JPH07503711A - Peptides with tachykinin antagonistic activity - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Technical field of peptides with tachykinin antagonistic activity The present invention relates to novel peptide compounds and pharmaceutically acceptable salts thereof. It is.

More specifically, the present invention provides tachykinin antagonism, particularly substance P antagonism. , has pharmacological activities such as neurokinin A antagonistic action and 22-kinin B antagonistic action. novel peptides and pharmaceutically acceptable salts thereof, methods for their production, It relates to pharmaceutical compositions containing the same and their pharmaceutical uses.

Disclosure of invention Therefore, one object of the present invention is to inhibit tachykinin antagonism, particularly substance P antagonism. It has pharmacological activities such as neurokinin A antagonistic activity and 22-kinin B antagonistic activity. An object of the present invention is to provide novel peptide compounds and pharmaceutically acceptable salts thereof. Ru.

Another object of the present invention is to provide a method for producing the peptide compound and its salt. It is.

Another object of the present invention is to provide the peptide compounds and their pharmaceutically acceptable salts. An object of the present invention is to provide a pharmaceutical composition containing the present invention as an active ingredient.

A further object of the present invention is to treat cuquikinin-mediated diseases in humans or animals. For example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, eczema, conjunctivitis, and spring fever. Eye diseases such as acne, contact dermatitis, atopic dermatitis, hives, and other eczema-like skin Skin diseases such as dermatitis, inflammatory diseases such as rheumatoid arthritis and osteoarthritis, and pain , treatment of pain (e.g. migraine, headache, toothache, cancer pain, back pain), or Tachykinin antagonists useful for prevention, especially substance P antagonists and neurokinins The peptide compound or its peptide compound as A antagonist or 22-rokinine B antagonist It is an object of the present invention to provide uses for pharmaceutically acceptable salts.

The object compound of the present invention can be represented by the following general formula (I): R' is aryl, pyridyl, pyrrolyl, or the formula [wherein the solid line and dotted line are represents a bond or double bond, X is CH or N, and Z is 10-1-S- or or -NH-], each of which may have a suitable substituent. Often, R' is ar-lower alkyl optionally with suitable substituents, and R1 is lower alkyl which may have a suitable substituent, and R4 is a suitable substituent. Al is lower alkyl which may have a group, and R6 is hydrogen or lower alkyl. , A is a bond, lower alkylene or lower alkenylene, and Y is 0 or is N-R' (R' is hydrogen or lower alkyl), and m is 0 or 1 and n is an integer from O to 2.

A preferred steric configuration of compound (1) can be represented by the following formula.

According to the present invention, the novel peptide compound (I) can be obtained by various methods shown in the reaction formulas below. It can be manufactured.

It's a method sexual derivatives or their salts (I-a) or its salt or its salt Hojinmi Method L (I-a) or its salt or its salt or reaction at its amine group sexual derivatives or their salts (I-k) or its salt In the above reaction formula, R', R1, R', R', R', R', A, X, Y, m and n are each defined above, Rl is cyano lower alkyl, R' is amidino lower alkyl and R6c is a protected amine lower alkyl and R1 is amino lower alkyl, R1 is guanidino lower alkyl or [2-lower alkyl-3-cyanoisothi Ouraid] lower alkyl, R″ is [2-lower alkyl-3-cyanoisothioureido] lower alkyl. the law of nature, Ri is [3-lower alkyl-2-cyanoguanidino] lower alkyl, and R 8 is amidino or (lower alkylthio)(cyanoimino)methyl, and L is It is a leaving group.

Regarding the starting compounds (11) and (II+), some of them are new. However, they can be prepared using the procedures described in the Preparation Examples and Examples below, or by conventional methods. , - can be prepared from.

Throughout this specification, amino acids, peptides, protecting groups, condensing agents, etc. are referred to in the art. IUPAC-IUB (Biochemical Nomenclature Committee) abbreviation commonly used in Was.

In addition, unless otherwise specified, amino acids and their residues are referred to by such abbreviations. are assumed to be L-configured compounds and residues. .

Suitable pharmaceutically acceptable salts of the starting and target compounds are conventional non-toxic salts. salts, such as organic acid salts (e.g. acetate, trifluoroacetic acid) salts, toluenesulfonates, etc.), inorganic acid salts (e.g. hydrochlorides, hydrobromides, Acid addition salts such as hydroiodides, sulfates, nitrates, phosphates, amino acids (and (e.g. arginine, aspartic acid, glutamic acid, etc.), alkali metal salts (e.g. sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g. potassium salts, etc.) metal salts such as lucium salts, magnesium salts, ammonium salts, and organic base salts (e.g. trimethylamine salt, triethylamine salt, lysine salt, picoline salt) , dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc. ), etc.

In the description above and below of this specification, various Preferred examples of the definition and individual specific examples will be explained in detail below.

Unless otherwise specified, the term "lower" refers to carbon atoms of 1 to 6, preferably 1. ~4.

Suitable "aryl" include phenyl, tolyl, xylyl, mesityl, cumenyl. aryl, naphthyl, etc., preferred are 06-C1, aryl, and especially Preferred is phenyl.

formula Suitable groups represented by include indolyl (e.g. indol-1-yl, indol-2-yl, indol-3-yl), benzofuryl (e.g. benzofuran-2-yl, benzofuran-3-yl), benzochenyl (e.g. penbutien-2-yl, penbutien-3-yl), indazole (For example, IH-indazol-1-yl, IH-indazol-3-yl, etc.) ), indolinyl (e.g. indolin-2-yl, indolin-3-yl, etc.) ), and indolyl is preferred.

The above aryl group and the group represented by the above formula are lower alkyl (for example, methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl ), amino lower alkyl (e.g. aminomethyl, aminoethyl, aminopro- (pil, aminobutyl, aminopentyl, aminohexyl, etc.); protected amino lower alkyl, i.e., an amino group is replaced by an acyl, e.g. common amino protecting groups such as carbonyl (e.g. tertiary butoxycarbonyl) The above amine lower alkyl protected by; cyano lower alkyl (e.g. Cyanomethyl, cyanoethyl, cyanopropyl, cyanobutyl, cyanopentyl , cyanohexyl, etc.); amidino lower alkyl (e.g. amidinomethyl, acyanohexyl, etc.); Midinoethyl, amidinopropyl, amidinobutyl, amidinopentyl, amidi guanidino-lower alkyl (e.g. guanidinomethyl, guar Nidinoethyl, guanidinopropyl, guanidinobutyl, guanidinopentyl, (guanidinohexyl, etc.); [2-lower alkyl-3-cyanoisothiouray ]lower alkyl [e.g. 2-(3-cyano-2-methylisothioureido) Ethyl etc; [3-lower alkyl-2-cyanoguanidinoureidoko lower Alkyl [e.g. 2-(2-cyano-3-methylguanidino)ethyl etc.]; mono- or di-lower alkylamino-lower alkyl [e.g. 2-(methylamino) Ethyl, 2-(dimethylamino)ethyl, 2-(diethylaminoconityl, 2- or 3-(dimethylamino)propyl, 2- or 3- or 4-(dimethyl one or more, preferably 1 to 3, suitable substituents such as You may do so.

Preferred "lower alkylene" is one having 2 to 6 carbon atoms, including methylene, ethylene, trimethylene, propylene, tetramethylene, methyltrimethylene, hexa Examples include methylene, among which methylene, ethylene, and trimene are preferred. It is tyrene.

Preferred "lower alkenylene" is one having 2 to 6 carbon atoms, including vinylene, propylene, Examples include penylene, and vinylene is preferred.

Suitable "lower alkyl which may have a suitable substituent" include the above-mentioned examples. lower alkyl, carboxy lower alkyl (such as carboxymethyl), Stellated carboxy lower alkyl, e.g. lower alkoxy carbonyl lower Protected carboxylic acids such as alkyl (such as methoxycarbonylmethyl) xy lower alkyl, carbamoyl lower alkyl (e.g. carbamoylmethyl, (e.g. carbamoylethyl), lower alkylamino lower alkyl (e.g. dimethyl lyaminomethyl, dimethylaminoethyl, etc.), hydroxy lower alkyl (and hydroxymethyl, hydroxyethyl, etc.), acyloxy lower alkyl ( protected hydroxy lower alkyl, such as acetyloxyethyl) , halo-lower alkyl (such as trifluoromethyl), etc. Examples include conventional groups used in .

Suitable "al lower alkyl which may have a suitable substituent" include amino Conventional groups used in the field of acid and peptide chemistry, such as al-lower alkyl For example, trityl, benzhydryl, benzyl, phenethyl, naphthylmethyl, (lylmethyl, xylylmethyl, mesitylmethyl, etc.), substituted al lower alkyl ( For example, 0-fluorobenzyl, m-fluorobenzyl, 0-tolylmethyl "Cyano lower alkyl", "Amidino lower alkyl", "Protected amine lower alkyl" ``alkyl'', ``amino lower alkyl'', ``guanidino lower alkyl'', `` [2-lower alkyl-3-cyanoisothioureido] lower alkyl" and "[ 3-lower alkyl-2-cyanoguanidino]lower alkyl" as shown above. The same things can be mentioned.

The preferred [(lower alkylthio)(cyanoimino)methyl] is (methyl thio)(cyanoimino)methyl, (ethylthio)(cyanoimino)methyl, etc. can be mentioned.

Suitable "leaving groups" include lower alkylthio (e.g. methylthio, ethylthio). etc.), substituted or unsubstituted pyrrol-1-yl (e.g. pyrrol-1-yl , 2,4-dimethylpyrrol-1-yl), and the like.

Preferred embodiments of the symbols R', R", R", R', R@, A, Y, m and n are , as follows.

