JPH10259184A - Production of tricyclic heterocyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a compound useful as a starting raw material for a tricyclic heterocyclic compound having an excellent tachykinin receptor-antagonizing action, especially a substance P receptor-antagonizing action. SOLUTION: A compound of formula II (R' is a substitutable 1-4C alkyl; Q is a substitutable 1-7c alkyl; L is a releasable group) or its salt. The compound of formula I is obtained by reacting an amine of formula II with a halogenated acetic ester of the formula: X-CH2 -COOR' (X is a halogen) in the presence of a base in a solvent at -30 to 100 deg.C for 1-5hr. A tricyclic heterocyclic compound of formula IV is obtained by condensing the compound of formula I with a compound of formula III (R is a substitutable 1-3C alkyl), subjecting the condensation product to a dehydrative ring-closing reaction, reacting the product with an amine, and subsequently subjecting the reaction product to a ring-closing reaction. The compound of formula IV is thus safely obtained in a good yield in a large scale and at a low cost.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an intermediate in an improved method for synthesizing a cyclic compound having an excellent tachykinin receptor antagonistic activity, and a method for producing the intermediate.

[0002]

2. Description of the Related Art Japanese Patent Application Laid-Open Publication No. Hei 8 (1994) discloses a compound having tachykinin receptor antagonistic activity (particularly, substance P receptor antagonistic activity) and the like, which is sufficiently satisfactory as a medicine.
-301849, JP-A-8-301871 and JP-A-8-337583 describe methods for producing bicyclic heterocyclic compounds. Further, a method for producing a tricyclic heterocyclic compound is described in Japanese Patent Application No. Hei 8-214698.

[0003]

The above prior arts have many difficulties in carrying out industrial mass synthesis, such as the use of hardly available raw materials and the large number of reaction steps. That is, an object of the present invention is to provide an excellent tachykinin receptor antagonistic action, in particular, a tricyclic heterocyclic compound having a substance P receptor antagonistic action, in good yield, and furthermore, safely and inexpensively suitable for large-scale synthesis. An object of the present invention is to provide a production method, and to provide an important intermediate for producing a tricyclic heterocyclic compound and a production method thereof.

[0004]

Means for Solving the Problems As a result of diligent studies, the present inventors have found that the method using the compound of the present invention shortens the synthetic route of the tricyclic heterocyclic compound, is inexpensive, and can be safely used on a large scale. The present inventors have found a new route suitable for the present invention and completed the present invention. That is, the present invention provides a compound (1) represented by the following formula:
Or a salt thereof, formula (1)

Embedded image [Wherein, R ¹ represents an optionally substituted C _1-4 alkyl group, Q represents a substituted C _1-7 alkylene group, and L represents a leaving group. (2) The compound or a salt thereof according to the above (1), wherein R ¹ is a methyl group, Q is a 3-methylbutylene group, and L is a 2-tetrahydropyraniloxy group.

Equation (3)

Embedded image [ _Wherein Q represents a substituted C _1-7 alkylene group, and L represents a leaving group. Wherein X-CH ₂ -COOR ¹ wherein the primary amine represented by], X is a halogen atom, R ¹ represents represents an C _1-4 alkyl group which may be substituted. And a halogenated acetate represented by the formula:

Embedded image Wherein R ¹ , Q and L are as defined above. The method for producing a compound represented by the formula (4):

Embedded image [Wherein, R ¹ represents an optionally substituted C _1-4 alkyl group, Q represents a substituted C _1-7 alkylene group, and L represents a leaving group. And a salt thereof and a compound represented by the formula

Embedded image [Wherein, R represents a C _1-3 alkyl group which may be substituted. A compound represented by the formula:

Embedded image [Wherein, R ¹ , R, Q and L have the same meanings as described above. The method for producing a compound represented by

Equation (5)

Embedded image [Wherein, R ¹ represents an optionally substituted C _1-4 alkyl group, R represents an optionally substituted C _1-3 alkyl group, Q
_{Represents a} substituted C _1-7 alkylene group, and L represents a leaving group. (6) The compound according to the above (5), wherein R ¹ and R are a methyl group, Q is a 3-methylbutylene group, and L is a 2-tetrahydropyraniloxy group.
Equation (7)

Embedded image [Wherein, R ¹ represents an optionally substituted C _1-4 alkyl group, Q represents a substituted C _1-7 alkylene group, and L represents a leaving group. And a salt thereof and a compound represented by the formula

Embedded image [Wherein, R represents a C _1-3 alkyl group which may be substituted. With a compound represented by the formula

Embedded image [Wherein, R ¹ , R, Q and L have the same meanings as described above. Wherein the compound is subjected to a ring closure reaction.

Embedded image [Wherein, R ¹ , R, Q and L have the same meanings as described above. The method for producing a compound represented by

Equation (8)

Embedded image [Wherein, R ¹ represents an optionally substituted C _1-4 alkyl group, R represents an optionally substituted C _1-3 alkyl group, Q
_{Represents a} substituted C _1-7 alkylene group, and L represents a leaving group. (9) The compound according to (8), wherein R ¹ and R are a methyl group, Q is a 3-methylbutylene group, and L is a 2-tetrahydropyraniloxy group.
(10) (R) -7,8-dihydro-5- (4-methylphenyl) -8-oxo-7- [3-methyl4- (2-
Tetrahydropyranyloxy) butyl] -6-pyrido [3,4-b] -pyridine-6-carboxylic acid or a salt thereof,

Equation (11)

Embedded image [Wherein, R ¹ represents an optionally substituted C _1-4 alkyl group, Q represents a substituted C _1-7 alkylene group, and L represents a leaving group. And a salt thereof and a compound represented by the formula

Embedded image [Wherein, R represents a C _1-3 alkyl group which may be substituted. With a compound represented by the formula

Embedded image [Wherein, R ¹ , R, Q and L have the same meanings as described above. To obtain a compound represented by the formula

Embedded image [Wherein, R ¹ , R, Q and L have the same meanings as described above. To obtain a compound represented by the formula

Embedded image [In the formula, ring A represents a benzene ring substituted with a halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group. A compound represented by the formula:

Embedded image [Wherein, rings A, R, Q and L are as defined above. The method for producing a compound represented by

Equation (12)

Embedded image [Wherein ring A represents a benzene ring substituted with a halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group, and R represents an optionally substituted C
_1-3 alkyl group, Q is a C _1-7 alkylene group substituted, L is a leaving group. A compound represented by the formula (13):
R represents a methyl group, Q represents a 3-methylbutylene group, and L represents 2
A tetrahydropyraniloxy group, wherein ring A is a 3,5-bis (trifluoromethyl) benzene ring (12).
(14) (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7- (4-chloro-3-methylbutyl) -7,8-dihydro-5- (4-
Methylphenyl) -8-oxo-6-pyrido [3,4-
b] -pyridine-6-carboxamide,

