JPH07116118B2 - Peptide analog having renin inhibitory activity - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Object] The present invention relates to a novel peptide analogue having excellent renin inhibitory activity and having good water solubility, oral absorbability and bioavailability, and a salt thereof.

<Industrial field of application> The novel peptide analogs and salts thereof of the present invention have excellent renin inhibitory activity, and are good in water solubility, oral absorption and bioavailability, -Useful as a diagnostic and therapeutic agent for hypertension based on angiotensin system, especially for oral use.

<Prior Art> Peptide analogs having a renin-inhibiting effect are conventionally known as tetrapeptides and tripeptide analogs, for example, JP-B-58-39149, JP-A-61-186366 and JP-A-61-186. The compound described in Japanese Patent No. 236770 is known.

<Problems to be Solved by the Invention> The present inventors have conducted extensive studies for many years on the synthesis of peptide analogs and their renin inhibitory activity, and as a result,
A peptide analogue having a novel structure which has not been known so far has excellent renin inhibitory activity, good water solubility, oral absorbability and bioavailability, and an important intermediate for synthesizing the analogue. They have found that they can become a body and completed the present invention.

[Structure] The peptide analog according to the present invention has the general formula [Wherein, m represents an integer of 0 to 2 and n represents 1 to 3
R ¹ is an alkyl group having 1 to 8 carbon atoms,
An optionally substituted heterocyclyl group bonded by a nitrogen atom or a group having the formula -N (R ⁵ ) (R ⁶ ) (in the formula, R ⁵ and R
⁶ is the same or different and represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an optionally substituted aralkyl group or a cycloalkyl group. ), R ² represents an optionally substituted phenyl group, an optionally substituted naphthyl group or a cyclohexyl group, R ³ represents an optionally substituted heteroaryl group, or an optionally substituted Represents a good phenyl group or an alkyl group having 1 to 8 carbon atoms, and R ⁴ has, as a substituent, an optionally substituted heterocyclyl group, imidazolyl, pyridyl, or a formula —N (R ⁷ ) (R ⁸ ). A group (in the formula, R ⁷ and R ⁸ are the same or different and represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms) or an alkyl group having 1 to 8 carbon atoms which may have a hydroxyl group. Shows,
R ⁴ ′ represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. ]] Is represented.

In the above general formula (I), the “alkyl group having 1 to 8 carbon atoms” in the definition of R ¹ , R ³ , R ⁴ , R ⁴ ′, R ⁵ , R ⁶ , R ⁷ and R ⁸ is, for example, Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl,
1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,
3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-
Dimethylpentyl, n-octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5
A linear or branched alkyl group having 1 to 8 carbon atoms such as dimethylhexyl, preferably a linear or branched alkyl group having 1 to 6 carbon atoms, and in the definition of R ³ Isopropyl is most preferable as the “alkyl group having 1 to 8 carbon atoms”.

Heterocyclyl of "optionally substituted heterocyclyl group of" optionally substituted heterocyclyl group bonded by nitrogen atom "in the definition of R ¹ and" optionally substituted heterocyclyl group "of the definition of R ^4. The group moiety represents a 5- to 6-membered saturated heterocyclic group containing one or two nitrogen atoms and optionally containing an oxygen atom or a sulfur atom,
Examples thereof include piperidyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, imidazolidinyl and piperazinyl, and morpholinyl, thiomorpholinyl, pyrrolidinyl and piperazinyl groups are preferable. Examples of the substituent moiety include an oxo group; an alkyl group having 1 to 8 carbon atoms; an optionally substituted phenyl group; a pyridyl group; a pyrimidyl group; an optionally substituted aralkyl group; An optionally substituted aralkyl-oxycarbonyl group; a carboxy group, an alkyl-oxycarbonyl group having 1 to 8 carbon atoms; a formyl group;
Carbamoyl group; carbamoyl group in which an alkyl group having 1 to 8 carbon atoms is mono- or di-substituted, and 1 to 8 carbon atoms
And an alkyl group having 1 to 8 carbon atoms; an optionally substituted phenyl group; a pyridyl group and a pyrimidyl group.

The "optionally substituted heterocyclyl group" as a whole is preferably an alkyl group having 1 to 8 carbon atoms, an oxo group,
A 5- to 6-membered heterocyclyl group optionally substituted with an optionally substituted phenyl group, a pyridyl group or a pyrimidyl group, and more preferably an alkyl group having 1 to 8 carbon atoms, an oxo group, or a substituted group Optionally a phenyl group,
A morpholinyl, thiomorpholinyl, pyrrolidinyl or piperazinyl group which may be substituted with a pyridyl group or a pyrimidyl group, and most preferably a morpholinyl, thiomorpholinyl or piperazinyl group which may be substituted with an alkyl group having 1 to 8 carbon atoms. Is.

The "optionally substituted aralkyl group" in the definition of R ⁵ and R ⁶ is a postscript "optionally substituted phenyl group" or a postscript "optionally substituted naphthyl group".
Represents a group substituted with the above-mentioned “alkyl group having 1 to 8 carbon atoms”, preferably a phenyl group and a naphthyl group.

The “cycloalkyl group” in the definition of R ⁵ and R ⁶ is a 3- to 7-membered cyclic saturated hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, preferably 5- to 6-membered cyclic group. It is a saturated hydrocarbon group.

The substituent of the “optionally substituted phenyl group” in the definition of R ² and R ³ is, for example, an alkyl group having 1 to 8 carbon atoms, a halogen atom such as fluorine, chlorine, bromine or iodine, or carbon. Examples thereof include an alkyl-oxy group having 1 to 8 carbon atoms, an alkyl-oxycarbonyl group having 1 to 8 carbon atoms, a trifluoromethyl group, an amino group, a cyano group or a nitro group, and preferably a halogen atom or It is an alkyl-oxy group having 1 to 8 carbon atoms.

“An optionally substituted naphthyl group” in the definition of R ²
Is the above-mentioned "optionally substituted phenyl group".
The same group as the substituent of is shown.

The “heteroaryl group” of the “optionally substituted heteroaryl group” in the definition of R ³ may be condensed with a phenyl ring and has 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms. A 5- or 6-membered heteroaromatic ring group containing, for example, furyl, thienyl, imidazolyl, oxazolyl,
Isoxazolyl, thiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl,
Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
Mention may be made of benzofuryl, benzothiophenyl, indolyl, benzthiazolyl, benzimidazolyl, quinolyl or isoquinolyl, with preference given to fused with a phenyl ring such as thienyl, isoxazolyl, thiazolyl, pyridyl, imidazolyl or indolyl. It may be a 5- or 6-membered heteroaromatic ring group containing 1 or 2 sulfur atom, oxygen atom and / or nitrogen atom. As the substitution component, the above-mentioned “optionally substituted phenyl group”
Shows the same group as the substitution of. “Heteroaryl group which may be substituted” as a whole is preferably unsubstituted 5
To 6-membered heteroaromatic ring group or indolyl group, more preferably, such as thienyl, isoxazolyl, thiazolyl, imidazolyl or indolyl, which may be condensed with a phenyl ring, a sulfur atom, an oxygen atom or / and It is an unsubstituted 5- or 6-membered heteroaromatic ring group containing 1 to 2 nitrogen atoms.

Examples of groups suitable as R ¹ , R ² , R ³ , R ⁴ and R ⁴ ′ in compound (I) are as follows.

-CH ₂ CH ₃ , -C ₃ H ₇ -n, -C ₃ H ₇ -i, -C ₄ H ₉ -n, -C ₄ H ₉ -i In the compound (I), more preferable groups of R ¹ , R ² , R ³ , R ⁴ and R ⁴ ′ are as follows.

When compound (I) has an optical isomer based on an asymmetric carbon, it includes an optically active substance and a racemate,
Preferably a formula Part is S-coordinate It is a compound in which the moiety is in the S configuration.

The compound having the above general formula (I) of the present invention can be made into a pharmaceutically acceptable salt. Examples of such salts include mineral salts such as hydrochlorides, sulfates, phosphates, oxalates, maleates, succinates, organic salts such as citrates, methanesulfonate, Acid addition salts such as benzene sulfonate, sulfonate such as p-toluene sulfonate, alkali metal salts or alkaline earth metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt, dicyclohexylamine salt Examples thereof include organic base salts.

In the compound (I), preferred compounds include (1) m, a compound of 0 to 1 (2) n, a compound of 1 (3) R ^{1 and a} branched chain of 1 to 6 carbon atoms. A chain alkyl group, an optionally substituted heterocyclyl group bonded by a nitrogen atom, or a group having the formula —N (R ⁵ ) (R ⁶ ) (in the formula, R ⁵ is a hydrogen atom or 1 to 6 carbon atoms) And an alkyl group of R ⁶ is
It represents an unsubstituted aralkyl group or a 5- to 6-membered cycloalkyl group. (4) R ¹ is alkyl having 1 to 6 carbons or optionally substituted phenyl (the substituent is halogen, trifluoromethyl or alkyl-oxy having 1 to 6 carbons). ), Which may be substituted with morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl,
Alternatively, it is piperazinyl or a group having the formula —N (R ⁵ ) (R ⁶ ), wherein R ⁵ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ⁶ is phenyl-carbon number. A compound which is 1 to 6 alkyl groups or cyclohexyl groups) (5) A compound wherein R ² is an optionally substituted phenyl group, an optionally substituted naphthyl group or a cyclohexyl group (6) A compound in which R ² is a phenyl group, a naphthyl group or a cyclohexyl group (7) A compound in which R ³ is an optionally substituted heteroaryl group (8) A compound in which R ³ is an unsubstituted heteroaryl group (9) R ³ is thienyl, isoxazolyl, thiazolyl or imidazolyl, compound (10) R ³ is a compound which is an isoxazolyl or thiazolyl (11) R ⁴ is, as a substituent, may be substituted Heteroshi Group (wherein with Lil group or formula ^{-N (R 7) (R 8} ), R
⁷ and R ⁸ are the same or different and each is a hydrogen atom or has 1 carbon atom.
6 to 6 alkyl groups are shown. A compound which is an alkyl group having 1 to 8 carbon atoms which may have (12) R ⁴ is a heterocyclyl group which may be substituted or a formula —N (R ⁷ ) (R ⁸ A group having)
⁷ and R ⁸ are the same or different and each represents an alkyl group having 1 to 6 carbon atoms. ) A compound which is an alkyl group having 1 to 8 carbon atoms which may have (13) R ⁴ has 1 carbon atom which may have, as a substituent, an optionally substituted heterocyclyl group. To compounds having 8 to 8 alkyl groups (14) R ⁴ is compounds having 1 to 8 carbon atoms which may have morpholyl or 2-oxopyrrolidyl as a substituent (15) R ^A compound (4) in which 4'is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (16) m is 0 to 1, n is 1 and R ¹ is
A branched alkyl group having 1 to 6 carbon atoms, an optionally substituted heterocyclyl group bonded by a nitrogen atom, or a group having the formula —N (R ⁵ ) (R ⁶ ), wherein R ⁵ is A hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ⁶ represents an unsubstituted aralkyl group or a 5 to 6 membered cycloalkyl group, and R ² represents optionally substituted phenyl. Group, an optionally substituted naphthyl group or a cyclohexyl group, R ³ is an optionally substituted heteroaryl group, R ⁴ is a substituent, an optionally substituted heterocyclyl group or a formula A group having —N (R ⁷ ) (R ⁸ ) (in the formula, R ⁷
And R ⁸ are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. A compound having 1 to 8 carbon atoms which may have), wherein R ⁴ ′ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (17) m is 0 to 1 Yes, n is 1, R ¹ is
A branched alkyl group having 1 to 6 carbon atoms, an optionally substituted heterocyclyl group bonded by a nitrogen atom, or a group having the formula —N (R ⁵ ) (R ⁶ ), wherein R ⁵ is A hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R ⁶ represents an unsubstituted aralkyl group or a 5 to 6 membered cycloalkyl group, and R ² represents optionally substituted phenyl. A group, an optionally substituted naphthyl group or a cyclohexyl group, R ³ is an unsubstituted heteroaryl group, R ⁴ is a substituent, an optionally substituted heterocyclyl group or formula -N ( R ⁷ ) (R ⁸ ) -containing group (wherein R ⁷ and R ⁸ are the same or different and each represents an alkyl group having 1 to 6 carbon atoms).
A compound (18) m which is an optionally substituted alkyl group having 1 to 8 carbon atoms, and R ⁴ ′ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, is 0 to 1. , N is 1 and R ¹ is
Optionally substituted by alkyl having 1 to 6 carbons or optionally substituted phenyl (the substituent represents halogen, trifluoromethyl or alkyl-oxy having 1 to 6 carbons), Morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl, or a group having the formula -N (R ⁵ ) (R ⁶ ) (wherein R
⁵ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ⁶ represents a phenyl-alkyl group having 1 to 6 carbon atoms or a cyclohexyl group. ), R ² is a phenyl group, a naphthyl group or a cyclohexyl group, R ³ is thienyl, isoxazolyl, thiazolyl or imidazolyl, R ⁴ is, as a substituent, an optionally substituted heterocyclyl group. A compound (19) m, which is an optionally substituted alkyl group having 1 to 8 carbon atoms, and R ⁴ ′ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, is 0 to 1; n is 1 and R ¹ is
Optionally substituted with alkyl having 1 to 6 carbons or optionally substituted phenyl (the substituent represents halogen, trifluoromethyl or alkyl-oxy having 1 to 6 carbons), Morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, or piperazinyl, or a group having the formula -N (R ⁵ ) (R ⁶ ) (wherein R
⁵ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ⁶ represents a phenyl-alkyl group having 1 to 6 carbon atoms or a cyclohexyl group. ), R ² is a phenyl group, a naphthyl group or a cyclohexyl group, R ³ is isoxazolyl or thiazolyl, and R ⁴ has morpholyl or 2-oxopyrrolidyl as a substituent. A good alkyl group having 1 to 8 carbon atoms, R ⁴ ′
However, a compound in which the hydrogen atom is an alkyl group having 1 to 6 carbon atoms can be mentioned.