R1 is aryl, preferably C0-C8 aryl (e.g. phenyl etc.), Pyridyl, pyrrolyl or formula [Here, Z is -N(R")- or -〇-, and R" is hydrogen, lower alkyl (such as methyl), di-lower alkylamino-lower alkyl, such as 2-( dimethylamino)ethyl, 3-(dimethylamino)propyl, etc.], lower amino alkyl (such as 2-aminoethyl), protected amine lower alkyl, Preferably lower alkoxycarbonylamino lower alkyl [e.g. 2-(tertiary acylamino lower alkyl, such as butoxycarbonylamino)ethyl, Cyano lower alkyl (e.g. 2-cyanoethyl), amidino lower alkyl (e.g. 2-amidinoethyl), guanidino lower alkyl (e.g. 2-amidinoethyl etc.) guanidinoethyl, etc.), [2-lower alkyl-3-cyanoisothioureido ] Lower alkyl [e.g. 2-(3-cyano-2-methylisothiourido)ethyl] ] or 3-lower alkyl-2-cyanoguanidino] lower alkyl [ For example, 2-(2-cyano-3-methylguanidino)ethyl, etc.] and R' is ar lower alkyl, preferably phenyl lower alkyl (e.g. benzyl ), mono- or di-lower alkylphenyl lower alkyl (e.g. 3-trimethyl), methyl, 3,4-xylylmethyl, etc.), naphthyl lower alkyl (e.g. 1-naphthyl), C1-C1l al-lower alkyl such as phthylmethyl, 2-naphthylmethyl, etc.) and R' is lower alkyl (eg, methyl, etc.).

R4 is a lower alkyl such as phenyl lower alkyl (e.g. benzyl) and R' is hydrogen or lower alkyl (such as methyl), and A is a bond or lower alkenylene (such as vinylene), and Y is O or N-R' [ R' is hydrogen or lower argyl (such as methyl)] and m is 0 or 1, where n is an integer 1.

The method for producing the target compound (I) will be explained in detail below.

Method l Compound (I-a) or a salt thereof is compound (11) or its amino group. Reactive derivatives or their salts to compound (II+) or its carboxy group It can be produced by reacting with reactive derivatives or salts thereof.

A suitable reactive derivative at the amino group of compound (TI) is compound (II). ) and bis(trimethylsilyl)acetamide, mono(trimethylsilyl)aceto Produced by reaction with silyl compounds such as amides and bis(trimethylsilyl)urea silyl derivative; by reaction of compound (11) with phosphorus trichloride or phosgene Examples include derivatives produced.

Suitable salts of compound (TI) and its reactive derivatives include compound (I). Here are some examples.

Suitable reactive derivatives at the carboxy group of compound (II+) include acid halo In peptide chemistry, such as genides, acid anhydrides, active amides, and active esters. Commonly used ones are mentioned. Suitable examples of these reactive derivatives include: monoacid chloride; acid azide; substituted phosphoric acid [e.g. dialkyl phosphoric acid, phenyl phosphoric acid, di- phenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.], dialkyl phosphorous acid, Sulfuric acid, sulfuric acid, sulfonic acid [e.g. methanesulfonic acid], aliphatic carboxylic acid [For example, acetic acid, propionic acid, butyric acid, isobutyric acid, bivaric acid, pentanoic acid, isobutyric acid] Benconic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.], aromatic carboxylic acids [and Mixed acid anhydrides with acids such as Nambaan, Se, Froic acid, etc.; Symmetrical acid anhydrides; Imidazole C, active amide with 4-@substituted imidazole and dimethyl pyrazole; active ester [For example, cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl] Chil [(CI(,), N”=Q(-) ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, Trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitro Phenylthioester, p-cresylthioester, carboxymethylthioester Tel, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolite ruthioester, etc.], N-hydroxy compounds [e.g. Roxylamine, 1-hydroxy-2-(IH)-pyridone, N-hydroxys succinimide, N-hydroxyphthalimide, 1-hydroxy-IH-benzoto Riazole, etc.]. These reactive derivatives are suitable for the compounds used Depending on the type of (II!), it can be selected as appropriate from among them.

Suitable salts of compound (II+) and its reactive derivatives include alkali metal salts. [e.g. sodium salts, potassium salts, etc.], alkaline earth metal salts [e.g. lucium salts, magnesium salts, etc.], ammonium salts, organic base salts [e.g. bases such as lyelamine salt, N,N'-dibenzylethylenediamine salt, etc. Salts and acid addition salts such as those exemplified for compound (1) can be mentioned.

The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, etc. chloroform, dichloromethane, ethylene chloride, tetrahydrofuran, acetic acid Ethyl, N, N-dimethylformamide, pyridine or Not carried out in any other solvent. These conventional solvents can be used as a mixture with water. May be used.

In this reaction, when compound (II+) is used in the form of a free acid or a salt thereof, is a carbodiimide compound (e.g. N, N'-dicyclohexylcarbodiimide imide, N-cyclohexyl-No-morpholinoethylcarbodiimide, N-cyclohexyl-No-morpholinoethylcarbodiimide, chlorhexyl-N'-(4-dimethylaminocyclohexyl)carbodiimide, N.

No-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N -ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc.); N .

No　-Carbonylbis(2-methylimidazole); Pentamethyleneketene- N-cyclohexylimine; diphenylketene-N-cyclohexylimine; Toxyacetylene; l-alkoxy-1-chloroethylene; trialkyl phosphite ; Ethyl polyphosphate, isopropyl polyphosphate; Phosphorus oxychloride (phosphoryl chloride) - Phosphorus trichloride; diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; halo Lower alkyl formate [e.g. ethyl chloroformate, inpropyl chloroformate, etc.] ;triphenylphosphine;2-ethyl-7-hydroxybenzisoxazo 2-ethyl-5-(m-sulfophenyl)inoxacillium hydroxide Inner salt; hexafluorophosphate benzotriazol-1-yloxytris (di methylamino)phosphonium 1l-(1)-chlorobenzenesulfonyloxy) -6-chloro-IH-benzotriazole iN, N-dimethylformamide and salts Reaction with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc. In the presence of customary condensing agents such as the so-called Vilsmeier reagent, prepared by Preferably, the reaction is carried out at

The reaction is carried out using alkali metal bicarbonates, tri-lower alkyl amines (e.g. triethyl amines, etc.), pyridine, N, N-di-lower alkyl-1,3-propanediami (e.g. N,N-dimethyl-1,3-propanediamine, etc.), N-lower amines, alkylmorpholine (such as N-methylmorpholine), N,N-dilower alkyl It can also be carried out in the presence of an inorganic or organic base such as kylbenzylamine. Wear.

The reaction temperature is not particularly limited, but the reaction is usually carried out under cooling or heating. Ru.

Directions Compound (I-c) or a salt thereof is a cyano-lower compound (I-b) or a salt thereof. It can be produced by subjecting it to an alkene addition reaction.

Suitable "cyano lower alkenes" include acrylonitrile and the like.

This reaction is usually carried out using a base that can remove a proton from the 1st position of the indole ring. For example, it is carried out in the presence of Triton B or the like.

This reaction usually involves dioxane, dimethyl sulfoxide, dimethyl formamide, Solvents such as methanol, ethanol, and tetrahydrofuran or those that adversely affect the reaction It is carried out in any other solvent that does not affect the reaction.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at ambient temperature, or under heating. implement response measures.

method correct Compound (I-d) or a salt thereof is prepared by adding compound (I-c) or a salt thereof to ammonia. Alternatively, it can be produced by reacting with a salt thereof.

Suitable salts of ammonia include the acid addition salts exemplified for compound (I). It will be done.

This reaction can be carried out by any conventional method capable of converting a cyano group into an amidino group.

In this reaction, as a first step, chemical reaction is performed in the presence of an acid (such as hydrogen chloride). Compound (1-c) with alcohol (e.g. methanol, ethanol, etc.) The intermediate imide ether compound is then converted into an imido ether compound. It is preferable to convert the compound (I-d) into a chemical compound (I-d).

This reaction is usually carried out using a customary solvent such as methanol, ethanol or It is carried out in any other solvent that does not have any adverse effects.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at ambient temperature, or under heating. implement response measures.

method soil Compound (1-f) or a salt thereof is an amino-protected compound (1-e) or a salt thereof. It can be produced by subjecting it to a group elimination reaction.

This elimination reaction includes all the components used in amino protecting group elimination reactions in peptide chemistry. Conventional methods such as hydrolysis, reduction, etc. can be applied. If the amino protecting group When it is a group, it can be removed by hydrolysis. Hydrolysis is a base Alternatively, it is preferably carried out in the presence of an acid.

Suitable bases include, for example, alkali metal hydroxides (e.g. sodium hydroxide). hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g. nesium, calcium hydroxide, etc.), alkali metal carbonates (e.g. sodium carbonate), alkaline earth metal carbonates (e.g. magnesium carbonate, potassium carbonate, etc.), alkaline earth metal carbonates (e.g. magnesium carbonate, calcium carbonate), alkali metal bicarbonates (e.g. sodium bicarbonate), , potassium bicarbonate, etc.), alkali metal acetates (e.g., sodium acetate, acetic acid potassium, etc.), alkaline earth metal phosphates (e.g., magnesium phosphate, potassium phosphate, (e.g. lucium), alkali metal hydrogen phosphates (e.g. disodium hydrogen phosphate, inorganic bases such as dipotassium hydroxide) as well as trialkylamines (e.g. trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine , N-methylmorpholine, 1,5-diazabicyclo[4,3,0]non-5-ethyl 1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo Examples include organic bases such as [5,4,0]undecene-5. hydration with base Decomposition is often carried out in water or a hydrophilic organic solvent or a mixture thereof. It will be carried out.

