituent"
_6-14 aryl "," _optionally substituted _C7-19 aralkyl "," _optionally substituted 5 to 10 aralkyl ".
Examples of the “substituent” that each of the “membered aromatic heterocyclic group” and “C _6-10 aryl-carbonyl _optionally substituted” may have include, for example, a halogen atom (eg,
Fluorine, chlorine, bromine, iodine, etc.), C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), nitro, cyano, optionally halogenated C
_1-6 alkyl, optionally halogenated C _3-6 cycloalkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio,
Hydroxy, amino, mono-C _1-6 alkylamino (eg, methylamino, ethylamino, propylamino,
Isopropylamino, butylamino, etc.), di-C _1-6
Alkylamino (eg, dimethylamino, diethylamino, dipropylamino, dibutylamino, ethylmethylamino, etc.), formyl, carboxy, carbamoyl,
An optionally halogenated C _1-6 alkyl - carbonyl, C _{1 -6} alkoxy - carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
tert- butoxycarbonyl, etc.), mono--C _1-6 alkyl - carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.), di -C _1-6 alkyl - carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.) Optionally halogenated C _1-6 alkylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl-carboxamide, C _1-6 alkoxy-carboxamide (eg,
Methoxycarboxamide, ethoxycarboxamide, propoxycarboxamide, butoxycarboxamide, etc., C _1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C
_1-6 alkyl-carbonyloxy (eg, acetoxy, propanoyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _6alkyl - carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy etc.), di -C _1-6 alkyl -
And 1 to 5 carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.).

The "aromatic group which may have a substituent" represented by the above Ar ¹ and Ar ² and the "substituent of the benzene ring which may have a substituent" represented by ring A "
As the “acyl” in “acyl”, “acylamino” and “acyloxy”, formyl, carboxy, carbamoyl, optionally halogenated C
_1-6 alkyl-carbonyl, C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), C _6-10 aryl-carbonyl optionally having substituent (s), C _6-10 aryloxy-carbonyl which may have a substituent, C _7-16 aralkyloxy-carbonyl which may have a substituent, 5- to 6-membered heterocyclic group which may have a substituent Ring carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl (eg,
Dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), optionally substituted C _6-10 aryl-carbamoyl, optionally substituted 5- to 6-membered heterocyclic carbamoyl, halogenated C _1-6 alkylsulfonyl, C _6-10 arylsulfonyl optionally having substituent (s), among others, optionally halogenated C _1-6 alkyl-carbonyl, C _1-6 Examples thereof include an alkoxy-carbonyl (eg, ethoxycarbonyl), an optionally substituted C _6-10 aryl-carbonyl, an optionally substituted C _6-10 arylsulfonyl, and the like.

The above "C optionally having substituent (s)"_6-10A
Reel-carbonyl "_6-10Aryl-carboni
As '', for example, benzoyl, 1-naphthoyl,
2-naphthoyl and the like. The above "having a substituent
May be C_6-10Aryloxy-carbonyl
"C _6-10“Aryloxy-carbonyl” includes, for example,
Examples include phenoxycarbonyl. The "place
C optionally having a substituent_7-16Aralkyloxy-cal
Bonil)_7-16Aralkyloxy-carbonyl "
For example, benzyloxycarbonyl, phenethyl
Loxycarbonyl and the like. The above "substituent
5 to 6-membered heterocyclic carbonyl which may be
As the "6-membered heterocyclic carbonyl", for example, nicotine
, Isonicotinoyl, 2-thenoyl or 3-tenoy
Or 2-furoil or 3-furoil
Which furoil, morpholinocarbonyl, piperidinocar
And bonyl, pyrrolidin-1-ylcarbonyl and the like.
It is. The above-mentioned “optionally substituted C_6-10Aryl
-Carbamoyl "_6-10Aryl-carbamoyl "
For example, phenylcarbamoyl, 1-naphthy
Rucarbamoyl, 2-naphthylcarbamoyl and the like.
Can be The above "5- to 6-membered heterocyclic group which may have a substituent"
“5- to 6-membered heterocyclic carbamoyl” of “cyclic carbamoyl”
For example, 2-pyridylcarbamoyl, 3-pyridyl
Jilcarbamoyl or 4-pyridylcarbamoyl, etc.
Pyridylcarbamoyl, 2-thienylcarbamoyl
Or thienylcarbamo such as 3-thienylcarbamoyl
And the like. The above "may have a substituent"
C_6-10Arylsulfonyl ”_6-10Arylsul
As “honyl”, for example, benzenesulfonyl, 1-
Naphthalenesulfonyl, 2-naphthalenesulfonyl, etc.
Is mentioned.

These "C _6-10 which may have a substituent"
Aryl-carbonyl "," optionally substituted _C6-10 aryloxy-carbonyl "," optionally substituted _C7-16 aralkyloxy-carbonyl ",
"Optionally substituted 5- to 6-membered heterocyclic carbonyl", "optionally substituted _C6-10 aryl-carbamoyl", "optionally substituted 5- Examples of the “substituent” of the “6-membered heterocyclic carbamoyl” and the “optionally substituted C _6-10 arylsulfonyl” include a halogen atom, C _1-3 alkylenedioxy, nitro, cyano, halogenated _Optionally C _1-6 alkyl, optionally halogenated C _1-6 alkoxy, optionally halogenated C _1-6 alkylthio, hydroxy, amino, mono-C _1-6 alkylamino, di -C _1-6 alkylamino, formyl, carboxy, carbamoyl, optionally halogenated C _1-6 alkyl-carbonyl, C
_1-6 alkoxy-carbonyl, mono-C _1-6 alkyl-carbamoyl, di-C _1-6 alkyl-carbamoyl, optionally halogenated C _1-6 alkylsulfonyl, formylamino, optionally halogenated C _1-6 alkyl - carboxamide, C _{1 -6} alkoxy - carboxamide, C _1-6 alkylsulfonylamino, C _1-6 alkyl - carbonyloxy, C _1-6 alkoxy - carbonyloxy, mono- -C _1-6 alkyl 1 to 5, preferably 1 to 3 substituents selected from -carbamoyloxy and di-C _1-6 alkyl-carbamoyloxy. Among them, a halogen atom, an optionally halogenated C _{1- 6} alkyl, optionally halogenated C
_1-6 alkoxy and the like are preferred.

The Ar¹And Ar^Two"Substituent represented by
An aromatic group which may have a) and ring A
"Substituent" of "optionally substituted benzene ring"
Examples of the “acylamino” include, for example,
In the "substituent" of the "aromatic group which may have a substituent"
Amino substituted with 1 to 2 "acyl" as described in detail above
And preferably formylamino, halogenated
C that may be_{1- 6}Alkyl-carboxamide,
C optionally having a substituent_6-10Aryl-carboxami
(E.g., phenylcarboxamide, naphthylcarboxa
Mid, etc.), C _1-6Alkoxy-carboxamide (eg,
Methoxycarboxamide, ethoxycarboxamide,
Ropoxycarboxamide, butoxycarboxamide
Etc.), C_{1- 6}Alkylsulfonylamino (eg, methyls
Ruphonylamino, ethylsulfonylamino, etc.)
No.

The "aromatic group which may have a substituent" represented by the above Ar ¹ and Ar ² and the "substituent of a benzene ring which may have a substituent" represented by ring A "
Examples of the "acyloxy" include, for example, oxy substituted with one "acyl" described in detail in the "substituent" of the "aromatic group which may have a substituent", preferably , C _1-6 alkyl-carbonyloxy (eg, acetoxy, propanoyloxy, etc.), and optionally substituted C _6-10 aryl-carbonyloxy (eg, benzoyloxy, 1-naphthoyloxy, 2 −
Naphthoyloxy, etc.), C _1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), mono-C _1-6 alkyl-carbamoyloxy (eg, methylcarbamoyl) Oxy, ethylcarbamoyloxy, etc.), di-C _1-6 alkyl-
Carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), optionally substituted C _6-10 aryl-carbamoyloxy (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), nicotinoyloxy, etc. No.

In the above compounds, Ar ¹ is preferably a phenyl group which may have a substituent or a quinolyl group which may have a substituent, and a phenyl group which may have a substituent is preferably More preferably, a halogen atom, a C _1-3 alkylenedioxy group, an optionally halogenated C
_1-6 alkyl group or C _1-6 which may be halogenated
A phenyl group optionally substituted with an alkoxy group is particularly preferred. Ar ² is preferably a monocyclic aromatic group which may have a substituent, more preferably a phenyl group, a furyl group, a thienyl group or a pyridyl group which may each have a substituent, and a halogen atom , A C _1-3 alkylenedioxy group, a phenyl group and a furyl group which may each be substituted with an optionally halogenated C _1-6 alkyl group or an optionally halogenated C _1-6 alkoxy group. , A thienyl group or a pyridyl group are particularly preferred,
A 3,4-dimethoxyphenyl group is most preferred. As the ring A, an unsubstituted benzene ring is preferable. X is N
R ⁵ (R ⁵ is as defined above) is preferred. As Y, CH is preferable.

The salts of the above compounds are preferably pharmaceutically acceptable salts, for example, salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids And the like. 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 and magnesium salt; and aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N ′, N′-dibenzylethylenediamine and the like. Is mentioned. Preferred examples of salts with inorganic acids include:
For example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be mentioned. Preferred 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 can be mentioned. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned.

Prodrugs of the above compounds are compounds which are converted into the above compounds by a reaction with an enzyme or stomach acid under physiological conditions in a living body, that is, enzymatic oxidation, reduction,
A compound that undergoes hydrolysis or the like to change to the above-mentioned compound, or a compound that undergoes hydrolysis or the like by gastric acid or the like to change to the above-mentioned compound. As prodrugs of the above compounds,
Compounds in which the amino group of the above compound is acylated, alkylated, and phosphorylated (e.g., the amino group of the above compound is eicosanoylated, alanylated, pentylaminocarbonylated,
(5-methyl-2-oxo-1,3-dioxolen-4
-Yl) methoxycarbonylation, tetrahydrofuranylation, tetrahydropyranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound, etc.); the hydroxyl group of the above compound is acylated, alkylated, phosphorylated. Oxidized, borated compounds (eg, compounds in which the hydroxyl group of the above compound is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumalylated, alanylated, dimethylaminomethylcarbonylated, tetrahydropyranylated, etc. A compound in which the carboxyl group of the above compound is esterified or amidated (eg, the carboxyl group of the above compound is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl ester) Chemical, ethoxy Rubo alkenyloxy ethyl esterification,
Phthalidyl esterification, (5-methyl-2-oxo-
1,3-dioxolen-4-yl) methyl esterification,
Cyclohexyloxycarbonylethyl esterified compound, methylamidated compound, etc.); These compounds can be produced from the above compounds by a known method. Further, the above compound may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.). Further, the above compound may be an anhydride or a hydrate.

The method for producing the above compound is described below. The following description of the production method applies not only to the above compounds but also to salts and prodrugs thereof, but in the following description, they may be simply referred to as the above compounds. Further, for each compound used in the production of the above compound,
For example, even when the compound is abbreviated as compound (II), a salt thereof is also included. The above compound can be produced by known methods, for example, by the method shown in the following production method. The compound thus obtained can be obtained from the reaction mixture by known means, for example, solvent extraction, concentration, neutralization,
The target product can be isolated and purified from the reaction solution with high purity by filtration, crystallization, recrystallization, column chromatography, high performance liquid chromatography, recrystallization, and the like.

The above compound may be a hydrate or an anhydrate. Examples of the hydrate include monohydrate, 0.5 hydrate, and dihydrate. Further, the above compound may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.). When the above-mentioned compound of the present invention or a salt thereof has an asymmetric carbon, the obtained mixture of optically active substances (racemic form) can be obtained by a conventional optical resolution means, for example, an optically active acid (eg, camphorsulfonic acid or the like) or an optically active acid. A method of forming a salt with an active base (eg, 1-methylbenzylamine), various types of chromatography (eg, liquid chromatography using an optically active column, etc.), and separation of each optical activity by separation means such as fractional recrystallization. Can be divided into bodies.

“Room temperature” usually indicates 0 to 30 ° C. Each symbol in the chemical structural formulas described in the production method has the same meaning as described above unless otherwise specified. In the present specification, `` leaving group ''
Represents a halogen atom (eg, chloro, bromo, iodo, etc.), optionally halogenated C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), and a substituent And C _6-10 arylsulfonyloxy, hydroxy and the like which may be present. Examples of the “substituent” of the “optionally substituted C _6-10 arylsulfonyloxy” include a halogen atom, an optionally halogenated C _1-6 alkyl or C _1-6 alkoxy. One to three. Specific examples of “ _optionally substituted C _6-10 arylsulfonyloxy” include:
Examples include benzenesulfonyloxy, p-toluenesulfonyloxy, 1-naphthalenesulfonyloxy, 2-naphthalenesulfonyloxy, and the like.

In the present specification, the “base” is: 1) For example, a hydride of an alkali metal or an alkaline earth metal (eg, lithium hydride, sodium hydride, potassium hydride, calcium hydride, etc.), an alkali metal Or alkaline earth metal amides (eg, lithium amide, sodium amide, lithium diisopropylamide, lithium dicyclohexylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, etc.), alkali metals Or lower alkoxides of alkaline earth metals (eg,
Strong bases such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.) 2) For example, hydroxides of alkali metals or alkaline earth metals (eg, sodium hydroxide, potassium hydroxide, lithium hydroxide, water Alkali metal or alkaline earth metal carbonate (eg, sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkali metal or alkaline earth metal bicarbonate (eg, sodium bicarbonate, potassium bicarbonate) Or 3) for example, triethylamine, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, DBU (1,8-diazabicyclo [5.4.0] undes-7-ene), DBN ( 1,5-diazabicyclo [4.3.0] non-5 En) amines such as is shown for example pyridine, imidazole, 2,6-lutidine and organic bases such as basic heterocyclic compounds such as. The reactions described herein, for example, alkylation reactions, hydrolysis reactions,
Known methods are used for the amination reaction, esterification reaction, amidation reaction, esterification reaction, etherification reaction, oxidation reaction, reduction reaction, and the like. Examples include Organic Functional Group Preparations (OR
GANIC FUNCTIONAL GROUP PR
EPARATIONS) Second Edition, Academic Press, Inc. 198
The method described in Ninth Year Publication and the like can be used.

In the present invention, the compound represented by the above formula (I), a salt thereof, or a prodrug thereof is used. Examples of the “lower alkyl group” of the optionally substituted lower alkyl group represented by R ¹ , R ² , R ³ , R ⁴ and R ⁵ include C _1-6 alkyl (eg, methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.). Preferred are methyl, ethyl and propyl.

In the compound represented by the formula (I) or a salt thereof or a prodrug thereof, the compound represented by the formula (I)
In the above, the description of the “substituent” of the “optionally substituted lower alkyl group” represented by R ¹ , R ² , R ³ , R ⁴ and R ⁵ is the same as that of the soluble beta-amyloid precursor protein described above. In the description of a compound having a secretion promoting action and an apoptosis inhibitory action or a salt thereof or a prodrug thereof,
It is the same as described as the “substituent” of the “optionally substituted lower alkyl group” represented by R ³ , R ⁴ and R ⁵ .

In the above formula (I), those in which R ¹ and R ² are bonded to form a 4- to 7-membered ring together with adjacent carbon atoms include

Embedded image [Wherein each symbol has the same meaning as described above. And the like. R ¹ is preferably a hydrogen atom, and R ² is preferably a hydrogen atom or a lower alkyl group which may have a substituent, more preferably C _1-6.
An alkyl group, more preferably a methyl group and the like are used. X is preferably NR ⁵ (R ⁵ is as defined above), and Y is preferably CH.

Ar ¹ and Ar ² each represent an aromatic group which may have a substituent. In the compound represented by the above formula (I), a salt thereof or a prodrug thereof, in the above formula (I), the “aromatic” of the “aromatic group which may have a substituent” represented by Ar ¹ and Ar ² The description of the `` family group '', in the description of the compound having a soluble beta-amyloid precursor protein secretion promoting action and apoptosis inhibitory action or a salt thereof or a prodrug thereof,
It is the same as described as the “aromatic group” of the “aromatic group which may have a substituent” represented by Ar ¹ and Ar ² .

Among the above, examples of the aromatic group represented by Ar ¹ and Ar ² include (1) phenyl, 2
Thienyl such as-or 3-thenyl, 2- or 3-
Monocyclic aromatic groups such as furyl such as furyl, pyridyl such as 2-, 3- or 4-pyridyl; (2) 2-, 3-
Or biphenylyl such as 4-biphenylyl, 3- (1
Naphthyl-substituted oxadiazolyl, such as -naphthyl) -1,2,4-oxadiazol-5-yl or 3- (2-naphthyl) -1,2,4-oxadiazol-5-yl; Benzofuranyl-substituted oxadiazolyl such as benzofuranyl) -1,2,4-oxadiazol-5-yl; phenyl-substituted oxadiazolyl such as 3-phenyl-1,2,4-oxadiazol-5-yl;
Benzoxazolyl-substituted oxadiazolyl such as 3- (2-benzoxazolyl) -1,2,4-oxadiazol-2-yl, 3- (3-indolyl) -1,2,4
Indolyl-substituted oxadiazolyl such as -oxadiazol-2-yl or 3- (2-indolyl) -1,2,4-oxadiazol-2-yl, phenyl-substituted thiazolyl such as 4-phenylthiazol-2-yl, 4-
Benzofuranyl-substituted thiazolyl such as (2-benzofuranyl) thiazol-2-yl, 4-phenyl-1,3-
Phenyl-substituted oxazolyl such as oxazol-5-yl, thienyl-substituted phenyl such as 4- (2-thienyl) phenyl, pyridyl-substituted phenyl such as 4- (3-pyridyl) phenyl, naphthyl such as 4- (2-naphthyl) phenyl Ring-assembled aromatic groups such as substituted phenyl, terphenylyl such as 4,4′-terphenylyl, (3) 2-,
Preferred are condensed aromatic groups such as quinolyl such as 3- or 4-quinolyl and indolyl such as 1-, 2- or 3-indolyl. Examples of the aromatic group represented by Ar ¹ include 2-cyclic aromatic groups such as phenyl.
Condensed aromatic groups such as quinolyl such as quinolyl, 3-quinolyl and 4-quinolyl are more preferable, and phenyl is particularly preferably used. Examples of the aromatic group represented by Ar ² include phenyl, thienyl such as 2- or 3-thienyl, furyl such as 2- or 3-furyl, 2
Monocyclic aromatic groups such as pyridyl such as-, 3- or 4-pyridyl are more preferred.