Specific examples of the compound having the general formula (I) of the present invention include the compounds shown in Table 1, but the present invention is not limited to these compounds.

The compound of the present invention having the general formula (I) can be easily produced according to the following method.

Method A Method B C method In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁴ ′, m and n have the same meanings as described above, and ▲ R ¹ _a ▼ represents an imino moiety (-NH 2) contained in R ^1. -), or addition to the amino group is protected, and R ⁴ the same meaning, ▲ R ⁴ _a ▼ is imino moiety (-N contained in R ⁴
H-) or an amino group is protected, and it has the same meaning as R ⁴ and R ⁹ represents an alkyl group having 1 to 8 carbon atoms or an aralkyl group.

The protecting group in ▲ R ¹ _a ▼ and ▲ R ⁴ _a ▼ is not particularly limited as long as it is a protecting group used in the field of amino acid chemistry, and examples thereof include aralkyl such as benzyloxycarbonyl and p-methoxybenzyloxycarbonyl. Mention may be made of carbonate residues such as oxycarbonyl groups, t-butyloxycarbonyl groups or 9-fluorenylmethyloxycarbonyl groups.

Method A is a method for producing compound (I).

The first step of this method is a step of producing compound (Ia) using compound (II) or its reactive derivative and compound (III). It is carried out by the acid anhydride method or the carbodiimide method.

In the above peptide synthesis, the azide method is a method in which an amino acid or an ester thereof is treated with hydrazine in an inert solvent (for example, dimethylformamide),
It is carried out by reacting an amino acid hydrazide produced by reacting at around room temperature with a nitrite compound to convert into an azide compound, and then treating with an amine compound.

Examples of the nitrite compound used include alkali metal nitrites such as sodium nitrite or alkyl nitrites such as isoamyl nitrite.

The reaction is preferably carried out in an inert solvent, and examples of the solvent used include amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and pyrrolidones such as N-methylpyrrolidone. Can be raised. Also, the two steps of this method are usually carried out in one reaction solution, and the reaction temperature is
The former is -50 ° C to 0 ° C, the latter is -10 ° C to 10 ° C, and the time required for the reaction is 5 minutes to 1 hour in the former and 10 hours to 5 days in the latter.

The active ester method is carried out by reacting an amino acid with an active esterifying agent to produce an active ester, and then reacting it with an amine compound.

Both reactions are preferably carried out in an inert solvent, examples of the solvent used include methylene chloride, halogenated hydrocarbons such as chloroform, ethers, ethers such as tetrahydrofuran, dimethylformamide, Amides such as dimethylacetamide may be mentioned.

Examples of the active esterifying agent used include N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole and N-hydroxy-5-norbornene-2,3-dicarboximide. The active esterification reaction can be carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide or carbonyldiimidazole.

The reaction temperature is −10 ° C. to 10 ° C. in the active esterification reaction, and is around room temperature in the reaction between the active ester compound and the amine, and the time required for the reaction is 30 minutes to 30 ° C. in both reactions.
10 hours.

The mixed acid anhydride method is carried out by producing a mixed acid anhydride of amino acids and then reacting it with an amine.

The reaction to produce the mixed acid anhydride is carried out in an inert solvent (for example,
In the above amides and ethers), ethyl chlorocarbonate,
This is accomplished by reacting the amino acid with a lower alkyl carbonate such as isobutyl chlorocarbonate or a lower alkyl cyanophosphate such as diethyl cyanophosphate.

The reaction is preferably carried out in the presence of an organic amine such as triethylamine or N-methylmorpholine, the reaction temperature is -10 ° C to 10 ° C, and the reaction time is 30 minutes to 5 hours. .

The reaction of the mixed acid anhydride and the amine is preferably carried out in an inert solvent (for example, the above amides and ethers) in the presence of the above organic amine, and the reaction temperature is 0 ° C to room temperature, The time required for the reaction is 1 hour to 24 hours.

The condensation method is carried out by directly reacting an amino acid with an amine in the presence of a condensing agent such as dicyclohexylcarbodiimide or carbonyldiimidazole. This reaction is carried out in the same manner as the above-mentioned reaction for producing an active ester.

In the second step, if desired, ▲ R ¹ _a in the compound (Ia) can be used.
In this step, the protective group such as imino group contained in ▼ and / or R ⁴ _a is removed to produce compound (I).

The reaction for removing the protecting group differs depending on the type of the protecting group,
It is performed according to the usual method.

For example, when the protecting group for the amino group and the imino group is a t-butyloxycarbonyl group, the corresponding compound is treated with an acid (for example, hydrochloric acid or tritium) in an inert solvent (for example, dioxane, methanol, dimethylformamide, etc.). Fluoroacetic acid, trifluoroboron / etherate, etc.) and 0 ° C to
It is carried out by treating at 30 ° C. for 20 minutes to 1 hour.

When the protecting group for the amino group and the imino group is an aralkyloxycarbonyl group or a carbonate residue, the corresponding compound in an inert solvent (for example, methanol, ethanol, tetrahydrofuran, etc.) in the presence of a catalytic reduction catalyst (for example, palladium- Carbon, palladium black, etc.), normal pressure to 10
It is carried out by reacting with hydrogen at atmospheric pressure at around room temperature for 1 to 8 hours.

The method B is a method for separately producing the compound (Ia), and the third step of the method is the method A using the compound (IV) and the compound (V).
It is performed in the same manner as the process.

Method C is a method for separately producing compound (Ia).

The fourth step is a step of producing a compound having the general formula (VII), and is achieved by reacting compound (IV) with compound (VI) and hydrolyzing the obtained compound. The reaction of compound (IV) with compound (VI) is carried out in the same manner as in the above-mentioned Method A 1st step, and the hydrolysis reaction is a deprotection reaction in the case where the carboxy-protecting group in Method A is a lower alkyl group. The same is done as.

The fifth step is a step for producing a compound having the general formula (Ia), wherein the compound (VII) is treated with the general formula (VIII) in an inert solvent.
Is achieved by reacting with an amine form having
This step is performed in the same manner as the method A first step.

After completion of the reaction in each of the above steps, each target compound can be collected from the reaction mixture according to a conventional method. For example, the desired product can be obtained by appropriately neutralizing the reaction mixture, or, if an insoluble substance is present, removing it by filtration and then distilling off the solvent. Further, if desired, it can be purified by a conventional method, for example, recrystallization, reprecipitation, column chromatography and the like.

The starting compound (II) of the present invention is obtained by reacting a compound produced according to the method D, E, F or G described later with a compound (XXXIV) produced according to the method H described below in accordance with the first step. It can be manufactured by

The raw material compound (III) is obtained, for example, from Bossier (J.Med.C.
hem., 28, 1779 (1985)) It can be produced by protecting the amino group of the compound (IX) having the following formula, carrying out according to the fifth step, and then removing the protecting group.

The starting compound (IV) can be produced according to the following method.

Method D E method F method In the above formula, ▲ R ¹ _a ▼, R ² , R ⁹ , m and n have the same meanings as described above, and X represents a halogen atom such as fluorine, chlorine, bromine or iodine. ▲ R ¹ _b ▼ is a group having an optionally substituted heterocyclyl group or a formula —N (R ⁵ ) (R ⁶ ) bonded to a nitrogen atom in the definition of R ¹ (in the formula, R ⁵ and R ⁶ has the same meaning as described above.), And represents the same group as the group in which the imino moiety (-NH-) or the amino moiety is protected.

Method D is a synthetic method using compound (IV) and a halide corresponding to malonic acid ester (for example, Organic Synthesis.
The method described in coll.vol.3,705.).

That is, a malonate (XI) is reacted with a halide compound (X) to form a mono-substituted compound (XII) (sixth step), and then a desired halide compound (XIII) is further reacted with the corresponding di-substituted malon. The acid ester (XIV) is obtained (7th step), and this is hydrolyzed by a conventional method, and then decarboxylation reaction is carried out to produce the compound (IV) (8th step).

Method E is a compound (IV) in which m is 0 (IV
This is the manufacturing method of a).

That is, an aldehyde compound (XV) is reacted with a glutaric acid diester or adipic acid diester represented by the formula (XVI) to produce a compound (XVII) (step 9), which is hydrolyzed according to a conventional method and then dried. The acid is ring-closed with acetic acid to obtain an acid anhydride (XVIII) (step 10). This is reacted with an amine compound represented by the formula (XIX) to open the ring to obtain a compound (XX) (step 11), and further, catalytic reduction is carried out under normal pressure to produce a compound (IVa) ( First
2 steps) method.

Method F is a method for producing compound (IVb) in which m is 1 in compound (IV).

That is, A propionate derivative having the formula (wherein R ² and R ⁹
Has the same meaning as above. ) In the presence of a metal base such as lithium diisopropylamide, n-butyllithium, sodium metal, sodium hydride. (In the formula, n and X have the same meanings as described above.) The compound (XXI) obtained by reacting with alkenyl halides such as allyl chloride and allyl bromide is converted into 3-chloroperbenzoic acid. After being oxidized with such an organic peracid to form an epoxy compound (XXII) (step 13), it is reacted with an amine compound having the formula (XIX) to produce compound (XXIII) (step 14). This is oxidized according to a conventional method using an oxidizing agent such as sulfur trioxide-pyridine complex, pyridinium chlorochromate and pyridinium dichromate to obtain compound (XXIV) (step 15), and then, if desired, carboxylic acid. This is a method of producing a compound (IVb) by removing the acid protecting group (step 16).

The compounds produced by the above methods D, E and F are obtained as a mixture of isomers, and each isomer can be isolated by a conventional method such as column chromatography.

The starting compound (IVa) can be stereoselectively synthesized as a preferred S-isomer according to the following method.

G method In the above formula, ▲ R ¹ _b ▼, R ² , R ⁹ , X and n have the same meanings as described above. R ¹⁰ is the above-mentioned “optionally substituted phenyl group”
Alternatively, a group similar to the “alkyl group having 1 to 8 carbon atoms” is shown.

That is, a compound having the formula (XXV) is treated with a base (for example, n-
Butyllithium) to give the corresponding alkali metal salt, which is then reacted with a compound having the formula (XXVI) (step 17), and the resulting compound (XXVII) is treated with a base (eg, diisopropyllithium amide). Then, the compound (XX
VIII) is stereoselectively reacted (step 18), and the obtained compound (XXIX) is catalytically reduced (eg, treated with hydrogen under a palladium-carbon catalyst) or hydrolyzed (step 19) according to a conventional method. ), A compound having the formula (XIX) and a condensing agent (for example, diethyl cyanophosphate-
In the presence of (triethylamine) (step 20),
Finally, the obtained compound (XXXI) is hydrolyzed (step 21) to produce the compound (IVa ′).