Equation (15)

Embedded image [Wherein, R ¹ represents an optionally substituted C _1-4 alkyl group, Q represents a substituted C _1-7 alkylene group, and L represents a leaving group. And a salt thereof and a compound represented by the formula

Embedded image [Wherein, R represents a C _1-3 alkyl group which may be substituted. With a compound represented by the formula

Embedded image [Wherein, R ¹ , R, Q and L have the same meanings as described above. And a compound represented by the formula

Embedded image [Wherein, R ¹ , R, Q and L have the same meanings as described above. To obtain a compound represented by the formula

Embedded image [In the formula, ring A represents a benzene ring substituted with a halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group. Is reacted with an amine represented by the formula

Embedded image [Wherein, rings A, R, Q and L are as defined above. Wherein the compound is subjected to a ring closure reaction.

Embedded image [Wherein, rings A, R and Q are as defined above. And a method for producing the compound represented by the formula: Hereinafter, the present invention will be described in detail. The compound (1) or a salt thereof according to the present invention has the formula

Embedded image [Wherein, R ¹ represents an optionally substituted alkyl group having 1 to 4 carbon atoms, Q represents a substituted C _1-7 alkylene group,
Represents a leaving group. ]. As the optionally substituted alkyl group having 1 to 4 carbon atoms represented by R ¹ ,
For example, methyl, ethyl, n-propyl, i-propyl,
Examples of the substituent include a halogen atom (fluorine, chlorine, bromine, and iodine), a phenyl group, a _C7-10 aralkyl group, a nitro group, and the like. The number of substituents is about 1 to 4. Examples of the leaving group represented by L include a halogen atom (eg, chlorine, bromine, iodine atom, etc.), a C _1-4 alkanesulfonyloxy group (eg, a methanesulfonyloxy group, etc.), and a C _6-10 arylsulfonyl. An oxy group (for example, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, etc.); When L is a protecting group for a hydroxyl group, for example, a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-
Butyl group, etc.), phenyl group, C _7-10 aralkyl group (eg, benzyl group), C _1-6 alkylcarbonyl group (eg, formyl, methylcarbonyl, ethylcarbonyl,
Butylcarbonyl group, etc.), aryloxycarbonyl group (eg, phenyloxycarbonyl group, etc.), C _7-10 aralkyl-carbonyl group (eg, benzyloxycarbonyl group, etc.), pyranyl group, furanyl group, hydroxyl group protected by silyl group, etc. In this case, the protecting group may be removed first to form a hydroxyl group, and the hydroxyl group may be converted to the above-mentioned L which is a leaving group.

The protective group can be removed by a known or equivalent method, for example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride,
A method of treating with palladium acetate or the like can be used. In the conversion reaction, usually, the compound corresponding to the leaving group (for example, thionyl chloride, thionyl bromide, About 1 to 5 molar equivalents of methanesulfonyl chloride, benzenesulfonyl chloride and the like are used in a solvent (for example, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as tetrahydrofuran, esters such as ethyl acetate and the like). Do. The reaction time is usually about 1-5.
In about an hour, the reaction temperature is usually about 0-100 ° C. The above-mentioned protecting group may have a substituent. Specific examples of the substituent include, for example, a halogen atom (fluorine, chlorine, bromine, iodine), a C _1-6 alkyl group, a phenyl group, a C _7-10
An aralkyl group, a nitro group, and the like;
Approximately four. Q represents a substituted C _1-7 alkylene group.

The C _1-7 alkylene group is preferably a C _1-5 alkylene group, more preferably a C ₃ or C ₄ alkylene group, and particularly preferably a C ₄ alkylene group. Preferred specific examples of Q include a propylene group, a butylene group, a methyl-substituted propylene group or a methyl-substituted butylene group, and a methyl-substituted butylene group is particularly preferable. In particular,

Embedded image [Wherein, m and n each represent an integer of 0 to 4, and the sum of m and n is 4 or less. ], More preferably,

Embedded image Is mentioned. This compound (1) can be produced, for example, by the method shown in the following reaction scheme A.

[Reaction scheme A]

Embedded image [Wherein, R ¹ , Q and L have the same meanings as described above, and X represents a halogen atom. Examples of the halogen atom represented by X include a fluorine, chlorine, bromine and iodine atom. The reaction represented by the reaction scheme A is carried out by reacting a primary amine (6) with X-
Halogenated acetic acid ester represented by CH ₂ COOR ¹ [wherein X represents a halogen atom, and R ¹ has the same meaning as described above. And N-alkylation to obtain the compound (1), and any known method or a method analogous thereto can be used. For example, based on 1 molar equivalent of the primary amine (6), about 1 to 5 molar equivalents of the base and about 1
Alternatively, the reaction can be carried out by adding 1.2 molar equivalents of a halogenated acetic ester and reacting. This reaction is usually performed in the presence of a solvent, and examples of the solvent include ethers (eg, diethyl ether, tetrahydrofuran,
Dioxane, etc.), esters (eg, methyl acetate, etc.), hydrocarbons (eg, benzene, toluene, etc.),
Nitriles (acetonitrile) and aprotic polar solvents (eg, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc.) are used. Bases that can be used include, for example, inorganic bases (sodium hydroxide,
Alkali metal hydroxides such as potassium hydroxide, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and metal hydrides such as sodium hydride and potassium hydride Organic bases (tri-C _1-3 alkylamines such as trimethylamine, triethylamine, diisopropylethylamine, etc., cyclic amines such as 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, N, N-
And aromatic amines such as dimethylaniline. The reaction temperature varies depending on the type of base used, but is usually about -30 to 100 ° C, preferably about 0 to 4 ° C.
0 ° C. The reaction time is usually about 1 to 5 hours.
The compound (1) may be formed into a salt by a conventional method. Examples of the salt include an inorganic salt (for example, hydrochloride, sulfate, phosphate, hydrobromide and the like), an organic acid salt ( For example,
Acetate, malate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate,
Fumarate, maleate, tartrate and the like). The compounds (3), (4) and (5) in the present invention can be produced, for example, by the method shown in the following reaction scheme B.

