JPH0776573A - Heterocyclic compound, production thereof and preparation therefrom - Google Patents

Abstract

PURPOSE:To obtain a novel compound which is useful as a medicine having excellent activities of calcium antagonist, cerebral ischemia protection, anti- cerebral edema, nerve cell disorder protection and tachykinin receptor antago nist. CONSTITUTION:A compound of the formula I (A and B rings are benzene ring; Ar is aryl, heterocyclic ring; Q is O, S; R is H, hydrocarbon, hydroxyl, amino; X is -O-, -NR<1>-; R<1> is H, hydrocarbon; Y is -O-, -NR<2>-; R<2> is H, hydrocarbon, bond; m is 1 to 3; n is 0 to 2), for example, N-[6-chloro-1,2-dihydro-2-methyl-1- oxo-4-phenylisoquinolin-3-yl)tachyl]-N'-(3-isopropoxyphenyl)urea. The compound of the formula I is obtained by acylatlon reaction of an isoquinoline of the formula II with another compound of the formula: Ar-(CH2)n-Y-CO-L<2> (L<1>, L<2> are the leaving groups in the reaction).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel isoquinolone compound having an excellent calcium antagonistic action, cerebral ischemic protective action, anti-cerebral edema action, neuronal cell injury protective action, tachykinin receptor antagonistic action and the like. Manufacturing method and agent

[0002]

2. Description of the Related Art In recent years, the role of calcium as an information transmitter in various cells of the living body has been attracting attention and its importance is being clarified. Disruption of calcium homeostasis is considered to be a factor that causes cell damage or cell death due to pathological or physical causes. Also in nerve cells, nerve cell damage or cell death during cerebrovascular disorder such as cerebral ischemia is a failure of calcium homeostasis, that is, excessive influx of calcium into nerve cells or excessive calcium from the endoplasmic reticulum in nerve cells. Release is said to be one of the causes [Stuart A. Lipton (Stua
rt A. Lipton), Advances in Phamacology, Volume 22, 271-
297 (published in 1991); Trends in Pharmacolo
gical Sciences), 10: 397-400 (198)
Issued for 9 years)]. In such a current situation, cerebral ischemic injury,
Treatment of neuronal disorders such as cerebral edema and other cerebrovascular disorders,
As a preventive drug, development of a novel compound having an excellent calcium antagonistic action directly acting on nerve cells and having excellent properties such as safety and durability is desired.
Tachykinin is a general term for a group of neuropeptides, and in mammals, substance P, neurokinin-
A and neurokinin-B are known, and these peptides are the receptors (neurokinin-1, neurokinin-2, neurokinin-) present in the living body.
It is known to exert various biological activities by binding to 3). Among them, substance P has one of the longest history among neuropeptides and is one of those studied in detail. Substance P is known to play an important role as a signal transmitter in peripheral and central regions, and is considered to be involved in various pathological conditions (eg, pain, inflammation, allergy, psychosis, etc.). There is. Therefore, it has an excellent tachykinin receptor antagonism, particularly a substance P receptor antagonism,
In addition, it is desired to develop a new compound having excellent properties in terms of safety and durability. Examples of the currently known compound having a substance P receptor action include (1) JP-A-1-287095, which has the formula: R ¹ -A-D-Trp (R ² ) -Phe-R ³ [wherein R ¹ is hydrogen or amino protecting group, R ² is hydrogen, amino protecting group, carbamoyl (lower) alkyl group, carboxy (lower) alkyl group or protected carboxy (lower) alkyl group, R ³ is ar (lower) alkyl group ,
formula:

[Chemical 6] (In the formula, R ⁴ and R ⁵ each represent hydrogen, an aryl group or a lower alkyl group which may have a suitable substituent, or R ⁴ and R ⁵ are differently bonded to each other and are benzene-fused lower alkylene. Forming a group) or a group represented by the formula: —OR ⁶ (wherein R ⁶ represents hydrogen, an aryl group or a lower alkyl group which may have a suitable substituent). , A represents a single bond or 1 or 2 amino acid residues, respectively, and when A represents an amino acid residue of -D-Trp-, then R ⁴ is not hydrogen. Salt, (2) EP-A-436,334, with the formula:

[Chemical 7] (3) EP-A-429,366 has the formula:

[Chemical 8] (4) Journal of Medicinal Chemistry, vol 34, p1751 (19)
91), the formula:

[Chemical 9] Compounds represented by are described. Also, ACA
Heterocyclic compounds [A] as shown in Table 1 below are known as compounds having a T-inhibitory effect.

[Table 1]

[0003]

[Problems to be Solved by the Invention] As a therapeutic or prophylactic agent for cerebral ischemic injury, neuronal cell damage during cerebrovascular accidents such as cerebral edema, excellent calcium antagonism directly acting on nerve cells and excellent tachykinin receptor There is a demand for the development of a novel compound having excellent properties in terms of safety and durability, which has a body antagonism, particularly a substance P receptor antagonism.

[0004]

Means for Solving the Problems As a result of intensive studies in view of the above circumstances, the present inventors have found that the side chain of the isoquinolone skeleton is substituted with an alkylene group at the 3-position in terms of chemical structure. A novel heterocyclic compound with features was first synthesized.Unexpectedly, this novel compound, based on the chemical structure of its unique side chain, suppresses calcium release from intracellular endoplasmic reticulum and protects against cerebral ischemic injury. The present invention was completed based on these findings, and was found to have excellent effects on anti-cerebral edema action, neuronal disorder protection action, tachykinin receptor antagonist action and the like. That is, the present invention provides (1) the general formula

[Chemical 10] [In the formula, A ring and B ring may have a benzene ring which may have a substituent, Ar represents an aryl group which may have a substituent or a heterocyclic group which may have a substituent, Q Is an oxygen atom or a sulfur atom, R is a hydrogen atom, a hydrocarbon group which may have a substituent, a hydroxyl group which may have a substituent or an amino group which may have a substituent, X Is —O— or —NR ¹ — (R ¹ represents a hydrogen atom or a hydrocarbon group which may have a substituent), Y is —O—, —
NR ² — (R ² represents a hydrogen atom or a hydrocarbon group which may have a substituent) or a bond, m represents 1, 2 or 3, and n represents 0, 1 or 2. Or a salt thereof], (2) A ring and B ring is a halogen atom, a C _1-6 alkyl group which may be halogenated,
C _1-6 alkoxy group which may be halogenated, C _1-6 alkylthio group which may be halogenated, C _1-7 acylamino group, C _1-3 acyloxy group, hydroxyl group, nitro group, cyano group , Amino group, mono- or di-
C _1-4 alkylamino group, pyrrolidino group, piperidino group, morpholino group, C _1-4 alkyl-carbonylamino group, C _1-4 alkylsulfonylamino group, C _1-4 alkoxy-carbonyl group, carboxyl group, C _{1 -6} alkyl-
Carbonyl group, carbamoyl group, mono- or di-C
The compound according to (1) above, which is a benzene ring optionally having 1 to 4 substituents selected from _1-4 alkylcarbamoyl group and C _1-6 alkylsulfonyl group, (3)
A ring and B ring is a halogen atom, an optionally halogenated C _1-4 alkyl group, optionally C _1-4 alkoxy group which may be halogenated, an optionally halogenated C
_{1 selected from 1-4} alkylthio group, hydroxyl group, amino group, mono- or di-C _1-4 alkylamino group, carboxyl group and C _1-4 alkoxy-carbonyl group
To the compound described in (1) above, which is a benzene ring optionally having 3 substituents,

(4) A ring and B ring are halogen atoms,
The above-mentioned benzene ring which may have 1 or 2 substituents selected from an optionally halogenated C _1-4 alkyl group and an optionally halogenated C _1-4 alkoxy group ( 1) the compound, (5) the B ring is unsubstituted, the (1) compound, (6) the A ring may be a halogen atom or a halogenated C _1-4 alkyl group.
Or a compound according to the above (1), wherein the benzene ring which may have two and the B ring is an unsubstituted benzene ring,
(7) The compound according to the above (1), wherein R is a hydrogen atom,
(8) The compound described in (1) above, wherein R is a C _1-6 alkyl group, (9) The compound described in (1) above, wherein Q is an oxygen atom,
(10) The compound according to the above (1), wherein X is -O-, (1
1) The compound described in (1) above, wherein X is -NH-, (1
2) The compound according to (1) above, wherein R ² is (i) a hydrogen atom or (ii) a C _1-4 alkoxy-carbonyl group or a C _1-4 alkyl group optionally substituted with a carboxyl group, (1)
3) The above, wherein R ² is a hydrogen atom or a C _1-4 alkyl group
(1) The compound according to (1), wherein (14) Y is —NH—.
The compound according to (1), wherein (15) Y is a bond, the compound according to (1), wherein (16) m is 1, and the compound according to (1), wherein (17) m is 2. Compound of (1,
8) The compound described in (1) above, wherein n is 0, (19) The compound described in (1) above, wherein n is 1.

(20) Ar is (i) an optionally halogenated C _1-4 alkyl group, (ii) a mono- or di-C _1-4 alkylamino-C _1-4 alkyl group, (iii ) Carboxy-C
_1-4 alkyl group, (iv) C _1-4 alkoxy-carbonyl-C
_1-4 alkyl group, (v) optionally halogenated C _1-4
Alkoxy group, (vi) carboxy-C _1-4 alkoxy group,
(vii) C _1-4 alkoxy-carbonyl-C _1-4 alkoxy group, (viii) halogen atom, (ix) mono- or di-C _1-4
The compound according to (1) above, which is a phenyl group optionally having 1 or 2 substituents selected from an alkylamino group, (x) C _1-4 alkoxy-carbonyl group and (xi) carboxyl group, (21) Ar is (i) an optionally halogenated C _1-4 alkoxy group, (ii) a carboxyl group, (iii)
Carboxy-C _1-4 alkyl group, (iv) mono- or di-
One substituent selected from C _1-4 alkylamino-C _1-4 alkyl group, (v) mono- or di-C _1-4 alkylamino group and (vi) carboxy-C _1-4 alkoxy group A compound according to the above (1), which may have a phenyl group,
(22) Ar is (i) amino group, (ii) mono- or di-C
_1-4 alkylamino group or (iii) a phenyl group optionally having 1 or 2 C _1-6 alkyl groups optionally having 5 to 9 membered cyclic amino groups (1) The described compound,

(23) Ar is (i) an optionally halogenated C _1-4 alkoxy group or (ii) a mono- or di-
The compound according to (1) above, which is a phenyl group which may be substituted with one of C _1-4 alkylamino-C _1-4 alkyl group, and (24) Ar which may be halogenated C _{1- 4} The compound according to (1) above, which is a phenyl group which may be substituted with an alkoxy group, (25) Ar is a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group. , A pyridazinyl group, a quinolyl group, an isoquinolyl group, an indolyl group, a thiazolyl group, a thiadiazolyl group or a thiophenyl group, (26) a compound of the above (1) wherein Ar is an indolyl group, (27) ) Q is an oxygen atom, R is a C _1-4 alkyl group, X is -NH- and Y is -NH- or a compound according to the above (1),
(28) (i) N-[(6-chloro-1,2-dihydro-
2-Methyl-1-oxo-4-phenylisoquinoline-
3-yl) methyl] -N '-(3-isopropoxyphenyl) urea, (ii) N-[(6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinoline-3 -Yl) methyl] -N '-(3-N, N-dimethylaminomethylphenyl) urea, (iii) N- (6-
Chloro-1,2-dihydro-2-methyl-1-oxo-
4-phenylisoquinolin-3-yl) methyl-α-
(3-isopropoxyphenyl) acetamide, (iv) N
-(6-chloro-1,2-dihydro-2-methyl-1-
Oxo-4-phenylisoquinolin-3-yl) methyl-α- (3-methoxycarbonylphenyl) acetamide, (v) N-[(6-chloro-1,2-dihydro-2-
Methyl-1-oxo-4-phenylisoquinoline-3-
Iyl) methyl] -N '-{(3- [2- (diethylamino) ethyl] phenyl} urea, (vi) N-[(6-chloro-1,2-dihydro-2-methyl-1-oxo-4 −
Phenylisoquinolin-3-yl) methyl] -N'-
{(3- [2- (Dimethylamino) ethoxy] phenyl} urea, (vii) N-[(6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl ) Methyl] -N '-[3- (1-imidazoyl) propyl] urea, (viii) N-[(6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinoline-3 -Yl) methyl] -N '-[3
-(Methylamino) methylphenyl] urea, (ix) N-
[(6-chloro-1,2-dihydro-2-methyl-1-
Oxo-4-phenylisoquinolin-3-yl) methyl] -N '-[3- (ethylaminoethyl) phenyl]
Urea or (x) N- [3- (aminomethyl) phenyl] -N '-[(6-chloro-1,2-dihydro-2-
Methyl-1-oxo-4-phenylisoquinoline-3-
Ile) methyl] urea, or their salts,

(29) General formula

[Chemical 11] A compound represented by or a salt thereof with the general formula _{Ar- (CH 2) n -Y-} CO-L 2 (III) wherein, L ¹ and L ² are both reactive to a group which desorbs, other symbols Has the same meaning as above. ] A general formula characterized by reacting with a compound represented by

[Chemical 12] [The symbols in the formulas have the same meaning as in the above (1). ] The manufacturing method of compound (I) or its salt represented by these,

(30) General formula

[Chemical 13] A compound represented by or a salt thereof with the general formula Ar- (CH ₂₎ a compound represented by _n -Y ¹ -L ⁴ (V) or the general formula which comprises reacting a salt thereof

[Chemical 14] [In the formula, L ³ and L ⁴ are groups that react with each other to leave; Y ¹
Is -O- or -NR ² -, the other symbols are as defined above. ] The manufacturing method of the compound or its salt represented by these, (3
1) A calcium antagonist characterized by containing the compound described in the above (1), (32) A therapeutic agent for cerebrovascular disorder characterized by containing the compound described in the above (1), (33) The above ( (1) A therapeutic agent for cerebral ischemic injury containing the compound according to (1), (34) A therapeutic agent for cerebral edema containing the compound according to (1) above, (35) (1) above Substance P containing the described compound
The present invention relates to a receptor antagonist.

In the above formula, ring A and ring B are "benzene ring which may have a substituent". The "benzene ring"
Examples of the substituent which may have include, for example, a halogen atom, an alkyl group which may be halogenated, an alkoxy group which may be halogenated, an alkylthio group which may be halogenated, C _1-7 Acylamino group (eg, formylamino, acetylamino, propionylamino, butyrylamino, benzoylamino etc.), C
_1-3 acyloxy group (eg, formyloxy, acetoxy, propionyloxy etc.), hydroxyl group, nitro group, cyano group, amino group, mono- or di-C _1-4
Alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), cyclic amino group (eg, containing 1 to 3 heteroatoms such as oxygen atom, sulfur atom, etc. in addition to nitrogen atom) A good 5- to 9-membered cyclic amino group, such as pyrrolidino, piperidino, morpholino), C
_1-4 alkyl-carbonylamino group (for example, acetylamino, propionylamino, butyrylamino, etc.),
C _1-4 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino, etc.), C
_1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), carboxyl group, C _1-6 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, propylcarbonyl, etc.), carbamoyl group, mono —Or a di-C _1-4 alkylcarbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, etc.), a C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.) and the like are used.

The term "halogen atom" used in the present specification includes, for example, fluorine, chlorine, bromine, iodine and the like, preferably chlorine, fluorine and the like. As the term “optionally halogenated alkyl group” used in the present specification, for example, a C _1-6 alkyl group or a group in which 1 to 5 halogen atoms as described above are substituted is used, For example methyl,
Chloromethyl, difluoromethyl, trichloromethyl,
Trifluoromethyl, ethyl, 2-bromoethyl, 2,
2,2-trifluoroethyl, pentafluoroethyl,
Propyl, 3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl, 4,
4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, 4-trifluoromethylbutyl, hexyl, 6,6,6-tri Fluorohexyl, 5-trifluoromethylpentyl and the like are commonly used, preferably, for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl,
Ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl,
A C _1-4 alkyl group such as 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl or the like in which 1 to 3 halogen atoms as described above are substituted is used.

As used herein, the term "optionally halogenated alkoxy group" includes, for example, C
_{A 1-6} alkoxy group or one having 1 to 5 halogen atoms as described above is used, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, Isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy, hexyloxy and the like are commonly used, and preferably, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2- C _1-4 alkoxy groups such as trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy and sec-butoxy, or ones thereof with 1 to 3 halogen atoms as described above. Are used.
As the term “optionally halogenated alkylthio group” used in the present specification, for example, a C _1-6 alkylthio group or a group in which 1 to 5 halogen atoms as described above are substituted is used, For example, methylthio, difluoromethylthio, trifluoromethylthio,
Ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like are generally used, and preferably, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio,
A C _1-4 alkylthio group such as butylthio, 4,4,4-trifluorobutylthio or a C _1-4 alkylthio group substituted with 1 to 3 halogen atoms as described above is used.

Preferred substituents which ring A and ring B may have include, for example, a halogen atom and an optionally halogenated C _1-4 alkyl group (eg, methyl, chloromethyl, difluoromethyl, trichloro). Methyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,
2-trifluoroethyl, propyl, isopropyl, etc.), hydroxyl group, optionally halogenated C
_1-4 alkoxy group (eg, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, etc.), optionally halogenated C _1-4 alkylthio group ( For example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, etc.), amino group, mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.) , A carboxyl group, a C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.) and the like, particularly a halogen atom (eg, fluorine, chlorine, bromine), halogenated which may C _1-4 alkyl group For example, methyl,
Chloromethyl, difluoromethyl, trichloromethyl,
Trifluoromethyl, ethyl, 2-bromoethyl, 2,
2,2-trifluoromethyl, propyl, isopropyl, etc.), an optionally halogenated C _1-4 alkoxy group (eg, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy) , Propoxy, isopropoxy, etc.) and the like are used.

The substituents on ring A and ring B may be substituted at any substitutable position on the ring, and when there are two or more substituents, they may be the same or different. The number may be 1 to 4, preferably 1 to 3, and particularly 1 or 2 is widely used.

[Chemical 15] [Wherein A ¹ is, for example, a halogen atom such as chlorine or fluorine, an optionally halogenated C _1-4 alkyl group such as methyl, ethyl, isopropyl, trifluoromethyl or methoxy, trifluoromethoxy,
Represents an optionally halogenated C _1-4 alkoxy group such as ethoxy],

[Chemical 16] [In the formula, A ² and A ³ are the same or different and each is a halogen atom such as chlorine or fluorine, or an optionally halogenated C _1-4 alkyl group such as methyl, ethyl, isopropyl or trifluoromethyl. Alternatively, it represents an optionally halogenated C _1-4 alkoxy group such as methoxy, trifluoromethoxy, ethoxy and the like. ] And the like are used. As A ¹ , A ² and A ³ , for example, a halogen atom (eg, fluorine, chlorine, bromine, etc.), and optionally halogenated C
_{A 1-4} alkyl group (eg, methyl, trifluoromethyl, ethyl, etc.) and the like are preferable.

[0015]

[Chemical 17] [Wherein B ¹ is a halogen atom such as chlorine and fluorine, an optionally halogenated C _1-4 alkyl group such as methyl, trifluoromethyl and ethyl, or a methoxy, trifluoromethoxy, ethoxy and the like. Represents a C _1-4 alkoxy group which may be halogenated],

[Chemical 18] [In the formula, B ² and B ³ are the same or different and each is a halogen atom such as chlorine or fluorine, or an optionally halogenated C _1-4 alkyl group such as methyl, trifluoromethyl, ethyl or the like. Represents an optionally halogenated C _1-4 alkoxy group such as methoxy, trifluoromethoxy and ethoxy] or

[Chemical 19] [Wherein B ⁴ , B ⁵ and B ⁶ are the same or different,
For example, halogen atom such as chlorine and fluorine, optionally halogenated C _1-4 alkyl group such as methyl, trifluoromethyl and ethyl, optionally halogenated such as methoxy, trifluoromethoxy and ethoxy. A group represented by C _1-4 alkoxy group] is used.