Suitable acids include organic acids (such as formic acid, acetic acid, propionic acid, etc.) and anhydrous acids. Examples include organic acids (eg, hydrogen chloride, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).

This hydrolysis is usually carried out in organic solvents (such as ethyl acetate), water, or The test is carried out in a mixed solvent consisting of:

The reaction temperature is not particularly limited and can be selected appropriately depending on the type of amino protecting group and the elimination method. All you have to do is choose.

Reductive elimination can be achieved by removing protective groups such as alkyl lower alkyl (e.g. benzyl). It can be preferably applied to desorption.

Reduction methods that can be applied to this elimination reaction include, for example, metals (e.g. zinc, zinc, (e.g. lead amalgam) or chromium salt compounds (e.g. chromous chloride, chromous acetate) chromium) and organic or inorganic acids (e.g. acetic acid, propionic acid, hydrochloric acid, etc.) and catalytic reduction by conventional methods in the presence of conventional metal catalysts. Examples include.

Method Σ Compound (I-g) or its salt is compound (I-f) or its salt is compound CN) It can be produced by reacting with

The reaction can be carried out in the presence of a base as exemplified in Method 1.

This reaction is typically carried out using conventional solvents such as dimethylformamide, methanol, Carry out in ethanol or any other solvent that does not adversely affect the reaction.

The reaction temperature is not particularly limited, but the reaction is usually carried out under cooling or heating. Ru.

method Compound (I-4) or a salt thereof is a compound (1-h) or a salt thereof in a lower alkyl It can be produced by reacting with ruamine.

Suitable "lower alkyl amines" used in this reaction include methylamine, Tylamine, propylamine, isopropylamine, butylamine, pentylamine C7-C, alkyl amines such as amine, hexylamine, etc. This reaction is usually solvents such as N,N-dimethylformamide, methanol, ethanol or or any other solvent that does not adversely affect the reaction.

The reaction temperature is not particularly limited, but the reaction is usually carried out under cooling or heating. Ru.

direction μd− Compound (I-j) or a salt thereof is a compound (I-j) or a salt thereof, which is a compound (I-j) or a salt thereof. ) or its salt.

The reaction involves a phosphorus compound (such as phosphorus pentachloride) and N,N-dimethylaniline. can be carried out in the presence of

This reaction is typically carried out using conventional solvents such as ethanol, dimethylformamide, Carry out in dichloromethane or any other solvent that does not adversely affect the reaction.

The reaction temperature is not particularly limited, but the reaction is usually carried out under cold assembly or under heating. Ru.

direction Compound (I-k) or a salt thereof is compound (I+) or its amine group. Can be produced by subjecting reactive derivatives or their salts to Mannich reaction .

The reaction is carried out by a conventional method, that is, reaction at the compound (TI) or its amine group. reactive derivatives or their salts in formalin and formula R'-H (preferably I). (where R' is as defined above) or a salt thereof, and an acid or can be carried out by reacting in the presence of a base.

The compounds obtained by the above methods are powders (t. recrystallization, column chromatography). Can be isolated and purified by conventional methods such as roughy and reprecipitation, and the target compound can be isolated in free form. If possible, it can be converted into its salt by conventional methods.

Compound (I) and other compounds may have one or more stereoisomers due to asymmetric carbon atoms. However, all such isomers and mixtures thereof are included within the scope of this invention. It is something that can be done.

The objective compound (I) and its pharmaceutically acceptable salts have tachykinin antagonistic activity, In particular, substance P antagonism, neurokinin A antagonism, 2-kinin B It has pharmacological activities such as antagonism, and therefore is effective against cukikinin-mediated diseases, especially sub- Stance P-mediated diseases, such as asthma, bronchitis, rhinitis, cough, and respiratory diseases diseases, eye diseases such as conjunctivitis, vernal conjunctivitis, contact dermatitis, atopic dermatitis, Skin diseases such as hives, other eczema-like dermatitis, rheumatoid arthritis, osteoarthritis, etc. Any inflammatory disease, aches or pains (e.g. migraines, headaches, toothaches, cancer pain, back pain) It is useful for the treatment or prevention of diseases such as

Furthermore, the object compound (I) of the present invention can be used to treat eye diseases such as glaucoma and uveitis, and ulcers. , ulcerative colitis, irritable bowel syndrome, gastrointestinal diseases such as food allergies, nephritis, etc. inflammatory diseases, hypertension, angina pectoris, heart failure, cardiovascular diseases such as thrombosis, epilepsy, Spastic paralysis, frequent urination, dementia, Alzheimer's disease, schizophrenia, Huntington's chorea, Useful for the treatment or prevention of carcinoid syndrome, etc., and as an immunosuppressant It is expected that it will be useful.

For therapeutic purposes, compound (I) of the invention and its pharmaceutically acceptable salts are solid or liquid organic or is a pharmaceutically acceptable excipient such as an inorganic excipient; It can be used in the form of pharmaceutical preparations containing it as an ingredient. The pharmaceutical formulation includes capsules, Tablets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants solid, semi-solid or liquid, such as eye drops, solutions, syrups, suspensions, and emulsions. That's fine. These formulations may optionally contain auxiliary substances, adjuvants, stabilizers, wetting agents or Alternatively, emulsifiers, buffers, and other commonly used additives may be added.

The dose of compound (I) varies depending on the age and condition of the patient, but As about 0.　1mg, 1mg, 10mg, 50mg, 100mg, 250mg ．． If the average dose is 500mg and 1000mg, it can be used to treat symptoms such as asthma. may be effective in treating cancer-mediated diseases. Generally, O.D. per day.　1mg/individual～ Amounts between about 1000 mg/individual can be administered.

In order to illustrate the usefulness of target compound (I), compounds representative of compound (I) are shown below. Pharmacological test data are shown below.

(1) 'H-Substance P receptor binding (a) Crude lung membrane specimen Male Bartley guinea pigs are killed by decapitation. Remove the bronchi and lungs and add buffer (0.25M sucrose, 50mM) Lis-○CI pH7.5, 0. 1 Homogenize in mM EDTA) using a Polytron (Kinematica).

The homogenate was centrifuged (100OXg, 10 min) to remove tissue clumps and The clear liquid is centrifuged (14000×g, 20 minutes) to obtain pellets. Beret Resuspend the sample in buffer solution (5 InM Tris-1 (CL pH 7.5) and transfer to Teflon fluoride. Homogenize using a modgenizer and centrifuge (14000 x g, 20 minutes) ) and get the beret. This is called the crude membrane fraction. The resulting beret is used Store at -70°C until time.

(b) Binding of 1H-Substance P to specimen membrane Thaw the frozen crude membrane fraction and add medium 1 (50mM) Lis-)IC1. pl (7.5, 5mM MnCl g, 0. 02% BSA, 2μg/ml Chymostatin, 4μg/ml Leubeptin, Hakuμ Resuspend in citrazine (g/ml). In medium 1, 'H-substance P( 1HM) with a 100 μm membrane specimen to a final volume of 500 μm at 4°C. and incubate for 30 minutes. At the end of the incubation time, mix the reaction. Filter the product through a Whatman GF/B glass filter (0.1% polyethylene filter 3 hours before use). Quickly aspirate the sample through a vacuum (pretreatment with Nimin). Next, add the r solution to the buffer solution (50m M Tris-HCL pH 7.5) Wash 4 times with 5+nl. paracard scintillation Aquasol using a solution counter (Packart Dry Curve 4530) Measure the radioactivity in -2 (5 ml).

Test results IC++=1.37nM (2) Effect bar of oral administration on substance P-induced bronchial edema in guinea pigs ~ Kurin (2001U/ Evans blue solution containing substance P (10 nanomol/kg) The solution (20 mg/kg) is injected intravenously. Thirty minutes before this injection, the test compound ( 10 mg/kg) dissolved in dimethyl sulfoxide and administered orally. 10 minutes later The animal is exsanguinated and the lungs are perfused with ml of saline. Remove the trachea and bronchial frame , in 0.5 ml of INK011 solution at 37° C. for 6 hours. Acetone-phosphoric acid After extraction with 4.5 ml of salt solution (0.6 NaHtPO4'acetone = 5.13) , the Evans blue content of the tissue is determined colorimetrically at 620 nm.

Test results Inhibition rate (%) = 95.7 The following examples are included to provide a detailed illustration of the invention.

In these examples, in addition to the abbreviations adopted by IUPAc-108, the following The following abbreviations will be adopted.

