JPH11246559A - New triazole derivative or its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new triazole derivative having tachykinin receptor antagonism, especially substance P (NK-1 receptor) antagonism, and useful for preventing or treating respiratory diseases, central nervous system diseases, pain, inflammatory diseases, vomiting, megrim or the like. SOLUTION: The compound of formula I [X is N or CH; R<1> is H, a lower alkyl, an aryl or an aralkyl; R<2> is H or a lower alkyl; the ring A and the ring B are each a (substituted) benzene ring; (n)=1, 2], for example, N-[3,5-bis(trifluoromethyl)benzyl]-N-methyl-6-phenyl-1,2,4-triazo[3,4- a]isoquinoline-5- carboxamide is obtained by reacting a carboxylic acid (reactive derivative) of formula II with an amine of formula III in a solvent such as dichloromethane in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a drug, in particular, a novel triazole derivative having a tachykinins receptor antagonistic action, in particular, a substance P (NK-1 receptor) antagonistic action, a salt thereof, and a compound containing the compound. Related to medicine.

[0002]

2. Description of the Related Art Tachykinin is a general term for a group of peptides having a similar structure, and these are neuropeptides widely present in the nervous system. In recent years, tachykinins have various physiological effects, such as airway constriction, induction of airway hyperreactivity, mucus hypersecretion,
It has been revealed that it has vascular hyperpermeability, histamine release from mast cells, cough induction and painfulness. Therefore, diseases in which these effects are deeply related to the pathology, such as central illness, asthma, chronic bronchitis, rheumatoid arthritis,
It has been suggested that tachykinin antagonists may be useful therapeutics for diabetes, irritable bowel syndrome or widely inflammation.

[0003] Tachykinins derived from mammals include substance P (SP), neurokinin A (NKA), and neurokinin B (NKB).
It is known that it is involved in various physiological actions via K-2 and NK-3 receptors. For example, it has been reported that NK-1 receptor antagonists significantly suppress various experimentally induced emesis such as chemotherapeutic agents such as cisplatin, analgesics such as morphine, and X-ray irradiation [Bountra, C.et a
l., Eur. J. Pharmacol., 249 , R3-R4 (1993), FDTatterall
et al., Eur, J. Pharmacol., 250 R5-R6 (1993)]. Furthermore, it has been suggested that these antiemetic effects may be based on antagonism with tachykinin near the vomiting center such as medulla oblongata [Koichi Yoshioka et al., Neuropsychopharmacology Vol. 16, No. 1, p.
11-23 (1994)].

Further, airway and nasal hypersensitivity in asthma and nasal allergy include SP (NK-1 receptor) and NK.
A (NK-2 receptor) is known to be involved [Ichinose et al., Clinical Science Vol. 26, No. 10, No. 1248-
1253 (1990)]. For central illnesses such as anxiety, N
It is known that KA (NK-2 receptor) is involved [SCStratton et al., British Journal of Pharmacol
ogy 112 (supplement) 49P (1993)].

[0005] Conventionally, compounds that antagonize the tachykinin receptors of the above types have been reported. For example, WO91
/ 09844 discloses the following compounds as typical examples.

Embedded image

[0006] Further, EP 652218 discloses an isoquinoline derivative represented by the following general formula having a tachykinin receptor antagonistic action.

Embedded image (For the symbols in the formula, see the above publication)

[0007]

The creation of a compound having an excellent novel tachykinin antagonism even now is
This is an important medical issue.

[0008]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that a novel triazole derivative has an excellent antagonistic effect on tachykinin receptors, particularly SP (NK-1 receptor). I found that. The novel triazole compounds discovered by the present inventors are particularly involved in respiratory diseases such as asthma, rhinitis, chronic bronchitis, airway hyperreactivity, SP (NK-1 receptor) including vomiting or migraine. High clinical utility for disease.

That is, the present invention relates to a triazole derivative represented by the following general formula (I) or a salt thereof.

Embedded image (The symbols in the above formulas have the following meanings, respectively: X: nitrogen atom or CH group, R ¹ : hydrogen atom, lower alkyl group, aryl group or aralkyl group, R ² : hydrogen atom or lower alkyl group, A Ring and ring B: the same or different, optionally substituted benzene ring, n = 1 or 2) According to the present invention, there is also provided a drug containing the above triazole derivative or a salt thereof. .

Further, according to the present invention, there is provided a tachykinin receptor antagonist comprising the above triazole derivative or a salt thereof. Examples of the tachykinin receptor antagonist include central nervous system diseases including tachykinin-mediated anxiety, depression, psychiatric disorders and schizophrenia; dementia in AIDS, Alzheimer-type senile dementia, Alzheimer's disease, Down's syndrome, demyelinating Diseases, neurodegenerative diseases including amyotrophic lateral sclerosis, neuropathy, peripheral neuropathy, and neuralgia; chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchoconstriction, respiratory diseases including asthma; inflammatory colon Diseases (IBD), inflammatory diseases including psoriasis, connective tissue inflammation, osteoarthritis, and rheumatoid arthritis; allergic diseases including eczema; and rhinitis; hypersensitivity diseases including sensitivity to vines; conjunctivitis, spring conjunctivitis, various Ophthalmological disorders including destruction of the blood-aqueous-water barrier, increased intraocular pressure, and miosis associated with inflammatory eye diseases in children; contact dermatitis, atopic dermatitis, hives, and other Skin disorders including eczema-like dermatitis; addiction including alcoholism; somatic disorders due to stress; reflex sympathetic dystrophy including shoulder-hand syndrome; mood swings; undesired immune reactions and systemic involvement including graft rejection Diseases related to immune enhancement or immunosuppression, including lupus erythematosus; diseases due to abnormalities in the nerves regulating the internal organs, ulcerative colitis, digestive disorders including Crohn's disease; X-ray irradiation and chemotherapeutic agents, toxicants, Vomiting, including vomiting induced by toxins, pregnancy, vestibular disorders, postoperative illness, gastrointestinal obstruction, gastrointestinal motility, visceral pain, migraine, increased intracranial pressure, decreased intracranial pressure, or side effects associated with administration of various drugs; urinary incontinence Includes bladder dysfunction; Collagen disease, scleroderma, eosinophilia due to fascioliasis; Insufficient blood flow due to vasodilation or contraction, including angina, migraine, and Raynaud's disease An antagonist is a prophylactic or therapeutic agent for tachykinin-mediated diseases consisting of pain pain nociceptive including migraine.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the compound (I) of the present invention will be described in detail. The compound (I) of the present invention is different from a conventional tachykinin receptor antagonist in that a triazolo [3,4-a] isoquinoline skeleton (I)
a) or a triazolo [4,3-h] [1,7] naphthyridine skeleton (Ib).

