JPH02243674A - Amino acid derivative, production thereof and pharmaceutical composition containing the same - Google Patents

Abstract

NEW MATERIAL:An amino acid derivative expressed by formula I [R<2> is H or alkyl; R<4> is aryl; R<5> is N-containing heterocyclic ring, (i) R<1> is alkyl substituted with acyl, etc.; R<3> is formula II (R<8> and R<9> are H or alkyl or both, together with the adjacent N, form a ring; X<1> is single bond, O, etc.; X<2> is NH, O or CH2; (ii) R<1> is heterocyclic ring; R<3> is formula II; X<1> is single bond; X<2> is O or CH2; (iii) R<1> is alkyl substituted with acyl, etc.; R<3> is alkyl; X<1> is NR<10> (R<10> is H or alkyl); X<2> is NH or CH2 or (iv) R<1> is alkyl substituted with acyl, etc.; R<3> is alkyl; X<1> is O; X<2> is NH, O or CH2] and salts thereof. EXAMPLE:(3S)-N,N-Dimethyl-3-tritylamino-4-cyclohexyl-2-hydroxybu- tanesulfonamide. USE:A medicine capable of exhibiting renin inhibitory activity. PREPARATION:For example, a compound expressed by formula III (Ra<5> is N-containing heterocyclic ring; R<11> is N-protecting group) is reacted with a compound expressed by formula IV to provide a compound expressed by formula V. The N-protecting group is then eliminated to afford a compound expressed by formula VI, which is subsequently reacted with a compound expressed by formula VII to provide the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel amino acid derivative having renin inhibitory activity, and is used in the medical field.

[Prior Art] Until now, peptide compounds having renin inhibitory activity have been disclosed in Japanese Patent Publication No. 13360/1982 and Japanese Patent Application Laid-open No. 1988-13360.
33153, JP-A-61-236770, JP-A-62-234052, JP-A-63-
No. 253097, Japanese Patent Publication No. 1983-503380, Japanese Patent Application Laid-Open No. 19071-1990, Japanese Patent Application Laid-open No. 1990-1
No. 9053 and many other reports have been made, and the development of renin inhibitors that can be administered orally is still continuing.

[Means for Solving the Problems] The amino acid derivative according to the present invention is novel and can be represented by the following general formula [1F].

[wherein R represents hydrogen or a lower alkyl group, R4 represents an aryl group, and R5 represents an N-containing heterocyclic group; Do you mean?
or (i) R is a heterocyclic group, and R3 is substituted with a substituent selected from the group consisting of the following formula: (wherein R is an acyl group and R7 is hydrogen or a lower alkyl group) lower alkyl group, R3 is the formula (in the formula, R8, R9 and A each have the same meaning as before)
(X is a single bond, X2 is 10- or -C)
t2-, or (i) R1 represents acyl and the formula (wherein R8 and R9 each represent hydrogen or a lower alkyl group optionally substituted with a suitable substituent, or R8 and R9 together with adjacent nitrogen atoms to form a heterocyclic group, A means a lower alkylene group), a group represented by Xl (wherein R and R7 each have the same meaning as before) a lower alkyl group substituted with a substituent selected from the group consisting of (R3 means a lower alkyl group or a lower alkyl group), X2 is a taste),
X means 1NH- or 1CH2-, or (iv) R' is a group consisting of acyl and a group of the formula 聚过 radical yu (wherein R and R7 each have the same meaning as before) A lower alkyl group substituted with a substituent selected from R3 is a lower alkyl group, X is -〇-1 can be produced by the production method explained in the reaction formula below, but the target compound [! ] The manufacturing method is not limited to the following manufacturing method.

or a reactive derivative thereof at the carboxy group or a salt thereof or a reactive derivative thereof at the amine group or a salt thereof [IV] or a salt thereof or a salt thereof or a salt thereof at the amine group. Reactive derivative or a salt thereof + [V co or a salt thereof [VI[] or a reactive derivative thereof at the carboxy group or a salt thereof or a salt thereof JlL main R'-X'-H [■] or a salt thereof m R-X -COOH [■ Reactive derivative thereof or a salt thereof in a co- or carboxy group or a reactive derivative thereof or a salt thereof in an amino group or a salt thereof [wherein R5 represents an N-protecting group] R, R, R, R, R, X and X2 each have the same meaning as before] In the description of the specification, preferred examples of various definitions included within the scope of the present invention will be described in detail below.

"Lower", unless otherwise specified, shall mean groups having 1 to 6 carbon atoms.

Suitable "lower alkyl groups" include methinoethyl,
Mention may be made of straight or branched alkyl groups such as propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, impentyl, hexyl, and the like.

Suitable 1-acyl groups include, for example, lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, invaleryl, pivaloyl, and 4-methylvaleryl, such as mesolaminoacetyl, methylaminopropionyl, dimethylaminobutyryl, and the like. mono- or di(lower)alkylamino(lower)alkanoyl groups, e.g. lower alkoxy(lower)alkanoyl groups such as methoxyacetyl, methoxypropionyl, ethoxypropionyl, aroyl groups such as benzoyl, toluoyl, e.g. cyclopropylcarbonyl, cyclo cyclo(lower) alkylcarbonyl groups such as butylcarbonylpentylcarbonyl, cyclohexylcarbonyl,
For example, amino r1 whose amino group may be protected, such as glycyl, benzoylglycyl, tertiary-butoxycarbonylglycyl, tertiary-butoxycarbonylleucyl, acetylleucyl, tertiary-butoxycarbonylhistidyl, etc.
one residue, a carbamoyl group, e.g. methylcarbamoyl,
Ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, pentelcarpamoyl, isobutylcarbamoyl, tertiary butylcarbamoyl, diethylcarbamoyl, diethylcarbamoylsopropylcarbamoylrubamoyl, such as bifrylcarbamoyl, pyridylethylcarbamoyl, thiazolylmethylcarbamoyl,
Heterocyclic (lower) alkylcarbamoyl L such as morpholinomedelcarpamoyl and morpholinoethylcarbamoyl
N-heterocycle (lower) such as N-picolyl-N-methylcarbamoyl, N-pyridylethyl-N-methylcarbamoyl, N-morpholinomethyl-N-ethylcarbamoyl, N-morpholinoethyl-N-methylcarbamoyl, etc.
Alkyl-N-lower alkylcarbamoyl groups, such as benzylcarbamoyl, phenedelcarbamoyl, benzhydrylcarbamoyl(lower)alkylcarbamoyl groups, such as N-benzyl-N-methylcarbamoyl
N-al(lower a)alkyl-N-lower alkylcarbamoyl groups such as phenethyl-N-methylcarbamoyl-N-ethylcarbamoyl, N-aryl-N- such as N-phenyl-N-methylcarbamoyl;
lower alkoxycarbonyl (lower) alkylcarbamoyl groups such as methoxycarbonylmethylcarbamoyl, ethoxycarbonylmedelcarbamoyl, ethoxycarbonylethylcarbamoyl, etc.; For example, aroylcarbamoyl groups such as benzoylcarbamoyl and doluoylcarbamoyl, heterocyclic carbamoyl groups such as pyridylcarbamoyl, morpholinocarbamoyl, thiazolylcarbamoyl, etc., such as N-pyridyl-N-methylcarbamoyl, N-thiazolyl-N-methylcarbamoyl, etc. N-heterocycle-N-lower alkylcarbamoyl group, heterocycle carbonyl group, more preferably morpholinocarbonyl, deomorpholinocarbonyl, piperidinocarbonylthyl-1-piperazinylcarbonyl, 1.2,3.

N-containing heterocycle-N optionally substituted with a lower alkyl group such as 6-tetrahydro-1-pyridylcarbonyl
-ylcarbonyl groups, e.g. lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, nyl groups, e.g. iodo ethoxycarbonyl,
Mono-( such as dichloroethoxycarbonyl, trichloroethoxycarbonyl, trifluoromethoxycarbonyl)
or di- or tri)halo(lower)alkoxycarbonyl groups, such as hydroxymethoxycarbonyl, hydroxyethoxycarbonyl, hydroxypropoxycarbonyl, hydroxybutoxycarbonyl, hydroxy(lower)alkoxycarbonyl groups, such as benzyloxycarbonyl, phenethyloxy carbonyl, 4-
Al(lower) alkoxycarbonyl groups such as nitrobenzyloxycarbonyl, trityloxycarbonyl, and benzhydryloxycarbonyl, lower alkenyloxycarbonyl groups such as vinyloxycarbonyl and allyloxycarbonyl, such as acetylmethoxycarbonyl, propionylmethoxycarbonylcarbonyl, etc. lower alkanoyl (lower) alkoxycarbonyl groups such as mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, lower alkylsulfonyl groups such as phenylsulfonyl, Examples include noarylsulfonyl groups such as tosyl.

Suitable aryl groups J include phenyl, naphthyl,
Examples include groups such as tolyl, xylyl, mesityl, cumenyl, etc., among which preferred are phenyl and naphthyl groups.

Suitable substituents for the "lower alkyl group optionally substituted with a suitable substituent" for R8 and R9 include, for example, the above-mentioned aryl group, the following heterocyclic group, and the like.

The preferred "heterocyclic group" for R as a substituent on the lower alkyl group of R8 and R9 and the preferred "heterocyclic group" formed by R8, R9 and the adjacent nitrogen atom include , morpholino, thiomorpholino, pyrrolidin-1-yl, pyrazolidine-1-
yl, piperidino, piperazin-1-yl, pyrroline-
1-yl and the like.

Suitable 1N-containing heterocyclic groups in R and R5 include, for example, saturated groups such as pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl, imidazolyl, thiazolyl, thiadiazolyl, oxasilyl, benzothiadiazolyl, benzoxadiazolyl, benzimidazolyl, etc. or unsaturated N-, N- and S-, or N- and O-containing heterocyclic groups.

The above-mentioned "N-containing heterocyclic group" may have an N-protecting group as described below.