With respect to ring B, more preferably the formula

[Chemical 20] [In the formula, B ¹ , B ² and B ³ have the same meanings as described above. ]
A group represented by is used. B ¹ , B ² and B ³ therein are, for example, halogen atoms such as fluorine, chlorine and bromine, and optionally halogenated C _1-4 alkyl groups such as methyl, trifluoromethyl and ethyl. Is preferred. Ring B is also commonly used when it is an unsubstituted benzene ring. In the above formula, R represents "a hydrogen atom, a hydrocarbon group which may have a substituent, a hydroxyl group which may have a substituent or an amino group which may have a substituent". Examples of the “hydrocarbon group” of the “hydrocarbon group which may have a substituent” represented by R include, for example, a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a C _3-6 cycloalkyl- A C _1-4 alkyl group or the like is used. Examples of the C _1-6 alkyl group include methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl and the like are used, preferably, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. And C _1-4 alkyl groups such as As the C _3-6 cycloalkyl group, for example, cyclopropyl, cyclopentyl or cyclohexyl is used. C _3-6 cycloalkyl-
Examples of the C _1-4 alkyl group include cyclopropylmethyl and cyclopropylethyl. Preferred examples of such a hydrocarbon group are C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl and butyl.

The substituent which the "hydrocarbon group" may have is, for example, (a) a halogen atom (eg, fluorine, chlorine, bromine, iodine), (b) nitro group, (c) cyano. Group, (d) hydroxyl group, (e) C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, butoxy, isopropoxy, etc.), (f) C _1-4 alkylthio group (eg, methylthio, ethylthio, propylthio) Such),
(g) amino group, (h) mono- or di-C _1-4 alkylamino group (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), (i)
Cyclic amino group which may be substituted with C _1-4 alkyl group (eg, methyl, ethyl, etc.) (including 1 to 3 hetero atoms such as oxygen atom, sulfur atom, etc. in addition to nitrogen atom and carbon atom) A 5- to 9-membered cyclic amino group which may be mentioned, specifically, for example, pyrrolidino, piperidino,
Piperazino, 4-methylpiperazino, morpholino etc.), (j) C _1-4 alkyl-carbonylamino group (eg acetylamino, propionylamino, butyrylamino etc.), (k) C _1-4 alkylsulfonylamino group (eg methyl Sulfonylamino, ethylsulfonylamino, etc.), (l) C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), (m) carboxyl group, (n) C
_1-6 alkyl-carbonyl group (for example, methylcarbonyl, ethylcarbonyl, propylcarbonyl, etc.),
(o) carbamoyl group, (p) mono- or di-C _1-4 alkylcarbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, etc.), (q) C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl) , Propylsulfonyl, etc.) and a phenyl group optionally substituted with an (r) C _1-3 alkoxy group (eg, phenyl, o
-, M- or p-methoxyphenyl etc.) and the like are used, preferably 1 to 5, and preferably 1 or 3.

Preferred substituents which the "hydrocarbon group" represented by R may have are, for example, a halogen atom (eg, fluorine, chlorine, bromine, etc.), a hydroxyl group, a C _1-4 alkoxy group. (Eg, methoxy, ethoxy, propoxy, etc.), amino group, mono- or di-C
_1-4 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.), C
_1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), carboxyl group, carbamoyl group, phenyl group and the like, particularly halogen atom (eg, fluorine, chlorine, bromine), carboxyl A group, a carbamoyl group and the like are commonly used. The number of these substituents is 1
Or two is preferable.

The "optionally substituted hydroxyl group" represented by R includes, for example, hydroxyl group, C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-). Butoxy etc.), C _6-10 aryloxy group (eg phenoxy, naphthyloxy etc.), C _1-4 alkyl-carbonyloxy group (eg formyloxy, acetoxy,
And C _6-10 aryl-carbonyloxy groups (eg, benzoyloxy, naphthoyloxy, etc.) and the like. These groups may have a substituent, and examples of the substituent which these groups may have include a “hydrocarbon group which may have a substituent” described in the above R. The same group and number as the substituent which may have are used. As the “hydroxyl group optionally having substituent (s)”, for example, a hydroxyl group or a C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, etc.) and the like are commonly used. Examples of the substituent of the “optionally substituted amino group” represented by R include (i) C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.), (ii) C _1-4 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, etc.), (iii) C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.) or (iv) halogen atom (eg, , Fluorine, chlorine etc.), a C _1-4 alkyl group (eg methyl, ethyl etc.) or a C _1-4 alkoxy group (eg methoxy, ethoxy etc.) which may be substituted with a phenyl group (eg phenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl,
4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl and the like) are used. The amino group may have one or two of the above substituents. R is a hydrogen atom, a C _1-4 alkyl group (eg, methyl, ethyl, n-propyl, n-butyl, etc.), a hydroxyl group, a C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, etc.), amino A group and the like are preferable, and a C _1-4 alkyl group (eg, methyl, ethyl, n-propyl and the like, especially methyl and the like) and the like are particularly preferable.

Q represents an oxygen atom or a sulfur atom, and the oxygen atom is generally used. In the formula, X represents —O— or —NR ¹ — (in the formula, R ¹ represents a hydrogen atom or a hydrocarbon group which may have a substituent). Examples of the hydrocarbon group of the “hydrocarbon group which may have a substituent” represented by R ¹ include, for example, a C _1-6 alkyl group, a C _3-6 cycloalkyl group or a C _3-6 cycloalkyl- A C _1-4 alkyl group and the like are preferable. As the C _1-6 alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl and the like can be used, preferably methyl, ethyl, propyl, isopropyl, A C _1-4 alkyl group such as butyl, isobutyl, sec-butyl, tert-butyl is used. As the C _3-6 cycloalkyl group,
For example, cyclopropyl, cyclopentyl or cyclohexyl is used. C _3-6 cycloalkyl-C _1-4
As the alkyl group, for example, cyclopropylmethyl, cyclopropylethyl and the like are used. As the "hydrocarbon group" represented by R ¹ , a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.) is preferable. Examples of the substituent which the “hydrocarbon group” represented by R ¹ may have are the same as the “substituent” described in the “hydrocarbon group which may have a substituent” represented by R. Groups and the like are used. Preferred substituents that the “hydrocarbon group” represented by R ¹ may have are a hydroxyl group, a C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, etc.), an amino group, a mono group. _{-Or a} di-C _1-4 alkylamino group (for example, methylamino, ethylamino, dimethylamino, diethylamino, etc.), a C _1-4 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl,
Propoxycarbonyl, etc.), carboxyl group, carbamoyl group, phenyl group, etc., and particularly C _1-4 alkoxy (eg, methoxy, ethoxy, etc.), mono-
Or a di-C _1-4 alkylamino group (eg, dimethylamino etc.), a carbamoyl group, a carboxyl group, C
_{A 1-4} alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.) and the like are commonly used.
The number of substituents is preferably 1 or 2. R ¹ is preferably a hydrogen atom or a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, etc.), and particularly preferably a hydrogen atom. As X, for example, —NH— is most commonly used.

In the above formula, Ar represents "an aryl group which may have a substituent or a heterocyclic group which may have a substituent". The "aryl group" of the "aryl group which may have a substituent" represented by Ar is preferably a C _6-10 aryl group such as phenyl or naphthyl, and particularly preferably a phenyl group. The aryl group represented by Ar may have 1 to 5 identical or different substituents, and preferably 1 to 3 substituents. Further, these substituents may be substituted at any substitutable position on the ring. Examples of such a substituent include (a) a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), (b) nitro group, (c) cyano group, (d) hydroxyl group, (e) halogenated group. which may be C _1-4 alkoxy group, (f) C _1-4 alkoxy group substituted with a carboxyl group (e.g., carboxymethoxy, 2- (carboxy) ethoxy, etc.), (g) C _1-4 alkoxy - C _1-4 alkoxy group substituted with a carbonyl group (for example, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, 2- (methoxycarbonyl) ethoxy, 2- (ethoxycarbonyl) ethoxy), (h) halogenated Optionally C _1-4 alkylthio group (eg, methylthio, ethylthio, trifluoromethylthio, etc.), (i) amino group, (j) mono- or di-
C _1-4 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.), (k) C _1-4 alkyl group (eg, methyl,
Cyclic amino group which may be substituted with ethyl, propyl, etc. (for example, 5- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms such as oxygen atom and sulfur atom in addition to nitrogen atom, etc.) , Specifically, for example, pyrrolidino, piperidino, piperazino, 4-methylpiperazino,
Morpholino, etc.), (l) C _1-4 alkyl-carbonylamino group (eg, acetylamino, propionylamino,
Butyrylamino, etc.), (m) aminocarbonyloxy group, (n) mono- or di-C _1-4 alkylaminocarbonyloxy group (eg, methylaminocarbonyloxy,
Ethylaminocarbonyloxy, dimethylaminocarbonyloxy, diethylaminocarbonyloxy, etc.),
(o) C _1-4 alkylsulfonylamino group (eg, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, etc.), (p) C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl) , Isobutoxycarbonyl, etc.), (q) benzyloxycarbonyl group, (r) carboxyl group, (s) C _1-4 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), (t) C _3-6 cycloalkyl-carbonyl (eg cyclohexylcarbonyl etc.), (u) carbamoyl group, (v) mono- or di-C _1-4 alkylcarbamoyl group (eg methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl) , Diethylcarbamoyl, dibutyl calc Moil, etc.), (w)
A C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, etc.),
(x) a hydrocarbon group which may have a substituent or (y) a mono- or di-C _1-4 alkylamino-substituted C
_1-4 alkoxy group (for example, dimethylaminomethoxy,
Such as dimethylaminoethoxy) is used. Examples of the “hydrocarbon group” used as the substituent of the “aryl group” and the substituent which the “hydrocarbon group” may have include, for example, the “hydrocarbon group having the substituent” described in R above. The same groups as the hydrocarbon groups and the substituents thereof, which are exemplified in the “may be a hydrocarbon group”, and the like are used. Further, the "aryl group" is the "aryl group" which is the "heterocyclic group which may have a substituent (s)" represented by Ar as described later.
Can be used as it is as a substituent. Preferred examples of the "heterocyclic group which may have a substituent (s)" include, for example, an optionally halogenated C _1-4 alkyl group (eg, methyl, chloromethyl, difluoromethyl, trichloromethyl, trialkyl Fluoromethyl, ethyl,
2-bromoethyl, 2,2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, butyl, etc.), C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) A halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a hydroxyl group, an optionally halogenated C _1-4 alkoxy group (eg, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,
2-trifluoroethoxy, propyloxy, butyloxy, isopropyloxy, etc.), an optionally halogenated C _1-4 alkylthio group (eg, methylthio,
Difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), amino group, mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, etc.) ), C
_1-4 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
5 or 6-membered optionally substituted with 1 to 3 selected from isobutoxycarbonyl, etc.), carboxyl group and C _1-6 alkyl-carbonyl group (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.) An aromatic monocyclic heterocyclic group (eg, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,
2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,
3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,
3,4-thiadiazolyl, 1,2,3-triazolyl, 1,
2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc.) and the like are used.

Preferable examples of the substituent which the “aryl group” represented by Ar may have include, for example, (i) an optionally halogenated C _1-4 alkyl group (eg,
Methyl, chloromethyl, bromomethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl,
2-bromoethyl, 2,2,2-trifluoroethyl, propyl, isopropyl, 3,3,3-trifluoropropyl, etc., (ii) halogen atom (for example, fluorine, chlorine,
Bromine etc.), (iii) amino group or mono- or di-C
_1-4 C _1-4 alkyl group substituted with an alkylamino group (e.g., aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethyl, 2- (methylamino) ethyl,
2- (dimethylamino) ethyl, 2- (diethylamino) ethyl etc.), (iv) C _1-4 alkyl group (eg methyl, ethyl, propyl etc.), optionally substituted cyclic amino group (eg nitrogen) In addition to the atoms, 5- to 7-membered cyclic amino groups which may contain 1 or 2 hetero atoms such as oxygen atom or sulfur atom, specifically, for example, pyrrolidino, piperidino, piperazino, 4
C substituted with (methylpiperazino, morpholino, etc.)
_1-4 alkyl group (for example, pyrrolidinomethyl, 2-pyrrolidinoethyl, piperidinomethyl, 2-piperidinoethyl, piperazinomethyl, 2-piperazinoethyl, 4-
Methylpiperazinomethyl, 2- (4-methylpiperazino) ethyl, morpholinomethyl, 2-morpholinoethyl, etc.), (v) a C _1-4 alkyl group substituted with a carboxyl group (eg, carboxymethyl, 2-carboxyethyl) Etc.), (vi) C _1-4 alkyl group substituted with a C _1-4 alkoxy-carbonyl group (for example, methoxycarbonylethyl, 2-ethoxycarbonylethyl, etc.), (vii) C ₁ substituted with a hydroxyl group _-4 alkyl groups (eg,
Hydroxymethyl, 2-hydroxyethyl, etc.), (vii
i) hydroxyl group, (ix) optionally halogenated C
_1-4 alkoxy group (for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, propoxy,
Isopropoxy, n-butoxy, t-butoxy, 2,2,
2-trifluoroethoxy, etc.), (x) a C _1-4 alkoxy group substituted with a carboxyl group (eg, carboxymethoxy, 2-carboxyethoxy, etc.), (xi) C _1-4
A C _1-4 alkoxy group substituted with an alkoxy-carbonyl group (for example, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, 2- (methoxycarbonyl) ethoxy, 2- (ethoxycarbonyl) ethoxy, etc.), (x
ii) C _1-4 alkylthio group (eg, methylthio, ethylthio, etc.), (xiii) amino group, (xiv) mono- or di-
C _1-4 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.), (x
v) A C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), (xvi) carboxyl group, (xvii) carbamoyl group, etc. are used. The number of substituents is preferably 1 to 3. The "aryl group"
More preferred examples of the substituent that may have have, for example, (i) to (xi) in the above (i) to (xvii) are generally used.
The number of substituents is preferably 1 or 2. Among these, for example, (iii), (iv), (vi), (vii), (ix), (xi) and the like are used in general. The number of substituents is preferably one.

The "heterocyclic group" of the "heterocyclic group which may have a substituent" represented by Ar includes, for example, 1 to 1 heteroatoms such as nitrogen, oxygen and sulfur atoms in addition to carbon atoms. A 5- to 9-membered, preferably 5- or 6-membered aromatic heterocyclic group which may contain 4, preferably 1 or 2, is used. Examples of such an aromatic heterocyclic group include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
Imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl,
Aromatic monocyclics such as 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl Heterocyclic groups, preferably, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, quinolyl,
Isoquinolyl, thiazolyl, thiadiazolyl, thiophenyl and the like are used, and especially furyl, thienyl, pyridyl and the like are widely used. Examples of the “heterocyclic group” include benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H.
-Indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl,
Quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α
-Carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenatridinyl, phenatrolinyl, indoridinyl, pyrrolo [1,2-b] pyridazinyl, pyrazolo [1,5-a] ] Pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2]
-B] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl,
Aromatic condensed heterocyclic groups such as 1,2,4-triazolo [4,3-b] pyridazinyl are also used, and preferably benzofuranyl, indolyl, benzimidazolyl, benzoxazolyl, quinolinyl, etc. are particularly preferable. In-drill etc. are commonly used.

As the "substituent" of the "heterocyclic group which may have a substituent" represented by Ar, for example, the same substituents as those in the above "aryl group" of Ar can be used. The number of groups is 1 to 3. Preferred as the substituent of the “heterocyclic group” represented by Ar are:
(i) halogen atom (eg, fluorine, chlorine, bromine, etc.), (ii) optionally halogenated C _1-4 alkyl group (eg, methyl, chloromethyl, difluoromethyl, trifluoromethyl, ethyl etc.) , (Iii) C _3-6 cycloalkyl group (for example, cyclopropyl, cyclobutyl etc.), (iv) amino group or mono- or di-C _1-4
A C _1-4 alkyl group substituted with an alkylamino group (for example, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethyl, 2- (methylamino) ethyl,
2- (ethylamino) ethyl, 2- (dimethylamino)
Ethyl, 2- (diethylamino) ethyl, etc.), (v) C
_1-4 Cyclic amino group optionally substituted by an alkyl group (eg, methyl, ethyl, propyl, etc.) (eg, containing 1 or 2 heteroatoms such as oxygen atom or sulfur atom in addition to nitrogen atom) A 5- to 7-membered cyclic amino group and the like, specifically, for example, a C _1-4 alkyl group substituted with, for example, pyrrolidino, piperidino, piperazino, 4-methylpiperazino, morpholino, etc. -Pyrrolidinoethyl, piperidinomethyl, 2-piperidinoethyl, piperazinomethyl, 2-
Piperazinoethyl, 4-methylpiperazinomethyl, 2-
(4-methylpiperazino) ethyl, morpholinomethyl,
And 2-morpholinoethyl), (vi) substituted with a carboxyl group C _{1 4} alkyl group (e.g., carboxymethyl, carboxyethyl, etc.), C substituted with (vii) C _1-4 alkoxycarbonyl group _{1 4} alkyl group (eg, methoxycarbonylethyl, ethoxycarbonylethyl, etc.), (viii) C _1-4 alkyl group substituted with a hydroxyl group (eg, hydroxymethyl, hydroxyethyl, etc.), (ix) hydroxyl group, (x ) An optionally halogenated C _1-4 alkoxy group (for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, propoxy, isopropoxy, etc.), (xi) amino group, (xii)
A mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.), (xiii) C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), (xiv) Carboxyl group or the like is used.

Preferred examples of Ar include (a) optionally halogenated C _1-4 alkyl group (eg, methyl, chloromethyl, bromomethyl, difluoromethyl, trifluoromethyl, ethyl, 2,2,2, 2-trifluoroethyl, propyl, isopropyl, etc.), (b) an optionally halogenated C _1-4 alkoxy group (eg,
Methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, etc.), (c) a C _1-4 alkoxy group substituted with a carboxyl group (eg, carboxymethoxy, 2 -Carboxyethoxy, etc.), (d) a C _1-4 alkoxy group substituted with a C _1-4 alkoxy-carbonyl group (eg, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, 2- (methoxycarbonyl) ethoxy, 2- (ethoxy) (Carbonyl) ethoxy, etc.), (e)
Amino or mono - or C _1-4 alkyl group substituted with a di -C _1-4 alkylamino group (e.g., aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-aminoethyl , 2- (methylamino) ethyl, 2- (ethylamino) ethyl, 2- (dimethylamino) ethyl, 2- (diethylamino) ethyl, etc.), (f) C _1-4 alkyl group (for example, methyl, ethyl, Cyclic amino group optionally substituted with propyl (eg, 5- to 7-membered cyclic amino group which may contain 1 or 2 heteroatoms such as oxygen atom or sulfur atom in addition to nitrogen atom, etc., Specifically, for example, a C _1-4 alkyl group substituted with pyrrolidino, piperidino, piperazino, 4-methylpiperazino, morpholino, etc. For example, pyrrolidinomethyl, 2
-Pyrrolidinoethyl, piperidinomethyl, 2-piperidinoethyl, piperazinomethyl, 2-piperazinoethyl,
4-methylpiperazinomethyl, 2- (4-methylpiperazino) ethyl, morpholinomethyl, 2-morpholinoethyl, etc.), (g) a C _1-4 alkyl group substituted with a carboxyl group (for example, carboxymethyl, 2- Carboxyethyl, etc.), (h) C _1-4 alkyl group substituted with a C _1-4 alkoxy-carbonyl group (eg, methoxycarbonylethyl, 2-ethoxycarbonylethyl etc.), (i) substituted with a hydroxyl group C _1-4 alkyl group (eg hydroxymethyl, 2-hydroxyethyl etc.), (j) amino group, (k) mono- or di-C _1-4 alkylamino group (eg methylamino, ethylamino, dimethyl) amino, diethylamino), (l) C _1-4 alkoxy - carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, etc.) and (m) carboxy Such as one or two phenyl group which may have a substituent selected from such groups can be used.