In the compound represented by the formula (I) or a salt thereof or a prodrug thereof, the compound represented by the formula (I)
In the above, "optionally substituted aromatic group", "optionally substituted monocyclic aromatic group", and "optionally substituted" represented by Ar ¹ and Ar ² A phenyl group which may be substituted, a phenyl group, a furyl group, a thienyl group or a pyridyl group which may be substituted, represented by Ar ² The description of the "substituent" of the "benzene ring" is represented by Ar ¹ and Ar ² in the above description of the compound having a soluble beta-amyloid precursor protein secretion promoting action and an apoptosis inhibiting action or a salt thereof or a prodrug thereof. An aromatic group which may have a substituent, a `` monocyclic aromatic group which may have a substituent '', a `` phenyl group which may have a substituent '', represented by Ar ¹ Phenyl which may have a substituent Or optionally quinolyl group which may have a substituent "," optionally substituted phenyl group represented by Ar ^2, furyl group, "substituent represented by a thienyl group or a pyridyl group" and the ring A This is the same as described as the “substituent” of the “benzene ring optionally having”.

In the compound represented by the above formula (I), R ¹ is preferably a hydrogen atom. R ² is preferably a hydrogen atom or a lower alkyl group which may have a substituent, more preferably a hydrogen atom or a C _1-6 alkyl group, and particularly preferably a methyl group. Ar ¹ is preferably a phenyl group which may have a substituent or a quinolyl group which may have a substituent, more preferably a phenyl group which may have a substituent, and a halogen atom, C 1 _1-3
Alkylenedioxy group, optionally halogenated C
_1-6 alkyl group or C _1-6 which may be halogenated
A phenyl group optionally substituted with an alkoxy group is particularly preferred. Ar ² is preferably a monocyclic aromatic group which may have a substituent, more preferably a phenyl group, a furyl group, a thienyl group or a pyridyl group which may each have a substituent, and a halogen atom , A C _1-3 alkylenedioxy group, a phenyl group and a furyl group which may each be substituted with an optionally halogenated C _1-6 alkyl group or an optionally halogenated C _1-6 alkoxy group. , A thienyl group or a pyridyl group are particularly preferred,
A 3,4-dimethoxyphenyl group is most preferred. As the ring A, an unsubstituted benzene ring is preferable. X is N
R ⁵ (R ⁵ is as defined above) is preferred. As Y, CH is preferable. In the compounds represented by the above formula (I), R ¹ is a hydrogen atom, R ² is a methyl group, Ar
¹ is a phenyl group which may have a substituent, and Ar ² is 3,4
A dimethoxyphenyl group, a benzene ring wherein the A ring is unsubstituted,
Compounds in which X is NR ⁵ (R ⁵ has the same meaning as described above) and Y is CH are preferably used.

The compound represented by the above formula (I)
As the salt of the compound (I), a pharmaceutically acceptable salt is preferable, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid And salts with basic or acidic amino acids. Preferred examples of the salt with an inorganic base include, for example, alkali metal salts such as sodium salt and potassium salt; calcium salt;
Alkaline earth metal salts such as magnesium salts; and aluminum salts, ammonium salts and the like. Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N ′, N′-dibenzylethylenediamine and the like. Is mentioned. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred 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 And salts with acids, p-toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned.

The prodrug of compound (I) is a compound which is converted into compound (I) by a reaction with an enzyme or stomach acid under physiological conditions in a living body, that is, a compound which is enzymatically oxidized, reduced, hydrolyzed, etc. Compound (I) which is converted to (I), which is hydrolyzed by gastric acid or the like to cause compound (I)
A compound that changes to Examples of the prodrug of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, and phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated). , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, tetrahydropyranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylation Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated) ,
Fumarylated, alanylated, dimethylaminomethylcarbonylated, tetrahydropyranylated compounds, etc.);
Compounds in which the carboxyl group of compound (I) is esterified and amidated (eg, the carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxy Methyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-
Methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound and the like). These compounds can be produced from compound (I) by a known method. Also,
Compound (I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.). Further, compound (I) may be an anhydride or a hydrate.

The production method of compound (I) is described below. The following description of the production method applies not only to the compound (I) but also to a salt thereof.
May be abbreviated as Further, each compound used in the production of compound (I), for example, even when abbreviated as compound (I '), includes salts thereof. Compound (I) can be produced using known means, for example, by the method shown by the following production method. The compound (I) thus obtained can be obtained from the reaction mixture by a known means, for example, solvent extraction, concentration, neutralization, filtration, crystallization, recrystallization, column chromatography, high performance liquid chromatography, recrystallization and the like. The target compound can be isolated and purified from the reaction solution with high purity.

Compound (I) may be a hydrate or an anhydrate. Examples of the hydrate include monohydrate, 0.5 hydrate, and dihydrate. Compound (I)
May be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.). When the compound (I) of the present invention or a salt thereof has an asymmetric carbon, the obtained mixture of optically active substances (racemic form) can be obtained by a conventional optical resolution means, for example, an optically active acid (eg, camphorsulfonic acid, etc.) Alternatively, the respective salts may be formed by a method of forming a salt with an optically active base (eg, 1-methylbenzylamine), various kinds of chromatography (eg, liquid chromatography using an optically active column, etc.), and separation means such as fractional recrystallization. It can be divided into optically active substances.

“Room temperature” usually indicates 0 to 30 ° C. Each symbol in the chemical structural formulas described in the production method has the same meaning as described above unless otherwise specified.

The specific production method of compound (I) is shown below. Production Method 1 Compound (I) can usually be produced by the following production method 1. Compound (I ′) can be prepared by a known method, for example, Bulletin
of the Chemical Society of Japan, Vol. 42, 2885-2894
Page (1969) or Can. J. CHEM. 52 (1974) or the method cited in the report.

Embedded image [Wherein each symbol has the same meaning as described above. The reaction described in Production Method 1 is an amidation reaction, and can be performed by a method using a dehydrating condensing agent, a method of temporarily converting carboxy to its reactive derivative and then condensing it.

I) Method using a dehydrating condensing agent Compound (I ′) or a salt thereof, 1 to 5 equivalents of the formula Ar ² —COOH (I ″) wherein Ar ² is as defined above. And 1 to 2 equivalents of a dehydrating condensing agent are reacted in an inert solvent at room temperature for 10 to 24 hours. As needed,
1 to 1.5 equivalents of 1-hydroxybenzotriazole (HO
BT), and / or a catalytic amount of up to 5 equivalents of a base (eg, triethylamine, 4-dimethylaminopyridine, etc.) may be added to carry out the reaction. Examples of the “dehydration condensing agent” include dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) and the like. Among them, WSC is preferable. Examples of the inert solvent include a nitrile solvent (preferably acetonitrile), an amide solvent (preferably dimethylformamide (DMF)), a halogenated hydrocarbon solvent (preferably dichloromethane), and an ether solvent (preferably tetrahydrofuran). THF)) or a mixture of two or more of these.

Ii) Method using a reactive derivative of carboxy The reactive derivative of compound (I ″) and 1 to 5 equivalents (preferably 1 to 3 equivalents) of compound (I ′) are prepared in an inert solvent. −20
° C to 50 ° C (preferably room temperature) for 5 minutes to 40 hours (preferably
(1 hour to 18 hours). If necessary, the reaction may be carried out in the presence of 1 to 10 equivalents, preferably 1 to 3 equivalents of a base. Examples of the `` reactive derivative '' of the compound (I '') include acid halides (eg, acid chloride, acid bromide, etc.), mixed acid anhydrides (eg, C _1-6 alkyl-carboxylic acid, C _6-10 aryl- Carboxylic acid or an acid anhydride with C _1-6 alkyl carbonic acid), active ester (e.g., optionally substituted phenol, 1-hydroxybenzotriazole or N-
And an ester with hydroxysuccinimide. The "phenol which may have a substituent"
The "substituent" include halogen atom, nitro, and five to no 1 optionally halogenated C _1-6 alkyl or halogenated which may be C _{1 -6} alkoxy. Specific examples of "phenol which may have a substituent" include phenol, pentachlorophenol, pentafluorophenol, p-nitrophenol and the like. Acid halides are preferred as reactive derivatives. As the "base", sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine and the like are preferable. As the inert solvent, for example, an ether solvent, a halogenated hydrocarbon solvent, an aromatic solvent, a nitrile solvent, an amide solvent, a ketone solvent, a sulfoxide solvent, water alone or a mixture of two or more thereof They can be used in combination. Among them, pyridine, acetonitrile, THF, dichloromethane, chloroform and the like are preferable. Among them, pyridine,
THF, acetonitrile and the like are more preferred.

Production Method 2 Compound (Ia) in which X is NR ⁵ and Y is CH is prepared by compound (IV)
For example, the method described in the literature (Tetrahedron Letters 38 (1
5) 2673 (1997)) and the like, and can be produced by once converting a hydroxy group into a reactive substituent and then substituting with a compound (IX) in the presence of a base.

Embedded image [Wherein each symbol has the same meaning as described above. Examples of the reactive substituent include a halogen atom (eg, chlorine, bromine, iodine, etc.), an optionally halogenated C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyl) Oxy), C _6-10 arylsulfonyloxy which may have a substituent, and the like. As the “substituent” in the “optionally substituted C _6-10 arylsulfonyloxy”, for example, a halogen atom (eg, chlorine, bromine, iodine, etc.), an optionally halogenated C ₁ such _-6 alkyl or C _1-6 alkoxy and the like. The number of substituents is, for example, 1 to 3. Specific examples of the "optionally substituted C _{6- 10} arylsulfonyloxy" are benzenesulfonyloxy, p- toluenesulfonyloxy, 1-naphthalene sulfonyloxy, such as 2-naphthalene sulfonyloxy and the like. The "reactive substituent" is preferably
Examples include a halogen atom (eg, chlorine, bromine, iodine, etc.), methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, and the like. The halogenation reaction is carried out, for example, by reacting compound (IV) with 1 to 10 equivalents of a halogenating agent in an inert solvent. Examples of the halogenating agent include inorganic acid halides such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride, and phosphorus oxychloride; hydrohalic acids such as hydrochloric acid and hydrobromic acid; and iodotrimethyl. Silyl halides such as silane are mentioned, and iodotrimethylsilane is preferably used. Examples of the "inert solvent" include, for example, ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, sulfoxide solvents, and the like.The reaction temperature is -20 ° C to 200 ° C. , Preferably 0 ° C to 100
° C. The reaction time is 0.1 to 48 hours, preferably 1 to 24 hours. The sulfonylation reaction is carried out, for example, by reacting compound (IV) with 1 to 5 equivalents of the corresponding sulfonyl halide in an inert solvent in the presence of a base. The base is preferably potassium carbonate,
Sodium hydrogencarbonate, triethylamine, N-methylmorpholine, pyridine and the like. The amount of the base used is preferably 1 to 10 equivalents. Examples of the `` inert solvent '' include, for example, ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, and the like.The reaction temperature is -20. ℃ ~ 200 ℃, preferably 0 ℃ ~ 100
° C. The reaction time is 0.1 to 48 hours, preferably 1 to 24 hours. Compound (IX) may be a commercially available aniline, or a new experimental chemistry course, Vol. 14 (III), Organic Functional Group Preparations (ORGANIC FUNCTIONAL GROUP)
PREPARATIONS) 2nd edition, Academic Press, INC. 1
989; Comprehensive Organic Transfor
mations) Anilines synthesized by the method described in VCH Publishers Inc., 1989, etc. are used. The amount used is preferably 1 to 10 equivalents. As the base, those described above are used, and preferably, potassium carbonate, barium carbonate, sodium hydrogencarbonate, triethylamine,
N-methylmorpholine, pyridine and the like. The amount of the base used is preferably 1 to 10 equivalents. This reaction is performed in an inert solvent. Examples of the "inert solvent" include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents and the like.
The temperature is from -20 ° C to 200 ° C, preferably from 0 ° C to 50 ° C.
The reaction time is 0.1 to 48 hours, preferably 1 to 24 hours.
Time.

Compound (IV) can be produced by reducing compound (V) with an appropriate reducing agent in an inert solvent.
As the "inert solvent", for example, alcohol solvents,
Examples include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, and organic acid solvents. These may be used as a mixture of two or more kinds at an appropriate ratio. Among them, methanol, ethanol and the like are preferable. As the reducing agent, for example, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride and the like are used. The amount of reducing agent used is usually
It is 1 to 20 equivalents, preferably 1 to 5 equivalents. The reaction temperature is generally -20 ° C to 150 ° C, preferably 0 to 50 ° C.
° C. The reaction time is generally 5 minutes to 24 hours, preferably 1 to 12 hours. Compound (V) can be produced by acylating compound (VI) in the same manner as in Production method 1. Compound (VI) can be prepared by a known method (for example, Bio Organic and Medicinal Chemistry Letters 9).
1009 (1999)).

Production method 3 Compound (Ia) is obtained by subjecting compound (Ib) obtained in production methods 1 and 2 to
In an inert solvent in the presence of a suitable base, compound R ⁵ Z (VI
I) [wherein Z is the aforementioned reactive substituent].

Embedded image [Wherein each symbol has the same meaning as described above. As the reactive substituent, those described in Production Method 1 can be used, and preferred are a halogen atom, an alkylsulfonyl group, an arylsulfonyl group and the like. As the “base”, those similar to the above can be used, and preferred are potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and the like. The amount of the base used is preferably 1 to 10 equivalents. Compound (VII) may be, for example, a commercially available alkyl chloride, alkyl bromide, alkyl iodide, or new experimental chemistry course 14
Volume (I), Organic Functional Group Preparations (ORGANIC FUNCTI)
ONAL GROUP PREPARATIONS) 2nd edition, Academic Press (ACADEMIC PR
ESS, INC. 1989, Comprehensive Organic Transformation (Comprehe
nsive Organic Transformations) VCHPublishers In
c., those synthesized by the method described in 1989 and the like are used. The amount used is preferably 1 to 20 equivalents. Examples of the “inert solvent” include alcohol solvents, ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, and the like. . These may be used as a mixture of two or more kinds at an appropriate ratio. Among them, acetonitrile, DMF, DMSO, acetone and the like are preferable. The reaction temperature is usually about -20 ° C to 100 ° C.
° C, preferably room temperature to 80 ° C. The reaction time is
For example, about 0.5 to 48 hours.

Production Method 4 Compound (Ic) wherein X is O and Y is CH can be produced by subjecting compound (IV) and compound (VIII) obtained in Production Method 2 to a condensation reaction. Examples of the condensation reaction include the Mitsunobu reaction (the method described in Synthesis 1 (1980)).

Embedded image [Wherein each symbol has the same meaning as described above. The compound Ar ¹ OH is a commercially available phenol or a new experimental chemistry course, Vol. 14 (I), organic functional
Group Preparations (ORGANICFUN
CIONAL GROUP PREPARATION
S) 2nd edition, Academic Press (ACADEMIC)
PRESS, INC. 1989, Comprehensive Organic Transformation (Co
mprehensive Organic Transformations) VCH Publisher
Phenols produced by the method described in s Inc., 1989, etc. are used. In the Mitsunobu reaction, compound (IV) and 0.5
To 5 equivalents (preferably 1 to 1.5 equivalents) of the compound (VII
Is reacted with 0.5 to 5 equivalents (preferably 1 to 1.5 equivalents) of azodicarboxylic acid diester and triallylphosphine or trialkylphosphine in an inert solvent. As the azodicarboxylic acid diester, dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate and the like are preferably used. As the phosphines, triphenylphosphine, tributylphosphine and the like are preferably used.
Examples of the inert solvent include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, and the like. These may be used as a mixture of two or more kinds at an appropriate ratio. Among them, THF, acetonitrile, dichloromethane, chloroform and the like are preferable. The reaction temperature is usually −20 ° C. to 50 ° C., preferably room temperature. The reaction time is generally 5 minutes to 40 hours, preferably 1 to
18 hours.

Production Method 5 The compound (Id) in which X is CR ³ R ⁴ and Y is N is a compound (X)
And compound (XI) wherein Z is a reactive substituent in the same manner as in Production Method 3.

Embedded image [Wherein each symbol has the same meaning as described above. Compound (XI) is, for example, commercially available alkyl chloride, alkyl bromide, alkyl iodide, or New Experimental Chemistry, Vol. 14 (1), Organic Functional Group
Preparations (ORGANIC FUNCIO)
NAL GROUP PREPARATIONS) 2nd
Edition, Academic Press (ACADEMIC PRE)
SS, INC. 1989, Comprehensive
Organic Transformation (Comprehens
ive Organic Transformations) VCH Publishers Inc.,
Those synthesized by the method described in 1989 and the like are used. Compound (X) can be produced by acylating compound (XII) in the same manner as in production method 1. Compound (X) can be produced by a known method (for example, the method described in Journal of Pharmaceutical Bretane 32 (6) 2421 (1984)).

In the present invention, the compound represented by the above formula (II), a salt thereof, or a prodrug thereof is used. Examples of the “lower alkyl group” of the lower alkyl group which may have a substituent represented by R ¹ and R ² include:
For example, C _1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and the like can be mentioned. Preferred are methyl, ethyl and propyl.

In the compound represented by the formula (II) or a salt thereof or a prodrug thereof, the compound represented by the formula (I)
In I), the description of the "substituent" of the "optionally substituted lower alkyl group" represented by R ¹ and R ² is based on the above-mentioned secretory promoting action of soluble beta-amyloid precursor protein and apoptosis inhibiting action. In the description of the compound having the formula (I) or a salt thereof or a prodrug thereof, the same as described as the “substituent” of the “optionally substituted lower alkyl group” represented by R ³ , R ⁴ and R ⁵ It is.

In the above formula (II), those in which R ¹ and R ² are bonded to form a 4- to 7-membered ring together with adjacent carbon atoms include

Embedded image [Wherein each symbol has the same meaning as described above. And the like. R ¹ is preferably a hydrogen atom, and R ² is preferably a hydrogen atom or a lower alkyl group which may have a substituent, more preferably C _1-6.
An alkyl group, more preferably a methyl group and the like are used.

Ar ¹ and Ar ² each represent an aromatic group which may have a substituent. In the compound represented by the above formula (II), a salt thereof or a prodrug thereof, in the above formula (II), the “aromatic group” of the “aromatic group which may have a substituent” represented by Ar ¹ and Ar ² Group ''
In the description of the compound having a secretory beta-amyloid precursor protein secretion promoting action and an apoptosis inhibitory action or a salt thereof or a prodrug thereof described above, even if it has a substituent represented by Ar ¹ and Ar ² This is the same as described as “aromatic group” of “good aromatic group”.