Suitable "lower alkylene groups" include straight or branched alkylene groups such as methylene, ethylene, trimeprene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylmethylene, propylmethylene, and the like. Among these, more preferred are C1-C, alkylene groups, and most preferred are methylene, ethylene, trimethylene, tetramethylene and methylmethylene.

Suitable rH-protecting groups include, for example, substituted or unsubstituted lower alkanoyl groups such as formyl, acetyl, propionyl, trifluoroacetyl, phthaloyl groups,
Lower alkoxycarbonyl groups such as tertiary butoxycarbonyl, tertiary amyloxycarbonyl, substituted or unsubstituted aralpoxycarbonyl groups such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, e.g. benzenesulfonyl, tosyl Substituted or unsubstituted arenesulfonyl groups such as, nitrophenylsulfenyl groups, alkylene groups such as littelle, benzyl, etc., and the like.

Suitable pharmaceutically acceptable salts of the target compound [I] are conventional non-toxic salts, such as formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate. salts, organic acid addition salts such as toluene sulfonates, inorganic acid addition salts such as hydrochlorides, hydrobromides, sulfates, phosphates, salts with amino acids such as aspartates, glutamates, etc. Can be mentioned.

The method for producing the target compound [1] will be explained in detail below.

Preparation Procedure 1 First Step Compound [IV] or a salt thereof is a compound [II] or a reactive derivative thereof at a carboxy group or a salt thereof, or a compound [m] or a reactive derivative thereof at an amino group or a salt thereof. It can be produced by reacting with salt.

For suitable salts of compound [IV], refer to those exemplified for compound [I].

Suitable reactive derivatives of the carboxy group of compound [11] include acid halides, acid anhydrides, activated amides, activated esters, and the like.

Suitable examples of such reactive derivatives include acid chlorides; acid azides; substituted phosphoric acids such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, Sulfuric acid, sulfonic acids such as methanesulfone, aliphatic carboxylic acids such as acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, impentanoic acid, 2-ethylbutyric acid, trichloroacetic acid M, or e.g. benzoic acid mixed acid anhydrides with acids such as aromatic carboxylic acids; symmetrical acid anhydrides; activated amides with imidazole, 4-substituted imidazoles, dimedelpi, razoles, triazoles or tetrazoles: or e.g. cyanomethyl esters, methoxymethyl Ester, dimethyliminomethylocu3)2
i=cu-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester,
Activation of pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenyl deoester, p-talesylthioester dimethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthioester, etc. Estheno muttering or for example N. N-dimethylhydroxylamine, 1-hydroxy-2-(IH)-
Examples include esters with N-hydroxy compounds such as pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, and 1-hydroxy-IH-benzotriazole. These reactive derivatives are the compounds to be used [
You can arbitrarily select one from among them depending on the type of 1[].

Suitable salts of compound #[II] and its reactive derivatives include, for example, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts such as trimethylamine salts, Triethylamine salt, pyridine salt, pilin salt, dicyclohexylamine salt, N. base salts such as organic base salts such as N'-dibenzylethylenediamine salts;
and compounds [! Examples include acid addition salts such as those exemplified above.

Suitable reactive derivatives of the amino group of compound [111] include Schiff's base-type imino group produced by the reaction of compound [11] with a carbonyl compound such as an aldehyde, a ketone, etc., or an enamine-type strain variant thereof. ; Compound [silyl derivative produced by the reaction of the apex with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, bis(trimethylsilyl)sulfur, etc.: Compound [111] and phosphorus trichloride, phosgene and Examples include derivatives produced by the reaction.

For suitable salts of compound [11[] and its reactive derivatives, refer to the salts exemplified for compound [I].

The reaction is usually carried out using water, alcohols such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N. The reaction is carried out in a commonly used solvent such as N-dimethylformamide or pyridine, but the reaction can be carried out in any other organic solvent as long as it does not adversely affect the reaction. These conventional solvents may be used in mixtures with water.

When compound []I] is used in the form of the free acid or its salt in this reaction, N,N'-dicyclohexylcarbodiimidosyl-N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4 -diedelaminocyclohexyl)carbodiimide HN+N'diethylcarbodiimide, N. N'-diisopropylcarbodiimide; N-
Ethyl-N'-(3-dimedelaminopropyl)carbodiimide+N.

N'-carbonylbis-(2-methylimidazole)
;pentamethyleneketene-N-cyclohexylimine;
diphenylketene-N-cyclohexylimine;ethoxyaceprene;1-alkoxy-1-chloroethylene;
Trialkyl phosphite; Nibble borophosphate; Isopropyl polyphosphate; Phosphorus oxychloride (phosphoryl chloride); Trichloride groove;
Phosphoryl diphenylazide; thionyl chloride; oxalyl chloride; lower alkyl haloformates such as ethyl chloroformate and isopropyl chloroformate; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5- ( m -sulfophenyl) isoxazolium hydroxide inner salt; 1-(
p-chlorobenzenesulfonyloxy)-6-chloro-
IH-benzotriazole, N. Preferably, the reaction is carried out in the presence of a conventional condensing agent, such as the so-called Vilsmeier reagent prepared by the reaction of N-dimedelformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, and the like.

The reaction also includes alkali metal bicarbonates, tri(lower)alkylamines, pyridine, N-(lower)alkylmorpholines, N. It may be carried out in the presence of an inorganic or organic base such as N-di(lower)alkylbenzylamine and the like.

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

Compound [V] or a salt thereof can be produced by subjecting compound [IV] or a salt thereof to an N-protecting group elimination reaction.

For suitable salts of compound [V], refer to those exemplified for compound [I].

This reaction is carried out according to conventional methods such as hydrolysis, reduction, etc.

Hydrolysis is preferably carried out in the presence of a base or an acid, including a Lewis acid.

Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, hydroxides or carbonates or bicarbonates of these metals, hydrazine, trimethylamines such as trimethylamine, triethylamine, etc. Alkylamine, picoline, 1.5-diazabicyclo[4.3.0]nona-5-
En, 1.

4-diazabicyclo[2.2.2]octane, 1.8-
Included are inorganic and organic bases such as diazabicyclo[5.4.0]undec-7-ene and the like.

Suitable acids include, for example, formic acid, acetic acid, propionic acid,
Examples include organic acids such as trichloroacetic acid and trifluoroacetic acid, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, and hydrogen fluoride, and acid addition salt compounds such as pyridine hydrochloride.

Desorption using a Lewis acid such as trihaloacetate, such as trichloroacetic acid, trifluoroacetic acid, etc., is preferably carried out in the presence of a cation scavenger, such as anisole, phenol, etc.

The reaction is usually carried out in water, an alcohol such as ethanol, a solvent such as methylene chloride, chloroform, tetrachloromethane, tetrahydrofuran, or a mixture thereof, or in any other solvent that does not adversely affect the reaction. The reaction can be carried out in any solvent. Liquid bases or acids can also be used as solvents.

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

Reduction methods that can be applied to the elimination reaction include chemical reduction and catalytic reduction.

Suitable reducing agents used for chemical reduction include, for example, tin,
Metals such as zinc and iron or metal compounds such as chromium chloride and chromium acetate, and formic acid, acetic acid, propionic acid,
It is a combination with an organic or inorganic acid such as trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, or hydrobromic acid.

Suitable catalysts used for catalytic reduction are platinum catalysts such as platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxide, platinum wires, platinum catalysts such as palladium sponges, palladium black, palladium oxide, palladium-hypochloride, colloids. palladium,
Palladium catalysts such as palladium-barium sulfate, palladium-barium carbonate, nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, cobalt catalysts such as reduced cobalt, Raney cobalt, iron catalysts such as reduced iron, Raney iron, etc. Commonly used materials include reduced steels, Raney steels, Ullmann steels, etc. with copper catalysts.

The reduction is usually carried out in conventional solvents that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, N,N-dimedelformamide, or mixtures thereof. Furthermore, if the acids used in the chemical reduction are liquids, they can also be used as solvents. Furthermore, suitable solvents used in the catalytic reduction include the above-mentioned solvents and other conventional solvents such as diethyl ether, dioxane, tetrahydrofuran, etc.
or a mixture thereof.

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

Third step target compound CI] or a salt thereof is a compound [V] or a reactive derivative thereof at an amino group or a salt thereof, and a compound [VI[] or a reactive derivative thereof at a carboxy group or a salt thereof. It can be produced by reacting and, if necessary, removing the N-protecting group.

For suitable salts of compound [VI], compound [1r
Refer to the salts with bases as exemplified above.

This reaction can be carried out in substantially the same manner as in 1. Therefore, the reaction method and reaction conditions such as the reactive derivative, condensing agent, solvent, and reaction temperature are described in 1.
Please refer to the explanation of construction work 1.

When the N-containing heterocyclic group of compound [V] is protected, the target compound [ I
] can be manufactured.

Since this elimination reaction can be carried out in substantially the same manner as the second step of this production method, the reaction method and reaction conditions such as base, acid, reducing agent, catalyst, solvent, reaction temperature, etc. Please refer to the explanation of LLL12 of this manufacturing method.

1. The target compound [1a] or a salt thereof can be obtained by subjecting a compound [■] or a salt thereof and a compound [■] or a salt thereof to a reaction for producing a ureido group or a carbamoyloxy group, and optionally N-protection. It can be produced by eliminating the group.

For suitable salts of compounds [Ia], [■] and [■], refer to those exemplified for compound [I].

This reaction is performed using phosgene, a haloformate compound such as ethyl chloroformate, trichloromethyl chloroformate, N
, N'-carbonyldiimidazole, a metal carbonyl compound such as cobalt carbonyl, manganese carbonyl, etc., in the presence of a reagent that introduces a carbonyl group, such as a combination of carbon oxide and a catalyst such as palladium chloride, etc. be exposed.

This reaction typically involves dioxane, tetrahydrofuran, benzene, toluene, chloroform, methylene chloride, N,
Although the reaction is carried out in a solvent such as N-dimethylformamide, the reaction can be carried out in any other solvent that does not adversely affect the reaction.