[Reaction scheme B]

Embedded image [In the formula, R ¹ , R, Q, L and ring A have the same meaning as described above. In the reaction scheme B, step 1 is a step of condensing the compound (1) or a salt thereof with the carboxyl group of the compound (2) or a salt thereof to obtain a compound (3). In this step, after converting the compound (2) or a salt thereof into a reactive derivative such as an acid halide by a conventional method, the compound (3) is reacted with the compound (1) or a salt thereof in the presence of a base. You may get it. The conversion into an acid halide, which is one of the reactive derivatives, uses, for example, thionyl chloride, thionyl bromide, phosphorus halide and the like. For example, when an acid chloride is prepared using thionyl chloride, compound (2) is usually added in the presence of a catalytic amount of an amide such as N, N-dimethylformamide.
Or about 1 to 10
Molar equivalents, preferably about 1 to 5 molar equivalents, are used. This reaction can be carried out in a solvent (for example, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as tetrahydrofuran, and esters such as ethyl acetate). For example, usually, compound (2)
Alternatively, about 1 to 30 times, preferably about 3 to 10 times, the volume of tetrahydrofuran or the like with respect to the salt thereof is used. The reaction time is usually about 1 to 5 hours,
The reaction temperature is usually about 0-100 ° C.

The subsequent reaction (N-alkylation reaction) with the compound (1) is usually carried out in an amount of about 1 to 1 mole equivalent of the acid halide.
The reaction can be carried out by reacting about 1 to 2 molar equivalents of the compound (1) with about 5 to 5 molar equivalents of a base.
This reaction is also usually performed in the presence of a solvent.
Ethers (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), esters (eg, methyl acetate, etc.), hydrocarbons (eg, benzene, toluene, etc.), nitriles (acetonitrile), aprotic polar solvents (eg, dimethyl Formamide, dimethylsulfoxide, hexamethylphosphoramide, etc.) are used. For example, it is usually good to use about 1 to 30 times, preferably about 3 to 10 times, the volume of tetrahydrofuran or the like to the acid halide. Examples of usable bases include inorganic bases (eg, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and alkali metal carbonates such as sodium carbonate and potassium carbonate). Metal hydrides such as sodium hydride, potassium hydride, etc.), and organic bases (tri-C _1-3 alkylamines such as trimethylamine, triethylamine, diisopropylethylamine, etc., 1,8-diazabicyclo [5.4.0] undec-) 7-
And cyclic amines such as ene and pyridine, and aromatic amines such as N, N-dimethylaniline. The reaction temperature varies depending on the type of the base used, but is usually about -30 to 1
At 00C, preferably about 0-50C. Further, the carboxyl group of the compound (2) is converted into an active ester by using a method generally used in peptide chemistry or the like (for example, a method using dicyclohexylcarbodiimide or water-soluble carbodiimide), After the esterification, the compound (1) may be reacted to obtain the compound (3). Compound (2) used in the above reaction is produced, for example, by the following method.

One equivalent of 2,3-pyridinedicarboxylic acid is dissolved in about 1 to 30 equivalents, preferably about 3 to 10 equivalents of acetic anhydride, and the mixture is heated under reflux. After completion of the reaction, the reaction solution is concentrated under reduced pressure, isopropyl ether is added to the remaining crystals, and the mixture is stirred under ice cooling or at room temperature, and the crystals are collected by filtration and washed with isopropyl ether. The crystals are dried under reduced pressure to give 2,3-pyridinecarboxylic anhydride. About 1.2 equivalents of metallic magnesium are added to tetrahydrofuran, and a catalytic amount of iodine is added with stirring. The expression

Embedded image [In the formula, X represents a halogen atom, and R represents a C _1-3 alkyl group which may be substituted. 1-alkyl-4-halogeno-benzene represented by the formula [1] is added while maintaining the internal temperature at 30 to 40 ° C. Thereafter, the mixture is stirred at about 40 ° C. for about 1 hour to prepare a Grignard reagent. Separately, a solution of 1.0 equivalent of 2,3-pyridinecarboxylic anhydride obtained above in tetrahydrofuran was added to N, N,
About 1.2 equivalents of N ′, N′-tetramethylethylenediamine were added, and the Grignard reagent prepared above was added dropwise while maintaining the internal temperature of the mixture at about 0 to 5 ° C., and then the mixture was added for about 1 hour. React at temperature. After concentrating the reaction solution under reduced pressure,
Water is added, and the pH is adjusted to about 1.0 with an acid such as concentrated hydrochloric acid while maintaining the internal temperature at about 30 ° C. Thereafter, after extraction with dichloromethane, the solvent is concentrated under reduced pressure, isopropyl ether is added, and the precipitated crystals are collected by filtration and dried to obtain the above compound (2). In the above formulas, X is a halogen atom (fluorine, chlorine, bromine, iodine) and, R represents for example methyl, ethyl, n- propyl, include C _1-3 alkyl groups such as i- propyl, this C _1-3 The alkyl group may be substituted with, for example, about 1 to 4 halogen atoms, a phenyl group, a _C7-10 aralkyl group, a nitro group, or the like.

In step 2, compound (3) is prepared in the presence of a base.
In this step, the compound is subjected to addition dehydration in the molecule to close the ring, thereby obtaining a compound (4). Bases used in this reaction include, for example, inorganic bases (metal hydrides such as sodium hydride and potassium hydride, metal amides such as sodium amide, alcoholates such as sodium methoxide, sodium ethoxide, sodium butoxide, potassium butoxide, n-butyllithium, lithium diisopropylamide, etc.), an organic base (1,5-diazabicyclo [4.3.0] non-5-ene, 1,8-diazabicyclo [5.4.0] undec-7-
And the like are preferred. These bases are used in an amount of about 0.5-10 molar equivalents, preferably about 1-5
It is preferred to use molar equivalents. This ring closure reaction is usually performed in a solvent. The solvent varies depending on the type of the base used, and includes, for example, ethers (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), esters (eg, methyl acetate, etc.), hydrocarbons (eg, benzene, toluene, etc.), Nitriles (acetonitrile) and aprotic polar solvents (eg, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc.) can be used. For example, usually
It is preferable to use about 1 to 30 times, preferably about 3 to 10 times, the volume of tetrahydrofuran or the like to the compound (3). The reaction temperature depends on the type of base used, and is, for example, about -80 to 100 ° C, preferably -50
The reaction time varies depending on the base, the reaction temperature, and the type of the solvent, and is, for example, about 30 minutes to 24 hours. In the above reaction, an intramolecular adduct is generated as an intermediate, but in order to promote the dehydration reaction,
As an additive, about 0.05 to 4.0 molar equivalents of the base used, preferably about 0.2 to 2.0 molar equivalents of a dehydrating agent (for example, anhydrous magnesium sulfate, anhydrous sodium sulfate or molecular sieve 4A, acetic anhydride, p-toluenesulfonic acid, methanesulfonic acid, etc.) may be co-present.

