JPH03127732A - Vasopressin antagonist - Google Patents

Abstract

PURPOSE:To obtain vasopressin antagonist containing specific indole derivative or salt of said derivative as active ingredient. CONSTITUTION:The aimed antagonist contains a compound expressed by the formula [R<1> is H, alkyl, alkenyl, phenylalkyl, tetrahydrofuryl or alkanoyl, etc.; R<2> is H, OH, alkoxy, alkyl or halogen, etc.; R<3> is OH, alkoxy, NR<6>R<7> (R<6> and R<7> are H, alkyl or alkenyl) or amino acid residue formable of amide bonding with bonded CO; R<4> is H, alkyl or phenylalkyl; R<5> is benzoyl, phenylalkenyl carbonyl or phenyl sulfonyl, etc.] or salt of said compound, e.g. methyl 2[Nalpha- methyl-Nalpha-(4-chlorobenzoyl)amino]-3-(3-indolyl)acrylate as active ingredient. Said antagonist is effective for prevention and remedy of hypertension, edema, abdominal dropsy, cardiac failure, renal insufficiency, vasopressin maladjustment, secretion syndrome, hyponatremia, hypopotassemia or circulatory failure, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a pap pressin antagonist, and more particularly to a pap pressin antagonist characterized by containing a specific indole derivative or a salt thereof as an active ingredient.

BACKGROUND OF THE INVENTION The present inventors have discovered that a series of compounds represented by the general formula (1,) described below have a hitherto unknown antagonistic effect on pap pressin.

Problems to be Solved by the Invention Accordingly, an object of the present invention is to provide a new pap pressin antagonist.

Means for Solving the Problems According to the present invention, the general formula [wherein R1 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a phenyl lower alkyl group, a tetrahydrofuryl group,
It represents a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group, or a lower alkanoyl group. R2 represents a hydrogen atom, a hydroxyl group, a lower alkoxy group, a phenyl lower alkyl group, a lower alkyl group, a phenyl lower alkoxy group, or a halogen atom. R3 is a hydroxyl group, a lower alkoxy group, a group -NR6R7 (
R6 and R7 are the same or different and represent a hydrogen atom, a lower alkyl group with or without 1 to 3 halogen atoms as a substituent, a phenyl lower alkyl group, a lower alkenyl group, or a cycloalkyl group, or L+"'77 which may have a phenyl group, 22nd alkyl group, or hydroxyl group as a substituent, without the need for an elementary atom or an oxygen atom, together with the nitrogen atom to which they are bonded.
represents a 6-membered saturated heterocyclic group. ), or applicable! Indicates an amino acid residue that can form an amide bond with the CO group bound to It may be converted to a certain 1-pyrrolidinylcarbonyl group, lower alkoxycarbonyl group or carbamoyl group. R4 represents a hydrogen atom, a lower alkyl group or a phenyl lower alkyl group. R5 is a halogen atom as a substituent on the phenyl ring,
A group selected from the group consisting of a nitro group, a cyanogen group, a lower alkoxy group, a phenyl group, and a lower alkyl group having or not having 1 to 3 halogen atoms as a substituent. Indicates a certain benzoyl group, a phenyl lower alkenylcarbonyl group that may have a nitro group as a substituent on the phenyl ring, a thienylcarbonyl group, or a phenylsulfonyl group that may have a lower alkyl group as a substituent on the phenyl ring. Furthermore, the bonds at the 1st and 2nd positions in the side chain of the indole skeleton represent a single bond or a double bond. ] There is provided a pap pressin antagonist characterized by containing an indole derivative or a salt thereof as an active ingredient.

According to the research conducted by the present inventors, it has been found that both the indole derivative represented by the above general formula (1) and its salt have an excellent pap pressin antagonistic effect.

The pap pressin antagonist of the present invention has, for example, vasodilatory action,
It has antihypertensive, diuretic, and platelet aggregation inhibitory effects, and is useful as a vasodilator, antihypertensive, diuretic, platelet aggregation inhibitor, etc., and is effective against hypertension, edema, ascites, heart failure, renal dysfunction, and vasopressin deficiency. Adaptation, secretory syndrome (S IAPH)
), is effective in the prevention and treatment of hyponatremia, hypokalemia, circulatory failure, etc.

In the above general formula (1) representing the active ingredient compound of the present invention and other groups used herein, each group is as follows.

Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,
Examples include straight chain or branched alkyl groups having 1 to 6 carbon atoms such as hexyl group.

Examples of lower alkenyl groups include vinyl, allyl, 2
Examples include straight or branched alkenyl groups having 2 to 6 carbon atoms such as -butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, and 2-hexenyl.

Examples of the phenyl lower alkyl group include benzyl, 2
-Phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 111-dimethyl-2
- Lower alkoxycarbonyl groups in which the alkyl moiety is a straight or branched alkyl group having 1 to 6 carbon atoms, such as phenylethyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3-phenylpropyl groups, etc. , for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc. having 1 to 6 carbon atoms
An example is a carbonyl group having a straight chain or branched alkoxy group.

Examples of lower alkoxycarbonyl lower alkyl groups include methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, isopropoxycarbonylmethyl, butoxycarbonylmethyl, isobutoxycarbonylmethyl, pentyloxycarbonylmethyl, hexyloxycarbonylmethyl, and 2-methoxycarbonylmethyl. Ethyl, 1-ethoxycarbonyl ethyl, 3-propoxycarbonylpropyl, 4-isopropoxycarbonylmethyl, 1,1-dimethyl-2-butoxycarbonyl ethyl, 5-isobutoxycarbonylpentyl, 6-
Pentyloxycarbonylhexyl, 2-methyl-3-
Examples include alkoxycarbonylalkyl groups in which the alkyl moiety and the alkoxy moiety are linear or branched alkyl groups having 1 to 6 carbon atoms or the same alkoxy groups, such as a hexyloxycarbonylprobyl group.

Examples of the carboxy lower alkyl group include carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 1,
1-dimethyl-2-carboxyethyl, 5-carboxypentyl, 6-carboxyhexyl, 2-methyl-3-
Alkyl moiety such as carboxypropyl group has 1 to 6 carbon atoms
Examples include carboxyalkyl groups which are straight-chain or branched-chain alkyl groups.

Examples of lower alkanoyl groups include straight-chain or branched alkanoyl groups having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, and hexanoyl groups.

Examples of lower alkoxy groups include those having 1 to 1 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, and hexyloxy groups.
6, a straight chain or branched alkoxy group can be exemplified.

Examples of phenyl lower alkoxy groups include benzyloxy, 2-phenylethoxy, 1-phenylethoxy, 3-phenylpropoxy, 4-phenylbutoxy, 1-dimethyl-2-phenylethoxy, 5-phenylpentyloxy, Examples include phenylalkoxy groups in which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms, such as 6-phenylhexyloxy and 2-methyl-3-phenylpropoxy groups.

Examples of halogen atoms include fluorine, chlorine, bromine and iodine atoms.

Examples of the cycloalkyl group include cycloalkyl groups having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

Examples of 5- or 6-membered saturated heterocyclic groups that can be formed by R4 and R5 together with the nitrogen atom to which they are bonded, with or without a nitrogen atom or an oxygen atom, include pyrrolidinyl, piperazinyl, morpholino, Examples of the saturated heterocyclic group having a phenyl group, lower alkyl group, or hydroxyl group as a substituent include 4-phenylpiperazinyl, 4-phenylpiperidinyl, 3-phenylmorpholino, 2- or 3-phenylpyrrolidinyl, 3-phenylpiperidinyl, 2-phenylpiperazinyl, 4-methylpiperazinyl, 3-ethylpiperazinyl, 2-propylpiperazinyl, 4-butylpiperazinyl Nyl, 3-hexylpiperidinyl, 2-methylpiperidinyl, 3-pentylpyrrolidinyl, 2-isopropylpyrrolidinyl, 3-hydroxypyrrolidinyl, 2-hydroxypyrrolidinyl, 3-hydroxymorpholino, 2-hydroxymorpholino, 4-hydroxypiperidinyl, 3-hydroxypiperidinyl, 2-hydroxypiperidinyl,
Phenyl groups such as 4-hydroxypiperazinyl, 3-hydroxypiperazinyl, 2-hydroxypiperazinyl groups,
The above-mentioned heterocyclic group substituted with a straight chain or branched alkyl group having 1 to 6 carbon atoms or a hydroxyl group can be exemplified.

Examples of amino acid residues that can form an amide bond with the CO group to which R3 is bonded include alanine residue, N2-arginine residue, N5-arginine residue, N6-arginine residue, N4-asparagine residue, aspartic acid residue,
N5-glutamine residue, cysteine residue, glutamic acid residue, glycine residue, histidine residue, isoleucine residue, leucine residue, N2-lysine residue, N6-lysine residue, methionine residue, phenylalanine residue, Examples include proline residue, serine residue, threonine residue, tryptophan residue, tyrosine residue, and valine residue. Also, those in which the carboxyl group present on the above amino acid residue is converted to a phenyl lower alkoxycarbonyl group, a pyrrolidinyl carbonyl group that may have a lower alkoxycarbonyl group as a substituent, a lower alkylcarbonyl group, or a carbamoyl group. Examples include alaninamide, arginamide, asparaginamide, asparatic α-amide, cystinamide, glutaminamide, glutamic α-amide, glycinamide, histidinamide, isoleucinamide, leucinamide, lysinamide, methionamide, phenylalaninamide, prolinamide, serinamid, threoninamide, Tylocinamide, Valinamide, Diethylglutamate, Methylcystinate, α-Ethylglutamate, Methylprolinate, Ethylglutamate, Methyltryptopfamate, Propylglycinate, Butylvalinate, Pentylserinate, Hexyllisinate, Methyl Aspartate, Ethylmethyl thionate, methyltyrodinate, ethylphenylalanate,
(1-pyrrolidinyl)-alaninamide, (2-ethoxycarbonyl-1-pyrrolidinyl)-arginamide, (2
Methoxycarbonyl-1-pyrrolidinyl)-asparaginamide, (3-propoxycarbonyl5 ■-pyrrolidinyl)-asparatic α-amide, (
2-isopropoxycarbonyl-1-pyrrolidinyl)-
cystinamide, (3-butoxycarbonyl-1-pyrrolidinyl)-glutaminamide, (2-isobutoxycarbonyl-1-pyrrolidinyl)-glutamic alpha amide,
(3-pentyloxycarbonyl-1-pyrrolidinyl)
-glycinamide, (2-hexyloxycarbonyl-1
-pyrrolidinyl)-histidinamide, (2-methoxycarbonyl-1-pyrrolidinyl)-isoleucinamide, (
2-Ethoxycarbonyl-■-pyrrolidinyl)-leucinamide, (2-ethoxycarbonyl-1-pyrrolidinyl)-lidinamide, (2-methoxycarbonyl-1-pyrrolidinyl)-methionamide, (2-methoxycarbonyl-1-pyrrolidinyl)-phenyl Alaninamide, (3-
Propoxycarbonyl-■-pyrrolidinyl)-prolinamide, (2-propoxycarbonyl-1-pyrroli6dinyl)-serinamide, (2-methoxycarbonyl-1
-pyrrolidinyl)-threoninamide, (3ethoxycarbonyl-1-pyrrolidinyl)-tylocinamide, (2-
methoxycarbonyl-1-pyrrolidinyl)-valinamide,
Benzyl glutamate, (2-phenylethyl)cystinate, α-(1-phenylethyl)glutamate,
(3-phenylpropyl)prolinate, (4-phenylbutyl)glutamate, (1,1-dimethyl-2-phenyl)tryptophamate, (5-phenylpentyl)
Glycinate, (6-phenylhexyl)valinate,
(2-methyl-3-phenylpropyl)serinate, pentylserinate, pentylserinate, pentylserinate, benzyltyrosinate, benzylphenylalanate, etc., where the carboxyl group of the amino acid residue has 1 to 6 carbon atoms. straight-chain or branched alkoxycarbonyl group,
Straight chain or branched phenyl alkoxycarbonyl group whose alkoxy moiety has 1 to 6 carbon atoms, 1-pyrroli which may have a straight chain or branched alkoxycarbonyl group having 1 to 6 carbon atoms as a substituent Examples of amino acid residues converted to dinylcarbonyl groups or carbamoyl groups can be given.

Examples of the phenyl lower alkoxycarbonyl group include benzyloxycarbonyl, 2-phenylethoxycarbonyl, 1-phenylethoxycarbonyl, 3-phenylpropoxycarbonyl, 4-phenylbutoxycarbonyl, 1,1-dimethyl-2-phenylethoxycarbonyl, 5 phenylpentyloxycarbonyl, 6-
Examples include phenylalkoxycarbonyl groups in which the alkoxy moiety is a linear or branched alkoxy group having 1 to 6 carbon atoms, such as phenylhexyloxycarbonyl and 2-methyl-3phenylpropoxycarbonyl groups.

Examples of the 1-pyrrolidinylcarbonyl group that may have a lower alkoxycarbonyl group as a substituent include 1-pyrrolidinylcarbonyl, 2-methoxycarbonyl-1-pyrrolidinylcarbonyl, and 2-ethoxycarbonyl-1-pyrrolidinylcarbonyl. Dinylcarbonyl, 3-propoxycarbonyl-1-pyrrolidinylcarbonyl, 2-isopropoxycarbonyl-1-pyrrolidinylcarbonyl, 3-butoxycarbonyl-1-pyrrolidinylcarbonyl, 2-isobutoxycarbonyl-1-pyrrolidinyl carbonyl,
Having a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms as a substituent, such as 3-pentyloxycarbonyl-■pyrrolidinylcarbonyl, 2-hexyloxycarbonyl-1-pyrrolidinylcarbonyl group, etc. An example is the 1-pyrrolidinylcarbonyl group.

Examples of the lower alkyl group having or not having 1 to 3 halogen atoms as a substituent include, in addition to the above-mentioned unsubstituted lower alkyl groups, io9tomethyl, trifluoromethyl, 2,2-difluoroethyl , 1,1-dichloroethyl, dichloromethyl, trichloromethyl, tribromomethyl, 2.2.2-trifluoroethyl, 2,2.2 trichloroethyl, 2-fluoroethyl, 2-chloroethyl, 1-fluoroethyl,
1-6 straight carbon atoms having 1-3 halogen atoms such as 1,2-dichloroethyl, 3.3.34-lichloropropyl, 3-fluoropropyl, 4-chlorobutyl, 3chloro-2-methylethyl group, etc. Examples include chain or branched alkyl groups.

Halogen atom, nitro group, as a substituent on the phenyl ring,
A benzoyl group that may have 1 to 3 groups selected from the group consisting of a cyano group, a lower alkoxy group, a phenyl group, and a lower alkyl group with or without 1 to 3 halogen atoms as a substituent. Examples include, in addition to the benzoyl group, 2-93- or 4-chlorobenzoyl, 20 3- or 4-fluorobenzoyl, 2-. 3- or 4-bromobenzoyl, 2-. 3- or 4-iodobenzoyl, 3,5-dichlorobenzoyl, 2,6
-dichlorobenzoyl, 3゜4-dichlorobenzoyl,
3,4-difluorobenzoyl, 3,5-dibromobenzoyl, 23- or 4-methylbenzoyl, 2-.
3 or 4-ethylbenzoyl, 3-isopropylbenzoyl, 4-hexylbenzoyl, 3,4 dimethylbenzoyl, 2,5-dimethylbenzoyl, 2-93- or 4-methoxybenzoyl, 2-13- or 4
-Ethoxybenzoyl, 4-isopropoxybenzoyl, 4-hexyloxybenzoyl, 3,4-dimethoxybenzoyl, 3,4-jethoxybenzoyl, 2,5-
Dimethoxybenzoyl, 2-. 3- or 4-nitrobenzoyl, 2,4-dinitrobenzoyl, 23- or 4-cyanobenzoyl, 2,4-dicyanobenzoyl, 3-methyl-4-chlorobenzoyl, 2-chloro-
6-methylbenzoyl, 2methoxy-3-chlorobenzoyl, 3. 4. 5-trimethoxybenzoyl, 3,
4.5-trimethylbenzoyl, 3. 4. 5-hlichlorobenzoyl, 2-. 3- or 4-phenylbenzoyl, 2-iodomethylbenzoyl, 3-trifluoromethylbenzoyl, 4-(2,2-difluoroethyl)benzoyl, 2-(dichloromethyl)benzoyl, 3-(2,2,2- 4-fluoroethyl)benzoyl, 4-(2-chloroethyl)benzoyl, 2-(1,
2-dibromoethyl)benzoyl, 4-(3-chloro-
Halogen atom, nitro group, cyano group, linear or branched alkoxy having 1 to 6 carbon atoms as a substituent on the phenyl ring, such as 2-methylethyl)benzoyl or 3-(3-fluoropropyl)benzoyl group. 1 to 3 groups selected from the group consisting of a phenyl group, and a straight or branched alkyl group having 1 to 6 carbon atoms with or without 1 to 3 halogen atoms as a substituent. An example is a benzoyl group that may have the following.

Examples of the phenyl lower alkenylcarbonyl group that may have a nitro group as a substituent on the phenyl ring include cinnamoyl, 4-phenyl-3-butenoyl, 4-phenyl-2-butenoyl, 5-phenyl-4-pentenoyl, 5- Phenyl-3-pentenoyl, 5-phenyl-2-pentenoyl, 6-phenyl-5-hexenoyl, 6-phenyl-4-hexenoyl, 6-phenyl-3-
hexenoyl, 6-phenyl-2-hexenoyl, 2-
Methyl-4-phenyl-3-butenoyl, 2-methyl-
Cinnamoyl, 1-methyl-cinnamoyl, 3-(4-
nitrophenyl)acryloyl, (3-nitrophenyl)-3-butenoyl, 5-(2-nitrophenyl)-4
-pentenoyl, 36-(4-nitrophenyl)-4-hexenoyl, etc. The alkenylcarbonyl moiety is a straight or branched alkenylcarbonyl group having 3 to 6 carbon atoms, and the nitro An example is a phenylalkenylcarbonyl group which may have a group.

Examples of the phenylsulfonyl group that may have a lower alkyl group as a substituent on the phenyl ring include phenylsulfonyl, toluenesulfonyl, xylenesulfonyl, trimethylbenzenesulfonyl, ethylbenzenesulfonyl, isopropylbenzenesulfonyl, butylbenzenesulfonyl, and hexylbenzenesulfonyl. Examples include phenylsulfonyl groups which may have a linear or branched alkyl group having 1 to 6 carbon atoms as a substituent on the phenyl ring.

The active ingredient compound of the present invention can be produced by various methods. As one specific method 4, for example, the following reaction scheme method can be exemplified.

<Reaction Scheme-1> The method shown in 1 (2) (1a) [In the formula, R11R2, R3, R4 and the bonds at the 1st and 2nd positions of the side chain are the same as above. R8 is a halogen atom, a nitro group, a cyano group, a lower alkoxy group as a substituent on the phenyl ring,
a benzoyl group which may have 1 to 3 groups selected from the group consisting of a phenyl group and a lower alkyl group with or without 1 to 3 halogen atoms as a substituent;
It represents a phenyl lower alkenylcarbonyl group, a thienylcarbonyl group, a pyridylcarbonyl group, or an imidazolylcarbonyl group, which may have a nitro group as a substituent on the phenyl ring. ] The method shown in the above reaction scheme-1 consists of a compound of general formula (2) or a compound with an activated amino group thereof, and a compound of general formula (
This is carried out by reacting the compound of 3) or a compound whose carboxyl group has been activated according to a conventional amide bond forming reaction.

Here, the amide bond formation reaction can be carried out by various known methods, such as (a) mixed acid anhydride method, for example, compound (3) is reacted with an alkyl halocarboxylic acid to form a mixed acid anhydride, and compound (2) is added to this. Reaction method; (b) active ester method, for example, compound (3) is reacted with p-nitrophenyl ester, N
- A method of preparing an active ester such as hydroxysuccinimide ester or 1-hydroxybenzotriazole ester and reacting it with compound (2); (c) Carbodiimide method, that is, compound (2) is added to compound (3) with dicyclohexyl A method of condensation in the presence of an activator such as carbodiimide or carbonyldiimidazole; (d) Other methods, for example, converting compound (3) to a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and adding compound (2) to this. A method of reacting compound (2) with an ester of compound (3) and a lower alcohol under high pressure and high temperature; A method of reacting compound (2) with an acid halide of compound (3), that is, a carboxylic acid halide. This can be carried out by a method such as In addition, compound (3) is triphenylphosphine,
Diethyl cyanophosphate, diphenylphosphinyl chloride, phenyl N-phenylphosphoramide chloridate,
Diethyl ether 7 is activated with a phosphorus compound such as sulfate, and then a compound (
2) may also be used.

