JPH07503701A - 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] Peptides with tachykinin antagonistic activity Technical field The present invention relates to novel peptide compounds and pharmaceutically acceptable salts thereof.

More specifically, tachykinin antagonism, especially substance P antagonism, Novel pharmacological activities such as nin A antagonistic action and neurokinin agonist action. Peptide compounds, pharmaceutically acceptable salts thereof, methods for their production, and their use as medicaments.

One object of the present invention is to provide tachykinin antagonism, particularly substance P antagonism, Pharmacological activities such as neurokinin A antagonism, neurokinin antagonism, etc. Novel and effective peptide compounds having and pharmaceutically acceptable salts thereof Our goal is to provide the following.

Another object of the present invention is to provide a method for producing the peptide compounds and their salts. It is about providing.

Another object of the invention is to use the peptide compound as an active ingredient and as a medicament. An object of the present invention is to provide a pharmaceutical composition containing an acceptable salt thereof.

Yet another object of the present invention is to treat diseases such as asthma, bronchitis, rhinitis, cough, eczema, etc. Respiratory diseases, conjunctivitis, eye diseases such as vernal keratitis, contact dermatitis, atopic - Skin diseases such as dermatitis, measles, other eczematous dermatitis, and rheumatoid arthritis. inflammatory diseases such as osteoarthritis, pain (e.g. migraine, headache, toothache, cancer pain, back pain, etc.) and other tachykinins found in humans and animals. Tachykinin antagonists, especially substance antagonists, effective for the treatment and prevention of diseases , the above-mentioned peptide compound as a neurokinin antagonist, or a neurokinin antagonist and to provide pharmaceutically acceptable uses for its salts.

Disclosure of the invention The target compound of the present invention is represented by the following general formula (I).

formula: [In the formula, R1 is a lower alkyl group, an aryl group, an a(lower)alkyl group, an aryl Ruamino group, pyridyl group, pyrrolyl group, pyrazolopyridyl group, quinolyl group, and is the formula: (In the formula, l is a single bond or 2-type packing, X is CH or N1, and Z is O, S or or NH, meaning that these groups may have appropriate substituents. ); R2 is hydrogen or a lower alkyl group; Rs is hydrogen or an appropriate substituent.

R4 is a lower alkyl group which may have a suitable substituent, and R6 is a suitable substituent. Al (lower) alkyl group or pyridyl (lower) alkyl group that may have a substituent or R4 and R8 are bonded to each other to form a benzene-fused lower alkyl group. Forms a ren group; A is an amino acid residue that may have a suitable substituent; and Y is -, lower alkylene group, lower alkenylene group or lower alkylimino group Each means However, R1 is an aryl group or a formula.

[In the formula, X has the same meaning as before, and Z is 0 or N-R: <In the formula, R: is hydrogen or or lower alkyl group], R2 is hydrogen, R4 is a lower alkyl group which may have an appropriate substituent, and R11 has an appropriate substituent. an optionally alkyl group, A is of the formula: (In the formula, R7 means a hydroxy group or a lower alkoxy group), and Y is - or lower alkenylene group, R3 is a suitable substituent. ] According to the present invention, the novel peptide compound (1) can be produced by the method described in the reaction formula below. Therefore, it can be manufactured.

Manufacturing method 1 (II) Manufacturing method 2 (IV) its reactive derivative or its salt Manufacturing method 3 (1-a) or its salt Manufacturing method 4 in or its salt Manufacturing example 5 its reactive derivative or its salt (1-a) or its salt Manufacturing example 6 (1-e) or its salt (1-f) or its salt (1-g) or its salt Manufacturing example 7 or its salt Manufacturing method 8 [In the formula, R1, R1, R3, R4, R3, A, X and Y each have the same meaning as before. It's the taste, R; is a protected carboxy (lower) alkyl group, R2 is a carboxy (lower) alkyl group; alkyl group, R: is a protected carboxy(lower) alkyl group or a protected alkyl group; mino (lower) alkyl group, R = carboxy (lower) alkyl group or amino (lower) alkyl group, R: is a mino (lower) alkyl group, R: is a guanidino (lower) alkyl group, R8 is hydrogen or halogen, Al is an amino acid residue containing an amino group, a hydroxy group, and/or a carboxy group. basis, A2 is a protected amine group, a protected hydroxy group and/or a protected amino acid residues containing a carboxy group, A3 is an amino acid residue containing a sulfonyloxy group with a suitable substituent, A4 is , an amino acid residue containing an azide group, A5 is an amino acid residue containing an amino group, Ma is an amino acid residue containing an amino group, , meaning alkali metal).

Regarding raw material compounds (n), (III), (IV) and (V), their These types of products are new and cannot be applied to the production method described later, the operation method explained in the examples, or the conventional method. Therefore, it can be manufactured.

Throughout the specification of the present invention, amino acids, peptides, protecting groups, condensing agents, etc. IUPAC-IUB (Biochemical Nomenclature Committee) commonly used for minute hands It will be indicated by the abbreviation .

Additionally, unless otherwise specified, amino acids and their residues designated by these abbreviations are When a group is designated by such an abbreviation, compounds and residues in the L-configuration are designated as means.

Suitable pharmaceutically acceptable salts of the starting and target compounds can be prepared using conventional non-toxic salts. salts, including organic acid salts (e.g. acetates, trifluoroacetates, maleates, alcoholic acid salts) stone salt, methanesulfonate, benzenesulfonate, formate, toluenesulfonate salts), inorganic acid salts (e.g. hydrochlorides, hydrobromides, hydroiodides, sulfates) , nitrates, phosphates, etc.), or amino acids (e.g. arginine). , aspartic acid, glutamic acid, etc.), or alkali metal salts (e.g., sodium thorium salts, potassium salts, etc.) and alkaline earth metal salts (e.g. calcium salts, metal salts such as magnesium salts, ammonium salts; salts with organic bases (e.g. , trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicycline lohexylamine salt, N,N’-dibenzylethylenediamine salt, etc.) may be included.

In the foregoing and following descriptions of this specification, species included within the scope of this invention Preferred examples and explanations of each definition will be described in detail below.

Unless otherwise specified, "lower" means carbon atoms with 5 to 6 carbon atoms (preferably carbon atoms). 4 stones).

Suitable "lower alkyl groups" include methyl, ethyl, propyl, and isopropyl. , butyl, isobutyl, tert-butyl, pentyl, hexyl etc. is a branched alkyl group, most preferably a methyl group.

A suitable “aryl group” and a suitable “aryl” moiety of an “arylamino group” The groups include phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl, etc. Among these, preferred are C6-C1o aryl groups, etc. Among them, the most preferred is phenyl group.

Suitable "al(lower) alkyl groups" include mono-, di-, or triphenyl groups. (lower) alkyl groups (e.g. trityl, benzhydryl, benzyl, phenethyl) Groups such as ru) and the like can be mentioned.

Suitable "lower alkylene groups" include methylene, ethylene, trimethylene, and polymer. Charcoal such as lopylene, tetramethylene, methyltrimethylene, hexamethylene etc. Alkylene groups having 1 to 6 atoms, preferably methylene group, ethylene group, or trimethylene group.

Suitable "lower alkenylene groups" include vinylene groups, propenylene groups, etc. alkenylene groups having 2 to 6 carbon atoms, preferred among them Examples include vinylene groups.

Suitable "lower alkylimino groups" include methylimino groups, ethylimino groups, etc. Can be mentioned.

Suitable "amino acid residue" refers to a divalent residue derived from an amino acid; Amino acids such as glycine (Gly), D- or L-alanine (Ala), β-alanine (βAla), D- or L-valine (Va l), D- or L-o isine (Leu), D- or L-isoleucine (Ile), D- or L-serine (Ser), D- or L-threony (Thr), D- or L-cystine (Cys), D- or L- Methionine (Met), D- or L-phenylalanine (Phe), D- or L-tryptophan (Trp), D- or L-tyrosine (Tyr ), D- or L-proline (P r o), 3. 4-didehydropro D- or L-didehydroprolyl such as phosphorus (△(3°4)Pro) (△Pro), 3-hydroxyproline (Pro (30H)) and D- or L such as 4-hydroxyproline (Pro (40H)) -Hydroproline (Pro (OH)), D- or L-azetidine-2 -Carboxylic acid (Azt), D- or L-thioproline (Tpr), 3- Aminoproline (Pro (3NH, )) and 4-aminoproline ( D- or L-aminoproline (Pro(4NH2)) like D- or L-aminoproline (Pro(4NH2)) NHz)), D- or L-pyroglutamic acid (pG l　u), D-ma or L-2-aminoisobutyric acid (Aib), D- or L-glutamine Acid (Glu), D- or L-aspartic acid (Asp), D- or L-glutamine (G]n), D- or L-asparagine (Asn ), D- or L-lysine (Lys), D- or L-arginine (A r g), D- or L-histidine (His), D- or L-ornichidine Orn, 5-hydroxypiperidine-2-carboxylic acid, etc. or L-hydroxypiperidinecarboxylic acid, 3-mercaptoproline (P r.

(3SH)) and 4-mercaptoproline (Pro (4SH)) D- or I7-mercaptoproline (Pro (SH)) is and these side chains can be amino groups, hydroxy groups, thiol groups or carboxyl groups. It is an xy group, and may be substituted with an appropriate substituent. The above substituents include Bamoyl group, lower alkanoyl group (e.g. formyl group, acetyl group, etc.) Acyl group, lower alkoxycarbonyl group (e.g. t-butoxycarbonyl group, etc.) ), trihalo(lower)alkoxycarbonyl group (e.g. 2. 2. 2-tri (chloroethoxycarbonyl group, etc.), al(lower) alkoxycarbonyl group (e.g. (e.g. benzyloxycarbonyl group), lower alkylsulfonyl group (e.g. ethylsulfonyl group, etc.), lower alkoxyallyl group (e.g. methoxyallyl group), , ethoxyallyl group, etc.), arylsulfonyl group (e.g. phenylsulfonyl group) , tolylsulfonyl group, etc.), haloal(lower) alkoxycarbonyl group (e.g. (0-chlorobenzyloxycarbonyl group, etc.), carboxy (lower) alkanoyl groups (e.g. carboxyacetyl group, carboxypropionyl group, etc.), glycyl group , β-alanyl group, N-lower alkoxycarbonylglycyl group (e.g. N- t-butoxycarbonylglycyl group, etc.) and N-lower alkoxycarbonyl -β-alanyl group (e.g. N-t-butoxycarbonyl-β-alanyl group, etc.) , N,N-di(lower)alkylamino(lower)alkanoyl group (e.g. N, N-dimethylaminoacetyl group, N, N-diethylaminoacetyl group, N, N -dimethylaminopropionyl group, N,N-diethylaminopropionyl group, etc.) , carboxyallyl group, morpholinocarbonyl group, amino (lower) alkanoyl groups (e.g. aminoacetyl group, aminopropionyl group, etc.), N-al(lower) a alkoxycarbonylamino(lower)alkanoyl group (e.g. N-benzyloxy carbonylaminoacetyl group, etc.), threonyl group, N-lower alkoxy carpo Nylthreonyl group (e.g. N-t-butoxycarbonylglycyl group, etc.), N-lower alkanoylthreonyl group (e.g. N-acetylthreonyl group, etc.), N-lower alkoxycarbonyl (lower)alkyl-N-lower alkoxycarbonyl Ruamino (lower) alkanoyl group (e.g. N-t-butoxycarbonylmethyl -N-t-butoxycarbonylaminoacetyl group, etc.), α-glutamyl group, N -al(lower)alkoxycarbonyl-〇-al(lower)-alkyl-α-glue Tamyl group (e.g. N-benzyloxycarbonyl-〇-benzyl-α-gluta (mil group, etc.), γ-glutamyl group, N-al(lower)alkoxycarbonyl-O- Al(lower)-alkyl-γ-glutamyl group (e.g. N-penzyloxycarboxyl group) Bonyl-〇-benzy-γ-glutamyl group, etc.), lower alkyl groups (such as methoxy carboxy (lower) alkyl group (e.g. carboxyl group, ethyl group, t-butyl group, etc.), carboxy (lower) alkyl group (e.g. (e.g., carboxymethyl group), esterified carboxyne (lower) alkyl group (e.g., etho protected carboxy (lower) alkyl groups such as (oxycarbonylmethyl, etc.) , morpholino group, glycinoamide group, threoninoamide group, N'-glutamino -N-lower alkylamide group (e.g. N'-glutamino-Nt-butyramide) groups), di(lower) alkylamino groups (e.g. dimethylamino groups, etc.), al(lower) alkylamino groups (e.g. dimethylamino groups, etc.), )alkyl group (e.g. benzyl group, phenylene group, etc.), trihalo(lower)alkyl group Kill group (e.g. 2,2゜2-trichloroethyl group etc.), lower alkoxycarbo Nyl (lower) alkyl groups (e.g. methoxycarbonylmethyl, ethoxycarbo nylmethyl group, t-butoxycarbonylmethyl group, etc.), or as used in the art. This includes the usual protecting groups. If such amino acids contain thio (sulfur), It may also be a sulfoxide or a sulfone.

Suitable "carboxy (lower) alkyl groups" include carboxymethyl, carbo Examples include groups such as quinethyl and carboquinpropyl.

Suitable [protected carboxy (lower) alkyl group] means that the carboxy group is Carboxynes protected by common protecting groups such as telated carboxy groups means the above-mentioned carboxyne (lower) alkyl group.

Suitable examples of the ester moiety of the esterified carboxy group include lower alkyl esters (e.g. methyl ester, ethyl ester, propyl ester, - butyl ester, etc.).

A suitable [carbamoyl (lower) alkyl group which may have a suitable substituent] carbamoyl (lower) alkyl group (e.g. carbamoylmethyl group, carbamoylmethyl group, bamoylethyl group, carbamoylpropyl group, etc.), lower alkylcarbamoyl ( carbamoyl (lower) alkyl with suitable substituents such as lower) alkyl groups; groups (e.g. methylcarbamoylmethyl group, ethylcarbamoylmethyl group, etc.), Amino(lower)alkylcarbamoyl(lower)alkyl group (e.g. aminomethyl group, carbamoylmethyl group, aminoethylcarbamoylmethyl group, etc.), lower atom lucylamino(lower)alkylcarbamoyl(lower)alkyl groups (e.g. dimethylene) dimethylaminoethylcarbamoylmethyl group, dimethylaminoethylcarbamoylmethyl group etc.).