In the step 3, after the compound (4) is subjected to hydrolysis of the ester in the presence of an acid or a base, the carboxyl group is converted into a reactive derivative such as an acid halide by a conventional method, and the reaction is carried out in the presence of a base. To the above formula

Embedded image Wherein ring A is as defined above. ] To give compound (5). The ester hydrolysis reaction is carried out, for example, by compound (4) in about 1
Or an alkali (preferably water) in a solvent (for example, alcohols such as methanol, ethanol and propanol, organic acids such as acetic acid and propionic acid, and ethers such as tetrahydrofuran) in a volume of 30 to 30 times, preferably about 2 to 10 times. Aqueous solution of an alkali metal hydroxide such as sodium oxide or potassium hydroxide) or an aqueous solution of an acid (preferably an inorganic acid such as hydrochloric acid, sulfuric acid, or hydrobromic acid) at a temperature of about 10 to 100 ° C. It can be performed by treating for about 0.5 to 10 hours. Conversion to an acid halide, which is one of the reactive derivatives, was carried out in the same manner as in Step 1.
For example, thionyl chloride, thionyl bromide, phosphorus halide and the like are used. For example, when the acid chloride is prepared by using thionyl chloride, thionyl chloride is usually added to the carboxylic acid obtained by hydrolyzing the compound (4) in the presence of a catalytic amount of an amide such as N, N-dimethylformamide. Is used in an amount of about 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents.

This reaction can be carried out in a solvent (for example, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as tetrahydrofuran, esters such as ethyl acetate, etc.). For example, usually, about 1 to 3 tetrahydrofuran is added to the compound (2).
It is good to use 0 times volume, preferably about 3 to 10 times volume. The reaction time is usually about 1-5 hours, and the reaction temperature is usually about 0-100 ° C. In this acid halogenation reaction, when L is a protected hydroxyl group and the protective group is a specific protective group (for example, a pyranyl group, a furanyl group, a silyl group, etc.), removal of the protective group and Conversion to the leaving group can be performed simultaneously. Subsequent reaction with the amine (N-alkylation) is usually carried out for about 1
The reaction can be carried out by reacting about 1 to 2 molar equivalents of the amine with about 1 to 2 molar equivalents of the base in a solvent. The amine used in the reaction has the formula

Embedded image [In the formula, ring A represents a benzene ring substituted with a halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group. And an amine represented by the following formula: Examples of the halogen atom include fluorine, chlorine, bromine and iodine atoms, and examples of the C _1-4 alkyl group include methyl, ethyl, n-propyl, i-propyl,
n-butyl, tert-butyl and the like; C _1-4 alkoxy as methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, tert-butoxy groups and the like.

Specific examples of the amine include benzylamine, 3-trifluoromethylbenzylamine, 4-trifluoromethylbenzylamine, 5-trifluoromethylbenzylamine, 3,5-bis (trifluoromethyl) benzylamine, Benzylamine such as 3,5-bis (difluoromethyl) benzylamine.
Examples of the solvent used in the reaction include ethers (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), esters (eg, methyl acetate, etc.),
Examples include hydrocarbons (eg, benzene, toluene, etc.), nitriles (acetonitrile), aprotic polar solvents (eg, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, etc.). It is preferable to use about 1 to 30 times, preferably about 3 to 10 times the volume of tetrahydrofuran or the like. Examples of usable bases include inorganic bases (eg, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and alkali metal carbonates such as sodium carbonate and potassium carbonate). Metal hydrides such as sodium hydride, potassium hydride, etc.), and organic bases (tri-C _1-3 alkylamines such as trimethylamine, triethylamine, diisopropylethylamine, etc., 1,8-diazabicyclo [5.4.0] undec-) And cyclic amines such as 7-ene and pyridine, and aromatic amines such as N, N-dimethylaniline. The reaction temperature varies depending on the type of the base to be used, but is usually about -30 to 100C, preferably about 0 to 50C. Further, the carboxyl group of the compound (4) is converted into an active ester by using a method generally used in peptide chemistry or the like (for example, a method using dicyclohexylcarbodiimide or a water-soluble carbodiimide), or After the ester,
The compound (5) may be obtained by reacting with an amine.

Step 4 is a step of subjecting compound (5) to a cyclization reaction in the presence of a base to obtain the desired compound. This step is usually performed in a solvent inert to the reaction. Examples of the solvent include ethers (eg, diethyl ether,
Tetrahydrofuran, dioxane, etc.), esters (eg, methyl acetate, etc.), hydrocarbons (eg, benzene, toluene, etc.), nitriles (acetonitrile),
An aprotic polar solvent (for example, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, or the like) is used, and the amount of the solvent used is, for example, generally about 1 to 3 or less of tetrahydrofuran or the like based on the compound (5).
It is good to use 0 times volume, preferably about 3 to 10 times volume. Examples of usable bases include inorganic bases (eg, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and alkali metal carbonates such as sodium carbonate and potassium carbonate). Metal hydrides such as sodium hydride and potassium hydride, metal amides such as sodium amide, alcoholates such as sodium methoxide, sodium ethoxide, sodium butoxide, potassium butoxide, n-butyllithium, lithium diisopropylamide, etc.), Organic bases (tri-C _1-3 alkylamines such as trimethylamine, triethylamine and diisopropylethylamine, cyclic amines such as 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, N, N-
Aromatic amines such as dimethylaniline), and the amount of the base to be used varies depending on the type of the solvent to be used, and is usually about 1 to 10 mol equivalent, preferably about 1 to 1 mol equivalent of compound (5). ５5 molar equivalents.

The reaction temperature varies depending on the type of base used, but is usually about -50 to 100 ° C., preferably
The reaction time is about -30 to 50 ° C, and the reaction time varies depending on the solvent used, the type of base, the amount of base, the reaction temperature and the like, but is, for example, about 1 to 72 hours, preferably about 1 to 24 hours. The target compound produced by such a method is
For example, it can be isolated and purified by ordinary separation means such as recrystallization, distillation and chromatography. Also,
When the target compound thus obtained is a free compound, a known method or a method analogous thereto (for example,
Neutralization, etc.), and when the obtained target compound is obtained in the form of a salt, it is converted to a free form or another salt by a known method or a method analogous thereto. be able to. The target compound or a salt thereof has an excellent tachykinin receptor antagonism, particularly an SP receptor antagonism, in addition to a capsaicin-induced increase in tracheal vascular permeability. Further, the target compound or a salt thereof has low toxicity and is safe.