In the mixed acid anhydride method shown in (a) above, the mixed acid anhydride used is generally obtained by Schotten-Baumann reaction, and by reacting it with compound (2) without isolation, The desired compound of the present invention (la
) is manufactured.

The above Schotten-Baumann reaction is usually carried out using basic compounds commonly used in the Schotten-Baumann reaction, such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimeglyaminopyridine, 1,5-diazabicycloC4,3,] Nonen (DBN
), 1,8-diazabicyclo(5,4,O)undecene-1 (DBU), 1,4-diazabicyclo[2,2
゜2] In the presence of an organic base such as octane (DABCO) and an inorganic base such as potassium carbonate, thorium carbonate, potassium hydrogen carbonate, or sodium hydrogen carbonate, about 20 to
It is carried out at 100°C, preferably about 0 to 50°C, for about 5 minutes to 10 hours, preferably about 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and compound (2) is approximately -2
About 5 minutes at 0 to 150°C, preferably about 10 to 50°C
It takes 10 hours, preferably about 5 minutes to 5 hours. The above mixed acid anhydride is generally a solvent commonly used in this type of mixed acid anhydride method, specifically halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, and aromatic hydrocarbons such as benzene, toluene, and xylene. ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, esters such as methyl acetate and ethyl acetate, N, N-dimethylformamide (DMF),
The reaction is carried out in or in the absence of a suitable solvent such as an aprotic polar solvent such as dimethyl sulfoxide (DMSO) or hexamethyl phosphoric acid triamide (MPA).

In addition, examples of the alkyl halocarbon alcohol used in the production of the above mixed acid anhydride include methyl chloroformate, ethyl bromoformate, isobutyl chloroformate, etc.
These are usually at least equimolar amounts relative to compound (3),
It is preferably used in an amount of about 1 to 2 times the mole. Also, the compound (2
) is usually at least an equimolar amount to compound (3),
Preferably, it is appropriate to use about 1 to 2 times the mole amount.

In the active ester method shown in (b) above, for example, when N-hydroxysuccinimide ester is used,
It is carried out in a suitable solvent that does not affect the reaction. Specifically, the solvent includes methylene chloride, chloroform,
Halogenated hydrocarbons such as dichloroethane, benzene,
Aromatic hydrocarbons such as toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane, esters such as methyl acetate and ethyl acetate, D
Examples include aprotic polar solvents such as MF, DMSO, and HMPA. The reaction is completed in about 5 to 30 hours at about 0 to 150°C, preferably about 10 to 100°C. Compound(
The ratio of 2) and N-hydroxysuccinimide ester to be used is usually at least equimolar, preferably equimolar to twice the molar amount of the latter to the former.

When employing the method of reacting compound (2) with carboxylic acid halide shown in (d) above, the reaction is carried out in a suitable solvent in the presence of a dehydrohalogenating agent. As this dehydrohalogenating agent, a common basic compound is used. As the basic compound, a wide variety of known compounds can be used; for example, in addition to the basic compounds used in the Schotten-Baumann reaction as described above, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, silver carbonate, etc. , alcoholades such as sodium methylate, sodium etherate, and the like. In addition, the compound (
2) can be used in excess as a dehalogenating and hydrogenating agent. In addition to the solvents used in the mixed acid anhydride method, examples of the solvent include methanol, ethanol, propatool, butanol, and 3-methoxy-1
Examples include alcohols such as -butanol, ethyl cellosolve, and methyl cellosolve, pyridine, acetone, acetonitrile, water, and mixed solvents on two sides of the above solvents.

The ratio of the amine (2) and the carboxylic acid halide to be used is not particularly limited and is appropriately selected within a wide range, but usually the latter is used in at least an equimolar amount of the former, preferably an equimolar to twice the molar amount. Good to use.

The reaction is usually carried out at about -30 to 180°C, preferably about 0 to 150°C, and is generally completed in 5 minutes to 30 hours.

Alternatively, compound (3) is activated with a phosphor compound such as triphenylphosphine, diphenylphosphineyl chloride, phenyl N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl cyanophosphate, etc., and compound (2) is reacted with this. This method can be carried out in a suitable solvent in the presence of a basic compound. As the solvent, any solvent can be used as long as it does not affect the reaction, but specific examples include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane, ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, Esters such as methyl acetate and ethyl acetate, DMF, DMSO.

Examples include aprotic polar solvents such as HMPA. Examples of the basic compound include triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, DBN, and DBU.

Organic bases such as DABCO and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc. can be used. The reaction takes place at about -20'C~
The reaction is carried out at 150°C, preferably about -20°C to 100°C, and the reaction time is about 1 to 30 hours. Compound (2
The amounts of the phosphorus compound and compound (3) to be used are usually at least equimolar amounts, preferably 1 to 3 times the molar amount.

<Reaction Scheme-2> 1 (2) (1b) [In the formula, R1, R2, R3, R4 and the bonds at the 1st and 2nd positions of the side chain are the same as above. R9 represents a phenylsulfonyl group which may have a lower alkyl group as a substituent on the phenyl ring. X represents a halogen atom. ] According to the method shown in the above reaction scheme-2, compound (2)
By reacting the compound (4) with the compound (4), the desired compound (1b) of the present invention can be obtained. The above compound (2)
The reaction of compound (4) with compound (4) is carried out by adding compound (4) to carboxylic acid halide (2) in the method shown in reaction scheme-1 above.
It can be carried out in the same manner as the reaction method 2).

<Reaction Scheme-3> 5 [In the formula, RI, R2, R4, R5 and the bonds at the 1st and 2nd positions of the side chain are the same as above. R3" represents a hydroxyl group or a lower alkoxy group. R3/ represents a group NR6R? (R6 and R7 are the same as above) or an amino acid residue capable of forming an amide bond with the C○ group bonded to R3/. The carboxyl group present on the amino acid residue is a lower alkoxycarbonyl group, a phenyl lower alkoxycarbonyl group, or 1 which may have a lower alkoxycarbonyl group as a substituent.
, -pyrrolidinylcarbonyl group or carbamoyl group. ] According to the method shown in Reaction Scheme-3 above, compound (1d) can be obtained by reacting compound (1c) and compound (6). The reaction between the compound (1c) and the compound (6) can be carried out in the same manner as the reaction between the compound (2) and the compound (3) shown in the reaction scheme-1 above.

Further, the hydrolysis reaction of compound (1d) can be carried out in the same manner as the hydrolysis reaction of compound (1e) shown in 6 Reaction Scheme-4 below.

<Reaction scheme-4> (1e) [In the formula, R1, R2, R4, R5 and I'I) 1 of the chain,
The bond at position 2 is the same as above. RIO represents a lower alkyl group. ] According to the above reaction scheme-4, 1- of compound (1c)
Compound (1e) can be obtained by the stellation reaction, and conversely, compound (1c) can be obtained by the hydrolysis reaction of compound (1e).
) can be obtained.

The esterification reaction of the above compound (1c) can be carried out by a conventional method. Examples of the method include (1) a method in which the reaction is carried out in an appropriate solvent in the presence of a dehydrating agent, and (2) a method in which the reaction is carried out in an appropriate solvent in the presence of an acid or a basic compound.

In the method (2) above, the solvents used include, for example, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, and xylene, diethyl ether, tetrahydrofuran, and dioxane. , ethers such as ethylene glycol monomethyl ether and dimethoxyethane, and aprotic polar solvents such as DMFXDMSO, HMPAXN, and N-dimethylaminopyridine. Examples of the dehydrating agent include dicyclohexylcarbodiimide and carbonyldiimidazole.

The amount of compound (7) to be used is usually at least equimolar, preferably equimolar - 1.5 times molar relative to compound (1c).

The amount of the dehydrating agent to be used is usually at least equimolar, preferably equimolar to 1.5 times the molar amount of compound (IC). The reaction is generally carried out at room temperature to about 150°C, preferably room temperature to about 100°C, for about 1 to 15 hours.

In the method (2), the acids used include, for example, hydrochloric acid gas, sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride,
Inorganic acids such as perchloric acid, organic acids such as trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, ethanesulfonic acid, trichloromethanesulfonic anhydride, trifluoromethanesulfonic acid Examples include acid anhydrides such as anhydrides, thionyl chloride, acetone dimethyl acetal, and the like. Furthermore, acidic ion exchange resins can also be used as the acid. Examples of basic compounds include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and silver carbonate, and alcoholades such as sodium methylate and sodium ethylate. Although the reaction can be carried out without a solvent, it can be advantageously carried out using the same solvents as those shown above. Furthermore, this reaction can proceed more advantageously by using a drying agent such as anhydrous calcium chloride, anhydrous copper sulfate, anhydrous calcium sulfate, phosphorus pentoxide, or the like. Compound (7) is usually used in a large excess amount relative to compound (1c) when reacting in a solvent-free system, and usually about 1 to 5 times as much when reacting in a solvent system. A molar amount, preferably about 1 to 2 times the molar amount, is suitable. The reaction is usually completed at about -20°C to 200°C, preferably about 0 to 150°C, in about 1 to 20 hours.

The hydrolysis reaction of compound (1e) can be carried out using conventional methods, such as hydrochloric acid, hydrochloric acid such as hydrobromic acid, mineral acids such as sulfuric acid and phosphoric acid, sodium hydroxide, potassium hydroxide, etc. The reaction is carried out in the presence of a hydrolysis catalyst such as an alkali metal hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, or a hydrogen carbonate, in a suitable solvent or in the absence of a solvent. Examples of the solvent used include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, and mixed solvents thereof. The reaction is usually carried out at about 50°C to 150°C,
Preferably, the process is completed at about 70 to 100°C for about 1 to 50 hours.

<Reaction scheme-5> (11) (1g) [In the formula, R1, R2, R3, R4 and R5 are the same as above.

] According to the above reaction scheme-4, compound (1g) can be obtained by dehydrogenation reaction of compound (1f).

The dehydrogenation reaction can be carried out by a conventional method in a suitable solvent using an oxidizing agent. Examples of the oxidizing agent include benzoquinones such as 2,3-dichloro-5,6-dicyazbenzoquinone and chloranil (2,3,5,6-titrachlorobenzoquinone), N-bromosuccinimide, N-bromosuccinimide, and N-bromosuccinimide.
- Halogenating agents such as chlorosuccinimide and bromine, hydrogenation catalysts such as selenium dioxide, palladium on carbon, palladium black, valadiram oxide, and Raney nickel, sulfur, lead tetranosate, and the like can be used. The amount of the oxidizing agent to be used is not particularly limited and can be appropriately determined from a wide range, but is usually about 1 to 5 times the molar amount of the starting material compound (11), preferably about 1
It is appropriate to set the amount to ~2 times the molar amount. Hydrogenation catalysts are available in conventional catalytic amounts. Examples of solvents include ethers such as dioxane, tetrahydrofuran, methoxyethanol, and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, xylene, and cumene, and halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride. , alcohols such as butanol, amyl alcohol, and hexanol, polar protic solvents such as acetic acid, and DMF.

Polar aprotic solvents such as DMSO and HMPA can be used. The reaction is usually carried out at -20 to 300'C.

Preferably carried out at about -20 to 200°C, generally at about 1
Finished in ~40 hours.

3. Under the above reaction conditions, when the R1 group of compound (if) is a hydrogen atom, a compound in which the R1 group of compound (11) is tetrahydrofurylated can be obtained without dehydrogenation reaction occurring. However, this compound can be easily separated from the reaction system.

<Reaction Scheme-6> (lh) (li) [In the formula, R2, R3, 45X and the bond at the 1°42 position of the side chain are the same as above. R1 represents a lower alkyl group, a lower alkenyl group, a phenyl lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl lower alkyl group, a carboxy lower alkyl group or a lower alkanoyl group. ] According to the method shown in the above reaction scheme-6, the compound (1h
) and compound (8) to form compound (1).
1) can be obtained.

This reaction can be carried out in the presence of a basic compound in a suitable solvent. Examples of basic compounds include inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium, sodium, sodium amide, potassium amide, etc.
Examples include organic bases such as triethylamine, diisopropylethylamine, and dimethylaminopyridine. Examples of solvents include water, dioxane, ethers such as diethylene glycol dimethyl ether, aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane,
Halogenated hydrocarbons such as dichloroethane, chloroform, carbon tetrachloride, DMF.

Polar aprotic solvents such as DMSO and HMPA, mixed solvents such as acetone, acetonitrile, etc. can be used.

The ratio of compound (1h) and compound (8) to be used is not particularly limited and can be selected as appropriate, but usually the latter is at least about equimolar to the former, preferably about equimolar to twice the molar amount. good.

The reaction is usually carried out under temperature conditions of about 0 to 70'C, preferably about 00C to about room temperature, and generally at about 0. 5-12
Finish in time.

Note that under the above reaction conditions, when the R4 group of compound (1h) is a hydrogen atom, a compound may be obtained in which the 1-position of the indole skeleton and the side chain amine are simultaneously reacted with compound (8). , the compound can be easily separated from the reaction system.

In addition to the above, the compound (11) in which Rl / is a lower alkanoyl group or a lower alkoxycarbonyl group,
For example, a lower alkalic acid anhydride such as acetic anhydride or a di-lower alkyl dicarbonate such as di-tert-butyl dicarbonate is added to the compound (1h) in the presence of a basic compound such as dimethylaminopyridine or pyridine, usually from room temperature to 1 hour.
It can also be produced by reacting at a temperature of about 50° C. for about 5 to 80 hours.

In the method shown in Reaction Scheme-1 above, the compound (2) used as a starting material includes a new compound, and such compound (2) can be, for example, represented by the following Reaction Scheme-1.
It can be manufactured by the methods shown in 7 and -8.

7 <Reaction scheme (2) (2) (2) Reaction scheme -8> [R1 and R in each formula shown in reaction scheme -7 and -8
2 is the same as above. R11 represents a hydroxyl group or a lower alkoxy group. R12 represents a phenyl group.

R13 represents a hydrogen atom or a lower alkyl group.

R14 represents a lower alkyl group. A represents a lower alkylene group. Outside indicates 0 or king. However, the number of carbon atoms in each base is 6
shall not exceed. ] According to the method shown in Reaction Scheme-7 above, compound (2a) and compound (9) are reacted to obtain compound (2b), and then compound (2b) is subjected to a dehydrogenation reaction to obtain compound ( 2C) can be induced.

The reaction between compound (2a) and compound (9) is carried out in the presence of a suitable reducing agent, without a solvent or in a suitable solvent, and in the presence or absence of a dehydrating agent. Examples of the solvent used here include alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, diethyl ether, glyme and diglyme, and mixed solvents thereof. Examples of the dehydrating agent used include the same basic compounds as those exemplified in the method shown in (d) of Reaction Scheme-1 above, that is, the method of reacting compound (2) with carboxylic acid halide. Can be done. Further, as the reducing agent to be used, various usual ones can be exemplified, but preferably a hydrogenated reducing agent can be used suitably. Examples of the hydrogenation reducing agent include lithium aluminum hydride, sodium borohydride,
Examples include sodium cyanoborohydride and diborane.

The amount used is usually about 0.1 to 10 times the mole of compound (2a).

The amount of compound (9) to be used is at least equimolar, preferably equimolar to about 7 times the molar amount of compound (2a). The reaction can be carried out at a temperature of usually -60°C to 50°C, preferably about -30'C to room temperature, for about 1.0 minutes to about 1-0 hours. In addition, when using lithium aluminum hydride, diborane, etc. as the reducing agent, it is preferable to use an anhydrous solvent such as an anhydrous diethyl ether, tetrahydrofuran, diglyme, etc. mixed solvent as the solvent.

The dehydrogenation reaction of compound (2b) thus obtained can be carried out in the same manner as the dehydrogenation reaction of compound (1g) shown in reaction scheme-5 above, whereby compound (2c)
can be obtained.

In addition, according to the method shown in Reaction Scheme-8, compound (2d) is obtained by the reaction of compound (2b) obtained in Reaction Scheme-7 above with compound (10), and the compound (2d)
Compound (2f) can be produced from compound (2e).

The reaction between the compound (2b) and the compound (1o) can be carried out in the same manner as the reaction between the compound (2a) and the compound (9) shown in the reaction scheme-7,
Furthermore, an acid such as acetic acid or formic acid may be added to the reaction system.

The reaction for converting compound (2d) obtained above to compound (2e) can be carried out using a suitable solvent such as water, lower alcohols such as methanol, ethanol, and isopropynol, ethers such as dioxane and tetrahydrofuran, acetic acid, etc. in the presence of a catalytic reduction catalyst such as platinum, palladium-carbon, palladium-black, etc., at a temperature of about 0 to 100°C and a hydrogen pressure of about 1 to 10 atm. It can take 5 to 30 hours to carry out. In addition, the reaction can be carried out by adding mineral acids such as hydrochloric acid and hydrobromic acid into the system.
proceed more favorably.

Thus, compound (2e) from compound (2d) obtained
) is produced by using the compound (1 g) shown in the reaction scheme-5 above.
It can be carried out in the same manner as the dehydrogenation reaction and under the same conditions.

In addition, in the above compounds (2a) to (21), the COR" group of the side chain is mutually converted into a carboxyl group and a lower alkoxycarbonyl group, respectively, by a reaction similar to that shown in the reaction scheme-4 above. be able to.

Furthermore, among compounds (2a) to (2e), those in which R1 is a hydrogen atom can be reacted in the same manner as the reaction between compound (1h) and compound (8) shown in Reaction Scheme-6 above. R1 can be converted into a lower alkyl group, a lower alkenyl group, a phenyl lower alkyl group, or a lower alkanoyl group.

Thus, compounds (2b) to (2]) obtained by the above reaction schemes -7 and -8 are of course useful as synthetic intermediates for the active ingredient compound (1) used in the present invention, Each of these compounds itself has a pap pressin antagonistic effect and is useful as a pap pressin antagonist like the active ingredient compound of the present invention.

The active ingredient compound (1) used in the present invention can also be produced by the methods shown in the following reaction schemes.

<Reaction scheme-9> 5 [In the formula, R1, R2, R4 and R5 are the same as above.

R15 represents a lower alkyl group. R16 and R17 each represent a lower alkoxy group. ] The reaction between compound (11) and compound (12) can be carried out in a suitable solvent in the presence of a basic compound such as lithium diisopropylamide.

The solvent used here is, for example, THF.

Examples include ethers such as diethyl ether and dimethoxyethane. The amount of compound (12) to be used is usually the same as that of compound (12).
The amount should be at least equimolar, preferably equimolar to about twice the molar amount of 11). The reaction is usually carried out at a temperature of about -80 to 50°C, preferably about -80°C to room temperature, and takes about 1 to 5 hours.

In addition, the hydrolysis reaction of compound (li) can be carried out using the compound (1
It is carried out under the same conditions as the hydrolysis reaction in e).

In the effective six component compound (1) of the present invention obtained by each of the above reaction schemes, the compound in which R4 is a hydrogen atom is similar to the reaction of the above-mentioned compound (1h) and compound (8) using this as a raw material. to give R4 to the raw material compound.
By reacting 'X (R4' represents a lower alkyl group or a phenyl lower alkyl group. X is the same as above), a desired compound having a lower alkyl group or a phenyl lower alkyl group as the corresponding R4 is induced. Can be done.

In addition, the compound (1) in which R1 is a lower alkoxycarbonyl group is prepared using this as a raw material in formic acid, usually at a concentration of 0 to 100%.
C., preferably at a temperature around 0 to 70.degree. C. for 1 to 30 hours, the corresponding desired compound (1) in which R1 is a hydrogen atom can be obtained.

Furthermore, in the hydrolysis reaction of compound (1j), when a compound in which R1 is a lower alkoxycarbonyl group or a lower alkoxycarbonyl lower alkyl group is used, the above R1 group of the compound is also hydrolyzed at the same time, and R1 becomes a hydrogen atom. or a compound that is a carboxy lower alkyl group (1k
) may be obtained, but this compound can be easily separated from the reaction system.

<Reaction scheme-10> (13) (14) (16) (16) (18) (2g ) 9 (2h) [In the formula, R1, R2, X and R4 are the same as above.

18 19 20 21 R, R, R, R and R22 each represent a lower alkyl group. R23 represents a lower alkanoyl group. ] The reaction leading to compound (14) from compound (King 3) can be carried out, for example, by the following two methods.