In the above formula, Y represents —O—, —NR ² — (wherein R ² represents a hydrogen atom or a hydrocarbon group which may have a substituent) or a bond. Examples of the “hydrocarbon group which may have a substituent” represented by R ² include
For example, those described for R ¹ of the group —NR ¹ — in X are used. Preferred examples of the “hydrocarbon group” of the “hydrocarbon group which may have a substituent” represented by R ² include, for example, a C _1-4 alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc. ) Etc. are generally used. Preferred examples of the substituent which the hydrocarbon group represented by R ² may have include, for example, a hydroxyl group, a C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), an amino group. , Mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino etc.), C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl etc.) , A carboxyl group, a carbamoyl group, a phenyl group and the like, and particularly, a C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), a mono- or di-C _1-4 alkylamino group (eg, , Methylamino, dimethylamino, etc.), carbamoyl group, carboxyl group, C _{A 1-4} alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.) and the like are commonly used. R ² is preferably a hydrogen atom or a C _1-4 alkyl group (eg, methyl, ethyl, propyl, etc.). In the above formula, m
Represents 1, 2 or 3 and n represents 0, 1 or 2.

Preferred examples of each part of the compound [I] of the present invention will be given below. 1) About ring A:

[Chemical 21] [In the formula, A ⁴ , A ⁵ and A ⁶ are each a halogen atom (eg, fluorine, chlorine, etc.), an optionally halogenated C _1-4 alkyl group (eg, methyl, chloromethyl, difluoromethyl) , Trifluoromethyl, ethyl, propyl, isopropyl etc.) or an optionally halogenated C _1-4 alkoxy group (eg methoxy, trifluoromethoxy, ethoxy, propoxy, isopropoxy etc.). ] Or

[Chemical formula 22] [Wherein A ⁷ is a halogen atom (eg, fluorine, chlorine, etc.), and A ⁸ and A ⁹ are optionally halogenated C
_{1-4 represents} an alkyl group (eg, methyl, trifluoromethyl, ethyl, propyl, etc.). 2) Regarding ring B:

[Chemical formula 23] [In the formula, B ⁷ , B ⁸ and B ⁹ are each a halogen atom (eg, fluorine, chlorine etc.) or an optionally halogenated C _1-4 alkyl group (eg, methyl, chloromethyl, difluoromethyl) , Trifluoromethyl, ethyl, propyl, isopropyl, etc.) and an optionally halogenated C _1-4 alkoxy group (eg, methoxy, trifluoromethoxy, ethoxy, propoxy, isopropoxy, etc.). ],

[Chemical formula 24] [In the formula, B ¹⁰ represents a halogen atom (eg, fluorine or chlorine) or an optionally halogenated C _1-4 alkyl group (eg, methyl, chloromethyl, trifluoromethyl, ethyl, propyl, etc.) . ] Or iii) an unsubstituted benzene ring

3) For R: i) hydrogen atom, or ii) C _1-4 alkyl group (eg, methyl, ethyl, propyl, etc.) 4) For Q: oxygen atom 5) For X: i) —NR ^1a — [In the formula, R ^1a represents a hydrogen atom or a C _1-4 alkyl group (eg, methyl, ethyl, propyl, etc.). ], Ii) —O— or iii) —NH-6) Y: i) —NR ^2a — [In the formula, R ^2a represents a hydrogen atom, a C _1-4 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl). Etc.) or a C _1-4 alkyl group which may be substituted with a carboxyl group (eg, methyl, ethyl, propyl, etc.). Ii) —NR ^2b — [In the formula, R ^2b represents a hydrogen atom or a C _1-4 alkyl group (eg, methyl, ethyl, etc.). Iii) —NH— iv) bond or v) —O-7) For m: i) 1 or ii) 2 8) For n: i) 0 or ii) 1

9) Regarding Ar: i) (1) an optionally halogenated C _1-4 alkyl group (eg, methyl, chloromethyl, bromomethyl, difluoromethyl, trifluoromethyl, ethyl, 2,2,2)
2-trifluoromethyl, propyl, isopropyl, etc.), (2) an amino group or a mono - or C _1-4 alkyl group substituted with a di -C _1-4 alkylamino group (e.g., aminomethyl, methylaminomethyl, Ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2
-Aminoethyl, 2- (methylamino) ethyl, 2-
(Ethylamino) ethyl, 2- (dimethylamino) ethyl, 2- (diethylamino) ethyl, etc.), (3) C _1-4 alkyl group (eg, methyl, ethyl, propyl, etc.) which may be substituted Amino group (eg, a hetero atom such as an oxygen atom or a sulfur atom in addition to the nitrogen atom
Or a C _1-4 alkyl group substituted with a 5- to 7-membered cyclic amino group which may contain two, specifically, for example, pyrrolidino, piperidino, piperazino, 4-methylpiperazino, morpholino, etc. For example, pyrrolidinomethyl, 2-pyrrolidinoethyl, piperidinomethyl,
2-piperidinoethyl, piperazinomethyl, 2-piperazinoethyl, 4-methylpiperazinomethyl, 2- (4-
(Methylpiperazino) ethyl, morpholinomethyl, 2-morpholinoethyl, etc.), (4) C _1-4 alkyl group substituted with a carboxyl group (eg, carboxymethyl, carboxyethyl, etc.), (5) C _1-4 alkoxy-carbonyl A C _1-4 alkyl group substituted with a group (eg, methoxycarbonylethyl, ethoxycarbonylethyl, etc.),
(6) optionally halogenated C _1-4 alkoxy group (for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, etc.), (7) A C _1-4 alkoxy group substituted with a carboxyl group (eg, carboxymethoxy, 2-carboxyethoxy, etc.), (8)
C _1-4 alkoxy group substituted by C _1-4 alkoxy-carbonyl group (for example, methoxycarbonylmethoxy, ethoxycarbonylmethoxy, 2- (methoxycarbonylethoxy, etc.), (9) halogen atom (for example, fluorine, chlorine, Bromine, etc.), (10) mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.), (11) C _1-4 alkoxy-carbonyl group (eg, methoxy) Carbonyl, ethoxycarbonyl, etc.) and (12) a phenyl group optionally having 1 or 2 substituents selected from a carboxyl group ii) (1) C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy) , isopropoxy etc.), (2) carboxyl group, (3) C _1-4 alkyl group substituted with a carboxyl group (e.g., carboxymethyl Le, such as carboxyethyl), (4) amino group or a mono - or di -C _1-4 alkylamino C _1-4 alkyl group substituted by group (e.g., aminomethyl, methylaminomethyl, ethylaminomethyl, dimethyl Aminomethyl, diethylaminomethyl, 2
-Aminoethyl, 2- (methylamino) ethyl, 2-
(Dimethylamino) ethyl, 2- (diethylamino) ethyl, etc.), (5) mono- or di-C _1-4 alkylamino group (eg, methylamino, ethylamino, dimethylamino, diethylamino, etc.) and (6) carboxyl A C _1-4 alkoxy group substituted with a group (eg, carboxymethoxy, 2-carboxyethoxy and the like) optionally having one substituent phenyl group iii) (1) C _1-4 alkoxy A group (eg, methoxy, ethoxy, propoxy, isopropoxy etc.) and (2) C substituted with a mono- or di-C _1-4 alkylamino group
_1-4 alkyl group (for example, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl,
Diethylaminomethyl, 2-aminoethyl, 2- (methylamino) ethyl, 2- (dimethylamino) ethyl, 2
A phenyl group optionally having one substituent selected from — (dimethylamino) ethyl, etc. iv) one C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.) An optionally substituted phenyl group v) furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl,
Pyridazinyl, quinolyl, isoquinolyl, indolyl,
Thiazolyl, thiadiazolyl or thiophenyl vi) indolyl. In addition, the object compound (I) of the present invention or a salt thereof is, for example, 1) C in which Q is an oxygen atom and R is optionally halogenated.
_1-4 alkyl group (eg, methyl, ethyl, propyl, etc.), X is —NH—, and Y is —NH— or a bond, 2) Q is an oxygen atom, and R is optionally halogenated C
_1-4 alkyl group (eg, methyl, ethyl, propyl, etc.), X is —NR ^1a — (in the formula, R ^1a has the same meaning as above),
And Y is —NR ^2b — (in the formula, R ^2b has the same meaning as above), 3) Q is an oxygen atom, and R may be halogenated C
_1-4 alkyl group (eg, methyl, ethyl, propyl, etc.), X is —NH—, and Y is a bond, 4) Q is an oxygen atom, and R may be halogenated C
_1-4 alkyl group (eg, methyl, ethyl, propyl, etc.), X is —NR ^1a — (in the formula, R ^1a has the same meaning as above),
And Y is a bond, 5) Q is an oxygen atom, and R is an optionally halogenated C
_1-4 alkyl group (eg, methyl, ethyl, propyl, etc.), X is —O—, and Y is —NH—, or 6) Q is an oxygen atom, and R is optionally halogenated C
_1-4 alkyl group (eg, methyl, ethyl, propyl, etc.), X represents —O—, Y represents a bond, etc., and A ring and B ring, Ar, m, n are preferably those described above. When it is a compound, it is used as a preferred compound (I).

In the above formula, L ¹ and L ² and L ³ and L ⁴ represent groups which react with each other to leave. Specifically, L
¹ and L ³ represent, for example, a hydrogen atom, and L ² and L 3
⁴ is, for example, hydroxyl, a halogen atom (chlorine, bromine, iodine, etc.), an acyloxy group (acetoxy, benzoyloxy, etc.), an oxy group substituted with a heterocycle or an aryl group (eg, succinimidoxy, benzotriazolyl) Oxy, 1-ethoxycarbonyl-1,
2-dihydroquinoline 2-oxy, 4-nitrophenoxy etc.) and the like are used. Compound (I) of this invention
Has a basic group such as an amino group or a substituted amino group, the compound (I) may form a physiologically acceptable acid addition salt. Examples of such salts include inorganic acids (for example, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid).
With hydrochloric acid or organic acid (for example, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid,
A salt with citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, etc. is used. Further, when the compound (I) of the present invention has an acidic group such as -COOH, the compound (I) is an inorganic base (for example, alkali metal such as sodium, potassium, magnesium or alkaline earth metal, Ammonia) or organic bases (eg tri-C such as triethylamine)
_1-3 alkylamine, etc.) to form a salt.

Next, a method for producing the compound (I) of the present invention or a salt thereof will be described. The compound (I) of the present invention or a salt thereof can be produced, for example, by the following methods and. That is, by reacting the isoquinoline derivative (II) with the compound (III), or by reacting the isoquinoline derivative (IV) with the compound (V), the compound (I) or (I-1) or their Salts can be produced. The method will be described in detail below. Method:
In this method, the alcohol compound in the case where X of the compound (II) is —O— and the amine compound in the case of —NR ¹ — are treated with the compound (I
II) is an acylation reaction.

In this acylation reaction, when the leaving group L ² of the compound (III) is a hydroxyl group, an appropriate condensing agent is usually used, or a hydroxyl group which is a leaving group is appropriately added.
It is preferable to convert it into another leaving group (for example, the above-mentioned acyloxy group, oxy group substituted with a heterocycle or an aryl group) and react with compound (II). Examples of such condensing agents include dicyclohexylcarbodiimide (DCC), diethyl cyanophosphate (DEPC), diphenylphosphoryl azide (DPPA), and the like. When using these condensing agents, usually a solvent (for example,
Tetrahydrofuran, dioxane, dimethoxyethane,
Ethers such as ethyl acetate, benzene, toluene, N, N-dimethylformamide, dimethylsulfoxide,
Ester, hydrocarbons, amides, sulfoxides, etc.). This reaction may be accelerated in the presence of a base, and the reaction is carried out at about -10 ° C to 100 ° C, preferably about 0 ° C to 60 ° C. The reaction time is usually 1 to 96 hours, preferably 1 to 72 hours. The amount of the compound (III) and the condensing agent used is the compound (I
The amount is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, per 1 mol of I) or a salt thereof. Examples of the base include alkylamines such as triethylamine,
Cyclic amines such as N-methylmorpholine and pyridine are used, and the amount thereof is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to 1 mol of compound (II).

The compound (III) may be used as a reactive derivative at the carboxyl group of a carboxylic acid in which L ² is a hydroxyl group, and examples of such a reactive derivative include acid halides (eg chloride, bromide). Etc.), acid anhydrides, mixed acid anhydrides (eg, anhydrides with methyl carbonate, anhydrides with ethyl carbonate, anhydrides with isobutyl carbonate, etc.), active esters (eg, esters with hydroxysuccinimide, Ester with 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide, p-
Esters with nitrophenol, esters with 8-oxyquinoline, etc.) are used, and acid halides (L ² is a halogen atom) are particularly preferable. Compound (III)
In, when Y is —NH—, the compound (III)
Is preferably used as an isocyanate compound obtained by removing HL ² from the compound (III). When the compound (II) and the compound (III) are reacted, usually a solvent (for example,
Chloroform, dichloromethane, ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, benzene, toluene, pyridine, halogenated hydrocarbons such as N, N-dimethylformamide, ethers, esters, hydrocarbons, amides, etc. ) Done in. This reaction may promote the reaction in the presence of a base. The reaction temperature is generally about -10 ° C to 120 ° C, preferably about 0 ° C to 100 ° C. The reaction time is usually 1 to 48 hours, preferably 1 to 24 hours. The amount of compound (III) used is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to 1 mol of compound (II). Examples of the base include alkylamines such as triethylamine, cyclic amines such as N-methylmorpholine and pyridine, aromatic amines such as N, N-dimethylaniline and N, N-diethylaniline, sodium carbonate,
An alkali metal carbonate such as potassium carbonate, an alkali metal hydrogen carbonate such as sodium hydrogencarbonate, potassium hydrogencarbonate, or the like is used, and the amount thereof is 1 to 5 mole equivalents per 1 mole of the compound (II), preferably Is 1 to 3
It is a molar equivalent. When a solvent immiscible with water is used in this reaction, water may be added to the reaction system to allow the reaction to proceed in a two-phase system.

Method: This method is the same acylation reaction as the method. In this method, an alcohol body in which Y ¹ of compound (V) is —O— and an amine body in which Y ¹ is —NR ² — are reacted with compound (IV) to give compound (I-
1) is manufactured. The reaction is carried out by a method similar to the method described in the method, using compound (V) instead of compound (II) and compound (IV) instead of compound (III) in the method. Also in this method, X of compound (IV)
When -is -NH-, the compound (IV) is the compound (IV)
Is preferably used as the isocyanate body H-L ⁴ is desorbed from. Among the compounds (I) of the present invention, the compound in which Q is a sulfur atom can be produced by reacting the compound in which Q is an oxygen atom with a suitable sulfide. Examples of the sulfide used in this reaction include phosphorus pentasulfide, Lowesson reagent, and the like. This reaction is
It is usually carried out under anhydrous conditions in a solvent such as dichloromethane, chloroform, dioxane, tetrahydrofuran, benzene or toluene. The amount of sulfide used is equimolar or more, preferably 2 to 5 mol, and the reaction temperature is 20 ° C to 120 ° C. The reaction time varies depending on the type of raw material compound or sulfide, reaction temperature, etc., but is usually 1 to 8 hours.

The compound (I), (I-1) or a salt thereof produced by the above-mentioned method has a lower (C _1-4 ) alkoxy group on the benzene ring in the group represented by A ring, B ring and Ar. When it contains, it can be converted into a hydroxyl group, if necessary, by reacting it with, for example, boron tribromide. This reaction is generally carried out in a solvent (eg, halogenated hydrocarbons such as dichloromethane, carbon tetrachloride, benzene, toluene, hydrocarbons, etc.) at about -20 ° C to 80 ° C, preferably about 0 ° C to 30 ° C. Done in
The amount of boron tribromide used is 1 lower alkoxy group,
It is about 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents. The reaction time is generally 15 minutes to 24 hours, preferably 30 minutes to 12 hours. Further, when the compound (I), (I-1) or a salt thereof produced by the above-mentioned method contains a hydroxyl group in the benzene ring among the groups represented by A ring, B ring and Ar, it may be optionally alkylated. It can be converted into an alkoxy or acyloxy group, respectively, by subjecting it to an alkoxylation or acylation reaction. The alkylation reaction of the hydroxyl group on the benzene ring is performed by using a solvent (for example, alcohols such as methanol, ethanol and propanol, ethers such as dimethoxyethane, dioxane and tetrahydrofuran, ketones such as acetone, N, N).
-Amides such as dimethylformamide) in a base (eg trimethylamine, triethylamine, N-
It may have a substituent in the presence of an organic base such as methylmorpholine, pyridine, picoline or N, N-dimethylaniline, or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide. Alkane halides (eg chloride, bromide, iodide, etc.), sulfates or sulfonates (eg methanesulfonate, p-toluenesulfonate,
Benzene sulfonate, etc.) and the like. The reaction temperature is generally -10 ° C to 100 ° C, preferably about 0 ° C to 80 ° C.
The amount of these alkylating agents used is about 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to 1 mol of the starting phenolic derivative. Reaction time is usually 15 minutes to 2
It is 4 hours, preferably 30 minutes to 12 hours.

The acylation reaction of the hydroxyl group on the benzene ring is carried out by reacting the desired carboxylic acid or its reactive derivative. This reaction varies depending on the type of acylating agent and the type of raw material phenolic derivative, but is usually a solvent (for example, benzene, toluene, ethyl ether, ethyl acetate, chloroform, dichloromethane, dioxane,
Tetrahydrofuran, N, N-dimethylformamide,
Hydrocarbons such as pyridine, ethers, esters,
Halogenated hydrocarbons, amides, aromatic amines, etc.) and an appropriate base (eg,
To give hydrogencarbonate such as sodium hydrogencarbonate and potassium hydrogencarbonate, carbonate such as sodium carbonate and potassium carbonate, acetate such as sodium acetate, tertiary amines such as triethylamine, aromatic amines such as pyridine) You can also As the reactive derivative of carboxylic acid,
Acid anhydrides, mixed acid anhydrides, acid halides (eg chloride, bromide) and the like are used. The amount of these acylating agents used is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to 1 mol of the starting phenolic derivative.
The reaction temperature is generally 0 ° C to 150 ° C, preferably about 10 ° C.
℃ to 100 ℃. The reaction time is generally 15 minutes to 12 hours, preferably 30 minutes to 6 hours.
When the compound (I) is obtained in a free state by the above method, the salt as described above can be prepared according to a method known per se or a method analogous thereto. When the compound (I) is obtained in a salt form Can also be converted into its free form or other salt according to a method known per se or a method analogous thereto. The target compound (I) or a salt thereof obtained by the above method can be purified and collected by using a separation / purification means known per se (eg, concentration, solvent extraction, column chromatography, recrystallization, etc.). .

The starting compounds (II) and (IV) used for producing the compound (I) of the present invention or a salt thereof are specifically represented by the following formulas [(S-1) to (S-7)]. Compounds and the like are used, for example, those represented by the following formula [(S-a)
(Sd)] can be used for the production.