[0023]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described below in more detail with reference to Reference Examples and Examples, which do not limit the present invention at all and do not depart from the scope of the present invention. It may be changed. Elution in column chromatography in Examples and Reference Examples is thin layer chromatography (hereinafter abbreviated as TLC) unless otherwise specified.
Under observation by In TLC observation, TL
As a C plate, 60F ₂₅₄ manufactured by Merck was used, and as a developing solvent, a solvent used as an elution solvent in column chromatography was used. A UV detector was used for detection. Silica gel 60 manufactured by Merck or BW-820 manufactured by Fuji Silysia Chemical Ltd. was used as silica gel for column chromatography. Unless otherwise specified, analysis by high performance liquid chromatography (hereinafter abbreviated as HPLC) was performed under the following conditions. Moving layer: acetonitrile / 0.05M potassium dihydrogen phosphate aqueous solution: = 1/1 flow rate: 1.0 ml / min Column: Develosil ODS-UG-3 75 mm × 4.6
mmφ Column temperature: room temperature Sample injection volume: 20 μL Detection: UV247 nm Room temperature usually means a temperature of about 10 ° C. to 35 ° C. The meanings of the abbreviations in Examples and Reference Examples are as follows. ¹ H-NMR: nuclear magnetic resonance spectrum, Hz: hertz, J: coupling constant, m: multiplet, q: quartet,
t: triplet, d: doublet, s: singlet,
b: Broad.

Reference Example 1 Synthesis of methyl (S) -2-methyl-3- (2-tetrahydropyraniloxy) -propionate (S) -3-hydroxy-2-methylpropionate 8
00g and 739 mL of 3.4-dihydro-2H-pyran were dissolved in 5.6 L of tetrahydrofuran. 12.9 g of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 7 hours. The reaction solution was concentrated under reduced pressure, and 5.6 L of ethyl acetate and 2 L of a 10% aqueous sodium hydrogen carbonate solution were added for extraction. After the organic layer was washed with 2 L of water, the solvent was distilled off under reduced pressure. Add 500 mL of ethyl acetate,
The residue was distilled under reduced pressure, and 500 mL of tetrahydrofuran was further added.

Reference Example 2 Synthesis of (R) -2-methyl-3- (2-tetrahydropyraniloxy) propan-1-ol 75% bis (2-methoxyethoxy) aluminum sodium hydride in 1 L of tetrahydrofuran under a stream of argon 481 g was added and cooled to 0 ° C. A solution of 300 g of methyl (S) -2-methyl-3- (2-tetrahydropyraniloxy) -propionate obtained in Reference Example 1 in 500 mL of tetrahydrofuran was added dropwise at -5 to 5 ° C, and the mixture was further stirred at the same temperature for 1 hour. . While maintaining the temperature below 5 ° C,
0.7 mL was added dropwise, and 2.1 L of a 20% aqueous solution of potassium sodium tartrate tetrahydrate was added, followed by extraction with 4.2 L of ethyl acetate. The organic layer was washed sequentially with 4.2 L of a 5% saline solution and 2.1 L of water, and the solvent was distilled off under reduced pressure to obtain 236 g (91%) of the title compound as an oil.

Reference Example 3 Synthesis of (R) -3-methyl-4- (2-tetrahydropyranyloxy) butyronitrile 310 g of p-toluenesulfonyl chloride was added to pyridine 700
After dissolving in (mL) and cooling to 0 to 10 ° C., a solution of (R) -2-methyl-3- (2-tetrahydropyraniloxy) propan-1-ol (236 g) in pyridine (126 mL) obtained in Reference Example 2 was added. It dripped at the same temperature. 4. at room temperature
After stirring for 5 hours, the water
mL was added dropwise, and the mixture was stirred at room temperature for 30 minutes. 2.4 L of water was added, and extracted with 3.4 L of ethyl acetate. The organic layer was treated with 2.4 L of water, 7.2 L of 10% phosphoric acid aqueous solution, and 2.4 L of water.
And the solvent was distilled off under reduced pressure. The residue was dissolved in 980 mL of dimethyl sulfoxide, 102.7 g of sodium cyanide was added, and the mixture was stirred at 55 to 60 ° C for 30 minutes. 2.4 L of water was added, and the mixture was extracted with 4 L of isopropyl ether. Further, the aqueous layer was extracted with 3 L of isopropyl ether. The organic layers were combined and washed sequentially with 2 L of 5% saline and 4 L of water. The solvent was distilled off under reduced pressure to obtain 220 g (89%) of the title compound as an oil.

REFERENCE EXAMPLE 4 (R) -3-methyl-4- (2-tetrahydropyranyloxy) butylamine (R) -3-methyl-4 obtained in Reference Example 3 in 150 mL of ethanol saturated with ammonia at 0 ° C. 15 g of-(2-tetrahydropyraniloxy) butyronitrile and 4.5 g of Raney nickel were added, and the mixture was reacted at a hydrogen pressure of 8 kg / cm ² and 50 ° C for 5 hours. After filtering off the catalyst, the filtrate was concentrated under reduced pressure to give 15.0 g (98%) of the title compound as an oil.

REFERENCE EXAMPLE 5 (R) -3-Methyl-4- (2-tetrahydropyranyloxy) butylamine (R) -3-methyl-4- obtained in Reference Example 3 in 500 mL of a 1 M sodium hydroxide in ethanol solution. 50 g of (2-tetrahydropyraniloxy) butyronitrile and 15 g of Raney nickel were added and reacted at 45 ° C. for 2 hours under a hydrogen pressure of 8 kg / cm ² . After filtering off the catalyst, the filtrate was concentrated under reduced pressure. 300 mL of methylene chloride was added, and the mixture was washed with 250 mL of water. Further, the aqueous layer was extracted with methylene chloride (600 mL). Combine the organic layers, wash with 200 mL of water,
The solvent was concentrated under reduced pressure to give 44.5 g (89%) of the title compound as an oil.

Reference Example 6 (R) -3-Methyl-4- (2-tetrahydropyranyloxy) butylamine 1.05 g of lithium aluminum hydride was added to 50 mL of tetrahydrofuran under an argon stream, and the mixture was cooled to 0 ° C. (R) -3-methyl-4- (2) obtained in Reference Example 3
-Tetrahydropyraniloxy) butyronitrile 5.0 g
Was added at −5 to 5 ° C. and then at the same temperature. While maintaining the temperature at 5 ° C or less, water 1.0
m, and 1% of a 15% aqueous sodium hydroxide solution
L and 3 mL of water were added, followed by stirring at room temperature for 20 minutes. After filtration through celite, the mixture was washed with 100 mL of ethyl acetate. 5% potassium carbonate aqueous solution 40 mL, 5% saline 20
Washed with mL. The solvent was concentrated under reduced pressure and distilled.
7 g (53%) of the title compound were obtained as an oil.