■ Compound (13) and 8 (R and R19 are the same as above) and Mannich reaction with formaldehyde.

0 ■ Compound (13) and ■8 (R and R19 are the same as above) react with.

The above method (1) is carried out in a suitable solvent in the presence of an acid. As the solvent, any solvent commonly used in Mannich reactions can be used, such as water,
Examples include alcohols such as methanol, ethanol and isopropanol, alkanoic acids such as acetic acid and propionic acid, acid anhydrides such as acetic anhydride, polar solvents such as acetone and DMF, and mixed solvents thereof. Examples of acids that can be used include mineral acids such as hydrochloric acid and hydrobromic acid, and organic acids such as acetic acid. Formaldehyde is usually about 20~
Aqueous solutions containing 40% by weight formaldehyde, trimers, polypolymers (paranel 18 aldehyde), etc. can be used.

The amount of compound (19) to be used is at least equimolar to compound (13), preferably equimolar to twice the molar amount. The amount of formaldehyde used is preferably at least an equimolar amount, generally in large excess, relative to compound (13).

The reaction is usually carried out at about 0 to 200°C, preferably from room temperature to 15°C.
It progresses favorably under temperature conditions around 0'C, and generally 0. 5
It took about 15 hours.

The above method (1) can be carried out in the presence of an acid, in a suitable solvent, or without a solvent. Examples of acids used include mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and organic acids such as acetic acid and acetic anhydride, with acetic anhydride being particularly preferred. In addition, as a solvent,
Those similar to those shown above can be used.

The amount of compound (19a) to be used is at least equimolar, preferably equimolar to 5 times the molar amount of compound (13). The reaction is usually 0 to i50'
The process proceeds under a temperature condition of approximately 100° C., preferably room temperature to 100° C., and generally finishes in about 0.5 to 5 hours.

The reaction between compound (14) and compound (15) can be carried out in a suitable solvent. As the solvent used here, the same solvents as those exemplified in the method (2) of reacting the compound (2) with the carboxylic acid halide in the method shown in Reaction Scheme-1 can be used. The reaction is usually 0 to
1 at a temperature of about 100°C, preferably around room temperature.
This process takes about 10 hours.

The amount of compound (↑5) to be used is at least equimolar, preferably about equimolar to 1.5 times the molar amount of compound (14).

The reaction between compound (16) and compound (17) can be carried out in a suitable solvent in the presence of a basic compound. The solvent and basic compound used here are the same as those exemplified when reacting compound (2) with carboxylic acid halide (2) in the method shown in Reaction Scheme-1 above. Both can be used.

The amount of compound (17) to be used is at least equimolar, preferably about equimolar to twice the molar amount of compound (16). The reaction is carried out at a temperature of 1 to 150°C, preferably around 0 to 100°C.
The process takes about 20 hours.

The hydrolysis reaction of compound (18) is carried out using the above compound (1e).
can be carried out under the same conditions as the hydrolysis reaction.

The reaction of leading compound (2g) to compound (2b) can be carried out under the same conditions as the reaction of leading compound (1f) to compound (1g).

In the reaction scheme-9, the compound (12) used as a raw material can be produced, for example, by the method shown in the following reaction scheme 11.

4 Reaction Scheme-11> (20) 5 (12) [In the formula, R4, R5, R15, R16 and R17 are the same as above. R24 represents a lower alkoxy group. ] Compound (1
The halogenation reaction (9) is carried out using a halogenating agent in a suitable solvent. Examples of the halogenating agent include hydrohalic acids such as hydrobromic acid and hydrochloric acid, halogen molecules such as bromine and chlorine, or -iodine chloride, sulfuryl chloride, N-bromosuccinimide, N-chlorosuccinimide, etc. Examples include halogenating agents such as N-halogenosuccinimide and dioxane-bromine complex.

The amount of the halogenating agent to be used is usually at least an equimolar amount, preferably an equimolar amount to about twice the molar amount of compound (20).

Examples of the solvent include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride, alkanoic acids such as acetic acid and propionic acid, and water. In this reaction, the reaction temperature is usually in the range of O'C to the boiling point of the reaction solvent, preferably in the range of about O to 120C, and usually 0. The reaction is completed in about 5 to 10 hours. Further, the above reaction proceeds advantageously by irradiation with light having a wavelength of visible light.

The compound (21) thus obtained can normally be used for subsequent reactions without being separated from the reaction system, but may of course be separated.

The reaction between compound (21) and compound (22) can be carried out in a suitable solvent. Examples of the solvent used here include those used when reacting the compound (2) with the carboxylic acid halide (2) in the method shown in Reaction Scheme-1 above.

The amount of compound (22) to be used is usually at least an equimolar amount, preferably about an equimolar to twice the molar amount of compound (20), which is the raw material for compound (21), and the reaction is Usually about 0 to 100°C, preferably about 0 to 70'C
It takes about 1 to 15 hours under similar temperature conditions.

Further, in the above reaction scheme -11, the compound (20) used as a raw material compound can be, for example, the following reaction scheme -
It can be manufactured by the method shown in 12.

<Reaction process formula (23) (3) %formula% (20) (20) [In the formula, R4, R8, R9, R15 and x are the same as above.

] The reaction between compound (23) and compound (3) can be carried out under the same conditions as the reaction between compound (2) and compound (3) shown in Reaction Scheme-1 above.

8 Furthermore, the reaction between compound (23) and compound (4) can be carried out under the same conditions as the reaction between compound (2) and compound (4) shown in Reaction Scheme-2 above.

In addition, in the active ingredient compound (1) of the present invention, R3 represents an amino acid residue capable of forming an amide bond with the C○ group to which R3 is bonded, and a carboxyl group present on the amino acid residue. is a lower alkoxycarbonyl group, the lower alkoxycarbonyl group can be converted into a free form by subjecting the compound to a hydrolysis reaction similar to that of compound (1e) shown in Reaction Scheme-4 above. Can be converted to carboxyl group.

In addition, the active ingredient compound (1) of the present invention, in which the carboxyl group present on the above amino acid residue is 1-pyrrolidinylcarbonino which may have a lower alkoxycarbonyl group as a substituent, A compound having a carboxyl group on an amino acid residue and 1-pyrrolidine, which may have a lower alkoxycarbonyl group as a substituent, are combined with compound (2) and compound (3) shown in the reaction scheme-1 above. It can be produced by reacting in the same manner as the reaction.

Among the compounds (1) used as active ingredients in the present invention,
Compounds with acidic groups can form salts with pharmacologically acceptable basic compounds. Such basic compounds include:
For example, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, alkali metal carbonates or bicarbonates such as sodium carbonate, sodium bicarbonate, alkalis such as sodium methylate, potassium ethylate, etc. Examples include metal alcoholades. In addition, the compound (1) used as an active ingredient in the present invention
Among them, compounds having basic properties can easily form salts with common pharmacologically acceptable acids. Examples of such acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, and hydrobromic acid, acetic acid, p
-Toluenesulfonic acid, ethanesulfonic acid, oxalic acid,
Examples include organic acids such as maleic acid, succinic acid, and benzoic acid. Salts such as these are also free forms of the compound (1)
Similarly, it can be used as an active ingredient compound in the present invention. Incidentally, the above compound (1) includes stereoisomers and optical isomers, and these can also be used as the active ingredient compound.

The target compound obtained by the method shown in each of the above reaction schemes can be separated from the reaction system by conventional separation means and further purified.

As this separation and purification means, for example, distillation method, recrystallization method, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, preparative thin layer chromatography, solvent extraction method, etc. can be adopted.

The active ingredient compound thus obtained is effective as a vasopre-1 antagonist, and the antagonist is used in the form of a pharmaceutical preparation. The formulation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants. Various forms of this pharmaceutical preparation can be selected depending on the therapeutic purpose, and representative examples include tablets, emulsions, powders, liquids, suspensions, emulsions, granules, capsules, heavy doses, and injections (
solutions, suspensions, etc.). When forming into a tablet, a wide variety of carriers that are well known in this field can be used. Examples include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid, water, ethanol, propatool, simple syrup, glucose solution, starch solution. , gelatin solution, carboxymethyl cellulose, shellac,
Methyl cellulose, potassium phosphate, binders such as polyvinyl vinyl 20 lidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, Disintegrants such as starch and lactose; disintegration inhibitors such as white sugar, stearin, cocoa butter, and hydrogenated oil;
Absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid, purified talc, stearate, and boric acid powder. ,
Lubricants such as polyethylene glycol can be used. Furthermore, the tablets may be coated with a conventional coating, if necessary, such as dragee-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, or multilayered tablets. When forming the emulsion into an emulsion, a wide variety of carriers conventionally known in this field can be used. Examples include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc, binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol, and disintegrants such as laminaran and agar. can be used. When molding into the form of heavy punishment, a wide variety of conventionally known carriers can be used. Examples include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like. Capsules are usually prepared by mixing the active ingredient compound with the various carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules, etc. according to conventional methods. When prepared as injections, solutions, emulsions and suspensions are preferably sterile and isotonic with blood, and when formulated into these forms, diluents commonly used in this field may be used. can all be used, e.g. water,
Ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be used. In this case, a sufficient amount of salt, glucose, or glycerin may be included in the pharmaceutical preparation to prepare an isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. You can. Furthermore, coloring agents, preservatives, perfumes, flavoring agents, sweeteners, etc., and other pharmaceuticals can also be included in the pharmaceutical preparation, if necessary.

The amount of the active ingredient compound to be contained in the pap pressin antagonist of the present invention is not particularly limited and is appropriately selected from a wide range, but usually about 1 to 70% by weight in the pharmaceutical composition.
Preferably it is about 5 to 50% by weight.

There are no particular restrictions on the method of administering the pap pressin antagonist of the present invention, and administration may be done in a manner appropriate to various formulation forms, age, sex and other conditions of the patient, degree of disease, etc. For example, tablets, emulsions, solutions, suspensions, emulsions, granules and capsules are administered orally.

In the case of an injection, it is administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acids, and if necessary, it is administered alone intramuscularly, subcutaneously, subcutaneously, or intraperitoneally. In cases of severe punishment, it is administered rectally.

The dosage of the pap pressin antagonist of the present invention is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of disease, etc., but usually the amount of the active ingredient compound is -1 kg of body weight per day.
The amount is preferably about 0.6 to 50 mg per g. In addition, in dosage unit formulations, the active ingredient compound is about 1.0
The content is preferably in the range of 1000 mg to 1000 mg.

EXAMPLES Hereinafter, in order to explain the present invention in more detail, examples of formulations of the pap pressin antagonist of the present invention will be given, and then reference examples will be given of production examples of 6 raw material compounds for producing the active ingredient compounds to be incorporated into the formulations. In addition, production examples of the above-mentioned active ingredient compounds are listed as examples, and test examples of the active ingredient compounds are also listed.

Formulation example 1 Methyl 2-[N-methyl-N-(4 chlorobenzoyl)amine]-3 (3-indolyl) acrylate 150 g Avicel (trade name, manufactured by Mukasei Co., Ltd.) 40 g Corn starch 30 g Magnesium stearate 2 g Hydroxypropyl methylcellulose 10 g Polyethylene glycol-60
003g castor oil
40g etano -
40 g of the effective compound of the present invention, Avicel, corn starch and magnesium stearate are mixed and polished, and then tableted using a sugar coater with a radius of 10 mm. The obtained tablets are coated with a film coating agent consisting of hydroxypropyl methylcellulose, polyethylene glycol-6000, castor oil, and ethanol to produce film-coated tablets.

Formulation Example 2 Methyl 2-[N-methyl-N-(4-bromobenzoyl)amino]-3-(3-indolyl)acrylate 150g phosphoric acid
1.0g lactose 33.5
g Dicalcium phosphate 70.0g Pluronic F-68 30. og sodium lauryl sulfate 15.0g polyvinylpyrrolidone
15.0g polyethylene glycol (Carbowax 1500) 4.5g polyethylene glycol (Carbowax 6000) 45.0g cornstarch 30. 0g dry sodium stearate 3. og dry magnesium stearate 3.0g ethanol
Appropriate amount of waterInvention active ingredient compound, citric acid, lactose, dicalcium phosphate, Pluronic F-
68 and sodium lauryl sulfate.

The above mixture was sieved with a No. 60 screen, polyvinylpyrrolidone, carbowax 1500 and carbowax 6000 were added.
wet granulation in an alcoholic solution containing Add alcohol if necessary to make the powder into a pasty mass. Add cornstarch and continue mixing until uniform particles are formed.

The mixture is passed through a No. 10 screen, placed in a tray and dried in an oven at 100°C for 12-14 hours. The dry particles are sieved through a No. 16 screen, mixed with dry sodium lauryl sulfate and dry magnesium stearate, and compressed into the desired shape using a tablet machine.

9. Treat the core with varnish and sprinkle with talc to prevent moisture absorption. A subbing layer is applied around the core. Apply varnish a sufficient number of times for internal use. Further subbing layers and smoothing coats are applied to make the tablet completely round and smooth. Pigmented coatings are applied until the desired shade is achieved. After drying, the coated tablets are polished to a uniform gloss.

Formulation Example 3 2-[N-methyl-N-(4-chlorobenzoyl)amino)-3-(3-indolyl)acrylic(N-isopropyl)amide 5g polyethylene glycol (molecular weight: 4000) 0.3g sodium chloride 0. 9g polyoxyethylene-sorbitan monooleate 0.4g sodium metabisulfite O,Ig0 Methyl-paraben 0.18g propyl-paraben 0. 02g distilled water for injection 10. Or/the above parabens,
Sodium metabisulfite and sodium chloride are dissolved in about half the amount of distilled water above at 80° C. with stirring. The resulting solution is cooled to 40° C., and the active ingredient compound of the present invention, followed by polyethylene glycol and polyoxyethylene sorbitan monooleate, are dissolved in the solution. The solution is then adjusted to the final volume by adding distilled water for injection, and sterilized by sterile filtration using a suitable filter paper to prepare an injection.

Reference Example 1 To a methanol solution of methyl 1,1-lyptophanate hydrochloride 51.og 60011, triethylamine 33.
51111 and benzaldehyde 24.5z/,
Furthermore, at OoC, 19 g of sodium borohydride was added to 30
The mixture was added over a period of minutes and stirred for 5 hours. After the reaction solution was adjusted to pH 7 with acetic acid, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in diethyl ether, washed successively with a 10% aqueous sodium carbonate solution, water and saturated brine, and then dried over anhydrous magnesium sulfate. Part of the diethyl ether was distilled off, and n-hexane was added for crystallization, followed by recrystallization from diethyl ether-n-hexane to obtain 57.3 g of methyl Na-benzyl-L-)liptophanate.

Melting point: 107.5-109°C Properties: Colorless needle crystal NMR (CD CA! 3) δ: 3, 05-3. 30 (2H, m)3, 62 (
3H,s) 3, 60-3. ．． 71 (2H, oyerlap)
3.82 (IH, d, J=13.2H2) 6.97
(IH, d, J=2.IH2)7, 01-7. 32
(8H, overlap)7. 56 (IH
, d, J-7, 5H2) 8, 16 (LH, b
rs) Reference Example 2 Methyl Nct-benzyltryptophanate 24.6
37% formalin to 400 zl of methanol solution
271 and 3.5 g of sodium cyanoborohydride were added, and the mixture was stirred at room temperature for 15 minutes.

After adding acetic acid to adjust the pH to 7, the mixture was further stirred for 1 hour, the solvent was distilled off under reduced pressure, the resulting residue was dissolved in diethyl ether, and the mixture was washed successively with a 10% aqueous sodium carbonate solution, water, and saturated brine. , dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to give methyl N. -Benzyl-Na-
28.5 g of methyltryptophanate was obtained.

Reference Example 3 28.5 g of methyl Na-benzyl-Na-methyltryptophanate was dissolved in IN hydrochloric acid-methanol 3 solution 50C)rA', 28 g of ]-]〇% palladium-carbon was added, and the mixture was heated at room temperature in a hydrogen stream. The catalytic reduction reaction was carried out for one day. After the reaction was completed, the catalyst was removed from the furnace and the solvent was distilled off. The obtained residue was purified by alumina and silica gel column chromatography (eluent: chloroform-methanol), converted into a hydrochloride with concentrated hydrochloric acid-methanol, and recrystallized from methanol-diethyl ether to give methyl Na-methyltryptophan. 9 g of nate was obtained.

Melting point: 164-167°C Properties: Colorless needle-like crystals NMR (CD CII 3 ) δ: 2, 37 (3H,s) 3, 12 (IH, dd, J=1-4.3H2
.

7.3Hz) 3, 20 (IH, dd, J=14. 3H2.

7.3H2) 3, 57 (LH,l, J=7.3H2)4 3, 66 (3H,s) 7,04 (IH,d, J=2.4H2)7
, 12 (LH,t, J-8,1,H2)7
, 19 (IH, l, J=8.IH2)7
, 35 (LH, d, J=8.1H2)7,
60 (IH, l, J=8.1H2)8,
25 (IH, brs) Reference Example 4 50% dimethylamine8. ↓2g was cooled to 0°C, 12g of acetic acid was gradually added thereto while stirring, and 6.96g of a 37% formalin solution cooled to 0°C was further slowly added. This solution was added to 13 g of 5-chloroindole at room temperature and stirred occasionally to obtain a solution. After stirring this overnight at room temperature, an aqueous solution of 12 g of sodium hydroxide 86y#
I poured it inside. After filtering the obtained solid, it was washed with water, dried (P20s), and recrystallized from methanol to obtain 9.01 g of 5-chlorogramin.

Melting point: 143-144°C Properties: colorless plate-like crystal Reference example 5 Using appropriate starting materials, 5-
Bromogramine was obtained.

Melting point: 150-151°C (recrystallized from methanol) Properties: Colorless plate-like crystals Reference example 6 4.97 g of 5-methoxygramine was dissolved in 20 g of dry ethanol.
yt (l) and stirred at room temperature under an argon atmosphere to obtain a solution, to which 1.68+1 iodomethane was added and stirred for 6 hours. The reaction mixture was cooled to 0 °C and filtered to obtain a solid. , washed with diethyl ether and dried (P20s)
7.69g of 5-methoxygramine methiodide
I got it.

IR (Nujol) cm”: 3260.1622.1581.1252, 1220.
1067.1030.948.803 NMR (DMS Oda) δ: 2.88.3.
05.3.13 (9 hours in total.

5 each) 3180.3.82 (total 3H, 8 each) 4.67.4.81 (total 2H, 8 each) 6.83 (LH, dd, J=8.7H2゜2,
IHx) 7.38 (IH, d, J=8.7H2) 7.43
(IH, d, J=2.1H2)7.62 (d,
J=2.6H2) 7.68 (d, J-2,6H2)11, 50
(IH, broad) Reference Example 7 The following compound was obtained in the same manner as in Reference Example 6 using appropriate starting materials.

o5-chlorogramin methiodide 7 IR (Nujol) cm': 3275.1568.1535.1110.1050.
947.892.880.863, 92 NMR (DMSO-da) δ: 2.93.3.
12.3.22 (Total 9H.

Each S) 4.76.4. 86 (g+2H, each S) 7, 15
(LH, dj, J=8.5H2.

2, IHx) 7.48 (IH, dd, J=8.5Hx.

2.1H2) 7.72 (IH, d, J=3.0Hz) 7.9
8 (d, J=2.1H2) 8.01 (d, J=2.IHx) 11, 73
(LH, btoad)05-Bromogramine Methiodide IR (Nujol) cm-': 8 3250.1565.1536.1110.1048.
975.946.882.812.792.759 NMR (DMSO-de) δ: 2.88.3
．． 06.3.15 (9 hours in total.

each S) 4.69.4.80 (total 2H, each S) 7, 29 (LH, dt, J=8.5H2゜2.1Hz) 7, 46 (LH, dd, J=8.5Hx
.

2, 1Hz) 7, 73 (d, J=2.6Hx) 7, 7
7 (d, J=2.6Hri8.10 (d,
J=1.7Hz)8, 16 (d, J=1
．． 7Hz) 11, 82 (IH, broad)
Reference Example 8 2.5 g of 5-methoxygramine methiodide.

2.83 g of diethyl (N-acetyl-N-methyl)aminomalonate and 145 mg of sodium hydroxide powder were added to 1.1 g of dry toluene. oxll and stirred under reflux for 6 hours at room temperature. After cooling the reaction mixture, diluted with ethyl acetate.
Extracted twice, saline, IN HCI.