[Chemical 25] (S-1) W = -CH 2 OH (S-7) W =
_{-CH 2 CH 2 NCO (S-} 2) W = -CH 2 NHR 1 (S-a) W =
_{-CO 2 H (S-3)} W = -CH 2 CO 2 H (S-b) W =
_{-CH 2 -L (S-4)} W = -CH 2 CH 2 OH (S-c) W =
_{-CH 2 CH 2 -L (S-} 5) W = -CH 2 CH 2 NHR 1 (S-d) W =
_{-CH 2 CH 2 CO 2 H (} S-6) W = -CH 2 NCO wherein, L is a leaving groups as with L ² and L ^4, and the other symbols are as defined above. ]

These raw material compounds or salts thereof include some known compounds and can be produced by the methods described in the following documents or methods analogous thereto. Specific examples of the production methods are shown below. Compounds (S-1) to (S-7)
Examples of the starting material for producing the compound include compound (S-a)
Is used. The compound (S-a) or its salt, or its ester is, for example,
agati) et al., Bolletino Chimico Farmaceutico, 125, 43
Pages 7-440 (issued in 1986), or Natsume (H.N.
atsugari) et al., EP-A-481383 (1992.
4.22) describes the synthetic method as an objective compound or a synthetic intermediate, and the compound can be produced by these methods or a method analogous thereto. Further, this compound can also be produced via the amide compound of (S-a). (S-
The amid compound (W = -CONH ₂ ) of a) is described in K. Unverferth et al., Archiv der Pharmazie, 324, 809.
-Page 814 (published in 1991) by the method according to it. The compound (S-a) can be produced by reacting the amide compound with diazotization reaction conditions (for example, reaction with sodium nitrite in an acidic solvent such as acetic acid or hydrochloric acid at about 0 ° C to 50 ° C). .

The compound (S-1) or a salt thereof can be produced by reducing the carboxyl group of the compound (Sa). This reduction is carried out by converting the carboxyl group into its reactive derivative (for example, acid halide, mixed acid anhydride, active ester,
Reaction temperature of about 0 ° C. to 100 ° C. in a reducing agent (eg, sodium borohydride, lithium aluminum hydride, etc.) and a solvent (eg, ethers such as tetrahydrofuran, dimethoxyethane, etc.). It is processed by. Compound (S-2) can be produced from compound (S-1) via compound (Sb). Compound (Sb) can be produced by converting the hydroxyl group of compound (S-1) to leaving group L. As the leaving group L, halogen (eg, chlorine, bromine, iodine, etc.),
A C _1-4 alkanesulfonyloxy group (for example, a methanesulfonyloxy group, an ethanesulfonyloxy group, etc.),
A C _6-10 arylsulfonyloxy group (eg, benzenesulfonyloxy group, p-toluenesulfonyloxy group, etc.) is preferably used. The conversion reaction is usually carried out in a solvent such as benzene, toluene, dichloromethane, 1,
2-dichloroethane, chloroform, tetrahydrofuran, ethyl acetate and the like), for example, treatment with thionyl chloride, thionyl bromide, methanesulfonyl chloride, benzenesulfonyl chloride and the like at a temperature of about 0 ° C to 100 ° C.

The compound (S-2) or a salt thereof is the leaving group of the compound (Sb) and has the formula R ¹ —NH ₂ [wherein the symbols have the same meanings as described above]. ] It manufactures by making it react with the amine compound represented by these. In this reaction, the amine compound may be used as it is in the free state, but may be used in the reaction as a salt, for example, an alkali metal salt such as lithium, sodium or potassium. The amine compound or a salt thereof is reacted with 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of the compound (Sb). Usually, the reaction is carried out in a solvent. As the solvent, for example, halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile, ethers such as dimethoxyethane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide and the like are preferably used. Addition of a base favors the reaction. As such a base, for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium amide, sodium methoxide, triethylamine, diisopropylethylamine, pyridine and the like are preferable. Further, instead of using the base as described above, the amine compound itself may be used as the base. The amount of the base used varies depending on the compound (Sb) used, the type of the amine compound and the solvent, and other reaction conditions, but it is usually the compound (S-b).
-B) It is 1 to 10 mol, preferably 1 to 5 mol, per 1 mol. The reaction temperature is about −50 ° C. to 200 ° C., preferably −
It is performed in the range of 20 ° C to 150 ° C. The reaction time depends on the type of compound (Sb), the type of amine compound or its salt,
Although it depends on the reaction temperature and the like, it is 1 to 72 hours, preferably 1 to 24 hours. Further, among the compounds (S-2), the compound in which R ¹ is hydrogen is described in K. Unverth et al., Archiv der Pharmazie, Volume 324, 809-814.
It can also be produced by the method described on page (published in 1991).

The compound (S-3) or a salt thereof can be produced, for example, by the following methods (a) and (b) or a method similar thereto. The method (a) is a reaction generally known as an Arndt-Eistert reaction [F. Arndt et al., Chemische Bechte].
richte), 68, p. 200, (published in 1935)], the carboxyl group of (S-a) is increased by 1 carbon by using diazomethane to give each (S-3). In this method, it may be isolated as an ester form of a carboxylic acid (for example, methyl ester, ethyl ester, etc.), but those ester forms are converted into a carboxylic acid by a hydrolysis reaction. This hydrolysis reaction is usually carried out in a solvent (eg, alcohol such as methanol, ethanol, propanol, organic acid such as acetic acid, etc.) with a mineral acid (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.) or a metal hydroxide (eg, For example, the treatment is performed in the presence of an aqueous solution of sodium hydroxide, potassium hydroxide, etc.) at a temperature of about 15 ° C to 130 ° C. The method (b) is a method of converting the leaving group L of the compound (Sb) into a cyano group and then subjecting it to a hydrolysis reaction to give a compound (S-3) having 1 carbon increased. The conversion reaction to a cyano group is usually carried out by treating with a cyanide compound such as sodium cyanide, potassium cyanide and copper cyanide in a solvent (eg, dimethyl sulfoxide, dimethylformamide, acetone, etc.) at a temperature of 0 ° C to 100 ° C. . This nitrile compound is hydrolyzed to produce a carboxylic acid (S-3). This hydrolysis reaction is usually carried out in a solvent (eg, alcohol such as methanol, ethanol, propanol, acetic acid, etc.) with a mineral acid (eg,
It is carried out by treating at a temperature of about 15 ° C. to 130 ° C. in the presence of an aqueous solution of hydrochloric acid, hydrobromic acid, sulfuric acid, etc.) or a metal hydroxide (eg, sodium hydroxide, potassium hydroxide, etc.).

The compound (S-4) is the same as (S-3)
The compound (S-5) can be produced by the same method as in the conversion from (S-a) to (S-1), and the compound (S-5) can be obtained by using (S-4) and (S
-C), then (S-1) to (S-b) (S-
It can be produced by the same method as the conversion into 2). Compounds (S-6) and (S-7) are the same as X in the compound (IV).
Is a compound corresponding to the compound (m = 1, 2) in which —NH—. These isocyanate compounds are usually produced from carboxylic acids (S-3) and (Sd) via an acid azide compound. Various methods are known in the literature,
Either method can be applied to (S-3) and (S-d). For example, an acid azide compound can be produced by reacting an azidating agent [for example, diphenylphosphoryl azide (hereinafter abbreviated as DPPA)] with the compound (S-3) or (Sd). This reaction is usually a solvent inert to the reaction (eg, ethers such as ethyl ether, isopropyl ether, dimethoxyethane, tetrahydrofuran, dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, methyl acetate, ethyl acetate, etc. Esters, ketones such as acetone and 2-butanone, aromatic amines such as pyridine, N, N
-Amides such as dimethylformamide). Also a base (eg trimethylamine,
The reaction may proceed in the presence of triethylamine, N-methylmorpholine, etc.). Reaction time is usually about 5 minutes to 1
It is 2 hours, preferably about 10 minutes to 6 hours. The reaction temperature is usually about -10 ° C to 150 ° C, preferably about -5 ° C.
It is 120 ° C. Azide agent (eg DPPA)
Is 1 to 3 molar equivalents, preferably 1 to 2 molar equivalents, relative to compound (S-3) or (Sd). The generated acid azide can be isolated and purified by a means known per se, but usually, the reaction solution is heated as it is without being isolated and converted into the isocyanate compound (S-6) or (S-7). It is preferable to use the same solvent as that used for the azidation in this conversion reaction, and it is usually carried out by heating to about 20 ° C to 200 ° C, preferably about 30 ° C to 150 ° C. The reaction time is usually about 5 minutes to 10 hours, preferably about 5 minutes to 6 hours. The compound (Sd) used in the production of the compound (S-7) is the same as the method (a), (in the production of the compound (S-3) described above from the compound (S-3) or (Sc). It can be manufactured according to b).

Compounds (S-1) to (S-7) having various substituents as R can be produced by the above-mentioned method, and when the substituents of R of these compounds further contain a functional group. Can be converted into other desired functional groups by various known methods. For example, when R is a group containing a carboxyl group or an ester thereof, for example, it is reacted with amines to be converted into an amide group or subjected to a reduction reaction to be converted into a hydroxymethyl group or the like to prepare a raw material for synthesizing compound (I). Can be Compounds (S-1) to (S-
In 7), the oxo group at the 1-position can be converted into a thioxo group by reacting with a suitable sulfide, and these also serve as raw material compounds for producing the compound (I). This method
It can be carried out in the same manner as the above-mentioned method of converting a compound (I) in which Q is an oxygen atom into a compound in which a sulfur atom is converted. As the other starting compound (III) or (V) used for producing the compound (I) of the present invention or a salt thereof, a compound produced by a method known per se or a method analogous thereto is used. The above-mentioned raw material compounds may form salts, and as these salts, for example, salts with inorganic acids (for example, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid), or organic acids (for example, acetic acid, Formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) and the like are used. Further, when these compounds have an acidic group such as -COOH, an inorganic base (for example, alkali metal or alkaline earth metal such as sodium, potassium, calcium, or magnesium, ammonia) or an organic base (for example, A salt may be formed with a tri-C _1-3 alkylamine such as triethylamine). Compounds (II), (IV) and other starting compounds obtained by the above method are purified by a known purification means such as concentration, liquid conversion, phase transfer, solvent extraction, column chromatography, crystallization and recrystallization. ,
It may be collected, or the mixture as it is may be used for each subsequent reaction.

In each reaction for synthesizing the above-mentioned target compound and starting compound, when the starting compound used has an amino group, a carboxyl group or a hydroxyl group as a substituent, these groups are generally used in peptide chemistry and the like. The compound of interest may be the one to which a protecting group such as that used in (1) is introduced, and the desired compound can be obtained by removing the protecting group after the reaction, if necessary. Examples of the amino-protecting group include C _1-6 which may have a substituent.
Alkylcarbonyl (eg, formyl, methylcarbonyl, ethylcarbonyl, etc.), phenylcarbonyl,
C _1-6 alkyl-oxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl etc.), phenyloxycarbonyl (eg benzoxycarbonyl etc.), C _7-10 aralkyl-carbonyl (eg benzyloxycarbonyl etc.), trityl, phthaloyl. Are used. As these substituents, a halogen atom (eg, fluoro, chloro, bromo, iodo, etc.),
C _1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro group and the like are used, and the number of substituents is about 1 to 3.

As the protecting group for the carboxyl group, for example, C _1-6 alkyl _optionally having a substituent (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.) , Phenyl, trityl, silyl and the like are used. These substituents include halogen atoms (eg, fluoro, chloro, bromo, iodo, etc.), C _1-6 alkylcarbonyl (eg, formyl,
(Methyl carbonyl, ethyl carbonyl, butyl carbonyl, etc.), nitro group and the like are used, and the number of substituents is about 1 to 3. Examples of the hydroxyl-protecting group include optionally substituted C _1-6 alkyl (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.), phenyl, C
_7-10 aralkyl (eg benzyl etc.), C _1-6 alkylcarbonyl (eg formyl, methylcarbonyl, ethylcarbonyl nad), phenyloxycarbonyl (eg benzoxycarbonyl etc.), C _7-10 aralkyl-carbonyl ( For example, benzyloxycarbonyl etc.), pyranyl, furanyl, silyl and the like are used. These substituents include halogen atoms (eg, fluoro, chloro, bromo, iodo, etc.), C _1-6
Alkyl, phenyl, C _7-10 aralkyl, nitro group and the like are used, and the number of substituents is about 1 to 4.

As a method for removing the protective group, a method known per se or a method analogous thereto can be used, and examples thereof include acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate and tetrabutylammonium. A method of treating with fluoride, palladium acetate or the like is used. The compound (I) obtained by the above method can be isolated and purified by a usual separation means such as recrystallization, distillation and chromatography. When the compound (I) thus obtained is obtained as a free form, it can be converted into a salt by a method known per se or a method analogous thereto (eg, neutralization etc.), and conversely when obtained as a salt. Can be converted into the free form or other salt by a method known per se or a method analogous thereto.

[0047]

The object compound (I) of the present invention or a salt thereof has a strong cerebral ischemic protective action, an anti-cerebral edema action, an inhibitory action on the release of calcium from the endoplasmic reticulum in nerve cells, and has low toxicity. [Example, acute toxicity of compounds of the following Examples 1-15 (HCl) (mouse, oral administration): LD ₅₀ > 1,000 mg / k
g], it is highly safe as a medicine. Therefore,
The object compound (I) of the present application or a salt thereof is used for acute and chronic cerebrovascular disorders in mammals (eg, mouse, rat, hamster, gerbil, rabbit, cat, dog, cow, sheep, monkey, human, etc.). Based on brain damage,
For example, it is useful as a safe therapeutic / preventive agent for cerebral infarction, subarachnoid hemorrhage, cerebral edema and the like. Further, the target compound (I) or a salt thereof is used for various diseases based on nerve cell disorders such as mental disorders (dementia, hallucinations, depression, etc.), movement disorders (paralysis, Parkinson's symptoms, etc.), consciousness disorders (coma, consciousness). It is also useful as a therapeutic / preventive agent for sensory disorders (pain, numbness, etc.). Further, the compound (I) of the present invention or a salt thereof has an excellent tachykinin receptor antagonistic action, particularly a substance P (hereinafter sometimes abbreviated as SP) receptor antagonistic action. Substance P
(SP) is a neuropeptide consisting of 11 amino acids whose structure was confirmed in 1971 and whose structure was confirmed in 1971. SP is widely distributed in the central and peripheral nervous system, and functions as a messenger of primary sensory neurons as well as physiology such as vasodilator action, smooth muscle contraction action, nerve cell excitatory action, salivary action and diuretic action. Have activity. In particular, it is known that SP released from the end of the dorsal horn of the spinal cord by a pain impulse causes an inflammatory reaction in its receptive field. It is also considered that SP is involved in Alzheimer's dementia. Therefore, the compound (I) of the present invention having an excellent SP receptor antagonistic activity or a salt thereof is used in mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.), etc. Safe for pain, inflammation,
It is useful as a prophylactic / therapeutic agent for allergy and dementia.

When the compound (I) of the present invention or a salt thereof is used as the above-mentioned medicine, an appropriate pharmacologically acceptable carrier or excipient (eg starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.) , Binders (eg starch, arabic gum, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, alginic acid, gelatin, polyvinylpyrrolidone etc.), lubricants (eg stearic acid, magnesium stearate, calcium stearate talc etc.), disintegrating agents ( For example, carboxymethylcellulose calcium, talc, etc.), a diluent (for example, physiological saline, etc.), etc., and mixed orally or non-orally in the form of powder, fine granules, granules, tablets, capsules or injections by a conventional method. It can be administered orally. The dose varies depending on the type of compound (I) or a salt thereof, administration route, symptoms, age of the patient, etc., but when administered orally to an adult patient, the daily dose is about 0.01 per 1 kg of body weight. To 200m
g, preferably about 0.1 to 20 mg, preferably in divided doses 1 to 3 times daily.

The experimental results showing the pharmacological effect of the compound (I) of the present invention or a salt thereof will be described below. Test Example 1 Cerebral ischemia protection male gerbil (Seiwa / 8-10 weeks old) (n
= 8 to 10) under ether anesthesia, after midline neck incision,
Bilateral common carotid arteries were ligated. After ligation for 15 minutes, reperfusion was performed. The test drug was intraperitoneally (ip) administered 30 minutes before ligation and 90 minutes after reperfusion. To the control group, the solvent of the test drug (distilled water, physiological saline or 5% gum arabic) was administered.
The survival rate (%) 8 hours after reperfusion was calculated [Table 2].

[Table 2] From this table, it is clear that the object compound (I) of the present invention or a salt thereof improves the survival rate in gerbil transient cerebral ischemic death, and is useful as an excellent therapeutic / protective agent for cerebral ischemic injury. It is shown that.

Test Example 2 Anti-cerebral edema action (cerebral edema model by occlusion reperfusion of middle cerebral artery) The animals were 9 week-old male JCL (Jcl): Wistarrat, and anesthetized during surgery. Used a halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) inhalation method. The neck is incised to expose the bilateral common carotid arteries, and an embolus (a nylon thread with a diameter of approximately 0.3 mm and a total length of 25 mm) is inserted into the internal carotid artery from the left external carotid artery, and at the same time, the bilateral common carotid aneurysm clip is used. The carotid artery was ligated. After 30 minutes of ischemia, the embolus and aneurysm clip were removed under halothane paralysis and blood was reperfused. On the day of the ischemia experiment, the test drug was intraperitoneally administered immediately after reperfusion and 5 hours after reperfusion, 1 and 2 days after reperfusion in the morning and afternoon, and 3 days after reperfusion, 1 hour before brain extraction. The control group was given the solvent of the test drug (distilled water, physiological saline or 5% gum arabic). Water content and Na, K content in the cerebral cortex and striatum were measured as indicators of the severity of cerebral edema 3 days after reperfusion. The water content was calculated from the ratio of brain weight and its dry weight [(1-
Dry weight / brain weight) X100], and Na and K contents were determined by a flame photometer from a solution extracted from dried brain tissue with 14% nitric acid [Table 3].

[Table 3] From this table, it is clear that the objective compound (I) of the present invention or a salt thereof decreases water content and sodium content in the brain and increases potassium content, and thus is useful as a therapeutic agent for cerebral edema. Shows.

Test Example 3 Effect of Neurons on Intracellular Ca ²⁺ Concentration Neurons were collected from hippocampus of SD (Sprague-Dawley) rat fetuses of 18-day-old embryo, and the method of Hatanaka & Tsukui [Developmental Brain] was used. Research (Developm
ental Brain Research), 30, 47-56 (19)
Issued in 1986)]. Hippocampal neurons were covered with a cover glass (10 × 20) encoding poly-L-lysine.
mm, Matsunami No.1, Osaka, Japan) 2.5 × 10 ⁵ cells / cover glass on a dish
ulbecco's modified Eagle's medium floating, sowing, 3
The cells were cultured at 7 ° C in a 5% CO ₂ furan vessel. 7 days later, HE
PES [N- (2-hydroxyethyl) piperazine-N'-
2-ethanesulfonic acid] buffered saline (HPSS)
(140 mM NaCl, 5 mM KCl, 1 mM MgSO ₄ , 1
mM Na ₂ HPO ₄ , 1 mM CaCl ₂ , 25 mM glucose,
Neurons were washed 3 times with 25 mM HEPES, pH 7.4), and furo-2acetoxymet prepared to 4 μM with HPSS.
A fluorescent agent was loaded by adding hyl ester and culturing at 37 ° C. for 60 minutes. Add 2.5 ml of 0.05% cover glass coated with neurons loaded with fluorescent agent
Attach to a cuvette containing HPSS containing bovine serum albumin, and use Hitachi F-2000 at 340 nm, 38
The fluorescence at 505 nm with 0 nm excitation was measured. The intracellular calcium ion (Ca ²⁺ ) concentration is determined by the method of Grynkiewicz et al. [Journal of Biological Chemistry, 260, 3].
Pp. 440-3450 (issued in 1985)]. The test drug treatment of nerve cells was performed 5 minutes before stimulation with L-glutamic acid. Ca ²⁺ concentration in nerve cells shows a biphasic increase curve upon stimulation with L-glutamic acid. The initial phase of this curve shows an increase in Ca ²⁺ concentration influx was mixed Ca ²⁺ from release and extracellular Ca ²⁺ from intracellular vesicles, secondary phase Ca from extracellular shows the increase in Ca ²⁺ concentration caused by the influx of ^2+. The effect of the test drug on these biphasic increases was investigated, and the concentration at which each increase was suppressed by 50% (IC ₅₀ ) was determined. Also, EGTA [ethylene gl
ycol-O, O'-bis (2-aminoethyl) -N, N,
[N ', N'-tetraacetic acid] is added, and the effect of Ca ^{2+ in} the extracellular fluid does not occur (the peak due to the release of Ca ²⁺ from intracellular endoplasmic reticulum in the above initial phase curve (Observed), the effect of the test drug was examined, and the IC ₅₀ was determined [Table 4].