Among the above, examples of the aromatic group represented by Ar ¹ and Ar ² include (1) phenyl, 2
Thienyl such as-or 3-thenyl, 2- or 3-
Monocyclic aromatic groups such as furyl such as furyl, pyridyl such as 2-, 3- or 4-pyridyl; (2) 2-, 3-
Or biphenylyl such as 4-biphenylyl, 3- (1
Naphthyl-substituted oxadiazolyl, such as -naphthyl) -1,2,4-oxadiazol-5-yl or 3- (2-naphthyl) -1,2,4-oxadiazol-5-yl; Benzofuranyl-substituted oxadiazolyl such as benzofuranyl) -1,2,4-oxadiazol-5-yl; phenyl-substituted oxadiazolyl such as 3-phenyl-1,2,4-oxadiazol-5-yl;
Benzoxazolyl-substituted oxadiazolyl such as 3- (2-benzoxazolyl) -1,2,4-oxadiazol-2-yl, 3- (3-indolyl) -1,2,4
Indolyl-substituted oxadiazolyl such as -oxadiazol-2-yl or 3- (2-indolyl) -1,2,4-oxadiazol-2-yl, phenyl-substituted thiazolyl such as 4-phenylthiazol-2-yl, 4-
Benzofuranyl-substituted thiazolyl such as (2-benzofuranyl) thiazol-2-yl, 4-phenyl-1,3-
Phenyl-substituted oxazolyl such as oxazol-5-yl, thienyl-substituted phenyl such as 4- (2-thienyl) phenyl, pyridyl-substituted phenyl such as 4- (3-pyridyl) phenyl, naphthyl such as 4- (2-naphthyl) phenyl Ring-assembled aromatic groups such as substituted phenyl, terphenylyl such as 4,4′-terphenylyl, (3) 2-,
Preferred are condensed aromatic groups such as quinolyl such as 3- or 4-quinolyl and indolyl such as 1-, 2- or 3-indolyl. Examples of the aromatic group represented by Ar ¹ include 2-cyclic aromatic groups such as phenyl.
Condensed aromatic groups such as quinolyl such as quinolyl, 3-quinolyl and 4-quinolyl are more preferable, and phenyl is particularly preferably used. Examples of the aromatic group represented by Ar ² include phenyl, thienyl such as 2- or 3-thienyl, furyl such as 2- or 3-furyl, 2
Monocyclic aromatic groups such as pyridyl such as-, 3- or 4-pyridyl are more preferred.

In the compound represented by the formula (II) or a salt thereof or a prodrug thereof, the compound represented by the formula (I)
In I), “optionally substituted aromatic group”, “optionally substituted monocyclic aromatic group”, and “optionally substituted substituent” represented by Ar ¹ and Ar ² A phenyl group which may be substituted, a phenyl group, a furyl group, a thienyl group or a pyridyl group which may have a substituent represented by Ar ² and a `` substituted The description of the "substituent" of the "good benzene ring" is indicated by Ar <sup>1</sup> and Ar <sup>2</sup> in the above description of the compound having a soluble beta-amyloid precursor protein secretion promoting action and an apoptosis inhibitory action or a salt thereof or a prodrug thereof. "Optionally substituted aromatic group", "optionally substituted monocyclic aromatic group", "optionally substituted phenyl group", Ar <sup>1</sup> Represented by an `` optionally substituted Le group or quinolyl group which may have a substituent "," optionally substituted phenyl group represented by Ar ^2, furyl group, represented by a thienyl group or a pyridyl group "and the ring A ' It is the same as described as the “substituent” of the “benzene ring which may have a substituent”.

In the compound represented by the above formula (II), R ¹
Is preferably a hydrogen atom. R ² is preferably a hydrogen atom or a lower alkyl group which may have a substituent, more preferably a hydrogen atom or a C _1-6 alkyl group, and particularly preferably a methyl group. Ar ¹ is preferably a phenyl group which may have a substituent or a quinolyl group which may have a substituent, more preferably a phenyl group which may have a substituent, and a halogen atom, C 1 _1-3
Alkylenedioxy group, optionally halogenated C
_1-6 alkyl group or C _1-6 which may be halogenated
A phenyl group optionally substituted with an alkoxy group is particularly preferred. Ar ² is preferably a monocyclic aromatic group which may have a substituent, more preferably a phenyl group, a furyl group, a thienyl group or a pyridyl group which may each have a substituent, and a halogen atom , A C _1-3 alkylenedioxy group, a phenyl group and a furyl group which may each be substituted with an optionally halogenated C _1-6 alkyl group or an optionally halogenated C _1-6 alkoxy group. , A thienyl group or a pyridyl group are particularly preferred,
A 3,4-dimethoxyphenyl group is most preferred. As the ring A, an unsubstituted benzene ring is preferable. Further, among the compounds represented by the above formula (II), particularly, R ¹ is a hydrogen atom,
Compounds in which R ² is a methyl group, Ar ¹ is a phenyl group which may have a substituent, Ar ² is a 3,4-dimethoxyphenyl group, and ring A is an unsubstituted benzene ring are preferably used.

As the salt of the compound represented by the above formula (II) (hereinafter sometimes abbreviated as compound (II)), a pharmaceutically acceptable salt is preferable. For example, a salt with an inorganic base, an organic base And salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. 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 and magnesium salt; and aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N ′, N′-dibenzylethylenediamine and the like. Is mentioned. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred 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 And salts with acids, p-toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned.

The prodrug of the compound (II) can be produced by a reaction with an enzyme or gastric acid under physiological conditions in vivo.
Compounds that convert to (II), i.e., enzymatic oxidation, reduction,
A compound that undergoes hydrolysis or the like to change to the compound (II), or a compound that undergoes hydrolysis or the like due to stomach acid or the like to change to the compound (II). As a prodrug of compound (II),
Compounds in which the amino group of compound (II) is acylated, alkylated, and phosphorylated (eg, the amino group of compound (II) is eicosanoylated, alanylated, pentylaminocarbonylated,
(5-methyl-2-oxo-1,3-dioxolen-4
-Yl) methoxycarbonylation, tetrahydrofuranylation, tetrahydropyranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); the hydroxyl group of compound (II) is acylated or alkylated. , Phosphorylated or borated compounds (eg, compound (II)
Acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylation, tetrahydropyranylation, etc. of the hydroxyl group of the compound of formula (II); esterification of the carboxyl group of compound (II) , Amidated compound (eg, carboxyl group of compound (II) is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified) ,
Phthalidyl esterification, (5-methyl-2-oxo-
1,3-dioxolen-4-yl) methyl esterification,
Cyclohexyloxycarbonylethyl esterified compound, methylamidated compound, etc.); These compounds can be produced from compound (II) by a known method. Compound (II) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.). Further, compound (II) may be an anhydride or a hydrate.

The production method of compound (II) is described below. The following description of the production method includes not only the compound (II) but also
The same applies to the salts thereof, but in the following description, they may be simply abbreviated as compound (II). Compound (II)
Each of the compounds used in the production of, for example, even when abbreviated as compound (II '), includes salts thereof. Compound (II) can be produced using known means, for example, by the method shown in the following production method. Compound (II) thus obtained
The target product can be purified from the reaction solution with high purity by a known means from the reaction mixture, for example, solvent extraction, concentration, neutralization, filtration, crystallization, recrystallization, column chromatography, high performance liquid chromatography, recrystallization, etc. Can be separated and purified.

Compound (II) may be a hydrate or an anhydrate. As the hydrate, monohydrate, 0.5
Hydrates and dihydrates. Compound (I)
I) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.). When the compound (II) or a salt thereof of the present invention has an asymmetric carbon, the obtained mixture of the optically active substances (racemic form) can be obtained by a conventional optical resolution means, for example, an optically active acid (eg, camphorsulfonic acid, etc.) Or an optically active base (eg, 1-methylbenzylamine, etc.)
Each of the optically active compounds can be separated by a separation method such as a method of forming a salt with the compound, various types of chromatography (eg, liquid chromatography using an optically active column, etc.), and fractional recrystallization.

“Room temperature” usually indicates 0 to 30 ° C. Each symbol in the chemical structural formulas described in the production method has the same meaning as described above unless otherwise specified.

The specific production method of compound (II) is shown below.

Production Method 6 Compound (II) can be produced by subjecting compound (IV) and compound (VIII) obtained in the above production method 2 to a condensation reaction.
Examples of the condensation reaction include Mitsunobu reaction (Synthesis 1 (1
980)).

[0080]

Embedded image [Wherein each symbol has the same meaning as described above. The compound Ar ¹ OH is a commercially available phenol or a new experimental chemistry course, Vol. 14 (I), organic functional
Group Preparations (ORGANICFUN
CIONAL GROUP PREPARATION
S) 2nd edition, Academic Press (ACADEMIC)
PRESS, INC. 1989, Comprehensive Organic Transformation (Co
mprehensive Organic Transformations) VCH Publisher
Phenols produced by the method described in s Inc., 1989, etc. are used.

In the Mitsunobu reaction, compound (IV) and 0.5 to 5
Equivalent (preferably 1 to 1.5 equivalent) of compound (VIII),
The reaction is carried out in an inert solvent in the presence of 0.5 to 5 equivalents (preferably 1 to 1.5 equivalents) of azodicarboxylic acid diester and triallylphosphine or trialkylphosphine. As the azodicarboxylic acid diester, dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate and the like are preferably used. As the phosphines, triphenylphosphine, tributylphosphine and the like are preferably used. Examples of the inert solvent include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, and the like. These may be used as a mixture of two or more kinds at an appropriate ratio. Among them, THF, acetonitrile, dichloromethane, chloroform and the like are preferable. The reaction temperature is usually −20 ° C. to 50 ° C., preferably room temperature. The reaction time is generally 5 minutes to 40 hours, preferably 1 to 18 hours.

In the present invention, the compound represented by the above formula (III), a salt thereof, or a prodrug thereof is used. Examples of the “lower alkyl group” of the optionally substituted lower alkyl group represented by R ¹ , R ² , R ³ , R ⁴ and R ⁵ include C _1-6 alkyl (eg, methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
Hexyl). Preferably methyl,
Ethyl and propyl.

In the compound represented by the formula (III) or a salt thereof or a prodrug thereof, the compound represented by the formula (I)
In II), the description of the “substituent” of the “optionally substituted lower alkyl group” represented by R ¹ , R ² , R ³ , R ⁴ and R ⁵ is the same as that of the soluble beta-amyloid described above. In the description of the compound having a precursor protein secretion promoting action and an apoptosis inhibitory action or a salt thereof or a prodrug thereof, "lower alkyl group optionally having substituent (s)" represented by R ³ , R ⁴ and R ⁵ The same as described for “substituent”.

In the above formula (III), those in which R ¹ and R ² are bonded to form a 4- to 7-membered ring together with adjacent carbon atoms include

Embedded image [Wherein each symbol has the same meaning as described above. And the like. R ¹ is preferably a hydrogen atom, and R ² is preferably a hydrogen atom or a lower alkyl group which may have a substituent, more preferably a C _1-6 alkyl group, further preferably a methyl group. X is preferably NR ⁵ (R ⁵ is as defined above), and Y is preferably CH.

Ar ¹ represents an aromatic group which may have a substituent. In the compound represented by the formula (III) or a salt thereof or a prodrug thereof, the compound represented by the formula (II)
In I), the description of the “aromatic group” of the “aromatic group optionally having substituent (s)” represented by Ar ¹ means that the compound has the above-mentioned secretory promoting action of soluble beta-amyloid precursor protein and apoptosis inhibiting action. In the description of the compound or a salt thereof or a prodrug thereof, it is the same as described as “aromatic group” of “aromatic group which may have a substituent” represented by Ar ¹ and Ar ² .

Among the above, examples of the aromatic group represented by Ar ¹ include (1) phenyl, 2- or 3
Monocyclic aromatic groups such as thienyl such as -thenyl, furyl such as 2- or 3-furyl, pyridyl such as 2-, 3- or 4-pyridyl, (2) 2-, 3- or 4-
Biphenylyl such as biphenylyl, 3- (1-naphthyl) -1,2,4-oxadiazol-5-yl or 3- (2-naphthyl) -1,2,4-oxadiazol-5-yl and the like Naphthyl-substituted oxadiazolyl, 3-
Benzofuranyl-substituted oxadiazolyl such as (2-benzofuranyl) -1,2,4-oxadiazol-5-yl, 3-phenyl-1,2,4-oxadiazole-5
Phenyl-substituted oxadiazolyl such as -yl, 3- (2
Benzoxazolyl-substituted oxadiazolyl, such as -benzoxazolyl) -1,2,4-oxadiazol-2-yl, 3- (3-indolyl) -1,2,4-oxadiazol-2-yl Or 3- (2-indolyl)-
Indolyl-substituted oxadiazolyl such as 1,2,4-oxadiazol-2-yl, 4-phenylthiazole-
Phenyl-substituted thiazolyl such as 2-yl, benzofuranyl-substituted thiazolyl such as 4- (2-benzofuranyl) thiazol-2-yl, phenyl-substituted oxazolyl such as 4-phenyl-1,3-oxazol-5-yl, 4-
Thienyl-substituted phenyl such as (2-thienyl) phenyl, pyridyl-substituted phenyl such as 4- (3-pyridyl) phenyl, naphthyl-substituted phenyl such as 4- (2-naphthyl) phenyl, terphenylyl such as 4,4′-terphenylyl and the like. (3) quinolyl such as 2-, 3- or 4-quinolyl, 1-, 2- or 3
-Preferred are condensed aromatic groups such as indolyl such as indolyl. As the aromatic group represented by Ar ¹ , for example, a condensed aromatic group such as quinolyl such as 2-quinolyl, 3-quinolyl or 4-quinolyl such as a monocyclic aromatic group such as phenyl is more preferable, and phenyl is particularly preferable. Is preferably used.

In the compound represented by the formula (III) or a salt thereof or a prodrug thereof, the compound represented by the formula (I)
During II), "optionally substituted aromatic group" represented by Ar ^1, "may have a substituent monocyclic aromatic group", have a "substituent The description of the “substituent” of the “optionally substituted phenyl group” and the “optionally substituted benzene ring” represented by ring A has the above-mentioned secretory promoting action of soluble beta-amyloid precursor protein and apoptosis inhibiting action. compound or in the description of a salt or a prodrug thereof, "optionally substituted aromatic group" represented by Ar ¹ and Ar ^2, "may have a substituent monocyclic aromatic group "," optionally substituted phenyl group "," optionally substituted phenyl group, or quinolyl group which may have a substituent represented by Ar ¹ ', Ar ² A phenyl group which may have a substituent, It is the same as described as the "substituent" of the "furyl group, thienyl group or pyridyl group" and "optionally substituted benzene ring" represented by ring A.

In the compound represented by the above formula (III), R
¹ is preferably a hydrogen atom. R ² is preferably a hydrogen atom or a lower alkyl group which may have a substituent, more preferably a hydrogen atom or a C _1-6 alkyl group, and particularly preferably a methyl group. Ar ¹ is preferably a phenyl group which may have a substituent or a quinolyl group which may have a substituent, more preferably a phenyl group which may have a substituent, and a halogen atom, C 1 _1-3
Alkylenedioxy group, optionally halogenated C
_1-6 alkyl group or C _1-6 which may be halogenated
A phenyl group optionally substituted with an alkoxy group is particularly preferred. As the ring A, an unsubstituted benzene ring is preferable. The ring B is preferably a benzene ring optionally substituted with a C _1-6 alkoxy group, a hydroxy group or a C _1-3 alkylenedioxy group. X is preferably NR ⁵ (R ⁵ is as defined above). CH for Y
Is preferred. Also, among the compounds represented by the above formula (III), in particular, R ¹ is a hydrogen atom, R ² is a methyl group, Ar ¹ is a phenyl group which may have a substituent, and ring A is unsubstituted benzene. A ring, X is NR ⁵ (R ⁵ is as defined above),
Compounds in which Y is CH (except when X is NH, Y is CH and Ar ¹ is an unsubstituted phenyl group) are preferably used.

As the salt of the compound represented by the above formula (III) (hereinafter sometimes abbreviated as compound (III)), a pharmaceutically acceptable salt is preferable. For example, a salt with an inorganic base, an organic base And salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. 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 and magnesium salt; and aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N ′, N′-dibenzylethylenediamine and the like. Is mentioned. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred 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 And salts with acids, p-toluenesulfonic acid and the like. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferred examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Is mentioned.

The prodrug of the compound (III) is a compound which is converted into the compound (III) by a reaction with an enzyme or a stomach acid under physiological conditions in a living body, that is, a compound which is enzymatically oxidized, reduced, hydrolyzed, etc. Compound which changes into (III), compound (III) which is hydrolyzed by gastric acid, etc.
A compound that changes to As a prodrug of compound (III), a compound in which the amino group of compound (III) is acylated, alkylated, and phosphorylated (eg, the amino group of compound (III) is eicosanoylated, alanylated, pentylaminocarbonylated , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, tetrahydropyranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylation Compounds in which the hydroxyl group of compound (III) is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of compound (III) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated) ,
Fumarylated, alanylated, dimethylaminomethylcarbonylated, tetrahydropyranylated compounds, etc.);
Compounds in which the carboxyl group of compound (III) is esterified and amidated (eg, the carboxyl group of compound (III) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxy Methyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-
Methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound and the like). These compounds can be produced from compound (III) by a known method. Also,
Compound (III) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.). Further, the compound (II
I) may be an anhydride or a hydrate.

The production method of compound (III) will be described below. The following description of the production method applies not only to the compound (III), but also to a salt thereof, but in the following description, it may be simply referred to as the compound (III). Compound (I)
For each compound used in the production of II),
For example, even when the compound is abbreviated as compound (III ′), it also includes a salt thereof. Compound (III) can be produced using known means, for example, by the method shown in the following production method. The compound (II) thus obtained
I) converts the target product from the reaction mixture with high purity by a known means, for example, solvent extraction, concentration, neutralization, filtration, crystallization, recrystallization, column chromatography, high performance liquid chromatography, recrystallization, etc. Can be isolated and purified.

Compound (III) may be a hydrate or an anhydrate. As the hydrate, monohydrate, 0.1.
Pentahydrate, dihydrate and the like can be mentioned. The compound (III) may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.). Compound (II) of the present invention
When I) or a salt thereof has an asymmetric carbon, the obtained mixture of the optically active isomers (racemic form) is obtained by a conventional optical resolution means,
For example, an optically active acid (eg, camphorsulfonic acid, etc.)
Alternatively, the respective salts may be formed by a method of forming a salt with an optically active base (eg, 1-methylbenzylamine), various kinds of chromatography (eg, liquid chromatography using an optically active column, etc.), and separation means such as fractional recrystallization. It can be divided into optically active substances.

“Room temperature” usually indicates 0 to 30 ° C. Each symbol in the chemical structural formulas described in the production method has the same meaning as described above unless otherwise specified.

The specific production method of compound (III) is shown below. Production Method 7 Compound (III) can usually be produced by the following Production Method 7. Compound (III ′) can be prepared by known methods, for example, Bulle
tin of the Chemical Society of Japan, 42 vol. 2885-289
It can be produced by the method described on page 4 (1969) or Can. J. CHEM. 52 (1974) or the method cited in the report.

Embedded image [Wherein each symbol has the same meaning as described above. The reaction described in Production Method 7 is an amidation reaction, and can be carried out by a method using a dehydrating condensing agent, a method of temporarily converting carboxy to its reactive derivative and then condensing it.