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

When the N-containing heterocyclic group of the compound [■] is protected, the target compound [■] can be obtained by removing the N-protecting group of the reaction product between the compound [■] and the compound [■]. 1a
] can be manufactured.

This elimination reaction can be carried out in substantially the same manner as in Section 31 of ``Neuro J1 Method'' 2. For conditions, please refer to the explanation of Step 1 in "JE Method" 2.

[1D] The target compound [1b] or a salt thereof can be prepared by reacting a compound [IX] or a reactive derivative thereof at an amino group or a salt thereof with a compound [IX] or a reactive derivative thereof at a carboxy group or a salt thereof. , can be produced by removing the N-protecting group as necessary.

For suitable salts of compound [Ib], compound [11
Please refer to the salts exemplified above.

For suitable salts of compound [IX], compound [1[
] may be referred to as salts with bases such as those exemplified.

This reaction can be carried out in substantially the same manner as earthwork 1 of the IL method, and therefore the reaction method and reaction conditions such as reactive derivative, condensing agent, solvent, reaction temperature, etc. Please refer to the explanation of earthworks in [Act] 2.

When the N-containing heterocyclic group of compound [■] is protected, the target compound [I
b] can be produced.

This elimination reaction can be carried out in substantially the same manner as Kamejiku 1 of ``AtsushijE method'' 2, so the reaction method of this reaction and, for example, the base, acid, reducing agent, catalyst, solvent, reaction temperature, etc. For reaction conditions, please refer to the explanation of LLL12 in Brain J [Method] 2.

Among the raw material compounds [■], some of them are new compounds and can be produced by the production method shown in the following reaction formula.

[Xl or a salt thereof R'-Xl-H [■] or a salt thereof [XI] and R1, R4 and Xl each have the same meaning as before] Suitable "protected carboxy groups" include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonylbonyl, butoxycarbonyl, secondary butoxycarbonyl, imbutoxycarbonyl, Lower alkoxycarbonyl groups such as tertiary butoxycarbonyl, pentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, optionally substituted alkoxycarbonyl groups, such as benzyloxycarbonyl, Commonly used protecting groups such as 7-no or di- or triphenyl (lower) alkyl dicarbonyl groups optionally substituted with nitro groups such as 4-nitrobenzyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, etc. Examples include carboxy groups protected by .

The method for producing the raw material compound will be explained in detail below.

ILΔ Kamedoko 1 Compound [XI] can be produced by subjecting compound [■] or a salt thereof and compound [Xl or a salt thereof to a reaction for producing a ureido group or a carbamoyloxy group.

For suitable salts of compound [Xl, refer to the salts exemplified for compound [I].

This reaction can be carried out in substantially the same manner as Hiroshi Oho, JL, and therefore, the method of this reaction and the reaction conditions, such as reagents, solvents, and reaction temperatures for introducing carbonyl groups, are provided by JL Hiroshi. Please refer to the explanation.

The second violet compound [VIa] or a salt thereof can be produced by subjecting compound [XI] to a carboxy-protecting group elimination reaction.

Compound [V! For suitable salts of compound [■
] Please refer to the salts exemplified above.

This reaction can be carried out in substantially the same manner as IJI's Scheme 1, and therefore the reaction method and reaction conditions such as base, acid, reducing agent, catalyst, solvent, reaction temperature, etc. Please refer to the explanation of the second step of "JE method" 1.

The compound obtained by the above production method can be isolated and purified by conventional methods such as pulverization, recrystallization, catem chromatography, thin layer chromatography, reprecipitation, and the like.

Compound [1] and other compounds include one or more stereoisomers based on asymmetric elementary atoms, and all such isomers and mixtures thereof are included within the scope of the present invention.

For treatment, the compound [I] of this invention and its pharmaceutically acceptable salts can be administered orally, containing one of the above compounds as an active ingredient in admixture with an organic or inorganic solid or liquid excipient; It can be used in the form of pharmaceutical preparations suitable for parenteral or topical administration. Pharmaceutical preparations include capsules, tablets, sugar-coated tablets, granules, solutions, suspensions, emulsions, and the like. If desired, auxiliaries, stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives may be included in these formulations.

The dose of compound [I] varies depending on the age and condition of the patient, but the average dose of compound [CI] is about 0.1 mg5
1 rag, 10mg, 50mg, loOmg,
250mg, 5QOmB.

A dose of 1000 mg is effective in treating hypertension and heart failure. - 0.1 mg/individual to about 1 per day in the membrane
000 mg/individual may be administered.

[Effect of the invention] In order to demonstrate the usefulness of the target compound [11], the compound [! ]
The pharmacological test results of representative compounds are shown below.

KasaluL Ryoso (1) (2R,3S)-3-[N”-[N-[N-
Methyl-N-(2-(N-morpholinocarbonyl-N-
methylamino)ethyl)aminocarbonyl]-L-phenylalanyl]-Na-methyl-L-histidylcoamino-4-cyclohexyl-2-hydroxy-1-impro and lyaminosulfonylbutane (Example 3-(2) ) (2) (2S,3S)-2-[Na-4N-[N-
Methyl-N-(2-(N-morpholinocarbonyl-N-
methylamine)ethyl)ami7carbonyl]-L-phenylalanyl]-Nα-methyl-L-hisdedylcoamino-1-cyclohexyl-3-hydroxy-6-methylhebutane (compound of Example 1) (3 ) (2S, 3S)-2-4Na-[N-(2-
(N-morpholinocarbonyl-N-mesolamino)ethoxycarbonyl)-L-phenylalanyl) -N(!
-Methyl-L-histidylcoamino-1-cyclohexyl-3-hydroxy-6-methylhebutane (compound of Example 3-(22)) U photophobic human plasma was collected from a male volunteer without drug pretreatment, Used as a pool. Ethylenediaminetetraacetic acid (
EDTA) disodium salt was used as an anticoagulant. Plasma endogenous renin and angiotensingen at pH
Incubate at 6,0 (37'C) a, angiotensin and plasma renin action! It was measured as the production rate. The incubation mixture contained 2501 dl of plasma, 5-1 sulfonyl fluoride buffer (sodium-potassium phosphate buffer, pH 6,0), 30- and 50% ethyl alcohol--test compound 154 at the appropriate concentration in the aqueous body. It was something. Angiotensin I generated after incubation for 90 minutes was collected using a commercially available kit RENIJK10.
0 [:Comm1ssariat A L'ener
It was measured by a radioimmunoassay method using a device manufactured by Gia Atomique. Samples were incubated in duplicate and each tube was measured in duplicate by radioimmunoassay. Percent inhibition of plasma renin activity was calculated by comparing the amount of angiotensin I produced in the presence and absence of the test compound. The concentration of the test compound that inhibited plasma renin action by 50% (IC5o) was determined by the Probit method.

As is clear from the above test results, the target compound [11 and its salts have a strong inhibitory effect on renin, and are particularly useful as orally administrable antihypertensive agents and agents for heart failure.

[Example] Preferred production examples of the target compound [I] will be explained below according to Examples, but the production methods of these compounds are not limited to the following Examples.

In the following examples, Kiesgel (Kies) was used as the TLC plate.
elgel) 60F254 (trademark: manufactured by Merck & Co., Ltd.)
(thickness: 0.25 mm) was used.

(1) A solution of N-tertiary-butoxycarbonyl-L-cyclohexylalanine methyl ester (8,561 g) in trifluoroacetic acid (8!1111) was stirred at 0°C for 30 minutes. The solvent was distilled off, and the residue was diluted with ethyl acetate (3001
11Q). The solution was mixed with saturated aqueous sodium bicarbonate solution (250ml) and brine (300ml).
11), dried over magnesium sulfate, and concentrated under reduced pressure to obtain L-cyclohexylalanine methyl ester (5,670 g) as an oil.

Rf: 0.50 (chloroform:methanol.

s: i * v/v) (2) A solution of trityl chloride (8,531 g) in dry methylene chloride (somi) was added to a solution of L-cyclohexylalanine methyl ester (5,670 g) and triethylamine (t2ssmn) in dry methylene chloride ( 80111”
) to the mixture over 10 minutes at 0°C. The mixture is stirred at 0° C. for 1 hour, then allowed to cool to room temperature and stirred for 2 hours. The mixture was concentrated under reduced pressure, and ethyl acetate (5
00 relative) and 10% citric acid aqueous solution c soome
om) and saline solution (500 mQ),
After drying with magnesium sulfate, it was concentrated under reduced pressure to give N-trityl-cyclohexylalanine methyl ester (13
, 560 g) as an oil.

Rf: 0.79 (n-hexane: ethyl acetate.

2:1, v/v) (3) Lithium aluminum hydride (1,335g
) to anhydrous diethyl ether (47+11Q) suspension was N-trityl-cyclohexylalanine methylnistyl (10.03g) in diethyl ether (47ml).
1 l) solution was added dropwise over 20 minutes at room temperature while stirring.

After stirring the mixture for 10 minutes, it was cooled to 0°C and water-saturated diethyl ether (2001111) was added to it.The precipitate was filtered and washed with diethyl ether (400!111). Dry over magnesium and concentrate in vacuo to give N-)richyl-monocyclohexylalaninol (9,085 g) as an oil.

Rf: 0.28 (n-hexane: ethyl acid.

2:1 tv/v) (4) A solution of sulfur trioxide pyridine complex (12,99 g) in dry dimethyl sulfoxide (40 ffl11) was mixed with N-trityl-L-cyclohexylalaninol (6,
00g) and triethylamine (11,37111) in dry dimethyl sulfoxide (6011111') under a nitrogen atmosphere over 10 minutes. After stirring for 5 minutes,
Pour the solution into ice water (500ffLQ).

The resulting slurry was mixed with diethyl ether (5001×3)
After combining the extracts and drying with magnesium sulfate,
Concentration under reduced pressure gives N-triple-L-cyclohexylalaninal (5.98 g) as an oil.