[0030]

【Example】

Example 1 (R) -N-[(methoxycarbonyl) methyl] -3-methyl-4- (2-tetrahydropyraniloxy) butylamine (R) -3-methyl-4- (2-tetrahydropyraniloxy) butylamine 18 .73 g was dissolved in 187 mL of tetrahydrofuran. Under stirring at room temperature, 12.14 g of triethylamine was added. Further, at room temperature, 15.30 g of bromoacetic acid methyl ester in 100 m of tetrahydrofuran
The L solution was added. Thereafter, the mixture was stirred at room temperature for 3 hours. Concentrate under reduced pressure, add 50 mL of water and add ethyl acetate 15
Extracted at 0 mL. The organic layer was sequentially washed with 100 mL of a diluted aqueous sodium hydroxide solution and 100 mL of water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 22.51 g (86.8%) of the title compound as a pale brown oil. ¹ H-NMR (300 MHz, CDCl ₃ ), ppm: 4.56-4.55 (1 Hm),
3.9-3.8 (1Hm), 3.70 (3H, s), 2.7-2.4 (2H, m), 3.54 (2H,
s), 3.3-3.1 (1H, m), 2.9-2.6 (1H, m), 1.9-1.4 (9H, m),
1.4-1.2 (1H, m), 1.1-0.9 (3H, m).

Reference Example 7 Synthesis of 2,3-pyridinedicarboxylic anhydride A mixture of 1.0 kg of 2,3-pyridinedicarboxylic acid and 3.5 L of acetic anhydride was heated under reflux for 7 hours. The solvent was removed under reduced pressure and isopropyl ether 3.0 was added to the remaining crystals.
L was added and stirred for 1 hour. The crystals were collected by filtration and washed with 0.5 L of isopropyl ether. Drying at 70 ° C. under reduced pressure gave 803 g (90%) of the title compound as white crystals.

Reference Example 8 Synthesis of 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid 193 g of magnesium metal was added to 6.7 of tetrahydrofuran.
L, and 700 mg of iodine was added with good stirring. 4-bromomagnesium toluene (4
-Synthesized from 13 g of bromotoluene and 1.8 g of magnesium. ) Was added, and 1.36 kg of 4-bromotoluene was added to tetrahydrofuran 200 while maintaining the internal temperature at 30 to 35 ° C.
The solution dissolved in mL was added dropwise. Thereafter, the mixture was reacted at 40 ° C. for 1 hour to prepare a Grignard reagent. Separately, 1.0 kg of 2,3-pyridinedicarboxylic anhydride and then 933 g of N, N, N ', N'-tetramethylethylenediamine were added to 4.0 L of tetrahydrofuran, and the internal temperature of the mixture was maintained at 0-5 ° C. Meanwhile, the Grignard reagent prepared above was added dropwise over 3 hours. Thereafter, the reaction was carried out at the same temperature for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, and 2.0 L of water was added to the residue. While maintaining the internal temperature at 30 ° C. or lower, concentrated hydrochloric acid is added dropwise,
The pH was adjusted to 1.0. After the adjustment, the mixture was extracted with 4 L of dichloromethane. The organic layer was washed with 4 L of water, concentrated, and the residue was crystallized from dichloromethane-isopropyl ether.
0 g (35.9%) of the title compound were obtained as white crystals.

Example 2 (R) -N-[(methoxycarbonyl) methyl] -N-
[3-methyl-4- (2-tetrahydropyraniloxy)
Synthesis of butyl] -3- (4-methylbenzoyl) -2-pyridinecarboxamide 3.62 g of 3- (4-methylbenzoyl) -2-pyridinecarboxylic acid was suspended in 30 mL of tetrahydrofuran. A catalytic amount of N, N-dimethylformamide and 2.14 g of thionyl chloride were added, and the mixture was refluxed for 1.5 hours. The solvent was distilled off under reduced pressure to obtain 3.9 g of brown crystals. Separately, Example 1
(R) -N-[(methoxycarbonyl) methyl]-obtained in
7.00 g of 3-methyl-4- (2-tetrahydropyraniloxy) butylamine and 4.14 g of potassium carbonate were added to 35 mL of tetrahydrofuran. To this was added a solution of the brown crystals (3.9 g) obtained above in 35 mL of tetrahydrofuran, and the mixture was heated under reflux for 2 hours. After cooling, 30 mL of water was added, and the mixture was extracted with 150 mL of ethyl acetate. The organic layer was further diluted with 30 mL of dilute sodium hydroxide solution and 30 mL of water.
Washed sequentially with mL. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 6.40 g (88
%) Of a brown oil. When the concentrate was analyzed using HPLC, the area percentage was 84%. The concentrate was separated and purified by column chromatography using silica gel (n-hexane / ethyl acetate = 1/1) to give the title compound as a colorless oil. ¹ H-NMR (CDCl ₃ ), ppm: 8.71-8.69 and 8.60-8.58 (1H, m),
7.80-7.76 (1H, m), 7.7-7.6 (2H, m), 7.41-7.38 (1H, m),
7.3-7.2 (2H, m), 4.54-4.49 (1H, m), 4.21 and 4.16 (2H, m
s), 3.9-3.7 (1H, m), 3.78 and 3.71 (3H, s), 3.6-3.4 (4
H, m), 3.2-3.1 (1H, m), 2.41 (3H, s), 2.0-1.4 (9H, m), 0.
92-0.89 and 0.83-0.80 (3H, m).

Example 3 Methyl (R) -7,8-dihydro-5- (4-methylphenyl) -8-oxo-7- [3-methyl-4- (2-
Tetrahydropyranyloxy) butyl] -6-pyrido [3,
Synthesis of 4-b] -pyridine-6-carboxyxylate (R) -N-[(methoxycarbonyl) methyl] -N-
[3-methyl-4- (2-tetrahydropyraniloxy)
Butyl] -3- (4-methylbenzoyl) -2-pyridinecarboxamide (44.3 g) in tetrahydrofuran 23
It was dissolved in 5 mL, and 3.3 g of magnesium sulfate was added at room temperature. 5.5 g of sodium hydride was added, and the mixture was stirred at 40 ° C for 2 hours. After completion of the reaction, 5.6 mL of methanol was added under cooling.
Was added followed by 2.5 mL of water. Insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL), diluted hydrochloric acid (100 mL), saturated saline (100 mL), and diluted sodium hydroxide aqueous solution (100 m).
L, and washed sequentially with 100 mL of water. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
7 g (88%) of a brown oil were obtained. HPLC of the concentrate
When analyzed using, the area percentage was 63%.
The concentrate was subjected to column chromatography using silica gel (n-hexane / ethyl acetate = 1/1).
Separation and purification according to 1) gave the title compound as a colorless oil. ¹ H-NMR (CDCl ₃ ), ppm: 8.91-8.89 (1H, dd, J = 4.3 and 1.6H
z), 7.65-7.61 (1H, dd, J = 8.3 and 1.6Hz), 7.48-7.44 (1
H, dd, J = 8.3 and 4.3Hz), 4.6 (1H, b), 4.3-4.0 (2H, m),
3.6-3.5 (1H, m), 3.57 (3H, s), 3.5-3.4 (1H, m), 3.3-3.2
(1H, m), 2.42 (3H, s), 2.0-1.4 (9H, m), 1.01 (3H, d, J = 6.6H
z).