Boc: t-butoxycarbonyl Bzl: benzyl E[:ethyl HOBT: N-hydroxybenzotriazole Me: Methyl 2Nal: (2-naphthyl)alanine WSCD: 1-ethyl-3-(3°-dimethylaminopropyl)carbodiimide de Preparation example I Boc-D-Met-OH (5,34g), HCl-H-2Na! -N (Me) Bz + (s, 3zg) and HOBT (3,16g) WSCD ( 4.27ml). Stir the solution at the same temperature for 2.5 hours and then at room temperature for an additional 2 hours. do. After concentration, the residue is extracted with ethyl acetate. Add the extract to sodium bicarbonate Washing with aqueous solution, water, 0.5N hydrochloric acid and saturated sodium salt aqueous solution, then Dry with magnesium sulfate. The resulting solution was concentrated under reduced pressure, and the residue was dissolved in acetic acid. Crystallized from tyl-diisopropyl ether, Boc-D-Met-2 Obtain NaI-N(Me)Bzl (9.06 g).

mr): 126.0-127.0℃ IR (Medi3-L) + 3330.　 1710.　1635. 1515 cm-'NMR (DMSO-d,, δ) : 1.347 (9H, s); 1.45-1.70 (21℃m); 1.85 9.1.902 (3H.

s); 2.10-2.35 (2H, m); 2.803.2.912 (3 H, s), 2.90-3.25 (2H, m) i3.90-4.15 (1) 1. m); 4.379 (J=15.11Hz), 4.515 (J=18 ．． 40Hz), 4.600 (J=15.38Hz), 4.7260=16. 62) 1z) (2H, d); 4.95-5.25 (IH, m); 6.8 30 (J=14.62tlz), 6.887 (J=8.20Hz) (IH , d); 6.95-7.90 (12) 1. m); 8.383 (J’8.31 1(z), 8.496 (J=8.50Hz) (1N, d) l! l made ff1 2 In the same manner as in Preparation Example 1, the corresponding starting compound was converted to Boc-D-Met- By reacting with OH or Boc-Met-OH, the following compounds get.

mp: 121.0℃ NMR (DMSO-d,, δ): 1.365 (9H, s); 1.50- 1.78 (2H, m); 1.989 (3H, s); 2.15-2.35 (2H, m); 2.792 and 2.896 (3tLs); 2.75-3 ．． 1 (2H, m) i3.95-4.1 (IH, m); 4.4-4.7 ( 21, m); 4.85-5.1 (IH, m)i 6. &3 and 6.89 (1)1. d, J=8.38Hz) i 7.0-7.2 (10H, m) i 8 ．． 32 and 8.42 (IH, d.

J’8.61.8.33Hz) NMR (DMSO-d,, δ): 1.3B (9t(,s); 1.6-1. 8 (21 (, m); 2.3-2.4 (2H, m); Q.73 and 2.80 (3t1.s); 2.8-3.1 (2H, m); 3.8- 4.1 (river, m); 4.3-4.5 (2I (.

m); 4.9-5.1 (IH, m); 6.9-7.35 (11H, m); 8.1-8.25 (IH, +n) IR: 3350. 1 682.　1659.　1641. 1519 cm-'NMR (DMSO-d ,,δ): 1.359 (9H, s), 1.45-1.80 (21℃m ); 1.96.1.98 (3H, sword j; 2.00-2.35 (2H, m); 2.14.2.17 (6H, s)i 2.80-3. (X) (2H, m); 2.80.2.90 (3t(,s); 3.90-4.10 (III, m); 4.30-5.05 (31 (, m) ; 6.65-7.40 (9H, m); 8.270 = 8.321 (z), 8. 38 (J=8.36Hz) (IH, d) Preparation example 3 A solution of the product (4.0 g) prepared in Preparation Example 1 in ethyl acetate (45 ml) was added to a room temperature. Add methyl iodide (20 ml) while warm. The mixture is stirred at the same temperature for 15 hours.

The solid precipitated from the solution was collected in a sintered glass FA vessel, washed with ethyl acetate, and subjected to the next reaction. The compound (3.70 g) is obtained as an amorphous solid.

IR (CIICL)' 3440.3300.3000.2940.1710 ．． 1642.1492.1454 cm-'NMR (DMSO-d,, δ): 1.358 (9H, s), 1.50-1.85 (21-1, m), 2 ．． 729.2,763゜2.800.2.922 (9H,s)i 3.00- 3.20 (4t(, m), 4.00-4.15 (IH, m); 4.30- 4. V0 (21℃m), 5.00-5.25 (]H, m), 7.009 (lH, d, J=5.02Hz); 7.05-7.95 (12N.

m); 8.50-8.70 (kawa, +n): I! 4 Example 4 Analogously to Preparation Example 3, the corresponding starting compounds were reacted with methyl iodide. The following compound is obtained.

IR(z)i-ru): 3200. 1714.　1675. 1630c mS NMR (DMSO-da, δ): 1.375 (91-1, s); 1. 60-1.85 (2t (, m) gate 2.15-2.35 (2HCm); 2.75-2.95 (2t(, m); 2.795.2.895 (3) i, s); 2.866 (68, s); 3.95-4.15 (LH, m); 4.35 -4.7 (2H, m); 4.9-5.1 (IH, m); 7.07.7.1 1 (IH, d.

J=7.27Hz, J=7.27Hz); 7.20-7.38 (IOH, m ); 8.99.8.58 (IH, d, J = 8.66Hz.

J=8.66Hz) mp: 98-99℃ NMR (DMSO-d,, δ): 1.33 (9H, s); 1.9-2. 05 (21℃m); 2.76 (2H, d, J-12H 噤j; 2.83 (6H, s); 3.2-3.3 (2tLm); 3.3-4.2 ( 1)1. m) i 4.4-4.6 (2H, m); 4.9-5.0 (1■, m ) i 7.0-7.4 (10) 1. m), 8.35 (IH, d, J=81 (z) NMR (DMSO-d,, δ): 1.38 (9H, s); 1.5 5-2.35 (2H, m); 2.12.2.17.2.18 (6H, s); 2.60-3.30 (13H, m); 3.90-4.20 (IH, m) ; 4.30-4.75 (2H, +n) 4.75-5.10 (IH, m) ; 6.70-7.40 (9) 1. +n); 8.20-8.60 (IH, m ) Preparation example 5 A solution of the product obtained in Preparation Example 3 (1.5 g) in tetrahydrofuran (3) was added with water. Under cooling and under nitrogen atmosphere, 60% sodium hydride (173.5 μm) is added. Mixed The mixture is stirred at the same temperature for 45 minutes. Add acetic acid (0.39 ml) to this. Mixed After stirring the mixture for a minute, water (25 ml) was added to it at the same temperature. After concentration, The residue is extracted with ethyl acetate. Add the extract to water, sodium bicarbonate aqueous solution, water, Wash sequentially with 0.5N hydrochloric acid and saturated sodium chloride solution, and then with magnesium sulfate. dry. The solution was concentrated under reduced pressure and the residue was dissolved in diethyl ether-diisopropyl Crystallization from ether gives the following compound (0.78 g).

mp: 140.5 143.5℃ IRCl v-4): 3303. 1722.　1680. 1650c rn-'NMR (DMSO-d,, δ): 1.362.1.378 (9H ,s); 1.65-1.95.2.15-2.30 (2H, m)G 2.732.2.792 (3H, s); 3.15-3.60 (4H, m)i 3.90-4.10 (1) 1. m); 4.10-4.40.4.60-4. 80 (2H, m); 5.203.5.362 (IH, ddJ=8.08) 1z.

Analogously to Preparation Example 5, the corresponding starting compounds are reacted with sodium hydride. The following compound is obtained.

IR(Ct(CI+)' 3340.2990.2950.1695.164 5.1495 cm-'NMR (DMSO-d,, δ): 1.371 (9 H, s), 1.65-1.80.2.15-2.35 (21(, m); 2. 65-2.95 (2) 1. m) i 2.772 (3) 1. s); 3.15 -3.30.3.40-3.55 (2H, m) i4, 00-4.20 (IH , m); 4.25-4.40.4.55-4.75 (21(, m); 5.0 0-5.25 (IH, m); 6.80-6.90 (LH, I++); 6. 90-7.40 (10H, m)IR(z)3-ru): 3440. 172 0.　1690. 1655 cm-'NMR (DMSO-d*, δ): 1 ．． 7-1.9 (IH, m); 2.15-2.3 (IH, m); 2.77 , 2.87 (38, s); 2.8-3.0 (ill, m); 3.1-3.4 (2)1. m) i 3.8-4.0 (IH, m) i 4.92 (s), 4 ．． 23.4.83 (ABq, J=16.9Hz) (2) 1) i 5.1-5 ．． 3 (IH, m); 6.3-7.4 (10H, m) m+): 117-119℃ IR(J)t-ru): 3260.　1700.　1665. 1610c mS NMR (DMSO-d,, δ): 1.38 (914, s); 1.20 -1.90 (2) 1. m); 2.13.2.19 (61-P, 5)i 2.73.2.79 (3H, s); 2.60-3.55 (4H, m); 3.80-4.80 (3H, ori; 4.95-5.25 (II-1, m); 6.60-7.35 (9H, m) Preparation Example 7 To a solution of the product (4.27 g) prepared in Preparation Example 5 in dichloromethane (2 to 1), Add 4N hydrogen chloride dioxane solution (40 ml) while cooling with water. solution at the same temperature Stir for 10 minutes and further stir for 50 minutes at room temperature. After concentration, add ether to the residue. The resulting precipitate was collected and dried to form the following compound (3.67 g) into an amorphous solid. Get it as a body.

IR (CHCl, ): 3430.2930.1690.1640 cm-' NMR (DMSO-d,, δ): 1.80-2.15.2.30-2.55 (2H,m)i 2.747.2.803 (3H,S)G 2.95-3.85 (4H, m); 3.95-4.75 (3H, m); 5 ．． 250.5.410 (IH, dd, J’6.20t (zB 8.82Hz) i 6.75-8.00 (12H, m); 8.621 (31 1, s) Shuken Eumudan Analogously to Preparation Example 7, the corresponding starting compound was reacted with a solution of hydrogen chloride in dioxane. By doing so, the following compound is obtained.