Rf: 0.82 (n-hexane: 9 ethyl acetate.

2:1, v/v) (5) N,N-dimedelmethanesulfonamide (2
,035g) of dry tetrahydrofuran (44mi)
n-butyllideum (10,33111) in solution.

A 1.6 M solution in n-hexane) is added dropwise over 5 minutes at -5° C. under nitrogen atmosphere. After stirring the mixture for 17 minutes, -6
Cooled to 8°C, N-trityl-cyclohexylalaninal (5,970 g) was dissolved in dry tetrahydrofuran (
33ml 1l) solution to treat the reaction mixture at the same temperature.
Stir for 0 minutes to stir the reaction in a saturated aqueous ammonium chloride solution (
201111+), the solvent was distilled off, and the residue was
Add ether (1501111) and 10% aqueous citric acid solution (150 ml!). The organic layer was diluted with water (150mM
), saturated sodium hydrogen oxide aqueous solution (15011Q)
, water (1501d) and saline solution (150!+11
) and dried with magnesium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (
Elution solvent: ethyl acetate-n-hexane) to purify with (
3S)-N,N-dumedel-3-tripleamino-4-
Cyclohexyl-2-hydroxybutanesulfonamide (4,778 g) is obtained as an oil.

Rf: 0.37 (n-hexane: ethyl acetate.

2: 1, v/v) 11 Wataru Yu The following compound is obtained in the same manner as in Production Example 1-(5).

(1>N-isopropyl methanesulfonamide (2,0
0 g), N-trityl-L-cyclohexylalaninal (4,91 g) and n-butyllithium (16,9
5 mm ) to obtain (3S>-N-isopropyl-3-tritylamino-4-cyclohexyl-2-hydroxybutanesulfonamide (3,94 g).

Rf: 0.23 (n-hexane: ethyl acetate.

4:1, V/V) (2) 1-methylsulfonylpiperidine (2,44
g), N-trityl-L-cyclohexylalaninal (5,96 g) and n-butyllithium (10,3 d
) to obtain 1-((3S)-3-)lytylamino-4-cyclohexyl-2-hydroxybutylsulfonyl)piperidine (4,07 g).

Rf: 0546 (n-hexane; ethyl acetate.

3:1, v/v)! j11 mutual (3S)-N,N-dimethyl-3-tritylamino-
4-Cyclohexyl-2-hydroxybutanesulfonamide (4,764g) at 50? ≦Aqueous acetic acid solution (100
mQ). The solution is stirred at room temperature for 5 minutes and the resulting precipitate is washed with water (401 x 3). 6011 filtrate
2 and diethyl ether (601111)
Add. The bathing suit is neutralized with sodium bicarbonate and the mixture is extracted with ethyl acetate (80ml x 3). The extracts were combined, washed with brine (2401111), dried over magnesium sulfate, and concentrated under reduced pressure to obtain (3S > -N,
N-dimethyl-3-amino-4-cyclohexyl-2-
Hydroxybutanesulfonamide (2,325 g) is obtained as a solid.

Melting point: 110.5-112°C Rf: 0.50 (chloroform:methanol:acetic acid, 8
:1:1. v/v) 11.1 The following compound is obtained in the same manner as in Production Example 3.

(1) (3S)-N-isopropyl-3-amino-
4-Cyclohexyl-2-hydroxybutanesulfonamide melting point? 154.5-155.5°C Rf: 0.19 (chloroform:methanol.

9: 11V/V) (2) 1-((33)-3-amino-4-cyclohexyl-2-hydroxybutylsulfonyl)piperidine Melting point 7108-112°C Rf: 0.39C Chloroform: Methanol: Acetic acid,
16: 1: 1. v/v) 1st generation J Na-tertiary-butoxycarbonyl-N(Z-methyl-
N1111-tosyl-L-histidine (4,216g
) and (3S)-N,N-dimethyl-3-amino-4
-Cyclohexyl-2-hydroxybutanesulfonamide (2,310 g) in dry methylene chloride (1 G Off
After cooling the middle compound to 0°C, the pH was adjusted to 8.0 with N-methylmorpholine (0.64ml)! ltL, then N-ethyl-N″-(3-dimethylaminopropyl)
Add carbodiimide hydrochloride (1,909 g). The mixture is stirred at the same temperature for 16 hours. The solvent is evaporated and the residue is dissolved in ethyl acetate (300-). The solution was mixed with 10% citric acid aqueous solution (300ml) and water (300ml).
), sodium hydrogen carbonate aqueous solution (300 relatives), water (30
0fflQ ) and brine (30011) ), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent:
(2R,3S)-3-(N
a-tertiary m--1/toxycarbonyl-N-methyl-
Nlrl'-tosyl-L-histidyl)amino-4-cyclohexyl-2-hydroxy-1-(N,N-dimethylaminosulfonyl)butane (2.41 g) is obtained as an oil.

Rf: 0.61 (chloroform:methanol.

9:1, v/v) Made by "L" The following compound is obtained in the same manner as in Production Example 5.

(1) (2R,3S)-3-(Na-Ei-/toxycarbonyl-N-methyl-NII'1-α-silyl-L-histidyl)amino-4-cyclohexyl-
2-hydroxy-1-isopro and ruaminosulfonylbutane Rf: 0.45 (chloroform:methanol.

9: 11V/V) (2) (2R,3S)-3-(Na-tertiary 4N-/toxycarbonyl-Na-methyl-N1111-tosyl-L
-Histidyl)amino-4-cyclohexyl-2-hydroxy-1-piperidinosulfonylbutane Rf: 0.66 (chloroform: methanol: acetic acid + 1
6: 1: 1, v/v) Rat JJLヱ(2R,3S)-3-(N-tertiary-butoxycarbonyl-N-methyl-N1°-tosyl-L-histidyl)amino-4-cyclo xyl-2-hydroxy-1
-(N,N-dimethylaminosulfonyl)butane (48
A solution of 0.2 mg) of trifluoroacetic acid (511111) was stirred at -5°C for 4 hours. The mixture is concentrated and the residue is dissolved in ethyl acetate (301111"). The solution is dissolved in saturated aqueous sodium bicarbonate (30ml!), water (30ml)
Q) and saline solution (301all),
After drying with magnesium sulfate, it was concentrated under reduced pressure to obtain (2R13
S)-3-(N-methyl-Nin-tosyl-L-histidyl)amino-4-cyclohexyl-2-hydroxy-1-(N,N-dimethylaminosulfonyl)butane (407,0 mg) as an amorphous powder. obtain.

Rf: 0.18 (chloroform:methanol.

9:1, v/v) Jui! Mutual The following compound is obtained in the same manner as in Production Example 7.

(1) (2R,3S)-3-(Na-yLf-Nll
11-Tosyl-histidyl)amino-4-cyclohexyl-2-hydroxy-1-isopro and ruaminosulfonylbutane Rf: 0.3 g (chloroform:methanol.

9: 1, v/v) (2) (2R, 3S)-3-(Na-MefNi''
'-Tosyl-histidyl)amino-4-cyclohexyl-2-hydroxy-1-piperidinosulfonylbutane Rf: 0.19 (chloroform:methanol.

io: 1r v/v) 11 counterfeit (1) 2-(N-methylamino)ethanol (2
, 253g) of dry tetrahydrofuran (45IQ)
The l solution was cooled to 0°C, and triethylamine (4,1
81111) and morpholinocarbonyl chloride (4,4
87g) of dry tetrahydrofuran (20ml)
Add solution. After stirring the mixture at 0° C. for 1.5 hours, the cooling bath is removed and the mixture is stirred for a further 24 hours at room temperature. Insoluble matters are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-1% methanol).
chloroform) to obtain 2-(N-morpholinocarbonyl-mino)ethanol (6.150 g) as an oil.

Rf: 0.44C chloroform:methanol.

9:1, v/v) (2) 2-(N-morpholinocarbonyl-N
-methylamino)ethanol (345.7mg)
Trichloromethyl chloroformate (0.1341111) in dry tetrahydrofuran (11111) solution
Add. Stir the mixture for 1 hour at room temperature. o” the solution
ct: Cool and add L-phenylalanine benzyl ester p-toluenesulfonate (855 mg) and triethylamine (0.27911!') (7) dry tetrahydrofuran (1 relative) solution after cooling to 0°C. The mixture is kept at pH 7 by adding triethylamine (0,307119) and stirred for 30 minutes at 0°C. The solvent is evaporated and the residue is dissolved in ethyl acetate (20111). The solution was mixed with 0.5M hydrochloric acid (2011LQ) and water (201Q
), saturated aqueous sodium hydrogen carbonate solution (20111'),
Wash sequentially with water (20K) and brine (201Q), dry over magnesium sulfate, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (l solvent: chloroform) to give N-[2-(N-morpholinocarbonyl-N-methylamino)ethoxycarbonyl]-L
-Phenylalanine benzyl ester (422mg)
Obtained as an oil.

Rf:Q, 64C chloroform:methanol.

9:1, v/v)
1) Add triethylamine (1,52 g) and trichloromethyl chloroformate (0,921 nll) to the solution, stir the mixture for 30 minutes, and concentrate the solution under reduced pressure.
), and to this, N-isobutyryl N,N'-
Dimethylethylenediamine trifluoroacetate (4,0
8 g) and triethylamine (1.52 g) in anhydrous tetrahydrofuran (40+111) at 0°C. The mixture is stirred at the same temperature for 3 hours. The solvent was distilled off, the residue was dissolved in ethyl acetate (150111'), and the solution was washed successively with 5% hydrochloric acid, a saturated aqueous sodium hydroxide solution, and water, dried over magnesium sulfate, and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate, 1:2, v/v) to give N-[N-(2-(N-isobutyryl-N-methylamine)ethyl)-N -methylaminocarbonyl]-L
-Phenylalanine benzyl ester (2.29 g) is obtained as an oil.