[0012]

Embedded image (R ¹ , R ² , A ring, B ring and n in the above formula are the same as described above.)

Embedded image (R ¹ , R ² , A ring, B ring and n in the above formula are the same as described above.)

Hereinafter, the present invention will be described in more detail. In the present specification, "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified. Accordingly, in the present invention, "lower alkyl group" includes, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group Group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1 , 1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl Group, 2-ethylbutyl group,
Examples thereof include a 1,2,2-trimethylpropyl group, a 1,2,2-trimethylpropyl group, a 1-ethyl-1-methylpropyl group, and a 1-ethyl-2-methylpropyl group. An "aryl group" preferably has 6 to 14 carbon atoms.
Aryl groups such as a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group.
The “aralkyl group” is a group in which an arbitrary hydrogen atom of the lower alkyl group is substituted with the aryl group.

The "optionally substituted benzene ring" in the rings A and B is an unsubstituted benzene ring or a benzene ring substituted with the same or different 1 to 4 substituents. And the substituent is a halogen atom,
A lower alkyl group optionally substituted with a halogen atom,
Lower alkoxy group, hydroxyl group, mercapto group, lower alkylthio group, carboxy group, lower alkanoyl group, lower alkoxycarbonyl group, lower alkylsulfinyl group,
Lower alkylsulfonyl, carbamoyl, cyano, nitro, amino, mono-lower alkylamino,
And a di-lower alkylamino group or a lower alkanoylamino group. Here, the “halogen atom” is specifically a chlorine atom, a fluorine atom, a bromine atom or an iodine atom. “A lower alkyl group optionally substituted with a halogen atom” means any one or two of the above lower alkyl groups.
A group in which at least two hydrogen atoms have been replaced by halogen atoms, specifically, fluoromethyl, chloromethyl, bromomethyl, iodomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl , 2-chloroethyl group, 2-bromoethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, tribromomethyl group, triiodomethyl group, dichlorobromomethyl group and the like. The "lower alkoxy group" is a lower alkoxy group having the lower alkyl group in the alkyl moiety, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, and a tert- group. Butoxy, pentyloxy (amyloxy), isopentyloxy, tert-pentyloxy, neopentyloxy, 2-methylbutoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, etc. Is mentioned. The "lower alkanoyl group" is a lower acyl group having 1 to 6 carbon atoms derived from a saturated aliphatic carboxylic acid, such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl. Group, pivaloyl group or hexanoyl group. The “lower alkylthio group”, “lower alkylsulfinyl group” or “lower alkylsulfonyl group” is preferably a thio group, a sulfinyl group or a sulfonyl group each having the lower alkyl group as an alkyl moiety.

A "mono-lower alkylamino group" or a "di-lower alkylamino group" is a group in which one or two hydrogen atoms of an amino group are substituted with a lower alkyl group. For example, as the amino group mono- or di-substituted with the lower alkyl group, specifically, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, pentylamino group Mono-lower alkylamino groups substituted with a linear or branched alkyl group having 1 to 6 carbon atoms, such as isopentylamino group, hexylamino group, isohexylamino group, dimethylamino group, diethylamino group, dipropyl A symmetric di-lower alkylamino group di-substituted with a linear or branched alkyl group having 1 to 6 carbon atoms such as an amino group, diisopropylamino group, dibutylamino group, dipentylamino group, dihexylamino group, ethyl Methylamino group, methylpropylamino group, ethylpropylamino group, butylmethylamino Group, butyl ethylamino group,
An asymmetric di-lower alkylamino group di-substituted with a different alkyl group among linear or branched alkyl groups having 1 to 6 carbon atoms such as a butylpropylamino group can be given. The “lower alkanoylamino group” is one in which an arbitrary hydrogen atom of an amino group is substituted with the lower alkanoyl group.

The salt of the compound represented by the general formula (I) is an acid addition salt with an inorganic acid or an organic acid, or a salt with an inorganic or organic base, and a pharmaceutically acceptable salt. It is preferred that Specific examples of these salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, or formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid,
Organic acids such as methanesulfonic acid or toluenesulfonic acid, or acid addition salts with acidic amino acids such as aspartic acid or glutamic acid, inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and organic acids such as methylamine, ethylamine, ethanolamine Bases, salts with basic amino acids such as lysine, ornithine and the like can be mentioned. Further, it can be a quaternary ammonium salt. The quaternary ammonium salt is specifically a salt with a lower alkyl halide, a lower alkyl triflate, a lower alkyl tosylate, a lower alkyl mesylate or a benzyl halide, preferably a methyl iodide, methanesulfonyl chloride or benzyl bromide. Salt.

The compound of the present invention may have an asymmetric carbon atom depending on the type of the substituent, and may exist in the form of an optically active compound or a diastereomer or a racemic mixture thereof, or may have a double bond or a cycloalkyl group. There may be geometric isomers based on the alkyl ring, all of which are included within the scope of the compounds of the present invention. As a starting material in the production method described below, a racemic mixture or an optically active substance can be used, and a stereoisomer in a product obtained by using the racemic mixture as a starting material can be obtained by a conventional chromatography or fractional crystallization method. And the like. The present invention further includes hydrates, various solvates, and polymorphs of the compound of the formula (I).

Next, the method for producing the compound (I) of the present invention will be described. The novel compound of the present invention represented by the general formula (I) can be produced by various methods utilizing the characteristics of the basic skeleton and the substituents. explain.

First manufacturing method

Embedded image (X, R ¹ , R ² , A ring, B ring and n in the above formula are the same as described above.)