IRCxno-h): 3400.　1693. 1640cm-'NMR (DMSO-d,, δ): 1.8-2.0.2.3-2.55 (2H, m ); 2.7-3.0 (2H, m); 2.780X (3H, S); 3.2-3.4 (211, m); 3.5-3.8 (2H, m); 4.0-4.1 (IH, tj=8Hz); 4.2-4.8 (28, m); 5.0-5.3 (1) 1. +n); 6.8-7.4 (10) 1. m ); 8.6476 (2H, sj NMR (DMSO-d,, δ): 1.9-2.2 (IH, m); 2.35 -2.5 (II (, m); 2.88 and 2.93 (3i1.s); 2.8 -3.25 (2H, m)i 3.35-3.6 (2H, m); 3.78 ( II (, q, J = 8.7 Hz); 6.9-7.4 (lit (, m); 8.71 (3H,5)IR(CHCI=): 3450.2940.1694.16 45 cm-'NMR (DMSO-d,, δ): 2.14.2.18.2. 20 (6H, s); 1.80-2.50 (2) 1. m); 2.75K 2.80 (3H, S); 2.55-3.45 (2) 1. +n); 3.10 -3.70 (21 (, m); 3.70-4.15 (Ig, m); 4, 15-4.75 (2H, m); 5.00-5.25 (IH, m); 6 ．． 75-7.30 (8H, m); 8.59 (3H, brs) Preparation example 9 Methyl indole-3-carboxylate (zsg) and 2-(N,N-dimethylachloride) dimethylformamide (500+1) with mino)ethyl hydrochloride (20,56 g) 11) Add sodium hydride (60% dispersion in oil) (n, +zg) to the solution under water cooling. ) was added in three parts (5 g, 4 g and 2.42 g) between the blades.

The reaction mixture is stirred at 100'C''M for 5 hours. After cooling, it is added with water (200ml). and concentrate the mixture. The residue was diluted with IN hydrochloric acid to pH 1 and washed with ether. cormorant. The aqueous layer was neutralized to pH 7 with a 24% aqueous sodium hydroxide solution, and dichloromethane was added. Extract twice. Wash the extract with aqueous sodium chloride solution and dry with magnesium sulfate. dry The resulting solution was concentrated to give 1-[2-(N,N-dimethylamino)ethyl Methyl tircoindole-3-carboxylate (34.22 g) was obtained as an oil. Ru.

IR (=-t): 3130.3060.2950.2B30.2780.171 0-1690.1618cta-'NMR (DMSO-dl, δ): 2.1 7 (6H, s); 2.62 (2H, t, M, 25Hz); 3.81 ( 3H, s); 4.33 (2H, L, d, J'6.25Hz); 7.15-7. 30.7.50-7.65.7.95-8.05 (4H, m) i8.15 ( 1B, s) Preparation example 10 In the same manner as in Preparation Example 9, methyl indole-3-carboxylate was converted to 3-(N.

By reacting with N-dimethylamino)propyl, 1-[3-(N,N -Methyl-dimethylamino)propylcoindole-3-carboxylate is prepared.

IR (knee 1): 1720-1690.1620, 1540.1470, 140 0.1385cm-'NMR (DMSO-d,, δ): 1.8-2.0 ( 2H, m); 2.1-2.2 (8) 1. m); 3.81 (3) 1. s) ;@4.27 (211, t, J=6.9tlz); 7.15-7.3 (2tLm); 7.5 5-7.6 (111, m); 7.95-8.0 (]11Dmi 8, 13 (IH, s) Preparation Example 1I In the same manner as in Fl Preparation Example 9, benzyl indole-3-carboxylate was added to methane sulfonate. By reacting with 2-(tert-butoxycarbonylamino)ethyl 1-[2-(tert-butoxycarbonylamino)ethylcoindole-3-cal Prepare benzyl bonate.

mp: 104-107℃ IR (Nunol): 3360. 1710. 1685cm-'NMR (CDCL+, δ): 1.41 (9H, s); 3.49 (21Ldt, J=6.04.5.94Hz); 4.20-4.4O (2H, m); 5°37 (2H, s); 7.10-7.50 (9H, m); 8.15-8.25 (IH, m); 7.82 (], H, s) ! ” Reiroku 1-[2-(N,N-dimethylamino)ethylcoindole-3-carboxylic acid Methyl (34.13g) and IN sodium hydroxide (277ml) in methanol Heat the warm mixture under reflux for 4 hours. After cooling to room temperature, mix Acidify the compound to 5 IN HCl. Concentrate this mixture to a volume of 200+ ol Then, adjust the temperature to 5 again with IN hydrochloric acid. Add seed crystals and leave the mixture under cooling . The precipitate was collected and 1-[2-(N,N-dimethylamino)ethylcoindole -3-Carboxylic hydrochloride (20.46 g) is obtained as crystals.

IR (Xi7g-ru): 2600.　2520.　2490.　1692. 　1614. 1538 c+a-'NMR (DMSO-d,, δ): 2. 79 (6H, s) i 3.50 (2H, t, J=7.22Hz); 4.7 4 (2H, t.

J=7.201(z); 7.15-7.40.7.65-7.80.7.95- 8.10 (48, m); 8.18 (LH, s); 11.18 (IN, b rs); 12.12 (1) 1. br　s) Preparation example 13 In the same manner as in Preparation Example 12, the corresponding methyl ester compound was hydrolyzed. From 1. -(3-(N,N-dimethylamino)propylcoindole-3- Prepare carboxylic acid.

IR (Nuno*-4): 3400.　1690.　1585. 1575.　 1530. 1410. 1310. 1225 on-’NMR (DMSO- d,, δ): 1.8-2.05 (4H, m); 2.1-2.3 (6H , m); 4.27 (21(, t.

J=6.8H2); 5.45 (IH, br s); 7.1-7.3 (2H , m); 7.5-7.6 (IH, m) i 7.15-8.05 (2H, m) Preparation example 14 1-[2-(tert-butoxycarbonylamino)ethylcoindole-3-ka Benzyl rubonate (3.70 g), ethanol (70 ml), tetrahydrofuric acid Dissolve in a mixed solvent consisting of lan (20 ml) and acetic acid (5 liters). 10% Using palladium charcoal (0.50 g), the solution was immersed in hydrogen (IJ) under atmospheric pressure for 5 hours. Ru. After removing the catalyst and evaporating the solvent, ether is added to the crystalline residue.

This product in the same solvent.

Wash with water, remove and dry to give 1-[2-(tert-butoxycarbonylamino) Ethylcoindole-3-carboxylic acid (2.43 g) is obtained.

mp: 170 177℃ IR(1')y-ru): 3430.　2545-2520. 16&8.　 1652. 1540 cm-'NMR (DMSO-d,, δ): 1.04 ．． 1.31 (9H, s); 3.15-3.50 (21 (, m); 4.10 -4.45 (2H, m); 6.80-8.10 (6t (, m); 11.88 (IH,br　s)! Kidney A piece The product obtained in Preparation Example 1 is dissolved in methyl iodide (300 ml). Bring the solution to room temperature Stir for 4 hours. Next, add ether (60011) to this mixture, and the resulting The mixture was stirred for 15 minutes and left at room temperature for 3 hours and 45 minutes. Methyl iodide in the mixture (150 ml) and ether (240 ml) were added and the mixture was stirred for another 15 hours. Leave at room temperature. The mixture is then concentrated using a rotary evaporator and The residue was dissolved in tetrahydrofuran (300 ml) and dimethylformamide ( ], 0.0 Dissolve in a mixed solvent consisting of 00ml. solution under water cooling and nitrogen atmosphere. 60% sodium hydride (8.73 g) is added in portions over 20 minutes. reaction After stirring the mixture at this temperature for 1 hour, acetic acid (19.6 ml) was added to the mixture. Add. After stirring the mixture for 30 minutes, water (100 ml) was added to it while cooling with water. Ru. After concentration, the residue is extracted with ethyl acetate. Remove the organic layer from water and sodium bicarbonate. Wash sequentially with an aqueous solution of water, water, 0.5N hydrochloric acid and saturated saline, and then wash with magnesium sulfate. Dry and concentrate under reduced pressure. The crystalline residue was dissolved in (a)% methanol (250 ml). The following compound (51.32 g) is obtained by recrystallization from .

mp: 150-157℃ IR(J)3-ru): 1692. 1640 cm-'NMR (DMSO- d,, δ): 1.29.1.32 (9H, s); 1.69.1.73. 1.84.1.98 (3H, s); 1.50-2.30 (2H, m); 2 ．． 83.2.87 (3H, s) i 3.05-3.70 (4H, m); 3 ．． 95-4.80 (31Lm) i 5.20-5.50 (IH, +o); 6 ．． 95-7.95 (12) 1. m) Preparation example 16 In the same manner as in Preparation Example 7, the product prepared in Preparation Example 15 was added to 4N hydrogen chloride in ethyl acetate. By reacting with the solution, the following compound is obtained.

IR: 2650. 1679. 1643 cm-'NMR ( DMSO-d,, δ): 2.15.2.27 (3H, s); 1.80- 2.45 (2H, w); 2.79.2. &3(3H,s); 3.0O-3 , 80 (4H, m); 4.05-4.75 (31 (, +++); 5.20 -5.50 (IH, m); 6.80-8.00 (12) 1. m); 9.4 4 (2H, brs) Large nose fall 1-Methylindole-3-carboxylic acid (1 portion ■), prepared from W4 in Preparation Example 7 (470mg) and HOBT (150+ng) in dichloromethane (1kg) ), and WSCD (0.20 ml) is added to this while cooling with water. blend was stirred for an audience at the same temperature and for 17 g at room temperature. During this time, add 2 ml of triethylamine. Add portions (0.04 ml and 0.03 ml) to the mixture. In the solution N,N-dimethyl-1,3-propanediamine was divided into three parts (0,022 ml. 0.03ml and 0.05ml) in 3 hours. After concentration, the residue was diluted with acetic acid. Extract with chill. The organic layer was treated with aqueous sodium hydrogen carbonate solution, water, 0.5N hydrochloric acid and and saturated saline, and dried over magnesium sulfate. Concentrate the solution under reduced pressure. , add diisopropyl ether to the residue. The precipitate was collected and washed with the same solvent. After drying, the following compound (0.34 g) is obtained as an amorphous solid.