The starting compound (V) is obtained by protecting the amino group of the compound (IX) and then reacting it with the compound (VIII) according to the fifth step, and then removing the protecting group and then reacting the compound (XXXII) with the first compound.
It is produced according to the method of reacting according to the steps.

Starting compound (VI) can be produced by protecting the amino group of compound (XXXII), esterifying compound (IX), and then reacting both according to the first step.

The starting compound (VIII) can be prepared by a known method or a known method [for example, RPAhlquis (RPAhlquis
t): Progress in Drug Research (Prog.Dr
ug.Res.) Volume 20, E. Junker, Ed., Birkhauser Verlag, 1976].

The formula As the amino acid having, a compound that is easily produced according to the following method or a commercially available amino acid is used.

H method In the above formula, R ³ , R ⁹ and X are as defined above, and R ¹¹ is
It represents an aliphatic acyl group such as acetyl, propionyl and butyryl.

The compound (XXXII) is prepared by first treating the compound having the formula (XXXIII) with a base (for example, an alkali metal hydride compound such as sodium hydride) and then reacting the compound having the formula (XXXIV) with the compound (XXII). Process), the obtained compound (XX
XV) is treated with an acid (for example, a mineral acid such as hydrochloric acid (step 23)).

〔effect〕

The results of the inhibitory action test of the peptides having the general formula (I) of the present invention on human renin are shown below. In addition, the test method is the method of Kokufu et al. [Hypertension, 5 , 191-19: 00
7 (1983)], the peptide of the present invention was premixed with a sheep renin substrate, and then human renin was added.

The object compound (I) of the present invention exhibited an excellent inhibitory action on human renin as shown in the above test examples.
Further, the compound (I) exhibited excellent effects upon oral administration using marmoset and had good solubility in water. Therefore, it is useful as a diagnostic and therapeutic agent for hypertension based on the renin-angiotensin system, especially for oral use. Examples of the dosage form include tablets, capsules,
Not only oral administration by granules, powders, syrups, etc., but also parenteral administration by injections, suppositories, etc. can be mentioned. The usage amount varies depending on the purpose of use, symptoms, age, etc., but is, for example, about 0.01 mg to 100 mg / kg body weight per day, and can be administered once or in several divided doses.

Next, the present invention will be described more specifically with reference to Examples and Reference Examples. In addition, in the following examples, cyclostatin is (3S, 4S) -4-amino-5-cyclohexyl-3.
-Hydroxypentanoic acid. The Rf value of the powdery compound was calculated by silica gel thin layer chromatography (developing solvent; methylene chloride: methanol = 10: 1).

Example 1 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionyl]-(4-thiazolyl)
-L-alanyl-cyclostatin- (2-morpholinoethyl) amide (A) N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanyl-cyclostatin- (2-morpholinoethyl) amide N- (t-butoxycarbonyl)-(4-thiazolyl)
-L-alanine 261 mg (0.96 mmol) and cyclostatin- (2-morpholinoethyl) amide dihydrochloride 384 m
g (0.96 mmol) was dissolved in 10 ml of anhydrous tetrahydrofuran and 0.16 ml (1.05 mmol) of diethyl cyanophosphate and 0.44 ml of triethylamine under ice cooling under a nitrogen atmosphere.
(3.15 mmol) was added, and the mixture was stirred at the same temperature for 2 hours, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel thin layer plate (chloroform: methanol = 10: 1) to give the title compound as white crystals. As a result, 450 mg (81%) was obtained.

Melting point 73-75 ° C Mass spectrum m / e: 582 (M ⁺ +1) (b) N-[(2R) -3-morpholinocarbonyl-2-
(1-Naphthylmethyl) propionyl]-(4-thiazolyl) -L-alanyl-cyclostatin- (2-morpholinoethyl) amide 310 mg (0.53 mmol) of the compound synthesized in Example 1 (a) was treated with 4N hydrochloric acid / dioxane. Add to 5 ml, room temperature 3
Stir for 0 minutes. Then, the solvent was distilled off under reduced pressure and the residue was dried sufficiently. This was suspended in 10 ml of anhydrous tetrahydrofuran and further (2R) -3-morpholinocarbonyl-2-
192 mg (0.59 mmol) of (1-naphthylmethyl) propionic acid was added, and 0.09 ml (0.59 mmol) of diethyl cyanophosphate and triethylamine under ice cooling under a nitrogen atmosphere.
0.36 ml (2.58 mmol) was added, and the mixture was stirred at the same temperature for 2 hours. Then, the solvent was distilled off under reduced pressure, and the residue was purified by a silica gel thin layer plate (chloroform: methanol = 10: 1) to obtain 220 mg (52%) of the title compound.

Melting point 93-96 ° C Elemental analysis value Calculated as C ₄₂ H ₅₈ N ₆ O ₇ S ・ H ₂ O: C; 62.35, H; 7.47, N; 10.39, S; 3.96 Actual value: C; 62.33, H; 7.34 , N; 10.09, S; 3.76% Example 2 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionyl]-(4-thiazolyl)
-DL-alanyl-cyclostatin- (2-morpholinoethyl) amide (A) N- (t-butoxycarbonyl) -3- (4-thiazolyl) -DL-alanyl-cyclostatin- (2-morpholinoethyl) amide N- (t-butoxycarbonyl)-(4-thiazolyl)
-DL-alanine 200 mg (0.73 mmol) and cyclostatin- (2-morpholinoethyl) amide dihydrochloride 31
Dissolve 4 mg (0.74 mmol) in 10 ml of anhydrous tetrahydrofuran, and under ice cooling under a nitrogen atmosphere, 0.13 ml (0.86 mmol) of diethyl cyanophosphate and 0.34 of triethylamine.
ml (2.44 mmol) was added, and the mixture was stirred at the same temperature for 2 hours,
The solvent was evaporated under reduced pressure, and the residue was purified by silica gel thin layer plate (chloroform: methanol = 10: 1) to obtain 404 mg (95%) of the title compound as white crystals.

Melting point 72-76 ° C Mass spectrum m / e: 582 (M ⁺ +1) (b) N-[(2R) -3-morpholinocarbonyl-2-
(1-Naphthylmethyl) propionyl]-(4-thiazolyl) -DL-alanyl-cyclostatin- (2-morpholinoethyl) amide 280 mg (0.48 mmol) of the compound synthesized in Example 2 (a) was added to 4N hydrochloric acid / dioxane. Add to 5 ml, room temperature 3
Stir for 0 minutes. Then, the solvent was distilled off under reduced pressure and the residue was dried sufficiently. This was suspended in 10 ml of anhydrous tetrahydrofuran and further (2R) -3-morpholinocarbonyl-2-
173 mg (0.53 mmol) of (1-naphthylmethyl) propionic acid was added, and while cooling with ice under a nitrogen atmosphere, diethyl cyanophosphate 0.09 ml (0.59 mmol) and triethylamine.
0.34 ml (2.44 mmol) was added, the mixture was stirred at the same temperature for 2 hours, the solvent was distilled off under reduced pressure, the residue was purified on a silica gel thin layer plate (chloroform: methanol = 10: 1), and 175 mg of the title compound ( 46%) got.

Melting point 92-95 ℃ Elemental analysis value Calculated as C ₄₂ H ₅₈ N ₆ O ₇ S ・ H ₂ O: C; 62.35, H; 7.47, N; 10.39, S; 3.96 Measured value: C; 61.98, H; 7.25 , N; 10.08, S; 3.77% Example 3 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionyl]-(5-isoxazolyl) -L-alanyl-cyclostatin- (2-morpholinoethyl) amide (A) N- (t-butoxycarbonyl)-(5-isoxazolyl) -L-alanyl-cyclostatin- (2-
Morpholinoethyl) amide N- (t-butoxycarbonyl) -cyclostatin-
0.125 g (0.29 mmol) of (2-morpholinoethyl) amide was dissolved in 5 ml of dioxane, 5 ml of 4N dioxane-hydrochloric acid was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Dioxane was concentrated to dryness under reduced pressure, and 89 mg (0.348 mmol) of N- (t-butoxycarbonyl)-(5-isoxazolyl) -L-alanine was added to the residue in 15 ml of dimethylformamide.
Add the melted solution. Triethylamine 0.
13 g (12.76 mmol) and diethyl cyanophosphate 57 mg
(0.348 mmol) was added, and the mixture was reacted at room temperature for 21 hours.
The solvent was distilled off under reduced pressure, water was added to the residue, extracted with methylene chloride, dried and the solvent was distilled off, and the residue was subjected to silica gel column chromatography (elution solvent; methanol / methylene chloride = 1/49). Purification was performed to give 85 mg (51.8%) of the title compound as an oil.

(B) N-[(2R) -3-morpholinocarbonyl-2-
(1-Naphthylmethyl) propionyl]-(5-isoxazolyl) -L-alanyl-cyclostatin- (2-
Morpholinoethyl) amide N- (t-butoxycarbonyl)-(5-isoxazolyl) -DL-alanyl-cyclostatin- (2-morpholinoethyl) amide 85 mg (0.15 mmol) was dissolved in 4N dioxane-hydrochloric acid 2 ml, and room temperature was dissolved. And stirred for 1.5 hours. Dioxane was concentrated to dryness under reduced pressure, the residue was suspended in tetrahydrofuran, and (2R) -3-morpholinocarbonyl-2- (1-naphthylmethyl) propionic acid 49 mg was stirred.
(0.15 mmol), 67 mg (0.66 mmol) of triethylamine and 29 mg (0.18 mmol) of diethyl cyanophosphate were added, and the mixture was stirred at room temperature for 3 hours. After standing for 4 days, the solvent was distilled off under reduced pressure, and the residue was purified by preparative thin layer chromatography (developing solvent: 10% methanol / methylene chloride) to obtain 74 mg (61.7%) of the title compound.

Melting point 84-86 ° C Elemental analysis: Calculated as C ₄₂ H ₅₇ N ₆ O ₈ H ₂ O: C; 63.70, H; 7.51, N; 10.61 Found: C; 63.75, H; 7.19, N; 10.41 % Example 4 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionyl] -L-phenylalanyl-cyclostatin- (2-morpholinoethyl) amide N- (t-butoxycarbonyl) -L-phenylalanyl-cyclostatin- (2-morpholinoethyl) amide
100 mg (0.17 mmol) and (2R) -3- (1-morpholinocarbonyl) -2- (1-naphthylmethyl) propionic acid 56 mg (0.17 mmol) were reacted according to Example 1 (b) to give the title compound. 23 mg was obtained as a colorless amorphous.

Rf: 0.56 Elemental analysis value: Calculated as C ₄₅ H ₆₁ N ₅ O ₇・ 2.5H ₂ O: C; 65.19, H; 8.02, N; 8.45 Actual value: C; 65.06, H; 7.87, N; 8.25 Implemented Example 5 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionyl] -3- (2-thienyl) -DL-alanyl-cyclostatin- (2-morpholinoethyl) amide (A) N- (t-butoxycarbonyl) -3- (2-thienyl) -DL-alanyl-cyclostatin- (2-morpholinoethyl) amide N- (t-butoxycarbonyl) -3- (2-thienyl) -DL-alanine 200 mg (0.74 mmol) and cyclostatin- (2-morpholinoethyl) amide dihydrochloride
300 mg (0.74 mmol) was reacted according to Example 2 (a) to give 310 mg of the title compound as a colorless amorphous.

Elemental analysis value: Calculated as C ₂₉ H ₄₈ N ₄ O ₆ S: C; 59.97, H; 8.33, N; 9.65, S; 5.52 Actual value: C; 59.50, H; 8.18, N; 9.62, S; 5.68 (B) N-[(2R) -3-morpholinocarbonyl-2-
(1-Naphthylmethyl) propionyl] -3- (2-thienyl) -DL-alanyl-cyclostatin- (2-morpholinoethyl) amide N- (t-butoxycarbonyl) -3- (4-thiazolyl) -DL- N- (t-butoxycarbonyl) -3- (2-thienyl) -DL-alanyl-cyclostatin- (2-morpholinoethyl) amide 70 mg (0.12 mmol) instead of alanyl-cyclostatin- (2-morpholinoethyl) amide ) And (2R) -3-morpholinocarbonyl-2-
40 mg (0.12 mmol) of (1-naphthylmethyl) propionic acid was reacted according to Example 2 (b) to obtain 27 mg of the title compound as a colorless amorphous substance.