In this production method, as shown in the above reaction formula,
This is a method for obtaining the compound (I) of the present invention by constructing a triazole ring from the compound represented by the general formula (II). That is, first, as a first step, the general formula (I
The amide moiety of the compound represented by I) is imino-halogenated and, in the second step, is coupled with hydrazine, and then, in the third step, a cyclization reaction is performed with various acid derivatives to obtain the compound (I) of the present invention. Is the way. The reaction in each of the above steps can be carried out as follows.
The imino halogenation is carried out by using, for example, phosphoryl chloride, phosphorous pentachloride, phosphorous pentabromide or the like without solvent or dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, benzene The reaction can be carried out in a solvent such as toluene, xylene or the like at -10 ° C to reflux with heating, preferably at 0 ° C to reflux with heating. In the second step, methanol, ethanol, isopropanol,
Tetrahydrofuran, 1,4-dioxane, benzene,
The reaction can be carried out in a solvent such as toluene or xylene at -10 ° C to heating under reflux, preferably at 0 ° C to heating under reflux. The cyclization reaction is carried out, for example, using a carboxylic acid halide, a carboxylic acid orthoester, or the like, without solvent or with tetrahydrofuran, 1,4-dioxane, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethoxyethane, benzene, toluene, xylene. In such a solvent, the reaction can be carried out at -10 ° C to under reflux, preferably at 0 ° C to under reflux.

Second manufacturing method

Embedded image (X, R ¹ , R ² , A ring, B ring and n in the above formula are the same as described above.)

This production method comprises reacting a carboxylic acid represented by the general formula (III) or a reactive derivative thereof with an amine represented by the general formula (IV), as shown in the above reaction formula. This is a method for obtaining (I).

When a free carboxylic acid is used, the reaction is carried out with a condensing agent such as N, N'-dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, N,
In the presence of N′-disuccinimidyl carbonate, 1- (3-dimethylaminopropyl-3-ethylcarbodiimide, or N, N′-bis (2-oxo-3-oxazolidinyl) phosphinic chloride, dichloromethane, Dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dimethylformamide, benzene,
The reaction can be carried out in a solvent such as toluene or ethyl acetate at -20 ° C to under reflux, preferably at 0 ° C to room temperature. In addition, this reaction is a reactive derivative of the general formula (III),
For example, using carboxylic acid halide, carboxylic acid azide, active ester (for example, 1-hydroxybenzotriazole or n-hydroxysuccinimide), symmetric acid anhydride, mixed acid anhydride (for example, isobutyl carbonate), dichloromethane, dichloroethane, chloroform , Carbon tetrachloride, tetrahydrofuran, dimethylformamide, benzene, toluene, ethyl acetate and the like at -20 ° C to under reflux, preferably at 0 ° C to room temperature.

Third manufacturing method

Embedded image (X, R ¹ , R ² , A ring, B ring and n in the above formula are the same as described above.)

This production method is a method for obtaining a compound (I) of the present invention by subjecting a compound represented by the general formula (V) to a cyclization reaction as shown in the above reaction formula. This reaction was carried out using 1,5-diazabicyclo [4.3.0] non-5-
Ene (DBN), 1,8-azabicyclo [5.4.0]
Undec-7-ene (DBU), N-benzyltrimethylammonium hydroxy (Triton B), sodium methoxide, sodium ethoxide, potassium
t-butoxide, sodium hydride, potassium hydride,
To be carried out by cyclization in the presence of a base such as lithium hydride, n-butyllithium, lithium diisopropylamide, or an acid such as p-toluenesulfonic acid, acetic acid, hydrochloric acid, sulfuric acid, aluminum chloride, titanium (IV) chloride. Can be. At this time, it is preferable to carry out the reaction in a solvent such as benzene, toluene, xylene, tetrahydrofuran, 1,4-dioxane, dimethoxyethane and the like at -78 ° C. while heating under reflux.

In order to isolate and purify the product from the reaction mixture obtained by each of the above-mentioned production methods, ordinary chemical operations such as solvent extraction, concentration, recrystallization, chromatography and the like are conventionally used as appropriate. Further, the salt of the compound of the present invention can be easily produced by subjecting the salt to a usual salt formation reaction.

[0027]

The compound of the present invention represented by the above general formula (I) has a drug, especially a tachykinin receptor antagonism, especially a SP (NK-1 receptor) antagonism.
Further, it has a more excellent antagonism than conventionally known compounds. Diseases of the central nervous system that are tachykinin-mediated diseases such as anxiety, depression, psychosis and schizophrenia;
Neurodegenerative diseases such as dementia in AIDS, senile dementia of the Alzheimer type, Alzheimer's disease, Down's syndrome, demyelinating diseases such as amyotrophic lateral sclerosis and other neurological disorders such as diabetic, AIDS Neuropathy due to chemotherapy, other peripheral neuropathy, and neuralgia;
Respiratory diseases, such as chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchoconstriction, asthma; inflammatory diseases such as inflammatory bowel disease (IBD), psoriasis, connective tissue inflammation, osteoarthritis, and rheumatoid arthritis; allergies Irritable diseases such as eczema and rhinitis; irritable diseases such as irritable diseases to vines; ophthalmic diseases such as conjunctivitis, spring conjunctivitis, destruction of the blood-aqueous humor barrier associated with various inflammatory eye diseases, Elevated intraocular pressure, miosis, etc .; skin disorders, such as contact dermatitis, atopic dermatitis, hives, and other eczema-like dermatitis; addiction, such as alcoholism; somatic disorders due to stress; Reflex sympathetic dystrophy, eg, shoulder-hand syndrome; dysthymia; undesirable immune response, eg, rejection of grafts, and disorders associated with immune enhancement or immunosuppression, eg, systemic Plaque lupus; gastrointestinal disorders, for example,
Diseases caused by abnormalities of nerves regulating the internal organs, ulcerative colitis,
For Crohn's disease; X-ray irradiation, chemotherapeutic agents, poisons, toxins, pregnancy, vestibular disorders, postoperative illness, gastrointestinal obstruction, gastrointestinal motility, visceral pain, migraine, increased intracranial pressure, decreased intracranial pressure, or administration of various drugs Vomiting such as vomiting induced by accompanying side effects; bladder dysfunction such as urinary incontinence; eosinophilia due to collagen disease, scleroderma, or fluke infection; disease due to abnormal blood flow due to vasodilation or contraction; For example, it is useful for the prevention or treatment of angina, migraine, and Raynaud's disease; pain nociception, for example, pain such as migraine pain. Above all, it is highly useful for respiratory diseases involving SP (NK-1 receptor), vomiting or migraine.