[Table 4] From this table, it is clear that the objective compound (I) of the present invention or a salt thereof strongly suppresses Ca ²⁺ release from the endoplasmic reticulum in nerve cells stimulated by L-glutamic acid, and is useful as a calcium antagonist. It indicates that there is. Test Example 4 [Radio ligand ( ¹²⁵ I-BHSP) receptor binding inhibitory activity] Binding inhibitory activity using a receptor from human lymphoblastoid cells (IM-9) Margaret [A. Margaret] [Molecular Phartmacology ) Volume 42, 458
Page (published in 1992)] and the like. Receptor pairs were prepared from human lymphoblast cells (IM-9).
IM-9 cells (2 × 10 ⁵ cells / ml) were inoculated and cultured for 3 days (1 liter), followed by centrifugation at 500 × g for 5 minutes to obtain a cell pellet. The obtained pellets were treated with a phosphate buffer solution (Flow Laboratory, CAT. No. 28-10).
After washing once with 3-05), 30 ml of 120 mM
Sodium chloride, 5 mM potassium chloride, 2 μg / ml chymostatin, 40 μg / ml bacitracin, 5 μg / m
1 phosphoramidon, 0.5 mM phenylmethylsulfonyl fluoride, 1 mM ethylenediaminetetraacetic acid in 50 mM Tris-hydrochloric acid buffer (pH 7.4) using a Polytron homogenizer [Kinematika (Kinematika), Germany] to crush, 20 at 40,000 xg
Centrifuge for minutes. The precipitate was washed twice with 30 ml of the above buffer solution and then frozen (-80 ° C) and stored as a receptor standard.
A reaction buffer solution [50 mM Tris / HCl buffer solution (pH 7.
4), 0.02% bovine serum albumin, 1 mM phenylmethylsulfonyl fluoride, 2 μg / ml chymostatin, 40 μg / ml bacitracin, 3 mM manganese chloride], and 100 μl volume was used for the reaction. Add sample, ¹²⁵ I-BHSP (0.4 KBq),
The reaction was carried out in 0.2 ml of reaction buffer at 25 ° C. for 30 minutes. The amount of non-specific binding was determined by adding substance P so as to be 2 × 10 ⁻⁶ M. After the reaction, the reaction was stopped by rapid filtration on a cell harvester (290 PHD, manufactured by Cambridge Technology, Inc., USA) to stop the reaction, and 250 μl of 0.
It was washed three times with 50 mM Tris-HCl buffer (pH 7.4) containing 02% bovine serum albumin, and the radioactivity remaining on the filter was measured by a gamma counter. The filter was soaked in 0.1% polyethyleneimine for one day before use, and then air-dried. Under the above-mentioned conditions, the antagonistic activity of a drug is the concentration of the drug (IC
₅₀ value) was expressed in μM. [Table 5]

[Table 5] From Table 5, it is understood that the object compound (I) of the present invention or a salt thereof has an excellent substance P receptor antagonistic action.

[0052]

The present invention will be further described in detail in the following reference examples and examples, but these examples are merely illustrative and do not limit the present invention, and do not depart from the scope of the present invention. You may change with. Room temperature is usually 1
It means 0 ° C to 35 ° C. The following abbreviations were used to describe the NMR spectrum data. s, singlet
t); d, doublet; t, triplet; q, quartet;
m, multiplet; b, bro
ad); Hz, Herz; like, approximation; DMF, dimethylformamide; THF, tetrahydrofuran; DM
SO, dimethyl sulfoxide

Reference Example 1 1,2-Dihydro-3-hydroxymethyl-2,6,7
-Trimethyl-1-oxo-4-phenylisoquinoline Step 1 2-Benzoyl-4,5-dimethylbenzoic acid (11.4
g), acetone (300 ml), DMF (10 ml), potassium carbonate (6.83 g) and diethyl bromomalonate (12.84 g) were stirred at room temperature for 60 hours. The solvent was distilled off, and ethyl acetate was added to the residue. The mixture was washed with water, dried (Na ₂ SO ₄ ) and the solvent was distilled off. Acetic acid (180 ml) and hydrochloric acid (180 ml) were added to the residue and the mixture was heated at 110 ° C. for 5 hours. The reaction solution was concentrated, water was added to the concentrated solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (Na ₂ SO ₄ ) and the solvent was distilled off to give colorless crystals. The crystals were recrystallized from ethyl acetate-isopropyl ether to give 6,7-dimethyl-4-phenylisocoumarin-3-carboxylic acid. Melting point 265-268 ° C. Step 2 To a solution of the compound (3.75 g) obtained by the method of Step 1 in methanol (50 ml) was added 40% methylamine-methanol solution (25 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, 4N-HCl-ethyl acetate (50 ml) was added to the residue, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, water was added to the residue, and the precipitated crystals were collected by filtration. The crystals were washed with water, acetone, and ethyl ether to give 2,6,7-trimethyl-4-phenyl-1 (2H) -isoquinolinone-3-carboxylic acid as colorless crystals (3.51 g). Melting point> 300 ° C. (recrystallized from ethanol) NMR (200 MHz, CDCl ₃ + DMSO-d ₆ ) ppm: 2.25 (3H, s), 2.3
9 (3H, s), 3.67 (3H, s), 6.91 (1H, s), 7.39-7.42 (5H, m),
8.24 (1H, s) Elemental analysis value Calculated value as C ₁₉ H ₁₇ NO ₃ C, 74.25; H, 5.58; N, 4.56 Actual value C, 74.40; H, 5.50; N, 4.41

Step 3 The compound (9.27 g) obtained by the method of Step 2 was treated with THF (1
00 ml) solution, oxalyl chloride (3.7 ml) and D
MF (10 drops) was added at room temperature and stirred for 30 minutes. The solvent was evaporated and the residue was dissolved in THF (50 ml). This solution was added slowly at 0 ° C. to a suspension of sodium borohydride (5.0 g) in dimethoxyethane (100 ml). After stirring at 0 ° C for 30 minutes, the reaction mixture was stirred at 0 ° C for 2 minutes.
N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with sodium hydrogen carbonate and water, dried (MgSO ₄₎
After that, the solvent was distilled off to give the title compound as colorless crystals (7.1
8 g). Melting point 209-210 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 2.09 (1H, bt, J = 5.8Hz), 2.2
0 (3H, s), 2.34 (3H, s), 3.81 (3H, s), 4.43 (2H, d, J = 5.8Hz),
6.73 (1H, s), 7.25-7.35 (2H, m), 7.45-7.55 (3H, m), 8.19 (1
H, s) In the same manner as in Reference Example 1 Step 3, 1 (2H) -isoquinolinone-3-carboxylic acid having a corresponding substituent was subjected to a reduction reaction to obtain the compounds of Reference Examples 2 and 3 as colorless crystals. Was given.

Reference Example 2 1,2-Dihydro-3-hydroxymethyl-2-methyl-1-oxo-4-phenylisoquinoline Melting point 158-159 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) Ppm: 1.88 (1H, bt), 3.83 (3H,
s), 4.48 (2H, d, J = 5.6Hz), 7.0-7.5 (8H, m), 8.43-8.50 (1
H, m) Reference Example 3 6-chloro-1,2-dihydro-3-hydroxymethyl-2-methyl-1-oxo-4-phenylisoquinoline Melting point 193-195 ° C (recrystallized from ethyl acetate-ethyl ether) NMR (200MHz, CDCl ₃ ) ppm: 2.04 (1H, bt), 3.81 (3H,
s), 4.45 (2H, d, J = 5.4Hz), 6.98 (1H, d, J = 2Hz), 7.28 (6H,
m), 8.36 (1H, d, J = 8.6Hz)

Reference Example 4 3-Aminomethyl-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenylisoquinoline Step 1 The compound (3.0 g) obtained in Reference Example 1 in dichloromethane ( To the solution (100 ml), triethylamine (3.8 ml) and methanesulfonyl chloride (1.3 ml) were added with stirring at 0 ° C., and the mixture was stirred for 30 minutes. Dichloromethane was added to the reaction solution, washed with 5% aqueous phosphoric acid solution and water, dried (MgSO ₄ ), and the solvent was distilled off to give 1,
2-dihydro-3-methanesulfonyloxymethyl-
2,6,7-Trimethyl-1-oxo-4-phenylisoquinoline was obtained as colorless crystals (2.98 g). Melting point 150-151 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 2.25 (3H, s), 2.40 (3H, s),
2.86 (3H, s), 3.77 (3H, s), 5.01 (2H, s), 6.82 (1H, s), 7.25-
7.35 (2H, m), 7.45-7.60 (3H, m), 8.27 (1H, s) Elemental analysis value Calculated value as C ₂₀ H ₂₁ NO ₄ S C, 64.67; H, 5.70; N, 3.77 Measured value C, 64.59; H, 5.69; N, 3.67 Step 2 Compound obtained in Step 1 (0.68 g), THF (20 ml)
And a mixture of 15% ammonia / methanol (20 ml) was heated in a sealed tube at 140 ° C. for 20 hours. The solvent was distilled off, ethyl acetate was added to the residue, potassium carbonate solution and successively washed with water, dried (MgSO _4). The solvent was evaporated to give the title compound as colorless crystals (0.37 g). Melting point 163-165 ° C (recrystallized from ethyl acetate) NMR (200MHz, CDCl ₃ ) ppm: 2.22 (3H, s), 2.37 (3H, s),
3.65 (2H, s), 3.84 (3H, s), 6.70 (1H, s), 7.24-7.50 (5H,
m), 8.24 (1H, s) Elemental analysis value Calculated value as C ₁₉ H ₂₀ N ₂ O C, 78.05; H, 6.89; N, 9.58 Measured value C, 77.86; H, 7.00; N, 9.41

By a method similar to Steps 1 and 2 of Reference Example 4, 1,2-dihydro-3- having a corresponding substituent was used.
Hydroxymethyl-1-oxoisoquinoline was reacted with methanesulfonyl chloride (step 1) and then with amines having the corresponding substituents (step 2) to give the compounds of Reference Examples 5-7. Reference Example 5 Step 1 1,2-Dihydro-3-methanesulfonyloxymethyl-2-methyl-1-oxo-4-phenylisoquinoline Melting point 149-150 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.88 (3H, s), 3.80 (3H, s),
5.05 (2H, s), 7.05-7.13 (1H, m), 7.29-7.58 (7H, m), 8.5
1-8.55 (1H, m) Step 2 3-Aminomethyl-1,2-dihydro-2-methyl-1
- oxo-4-phenyl-isoquinoline mp 186-188 ° C. (ethyl acetate - recrystallized from _{methanol) NMR (200MHz, CDCl 3)} ppm: 3.68 (2H, s), 3.86 (3H, s),
6.95-7.0 (1H, m), 7.26-7.52 (7H, m), 8.45-8.52 (1H, m) Reference Example 6 Step 1 6-chloro-1,2-dihydro-3-methanesulfonyloxymethyl-2- Methyl-1-oxo-4-phenylisoquinoline Melting point 163-165 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.88 (3H, s), 3.78 (3H, s),
5.01 (2H, s), 7.05 (1H, d, J = 2.2Hz), 7.27-7.56 (6H, m),
8.46 (1H, d, J = 8.6Hz)

Step 2 3-Aminomethyl-6-chloro-1,2-dihydro-2
-Methyl-1-oxo-4-phenylisoquinoline Melting point 175-177 ° C (recrystallized from ethyl acetate-methanol) NMR (200MHz, CDCl ₃ ) ppm: 3.66 (2H, s), 3.85 (3H, s),
6.92 (1H, d, J = 1.8Hz), 7.23-7.52 (6H, m), 8.41 (1H, d, J =
8.4 Hz) Reference Example 6A 6-chloro-1,2-dihydro-2-methyl-3- (N
- methylamino) methyl-1-oxo-4-phenyl-isoquinoline _{NMR (200MHz, CDCl 3) ppm} : 2.30 (3H, s), 3.46 (2H, s),
3.84 (3H, s), 6.94 (1H, d, J = 1.8Hz), 7.22-7.51 (6H, m),
8.42 (1H, d, J = 8.8Hz) [Used in the next reaction without purification. ]

Reference Example 7 1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolineacetic acid Step 1 Compound obtained by the method of Step 1 of Reference Example 4 (6.4 g ) To D
Dissolve in MSO (80 ml) and add sodium cyanide (5.
0 g) was added and the mixture was stirred at room temperature for 30 minutes. Ethyl acetate was added to this reaction solution, washed with water, dried (MgSO ₄ ),
When the solvent was distilled off, 3-cyanomethyl-1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenylisoquinoline was obtained as colorless crystals (4.7 g). Melting point 186-188 [deg.] C. (recrystallized from ethyl acetate-isopropyl ether) Step 2 A mixture of the compound (4.7 g) obtained in Step 1, acetic acid (150 ml) and hydrochloric acid (150 ml) was heated at 110 [deg.] C. for 7 hours. The solvent was distilled off, and ethyl acetate was added to the residue. The mixture was washed with water, dried (MgSO ₄ ), and the solvent was evaporated to give the title compound as colorless crystals (3.7 g). Melting point 217-220 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.22 (3H, s), 2.37 (3H, s),
3.63 (2H, s), 3.67 (3H, s), 5.90 (1H, bs), 6.75 (1H, s), 7.20-
7.35 (2H, m), 7.40-7.55 (3H, m), 8.24 (1H, s) Calculated elemental analysis _{C 20 H 19 NO 3 C,} 74.75; H, 5.96; N, 4.36 Found C, 74.69 H, 6.08; N, 4.23 By a method similar to steps 1 and 2 of Reference Example 7, 1,2-dihydro-3-methanesulfonyloxymethyl-1-oxoisoquinoline having a corresponding substituent and sodium cyanide After reacting (step 1) and then subjected to acid hydrolysis reaction (step 2), the compounds of Reference Examples 8 to 9 were obtained. The physicochemical data of the compound obtained in each step are shown below.

Reference Example 8 Step 1 3-Cyanomethyl-1,2-dihydro-2-methyl-1
- oxo-4-phenyl-isoquinoline mp 253-255 ° C. (ethyl acetate - recrystallized from _{methanol) NMR (200MHz, CDCl 3)} ppm: 3.60 (2H, s), 3.85 (3H, s),
7.02-7.07 (1H, m), 7.28-7.59 (7H, m), 8.49-8.54 (1H, m) Step 2 1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolineacetic acid mp 200-201 ° C. (ethyl acetate - recrystallized from _{acetone) NMR (200MHz, CDCl 3)} ppm: 3.67 (2H, s),
3.69 (3H, s), 6.99-7.04 (1
H, m), 7.26-7.53 (7H, m), 8.
47-8.52 (1H, m) Reference Example 9 Step 1 6-chloro-3-cyanomethyl-1,2-dihydro-2
- methyl-1-oxo-4-phenyl-isoquinoline mp 229-231 ° C. (recrystallized from ethyl _{acetate) NMR (200MHz, CDCl 3)} ppm: 3.58 (2H, s),
3.83 (3H, s), 6.99 (1H, d, J = 0.8Hz), 7.26-7.58 (6H, m),
8.44 (1H, d, J = 8.8Hz) Step 2 6-Chloro-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolineacetic acid Melting point 216-217 ° C (from ethyl acetate-acetone) Recrystallization) NMR (200MHz, CDCl ₃ ) ppm: 3.65 (2H, s), 3.66 (3H, s),
6.96 (1H, d, J = 0.9Hz), 7.23-7.51 (6H, m), 8.41 (1H, d, J =
(8.6Hz)

Reference Example 10 3- (1,2-Dihydro-2,6,7-trimethyl-1)
-Oxo-4-phenylisoquinolin-3-yl) propionic acid Step 1 1,2-dihydro-3-hydroxymethyl-2,6,7
To a solution of -trimethyl-1-oxo-4-phenylisoquinoline (Reference Example 1) (1.44 g) in DMSO (30 ml) was added triethylamine (2.25 ml) and sulfur trioxide / pyridine complex (2.5 g) at room temperature. Stir for 15 minutes. Chloroform was added to the reaction solution, which was washed with 2N-hydrochloric acid and water. Dry (MgSO ₄ )
After the solvent was distilled off, 1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinecarbaldehyde was obtained as colorless crystals (1.03 g). Mp 178-179 ° C. (ether - hexane from _{recrystallization) NMR (200MHz, CDCl 3)} ppm: 2.27 (3H, s),
2.43 (3H, s), 3.90 (3H, s),
6.96 (1H, s), 7.30-7.40 (2H,
m), 7.48-7.56 (3H, m), 8.32
(1H, s), 9.52 (1H, s) Elemental analysis value Calculated value as C ₁₉ H ₁₇ NO ₂ C, 78.33; H, 5.88; N, 4.81 Measured value C, 78.46; H, 5.90; N, 4.67 Step 2 Ethyl diethylphosphonoacetate (1.66 g), sodium hydride (60% oil) (330 mg) and DMF (6
0 ml) of the mixture was stirred at room temperature for 30 minutes. The mixture was cooled to 0 ° C. and the compound (2.0
5 g) was added and the mixture was stirred at room temperature for 20 minutes. The reaction solution was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried (MgSO ₄ ), and the solvent was distilled off (E) -3-
(1,2-Dihydro-2,6,7-trimethyl-1-oxo-4-phenylisoquinolin-3-yl) propenoic acid ethyl ester was obtained as colorless crystals (1.84 g). Melting point 143-145 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.23 (3 H, t, J = 7.2 Hz), 2.2
4 (3H, s), 2.39 (3H, s), 3.66 (3H, s), 4.13 (2H, q, J = 7.2H
z), 5.71 (1H, d, J = 16Hz), 6.86 (1H, s), 7.15-7.24 (2H,
m), 7.34 (1H, d, J = 16Hz), 7.36-7.50 (3H, m), 8.25 (1H, s) Elemental analysis value Calculated as C ₂₃ H ₂₃ NO ₃ C, 76.43; H, 6.41; N , 3.88 Found C, 76.15; H, 6.43; N, 3.83