Example 4 (R) -7,8-Dihydro-5- (4-methylphenyl) -8-oxo-7- [3-methyl-4- (2-tetrahydropyranonyloxy) butyl] -6 Pyrido [3,4-
Synthesis of b] -pyridine-6-carboxylic acid Methyl (R) -7,8-dihydro-5- (4-methylphenyl) -8-oxo-7- [3-methyl-4- (2-
Tetrahydropyranyloxy) butyl] -6-pyrido [3,
25.5 g of 4-b] -pyridine-6-carboxylate
Was dissolved in 130 mL of methanol. To this was added an aqueous solution (29 mL) of sodium hydroxide (6.59 g), and the mixture was heated under reflux for 7 hours. The reaction solution was concentrated under reduced pressure, 295 mL of ethyl acetate was added to the residue, and the mixture was separated. The aqueous layer was extracted with 50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 24.0 g (93%) of a brown solid.

Example 5 (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7- (4-chloro-3-methylbutyl) -7,8
Synthesis of -dihydro-5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] -pyridine-6-carboxamide (R) -7,8-dihydro-5- (4-methyl Phenyl) -8-oxo-7- [3-methyl-4- (2-tetrahydropyranonyloxy) butyl] -6-pyrido [3,4
-B] -Pyridine-6-carboxylic acid (24.0 g) was dissolved in tetrahydrofuran (260 mL). 2 mL of N, N-dimethylformamide and 30.2 g of thionyl chloride were added, and 2
Heated to reflux for an hour. Concentration under reduced pressure gave a brown residue.
Separately, 15.56 g of 3,5-bis (trifluoromethyl) benzylamine hydrochloride was added to 325 mL of tetrahydrofuran.
And 24.6 g of triethylamine was added. To this was added a 440 mL solution of the previously obtained residue in tetrahydrofuran, and the mixture was stirred at room temperature for 3 hours. After concentrating the reaction solution under reduced pressure, 100 mL was added with dilute hydrochloric acid, and the mixture was extracted with 500 mL of ethyl acetate. The organic layer was further washed sequentially with 50 mL of dilute hydrochloric acid, 100 mL of saturated saline, 100 mL of a saturated aqueous solution of sodium hydrogen carbonate, and 100 mL of water.
After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and isopropyl ether was added.
2 g (72%) of the title compound were obtained as white crystals. ¹ H-NMR (CDCl ₃ ), ppm: 8.69 (1H, dd, J = 1.6 and 4.3 Hz),
8.26 (1H, t, J = 5.5Hz), 7.78 (1H, s), 7.70 (2H, s), 7.55 (1
H, dd, J = 1.6 and 8.4Hz), 7.41 (1H, dd, J = 4.3 and 8.4H
z), 7.21 (2H, d, J = 8.0Hz), 7.06 (2H, d, J = 7.9Hz), 4.50 (2
H, d, J = 5.9Hz), 3.4-3.3 (4H, m), 2.28 (3H, s), 1.8-1.6 (3
H, m), 0.92 (3H, d, J = 6.3Hz). Elemental analysis: calculated as C ₃₀ H ₂₆ N ₃ O ₂ ClF ₆ Calculated (%): C 59.07, H 4.30, N 6.89, Cl 5.8
1, F 18.69. Obtained value (%): C 58.71, H 4.31, N 6.70, Cl 5.7
8, F 18.69.

Example 6 (9R) -7- [3,5-bis (trifluoromethyl) benzyl] -6,7,8,9,10,11-hexahydro-9-
Methyl-5- (4-methylphenyl) -6,13-dioxo-13H- [1,4] diadicino [2,1-g] [1,7]
Synthesis of -naphthyridine (hereinafter abbreviated as compound A) (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7- (4-chloro-3-methylbutyl) -7,8
0.772 g of -dihydro-5- (4-methylphenyl) -8-oxo-6-pyrido [3,4-b] -pyridine-6-carboxamide was dissolved in 10 mL of tetrahydrofuran. 0.134 g of sodium tert-butoxide was added,
Heated to reflux for 20.5 hours. 10 mL of water was added, and the mixture was extracted with 40 mL of acid ethyl ester. The organic layer is composed of 20 mL of dilute aqueous sodium hydroxide, 20 mL of water,
0 mL, water 20 mL, saturated sodium hydrogen carbonate aqueous solution 2
Washed sequentially with 0 mL. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and isopropyl ether was added to obtain 0.635 g of white crystals. This was crystallized from a mixed solution of ethyl acetate-isopropyl ether to obtain 0.302 g (42%) of the title compound as colorless crystals. The obtained crystals were identical in ¹ H-NMR spectrum with the title compound as a standard. ¹ H-NMR (CDCl ₃ ), ppm: 8.89 (1H, dd, J = 4.2 and 1.6 Hz),
7.81 (1H, s), 7.56 (1H, dd, J = 8.3 and 1.6Hz), 7.47 (2H,
s), 7.46 (1H, dd, J = 8.3 and 4.2Hz), 7.33 (1H, dd, J = 7.8
and 1.6Hz), 7.26 (1H, d, J = 7.8Hz), 7.04 (1H, d, J = 7.8H
z), 6.84 (1H, dd, J = 7.8and 1.6Hz), 5.45 (1H, d, J = 14.9H
z), 5.10 (1H, dd, J = 14.3 and 5.4Hz), 3.99 (1H, d, J = 14.9
Hz), 3.56-3.41 (2H, m), 2.97 (1H, d, J = 15.2Hz), 2.37 (3
H, s), 2.30-2.25 (1H, m), 2.1-2.0 (1H, m), 1.73 (1H, m),
0.91 (3H, d, J = 6.8Hz). Melting point: 227-230 ° C (ethyl acetate-isopropyl ether)

Preparation Example of Tablet Compound A, lactose, and corn starch were mixed in a fluidized bed granulating dryer, and an aqueous solution in which hydroxypropyl cellulose was dissolved was sprayed and granulated in a fluidized bed granulating dryer.
Then, it is dried in a fluidized bed granulation dryer. The obtained granules were crushed using a power mill to obtain granules. Croscarmellose sodium and magnesium stearate were added to the granulated powder, and mixed with a tumbler mixer to obtain granules for tableting. The granules were tableted with a tableting machine at a weight of 130 mg to give naked tablets. The obtained uncoated tablet is treated with hydroxypropylmethylcellulose 29 in a Doria coater coating machine.
Dissolve 10 (TC-5) and Macrogol 6000,
A liquid in which titanium oxide was dispersed was sprayed to obtain a film tablet.
The formulation is as follows.