After washing successively with brine, it was dried (Na2S04) and concentrated under reduced pressure to give an oil.

This product was subjected to column chromatography (Fuco-C-20
0 gel, 300 g, eluent; chloroform:methanol-200:1), and the resulting crystals were recrystallized from methanol to give ethyl 2(N-acetyl-N-methyl)amino-2-carboethoxy- 1.90 g of 3-(5-methoxyindolyl)propione) was obtained.

Melting point = 128°C Properties: Colorless cubic crystals Reference example 9 Methylglycinate hydrochloride 25, 1g
was suspended in dry dichloromethane 500 z/ under a stream of argon, and after cooling to OoC, dried triethylamine 92
．． Ozl was added and stirred for 30 minutes. Next, 48.3 g of p-bromobenzoyl chloride was added in 4 to 5 portions, and the mixture was stirred at room temperature for 4 hours. Add water to the reaction mixture, water, IN HCl2. Wash with water, Na HC03 water, water in this order, and dry (N,, a 2 S 04 ) L
, and concentrated under reduced pressure to obtain crystals.

This product was subjected to column chromatography (Fuco-C-20
0 gel, 1. The resulting crystals were recrystallized from chloroform-hexane to obtain 53.63 g of methyl N-p-bromobenzoylglycinate.

IR (Nujol) cm': 3280.3095.1748.1642.1595.
1562.1553.1208, 1 1014.852.766 NMR (CDC123) δ: 3, 81 (3H, s) 4.23 (2H, d, J-5, IN2) 6, 8
0 (LH,broad)7.57 (2H,d
, J-8,8Hz)7.69 (2H,d,J
-8,8H2) Reference Example 10 Methyl N-methylglycinate hydrochloride F25. Og, dry di'7oo methane 500-zl, dry triethylamine 82.4z# and p-bromobenzoyl chloride 4
3.23g was reacted to obtain an oily substance, which was subjected to column chromatography (Fuko-C-200 gel, 1.1kg
, eluent: chloroform:acetone-200:1) to obtain 48.85 g of methyl N-p-bromobenzoyl-N-methyl 2 glycinate.

IR) cm-': 1744.1637.1591.1399.1213.
1076.1012.838, 6O NMR (CDCA'3) δ (50°C): 3.05 (
3H,s) 3.77 (3H,s) 4, 22 (2H,broad) 7.37 (2H,d, J=8.4H2) 7.55
(2H, d, J=8.4H2)MS (70e V)
m/2: 288.286 (M”), 284
．． 228.226.185.183.157.155 Reference Example 11 Methyl N-p-bromobenzoylglycine-1-',
6.54 g of O,0gXN-bromosuccinimide were dried with 110. v# and refluxed under a stream of nitrogen. The resulting mixture was irradiated with light for 3 hours using a 500W sunlamp, cooled to room temperature, and filtered to obtain a solid. This was dissolved in 12,011 l of dry dichloromethane and 4.77 rI of trimethylphosphite was added at room temperature under a stream of argon with stirring, followed by stirring overnight.

The reaction mixture was diluted with water, NaHCO3 water, INNa2S2O3
and water, dried (Na2S4), and concentrated under reduced pressure to obtain a solid.

This product was subjected to column chromatography (Wako (, -2
00 gel, 1. The resulting crystals were recrystallized from ethyl acetate-n-hexane to give methyl 2-(p
-1.1 g of -bromobenzoyl)amino-2-(dimethoxyphosphinyl)acetate-) was obtained.

Melting point = 156-i, 57.5°C Properties: Colorless prismatic crystals Example 1 Methyl N. - 1.0 g of methyltryptophanate,
Dry dichloromethane 3 (Jtll) was added to this, and 1.6377' of dry triethylamine was added thereto while stirring at 0°C in an argon stream.Next, 901 mg of 3°4.54rimethoxybenzoyl chloride was gradually added. Stirred at room temperature for 40 minutes. Ice was added to the reaction mixture, extracted twice with ethyl acetate, washed successively with brine, 1N hydrochloric acid, brine, aqueous sodium bicarbonate, and brine, and dried over sodium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent; chloroform:methanol-200:1).
Methyl Na-methyl-N.

1.459 g of -(3,4,54rimethoxybenzoyl)tryptophanate was obtained.

IR (CDC/3.v:cm-') 5 3475.1738.1627.1585.141■,
1238.12■5.1128NMR(CD CA'
3) δ near, 32 (d, J-8, 4Hz)
7, 65 (broad), 8. 42 (br
oad ) 8, 44 (broad), 2. 8
2 (broad s ) 3, 10 (broad
s) 3, 50 (3H, broad s) 3, 63
(3H, broad s ) 3.78 (3H, s
), 3.84 (3H,s) 3.1-3.7
(2H, m) 4.90 (m) , 5.56 (m) 6, 07
(btoad), 6. 22 (broad)
6.93 (m), 7.15 (m) MS (mass spectrum, 70eV): m/z426 (M”)
, 226.225.202.201.196.195.
170,152.131.130 6 Examples 2 to 58 Each compound shown in Table 1 below was obtained in the same manner as in Example I using appropriate starting materials.

In addition, the properties of each compound obtained (melting point, NMR).

IR, MS) and crystal forms (recrystallization solvent) are shown in Table 2.

8 9 100 1 02 03 104 Table 05 06 07 108 ↓O9 10 111 Note that (1) to (30) in the properties section of Table 2 above are as follows.

Example 2: Properties (1) IR (CDCI!3) cm-': 3475.1
741.1630,1593゜1400.1265,1
212,1071°012 NMR (CDCA'3) δ: 2.74.3.07.3.53-3.33.3, 81
(3H,s) 4, 63 (dd, J=5. IHx, 10.
8Hx)5, 45 (dd, J=5.I
H2, 10, 8H2) 6.40 (d, J=7.5H
2) 6.82 (s) 6.91 (t, J=7.3Hz) 7, 30-7. 0.7. 41 (d, J=7
．． 9H2) 7.62 (d, J=7.3Hz) 12 8, 70.8.76 M5 (70e V) m/z:416, 41
4 (M”), 357. 355°202,
201. 185. 170. 157°155, 1
31. 130 Example 3: Properties (2) IR(CDCA' 3 ) cm-': 3475.
1741, 1627, 1522゜1264.1215,
1071,101009N (CDC/3) δ: 2, 82 (s), 3. 11 (s) 3.6-3.
36 (2H) 3, 80 (3H,s) 4.76 (dd, J=3.3Hz, 10.1Hz)
5.52 6.64.6. 84 (m), 7. 557.02.
7.65.8.77.8.92M5 (70e V)
m/z: 412 (M”), 353,212,
202°201, 182. 181. 170. 1
53°152, 131. 130 Example 5: Properties (3) I R (CDCA'3) cm': 3475.17
41,1632,1536°35O NMR (CD CA' 3) δ: 2.78 (s), 3. 11 (s), 3゜14 (S
) 3.61-3.33.3.85(S) 3.90(s) 4, 63 (dd, J=3.3H2,11,2
HX)5, 49 (dd, J=5.2H2,
10,8Hz)6.78 (1,J=7.4H2) 7, 52-6. 92 7.65 (d, J=8.0H2) 7.94.8.22.8.31 MS (70e V) m/z:381
(M”), 322,251,202゜201.17
2,170,150. ■43゜131.130 Example 6: Properties (4) IR (CDCl2) cm-': 3475, ↑739,1638.1532゜348 NMR (CD CA! 3) δ: 2.71 (S) 3.20 -3.28 (m) 3, 41 (d+l, J=10.6H2,15
,3'Hz)3.60 (dd, J=5.3H2,1
4,3H2) 3.72 (s) 3.85 (s) 4.15 (S) 5.65 (m) 6.66 (m) 15 6, 9-7. 7 (m) 8.02 (d, J=8.2H2) 8.16
(d, J=8.IR2)8, 15-8. 4
(broad) MS (70e V) m/
2:381 (M”), 322. 201.
170°150, 130 Example 8: Properties (5) I R (CDC13) cm-': 3475.1742, 1625. ↑590°126
5.1.009 NMR (CD CA! 3) δ: 2.76 (s) 3.07 (S) 3.11 (m) 3, 35-3. 61 (m) 3.82 (s) 4.65 (m) 16 5, 48 (m) 6.30 (d, J=7.5H2) 6.86-7, 36 (m) 7.64 (d , J=7.5H2) 8, 30 (broad) 8, 34 (broad) MS (70e V) m/2:462 (
M"), 403,262,231°201, 130 Example 9: Properties (6) IR (CDCA'3) cm-': 3475.1737, 1644, 1603°1400.
1112 NMR (CDCA'3) δ: 2.98 (s) 3.01 (s) 3, 15 (dd, J=10.2H2,14,6
H2) 3, 33 (dd, J=10.2Hz,
↓5.3H2) 3, 46-3. 63 (m) 3.75 (s) 3.79 (s) 4, 93 (dd, J=3.5H2,10,
2H2) 5, 55 (dd, J=5.4H2
,10,2H2)6.02 (d, J=15.3
H2) 6.77 (d, J=15.IR2)6,
83-7. 63 (m) 7.70 (d, J=15.3H2)8, 35
(broad) MS (70e V) m/z:362 (M
”), 303. 202. 201゜131, 1
30 Example 10: Properties (7) I R (CDCA73) cm-': 3475.17
38,1610,1523゜1220.1010 58N (CD C(13)δ: 3, 07 (3H,s) 3.20-3.40 (m) 3,51 (dd, J=5.5Hz, 15.
3H2) 3, 78 (3H,s) 5.33 (IH,m) 6, 85-7. 55 (8H, m)8, 31
(LH, broad) MS (70e V)
m/z: 342 (M”), 283.
201. 170°131, 130. 111 Example 11: Properties (8) IR (CDCA'3) cm-': 3480.17
40.1626,1600°1089.1015.83
8 NMR (CDCI!3) δ: 2.77 (s) 3.08 (s) 3, 05-3. 18 (m) 19 3, 34-3. 61 (m) 3, 83 (3H,s) 4, 65 (dd, J-10,2HL3.8
Hz)5.49 (dd, J=10.6H2,
5,5H2)6,50 (d, J=7.8H
z) 6.86-7.38 (m) 7.64 (d, J=7.8H2)8, 39
(broad) 8, 43 (broad) MS (70e V) m/z: 370
(M”), 311. 202. 201°170
, 141. 139. 131. 130°11 Example 12: Properties (9) IR(CDCA'3) cm'(: 3475.3500-2400 (broad).

1712.1623, 1595.1264°1088.
835 2O NMR (CDC73) δ: 2.78 (s) 3.09 (s) 3.04-3.20 (m) 3.33-3.60 (m) 4.68 (dd, J=11. 4HL3.5Hz)5
．． 33 (dd, J=8.9H2,5,7H2)6.
51 (IH, d, J=7.6H2)6.86-
7.49 (m) 7.65 (d, J=7.6Hz) 8.05
(btoad), 8. 348, 39 (br
oad ) MS (70e V) m/! :404.40
2 (M”), 356,292°291.256,
201,187,170°139, 130 Example 13: Properties (10) I R (CDCA'3) cm-': 3490,
1625. 1600, 1230° 1092, 101
5. 838 NMR (CDCA'a) δ: 2.60-3.17 (4H, m) 2, 99 (3H, s) 3.32 (LH, dd, J=14.3Hx, 7
．． 2H2) 3.48 (IH, dd, J=14.3Hx
7.8H2) 3.55-3.90 (4H, m) 6.01 (LH, l, J=7.5H2) 6.8
0-7.37 (13H, m) 7.77 (IH,
dd, J-'/, 2H2, 1, 4Hz) 8, 27 (IH, broad) MS (70
eV) m/2:502.500 (M”
), 371,332°331, 311. 232
．． 214. 212°210, 189. 171.
170. 162°161 Example 14: Properties (11) I R (CDCj23) cm-': 3480.16
24.1597,1114゜1090.1015.83
7 NMR (CD CII3) δ: 3,00 (3H,s) 3.31-3.63 (IOH,m) 5,93 (1,H,l, J=7.6H2)
7, 07-7, 38 (8H, m)7, 74 (
IH, d, J=7. 3H2) 8, 27 (I
H, broad) MS (70e V) m/X: 427.425
(M”), 313,312°311.310,29
6,258,257°256.211,210,209
, 172° 171.170 23 Examples] -6 = Properties (12) IR (CDCA3) cm-': 3480.1,637,1622. Soil 600°10
90.1017.838 NMR (CDCA'3) δ: 2, 0-3. 4 (4H, m) 2, 22 (3H, s) 2, 97 (3H, s) 3, 30 (II-1, dd, J=14.6H
27,6H2) 3, 44 (IH, dd, J=14.6H27
, 6Hz) 3, 3-3. 7 (4H, m) 5.95 (IH, t, J=7.6Hz) 7.07'
(2H, d, J=8.5H2)7, 31 (
2H,d, J=8. 5H2) 7, 0
5-7. 4 (4H, m) 7, 75 (IH, d, J=7.0H2) 24 8, 42 (LH, broad) MS (70
eV) m/z:440, 438 (M+
), 339°270, 269. 212. 21
0°171, 170. 141 Example 19: Properties (13) NMR (CD C123) δ: 2.77 (s) 3.06 (S) 3, 05-3. 20 (m) 3.25-3.65 (m) 3.75 (s) 3.81 (S) 4.25 (m) 4.63 (m) 5.42 (m) 6.55 (d, J=6.7H2) 6.80-7.35 (m) 311°186°7.63(d) MS (70e V) m/Z:384 (M”
), 325,246°184, 144. 139 Example 20: Properties (14) NMR (CDCA'3) δ: 2.78 (S) 3.07 (S) 3, 05-3. 20 (m) 3, 25-3. 60 (m) 3.82 (S) 4.69 (d, J=5.3H2) 5, 0-5. 3 (m) 5.45 (m) 5.95 (m) 6, 60 (d, J=7.2H2) 6, 8
-7. 4 (m) 7.64 (d, J=7.5Hz) 215゜MS (70e V) m/z:412.41
0 (M”), 353,351°241, 210.
170. 139 Example 21: Properties (15) NMR (CDCA'3) δ: 2.76 (S) 3.06 (s) 3, 05-3. 25 (m) 3-3 3. 6 (m) 3.82 (s) 4.69 (m) 5.28 (S) 5.46 (m) 6.54 (d, J=8.IH2) 6.8-7.4 (m) 7.65 (d, J=7.5H2) Example 29: Properties (16) I R (CDCA'3) cm-': 27 3470.1710. 1621. 1522゜266 NMR (CD CII 3) δ: 3, 30 (3H, s) 3, 74 (3H, s) 7.49-7.24 (12H, m) 7.70
(IH, dd, J=1.2H!, 6.6H2) 7.86 (IH, d, J=3.OHx) 7.90
(IH,s) 9, 83 (LH,broad)MS (70
eV) m/X: 410 (M”), 39
3,351,229°194, 188. 181.
170 Example 30: Properties (17) IR (CDCl2) cm-': 3450.1703, 1650.1620°1545.
1518,1345.1259゜28 237 NMR (C, D CIt3) δ:3, 37
(3H,s) 3, 88 (3H,s) 7, 23 (IH,t, J=7.8H2)7
, 32 (IH,!, J=7.5Hz)7,
48 (IH, d, J=7.8H2)7.
62 (IH, d, J='7.5H2)7, 7
4 (LH, d, J=2.8H2)7, 87
(IH,s) 8, 45 (2H,d, J=2.OHx
)8.89 (LH, l, J=2.0Hx)9
, 15 (IH, broad) MS (70e
V) m/z: 424 (M”), 3
65. 229. 208°197, 188. 17
0. 160. 155 Example 31: Properties (18) I R (CDCA'3) cm-': 3460.1
710,1642.1620°1538, 1350.
1263 NMR (CDCj?3) δ: 3.33 (3H, s) 3.81 (3H, s) 7.20-7.34 (3H, m) 7.47 (IH, d, J=7.0H2 )7.64
(IH, d, J=8.IHg) 7.70 (IH,
dt, J=7.7H2, 1,3Hz) 7.70 (IH, d, J=7.0H2) 7.80
(IH, d, J=2.7H2)7.87 (
IH,s) 8.13 (IH,dm,J=8.2H2)8.24
(LH, t, J=1.8Hz)9, 30 (I
H, broad) MS (70e V) m/
z: 379 (M”), 229, 197, 188°1
70, 163. 160. 155. 150 Example 36: Properties (19) IR (CDC13) cm-': 3465.1707, 1645, 1610°1578.
1520, 1329, 1241゜1206.1010 9ON (CDCA'3) δ: 3, 24 (3H,s) 3, 87 (3H2s) 6.72 (LH, d, J=15.7H2) 7, 21
-7. 33 (7H, m>7.56 (IH, m) 7.59 (LH, d, J=3.IH2) 7.72 (
IH, d, J = 15.7H2) 7, 87 (IH, m
) 8.24 (IH,s) 10, 48 (IH,broad)MS (70e
V) m/z: 31 360 (M”), 301,230,229°20
6.197,188,170. 155 Example 39: Properties (20) IR (CDCl2) cm-': 3475.1,620,1522,1413°1267
, King 115, 1090, 10 King 5゜37 NMR (CD C13) δ: 3, 10-3. 92 (8H, m)3, 36 (
3H,s) 6, 85 (IH,s) 7.20 (2H,d, T-7, r'HT□)7,
25 (LH, l, J=8.OH2)7,
31 (LH,t, J-8,OHx)7.4
1 (2H, d, J=7.6Hz)7.48 (IH
, d, J=8.0H7) 7, 63 (IH, d,
J=8. 0T-Iz)7, 74 (IH,br
oad) 32 9, 47 (LH, broad) MS (70
eV) m/2:425.423 (M”
), 337, 284° 268, 243. 215.
197. 170°169, 155. ■54.
152. 139 Example 43: Properties (21) IR (CDC13) cm-': 3470.1635.1618.1523°1088.
1012.835 NMR (CDC13) δ: 1, 4-1. 9 (4H, m) 3, 05-3. 35 (4H, m)3, 35 (
3H,s) 6, 99 (IH,s) 7, 18 (2H,d, J=8.2H2)7
．． 37 (2H, d, J28.2H2)7, 15-7
．． 3 (2'H, m) 7.48 (IH, d, J-8
,5Hz)7.64 (IH,d,J=7.5H2
)7.72 (IH, d, J=2.4H2)9,
79 (IH, broad) MS (70e
V) m/z 409.408,40, M+), 338°337
．． 336,309,268,227°199.197.
17 kings, 170, 169° 155, 154. 15
2. 141 Example 47: Properties (22) NMR (CD CII 3 ) δ: 3, 21 (3H,s) 3, 72 (3H,s) 5, 43 (2H,s) 7, 05-7. 45 (IOH,m)7, 72
(LH,,s) 7.75-7.80 (LH,m) 7, 84 (IH,s) MS (70e V) m/z:460.458
(M”), 319,228°169.152.
91 Example 40: Properties (23) IR (Nujol) cm': 3350.3255, 1656.1630°1607.
1578, 1513, 1252°1135.1092.
1015.933°840.747 NMR (CDCA'3) δ: 1.14 (3H, d, J=6.7H2) 1.18 (
3H, d, J = 6.7H7) 3, 32 (3H, s
) 4.16 (IH, m) 5.74 (IH, d, J=8.6H2) 7.11 (
2H, d, J = 8.6Hx) 7.36 (2H, d, J
=8.6H2)7, 17-7, 45 (3H, m)
7.56 (IH, d, J=2.9H2) 35 7, 71 (LH, d, J=7.3H2)7
, 78 (IH,s) 9, 22 (IH,broad)MS (7
0e V) m/Z: 397.396,395
(M”), 336°309, 269.25
6. 215. 187°172, 171. 170
．． 155. 154 Example 42: Properties (24) IR (Nujol) cm→: 3325.3180,1650,1616°1597.
1253.1148,1093゜1010.745 NMR (CDCA'3) δ: 3.30 (3H,S) 4.43 (IH, dd, J=14.6H25,4Hz
) 4, 65 (LH, dd, J=14.6H2.