(Pharmacological action) It was confirmed by the following test method that the compound of the formula (I) exhibits excellent NK-1 receptor antagonistic action.

(1) Method of Receptor Binding Test The receptor binding test was carried out with a slight modification of the method of Burcher et al. [European Journal of Pharmacology, 128 , 165-177 (1986)]. That is, ¹²⁵ I-Bolton-Hunter-substance P
Guinea pig bladder membrane preparation (NK) of ( ¹²⁵ I-BH-SP)
-1 receptor). Bladder extirpated from Hartley guinea pigs or Syrian Golden hamsters was homogenized in 50 mM Tris-HCl (pH 7.4) containing 10% (W / V) saccharose and 1 mM-EDTA. The homogenate was spun down at 48,000 g and 4 ° C. for 20 minutes. The resulting pellet was combined with 10 volumes of 300 mM KCl and 1 volume.
50 mM Tris-HCl containing 0 mM-EDTA (pH 7.
After suspending in 4) and incubating at 4 ° C for 1 hour,
The mixture was spun down at 48,000 g and 4 ° C. for 20 minutes. The obtained pellet was washed twice with 50 mM Tris-HCl (pH 7.4), and then 10 volumes of 50 mM Tris-HCl (pH 7.4).
Suspended in 4) and stored at -80 ° C until use. 2%
(W / V) membrane preparation was prepared using 0.1% bovine serum albumin (BSA), 40 μg / ml bacitracin, 4 μg / m
1 leupeptin, 4 μg / ml chymostatin and 3 mM
50mM Tris-HCl containing -MnCl ₂ (pH7.4)
Was incubated with a radioligand (1 × 10 ⁻¹⁰ M) at 25 ° C. for 20 minutes. The reaction solution was added to 0.
Suction-filter through a GF / B filter pretreated with 1% polyethyleneimine or 0.5% BSA, and further add 3 mM
50mM Tris-HCl containing -MnCl ₂ (pH7.4)
After washing with 3 ml, the radioactivity in the filter was measured with a gamma counter. The radioactivity in the presence of 1 μM non-radioactive ligand was defined as non-specific binding, and pseudo-Hill analysis (pseudo-Hill equiatio) was performed.
n) the concentration that inhibits specific binding by 50% (IC ₅₀ )
Was calculated.

(2) NK-1 receptor antagonist by intravenous administration
Anti-test Urinary anaesthetized (1.2 g / kg ip) male Hartley guinea pigs (350-550 g) were invasively instiated with a catheter for administration in the external jugular vein and intubated with a tracheal tube. Gallamine (2 mg / kg iv)
The spontaneous respiration was stopped, and artificial respiration was performed 60 times per minute at a tidal volume of 10 ml / kg, and the airway resistance of the guinea pig was measured. The NK-1 receptor antagonism of the test drug is a selective agonist of the NK-1 receptor [Sar ⁹ , Met
(O ₂ ) ¹¹ ] -substance P (1 nmol / kg
i. v. ) Was evaluated as an inhibitory effect on the increase in airway resistance. In other words, the increase in airway resistance caused by the agonist
The test drug was administered 2-3 times after reproducibility was observed, and 15 minutes later, the response to the agonist was measured again. The inhibitory effect of the test drug on the increase in airway resistance due to NK-1 receptor stimulation was determined by the following formula. Inhibition rate by drug (%) = ((mean increase in airway resistance before drug administration-increase in airway resistance after drug administration) / (average increase in airway resistance before drug administration)) x 100 Inhibition rate of each dose (% ) To 50 by the probit method.
% Dose (ID ₅₀ , ug / kg iv)
Was calculated. The drug was dissolved and diluted in a physiological saline solution containing 10% dimethyl sulfoxide as a solvent, and 1 ml /
It was administered in a volume of kg. Further, 1N hydrochloric acid and several drops of Tween 80 were used as needed.

(3) NK-1 receptor antagonism by oral administration
Test male Hartley guinea pigs (280-350 g)
The test drug or solvent was orally administered using a probe.
15 minutes after administration, urethane anesthesia (1.2 g / kg i.p.
p. ) And a polyethylene catheter was placed in the external jugular vein. 1 mg / kg each i. v. Atropine and propranolol were administered 30 minutes after administration of the test drug, and 30 minutes later, the pigment (Evans blue, 10 mg / kg) was administered.
i. v. ) And saline or substance P (1
nmol / kg i. v. ) Was administered. Five minutes later, the chest was opened, 60 ml of physiological saline was injected from the left ventricle, and the right atrium was incised to release blood. The esophagus and trachea are removed and the pigment is extracted therefrom with 5 ml of formamide.
The amount of dye per unit weight tissue was calculated by colorimetric quantification in nm. As shown in the following formula, an increase in the amount of dye due to substance P was determined by comparing with a guinea pig to which physiological saline was administered instead of substance P, and the inhibition rate of the increase by the test drug was calculated. Inhibition rate by drug (%) = ((average amount of dye in solvent-administered group−average amount of dye in drug-administered group) / (average amount of dye in solvent-administered group) −administered physiological saline instead of substance P Dose showing 50% inhibition based on the inhibition rate of each dose (ID ₅₀ ,
mg / kg p. o. ) Was calculated by the probit method. The test drug was dissolved or suspended in a 5% methylcellulose solution containing 5% dimethyl sulfoxide after adding a few drops of 1N hydrochloric acid and Tween 80, and further diluted with a 5% methylcellulose solution. The dose volume was 4 ml / kg,
To the solvent-administered group, 80 drops of Tween and a 5% methylcellulose solution containing 5% dimethyl sulfoxide were administered.