I) Method using a dehydrating condensing agent Compound (III ′) or a salt thereof, in an amount of 1 to 5 equivalents of the compound of the formula (II)
I '')

Embedded image [Wherein, ring B represents the same meaning as described above. And 1 to 2 equivalents of a dehydration condensing agent in an inert solvent,
The reaction is carried out at room temperature for 10 to 24 hours. 1 to 1.5 equivalents of 1-hydroxybenzotriazole (HOB
The reaction may be carried out by adding T) and / or a catalytic amount to 5 equivalents of a base (eg, triethylamine, 4-dimethylaminopyridine, etc.). Examples of the "dehydration condensing agent" include dicyclohexylcarbodiimide (DCC), 1-ethyl-
3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) and the like. Among them, WSC is preferable. Examples of the inert solvent include a nitrile solvent (preferably acetonitrile), an amide solvent (preferably dimethylformamide (DMF)), a halogenated hydrocarbon solvent (preferably dichloromethane), and an ether solvent (preferably tetrahydrofuran). THF)) or a mixture of two or more of these.

Ii) Method using a reactive derivative of carboxy The reactive derivative of compound (III '') and 1 to 5 equivalents (preferably 1 to 3 equivalents) of compound (III ') are prepared in an inert solvent.
The reaction is carried out at -20 ° C to 50 ° C (preferably room temperature) for 5 minutes to 40 hours (preferably 1 hour to 18 hours). 1 equivalent to 1 as needed
The reaction may be carried out in the presence of 0 equivalents, preferably 1 to 3 equivalents of a base. `` Reactive derivative '' of compound (III '')
The acid halide (e.g., acid chloride, acid bromide, etc.), mixed acid anhydride (e.g., C _1-6 alkyl - carboxylic acid, C
_6-10 aryl-carboxylic acid or acid anhydride with C _1-6 alkyl carbonic acid), active ester (e.g., optionally substituted phenol, 1-hydroxybenzotriazole or N-hydroxysuccinimide (Such as esters)
And the like. As the "substituent" of the "optionally substituted phenol", a halogen atom, nitro, optionally halogenated C _1-6 alkyl or optionally halogenated C _1-6 Alkoxy includes 1 to 5 alkoxy groups. "Phenol optionally having substituent (s)"
Specific examples include phenol, pentachlorophenol, pentafluorophenol, p-nitrophenol and the like. Acid halides are preferred as reactive derivatives. As the "base", sodium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine and the like are preferable. Examples of the inert solvent include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents,
A ketone-based solvent, a sulfoxide-based solvent, water and the like can be used alone or as a mixture of two or more thereof. Among them, pyridine, acetonitrile, THF, dichloromethane, chloroform and the like are preferable. Among them, pyridine, THF, acetonitrile and the like are more preferable.

Production method 8 Compound (II1a) wherein X is NR ⁵ and Y is CH is prepared by reacting compound (I
V ') by the method described in the literature (tetrahedron letters 3
8 (15) 2673 (1997)), and can be produced by once converting a hydroxy group into a reactive substituent and then substituting the compound with a compound (IX) in the presence of a base.

Embedded image [Wherein each symbol has the same meaning as described above. Examples of the reactive substituent include a halogen atom (eg, chlorine, bromine, iodine, etc.), an optionally halogenated C _1-6 alkylsulfonyloxy (eg, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyl) Oxy), C _6-10 arylsulfonyloxy which may have a substituent, and the like. As the “substituent” in the “optionally substituted C _6-10 arylsulfonyloxy”, for example, a halogen atom (eg, chlorine, bromine, iodine, etc.), an optionally halogenated C ₁ such _-6 alkyl or C _1-6 alkoxy and the like. The number of substituents is, for example, 1 to 3. Specific examples of the "optionally substituted C _{6- 10} arylsulfonyloxy" are benzenesulfonyloxy, p- toluenesulfonyloxy, 1-naphthalene sulfonyloxy, such as 2-naphthalene sulfonyloxy and the like. The "reactive substituent" is preferably
Examples include a halogen atom (eg, chlorine, bromine, iodine, etc.), methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, and the like. The halogenation reaction is performed, for example, by reacting compound (IV ′) with 1 to 10 equivalents of a halogenating agent in an inert solvent. Examples of the halogenating agent include inorganic acid halides such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride, and phosphorus oxychloride; hydrohalic acids such as hydrochloric acid and hydrobromic acid; and iodotrimethyl. Silyl halides such as silane are mentioned, and iodotrimethylsilane is preferably used. Examples of the "inert solvent" include, for example, ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, sulfoxide solvents, and the like.The reaction temperature is -20 ° C to 200 ° C. , Preferably 0 ° C to 100
° C. The reaction time is 0.1 to 48 hours, preferably 1 to 24 hours. The sulfonylation reaction is carried out, for example, by reacting compound (IV ′) with 1 to 5 equivalents of the corresponding sulfonyl halide in an inert solvent in the presence of a base. The base is preferably potassium carbonate, sodium hydrogen carbonate, triethylamine, N-methylmorpholine, pyridine and the like. The amount of base used is
Preferably it is 1 to 10 equivalents. As the "inert solvent", for example, ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents,
Ketone solvents, sulfoxide solvents and the like are mentioned.The reaction temperature is -20 ° C to 200 ° C, preferably 0 ° C to 100 ° C.
° C. The reaction time is 0.1 to 48 hours, preferably 1 to 24 hours. Compound (IX) may be a commercially available aniline, or a new experimental chemistry course, Vol. 14 (III), Organic Functional Group Preparations (ORGANIC FUNCTIONAL GROUP)
PREPARATIONS) 2nd edition, Academic Press, INC. 1
989; Comprehensive Organic Transfor
mations) Anilines synthesized by the method described in VCH Publishers Inc., 1989, etc. are used. The amount used is preferably 1 to 10 equivalents. As the base, those described above are used, and preferably, potassium carbonate, barium carbonate, sodium hydrogencarbonate, triethylamine,
N-methylmorpholine, pyridine and the like. The amount of the base used is preferably 1 to 10 equivalents. This reaction is performed in an inert solvent. Examples of the `` inert solvent '' include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, and the like.The reaction temperature is -20. ℃ ~ 200 ℃, preferably 0 ℃ ~ 50
° C. The reaction time is 0.1 to 48 hours, preferably 1 to 24 hours.

Compound (IV ') can be produced by reducing compound (V') with an appropriate reducing agent in an inert solvent.
As the "inert solvent", for example, alcohol solvents,
Examples include ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, and organic acid solvents. These may be used as a mixture of two or more kinds at an appropriate ratio. Among them, methanol, ethanol and the like are preferable. As the reducing agent, for example, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride and the like are used. The amount of reducing agent used is usually
It is 1 to 20 equivalents, preferably 1 to 5 equivalents. The reaction temperature is generally -20 ° C to 150 ° C, preferably 0 to 50 ° C.
° C. The reaction time is generally 5 minutes to 24 hours, preferably 1 to 12 hours. Compound (V ') is compound (VI)
Can be produced by acylation in the same manner as in Production Method 1. Compound (VI) can be prepared by a known method (for example, Bio Organic and Medicinal Chemistry Letters
9 1009 (1999)).

Production method 9 Compound (IIIa) was obtained from compound (I) obtained in production methods 7 and 8.
IIb) in an inert solvent in the presence of a suitable base, compound R ⁵
It can be produced by reacting with Z (VII) [wherein Z is the reactive substituent].

Embedded image [Wherein each symbol has the same meaning as described above. As the reactive substituent, those described in Production Method 7 can be used, and preferred are a halogen atom, an alkylsulfonyl group, an arylsulfonyl group and the like. As the “base”, those similar to the above can be used, and preferred are potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and the like. The amount of the base used is preferably 1 to 10 equivalents. Compound (VII) may be, for example, a commercially available alkyl chloride, alkyl bromide, alkyl iodide, or new experimental chemistry course 14
Volume (I), Organic Functional Group Preparations (ORGANIC FUNCTI)
ONAL GROUP PREPARATIONS) 2nd edition, Academic Press (ACADEMIC PR
ESS, INC. 1989, Comprehensive Organic Transformation (Comprehe
nsive Organic Transformations) VCHPublishers In
c., those synthesized by the method described in 1989 and the like are used. The amount used is preferably 1 to 20 equivalents. Examples of the “inert solvent” include alcohol solvents, ether solvents, halogenated hydrocarbon solvents, aromatic solvents, nitrile solvents, amide solvents, ketone solvents, sulfoxide solvents, and the like. . These may be used as a mixture of two or more kinds at an appropriate ratio. Among them, acetonitrile, DMF, DMSO, acetone and the like are preferable. The reaction temperature is usually about -20 ° C to 100 ° C.
° C, preferably room temperature to 80 ° C. The reaction time is
For example, about 0.5 to 48 hours.

Production Method 10 The compound (IIId) in which X is CR ³ R ⁴ and Y is N is a compound (IIId)
Compound (XI) and compound (XI) [wherein, Z is a reactive substituent] can be produced in the same manner as in Production Method 9.

Embedded image [Wherein each symbol has the same meaning as described above. Compound (XI) is, for example, commercially available alkyl chloride, alkyl bromide, alkyl iodide, or New Experimental Chemistry, Vol. 14 (1), Organic Functional Group
Preparations (ORGANIC FUNCIO)
NAL GROUP PREPARATIONS) 2nd
Edition, Academic Press (ACADEMIC PRE)
SS, INC. 1989, Comprehensive
Organic Transformation (Comprehens
ive Organic Transformations) VCH Publishers Inc.,
Those synthesized by the method described in 1989 and the like are used. Compound (X ′) can be produced by acylating compound (XII) in the same manner as in Production method 1. Compound (XII)
Can be produced by a known method (for example, a method described in Journal of Farmer's Chemical Bretane 32 (6) 2421 (1984)).

The compounds of the present invention described above (hereinafter, also referred to as the compounds of the present invention) or salts or prodrugs thereof have an excellent secretory beta-amyloid precursor protein secretion promoting action, have low toxicity, and It can be used as a safe soluble beta-amyloid precursor protein secretion promoter for mammals (eg, mouse, rat, guinea pig, rabbit, dog, cat, cow, pig, sheep, monkey, chimpanzee, etc.), and an apoptosis inhibitor Accordingly, the compound of the present invention or a salt thereof or a prodrug thereof can be used as a neurodegenerative disease such as Alzheimer's disease, Parkinson's disease, prion disease or neuropathy (preferably diabetic neuropathy or the like). , Cerebrovascular dementia,
It can be safely used for humans and mammals as a prophylactic / therapeutic agent for neuronal damage during cerebrovascular disorders.

When the compound of the present invention or a salt thereof or a prodrug thereof is used as a medicament, it is mixed with itself or an appropriate pharmacologically acceptable carrier, excipient, diluent or the like, and the compound is orally administered ( E.g. powders, granules, tablets,
Capsules (including soft capsules and microcapsules), syrups, etc., parenteral administration agents (eg, injections,
It is safely orally or parenterally administered as a pharmaceutical composition of an external preparation (eg, a preparation for nasal administration, a preparation for transdermal administration, etc.), a suppository (eg, rectal suppository, vaginal suppository, etc.), a pellet, etc. can do.

These preparations can be produced, for example, by applying known methods generally used in the production of preparations. The compounding ratio of the compound of the present invention in the preparation varies depending on its form, but is preferably, for example, about 10 to 95% by weight for the above-mentioned oral preparation, and about 0.001 to 95% for the above-mentioned parenteral preparation. % Is preferred.

For example, injections include compounds of the present invention solubilizing agents (eg, β-cyclodextrins), dispersing agents (eg,
Tween 80 (manufactured by Atlas Powder, USA), HCO60 (manufactured by Nikko Chemicals), carboxymethylcellulose, sodium alginate, etc., preservatives (eg, methylparaben, propylparaben, benzyl alcohol, chlorobutanol, etc.), isotonic Aqueous injections can be prepared according to a conventional method together with preparations (eg, sodium chloride, glycerin, sorbitol, glucose, etc.), or vegetable oils (eg, olive oil, sesame oil, peanut oil, cottonseed oil, corn oil, etc.), propylene glycol, etc. And then appropriately dissolved, suspended or emulsified to form an oily injection. For oral administration, the compound of the present invention may contain, for example, excipients (eg, lactose, sucrose, starch, etc.), disintegrants (eg, starch, calcium carbonate, etc.),
A binder (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) is appropriately added and compression-molded. If necessary, it can also be produced by applying a coating by a known method for taste masking, enteric coating or long-lasting purposes. Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, and Eudragg (manufactured by Rohm). , West Germany, methacrylic acid, acrylic acid copolymer), pigments (eg, titanium oxide,
And the like are appropriately used.

The compound of the present invention can be used as a solid, semi-solid or liquid external preparation. For example, as a solid external preparation, the compound of the present invention can be used as it is or as an excipient (eg, glycol, mannitol, starch, microcrystalline cellulose, etc.), a thickener (eg, natural gums, cellulose derivatives, polyacrylic acid). Coalescence etc.)
It can also be manufactured by preparing a powdery composition. The semi-solid external preparation is preferably produced according to a conventional method and used as an aqueous or oily gel or ointment. Liquid external preparations can also be produced by preparing them as oily or aqueous suspensions by the means used for the production of injections or the equivalent. Also,
A solid, semi-solid or liquid external preparation may be added to a pH adjuster (eg,
Carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoic acid esters, chlorobutanol, benzalkonium chloride, etc.) may be added as appropriate. Specifically, it can be used as an ointment containing, for example, about 0.1 to about 100 mg of the compound of the present invention per gram, usually based on petrolatum, lanolin and the like. The compound of the present invention is an oily or aqueous solid,
Semi-solid or liquid suppositories can also be used. As an oily base for producing a suppository, for example, glyceride of a higher fatty acid (eg, cocoa butter, witepsol (manufactured by Dynamite Nobel), etc.) and intermediate fatty acid (eg, miglyolic acid (manufactured by Dynamite Nobel) And vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.) and the like are used as appropriate. Examples of the aqueous base include polyethylene glycols and propylene glycol, and examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.

The dose of the compound of the present invention or a salt thereof varies depending on the target disease, the target human or mammal, symptoms, age, body weight, symptoms, dosage form, administration method, administration period and the like. In the case of oral administration in the treatment, the compound of the present invention or a salt thereof is usually about 0.1 to 100 m per 60 kg body weight of a human or mammal.
g, preferably about 0.1 to 50 mg, more preferably about 1 to 50 mg, especially about 2.5 to 50 mg,
Administer 1 to 3 divided doses. Of course, as described above, since the dose varies under various conditions, a dose smaller than the above dose may be sufficient, or the dose may be out of the range in some cases.

[0107]

EXAMPLES The present invention will now be described in more detail with reference to Examples and Experimental Examples, but the present invention is not limited to these Examples and Experimental Examples. Example 1 cis- (4-anilino-2-methyl-3,4-dihydro-1 (2H) -quinolinyl) (2-thienyl) methanone

Embedded image cis-N- (2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)
Acid chloride (0.42 g) was added dropwise to a solution of -N-phenylamine (0.66 g) in THF (20 ml) under ice-cooling, and triethylamine (0.5 ml) was further added. After stirring at room temperature overnight, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. The residue was recrystallized from IPE to give the title compound.
(0.7 g) was obtained. Example compound 1-2 was prepared in a similar manner.
Were synthesized from 1-5.

Embedded image Example Ar ¹ Ar ² R ¹ R ² Stereochemistry Melting point Recrystallization number (° C) Solvent 1-1 Ph 2-thienyl H Me cis 172-173 IPE 1-2 Ph 2-furyl H Me cis 128-129 IPE 1- 3 Ph 3,4-dimethoxyphenyl H Me cis 110-111 IPE 1-4 Ph 2-benzothienyl H Me cis 122-123 IPE 1-5 Ph 3,5-dimethoxyphenyl H Me cis 202-203 Hex / EtOAc IPE is isopropyl ether , Hex indicates hexane, EtOAc indicates ethyl acetate, and the stereochemistry indicates the stereochemistry of NHAr ¹ and R ² .

Example 2 (4-anilino-2-methyl-3,4-dihydro-1 (2H) -quinolinyl) (4-chlorophenyl) methanone

Embedded image Trans-N- (2-methyl-1,2,3,4-tetrahydro-4-quinolinyl) -N-phenylamine (0.46 g) pyridine solution (15 ml) under ice cooling, p-chlorobenzoyl chloride (0.35 g) g) was added. After stirring at room temperature overnight, ethyl acetate was added to the reaction solution, washed with water, dried and concentrated. The residue was recrystallized from IPE / ethyl acetate to give the title compound (0.4 g). Example compounds 2-2 to 2-9 were synthesized in the same manner.

Embedded image Example Ar ¹ Ar ² R ¹ R ² Stereochemistry Melting point Recrystallization number (° C) Solvent 2-1 Ph 4-chlorophenyl H Me trans 173-175 IPE / EtOAc 2-2 Ph 2-furyl H Me trans 122-123 IPE 2-3 Ph 2-thienyl H Me trans 138-139 Hex / EtOAc 2-4 Ph 3,4-dimethoxyphenyl H Me trans 208-209 Hex / THF 2-5 Ph 3,5-dimethoxyphenyl H Me trans 166-167 IPE / EtOAc 2-6 Ph 4-bromophenyl H Me trans 170-171 IPE / EtOAc 2-7 Ph 3-methoxyphenyl H Me trans 156-157 IPE / EtOAc 2-8 Ph 1-methylindol-2-yl H Me trans 194- 195 Hex / EtOAc 2-9 Ph isooxazol-5-yl H Me trans 82-83 Hex / EtOAc IPE indicates isopropyl ether, Hex indicates hexane, EtOAc indicates ethyl acetate, stereochemistry is NHAr ¹ and R ² Shows the stereochemistry of

Reference Example 1 cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4
-Tetrahydro-4-quinolinol

Embedded image 1) 1- (3,4-dimethoxybenzoyl) -2-methyl-2,3-dihydro-4 (1H) -quinolinone A method known in the literature (Bio-Organic and Medicinal Chemistry Letters
9 1009 (1999)) was synthesized with 2-methyl-2,3-dihydro -4 (IH) - pyridine quinolone 1.19 g (7.38 mmol) 15 m
l, 1.63 g of 3,4-dimethoxybenzoyl chloride
(8.12 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated, and extracted by adding ethyl acetate and water. The organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/2), and the eluate was recrystallized from ethyl acetate-hexane to give the desired product, cis- 1- (3,4-dimethoxybenzoyl) -2-methyl-2,3-
1.57 g (65% yield) of dihydro-4 (1H) -quinolinone was obtained as white crystals. Elemental analysis: C ₁₉ H ₁₉ NO ₄ Calculated: C, 70.14; H, 5.89; N, 4.31 Experimental: C, 70.18; H, 5.86; N, 4.46 2) cis-1- (3,4-dimethoxy) Benzoyl) -2-methyl-1,2,
Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-2,3-dihydro-4 (1H) -quinolinone 4.65 g (14.3 mmol) obtained in 3,4-tetrahydro-4-quinolinol 1) Was dissolved in a mixed solution of methanol (40 ml) and THF (80 ml), sodium borohydride (540 mg, 14.3 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was recrystallized from THF-hexane to obtain the desired product, cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-. 3.84 g (82% yield) of 4-quinolinol was obtained as white crystals. Elemental analysis: C ₁₉ H ₂₁ NO ₄ Calculated: C, 69.71; H, 6.47; N, 4.28 Experimental: C, 69.88; H, 6.51; N, 4.18

Reference Example 2 1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-
4-quinolinol

Embedded image 1) 1- (3,4-dimethoxybenzoyl) -2,3-dihydro-4
(1H) -quinolinone From 2.60 g (16.54 mmol) of 2,3-dihydro-4 (1H) -quinolone, 1- (3,4-dimethoxybenzoyl) -2,3- was obtained in the same manner as in Reference Example 1-1). 4.42 g of dihydro-4 (1H) -quinolinone (yield 86
%) As white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.90 (2H, t, J = 6.3 Hz), 3.80 (3H,
s), 3.90 (3H, s), 4.35 (2H, t, J = 6.3Hz), 6.76 (1H,
d, J = 8.4Hz), 6.95 (1H, d, J = 7.5Hz), 7.03-7.29 (4H,
m), 8.01 (1H, dd, J = 1.2Hz, 7.8Hz). 2) 1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinol 1- (3,4-dimethoxybenzoyl) -2,3-dihydro-4 obtained in 1) From (1H) -quinolinone 2.00 g (14.3 mmol), 1- (3,4-dimethoxybenzoyl)-was obtained in the same manner as in Reference Example 1-2).
1.54 g of 1,2,3,4-tetrahydro-4-quinolinol (yield 77
%) As white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.05-2.13 (1H, m), 2.21-2.27 (1H,
m), 3.76 (3H, s), 3.76-3.84 (1H, m), 3.88 (3H, s), 4.
09-4.20 (1H, m), 4.89-4.90 (1H, m), 6.74 (1H, d, J = 7.
8Hz), 6.88 (1H, d, J = 7.8Hz), 6.96-7.12 (4H, m), 7.45
(1H, d, J = 6.0Hz).