Suitable "lower alkyl groups which may have appropriate substituents" include lower alkyl groups. Kyl group, carboxy (lower) alkyl group, protected carboxy (lower) alkyl group carbamoyl lower alkyl group which may have a suitable substituent, examples thereof is as shown above, with an amino (lower) alkyl group, a protected amino (lower) alkyl groups, examples of which are as shown below, Lower alkylamino (lower) alkyl groups (e.g., dimethylaminomethyl, thylaminoethyl, etc.), hydroxy (lower) alkyl groups (e.g., hydro groups such as oxymethyl, hydroxyethyl, etc.), acyloxy (lower) alkyl groups ( Protected hydroxy (lower) alkyl groups such as acetylthreonyl, etc.) Kyl group, halo (lower) alkyl group (e.g. trifluoromethyl group, etc.), pyro Lysinyl (lower) alkyl group (e.g. pyrrolidin-1-ylethyl group, etc.), etc. Commonly used groups used in the field of amino acid and peptide chemistry such as can be lost.

Suitable “amine, hydroxy and/or carboxine-containing amino acid residues” and divalent residues such as Pro (40H), Ser, Thr, Tyr, etc. can be mentioned.

A suitable [protected amino group, protected hydroxy group and/or protected "Amino acid residue containing a carboxy group" refers to a carbamoyl group, a lower alkyl sulfur group, Honyl group (e.g. mesyl group, ethylsulfonyl group, etc.), arylsulfonyl group (e.g. phenylsulfonyl group, tolylsulfonyl group, etc.), lower alkoxylic acid Carbonyl (lower) alkyl groups (e.g. methoxycarbonylmethyl, ethoxycarbonyl) Used in the field of chemistry of amino acids and peptides, such as carbonylmethyl groups, etc. The above amino groups, hydroxy groups and/or carboxyl groups protected with commonly used groups means xy group.

Suitable "pyridyl (lower) alkyl groups" include 2-pyridylmethyl groups, 3- Examples include pyridylmethyl group and 4-pyridylmethyl group.

(In the formula, R4 and R5 combine with each other to form a benzene-fused lower alkylene group. ) are preferable examples of 1-indolinyl group, 2-isoindolinyl group, 1゜2 , 3. 4-tetrahydroquinolin-1-yl group, 1. 2. 3. 4-Te Examples include trahydroisoquinolin-2-yl group.

Suitable "hydroxy (lower) alkyl groups" include hydroxymethyl group, hydroxy Examples include a roxyethyl group and a hydroxypropyl group.

A suitable "protected hydroxy (lower) alkyl group" is one in which the hydroxy group is an acyl group. The above-mentioned hydroxy ( (lower) alkyl group, such as acetyloxyethyl group.

Suitable "amino protecting groups" include those used in the field of amino acid and peptide chemistry. commonly used protecting groups such as lower alkanoyl groups (e.g. formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, vivaoyl group, hexanoyl group, etc.), lower alkoxycarbonyl group (e.g. meth Oxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxy carbonyl group, t-butoxycarbonyl group, etc.), lower alkanesulfonyl group (e.g. For example, acyl groups such as methanesulfonyl group, ethanesulfonyl group, etc. It will be done.

Suitable "carboxy (lower) alkoxy groups" include carboxymethoxy groups, Examples include carboxyethoxy group and carboxypropoxy group.

Suitable [protected carboxy (lower) alkoxy] means that the carboxy group is The above-mentioned carbo means a xy (lower) alkoxy group. A preferable example of the ester part is , lower alkyl esters (e.g. methyl ester, ethyl ester, propyl ester) ster, t-butyl ester, etc.).

Suitable "lower alkoxy" includes methoxy, ethoxy, propoxy, and isopoxy. Straight chain or branched alkoxy such as ropoxy, butoxy, hexyloxy etc. Can be mentioned.

``A suitable sulfonyloxy-containing amino acid residue with a suitable substituent'' means a suitable sulfonyloxy-containing amino acid residue A sulfonyloxy group having a substituent is a lower alkylsulfonyloxy group (e.g. (methylsulfonyloxy group, ethylsulfonyloxy group, etc.), halo (lower) a rukylsulfonyloxy group (e.g. trifluorosulfonyloxy group, etc.), ali lsulfonyloxy group (e.g. phenylsulfonyloxy group, tolylsulfonyloxy group) Amino acids containing sulfonyloxy with a suitable substituent such as sulfonyloxy group, etc. means a divalent residue derived from

Suitable “amino acid residues containing azide” include Pro (4N3) and the like. Examples include divalent residues of amino acids.

Suitable "amino acid residues containing amino" include Pro (4NH, ), etc. Examples include divalent residues of amino acids.

Suitable "amino (lower) alkyl groups" include aminomethyl group, aminoethyl group, group, aminopropyl group, etc.

A suitable "protected amino (lower) alkyl group" means that the amino group is an acyl amino group. means the above amino (lower) alkyl group protected with a commonly used protecting group such as Ru. Preferred examples of the acyl moiety include lower alkoxycarbonyl groups (e.g. , t-butoxycarbonyl group, etc.).

Suitable "guanidino (lower) alkyl groups" include guanidinomethyl group, guanidinomethyl group, guanidinomethyl group, guanidino(lower) alkyl group, etc. Examples include nidinoethyl group and guanidinopropyl group.

Suitable "halogens" include chloro, fluoro, and the like.

Suitable "alkali metals" include sodium, potassium, and the like.

Suitable substituents for R1 include those having suitable substituents as described above. lower alkyl groups, amine protecting groups as described above, hydroxy groups, halogens ( (e.g. fluoro, chloro, etc.), lower alkoxy groups (e.g. methoxy, butoxy) groups), N,N-di(lower)alkylamino groups (e.g. dimethylamino groups, etc.), lower alkoxycarbonyl group (e.g. methoxycarbonyl group, t-butoxycarbonyl group) (bonyl group, etc.), lower alkyleneamino(lower) alkyl group (e.g. pyrrolidine- In the field of amino acid and peptide chemistry, such as 1-ylethyl group, etc. Mention may be made of the commonly used groups.

Suitable substituents for R3 include the above-mentioned suitable substituents. May be lower alkyl, carboxy (lower) alkoxy, protected carboxy ( (lower) alkoxy, halogen (e.g. fluoro, chloro, etc.), lower alkoxy ( For example, methoxy, butoxy), nitro, amino, amino protecting groups are is used in the field of chemistry of amino acids and peptides such as protected amino etc. Commonly used groups are mentioned.

Preferred embodiments of R1, R2, R3, R4, R5, A and Y are as follows. Ru.

R1 is a di(lower) alkoxyphenyl group, a moiety which may have lower alkoxy; - or di- or triphenyl (lower) alkyl group, indolinyl group, pyridyl group Group or formula: (In the formula, R6 is a lower alkyl group, a di(lower)alkylamino(lower)alkyl group , pyrrolidinyl (lower) alkyl group, carboxy (lower) alkyl group, ester carboxy (lower) alkyl group, amino (lower) alkyl group, guanidine (lower) alkyl group, pyridyl (lower) alkyl group or acylamino (lower) ) alkyl group, and R8 means hydrogen or halogen. ), R2 is hydrogen or or lower alkyl group, R3 is a lower alkyl group or halogen, R4 is a lower alkyl group, carboxy (lower (lower) alkyl group, or an esterified carboxy (lower) alkyl group, R5 is mono-, di- or triphenyl (lower) alkyl group or pyridyl (lower) class) alkyl group, A has a side chain that is a lower alkoxycarbonyl group, a carboxy (lower) alkyl group, or an Terified carboxy (lower) alkyl group and (lower) alkylsulfonyl group Hydroxyproline, which may be substituted with a group selected from the group consisting of Serine, methionine, lysine, histidine, glutamine, thioproline and derived from amino acids that may have suitable substituents such as aminoproline and aminoproline. a divalent residue, and Y is a lower alkylene group, a lower alkenylene group or a lower alkylimino group. be.

Particularly preferred embodiments of RIR2R3R4R5A and Y are as follows.

R1 is the formula (In the formula, R6 means lower alkyl and R8 means hydrogen), R2 is hydrogen, R3 is a lower alkyl group or halogen, R4 is a lower alkyl group, R5 is a phenyl (lower) alkyl group, A is hydroxyproline, and Y is -.

Further, preferred embodiments of R1, R2, R3, R4, R5, A and Y are as follows. It is.

R1 is a di(lower) alkoxyphenyl group, a moiety which may have lower alkoxy; - or di- or triphenyl (lower) alkyl group, indolinyl group, pyridyl group group or formula; R6 (In the formula, R6 is a lower alkyl group, a di(lower)alkylamino(lower)alkyl group , pyrrolidinyl (lower) alkyl group, carboxy (lower) alkyl group, ester carboxy (lower) alkyl group, amino (lower) alkyl group, guanidine (lower) alkyl group, pyridyl (lower) alkyl group or anruamino (lower) ) alkyl group, and R8 means hydrogen or halogen. ), R2 is hydrogen or or lower alkyl group, R3 is hydrogen, R4 is a lower alkyl group, a carboxy(lower) alkyl group, or an esterified carboxy (lower) alkyl group, R5 is a mono-, di-, or triphenyl (lower) alkyl group, and A is a lower alkyl group in the side chain. Rukoxycarbonyl, carboxy(lower)alkyl, esterified carboxy A radical selected from the group consisting of (lower) alkyl and (lower) alkylsulfonyl. Glycine, serine, methionine, lysine, histide that may be substituted with substituents with suitable substituents such as glutamine, glutamine, thioproline and aminoproline. Divalent residues derived from optional amino acids, excluding hydroxyproline things, and Y is a lower alkylene group, a lower alkenylene group or an alkylimino group .

Further, preferred embodiments of R1, R2, R3, R4, R5, A and Y are as follows. It is.

R1 is a di(lower) alkoxyphenyl group, a moiety which may have lower alkoxy; - or di- or triphenyl (lower) alkyl group, indolinyl group, pyridyl group Group or formula: (In the formula, R6 is a di(lower)alkylamino(lower)alkyl group, pyrrolidinyl (lower) alkyl group, carboxy (lower) alkyl group, esterified carbo xy(lower)alkyl group, amino(lower)alkyl group, guanidino(lower)alkyl group Kyl group, pyridyl (lower) alkyl group or acylamino (lower) alkyl group, and R8 means hydrogen or halogen. ), R2 is hydrogen or lower alkyl group, R3 is hydrogen, R4 is a lower alkyl group, a carboxy(lower) alkyl group, or an esterified carboxy (lower) alkyl group, R5 is a mono-, di-, or triphenyl (lower) alkyl group, and A is carboxy ( lower) alkyl, esterified carboxy lower alkyl and (lower) alkyl Hydroxy which may be substituted with a substituent selected from the group consisting of sulfonyl Divalent residue derived from proline, and Y is 11 lower alkylene group, lower It is an alkenylene group or an alkylimino group.

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

Manufacturing method The target compound (I) or its salt is compound (II) or its salt in the amino group. or a salt thereof at the compound (II) or the carboxy group can be produced by reacting with a reactive derivative thereof or a salt thereof. Ru.

A suitable reaction derivative at the amino group of compound (II) is compound (T I) produced by the reaction with carbonyl compounds such as aldehydes, ketones, etc. Schiff base type imino compound or its tautomeric enamine type isomer, compound (II) and bis(trimethylsilyl)acetamide, mono(trimethylsilyl) ) Acetamide [e.g. N-(trimethylsilyl)acetamitoco, bis(trimethylsilyl)acetamide] (realkyl) silyl derivatives produced by reaction with silyl compounds such as urea, etc. derivative produced by the reaction of compound (II) with phosphorus trichloride or phosgene The body and others can be mentioned.

Suitable salts of compound (II) and its reactive derivatives include compound (1) Examples of salts mentioned above can be mentioned.

As a preferable example of a reactive derivative at the carboxy group of compound (II) can include acid halides, acid anhydrides, activated amides, activated esters, etc. Wear. Suitable examples thereof include acid chlorides; acid azides, substituted phosphoric acids (e.g. dialkylated phosphoric acids); phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.) , dialkyl phosphorous acids, lower alkanesulfonic acids (e.g. methanesulfonic acid, ethane sulfonic acid, etc.), sulfite, thiosulfuric acid, sulfuric acid, aliphatic carboxylic acids (such as acetic acid) , propionic acid, butyric acid, isobutyric acid, bivaric acid, valeric acid, isovaleric acid, 2-ethyl Acids such as butyric acid, trichloroacetic acid, etc.) or aromatic carboxylic acids (e.g. benzoic acid, etc.) mixed acid anhydrides; symmetrical acid anhydrides; imidazole, 4-substituted imidazole, dimethyl Active amides, or active with tilpyrazoles, triazoles or tetrazoles Esters (e.g. cyanomethyl ester, methoxymethyl ester, dimethyl ester) Minomethyl [(CH3)2 N=CH-] ester, vinyl ester, propane Lugyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester tel, trichlorophenyl ester, pentachlorophenyl ester, mesylf phenyl ester, phenylazophenyl ester, phenylthioester, p- Nitrophenyl thioester, p-talesyl thioester, carboxymethyl thioester Oester, pyranyl ester, pyridyl ester, piperidyl ester, 8- (e.g. quinolyl thioester) or N-hydroxy compounds (e.g. N,N-dimethyl hydroxylamine, l-hydroxy-2-(IH)-pyridone, N-hydro Reactive inducers of oxysuccinimide, N-hydroxyphthalimide, and 1-hydrochloride The conductor can be selected from among these depending on the type of compound (II) to be used. You can choose.

Suitable salts of compound (II) and its reactive derivatives include salts with inorganic bases and salts, such as alkali metal salts (e.g. sodium salts, potassium salts, etc.), alkali Earth metal salts (e.g. calcium salts, magnesium salts, etc.), salts with organic bases, e.g. organic amine salts (e.g. tritylamine salt, triethylamine salt, pyridine salt, Examples of compounds <I) (N, N'-dibenzylethylenediamine salt, etc.) Examples include acid addition salts.

The reaction usually involves water, alcohol (e.g. methanol, ethanol, etc.), acetone. , dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, Tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent that does not adversely affect the reaction. It will be done. These conventional solvents may be used in combination with water.

When compound (II) is used in this reaction in the form of a free acid or its salt, the reaction In addition, conventional condensing agents such as N,N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl sil-N'-(4-diethylaminonechlorohexyltylcarbodiimide, N, N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethy carbodiimide, N,N'-carbonylbis-(2-methylaminopropyl)carbodiimide, limidazole); pentamethylene ketene-N-cyclohexylimine, dife Nylketene-N-cyclohexylimine; ethoxyacetylene,1-alkoxy C-1-chloroethylene; Trialkyl phosphite: Ethyl polyphosphate; Polyphosphorus Isopropyl acid; Phosphorous oxychloride (phosphoryl chloride); Phosphorus trichloride; Thionyl chloride: Oxalyl chloride; lower alkyl haloformates (e.g. ethyl chloroformate, chloroformate isopropyl, etc.), triphenylphosphine: 2-ethyl-7-hydroxyben Diisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxa Zolium hydroxide inner salt. 1-, (p-chlorobenzenesulfonyloxy )-6-chloro-IH-benzotriazole, N,N-dimethylformamide and So-called buildings prepared by reacting with thionyl chloride, phosgene, phosphorus oxychloride, etc. Preferably, this is carried out in the presence of a conventional condensing agent such as Smeyer's reagent.