The compound (I) of the present invention can be used in the form of a pharmaceutical preparation mixed with a pharmaceutically acceptable carrier such as a commonly used organic or inorganic solid or liquid excipient. Pharmaceutical preparations are capsules, tablets, pills,
Granules, powders, fine granules, oral liquids, suspensions, emulsions, injections, suppositories, inhalants, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal It is prepared as an oral or parenteral preparation such as a liquid or transmucosal patch. If desired, auxiliaries, stabilizers, wetting or emulsifying agents, buffers and other commonly used additives may be included in the above formulations.
The dose is appropriately determined depending on the individual case in consideration of symptoms, age of the subject, sex, etc. In the case of oral administration, it is usually 0.01 to 100 mg / kg per day for an adult, preferably 0 to 100 mg / kg. 0.1 to 10 mg / kg.
Dosing twice or in two to four doses. In the case of intravenous administration, it is usually 0.001 to 10 per adult per day.
mg / kg, preferably in the range of 0.05 to 5 mg / kg, administered once or more than once a day. Furthermore, in the case of nasal administration, usually 0.001-10 mg /
kg, preferably in the range of 0.01 to 1.0 mg / kg, administered once to several times a day.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, the one or more active substances is an inert diluent, such as lactose, mannitol,
It is mixed with glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and magnesium aluminate metasilicate. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing agent such as an acid may be contained. The tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like, or may be coated with two or more layers, if necessary. Further, capsules made of an absorbable substance such as gelatin may be used.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents, For example, it contains purified water and ethanol. The composition may contain, in addition to the inert diluent, auxiliaries such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances and preservatives.
Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se. Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, and suspensions include, for example, distilled water for injection and physiological saline. Includes insoluble solutions, suspensions, and emulsions. Examples of aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. Such compositions may also contain preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg,
Lactose) and solubilizers (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used in the preparation of a sterile solid composition which is dissolved in sterile water or a sterile solvent for injection before use.

When used as a nasal preparation, the preparation can be produced according to a method known per se. For example, a small amount of a pH adjuster, a preservative or a thickener (eg, natural gums, cellulose derivatives, acrylic acid polymers, vinyl polymers, etc.) or excipients are added. The intranasal preparation containing the compound of the present invention is formed into a solid, liquid or semi-solid.
In the case of a solid state, the above components may be mixed to form a simple powdery composition, but may be a lyophilized product, preferably having a particle size of about 5 to 250 microns. If liquid,
Aqueous solutions, aqueous suspensions or oil suspensions are preferred.
In the case of semi-solid, an aqueous or oily gel or ointment is preferred. As a method of administering a nasal preparation,
In the case of solid preparations, the powder-filled capsule is set in a special spraying device equipped with a needle and the needle is penetrated, thereby making small holes above and below the capsule, and then blowing air with a rubber ball. A method of ejecting the powder into the nasal cavity may, for example, be mentioned. In the case of a liquid preparation, there may be mentioned, for example, a method in which the preparation is placed in a nasal drop container, a spray container or a similar container suitable for applying such a liquid preparation to the nasal cavity, and is dropped or sprayed into the nasal cavity. In the case of semi-solid preparations, the preparation is filled into a tube and administered directly to the nasal cavity with an applicator attached to the mouth of the tube at the time of administration, or a certain amount of the preparation is taken into the nasal cavity using an intranasal insert. And the like. The dose of the compound of the present invention varies depending on the type and disease state, but the amount of the preparation is about 5 mg to 100 mg for a solid preparation, about 0.05 ml to 0.5 ml for a liquid preparation, and about half. In the case of a solid preparation, the appropriate range is about 50 mg to 500 mg.

The solid preparation can be produced by a method known per se. For example, an excipient is placed in a mixer, and a compound dissolved in a mixture of the compound of the present invention and a small amount of water or ethanol is gradually added to carry out kneading. Thereafter, it is dried at a suitable temperature under vacuum, and the dried product is pulverized to obtain a solid preparation. Alternatively, a mixed solution of water and ethanol is added to the mixed powder of the compound of the present invention and an excipient, and the mixture is completely dissolved, and then dehydrated and dried by freeze-drying or spray-drying. The dried product is appropriately pulverized to obtain a solid preparation. Examples of the excipient include glucose, mannitol, inositol, sucrose, lactose, fructose, starch, corn starch, microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and the like.

The liquid preparation can be prepared according to a method known per se. For example, an aqueous solution for transmucosal preparation can be produced by dissolving, suspending or emulsifying the compound of the present invention in water, a buffer solution or an aqueous solution. The transmucosal oily suspension can be produced by suspending or emulsifying the compound of the present invention in an oily base. Examples of the oily base include sesame oil, olive oil, corn oil, soybean oil, cottonseed oil, peanut oil, lanolin, petrolatum, paraffin, isoper, silicone oil, and fatty acids having 6 to 30 carbon atoms or glycerin or alcohol esters thereof. These may be used alone or as a mixture of two or more.

As a method for producing a semisolid preparation, an aqueous or oily gel or ointment can be produced by a means known per se. For example, an aqueous gel solution or aqueous suspension for transmucosal preparation is prepared, and if necessary, a pH adjuster, a preservative and the like are added thereto. This solution is divided into two, and the aqueous gel base is dissolved or dispersed in one of them, and is heated or cooled appropriately to form a stable gel. An aqueous gel can be produced by dissolving the compound of the present invention in the other solution and uniformly mixing the two. The adjustment of the pH in the above can be performed by, for example, adding an acid, a base, a buffer, and the like during the production process of the preparation.

Examples of the aqueous gel base include natural gums (eg, tragacanth gum, acacia gum, karaya gum,
Irish moss, guaiac gum, xanthan gum, locust bean gum, etc.), cellulose derivatives (eg, methylcellulose, carboxymethylcellulose, etc.), acrylic polymers (eg, polyacrylic acid, polymethacrylic acid, etc.), vinyl polymers (eg, polyvinyl) Pyrrolidone,
Polyvinyl alcohol, polyvinyl methyl ether, carboxypolymethylene, etc.), synthetic polysaccharides (eg, polysucrose, polyglucose, polylactose, etc.), starch, dextrin, pectin, sodium alginate,
Proteins (gelatin, collagen) and the like. These bases can be used as a mixture of two or more kinds as appropriate.