6.0H2) 36 6.71 (LH, l, J=5.1Hz)7.02
(2H, d, J=8.6H2)7.24 (
2H, d, J-8, 6H2) 7, 15-7.32
(7H, m) 7.43 (1, H, dd, J=3.
3Hz, 1,7Hx) 7.56 (IH, d, J=2.9H2) 7.72
(IH, d, J=7.3Hx) 7.86 (IH,
s) 9, 12 (IH, broad) MS (70
eV) m/2:445.444,443
(M”), 336°309.304,276.26
9,235°213.172,171,170,155
゜54 Example 22: Properties (25) NMR (CDCA'3) δ: 2, 93 (3H, broads) 3.15-3
．． 60 (2H, m) 3, 73 (3H, s) 3, 80 (3H, s) 4, 60-5.60 (IH, m) 6.30-7.
70 (9H, m) 8, 75 (IH, broads) Example 23
:Properties (26) NMR (CDCA's) δ: 2, 97 (3H, broads) 3, 15-
3. 60 (2H, m) 3, 60 (3H, s) 3, 80 (3H, s) 4.60-5.60 (, IH, m) 6.2077.70 (9H, m) 8, 80 (LH , broa, d s ) Example 24
: Properties (27) NMR (CD CII 3 ) δ: 2, 80 (broad s ) 3, 07 (broad s ) 3. 20-
3. 70 (2H, m)3, 80 (3H, s
) 4, 50-4. 80 (m) 5, 30-5. 70 (m) 6.40-7.90 (9H, m) 9, 87 (LH, broads) Example 2
5: Properties (28) NMR (CD C123) δ: 2.70 (S) 3.10 (S) 3, 20-3. 60 (2H, m)3, 83 (
3H,s) 4, 33-4. 70 (m) 5, 33-5. 55 (m) 6, 50-8.40 (9H, m) 9.05 (broad s) 9, 15 (broad s) 39 Example 26: Properties (29) NMR (CD CI23) δ: 2, 34 ( 3H,s) 2, 90 (3H,s) 3, 00-3. 40 (2I-I, m)3,
50 (3H,s) 4, 95 (d, J=7H2)5.05 (d
, J-7Hx) 6, 95-7. 80 (9H, m)8, 40 (
IH, broads) Example 39: Properties (30) NMR (CDCl13) δ: 2, 37 (3H,s) 3, 13 (3H,s) 3, 53 (3H,s) 7, 10-7. 40 (5H, m)7, 65-7
．． 85 (3H, m) 8, 20 (IH, s) 40 8, 38 (IH, d, J=3H2) 8, 2
0 (IH, s) 8, 38 (LH, d, J=3H2) 9, 6
5 (IH, broads) Example 59 2-(N-methyl-N-benzoyl)amino-3-(3
- 500 mg of (indolyl) acrylic acid is added to 1011 l of dry dichloromethane to dissolve it, and 222 μl of dry triethylamine is added to the solution while stirring under a stream of argon.
was added at room temperature. After stirring for 20 minutes, 426 mg of phenyl N-phenylphosphorylamide chloridate was added to this solution.
After stirring for 10 minutes, add isopropylamine 14
0zl and 228 μl of triethylamine in dry dichloromethane3. yA' solution was added gradually. After stirring at room temperature for 2.5 hours, the mixture was concentrated under reduced pressure, and the resulting residue was extracted twice with ethyl acetate and washed successively with brine, IN hydrochloric acid, brine, aqueous sodium bicarbonate, and brine. After drying with sodium sulfate, the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol 50:1) and recrystallized from chloroform-n-hexane to give 2-(N-methyl-
383 mg of N-benzoyl)amino-3-(3-indolyl)acrylic(N-isopropyl)amide was obtained.

Melting point: 214-215°C Properties: Yellow prismatic Example 6O 900 mg of N4-methyl-N,-(4-chlorobenzoyl)tryptophan was dissolved in 30 zl of dry dichloromethane.
The solution was cooled to -100 C with stirring under an argon stream, and 369 μβ of triethylamine was added to the solution.
and then add 529μ of diphenylphosphinyl chloride.
1 was added gradually over a period of 10 minutes. 15 at -10℃
After stirring for a minute, 369 μl of dry triethylamine and 405 μl of N-phenylpiperazine were added, and the mixture was stirred at −10° C. for 30 minutes and further stirred at room temperature for 1 hour. After adding water to the reaction mixture, it was concentrated under reduced pressure, and the resulting residue was extracted twice with ethyl acetate, and the extract was washed successively with brine, an aqueous sodium bicarbonate solution, and brine. After drying with sodium sulfate, the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol 125:1) to obtain N,-methylNa-(4-chlorobenzoyl)tryptophan (4-
871 mg of phenyl-1-piperazinyl)amide was obtained.

IR(CDCA'3) cm-': 3490.1
625. ■600,1230°1092.1015
．． 838 NMR (CDC/3) δ: 2.60-3.17 (4H, m) 43 2, 99 (3H, s) 3, 32 (LH, dd, J=14.3H2.

7.2H2) 3.48 (IH, dd, J=14.3H2J=
7. 8Hz) 3, 55-3. 90 (4H, m)6.01
(IH, l, J=7.5H2)6.80-7.37
(13H, m) 7.77 (LH, dd, J=7
．． 2H2,1,4Hz) 8, 27 (LH, broad) MS (70
eV) m/z:502.500 (M”)
, 371, 332° 331, 311. 232. 2
14. 212°210.189,171,170,1
62゜161゛Examples 14-18.39-44 44.75-95.101.119-122.135-
139.144-178.180-184.186.1
Compounds identical to those obtained in 87.190-201.203 and 204 can be produced.

Example 61 Methyl 2-[N-methyl-N-(4-chlorobenzoyl)amino)-3-(3-indolyl)acrylate 1
．． 70 g was dissolved in a mixed solution of 2Or of methanol and 2011 of tetrahydrofuran, 1 mol of potassium hydroxide aqueous solution was added to this solution, and the mixture was heated under reflux for 8 hours under an argon atmosphere. After the reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, which was then washed with ethyl acetate and acidified with IN hydrochloric acid. It was extracted twice with ethyl acetate, and the extract was washed with brine and dried over sodium sulfate. The residue obtained after concentration was subjected to silica gel column chromatography (eluent; chloroform:methanol:acetic acid = 1000:2
5:3.5) and recrystallized from benzene-dichloromethane to obtain 2-[N-methyl-N-(4-chlorobenzoyl)amino]-3-(3-indolyl)acrylic acid 1.
．． 43g was obtained.

Melting point = 238-240°C (decomposition) Example 62 Methyl N. -Methyl-Na-(4-chlorobenzoyl)tryptophanate 5.0g was mixed with methanol 40r/
21 x 1 of a 1M aqueous sodium hydroxide solution was added thereto, and the mixture was stirred at room temperature under an argon stream for 4 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and then 6N hydrochloric acid was added to make it acidic. It was extracted twice with ethyl acetate, and the extract was washed with brine and dried over sodium sulfate. The residue obtained after concentration was subjected to silica gel column chromatography (
Eluent; chloroform:methanol:acetic acid 100:4:
1) to obtain 4.5 g of N,r-methyl N,-(4-chlorobenzoyl)tryptophan.

IR (CDC/3) cm-’: 3475.350C1-2400 (broad).

1712.1623,1595,1264°1088.
835 NMR (CD CA' 3 ) δ: 2.78 (s) 3.09 (s) 3.04-3.20 (m) 3.33-3.60 (m) 4.68 (dd, J= 41.4H2,3,5H2)5
．． 33 (dd, J=8.9H2,5,7H2)6.5
1 (IH, d, J=7.6H2)6.80-7.49
(m) 7.65 (d, J=7.6H2) 8, 05 (broad) 8.34 47 8, 39 (broad) MS (70e V) m/z: 404,
402 (M+), 356. 292°29
1.256,201,187. King 70°139,
130 Example 54.1-02.115.13 in a similar manner to Examples 61 and 62 above using appropriate starting materials
Compounds identical to those obtained in 3.134.185 and 202 can be prepared.

Example 63 Methyl N. -Methyl-N,,-(3,4,5trimethoxybenzoyl)amino-3-(3-indolyl)acrylate 1.30g in 30ytll of tetrahydrofuran
A solution of 0.91 g of 2,3-dichloro-5,6-diciazoquinone (DDQ) in dry tetrahydrofuran 411 was added dropwise to the solution at 0° C. over a period of 8 minutes. After stirring the mixture at room temperature for 3 hours, it was added to
Thiosulfuric acid]-48 The reaction was stopped by adding a thorium aqueous solution, and then extracted with ethyl acetate. After sequentially washing with an aqueous solution of sodium hydrogen carbonate and a saline solution, the solution was dried with sulfuric acid), the solvent was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent: chloroform:methanol-20).
0:1) and recrystallized from dichloromethane-n-hexane.

Thus, methyl 2-[N-methyl-N-(3°4.5
1.11 g of 4-rimethoxybenzoyl]amino-3(3-indolyl)acrylate was obtained.

Melting point = 140 to 141°C Properties: white needle-like crystals Example 64 To a solution of 889 mg of methyl Na-methyl-Na-(4-phenylbenzoyl)tryptophanate in dry tetrahydrofuran 3011 was added D at room temperature under an argon stream.
A solution of 636 mg of DQ in dry tetrahydrofuran 511 was added dropwise over a period of 10 minutes.

After the mixture was stirred at room temperature for 2 hours, an aqueous IN sodium thiosulfate solution was added to stop the reaction, and the mixture was extracted twice with ethyl acetate. After sequentially washing with an aqueous sodium bicarbonate solution and brine, drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent; chloroform:methanol = 2
00:1) to produce methyl 2-[N-methyl-N
900 mg of (4-phenylbenzoyl)amino-3-(3-indolyl)acrylate was obtained.

IR (CDC#3) cm-' 3470.1710, 1621, 1522°266 NMR (CDC'3) δ: 3.30 (3H,s) 3.74 (3H,s) 7.49-7.24 (12H, m)7.70 (
IH, dd, J=1.2H2,6,6Hz) 7.86 (LH, d, J=3.OHx)7
, 90 (LH,s) 9, 83 (IH,broad)MS (70
eV) m/z:410 (M”), 393
,351,229°19.4. 188. 181.
170 Examples 28.30 to 58.75 were prepared similarly to Examples 63 and 64 above using appropriate starting materials.
~86.96~133.135~139.141~14
8.163-178.184.187.189-191
．． 197-200. Compounds identical to those obtained in 203 and 204 can be produced.

Example 65 561 mg of methyl (Na-methyl-Na-(4-chlorobenzoyl)tryptophane) was dissolved in 5xll of dimethylformamide, and 91 mg of sodium hydride was added to this solution under water cooling, and after stirring for 15 minutes,
Furthermore, 140 μl of methyl iodide was added, and the mixture was stirred for 1 hour while cooling with water. The reaction mixture was poured into ice water and extracted with ethyl acetate. After sequentially washing with water and saturated brine, drying over anhydrous sodium sulfate, distilling off the solvent under reduced pressure and concentrating, the resulting residue was subjected to silica gel column chromatography (eluent: dichloromethane: ethyl acetate = 9:1). ) to produce methyl 1. 500 mg of Na-dimethyl-Na-(4-chlorobenzoyl)tryptophanate was obtained.

NMR (CDCA'3) δ: 2.77 (S) 3.06 (s) 3.05-3.20 (m) 3.25-3.65 (m) 3.75 (S) 52 3.81 (8) 4.25 (m) 4.63 (m) 5.42 (m) 6.55 (d, J=6.7Hz) 6.80-7.35 (m) 7.63 (d) Above Examples 20.21.45 to 47.96.97.99.
104-109.113.123.124.126.1
27.129.131.135-139.142-14
Compounds identical to those obtained in 8.179-182.184 and 204 can be prepared.

Example 66 2-[N-methyl-(4-chlorobenzoyl)amino)
6.1 g of -3-(3-indolyl)acrylic acid was suspended in 5C)tll of methanol. To this was added dropwise 5.3 g of thionyl chloride while stirring under water cooling, and the mixture was stirred overnight at room temperature. After methanol and thionyl chloride were distilled off under reduced pressure, the residue was recrystallized from methanol-chloroform to give methyl
3 g of 2=[N-methyl-N=(4-chlorobenzoyl)amino]-3-(3-indolyl)acrylate was obtained.

Melting point = 224°C Properties: White prismatic crystals Examples 1 to 11.19 to 34.36 to 37.45 to 5 were prepared in the same manner as in Example 66 above using appropriate starting materials.
3.56~58.96~100°103~114.12
3-132.140-143.179.188 and 18
Compounds identical to each compound obtained in 9 can be produced.

Example 67 Methyl Ncl-methyltryptophanate 1.4 g,
3 g of DCCl and 1.35 g of 3,4.5-trimethoxybenzoic acid were suspended in dioxane 1011,
Stir at ~70°C for 5 hours. After the reaction was completed, the solvent was distilled off, diethyl ether was added, and the precipitated crystals were removed in the oven. After concentrating the furnace solution, chloroform was added to the residue to dissolve it, and the solution was washed successively with water and saturated brine. The obtained residue was subjected to silica gel column chromatography (eluent, chloroform:
Purification with methanol-200:1) to give methyl N,!
-Methyl-N. 300 mg of -(3,4,5-trimethoxybenzoyl)tryptophanate was obtained.

IR (CDC13) Cm-': 3475.1738, 1627.1585°1411.
1238.1215,1128NMR (CDC1?3)
δ: 2, 82 (broad s) 3, 10 (broad s) 3, 50 (3H, broad s) 55 3, 63 (3H, broad s) 3.78
(3H,s) 3.84 (3H,s) 3.1-3.7 (2H,m) 4.90(m) 5.56(m) 6, 07 (broad) 6, 22 (broad) 6 .93 (m) 7.13 (m) 7.32 (d, J-8, 4H2) 7, 65 (broad) 8, 42 (broad) 8, 44 (broad) MS (70e V) m /2: 426 (M
”), 226,225,202゜201.196,1
．． 95,170,152°131,. 130 56 Example 68 1.4g of methyl Na-methyltryptophanate and 0.8zA' of triethylamine were dissolved in tetrahydrofuran.
0111 and 1.0 g of diethyl chlorophosphate in 1.0 ytl of tetrahydrofuran under stirring at room temperature.
! The solution was added dropwise and stirred for 3 hours.

3 for this one. 4. 5-trimethoxybenzoic acid 1.
35 g of tetrahydrofuran 1011 solution was added dropwise, and the mixture was further stirred at room temperature for 10 hours. After the reaction was completed, the precipitated crystals were removed from the oven, the oven solution was concentrated, saturated sodium bicarbonate was poured into the residue, and the mixture was extracted with chloroform.

The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, and then the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography (eluent; chloroform:
Purify with methanol = 200:1) to obtain methyl Na
-Methyl-Na-(,3°4.5-)rimethoxybenzoyl) 0.85 g of l-liptophanate was obtained.

IR(CDC1?3)cm-' :3475.17
38,1627. 1585°1411, 1238.
1215. 11.28NMR (CDCl2)
δ near, 32 (d, J=8.4Hz)7, 65
(broad) 8, 42 (broad) 8, 4.4 (broad) 2, 82 (broad s) 3,, 10
(broad s ) 3, 50 (3H, bro
ad s ) 3, 63 (3H, broad
s) 3.78 (3H, s) 3.84 (3H, s) 3, 1-3. 7 (2H, m) 4.90 (m) 5.56 (m) 6, 07 (broad) 6, 22 (broad) 6.93 (m) 7.13 (m) MS (70e V) m /2 :426
(M”), 226. 225. 202°20
1, 196. 195. 170. 152°131
, 130 Example 69 3, 4. 5-4 Rimethoxybenzoic acid 6. To a solution of 56 g and 4 ytll of triethylamine in dimethylformamide 50zA', 3.8 g of isobutyl chloroformate was added.
A solution of 7 g of dimethylformamide in 2xll was added dropwise.

After stirring for 30 minutes at room temperature, 7.08 g of methyl N,-methyl-tryptophanate in dimethylformamide 3
ytll solution dropwise for 30 min at room temperature, then for 50 min.
Stir at ~60°C for 1 hour.

The reaction mixture was poured into a large amount of saturated brine, extracted with chloroform, washed with water, and then dried. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (eluent; chloroform:methanol = 200:1).
) to give methyl Na-methyl-N. −(3,
3.8 g of 4,5-)rimethoxybenzoyl)tryptophanate was obtained.

IR (CDCl2) cm-': 3475.1738.1627.1585°1411.
1238, 1215. ．． 1128NMR (CD CA'
3) δ near, 32 (+I, J=8.4Hz) 7.65 (broad) 8, 42 (broad) 8, 44 (broad) 2, 82 (broad s) 3, I Q (broad s)'3 , 50
(3H,broad s )3, 63 (3H,br
oad s )3y 78' (3H,s) 60 3.84 (3H,s) 3, 1-3. 7 (2H, m) 4.90 (m) 5, 56 (m) 6, 07 (broad) 6, 22 (broad) 6.93 (m) 7.13 (n+) MS (70e V) m /z :426 (
M"), 226. 225. 202° 201,
196. 195. 170. 152°131,
130 Example 70 Ethyl 3.4.5-1 Rimethoxybenzoate 2.16g, Sodium Ethylate 0 in 10011 ethanol
．． 5g and methyl Na-methyltryptophanate 2
．． Add 45g and heat in autoclave at 110 atm, 14
The reaction was carried out at 0 to 150°C for 6 hours. After cooling, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 200 rIl of chloroform, and washed sequentially with a 1% aqueous potassium carbonate solution, diluted hydrochloric acid, and water, and the resulting residue was subjected to silica gel column chromatography (eluent; chloroform:methanol = 200 :1
) to produce methyl N. -Methyl-N4- (3
, 4,5-1rimethoxybenzoyl) tryptophanate (320 mg) was obtained.

IR (CD'CA'3) cm': 3475.17
38,1627,1585°1411.1238,12
15,1128NMR (CDCA'3) δ near, 32 (d, J=8.4Hri'1-65 (broad) 8.42 (broad) 8°44 (broad) 2, 82 (broad s) 3y 10 ( broad s ) 3, 50 (3H, broad s ) 3.
63 (3H, broad s ) 3, 78
(3H,s) 3, 84 (3H,s) 3, 1-3. 7 (2H, m) 4.90 (n+) 5.56 (m) 6, 07 (broad) 6, 22 (broad) 6.93 (m) 7.13 (m) MS (70e V) m /z :426
(M”), 226. 225. 202゜2
01, 196. 195. 170. 152°13
1, 130 Compounds identical to the compounds obtained in Examples 2 to 58 and 75 to 204 can be prepared in the same manner as in Examples 66 to 70 above using appropriate starting materials.

Example 71 0.41 g of isopropylamine and 2.4 g of potassium carbonate
was dissolved in 60 ml of acetone and 30 ydl of water. A solution of 2.32 g of 2-(N-methylN-benzoyl)amino-3-(3-indolyl)acrylic acid chloride in acetone]-0z was added to this while stirring under water cooling. After stirring for 2 hours under water cooling, acetone was distilled off, recrystallized from chloroform-〇-hexane, and 2-(N-methyl-N
1.4 g of -benzoyl)amino-3-(3-indolyl)acrylic(N-isopropyl)amide was obtained.

Melting point = 214-215°C Properties: Yellow prismatic crystals Example 72 Isopropylamine 0.36gXDCC1,3g and 2
-(N-methyl-N-benzoyl)amino-3-(3-
Indolyl) acrylic acid 2.041.64 g dioxane 1011! Suspend at 60-70'C
The mixture was stirred for 5 hours. After the reaction was completed, the solvent was distilled off, diethyl ether was added, the precipitated crystals were removed from the furnace, and the furnace liquid was concentrated.
Add chloroform to the residue and dissolve 5.

and washed with water and saturated saline. After drying over sodium sulfate, the solvent was distilled off and recrystallized from chloroform-nhexane to give 1-(N-methyl-Nbenzoyl)amino-
340 mg of 3-(3-indolyl)acryl-(N-isopropyl)amide was obtained.

Melting point: 214-215°C Properties: Yellow prismatic crystals Example 73 2-(N-methyl-N-benzoyl)amino 3-(3-
A solution of 3.87 g of isobutyl chloroformate in 2 ytll of dimethylformamide was added dropwise to a 507N solution of 9.90 g of indolyl acrylic acid and 411 triethylamine in dimethylformamide. After stirring at room temperature for 30 minutes, a solution of 1.82 g of isopropylamine in 3yl of dimethylformamide was added dropwise, and the mixture was blown for 30 minutes at room temperature.
Stirred at 60'C for 1 hour. The reaction mixture was poured into a large amount of saturated brine, extracted with chloroform, washed with water, and dried. The crude crystals obtained by distilling off the solvent were mixed with chloroform-n
-2-(N-methyl-N-benzoyl)amino-3-(3indolyl)acrylic-(
3.6 g of N-isopropyl)amide were obtained.