Rf: 0.59 Elemental _{analysis: C 43 H 59 N 5 O} 7 S · 2.5H 2 O Calculated: C; 61.85, H; 7.73 , N; 8.39, S; 3.84 Found: C; 61.74, H; 7.50 , N; 8.18, S; 3.62 Example 6 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionyl] -L-histidyl-cyclostatin- (2-morpholinoethyl) amide N- (t-butoxycarbonyl) -N ^im -tosyl-L-
Histidine 344 mg (0.84 mmol) and N- (t-butoxycarbonyl) -cyclostatin- (2-morpholinoethyl) amide 300 mg (0.70 mmol) were used in Example 3 (a).
N- (t-butoxycarbonyl) -N
^im -tosyl-L-histidyl-cyclostatin- (2-
240 mg of morpholinoethyl) amide were obtained as a white powder. 220 mg (0.31 mmol) of this compound and (2R) -3-
100 mg (0.31 mmol) of morpholinocarbonyl-2- (1-naphthylmethyl) propionic acid was reacted for 15 hours according to Example 1 (b), and then 83 mg (0.61 mmol) of 1-hydroxybenzotriazole in methanol was added to the reaction solution. The solution was added and stirred at room temperature for 1 hour. After the solvent was distilled off, the residue was purified by silica gel thin layer plate (methylene chloride; methanol = 8: 1) to obtain 50 mg of the title compound 2.5 hydrate as white crystals.

Melting point 105-109 ° C Elemental analysis: Calculated as C ₄₂ H ₅₉ N ₇ O ₇・ 2.5H ₂ O: C; 61.59, H; 7.88, N; 11.97 Found: C; 61.65, H; 7.65, N; 11.73 Example 7 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionyl] -L-leucyl-cyclostatin- (2-morpholinoethyl) amide 1.22 mg (0.373 mmol) of (2R) -3-morpholinocarbonyl-2- (1-naphthylmethyl) propionic acid and N
-(T-Butoxycarbonyl) -L-leucyl-cyclostatin- (2-morpholinoethyl) amide 200 mg (0.3
(70 mmol) was obtained according to Example 1 (b) to give 154 mg of the title compound as a pale yellow amorphous substance.

Rf: 0.44 Elemental analysis value: Calculated as C ₄₂ H ₆₃ N ₅ O ₇・ 2H ₂ O: C; 64.18, H; 8.59, N; 8.91 Actual value: C; 63.82, H; 8.31, N; 8.81 Example 8 N-[(2R) -2- (1-naphthylmethyl) -3- (2,
6-Dimethylmorpholinocarbonyl) propionyl]-
3- (4-thiazolyl) -DL-alanyl-cyclostatin- (2-morpholinoethyl) amide (2R) -3- (2,6-dimethylmorpholinocarbonyl)
-2- (1-Naphthylmethyl) propionic acid 90mg (0.25
Compound 15 synthesized in Example 2 (a) using
React with 0 mg (0.25 mmol) according to the method of Example 2 (b) to give 4.5 hydrate of the title compound as a white powder in 90 m
g got.

Rf = 0.46 Elemental analysis _{C 44 H 62 N 6 O 7} S · 4.5H 2 O Calculated: C; 58.71, H; 7.95 , N; 9.34, S; 3.56 Found: C; 58.73, H; 7.72 , N; 9.51, S; 3.60 Example 9 N-[(2R) -2- (1-naphthylmethyl) -3-thiomorpholinocarbonylpropionyl] -3- (4-thiazolyl) -DL-alanyl-cyclostatin- ( 2-morpholinoethyl) amide Using (2R) -2- (1-naphthylmethyl) -3-thiomorpholinocarbonylpropionic acid 76 mg (0.22 mmol), the compound synthesized in Example 2 (a) 130 mg (0.22 mmol) and Example 2 (b). The reaction was carried out according to the method of 1) to give 80 mg of 2.5 hydrate of the title compound as a white powder.

Rf = 0.56 Elemental analysis value Calculated as C ₄₂ H ₅₈ N ₆ O ₆ S ₂ · 2.5H ₂ O: C; 59.20, H; 7.45, N; 9.86, S; 7.52 Actual value: C; 59.23, H; 7.22 , N; 9.66, S; 7.82 Example 10 N-[(2R) -2- (1-naphthylmethyl) -3- (1
-Pyrrolidinylcarbonyl) propionyl] -3- (4
-Thiazolyl) -DL-alanyl-cyclostatin- (2
-Morpholinoethyl) amide 80 mg (0.26 mmol) of (2R) -2- (1-naphthylmethyl) -3- (1-pyrrolidinylcarbonyl) propionic acid and N- (t-butoxycarbonyl) -3- (4-thiazolyl) -DL- 180 mg (0.308 mmol) of alanyl-cyclostatin- (2-morpholinoethyl) amide was reacted according to Example 2 (b) to obtain 140 mg of the title compound as a colorless amorphous substance.

Rf = 0.56 Elemental _{analysis: C 42 H 58 N 6 O} 6 S · 2.5H 2 O Calculated: C; 61.51, H; 7.74 , N; 10.25, S; 3.91 Found: C; 61.42, H; 7.39 , N; 10.29, S; 3.75 Example 11 N-[(2R) -2- (1-naphthylmethyl) -3- (piperidinocarbonyl) propionyl] -3- (4-thiazolyl) -DL-alanyl- Cyclostatin- (2-morpholinoethyl) amide Using (2R) -2- (1-naphthylmethyl) -3- (piperidinocarbonyl) propionic acid 104 mg (0.32 mmol), the compound 186 mg (0.32 mmol) synthesized in Example 2 (a) and The reaction was performed according to the method of 2 (b) to obtain 95 mg of the title compound monohydrate as a white powder.

Rf = 0.39 Elemental analysis value C ₄₃ H ₆₀ N ₆ O ₆ S ・ H ₂ O Calculated value: C; 63.99, H; 7.74, N; 10.41 Measured value: C; 63.85, H; 7.78, N; 10.68 Example 12 N-[(2R) -2- (1-naphthylmethyl) -3-propylcarbamoylpropionyl] -3- (4-thiazolyl) -DL-alanyl-cyclostatin- (2-morpholinoethyl) amide Using (2R) -2- (1-naphthylmethyl) -3-propylcarbamoylpropionic acid 81 mg (0.27 mmol),
160 mg (0.27 mmol) of the compound synthesized in Example 2 (a) was reacted according to the method of Example 2 (b) to obtain 100 mg of the hemihydrate of the title compound as a white powder.

Rf = 0.52 Elemental analysis value Calculated as C ₄₁ H ₅₈ N ₆ O ₆ S ・ 1 / 2H ₂ O: C; 63.79, H; 7.70, N; 10.89, S; 4.15 Actual value: C; 63.70, H; 7.62 , N; 10.66, S; 4.05 Example 13 N-[(2R) -2- (1-naphthylmethyl) -3- (phenethylcarbamoyl) propionyl] -3- (4-thiazolyl) -L-alanyl-cyclostatin -(2-morpholinoethyl) amide (2R) -2- (1-Naphthylmethyl) -3- (phenethylcarbamoyl) propionic acid 100 mg (0.28 mmol)
And N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanyl-cyclostatin- (2-morpholinoethyl) amide 133 mg (0.23 mmol) were used according to Example 1 (b). The title compound (133 mg (71
%)Obtained.

Melting point 110-115 ° C Elemental analysis value Calculated as C ₄₆ H ₆₀ N ₆ O ₆ S ・ 1 1 / 2H ₂ O: C; 64.84, H; 7.45, N; 9.86; S; 3.76 Actual value: C; 64.85, H; 7.26, N; 9.64; S; 3.64 Example 14 N-[(2R) -3- (4-methyl-1-piperazinylcarbonyl) -2- (1-naphthylmethyl) propionyl] -3- ( 4-thiazolyl) -L-alanyl-cyclostatin- (2-morpholinoethyl) amide (2R) -3- (4-Methyl-1-piperazinylcarbonyl) -2- (1-naphthylmethyl) propionic acid 100 mg
(0.294 mmol) and N- (t-butoxycarbonyl)
190 mg (0.32 mmol) of 3- (4-thiazolyl) -DL-alanyl-cyclostatin- (2-morpholinoethyl) amide was reacted according to Example 2 (b), and then separated and purified by silica gel thin layer chromatography. 34 mg of the title compound was obtained as a colorless amorphous.

Rf = 0.12 Elemental analysis value C ₄₃ H ₆₁ N ₇ O ₆ S ・ Calculated as 2H ₂ O: C; 61.48, H; 7.80, N; 11.67, S; 3.82 Actual value: C; 61.56, H; 7.82, N 11.52, S; 3.87 Example 15 N-[(2R) -2- (1-naphthylmethyl) -3- (4
-Phenyl-1-piperazinylcarbonyl) propionyl] -3- (4-thiazolyl) -DL-alanyl-cyclostatin- (2-morpholinoethyl) amide (2R) -2- (1-Naphthylmethyl) -3- (4-phenyl-1-piperazinylcarbonyl) propionic acid 90mg
(0.22 mmol) was used to react with 130 mg (0.22 mmol) of the compound synthesized in Example 2 (a) according to the method of Example 2 (b) to obtain 103 mg of the monohydrate of the title compound as a white powder. Obtained.

Rf = 0.52 Elemental analysis value Calculated as C ₄₈ H ₆₃ N ₇ O ₆ S ・ H ₂ O: C; 65.21, H; 7.41, N; 11.09, S; 3.63 Actual value: C; 65.36, H; 7.51, N 11.22, S; 3.39 Example 16 N-[(2R) -3- (N, N-diethylcarbamoyl)-
2- (1-naphthylmethyl) propionyl] -3- (4
-Thiazolyl) -DL-alanyl-cyclostatin- (2
-Morpholinoethyl) amide (2R) -3- (N, N-diethylcarbamoyl) -2-
95 mg (0.3 mmol) of (1-naphthylmethyl) propionic acid and 210 mg (0.36 mmol) of N- (t-butoxycarbonyl) -3- (4-thiazolyl) -DL-alanyl-cyclostatin- (2-morpholinoethyl) amide. Was reacted according to Example 2 (b) to give 160 mg of the title compound as a colorless amorphous.

Rf = 0.52 Elemental analysis value Calculated as C ₄₂ H ₆₀ N ₆ O ₆ S ・ 2.5H ₂ O: C; 61.36, H; 7.97, N; 10.22, S; 3.90 Actual value: C; 61.45, H; 7.79, N; 10.10, S; 3.88 Example 17 N-[(2R) -3- (N-benzyl-N-methylcarbamoyl) -2- (1-naphthylmethyl) propionyl]
-3- (4-thiazolyl) -L-alanyl-cyclostatin- (2-morpholinoethyl) amide 125 mg of (2R) -3- (N-benzyl-N-methylcarbamoyl) -2- (1-naphthylmethyl) propionic acid
(0.35 mmol) and N- (t-butoxycarbonyl)-
200 mg (0.34 mmol) of 3- (4-thiazolyl) -L-alanyl-cyclostatin- (2-morpholinoethyl) amide was reacted according to Example 1 (b) to give 214 mg (75%) of the title compound. Obtained.

Mp 82-86 ° C. Elemental analysis _{C 46 H 62 N 6 O 6} S · H 2 O Calculated: C; 65.38, H; 7.63 , N; 9.94, S; 3.79 Found: C; 65.30, H; 7.53 , N; 9.94, S; 3.90 Example 18 N-[(2R) -3- (N-benzyl-N-methylcarbamoyl) -2- (1-naphthylmethyl) propionyl]
-L-phenylalanyl-cyclostatin- (2-morpholinoethyl) amide N- (t-butoxycarbonyl) -L-phenylalanyl-cyclostatin- (2-morpholinoethyl) amide
207 mg (0.36 mmol) and (2R) -3- (N-benzyl-N-methylcarbamoyl-2- (1-naphthylmethyl) propionic acid 130 mg (0.36 mmol) were used in Example 1.
The reaction was performed according to (b) to obtain 57 mg of a white crystal of a monohydrate of the title compound.