IR (1 sol 1-l): 3330.　1693. 1640 cra-'NM R (DMSO-d,, δ): L80-2.00.2.20-2.40 (2H , m) i 2.75B, 2. &31 (3Ls)? 2.90-3.75 (4 H, l)i 3.819.3.831 (38,s); 4.15-4.80 (3H,m)i 5.20-5. T0 (1)1. m); 6.75-8.15 (18H, m) Example 2 In the same manner as in Example 1, the following compound is obtained.

IR(CHCIm)' 3300.3003.1690.1655.1640 ．． ], 596.1562.1510 cm-'NMR (DMSO-d,, δ) : 2.00-2.50 (2H, II+); 2.757.2.815 ( 3H,S); 2.90-3D80 (4H, m); 4.10-4.80 (3H, m); 5.251.5.42 1 (1N, dd); 6.70-8.00 (181 (, incense j IR: 3280.　1640. 1538cm-'NMR (DMSo-ds, δ): 1.75-2.25 (2H, m); 2.14 ．． 2.20 (6H, s); 2.25-2.90 (2H, m); 2.76, 2.82 (3H, s) i 3.20-3.65 (2H, m); 3.82.3 ．． 83 (3H, s); 4.20-4.80 (3H, m); 5.05-5. 30 (IH, o+)i 6.80-7.30.7.40-7.55°7, 90 -8.20 (14H, m) MASS (M”): 536 NMR (DMSO-d,, δ): 1.80-2.45 (2H, m); 2 ．． 18.2.19 (6H, s) i 2.55-2.65 (2H, m); 2. 76-2.83 (3H, s); 2.90-3.75 (4H, m); 4. 15-4.80 (5H, m) i5.20-5.50 (1) 1. m); 6. 70-8.20 (18N, m) MASS (M’): 615 IR(1')v-k): 3330. 1695. 1645. 1539 cm-'NMR (DMSO-d,, δ): 1.14.1.33 (9H, S ); 1.70-2.45 (2i(,m); 2.76, 2.81K 2.83 (31L s); 2.90-3.80 (6H, m); 4.10 -4.80 (5H, m); 5.15-5.50 (1! (Am); 6.70-8.20 (19H, m) MASS (M”): 687 IR (CHCIs)’ 3330.1695.1645.1, 545.147 f) -1450,1280cm-'NMR (DMSO-d,, δ): 1.8 -2.0 (5) 1. m); 2.1-2.5 (7) 1. m); 2.76, 2, &3 (3H.

s); 2.8-3.15 (2Lm); 3.25-3.75 (2t1.m) ; 4.15-4.8 (5N, m); 5.2-5.5 (111, m)', 6. 75-8.15 (1811m) MASS (M”) + 629 Knocking down Yu The product prepared in Preparation Example 8-(1) (0.63 g) and bis(trimethylsilyl) ) in a solution of acetamide (o, 99 g) in dichloromethane (20 ml) , Indole-3-carbonyl chloride (0.35 g) was added to the mixture under water cooling. Stir at the same temperature.

The reaction mixture is concentrated and the concentrate is dissolved in tetrahydrofuran (2). child IN hydrochloric acid (2 ml) was added to the solution under water cooling, and the mixture was stirred for the duration of addition.

Concentrate the reaction mixture, extract the concentrate with ethyl acetate, and dilute the extract with sodium bicarbonate. Wash with magnesium aqueous solution and saline and dry with magnesium sulfate. Solution under reduced pressure Evaporate and chromatograph the residue (0.8 g) on silica gel (30 g). attach Elution was performed using chloroform, then chloroform-methanol (99:1 to 9). 8: Perform 2). Fractions containing the desired compound were combined and evaporated under reduced pressure to leave a residue (5 60 mg) was powdered using an ethyl acetate-diisopropyl ether mixture. , to obtain the following compound (440 mg).

IR (77*-ru): 3250.　1674.　1623. 15B2.　 1554. 1492 am-'NMR (DMSO-d,, δ): 1.8- 2.0.2.2-2.5 (2)1. m) i 2.75B, 2.806 (3 )1. s); 2.7-3.0 (2t(, m); 3.3-3.7 (2H, m ); 4.2-4.6 (IH, m); 4.6-4.8 (2H, m); 5, 1 -5.4 (IH, m); 6.8-7.3 (2H, m) (10) 1. m) ;7.4-7.5 (IH, s); 8.0-8.2 (2H, m) (IH, s ); 11.5776 (IH, s) Ohe Toppou Analogously to Example 3, the corresponding starting compound was converted to indole-3-carbonyl chloride. Alternatively, the following compound is obtained by reacting with cinnamoyl chloride.

IR(7)1-ru): 3220.　1685.　1640.　1630.　 1535 cm-'NMR (DMSO-d,, δ): 1.85-2.1 ( IH, m) i 2.3-2.4 (IH, m) i 2.81.2.93 (3) P. s); 2.9-3.2 (2tl, m); 3.4-3.6 (2H, m); 4.4 (IH, m); 4.43.4.63 (ABq.

J=14.9Hz) i 4.35.4.93 (J-16,9Hz); 5.1 9.5.32 (IH, t); 6.95-7.5 (13H, m); 8.0- 8.2 (3N, m); 11.57 (IH, 5)IR(O(C1i)' 3300.3175.1692.1655.1546 crn-'NMR (DM SO-d,, δ): 1.60-2.40 (2H, m)i 2.831.2 ．． 767 (3H, S); 2.95-3.7O (4H, m); 4.15-4.80 (3H, m); 5.262.5.417 (LH, d, d, J=7.0Hz, 8.2Hz) i6, 50-8.00 (2 0)1. m) IR (nunoy-4): 3200.　1615.　1525　 crn-'NMR (DMSO-d, δ): 1.75-2.45 (2H, m); 2.76, 2. &3 (3H, s); 2.90-3.75 (4H, m) i 4.15-4.80 (3H, m); 5.20-5.50 (IH, m) ; 6.75-8.20 (18H, m); 11.57 (IH, s) Big nose The product obtained in Example 2-(3) (0.32 g) was dissolved in ethyl acetate (10 ml). A 4N hydrogen chloride ethyl acetate solution (0.19 ml) is added to the solution while cooling with water. anti Stir the reaction mixture for 5 minutes. After evaporating the solvent, ether was added to the residue, The resulting precipitate was collected and dried to obtain the following compound (0.34 g) as an amorphous solid. get it.

IR (Nuk1-ru): 3300-3450. 1644. 1547 cm -'NMR (DMSO-d,, δ): 1.80-2.55 (2H, m); 2.76, 2.83 (9) 1. s); 2.90-3.80 (6H, m)i 4.15-4.80 (5tlm); 5.20-5.50 (IH, a+) ; 6.70-8.30 (18H, m); 10.85 (IH, br s) Great Retrospective Day In the same manner as in Example 5, the following compound is obtained.

IR(CHClm)' 1,695.1645.1545.1465.140 0.1280 cm-'NMR (DMSO-d,, δ) + 1.85-2.0 5 (IH, m); 2.1-2.45 (3H, m); 2.6-2.8 (6 H, incense ji 2.83 (3H, s); 2.95-3.2 (4H, m); 3.3-3.7 5 (21 (, m) i 4.L5-4.75 (51 (, mji 5.2-5.5 (1.m/month): 6.95-8.2 (18ftm); 10.6 5 (LH, brs) i harm retroactively The product obtained in Example 4-(3) (1,19 g) and acrylonitrile (0,5 Triton B (4 g) was added to a solution of dioxane (25 IIll) with 0% methanol solution) (0, 1, 1 ml) was added dropwise. The solution was kept at the same temperature for 20 minutes. The mixture was stirred for 2 hours, and further stirred at room temperature for 2 hours.

Add chloroform to this mixture to dissolve the precipitate. Add water to this solution, Separate 11 aircraft layers. Extract the aqueous layer twice with chloroform. The organic layer is erupted and sulfur is removed. Dry with magnesium acid and concentrate in a vacuum sieve. Pour the concentrate into silica gel (40g). Lamb chromatography was performed using a chloroform-methanol mixed solvent (0% or 526). Remove the solvent and remove any remaining residue. Purify by medium pressure silica gel column chromatography. Ethyl-1-yl acetate Ene mixed solvent (2:l and 4:]), ethyl acetate alone and ethyl acetate-meth Elute sequentially with a mixed solvent of alcohol (5! l'fi). Concentrate the fraction containing the desired compound. The following compound (0.56 g) was obtained as an amorphous solid.

IR(CDCl2)' 3440.3000.1695.1650.1547 cm-'NMR (DMSO-d,, δ): 1.80-2.10. 2. 25-2.45 (21 (, m) Bodhisattva 2.76, 2.83 (3H, sword j; 3.00-3.15 (2Lm) i 2.90-3.75 (4H, m) i 4 ．． 15-4.80 (5H, m)i 5.20-5.50 (IH, m); 6.7 0-8.25 (18H, m) FAB-MASS (M+], )”: 598 ．． 3 Great Tragedy The product obtained in Example 7 was added to a saturated hydrogen chloride ethanol solution (25 ml) under water cooling. (0.45g) is added. The solution is stirred at the same temperature for 1.5 hours. Remains after concentration Dissolve the material in absolute ethanol (10 ml). Add 4N ammonia to the solution under water cooling. Add near ethanol solution (s7ml). Stir the mixture at room temperature for 2.5 hours. . After concentration, ether was added to the residue, the resulting precipitate was collected and dried, and the following compound was prepared. (0130 g) is obtained as an amorphous solid.