Melting point: 214-215°C Properties: Yellow prismatic crystals Example 74 Methyl 2-(N-methyl-
3.01 g of N-benzoyl)amino-3-(3-indolyl)acrylate, 0.5 g of sodium ethylate, and 0.63 g of isopropylamine were added and reacted in an autoclave at 110 atm and 140 to 150°C for 6 hours. . After cooling, the reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform 20011, washed successively with 1% potassium carbonate aqueous solution, diluted hydrochloric acid and water, dried over sodium sulfate, the solvent was distilled off, and the residue was dissolved in chloroform-n-hexane. Recrystallized from 2-(N-methyl-N-benzoyl)amino-3-
280 mg of (3-indolyl)acryl-(N-isopropyl)amide was obtained.

Melting point = 214-215°C Properties: Yellow prismatic crystals Examples 14-18.39-44.60.75-
95.101.119-122.135-139.14
4~178.180~184.186.187.190
~201.2 Compounds identical to those obtained in 03 and 204 can be produced.

Examples 75 to 204 67 In the same manner as in Example 1, each compound shown in Table 3 below was obtained using appropriate starting materials.

In addition, the properties of each compound obtained (melting point, NMR.

IR, MS) and crystal forms (recrystallization solvent) are shown in Table 4.

68 69 70 73 174 71 72 77 178 75 76 81 182 17 80 85 186 83 84 Table 4 87 King 88 -89 90 91 192 93 94 95 196 97 -98 199 In addition, in the properties section of Table 4 above (31)-(92)
is as follows.

Properties (31) I R (CDCA'3) cm-1+ 3470.3280, 1657.1637°1610.
1500.1270, 1222°1204.1090.
1010 13N (CD CII 3 ) δ: 1.33 (9H, s), 3.31 (3H, s) 5
, 69 (L H, broads) 7.13 (2H
, d, J=8.5Hx) 7.37 (2H, d, J=8
．． 5H2) 7.21-7.55 (2H, m) 7.56 (IH, d, J=2.6H2) 7.71 (
LH, d, J = 7.0Hz) 7.72 (LH, s) 9, 34 (IH, broad) MS (70e V) m /Z: 00 411.409 (M”), 309,269°240
．． 229,198,197,171゜170.155,
152,145,141°139, 130 Properties (32) IR (CDCA'3) cm-': 3460.16
53,1622,1600°1525.1490,10
90,1067°1012.838 NMR (CDC(13) δ: 2, 67 (broad), 2.77 (
s) 2.94 (S), 3.28 (s) 3.3
6 (s), 6.85 (LH, s) 7.17 (2
H, d, J = 8.2Hz) 7.36 (2H, d, J
=8.2H2)7.15-7.4 (2H,m) 7,. 46 (LH, d, J=8.2H2)7, 6
1. (LH, d, J=7.5H2) 7, 68 (1
B, d, J=2. 4H28, 99 (broa
d), 9. 81 (broad) properties (33
) IR(CDCA'3)cm-' :3470, 1
635. 1618. 1524°1377, 127
2. 1089. 101013N (CDCA'3
) δ: 1, 07 (6H, t, J=6.
8Hz) 2.93 (2H, d, m, J=, 1
3.6H2) 3, 31 (2H, dm, J=1
3. 6Hr) 3.37 (3H,s), 6.85
(LH, s) 7, 16 (2H, d, J-8
y2Hz)7,. 2-7. 35 (2H, m)7
．． 38 (IH, d, J=8.2Hz)7.4
9 (IH, d, J=8.2H2)7, 60
(IH, d, J=7.5H2)7, 71
(LH, d, J=2.7H1!-)9, 79
(IH,btoad)MS (70e V)
m/Z: 411,409 (M”), 408,33
7゜336.270, 240, 201, 152゜00 Properties (34) IR (Nujol) cm”: 3270, 3075. 1660. 1617゜15
97.1555,1081. 1070°1013,
742 Properties (35) IR (CDC/3) cm-': 3480, 1625. 1091. 1070°10
18, 74O NMR (CDC13) δ: 1.62-1.86 (2H, m) 2.97 (s), 3.04 (s) 3.06
(s) , 3.11 (s) 3.2-3.65
(m) 03 3, 81 (t, J=8. 3H2) 4, 1
7 (s), 4. 24 (s)4.62 (
m) ,5.64 (m)5.71 (m) ,7
．． 01--7.4 (m)7, 68 (t,
J=7. 5H2) 7.74 (t, J = 7.
5H2) 8, 52 (broad), 8.
64 (broad) MS (70e V)
m/2: 426 (M+1), 408,342
, 339° 313, 311. 256. 209.
171°170, 157. 141. 140. 1
30 Properties (36) IR (Nujol) cm-': 3410, 1735. 1717. 1678°16
29.1605. 1587. 1536°1288,
1265. 1215. 1081°812, 74
5 NMR (CDCA3) δ: 04 1.50 (9H, s), 3.86 (3H, s)
3, 90 (3H, s) 6.96 (IH, dd, J=9.1H2゜2.
6Hz) 7, 14 (IH, d, J=2.6H2)7
, 37 (IH,s) 7, 63 (2H,d, J=8.4H2)7,
71 (LH, broad)7, 77 (L
H, s) 7.80 (2H, d, J-8, 4H2) 8.0
2 (LH, d, J=9.1H2)MS (7
0e V) m/z:474.472 (M”
), 430, 428° 398, 396. 245.
185. 183°157, 155. 105 Properties (37) IR (Nujol) cm”: 3275, 1723. 1645. 1592°1.
551,1527. 1370, 1293°1275.
1254, 1215, 1154°893, 857.
761 NMR (CDCA'3) δ: 1.69 (9H, s), 3.85 (3H, s
) 3.88 (3H, s) 6.96 (LH, dd, J=8.8H2゜2.6H
2) 7.08 (IH, d, J=2.6H2) 7.77
(2H, d, J=8.4H2)7.64 (2H,
d, J=8.4H2) 8.03 (IH, d, J=8
．． 8H2) 8,, 16 (LH, s) 8, 41 (IH, broad) 8.43 (
IH, s) MS (70e V) m/z:530.528
(M”), 474,472°431, 430,
429,428. 398°396.245,213.
185 Properties (38) I R (CDC13) c “1: 1732.1710.1650.1621°1588.
1534.1257, 1213°1150, 1082
．． 835 NMR (CD CA'3) δ: 1.70. (9H,,s) ,3.25 (3H,s
) 3.73 (3H, s), 3.88 (3H,
s) 7.03 (LH, dd, J=9.0H2゜2, 2H2) 7.11 (1)1. d,]=2.2Hz)7.2
5 (2H, d, J=8.'8Hz)7.34
(2H,,d,J=8.8H2)7.67 (IH,
s) 8.07 (IH, d, J=9.OH2) 8.08
(LH, s) MS (70e V) m /2 :07 544, 542 (M”), 444. 442
゜259, 200. 198. ．． 196. 185°109, 97. 95. 86. 84 Properties (39) IR (CDCA'3) cm-': 3450, 1703. 1615. 1587°15
10, 1294. 1262. ．． 1207°1074
, 834 NMR (CDCl2) δ: 3.26 (3H,s), 3.74 (3H,s
)3, 88 (3H,s) 6.95. (IH, dd, J=8.8Hz.

2.2Hz) 7.16 (LH, d, J=2.2H1) 7.25
(2H, d, J=8.8H2)7.29 (2
H, d, J=8.8H2)7, 34 (IH,
d, J=8.8H2) 7.74 (LH, d,
J-3,3H2)08 7,82 (IH,s) 9,66 (IH,broad)MS (70
eV) m/v:444.442 (M”
), 260, 259° 228, 227. 218.
200. 199°198, 196. 190. ．．
186. 185 Properties (40) IR (CDCA'3) cm-': 3465
, 1655. 1637. 1606°1590,
1502. 1256. 1213°835, 803 NMR (CD CIIs) δ:1, 15
(3H, d, J=7.7H!)1, 19
(3H,,d, J=6.9I(2)3.30 (
3H,s), 3. ．． 81 (3H,s)4, 17
(1) (, m) 5.8 (L (IH, d, J = 8., OH2) 6,
91 (LH, dd, J=8.8H2.

2.2Hri7.10 (IH, d, J=2.2H2)7.2
7 (4H, s) 7.30 (LH, d, J=8.8H2) 7.50
(, IH, d, J=2-8Hz) 7.77
(IH,s) 9, 42 (IH,broad)MS (70
e V) m /z: 471.469 (M''), 38.5,383°345.343,286,245,217°202.2
01,200,198,196°85 Properties (41) IR (Nujol) cm-': 3600-2400. 1664. 1628°161
2. 15.87. 1513. ．． 1,225°108
1, 844.762.743 NMR (CDClS+pyridine-d5) δ: 3, 34
(3H, s) 6. 5 (IH, broad) 7, 26 (2H, d, J = 8. 4H2)
7, 41 (2H, d, J=8.4H2)7
, 1-7. 5 (3H, m) 7, 81 (IH, m) 7, 89 (IH, d, J=2.9H2) 8
, 02 (IH,5) 12, 24 (IH,broad)MS (7
0e V) rn /Z:400.398 (M
”), 356. 354°310, 276, 2
15. 198. 196°185.183,172,
171. IVo.

55 Properties (42) IR (Nujol) cm-': 3400, 1736. 1720. 1676°16
33, 1585. 1542. 1272゜11 1235.1153,1065,81ONMR(CD
CII 3) δ: 1.50 (9H, s), 3.90 (3H, s) 7
．． 29 (iH, dd, J=8.8H7.

2.0Hx) 7.62 (2H, d, J-8, 6H2) 7.69 (King H, d, J=2.O■(z) 7.70 (1,H
,s) ,7.72 (II-T,s)7.78 (2
H, d, J = 8.6H2) 7, 83 (IH, br
oad ) 8.06 (LH, d, J = 8.8H2) M
S (70e V) m/z: 534.532
(M”), 478,476°446.444,43
4,432,402゜400.249,189,185
, 183 Properties (43) IR (Nujol) cm-': 3230.1711, 1642, 1591°12 1552, 1525. 1364. 1286°12
13, 1155. 1073. 857゜64 NMR (CD C(13) δ: 1.69 (9H,s), 3.86 (3H,s
)7.29 (LH, dd, J=8.8H2.

2.0H2) 7.59 (LH, d, J-2, 0H2) 7.6
4 (2H, d, J-8, 6H2) 7.75
(2H, d, J=8.6Hz)8, 07
(LH, d, J=8.8Hz)8, 20 (
LH, s) 8.40 (IH, d, J=1.OH2) 8, 43
(IH, broad) MS (70e V)
m/z: 536.534,532 (M"),
477°475, 445,443,433,431°401,, 399. 251. 249. 185°83 Properties (44) IR (Nujol) cm': 3425.1740,1723,1680°1635.
1587. 1570. 1543°1275.123
8,1156,1094°1022.8 King 2 NMR (CDCA'3) δ: 1.50 (9H,s), 3.89 (3H,s
) 7.42 (IH, dd, J = 8.88Z.

1.9H2) 7.61 (2H, d,, T=8.5H) 7.68
(LH,s) ,7.70 (LH,5)7y77
(2H, d, J=8.5H2)7.83 (IH
, d, J-1, 9H2) 7, 88 (I H, br
oads) 8.01 (IH, d, J-8, 8H2)
MS (70e V) m/z 578 (M”), 524.522.5
20°480. 478. 476, 448. 44
6°444.295,293. 185. 183 Properties (45) IR (Nujol) cm': 3220, 1722. 1643. 1590°15
53, 1526. 1371. 1284°1212
, 1155. 763 NMR (CDCA'3) δ: 1.69 (IH, s), 3.85 (3H, s)
7, 43 (IH, dd, J=8.8H2.

2.0Hx) 7.64 (2H, d, J=8.6H2) 7.75
(2H, d, J=8.6H2)7.75 (I
H, d, J-2,0Hz) 8.02 (LH, d
, J=8.8H2)8.17 (LH,d,
J-1, IH2) 8.41 (IH, d, J=1
．． 1Hz) 15 8, 42 (I H, btoads) MS (7
0e V) m/z: 578 (M”), 5
21,480,478°476.447,445,44
3,295°293, 214. 185. 183 Properties (46) IR (Nujoule) cm': 3400,. 1732. 1677, 1633°15
86, 1541 NMR (CDCA'3) δ: 1.50 (9H, s), 3.88 (3H, s)
5, 07 (2H, s) 7.02 (IH, dd, J=9.0Hz.

2.4Hz) 7.23 (IH, d, J=2.4Hz)7,
3-7. 47 (5H, m) 7.59 (2H
, d, J=8. 5H2) 7.70 (IH,s
), 7.73 (], H, s) 16 7, 78 (2H, d, J-8, 5Hz) 8
．． 02 (IH, d, J=9.OHx)MS
(70eV) m/2:506.504,
474,472,383°381, 355. 353
．． 321. 261°213, 185. 183.
91 Properties (47) IR (CDCA!3) cm-': 3390
, 1?26. 1670. 1589°1516,
1371. 1275. 1154NMR (CD C1
3) δ: 1.68 (9H, s), 3.83 (3H, s
)5.12 (2H,s) 7.03 (IH,dd, J=9.OH2.

2.4H2) 7, 18 (LH, d, J=2.4H2)7,
31-7. 42 (3H, m)7, 48 (
2H, m) 7, 62 (2H, d, J=8.7Hg)
7, 75 (2H, d, J=8.7H!)
8, 02 (IH, d, J=9. OHx
)8.16 (IH,s) 8, 40 (IH,d, J=1.OHx
)8.41 (IH,s) MS (70e V) m/! :606.60
4 (M”), 550,548°506, 504
．． 474. 472. 415°413, 383.
381. 365. 321 Properties (48) IR (CDCA3) cm-': 3410, 1726. 1670. 1593°15
19, 1325. 1264 NMR (CD CA' 3 ) δ: 1.70 (
9H,s), 2.57 (3H,s)3, 54
(3H,s) 7, 11-7. 31 (3H, m)7, 63
(2H, d, J=8.6Hz)7.76
(2H, d, J=8.6H2)8, 11 (
LH, d+I, J=7. IH2゜1.3H2) 8.30 (LH, d, J=0.9H2)8,
53 (IH, broad) MS (70e
V) m/2: 514, 512 (M”)
, 458. 456°414.412,382,380
,229°197, ■85. 183. 169 Properties (49) IR (CDC13) cm-': 3460, 1653.1633. 1610°158
8, 1499 NMR (CDC13) δ: 1, 15 (3H, d, J=6.8I-Tz
)1, 18 (3I(,,d, J=7.2H
2) 3, 30 (3H,s), 4. 16 (
1, H, m) 19 5, 04 (2H, s) 5, 73 (1, H, d, J=8. OH2
)7, 00 (], H, dd, J=8.
9 To Iz.

2.3H2) 7.20 (LH, d, J=2.3H2)7,
25-7. 52 (IH, m)7, 73 (
IH,s) 9, 10 (1,H,broad)MS (7
0e V) m/z:547, 545 (M”
), 461. 4.59°277, 276, 19
8. 1.96. 186゜185.183 Properties (50) IR(CDCl2)cm-': 1727.16
39,1592. King 535゜↓370. 1,27
6. 1,215. 1.152NMR (CDCβ3)
δ: 1, 67 (9H, s), 3.
34 (3J-■, s) 20 3, 73 (3H, S), 5. 10 (2H,
s) 6, 82. (IH, b "oad) 6, 86 (IH, s) 7, 02 (IH, dd, J=9. OH2
.

2.4H2) 7, 32-7. 51 (9H, m)8, 01
(LH, d, , T=9.0Hz)8, 37
(LH, s) MS (70e V) m/X: 520,
518. 369. 367, 335°294, 2
44. 228. 198. 196°185, 18
3 Properties (51) IR(CDCl2) cm-': 1725,
1637. 1590. 1370°1.354.
1325. 1144. 1122NMR (CDCl2
) δ: 1, 67 (9H, s) 2, 36 (3H, broad) 3.35 (
3H,s), 3.52 (3H,s)6, 79
(LH,broad)6, 95 (IH,br
oad ) 7, 13-7. 26 (2H, m)7,
48 (4H, m) 8.05 (IH, d, J-7, 5H2) MS (
70e V) m/z:528.526 (M”
), 472,470°428.426,243,202
．． 1.98°196, 185. 184. 183
．． 1.69 Properties (52) IR (CDC13) cm-': 3465, 1728.1626. 159],.

1153, 1074. 1013. 835NMR(
CD Cl 3 ) δ: 1, 52 (9H,s), 2.74 (s)3
, 06 (s) , 3.0-3.6 (2H, m
)4, 50 (dd, J=4.2H,10,
7H2) 5.41 (m) 6.46 (d, J=8.OH2)6, 91-
7. 45 (m) 7.65 (d, J=7.2H2)8, 35
(LH, broad) MS (70e V)
m/z: 458.456 (M"), 403,4
01°385, 383. 357. 355. 24
3°187, 185. 183. 130 properties (53
) IR(CDCA'3) cm-' :3460
, 1694. 1617. 1590°1519,
1270. 1248. 1155NMR (CDCA'
3) δ: 1, 42 (9H, s), 3. 25 (3H
, s) 7, 24-7. 35 (6H, m)7,
46 (IH, m) 23 7, 72-7. 77 (2H, m)7, 80
(IH,s) 9, 61 (IH,broad)MS (70
eV) m/z:456.454 (M”)
, 400, 398° 383, 381. 215. 1
98. 196°185, 183. '171. 17
0. 155 Properties (54) NMR (CDC/3) δ: 2.74 (3H,s), 3', 29 (3H
, s) 3, 78 (3H, s) 7, 1-7. 5 (6H, m) 7.67 (IH, d, J=7.3H2) 7,
71 (IH, s) 7, 91 (IH, s) 8.49 (IH, d, J=8.3H2) Properties (
55) NMR (CDCA3) δ: 24 1, 51 (3H, t, J=7. IH2)
3.26 (3H,s), 3.71 (3H,s
)4.58 (2H, q, J=7.1Hz)7,
1-7.5 (6H, m) 7.65-7.75 (2H, m) 8, 14 (IH, s) 8.28 (IH, brd, J=7.6H2)
Properties (56) NMR (CD C123) δ: 1.16 (6H, d, J=6.3Hx) 3.3
6 (3H, s) , 3.93 (3H, s) 4,
14 (IH, oclet, J-6, 3) (
X)5.67 (IH, d, J=6.3H2)
7, 25 (LH, td, J=8.3H!
.

1.2Hz) 7, 35 (LH, jd, J=8.3Hx
.

1, 2H2) 7, 39 (IH,brd, J=8.3H
z ) 7, 42 (IH, s) 7, 53 (2H, d, J=8.7Hz) 7
．． 71 (LH,brd, J=8.3Hz)
7, 72 (IH,S) 8, 00 (2H,d, J=8.7H2)M
S (70e V) m/x:420 (
M"), '184. 163. 144 Properties (57) NMR (CDCA'3) δ: 1, 03 (6H, d, J=6.3Hz)
3.32 (3H,s), 3.76 (3H,s
)4.14 (IH, octej, J=6.3
H2) 5.71 (iH, d, J=6t 3H
2) 6, 61 (IH, s) 7, 16 (LH, jd, J=1.9Hx.