Rf: 0.48 (ethyl acetate) Mouse zti The following compound is obtained in the same manner as in Production Example 10.

(1) L-phenylalanine benzyl ester p-
Toluenesulfonate (3,42g), 4-[3-(
N-[N-(2-morpholinocarbonyl: carbonyl]-L-phenylalanine benzyl ester (
1.10 g).

Rf: 0.30 (ethyl acetate) (2) L-phenylalanine benzyl ester p-
Toluenesulfonate (7,09 g), N-morpholinocarbonyl-N,N'-dimethylethylenediamine trifluoroacetate (5,00 g) and trichloromethyl chloroformate (0,92111) to N-[N-(2
-(N-morpholinocarbonyl-N-methylamino)ethyl)-N-methylaminocarbonyl-phenylalanine benzyl ester (4.00 g) is obtained.

Rf: 0.56 (ethyl acetate) 11 Takudan N-[N-(2-(N-inbutyryl-N-methylamino)ethyl iN-methylaminocarbonyl]-L-phenylalanine benzyl ester (2.07 g) in methanol (20ai) solution to 10% palladium-carbon (2
00mg) in a hydrogen gas atmosphere of 3 atm over 2 hours. The solution was filtered and concentrated under reduced pressure with N
-[N-(2-(N-inbutyryl-N-methylamino)ethyl)-N-methylaminocarbonyl]-L-phenylalanine (1.58 g) is obtained as an amorphous powder.

Rf: 0.14 (10% methanol-chloroform)
11 The following compound was obtained in the same manner as in Goudan Production Example 12.

(1) N-[N-(2-morpholinocarponylethyl)-N-methylaminocarbonyl]-L-phenylalanine Rf: 0.16 (10% methanol-chloroform>
(2) N1N-(2-(N-morpholinocarbonyl-N-methylamine)ethyl)-N-mesolaminocarbonylalanine Rf: 0.43 (chloroform:methanol:acetic acid,
s: 1: 1 1 v/v) (3) N-[2-
(N-morpholinocarbonyl)-L-phenylalanine Rf: 0.36 (chloroform:methanol:acetic acid.1
6:1:1, v/v) 11 Todoroki'' The following compound is obtained in the same manner as in Production Example 1-(5).

(1) 4-methylsulfonylmorpholine (1.87
g), 4-((3S)-3-tritylamino-4-cyclohexyl-2-hydroxy butylsulfonyl)morpholine (2,69 g) is obtained.

Rf: 0.28 (n-hexane:ethyl acetate.

2:1, v/v) (2) N-isopentyl methanesulfonamide (t
t3g), N-trityl-L-cyclohexylalaninal (7.8Lg) and n-butyllithium (28.
75 relative) to obtain (3S)-N-isobenthyl-3-tritylamino-4-cyclohexyl-2-hydroxybutanesulfonamide (3.79 g).

Rf: 0.86 (chloroform:methanol 2s:
1 1V/V) (3) N-isobutyl methanesulfonamide (5.68
g), N-trityl-L-cyclohexylalaninal (11.94 g) and n-butyllithium (4
(3.2 ml) to obtain (38)-N-inbutyl-3-tritylamino-4-cyclohexyl-2-hydroxybutanesulfonamide (5.31 g).

Rf: 0.54 (n-hexane: ethyl acetate.

2:1, v/v) (4) N-butyl-N-methylmethanesulfonamide (
4,03g), N-trityl-L-cyclohexylalaninal (7.75g) and n-butyllithium (
13,401Q) to (3S)-N-butyl-N-methyl-3-tritylamino-4-cyclohexyl-2-
Hydroxybutanesulfonamide (7.16 g) is obtained.

Rf: 0.54 (n-hexane: ethyl acetate.

2:1, v/v) (5) N-(4-phenylbutyl)methanesulfonamide (3.09 g), N-)lithyl monocyclohexylalaninal (4.50 g) and n-butyllithium (15. 56dl) to (3S)-N-(4
-phenylbutyl)-3-tritylamino-4-cyclohexyl-2-hydroxybutanesulfonamide (3.
87 g) is obtained.

Rf: 0.88 (chloroform:methanol.

9:1 1V/V) (6) N-(2-morpholinoethyl)methanesulfonamide (2.69 g), N-trityl-cyclohexylalaninal (4.28 g) and n-butyllithium ( (3S)-N-(2-morpholinoethyl)-3-tritylamino-4-cyclohexyl-2-hydroxybutanesulfonamide (3.53 g
).

Rf: 0.35 (n-hexane: ethyl acetate.

1: 1 1 v/v) 11λ length The following compound is obtained in the same manner as in Production Example 3.

(1) (33)-N-Butyl-N-methyl-3-amino-4-cyclohexyl-2-hydroxybutanesulfonamide melting point. 6 low 67, 5℃ HfHO. 32 (chloroform: methanol.

9:1, v/v) (2) 4-((3S)-3-amino-4-cyclohexyl-2-hydroxybutylsulfonyl)morpholine Melting point: 88-90°C Rf: 0.13 (chloroform:methanol .

9:1, v/v) (3) (3S)-N-isopendel-3-amino-
4-Cyclohexyl-2-hydroxybutanesulfonamide Melting point: 117.5-119.5°C Rf: 0.15 (chloroform; methanol.

9:1, v/v) (4)(3S)-N-Inbutyl-3-amino-4-cyclohexyl-2-hydroxybutanesulfonamide Melting point: 119.5-121.5°C Rf2 0.27 (Chloroform: Methanol-J.

9:1, v/v) (5) (3S)-N-(4-phenylbutyl)-3
-Amino-4-cyclohexyl-2-hydroxybutanesulfonamide Melting point: 104-105°C Rf: 0.17 (chloroform:methanol.

9: 11 v/v) (6) (3S)-N-(2-morpholinoethyl)-
3-Amino-4-cyclohexyl-2-hydroxybutanesulfonamide Rf: 0.33 (chloroform: methanol, acetic acid, 1
0:1:1. v/v) kJ''1■ The following compound is obtained in the same manner as in Production Example 5.

(1) (2R,3S)-3-(Na-gEi-/Toxycarbonyl-Na-methyl-N tl''-tosyl-L-
histidyl)amino-4-cyclohexyl-2-hydroxy-1-morpholinosulfonylbutane Rf: 0.57 (chloroform:methanol.

9: 11V/V) (2) (2R,3S)-3-(Na,J tertiary-butoxycarbonyl-N-methyl-Nl11-tosyl-L-hisdecyl)amino-4-cyclohexyl-2-hydroxy-1 -isobutylaminesulfonylbutane Rf: 0.68C chloroform: methanol.

9:1, v/v) (3)(33)-3-(Na-gEi-but+dicarbonyl-Na-methyl-Ni-tagtosyl-L-histidyl)
Amino-4-cyclohexyl-2-hydroxy-1-isopentylaminosulfonylbutane Rf: 0.66 (chloroform:methanol.

9 two 1. v/v) (4) (2R,3S)-3-(N-tertiary-butoxycarbonyl-N-methyl-N1″l-tosyl-L-
histidyl)amino-4-cyclohexyl-2-hydroxy-1-(N-butyl-N-mesolaminosulfonyl)butane Rf: 0.66 (chloroform:methanol.

9:1, v/v) (5) (2R,3S)-3-[Na-tertiary m-/α-toxycarbonyl-N methyl-3-(4-thiazolyl)-L-acyelcoamino-4 -cyclohexyl-2
-Hydroxy-1-isopentylaminosulfonylbutane Rf2O,60 (chloroform: methanol 9: t
+ v/v) (6) (3S)-3-(Na-E class-/t+dicarbonyl-Na-methyl-N 111-tosyl-L-histidyl)amino-4-cyclohexyl-2-hydroxy-1- (4-phenylbutylaminosulfonyl)butane Rf: 0.52C chloroform: methanol.

9: 1 1V/V) (7) (3S)-3-(Na-gE&l-p)*dicarbonyl-N-methyl-N i″1++ tosyl α 1L-hisdecyl)amino-4-cyclohexyl-2-
Hydroxy-1-(2-morpholinoetheraminosulfonyl)butane Rf: 0.67 (chloroform:methanol.

1o: 1 * v/v) kesa jLL get The following compound is obtained in the same manner as in Production Example 7.

(1) (2R,3S)-3-(N-methyl-N i
m-tosyl-histedyl)amino-4-cyclohexyl-2-hydroxy-1-morpholinosulfonylbutane Rf: 0.41 (chloroform:methanol.

9:1, v/v) (2) (3S)-3-(Na-1f-Nim-tosyl-L-hisdecyl)amino-4-cyclohexyl-2
-Hydroxy-1-isopentylaminosulfonylbutane Rf: 0.50 (chloroform:methanol.

9:1. v/v) (3) (2R,3S)-3-(Na-Mel N1ff
1-Tosyl-L-histidyl)amino-4-cyclohexyl-2-hydroxy-1-isobutylaminosulfonylbutane Rf: 0.3 g (chloroform:methanol.

9:1, v/v) (4)(2R,3S)-3-(Na-methyl-N11-
Tosyl-histidyl)amino-4-cyclohexyl-2-hydroxy-1-(N-butyl-N-methylaminosulfonyl)butane Rf: 0.48 (chloroform:methanol.

9: 11V/V) (5) (2R, 3S) -3-[Na-1f Roux 3-(
4-thiazolyl)-L-acyelcoamino-4-cyclohexyl-2-hydroxy-1-isopro and ruaminosulfonylbutane Rf: 0.37 (chloroform:methanol.

9: 11V/V) (6) (2S, 3S)-3-(N"-Mef N1"'
-tosyl-L-histidyl)amino-4-cyclohexyl-2-hydroxy-1-(N,N-dimethylaminosulfonyl)butane Rf:o,22c Chloroform:methanol.