The reaction involves alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N -(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, etc. It can also be carried out in the presence of an inorganic or organic base.

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

Manufacturing method 2 The target compound (I) or its salt is compound (IV) or its salt in the amine group. Reaction of the reactive derivative or its salt to compound (V) or its reaction at the carboxy group It can be produced by reacting with a chemical derivative or a salt thereof.

Suitable salts of compound (IV) and its reactive derivatives include compound (II) The salts exemplified above can be mentioned.

Suitable salts of compound (V) and its reactive derivatives include compound (II ) can be mentioned as examples of salts.

This reaction can be carried out in the same manner as in Production Method 1 above, and the reagents to be used and For reaction conditions such as solvent and reaction temperature, please refer to the explanation of Production Method 1. Good.

Manufacturing method 3 The target compound (1-b) or a salt thereof is obtained by combining compound (1-a) or a salt thereof with an amine, Manufactured by subjecting to elimination reaction of hydroxy and/or carboxine protecting groups can do.

In this elimination reaction, conventional methods used in the elimination reaction of carboxy protecting groups, such as For example, hydrolysis, reduction, elimination using Lewis acids, etc. are all applicable.

If the carboxy protecting group is an ester, the protecting group can be hydrolyzed or Vine is desorbed by the desorption method using

Hydrolysis is preferably carried out in the presence of a base or acid.

Suitable bases include alkali metal hydroxides (e.g. sodium hydroxide, hydroxide potassium, etc.), alkaline earth metal hydroxides (e.g. magnesium hydroxide, hydroxide calcium, etc.), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, etc.) ), alkaline earth metal carbonates (e.g. magnesium carbonate, calcium carbonate, etc.), Alkali metal bicarbonate (e.g. sodium bicarbonate, potassium bicarbonate, etc.), Alkali metal acetates (e.g. sodium acetate, potassium acetate, etc.), alkaline earths Metal phosphates (e.g. magnesium phosphate, calcium phosphate, etc.), alkali gold Hydrogen phosphates (e.g. disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), etc. inorganic bases and trialkylamines (e.g. trimethylamine, triethylamine) ), picoline, N-methylpyrrolidine, N-methylmorpholine, 1.5- diazabicyclo[4,3,0con-5-ene, 1,4-diazabicyclo[2, 2,2] octane, 1. 5-diazabicyclo[5,4,0 undecene-5 Organic bases such as

Suitable acids include organic acids (e.g. formic acid, acetic acid, propionic acid, etc.) and inorganic acids. (For example, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).

This hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof.

The reaction temperature is not particularly limited and depends on the type of carboxy protecting group and the type of elimination method. You can select it as appropriate.

In the elimination reaction using a Lewis acid, compound (1-a) or its salt is converted into boron trihalide. (e.g., boron trichloride, boron trifluoride, etc.), titanium tetrahalide (e.g., boron trifluoride, etc.) titanium chloride, titanium tetrabromide, etc.), tin tetrahalide (e.g., tin tetrachloride, tin tetrabromide, etc.) ), aluminum halides (e.g. aluminum chloride, aluminum bromide, etc.) , trihaloacetic acids (e.g. trichloroacetic acid, trifluoroacetic acid, etc.), etc. This is done by reacting with sulfuric acid. This elimination reaction is caused by a cation scavenger (e.g. Anisole, phenol, etc.) is preferable, and nitroalcohol is usually used. (e.g. nitromethane, nitromethane, etc.), halogenated alcohol (e.g. Solvents such as methylene chloride, ethylene chloride, diethyl ether, carbon disulfide, etc. Any other solvent that does not adversely affect the reaction may be used. It takes place inside. These solvents may be used as a mixture thereof.

The reductive elimination method uses halo (lower) alkyl esters (e.g. 2-iodoethyl ester). , 2. 2. 2-trichloroethyl ester, etc.), Al(lower) alkyl ester It is preferably applied to the removal of protecting groups such as benzyl esters, etc. Yes. Reduction methods that can be applied to this elimination reaction include metals (e.g. zinc, zinc malgam, etc.), or chromium compound salts (e.g. chromous chloride, chromous acetate, etc.) and an organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, etc.) and, for example, conventional metal catalysts (e.g. palladium-carbon, Raney nickel, etc.); ) can be cited as an example of the conventional catalytic reduction method.

The reaction temperature is not particularly limited, but the reaction is usually carried out under cooling, at room temperature, or under heating. It will be done.

Manufacturing method 4 The target compound (I-d) or a salt thereof is a compound (I-c) or a salt thereof that is It can be produced by subjecting it to an elimination reaction of an xy or amino protecting group.

This reaction can be carried out in the same manner as in Production Method 3 above, and therefore the reagents to be used and and reaction conditions such as base, acid, reducing agent, catalyst, solvent, reaction temperature, etc. Please refer to the explanation of manufacturing method 3.

Manufacturing method 5 Target compound (1-a) or its salt is compound (1-b) or amino, hydroxy its reactive derivatives or salts thereof at the carboxy and/or carboxy groups. , by subjecting it to a reaction for introducing hydroxy and/or carboxy protecting groups. can be built.

This reaction can be carried out in the same manner as in Production Method 1 above, and therefore the reagents and For reaction conditions such as solvent and reaction temperature, please refer to the description of Production Method I. Good.

This also applies if the amino group in R1 reacts during this reaction or in the post-treatment of the manufacturing method. within the scope of the invention.

Manufacturing method 6-(i) Compound (I-f) or its salt is compound (I-e) or its salt, compound (V It can be produced by reacting with l).

This reaction is usually caused by the use of conventional solvents such as dimethyl sulfoxide or It is carried out in other solvents that do not affect

The reaction temperature is not particularly limited, and the reaction is usually carried out with or without heating.

Manufacturing method 6-(ii) The target compound (I-g) or its salt can be obtained by hydrogenating the compound (I-f) or its salt. It can be produced by subjecting it to an addition reaction. This reaction is usually It is carried out in the presence of sphine, palladium-carbon, etc.

The reaction is usually carried out using a conventional alcohol such as alcohol (e.g. methanol, ethanol, etc.). It is carried out in a solvent or any other organic solvent that does not adversely affect the reaction.

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

Manufacturing method 7 The target compound (1-i) or a salt thereof is a carboxylic compound (1-h) or a salt thereof. It can be produced by subjecting it to an elimination reaction of a protecting group.

This reaction can be carried out in the same manner as in Production Method 3 above, and therefore the reagents to be used and and reaction conditions such as base, acid, reducing agent, catalyst, solvent, reaction temperature, etc. Please refer to the explanation of manufacturing method 3.

Manufacturing method 8 The target compound ([-K) or a salt thereof is obtained by converting the compound (1-f) or a salt thereof into an amidite It can be produced by subjecting it to a reaction for introducing a group.

This reaction is performed using amino acids such as 3,5-dimethylpyrazole-1-carboxamide, etc. In the presence of a dino-introducing agent and a trialkylamine (e.g. triethylamine) etc.) in the presence of a base such as

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

The compound obtained by the above production method is subjected to powdering, recrystallization, column chromatography, It can be isolated and purified by conventional methods such as reprecipitation.

Compound (1) and other compounds have one or more stereoisomers based on asymmetric carbon atoms. All these isomers and mixtures thereof are included in the present invention. included in the range.

The target compound (1) and its pharmaceutically acceptable salts have tachykinin antagonistic activity, Especially substance P antagonism, neurokinin A antagonism, neurokinin Diseases that have pharmacological activities such as B-antagonism and are therefore mediated by tachykinins, In particular, diseases mediated by substance P, such as asthma, bronchitis, rhinitis, cough, Respiratory diseases such as conjunctivitis, eye diseases such as vernal conjunctivitis, etc., contact skin diseases Chronic skin diseases such as dermatitis, atopic dermatitis, measles, other eczematous dermatitis, etc. Inflammatory diseases such as rheumatoid arthritis and osteoarthritis, pain (e.g. migraines, headaches, dental It is effective for the treatment and prevention of pain, cancer pain, back pain, etc.).

Furthermore, the object compound (1) of the present invention can be used to treat glaucoma, uveitis and other eye diseases, and ulcers. , ulcerative colitis, irritable bowel syndrome, food allergies and other gastrointestinal diseases, nephritis, etc. Other inflammatory diseases such as hypertension, angina, heart failure, thrombosis and others It is effective for the treatment and prevention of ring diseases, epilepsy, spasmodic paralysis, and others.

For therapeutic administration, the objective compound (1) of this invention and a pharmaceutically acceptable The salts thereof may be prepared in organic or in admixture with a pharmaceutically acceptable carrier such as an inorganic solid or liquid excipient, The compounds are used in the form of customary pharmaceutical preparations containing them as active ingredients. Pharmaceutical product The drug may be a capsule, tablet, sugar-coated tablet, granule, solution, suspension, emulsion, etc. Good too. Auxiliary agents, stabilizers, wetting or emulsifying agents, buffering agents, etc. may be added to the above formulations as necessary. and other conventional additives may also be included.

The dosage of compound (1) varies depending on the patient's age, condition, etc. For (1), the average single dose is approximately 0.1 mg, 1 mg, 10 mg, and 50 mg.

], 00mg, 250mg, 500mg is effective in treating asthma etc. Ru. Generally, the range is 0.1 mg/individual to approximately 1,000 mg/individual per day. Just administer it to the patient.

In order to explain the effectiveness of the target compound (1), we will use representative compounds of the compound (1). Pharmacological test data are shown below.

test compound (a) (1) 'H-substance P receptor binding test method (a) Preparation of crude lung membrane tissue Decapitate and sacrifice a Male Hartly guinea pig Served. The trachea and lungs were removed and buffered (0.25M sucrose, 50mM Tris). - Polytron (Kinema) in HCIS pH 7, 5, 0, 1mM EDTA) tica). This homogenate was centrifuged (1,00x g, for 10 minutes) to remove tissue clumps, and the upper groove was further centrifuged ( 14, OOOxg for 20 minutes) to generate pellets.

This pellet was placed in a buffer solution (50mM Tr i 5-Hc L pH 7.5). Suspend and homogenize with a Teflon homogenizer, centrifuge, e! (14,00 0xg for 20 minutes) to produce a pellet as a crude membrane fraction. This page The pellets were stored at -70°C until use.

(b) Combination of 'H-substance P and prepared membrane tissue Thawing the frozen crude membrane part and medium 1 (50mM Tris-HCI, pH 7,5,5mM MnCL O, 02% BSA, 2 μg/ml Chymostatin, 4 μg/ml o Ipep Chin, 40 tt g/m + bacitracin). 3H-sa Bustane P (1 day M) was combined with 100 μm of the prepared membrane sample and heated for 30 minutes at 4°C. Culture was carried out in medium 1 with a final volume of 500 ml per minute. After completing the culture, remove the reaction mixture. Immediately aspirate the compound while using Whatman's G F/B graph. filter (pretreated with 0.1% polyethyleneimine for 3 hours before use) . ) was filtered. Then add this filter to 5ml of buffer (50mM T Washed 4 times with ris-Hcl, pH 75). Radioactivity is paso card cinch Ration counter (Packard TRI-CARB 4530) Counting was performed using 5ml Aquazol-2.

Test results Hereinafter, the present invention will be explained in detail with reference to production examples and examples.

In these production examples and examples, the starting compound and target compound are the following IUPAC-I The following abbreviations are used together with the abbreviations adopted by UB.

Ac/acetyl Boc: t-butoxycarbonyl Bu': t-butyl Bzh: Benzhydryl Bzl・Benzil DMF dimethylformamide DMSO/dimethyl sulfoxide Et, ethyl HOBT: N-hydroxybenzotriazole IPE isopropyl nityl Me, methyl 2Nal: 3-(2-naphthyl)alanine 2Na I (6-CI) + 3- [2-(6-chloronaphthyl)]alanine 2Na l (6-Me): 3 [2(6-methylnaphthyl)]alanine HC]/DOX: 1.4 dioxane Hydrochloric acid Pro (40H): 4-hydroxyproline TEA: Triethyl acetate min TFA nitrifluoroacetic acid THF: Tetrahydrofuran Tpr: thioproline WSC: 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide Z : Penzyloxycarbonyl The starting compounds used in the following production examples and examples, and the target compounds obtained are shown below. The formula of the starting compound is shown in the upper row, and the formula of the target compound is shown in the lower row. be done.

Manufacturing example 1 In a solution of sodium ethoxide (6.03 g) in ethanol (340 ml), 2- Diethyl acetamidomalonate (17.5 g) and the starting compound (17 g) were placed in a room. Add warm. The mixture is refluxed for 2.5 hours. After cooling, filter the mixture and reduce the filtrate. Concentrate under pressure. The formed crystalline solid was collected by filtration, washed with ethanol, and dried. , to obtain the target compound (17.1 g).

mp: 139-141'C IR (Nujol): 3380, 1750, 1640, 1510.1310° 1295.1210.1190 cm-'NMR (DMSO-d,, δ): 1 ．． 18 (6H, t, J=7°06Hz), 1.98 (3H, s), 3.60 (2H, s), 4.17 (4H.

q, J=7.03Hz), 7.15-8.35 (7H, m) MASS: M”3 91 Manufacturing example 2 Starting compound (16.9 g) in ethanol (170 ml) and water (170 ml) Potassium hydroxide (1.45 g) is added to the medium suspension mixture and the solution is refluxed. The reflux After the start, add potassium hydroxide (1.45 g each) in two doses; 3 hours after the start of reflux, and a second time after another 2 hours of reflux. total reflux The time is 7 hours. After cooling, the solution was acidified to pH 1 using concentrated hydrochloric acid and cooled with water. Stir at the bottom for 30 minutes. The precipitate was collected by filtration, washed with water, dried, and the desired A compound (11.89 g) is obtained.

IR (nujijiru) +3600.3520,3300,1730,1620゜1 570.1220.1185cm 'NMR (DMSO-d6, δ): 1 ．． 77 (3H, S’) 3.　00　(IH.

dd, J=13.7Hz and 9. 4Hz), 3. 21 (LH.

dd, J=13.8Hz and 5. 1Hz), 4.45-4. 60 (IH, m), 7. 45-8. 0 (6H, m), 8. 26 (IH, d , J=8°1Hz), 12.74 (IH, brs) MASS+M”291 Manufacturing example 3 A suspension of the starting compound (8.8 g) in water (176 ml) was added with IN sodium hydroxide. Add aqueous solution (31 ml). The solution was warmed to 37°C and adjusted to pH 7.0 with 1N hydrochloric acid. Adjust to 5. Cobalt chloride hexahydrate (44mg) and acylase (trademark) Niacylase Amino 15000) (440 mg) is added to the solution. reaction mixture Stir overnight at 37 °C while maintaining pH at 7.5 with IN sodium hydroxide solution. . The precipitate is collected by filtration, washed with water, and dried to obtain the target compound (3.6 g).