IR (7sol): 3260.　1700-1660. 1545 cr m-'NMR (DMSO-d,, δ): 1.85-2.05.2.25-2 ．． 45 (2H, m); 2.76, 2.83 (3H, 5) i2.90-3. 05 (2H, m); 3.05-3.80 (4H, m); 4.15-4. 80 (5H, m); 5.20-5.50 (1) 1. m); 6.75-8. 30 (181-1, m) i 8.69.9.25 (4H, br s) Past biography And Solution of the product obtained in Example 2-(4) (3.96 g) in ethyl acetate (40 ml) Then, under ice-cooling, add anisole (4.0 ml) and 4N hydrogen chloride ethyl acetate solution. (40111>) was added sequentially. The solution was heated at the same temperature for 15 minutes, then at room temperature for 2 hours. Stir. After concentration, ether was added to the residue, the resulting precipitate was collected and dried, The following compound (3.04 g) is obtained as an amorphous solid.

IR (7), -k): 35 (X) 3100 (br), 1630. 153 0 cm-'NMR (DMSo-ds, δ): 1.80-2.25 (2) 1. +++); 2.76, 2.81.2.83 (3H, s); 2. X0− 3.80 (611, m) i 4.10-4.80 (5) 1. m); 5.2 0-5.50 (IH, a+); 6.75-8.40 (21) 1. m) big nose The product obtained in Example 9 (0.50 g) and 3,5-dimethylpyrazole-1-ka dimethylformamide (15 ml) with ruboxiamidine nitrate (0.32 g) ) Add triethylamine (0.22ml) to the solution at room temperature, and leave the solution at the same temperature. Stir for 7 hours at 30°C. Add 3,5-dimethylpyrazole-1-carboxylate to the solution. Add midine nitrate (0.32 g) and triethylamine (0.44 ml). After addition, the mixture is stirred at the same temperature for 5 days. After concentration, water was added to the residue and I Adjust the temperature to 4 with N-hydrochloric acid. After extracting the aqueous layer with ethyl acetate, the extract was extracted under reduced pressure. Concentrate into. The residue is purified by an alumina (20 g) column. Chloroform - Elute sequentially with methanol mixed solvent (10:1, then 1:1). evaporation residue Add ether to the solution, collect the resulting precipitate, dry it, and prepare the following compound (0.32 g). ) is obtained as an amorphous solid.

IR (Nuk1-ru): 3300.　3150.　1620. 1530c ln-'NMR (DMSO-d,, δ): 1.80-2.45 (2) 1. l11); 2.76, 2. &3 (31-1,s);2.90-3D75 (6tLm); 4.15-4.80 (5H, m)i 5.20-5.50 (IH, m); 6.75-8.20 (22) 1. m) FAB-MASS ( M÷1)”: 630.3 A fell down Triethyl was added to the ethanol solution of the product obtained in Example 9 (624 mg) under water cooling. Add Ruamine (6 ml). After stirring for 20 minutes, the resulting solution was mixed with carbonimide. Dodithioic acid cyanodimethyl ester [(MeS), C=N-CN] (324m g) in ethanol (6 ml) at room temperature. Stir the solution at the same temperature for 1 day. Stir. After concentration, the residue is extracted with ethyl acetate. The extract was diluted with 0.5N hydrochloric acid and and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Residue The distillate is purified by column chromatography on silica gel (20 g). Taro Roform-methanol mixed solvent (gradient elution from methanol 0% to 2%) The following compound (0.58 g) is obtained as an amorphous solid.

IR(Ct(CI+)' 3300.3000.2180.1622.153 5 cm-'NMR (DMSO-d, δ): 1.85-2.45 (2N , m); 2.38.2.39 (3H, s); 2.76, 2.83 (3H, s); 2.90-3.75 (6H, +n); 4.15-4.80 (5H , +n); 5.20-5.50 (1) 1. m) i6.75-8.50 (19 H, m) FAB-MASS (M+1)”: 686.3 Example 12 A solution of the product obtained in Example 11 (0.55 g) in methanol (5 ml) was added at room temperature. Then, add 40% methylamine methanol solution (10 ml). solution at the same temperature Stir for 21 hours. After concentration, the residue is extracted with ethyl acetate. Add saturated salt to the extract Wash with water, dry over magnesium sulfate and concentrate under reduced pressure. Silica gel residue (20 g) Purify by column chromatography. Chloroform-methano Elute with a mixed solvent (gradient elution from 0% methanol to 1.5% methanol).

The solvent is removed from both parts and diisopropyl ether is added to the residue. occured The precipitate was collected, washed with the same solvent, and dried to obtain the following compound (0.34 g). Obtained as a solid form.

IR(J)i-4) 2 3300.　2180. 16B0.　1640.　 1580. 1540 cm-'NMIII (DMSO-d,, δ): 1 ．． 75-2.45 (2H, m); 2.58.2.60 (3H, s); 2. 76, 2. &R (3H, s); 2.90-3.75 (6) 1. m); 4.10-4.80 (5H, m); 5.20-5.50 (IH, m); 6, 70-8.35 ( 20)1. m) FAB-MASS (M+1)”: 669.2X maximum Analogously to Example 1, the corresponding starting compounds were mixed with benzofuran-2-carboxylic acid. By reacting, the following compound is obtained.

IR (Nuk1-ru): 3250. 1645. 1595cm-'NMR (DMSO-d,, δ): 1.75-2.95 (4H, m); 2.14 ．． 2.20 (6H, s); 2.76, 2.81 (3H, s); 3.15-3 ゜70　(2!Lo+); 4.15-4.80　(3H, m); 5.00-5. 30 (LH, m); 6.70-7.85.8.85-9.10 (14H, m ) Daishu ki In the same manner as in Example 1, the following compound is obtained.

N&lR(D&lSO-dl, δ): 1.60-1.95.2.25-2. 50 (21 (, m) i 2.77, 2.83 (3) 1. sword j; 2.90-3.75 (4H, m); 4.15-4.80 (3N, m)i 5.20-5.50 (IH, i); 6.65-8.80 (19H, m) IR (Nunofukiru): 3300.　1685.　1640. 1562.　 1525 cra-'NMR (DMSO-d,, δ): 1.75-2.45 (2H, m); 2.74.2.81 (3H, s); 2.85-3.75 ( 4Lm) i 4.10-4.80 (38, m) i 5.20-5.50 (I La+); 6.09 (IH, m); 6.65-8. R5 (15)1. m); 11.49 (IH, 5) IR (CHCI*): 332 0.2940. 1645. 1540.755.700 cm-'NMR (D MSO-d,,δ)21.80-2.45(2H,m)i2.18.2. l9( 121-1, s), 2.55-2.65 (2H, m); 2.76, 2.82 (3H,s); 2.65-2.90.3.20-3.40 (2)1. m); 3.20-3.7O (2H, m); 4.20-4.80 (5) 1. m) i 5.05-5.35 (it(, m); 6.80-7.30.7.50-7.6O゜ 8.00-8.20 (1411, m) IR (Zuno v-4): 1690.　 1640.　1530. 740 cm-'NMR (DMSO-d,, δ) + 1.65-2.40 (5H, m) i 2.84.2.88 (3H, s); 3.10-3.40゜3.55-3.75 (4H, m); 3.78.3.80 (3H, s); 4.25-4.75.5.00-5.20 (3H, [11 )G 5.35-5.55 (ltl, m); 6.90-7.90 (178, m) NMR (DMSO-d,, δ) + 1.70-2.20 (2t1.m); 2 ．． 12.2.15 (9H, s); 2.50-2.65 i21° m); 2.84.2.88 (3H, s); 3.10-3.40 (4H, m ); 3.60-3.75 (1) 1. m); 4.15-4.35 (2H, m ); 4.35-4.70 (2H, m); 5.00-5.55 (1) 1, 111) Essay 6.90-7. X0 In the same manner as in Example 5, the following compound is obtained.

IR(1)*-4): 3430-3200.　1640. 1547. 8 10 ca+-'NMR (DMSO-d,, δ): 1.65-1.95.2 ．． 25-2.50 (211, m); 2.77, 2°83 (31 (, s); 2 , 90-3.75 (4H, m) 54.15-4.80 (3+1.m); 5.15-5.45 (IH, m)i 5.00-6. O0 (IH, br s); 6.75-9.05 (19H, m) IR (7 noyol ): 3400.　1640.　1540. 750 mark -1NMR (DMS O-d,, δ): 1.80-2.40 (2) 1. m);2.14.2.2 0 (61 (, s); 2.76, 2.82 (9H, s); 2.70-2.9 5.3.20-3.65 (6H, m); 4.20-4.80 (5H, m); 5.00-5.30 (1) 1. n+)i 6.80-7.40.7.80-7 ．． 75.8.10-8.30 (14H, m); 10.92 (1N, br sj IR (Nunol 1-R): 3400.　1692.　1643-1612. 1 535. 740 cffl-'NMR (DMSO-d, +D, 0.δ): 1.65-2.40 (5) 1. m) i 2.80.2.81 (6H, s); 2. &4-Q. 88 (3H,s)? 3.10-3.80 (7H, m); 4.25-4.75 ( 4 (, m); 5.00-5.55 (IH, m) i6.90-7.90 (1 7H, m) The old man's father A solution of the product prepared in Example 1 in methylene chloride (401111) was added to a solution of the product prepared in Example 1 with nitrogen at -ca. N,N-dimethylaniline (242 mg) was dissolved in methylene chloride (10 ml') solution and stir the solution for 15 minutes at the same temperature. Next, this reaction mixture Phosphorus pentachloride (416 mg) was added to the mixture while maintaining the temperature between -30°C and -30°C. and the solution was heated at -40°C for 1. Stir for an hour. Ethanol solution of ammonia in solution (lml) is added dropwise and the solution is stirred at the same temperature for 1 hour. Raise the temperature of the solution to room temperature The mixture is allowed to rise to temperature, saturated potassium carbonate solution is added and the mixture is extracted with methylene chloride. organic Dry the layers over magnesium sulfate and concentrate under reduced pressure. The residue is alumina (25g ) Purify by column chromatography. Taloloform-methanol (1 0:1) Elute with mixed i solvent to turn the following compound (0.33g) into an amorphous solid. get it.