Reference Example 3 1- (2-furoyl) -1,2,3,4-tetrahydro-4-quinolinol

Embedded image 1) 1- (2-furoyl) -2,3-dihydro-4 (1H) -quinolinone 2.00 g (12.7 mmol) of 2,3-dihydro-4 (1H) -quinolone, 3.32 g of 2-furoyl chloride (0.025 mmol) to obtain 2.90 g (95% yield) of 1- (2-furoyl) -2,3-dihydro-4 (1H) -quinolinone as white crystals in the same manner as in Reference Example 1-1). ¹ H-NMR (CDCl ₃ ) δ: 2.88 (2H, t, J = 6.0Hz), 4.37 (2H,
t, J = 6.0Hz), 6.48-6.50 (1H, m), 7.02-7.05 (2H, m),
7.20-7.26 (1H, m), 7.36-7.42 (2H, m), 8.04 (1H, dd, J
= 1.8Hz, 7.8Hz). 2) 1- (2-furoyl) -1,2,3,4-tetrahydro-4-quinolinol 1- (2-furoyl) -2,3-dihydro-4 (1H) obtained in 1)
1- (2-furoyl) -1,2,3,4-tetrahydro-4-quinolinol 0.90 g (89% yield) was obtained from 1.00 g (4.14 mmol) of 1-quinolinone in the same manner as in Reference Example 1-2). Obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 2.04-2.11 (1H, m), 2.22-2.27 (1H,
m), 3.76-3.85 (1H, m), 4.17-4.26 (1H, m), 4.86-4.88 (1
H, m), 6.42-6.44 (1H, m), 6.84 (1H, d, J = 3.6Hz), 7.
04-7.17 (3H, m), 7.37 (1H, m), 7.46-7.49 (1H, m).

Reference Example 4 1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoxaline

Embedded image 660 mg (4.92 mmol) of tetrahydroquinoxaline synthesized by a method known in the literature (Journal of Farmer Chemical Bretane 32 (6) 2421 (1984)) is dissolved in pyridine (20 ml), and 3,4-dimethoxybenzoyl chloride is dissolved.
987 mg (4.92 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction solution was concentrated, ethyl acetate and water were added thereto for extraction. The organic layer was dried and concentrated, and the residue was subjected to alumina column chromatography (developing solvent: ethyl acetate / hexane = 1/1), and the eluate was recrystallized from ethyl acetate-hexane to obtain the desired product 1-. 780 mg (yield 53%) of (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoxaline were obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 3.55-3.60 (2H, m), 3.76 (3H, s),
3.88 (3H, s), 3.97-4.01 (2H, m), 4.06 (1H, brs), 6.3
6-6.41 (1H, m), 6.58-6.61 (2H, m), 6.76 (1H, d, J = 8.4
Hz), 6.84-6.90 (1H, m), 7.02-7.07 (2H, m).

Reference Example 5 6-chloro-1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinol

Embedded image 1) 6-chloro-1- (3,4-dimethoxybenzoyl) -2,3-dihydro-4 (1H) -quinolinone 6-chloro-2,3-dihydro-4 (1H) -quinolone 3.00 (16.5 mmo
l) to 6-chloro-1- (3,4-dimethoxybenzoyl) -2,3-dihydro-4 (1H) -quinolinone in the same manner as in Reference Example 1-1).
5.80 g (100% yield) was obtained as pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.89 (2H, t, J = 6.6Hz), 3.85 (3H,
s), 3.91 (3H, s), 4.33 (2H, t, J = 6.6Hz), 6.78 (1H, d,
J = 8.4Hz), 6.87 (1H, d, J = 8.7Hz), 7.01 (1H, dd, J = 8.
4,2.1Hz), 7.11 (1H, d, J = 1.8Hz), 7.23 (1H, dd, J = 8.
7,2.1Hz), 7.97 (1H, d, J = 1.8Hz). 2) 6-chloro-1- (3,4-dimethoxybenzoyl) -1,2,3,4
-Tetrahydro-4-quinolinol 6-chloro-1- (3,4-dimethoxybenzoyl) -2,3-dihydro-4 (1H) -quinolinone obtained in 1) 5.00 g (14.5 mmo)
From l), 4.50 g (89% yield) of 6-chloro-1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinol was obtained in the same manner as in Reference Example 1-2). Obtained as pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.01-2.09 (1H, m), 2.23-2.30 (1H,
m), 3.73-3.81 (2H, m), 3.81 (3H, s), 3.89 (3H, s), 4.0
8-4.16 (1H, m), 4.82-4.87 (1H, m), 6.75 (1H, d, J = 8.4H
z), 6.85 (1H, d, J = 9.0Hz), 6.92-7.03 (3H, m), 7.45 (1
H, d, J = 2.7Hz).

Reference Example 6 7-chloro-1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinol

Embedded image 1) 7-chloro-1- (3,4-dimethoxybenzoyl) -2,3-dihydro-4 (1H) -quinolinone 2.00 g (11.0 mmo) of 7-chloro-2,3-dihydro-4 (1H) -quinolone
l) to 7-chloro-1- (3,4-dimethoxybenzoyl) -2,3-dihydro-4 (1H) -quinolinone in the same manner as in Reference Example 1-1).
3.50 g (yield 92%) was obtained as pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.86 (2H, t, J = 6.3Hz), 3.86 (3H,
s), 3.92 (3H, s), 4.31 (2H, t, J = 6.3Hz), 6.82 (1H, d,
J = 8.1Hz), 7.03-7.14 (4H, m), 7.95 (1H, d, J = 8.4Hz) 2) 7-Chloro-1- (3,4-dimethoxybenzoyl) -1,2,3,4
7-chloro-1- (3,4-dimethoxybenzoyl) -2,3-dihydro-4 (1H) -quinolinone obtained in 1) -tetrahydro-4-quinolinol 3.00 g (8.70 mmo)
From l), in the same manner as in Reference Example 1-2), 7-chloro-1- (3,4-
2.20 g (yield 73%) of dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinol were obtained as pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.01-2.09 (1H, m), 2.14-2.23 (1H,
m), 3.72-3.83 (2H, m), 3.83 (3H, s), 3.91 (3H, s), 4.0
6-4.14 (1H, m), 4.82-4.87 (1H, m), 6.79 (1H, d, J = 8.4H
z), 6.99-7.09 (4H, m), 7.38 (1H, d, J = 7.8Hz)

Reference Example 7 1- (5-bromo-2-furoyl) -1,2,3,4-tetrahydro-4-quinolinol

Embedded image 1) 1- (5-bromo-2-furoyl)-2,3-dihydro-4 (1H)-
From 1.00 g (6.8 mmol) of quinolinone 2,3-dihydro-4 (1H) -quinolone and 1.42 g (6.8 mmol) of 5-bromo-2-furoyl chloride, Reference Example 1-1)
1- (5-bromo-2-furoyl) -2,3-dihydro
1.00 g (46% yield) of 4 (1H) -quinolinone was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 2.88 (2H, t, J = 6.3Hz), 4.36 (2H,
t, J = 6.3Hz), 6.43 (1H, d, J = 3.3Hz), 6.96 (1H, d, J =
3.3Hz), 7.10 (1H, d, J = 8.1Hz), 7.23-7.28 (2H, m), 7.
39-7.45 (1H, m), 8.03 (1H, dd, J = 8.1,1.5Hz) 2) 1- (5-bromo-2-furoyl) -1,2,3,4-tetrahydro-4
1- (5-bromo-2-furoyl) -2,3-dihydro-4 (1H) -quinolinone obtained in 1) -900 mg (2.8 mmol) Reference Example 1
In the same manner as in 2), 0.81 g (90% yield) of 1- (5-bromo-2-furoyl) -1,2,3,4-tetrahydro-4-quinolinol was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 2.00-2.10 (1H, m), 2.21-2.26 (1H,
m), 3.76-3.85 (1H, m), 4.16-4.23 (1H, m), 6.36 (1H, d,
J = 3.3Hz), 6.76 (1H, d, J = 3.3Hz), 7.09-7.21 (3H, m),
7.23-7.28 (2H, m), 7.46-7.49 (1H, m)

Reference Example 8 cis-1- (3,4-dimethoxybenzoyl) -2-ethyl-1,2,3,4
-Tetrahydro-4-quinolinol

Embedded image 1) From 401 mg (2.29 mmol) of 1- (3,4-dimethoxybenzoyl) -2-ethyl-2,3-dihydro-4 (1H) -quinolinone 2-ethyl-2,3 dihydro-4 (1H) -quinolinone In the same manner as in Reference Example 1-1), 1- (3,4-dimethoxybenzoyl) -2-ethyl-2,3-dihydro-4 (1H) -quinolinone (565 mg, yield 73%) was obtained as white crystals. Was. Melting point: 157-158 ° C (crystallization solvent: ethyl acetate-hexane) FABMS (pos) 340.2 [M + H ⁺ ] 2) cis-1- (3,4-dimethoxybenzoyl) -2-ethyl-1,
2,3,4-tetrahydro-4-quinolinol From 1- (3,4-dimethoxybenzoyl) -2-ethyl-2,3-dihydro-4 (1H) -quinolinone 520 mg (1.53 mmol) obtained in 1). In the same manner as in Reference Example 1-2), cis-1- (3,4-dimethoxybenzoyl) -2-ethyl-1,2,3,4-tetrahydro-4-quinolinol (447 mg, yield 86%) was obtained as white crystals. As obtained. Melting point: 168-169 ° C (crystallization solvent: ethyl acetate-hexane)

Example 3 cis-1-isonicotinoyl-2-methyl-N-phenyl-1,2,3,
4-tetrahydro-4-quinolinamine

Embedded image 500 mg (2.10 mmol) of isonicotinic acid and 0.1 ml of DMF were added to THF (1
Oxalyl chloride 0.55 ml (6.3 ml) under ice-cooling.
mmol) was added dropwise. After stirring at room temperature for 2 hours, the mixture was concentrated, and cis-2-methyl-N-phenyl-1,2,3,4-tetrahydro-4-
Quinolinamine 500mg (2.10mmol) pyridine solution (20ml)
Was added under ice cooling. After stirring at room temperature overnight, the reaction solution was diluted with ethyl acetate, washed with water, dried and concentrated. The residue is subjected to silica gel column chromatography (developing solvent: ethyl acetate /
Hexane = 1/1), and the eluate was recrystallized from THF-hexane to give the desired product, cis-1-isonicotinoyl-2-methyl-N-phenyl-1,2,3,4-tetrahydro-4 -Quinolinamine 1
78 mg (yield 24%) were obtained as white crystals. Elemental analysis _{C 22 H 21 N 3 O ·} 0.25H 2 O Calculated: C, 75.95; H, 6.23 ; N, 12.08 Found: C, 76.12; H, 6.15 ; N, 12.23 mp: 210 ° C. (crystallization Solvent: Tetrahydrofuran-
Hexane)

Example 4 cis-2-methyl-N-phenyl-1- (2-pyridinylcarbonyl) -1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 500 mg (2.1 mmol) of cis-2-methyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine was dissolved in a pyridine solution (20 ml), and under ice-cooling, picolinoyl chloride hydrochloride 411 mg (2.31
mmol) was added. After stirring at room temperature overnight, the mixture was diluted with ethyl acetate, washed with water, dried and concentrated. The residue is subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane =
1/1), and the eluate was recrystallized from ethyl acetate-hexane to obtain the desired product, cis-2-methyl-N-phenyl-1- (2-pyridinylcarbonyl) -1,2,3 134 mg (19% yield) of 1,4-tetrahydro-4-quinolinamine were obtained as white crystals. Melting point: 157 ° C (crystallization solvent: ethyl acetate-hexane) FABMS (pos) 343.1 [M + H ⁺ ]

Example 5 cis-1- (1,3-benzodioxol-5-ylcarbonyl)-
2-methyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image As in Example 4 from 500 mg (2.1 mmol) of cis-2-methyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine and 453.5 mg (2.73 mmol) of 3,4-methylenedioxybenzoyl chloride Cis-1- (1,3-benzodioxole-
5-37 mg (5-ylcarbonyl) -2-methyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine (66% yield) was obtained as white crystals. Mp: 175 ° C. (crystallization solvent: ethyl acetate - hexane) Elemental analysis _{C 24 H 22 N 2 O 3} · 0.5H 2 O Calculated: C, 72.89; H, 5.86 ; N, 7.08 Found: C, 73.07; H, 6.01; N, 7.04

Example 6 cis-2-methyl-N-phenyl-1- (3,4,5-trimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine

Embedded image In the same manner as in Example 3 from 800 mg (3.36 mmol) of cis-2-methyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine and 898 mg (4.23 mmol) of 3,4,5-trimethoxybenzoic acid The desired product, cis-2-methyl-N-phenyl-1- (3,4,5-trimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine, 1.07 g (74% yield) ) Was obtained as white crystals. Melting point: 300 ° C or higher (crystallization solvent: ethyl acetate-hexane) FABMS (pos) 433.2 [M + H ⁺ ]

Example 7 trans-1- (1,3-benzodioxol-5-ylcarbonyl) -2-methyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image Trans-2-methyl-N-phenyl-1,2,3,4-tetrahydro-
In the same manner as in Example 4 from 800 mg (3.36 mmol) of 4-quinolinamine and 726 mg (4.37 mmol) of 3,4-methylenedioxybenzoyl chloride, the target product, trans-1- (1,3-benzodioxol- 5-ylcarbonyl) -2-methyl-N-phenyl-
637 mg of 1,2,3,4-tetrahydro-4-quinolinamine (yield 49
%) As white crystals. Mp: 175 ° C. (crystallization solvent: ethyl acetate - hexane) Elemental analysis C ₂₄ H ₂₂ N ₂ O ₃ Calculated: C, 74.59; H, 5.74 ; N, 7.25 Found: C, 74.49; H, 5.62 ; N, 7.36

Example 8 trans-2-methyl-N-phenyl-1- (3,4,5-trimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine

Embedded image Trans-2-methyl-N-phenyl-1,2,3,4-tetrahydro-
From 4-quinolinamine 800 mg (3.36 mmol), 3,4,5-trimethoxybenzoic acid 898 mg (4.23 mmol) in the same manner as in Example 3,
Trans-2-methyl-N-phenyl-1- (3,4,5-
745 mg (trimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine (51% yield) was obtained as white crystals. Mp: 205 ° C. (crystallization solvent: ethyl acetate - hexane) Elemental analysis C ₂₆ H ₂₈ N ₂ O ₄ Calculated: C, 72.20; H, 6.53 ; N, 6.48 Found: C, 72.28; H, 6.68 ; N, 6.65

Example 9 1- (2-furoyl) -N-phenyl-1,2,3,4-tetrahydro-4-
Quinolinamine

Embedded image 200 mg (0.82 mmol) of 1- (2-furoyl) -1,2,3,4-tetrahydro-4-quinolinol obtained in Reference Example 3 was added to chloroform (1
0 ml) and 576 mg of iodotrimethylsilane (2.
88 mmol) and stirred for 3 hours. The reaction mixture was concentrated, THF (10 ml) was added to the residue, aniline (153 mg, 1.64 mmol) and barium carbonate (324 mg, 1.64 mmol) were added, and the mixture was stirred at room temperature for 48 hours. The insoluble material was removed by filtration and then concentrated. The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane =
1/3), and the desired product, 1- (2-furoyl) -N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine, 120 mg (yield 4)
6%) as a colorless oil. FABMS (pos) 318.1 [M ⁺ ]

Example 10 1- (2-furoyl) -4-phenoxy-1,2,3,4-tetrahydroquinoline

Embedded image 1- (2-furoyl) -1,2,3,4-tetrahydro-4-quinolinol 200 mg (0.82 mmol) obtained in Reference Example 3, phenol 77 mg
(0.82 mmol), 216 mg (0.82 mmol) of triphenylphosphine
Was dissolved in THF (5 ml), diethyl azodicarboxylate 143 mg
(0.82 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the residue was subjected to alumina column chromatography (developing solvent: ethyl acetate / hexane = 2/8) to give 1- (2-furoyl) -4-phenoxy-1,2, 72 mg (yield 27%) of 3,4-tetrahydroquinoline was obtained as a colorless oil. FABMS (pos) 320.1 [M + H ⁺ ]

Example 11 trans-1-isonicotinoyl-2-methyl-N-phenyl-1,
2,3,4-tetrahydro-4-quinolinamine

Embedded image Isonicotinic acid 284mg (2.31mmol), DMF (0.1ml) in THF
(10 ml) and oxalyl chloride 0.88 ml (1
0.1 mmol) was added dropwise. After stirring at room temperature for 1 hour, the mixture was concentrated.The residue was dissolved in THF (15 ml), and triethylamine (15 m
l), 500 mg (2.1 mmol) of trans-2-methyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water, dried and concentrated. The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/1),
The eluate was recrystallized from ethyl acetate-hexane to give the target compound, cis-1-isonicotinoyl-2-methyl-N-phenyl-1,
284 mg of 2,3,4-tetrahydro-4-quinolinamine (25% yield)
Was obtained as white crystals. Melting point: 121 ° C (crystallization solvent: ethyl acetate-hexane) FABMS (pos) 344.1 [M + H ⁺ ]