9:1, v/v) (7) (38)-3-(Na-Mef-N"tosyl-histidyl)amino-4-cyclohexyl-2-
Hydroxy-1-(4-phenylbutylaminesulfonyl)butane Rf: 0.34 (chloroform:methanol.

9:1, v/v) (8) (3S)-3-(Na-methyl-N"tosyl-L-histidyl)amino-4-cyclohexyl-2-
Hydroxy-1-(2-morpholinoetheraminosulfonyl)butane Rf: 0.30 (chloroform:methanol.

lO:1. v/v) 11λ length (1) Methyl 3-morpholinocarbonylpropionate (12,59 g) from 3-methoxycarbonylpropylene chloride (9,03 g), morpholine (5,75 g) and triethylamine (9,2111) get.

Rf: 0.37 (chloroform:methanol.

9: 1 1V/V) (2) Methyl 3-morpholinocarbonylpropionate (12,52K) in methanol (160111+
) solution and IN sodium hydroxide aqueous solution (93.3ml)
The mixture is stirred at room temperature for 1 hour. Methanol is distilled off, and the remaining alkaline aqueous solution is made acidic with 6N hydrochloric acid and extracted with ethyl acetate (120 Tsuru x 3). The extracts are combined, washed with brine (3001d), dried over magnesium sulfate, and concentrated under reduced pressure to give 3-morpholinocarbonylpropionic acid (9.27 g) as an oil.

Rf: 0.62 (chloroform:methanol.

9:1, v/v) 11λ length<1) A solution of 4-(N-tertiary-butoxycarbonylamino)butyric acid (20.32 g) in dry N,N-dimethylformamide (200111Q) with sodium hydride (mineral oil) A 60% dispersion in 16.oK ) and methyl iodide (49,81119) are added at 0° C. under a nitrogen atmosphere and the mixture is stirred at room temperature for 16 hours.

The solvent is evaporated and the residue is partitioned between ethyl acetate (5001M) and water (500ml). organic layer to 0.5
N hydrochloric acid (500!all), water (500ml!),
Saturated sodium hydrogen oxide aqueous solution (500ml), water (500III11) and saline <5001111
), dried over magnesium sulfate, and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (eluent: 8-67% ethyl acetate-n-hexane),
Methyl 4-(N-tertiary-butoxycarbonyl-N-methylamino)butyrate (16,6 g) is obtained as an oil.

Rf: 0.55 (n-hexane: ethyl acetate.

2: 11V/V) (2) 4- (N-tertiary-butoxycarbonyl-
A solution of ethyl (N-methylamine)butyrate (7,755 g) in trifluoroacetic acid (78+1112) is stirred at room temperature for 30 minutes. The solvent was distilled off and the residue was dissolved in chloroform933
% methanol (500111X3) and saturated sodium bicarbonate solution (6001Q). The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in chloroform (500+1111). The solution was dried over magnesium sulfate and concentrated under reduced pressure to give 4-(N-
Methyl methylamino)butyrate (1.98 g) is obtained as an oil.

Rf: 0.18 (chloroform:methanol.

9:1, v/v) (3) Methyl 4-(N-morpholinocarbonyl-N-methylamine) acetate is obtained in the same manner as in Production Example 9-(1).

Rf: 0.48 (chloroform:methanol.

9:1, v/v) (4) 4-(N-morpholinocarbonyl-butyric acid is obtained in the same manner as in Production Example 1g-(2).

Rf: 0.16 (chloroform:methanol.

9:1, v/v) Ki Wataru N-[N-(2-(N-morpholinocarbonyl-N-methylamino)ethyl)-N-methylaminocarbonyl]
-L-phenylalanine (140 mg) and (2S
．． 3S)-2-m-(Na-methyl-N-tosyl-L-histidyl)amino-1-cyclohexyl-3-hydroxy-6-ethylhebutane (190 mg) in dry methylene chloride (201
Q) Cool the solution to 0°C and add N-ethyl-N'-
Add (3-diethylaminopropyl)carbodiimide hydrochloride (82 mg). The fli mixture was stirred at the same temperature for 2 hours and then at 5°C overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate (20111''). The solution was washed successively with 5% hydrochloric acid, 1M sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under reduced pressure to give (20111''). S
．． 3S)-2-α- [N [N-[N-methyl-N-(2-(N-morpholinocarbonyl-N-methylamino)ethyl)aminocarbonyl]-L-phenylalanyl]-Na-methyl -N111Tosyl-L-histidylcoamino-1-cyclohexyl-3-hydroxy-6-methylhebutane is obtained. The residue is N. N-diethylformamide (201d
), and to this solution was added pyridine hydrochloride (401 mg
) at room temperature. Stir the mixture at the same temperature for 2 hours. The solvent was distilled off and the residue was dissolved in ethyl acetate (20%). The solution is washed successively with brine, 1M sodium bicarbonate solution, and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (chloroform:methanol, 9:1, v/v) (2S.

3 S) - 2 - C Na- [ N - [
N-ylf-N-(2-(N-morpholinocarbonyl-N-methylamino)ethyl)aminocarbonyl-L
-phenylalanyl]-Na-methyl-L-histidylcoamino-1-cyclohexyl-3-hydroxy-6-
Methylhebutane (203a+g) is obtained as an amorphous powder.

Melting point: 89-92°C Rf: 0.51 (10% methanol-chloroform)
1) N-[N-(2-(N-isobutyryl-N-methylamine)ethyl)-N-methylaminocarbonyl]-L-phenylalanine (230.6 mg) and (2R,3S)
-3-(N-methyl-N 1ffl)-silu L-
A solution of dry methylene chloride (10-) of histidyl)amino-4-cyclohexyl-2-hydroxy-1-(N,N-dimethylaminosulfonyl)butane (350 mg) was cooled to 0°C and added with N- Ethyl-N'-(3
-dimethylaminopropyl)carbodiimide hydrochloride (1
38 mg). The W1 compound is stirred at 5° C. for 2 hours. The solvent is evaporated and the residue is dissolved in ethyl acetate (301d).

The solution was washed sequentially with 5% hydrochloric acid, 1 Mll, M sodium hydrogen solution, and water, dried over magnesium sulfate, and concentrated under reduced pressure to give (2R,3S)-3α--[N [N-[N-(2 -(N-inbutyryl-
N-methylamine)ethyl)-N-methylaminocarbonyl]-L-phenylalanylcoN(2-methyl-N
im-tosyl-L-histidylcoamino-4-cyclohexyl-2-hydroxy-1-(N,N-dimethylaminosulfonyl)butane is obtained. The residue is dissolved in N,N-dimethylformamide (1ornQ) and pyridine hydrochloride (693 mg) is added to this solution at room temperature. The mixture is stirred at the same temperature for 2 hours. The solvent was distilled off, the residue was dissolved in ethyl acetate (30 mi), and the solution was washed successively with IM* sodium hydrogen oxide aqueous solution and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (2.5% methanol-chloroform) (2R.

α-3S)-3-[N [N-[N-(2-(N-isobutyryl-N-methylamine)ethyl)-N-methylaminocarbonyl]-L-phenylalanyl]-Na-methyl-I , -histidylcoamino-4-cyclohexyl-2-hydroxy-1-(N,N-dimethylaminosulfonyl)butane (427eag) is obtained.

Rf: 0.39 (10% methanol-chloroform) IL Wataru The following compound is obtained in the same manner as in Example 1 or 2.

α- (1) (2R,3S)-3-[N [N-(N
-(2-morpholinocarbonylethyl)-N-mesolaminocarbonyl)-Lyenylalanyl]-NC1-
Methyl-L-histidylcoamino-4-cyclohexyl-2-hydroxy-1-(N,N-dimethylaminosulfonyl)butane Rf: 0.44 (10% methanol-chloroform>α- (2) (2R ,3S)-3-[N [N-[N-methyl-N-(2-(N-morpholinocarbonyl-N-methylamino)ethyl)aminocarbonyl]-L-phenylalanyl]-Na-methyl-L -Histidylcoamino-4-cyclohexyl-2-hydroxy-1-isopro and ruaminosulfonylbutane Melting point, 89-95°C Rf: 0.26 (chloroform:methanol.

9: 1, v/v) α- (3) (2R,3S)-3-[N [N-(2-(
N-morpholinocarbonyl-N-methylamino)ethoxycarbonyl)-L-phenylalanyl]-Na-methyl-L-histidylcoamino-4-cyclohexyl-
2-Hydroxy-1-isopropylaminesulfonylbutane Melting point: 89-98°C Rf: 0.26 (chloroform:methanol.

9 : 1, v/v) α- (4) (2R,3S)-3-[N [N-[N
-MemethyN-(2-(N-morpholinocarbonyl-carbonyl)-L-phenylalanyl]-Na-methyl-L-histidylcoamino-4-cyclohexyl-2-
Hydroxy-1-(N.N-dimethylaminosulfonyl)butane Melting point: 103-107°C Rf: 0.30 (chloroform:methanol.

9:1, v/v) α-(5)(2R,33)-3-[N[N-[N-methyl-N-(2-(N-morpholinocarbonyl-carbonyl)]-L-phenylalanyl ]-Na-methyl-L-histidylcoamino-4cyclohexyl-2-hydroxy-1-piperidinosulfonylbutane Melting point: 89-93°C Rf: 0.32 (chloroform:methanol.

9 : 1, v/v) α- (6) (2R.3S)-3-[N [N-[N
-Methyl-N-(2-(N-morpholinocarbonyl-N
-Mesolamino)ethyl)aminocarbonyl]-L-phenylalanyl]-Na-methyl-3-(4-thiazolyl)-L-alanyl]amino-4-cyclohexyl-2
-Hydroxy-1-isopropylaminosulfonylbutane Melting point: 74-80°C Rf: 0.46 (chloroform:methanol.

9:1, v/v) α- <7) (2S.3S)-3-[N [(S)-2-
[N-(2-(N-inbutyryl-N-methylamino)ethyl)-N-methylaminecarbonyloxy]-3-phenylpropionyl]-N-methyl-L
-Histidylcoamino-4-cyclohexyl-2-hydroxy-1-CN. N-dimethylaminosulfonyl)butane Melting point: 79-86°C Rf: 0.34 (chloroform:methanol.