IR (OICIm): 3370.3060.3020.2940.1640 ．． 1600.1543 cm-'NMR (DMSO-d,, δ): 1.75 -2.00.2.25-2.50 (21 (, m); 2.79.2.85 ( 3H, 5) i2.90-3.85 (4H, Ol); 3.78.3.79 ( 3H,s)i 4.00-4.85 (3H,m); 5.20-5.4T (IH, m)i 6.09 (1) 1. br　s)；　6.80-8.35　( 18H, a+) Forgotten nose■ The following compound is obtained in the same manner as in Example 16.

IR(CHCIm)' 3400.2950.16B0.1642.1540 cm-'NMR (DMSO-d,, δ): 1.70-2.20 (2) 1 ．． m) i 2.61.2.65 (3H, s)? 2.70.2.79 (3H, s) i 2.90-3.70 (4H, m); 3.76 (3) 1. s); 3.80-4.75 (3+l, m)i 5.15|5.40 (IH, m) 16.11 (IH, br s); 6.70-7.95 (17 )1. m) Cold nose case The product prepared in Preparation Example 7 was mixed between chloroform and aqueous sodium bicarbonate solution. Partition, separate the organic layer, dry over magnesium sulfate, and concentrate under reduced pressure.

Dissolve the residue in a mixed solution of 1,4-dioxane (2 ml) and ethyl acetate (2 ml). Lend.

Add formalin solution (37%) (0.0 hl) to the solution under water cooling, and pour the solution into Stir for 1.5 hours at a temperature of . Next, at this temperature, add 1-methylindo to the mixture. A solution of diol (150 mg) in 1,4-dioxane (2 ml) is added. water mixture Stir for 15 minutes in the cold and then for 4 hours at room temperature. During this time, formalin solution (3 7%) (0,09m1) is added. Leave the solution in the refrigerator overnight and then leave it at room temperature. Warm and stir for 1.5 hours. Add water to the mixture to adjust the acidity of the mixture to sodium bicarbonate. The mixture was extracted with ethyl acetate. Saturate the organic layer with salt Wash with water, dry over magnesium sulfate and concentrate under reduced pressure. Silica gel residue (30 g) Purified by column chromatography. Chloroform-methanol Elute with a mixed solvent (gradient from 0% to 1%). Product (1somg) Dissolve in tetrahydrofuran (7.5 ml) and add 4N hydrogen chloride dioxane solution. (0.12ml) was added under water cooling. Stir the solution for 40 minutes at room temperature. After concentration , add diisopropyl ether to the residue, remove the resulting precipitate, dry it, and then The compound (0.14 g) is obtained as an amorphous solid.

IR(j)y-ru)'3450.　1697. 1646cm-'NMR (DMSO-d,, δ): 2.00-2.55 (2H, m), 2.78 2.2.844 (31-1,s), 2.80-3D90 (61+, +n), 3.792 (3 days, s), 4.00-4.80 (3 H, m), 5.25-5.55 (IH, m), 6.7T- 7.95 (17H, m), 9.40-9.70 (IH, br s) Freon continuation of tovage (51) Int, C1,' Identification symbol Internal office reference number C07D 207/3 4 8217-4C401/12 207 7602-4C403/12 20 7 7602-4C405/12 207 7602-4CC07K 5107 8 8318-4HI

Claims (1)

[Claims] 1. formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ Compounds of (I) or their pharmaceutically acceptable Urushio. In the formula, R1 is aryl, pyridyl, pyrrolyl, or formula ▲ mathematical formula, chemical formula There are tables, etc.▼ [Here, the solid line and dotted line represent single bonds or double bonds, and X is CH or is N and Z is -O-, -S- or -NH-], and their Each may have a suitable substituent, R1 is al-lower alkyl which may have a suitable substituent, and R■ is a suitable substituent. R4 is lower alkyl which may have a suitable substituent, and R4 is lower alkyl which may have a suitable substituent. R6 is hydrogen or lower alkyl, and R6 is hydrogen or lower alkyl. , A is a bond, lower alkylene or lower alkenylene, and Y is O or N- R7 (R7 is hydrogen or lower alkyl), m is 0 or 1, n is an integer from 0 to 2. 2. R1 is C6-C10 aryl, pyridyl, pyrrolyl or formula ▲ Numerical formula, chemical formula There are tables, etc.▼ [Here, Z is -N(R■)- or -O-, and R■ is hydrogen, lower alkyl , di-lower alkylamino lower alkyl, amino lower alkyl, acylamino lower Alkyl, cyano lower alkyl, amidino lower alkyl, guanidino lower alkyl , [2-lower alkyl-3-cyanoisothioureido] lower alkyl or [ 3-lower alkyl-2-cyanoguanidino] lower alkyl] group, R1 is C6-C10 alkyl lower alkyl, R■ is lower alkyl, R4 is C6-C10 alkyl lower alkyl, R6 is hydrogen or lower alkyl , A is a bond or lower alkenylene, and Y is O or N-R7 (R7 is hydrogen or lower alkyl), m is 0 to 1, n is an integer 1 A compound according to claim 1. 3. R1 is phenyl, biridyl, pyrrolyl or formula ▲ There are mathematical formulas, chemical formulas, tables, etc. Masu▼ [Here, Z is -N(R1)- or -O-, and RI is hydrogen, lower alkyl , di-lower alkylamino lower alkyl, amino lower alkyl, lower alkoxyca Rubonylamino lower alkyl, cyano lower alkyl, amidino lower alkyl, group Anidino lower alkyl, [2-lower alkyl-3-cyanoisothioureido] low or [3-lower alkyl-2-cyanoguanidino] lower alkyl is the basis of R■ is phenyl lower alkyl, mono- or di-lower alkylphenyl lower alkyl , naphthyl lower alkyl, R4 is phenyl lower alkyl Claim 2 Compound. 4. (1) Formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [Here, R■, R■, R4, R6 and n are each as defined above] or in its amino group The reactive derivatives or their salts have the formula R1-A-COOH(III) [wherein R1 and A are each as defined above] or a compound thereof By reacting with a reactive derivative at the carboxy group or a salt thereof, the formula ▲mathematical formula, There are chemical formulas, tables, etc. ▼ (I-a) [Here, R1, R2, R3, R4, R6 , A and n are each as defined above] or a salt thereof. Or, equation (2) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I-b) [Here, R2, R3, R4, R 6, A, X, Y, m and n are each as defined above] or its The salt of is subjected to cyano lower alkene addition reaction to form the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I-c) [Here, R2, R3, R4, R 6, A, X, Y, m and n are each as defined above, and R6 is cyano lower alkyl] or a salt thereof, or (3) Reacting compound (I-c) or a salt thereof with ammonia or a salt thereof, formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I-d) [Here, R■, R■, R4, R 6, A, X, Y, m and n are each as defined above, and R is the amidino lower alkyl] or its salts, or (4) Formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I-e) [Here, R■, R■, R4, R ■, A, X, Y, m, and n are each as defined above, and R■ is a protected amino-lower alkyl] or its salt, amino-protected at R■ For group elimination reactions, there are formulas ▲mathematical formulas, chemical formulas, tables, etc.▼(I-f) [Here , R2, R3, R4, R6, A, X, Y, m and n are each as defined above. and R■ is amino-lower alkyl] or its salts. , (5) Compound (I-f) or its salt has the formula L-R (IV) [Here, R is amidino or lower alkylthio(cyanoimino)methyl; and L is a leaving group], the formula ▲ has mathematical formulas, chemical formulas, tables, etc. ▼(I-g) [Here, R2, R3, R4, R6, A, X, Y, m and n are each as defined above and R5 is guanidino lower alkyl or [2-lower [lower alkyl] or will produce that salt, (6) Formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I-h) [Here, R2, R3, R4, R 6, A, X, Y, m and n are each as defined above, and R5 is [2-lower alkyl-3-cyanoisothioureido] lower alkyl] or The salt is reacted with a lower alkylamine to give the formula 6 ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I-i) [Here, R2, R3, R4, R 6, A, X, Y, m and n are each as defined above, and R5 is [3-lower alkyl-2-cyanoguanidino] lower alkyl] or a salt thereof or (7) compound (I-a) or a salt thereof with formula R7NH2(V) Reaction with a compound or a salt thereof [wherein R7 is hydrogen or lower alkyl] Let me, expression ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I-j) [Here, R1, R2, R3, R 4, R6, R7, A and n are each as defined above] or its or (8) the reactivity of compound (II) or its amino group. By subjecting the derivatives or their salts to the Mannich reaction, the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I-k) [Here, R1, R2, R3, R 4, R6 and n are each as defined above] or a salt thereof A method for producing compound (I) or a salt thereof, which comprises: 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable compound. A pharmaceutical composition comprising a substantially non-toxic carrier or excipient. 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof is administered to humans or animals. A method for treating or preventing a tachykinin-mediated disease, the method comprising: administering a tachykinin-mediated disease. 7. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof as a medicament . 8. a tachykinin antagonist of the compound of claim 1 or a pharmaceutically acceptable salt thereof; Use as. 9. The compound of claim 1 or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable compound. Preparation of pharmaceutical compositions characterized in that they are mixed with substantially non-toxic carriers or excipients. Manufacturing method.