Step 3 A mixture of the compound obtained in the method of Step 2 (1.0 g), 10% palladium-carbon (300 mg), THF (15 ml) and ethanol (15 ml) at room temperature under a hydrogen atmosphere was used.
Stir for 5 hours. The catalyst was filtered off, and the filtrate was evaporated. The residue was dissolved in ethyl acetate and washed successively with 2N-hydrochloric acid, aqueous sodium hydrogencarbonate and water. Dry (Mg
SO ₄₎ after the solvent was distilled off 3- (1,2-dihydro -2,6,7- trimethyl-1-oxo-4-phenyl-3-yl) propionic acid ethyl ester as colorless crystals (0. 85 g). Mp 138-139 ° C. (ethyl acetate - recrystallized from isopropyl _{ether) NMR (200MHz, CDCl 3)} ppm: 1.20 (3H, t, J = 7.1Hz), 2.2
1 (3H, s), 2.37 (3H, s), 2.43 (2H, t like, J = 8.2Hz), 2.85
(2H, t like, J = 8.2Hz), 3.70 (3H, s), 4.07 (2H, q, J = 7.1H
z), 6.65 (1H, s), 7.15-7.30 (2H, m), 7.40-7.55 (3H, m),
8.21 (1H, s) Elemental analysis value Calculated as C ₂₃ H ₂₅ NO ₃ C, 76.01; H, 6.93; N, 3.85 Measured value C, 76.28; H, 6.92; N, 3.87 Step 4 Obtained by the method of Step 3 Compound (825 mg), THF (5 m
A mixture of l), ethanol (20 ml) and 1N sodium hydroxide (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated, water was added to the concentrate, and the mixture was washed with ether.
The aqueous layer was acidified with 2N-hydrochloric acid, then ethyl acetate-THF
It was extracted with. The extract was washed with aqueous sodium chloride, dried (MgSO ₄ ), and the solvent was evaporated to give the title compound as colorless crystals (678 mg). Melting point 261-262 ° C. (recrystallized from THF-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.21 (3H, s), 2.36 (3H, s),
2.43 (2H, t like, J = 8.2Hz), 2.84 (2H, t like, J = 8.2Hz),
3.71 (3H, s), 6.64 (1H, s), 7.18-7.30 (2H, m), 7.40-7.5
5 (3H, m), 8.20 (1H, s) Elemental analysis value Calculated value as C ₂₁ H ₂₁ NO ₃ C, 75.20; H, 6.31; N, 4.18 Found value C, 75.61; H, 6.38; N, 4.10

Example 1 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-(3-isopropoxyphenyl) urea [Method A] benzene solution of 3-isopropoxyphenylisocyanate [3-isopropoxybenzoic acid (2. 1
6 g) in a suspension of benzene (100 ml) with diphenylphosphoryl azide (3.09 ml) and triethylamine (2.0 g).
1 ml) and stirred for 20 minutes at room temperature and then for 40 minutes with heating under reflux] to prepare 3-aminomethyl-
6-Chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinoline (Reference Example 6, Step 2)
(3.0 g) was added and the mixture was heated under reflux for 1.5 hr. The solvent was distilled off, and ethyl acetate was added to the residue. The mixture was washed successively with water, diluted hydrochloric acid, water, aqueous sodium carbonate and water, dried (Na ₂ SO ₄ ), and the solvent was evaporated to give the title compound as colorless crystals (3.91 g). Mp 257-259 ° C. (recrystallized from _{THF) NMR (200MHz, CDCl 3} ) ppm: 1.32 (6H, d, J = 6Hz), 3.70
(3H, s), 3.75 (1H, b), 4.27 (2H, bs), 4.53 (1H, quintet),
5.29 (1H, b), 6.59-7.53 (11H, m), 8.29 (1H, d, J = 8.6Hz) Elemental analysis value Calculated value as C ₂₇ H ₂₆ N ₃ O ₃ Cl C, 68.13; H, 5.51; N, 8.83 Found C, 67.90; H, 5.70; N, 8.71

[Method B] 6-Chloro-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolineacetic acid (Reference Example 9 Step 2) (330 mg), diphenylphosphoryl azide (0. 29 ml) and benzene
Triethylamine (0.14 ml) was added dropwise to the mixture (20 ml) with stirring at room temperature. This mixture at room temperature
The mixture was stirred for 30 minutes with heating under reflux [(6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl in the reaction solution.
Isocyanate is generated], 3-isopropoxyaniline (180 mg) was added, and the mixture was heated under reflux for 30 minutes. The solvent was distilled off, and ethyl acetate was added to the residue. The mixture was washed successively with water, diluted hydrochloric acid, water, aqueous sodium hydrogen carbonate solution and water, dried (Na ₂ SO ₄ ) and the solvent was evaporated to give the title compound as colorless crystals (390 mg). The physicochemical data of this product were in agreement with those of the compound obtained by [Method A]. By the method similar to [Method A] or [Method B] of Example 1, reaction treatment was carried out with amines and isocyanates each having a corresponding substituent, and the compounds of Examples 2 to 16 were obtained. A production example according to [Method B] is described as [B] after the compound name. Unless otherwise stated, it is a production example by [Method A].

Example 2 N-[(1,2-dihydro-2,6,7-trimethyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-(3-methylphenyl) urea melting point 2
62-264 ° C (recrystallized from ethanol) NMR (200MHz, CDCl ₃ ) ppm: 2.09 (3H, s), 2.24 (3H, s),
2.30 (3H, s), 3.62 (3H, s), 4.18 (2H, d, J = 4.4Hz), 5.85
(1H, b), 6.45 (1H, s), 6.81 (9H, m), 7.67 (1H, s), 8.06 (1
H, s) Example 3 N-[(1,2-dihydro-2-methyl-1-oxo-
4-Phenylisoquinolin-3-yl) methyl] -N '
-(3-Methylphenyl) urea Melting point 240-242 ° C (recrystallized from chloroform-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 2.30 (3H, s), 3.68 (3H, s),
4.26 (2H, d, J = 5Hz), 5.54 (1H, b), 6.77-7.49 (13H, m),
8.33-8.40 (1H, m) Example 4 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenyl-3-yl) methyl] -N '- (3- methylphenyl) urea mp 257-259 ° C. (recrystallized from _{ethanol) NMR (200MHz, CDCl 3)} ppm: 2.30 (3H, s), 3.66 (3H, s),
4.24 (2H, d, J = 4.8Hz), 5.54 (1H, b), 6.77-7.49 (12H, m),
8.23 (1H, d, J = 8.6Hz) Example 5 N- (2,4-difluorophenyl) -N '-[(1,
2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl] urea melting point 241-243 ° C. (recrystallized from ethanol) NMR (200 MHz, CDCl ₃ ) ppm: 3.69 (3H, s),
4.28 (2H, d, J = 4.6Hz), 6.21
(1H, b), 6.72-6.87 (3H, m),
7.13-7.48 (7H, m), 7.74 (1H,
b), 8.00-8.13 (1H, m), 8.29
-8.33 (1H, m)

Example 6 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N ′-(2,4-difluorophenyl) urea Melting point 258-260 ° C. (recrystallized from ethanol) NMR (200 MHz, CDCl ₃ ) ppm: 3.74 ( 3H, s),
4.27 (2H, d, J = 5.4Hz), 6.51 (1H, b), 6.74-7.52 (9H, m),
8.01 (1H, b), 8.07-8.20 (1H, m), 8.41 (1H, d, J = 8.8Hz) Example 7 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-(3-isopropoxyphenyl) -N-
Methylurea Melting point 177-178 ° C. (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.32 (6H, d, J = 6Hz), 2.76
(3H, s), 3.65 (3H, s), 4.53 (1H, quintet), 4.65 (2H, s),
6.31 (1H, b), 6.57-7.53 (11H, m), 8.44 (1H, d, J = 8.6Hz) Example 8 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-(3-ethoxycarbonylphenyl) urea [B] Melting point 223-226 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 1.36 (3H, t, J = 7.0Hz), 3.7
0 (3H, s), 4.29 (2H, d, J = 3.0Hz), 4.34 (2H, q, J = 7.0Hz),
5.7 (1H, b), 6.81 (1H, d, J = 1.8Hz), 7.1-7.2 (2H, m), 7.3-
7.4 (2H, m), 7.5 (3H, m), 7.6-7.8 (2H, m), 7.84 (1H, s),
8.23 (1H, d, J = 8.6Hz) Example 9 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N ′-(4-ethoxycarbonylphenyl) urea [B] Melting point 232-234 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.38 (3H, t, J = 7.0Hz), 3.6
6 (3H, s), 4.27 (2H, m), 4.34 (2H, q, J = 7.0Hz), 5.8 (1H,
b), 6.77 (1H, d, J = 2.0Hz), 7.12 (1H, m), 7.27 (1H, m), 7.
4-7.6 (4H, m), 7.83 (1H, s), 7.95 (2H, d, J = 8.8Hz), 8.20
(1H, d, J = 8.6Hz)

Example 10 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-(2-ethoxycarbonylphenyl) urea [B] melting point 245-247 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 1.39 (3H, t, J = 7.2Hz), 3.7
5 (3H, s), 4.33 (2H, q, J = 7.2Hz), 4.36 (2H, d, J = 7.0Hz),
5.07 (1H, b), 6.90 (1H, d, J = 1.8Hz), 6.98 (1H, t, J = 8.2H
z), 7.3-7.4 (3H, m), 7.5-7.6 (4H, m), 8.00 (1H, dd, J = 8.0
Hz, J = 1.4Hz), 8.35 (1H, d, J = 8.4Hz), 8.45 (1H, d, J = 7.8H
z) Example 11 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N ′-(3-methoxycarbonylmethoxyphenyl) urea [B] melting point 198-200 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.68 (3H, s), 3.78 (3H, s),
4.28 (2H, d, J = 4.8Hz), 4.61 (2H, s), 5.43 (1H, b), 6.58
(1H, dd, J = 8.4Hz, J = 2.2Hz), 6.83 (1H, d, J = 2.0Hz), 6.93 (1
H, d, J = 8.8Hz), 7.02 (1H, s), 7.1-7.2 (3H, m), 7.31 (1H, d
d, J = 8.4Hz, J = 1.8Hz), 7.4-7.6 (3H, m), 8.27 (1H, d, J = 8.6
Hz) Example 12 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N ′-(3-methoxycarbonylmethyl) urea [B] Melting point 177-180 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 3.56 (2H, s), 3.63 (3H, s),
3.66 (3H, s), 4.25 (2H, d, J = 5.0Hz), 5.55 (1H, b), 6.80
(1H, d, J = 1.8Hz), 6.90 (1H, m), 7.1-7.3 (7H, m), 7.4-7.5
(2H, m), 8.23 (1H, d, J = 8.6Hz)

Example 13 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-(3-isopropoxyphenyl) -N'
-Methoxycarbonylmethylurea [B] NMR (200MHz, CDCl ₃ ) ppm: 1.32 (6H, d, J = 6.2Hz), 3.7
3 (3H, s), 3.74 (3H, s), 4.24 (2H, m), 4.31 (2H, s), 4.51
(1H, m), 6.8-7.0 (6H, m), 7.3-7.5 (5H, m), 8.40 (1H, d, J =
8.4 Hz) [The product obtained as colorless crystals was purified without any purification in Example 22.
Was converted to the compound of Example 14 (1) N-[(6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl] -N ′-(3-N, N -Dimethylaminophenyl) urea [B] Melting point 252-254 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 2.92 (6H, s), 3.96 (3H, s),
4.27 (2H, d, J = 5.0Hz), 5.3 (1H, b), 6.4-6.5 (2H, m), 6.7
-6.9 (2H, m), 7.1-7.2 (3H, m), 7.3-7.4 (2H, m), 7.4-7.5
(2H, m), 8.29 (1H, d, J = 8.6Hz) (2) N-[(6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl ) Methyl] -N '-(3-N, N-dimethylaminophenyl) urea hydrochloride The compound (180 mg) obtained in Example 14 (1) was dissolved in methanol (5 ml) -ethyl acetate (5 ml),
4N hydrochloric acid-ethyl acetate (3 ml) was added. This compound was concentrated, and ethyl ether was added to the concentrate to give the title compound as a white powder (180 mg). NMR (200MHz, DMSO-d ₆ ) ppm: 3.02 (6H,
s), 3.63 (3H, s), 4.14 (2H,
d, J = 3.8 Hz), 6.84 (1H, d, J = 2.
2Hz), 6.8-6.9 (1H, m), 6.9-
7.0 (1H, b), 7.1-7.2 (1H, m),
7.2-7.3 (1H, m), 7.4-7.5 (3
H, m), 7.5-7.6 (4H, m), 8.32
(1H, d, J = 8.4Hz), 9.0 (1H, b)

Example 15 (1) N-[(6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-(3-N , N-dimethylaminomethylphenyl) urea [B] Melting point 204-206 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.22 (6H, s),
3.40 (2H, s), 3.69 (3H, s), 4.26 (2H, d, J = 5.0Hz), 5.55
(1H, b), 6.80 (1H, d, J = 2.0Hz), 6.9-7.1 (2H, m), 7.1-7.2
(2H, m), 7.2-7.4 (4H, m), 7.4-7.5 (2H, m), 8.25 (1H, d, J =
8.4Hz) (2) N-[(6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-(3-N, N- Dimethylaminomethylphenyl) urea hydrochloride Using the compound obtained in Example 15 (1), Example 1
Treatment as in 4 (2) gave the title compound as a white powder. NMR (200MHz, DMSO-d ₆ ) ppm: 2.68 (6H, d, J = 4.6Hz),
3.63 (3H, s), 4.1-4.2 (2H, m), 6.84 (1H, d, J = 2.0Hz), 6.9
9 (1H, b), 7.07 (1H, d, J = 6.4Hz), 7.31 (1H, t, J = 7.4Hz),
7.4-7.5 (3H, m), 7.5-7.6 (5H, m), 8.33 (1H, d, J = 6.8Hz),
9.01 (1H, bs) Example 16 N-[(1,2-dihydro-2-methyl-1-oxo-
4-Phenylisoquinolin-3-yl) methyl] -N '
- (3-isopropoxyphenyl) urea mp 205-207 ° C. (ethyl acetate - recrystallized from _{methanol) NMR (200MHz, CDCl 3)} ppm: 1.31 (6H, d, J = 6.0Hz), 3.6
8 (3H, s), 4.26 (2H, d, J = 4.8Hz), 4.53 (1H, m), 5.53 (1H,
m), 6.58 (1H, m), 6.7-6.9 (2H, m), 7.0-7.1 (3H, m), 7.15
(1H, t, J = 8.0Hz), 7.3-7.5 (5H, m), 8.36 (1H, m)

Example 17 (1) N- (3-carboxyphenyl) -N '-[(6
-Chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl] urea The compound (0.88 g) obtained in Example 8 in ethanol (2
0 ml) and THF (40 ml) mixed solution with sodium hydroxide aqueous solution (1.0 g / 30 ml), and the mixture was stirred at room temperature for 1 hour.
Stir for 0 hours. The solvent was evaporated, 2N-hydrochloric acid was added to acidify, the mixture was extracted with ethyl acetate, washed with water and dried (MgSO 4.
After ₄ ), the solvent was distilled off to give the title compound as colorless crystals (0.
74 g). Melting point 236-239 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, DMSO-d ₆ ) ppm: 3.63 (3H, s), 4.16 (2H,
d, J = 5.0Hz), 6.6 (1H, b), 6.85 (1H, d, J = 2.0Hz), 7.3-7.4
(3H, m), 7.4-7.6 (6H, m), 8.03 (1H, s), 8.33 (1H, d, J = 8.6
Hz), 8.67 (1H, bs) (2) N- (3-carboxyphenyl) -N '-[(6
-Chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl] urea sodium salt To the compound of Example 17 (0.74g) was added 1N-NaOH.
(1.6 ml) and water (30 ml) were added to make a homogeneous solution, which was then filtered. Lyophilization of the filtrate gave the title compound as a white powder. NMR (200MHz, DMSO-d ₆ ) ppm: 3.64 (3H, s), 4.14 (2H,
d, J = 5.0Hz), 6.86 (1H, d, J = 2.2Hz), 7.00 (1H, t, J = 7.8H
z), 7.25 (1H, d, J = 7.4Hz), 7.4-7.6 (6H, m), 7.72 (1H, s),
7.81 (1H, d, J = 8.0Hz), 8.33 (1H, d, J = 8.8Hz), 8.8 (1H, b) By the same method as in Example 17, a compound having a carboxylic acid ester group was subjected to alkaline hydrolysis. After reaction and treatment, the compounds of Examples 18 to 22 were obtained.

Example 18 (1) N- (4-carboxyphenyl) -N '-[(6
-Chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl] urea melting point 225-228 ° C (recrystallized from ethyl acetate-isopropyl ether) (2) N- ( 4-carboxyphenyl) -N '-[(6
- chloro-1,2-dihydro-2-methyl-1-oxo-4-phenyl-isoquinoline over 3-yl) methyl] urea sodium salt white powder _{NMR (200MHz, DMSO-d 6} ) ppm: 3.62 (3H, s) , 4.13 (2H,
m), 6.85 (1H, d, J = 1.8Hz), 7.31 (2H, d, J = 8.6Hz), 7.3-7.6
(6H, m), 7.68 (2H, d, J = 8.6Hz), 8.33 (1H, d, J = 8.4Hz), 9.
6 (1H, b)

Example 19 (1) N- (2-carboxyphenyl) -N '-[(6
-Chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl] urea melting point 240-242 ° C (recrystallized from ethyl acetate-isopropyl ether) (2) N- ( 2-carboxyphenyl) -N '-[(6
- chloro-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-yl) methyl] urea sodium salt white powder _{NMR (200MHz, DMSO-d 6} ) ppm: 3.53 (2H, d, J = 8.0Hz),
3.69 (3H, s), 6.64 (1H, s), 7.0-7.2 (4H, m), 7.2-7.3 (3H,
m), 7.5-7.8 (3H, m), 8.28 (1H, d, J = 8.4Hz)

Example 20 (1) N- (3-carboxymethoxyphenyl) -N '
-[(6-chloro-1,2-dihydro-2-methyl-1
-Oxo-4-phenylisoquinolin-3-yl) methyl] urea melting point 223-225 ° C (recrystallized from ethyl acetate-methanol) (2) N- (3-carboxymethoxyphenyl) -N '
-[(6-chloro-1,2-dihydro-2-methyl-1
- oxo-4-phenyl-3-yl) methyl] urea sodium salt white powder _{NMR (200MHz, DMSO-d 6} ) ppm: 3.59 (3H,
s), 4.09 (4H, m), 6.32 (1H,
d, J = 8.4 Hz), 6.76 (1H, s), 6.
82 (1H, d, J = 1.6 Hz), 6.98 (1
H, t, J = 8.4 Hz), 7.16 (1H, d, J
= 8.6 Hz), 7.4-7.6 (6H, m), 7.
7 (1H, b), 8.31 (1H, d, J = 8.4H
z), 9.77 (1H, b)

Example 21 N- (3-carboxymethylphenyl) -N '-[(6
- chloro-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-yl) methyl] urea sodium salt white powder _{NMR (200MHz, DMSO-d 6} ) ppm: 3.10 (2
H, s), 3.58 (3H, s), 4.05 (2H, d, J = 4.0Hz), 6.56 (1H, d, J =
6.6Hz), 6.85 (1H, d, J = 2.2Hz), 6.95 (1H, t, J = 7.4Hz), 7.
4-7.6 (7H, m), 7.73 (1H, d, J = 6.0Hz), 8.32 (1H, d, J = 8.4H
z), 9.05 (1H, b)

Example 22 N-carboxymethyl-N '-[(6-chloro-1,2
- dihydro-2-methyl-1-oxo-4-phenyl-3-yl) methyl]-N-(3- isopropoxyphenyl) urea sodium salt white powder _{NMR (200MHz, DMSO-d 6} ) ppm: 1.23 ( 6H, d, J = 6.0Hz),
3.64 (3H, s), 3.78 (3H, s), 4.05 (2H, d, J = 4.4Hz), 4.50 (1
H, m), 6.60 (1H, m), 6.83 (1H, d, J = 2.0Hz), 6.9-7.0 (2H,
m), 7.13 (1H, t, J = 8.2Hz), 7.3-7.4 (2H, m), 7.5-7.6 (4H,
m), 8.32 (1H, d, J = 8.8Hz), 8.32 (1H, b)