The oily ointment for transmucosal preparation can be produced by uniformly dispersing the compound of the present invention in a heat-melted oily base and cooling with stirring. Examples of the oil base include the same ones as described above. Preservatives may be added to the present preparation. Examples of the preservatives include phenolic substances such as paraoxybenzoates, phenol and cresol, chlorobutanol, phenylethyl alcohol, and the like.
Alcohols such as propylene glycol, inverted soaps such as benzalkonium chloride and benzethonium chloride, benzoic acid, sorbic acid, dehydroacetic acid, sulfurous acid and salts thereof, and acids such as sodium bisulfite or salts thereof can be used.

[0041]

The production examples of the compound (I) of the present invention will be described below in detail with reference to examples. In addition, since novel compounds are also contained in the starting compounds used for producing the compound (I) of the present invention, production examples of the starting compounds will be described as reference examples. The compound required in the process of producing the compound of the present invention can be produced by a conventional method in the same manner as in the production method described in the present specification or in Reference Examples described later. The compound of the present invention is not limited to the compounds described in the following Examples, and furthermore, the compound represented by the aforementioned general formula (I), a salt thereof, a hydrate thereof, a solvate thereof, its geometry and optical properties It includes all isomers and polymorphs.

Reference Example 1 4-phenyl-3-isocoumarincarboxylic acid (5.00
g, 19 mmol) in methanol (63 ml) was added with a saturated ammonia-methanol solution (32 ml).
Stirred at room temperature for hours. Further, a saturated ammonia-methanol solution (32 ml) was added, and the mixture was stirred at room temperature for 25 hours, and then the reaction mixture was concentrated under reduced pressure. A 4N hydrochloric acid-ethyl acetate solution (63 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 4.5 hours, and the precipitated solid was collected by filtration, washed with ethyl acetate, and washed with 1-oxo-4-phenyl-1. , 2-dihydro-3
-Isoquinoline carboxylic acid (5.70 g) was obtained as a colorless solid. Mass spectrometry value (m / z): FAB 266 [(M +
H) ⁺ ] Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ: 6.71 (1H, brs), 7.00-7.95
(8H, m), 8.32 (1H, dd, J = 6.3H
z, 3.2Hz)

In the same manner as in Reference Example 1, the following compound of Reference Example 2 was obtained. Reference Example 2 4- (4-fluorophenyl) -1-oxo-1,2-
Dihydro-3-isoquinoline carboxylic acid Starting compound: 4- (4-fluorophenyl) -3-isocoumarin carboxylic acid Mass spec (m / z): FAB 284 [(M +
H) ⁺ ] Nuclear magnetic resonance spectrum (DMSO-d ₆ ) δ: 7.10 (1H, d, J = 8.0 Hz), 7.27
−7.34 (4H, m), 7.61-7.64 (1H,
m), 7.69-7.72 (1H, m), 8.31-
8.33 (1H, m), 11.10 (1H, brs),
13.61 (1H, brs)

Reference Example 3 3- (4-fluorobenzoyl) picolinic acid (2.45)
g, 10 mmol), ethyl glycinate hydrochloride (1.
54 g, 11 mmol) and a suspension of 1-hydroxybenzotriazole (1.49 g, 11 mmol) in dichloroethane (30 ml) were cooled under ice-cooling with 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide hydrochloride (2.
11 g, 11 mmol) and stirred at room temperature for 3 hours. Water was added to the reaction mixture, extracted with chloroform, washed successively with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent; chloroform: methanol: saturated aqueous ammonia = 100: 2:
By purifying in 1), ethyl N-[[3- (4-
Fluorobenzoyl) -2-pyridyl] carbonyl] glycinate (2.12 g, 64%) was obtained as a colorless solid. Mass spectrometry value (m / z): FAB 331 [(M +
H) ⁺ ] Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.1 Hz), 3.60
(1H, d, J = 19.4 Hz), 4.21 (2H,
q, J = 7.1 Hz), 4.65 (1H, d, J = 1)
9.4 Hz), 6.95-7.85 (6H, m), 8.
88 (1H, d, J = 9.0 Hz)

Reference Example 4 Ethyl N-[[3- (4-fluorobenzoyl) -2]
-Pyridyl] carbonyl] glycinate (8.60 g,
26 mmol) and 1,8-diasabicyclo [5.4.
0] Undec-7-ene (5.80 ml, 39 mmol
A solution of 1) in toluene (200 ml) was refluxed while dehydrating with a Dean-Stark dehydrator for 20 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent: ethyl acetate, and then chloroform: methanol: saturated aqueous ammonia = 10%).
0: 2: 1) to give ethyl 5- (4
-Fluorophenyl) -8-oxo-7,8-dihydro-1,7-naphthyridine-6-carboxylate (1.
23g, 15%) as a pale yellow solid. Mass spectrometry value (m / z): FAB 313 [(M +
H) ⁺ ] Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 1.00 (3H, t, J = 7.3 Hz), 4.14
(2H, q, J = 7.3 Hz), 7.17-7.26
(4H, m), 7.54-7.58 (2H, m), 8.
98 (1H, dd, J = 3.3 Hz, 2.7 Hz)

Reference Example 5 Ethyl 5- (4-fluorophenyl) -8-oxo-
To a solution of 7,8-dihydro-1,7-naphthyridine-6-carboxylate (1.22 g, 3.9 mmol) in ethanol (40 ml), 40 ml of a 10% aqueous sodium hydroxide solution was added at room temperature, and the mixture was stirred at room temperature for 1 hour. . The reaction mixture was concentrated under reduced pressure until the liquid volume was reduced to about 40 ml, concentrated to pH 1 by adding concentrated hydrochloric acid, extracted with a mixed solution of chloroform and isopropanol (3: 1), and dried over anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure to give 5- (4-fluorophenyl) -8-oxo-
7,8-Dihydro-1,7-naphthyridine-6-carboxylic acid (1.02 g, 92%) was obtained as a pale yellow solid. Mass spectrometry value (m / z): FAB 285 [(M +
H) ⁺ ] Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 7.19-7.26 (4H, m), 7.61-7.
70 (2H, m), 9.00-9.20 (1H, m),
12.90 (1H, brs)