IR (Nujol): 2600-2450.1615, 1555, 1530° 1420.1310cm-' MASS: M" 249 [α　　　　：　1　1. 56 (C-0,5,IN NaOH) Production Example 4 Cetyltrimethyl was added to a solution of the starting compound (3.0 g) in methylene chloride (60 ml). Ammonium chloride (0,55gL powdered sodium hydroxide (3,42g) and and 1-(2-chloroethyl)pyrrolidine hydrochloride (2.94 g) under water cooling. I can do it. The mixture is stirred at room temperature overnight. After filtration, the filtrate was washed with saline and sulfuric acid macerate was added. Dry with gnesium. Mixture of chloroform-methanol (50:1 to 30:1) The crude product was purified using a silica gel column (105 g) using the compound as an eluent, and the desired The compound (2.90 g) is obtained as an oil.

IR (CHCI) + 1700 cm’NMR (DMSO-d δ) + 1.65 (4H, m), 2.506+ (4H, m), 2.81 (2H, t, J=6.4Hz), 3.81 (3 H.

s), 4. 36 (2H, t, J=6.4Hz), 7. 17-7, 3 (2H.

m), 7.60 (IH, m), 8.0 (IH, m), 8.16 (IH.

S) Manufacturing example 5 The starting compound (2.9 g) was dissolved in methanol (58 ml) and IN sodium hydroxide (2.9 g). 2 ml) of the mixture. The mixture is refluxed for 4 hours. After cooling, concentrate the mixture Then add ethyl acetate and water and separate the aqueous layer. Adjust the pH to 4 with 1N hydrochloric acid and reduce Concentrate to dryness under pressure to obtain the desired compound. This target compound can be refined further. Used in the next step without manufacturing.

NMR (DMSO-d δ): 1.65 (4H, m), 2.506° (4H, m), 2. 81 (2H, t, J=6Hz), 4. 34 (2 H,t.

J=6.5Hz), 7.1-7.25 (2H, m), 7.55 (IH.

m), 8. 0 (2H, m) MASS: M+ 258 Manufacturing example 6 The target compound is obtained in the same manner as in Production Example 4.

TR (Film): 1700 cm-1BMR (DMSO-d δ): 2.17 (6H, S), 2.62I (2H, t, J=6Hz), 3.80 (3H, s), 4.33 (2H, t .

J=8Hz), 7. 2-7. 3 (2H, m), 7. 6 (IH, m ), 8°0 (IH, m), 8. 15 (IH,s) Production example 7 The target compound is obtained in the same manner as in Production Example 5.

(1) mp: 229℃-(dec,)IR (Nujol): 2700 ．． 1695. 1665 cm-'NMR (DMSO-d δ): 2.7 9 (6H, s), 3.506' (2H, t, J=6Hz), 4.75 (2H, t, J=6Hz), 7.2 0-7.35 (2H, m), 7.77 (IH, m), 8.04 (IH, m) .

8, 18 (IH, 5) (2) mp: 212℃- IR (Nujol): 3450.　2610. 1681.　1520゜8 80, 850. 815. 795. 760. 732 cm’NMR ( DMSO-d　δ)　+　3.38(IH,br　s), 4゜6' 02 (3H, m), 7. 15-7. 80 (4H, m) Production example 8 Starting compound (2.0 g) in a mixed solvent of water (20 ml) and acetone (20 ml) Add TEA (2.46 ml) to the suspension under water cooling. In solution, di-t-butyl A solution of dicarbonate (2.1 g) in acetone (5 ml) was added and the solution was diluted with triethyl chloride. Stir at the same temperature for 2 hours while adding Ruamine (1.23ml), and then stir at room temperature for 2 hours. Stir. After removing acetone, water (50 ml) was added and the aqueous layer was diluted with diethyl ether. Wash once with water. The aqueous layer was adjusted to pH 1 with 1N hydrochloric acid and extracted with ethyl acetate.

The extract is washed with brine and dried over magnesium sulfate. After distilling off the solvent, The crystalline solid is collected and dried to obtain the desired compound (2.66 g).

mp: 146-148℃ IR (Nujol): 3370.　1720. 1695.　1520゜1 270, -1170 cm-” NMR (DMSO-d δ): 1.28 (9H, s), 2.966° (IH, dd, J=23.8Hz and 10.2Hz), 3.20 (IH , dd, J=13.6Hz and 4. 5Hz), 4. 15-4.3 ( IH,s), 7. 19 (IH, d, J=8.4Hz), 7. 45- 7゜55 (2H, m), 7. 75-8. 05 (4H, m), 12. 65 (1B.

Production example 9 The target compound is obtained in the same manner as in Production Example 8.

mp: 122℃ (dec,) IR (Nujol): 3380.　1720.　1690.　1520゜1 270.　1180　cm　’ NMR (DMSO-d δ): 1.29 (9H, s), 2.456' (3H, s), 2.97 (IH, dd, J=23.9Hz and 10. 2Hz), 3.17 (IH, dd, J=18.4Hz and 4°6Hz) ,4. 1-4. 3 (IH, m), 7. 1-7. 8 (7H, m).

12.64 (IH,brs) MASS: M+1329 Production example 1O Starting compound (2.0g), histidine methyl ester dihydrochloride (2°76g) and HOBT (1,54 g) (7) WSC ( 2.08ml) was added under water cooling. Stir the solution at the same temperature for 1 hour and at room temperature overnight. . After distilling off the solvent, water and diethyl ether are added to the residue. Separate the aqueous layer and release place The resulting crystals were collected, washed, and dried to obtain the target compound (2.06 g). obtain.

IR (Nujol): 3180. 1745.　1635. 1545゜1 400 am NMR (DMSO-d δ) + 3.07 (2H, d, J = 7゜6' 12Hz), 3.62 (3H, s), 3.84 (3H, s), 4.7 3 (IH, dd, J=13.9Hz and 7.41Hz), 6. 95- 8゜30 (9H, m) MASS + M+1326 Production example II Hydrazine hydrate was added to a solution of the starting compound (2.0 g) in methanol (40 ml). Add (1,79ml). The solution is stirred at room temperature overnight. Collect the precipitate and add methanol The target compound (1.08 g) is obtained by washing with water and drying.

mp: 26]℃-(dec,) IR (Nujol) +3400.　3300.　1660.　1635゜1 555, 1530 am-1 HMR (DMSO-d δ): 2.95 (2H, d, J=7°6″ 79Hz), 3.85 (3H, s), 4.22 (2H, br s), 4°67 (IH, dd, J=14.1Hz and 7.5Hz), 6.82 (IH, s), 7.1-8.2 (7H, m), 9.15 (IH, s).

11.77 (IH,brs) MASS: M+1326 Production example 12 To a solution of the starting compound (2.0 g) in DMF (40 ml) was added methyl iodide (5°0 9 ml) and powdered potassium carbonate (5.30 g). The mixture was heated at 75°C Stir for an hour. The mixture is filtered, the filtrate is concentrated under reduced pressure, and water is added to the residue. crystal The precipitate was collected by filtration, washed with water, and dried at 40°C to obtain the target compound (2.94 g). obtain.

mp:94-96℃ IR (Nujol): 1710. 1520. 875. 850°800 , 767, 733 cm-'NMR (DMSO-d δ): 3.87 ( 3H,s), 4.026° (3H,s), 7. 20-7. 80 (4H, m) Production example 13 Starting compound (2,43 g), N-methylbenzylamine (0,91 ml) and HOBT (0.94g) (7) WSC-hydrochloride (1,3 3g) was added under water cooling. The solution is stirred at the same temperature for 1 hour and at room temperature overnight.

After distilling off the solvent, the reaction mixture was extracted with ethyl acetate, and the separated organic layer was washed with water and charcoal. Wash with sodium hydroxide aqueous solution, 0.5N hydrochloric acid, water and saline in order, and remove sulfuric acid. Dry with gnesium. The solvent was distilled off to give the target compound (1.40 g) as a crystalline solid. Get it as a body.

mp:99-103℃ IR (Nujol)+3370.1685,1645,1515°1405, 1250. 1170 cm-'NMR (DMSO-d δ): ], 15 -7. 35 (9H, m).

6゜ 2, 75-3. 20 (5H, m), 4.40-4. 85 (3H, m) , 6°95-8.05 (12H, m) Production example 14 The target compound is obtained in the same manner as in Production Example 13.

NMR (DMSO-d δ) = 1°22 and 1.32 (9H.

6' 43m), 2.46 (3H, s), 2.75 and 2. 85 (3H,s ).

2, 9-3. 1 (2H, m), 4. 4-4. 8 (3H, m), 6. 9-7. 8(12)(,m) Production example 15 Starting compound (3.08 g) (7) J chloride + Lin (30 ml) solution, Add 4NHC1/DOX (27.5ml) while cooling with water. Keep the solution at the same temperature for 5 minutes Stir for a while. Remove the water bath and stir the solution for 30 minutes at room temperature. Distill the solvent and leave the residue The residue was crystallized with diisopropyl ether, the product was collected by filtration, and sodium hydroxide was added. The mixture was dried under reduced pressure to obtain the target compound (2.36 g).

mp: 177-185℃ IR (Nujol): 3420.　1650.　1600. 1495゜1 285cm” NMR (DMSO-d, 5): 2.65 and U 2.70 (3H.

6′ s), 3. 15-3. 40 (2H, m), 4. 0-4. 8 (3 H, m).

7, 0-8. 1 (IIH, m), 8. Made of 5'8 (3H, brs) Example 16 The target compound is obtained in the same manner as in Production Example 15.

mp:170-172℃ IR (Nujol): 3500-3350.　1650, 1605゜151 0.1450 cm’ NMR (DMSO-d δ): 2.47 (3H, s), 2.61 o 6° and 2. 70 (3H, s), 3. 1-3. 3 (2H, m), 3. 95-4°8 (3H, m), 6. 95-7. 8 (IIH, m), 8. 49 (2H,brS) Production example 17 Starting compound (1,3g), Boa-(2S,4R)-Pro(40H)-O H (0,77 g) and HOBT (0,45 g) in methylene chloride (26 ml) WSC (0.61 ml) is added to the medium temperature mixture under water cooling. The solution was kept at the same temperature for 1 hour. , stir overnight at room temperature. The solvent was distilled off, the reaction mixture was extracted with ethyl acetate, and the preparative The organic layer was mixed with an aqueous sodium bicarbonate solution, water, 0.5N hydrochloric acid, water and brine. Wash sequentially and dry with magnesium sulfate. The solvent was distilled off to obtain the target compound (1° 88 g) as an amorphous solid.

NMR (DMSO-d δ): 1.10-1.40 (9H, m).

6″ 1, 50-1. 80 (IH, m), 1. 80-2. 10 (IH, m), 2°70-3. 30 (7H, m), 4. 10-5. 20 ( 6H, m), 6. 90-8. 0 (IIH, m), 8. 35-8.　 50 (IH, m) Production example 18 The target compound is obtained in the same manner as in Production Example 17.

NMR (DMSO-d δ): 1.21 and 1. 39 (9H.

6゛ s), 1.6-1.8 (IH, m), 1.8-2.0 (IH, m), 2゜40 ( 3H, s), 2.7-3.5 (7H, m), 4.1-5.2 (6H.

m), 6.9-7.8 (IIH, m), 8.35-8.5 (IH, m) (2 ) IR (CHCI): 3300. 1710.　1640゜1485, 　1365. 1165 am 'NMR (DMSO-d δ): 1.37 (9H,s), 2.756' and 2. 83 (3H, s), 2. 90-3. 25 (2H, m) , 3゜43-3. 60 (2H, m), 4. 20-4. 75 and 4. 90-5°20 (3H, m), 6.85-7. 95 and 8. 25-8.40 (14H, m) (3) rR (CHCI) + 3300.　1710-1620゜1515 -1490.　1450.　1360. 1160cm’NMR (DMSO -d δ): 1.37 (9H, s), 1.55-6' 1, 9 (2H, m), 1. 95-2. 2 (2H, m), 2. 7 3 and 2, 82 (3H, s), 2.9-3.25 (3H, m), 3.85- 4.0 (2H, m), 4.3-4.6 (2H, m), 4.9-5.2 (IH .

m), 6.7-7, 9 (13H, m), 8.3-8.4 (LH, m) (4) IR (CHCI): 3330. 1715.　1635゜1500,　 1460. 1170 cm 'NMR (DMSO-d δ), : 1.38 (9H,s), 2.736° and 2. 82 (3H, s), 2. 9-3. 3 (2H, m), 3 ．． 4-3, 6 (2H, m), 3.9-5.2 (5H, m), 6.65-7.95 (13H, m), 8. 15-8. 3 (IH, m) (5) IR (CHCI ): 3320.　1720. 1635°1495, 1460. 13 20. 1170 cm 'NMR (DMSO-d δ) + 1.37 (9H ,s), 1.6-6° 1, 85 (2H, m,), 1.9-2.0 (3H, m), 2.25-2.4 (2H, m), 2. 74 and 2. 83 (3H, s), 2.　 95-3゜25 (2H, m), 3.9-5.2 (4H, m), 6.9- 7.9 (13H, m), 8.26 (IH, d, J = 7.92Hz) NMR ( DMSO-d δ): 1. 1-1. 5 (9H, m), 2゜6゜ 7-3. 4 (7H, m), 4. 3-5. 2 (6H, m), 6. 9 -7. 9 (12H, m), 8.45-8.6 (IH, m) NMR (DMS O-d δ) + 1.1-1.55 (6H, m).

6' 1, 37 (9H, s), 2. 74 and 2. 82 (3H,s ), 2°85-3. 3 (4H, m), 3. 9-5. 15 (6H , m), 6. 7-7゜95 (19H, m), 8.35-8.45 (I H, m) (8) mp: 126.0-127.0℃ IR (Nujol): 　3330. 1710.　1635. 1515°859, 820cm- 1 NMR (DMSO-d δ) = 1°347 (9H, s), 1.456° -1,70 (2H, m), 1.859, 1.902 (3H, s), 2.10 -2.35 (2H, m), 2.803, 2.912 (3H, s), 2.90 -3.25 (2H, m), 3.90-4.15 (LH, m), 4.37 9 (J=15.11Hz), 4.515 (J=18.40Hz), 4.6 00 (J=15.38Hz), 4.726 (2H, d, J=16.62Hz ).

4.95-5.25 (IH, m), 6.830 (J=14.62Hz).