[Table 1]

[0039]

According to the present invention, a tricyclic heterocyclic compound having excellent tachykinin receptor antagonism, in particular, substance P receptor antagonism, can be produced in good yield, safely, on a large scale and at low cost. it can.

Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/505 AED A61K 31/505 AED

Claims (15)

[Claims] (1) Formula (1) [Wherein, R ¹ represents an optionally substituted C _1-4 alkyl group, Q represents a substituted C _1-7 alkylene group, and L represents a leaving group. Or a salt thereof. 2. The compound according to claim 1, wherein R ¹ is a methyl group, Q is a 3-methylbutylene group, and L is a 2-tetrahydropyraniloxy group, or a salt thereof. 3. A compound of the formula [ _Wherein Q represents a substituted C _1-7 alkylene group, and L represents a leaving group. Wherein X-CH ₂ -COOR ¹ wherein the primary amine represented by], X is a halogen atom, R ¹ represents represents an C _1-4 alkyl group which may be substituted. Wherein the compound is reacted with a halogenated acetate represented by the formula: Wherein R ¹ , Q and L are as defined above. ] The manufacturing method of the compound represented by this. 4. A compound of the formula [Wherein, R ¹ represents an optionally substituted C _1-4 alkyl group, Q represents a substituted C _1-7 alkylene group, and L represents a leaving group. And a salt thereof and a compound represented by the formula: [Wherein, R represents a C _1-3 alkyl group which may be substituted. Wherein the compound represented by the formula (I) or a salt thereof is reacted: [Wherein, R ¹ , R, Q and L have the same meanings as described above. ] The manufacturing method of the compound represented by this. 5. A compound of the formula [Wherein, R ¹ represents an optionally substituted C _1-4 alkyl group, R represents an optionally substituted C _1-3 alkyl group, Q
_{Represents a} substituted C _1-7 alkylene group, and L represents a leaving group. ] The compound represented by these. 6. The compound according to claim 5, wherein R ¹ and R are a methyl group, Q is a 3-methylbutylene group, and L is a 2-tetrahydropyraniloxy group. 7. A compound represented by the formula: [Wherein, R ¹ represents an optionally substituted C _1-4 alkyl group, Q represents a substituted C _1-7 alkylene group, and L represents a leaving group. And a salt thereof, and a compound represented by the formula: [Wherein, R represents a C _1-3 alkyl group which may be substituted. And a salt thereof to react with a compound represented by the formula: [Wherein, R ¹ , R, Q and L have the same meanings as described above. And subjecting the compound to a ring closure reaction. [Wherein, R ¹ , R, Q and L have the same meanings as described above. ] The manufacturing method of the compound represented by this. 8. A compound of the formula [Wherein, R ¹ represents a C _1-4 alkyl group which may be substituted differently, R represents a C _1-3 alkyl group which may be substituted, and Q represents a substituted C _1-7 alkylene group. And L represents a leaving group. ] The compound represented by these. 9. The compound according to claim 8, wherein R ¹ and R are a methyl group, Q is a 3-methylbutylene group, and L is a 2-tetrahydropyraniloxy group. (10) (R) -7,8-dihydro-5- (4-
Methylphenyl) -8-oxo-7- [3-methyl4-
(2-tetrahydropyraniloxy) butyl] -6-pyrido [3,4-b] -pyridine-6-carboxylic acid or a salt thereof. 11. A compound of the formula [Wherein, R ¹ represents an optionally substituted C _1-4 alkyl group, Q represents a substituted C _1-7 alkylene group, and L represents a leaving group. And a salt thereof, and a compound represented by the formula: [Wherein, R represents a C _1-3 alkyl group which may be substituted. And a salt thereof is reacted to give a compound of the formula [Wherein, R ¹ , R, Q and L have the same meanings as described above. And subjecting the compound to a ring closure reaction to give a compound of the formula [Wherein, R ¹ , R, Q and L have the same meanings as described above. And hydrolyzing this compound to give a compound of the formula [In the formula, ring A represents a benzene ring substituted with a halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group. Wherein an amine represented by the following formula is reacted: [Wherein, rings A, R, Q and L are as defined above. ] The manufacturing method of the compound represented by this. 12. A compound of the formula [Wherein ring A represents a benzene ring substituted with a halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group, and R represents an optionally substituted C
_1-3 alkyl group, Q is a C _1-7 alkylene group substituted, L is a leaving group. ] The compound represented by these. 13. R is a methyl group, Q is a 3-methylbutylene group, L is a 2-tetrahydropyraniloxy group, ring A
Is a 3,5-bis (trifluoromethyl) benzene ring. (R) -N- [3,5-bis (trifluoromethyl) benzyl] -7- (4-chloro-3-methylbutyl) -7,8-dihydro-5- (4-methylphenyl) ) -8-Oxo-6-pyrido [3,4-b] -pyridine-6-carboxamide. 15. A compound of the formula [In the formula, R ¹ represents an optionally substituted C _1-3 alkyl group, Q represents a substituted C _1-7 alkylene group, and L represents a leaving group. And a salt thereof and a compound represented by the formula: [Wherein, R represents a C _1-3 alkyl group which may be substituted. And a salt thereof to react with a compound represented by the formula: [Wherein, R ¹ , R, Q and L have the same meanings as described above. And subjecting the compound to a ring closure reaction to give a compound of the formula [Wherein, R ¹ , R, Q and L have the same meanings as described above. And hydrolyzing the compound to give a compound of the formula [In the formula, ring A represents a benzene ring substituted with a halogenated C _1-4 alkyl group or an optionally halogenated C _1-4 alkoxy group. With an amine represented by the formula: [Wherein, rings A, R, Q and L are as defined above. Wherein the compound is subjected to a ring-closure reaction. [Wherein, rings A, R and Q are as defined above. ] The manufacturing method of the compound represented by this.