9 : 1, v/v) α- (s) (zR.ss)-s-[i [(S)-2-
(N-methyl-N-(2-morpholinocarbonylethyl)aminocarbonyloxy)-3-phenylpropionyl]-Nα-methyl-L-histidylcoamino-4-cyclohexyl-2-hydroxy-1-(N,N -dimethylaminosulfonyl)butane Melting point: 73-79°C Rf: 0.31 (chloroform:methanol.

9: 1, v/v) α- (9) (2R.3S)-3-[N [(S)-2-
[N-(2-(N-inbutyryl-N-methylamine)
ethyl)-N-methylaminocarbonyloxy]-3-
7enylpropionyl]-NCl-methyl-L-histidylcoamino-4-cyclohexyl-2-hydroxy-1-morpholinosulfonylbutane Melting point: 74-80°C Rf: 0.32C Chloroform:methanol.

9:1, v/v) α-(10)(2R,3S)-3-[N[(S)-2
-[N-(2-(N-inbutyryl-N-methylamine)ethyl)-N-methylaminocarbonyloxy]-3
-phenylpropionyl-Na-mesol-monohedyl]amino-4-cyclohexyl-2-hydroxy-
1-Inpropylaminesulfonylbutane Melting point: 85
-91°C Rf: 0.34 (chloroform:methanol.

9 : 1, v/v) α- (11) (2R,3S)-3-[N [(S)-2
-CN-(2-CN-morpholinocarbonyl-N-methylamine)ethyl)-N-methylaminocarbonyloxy]-3-phenylzoα-ropyridyl]-N methyl-L-histidylcoamino-4- cyclohexyl-2-hydroxy-1-(N
, N-dimethylaminosulfonyl)butane Melting point: 74-81°C Rf: 0.31 (chloroform:methanol.

9:1, v/v) (12)(2R.3S)-3-[N-[(S)
-2-[N-(2-[N-morpholinocarbonyl-N-
methylamino)ether)-N-methylaminocarbonyloxy]-3-phenylbropionyl]-N-methyl-histidylcoamino-4-cyclohexyl-2-
Hydroxy-1-isopropylaminosulfonylbutane Melting point: 86-92°C Rf: 0.30 (chloroform:methanol.

9: t + v/v) <13>(2R,3S)-3-[Na-[(S)-2-
[N-(2-(N-inbutyryl-N-mesolamino)
ethyl)-N-methylaminocarbonyloxy]-3-
phenylpropionyl]-N Ci-methyl-L-hisdedylcoamino-4-cyclohexyl-2-hydroxy-1-(N-butyl-N-methylaminosulfonyl)butane Melting point: 63-68.5°C Rf: 0.32 (chloroform:methanol.

9,1,V/V) (14)(2R,35)-3-[Na-[(S)-2-
[N-(2-(N-inbutyryl-N-methylamine)
Ethyl 1-N-methylaminocarbonyloxy]-3-
phenylpropionyl] + N C1-Methyl-L-histidylcoamino-4-cyclohexyl-2-hydroxy-1-isopentylaminosulfonylbutane Melting point:
83-90°C Rf70.35C Chloroform:methanol.

9:1, v/v) α- (15) (2R,3S)-3-[N [(S)-2
-[N-(2-(N-isobutyryl-N-methylamino)ethyl)-N-methylaminocarbonyloxy]-3
-phenylpropionyl] + N (X-methyl-
Histidylcoamino-4-cyclohexyl-2-hydroxy-1-isobutylaminosulfonylbutane Melting point:
90-97°C Rf: 0.28C Chloroform: Methanol.

9:1, v/v) (16)(2R,aS)-3-[Na-[N-[N-mesol-N-(2-(N-morpholinocarbonyl-N-methylamine)ethyl)aminocarbonyl] -L-phenylalanyl]-Na-methyl-L-histidylcoamino-4-cyclohexyl-2-hydroxy-1-isobutylaminosulfonylbutane Melting point: 93-100°C Rf: 0.20 (chloroform: methanol .

9:1, v/v) α- (17)(2R,3S)-3-[N [N-[N-
(2-(N-inbutyryl-N-methylamine)ethyl)-N-methylaminocarbonyl]-L-phenylalanyl]-N(Z-methyl-histidylcoamino-4
-Cyclohexyl-2-hydroxy-1-(N-butyl-N-methylaminosulfonyl)butane Melting point: 64-
70.5°C Rf: 0131 (/F Fluororum: Methanol.

9:1, v/v) α- (18) (2R,3S)-3-IN [(S)-2
-[N-(5-(N-morpholinocarbonyl-laminocarbonyloxy]-3-phenylpropionyl]-N
-Methyl-L-histidylcoamino-4-cyclohexyl-2-hydroxy-1-(N.N-dimethylaminosulfonyl)butane Melting point: 67-70°C Rf: 0.32 (chloroform:methanol.

9: 1, v/v) α- (19) (2R.3S)-3-[N [(S)-2
-[: N- (2-(N-morpholinocarbonyl-
aminecarbonyloxy]-3-phenylpropionyl]-N-methyl-L-histidylcoamino-4-cyclohexyl-2-hydroxy-1-piperidinosulfonylbutane Melting point: 70-76°C Rf: 0.21 (chloroform :methanol.

10: 1, v/v) α-(20)(2R,3S)-3-[N[(S)-
2-[N-(2-(N-inbutyryl-N-methylamine)ethyl)-N-methylaminocarbonyloxy]-
3-phenylpropionyl]-Na-methyl-L-histidylcoamino-4-cyclohexyl-2-hydroxy-1-piperidinosulfonylbutane Melting point: 75-82°C Rf: 0.25 (chloroform:methanol.

10: 1, v/v) α-(21)(2R,3S)-3-[N[(R)-2
-morpholino-J levonylmethyl-3-(1-naphthyl)propionyl]-N (E-methyl-L-hisdedylcoamino-4-cyclohexyl-2-hydroxy-1-
(N,N-dimethylaminosulfonyl)butane Melting point: 106-110°C Rf: 0.39 (chloroform:methanol.

9: 11V/V) α − (22) (2S, 3S) −2−[N [N−(2
-(N-morpholinocarbonyl-N-methylamine)ethoxycarbonyl)-L-phenylalanyl]-N
-Mesol-L-histidyl]amino-1-cyclohexyl-3-hydroxy-6-methylhebutane Melting point: 78-85°C Rf: 0.35 (chloroform:methanol.

9: 11 V/V) (23)(2R,3S)-3-[Na-[N-(2-(
N-morpholinocarbonyl-N-methylamino)ethoxycarbonyl)-L-phenylalanyl]-N-methyl-L-histidylcoamino-4-cyclohexyl-
2-hydroxy-1-isopro and ruaminosulfonylbutane Melting point: 66-72°C Rf: 0.45 (chloroform:methanol.

9 : 1, v/v) α- (24)(3S)-3-[N [(S)-2-[N
-(2-(N-isobutyryl-N-methylamino)ethyl)-N-methylaminocarbonyloxy]-3-phenylpropionyl]-Na-methyl-L-hisdedylcoamino-4-cyclohexyl-2-hydroxy- 1-(
4-phenylbutylaminosulfonyl)butane Melting point: 78.5-85.5°C Rf: 0.33 (chloroform:methanol.

9: 11V/V) α- (25)(38)-3-[N [(S)-2-[N
-(2-(N-morpholinocarbonyl-N-mesolamino)ethyl)-N-methylaminocarbonyloxy-3-phenylpropylene] -N (!-Methyl-L
-hisdecyl]amino-4-cyclohexyl-2-hydroxy-1-(2-morpholinoethylaminosulfonyl)butane Melting point: 96-105°C Rf: 0.2G (chloroform:methanol.

ro: 1, V/V) dog'11A (1) (S)-2-[N-methyl-N-(2-(N
-isobutyryl-N-methylamine)ethyl)aminocarbonyloxy]-3-phenylpropionic acid (235
, 3 mg) in dry methylene chloride (3°5-).
Cool to °C and add oxalyl chloride (64,44) and N,N-dimethylformamide (3 drops). After stirring the mixture for 30 minutes, it was allowed to cool to room temperature, and then
Stir for 0 minutes. This solution (2R93S)-3-(N
-Methyl-N”-t:Flu-L-histidyl)amino-4-cyclohexyl-2-hydroxy-1-(N,
N-dimethylaminosulfonyl)butane (392mg)
and N-methylmorpholine (162,44) in dry methylene chloride (6aQ) at 0°C. The mixture is stirred at the same temperature for 20 minutes. The solvent was distilled off, and the residue was mixed with ethyl acetate (40111) and 10% citric acid aqueous solution (40ml).
to be distributed between. Water (4011Q), saturated sodium bicarbonate aqueous solution (40111Q), water (4011Q),
omu ) and brine (4011+), dried over magnesium sulfate, and concentrated under reduced pressure to obtain (2R,
3S)-3-α- [N [(S)-2-[N-methyl-N-(2-(
N-isobutyryl-N-methylamine)ethyl)aminocarbonyloxy]-3-phenylpropionyl]-N
-Methyl-N1111-tosyl-L-histidylcoamino-4-cyclohexyl-2-hydroxy-1-(
N,N-dimethylaminosulfonyl)butane (561,
8+ag) is obtained as an oil.

Rf: 0.48 (chloroform:methanol.

9:1, v/v) (3) Pyridine hydrochloride (697.4 mg) was mixed with (2
R13S)-3-[Na-[(S)-2-[N-methyl-N-(2-(N-inbutyryl-N-methylamino)
ethyl)aminocarbonyloxy]-3-phenylpropionyl]-N(Z-methyl-Nll11-tosyl-L
-Histidylcoamino-4-cyclohexyl-2-hydroxy'/1-(N,N-'; mesolaminosulfonyl)butane (552,9a+g) in dry N,N-dimethylformamide (5,5mA) Add to solution at room temperature.