6.887 (IH, d, J=8.20Hz), 6.95-7.90 (12 H.

m), 8.383 (J=8.31Hz), 8.496 (LH, d, J= 8゜50Hz) Production example 19 A solution of the starting compound (1,72 g) in methylene chloride (20 ml) was added with 4N HCl/D Add OX (12.3 ml) under water cooling. The solution was heated at the same temperature for 5 minutes, then at room temperature for 20 minutes. Stir for a minute. The solvent was distilled off, and the residue was triturated with diisopropyl ether and collected by filtration. and drying to obtain the target compound (1.52 g).

mp + 131℃-(dec,) IR (Nujol): 3350-3150.　1670.　1640゜15 30cm’ NMR (DMSO-d δ): 1. 7-1. 9 (LH, m), 2゜ 6゜ 2-2. 4 (IH, m), 2. 77 and 2. 85 (3H, s), 2゜9-3. 4 (4H, m), 4. 2-4. 6 and 5. 0-5. 2 and 5, 5-5. 65 (6H, m), 7. 9 -8. 05 (IIH, m), 8゜58 (IH, brs), 9.26 (IH, d, J=7.70Hz).

10.05 (IH,brs) Production example 20 The target compound is obtained in the same manner as in Production Example 19.

NMR (DMSO-d δ): 1. 7-1. 9 (IH, m), 2゜ 6゜ 2-2.4 (IH, m), 2.47 (3H, s), 2. 77 and 2゜83 (3H, s), 2.95-3.35 (4H, m), 4.2-5 ．． 6 (6H, m), 6.9-7.8 (IIH, m), 8.6 (IH, b rs), 9.23 (LH, d, J=7.6Hz), 9.85 (IH, b rS) NMR (DMSO-d δ): 2.79 and 2.87 (3H.

6゜ s), 2.90-3.30 (2H, m), 3.40-3.50 (2H.

m), 4.20-5.25 (3H, m), 6.80-7.95 (12H .

m), 8. 18 (3H, brs), 9. 00-9. 15 (IH , m) NMR (DMSO-d δ): 1.9-2.05 (2H, m).

6゜ 2, 2-2. 35 (2H, m), 2. 76 and 2. 85 ( 3H, m).

3.0-3. 3 (2H, m), 3. 7-3. 9 (3H, m) , 4. 35-5.2 (3H, m), 6.85-7.95 (12H, m ), 8.36 (3H, br s), 9.17 (LH, d, J=8.46H z) NMR (DMSO-d δ): 2.76 and 2. 85 (3H.

6゜ s), 3.0-3.3 (2H, m), 3.65-3.95 (2H, m) .

4.3-5.6 (5H, m), 6.9-7.95 (12H, m), 8.22 (3H,br　s),　9.0-9.1　(IH,m)NMR(DMSO-d) δ): 1.95-2.1 (5H, m).

6゛ 2, 45-2. 55 (2H, m), 2. 76 and 2. 85 ( 3H.

s), 3.0-3.3 (2H, m), 3.8-5.2 (4H, m), L9 -7.95 (12H, m), 8.37 (3H, br s), 9.1-9 ゜2　(IH, m) (6) mp: 190℃-(dec,)IR (Nujol): 3200 ．．　2700.　1680.　1650゜1555,　1450　am　’ NMR (DMSO-d δ): 2.77 and 2. 86 (3H.

s), 2.95-3.6 (4H, m), 4.2-4.7 (5H, m).

5.0-5.25 (IH, m), 6.9-8.0 (13H, m), 9. Hl (IH, d, J=7.5Hz) Production example 21 A solution of the starting compound (0.50 g) in ethyl acetate (10 ml) was added with 4N hydrochloric acid/ethyl acetate. Chill (20 ml) is added under water cooling. The solution is stirred at the same temperature for 1 hour. Remove the residue Triturate with ethyl ether, filter, dry over sodium hydroxide under reduced pressure, and The compound (0.38 g) is obtained.

IR (Nujol): 3400.　1678.　1630.　1562゜1 546, 815. 730 cm”NMR (DMSO-d δ): 1. 74. 1.83. 1.916' (3H, s), 1.55-1.95 (2H, m), 2.00-2.30 ( 2H, m), 2. 86. 2. 99 (3H, s), 2. 90-3. 45 (2H, m), 3. 75-3. 90 (IH, m), 4. 25 -4. 40°4, 60-4. 85 (2H, m), 5. 00-5.　 30 (IH, m), 6°90-7. 90 (13H, m), 8. 21 (2H,brs), 9. 05-9, 20 (IH, m) Production example 22 The starting compound (257 g) was dissolved in methanol (50 ml) and 10% palladium - Add carbon (0,26 g). The mixture was hydrogenated for 3.5 hours at room temperature under atmospheric pressure. Add. Add 2 drops of concentrated hydrochloric acid and continue hydrogenation for 1 hour. After filtration, dissolve until dry. The solvent was distilled off to obtain the target compound (1.93 g) as an amorphous solid.

NMR (DMSO-d δ): 1. 1-1. 6 (6H, m), 1゜ 6+ 37 (9H, s), 2. 77 and 2.85 (3H, s), 2. 9 5-3, 4 (4H, m), 4. 3-5. 2 (4H, m), 6 ．． 7-7, 95 (15H, m), 8.55-8.65 (IH, m) production Example 23 Starting compound (315 g) and methyl iodide (5.0 ml) in THF (30 ml) 60% sodium hydride (1.20 g) was added to the solution under water cooling in a nitrogen atmosphere. Ru. The mixture is stirred at room temperature overnight. Water is added to the mixture and THF is distilled off. residue Add diethyl ether and water, separate the aqueous layer, and wash the organic layer again with water. 2 The two aqueous layers were combined, the pH was adjusted to 2 with 6N hydrochloric acid, and the separated oil was diluted with ethyl acetate. Extract. The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off. The desired compound (2.05 g) was obtained as a crystalline solid.

mp: 135-136.5℃ IR (Nujol): 1750. 1645 cm’NMR (CDC1, , δ): 1.27 and 1. 36 (9H, s).

2.69 and 2.77 (3H,s), 4. 74 (dd, J=4゜3 Hz, 10.7Hz), 4.98 (dd, J=5.2Hz, 10°7Hz) , 7.3-7.85 (7H, m), 9.16 (IH, brs) production example 24 The target compound is obtained in the same manner as in Production Example 13.

mp: 122-123℃ IR (Nujol): 1680. 1646 cm’NMR (CDCl2 ．． δ): 0.96.1.058.1.148 and 1. 30 (9H, s), 2. 85 (3H, s), 2. 90 (3H.

s), 3.0-3.5 (2H, m), 4.35-4.8 (2H, m).

5.13 and 5.50 (IH, m), 6.8-7.8 (12H, m ) Elemental analysis: Calculated value: C74,97, H7,46, H6,48 Actual value: C74,93, H7,70, H6,66 Production Example 25 The starting compound (2.42 g) is dissolved in ethyl acetate (15 ml) and cooled on ice. this Add 4N hydrochloric acid in ethyl acetate (30 ml) to the solution. The solution was kept at the same temperature for 40 minutes. Stir and concentrate. Add methylene chloride (50 ml) and saturated sodium bicarbonate to the residue. Add aqueous solution of chlorine, separate the organic layer, and extract the aqueous layer again with methylene chloride. extract liquid were combined, washed with brine, and dried over magnesium sulfate to obtain the target compound. Example 26 The target compound is obtained in the same manner as in Production Example 25.

NMR (DMSO-d δ): 2.49. 2.50.　2.51゜6゛ 2.54, 2. 57 (6H, s), 3. 19 (IH, dd, J=1 3゜2Hz, 3.5Hz), 3.55 (IH, dd, J=13.2Hz, 9 ゜2Hz), 3. 99 and 4. 39 (J=16.2Hz), 4. 32 and 4.55 (J=14.7Hz), 4.85 (IH, m), 6 ．． 85-7. 94 (12H, m), 9. 53 (2H,brs) element Analysis: Calculated value: C71,63, H6,83, H7,59°C10,61 Actual measurements: C71,40, H6,87, H7,57°C19,65 Production example 27 The target compound is obtained in the same manner as in Production Example 17.

Production example 28 Starting compound (4,5 g), ethyl bromoacetate (3,01 g) and potassium carbonate (4.97 g) in dimethylformamide (60 ml) was stirred at room temperature for 3 hours. Stir. Filter the mixture, evaporate the filtrate, dilute with water, and extract with ethyl acetate. do. The separated organic layer was mixed with water, sodium hydrogen carbonate aqueous solution, water, 0.5N hydrochloric acid and Wash with water and brine, and dry with magnesium sulfate. Distill the solvent and target The compound (6,10g) is obtained as a crystalline solid.

mp: 73-75.5℃ IR (Nujol): 1748. 1690 cm-1HMR (DMSO- d6. δ): 1.24 (3H, t, J=7Hz).

4.21 (2H, q, J=7Hz), 4.84 (2H, s), 5. 3 8 (2H, s), 7. 24-7. jO(8H,m), 7. 84 (I H,s).

8.22 (IH, m) Production example 29 The starting compound (6, IOg) is dissolved in ethanol (100ml). in this solution 4N hydrochloric acid in dioxane (0.3 ml) and 10% palladium on carbon (0°6 g) Add. The mixture is hydrogenated under atmospheric pressure for 5 hours. Filter the mixture and concentrate the filtrate The desired compound (3.5 g) was obtained as a crystalline solid.

mp: 145-146℃ IR (Nujol): 2600.　1734.　1660.　1640゜□ -1 NMR (DMSO-d6. δ): 1.22 (3H, d, J = 7Hz) .

4°16 (2H, q, J=7Hz), 5. ．． 23 (2H, s) 7.17-7 ．． 28 (2H, m), 7.44-7.52 (IH, m), 8.0-8.1 ( LH.

rn), 8. 06 (IH,s) Production example 30 In a solution of the starting compound (2,51 g) and ethyl 4-bromobutyrate (1,95 g), 6 Add 0% sodium hydride (0.40 g) under water cooling. Leave the mixture overnight at room temperature. Stir. The mixture is evaporated, diluted with water and extracted with ethyl acetate. Preparative separation The organic layer was washed sequentially with sodium bicarbonate solution and brine, and then washed with magnesium sulfate. Dry in a vacuum. The solvent was distilled off and the residue was decanted with petroleum ether to obtain the target compound NM. R (CDCl δ): 1.23 (3H, t, J = 7Hz).

3′ 2, 2<2H, m), 2. 3 (2H, t, J=7Hz), 4. 12 (2H.

q, J=7Hz), 4.22 (2H, t, J=7Hz), 5.38 (2H .

s), 7.25-7.51 (8H, m), 7.83 (IH, s), 8°20 (IH, m) Production example 31 The target compound is obtained in the same manner as in Production Example 29.

mp　・　92-93℃ IR (Nujol): 1740. 1655 cm-1HMR (CDCI) 6) +1.25 (3H, t, J=7Hz).

3′ 2.20 (3H, t, J=6.5Hz), 2.33 (2H, m), 4.14 (2H, q, J=7Hz), 4.25 (2H, t, J=6.5Hz), 7 ゜25-7.44 (3H, m), 7.92 (IH, s), 8.21-8 ．． 3 (IH, m) Production example 32 The target compound was obtained in the same manner as in Production Example 30 and used in the next reaction without purification.

Production example 33 The target compound is obtained in the same manner as in Production Example 5.

mp: 124.5-125℃ IR (Nujol): 2500.　1680.　1660.　1535cm ’ NMR (DMSO-d δ): 5. 60 (2H, s), 7. 16- 6' 7.30 (4H, m), 7.5 (LH, m), 7.75 (IH, m) .

8.05 (LH, m), 8.24 (IH, s), 8.53 (LH, m).

12.07 (IH, m) Elemental analysis: Calculated values: C68,95, H5,01, NIo, 72 (0°5H2 (as 0) Actual measurements: C69,43, H5,02, N10.39 Production example 34 Starting compound (6.1g) in a mixed solvent of acetone and water (1:1.100ml) Into the medium solution, di-t-butyl dicarbonate (2 1.8 g) was added under water cooling. The resulting solution is stirred at room temperature for 3 hours. acetone is distilled off and the residue is extracted twice with methylene chloride. Combine the extracts and add 0.5N hydrochloric acid. and brine, and dried over magnesium sulfate. Distill the solvent and remove the The compound (16.7 g) is obtained as an oil.

IR (Fth m): 3370.　1690. 1525 cm’NMR (C DCI δ): 1.45 (9H, s), 3.283゛ (2H, t, J=5Hz), a, 69 (2H, t, J=5Hz) Production example 35 Methyl chloride of the starting compound (16,7 g) and triethylamine (12,63 g) Methanesulfonyl chloride (12.6 g) was added to a solution of (140 ml) at -20°C. Add in 20 minutes. The resulting mixture is stirred at 0° C. for 1 hour. The solution was diluted with water, 0. Wash sequentially with 5N hydrochloric acid and brine, and dry over magnesium sulfate. Distill the solvent The desired compound (22.34 g) was obtained as an oil. Prevents target compound from decomposition Put it in the freezer.

IR (Film): 3410.　1700. 1520.　1350゜m- m -1N (CDCl δ): 1.45C9H,s), 3.153・ (3H,s), 3. 46 (2H, m), 9. 29 (2H, t, J= 5°2Hz), 4. 93 (IH, s, br) Production example 36 The target compound was obtained in the same manner as in Production Example 28 and used in the next reaction without purification.

Production example 37 The target compound is obtained in the same manner as in Production Example 29.

mp: 185-186.5℃ (dec,) IR (Nujol): 345 0.　1680. 1650 cm-1HMR (DMSO-d δ): 1. 31 (9H, s), 3.326° (2H, m), 4. 27 (2H, t, J=6Hz), 6. 97 (I H,t.

J=5. 5Hz), 7. 2 (2H, m), 7. 55-7. 6 ( IH, m).

7.99 (IH, s), 8.0 (IH, m), 11.94 (IH, s) element Analysis: Calculated value: C63,14, H6,62, N9.20 Actual value: C61 , 68, H6, 70, N8.93 Production example 38 The target compound is obtained in the same manner as in Production Example 13.

Summer R (C) (CI): 3320. 1740. 1700. 1650° 1500, 1450 am NMR (DMSO-d6): 1.1-1.3 (12H, m).

6' 2, 85-3. 15 (2H, m), 3. 9-4. 9 (7H, m) , 7. 15-7. 9 (13H, m) MASS: M" 490 Production example 39 The target compound is obtained in the same manner as in Production Example 15.

IR (CHCI): 3400. 1745.　1665.　1605゜1 490, 1470. 1455 cm NMR (DMSO-d δ): 1 ．． 18 (3H, t, J=7゜CI IHz), 3.2-3.45 (2H, m), 3.65-4.85 (7H .

m), 7. 1-8. 0 (12H, m), 8. 51 (3H,br s) Production example 4゜ The target compound is obtained in the same manner as in Production Example 17.