Melting point 89-94 ℃ Elemental analysis value Calculated as C ₄₉ H ₆₃ N ₅ O ₆ H ₂ O: C; 70.39, H; 7.84, N; 8.38 Actual value: C; 70.58, H; 7.87, N; 8.10 Implemented Example 19 N-[(2R) -3- (N-cyclohexyl-N-methylcarbamoyl) -2- (1-naphthylmethyl) propionyl] -3- (4-thiazolyl) -L-alanyl-cyclostatin- (2 -Morpholinoethyl) amide (2R) -3- (N-cyclohexyl-N-methylcarbamoyl) -2- (1-naphthylmethyl) propionic acid 12
2 mg (0.35 mmol) and N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanyl-cyclostatin- (2-morpholinoethyl) amide 200 mg (0.3
4 mmol) and reacted according to Example 1 (b),
215 mg (77%) of the title compound was obtained.

Melting point 93-96 ° C Elemental analysis C ₄₅ H ₆₄ N ₆ O ₆ S ・ H ₂ O Calculated value: C; 64.72, H; 7.97, N; 10.06, S; 3.84 Actual value: C; 64.52, H; 7.81, N; 9.81, S; 3.91 Example 20 N-[(2R) -3- (N-cyclohexyl-N-methylcarbamoyl) -2- (1-naphthylmethyl) propionyl] -L-leucyl-cyclostatin- (2 -Morpholinoethyl) amide 50 mg of 2R-3- (N-cyclohexyl-N-methylcarbamoyl) -2- (1-naphthylmethyl) propionic acid
(0.141 mmol) and N- (t-butoxycarbonyl)
73 mg (0.135 mmol) of L-leucyl-cyclostatin- (2-morpholinoethyl) amide was used in Example 1 (b).
According to the above, 81 mg of the title compound was obtained as a colorless amorphous.

Rf = 0.50 Elemental analysis value Calculated as C ₄₅ H ₆₉ N ₅ O ₆ · 3H ₂ O: C; 65.11, H; 9.11, N; 8.44 Actual value: C; 64.92, H; 8.91, N; 8.48 Example 21 N-[(2R) -3- (N-cyclohexyl-N-methylcarbamoyl) -2- (1-naphthylmethyl) propionyl] -3- (5-isoxazolyl) -L-alanyl-cyclostatin- (2-morpholino Ethyl) amide (2R) -3- (N-cyclohexyl-N-methylcarbamoyl) -2- (1-naphthylmethyl) propionic acid 10
0 mg (0.28 mmol) and N- (t-butoxycarbonyl) -3- (5-isoxazolyl) -L-alanyl-
Cyclostatin- (2-morpholinoethyl) amide 160m
g (0.28 mmol) was reacted according to Example 3 (b),
100 mg of the title compound was obtained as a colorless amorphous.

Rf = 0.52 Elemental analysis value Calculated as C ₄₅ H ₆₄ N ₆ O ₇ · 2H ₂ O: C; 64.57, H; 8.19, N; 10.14 Measured value: C; 64.36, H; 7.66, N; 10.06 Example 22 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionyl] -3- (4-thiazolyl) -DL-alanyl-cyclostatin- (2-piperidinoethyl) amide (A) N- (t-butoxycarbonyl) -DL-3- (4
-Thiazolyl) alanyl-cyclostatin- (2-piperidinoethyl) amide N- (t-butoxycarbonyl) -cyclostatin-
450 mg (1.06 mmol) of (2-piperidinoethyl) amide was added to 10 ml of 4N hydrochloric acid / dioxane, and the mixture was stirred at room temperature for 30 minutes.
Stir for minutes. Then, the solvent was distilled off under reduced pressure and the residue was dried sufficiently. This was suspended in 20 ml of anhydrous methylene chloride, 260 mg (1.60 mmol) of diethyl cyanophosphate and 482 mg (4.77 mmol) of triethylamine were added under ice cooling, and the mixture was stirred at room temperature for 3 hours, and then the solvent was distilled off under reduced pressure to leave a residue. Was purified by silica gel thin layer plate (chloroform: methanol = 5: 1) to obtain 590 mg (96%) of the title compound as white crystals.

(B) N-[(2R) -3-morpholinocarbonyl-2-
(1-Naphthylmethyl) propionyl] -3- (4-thiazolyl) -DL-alanyl-cyclostatin- (2-piperidinoethyl) amide Compound 179 mg (0.31 mmol) synthesized in Example (a)
Was added to 10 ml of 4N hydrochloric acid / dioxane, and the mixture was stirred at room temperature for 30 minutes. After that, the solvent was distilled off under reduced pressure and the residue was thoroughly dried. This was suspended in 10 ml of methylene chloride, and (2
R) -3-morpholinocarbonyl-2- (1-naphthylmethyl) propionic acid 100 mg (0.31 mmol) was added,
With ice cooling, diethyl cyanophosphate 75 mg (0.46 mmol)
And 186 mg (1.84 mmol) of triethylamine were added,
The mixture was stirred at room temperature for 3 hours. After that, the solvent was distilled off under reduced pressure, and the residue was purified by a silica gel thin layer plate (chloroform: methanol = 5: 1) to obtain 80 mg (31%) of the title compound.

Mp 78 ° C. to 87 ° C. Elemental analysis _{C 43 H 60 N 6 O 6} S 1 · 2H 2 O Calculated: C; 62.60, H; 7.81 , N; 10.19, S; 3.89 Found: C; 62.44, H ; 7.62, N; 10.13, S; 4.06 Example 23 N-[(2R) -3-morpholino-2- (1-naphthylmethyl) propionyl] -3- (4-thiazolyl) -DL-
Alanyl-cyclostatin- [2- (1-pyrrolidinyl) ethyl] amide (A) N- (t-butoxycarbonyl) -DL-3- (4
-Thiazolyl) alanyl-cyclostatin- [2- (1
-Pyrrolidinyl) ethyl] amide N- (t-butoxycarbonyl) -cyclostatin-
[2- (1-Pyrrolidinyl) ethyl] amide 350 mg (0.8
5 mmol) was added to 10 ml of 4N hydrochloric acid / dioxane, and the mixture was stirred at room temperature for 30 minutes. Then, the solvent was distilled off under reduced pressure and the residue was dried sufficiently. This was suspended in 20 ml of anhydrous methylene chloride, 208 mg (1.28 mmol) of diethyl cyanolinate and 386 mg (3.82 mmol) of triethylamine were added under ice cooling, and the mixture was stirred at room temperature for 3 hours, then the solvent was distilled off under reduced pressure and the residue was removed. A silica gel thin layer plate (chloroform: methanol =
5: 1) to give the title compound as white crystals, 430 mg (90
%)Obtained.

(B) N-[(2R) -3-morpholinocarbonyl-2-
(1-Naphthylmethyl) propionyl] -3- (4-thiazolyl) -DL-alanyl-cyclostatin- [2-
(1-Pyrrolidinyl) ethyl] amide 175 mg (0.31 mmol) of the compound synthesized in Example (a)
Was added to 10 ml of 4N hydrochloric acid / dioxane, and the mixture was stirred at room temperature for 30 minutes. After that, the solvent was distilled off under reduced pressure and the residue was thoroughly dried. This was suspended in 10 ml of methylene chloride, and (2
R) -3-morpholinocarbonyl-2- (1-naphthylmethyl) propionic acid 100 mg (0.31 mmol) was added,
With ice cooling, diethyl cyanophosphate 75 mg (0.46 mmol)
And 186 mg (1.84 mmol) of triethylamine were added,
The mixture was stirred at room temperature for 3 hours. After that, the solvent was distilled off under reduced pressure, and the residue was purified by a silica gel thin layer plate (chloroform: methanol = 5: 1) to obtain 60 mg (23%) of the title compound.

Mp eighty-six to ninety-three ° C. Elemental analysis _{C 42 H 58 N 6 O 6} S 1 · 4H 2 O Calculated: C; 59.50, H; 7.85 , N; 9.92, S; 3.79 Found: C; 59.21, H; 7.55, N; 9.68, S; 4.00 Example 24 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionyl] -3- (4-thiazolyl) -DL-alanyl-cyclostatin- (3-morpholinopropyl) amide (A) N- (t-butoxycarbonyl) -3- (4-thiazolyl) -DL-alanyl-cyclostatin- (3-morpholinopropyl) amide N- (t-butoxycarbonyl) -3- (4-thiazolyl) -DL-alanine 2.71 g (9.94 mmol) and cyclostatin methyl ester hydrochloride 2.64 g (9.94 mmol)
Was dissolved in 50 ml of anhydrous tetrahydrofuran, and under ice cooling,
Diethyl cyanophosphate (1.97 ml, 10.85 mmol) and triethylamine (2.76 ml, 19.89 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography (methylene chloride: methanol = 30:
Purified in 1), N- (t-butoxycarbonyl) -3
3.76 g of-(4-thiazolyl) -DL-alanylcyclostatin methyl ester was obtained as a white powder. 3.5 g (7.24 mmol) of this methyl ester was dissolved in 10 ml of methanol, 7.96 ml (7.96 mmol) of 1N sodium hydroxide solution was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. 1N hydrochloric acid 7.
96 ml (7.96 mmol) was added for neutralization, the solvent was distilled off, the residue was dissolved in 1N sodium hydroxide solution, washed with diethyl ether, the aqueous layer was acidified with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. N-hexane was added to the residue to give N- (t-butoxycarbonyl) -3.
3.18 g was obtained as white crystals of-(4-thiazolyl) -DL-alanyl-cyclostatin. 300 mg of this carboxylic acid
(0.64 mmol) and N- (3-aminopropyl) morpholine 138 mg (0.96 mmol) were dissolved in 5 ml of methylene chloride, diethyl cyanophosphate 0.17 g (0.96 mmol) and triethylamine 0.13 ml (0.96 mmol) were added at room temperature under ice cooling. It was stirred for 18 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel thin layer plate (methylene chloride: methanol = 10: 1) to give the title compound as a white powder.
0 mg was obtained.

(B) N-[(2R) -3-morpholinocarbonyl-2-
(1-Naphthylmethyl) propionyl] -3- (4-thiazolyl) -DL-alanyl-cyclostatin- (3-morpholinopropyl) amide Compound 145 mg (0.24 mmol) and (2R) synthesized in Example 24 (a) -3-morpholinocarbonyl-2- (1-
80 mg (0.24 mmol) of naphthylmethyl) propionic acid was reacted according to Example 2 (b) to obtain 140 mg of the title compound monohydrate as white crystals.

Mp 94-98 ° C. Elemental analysis _{C 43 H 60 N 6 O 7} S · H 2 O Calculated: C; 62.75, H; 7.59 , N; 10.21, S; 3.90 Found: C; 62.73, H; 7.56 , N; 10.04, S; 3.61 Example 25 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) -propionyl] -3- (4-thiazolyl) -L-alanyl-cyclostatin- [3- (2-
Oxo-1-pyrrolidinyl) propyl] amide (A) N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanyl-cyclostatin- [3-
(2-Oxo-1-pyrrolidinyl) propyl] amide N- (t-butoxycarbonyl) -cyclostatin-
[3- (2-Oxo-1-pyrrolidinyl) propyl] amide 1.0 g (2.3 mmol) and N- (t-butoxycarbonyl) -L-3- (4-thiazolyl) alanine 0.63 g
(2.3 mmol) was used and reacted according to the method of Example 3 (a) to obtain 1.08 g of the title compound as an oil.

(B) N-[(2R) -3-morpholinocarbonyl-2-
(1-Naphthylmethyl) propionyl] -3- (4-thiazolyl) -L-alanyl-cyclostatin- [3-
(2-Oxo-1-pyrrolidinyl) propyl] amide 207 mg (0.35 mmol) of the compound synthesized in Example 25 (a) and (2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionic acid 115 mg (0.35 mmol)
Was reacted according to the method of Example 1 (b) to give 207 mg of the dihydrate of the title compound as a white powder.