Example 12 N- (4-bromophenyl) -1- (3,4-dimethoxybenzoyl)-
2-methyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 20 obtained in Reference Example 1
0 mg (0.61 mmol) was dissolved in chloroform (10 ml), 427 mg (2.14 mmol) of iodotrimethylsilane was added under ice cooling, and the mixture was stirred for 2 hours. The reaction solution was concentrated, THF (10 ml) was added to the residue for dissolution, parabromoaniline (315 mg, 1.83 mmol) and barium carbonate (241 mg, 1.22 mmol) were added, and the mixture was stirred at room temperature for 24 hours. The insoluble material was removed by filtration, and then concentrated. The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/3), and the eluate was recrystallized from diethyl ether-hexane to give the target compound, N 80 mg (yield 27%) of-(4-bromophenyl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinamine were obtained as white crystals.
(Cis-trans = 1: 6) Melting point: 173-175 ° C. (crystallization solvent: diethyl ether-hexane) FABMS (pos) 480.1 [M + H ⁺ ]

Example 13 trans-1- (3,4-dimethoxybenzoyl) -2-methyl-N-
(6-Methyl-2-pyridinyl) -1,2,3,4-tetrahydro-4-quinolinamine

Embedded image Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 20 obtained in Reference Example 1
0 mg (0.61 mmol), 198 mg of 2-amino-6-methylpyridine (1.8 mg
3 mmol) to give trans-1- (3,4-dimethoxybenzoyl) -2-methyl-N- (6-methyl-2-pyridinyl) -1,2,3,4 in the same manner as in Example 12. -Tetrahydro-4-quinolinamine (20 mg, yield 8%) was obtained as white crystals. Melting point: 184-186 ° C (crystallization solvent: diethyl ether-hexane) FABMS (pos) 418.2 [M + H ⁺ ]

Example 14 N- (4-chlorophenyl) -1- (3,4-dimethoxybenzoyl)-
1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 1- (3,4-dimethoxybenzoyl) -1,2, obtained in Reference Example 2.
3,4-tetrahydro-4-quinolinol 300 mg (0.96 mmol), 4
-From 367 mg (2.88 mmol) of chloroaniline, N- (4-chlorophenyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4 which is a target substance is obtained in the same manner as in Example 12. -Quinolinamine (174 mg, 43% yield) was obtained as white crystals. Melting point: 131 ° C (crystallization solvent: ethyl acetate-hexane) FABMS (pos) 445.1 [M + H ⁺ ]

Example 15 1- (2-furoyl) -N-methyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 122 mg (0.50 mmol) of 1- (2-furoyl) -1,2,3,4-tetrahydro-4-quinolinol obtained in Reference Example 3 was added to chloroform (1
0 ml) and 350 mg of iodotrimethylsilane (1.
75 mmol) and stirred for 3 hours. The reaction solution was concentrated, THF (10 ml) was added to the residue, and N-methylaniline 429 mg (2.00 mmo
l) and 197 mg (1.00 mmol) of barium carbonate were added, followed by stirring at room temperature for 30 hours. The insoluble material was removed by filtration, and then concentrated. The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 3/7) to obtain 1- (2-furoyl) -N-
110 mg (66% yield) of methyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine was obtained as a colorless oil. FABMS (pos) 333.2 [M + H ⁺ ]

Example 16 1- (2-furoyl) -N-ethyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image The same as in Example 15 from 300 mg (1.23 mmol) of 1- (2-furoyl) -1,2,3,4-tetrahydro-4-quinolinol obtained in Reference Example 3 and 447 mg (3.69 mmol) of N-ethylaniline In the method, 1- (2-furoyl) -N-ethyl-N-phenyl-1,2,
240 mg of 3,4-tetrahydro-4-quinolinamine (56% yield) was obtained as a colorless oil. FABMS (pos) 347.2 [M + H ⁺ ]

Example 17 1- (3,4-dimethoxybenzoyl) -N-phenyl-1,2,3,4-
Tetrahydro-4-quinolinamine

Embedded image 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
From 300 mg (0.96 mmol) of 2,3,4-tetrahydro-4-quinolinol and 267 mg (2.87 mmol) of aniline in the same manner as in Example 12, 1- (3,4-dimethoxybenzoyl) -N- Phenyl-1,2,3,4-tetrahydro-4-quinolinamine 260mg
(70% yield) as white crystals. Melting point: 155-6 ° C (crystallization solvent: diisopropyl ether-hexane) Elemental analysis: C ₂₄ H ₂₄ N ₂ O ₃ Calculated: C, 74.21; H, 6.23; N, 7.21 Experimental: C, 73.71; H , 6.21; N, 7.21

Example 18 1- (3,4-dimethoxybenzoyl) -N-methyl-N-phenyl-
1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
2,3,4-tetrahydro-4-quinolinol 300 mg (0.96 mmol)
From 308 mg (2.87 mmol) of N-methylaniline, the target compound, 1- (3,4-dimethoxybenzoyl) was obtained in the same manner as in Example 12.
-250 mg (65% yield) of N-methyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine were obtained as white crystals. Melting point: 143-4 ° C (crystallization solvent: ethyl acetate-diisopropyl ether) Elemental analysis: C ₂₅ H ₂₆ N ₂ O ₃ Calculated: C, 74.60; H, 6.51; N, 6.96 Experimental: C, 74.32; H, 6.52; N, 6.80

Table 1 summarizes the title compounds of Examples 3 to 18. However, stereochemistry indicating the stereochemistry of XAR ¹ and R ^2.

[Table 1]

Example 19 4- (4-bromophenoxy) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
250 mg (0.80 mmol) of 2,3,4-tetrahydro-4-quinolinol
From 138 mg (0.80 mmol) of 4-bromophenol, the target compound, 4- (4-bromophenoxy) -1- was obtained in the same manner as in Example 10.
(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydro-4
-248 mg (66% yield) of quinolinamine was obtained as a white powder. Mp: 56-7 ° C. (crystallization solvent: ethyl acetate - hexane) Elemental analysis C ₂₄ H ₂₂ NO ₄ Br Calculated: C, 61.55; H, 4.73 ; N, 2.99 Found: C, 61.66; H, 4.90; N, 2.92

Example 20 1-benzyl-4- (3,4-dimethoxybenzoyl) -1,2,3,4-
Tetrahydroquinoxaline

Embedded image 1- (3,4-dimethoxybenzoyl) -1, synthesized in Reference Example 4
2,3,4-tetrahydroquinoxaline 200 mg (0.67 mmol) in DMF
(10 ml), 54% 60% sodium hydride (1.34 mmol)
Was added and stirred at 60 ° C. for 20 minutes. Benzyl bromide 344m
g (2.01 mmol) was added and the mixture was stirred for 2 hours, and extracted with ethyl acetate and water. The organic layer was dried, concentrated, and the residue was subjected to alumina column chromatography (developing solvent: ethyl acetate / hexane = 3/7). The eluate was recrystallized from ethyl acetate-diisopropyl ether to obtain the desired product. 1-benzyl-4
182 mg (70% yield) of-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinoxaline was obtained as white crystals. Melting point: 111-2 ° C (crystallization solvent: ethyl acetate-diisopropyl ether) Elemental analysis: C ₂₄ H ₂₄ N ₂ O ₃ Calculated: C, 74.21; H, 6.23; N, 7.21 Experimental: C, 73.97; H, 6.18; N, 7.15

Example 21 1- (3,4-Dimethoxybenzoyl) -N- (6-quinolinyl)-1,
2,3,4-tetrahydro-4-quinolinamine

Embedded image 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
2,3,4-tetrahydro-4-quinolinol 400 mg (1.28 mmol),
From 554 mg (3.84 mmol) of 6-aminoquinoline, 1- (3,4-dimethoxybenzoyl) -N
-(6-Quinolinyl)-1,2,3,4-tetrahydro-4-quinolinamine (122 mg, yield 22%) was obtained as white crystals. Melting point: 116-118 ° C (crystallization solvent: THF-hexane) FABMS (pos) 440.2 [M ⁺ ]

Example 22 1- (3,4-dimethoxybenzoyl) -N- (2-pyridinyl) -1,
2,3,4-tetrahydro-4-quinolinamine

Embedded image 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
2,3,4-tetrahydro-4-quinolinol 400 mg (1.28 mmol),
From 361 mg (3.84 mmol) of 2-aminopyridine, 1- (3,4-dimethoxybenzoyl) -N which is a target substance in the same manner as in Example 12
131 mg (26% yield) of-(2-pyridinyl) -1,2,3,4-tetrahydro-4-quinolinamine was obtained as white crystals. Melting point: 156-157 ° C (crystallization solvent: diethyl ether-hexane) Elemental analysis: C ₂₃ H ₂₃ N ₃ O ₃ Calculated: C, 70.93; H, 5.95; N, 10.79 Experimental: C, 70.64; H , 6.00; N, 10.79

Example 23 N- (2-chlorophenyl) -1- (3,4-dimethoxybenzoyl)-
1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
2,3,4-tetrahydro-4-quinolinol 300mg (0.957mmo
l), Example 12 from 367 mg (2.87 mmol) of 2-chloroaniline
N- (2-chlorophenyl) -1- (3,
227 mg (56% yield) of 4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine were obtained as white crystals. Melting point: 92-93 ° C (crystallization solvent: diethyl ether-
Hexane) Elemental analysis: C ₂₄ H ₂₃ N ₂ O ₃ Cl · 0.4H ₂ O Calculated: C, 67.02; H, 5.58; N, 6.51 Experimental: C, 67.32; H, 5.86; N, 6.22

Example 24 1- (3,4-Dimethoxybenzoyl) -N- (2-fluorophenyl) -1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
2,3,4-tetrahydro-4-quinolinol 300mg (0.957mmo
l), the desired product 1- (3,4-dimethoxybenzoyl) -N- (2-fluorophenyl) -1,2,3,4 in the same manner as in Example 12 from 213 mg (1.92 mmol) of orthofluoroaniline -Tetrahydro-4-quinolinamine (160 mg, yield 41%) was obtained as white crystals. Melting point: 133-134 ° C (crystallization solvent: ethyl acetate-hexane) Elemental analysis: C ₂₄ H ₂₃ N ₂ O ₃ F Calculated: C, 70.92; H, 5.70; N, 6.89 Experimental: C, 70.80; H, 5.71; N, 6.61

Example 25 1- (3,4-Dimethoxybenzoyl) -N-methyl-N- (2-methylphenyl) -1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
2,3,4-tetrahydro-4-quinolinol 300mg (0.957mmo
l), 1- (3,4-dimethoxybenzoyl) -N-methyl-N- (2-methylphenyl), which is the target substance, in the same manner as in Example 12 from 233 mg (1.92 mmol) of N-methyl-2-toluidine 157 mg (yield 39%) of -1,2,3,4-tetrahydro-4-quinolinamine was obtained as white crystals. Melting point: 170-171 ° C (crystallization solvent: ethyl acetate-hexane) Elemental analysis: C ₂₆ H ₂₈ N ₂ O ₃ Calculated: C, 74.97; H, 6.78; N, 6.73 Experimental: C, 75.10; H , 6.81; N, 6.58

Example 26 N- (2,6-dichlorophenyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
2,3,4-tetrahydro-4-quinolinol 300mg (0.957mmo
l), N- (2,6-dichlorophenyl) -1- (3,4-dimethoxybenzoyl) -1,2 which is the target compound in the same manner as in Example 12 from 3,11 mg (1.92 mmol) of 2,6-dichloroaniline 142 mg of 3,3,4-tetrahydro-4-quinolinamine (yield 32%) were obtained as white crystals. Melting point: 154-156 ° C (crystallization solvent: ethyl acetate-hexane) Elemental analysis: C ₂₄ H ₂₂ N ₂ O ₃ Cl ₂ Calculated: C, 63.03; H, 4.85; N, 6.13 Experimental: C, 62.81 ; H, 4.84; N, 5.91

Example 27 N- (2-chlorophenyl) -1- (3,4-dimethoxybenzoyl)-
2-methyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 40 obtained in Reference Example 1
0 mg (0.61 mmol), orthochloroaniline 467 mg (3.66 mmol)
From N- (2-chlorophenyl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1, which is the target compound in the same manner as in Example 12.
216mg of 2,3,4-tetrahydro-4-quinolinamine (41% yield)
Was obtained as white crystals. (Cis: trans = 1: 1) Melting point: 148-150 ° C (crystallization solvent: diethyl ether-
Hexane) FABMS (pos) 437.2 [M + H ⁺ ]

Example 28 cis-1- (3,4-dimethoxybenzoyl) -N, 2-dimethyl-N-
Phenyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 1.20 g (2.98 mmol) of cis-1- (3,4-dimethoxybenzoyl) -2-methyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine obtained in Example 1-3 Dissolve in DMF (50 ml), 60%
1.20 g (29.8 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 1 hour. Methyl iodide (3.6 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 24 hours, and extracted with ethyl acetate and water. The organic layer was washed with water, dried and concentrated, and the residue was recrystallized from ethyl acetate-hexane to obtain the desired product, cis-1- (3,4-dimethoxybenzoyl) -2, N-dimethyl-N-phenyl-1. 849 mg (68%) of 2,2,3,4-tetrahydro-4-quinolinamine were obtained as white crystals. Melting point: 180-181 ° C (crystallization solvent: ethyl acetate-hexane) FABMS (pos) 416.2 [M ⁺ ]

Example 29 (+)-cis-1- (3,4 dimethoxybenzoyl) -N, 2-dimethyl-
N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 548 mg of racemic cis-1- (3,4-dimethoxybenzoyl) -N, 2-dimethyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine obtained in Example 28 was subjected to HPLC (CHIRALPAK A
D, developing solvent: hexane / EtOH = 1/1, UV254nm detection)
Perform optical separation by preparative separation, and the target product (+)-cis-1
234 mg of-(3,4-dimethoxybenzoyl) -N, 2-dimethyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine was obtained as a white powder. [α] _D = + 456.2 ° (0.5% EtOH)

Example 30 (-)-cis-1- (3,4-dimethoxybenzoyl) -N, 2-dimethyl
-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 548 mg of racemic cis-1- (3,4-dimethoxybenzoyl) -N, 2-dimethyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine obtained in Example 28 was subjected to HPLC ( CHIRALPAKAD, developing solvent: hexane / EtOH = 1/1, UV254 nm detection) Performed optical resolution by preparative separation to obtain the target product (-)-cis-1- (3,
4-dimethoxybenzoyl) -N, 2-dimethyl-N-phenyl-1,
201 mg of 2,3,4-tetrahydro-4-quinolinamine was obtained as a white powder. [α] _D = -456.2 ° (0.5% EtOH)

Example 31 N- (1,3-benzodioxol-5-yl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
2,3,4-tetrahydro-4-quinolinol 300mg (0.957mmo
l), 3,4-methylenedioxyaniline from 395 mg (2.88 mmol) in the same manner as in Example 12 to give N- (1,3-benzodioxol-5-yl) -1- (3 , 4-Dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine 214 mg (Yield
49%) as yellow crystals. Melting point: 135-136 ° C (crystallization solvent: ethyl acetate-hexane) Elemental analysis: C ₂₅ H ₂₄ N ₂ O ₅ · 0.25 H ₂ O Calculated: C, 68.72; H, 5.65; N, 6.41 Experimental: C, 68.51; H, 5.52; N, 6.21

Example 32 N- (3-Chlorophenyl) -1- (3,4-dimethoxybenzoyl)-
1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
2,3,4-tetrahydro-4-quinolinol 300mg (0.957mmo
l), 367 mg (2.88 mmol) of 3-chloroaniline from Example 12
N- (3-chlorophenyl) -1-
(3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-
227 mg of quinolinamine (56% yield) were obtained as white crystals. Melting point: 160 ° C (crystallization solvent: diethyl ether-hexane) Elemental analysis: C ₂₄ H ₂₃ N ₂ O ₃ Cl Calculated: C, 68.16; H, 5.48; N, 6.62 Experimental: C, 67.95; H, 5.46; N, 6.53

Example 33 1- (3,4-Dimethoxybenzoyl) -N- (4-methylphenyl)-
1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
280 mg (0.89 mmol) of 2,3,4-tetrahydro-4-quinolinol,
In the same manner as in Example 12 from 286 mg (2.67 mmol) of 4-toluidine, 1- (3,4-dimethoxybenzoyl) -N-
227 mg (56% yield) of (4-methylphenyl) -1,2,3,4-tetrahydro-4-quinolinamine were obtained as white crystals. Melting point: 97-99 ° C (crystallization solvent: diethyl ether-
Hexane) FABMS (pos) 400.2 [M ⁺ ]

Example 34 N- (4-Bromophenyl) -1- (3,4-dimethoxybenzoyl)-
1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
2,3,4-tetrahydro-4-quinolinol 600 mg (1.91 mmol),
In the same manner as in Example 12 from 986 mg (5.73 mmol) of 4-bromoaniline, N- (4-bromophenyl) -1- (3,4-
193 mg (yield 22%) of dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine were obtained as white crystals. Melting point: 130 ° C (crystallization solvent: diethyl ether-hexane) Elemental analysis: C ₂₄ H ₂₃ N ₂ O ₃ Br · 0.4H ₂ O Calculated: C, 60.74; H, 5.05; N, 5.90 Experimental: C , 60.96; H, 5.31; N, 5.61

Table 2 summarizes the title compounds of Examples 19 to 34. However, stereochemistry indicating the stereochemistry of XAR ¹ and R ^2.