Reference Example 6 1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxylic acid (1.00 g, 3.8 mmol)
And dimethylformamide (2 drops) in dichloromethane (1
Oxalyl chloride (0. 0 ml) under ice-cooling.
After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure to give crude 1-oxo-
4-phenyl-1,2-dihydro-3-isoquinoline carboxylic acid chloride was obtained. 3,5-bis (trifluoromethyl) -N-methylbenzylamine (970 mg,
3.8 mmol) and triethylamine (0.79 ml,
5.7 mmol) in dichloroethane (10 ml) was added to the crude 1-oxo-4-phenyl-1,2 obtained above.
A solution of -dihydro-3-isoquinolinecarboxylic acid chloride in dichloroethane (10 ml) was added over 15 minutes at room temperature, and the mixture was further stirred at room temperature for 3 hours. Water was added to the reaction mixture, extracted with chloroform, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 10: 1) to give
N- [3,5-bis (trifluoromethyl) benzyl]
-N-methyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxamide (973 m
g, 51%) as a colorless solid. Mass spectrometry value (m / z): FAB 505 [(M +
H) ⁺ ] nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 2.74 (3H, s), 4.72 (2H, s),
7.30-7.90 (11H, m), 8.50 (1H,
m)

In the same manner as in Reference Example 6, the following Reference Examples 7 to 8
Was obtained. Reference Example 7 N- [3,5-bis (trifluoromethyl) benzyl]
-4- (4-Fluorophenyl) -N-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxamide Starting compound: 4- (4-fluorophenyl) -1-oxo-1,2-dihydro- 3-isoquinolinecarboxylic acid,
And 3,5-bis (trifluoromethyl) -N-methylbenzylamine mass spec (m / z): FAB 523 [(M +
H) ⁺ ]

Reference Example 8 N- [3,5-bis (trifluoromethyl) benzyl]
-5- (4-Fluorophenyl) -N-methyl-8-oxo-7,8-dihydro-1,7-naphthyridine-6
Carboxamide Starting compound: 5- (4-fluorophenyl) -8-oxo-7,8-dihydro-1,7-naphthyridine-6-carboxylic acid and 3,5-bis (trifluoromethyl)-
N-methylbenzylamine mass spectrometry (m / z): FAB 524 [(M +
H) ⁺ ] nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 2.79 (3H, s), 4.55-4.80 (2
H, m), 6.90-7.85 (9H, m), 8.90
-9.00 (1H, m)

Example 1 N- [3,5-bis (trifluoromethyl) benzyl]
-N-methyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxamide (970 m
g, 1.9 mmol) and phosphorus oxychloride (10 ml) were refluxed for 1.5 hours. The reaction mixture was cooled in air, poured into ice water, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. After filtering off magnesium sulfate, the filtrate was concentrated under reduced pressure, and the obtained residue was treated with hydrazine monohydrate (0.93 m
and 19 mmol) and refluxed in ethanol (20 ml) for 1 hour. The reaction mixture was concentrated under reduced pressure, water was added to the obtained residue, extracted with chloroform, washed with brine, and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue and trimethyl orthoformate (20 ml) were refluxed for 1 hour. The residue obtained after concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 1: 4) to give N- [3,5
-Bis (trifluoromethyl) benzyl] -N-methyl-6-phenyl-1,2,4-triazolo [3,4-
a] isoquinoline-5-carboxamide (560 mg,
55%) as a colorless solid. Mass spectrometry value (m / z): FAB 529 [(M +
H) ⁺ ] nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 2.68 (3H, s), 4.23 (1H, d, J =
15 Hz), 5.10 (1H, d, J = 15 Hz),
7.29-7.84 (11H, m), 8.11 (1H,
s), 8.84 (1H, d, J = 7.5 Hz)

In the same manner as in Example 1, the following Examples 2-3
Was obtained. Example 2 N- [3,5-bis (trifluoromethyl) benzyl]
-6- (4-fluorophenyl) -N-methyl-1,
2,4-triazolo [3,4-a] isoquinoline-5
Carboxamide Starting compound: N- [3,5-bis (trifluoromethyl) benzyl] -4- (4-fluorophenyl) -N-
Methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxamide mass spectrometry (m / z): FAB
547 [(M + H) ⁺ ] nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 2.75 (3H, s), 4.26 (1H, d, J =
14Hz), 5.12 (1H, d, J = 14Hz),
6.97-7.02 (1H, m), 7.07-7.12
(1H, m), 7.27 (1H, s), 7.29-7.
33 (1H, m), 7.38-7.46 (2H, m),
7.60-7.66 (2H, m), 7.76-7.79
(1H, m), 7.88 (1H, s), 8.69 (1
H, s), 8.85 (1H, d, J = 7.6 Hz)

Example 3 N- [3,5-bis (trifluoromethyl) benzyl]
-6- (4-fluorophenyl) -N-methyl-1,
2,4-Triazolo [4,3-h] [1,7] naphthyridine-5-carboxamide Starting compound: N- [3,5-bis (trifluoromethyl) benzyl] -5- (4-fluorophenyl)- N-
Methyl-8-oxo-7,8-dihydro-1,7-naphthyridine-6-carboxamide Mass spec (m / z): FAB 548 [(M +
H) ⁺ ] nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 2.76 (3H, s), 4.23 (1H, d, J =
18.0 Hz), 5.15 (1H, d, J = 18.0H)
z), 7.00-7.90 (9H, m), 8.75 (1
H, s), 9.10 (1H, dd, J = 7.2 Hz,
1.0Hz)

Example 4 N- [3,5-bis (trifluoromethyl) benzyl]
-N-methyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxamide (500 m
g, 1.0 mmol) and phosphorus oxychloride (5 ml) was refluxed for 1.5 hours. The reaction mixture was air-cooled, poured into ice water, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. After filtering off magnesium sulfate, the filtrate was concentrated under reduced pressure, and the obtained residue was treated with hydrazine monohydrate (0.47 m
1, 1.0 mmol) and ethanol (10 ml),
Refluxed for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the obtained residue, extracted with chloroform, washed with brine, and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue and trimethyl orthoacetate (10 ml) were refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 1: 1, then 1: 4) to give N- [3,5- Bis (trifluoromethyl) benzyl] -N, 3-dimethyl-6-phenyl-1,2,4-
Triazolo [3,4-a] isoquinoline-5-carboxamide (150 mg, 28%) was obtained as a colorless solid. Mass spectrometry value (m / z): FAB 543 [(M +
H) ⁺ ] nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 2.69 (3H, s), 2.77 (3H, s),
4.17 (1H, d, J = 14 Hz), 4.94 (1
H, d, J = 14 Hz), 7.30-7.83 (11
H, m), 8.80 (1H, d, J = 9.6 Hz)