NMR (DMSO-d δ): 1.0-1.15 (9H, m).

6' 1.3-1.4 (3H, m), 1.5-1.7 (IH, m), 1.8-2° 0 (LH, m), 2.9-3.4 (4H, m), 3.95-5.1 (IO H, m), 6. 9-8. 0 (12H, m), 8. 4-8. 6 ( IH.

m) Production example 41 Starting compound (4.9 g), ethyl bromoacetate (1.69 g), cetyltrimethyl Ammonium chloride (0.32g) and powdered sodium hydroxide (1°84g) ) in methylene chloride (100 ml) was stirred at room temperature for 3 days. powder mixture Filter through a pad of cellulose. Concentrate the filtrate, dilute with water and extract with ethyl acetate. put out The separated organic layer was added to sodium bicarbonate solution, IN hydrochloric acid, water and brine. and dry with magnesium sulfate. Distill the solvent, add chloroform and The residue was purified using a silica gel column (150 g) using a mixture of tanol (50:1) as the eluent. The residue was purified to obtain the target compound (2.89 g) as an amorphous solid.

NMR (DMSO-d δ): 1.15-1.25 (9H, m).

6' 1.29 (3H, s), 1.6-1.8 (IH, m), 2.05-2.3 (IH, m), 2.7-3.25 (5H, m), 3.4-3.5 (2H .

m), 4.0-5.2 (9H, m), 6.85-7.9 (12H, m) ,.

8.4-8.5 (IH, m) MASS + M+ 617 Production example 42 The target compound is obtained in the same manner as in Production Example 19.

NMR (DMSO-d δ): 1.17 (3H, t, J = 7゜6゜ 15Hz), 1. 7-1. 9 (IH, m), 2. 15-2. 35 ( IH, m).

2, 95-3. 4 (4H, m), 4. 0-5. 2 (IOH, m), 7. 0-8゜0 (12H, m), 8. 57 (IH, br-s), 9.　 25-9. 4 (IH.

m), 9.81 (IH, br-s) NMR (DMSO-d δ): L 21 (3H, t, J = 7゜6゜ IHz), 1. 7-1. 95 (IH, m), 2. 45-2. 65 ( IH, m).

2.77 and 2.85 (3H, s), 3.0-3.45 (4H, m), 4゜05-5.2 (9H, m), 6.85-7.95 (12H, m), 8 ．． 7 (LH, br-s, 9. 2-9. 3 (IH, m), 10. 25 (IH, br - Example 1 1-methylindole-3-carboxylic acid (0.47 g), starting compound (1°35 g) and HOBT (0.36 g) in methylene chloride (25 ml), add WS C (0.49 ml) is added under water cooling. Stir the solution at the same temperature for 1 hour and at room temperature overnight. do. The solvent was distilled off, the reaction mixture was extracted with ethyl acetate, and the separated organic layer was diluted with carbonate. Wash sequentially with sodium hydrogen aqueous solution, water, 0.5N hydrochloric acid, water and saline, and wash with sulfuric acid. Dry with magnesium. The solvent was distilled off and the residue was dissolved in a mixture of chloroform and methanol. Purify with a silica gel column (50 g) using liquid (30:1) as eluent. Purification The two parts containing the compound were combined, the solvent was distilled off, and the target compound (1.15 g) was amorphous. Obtained as a solid.

NMR (DMSO-d δ) + 1.7-1.9 (IH, m), 1°6° 9-2. 1 (IH, m), 2. 72 and 2. 82 (3H,s ), 2゜95-3.3 (2H, m), 3.6-4.0 (2H, m), 3.85 (3H, s), 4.2-5.15 (6H, m), 6.9-8.1 (16H.

m), 8.45-8.6 (IH, m) Example 2 The target compound is obtained in the same manner as in Example 1.

(1) mp: 126℃-(dec,)IR (Nujol): 3420 ．．　3270.　1660.　1630゜1605,　1535.　1320. 1245 cm”NMR (DMSO-d δ): 1. 7-1. 9 (IH, m), 1゜6゜ 9-2. 1 (IH, m), 2.46 (3H, s), 2.70 and 2°78 (3H, s), 2.9-3.25 (2H, m), 3.6-3. 75 (2H, m), 3.85 (3H, s), 4.2-5.15 (6H, m).

6, 85-8. 1 (16H, m), 8. 4-8. 55 (IH, m ) NMR (DMSO-d δ): 2.78 and 2. 86 (3H.

6′ s), 2.95-3.30 (2H, m), 3.83 (3H, s), 3 ゜85-3. 95 (2H, m), 4. 20-5. 25 (3H, m) , 6. 85-8. 20 (18H, m), 8. 40-8.　60　 (LH, m) (3) IR (Nujol): 3275.　1635. 15 48°740cm’ NMR (DMSO-d δ) + 1. 89. 1. 94 (3H, s).

6' 1.50-2.00 (2H, m), 2.20-2.45 (2H, m).

2.81. 2.94 (3H, s), 2.90-3.30 (2H, m).

3, 82 (3H, s), 4. 30-4. 85 (3H, m), 4. 95-5゜25 (LH, m), 6. 90-7. 90 (16H, m) , 8. 12 (IH.

s), 8. 14 (IH, d, J=7.70Hz), 8. 52. 8.65 (IH, d, J = 8.18Hz and 8.60Hz) (4) mp: 1 58-160℃ IR (Nujol): 3550.　3300.　1690.　1675゜1 595, 1530. 1240 cm’NMR (DMSO-d δ): 1.8-2.0 (2H, m), 2゜6゜ 1-2.3 (2H, m), 2. 75 and 2.84 (3H, m), 2゜9-3. 3 (2H, m), 3.84 (3H, s), 4. 05 -5. 2 (4H, m), 6. 75-8. 6 (19H, m) (5) mp : 108-113℃ IR (Nujol): 3460.　3330.　1625.　1540゜1 240cm” NMR(DMSO-d　δ)+2.73 and 2. 84 (3H.

6゜ s), 2.95-3.3 (2H, m), 3.6-3.75 (2H, m).

3, 85 (3H, s), 4.25-5.25 (5H, m), 6.85-8° 5 (19H, m) NMR (DMSO-d δn: 1. 8-2. 0 (2H, m), 2゜ 6゜ 01 (3H, s), 2. 4-2. 55 (2H, m), 2. 75 and 2, 85 (3H9s), 3.0-3.3 (2H, m), 3.84 (3H.

s), 4.3-5.2 (4H, m), 6.9-8.5 (19H, m) NMR (DMSO-d δ): 1.2-1.75 (6H, m).

6゜ 1, 62 (91 I, s), 2.74 and 2. 84 (3H, s) , 2. 9-3.3 (4H, m), 3.84 (3H, s), 4.35-5.2 (4H.

m), 6.7-8.5 (20H, m) Example 3 Diphenylacetic acid (424.5g) and HOBT (270mg) in methylene chloride WSC hydrochloride (382 mg) was added to the suspension in (15 ml) at room temperature. solution Stir at the same temperature for 1 hour. Starting compound (1,09g) and TEA (0° 41 g) is added and the solution is stirred at room temperature overnight. Concentrate the solution and dissolve the residue in ethyl acetate. The organic layer was extracted with saturated aqueous sodium bicarbonate solution, water, 0.5N hydrochloric acid and food. Wash sequentially with brine and dry with magnesium sulfate. Concentrate the solution and diethify the residue. The desired compound (1.12 g) was obtained by crystallization from ether and filtered.

mp: 200-202℃ IR (Nujol): 3400. 1695. 1645.　1630゜1 530cm” NMR (DMSO-Ld δ): 1. 7-2. 2 (2H, m), 2 ゜6' 77 and 2. 85 (3H, s), 3.0-3. 3 (2H, m), 3゜3-3. 6 (2H, m), 4. 2-4. 6 (4H, m), 4.　 9-5. 3 (2H, m), 6.7-7.9 (23H, m), 8.48 (d, J=8Hz) and 8. 97 (IHlm) Example 4 The target compound is obtained in the same manner as in Example 3.

(1) mp: 197.0-200.5℃ IR (Nujol) + 340 0.　3310.　3130. 1678°1643, 1578.　1530 ．． 745 cm-1HMR (DMSO-d δ): 1. 60-2. 2 5 (2H, m).

6' 2.57. 2.73. 2.82 (3H, s), 2.90-3.45 (2 H, m), 3.75. 3.82 (3H, s), 3. 50-3. 95 (2H, m), 3.95-5.25 (8H, rn), 6.55-8.00 (16H, m), 8.50-8.75 (IH, m) (2) mp: 98 ℃-(dec,)IR (Nujol): 3430-3220.　1630 ．．　1600゜1530cm' NMR (DMSO-d δ): 1.6-2.1 (6H, m), 2゜6' 4-3.3 (IIH, m), 3.6-4.0 (2H, m), 4.2-5゜2 (8H, m), 6.8-8.15 (17H, m), 8.45-8.75HMR (DMSO-d δ) + 1.75-1.9 (IH, m).

1, 9-2.1 (IH, m), 2. 19 (6H, s), 2.6-2.75 ( 4H, m), 2.80 (3H, s), 3.0-3.3 (2H, m).

3, 6-4.05 (2H, m), 4.25-5.20 (6H, m), 6°8 5-8.1 (17H, m), 8.5-8.65 (IH, m) Example 5 Trichlorochloroformate was added to a solution of indoline (238 mg) in methylene chloride (8 ml). Lomethyl (0.12 ml) is added under water cooling. The mixture was stirred at room temperature for 1 hour and then pipetted. Lysine (0.16 ml) is added and the mixture is stirred for a further hour and cooled on ice. departure Add the compound (818 mg) and TEA (0.21 ml) at the same temperature, and leave at room temperature for 5 hours. Over time, add TEA (0.10 ml) to the mixture with stirring. Distill the solvent The residue was extracted with ethyl acetate, and the separated organic layer was dissolved in sodium hydrogen carbonate solution, 0. ．． Wash sequentially with 5N hydrochloric acid and brine, and dry with magnesium sulfate. distill off the solvent , the residue was filtered into a silica gel column using chloroform-methanol (2%) as the eluent. The target compound (480 mg) was purified as an amorphous solid by chromatography (20 g). get as.

IR (Nujol): 3400.　3300.　1640. 1630゜m -m -1N (DMSO-d δ): 1.6-1.85 (IH, m).

6′ 1, 95-2. 2 (IH, m), 2. 71 and 2. 80 ( 3H,s).

2, 9-4.0 (8H, m), 4.2-4.7 (4H, m), 4.9- 5.2 (2H, m), 6.8-7.9 (16H, m), 8.4 (IH, m) MASS: M+ 576 Example 6 Starting compound 1 (1.0 g) is suspended in DMF (20 ml). suspension Cool to =15°C and add 4N HCl/DOX (1,53 ml). obtained Add t-butylnitrile (0.35ml) to the solution at the same temperature, and leave the solution for 20 minutes. Stir and add TEA (0.86 ml). In a separate reaction vessel, starting compound 11 ( Prepare a DMF (10ml) solution of TEA (0.99g) and TEA (0.43ml). do. This solution was added to the former reaction mixture at -20°C and the solution was heated at -10°C for 1 hour. , stir at 0° C. for 3 hours. The reaction mixture was poured into water (150 ml) and diluted with sodium bicarbonate. Adjust the pH to 8 with sodium chloride solution. Extract the product with ethyl acetate and separate the organic layer Wash with sodium bicarbonate and brine and dry with magnesium sulfate. melt The medium was distilled off, and the residue was eluted with chloroform-methanol (30+1 to 20:1). The target compound (1.41g) was subjected to silica gel column chromatography. ).

NMR (DMSO-d δ): 2.74 and 2. 81 (3H.

s), 2.85-3.25 (4H, m), 3.84 (3H, s), 4.2 -5. 2 (4H, m), 6.8-8.5 (21H, m), 11.79 (IH, br　s) Example 7 Starting compound (1,0 g) and TEA (0,59 ml) in methylene chloride (20 ml) ) Add indole-3-carbonyl chloride (0.41 g) to the solution under water cooling. Ru. The solution is stirred at the same temperature for 3 hours and at room temperature overnight. The solvent was distilled off and the reaction mixture Extract with ethyl acetate, and add the separated organic layer to an aqueous solution of sodium hydrogen carbonate, water, 0.5 Wash sequentially with N-hydrochloric acid, water and brine, and dry over magnesium sulfate. Retain the solvent The residue was purified using silica using a mixture of chloroform and methanol (30:1) as the eluent. Apply to Kagel column (65g). Combine both parts containing the target mixture and distill off the solvent. The target compound (1.0 g) was obtained as an amorphous solid.

IR (CHCI): 3350-3250. 1640cm’NMR ( DMSO-d δ): 2.76 and 2. 86 (3H.

6゛ s), 2. 95-3. 3 (4H, m), 3. 80 and 3. 83 (3H, s), 4. 3-4. 75 (3H, m), 5. 0-5. 25 (3H.

m), 6. 9-8. 0 (17H, m), 8. 65-8. 75 ( IH, m) Example 8 To a solution of the starting compound (0.86 g) in methylene chloride (18 ml) was added 4N hydrochloric acid/acetic acid. Add ethyl (16 ml) under water cooling. The solution is stirred for 30 minutes at the same temperature. ice bath is removed and the solution is stirred at room temperature for 1 hour. The solvent was distilled off and the residue was diluted with diethyl ether. Grind with a filter, collect by filtration, and dry under reduced pressure with sodium hydroxide. get. This material is partitioned between a sodium bicarbonate solution and a methylene chloride solution. minutes The separated organic layer is washed with water and dried over magnesium sulfate. Distill the solvent and remove the residue Dissolve in methylene chloride (5 ml) and add 4N HCl/DOX (0°153 ml) Add. The solvent was distilled off and the residue was dried under reduced pressure to remove the target compound (0.36 g). Obtained as a shaped solid.

NMR (DMSO-d δ): 1. 1-1. 8 (6H, m), 2゜ 6' 65-3. 3 (4H, m), 2.74 and 2.84 (3H, s ).

3.84 (3H, s), 4.3-5.2 (4H, m), 6.9-8.5 ( 22H, m) Example 9 The starting compound (0.50 g) was dissolved in THF (loml) and 4N HCl/DO Add X (0.39 ml) at room temperature. Add methylene chloride (10 ml) to the solution. Stir for 30 minutes. The solvent was distilled off, the residue was triturated with diisopropyl ether, It is filtered and dried to obtain the target compound (0.53 g) as an amorphous solid.

NMR (DMSO-d δ): 1.75-2.15 (2H, m).