[Table 2]

Example 35 N- (2-chlorophenyl) -1- (3,4-dimethoxybenzoyl)-
N-methyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 132 mg (0.312 mmol) of N- (2-chlorophenyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine obtained in Example 23 was added to DMF (8 ml). It melt | dissolved, 125 mg (3.12 mmol) of sodium hydride was added, and it stirred at room temperature for 45 minutes. Methyl iodide (0.38 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 18 hours, and then extracted with water and ethyl acetate. The organic layer is washed with water, dried and concentrated, and the residue is subjected to silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/1/4).
1), the eluate was recrystallized from ethyl acetate-hexane, and N- (2-chlorophenyl) -1- (3,4-dimethoxybenzoyl) -N-methyl-1,2,3 105 mg (77% yield) of 1,4-tetrahydro-4-quinolinamine were obtained as white crystals. Melting point: 146-147 ° C (crystallization solvent: ethyl acetate-hexane) FABMS (pos) 459.1 [M + Na ⁺ ]

Example 36 N- (4-chlorophenyl) -1- (3,4-dimethoxybenzoyl)-
N-methyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
2,3,4-tetrahydro-4-quinolinol 300mg (0.957mmo
l) 4-Chloro-N-methylaniline from 408 mg (2.88 mmol) of N- (4-chlorophenyl) -1- (3,4-dimethoxybenzoyl) -N-methyl -1,2,
145 mg (35% yield) of 3,4-tetrahydro-4-quinolinamine was obtained as yellow crystals. Melting point: 72-74 ° C (crystallization solvent: diethyl ether-
Hexane) FABMS (pos) 436.2 [M ⁺ ]

Example 37 N- (4-bromophenyl) -1- (3,4-dimethoxybenzoyl)-
N-methyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image From N- (4-bromophenyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine 150 mg (0.33 mmol) obtained in Example 34, Similarly, N- (4-bromophenyl) -1- (3,4-dimethoxybenzoyl) -N-methyl-1,2,3,4-tetrahydro-4-quinolinamine (85 mg, yield: 52%) ) Was obtained as white crystals. Melting point: 73-74 ° C (crystallization solvent: diethyl ether-
Hexane) FABMS (pos) 480.0 [M ⁺ ]

Example 38 N- (3-Chloro-4-methylphenyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
2,3,4-tetrahydro-4-quinolinol 400 mg (1.28 mmol),
From 544 mg (3.84 mmol) of 4-amino-2-chlorotoluene, N- (3-chloro-4-methylphenyl) -1- (3,4-dimethoxybenzoyl) -1 which is a target substance in the same manner as in Example 12. 205 mg (37% yield) of 2,2,3,4-tetrahydro-4-quinolinamine were obtained as white crystals. Melting point: 94-96 ° C (crystallization solvent: diethyl ether-
Hexane) FABMS (pos) 459.0 [M + Na ⁺ ]

Example 39 6-Chloro-N- (2-chlorophenyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 6-chloro-1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinol 400 mg obtained in Reference Example 5
(1.15 mmol) and 440 mg (3.45 mmol) of 2-chloroaniline in the same manner as in Example 12 to obtain 6-chloro-N- (2-
(Chlorophenyl) -1- (3,4-dimethoxybenzoyl) -1,2,
232mg of 3,4-tetrahydro-4-quinolinamine (44% yield)
Was obtained as pale yellow crystals. Melting point: 87-89 ° C (crystallization solvent: diethyl ether-
Hexane) FABMS (pos) 479.0 [M + Na ⁺ ]

Example 40 1- (5-Bromo-2-furoyl) -N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride

Embedded image 1- (5-bromo-2-furoyl) -1,2,3,4 obtained in Reference Example 7
-From 400 mg (1.24 mmol) of tetrahydro-4-quinolinol and 346 mg (3.72 mmol) of aniline, 1- was obtained in the same manner as in Example 9.
(5-Bromo-2-furoyl) -N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine was obtained. Dissolve the obtained target substance in diethyl ether, and add 4N hydrogen chloride-ethyl acetate solution.
0.5 ml was added and stirred. The crystallized product was collected by filtration and 1- (5-bromo
271 mg (yield 50%) of 2--2-furyl) -N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride were obtained as white crystals. FABMS (pos) 419.0 [M + Na ⁺ ]

Example 41 trans-1- (5-bromo-2-furoyl) -2-methyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image Trans-2-methyl-N-phenyl-1,2,3,4-tetrahydro-
In the same manner as in Example 4 from 4-quinolinamine and 5-bromo-2-furoyl chloride, the intended product, trans-1- (5-bromo-2-furoyl) -2-methyl-N-phenyl-1, 2,3,4-Tetrahydro-4-quinolinamine was obtained as white crystals. Melting point: 117-118 ° C (crystallization solvent: diethyl ether-hexane) Elemental analysis: C ₂₁ H ₁₉ N ₂ O ₂ Br Calculated: C, 61.33; H, 4.66; N, 6.81 Experimental: C, 61.39; H, 4.60; N, 6.75

Example 42 1-([1,1'-biphenyl] -4-ylmethyl) -4- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydroquinoxaline

Embedded image 1- (3,4-dimethoxybenzoyl) -1, synthesized in Reference Example 4
From 2,3,4-tetrahydroquinoxaline 75 mg (0.25 mmol) and 4-bromomethylbiphenyl 247 mg (1.00 mmol), Example 2 was obtained.
In the same manner as 0, the target compound, 1-([1,1′-biphenyl] -4-ylmethyl) -4- (3,4-dimethoxybenzoyl) -1,
32 mg (yield 28%) of 2,3,4-tetrahydroquinoxaline was obtained as white crystals. Mp: 133-4 ° C. (crystallization solvent: ethyl acetate - diisopropyl ether) Elemental analysis C ₃₀ H ₂₈ N ₂ O ₃ Calculated: C, 77.56; H, 6.08 ; N, 6.03 Found: C, 77.29; H, 5.89; N, 5.93

Example 43 N- (2,4-Dichlorophenyl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 20 obtained in Reference Example 1
0 mg (0.61 mmol), 593 mg (3.66 mmol) of 2,4-dichloroaniline
From N- (2,4-dichlorophenyl) -1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinamine as in Example 12 302mg (Yield 5
3%) as white crystals. (Cis / trans = 1 / 1.6) Melting point: 165-167 ° C. (crystallization solvent: diethyl ether-hexane) FABMS (pos) 493.0 [M + Na ⁺ ]

Example 44 1- (3,4-Dimethoxybenzoyl) -N- (2-isopropylphenyl) -1,2,3,4-tetrahydro-4-quinolinamine hydrochloride

Embedded image 1- (3,4-dimethoxybenzoyl) -1, obtained in Reference Example 2
2,3,4-tetrahydro-4-quinolinol 300mg (0.957mmo
l), 1- (3,4-dimethoxybenzoyl) -N from 260 mg (1.92 mmol) of ortho-isopropylamine in the same manner as in Example 12.
-(2-isopropylphenyl) -1,2,3,4-tetrahydro-4-
Quinolinamine was obtained. The obtained target product was dissolved in diethyl ether, and a 4N hydrogen chloride-ethyl acetate solution (0.5 ml) was added thereto, followed by stirring. The crystallized product was collected by filtration and 1- (3,4-dimethoxybenzoyl) -N- (2-isopropylphenyl) -1,2,3,4-tetrahydro-4-quinolinamine hydrochloride 57 mg (8% yield) Was obtained as white crystals. Melting point: 93-96 ° C (crystallization solvent: diethyl ether) FABMS (pos) 453.1 [M + Na ⁺ ]

Example 45 1- (3,4-Dimethoxybenzoyl) -N-ethyl-2-methyl-N-
Phenyl-1,2,3,4-tetrahydro-4-quinolinamine hydrochloride

Embedded image Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 25 obtained in Reference Example 1
From 0 mg (0.76 mmol) and 368 mg (3.04 mmol) of N-ethylaniline, 1- (3,4-dimethoxybenzoyl) -N-ethyl-2-methyl-N-phenyl- which is the target substance was obtained in the same manner as in Example 44. 1,2,
76.7 mg of 3,4-tetrahydro-4-quinolinamine hydrochloride (yield 2
2%) as white crystals. (Cis / trans = 3/2) FABMS (pos) 453.1 [M + Na ⁺ ]

Example 46 N- (2-chlorophenyl) -1- (3,4-dimethoxybenzoyl)-
N, 2-dimethyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 40 obtained in Reference Example 1
0 mg (1.22 mmol), 518 mg of 2-chloro-N-methylaniline (3.6 mg
6 mmol) in the same manner as in Example 12 to obtain N- (2
-Chlorophenyl) -1- (3,4-dimethoxybenzoyl) -N, 2-
Dimethyl-1,2,3,4-tetrahydro-4-quinolinamine 80mg
(15% yield). (Cis / trans = 3/1) FABMS (pos) 473.2 [M + Na ⁺ ]

Example 47 6-Chloro-N- (4-chlorophenyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 400 mg of 6-chloro-1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinol obtained in Reference Example 5 (1.1
5 mmol) and 440 mg (3.45 mmol) of 4-chloroaniline in the same manner as in Example 12 to obtain 6-chloro-N- (4-chlorophenyl) -1- (3,4-dimethoxybenzoyl) -1, which is the desired product. 2,3,4-
250 mg (yield 48%) of tetrahydro-4-quinolinamine was obtained as pale yellow crystals. Melting point: 176-178 ° C (crystallization solvent: ethyl acetate-hexane) FABMS (pos) 479.1 [M + Na ⁺ ]

Example 48 6-Chloro-1- (3,4-dimethoxybenzoyl) -N-phenyl
-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 400 mg of 6-chloro-1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinol obtained in Reference Example 5 (1.1
5 mmol) and aniline 321 mg (3.45 mmol) in the same manner as in Example 12 to obtain 6-chloro-1- (3,4-dimethoxybenzoyl) -N-phenyl-1,2,3,4-tetrahydro 188 mg (34% yield) of 4-quinolinamine were obtained as pale yellow crystals. Melting point: 188-189 ° C (crystallization solvent: ethyl acetate-hexane) FABMS (pos) 445.1 [M + Na ⁺ ]

Example 49 7-chloro-N- (4-chlorophenyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 7-chloro-1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinol 400 mg obtained in Reference Example 6
(1.15 mmol) and 440 mg (3.45 mmol) of 4-chloroaniline in the same manner as in Example 12 to obtain 7-chloro-N- (4-
(Chlorophenyl) -1- (3,4-dimethoxybenzoyl) -1,2,
168 mg of 3,4-tetrahydro-4-quinolinamine (yield 32%) was obtained as pale yellow crystals. FABMS (pos) 479.1 [M + Na ⁺ ]

Table 3 summarizes the title compounds of Examples 35 to 49. However, stereochemistry indicating the stereochemistry of XAR ¹ and R ^2.

[Table 3]

Example 50 7-Chloro-1- (3,4-dimethoxybenzoyl) -N-phenyl
-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image 7-chloro-1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinol 400 mg obtained in Reference Example 6
(1.15 mmol) and 321 mg (3.45 mmol) of aniline from Example 12
7-chloro-1- (3,4-dimethoxybenzoyl) -N-phenyl-1,2,3,4-tetrahydro-4
-Quinolinamine (230 mg, yield 44%) was obtained as pale yellow crystals. Melting point: 125-126 ° C (crystallization solvent: ethyl acetate-hexane) FABMS (pos) 445.1 [M + Na ⁺ ]

Example 51 7-Chloro-N- (2-chlorophenyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine hydrochloride

Embedded image 7-chloro-1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinol 400 mg obtained in Reference Example 6
(1.15 mmol) and 440 mg (3.45 mmol) of 2-chloroaniline in the same manner as in Example 12 to obtain 7-chloro-N- (2-
(Chlorophenyl) -1- (3,4-dimethoxybenzoyl) -1,2,
3,4-Tetrahydro-4-quinolinamine was obtained. The obtained target product was dissolved in diethyl ether, and a 4N hydrogen chloride-ethyl acetate solution (0.5 ml) was added thereto, followed by stirring. The crystallized product was collected by filtration, and 29 mg of 7-chloro-N- (2-chlorophenyl) -1- (3,4-dimethoxybenzoyl) -1,2,3,4-tetrahydro-4-quinolinamine hydrochloride (yield) 5%) as pale yellow crystals. Melting point: 74-76 ° C (crystallization solvent: diethyl ether-
Hexane) FABMS (pos) 479.1 [M + Na ⁺ ]

Example 52 cis-1-[(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -2-methyl-N-phenyl 1,2,3,4-tetrahydro-4 -Quinolinamine

Embedded image From 477 mg (2.00 mmol) of cis-2-methyl-N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine and 233 mg (1.00 mmol) of 4′-chlorobiphenylcarboxylic acid in the same manner as in Example 2. ,
Cis-1-[(4'-chloro [1,1'-biphenyl] -4-yl) carbonyl] -2-methyl-N-phenyl 1,2,3,4-tetrahydro-4-quinolinamine 240 mg (yield 45%) as white crystals. Melting point: 193-194 ° C (crystallization solvent: ethyl acetate-hexane) Elemental analysis: C ₂₉ H ₂₅ N ₂ OCl Calculated: C, 76.89; H, 5.56; N, 6.18 Experimental: C, 76.87; H, 5.58; N, 6.14

Example 53 trans-1- (2,4-difluorobenzoyl) -2-methyl-N-
Phenyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image Trans-2-methyl-N-phenyl-1,2,3,4-tetrahydro-
From 4-quinolinamine and 2,4-difluorobenzoyl chloride, trans-1- (2,4-difluorobenzoyl) -2-methyl-N-phenyl-1,2,3,4- Tetrahydro-4-quinolinamine was obtained as white crystals. Melting point: 143.6 ° C (crystallization solvent: ethyl acetate-hexane)

Example 54 1- (3,4-Dimethoxybenzoyl) -2-ethyl-N-methyl-N-
Phenyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image Cis-1- (3,4-dimethoxybenzoyl) -2-ethyl-1,2,3,4-tetrahydro-4-quinolinol 40 obtained in Reference Example 8
From 0 mg (1.17 mmol) and 376 mg (3.51 mmol) of N-methylaniline in the same manner as in Example 12, 1- (3,4-dimethoxybenzoyl) -2-ethyl-N-methyl-N- Phenyl-1,2,
190 mg (38% yield) of 3,4-tetrahydro-4-quinolinamine were obtained as white crystals (cis / trans = 1/3). Melting point: 146-148 ° C (crystallization solvent: diethyl ether
-Hexane) FABMS (pos) 453.2 [M + Na ⁺ ]

Example 55 6- (4-[[1- (3,4-Dimethoxybenzoyl) -2-methyl-1,2,
3,4-tetrahydro-4-quinolinyl] amino] phenoxy) ethyl hexanoate

Embedded image Cis-1- (3,4-dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinol 50 obtained in Reference Example 1
0 mg (1.60 mmol) and ethyl 6- (4-aminophenoxy) hexanoate from 1.50 g (6.40 mmol) in the same manner as in Example 12 to obtain 6- (4-[[1- (3,4- 337 mg (yield 39%) of ethyl dimethoxybenzoyl) -2-methyl-1,2,3,4-tetrahydro-4-quinolinyl] amino] phenoxy) hexanoate was obtained.
(Cis / trans = 3/1) ¹ H-NMR (CDCl ₃ ) δ: 1.23-1.41 (9H, m), 1.47-1.55 (2H,
m), 1.63-1.83 (3H, m), 2.33 (2H, t, J = 7.2Hz), 2.55
(0.25H, m), 2.61 (0.75H, m), 3.18 (0.75H, s), 3.67
(2.25H, s), 3.82-3.93 (2H, m), 3.85 (3H, s), 4.13 (2H,
q, J = 7.2Hz), 4.39 (0.75H, m), 4.58 (0.25H, m), 4.89
(1H, m), 6.57-7.10 (10H, m), 7.34-7.43 (1H, m)

Example 56 trans-2-methyl-1- (3-methyl-2-furoyl) -N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine

Embedded image Trans-2-methyl-N-phenyl-1,2,3,4-tetrahydro-
From 953 mg (4.00 mmol) of 4-quinolinamine and 500 mg (4.00 mmol) of 3-methyl-2-furancarboxylic acid, trans-2-methyl-1- (3-methyl-2-furoyl) was obtained in the same manner as in Example 2. 535 mg (39% yield) of -N-phenyl-1,2,3,4-tetrahydro-4-quinolinamine were obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.35 (3H, d, J = 6.6 Hz), 1.93-2.00
(1H, m), 2.25 (3H, s), 2.43-2.52 (1H, m), 4.06 (1H, b
rs.), 4.72-4.78 (2H, m), 6.26 (1H, s), 6.64-6.79 (4H,
m), 7.06-7.43 (6H, m)

Table 4 summarizes the title compounds of Examples 50 to 56. However, stereochemistry indicating the stereochemistry of XAR ¹ and R ^2.

[Table 4]

Experimental Example 1 sAPP Secretion-Promoting Activity in Rat-Derived Pheochrome Cyto-PC12h Cells (1) Experimental Material Sub-strain PC12 of rat-derived pheochrome cyto-ma PC12 cells
h cells (Brain Res., 222 (1981) p.225-233) were provided by Osaka University / Prof. Hiroshi Hatanaka. Dulbecco's modified Eagle's medium: DME
M) is Nissui Pharmaceutical, HEPES (N-2-hydroxyethylpiperazine-N'-
2-ethanesulfonic acid) buffer (pH 7.4), horse serum (Horse
serum: HS), Penicillin (5000 U / ml) / Streptomycin (5 mg / ml) mixture is Gibco, fetal calf serum (Fetal calf
serum: FCS) was purchased from BioWhittaker. The culture flask used was Falcon and the collagen-coated 6-well multiwell plate was manufactured by Iwaki Glass. Anti-βAPP, 2
The 2C11 antibody was purchased from Roche Diagnostics. Other reagents used were commercial grade products.

(2) Experimental Method PC12h cells were grown in a 10% FCS / 5% HS / penicillin-streptomycin / DMEM culture solution, and then the cells were detached by pipetting. The cells were sowed in collagen-coated 6-well plates so as to be 50-70% confluent and allowed to stand for 1 day. The next day, the wells were washed twice with 1 ml of 10 mM HEPES / DMEM, replaced with 0.5 ml of 10 mM HEPES / DMEM culture solution, and the compound was added. After 3 hours, the culture supernatant was collected. The culture supernatant was concentrated by ultrafiltration using Microcon 10 (Amicon). SDS-PAGE sample buffer (Daiichi Kagaku)
And boiled for 5 minutes. The sample was subjected to SDS-PAGE (10/20% gel, ATTO), and the PVDF membrane (Bio-Rad Laborator
ies) (2 mA / cm ² 60 min). 0.1% Tween 20/20 mM Tris-buffered saline containing 5% skim milk
(pH 7.4) and blocking was performed at 4 ° C. overnight. Anti-βAPP 2
The 2C11 antibody was added at 30-fold dilution and allowed to react for 1 hour. The secondary antibody used was a 10,000-fold dilution of a horse-radish peroxidase (HRP) -conjugated anti-mouse antibody (Vector). ECL Plu for detection
s (Amersham) using Fluor-S max (Bio-Rad Labora
tories), and quantification was performed using NIH-image.

(3) Experimental Results In Table 5, FIGS. 1 and 2, Compound 1-2 and Compound 2-
2. sA 3 hours after addition of compound 1-3 and compound 2-3
It showed a PP secretion promoting effect. FIG. 1 shows the results of typical Western blotting when 3 μM of each compound was added. For each compound, the amount of sAPP in the culture solution was increased as compared to the control group. In FIG. 2, the images were quantified using the NIH image, and the average value of the sAPP secretion amount of each compound in 3 wells relative to the control group was shown. The sAPP secretion was about 1.4 times that of the control group by compound 1-2, 2.8 times that of the control group by compound 2-2, 3.3 times that of the control group by compound 1-3, and 3 times that of the control group by compound 2-3. Had increased by a factor of two each.