Rf = 0.53 Elemental analysis value C ₄₃ H ₅₈ N ₆ O ₇ S ・ Calculated as 2H ₂ O: C; 61.55, H; 7.45, N; 10.02, S; 3.82 Actual value: C; 61.74, H; 7.43, N ; 9.77, S; 3.97 Example 26 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionyl] -3- (4-thiazolyl) -DL-alanyl-cyclostatin-[(1-ethyl-2-pyrrolidinyl) methyl] amide 2-instead of N- (3-aminopropyl) morpholine
Example 24 Using Aminomethyl-1-ethylpyrrolidine
141 mg (0.24 mmol) of N- (t-butoxycarbonyl) -3- (4-thiazolyl) -DL-alanyl-cyclostatin-[(1-ethyl-2-pyrrolidinyl) methyl] amide obtained according to (a) ) And (2R) -3-morpholinocarbonyl-2- (1-naphthylmethyl) propionic acid 80 mg (0.24 mmol) were reacted according to Example 2 (b) to give 1.5 hydrate of the title compound as white crystals. 28 mg
Obtained.

Mp 85-89 ° C. Elemental analysis _{C 43 H 60 N 6 O 6} S · 1.5H 2 O Calculated: C; 63.29, H; 7.78 , N; 10.30, S; 3.93 Found: C; 63.50, H; 7.58, N; 10.07, S; 3.70 Example 27 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionyl] -3- (4-thiazolyl) -DL-alanyl-cyclostatin- (2-pyridylmethyl) amide N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionyl] -3- (4-thiazolyl) -DL-alanine 230 mg (0.50 mmol) and cyclostatin- (2-pyridylmethyl) amide dihydrochloride
187 mg (0.50 mmol) was suspended in 10 ml of anhydrous methylene chloride, 123 mg (0.75 mmol) of diethyl cyanophosphate and 230 mg (2.3 mmol) of triethylamine were added under ice cooling, and the mixture was stirred at room temperature for 3 hours, and then the solvent was added. It was evaporated under reduced pressure and the residue was purified by silica gel thin layer plate (chloroform: methanol = 10: 1) to give the title compound as a white powder.
mg was obtained.

Mp seventy-eight to eighty-six ° C. Elemental analysis _{C 42 H 52 N 6 O 6} S 1 · 2H 2 O Calculated: C; 62.67, H; 8.13 , N; 10.44, S; 3,98 Found: C; 62.64, H; 7.87, N; 10.70, S; 4.20 Example 28 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionyl] -3- (4-thiazolyl) -DL-alanyl-cyclostatin- [2- (4-methyl-1-piperazinyl) ethyl] amide N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionyl] -3- (4-thiazolyl) -DL-alanine 230 mg (0.50 mmol) and cyclostatin- [2- (4-methyl-1-piperazinyl)
Ethyl] amide trihydrochloride 223 mg (0.50 mmol) was suspended in anhydrous methylene chloride 10 ml, and under ice cooling, diethyl cyanophosphate 123 mg (0.75 mmol), triethylamine 3
After adding 00 mg (3.0 mmol) and stirring at room temperature for 3 hours, the solvent was distilled off under reduced pressure and the residue was purified on a silica gel thin layer plate (chloroform: methanol = 5: 1) to give 50 mg of the title compound as a white powder. Obtained.

Mp 80-88 ° C. Elemental analysis _{C 43 H 61 N 7 O 6} S 1 · 3H 2 O Calculated: C; 60.19, H; 7.86 , N; 11.43, S; 3.74 Found: C; 60.02, H; 7.53, N; 11.16, S; 4.00 Example 29 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) -propionyl] -3- (4-thiazolyl) -L-alanyl-cyclostatin-[(S) -2
-Methylbutyl] amide (A) N- (t-butoxycarbonyl) -cyclostatin-[(S) -2-methylbutyl] amide (S) -2-methylbutylamine 0.33 g (3.81 mmol) and N- (in place of 2-morpholinoethylamine. t-
Butoxycarbonyl) -cyclostatin 1.00 g (3.17 mmol) was reacted according to Reference Example 17 to obtain 1.13 g of white powder.

(93%) (b) N-[(2R) -3-morpholinocarbonyl-2-
(1-Naphthylmethyl) -propionyl] -3- (4-
Thiazolyl) -L-alanyl-cyclostatin-
[(S) -2-Methylbutyl] amide 0.50 g (1.30 mmol) of the compound of Example 29 (a) and N
354 mg (1.30 mmol) of-(t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanine was used in Example 1.
After reacting according to (a), further reacting according to 1 (b) to obtain 211 mg (61 mg) of the monohydrate of the title compound as a white powder.
%)Obtained.

Rf = 0.63 Elemental analysis value Calculated as C ₄₁ H ₅₇ N ₅ O ₆ S ・ H ₂ O: C; 64.29, H; 7.76, N; 9.14, S; 4.19 Actual value: C; 63.99, H; 7.56, N ; 9.20, S; 4.01 Example 30 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) -propionyl] -3- (5-isoxazolyl) -L-alanine-cyclostatin-
[(S) -2-methylbutyl] amide N- (t-butoxycarbonyl) -3- (5-isoxazolyl) -L-alanine instead of N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanine
Using 330 mg (1.3 mmol), while removing the t-butoxycarbonyl group from 500 mg (1.3 mmol) N- (t-butoxycarbonyl) -cyclostatin-[(S) -2-methylbutyl] amide, Example 1 After the reaction according to (a), the reaction was further performed according to Example 1 (b) to obtain 170 mg of a hydrate of the title compound as white crystals.

Melting point 68-72 ° C Elemental analysis: Calculated as C ₄₁ H ₅₇ N ₅ O ₇・ 2.5H ₂ O: C; 63.38, H; 8.04, N; 9.01 Found: C; 63.41, H; 7.79, N; 8.81 Example 31 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) -propionyl] -3- (4-thiazolyl) -L-alanyl-cyclostatin-[(S) -1
-Hydroxymethyl-2-methylbutyl) amide (A) N- (t-butoxycarbonyl) -cyclostatin-[(S) -1-hydroxymethyl-2-methylbutyl) amide (S) -2-amino-3-methylpentanol instead of 2-morpholinoethylamine 446 mg (3.81 mmol) and N- (t-butoxycarbonylcyclostatin 1.00 g
(3.17 mmol) was reacted according to Reference Example 17 to obtain the title compound.

(B) Instead of cyclostatin- (2-morpholinoethyl) amide, 500 mg (1.21 mmol) of the above compound and N-
(T-Butoxycarbonyl) -3- (4-thiazolyl)
330 mg (1.21 mmol) of L-alanine was used in Example 1
After reacting according to (a), further reacting according to 1 (b) to obtain 320 mg of a hydrate of the title compound as a white powder.
(47%) Rf = 0.63 Elemental analysis value: C ₄₂ H ₅₉ N ₅ O ₇ S ・ H ₂ O Calculated value: C; 63.37, H; 7.72, N; 8.80, S; 4.03 Actual value: C; 63.31, H; 7.50, N; 8.59, S; 4.00 Example 32 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionyl] -3- (4-thiazolyl) -DL-alanyl-cyclostatin- [2- (N, N-
Diethylamino) ethyl] amide N, N instead of N- (3-aminopropyl) morpholine
-N- (t-butoxycarbonyl) -3-obtained according to Example 24 (a) using diethylethylenediamine.
(4-thiazolyl) -DL-alanyl-cyclostatin-
[2- (N, N-diethylamino) ethyl] amide 139 mg
(0.24 mmol) and (2R) -3-morpholinocarbonyl-2- (1-naphthylmethyl) propionic acid 80 mg (0.24 mmol)
To give 34 mg of 2.5 hydrate of the title compound as white crystals.

Melting point 80-85 ° C Elemental analysis: C ₄₂ H ₆₀ N ₆ O ₆ S ・ Calculated as 2.5H ₂ O: C; 61.36, H; 7.97, N; 10.22, S; 3.90 Actual value: C; 61.49, H ; 7.74, N; 9.94, S; 3.60 Example 33 N-[(2R) -5,5-dimethyl-2- (1-naphthylmethyl) -4-oxohexanoyl] -3- (4-thiazolyl)- L-alanyl-cyclostatin- (2-morpholinoethyl) amide Instead of (2R) -3-morpholinocarbonyl-2- (1-naphthylmethylpropionic acid) (2R) -5,5-dimethyl-2- (1-naphthylmethyl) -4-oxohexanoic acid
Using 105 mg (0.35 mmol) and 170 mg of N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanyl-cyclostatin- (2-morpholinoethyl) amide, according to Example 1 (b). After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by a silica gel thin layer plate (chloroform: methanol = 10: 1).
84 mg of the compound with the higher Rf value as the title compound
(38%) obtained.

Melting point 84-87 ° C Elemental analysis: Calculated as C ₄₂ H ₅₉ N ₅ O ₆ S ・ H ₂ O: C; 64.67, H; 7.88, N; 8.98, S; 4.11 Found: C; 64.49, H; 7.74, N; 8.70, S; 3.90 Example 34 N- [5- (N-benzyl-N-methylamino) -2-
(1-Naphthylmethyl) -4-oxopentanoyl]-
L-leucyl-cyclostatin- (2-morpholinoethyl) amide 5- (N-benzyl-N-methylamino) -2- (1-
Naphthylmethyl) -4-oxopentanoic acid 210 mg (0.559
300 mg (0.555 mmol) of N- (t-butoxycarbonyl) -L-leucyl-cyclostatin- (2-morpholinoethyl) amide were reacted according to Example 1 (b) to give the title compound as a pale brown amorphous substance. As 141 mg
Obtained.

Rf = 0.47 Elemental _{analysis: C 47 H 67 N 5 O} 6 · 4H 2 O Calculated: C; 64.88, H; 8.69 , N; 8.05 Found: C; 65.14, H; 8.59 , N; 8.02 Example 35 N- [5- (N-benzyl-N-methylamino) -2-
(1-Naphthylmethyl) -4-oxopentanoyl]-
3- (4-thiazolyl) -L-alanyl-cyclostatin- (2-morpholinoethyl) amide 5- (N-benzyl-N-methylamino) -2- (1-
Naphthylmethyl) -4-oxopentanoic acid 130mg (0.346
Mmol) and N- (t-butoxycarbonyl) -3-
(4-thiazolyl) -L-alanyl-cyclostatin-
200 mg (0.344 mmol) of (2-morpholinoethyl) amide was synthesized according to Example 1 (b) to obtain 26 mg of the title compound as a pale brown amorphous substance.

Rf = 0.42 Elemental analysis value: C ₄₇ H ₆₂ N ₆ O ₆ S ・ Calculated as 3H ₂ O: C; 63.20, H; 7.67, N; 9.41, S; 3.59 Actual value: C; 63.36, H; 7.55, N; 9.31, S; 3.23 Example 36 N-[(2R) -5-morpholinocarbonyl-2- (1-
Naphthylmethyl) pentanoyl] -3- (4-thiazolyl) -L-alanyl-cyclostatin- (2-morpholinoethyl) amide (A) 5-morpholinocarbonyl-2- (1-naphthylmethyl) pentanoic acid Dimethyl adipate 26.4 g (0.15 mol) and 1-naphthaldehyde 23.7 g (0.15 mol) were dissolved in 200 ml of anhydrous methanol and cooled to 55% under ice cooling. Sodium hydride 7.96g (0.18mol)
After adding, the mixture was heated under reflux for 30 minutes. 150 ml (0.15 mol) of 1N sodium hydroxide solution was added to this solution, and the mixture was heated under reflux for 1 hour. After the solvent was distilled off under reduced pressure, water was added to the residue and the mixture was washed with ether. The aqueous layer was acidified and extracted with ether.
The ether layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, isopropyl ether was added to the residue, and the precipitated crystals were taken,
14.2 g of (1-naphthylidene) adipic acid was obtained.

100 g of acetic anhydride was added to 10 g (35 mmol) of 2- (1-naphthylidene) adipic acid, and the mixture was stirred at 60 ° C. for 1 hour.
After distilling off the solvent, a mixed solution of benzene / hexane (1: 1) was added to the residue and decanted to obtain 8.8 g of oily 2- (1-naphthylidene) adipic anhydride.