After stirring the mixture for 2.5 hours, the solvent is distilled off. The residue is partitioned between ethyl acetate (301119) and brine (30 proof). The organic layer was dissolved in saturated aqueous sodium hydrogen carbonate solution (3
011) and brine (30 m ), dried over magnesium sulfate, and concentrated under reduced pressure. Thin layer chromatography (chloroform:methanol, 8:1, v/v
) to give (2R,3S)-3-[Na-[(S
)-2-[N-Mesol-N-(2-(N-inbutyryl-N-methylamino)ethyl)aminecarbonyloxynylpropionyl]-N-methyl-histidylcoamino-4-cyclohexyl-2 -Hydroxy-1
- (N.N-dimethylaminosulfonyl)butane (
429 mg) as an amorphous powder.

Melting point: 79-86℃ Rf: 0.32C chloroform:methanol.

9: 1, v/v) Tu'L'- (1) In the same manner as in Example 1, (2R.3S)-3α- -[N (N-tertiary-butoxycarbonyl-3-
(1-naphthyl)-L-alanyl)-N methyl-N
Illll-tosyl-L-hisdeα-zircoamino-4-cycloto, xyl-2-hydroxy-1-isopropylaminesulfonylbutane is obtained.

Rf: 0.59 (chloroform; methanol.

9:1, v/v) (2) In the same manner as Production Example 7 (2 R.3 S)-
3α--[N (3-(1-naphthyl)-L-acyel)
-N CI-methyl-N111-tosyl-L-histidylcoamino-4-cyclohexyl-2-hydroxy-
1-isopropylaminosulfonylbutane (fold.

Rf: 0.42 (chloroform:methanol.

9: 1, v/v) (3) Same as Production Example 9-(2) (2R.

38)-3-[Na-[N-(2-(N-methyl-N-
Morpholinocarbonylamino)ethoxycarbonyl)-
3-(1-naphthyl)4m- 1L-alanyl]- NCl-methyl-N tosyl-
L-hisdedylcoamino-4-cyclohexyl-2-hydroxy-1-isopropylaminosulfonylbutane is obtained.

Rf: 0.54 (chloroform:methanol.

9:1, v/v) 4) In the same manner as in Example 1, the tosyl group of the compound of Example 5-(3) was removed. (2R,3S)α--3-[N[N-(2-(N-methyl-N-morpholinocarbonylamino)ethoxycarbonyl)-3-
(1-naphthyl)-L-alanyl]-N-methyl-L
-Histidylcoamino-4-cyclohexyl-2-hydroxy-1-isopro and ruaminosulfonylbutane are obtained.

Melting point: 89-96℃ Rf: 0.28 (chloroform:methanol.

9: 1, v/v) and five turns J (1) In the same manner as in Example 1, (2R, 35)-3
-[N-(N-tertiary-butoxycarbonyl-butenylalanyl)-Na-methyl-N1r1'-tosyl-L-histidylcoamino-4-cyclohexyl-2
-Hydroxy-1-isopropylaminosulfonylbutane is obtained.

Rf: o, ezc chloroform: methanol.

9: I TV/V) (2) In the same manner as in Production Example 7, (2R,35)-3-(N
a-L-phenylalanyl-Na-methyl-N 1ff
i-Tosyl-L-histidyl)amino-4-cyclohexyl-2-hydroxy-1-isopropylaminosulfonylbutane is obtained.

Rf: 0.39 (chloroform:methanol.

9:1, v/v) (3> In the same manner as in Example 1, 3-morpholinocarbonylpropion H (39 mg), (2R.

3S) -3-(Na-L-)xNir-r=
4-Na-Mesol-N°-ton-L-Histidyl)
(2R,3S)- from amino-4-cyclohexyl-2-hydroxy-1-isopropylaminesulfonylbutane (130 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 mg)
3-α- [N (N-(3-morpholinocarbonylpropionyl)-L-phenylalanyl]-N -Mesol-N
im -tosyl-L-histidyl]amino-4-cyclohexyl-2-hydroxy-1
-isopropylaminesulfonylbutane (152,8m
g) is obtained.

Rf: 0.48 (chloroform:methanol.

9:1, v/v) (4) In the same manner as in Example 1, the tosyl group of the compound of Example 6-(3) was removed to form (2R,3S)α--3-[N[N- (3-morpholinocarbonylpropionyl)-L-phenylalanylco-Na-methyl-L-histidylcoamino-4-cyclohexyl-2-
Hydroxy-1-isopropylaminesulfonylbutane is obtained.

Melting point: 101-108℃ Rf: 0.48C chloroform:methanol.

4:1, V/V) ILL1 21) In the same manner as in Example 6-(3), 4-(N-
Morpholinocarbonyl-butyric acid (63 mg), (2R,3S)-3-
(Na-L-phenylalanyl-N-methyl-N
i″++ tosyl-L-histidyl)amino-4-cyclohexyl-2-hydroxy-1-isopropylaminesulfonylbutane (170 og) and 1-ethyl-
3-(3-dimethylaminopropyl)carbodiimide hydrochloride (52.5 mg) α- to (2R.3S)-3-[N [N-( 4-(
N-morpholinocarbonyl-N-methylamino)phthyryl)-L-phenylalanyl]-N-methyl-N1
11-Tosyl-L-hyalpha stidyl]amino-4-cyclohexyl-2-hydroxy-1-isopropylaminosulfonylbutane (22
9. 5 mg).

u: o. 50 (chloroform: methanol.

9: 1 1 V/V) (2) In the same manner as in Example 1, the tosyl group of the compound of Example 7-(1) was removed (2R.3S) α- -3-CN [N-( 4-(N-morpholinocarbonyl-N-methylamino)phthyryl)-L-phenylalanyl]-Nα-methyl-L-histidylcoamino-4
-Cyclohexyl-2-hydroxy-1-isopropylaminosulfonylbutane Melting point. 86-93°C Rf: 0.26 (chloroform:methanol.

9:1, v/v)

Claims (6)

[Claims] (1) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^2 means hydrogen or a lower alkyl group, R^4 means an aryl group, R^5 means an N-containing heterocyclic group, (i) R^1 is acyl and a group represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. a lower alkyl group substituted with a substituent selected from the group R^3
is the formula ▲ Numerical formula, chemical formula, table, etc. and R^9 together with adjacent nitrogen atoms form a heterocyclic group, A means a lower alkylene group), X^1 is a single bond, -O- or ▲ mathematical formula, chemical formula , tables, etc. ▼ (In the formula, R^1^
0 means hydrogen or a lower alkyl group), X^2 means -NH, -O- or -CH_2-, or (ii) R^1 is a heterocyclic group, R^3 is the formula ▲ Formula , chemical formulas, tables, etc. ▼ (In the formula, R^8, R^9 and A each have the same meaning as before), X^1 is a single bond, X^2 is -O- or -CH_2 - or (iii) R^1 is acyl and the formula ▲ has a mathematical formula, chemical formula, table, etc. ▼ (in the formula, R^6 and R^7 each have the same meaning as before)
a lower alkyl group substituted with a substituent selected from the group consisting of the groups represented by R^3 is a lower alkyl group,
^1 has ▲mathematical formulas, chemical formulas, tables, etc.▼(In the formula, R^
1^0 means the same as before), X^2 is -NH- or -C
H_2-, or (iv) R^1 is acyl and the formula ▲ has a mathematical formula, chemical formula, table, etc. ▼ (in the formula, R^6 and R^7 each have the same meaning as before)
a lower alkyl group substituted with a substituent selected from the group consisting of the groups represented by R^3 is a lower alkyl group,
^1 is -O-, X^2 is -NH-, -O- or -CH
_2-] Amino acid derivatives and salts thereof. (2) R^1 is acyl and a lower alkyl group substituted with a substituent selected from the group consisting of the formula ▲ Numerical formula, chemical formula, table, etc. ▼, R^3 is the formula ▲ Numerical formula, Chemical formula,
There are tables, etc. ▼ (In the formula, R^8 and R^9 each mean hydrogen or a lower alkyl group optionally substituted with a substituent selected from the group consisting of a heterocycle and an aryl, or R^8 and R^9 together with adjacent nitrogen atoms form a heterocyclic group, and A means a lower alkylene group)
A group represented by, X^1 is a single bond, -O- or ▲ formula,
There are chemical formulas, tables, etc. ▼, X^2 is -NH-, -O-
or -CH_2-. (3) R^1 is a heterocyclic group, R^3 is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^8 and R^9 are each hydrogen or a group consisting of a heterocycle and aryl. means a lower alkyl group optionally substituted with selected substituents, or R^8 and R^9 together with adjacent nitrogen atoms form a heterocyclic group, and A is a lower alkylene group. )
The compound according to claim 1, wherein in the group represented by , X^1 is a single bond, and X^2 is -O- or -CH_2-. (4) R^1 is acyl and a lower alkyl group substituted with a substituent selected from the group consisting of the formula ▲ Numerical formula, chemical formula, table, etc. ▼, R^3 is a lower alkyl group, X
^1 is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, X^2 is -
The compound according to claim 1, which is NH- or -CH_2-. (5) R^1 is acyl and a lower alkyl group substituted with a substituent selected from the group consisting of the formula ▲ Numerical formula, chemical formula, table, etc. ▼, R^3 is a lower alkyl group, X
^1 is -O-, X^2 is -NH-, -O- or -CH
The compound according to claim 1, which is _2-. (6) R^1 is morpholinocarbonyl and formula ▲ formula,
There are chemical formulas, tables, etc.▼ (In the formula, R^6 means a morpholinocarbonyl group or lower alkanoyl group, and R^7 means hydrogen or a lower alkyl group.) A substituent selected from the group consisting of the groups shown below. 6. The compound according to claim 2, 4 or 5, which is a substituted lower alkyl group.