6゜ 2, 7-3. 35 (IIH, m), 3. 45-4. 2 (5H, m), 4. 3-5.2 (7H, m), 6. 85-8. 15 (17H, m ), 8. 5-8゜65 (LH, m) Example 10 Triethylamine was added to a solution of the starting compound (1.73 g) in methylene chloride (25 ml). (0,707g) and trimethylacetyl chloride (0,844g) under water cooling. and stir the resulting solution for 15 minutes at the same temperature. Add solution to trifluoroacetic acid (3,82 g) and triethylamine (0,707 g) in methylene chloride (35 g). ml) to the medium-hot mixture while cooling with water. The mixture was stirred at the same temperature for 1 hour and at room temperature overnight. Ru. Triethylamine (0.35 ml) was added to the mixture and the solution was stirred for a further 6 hours. Stir. The reaction mixture was mixed with water, dilute sodium bicarbonate solution, 0.5N hydrochloric acid and salt. Wash sequentially with water and dry with magnesium sulfate. The solvent was distilled off and the residue silica using a mixture of lume and methanol (98:8 to 96.5:3.5) as the eluent. Apply the target compound (2.70 g) to a gel column (80 g) as an amorphous solid. obtain.

NMR (DMSO-d δ) = 1.22 (3H, t, J = 7Hz).

6' 1, 7-2. 1 (2H, m), 2. 72 and 2.81 (3H ,s).

3, 0-3.2 (2H, m), 3. 6-4. 0 (2H, m), 4 ．． 17 (2H, q, J=7Hz), 4. 2-4. 6 (3H, m), 4. 7 (IH.

m), 5.0-5.25 (3H, m), 5.23 (2H, s), 6.8- 8, 1 (17H, m), 8. 56 (IH, m) Example 11 A solution of the starting compound (2.70 g) in ethanol (50 ml) was added with IN sodium hydroxide. A mixture of ethanol (4.1 ml) and ethanol (5 ml) is added dropwise at room temperature. blend Stir for 1.5 hours. The ethanol was distilled off, the residue was diluted with water, and the residue was diluted with diethyl ether. Extract once with tel. The separated organic layer and aqueous layer were adjusted to pH 1 with IN hydrochloric acid and chlorinated. Extract twice with methylene. The extract and the organic layer were combined, washed with brine, and washed with sulfuric acid. Dry with magnesium. The solvent was distilled off and the target compound (2.20g) was amorphous. Obtained as a solid.

IR (Nujol) + 1730.　1620. 3300cm’NMR (DMSO-d　δ)　+1. 7-2. 1 (2H, m), 2゜6゛ 71 and 2.81 (3H, s), 3. 1-3.5 (2H, m), 3 ゜65 and 3. 9 (2H, m), 4. 3-4. 6 (2H, m) , 4゜72 (LH, t, J=7Hz), 5.05 (2H, m), 5.1 2 (2H.

s), 6. 8-8. 2 (18H, m), 8. 6 (IH, m) Implementation Example 12 Starting compound (654 mg), 3,5-dimethylpyrazole-1-carboxamide Mixture of ginnidrade (201 ml) and triethylamine (202 ml) Stir overnight at room temperature. Triethylamine (145 mg) and 3,5-dimethyl Pyrazole-1-carboxamidine nidrade (402 mg) was added and the mixture Stir for an additional 4 days. The mixture was concentrated, diluted with water and adjusted to pH 4 with IN hydrochloric acid. do. Extract the solution twice with a mixed solvent of chloroform and n-butanol (4:1) do. The extracts were combined, the solvent was distilled off, the residue was triturated with ethyl acetate, and the precipitate was filtered. The sample was taken and dried to obtain the target compound (680 mg) as an amorphous solid.

IR (Nujol): 3350.　3200.　1635.　15300m NMR (DMSO-d δ): 1. 8-2. 2 (2H, m), 2゜ 6゜ 73 and 2.80 (3H, s), 3.0-3. 3 (2H, m) , 3°5-3. 75 (3H, m), 3. 9 (IH, m), 4. 3-4 ．． 8 (6H.

m), 5. 1 (2H, m), 6. 9-7. 3 (IOH, m), 7 ．． 4-7, 6 (5H, m), 7. 7-7, 95 (5H, m), 8. 1 (If I.

m), 8.56 (IH, m) MASS (FAB) + M+H660 Example 13 A solution of N-benzylmethylamine (0.50 g) in methylene chloride (20 ml) was added. Trimethyl roroformate (0.41 g) is added under water cooling. Stir at room temperature for 1 hour, then Add lysine (0.32 g) to the mixture. The reaction mixture is stirred for a further 2 hours.

Starting compound (1,69 g) and triethylamine (0,47 g) were added to the mixture; Add 4-dimethylaminopyridine (0.50 g) to the mixture at room temperature to complete the reaction. Stir overnight while adding to the mixture. The mixture was concentrated, diluted with water and extracted with ethyl acetate. put out The separated organic layer was mixed with sodium bicarbonate solution, water, 0.5N hydrochloric acid, water and Wash with water and brine, and dry with magnesium sulfate. Distill the solvent and clean the residue. Silica gel column with a mixture of loloform and methanol (20:1) as the eluent (50 g) to obtain the target compound (1.17 g) as an amorphous solid.

NMR (DMSO-d δ): 1. 5-1. 7 (IH, m), 1゜ 6′ 8-2. 0 (IH, m), 2. 63 (3H, m), 2.77 and 2゜85 (3H, s), 2. 9-3. 3 (2H, m), 3. 5-3 ．． 7 (2H.

m), 4.1-5.3 (8H, m), 6.8-8.2 (17H, m).

8, 8-8. 9 (IH, m) MASS: M+ 578 Example 14 A solution of the starting compound (1.97 g) in ethanol (40 ml) was added with IN sodium hydroxide. Add 2.69g of rum (2.69g). The solution is stirred at room temperature for 2 hours. distill off ethanol , add water and ethyl acetate, and separate the aqueous layer. Adjust the pH to 5 with IN hydrochloric acid and dissolve the solution. Leave it overnight. The formed precipitate is collected by filtration, washed with water, and dried to obtain the target compound (1, 60g).

IR (Nujol): 3470.　3150.　1650.　1595゜1 540, 1400. 1230 cm NMR (DMSO-d δ): 1.8-2.0 (IH, m), 2゜6゜ 1-2. 3 (IH, m), 2. 23 (6H, s), 2.6-2.9 (5H.

m), 3. 0-3. 3 (2H, m), 3. 8-5. 2 (12H , m).

6, 85-8. 1 (17H, m), 8.5-8. 7 (IH, m) Implementation Example 15 Triethylamine was added to a solution of the starting compound (4.69 g) in methylene chloride (47 ml). (1,44 g) and methanesulfonyl chloride (0,814 g). Obtained The resulting mixture was mixed with methanesulfonyl chloride (0.82 g) and triethylamine (1 , 44 g) and stirred at room temperature for 3 hours. Wash the solution with water and collect the sample. Dry the machine layer with magnesium sulfate. This crude product was mixed with chloroform and methanol. The eye was applied to a silica gel column (162 g) using a mixture (40:1) of The target compound (4.77 g) is obtained as an amorphous solid.

NMR (DMSO-d δ): 1.1-1.25 (3H, m).

6゜ 2.0-2.2 (IH, m), 2.3-2.6 (IH, m), 2.73 and Bi 2. 78 (3H, s), 3. 22 (3H, s), 3. 0-3 ．． 3 (2H, m), 3.8-5.4 (IIH, m), 6.85-8.1 (17H, m), 8. 4-8. 8 (IH, m) Example 16 Starting compound (4,73 g) and sodium azide (0,83 g) in dimethylsulfate Heat the phoxide (25 ml) solution at 70° C. overnight. After cooling, ethyl acetate (10 0 ml) and water (100 ml). Separate the organic layer and add water (twice) and saline. Wash and dry with magnesium sulfate. After filtration, the filtrate is concentrated to 50 ml.

Triphenylphosphine (1.68 g) was added to this solution and the mixture was stirred at 50 °C for 3 Stir for an hour. Water (0°35ml) was then added and the mixture was stirred at 65°C for 5 hours. do. The solvent was distilled off, and the residual oil was dissolved in a mixture of chloroform and methanol (10:1). ~4:1. It was applied to a silica gel column (150 g) using gradient elution) as the eluent, The target compound (3.11 g) is obtained.

IR (CHCl, ): 3200.　1750.　1630.　1540゜1 490, 1420. 1200 cm-1HMR (DMSO-d, δ): 1. 1-1. 3 (3H, m), 1. 5-1. 7 (IH, m), 2. 25-2. 45 (IH, m), 2. 65-2゜85 (3H, m ), 3. 0-3. 5 (6H, m), 3. 7-5. 3 (9H.

m), 6. 8-8. 1 (17H, m), 8. 5-8. 8 (IH ,m)+ MASS (FAB): 660.2 (M+1), 682.3 (M+N a)” Example 17 The target compound is obtained in the same manner as in Example 1.

(1) mp: 196-200℃ IR (Nujol): 3450. 1660 (sh), 1640°159 0,1575. 1530 cm-1HMR (DMSO-d,, δ): 1. 5-2. 2 (2H, m), 2゜71 and 2. 76 (3H,s ), 2.8-3. 0 (IH, m), 3°5-3. 6 (IH, m), 3. 18 and 3. 23 (3H, s), 3°7-4. 0 (2H , m), 3. 85 and 3. 86 (3H, s), 4゜3-4. 6 (3H, m), 5.1 (3H, m), 5.7 (IH, m).

6, 8-8. 2 (17H, m) Elemental analysis: Calculated value: C73,61, H6,51, H9,28 Actual value: C 73, 45, H6, 44, H9, 12 (2) IR (Nujol) + 164 0 cm-1 NMR (DMSO-d,, δ): 1.5-2.3 (2H, m) , 2.71 and 2.74 (3H, s), 2.8-3.0 (IH, m ), 3゜13-3.18 (3H, s), 3.4-3.8 (3H, m), 4.3-4゜6 (3H, m), 4.8-5.0 (IH, m), 5.4 and and 5.6-5.8 (2H, m), 6.8-8.0 (14H, m), 8. 85 (2H.

m), 9.30 (LH, m) (3) IR (CHCl, ) + 3450.　3300.　1660゜160 0,1510.　1450. 1280 cm-1HMR (DMSO-d, δ ) + 1. 6-2. 4 (4H, m), 2. 7-2.9 (5H, m), 2.9-3.8 (IOH, m), 4.1-5.2 (6H, m), 6. 5 -7. 9 (14H, m), 8. 4-8. 5 (LH.

m), 8.7-8.9 (LH, m) MASS: M” 623 (4) IR (CHCl, ): 3270.　1740.　1650゜160 0,1530.　1470. 1200 cm-1HMR (DMSO-d, δ ) + 1.0-11 (3H, m), 1.65-2.1 (2H, m), 2.19 (6H, s), 2.6-2.7 (2H.

m), 2.8-3.3 (2H, m), 3.6-5.1 (14H, m).

6.9-8.1 (17H, m), 8.4-8.6 (IH, m) MASS (FAB) + 718.3 (M+1)’, 740.3 (M+Na)” ( 5) IR (CHCl3) + 3320.　1755.　1630゜1530 , 1460. 1430. 1210. 1130cm-1HMR (DMSO -d6. δ): 1. 16 (3H, t, J=7°1Hz), 1.75 -1.95 (LH, m), 2.19 (6H, s).

2.05-2.35 (IH, m), 2.5-2.9 (5H, m), 3.0- 3.3 (2H, m), 3.75-5.20 (13H, m), 6.85-8 ゜15 (17H, m), 8.5-8.7 (IH, m) MASS (FAB ): 732.5 (M+1)゛, 754.4 (M+Na)' Example 18 The target compound is obtained in the same manner as in Example 10.

(1) IR (Nujol): 3430.　3300.　1732゜165 0 (sh), 1630. 1605 cm-1HMR (DMSO-d, δ ): 1.7-2.1 (3H, m), 1°14 (3H, t, J=7Hz ), 2.29 (2H, t, J=7Hz), 2°71 and 2. 81 (3H, s), 3. 0-3. 3 (2H, m), 3゜65 (IH, m) , 3.9 (LH, m), 4.02 (2H, q, J=7Hz), 4.2-4 ．． 55 (5H, m), 4.71 (IH, m), 5°0-5. 2 (2H, m), 6. 87-8. 07 (17H, m), 8. 54(], H, m ) Elemental analysis: Calculated value: C69,67, H6,56, H7,93 actual measurement 1i1: C69,54, H6,56, H7,83 (2) mp: 184-187℃ (dec,) IR (Nujol): 3400.　3300.　1660.　 1625°1600cm-1 NMR (DMSO-d,, δ): 1. 7-2. 1 (2H, m), 2 ゜71 and 2. 81 (3H, s), 3. 0-3. 3 (2H, m ), 3゜7 and 3. 97 (2H, m), 4. 2-4. 6 (3 H, m), 4°73 (LH, m), 5.0-5.2 (2H, m), 5.61 (2H, s).

6, 8-7. 9 (IH, m), 8. 11 (2H, brs), 8. 55 (2H, m) Elemental analysis: Calculated value: C73,96, H5,90, N10.52 Actual value: C72,83, H5,8B, NIo, 10(3) mp: 115-120℃ IR (Nujol): 3430.　3300. 1710. 1655゜1 630, 1600 cm-1 HMR (DMSO-d, δ): 1.74 and 1. 35 (9H.

s), 1.7-2.1 (2H, m), 2.71 and 2. 80 (3 H.

s), 3. 0-3. 3 (2H, m), 3. 3 (2H, m), 3 ．． 7 and 3.9 (2H, m), 4.2-4.6 (5H, m), 4.7 (LH.

m), 5.0-5.2 (2H, m), 6.8-7.9 (17H, m).

8.06 (IH, d, J=8Hz), 8.53 (LH, m) Elemental analysis-meter Calculated value: C7Q, 27. H6,60,N9.76 actual measurement value: C69,19 , H6, 61, N9.57 (4) IR (CHCl, ): 3450-330 0.　1750゜1640, 1535. 1190 cm-1HMR (DMSO -d,,δ): 1. 22 (3H, t, J=7°06Hz), 1.65 -2.15 (2H, m), 2.71 and 2°81 (3H, s), 2.9-3.3 (2H, m), 3.34 (2H, s).

3.5-5.3 (IOH, m), 6.8-8.15 (17H, m), 8 ゜45-8.6 (IH, m) MASS (FAB): 661.3 (M+1)”, 683.2 (M+ Na)''Example 19 The target compound is obtained in the same manner as in Example 11.