4.4 g (16.5 mmol) of 2- (1-naphthylidene) adipic anhydride was dissolved in 80 ml of methylene chloride, 1.58 ml (18.2 mmol) of morpholine was added thereto, and the mixture was stirred at room temperature for 14 hours. The reaction solution was washed with a 5% citric acid solution and saturated saline,
It was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (methylene chloride: methanol = 30: 1) to obtain 1.12 g of 5-morpholinocarbonyl-2- (1-naphthylidene) pentanoic acid.

350 mg (0.99 mmol) of this pentanoic acid was added to 10 m of methanol.
It was dissolved in 1 l, 100 mg of 10% palladium carbon was added, and hydrogenated at atmospheric pressure. After removing the catalyst, the solvent was concentrated under reduced pressure to obtain 305 mg of a monohydrate of the title compound as a white powder.

Mass spectrum m / e: 355 Elemental _{analysis: C 21 H 25 NO 4 ·} H 2 O Calculated: C; 67.54, H; 7.29 , N; 3.75 Found: C; 67.88, H; 7.03 , N; 3.61 (B) N-[(2R) -5-morpholinocarbonyl-2-
(1-Naphthylmethyl) pentanoyl] -3- (4-thiazolyl) -L-alanyl-cyclostatin- (2-morpholinoethyl) amide (2R) -3-morpholinocarbonyl-2- (1-naphthylmethyl) propionic acid Instead of 5-morpholinocarbonyl-2- (1-naphthylmethyl) pentanoic acid 275mg
(0.77 mmol) while using N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanyl-
Cyclostatin- (2-morpholinoethyl) amide 360m
After removing the t-butoxycarbonyl group from g (0.77 mmol), the reaction was carried out according to Example 3 (a), and the lower spot of the two main spots was the silica gel thin layer plate (methylene chloride: methanol = 8: 1). 80 mg of 3.5 hydrate of the title compound was obtained as white crystals.

Melting point 101-105 ℃ Optical rotation ▲ [α] ²⁷ _D ▼ ＝ −21.9 ° (C = 0.3, Methanol) Rf value 0.54 Elemental analysis value: Calculated as C ₄₄ H ₆₂ N ₆ O ₇ S ・ 3.5H ₂ O: C; 59.91, H; 7.88, N; 9.53, S; 3.63 Found: C; 60.06, H; 7.79, N; 9.45, S; 3.59 Example 37 N-[(2R) -3- (benzylcarbamoyl)- 2-
(1-Naphthylmethyl) propionyl] -3- (4-thiazolyl) -DL-alanyl-cyclostatin- (2-morpholinoethyl) amide (2R) -3- (Benzylcarbamoyl) -2- (1-naphthylmethyl) propionic acid 100 mg (0.32 mmol) and N- (t-butoxycarbonyl) -3- (4-thiazolyl) -DL-alanyl-cyclostatin 180 mg (0.32 mmol) of-(2-morpholinoethyl) amide was used in Example 2
The reaction was carried out according to (b), and 77 mg of the title compound was obtained as a colorless amorphous.

Rf = 0.50 Elemental analysis value: C ₄₅ H ₅₈ N ₆ O ₆ S ・ Calculated as 1.5H ₂ O: C; 64.49, H; 7.34, N; 10.03, S; 3.83 Actual value: C; 64.43, H; 7.03 , N; 9.82, S; 3.82 Example 38 N-[(2R) -4-morpholinocarbonyl-2- (1-
Naphthylmethyl) butanoyl] -3- (4-thiazolyl) -L-alanyl-cyclostatin- (2-morpholinoethyl) amide In place of (2R) -3-morpholinocarbonyl-2- (1-naphthylmethyl) propionic acid, 4-morpholinocarbonyl-2- (1-naphthylmethyl) butyric acid 249 mg (0.73
Mmol) and N- (t-butoxycarbonyl) -3-
(4-thiazolyl) -L-alanyl-cyclostatin-
384 mg (0.66 mmol) of (2-morpholinoethyl) amide was reacted according to Example 1 (a), and the lower spot of the two main spots was separated with a silica gel thin layer plate (methylene chloride: methanol = 8: 1). After separation and purification, 110 mg of a monohydrate of the title compound was obtained as white crystals.

Melting point 87-90 ℃ Optical rotation ▲ [α] ²⁵ _D ▼ ＝ −24.4 ° (C = 0.5, methanol) Rf value 0.58 Elemental analysis value C ₄₃ H ₆₀ N ₆ O ₇ S ・ H ₂ O Calculated value: C; 62.73, H; 7.59, N; 10.21, S; 3.89 Found: C; 62.95, H; 7.76, N; 9.90, S; 4.10 Example 39 N-[(2R) -3- (N-benzyl-N- Methylcarbamoyl) -2- (1-naphthylmethyl) propionyl]
-3- (5-isoxazolyl) -L-alanyl-cyclostatin- (2-morpholinoethyl) amide (2R) -3- (N-benzyl-N-methylcarbamoyl) -2- (1-naphthylmethyl) propionic acid 100 mg
(0.28 mmol) and N- (t-butoxycarbonyl)-
160 mg of 3- (5-isoxazolyl) -L-alanyl-cyclostatin- (2-morpholinoethyl) amide (0.2
8 mmol) was reacted according to Example 3 (b) to give 56 mg of the title compound as a colorless amorphous.

Rf 0.41 Elemental analysis value: Calculated as C ₄₆ H ₆₀ N ₆ O ₇・ 2H ₂ O: C; 65.38, H; 7.63, N; 9.95 Actual value: C; 65.40, H; 7.38, N; 9.94 Reference example 1 N- [3- (1-naphthyl) propionyl]-(S)-
(−)-4-Benzyl-2-oxazolidinone (S)-(−)-4-in 50 ml of anhydrous tetrahydrofuran
Benzyl-2-oxazolidinone (2.63 g, 14.8 mmol) was dissolved, and n-butyllithium / hexane solution (14.8 mmol) was added dropwise at -78 ° C under a nitrogen atmosphere. After stirring for 30 minutes, 1-naphthylpropionyl chloride was added. 2.95g (1
A solution of 3.5 mmol) dissolved in 15 ml of anhydrous tetrahydrofuran was slowly added dropwise at the same temperature, and the mixture was stirred for 3 hours. Then, saturated saline was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 4) to give the title compound as a white amorphous product, 4.65 g (96%). Obtained.

Mass spectrum m / e: 359 (M ⁺ ) Reference Example 2 N-[(2-benzyloxycarbonyl) methyl-3-
(1-Naphthyl) propionyl]-(S)-(-)-4
-Benzyl-2-oxazolidinone 2.18 ml (15.6 mmol) of diisopropylamine was dissolved in 40 ml of anhydrous tetrahydrofuran, and under nitrogen atmosphere,
At 78 ° C., a n-butyllithium / hexane solution (15.6 mmol) was added dropwise, and the mixture was stirred for 15 minutes. Furthermore, Reference Example 1
N- [3- (1-naphthyl) propionyl] synthesized in
-(S)-(-)-4-benzyl-2-oxazolidinone 4.65 g (12.9 mmol) was added to anhydrous tetrahydrofuran 15 m.
The solution dissolved in 1 was slowly added dropwise at the same temperature, and the mixture was further stirred for 30 minutes. Thereafter, benzyl acetic acid benzyl ester (6.13 ml, 38.7 mmol) was added, the mixture was stirred at the same temperature for 6 hours, 1N hydrochloric acid (15.6 ml) and saturated saline (100 ml) were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (ethyl acetate: n-hexane = 1: 6) to give 3.23 g (49%) of the title compound, Obtained as a colorless oil.

Mass spectrum m / e: 507 (M ⁺ ) Elemental analysis value: Calculated as C ₃₂ H ₂₉ NO ₅ : C; 75.72, H; 5.76, N; 2.76 Actual value: C; 75.34, H; 5.90, N; 2.76 % Reference Example 3 N- [2- (morpholinocarbonyl) methyl-3- (1
-Naphthyl) propionyl]-(S)-(-)-4-benzyl-2-oxazolidinone 1.60 g (3.15 mmol) of the compound synthesized in Reference Example 2 was dissolved in 100 ml of ethanol, and 10% palladium-carbon (200 mg) was dissolved.
Was added, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. Then, the catalyst was removed, the solvent was distilled off under reduced pressure, and the carboxylic acid 1.30 was added.
g (99%) was obtained. This compound was dissolved in 20 ml of anhydrous tetrahydrofuran to give 0.33 ml (3.78 mmol) of morpholine.
Furthermore, 0.57 ml (3.76 mmol) of diethyl cyanophosphate and 0.52 ml of triethylamine were added under a nitrogen atmosphere under ice cooling, and the mixture was stirred at the same temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (ethyl acetate: n-hexane = 2: 1) to obtain 1.23 g (81%) of the title compound as white crystals.

Melting point 80-82 ℃ Mass spectrum m / e: 486 (M ⁺ ) ▲ [α] ²⁵ _D ▼ +107.9 (C = 0.42, methanol) Elemental analysis value: Calculated as C ₂₉ H ₃₀ N ₂ O ₅ : C 71.59, H; 6.21, N; 5.76 Actual value: C; 70.07, H; 6.12, N; 5.71% Reference Example 4 (2R) -3- (morpholinocarbonyl) -2- (1-naphthylmethyl) propionic acid Reference 1.28 g (2.63 mmol) of the compound synthesized in Example 3 was dissolved in 40 ml of tetrahydrofuran and 10 ml of water, and 221 mg (5.27 mmol) of lithium hydroxide monohydrate was added under ice-cooling for 3 hours at the same temperature. It was stirred. Concentrate the solvent under reduced pressure to 10
% Aqueous sodium hydroxide, and extract with methylene chloride,
The aqueous layer was adjusted to pH 2 with hydrochloric acid, further extracted with methylene chloride, and dried over magnesium sulfate. The solvent was distilled off to obtain 750 mg (87%) of the title compound as a white crystal.

Melting point 62-66 ° C Mass spectrum m / e: 328 (M ⁺ +1) ▲ [α] ²⁵ _D ▼ + 5.0 ° (C = 0.18, methanol) Reference Example 5 5-isoxazolylmethyl-acetaminomalonic acid Diethyl ester Acetaminomalonic acid diethyl ester (14.0 g, 6.43 mmol) was dissolved in dimethylformamide (150 ml), and 55% sodium hydride (3.1 g, 70.7 mmol) was added under ice-cooling, followed by stirring for 1 hour. 23.9 g (0.148 mol) of 5-bromomethylisoxazole was added to this reaction solution, and the mixture was kept at room temperature.
It was stirred for 4.5 hours. The reaction mixture is concentrated under reduced pressure, water is added to the residue and the mixture is extracted with ethyl acetate. After washing with water and drying over anhydrous magnesium sulfate, ethyl acetate was distilled off, and the residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate / n-hexane = 1/2) to give 14.78 g of the title compound.
(77.1%) was obtained.

Melting point 75-76 ° C Reference Example 6 3- (5-isoxazolyl) -DL-alanine hydrochloride 5-isoxazolyl-acetaminomalonate diethyl
19.0 g (63.7 mmol) was suspended in 40 ml of ethanol, and 6
120 ml of normal hydrochloric acid was added, and the mixture was heated under reflux with stirring for 13 hours.
The reaction solution was concentrated under reduced pressure, acetone was added to the residue, and the mixture was crystallized and then collected. The crystals were washed with acetone and dried to give 12.45 g (100%) of the title compound.

Elemental analysis value: Calculated as C ₆ H ₈ N ₂ O ₃ .HCl: C; 37.42, H; 4.71, N; 14.55, Cl; 18.41 Actual value: C; 37.54, H; 4.68, N; 14.43, Cl; 18.37% Reference Example 7 N-acetyl-3- (5-isoxazolyl) -DL-alanine 3- (5-isoxazolyl) -DL obtained in Reference Example 6
-Dissolve 12.45 g of alanine hydrochloride in 100 ml of methanol,
20 ml of pyridine and 20 ml of acetic anhydride are added under ice cooling, and the mixture is stirred at room temperature for 8 hours. After standing overnight, the solvent was distilled off under reduced pressure, water was added to the residue, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 10.39 g of the title compound as a brown oil. (82.3%) obtained.