1.6H2) 7, 24 (LH, jd, J=7.9H2゜1.6Hz) 7.28 (IH, bad, J=7.9Hz
)7.40 (IH,brd,J=7.9H)7.6
5 (IH, s) 7.90 (2H, d, J=8.3H2) 8.11
(2H, d, J=8.3H2)MS (70e
V) m/2: 420 (M”), 184,
163. 144 Properties (58) NMR(CD CII 3-DMS○-da
) δ: 2.85 (s), 3.07 (s)
3.70 (s), 3.74 (s)3, 8
4. 1 (m), 4. 43 (bad)5
．． 55 (t, J=7.3H2) 6.53 (d, J=7.9H2) 6.81 (t, J=7.4H2) 6.9-7.2 (m) 7.35 (d, J=8.IHx) 7.48 (d, J=7.8H2) 27 7, 64 (d, J=6.9Hz) 8, 2
(brs), 8. 57 (brs)10
, 60 (brs) MS (70e V) m/z: 473 (M”), 471.442.4
40°385, 383. 357. 355. 25
8°226, 185. 183. 170. 130
゜03 Properties (59) NMR (CDC/3) δ: 0.90 (3H, d, J=7.IH2)0
．． 95 (3H, d, J=7.1H7)2, 2
1 (iI-(,m), 2.85 (s)2.
87 (s), 3.13 (s)3, 3-3.
5 (m), 3. 70 (s)3, 78
(s), 4. 47 (m) 4, 59 (m
), 5. 58 (m)6, 52 (broa
d), 6. 9-7. 3 (m) 28 7, 38 (d, J-7, 7H2) 7, 49
(d, J=8.2H2)7, 59 (d
, J=7. 7HX) 8, 15 (LH,br
s) MS (70eV) m/2:513
(M”), 515.484.482°38
5, 383. 357. 355. 300°255
, 253. 1.85. 183. 170゜30 Properties (60) NMR (CD CA'3) δ:2, 55
(s), 2. 79 (s) 2.9-3. 5
(m), 3. 69 (s)3, 75 (s)
), 3. 81 (s) 4, 45 (broa
d), 4. 85 (m)5, 52 (Q,
J-5, 9H2) 6, 25 (broad) 6, 8-7. 4 (m) 7, 45 (d, J=8. 3H2) 7, 6
5 (brs), 8. 13 (LH,brs
) Properties (61) NMR (CD CII 3) δ: 2, 65 (s), 2. 82 (s)2.8-
3. 5 (overlap), 3. 71
(s)3.74 (s), 3.80 (s)4,
46 (broad), 4. 83 (IH
, m) 5, 50 (m), 6. 17 (b
road) 6, 29 (broad) 6, 5-7. 6 (overlap)7, 6
2 (d, J=6.8H2)8, 24 (b
rs), 8. 29 (brs) MS (7
0e V) m/2: 364, 255. 2
53. 1.86. 170°30 Properties (62) NMR (CDC(23) δ.

2, 89 (s), 3. 09 (s)2.2
-2.6 (m), 3.74 (s) 3.77
(s), 3.7-4. 1 (m)41. 62
(m), 4. 71 (br)5, 35
(t, J=8.2H2)6, 30 (d,
J=7.3Hz)6, 8-7. 2 (m) 7, 37 (d, J=7.7H2) 7, 47
(d, J=7.7H2)7, 65 (d
, J=”/, 7H2) 8, 20 (IH, br
s) Properties (63) NMR (CDCIa) δ: 2.88 (s), 3.08 (s) 2.3-2
．． 6 (m), 3.75 (s)3, 7-4.
1 (overlap(3,95,d))4,
59 (br), 4. 67 (br)5,
38 (t, J=7.9H2) 31 6, 44 (br), 6. 9-7. 3 (
m) 7.38 (d, J=7.7Hz) 7.46
(d, J=8.2Hz)7.66 (d,
J=7.3H2)8, 19 (IH, brs) Properties (64) NMR (CDCA'3) δ: 1, 9-2. 2 (5H, overlap, 2.
07 (s) ) 2.44 (2H, m) , 2.8
7 (s)3, 0-3. 2 (m) 3, 2-3. 6 (2H, m) 3.72 (s) , 3.74 (s) 4, 71
(broad, IH), 5. 35 (
m) 6, 53 (br), 6. 9-7. 2
(m) 7.38 (IH, d, J = 7.3H
2) 7.48 (LH, d, J=7.7Hz)7
, 68 (LH, t, J=7.3H2)8,
20 (bts) 32 Properties (65) NMR (CD CII 3) δ: 2.80 (
s), 2.87 (s) 2.94 (d,, J=4
．． 7Hz) 2.95-3.2 (m) 3.2-3.5 (m) 3.63 (s), 3.69 (s) 3.71
(s), 3.76 (s)4, 65 (br
oad) 4.90 (IH, m) 5.32 (t, J=7.3Hz) 5.63
(t, J=7.3H2)6.46 (m), 6
．． 9-7.5 (m) 7.68 (d, J=6
．． 9Hz) 8, 21 (bts) Properties (66) NMR (CD CII 3) δ: 1, 41 (3H, d, J=7°2H2) 2.87 (S), 3.08 (S) 3.41
(d, J=7.9H2)3.73 (s),
3.79 (s) 4, 5-4. 7 (over
lap) 4.52 (t, J=7.9Hri6.
50 (d, J=7.6H2)6.65 (b
td, J=8.0H26, 9-7,2 (over
lap ) 7.38 (d, J=7.9H2) 7.47
(d, J=8.3Hx)7.68 (d, J
=8.2H2)8, 22 (brs) Properties (67) NMR (CDC13) δ: 1, 1-1. 2 (m) 1, 3-1. 7 (overlap)1, 7
-1. 9 (m) 2, 93 (3H, s) ) 3, 0-3. 3 (3H,overlap)3
．． 51 (2H, dd, J=14.6H2.

8.0H2) 3, 69 (3H,s), 4. 54 (1,
H, m) 4, 91 (br), 5. 12 (
2H, s) 5, 51 (t, J=s, 0H
2) 6.8-7.4 (overlap) 7, 5
1 (d, J=8.4H2)7, 68 (
d, J=7. 3I-(z)8, 74 (br
s) Properties (68) NMR (CDCA'3) δ: 1, 15-1
．． 25 (m) 1, 25-1. 9 (ove “lap”) 2, 8
8 (S), 2. 8-3. 25 (over
lap) 3, 41 (d, J=7.58x
)3, 71 (s), 4. 52 (br)4
, 63 (brs), 4. 93 (bu
s) 35 5, 07 (s) 5, 45 (t, J-8, 1H2) 6, 63
(br), 6. 9-7. 6 (overl
ap) 7, 68 (d, J=8.1H2)
8, 32 (brs), 8. 39 (br
) MS (70e V) m/z:678, 6
76 (M”), 463. 385°383, 35
5. 185. 183. 170°130, 108
．． 91 Properties (69) NMR (CD CA'3) δ:2, 87
(s), 3. 06 (s)2, 9-3. 1
5 (overlap)3, 18 (d+I,
J=10.2H2, 7,8H2) 3.50 (+
Id, J=10.2H2,5,1)-12)3,
67 (s), 4. 57 (brd)4,
79 (m) 5.47 (+Id, J=7.8H2,5,LH
2) 36 6, 52 (d, J=7.7Hz) 6.60
(s), 6.75 (s)6, 9-7. 2
(overlap) 7, 3-7. 5 (ov
eiap) 7, 56 (s) 7.61 (d, J=7.4H2) 7.73
(d, J=7.5H2)8, 50 (brs
) 8.76 (brd, J=7.0Hx)9, 0
2 (brs) MS (70e V) m/Z: 553,
551 (M”), 338. 186°185,
183. 170. 154. 130°17 Properties (70) NMR (CD CII 3) δ: 1, 8-2. 0 (3H,overlap)2
, 18 (LH,m) ,2. 92 (s)
2, 97 (s), 3. 72 (s) 3.1
9 (dd, J=14.6H,6,9H2)3.
39 (d, J=7.7HX)3, 3-3.
6 (overlap)3.58 (s), 3
．． 73 (s) 3, 74 (s), 4. 4-
4. 6 (overlap)5, 85 (t
, J=7. 7H2) 5.89 (dd, J=8
．． 4H2, 6, 9H2) 7, 0-7. 25 (o
verlap) 7, 3-7. 5 (overl
ap)7, 68 (d, J=8.OH2)7
, 85 (d, J=8.0H2)8, 32
(br) Properties (71) NMR (CD C13) δ: 3.35 (3H,s), 3.79 (3H,s
)4, 13 (LH, dd, J=18.3H
2.

5.5Hz) 4, 25 (IH, dd, J=18.3)I
Z.

5.5H2) 6,84 (IH, t, J=5.5H2)7,
15-7. 43 (7H,overlap)7
, 55 (LH, d, J=2.9H2)7,
66 (IH,brd, J=7,3H2)7.
83 (LH,s), 9.24 (LH,brs
) MS (70e V) m IZ: 471,
469 (M”), 384. 381°355,
353. 315. 313. 286°245,
217. 197. 185. 183°171, 1
55. 130 Properties (72) NMR (CDCI13) δ: 0.89 (d, J=7.0H2) 0, 93
(d, J=7.OH2)0, 96 (d
, J=7. 0H2) 2, 24 (IH, m)
, 3. 36 (s) 39 3, 39 (s), 3. 78(s)3,
79 (S) 4.65 (d, J=8.9H2) 4, 68
(dd, J=8.9Hz, 1.3Hz
)6.46 (d, J=8.9H2) 6.56 (d, J=8.9H7, 2-7.45 (7H,ovetlap)
7, 58 (d, J=3.2H2)7, 59
(d, J=3.2H2)7, 68 (LH
,brj, J=8. 3Hx)7, 78
(s), 7.38 (s)9, 24 (IH,
brs) MS (70e V) m IZ: 513.5
11 (M”), 383. 381°355, 35
3. 315. 313. 198°196, 185
．． 183. 171. 155゜30 Properties (73) 4O NMR (CD CA' 3 ) δ: 3, 09
(S) 3.11 (dd, J=11H2,7,7H2)
3.15 (dd, J=13.2Hz, 6.3
H2) 3.26 (dd, J=11H2,4,2
H2) 3, 28 (S) 3.28 (dd, J=13.2H2,5,5H
2) 3.78 (s), 3.80 (s) 4.9
3 (m), 4.98 (m) 6.38 (d
, J=7.7Hx)6.45 (d, J=7
．． 7H2) 7.07 (d, J=8.5H2)7
, 04-7. 41 (overlap)7.5
0 (d, J=2.8H2)7.51 (d,
J=2.8H2)7, 62 (t, J=7.5
H2) 7, 70. (s), 7. 75 (s)9
, 03 (d, J=2.8H,z)9.0
6 (d, J=2.8H!)MS (70e
V) m/! :561.559 (M”)
, 383, 381° 376, 315. 313. 1
98. 196°185.183. 171. 155
．． 130 Properties (74) NMR (CD CII 3) δ: 3.04 (s), 3.25 (s) 3, 0-
3. 3 (ovetlzp)3.775 (s
) , 3.784 (s) 4.86 (m) , 4
．． 94 (m) 6.41 (d, J=7.7H
2) 6.5↓ (d, J = 8.0Hz) 6.7
7 (d, J-6,2H2)6, 81 (d
, J=6.2H2)6, 9-7. 5 (ov
erlap) 7, 57 (d, J=8.2
H2) 7, 71 (s), 7. 75 (s'
)9, 27 (bus), 9. 33
(brs) MS (70eV) m/z 577, 575 (M”), 254. 252
゜198, 196. 185. 183. 171゜155, 107 Properties (75) I R (KB r) cm''1: 3350, .1735. 1625. 1,500゜1
425, 1135. 1070. 1005°830
, 74O NMR (CDC13) δ: 3.28 (King, 5H,s) 3, 33 (1,5H,s) 3, 71 (1,5H,s) 3, 80 (1,5H,s) 3, 98 (LH, dd, J=11.3H2
.

2.9Hz) 4, 4 (0,5H, dd, J-1,1,3H
2.

43 3.6H2) 4, ↑5 (0,5H,dd, J=11-,
3H2.

3.6H2) 4, 83 (LH,m) 7, 1-7. 8 (IOH, overlap)
7, 79 (0,5I-(,s) 7, 83 (0,5H,s) 9, 40 (IH, bus) MS (70e V) m/l: 501.
499 (M”), 483,481°381, 2
98. 286. 268. 198°197, 19
6. 185. 183. ↑71°155, 13
0 Properties (76) NMR (, CDC12s) δ:1, 93-2
．． 32 (overlap)2, 10 (s
), 2. 13 (s)2, 41 (LH,m
), 2. 35 (LH, m) 44 3, 34 (s), 3. 38 (s)3,
79 (s), 3. 80 (s) 4, 81
(IH, m) 6.86 (d, J=8. OH2) 7, 1
-7. 5 (overlap)7.59 (m
) 7, 70 (t, J: 8. 4H2) 7.78
(s), 7.87 (s) 9.09 (Wang H, b
rs) MS (70eV) m/2:545.5
43 (M”), 383. 381°360,
355. 353. 315. 314°313,
312. 197. 185. 183°171, 1
55. 130 Properties (77) NMR (CD C13) δ: 2, 82 (dd, J=17. 2H2, 1,
6H2) 2, 84 (+Id, J=17.2
H2, l, 6Hz) 3, 10 (LH, dd,
J=17. 2H2.

4.5H2) 3, 30 (S), 3. 39 (s) 3.7
2 (s), 3.74 (s)3, 79 (
s), 3. 80 (s)4, 95 (IH,
m) 7, 09-7. 41 (overlap)7,
59 (IH, m), 7. 79 (s)7.
84 (s), 9. 17 (IH, bus)
MS (70eV) m/z: 543, 54
1 (M”), 383. 381° 330.3 King 5. 312, 198, 197° 196, 185. 1
83. 171. 155゜30 Properties (78) NMR (CD CA! 3) δ: 1, 42 (3/2H, d, J-7, 3H2)
1, 46 (3/2H, d, J=7.3Hz
)3, 33 (3/2H,s) 3.37 (3/2H,S) 3.79 (3/2H,s) 3.80 (3/2H,s) 4.69 (1/2H,m ) 4.71 (1/2H, m) 6.61 (1/2H, d, J=7.7H2) 6.6
9 (1/2H, d, J=7.7H2)6, 15-
6. 45 (7H,overlap)7.56 (
1/2H, d, J=2.9H2) 7.59 (1/2
H, d, J = 2.9H2) 7.69 (LH, brt
, J=7.7H2) 7.78 (1/2H, S) 7.83 (1/2H, s) 9, 28 (IH, brs) MS (70e V) Ill /2:485.
483 (M”), 383,381°355.35
3,315,313,300°47 198.197,196,185,183°171,
155. 130 Properties (79) NMR (CDCA'3) δ: 1, 26 (m), 1. 4-1. 9 (o
verlap) 2.00 (m), 3.19
(m) 3.31 (s), 3.32 (s) 3.
73 (s), 3.74 (s) 4.65 (
IH, m) 4, 9-5. 2 (overllp)5.06
(s), 5. t”<(s)6.80
(m), 7. 1-7. 7 (overlap
)7.76 (s), 7.86 (s)9, 4
8 (brs), 9. 88 (brs)M
S (70e V) m/2: 676.67
4 (M”), 568,566°383, 381,
355,353. 3i3゜315, 198. 19
7. 196. 171°48 170, 108. 91 Properties (80) NMR (CDC13+DMSO-d6) δ:2,.
92 (2H, m) 3, 05 (3/2H, s) 3, 06 (3/2H, s) 3, 42 (3/2H, s) 4, 55 (IH, m) 6.59 (1/ 2H, s) 6.62 (1/2H, s) 6, 63-6. 94 (overlap)7.
06 (IH, d, J=8.5H2)7, 17
(IH,brd, J=7.3H2)7, 3
1 (IH,overlap)7, 36 (I
H,s) 7, 42 (IH,overlap)7, 49
(IH, s) 8.45 (1/2H, d, J=7.7Hz)
8.65 (1/2H, d, J=7.1H2) MS
(70eV) m/z:551.549 (M
”), 381,254°252.198,197,19
6,185°183, 170 Properties (81) NMR (CDC/3) δ: 1, 75-2. 05 (overlap)2.
16 (m), 3.07 (IH, brt) 3.3
3 (s) , 3.37 (s) 3.53 (LH, m
) , 3.73 (s) 3.77 (s), 4.31 (t, J=7.7H2) 7, 05 (s) , 7. 1-7. 7 (ove
rl, ap) 9, 67 (IH, brs) MS (70e V) m/z: 511.509. (M”), 383,382°381.
326,197,156,128 Properties (82) NMR (CDC/3) δ: 0, 89 (d, J-6,8H2) 0.93
(d, J=6.7H2)0.96 (d,
J=6. 6H2) 2, 24 (LH, m) 3, 36 (3/2H, s) 3, 39 (3/2H, s) 3, 77 (3/2H, s) 3, 79 (3/2H, s) 4, 67 (IH, m) 6, 45 (1/2H, d, J6, 55
(1/2H, d, J7, King-7, 45 (overl
ap) 7, 60 (IH, m) 7, 65 (1/2H, d, J7, 70
(1/2H, d, J7, 78 (1/2H, s
) 7.6H2) 7, 6H2) 8.9H2) 8.7H2) 51 7, 88 (1/2H, s) 9, 25 (LH, brs) MS (70e V) m/2:5], 3,
51 King (M"'), 383, 381.

355, 353, 328. 315. 31.3゜1
98, 196. 171. 170. 130 properties (
83) NMR (CD C123+DM S○-d6)
δ: 1, 8-2. 2 (overlap)
1.99 (3/2H, s) 2, 00 (3/2H, s) 2, 41 (2H, m) , 2. 8 (ove
rlap ) 3, 21 (3/2H, s) 3, 22 (3/2H, s) 4, 57 (LH, m) , 5.75 (LH,
brs6, 62 (LH, brs) 7, 1-7. 7 (overlap)7,
6 8 (1/2 I-1, s)) 52 7.73 (1/2H, s) MS (70e V) m/z: 530.528 (M”), 383,381°328
．． 197,185,183', 171°170.155
, 130, 61.44 Properties (84) NMR (CD CA! 3) δ: 1.47 (3H, m), 2.81 (s) 3.06
(s) , 3.2-3.6 (m) 3.84 (3H,
s), 4.49 (2H, m) 4.75 (dd, J
=10.4H2', 4.8H2)5.32 (dd, J
=9.9H2,5,5H2)6.69 (IH,J=
7.8H2) 6.9 7.7 (7H, m) 8, i9 (IH, d, J-8, 2H2) 1 ivis
(70eV) m/2:442 (M+)
, 383,273,202゜Sat58,139,130 Properties (85) NMR (CDCA'3) δ: 1, 05-1. 20 (6H,overlap
) 2.90 (s), 3.08 (s) 3.2-3
．． 5 (m), 3.74 (s) 4.07 (
m) ,4.68 (m)5.38 (t, J
=7.7. H2) 6, 34 (br), 6. 5
5 (br)6, 7-7, 4 (overla
p) 7, 68 (d, J=7.7H7)M
S (70e V) m/2: 413.41
1 (M”), 327. 325°242, 185
．． 157. 1.44. 139° 11 Properties (86) NMR (CDCl2) δ: 2, 0-2. 2 (m), 2. 2-2.
5 (m)2, 82 (s), 2. 85
(s') 3, 11 (brs) 3.39 (d, J=7.9H2) 3, 74
(s), 3. 7-4. 3 (overlap)
3, 59 (broad) 5.54 (t, J=7.9H2) 5.60 (t, J=7.9H2) 6.19
(dd, J=6.3H2,4,' 3H2)6, 53
(broad) 6, 9-7. 6 (overlap)7.65
(d, J=”7.9H2)MS (70e
V) m/2:543.541 (M”)
, 455,453°357.355,328,248,
200゜30 Properties (87) NMR (CD C123) δ: 0.77 (3H, t, J=6.8H2) 2.8
0 (IH, m) , 3.12 (LH, m) 55 3.42 (IH, br) , 3.62 (LH,
m) 3.81 (IH, m), 4.35 (IH
, m) 4, 96 (br) 7, 05-7. 26 (ovetlap)7.
40 (1'H, d, J=7.8H2)7.48
(2H, d, J=7.8H!)7.65
(IH, d, J-7, 5H2) 8.23 (IH
, s) MS (70e ■) m/z: 416, . 414 (M”), 398,396°2
99, 297. 230. 228. 187°18
5, 183. 157. 155. 130 properties (8
8) MS (70eV) m/z:457.455
(M”), 371,369°328, 326.
228. 185. 183°171, 143. 1
30 Properties (89) 56 NMR (CD CA's) δ: 1.08 (
3H, d, J=6.5H2) 1.14 (3H,
d, J-6,5H2) 1.30 (3H,t,
J=7. 1Hz) 3, 46 (IH, m)
,4. 10 (2H, m)5, 73 (IH,
d, J=8. 2H2)7, 2'0-7. 35
(4H,overlap)7.43 (2H,
d, J=8. 0H2)7, 59 (LH,d
, J=2. 882 ) 7, 74 (IH, d
, J=7. 5HX)7, 85 (IH,s
), 9. 31 (LH,brs)MS (7
0e V) m/z:455, 453 (
M"), 315. 313°270, 2'12
．． 210. 184. 155゜30 Properties (90) NMR (CD CA'3) δ: 0, 93
(3H, t, J=7.3Hz) 1, 06
(3H, d, J=6.5H2)1, 15 (
3H, d, J=6. 5H2) 1.90 (LH
, m) , 3.29 (LH, m) 4, 08 (
2H, m) 5, 71 (IH, d, J=8.0Hz)
7, 22-7. 32 (overlap)7,
45 (IH, d, J=7.5H2)7.6
1 (LH, s) 7.78 (IH, d, J=7.5H2) 7,
8.5 (LH,s), 9. 02 (IH,
brs) MS (70e V) m/Z:
469.467 (M”), 315,313°28
4, 198. 185. F83. 155°30 Properties (91) NMR (CD CII 3) δ: 1, 09. 1. 96 (i+6H,d, J=
6. 5H2) 3, 29 (3H,s), 3. 67 (3H
,s)3. 97-4. 33 (IH, m)5,
76 (LH, d, J=8.1-H2)6, 6
3 (2H, d, J=8.9H2)7, 06-
7.83 (7H, m) 7.85 (↑H, s) , 9
．． 64 (IH, brs) Properties (92) NMR (CDC13+DMSO-da) δ: 0.
88 (d, J=6.7H)0.94 (d
, J=6.7HX)0, 95 (d, J=
6.6H2)2, 01 (3H,s),2. 1
2 (LH, m) 3.31 (s), 3.32
(s) 4.41 (LH, m) , 6.02 (
LH,brs)6, 43(brs),6.
51 (brs)7, 00 (d, J-
7,8HX)7, 13-7. 35 (over
lap) 7, 45 (IH, m) 59 7, 63-7. 71 (2H,overlap
)7, 77 (s), 7. 85 (s)9,
54 (brs) -, 9,61 (b's)M
S (70e V) m/2: 498.49
6 (M+), 296. 198°197, ], 96
．． 170. 130 Properties (93) NMR (CD CA' 3) δ: 2, 78 (s), 3. 09 (s)3,
0-3. 2 (ovetlap) 3, 40
(dd, J=11.4H2,3,5H2)3,
56 (m) 4, 68 (dd, J=10.8Hz,
3. 5H2) 5, 32 (d+I, J
-9.2Hz, 6. 7H2)6,
45 (d, J=7.9H2)6, 74
(br) 6, 9-7. 5 (verlap)7, 66
(d, J=7.8Hz) 60 8, 32 (brs), 8. 36 (br
s) Example 205 LDA [1.04xll of diisopropylamine, 5.46zl of 1.3M n-butyllithium] prepared at -78°C under a stream of argon! and dry tetrahydrofuran 77A
2.7 g of methyl 2(N a p -bromobenzoyl)amino-2(dimethoxyphosphinyl) acetate was added to a solution of 137 g of dry tetrahydrofuran.
1 was added dropwise, stirred at -10'C for 20 minutes, and then cooled to -78C. In addition, 1-t-
A solution of 1.78 g of butoxycarbonyl-5-methoxy-3-formylindole in dry tetrahydrofuran 10z/solution was gradually added, and after stirring at room temperature for 2.5 hours, the reaction was stopped by adding water, concentrated under reduced pressure, and the remaining The material was extracted twice with ethyl acetate, washed with NaHCO3 and brine, dried over sodium sulfate, and concentrated to give an oil.