Example 23 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-(3-isopropoxyphenyl) -N'
-Methylurea DMF (4 ml) of the compound (0.30 g) obtained in Example 1
Sodium hydride (60%
Oil) (33 mg) was added, followed by methyl iodide (0.0
55 ml) was added. The mixture was stirred for 30 minutes, added to dilute hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (Na ₂ SO ₄ ) and the solvent was distilled off. Chromatography of the residue on silica gel (hexane →
Hexane: ethyl acetate = 3: 2 → 3: 1) and separated and purified. The compound (N-methyl form) (10 mg) obtained in Example 7 was obtained from the first fraction, and the N, N'-dimethyl form (compound of Example 24) (65 m) was obtained from the second fraction.
g), N'-methyl form from the third fraction (title compound)
(115 mg) was obtained as colorless crystals. Melting point 185-186 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 1.33 (6H, d, J = 6.2Hz), 3.2
2 (3H, s), 3.74 (3H, s), 4.21 (2H, d, J = 5.8Hz), 4.32 (1H,
b), 4.52 (1H, m), 6.65-7.43 (11H, m), 8.38 (1H, d, J = 8.2H
z) Elemental analysis value Calculated value as C ₂₈ H ₂₈ N ₃ O ₃ Cl C, 68.63; H, 5.76; N, 8.58 Measured value C, 68.44; H, 5.89; N, 8.44 Example 24 N-[(6- Chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-(3-isopropoxyphenyl) -N,
N′-Dimethylurea Prepared in the same manner as in Example 23. Melting point 143-144 ° C. (recrystallized from acetone-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.27 (6H, d, J = 6.2 Hz), 2.3
3 (3H, s), 3.17 (3H, s), 3.67 (3H, s), 4.41 (2H, s), 4.45
(1H, m), 6.49-7.46 (11H, m), 8.40 (1H, d, J = 8.8Hz) Elemental analysis value Calculated value as C ₂₉ H ₃₀ N ₃ O ₃ Cl C, 69.11; H, 6.00; N , 8.34 Found C, 68.70; H, 6.05; N, 8.33

Example 25 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -2-indolecarboxamide indole-2-carboxylic acid (161 mg) in THF (5
oxalyl chloride (0. ml) and DMF (1 drop) solution.
10 ml) was added and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue was dissolved in dichloromethane (5 ml). This solution was treated with 3-aminomethyl-6-chloro-1,2-dihydro-2-methyl-4-phenylisoquinoline (Reference Example 6).
Step 2) (309 mg), triethylamine (0.15
To a mixture of 4 ml) and dichloromethane (10 ml) at 0 ° C.
Add while stirring. After stirring this mixture at room temperature for 3 hours, the solvent was distilled off. Water was added to the residue and the precipitated crystals were collected by filtration and washed successively with water and acetone to give the title compound as colorless crystals (277 mg). Melting point> 305 ° C. (recrystallized from THF-ethanol) NMR (200 MHz, DMSO-d ₆ ) ppm: 3.62 (3H, s), 4.33 (2H,
d, J = 3.4Hz), 6.90 (1H, d, J = 1.8Hz), 7.03 (1H, t, J = 7.3H
z), 7.18-7.60 (10H, m), 8.37 (1H, d, J = 8.6Hz), 8.74 (1H,
b), 11.59 (1H, b)

Example 26 N-[(1,2-dihydro-2,6,7-trimethyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -2-indolecarboxamide The title compound was obtained by reacting and treating the compound of Reference Example 4 with the indole-2-carboxylic acid in the same manner as in Example 25. was gotten. Melting point 303-305 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 2.06 (3H, s), 2.14 (3H, s),
3.70 (3H, s), 4.46 (2H, d, J = 4.4Hz), 6.50 (1H, s), 7.08-
7.68 (10H, m), 7.96 (1H, b), 7.98 (1H, s), 9.96 (1H, b)

By reacting and treating the corresponding amines and acid chlorides in the same manner as in Example 25, Example 27
~ 28 compounds were obtained. Example 27 N- (6-chloro-1,2-dihydro-2-methyl-1
-Oxo-4-phenylisoquinolin-3-yl) methyl-α- (3-isopropoxyphenyl) acetamide Melting point 158-161 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 1.31 ( 6H, d, J = 6.0Hz), 3.5
2 (2H, s), 3.63 (3H, s), 4.23 (2H, d, J = 5.4Hz), 4.54 (1H,
m, J = 6.0Hz), 5.45 (1H, b), 6.7-6.8 (2H, m), 6.85 (2H, m),
7.0 (2H, m), 7.28 (1H, t, J = 7.4Hz), 7.4-7.5 (4H, m), 8.3
7 (1H, d, J = 8.4Hz)

Example 28 (1) N- (6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl-α- (3-methoxycarbonylphenyl)
Acetamide Melting point 135-136 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 3.61 (3H, s), 3.64 (2H, s),
3.92 (3H, s), 4.26 (2H, d, J = 5.2Hz), 5.79 (1H, b), 6.83
(1H, d, J = 2.2Hz), 7.0-7.1 (2H, m), 7.32 (1H, dd, J = 8.6,2.
0Hz), 7.4-7.5 (5H, m), 7.95 (1H, s), 8.0 (1H, m), 8.30 (1
H, d, J = 8.6Hz) (2) N- (6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl-α- (3-carboxy Phenyl) acetamide carboxylic acid: melting point 242-246 ° C (ethyl acetate-
Recrystallized from isopropyl ether) (3) N- (6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl-α- (3-carboxyphenyl) acetamide Sodium salt: White powder NMR (200MHz, DMSO-d ₆ ) ppm: 3.40 (2H, s), 3.48 (3H,
s), 4.03 (2H, d, J = 3.0Hz), 6.85 (1H, d, J = 2.0Hz), 7.16 (2
H, m), 7.35 (2H, m), 7.4-7.6 (3H, m), 7.71 (1H, m), 7.78 (1
H, m), 8.33 (1H, d, J = 8.4Hz), 8.5 (1H, b)

Example 29 3-Isopropoxyphenyl N-[(6-chloro-
1,2-Dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl] carbamate Reference Example 9 Compound (211 mg) obtained in Step 2, benzene (20 ml), triethylamine (0.108 ml) A mixture of and diphenylphosphoryl azide (0.195 ml) was stirred at room temperature for 1 hour and then with heating under reflux for 1 hour. 3-isopropoxyphenol (1
50 mg) was added and the mixture was heated under reflux for 1 hr. The solvent was evaporated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO _4), and evaporated. The residue was subjected to column chromatography using silica gel (hexane: ethyl acetate = 3: 1) and purified to give the title compound as colorless crystals (134 mg). Melting point 158-160 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.32 (6H, d, J = 6.2 Hz), 3.7
6 (3H, s), 4.35 (2H, d, J = 5.2Hz), 4.50 (1H, m), 5.1 (1H,
m), 6.6-6.8 (3H, m), 6.94 (1H, s), 7.2-7.3 (3H, m), 7.40
(1H, d, J = 8.0Hz), 7.54 (3H, m), 8.40 (1H, d, J = 8.4Hz)

Example 30 Benzyl N- [2- (1,2-dihydro-2,6,7)
-Trimethyl-1-oxo-4-phenylisoquinolin-3-yl) ethyl] carbamate 3- (1,2-dihydro-2,6,7-trimethyl-1
-Oxo-4-phenylisoquinolin-3-yl) propionic acid (Reference Example 10) (650 mg), triethylamine (0.30 ml) and benzene (20 ml) while stirring at room temperature with diphenylphosphoryl azide (0.30 ml). Was added. The mixture was stirred at room temperature for 30 minutes with heating under reflux for 1 hour, benzyl alcohol (1.0 ml) was added, and the mixture was heated under reflux for 30 minutes. Ethyl acetate was added to the reaction mixture water, dilute hydrochloric acid, successively washed with sodium bicarbonate and water, dried (MgSO _4), the title compound and the solvent was distilled off was obtained as colorless crystals (623 mg). Melting point 227-228 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.20 (3H, s), 2.36 (3H, s),
2.76 (2H, t, J = 7.5Hz), 3.28 (2H, bdt), 3.79 (3H, s), 4.7
7 (1H, bt), 5.04 (2H, s), 6.62 (1H, s), 7.18-7.50 (10H,
m), 8.21 (1H, s) Elemental analysis value Calculated value as C ₂₈ H ₂₈ N ₂ O ₃ C, 76.34; H, 6.41; N, 6.36 Measured value C, 76.01; H, 6.49; N, 6.33

Example 31 (6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl
N- (3-isopropoxyphenyl) carbamate 3-isopropoxyphenylisocyanate in benzene (25 ml) [3-isopropoxybenzoic acid (40
5 mg) was prepared according to the method described in Example 1, Method A].
Chloro-1,2-dihydro-3-hydroxymethyl-2
-Methyl-1-oxo-4-phenylisoquinoline (Reference Example 3) (300 mg) was added, and the mixture was heated under reflux for 1.5 hr. The solvent was distilled off, and ethyl acetate was added to the residue. The mixture was washed successively with water, diluted hydrochloric acid, water, aqueous sodium carbonate and water, dried (Na ₂ SO ₄ ) and evaporated to give the title compound as colorless crystals (435 mg). Melting point 205-207 ° C. (recrystallized from acetone-ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.32 (6H, d, J = 6.0 Hz), 3.7
2 (3H, s), 4.52 (1H, quintet), 4.96 (2H, s), 6.59-7.49 (1
2H, m), 8.44 (1H, d, J = 8.4Hz) Elemental analysis value Calculated as C ₂₇ H ₂₅ N ₂ O ₄ Cl C, 67.99; H, 5.28; N, 5.87 Measured value C, 67.72; H, 5.36; N, 5.82

Example 32 (6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl
α- (3-isopropoxyphenyl) acetate α- (3-isopropoxyphenyl) acetic acid (297 m
To a solution of g) in THF (25 ml) was added DMF (1 drop) and oxalyl chloride (0.184 ml) at room temperature to give 30
Stir for a minute. The solvent was distilled off, and the residue was treated with THF (20
ml). In this solution, the compound (370 mg) obtained in Reference Example 3 and triethylamine (0.215 ml) were added.
THF solution (20 ml) was added at room temperature and stirred for 1 hour. The solvent was evaporated, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N-hydrochloric acid, aqueous sodium hydrogencarbonate and water, dried (MgSO ₄ ), and the solvent was evaporated. Column chromatography of the residue using silica gel (hexane: ethyl acetate = 3: 1 → 2:
After purification by 1), the title compound was obtained as colorless crystals (127
mg). Melting point 130-132 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 1.30 (6H, d, J = 6.2Hz), 3.5
6 (3H, s), 3.60 (2H, s), 4.53 (1H, m), 4.85 (2H, s), 6.8-
6.9 (3H, m), 7.04 (1H, d, J = 1.2Hz), 7.1-7.3 (3H, m), 7.4-
7.5 (4H, m), 8.44 (1H, d, J = 8.4Hz) The compounds of Examples 33 to 35 were produced in the same manner as in Examples 25 and 26. Example 33 3,5-bis (trifluoromethyl) -N-[(1,2
-Dihydro-2,6,7-trimethyl-1-oxo-4
-Phenylisoquinolin-3-yl) methyl] benzamide Melting point 235-237 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 2.02 (3H, s), 2.09 (3H, s),
3.63 (3H, s), 4.46 (2H, d, J = 3.4Hz), 6.44 (1H, s), 7.35-
7.56 (5H, m), 7.85 (1H, s), 8.02 (1H, s), 8.60 (1H, bs),
8.80 (2H, s) Example 34 3,5-bis (trifluoromethyl) -N-[(1,2
- dihydro-2-methyl-1-oxo-4-phenyl-3-yl) methyl] benzamide mp 228-230 ° C. (ethyl acetate - recrystallized from isopropyl _{ether) NMR (200MHz, CDCl 3)} ppm: 3.70 (3H , s), 4.52 (2H, d, J
= 4.2Hz), 6.72 (1H, s), 7.12-7.21 (2H, m), 7.32-7.41 (2
H, m), 7.45-7.56 (3H, m), 8.02 (1H, s), 8.17 (1H, m), 8.3
5 (1H, bs), 8.73 (2H, s) Example 35 3,5-bis (trifluoromethyl) -N-[(6-chloro-1,2-dihydro-2-methyl-1-oxo-4
- phenyl-3-yl) methyl] benzamide mp 238-239 ° C. (ethyl acetate - isopropyl recrystallized from _{ether) NMR (200MHz, CDCl 3)} ppm: 3.64 (3H, s), 4.49 (2H, d, J
= 3.8Hz), 6.75 (1H, d, J = 1.8Hz), 7.11 (1H, dd, J = 8.6,1.8H
z), 7.33-7.41 (2H, m), 7.50-7.60 (3H, m), 8.03 (1H, s),
8.07 (1H, d, J = 8.6Hz), 8.22 (1H, bs), 8.70 (2H, s) Example 36 3,5-bis (trifluoromethyl) -N-[(1,2
-Dihydro-2,6,7-trimethyl-1-oxo-4
-Phenylisoquinolin-3-yl) methyl] -N-methylbenzamide DMF (5 m) of the compound (250 mg) obtained in Example 33
l) Sodium hydride (60% oil) in the solution (26 m
g) was added, and the mixture was stirred at room temperature for 30 minutes, methyl iodide (0.5 ml) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate.
The extract was washed with water, dried (MgSO ₄ ) and the solvent was evaporated to give the title compound as colorless crystals (144 mg). Melting point 223-224 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 2.25 (3H, s), 2.41 (3H, s),
2.69 (3H, s), 3.71 (3H, s), 4.83 (2H, s), 6.75 (1H, s),
7.22-7.29 (2H, m), 7.47-7.56 (3H, m), 7.78 (2H, s), 7.94
(1H, s), 8.28 (1H, s) Example 37 3,5-bis (trifluoromethyl) -N-[(1,2
-Dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl] -N-methylbenzamide Using the compound obtained in Example 34, a methylation reaction was carried out in the same manner as in Example 36. Treatment gave the title compound. Melting point 229-230 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (200MHz, CDCl ₃ ) ppm: 2.72 (3H, s), 3.73 (3H, s),
4.87 (2H, s), 7.03 (1H, m), 7.24-7.32 (2H, m), 7.46-7.5
9 (5H, m), 7.79 (2H, s), 7.94 (1H, s), 8.54 (1H, m) Example 38 3,5-bis (trifluoromethyl) -N-[(6-chloro-1 , 2-dihydro-2-methyl-1-oxo-4
-Phenylisoquinolin-3-yl) methyl] -N-methylbenzamide The compound obtained in Example 35 was subjected to a methylation reaction and treated in the same manner as in Example 36 to give the title compound. Melting point 196-197 ° C. (recrystallized from ethyl acetate-isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 2.71 (3H, s), 3.71 (3H, s),
4.85 (2H, s), 6.97 (1H, d, J = 1.8Hz), 7.22-7.31 (2H, m),
7.47 (1H, dd, J = 8.8,1.8Hz), 7.48-7.59 (3H, m), 7.79 (2H,
s), 7.95 (1H, s), 8.46 (1H, d, J = 8.8Hz)

Using 6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolineacetic acid, diphenylphosphoryl azide and an amine having a substituent corresponding to each of the compounds of Examples, it was carried out. Example 1 Example 39 by subjecting it to a reaction similar to Method B
Got through 47. The obtained hydrochloride salt of the example compound was obtained in the same manner as in the production method described in Example 14 (2). Example 39 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-[3- (diethylaminomethyl) phenyl] urea (1) free form melting point 196-198 ° C (recrystallized from ethyl acetate-isopropyl ether) ( 2) Hydrochloride White powder NMR (200MHz, DMSO-d ₆ ) ppm: 1.22 (6H, t, J = 7.4Hz),
3.03 (4H, m), 3.63 (3H, s), 4.21 (2H, d, J = 4.4Hz), 6.84 (1
H, d, J = 1.8Hz), 7.04 (1H, b), 7.13 (1H, m), 7.30 (1H, t, J =
7.4Hz), 7.42 (3H, m), 7.5-7.6 (5H, m,), 8.32 (1H, d, J = 8.
6Hz), 9.06 (1H, bs) Example 40 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-[3- (1-pyrrolidinomethyl) phenyl] urea (1) educt mp 168-170 ° C (reproduced from ethyl acetate-isopropyl ether) (Crystalline) (2) Hydrochloride white powder NMR (200MHz, DMSO-d ₆ ) ppm: 1.8-2.1 (4H, m), 3.0 (2
H, m), 3.3 (2H, m), 3.63 (3H, s), 4.14 (2H, d, J = 4.4Hz),
4.26 (2H, d, J = 5.4Hz), 6.85 (1H, d, J = 2.0Hz), 7.04 (1H,
b), 7.1-7.5 (5H, m), 7.5-7.6 (5H, m), 8.32 (1H, d, J = 8.4H
z), 9.06 (1H, bs)

Example 41 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-{3- [2- (diethylamino) ethyl] phenyl} urea (1) free form melting point 202-204 ° C (from ethyl acetate-isopropyl ether recrystallization) (2) hydrochloride white powder _{NMR (200MHz, DMSO-d 6} ) ppm: 2.78 (3H, s), 2.80 (3H,
s), 2.90 (2H, m), 3.20 (2H, m), 3.62 (3H, s), 4.13 (2H, d,
J = 4.6Hz), 6.94 (1H, b), 6.95 (1H, m), 7.2-7.3 (2H, m),
7.3-7.5 (3H, m), 7.5-7.6 (5H, m), 8.32 (1H, d, J = 8.6Hz),
8.94 (1H, bs) Example 42 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-[2- (dimethylaminomethyl) phenyl] urea (1) free form melting point 221-223 ° C (recrystallized from ethyl acetate-isopropyl ether) (2) Hydrochloride white powder NMR (200MHz, DMSO-d ₆ ) ppm: 2.71 (3H,
s), 2.77 (3H, s), 3.65 (3H,
s), 4.16 (2H, d, J = 4.0Hz),
4.45 (2H, d, J = 4.8Hz), 6.84
(1H, d, J = 2.0 Hz), 7.09 (1H,
t, J = 7.6 Hz), 7.3-7.6 (8H, m),
7.71 (1H, b), 7.87 (1H, d, J =
8.0 Hz), 8.32 (1H, d, J = 8.4H)
z), 9.04 (1H, bs)

Example 43 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-[4- (dimethylaminomethyl) phenyl] urea (1) free form melting point 199-201 ° C (recrystallized from ethyl acetate-isopropyl ether) (2) Hydrochloride White powder NMR (200 MHz, DMSO-d ₆ ) ppm: 2.64 (3
H, s), 2.66 (3H, s), 3.63 (3H, s), 4.14 (4H, m), 6.84 (1H,
d, J = 2.0Hz), 7.03 (1H, b), 7.3-7.5 (5H, m), 7.5-7.6 (5H,
m), 8.32 (1H, d, J = 8.8Hz), 9.20 (1H, bs) Example 44 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenyl-3-yl) methyl] -N '- {3- [3- (dimethylamino) propyl] phenyl} urea (1) educt colorless oil NMR (200MHz, CDCl ₃₎ ppm : 1.71 (2H, m), 2.18 (6H, s),
2.31 (2H, m), 2.44 (2H, m), 3.57 (3H, s), 4.17 (2H, s),
6.2 (1H, b), 6.7-6.8 (2H, m), 7.0-7.2 (6H, m), 7.37 (3H,
m), 8.29 (1H, d, J = 8.8Hz), 8.38 (1H, b) (2) Hydrochloride white powder NMR (200MHz, DMSO-d ₆ ) ppm: 1.91 (2H, m), 2.71 (3H,
s), 2.73 (3H, s), 3.00 (2H, m), 3.53 (2H, m), 3.63 (3H,
s), 4.12 (2H, m), 6.7-6.8 (2H, m), 6.59 (1H, b), 7.1-7.3
(4H, m), 7.4-7.5 (2H, m), 7.5-7.6 (3H, m), 8.32 (1H, d, J =
8.4Hz), 8.92 (1H, bs)