(1) IR (Nujol): 3400-3300.　1720゜1630 cm-1 NMR (DMSO-d@, δ): 1. 7-2. 1 (3H, m), 2 ゜22 (2H, m), 2. 71 and 2. 81 (3H, s), 3. 0-3, 3 (2H, m), 3. 64-3. 69 (IH, m ), 3. 92 (LH.

m), 4.2-4. 5 (5H, m), 4. 71 (IH, m), 4. 9-5, 2 (2H, m), 6. 9-8. 1 (17H, m), 8. 54 (IH.

m), 12.2(N(, br 5) (2) IR (Nujol): 3420.　3260.　1650-159 0,1530. 1310. 1260. 1200 am-INMR (DMS O-d,, δ): 1. 8-2. 0 (IH, m), 2. 4-2. 6 (IH, m), 2.70 and 2.73 (3H, s), 2. 9- 3.3 (2H, m), 3.7-5.2 (12H, m), 6.8-8.1 (17H , m), 8. 8-9.0 (IH, m) MASS (FAB): 632 ．． 3 (M+1)', 654.2 (M+Na)' Example 20 The target compound is obtained in the same manner as in Example 19.

MASS (FAB): M+H618, 3 Example 21 The target compound is obtained in the same manner as in Example 11.

IR (Nujol) +3400-3200.　1640.　1600゜15 50, 1200 cm-1 HMR (DMSO-d,, δ): 1. 7-1. 9 (LH, m), 1. 9-2. 1 (IH, m), 2. 24 and 2. 26 (6H, s), 2. 7-3. 3 (4H, m), 3. 6-5. 1 (12H, m ), 7. 0-8. 1 (18H, m), 8. 60 (IH,brs) Example 22 The target compound is obtained in the same manner as in Example 13.

IR (CHt, ts): 3450-3300.　1640.　1480゜1 390, 1200 cm-1 HMR (DMSO-d,, δ): 1. 5-1. 7 (IH, m), 1. 8-2. 0 (IH, m), 2. 65-2. 85 (6H, m), 3. 0-3. 7 (4H, m), 3.80 (3H, s), 4.05-5.3 (8H, m).

6, 8-8. 2 (161-1, m), 8. 8-8. 9 (IH, m) MASS: M”608 International Investigation Report...↑ノ16◇ri/I'll'17 (In front page) continuation (51) Int, C1,' Identification symbol Internal office reference number A61K 38100 ABJ CO7K 1106 I A61K 37102 ABA BJ Ah

Claims (1)

[Claims] 1. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R1 is a lower alkyl group, an aryl group, an alkyl group, an aryl Ruamino group, pyridyl group, pyrrolyl group, pyrazolopyridyl group, quinolyl group, and is a formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula: is a single bond or double weight bond, X is CH or N, and Z is O, S or or NH, meaning that these groups may have appropriate substituents. ); R2 is hydrogen or a lower alkyl group; R3 is hydrogen or a suitable substituent; R4 is a lower alkyl group which may have a suitable substituent; and R5 is a suitable substituent. Al (lower) alkyl group or pyridyl (lower) alkyl group that may have a substituent or R4 and R5 are bonded to each other to represent a benzene-fused lower alkyl group. Forms a lene group; A is an amino acid residue that may have an appropriate substituent; and Y means -, a lower alkylene group, a lower alkenylene group, or a lower alkylimino group, respectively, provided that R1 is an aryl group Or formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, X has the same meaning as before, and Z is O or N-R (In the formula, R is hydrogen or means a lower alkyl group], R2 is hydrogen, R4 is a lower alkyl group that may have an appropriate substituent, and R5 is an alkyl group that may have an appropriate substituent. (lower) alkyl group, A is the formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. It is a substituent. ] or pharmaceutically acceptable compounds thereof. salt. 2. R1 is a di(lower)alkoxyphenyl group, a mono-, di- or triphenyl(lower)alkyl group which may have a lower alkoxy group, an indolinyl group, a Lysyl group or formula: ▲ Numerical formulas, chemical formulas, tables, etc. , esterified carboxy (lower) alkyl group, amino (lower) alkyl group, guanidine (lower) alkyl group, pyridyl (lower) alkyl group or acylamino (lower) alkyl group, and R8 mean hydrogen or halogen. ), R3 is a lower R4 is a lower alkyl group, a carboxy (lower) alkyl group, or an esterified carboxy (lower) alkyl group, R5 is a mono-, di-, or triphenyl (lower) alkyl group or a pyridyl (lower) alkyl group; A is a lower alkoxycarbonyl group, a carboxy (lower) alkyl group, Hydroxyproline, which may be substituted with a substituent selected from the group consisting of terified carboxy (lower) alkyl group and (lower) alkyl sulfonyl group. 2. A compound according to claim 1, which is a divalent residue derived from an amino acid selected from the group consisting of lysine, serine, methionine, lysine, histidine, glutamine, thioproline and aminoproline. 3. R1 is a formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R6 means a lower alkyl group and R8 means hydrogen.), R2 is hydrogen, R4 is a lower alkyl group, R5 is phenyl (lower) 3. The compound according to claim 2, wherein the alkyl group A is a divalent residue derived from hydroxyproline, and Y is -. 4. The compound according to claim 3, which is selected from the group consisting of (1) ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ (2) ▲ ▲ Contains mathematical formulas, chemical formulas, tables, etc. ▼ 5. R1 is a di(lower)alkoxyphenyl group, a mono-, di- or triphenyl(lower)alkyl group which may have a lower alkoxy group, an indolinyl group, a Lysyl group or formula: ▲ Numerical formulas, chemical formulas, tables, etc. , esterified carboxy (lower) alkyl group, amino (lower) alkyl group, guanidine (lower) alkyl group, pyridyl (lower) alkyl group or acylamino (lower) alkyl group and R8 mean hydrogen or halogen. ), R3 is hydrogen, R4 is a lower alkyl group, carboxy (lower) alkyl group, or esterified carboxy (lower) alkyl group, R5 is a mono-, di-, or triphenyl (lower) alkyl group, and A is a side chain. glycine, serine, which may be substituted with a substituent selected from a group consisting of a lower alkoxycarbonyl group, a carboxy (lower) alkyl group, an esterified carboxy (lower) alkyl group, and a (lower) alkylsulfonyl group; Methionine, Ri 2. The compound according to claim 1, which is a divalent residue derived from an amino acid selected from the group consisting of zine, histidine, glutamine, thioproline and aminoproline. 6. R1 is a formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R6 means a lower alkyl group and R8 means hydrogen.), R2 is hydrogen, R4 is a lower alkyl group, R5 is phenyl (lower) Alkyl group, A is glycine, serine, methionine, lysine, histidine, glutamine, thiop 6. The compound according to claim 5, wherein the divalent residue is derived from an amino acid selected from the group consisting of loline, and Y is -. 7. (1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (2) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (3) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (4) ▲There are mathematical formulas, chemical formulas, tables, etc. Yes ▼ (5) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or their hydrochloride (6) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (7) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (8) ▲ Mathematical formulas , a chemical formula, a table, etc. ▼ The compound according to claim 6, which is selected from the group consisting of ▼. 8. R1 is a di(lower)alkoxyphenyl group, a mono-, di- or triphenyl(lower)alkyl group which may have a lower alkoxy group, an indolinyl group, a Lysyl group or formula: ▲ Numerical formulas, chemical formulas, tables, etc. , esterified carboxy (lower) alkyl group, amino (lower) alkyl group, guanidine (lower) alkyl group, pyridyl (lower) alkyl group or acylamino (lower) alkyl group, and R8 mean hydrogen or halogen. ), R3 is hydrogen, R4 is a lower alkyl group, carboxy(lower) alkyl group, or esterified carboxy(lower) alkyl group, R5 is a mono-, di-, or triphenyl(lower) alkyl group, and A is a carboxy(lower) alkyl group. Optionally substituted with a substituent selected from a group consisting of a xy(lower)alkyl group, an esterified carboxy(lower)alkyl group, and a lower alkylsulfonyl group. 2. A compound according to claim 1, which is a divalent residue derived from hydroxyproline. 9. R1 is a di(lower) alkoxyphenyl group, a diphenyl(lower) alkyl group, an indolinyl group, a pyridyl group, or a formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R6 is a di(lower) alkylamino (lower) alkyl group, pyrrolidinyl (lower) alkyl group, carboxy (lower) alkyl group, amino (lower) alkyl group, guanidino (lower) alkyl group, or pyridyl (lower) alkyl group, and R8 means hydrogen), R4 is a lower alkyl group or a carboxy (lower) alkyl group, R5 is a phenyl (lower) alkyl group, A is a divalent residue derived from hydroxyproline optionally substituted with a carboxy (lower) alkyl group, and The compound according to claim 8, wherein Y is -, a lower alkylene group or a lower alkenylene group. thing. 10. (1) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (2) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (3) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or its hydrochloride (4) ▲Mathematical formulas, chemical formulas , tables, etc. ▼ (5) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or its hydrochloride (6) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or its hydrochloride (7) ▲ Mathematical formulas, chemical formulas, tables, etc. There are ▼ (8) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (9) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (10) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (11) ▲ Mathematical formulas, chemical formulas, The compound according to claim 9, which is selected from the group consisting of ▼ (12) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (13) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼. 11. Formula: Formula: ▲Mathematical formula, chemical formula, table, etc.▼ [In the formula, R1 is a lower alkyl group, an aryl group, an alkyl group, an aryl Ruamino group, pyridyl group, pyrrolyl group, pyrazolopyridyl group, quinolyl group, and is a formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula: is a single or double bond, X is CH or N, and Z is O, S or NH, these groups have appropriate substituents. ); R2 is hydrogen or a lower alkyl group; R3 is hydrogen or a suitable substituent; R4 is a lower alkyl group which may have a suitable substituent; and R5 is a suitable Placed Al (lower) alkyl group or pyridyl (lower) alkyl group that may have a substituent or R4 and R5 are bonded to each other to represent a benzene-fused lower alkyl group. Forms a lene group; A is an amino acid residue that may have an appropriate substituent; and Y means -, a lower alkylene group, a lower alkenylene group, or a lower alkylimino group, respectively, provided that R1 is an aryl group Or formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, X has the same meaning as before, and Z is O or N-R (In the formula, R is hydrogen or means a lower alkyl group], R2 is hydrogen, R4 is a lower alkyl group that may have an appropriate substituent, and R5 is an alkyl group that may have an appropriate substituent. (lower) alkyl group, A is the formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. It is a substituent. ] Formula (1): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R2, R3, R4, R5 and A each have the same meaning as before. Yes] or a reactive derivative thereof at the amino group or a salt thereof is reacted with a compound represented by the formula: R1-Y-COOH (wherein R1 and Y each have the same meaning as before) to form a compound of the formula : ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1, R2, R3, R4, R5, A and Y each have the same meanings as before) to obtain the compound or its salt, or ( 2) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R2, R3, R4, and R5 each have the same meanings as before) The compound or its reactive derivative in the amino group or its salt and a compound represented by the formula: R1 -Y-CO-A-OH (wherein R1, A and Y each have the same meaning as before) or or a reactive derivative thereof at the carboxy group or a salt thereof, the formula: ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ (wherein R1, R2, R3, R4, R5, A and Y are respectively have the same meaning) or a salt thereof, or obtain a compound represented by the formula (3): ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R1, R2, R3, R4, R5 and Y are each same meaning, A is a protected amino group, a protected hydroxy group and/or a protected carboxyl group. (meaning an amino acid residue containing an xyl group) or a salt thereof is subjected to an elimination reaction of an amino protecting group, a hydroxy protecting group and/or a carboxy protecting group, and the formula: ▲Mathematical formula, chemical formula, table, etc. ▼ (wherein R1, R2, R3, R4, R5 and Y each have the same meaning as before, A means an amino acid residue containing an amino group, a hydroxy group and/or a protected carboxy group) Obtain the compound shown or a salt thereof, or formula (4): ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R2, R3, R4, R5, A, X and Y each have the same meaning as before, R is a protected carboxy (lower) alkyl group or a protected amino (lower) alkyl group, and R8 means hydrogen or halogen) or a salt thereof. For the elimination reaction of xy-protecting group or amino-protecting group, formula: Formula: ▲Mathematical formula, chemical formula, table, etc.▼ (In the formula, R2, R3, R4, R5, R6, A, X and Y are Each has the same meaning as the previous one Taste, R■ means carboxy (lower) alkyl group or amino (lower) alkyl group. or a compound represented by the formula (5): ▲Mathematical formula, chemical formula, table, etc.▼ (In the formula, R1, R2, R3, R4, R5, A1, and Y are each same meaning as before compounds with amino groups, hydroxyl groups, and/or carbon A reactive derivative thereof or a salt thereof at the carboxy group is subjected to an amino-protecting group, hydroxy-protecting group, and/or carboxy-protecting group introduction reaction with the formula: ▲Mathematical formula, chemical There are formulas, tables, etc.▼ (In the formula, R1, R2, R3, R4, R5, A2, and Y each have the same meaning as before. or a salt thereof, or obtain a compound represented by formula (6): ▲Mathematical formula, chemical formula, table, etc.▼ (wherein R1, R2, R3, R4, R5, and Y are each A3 means an amino acid residue containing sulfonyloxy with a suitable substituent) or a salt thereof and a compound represented by the formula: MaN3 (wherein Ma means an alkali metal) When reacted with a compound, the formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. A compound or a salt thereof is obtained and then subjected to a hydrogenation reaction to form the formula: ▲Mathematical formula, chemical formula, table, etc.▼ (In the formula, R1, R2, R3, R4, R5, and Y are Each has the same meaning as before, and A5 means an amino acid residue having an amino group) or a salt thereof, or formula (7): ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R1, R2, R3 , R5, A and Y each have the same meaning as before, and R■ means a protected carboxy (lower) alkyl group) or a salt thereof is subjected to an elimination reaction of the carboxy protecting group to form the formula : ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R1, R2, R3, R5, A and Y each have the same meaning as before, and R means a carboxy (lower) alkyl group) (8) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R2, R3, R4, R5, R8, A, X and Y each have the same meaning as before. taste, and R■ means an amino (lower) alkyl group) or The salt is subjected to an amidino group introduction reaction and the formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R2, R3, R4, R5, R8, A, X and Y each have the same meaning as before, and R means a guazino (lower) alkyl group) or 1. A method for producing a peptide compound, characterized in that a salt thereof is obtained. 12. A pharmaceutical product prepared by mixing the compound of claim 1 with a pharmaceutically acceptable carrier or excipient. Pharmaceutical composition. 13. The compound of claim 1 is mixed with a pharmaceutically acceptable carrier or excipient. A method for producing a pharmaceutical composition. 14. Use of the compound of claim 1 as a medicament. 15. Use of the compound of claim 1 as a tachykinin antagonist. 16. Use of the compound of claim 1 as a substance P antagonist. 17. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment of tachykinin-mediated diseases. 18. A method of treating a tachykinin-mediated disease comprising administering a compound of claim 1 to a human or animal.