Example 5 N- [3,5-bis (trifluoromethyl) benzyl]
-N-methyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinecarboxamide (500 m
g, 1.0 mmol) and phosphorus oxychloride (5 ml) was refluxed for 1.5 hours. The reaction mixture was cooled in air, poured into ice water, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. After filtering off magnesium sulfate, the filtrate was concentrated under reduced pressure, and the obtained residue was treated with hydrazine monohydrate (0.47 m
1,1.0 mmol) and 3 in ethanol (10 ml).
Refluxed for hours. The reaction mixture was concentrated under reduced pressure, water was added to the obtained residue, extracted with chloroform, washed with brine, and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was treated with benzoyl chloride (4 drops) and 1,4-dioxane (1 drop).
(0 ml) under reflux for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate) to give N- [3,5-bis (trifluoromethyl) benzyl]. ] -N-methyl-3,6-diphenyl-
1,2,4-triazolo [3,4-a] isoquinoline-
5-Carboxamide (120 mg, 20%) was obtained as a pale yellow solid. Mass spectrometry value (m / z): FAB 605 [(M +
H) ⁺ ] Nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 2.53 (3H, s), 4.46-4.51 (2
H, m), 7.02-7.90 (16H, m), 8.9.
1 (1H, d, J = 7.6Hz)

Table 1 shows the chemical structural formulas of the compounds obtained in Reference Examples 1 to 8, and Table 2 shows the chemical structural formulas of the compounds obtained in Examples 1 to 5.

[0056]

[Table 1]

[0057]

[Table 2]

In addition to the examples described above, compounds that can be synthesized according to the present invention are shown below. These compounds can be synthesized using the above-mentioned production methods and the synthetic routes and methods described in the examples, and ordinary production methods known to those skilled in the art, and do not require special experiments.

Compound 1 N- [3,5-bis (trifluoromethyl) benzyl]
-6- (4-Fluorophenyl) -N, 3-dimethyl-
1,2,4-triazolo [4,3-h] [1,7] naphthyridine-5-carboxamide Compound 2 N- [3,5-bis (trifluoromethyl) benzyl]
-3-Ethyl-6- (4-fluorophenyl) -N-methyl-1,2,4-triazolo [4,3-h] [1,
7] Naphthyridine-5-carboxamide compound 3 6- (4-Fluorophenyl) -N- (2-methoxybenzyl) -N-methyl-1,2,4-triazolo [4
3-h] [1,7] naphthyridine-5-carboxamide Compound 4 N- (2-chlorobenzyl) -6- (4-fluorophenyl) -N-methyl-1,2,4-triazolo [4,3
-H] [1,7] naphthyridine-5-carboxamide compound 5 N- [3,5-bis (trifluoromethyl) benzyl]
-N-methyl-6-phenyl-1,2,4-triazolo [4,3-h] [1,7] naphthyridine-5-carboxamide

Compound 6 N- [3,5-bis (trifluoromethyl) benzyl]
-N-methyl-6- (4-methylphenyl) -1,2,2
4-triazolo [4,3-h] [1,7] naphthyridine-5-carboxamide Compound 7 N- [3,5-bis (trifluoromethyl) benzyl]
-N-ethyl-6- (4-fluorophenyl) -1,
2,4-Triazolo [4,3-h] [1,7] naphthyridine-5-carboxamide Compound 8 N- [3,5-bis (trifluoromethyl) benzyl]
-N-ethyl-6- (4-fluorophenyl) -3-methyl-1,2,4-triazolo [4,3-h] [1,
7] Naphthyridine-5-carboxamide Compound 9 N- [3,5-bis (trifluoromethyl) benzyl]
—N-methyl-6- (2-methylphenyl) -1,2,2
4-triazolo [3,4-a] isoquinoline-5-carboxamide Compound 10 N- [3,5-bis (trifluoromethyl) benzyl]
-6- (4-Fluorophenyl) -N, 3-dimethyl-
1,2,4-triazolo [3,4-a] isoquinoline-
5-carboxamide

Compound 11 N- (2-chlorobenzyl) -6- (4-fluorophenyl) -N, 3-dimethyl-1,2,4-triazolo [3,4-a] isoquinoline-5-carboxamide Compound 12 N- (3,5-dimethylbenzyl) -6- (4-fluorophenyl) -N-methyl-1,2,4-triazolo [4,3-h] [1,7] naphthyridine-5-carboxamide Compound 13 N- (2-chlorobenzyl) -6- (4-fluorophenyl) -N, 3-dimethyl-1,2,4-triazolo [4,3-h] naphthyridine-5-carboxamide Compound 14 N- [3 5-bis (trifluoromethyl) benzyl]
—N-methyl-6- (2-methylphenyl) -1,2,2
4-triazolo [4,3-h] [1,7] naphthyridine-5-carboxamide Compound 15 N- (3,5-dimethylbenzyl) -N-methyl-6
Phenyl-1,2,4-triazolo [4,3-h]
[1,7] Naphthyridine-5-carboxamide

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 471/14 102 C07D 471/14 102 (72) Inventor Ken Ikeda 1-2-25 Tsukushino, Abiko-shi, Chiba Pref. No. (72) Inventor Isomura Yasushio 3-4-8 Yakushidai, Moriya-cho, Kitasoma-gun, Ibaraki

Claims (3)

[Claims] 1. A triazole derivative represented by the following general formula (I) or a salt thereof. Embedded image (The symbols in the above formulas have the following meanings, respectively: X: nitrogen atom or CH group, R ¹ : hydrogen atom, lower alkyl group, aryl group or aralkyl group, R ² : hydrogen atom or lower alkyl group, A Ring and ring B: the same or different, optionally substituted benzene ring, n: 1 or 2) 2. A medicament comprising the triazole derivative according to claim 1 or a salt thereof. 3. A tachykinin receptor antagonist comprising the triazole derivative according to claim 1 or a salt thereof.