Example 45 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenyl-3-yl) methyl] -N '- {3- [2- (dimethylamino) ethoxy] phenyl} urea (1) educt colorless oil NMR (200MHz, CDCl ₃₎ ppm : 2.30 (6H, s), 2.70 (2H, t, J
= 5.6Hz), 3.65 (3H, s), 4.01 (2H, t, J = 5.6Hz), 4.24 (2H,
d, J = 4.4Hz), 5.65 (1H, b), 6.57 (1H, m), 6.8-7.2 (6H, m),
7.26 (1H, m), 7.45 (4H, m), 8.27 (1H, d, J = 8.8Hz) (2) Hydrochloride white powder NMR (200MHz, DMSO-d ₆ ) ppm: 2.84 (3H, s), 2.85 (3H,
s), 3.50 (2H, m), 3.63 (3H, s), 4.14 (2H, m), 4.27 (2H,
m), 6.51 (1H, m), 6.85 (3H, m), 7.1-7.3 (3H, m), 7.41 (2
H, m), 7.4-7.6 (3H, m), 8.34 (1H, d, J = 8.8Hz), 8.89 (1H, b
s) Example 46 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-[3- (dimethylaminomethyl) benzyl] urea (1) free form melting point 185-187 ° C (recrystallized from ethyl acetate-isopropyl ether) (2) Hydrochloride white powder NMR (200MHz, DMSO-d ₆ ) ppm: 2.66 (3H, s), 2.68 (3H,
s), 3.58 (3H, s), 4.07 (2H, m), 4.24 (4H, m), 6.6 (1H, b),
6.82 (1H, s), 7.17 (1H, b), 7.3-7.5 (5H, m), 7.5-7.6 (5
H, m), 8.31 (1H, d, J = 8.8Hz)

Example 47 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-[3- (1-imidazolyl) propyl]
Urea (1) Free form Melting point 190-192 ° C (recrystallized from ethyl acetate-isopropyl ether) (2) Hydrochloride white powder NMR (200MHz, DMSO-d ₆ ) ppm: 1.89 (2H, m), 2.98 (2H,
m), 3.58 (3H, s), 4.04 (2H, s), 4.19 (2H, m), 6.63 (1H,
b), 6.81 (1H, s), 7.17 (1H, d, J = 7.2Hz), 7.3-7.4 (2H, m),
7.5-7.6 (4H, m), 7.68 (1H, s), 7.82 (1H, s), 8.30 (1H, d,
J = 8.8Hz), 9.21 (1H, bs) Example 48 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-[3- (methylamino) methylphenyl] urea hydrochloride 6-chloro-1,2-dihydro-2-methyl-1-oxo- When 4-phenyl-3-isoquinolineacetic acid, diphenylphosphoryl azide and 3- (Nt-butoxycarbonyl-N-methylaminomethyl) aniline were used and reacted in the same manner as in Example 1, Method B, N- {3 −
[Nt-butoxycarbonyl-N-methylamino) methyl] phenyl} -N '-[(6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) Methyl] urea was obtained as a colorless oil. _{NMR (200MHz, CDCl 3) ppm} : 1.38 (9H, s), 2.78 (3H, s),
3.71 (3H, s), 4.29-4.35 (4H, m), 5.8 (1H, b), 6.60 (1H,
b), 6.86 (1H, d, J = 1.8Hz), 7.1-7.3 (5H, m), 7.3-7.6 (5H,
m), 8.25 (1H, d, J = 8.8Hz) The product was reacted with excess hydrochloric acid in ethyl acetate at room temperature to give the title compound as a white powder. NMR (200MHz, DMSO-d ₆ ) ppm: 2.52 (3H, m), 3.63 (3H,
s), 4.03 (2H, m), 4.14 (2H, d, J = 4.6Hz), 6.84 (1H, d, J = 2.
0Hz), 7.05 (1H, d, J = 11.8Hz), 7.13 (1H, b), 7.31 (1H, t, J
= 13.4Hz), 7.4-7.5 (3H, m), 7.54 (5H, m), 8.32 (1H, d, J =
8.6Hz), 9.01 (1H, b), 9.18 (1H, bs)

Example 49 N-[(6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-[3- (ethylaminomethyl) phenyl] urea hydrochloride 6-chloro-1,2-dihydro-2-methyl-1-oxo- When 4-phenyl-3-isoquinolineacetic acid, diphenylphosphoryl azide and 3- (Nt-butoxycarbonyl-N-ethylamino) methylaniline were used and reacted in the same manner as in Example 1 Method B, N- [3 −
(Nt-butoxycarbonyl-N-ethylamino) methylphenyl] -N '-[(6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl ] Urea was obtained as a colorless oil. NMR (200MHz, CDCl ₃ ) ppm: 1.02 (3H, t, J = 7.0Hz), 1.3
8 (9H, s), 3.17 (2H, m), 3.72 (3H, s), 4.34 (4H, m), 5.70
(1H, b), 6.8-6.9 (2H, m), 6.99 (1H, b), 7.1-7.3 (4H, m),
7.4-7.5 (5H, m), 8.27 (1H, d, J = 8.6Hz) The product was reacted with excess hydrochloric acid in ethyl acetate at room temperature to give the title compound as a white powder. NMR (200MHz, DMSO-d ₆ ) ppm: 1.20 (3H, t, J = 7.2Hz),
2.94 (2H, m), 3.63 (3H, s), 4.04 (2H, m), 4.15 (2H, d, J = 4.8
Hz), 6.84 (1H, d, J = 2.0Hz), 7.0-7.1 (2H, m), 7.3-7.5 (3
H, m), 7.5-7.6 (6H, m), 8.33 (1H, d, J = 8.6Hz), 8.90 (1H,
b), 9.02 (1H, bs) Example 50 N- (1-aminoindan-5-yl) -N '-[(6
-Chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl] urea hydrochloride 6-chloro-1,2-dihydro-2-methyl-1-oxo-4 -Phenyl-3-isoquinolineacetic acid, diphenylphosphoryl azide and 1- (t-butoxycarbonylamino) -5-aminoindan, Example 1 Method B
When reacted in the same manner as in N- [1- (t-butoxycarbonylamino) indan-5-yl] -N'-
[(6-chloro-1,2-dihydro-2-methyl-1-
Oxo-4-phenylisoquinolin-3-yl) methyl] urea was obtained as colorless crystals. Mp 225-227 ° C (recrystallized from ethyl acetate-isopropyl ether) The product was reacted with excess hydrochloric acid in ethyl acetate at room temperature to give the title compound as a white powder. NMR (200MHz, DMSO-d ₆ ) ppm: 1.98 (1H, m), 2.44 (1H,
m), 2.80 (1H, m), 2.93 (1H, m), 3.63 (3H, s), 4.14 (2H, d,
J = 4.0Hz), 4.62 (1H, m), 6.84 (1H, d, J = 1.8Hz), 7.11 (1H,
b), 7.15 (1H, d, J = 8.4Hz), 7.30 (1H, d, J = 7.4Hz), 7.4-7.
5 (2H, m), 7.5-7.6 (4H, m), 7.68 (1H, s), 8.22 (1H, d, J = 8.
4Hz), 9.18 (1H, bs)

Example 51 N- [3- (aminomethyl) phenyl] -N '-[(6
-Chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl] urea hydrochloride 6-chloro-1,2-dihydro-2-methyl-1-oxo-4 -Phenyl-3-isoquinolineacetic acid, diphenylphosphoryl azide and 3- (1-phthalimidomethyl) aniline were reacted in the same manner as in Example 1 Method B, and the resulting product was treated with hydrazine to give the title compound. The free base was obtained as colorless crystals. _{NMR (200MHz, CDCl 3) ppm} : 3.67 (3H, s), 3.81 (2H, s),
4.26 (2H, d, J = 5.0Hz), 5.55 (1H, b), 6.80 (1H, d, J = 2.0H
z), 6.98 (1H, m), 7.1-7.3 (7H, m), 7.4-7.6 (3H, m), 8.24
(1H, d, J = 8.8Hz) The product was converted to the title compound by treatment with hydrochloric acid in ethyl acetate. White powder NMR (200MHz, DMSO-d ₆ ) ppm: 3.63 (3H, s), 3.93 (2H,
m), 4.14 (2H, d, J = 5.2Hz), 6.84 (1H, d, J = 2.2Hz), 7.01 (1
H, d, J = 7.4Hz), 7.09 (1H, b), 7.2-7.5 (3H, m), 7.5-7.6 (6
H, m), 8.3 (2H, b), 8.32 (1H, d, J = 8.4Hz), 8.99 (1H, bs) Example 52 N-[(1,2-dihydro-2-methyl-1-oxo −
4-Phenylisoquinolin-3-yl) methyl] -N '
-[3- (Dimethylaminomethyl) phenyl] urea hydrochloride 1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolineacetic acid, diphenylphosphoryl azide and 3- (dimethylaminomethyl) aniline It was used and reacted in the same manner as in Example 1 Method B, and the obtained product was treated with hydrochloric acid in ethyl acetate to give the title compound as a white powder. NMR (200MHz, DMSO-d ₆ ) ppm: 2.67 (3H, s), 2.69 (3H,
s), 3.64 (3H, s), 4.17 (4H, m), 6.9-7.2 (4H, m), 7.3-7.7
(9H, m), 8.32 (1H, m), 9.09 (1H, bs)

Example 53 N-{[4- (4-fluorophenyl) -1,2-dihydro-2-methyl-1-oxoisoquinolin-3-yl) methyl] -N '-[3- (dimethylamino Methyl)
Phenyl] urea hydrochloride 4- (4-fluorophenyl) -2-methyl-1 (2
4- (4-fluorophenyl) -1,2-dihydro-2-methyl-1-oxo-3-isoquinoline obtained from (H) -isoquinolinone-3-carboxylic acid by the same carbon-addition reaction as in Reference Example 7. With acetic acid, diphenylphosphoryl azide and 3- (dimethylamino) methylaniline,
When reacted in the same manner as in Example 1, Method B, the free base of the title compound was obtained as colorless crystals. Mp 154-156 ° C (recrystallized from ethyl acetate-isopropyl ether) The product was converted to the title compound by treatment with hydrochloric acid in ethyl acetate. White powder NMR (200MHz, DMSO-d ₆ ) ppm: 2.67 (3H, s), 2.70 (3H,
s), 3.64 (3H, s), 4.20 (4H, m), 6.9-7.2 (4H, m), 7.3-7.5
(6H, m), 7.5-7.7 (2H, m), 8.32 (1H, d, J = 8.2Hz), 9.01 (1
H, bs)

[0093]

INDUSTRIAL APPLICABILITY The present invention has an excellent inhibitory action on calcium release from endoplasmic reticulum in nerve cells as a therapeutic or prophylactic agent for the treatment and prevention of cerebrovascular disorders such as cerebral ischemic injury and cerebral edema and / or nerve cell disorders. Tachykinin receptor antagonism,
In particular, a novel heterocyclic compound having a substance P receptor antagonistic action and a salt thereof can be provided.

Continuation of front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location C07D 401/12 209 233 405/12 217 409/12 217 413/12 217 417/12 217 // (C07D 401 / 12 209: 00 217: 00)

Claims (35)

[Claims] 1. A general formula: [In the formula, A ring and B ring may have a benzene ring which may have a substituent, Ar represents an aryl group which may have a substituent or a heterocyclic group which may have a substituent, Q Is an oxygen atom or a sulfur atom, R is a hydrogen atom, a hydrocarbon group which may have a substituent, a hydroxyl group which may have a substituent or an amino group which may have a substituent, X Is —O— or —NR ¹ — (R ¹ represents a hydrogen atom or a hydrocarbon group which may have a substituent), Y is —O—, —
NR ² — (R ² represents a hydrogen atom or a hydrocarbon group which may have a substituent) or a bond, m represents 1, 2 or 3, and n represents 0, 1 or 2. ] The compound or its salt represented by these. Wherein ring A and ring B, halogen atom, optionally halogenated C _1-6 alkyl group, optionally halogenated a C _1-6 alkoxy group, may be halogenated C _1-6 alkylthio group, C _1-7 acylamino group, C _1-3 acyloxy group, hydroxyl group, nitro group, cyano group, amino group, mono- or di-C _1-4 alkylamino group, pyrrolidino group, piperidino Group, morpholino group, C _1-4 alkyl-carbonylamino group, C _1-4 alkylsulfonylamino group, C _1-4 alkoxy-carbonyl group, carboxyl group, C _1-6 alkyl-carbonyl group, carbamoyl group, mono- The compound according to claim 1, which is also a benzene ring optionally having 1 to 4 substituents selected from a di-C _1-4 alkylcarbamoyl group and a C _1-6 alkylsulfonyl group. Wherein ring A and ring B, halogen atom, halogenated which may be C _1-4 alkyl group, halogenated which may be C _1-4 alkoxy group, or halogenated It has 1 to 3 substituents selected from C _1-4 alkylthio group, hydroxyl group, amino group, mono- or di-C _1-4 alkylamino group, carboxyl group and C _1-4 alkoxy-carbonyl group. The compound according to claim 1, which is an optionally substituted benzene ring. 4. Ring A and ring B are selected from a halogen atom, an optionally halogenated C _1-4 alkyl group and an optionally halogenated C _1-4 alkoxy group.
The compound according to claim 1, which is a benzene ring which may have two substituents. 5. The compound according to claim 1, wherein ring B is unsubstituted. 6. A benzene ring in which ring A may have one or two halogen atoms or optionally halogenated C _1-4 alkyl groups, and ring B is an unsubstituted benzene ring. Item 1. The compound according to Item 1. 7. The compound according to claim 1, wherein R is a hydrogen atom. 8. The compound according to claim 1, wherein R is a C _1-6 alkyl group. 9. The compound according to claim 1, wherein Q is an oxygen atom. 10. The compound according to claim 1, wherein X is --O--. 11. The compound according to claim 1, wherein X is —NH—. 12. The compound according to claim 1, wherein R ² is (i) a hydrogen atom or (ii) a C _1-4 alkoxy-carbonyl group or a C _1-4 alkyl group optionally substituted with a carboxyl group. 13. The compound according to claim 1, wherein R ² is a hydrogen atom or a C _1-4 alkyl group. 14. The compound according to claim 1, wherein Y is —NH—. 15. The compound according to claim 1, wherein Y is a bond. 16. The compound according to claim 1, wherein m is 1. 17. The compound according to claim 1, wherein m is 2. 18. The compound according to claim 1, wherein n is 0. 19. The compound according to claim 1, wherein n is 1. 20. Ar is (i) an optionally halogenated C _1-4 alkyl group, (ii) a mono- or di-C _1-4 alkylamino-C _1-4 alkyl group, (iii) Carboxy-C _1-4 alkyl group, (iv) C _1-4 alkoxy-carbonyl-C _1-4 alkyl group, (v) optionally halogenated C _1-4 alkoxy group, (vi) carboxy-C _1-4 alkoxy group, (vii) C
_1-4 alkoxy-carbonyl-C _1-4 alkoxy group, (vii
i) halogen atom, (ix) mono- or di-C _1-4 alkylamino group, (x) C _1-4 alkoxy-carbonyl group and (x
The compound according to claim 1, which is i) a phenyl group optionally having one or two substituents selected from a carboxyl group. 21. Ar is (i) an optionally halogenated C _1-4 alkoxy group, (ii) a carboxyl group, (iii) a carboxy-C _1-4 alkyl group, (iv) a mono- or di- -C _1-4 alkylamino-C _1-4 alkyl group, (v) mono- or di-
The compound according to claim 1, which is a phenyl group optionally having one substituent selected from a C _1-4 alkylamino group and (vi) a carboxy-C _1-4 alkoxy group. 22. Ar is (i) an amino group, (ii) a mono- or di-C _1-4 alkylamino group or (iii) a C _1- which may have a 5- to 9-membered cyclic amino group. ₆ alkyl groups
Or a phenyl group which may have two.
The described compound. 23. Ar is one of (i) an optionally halogenated C _1-4 alkoxy group or (ii) a mono- or di-C _1-4 alkylamino-C _1-4 alkyl group. The compound according to claim 1, which is a phenyl group which may be substituted. 24. Ar optionally halogenated C _1-4
The compound according to claim 1, which is a phenyl group which may be substituted with an alkoxy group. 25. Ar is a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyridazinyl group, a quinolyl group, an isoquinolyl group, an indolyl group, a thiazolyl group, a thiadiazolyl group or thiophenyl. The compound according to claim 1, which is a group. 26. The compound according to claim 1, wherein Ar is an indolyl group. 27. Q is an oxygen atom, R is a C _1-4 alkyl group,
The compound according to claim 1, wherein X is -NH- and Y is -NH- or a bond. 28. (i) N-[(6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-(3-isopropoxy Phenyl) urea, (ii) N-[(6-chloro-1,2
-Dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl] -N '-(3-N, N
-Dimethylaminomethylphenyl) urea, (iii) N-
(6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinolin-3-yl) methyl-
α- (3-isopropoxyphenyl) acetamide, (i
v) N- (6-chloro-1,2-dihydro-2-methyl-
1-oxo-4-phenylisoquinolin-3-yl) methyl-α- (3-methoxycarbonylphenyl) acetamide, (v) N-[(6-chloro-1,2-dihydro-
2-Methyl-1-oxo-4-phenylisoquinoline-
3-yl) methyl] -N '-{(3- [2- (diethylamino) ethyl] phenyl} urea, (vi) N-[(6-
Chloro-1,2-dihydro-2-methyl-1-oxo-
4-Phenylisoquinolin-3-yl) methyl] -N '
-{(3- [2- (dimethylamino) ethoxy] phenyl} urea, (vii) N-[(6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinoline-3- Iyl) methyl] -N ′-[3- (1-imidazoyl) propyl] urea, (viii) N-[(6-chloro-1,2-dihydro-2-methyl-1-oxo-4-phenylisoquinoline- 3-yl) methyl] -N '-[3
-(Methylamino) methylphenyl] urea, (ix) N-
[(6-chloro-1,2-dihydro-2-methyl-1-
Oxo-4-phenylisoquinolin-3-yl) methyl] -N '-[3- (ethylaminoethyl) phenyl]
Urea or (x) N- [3- (aminomethyl) phenyl] -N '-[(6-chloro-1,2-dihydro-2-
Methyl-1-oxo-4-phenylisoquinoline-3-
Il) methyl] urea, or salts thereof. 29. A general formula: A compound represented by or a salt thereof with the general formula _{Ar- (CH 2) n -Y-} CO-L 2 wherein, L ¹ and L ² are both reactive to a group which desorbs, and the other symbols claims 1 has the same meaning as described in 1. ] The compound represented by the following formula or a salt thereof is reacted with a general formula: [The symbols in the formulas have the same meaning as in claim 1. ] The manufacturing method of the compound or its salt represented by these. 30. A general formula: The compound represented by the formula or a salt thereof is reacted with the compound represented by the general formula Ar- (CH ₂ ) _n- Y ¹ -L ⁴ or a salt thereof. [In the formula, L ³ and L ⁴ are groups that react with each other to leave, Y ¹
Is -O- or -NR ² -, the other symbols are as defined claim 1. ] The manufacturing method of the compound or its salt represented by these. 31. A calcium antagonist comprising the compound according to claim 1. (32) A therapeutic agent for cerebrovascular disease, which comprises the compound according to (1). 33. A therapeutic agent for cerebral ischemic injury comprising the compound according to claim 1. 34. A therapeutic agent for cerebral edema, which comprises the compound according to claim 1. [35] A substance P receptor antagonist, which comprises the compound according to [1].