This product was subjected to column chromatography (Fuco-gel C
Methyl (Z) -2 (Nc p-
Bromobenzoyl)amino-3[3-(1-t-butoxycarbonyl-5-methoxy)indolyl coacrylate (compound A) 1.98 g (58%) was obtained.

On the other hand, the purified product was recrystallized from benzene-n-hexane to give methyl (E)-2-(N,2-pbromobenzoyl)amino-3-C3-(1-t-butoxycarbonyl-5-methoxy). 583 mg (17%) of indolyl coacrylate (compound B) was obtained.

(Compound A) Melting point: 171-73°C (decomposition) Properties: Colorless needle crystals IR (nujol) cm-': 3410, 1735, 1717. 1678°162
9. 1605, 1587, 1536°1288, 1
265. 1215,1081°812,745 NMR (CDCA'3) δ: 1.50 (9H,s), 3.86 (3H,s
)3.9.0 (3H,s) 6.96 (IH,dd, J=9.IHx.

2.6H2) 7, 14 (LH, d, J=2.6Hz)7
, 37 (IH,s) 7.63 (2H,d, J=8.4Hz)7,
71 (IH, broad)7, 77 (LH
,s) 7.80 (2H, d, J=8.4H!)8,
02 (LH, d, J=9. IH2) MS
(70eV) m/Z: 474, 47
2 (M”), 430.428°63 398.396,245.185,183°157,
155. 105 (Compound B) Melting point = 188-189°C (decomposition) Properties: Colorless needle crystals IR (Nujol) cm-': 3275.1723, 1,645, 1592° 1551
．． 1527, 1370, 1293° 1275.1254
,1215,1154°893.857,761 NMR (CDCA'3) δ: 1, 69 (9H, s), 3. 85 (3H,s
) 3, 88 (3H, s)' 6, 96 (IH, dd, J-8, 8H!

2.6H2) 7, 08 (IH, d, J=2.6H2)7,
64 (2H, d, J=8.4H2)7, 7
7 (2H, d, J=8.4H2)64 8.03 (LH,d, J=8.8H2)8,
16 (IH,s) 8, 41 (IH,broad)8.43 (
IH, s) MS (70e V) m/z:530.528
(M”), 474,472°431.430,4
29,428,398°396, 245. 213.
185 In the same manner as in Example 205, using appropriate starting materials, Examples 27-58.75-86.96-1 were prepared.
33.135-139.141-148.163-17
8.184.187.189~191.197~200
．． Compounds identical to those obtained in 203 and 204 can be prepared.

Example 206 Methyl 2-(N, r-p-bromobenzoyl)amino-3-(3-(1=t-butoxycarbonyl-5-methoxy)indolyl coacrylate 1.0 g suspended in 60% sodium hydride in mineral oil) 68 mg of the suspension was stirred at 0°C in dry dimethylformamide 8zA+ under a stream of argon. After stirring was continued until no air bubbles appeared, 235 μl of iodomethane was added and the solution was stirred at 0°C for 1.5 hours, then at room temperature. 0
．． Each was stirred for 5 hours. The reaction mixture was quenched with water, concentrated under reduced pressure, extracted twice with ethyl acetate, washed successively with NaHCO3 and brine, dried over sodium sulfate, and concentrated to give an oil.

This product was subjected to column chromatography (Wakogel C-
200; 110g: Chloroform/acetone-20
0/1) to give methyl 2-(Na p-bromobenzoyl-Na-methyl)amino-13-(3-(
934 mg of 1-t-butoxycarbonyl-5-methoxy)indolylacrylate was obtained.

IR (CDCl2) cm-': 1732.1710.1650', 1621°1588
．． 1534,1257.1213゜1150.1082
．． 835 NMR (CDCA'3) δ: 1.70 (9H, s), 3.25 (3H, s) 3
．． 73 (3H,s), 3.88 (3H,s)7.
03 (IH, dd, J=9.OH2.

2.2Hz) 7.11 (IH, d, J=2.2HX) 7.25
(2H, d, J=8.8H2)7.34 (2H,
d, J=8.8H2) 7.67 (IH, s) 8.07 (IH, d, J=9.0H2) 8.08
(IH, s) MS (70e V) m/z: 544.5
42 (M”), 444,442°259.200,
198,196,185°109.97.95.86.
84 67 In the same manner as in Example 206, using appropriate starting materials,
Said Examples 1-58.75-95.99-103.11
The same compounds as those obtained in -5 to 204 can be produced.

Example 207 Methyl 2-(Nct-4-bromobenzoyl Nct-
1.82 g of methyl)amino-,3-[3-t-butoxycarbonyl-(5-chloroindolyl)]acrylate
20 ml of formic acid and 1 ml of chloroform under a stream of argon.
07A', stirred at about 40°C for 1 day, concentrated under reduced pressure, extracted twice with chloroform, and extracted with saturated Na
Washed sequentially with HCO3 solution and water, dried over sodium sulfate, and concentrated to obtain a solid.

This product was subjected to column chromatography (Wakogel C-
200,230g: Chloroform/methanol 10
0/1) and further recrystallized from dichloromethane-n-hexane to give methyl 268 [N, -(4-bromobenzoyl)-Nct-methylcoamino-3-(3-(5-chloroindolyl) ] 1.45 g of acrylate was obtained.

Melting point: 214-215°C Properties: Colorless rectangular crystals Example 208 [N a (p-bromobenzoyl)-N. -Methyltryptophanyl coglycine methyl ester (Compound I) 133 mg solution in dry tetrahydrofuran 2011
5 yt of a solution of 5 equivalents (relative to compound I) of DDQl in dry tetrahydrofuran at room temperature under a stream of argon.
1 ml was added and stirred overnight. After distilling off the solvent from the reaction solution,
DDQ was removed with a short column of alumina (20% ethyl acetate in chloroform) and then reversed phase high performance liquid chromatography (HPLC, ERC-ODS; 8
0% CH3CN) to obtain 51 mg of CNa (p-bromobenzoyl)-N6-methyl-ni(2-tetrahydrofuryl)tryptophanylcoglycine methyl ester as a resinous substance.

NMR (CDCA'3): 2.0-2. 2 (m), 2. 2-2. 5 (
m) 2.82 (s) , 2.85 (s) 3, 11
(brs) 3.39 (d, J=7.9H2) 3, 7.4 (s), 3. 7-4. 3 (ov
erlap ) 3, 59 (broad) 5.54 (t, J=, 7.9H2) 5, 60 (t, J=7', 9H2) 6.1
9 (dd, J=6.3H2,4,3H2)6, 53
(broad) 6.9-7. 6 (overlap)7.65 (
d, J=7.9H2) MS (70e V) m/z: 543.541 (M”), 455,453°357.
355,328,248,200゜130 Example 209 1.34 g of [N a (p-bromobenzoyl)-N,,-methyl-α,β-didehydrotryptophanyl]valine methyl ester was dissolved in acetic anhydride 42A' A mixed solution of pyridine 411 and pyridine 411 was prepared and stirred at room temperature for 3 days. Ice water was added to the reaction mixture to decompose acetic anhydride, followed by extraction with ethyl acetate 20 (lrA'), and the ethyl acetate layer was washed successively with IN hydrochloric acid, 10% NaCO3, water and saturated brine, and then extracted with anhydrous magnesium sulfate. It was dried and the solvent was distilled off.

This material was subjected to silica gel column chromatography (0,
2% methanol in chloroform) and recrystallized from ethyl acetate-n-hexane to obtain
571 mg of Na (p-bromobenzoyl)-Na-methyl-α,β-didehydrotryptophanyl]valine methyl ester was obtained.

71 Melting point: 172-173°C Properties: Colorless prismatic crystal Using appropriate starting materials in the same manner as in Example 209,
Compounds identical to those obtained in Examples 142 and 145 above can be prepared.

Pharmacological test examples> Test 1) ■1 Receptor binding assay (
Vl receptor binding assay
) Akira I chihara's method [J.

Bio, Chem, 258.9283 (1983)
) using a rat liver membrane specimen prepared according to 3.
(H) -Arg-pappressin (vasopress
1100000 dp (10-6 M) membrane specimens 1100n test drug (10-7 to 10-4 M) of
mmMg CI! 2.1 mMEDTA and 0. 1
%BSA in 100mM) Lis-HCl buffer (pH=
8.0) Incubation in a total volume of 250 μm for 10 minutes at 37°C. Thereafter, filtration was performed three times using a glass filter (GF/F) to separate the membrane specimen bound to pap pressin. This glass filter was taken out, mixed with a liquid scintillation cocktail, and the amount of 3[H]pap pressin bound to the membrane was measured using a liquid scintillation counter, and the inhibition rate was calculated using the following formula.

C1; Amount of binding of 3[H]-Pappressin to the membrane in the coexistence of a known amount of the test drug and 3[H]-Pappressin Co; 3[H]-Pappressin membrane when the test drug is removed Binding amount B1 to 3[H]-Pap resin glass filter excluding membrane specimen The concentration of the test drug at which the inhibition rate calculated above was 50% was determined, and this was taken as the IC5o value.

The results are shown in Table 5.

Test 2) ■2 receptor binding assay (
V2 receptor binding assembly
) Oscar Hechter's method (
J.

Bio, Chem, 253.3219 (1978)
) using a bovine kidney membrane specimen prepared according to 3[H
]-Arg-1000o of papresin.

dpm (10-6M) membrane specimen 0. 1mg test drug (
10-7 to 10-4 M) to 5 mM MtCI!
100 containing 2.1mM EDTA and 0.4% BSA
Total amount of M Tris-HCl buffer (pH = 8.0) 250
Incubation in μl for 2 hours at 4°C. Thereafter, filtration was performed three times using a glass filter (GF/F) to separate the membrane specimen bound to Pap pressin. This glass filter was taken out, mixed with a liquid scintillation cocktail, the amount of 3[H]-Pap pressin bound to the membrane was measured using a liquid scintillation counter, and the inhibition rate (%) was calculated in the same manner as in 1) above. 5
The concentration of the test drug (ICso value) exhibiting 0% inhibition rate was determined.

The results obtained are shown in Table 5 below.

The following compounds were used as test chemicals.

<Test drug> 1 Methyl 2-(Na-methyl-Na-(4-chlorobenzoyl)amino)-3-(3-indolyl)acrylate 2 Methyl 2-(N, -methyl-N.-(4bromobenzoyl) )Amino)-3-(3-indolyl)acrylate 3 Methyl 1-(N,-methyl-Na-(4iodobenzoyl)amino)-3-(3-indolyl)acrylate 4 Methyl 2-[Na-methyl-N , -(4-nitrobenzoyl)amino)-3-(3-indolyl)acrylate 5 Methyl 2- (Na-methyl-N,, -(4-cyanobenzoyl)amino)-3-(3-indolyl)acrylate 6 Methyl 2- (N, -methyl-N, -(4-chlorobenzoyl)amino: l -3-(3-indolyl)acrylate 72-[NQ-methyl-N, -(4-chlorobenzoyl)amino]-3 -(3-indolyl)acrylic(N-isopropyl)amide 82-[:Na-methyl-N(r-(4-bromobenzoyl)amino]-3-(3-indolyl)acrylic(N
-isopropyl)amide 92-(Na-methyl-N, -(4-=trobenzoyl)amine)-3-(3-indolyl)acrylic(N-isopropyl)amide 10 2-CNa-methyl-Na(4- o.

benzoyl)amino)-3-(3-indolyl)acrylic[N-(2,2,2-trifluoroethyl)]amide 11 2-CN, -methyl-N,, -(4-chlorobenzoyl)amine )-3-(3-indolyl)acrylic (
N-allyl)amide 12 2-[N,-methyl-N,r-(4-chlorobenzoyl)amino:] -3-(3-indolyl)acrylic(N-butyl)amide 13 2-(N,-methyl -Na-(4-chlorobenzoyl)amino)-1(3-indolyl)acrylic(N-
t-butyl)amide 14 2-[:N, -methyl-Na
-(4-bromobenzoyl)amino] -3-(5-bromo3-indolyl)acrylic(N-isopropyl)amide 15 2-(Na-methyl-N, -(4-bromobenzoyl)amine) -3-( 1-Methyl-3-indolyl)acrylic(N-isopropyl)amide 16 2-(Na-methyl-N,-(4-bromobenzoyl)amine)-3-(1-ethyl3-indolyl)acrylic(N-isopropyl) Amide 17 2-(N, -methyl-Na-(4-bromobenzoyl)amino)-3-(1-propyl 3-indolyl)
Acrylic (N-isopropyl)amide 18 2-(Na-methyl-N-(4-bromobenzoyl)amino)-3-(1-ethoxycarbonylmethyl-3-indolyl)acrylic (N-isopropyl)amide 19 Methyl 2 -(N, -methyl-N, -(4chlorobenzoyl)amino)-:3- (1acetyl-3-
indolyl) acrylate 20 2-[N, -methyl-
N. -(4-chlorobenzoyl)amine]-3-(1-
Methyl 1 22 3 4 5 3-indolyl)acrylic(N-isopropyl)amide 2-CNa-methyl-NQ-(4-bromobenzoyl)
amino) -3(1-acetyl-3-indolyl)acrylic(N-isopropyl)amide 2-(Na-methyl-Na-.(4-nitrobenzoyl)amino:1-3-(1-methyl-3-indolyl) Acrylic (N-methyl-N-isopropyl)amide [stereoisomer A] 2-[Na-methyl-NQ-(4-nitrobenzoyl)amino)-3-(1-methyl-3-indolyl)acrylic (N-methyl- N-isopropyl)amide [
Stereoisomer B] [N, -(4-bromobenzoyl)-N
.

-Methyl-α,β-didehydrotryptophanyl]glycine methyl ester [Na-(4-bromobenzoyl) -Na79 6 7 8 9 0 1 Methyl-α,β-didehydrotryptophanyl]serine methyl ester [Na -(4-bromobenzoyl)-N.

Methyl-α,β-didehydrotryptophanyl]methionine methyl ester [a-(,4-bromobenzoyl)-N4-methyl-α
, β-didehydrotryptophanyl]aspartic acid
Dimethyl ester (Na-(4-bromobenzoyl)-
N.

Methyl-α,β-didehydrotryptophanyl]alanine methyl ester (Na-(4-bromobenzoyl)-Na-methyl-
α,β-didehydrotryptophanyl)-D-methionine methyl ester (Na-(4-bromobenzoyl)
Sa dimethyl α,β-didehydrotryptophanyl]methioninamide 2-[Na-ethyl-N,, -(4-bromo80 benzoyl)amino] -3-(3-indolyl)acrylic(N-isopropyl)amide 322- [N, -n
-propyl-N, -(4-bromobenzoyl)amino]
-3-(3-indolyl)acrylic(N-isopropyl)amide 33 [N,-methyl-N12- (4-bromobenzoyl)-α,β-didehydrotryptophanyl]-
D-valine methyl ester Table 283 From Table 5 above, it is clear that all of the test drugs are effective as pap pressin antagonists.

(that's all) 84

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a phenyl lower alkyl group, a tetrahydrofuryl group, a lower alkoxycarbonyl group, a lower alkoxycarbonyl group. Indicates a lower alkyl group, a carboxy lower alkyl group, or a lower alkanoyl group. R^2 represents a hydrogen atom, a hydroxyl group, a lower alkoxy group, a phenyl lower alkyl group, a lower alkyl group, a phenyl lower alkoxy group, or a halogen atom. R^3 is a hydroxyl group, a lower alkoxy group, a group -NR
^6R^7 (R^6 and R^7 are the same or different and are a hydrogen atom, a lower alkyl group with or without 1 to 3 halogen atoms as a substituent, a phenyl lower alkyl group, a lower alkenyl group, or A 5- or 6-membered cycloalkyl group, or a 5- or 6-membered cycloalkyl group that may have a phenyl group, lower alkyl group, or hydroxyl group as a substituent, with or without a nitrogen atom or an oxygen atom, together with the nitrogen atom to which they are bonded. ), or an amino acid residue that can form an amide bond with the CO group bonded to R3, and the carboxyl group present on the amino acid residue is a phenyl lower alkoxycarbonyl group, a substituted 1- which may have a lower alkoxycarbonyl group as a group
It may be converted to a pyrrolidinylcarbonyl group, lower alkoxycarbonyl group or carbamoyl group. R^4 represents a hydrogen atom, a lower alkyl group, or a phenyl lower alkyl group. R^5 is a group consisting of a halogen atom, nitro group, cyano group, lower alkoxy group, phenyl group, and a lower alkyl group having or not having 1 to 3 halogen atoms as a substituent on the phenyl ring. A benzoyl group which may have 1 to 3 of the groups selected from the following, a phenyl lower alkenylcarbonyl group which may have a nitro group as a substituent on the phenyl ring, a thienyl carbonyl group, a lower substituent on the phenyl ring. It represents a phenylsulfonyl group, a pyridylcarbonyl group, or an imidazolylcarbonyl group that may have an alkyl group. In addition, the bonds at the 1st and 2nd positions in the side chain of the indole skeleton ▲There are mathematical formulas, chemical formulas, tables, etc.▼ indicate single bonds or double bonds. ] A vasopressin antagonist characterized by containing an indole derivative or a salt thereof as an active ingredient.