[Table 5]

Experimental Example 2 Cell Death Inhibitory Effect on Rat-Derived Pheochrome Cyto-PC12h Cells (1) Experimental Material
h cells were provided by Osaka University / Prof. Hiroshi Hatanaka. Dulbecco's modified Eagl medium
e's medium: DMEM) and phosphate / saline buffer (p
hosphate buffered saline (PBS) is Nissui Pharmaceutical, HEPES (N
-2-hydroxyethylpiperazine-N'-2-ethanesulfonic aci
d) Buffer (pH 7.4), Horse serum (HS), Penicillin (5000 U / ml) / Streptomycin (5 mg / ml) mixture
Gibco, Fetal calf serum (FCS) is BioWhitt
aker, transferrin, insulin and progesterone are Si
Purchased from gma. The culture flask is Falcon,
A 96-well multiwell plate with collagen coating was manufactured by Iwaki Glass Co., Ltd. LDH cytotoxic test Wako was purchased from Wako Pure Chemical. Other reagents used were commercial grade products.

(2) Experimental method PC12h cells were seeded at 2 × 10 ⁴ cells / cm ² in a 96-well plate. On the next day, the medium was replaced with a HEPES / DME medium containing 5 mg / ml transferrin, 5 mg / ml insulin and 20 nM progesterone, and 1 mM of glutamic acid and a compound were added.
After 72 hours, the number of surviving cells was determined. The cell number was determined by removing the culture solution, solubilizing the viable cells with PBS containing Tween 20,
It was determined by measuring with LDH activity.

(3) Experimental Results In PC12h cells, glutamic acid in the culture medium prevents the incorporation of cystine, a raw material of glutathione, into cells. Therefore, it is known that, when 1 mM or more of glutamic acid is added to a culture solution and cultured for 3 days or more, PC12h cells are killed by apoptosis as the amount of intracellular glutathione decreases. All of the compounds of the present invention used in Experimental Example 1 inhibited the cell death caused by the addition of 1 mM glutamic acid in a concentration-dependent manner within a range of 0.1-3 μM, and had an EC ₅₀ value of 0.3-1 μM. Among the compounds measured, compound 2-3 was the strongest and showed the greatest inhibitory effect at 1 μM, with a survival rate of about 90% (Table 6 and FIG. 3).

[Table 6]

[0181]

EFFECT OF THE INVENTION The compound of the present invention is a strong soluble beta.
It has an action to promote secretion of amyloid precursor protein and suppresses dysfunction and apoptosis of cells, particularly nerve cells, through a secreted soluble beta-amyloid precursor protein having a neurotrophic factor-like action. Examples of useful target disease names include, for example, Alzheimer's disease, Parkinson's disease, prion disease, neuropathy (preferably diabetic neuropathy, etc.), senile dementia, neuronal disorder in cerebrovascular disorder, cerebrovascular dementia, cerebrovascular disorder. Neuropathy at the time, and can be used for the prevention or treatment of these diseases.

[Brief description of the drawings]

BRIEF DESCRIPTION OF DRAWINGS FIG. 1 shows the results of measuring the action of the compound of the invention for promoting secretion of soluble beta-amyloid precursor protein by Western blotting. In the figure, lane 1 shows the group without compound addition, lane 2 shows the group with compound 1-2 added, and lane 3
Indicates a group to which compound 2-2 was added, lane 4 indicates a group to which compound 1-3 was added, and lane 5 indicates a group to which compound 2-3 was added.

FIG. 2 shows the results of the action of the compound of the present invention to promote secretion of soluble beta-amyloid precursor protein (average value of 3 wells).
FIG. In the figure, the numbers on the X axis correspond to each lane in FIG.

FIG. 3 is a graph showing the concentration dependence of the inhibitory action of glutamate-induced cell death (average value in 3 wells) of PC12h cells by a compound of the present invention. In the figure,-●-indicates compound 1.
The -2 addition group,-○-indicates the compound 2-2 addition group,-▼-indicates the compound 1-3 addition group, and-▽-indicates the compound 2-3 addition group.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 25/16 A61P 25/16 25/28 25/28 43/00 105 43/00 105 111 111 C07D 401 / 06 C07D 401/06 401/12 401/12 405/06 405/06 405/12 405/12 409/06 409/06 // C07D 215/44 215/44 241/42 241/42 (72) Inventor Yamashita Toshiro 1-7-7 Kasuga, Tsukuba-shi, Ibaraki-ken No.702 Takeda Kasuga Heights F-term (reference) 4C031 LA05 4C063 AA01 BB03 BB09 CC14 CC75 CC81 CC92 DD12 DD14 EE01 4C084 AA17 NA14 ZA02 ZA15 ZA16 ZA18 AB02 AC02A04A GA02 GA07 GA08 MA01 MA04 NA14 ZA02 ZA15 ZA16 ZA18 ZB21 ZC02

Claims (46)

[Claims] 1. A pharmaceutical composition comprising a compound having a promoting action on secretion of soluble beta-amyloid precursor protein and an inhibitory action on apoptosis, a salt thereof, or a prodrug thereof. 2. Formula (a): ## STR1 ## [In the formula, ring A represents a benzene ring which may have a substituent, and Y represents CH or N. A partial structure represented by the formula (b): [Wherein, Ar ² represents an aromatic group which may have a substituent. Or a partial structure represented by the formula (c): [In the formula, Ar ¹ represents an aromatic group which may have a substituent, and X represents an oxygen atom, CR ³ R ⁴ or NR ⁵ (R ³ ,
R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group which may have a substituent. )
And Y is as defined above. The pharmaceutical composition according to claim 1, which comprises a compound having a partial structure represented by the formula: or a salt thereof, or a prodrug thereof. 3. A compound of the formula (I) Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may have a substituent, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and Ar ¹ and Ar ² are each a substituent A ring represents an optionally substituted benzene ring, X represents an oxygen atom, CR ³ R ⁴ or NR ⁵ (R ³ , R ⁴ , R ⁵ are the same or different and each represents a hydrogen atom or a lower alkyl group which may have a substituent.), And Y is CH
Or N. ] The soluble beta-amyloid precursor protein secretion promoter containing the compound represented by these, its salt, or its prodrug. 4. The agent according to claim 3, wherein R ¹ is a hydrogen atom. 5. The agent according to claim 3, wherein R ² is a hydrogen atom or a lower alkyl group which may have a substituent. 6. The agent according to claim 3, wherein R ² is a hydrogen atom or a C _1-6 alkyl group. 7. The agent according to claim 3, wherein Ar ¹ is a phenyl group which may have a substituent or a quinolyl group which may have a substituent. 8. The agent according to claim 3, wherein Ar ¹ is a phenyl group which may have a substituent. 9. Ar ¹ is substituted by a halogen atom, a C _1-3 alkylenedioxy group, an optionally halogenated C _1-6 alkyl group or an optionally halogenated C _1-6 alkoxy group. The agent according to claim 3, which is an optionally substituted phenyl group. 10. The agent according to claim 3, wherein Ar ² is a monocyclic aromatic group which may have a substituent. 11. The agent according to claim 3, wherein Ar ² is a phenyl group, a furyl group, a thienyl group or a pyridyl group, each of which may have a substituent. 12. Ar ² is substituted by a halogen atom, a C _1-3 alkylenedioxy group, an optionally halogenated C _1-6 alkyl group or an optionally halogenated C _1-6 alkoxy group. The agent according to claim 3, which is an optionally substituted phenyl group, furyl group, thienyl group or pyridyl group. 13. The agent according to claim 3, wherein ring A is an unsubstituted benzene ring. 14. The agent according to claim 3, wherein X is NR ⁵ (R ⁵ has the same meaning as in claim 3) and Y is CH. 15. R ¹ is a hydrogen atom, R ² is a methyl group, Ar ¹ is a phenyl group which may have a substituent, Ar ² is a 3,4-dimethoxyphenyl group. , A
The agent according to claim 3, wherein the ring is an unsubstituted benzene ring, X is NR ⁵ (R ⁵ has the same meaning as in claim 3), and Y is CH. 16. A compound of the formula (I) Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may have a substituent, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and Ar ¹ and Ar ² are each a substituent A ring represents an optionally substituted benzene ring, X represents an oxygen atom, CR ³ R ⁴ or NR ⁵ (R ³ , R ⁴ , R ⁵ are the same or different and each represents a hydrogen atom or a lower alkyl group which may have a substituent.), And Y is CH
Or N. And an apoptosis inhibitor comprising the compound or a salt thereof, or a prodrug thereof. (17) the agent according to the above (3) or (16), which is an agent for improving neurological dysfunction; (18) The agent according to (3) or (16), which is a prophylactic / therapeutic agent for a neurodegenerative disease. 19. The agent according to claim 18, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, prion disease or neuropathy. 20. Use of a compound having soluble beta-amyloid precursor protein secretion promoting action and apoptosis inhibitory action, or a salt thereof, or a prodrug thereof for the manufacture of a medicament having a neurological dysfunction improving action. 21. Use of a compound having soluble beta-amyloid precursor protein secretion promoting action and apoptosis inhibitory action, a salt thereof, or a prodrug thereof for producing a preventive / therapeutic agent for a neurodegenerative disease. 22. A compound or a salt thereof, which has an activity of promoting secretion of soluble beta-amyloid precursor protein and an activity of inhibiting apoptosis, for producing a medicament having a preventive / therapeutic activity for Alzheimer's disease, Parkinson's disease, prion disease or neuropathy. Use of drag. 23. A method for producing a medicament having an action of promoting secretion of soluble beta-amyloid precursor protein and an action of inhibiting apoptosis, which is represented by the following formula (a): [In the formula, ring A represents a benzene ring which may have a substituent, and Y represents CH or N. And a partial structure represented by the formula (b): [Wherein, Ar ² represents an aromatic group which may have a substituent. Or a partial structure represented by the formula (c): [In the formula, Ar ¹ represents an aromatic group which may have a substituent, and X represents an oxygen atom, CR ³ R ⁴ or NR ⁵ (R ³ ,
R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group which may have a substituent. )
And Y is as defined above. Or a salt thereof or a prodrug thereof having a partial structure represented by the formula: 24. A compound of the formula (I) for producing a medicament having an action of promoting secretion of soluble beta-amyloid precursor protein and / or inhibiting apoptosis. Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may have a substituent, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and Ar ¹ and Ar ² are each a substituent A ring represents an optionally substituted benzene ring, X represents an oxygen atom, CR ³ R ⁴ or NR ⁵ (R ³ , R ⁴ , R ⁵ are the same or different and each represents a hydrogen atom or a lower alkyl group which may have a substituent.), And Y is CH
Or N. Or a salt thereof or a prodrug thereof. 25. A method for ameliorating neurological dysfunction, which comprises administering a compound having a secretory action of soluble beta-amyloid precursor protein secretion and an inhibitory action on apoptosis, a salt thereof or a prodrug thereof to a mammal. 26. A method for preventing or treating a neurodegenerative disease, which comprises administering a compound having a secretory promoting action of soluble beta-amyloid precursor protein and an inhibitory action on apoptosis, or a salt thereof or a prodrug thereof to a mammal. 27. The method according to claim 26, wherein the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, prion disease or neuropathy. 28. A compound of the formula (a) [In the formula, ring A represents a benzene ring which may have a substituent, and Y represents CH or N. A partial structure represented by the formula (b): [Wherein, Ar ² represents an aromatic group which may have a substituent. Or a partial structure represented by the formula (c): [In the formula, Ar ¹ represents an aromatic group which may have a substituent, and X represents an oxygen atom, CR ³ R ⁴ or NR ⁵ (R ³ ,
R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group which may have a substituent. )
And Y is as defined above. Or a salt thereof or a prodrug thereof is administered to a mammal, the method of promoting secretion of soluble beta-amyloid precursor protein and / or inhibiting apoptosis. 29. A compound of the formula (I) Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may have a substituent, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and Ar ¹ and Ar ² are each a substituent A ring represents an optionally substituted benzene ring, X represents an oxygen atom, CR ³ R ⁴ or NR ⁵ (R ³ , R ⁴ , R ⁵ are the same or different and each represents a hydrogen atom or a lower alkyl group which may have a substituent.), And Y is CH
Or N. Or a salt thereof or a prodrug thereof is administered to a mammal, the method of promoting secretion of soluble beta-amyloid precursor protein and / or inhibiting apoptosis. 30. A compound of the formula (II) Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may have a substituent, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and Ar ¹ and Ar ² are each a substituent And the ring A represents a benzene ring which may have a substituent. Or a salt thereof or a prodrug thereof. 31. R ¹ is a hydrogen atom, R ² is a methyl group, Ar ¹ is a phenyl group which may have a substituent, Ar ² is located in the 3,4-dimethoxyphenyl group , A
31. The compound according to claim 30, wherein the ring is an unsubstituted benzene ring, a salt thereof, or a prodrug thereof. 32. A pharmaceutical composition comprising the compound according to claim 30 or a salt thereof or a prodrug thereof. 33. The formula Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may have a substituent, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and Ar ² has a substituent. And the ring A represents a benzene ring which may have a substituent. And a salt thereof represented by the formula: Ar ¹ OH [wherein, Ar ¹ represents an aromatic group which may have a substituent. Wherein the compound represented by the formula (II) or a salt thereof is subjected to a condensation reaction: [Wherein, R ¹ , R ² , Ar ¹ , Ar ² and ring A have the same meanings as described above. Or a salt thereof or a prodrug thereof. 34. A compound of the formula (III) Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may be substituted, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and Ar ¹ is an aromatic group which may have a substituent. Group A, ring A represents an optionally substituted benzene ring, and ring B is an optionally halogenated C _1-6 alkoxy group, hydroxy group or C _1-3 alkylenedioxy group And X represents CR ³ R ⁴ or NR ⁵ (R ³ , R ⁴ and R ⁵ are the same or different, and each may be a hydrogen atom or a lower group which may have a substituent.) Y represents CH.
Or N (provided that X is NH, Y is CH and Ar ¹
Is an unsubstituted phenyl group). Or a salt thereof or a prodrug thereof. 35. The compound according to claim 34, wherein R ¹ is a hydrogen atom, a salt thereof, or a prodrug thereof. 36. The compound according to claim 34, wherein R ² is a hydrogen atom or a lower alkyl group which may have a substituent, or a salt thereof or a prodrug thereof. 37. The compound according to claim 34, wherein Ar ¹ is a monocyclic aromatic group which may have a substituent, or a salt thereof or a prodrug thereof. 38. The compound according to claim 34, wherein Ar ¹ is a phenyl group which may have a substituent, a salt thereof, or a prodrug thereof. 39. The compound according to claim 34, wherein Ring A is an unsubstituted benzene ring, a salt thereof, or a prodrug thereof. 40. The compound according to claim 34, wherein X is NR ⁵ (R ⁵ is as defined in claim 34) and Y is CH, or a salt thereof or a prodrug thereof. 41. R ¹ is a hydrogen atom, R ² is a methyl group, Ar ¹ is a phenyl group which may have a substituent, ring A is an unsubstituted benzene ring, Is NR
⁵ (R ⁵ is as defined in claim 34), wherein Y is CH (except when X is NH, Y is CH and Ar ¹ is an unsubstituted phenyl group). Or a salt thereof or a prodrug thereof. 42. A pharmaceutical composition comprising the compound according to claim 34, a salt thereof, or a prodrug thereof. 43. The formula: Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may be substituted, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and ring A is an optionally substituted benzene And ring B represents a benzene ring which may be substituted with an optionally halogenated C _1-6 alkoxy group, hydroxy group or C _1-3 alkylenedioxy group. A compound represented by the formula: Ar ¹ -NR ⁵ H wherein R ⁵ represents a hydrogen atom or a lower alkyl group which may have a substituent, and Ar ¹ represents a substituent An aromatic group which may be possessed (except when R ⁵ is H and Ar ¹ is an unsubstituted phenyl group). Wherein the compound is substituted with a compound represented by the formula: or a salt thereof. [Wherein, R ¹ , R ² , R ⁵ , ring A, ring B, and Ar ¹ have the same meanings as described above. Or a salt thereof or a prodrug thereof. 44. The formula: Wherein R ¹ and R ² are the same or different,
A hydrogen atom or a lower alkyl group which may be substituted, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring with an adjacent carbon atom, and Ar ¹ is an aromatic group which may have a substituent; A group represents a ring, A ring represents a benzene ring which may have a substituent, and B ring represents an optionally halogenated C _1-6 alkoxy group, hydroxy group or C _1-3 alkylenedioxy group. Represents a benzene ring which may be substituted. ] Or a salt thereof, a compound represented by the formula: R ⁵ Z wherein R ⁵ represents a hydrogen atom or a lower alkyl group which may have a substituent, and Z represents a reactive substituent. . Wherein the compound represented by the formula (I) or a salt thereof is reacted: [Wherein, R ¹ , R ² , R ⁵ , ring A, ring B, and Ar ¹ have the same meanings as described above (except when R ⁵ is H and Ar ¹ is an unsubstituted phenyl group) ). Or a salt thereof or a prodrug thereof. 45. The formula: Wherein R ¹ and R ² are the same or different,
Represents hydrogen atom or optionally substituted lower alkyl group, R ¹ and R ² for 4 to together with the carbon atom bonded to the adjacent form a 7-membered ring, Ar ¹ is aromatic may have a substituent A represents a benzene ring which may have a substituent, and X represents CR ³ R ⁴ or NR ⁵ (R ³ ,
R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom or a lower alkyl group which may have a substituent. )
Y represents CH or N (provided that X is NH,
Except when Y is CH and Ar ¹ is an unsubstituted phenyl group). With a compound represented by the formula: [In the formula, ring B represents a benzene ring which may be substituted with an optionally halogenated C _1-6 alkoxy group, hydroxy group or C _1-3 alkylenedioxy group. Wherein the compound represented by the formula (III) or a salt thereof is reacted: [Wherein R ¹ , R ² , Ar ¹ , X, Y, ring A and ring B have the same meanings as described above. Or a salt thereof or a prodrug thereof. 46. The formula Wherein R ¹ and R ² are the same or different,
Represents a hydrogen atom or a lower alkyl group which may be substituted, or R ¹ and R ² are bonded to each other to form a 4- to 7-membered ring together with an adjacent carbon atom, and ring A is an optionally substituted benzene And ring B represents a benzene ring which may be substituted with an optionally halogenated C _1-6 alkoxy group, hydroxy group or C _1-3 alkylenedioxy group. And a salt thereof represented by the formula: Ar ¹ CR ³ R ⁴ Z wherein Ar ¹ represents an aromatic group which may have a substituent, and R ³ and R ⁴ are the same as each other. Or differently, it represents a hydrogen atom or a lower alkyl group which may have a substituent, and Z represents a reactive substituent. Wherein a compound represented by the formula: or a salt thereof is reacted. [Wherein R ¹ , R ² , R ³ , R ⁴ , ring A, ring B, and Ar ¹
Is as defined above. Or a salt thereof or a prodrug thereof.