Reference Example 8 N- (t-butyroxycarbonyl)-(5-isoxazolyl) -L-alanine 10.39 g (52.4 mmol) of N-acetyl-3- (5-isoxazolyl) -DL-alanine was dissolved in 100 ml of water, Two
Adjust to pH 7.5 by adding normal sodium hydroxide. To this solution, 2.0 g of acylase was added and stirred at 30 ° C. for 24 hours.
Pass the reaction solution, add concentrated hydrochloric acid to the solution to adjust to pH 1,
After mixing with ethyl acetate, the aqueous layer is separated and potassium carbonate is added to adjust the pH to 10. Then, 20 g of di-t-butoxydicarbonate, 40 ml of acetone and 100 ml of methanol are added, and the mixture is stirred at room temperature for 2.5 hours. After standing overnight, concentrate under reduced pressure, add 100 ml of water to the residue, add citric acid, and p.
Adjust to H2.0. The reaction solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform / methanol = 95/5) to give the title compound.
2.99 g (22.3%) was obtained as an oil.

Reference Example 9 t-butyl 3- (1-naphthyl) propionate diethyl (1-naphthyl) methyl malonate 20 g (66.6 m
mol) was dissolved in 200 ml of 80% water-containing methanol, 18.7 g (0.333 mol) of potassium hydroxide was added, and the mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in water, washed with ethyl acetate, the aqueous layer was acidified with concentrated hydrochloric acid and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. Heat the residue at 200 ° C for 30 minutes,
After decarboxylation, 200 ml of ether was added to the reaction mixture and suspended, and 19 ml of t-butanol, 16.5 g (80 mmol) of dicyclohexylcarbodiimide and 0.8 g of N, N-dimethylaminopyridine were added to the suspension, and the mixture was reacted for 24 hours. . The precipitated insoluble matter was separated, the solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (CH ₂ Cl ₂ ) to obtain 12.18 g (71.4%) of the desired compound as a pale yellow oil.

NMR (CDCl ₃ ) δ: 1.43 (9H, s), 7.2 to 8.2 (7H, m) Reference Example 10 t-Butyl 2- (1-naphthyl) methyl-4-pentenoate Diisopropylamine 1 in 100 ml of anhydrous tetrahydrofuran.
0 ml was added, and 1.4 Nn-butyllithium 51 ml (7
(1.4 mmol) and stirred for 15 minutes, and then compound 12.
A solution prepared by dissolving 18 g (47.5 mmol) in 200 ml of anhydrous tetrahydrofuran was added, and the mixture was stirred for 15 minutes. Next, 6.9 g of allyl bromide
(57 mmol) was added and the temperature was raised to room temperature, followed by stirring for 2 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% Aco Et / hexane) to obtain 12.92 g (91.8%) of the target compound as a pale yellow oily substance.

NMR (CDCl ₃ ) δ: 1.30 (9H, s), 7.2 to 8.2 (7H, m) Reference Example 11 t-Butyl 4,5-epoxy-2- (1-naphthyl) methylpentanoate Reference Example 10 compound 12.92 g (43.6 mmol) and m-chloroperbenzoic acid 11.29 g (65.4 mmol) were added to 100 ml of dichloromethane, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% MeOH / CH ₂ Cl ₂ ) to give the target compound. As a pale yellow oil, 4.57 g (33.6%)
Obtained.

NMR (CDCl ₃ ) δ: 1.33 (9H, d), 7.2 to 8.2 (7H, m) Reference Example 12 t-butyl 4-hydroxy-5-morpholino-2-
(1-Naphthyl) methylpentanoate 2 g (6.4 mmol) of the compound of Reference Example 11 and 0.84 ml of morpholine were added to 50 ml of methanol, and the mixture was stirred at room temperature for 6 hours and left overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (10% MeOH / CH ₂ Cl ₂ ) to give 1.96 g (76.6%) of the desired compound as a pale yellow oil.
Obtained.

NMR (CDCl ₃ ) δ: 1.30 (9H, s), 7.2 to 8.2 (7H, m) Reference Example 13 t-Butyl 5-morpholino-2- (1-naphthyl) methyl-4-oxopentanoate Reference Example 12 1.96 g (4.91 mmol) of the above compound was dissolved in 20 ml of anhydrous N, N-dimethylsulfoxide, and sulfur trioxide and pyridine complex 2.3 g (14.7 mmol) and triethylamine were dissolved at room temperature.
2.1 ml was added, and the mixture was stirred for 6 hours and left overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate,
It was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% MeOH / CH ₂ Cl ₂ ) to obtain 1.30 g (66.7%) of the target compound as a light brown oily substance.

NMR (CDCl ₃ ) δ: 1.38 (9H, s), 7.2 to 8.2 (7H, m) Reference Example 14 5-morpholino-2- (1-naphthylmethyl) -5-oxopentanoic acid Dimethyl glutarate 25 g (0.16 mol ) And 1-naphthaldehyde (23.4 g, 0.16 mol) were dissolved in 200 ml of anhydrous methanol, and 8.17 g (0.19 mol) of 55% sodium hydride was added under ice cooling, followed by heating under reflux for 30 minutes. To this solution was added 190 ml (0.19 mol) of 1N aqueous sodium hydroxide solution, and the mixture was heated under reflux for 1 hour. After the solvent was distilled off under reduced pressure, water was added to the residue and the mixture was washed with ether. The aqueous layer was acidified and extracted with ether. The ether layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, isopropyl ether was added to the residue, and the precipitated crystals were collected.
18.5 g of (1-naphthylmethylene) glutaric acid was obtained.

100 ml of acetic anhydride was added to 10 g (37 mmol) of 2- (1-naphthylmethylene) glutaric acid, and the mixture was stirred at 60 ° C. for 1 hour. After distilling off the solvent under reduced pressure, benzene / hexane (1:
The mixed solution of 1) was added, and the precipitated crystals were collected by filtration, and 2- (1-
8.1 g of glutaric anhydride was obtained.

7.5 g of 2- (1-naphthylmethylene) glutaric anhydride
(Mmol) was dissolved in 70 ml of methylene chloride, 2.85 ml (33 mmol) of morpholine was added thereto, and the mixture was stirred at room temperature for 4 hours. The reaction solution was washed with a 5% citric acid solution and saturated saline,
It was dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 10.0 g (30 mmol) of 5-morpholino-2- (1-naphthylmethylene) -5-oxopentanoic acid.

5.0 g (14.8 mmol) of this pentanoic acid was added to 50 ml of methanol.
Was dissolved in 10% palladium carbon (1.0 g), and the mixture was hydrogenated under normal pressure. After removing the catalyst by filtration, the solvent was distilled off under reduced pressure, ether was added to the residue, and the precipitated crystals were collected by filtration to give 4.5 g of 5-morpholino-2- (1-naphthylmethyl) -5-oxopentanoic acid as white crystals. Obtained. Mp: 130-135 ° C. Elemental analysis: Calculated _{C 20 H 23 NO 4: C} ; 70.36, H; 6.79, N; 4.10 Found: C; 69.86, H; 6.90 , N; 3.98 Reference Example 15 (3.3- Dimethyl dimethyl-2-oxobutyl)-(1naphthylmethyl) malonate Diethyl (1-naphthyl) methylmalonate 5.00g (16.9
Was dissolved in 50 ml of anhydrous dimethylformamide, 1.00 g (18.5 mmol) of sodium methoxide was added under ice cooling, and the mixture was stirred for 30 minutes. After 30 minutes, a solution prepared by dissolving 3.31 g (18.5 mmol) of 1-bromopinacolone in 10 ml of anhydrous dimethylformamide was added dropwise, and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, saturated brine was added to the residue, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, ethyl acetate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 6: 1).
The title compound was obtained as a colorless oily substance in an amount of 5.51 g (82%).

Mass spectrometry m / e 398 (M ⁺ ) Reference Example 16 5,5-Dimethyl-2- (1-naphthylmethyl) -4-oxopentanoic acid 5.13 g (12.9 mmol) of the diester compound synthesized above was converted into methanol: water = It was dissolved in 200 ml of a 4: 1 solution, 2.57 g (64.3 mmol) of sodium hydroxide was added, and the mixture was stirred at room temperature for 3 hours. After 3 hours, the solvent was distilled off under reduced pressure, a 10% aqueous sodium hydroxide solution was added to the residue, and the mixture was washed with methylene chloride. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, and the precipitated crystals were taken. After drying, 3.60 g (82%) of dicarboxylic acid was obtained as white crystals. 2.00 g (5.84 mmol) of this dicarboxylic acid
Was heated at 200 ° C. for 1 hour for decarbonation to give 1.65 g (95%) of the title compound as white crystals.

Mass spectrometry m / e 298 (M ⁺ ) Reference Example 17 (a) N- (t-butoxycarbonyl) -cyclostatin- (2-morpholinoethyl) amide Nt-butoxycarbonylcyclostatin 3.16 g in anhydrous tetrahydrofuran 30 ml, 2-morpholinoethylamine 1.43 g and triethylamine 2.1 ml were added, and the mixture was cooled with ice.
2 g of diethyl cyanophosphate (90%) was added dropwise, the mixture was stirred for 4 hours, and then left overnight. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; dichloromethane and methanol: dichloromethane = 1: 9) to obtain 3.4 g of the title compound as a colorless amorphous substance.

(B) Cyclostatin- (2-morpholinoethyl) amide dihydrochloride To 30 ml of methanol was added 3.4 g of Nt-butoxycarbonyl-cyclostatin-2-morpholinoethylamide and 30 ml of 1N-hydrochloric acid-dioxane, and the mixture was stirred at room temperature for 1 hour. Stir for hours. The reaction mixture is concentrated under reduced pressure and the residue is washed with ether to give 3.7 g of the title compound as colorless powder crystals with a melting point of 70-80 ° C.
Got

Reference Example 18 (2R) -3- (2,6-dimethylmorpholinocarbonyl)
-2- (1-Naphthylmethyl) propionic acid (a) (4S) -4-benzyl-3-[(2R) -3- (2,
6-Dimethylmorpholinocarbonyl) -2- (1-naphthylmethyl) propionyl] -2-oxazolidinone 340 mg (0.67 mmol) of the compound synthesized in Reference Example 2 was prepared according to the method of Reference Example 3 to give 2,6-dimethylmorpholine 80 mg.
By reacting with (0.67 mmol), 260 mg of the title compound was obtained as a white powder.

(B) (2R) -3- (2,6-dimethylmorpholinocarbonyl) -2- (1-naphthylmethyl) propionic acid 0.24 g (0.47 mmol) of the compound synthesized in Reference Example 18 (a) was used in Reference Example 4 The reaction was performed according to the method described in (1) to give 97 mg of the title compound as a white powder.

Mass spectrum m / e: 355 (M ⁺ ) Elemental analysis value Calculated as C ₂₁ H ₂₅ NO ₄・ 1 / 2H ₂ O: C; 69.21, H; 7.19, N; 3.84 Found: C; 68.98, H; 7.14, N; 4.09 Reference Example 19 (2R) -3- (1-naphthyl) -2-thiomorpholinocarbonylmethylpropionic acid (a) (4S) -4-benzyl-3-[(2R) -3- (1
-Naphthyl) -2-thiomorpholinocarbonylmethylpropionyl] -2-oxazolidinone 340 mg (0.67 mmol) of the compound synthesized in Reference Example 2 was reacted with 70 mg (0.67 mmol) of thiomorpholine according to the method of Reference Example 3 to give the title compound. 220 mg of the compound was obtained as a white powder.

(B) (2R) -3- (1-naphthyl) -2-thiomorpholinocarbonylmethylpropionic acid The compound 0.20 g (0.4 mmol) synthesized in Reference Example 19 (a) was reacted according to the method of Reference Example 4. Then, 84 mg of the title compound was obtained as a white powder.

Mass spectrum m / e: 343 (M ⁺ ) Elemental analysis value Calculated as C ₁₉ H ₂₁ NO ₃ S ・ 1 / 2H ₂ O: C; 64.75, H; 6.29, N; 3.97, S; 9.10 Measured value: C ; 65.05, H; 6.34, N; 4.21, S; 8.80 Reference Example 20 (2R) -2- (1-naphthylmethyl) -3- (1-pyrrolidinylcarbonyl) propionic acid (a) (4S) -4 -Benzyl-3-[(2R) -2- (1
-Naphthylmethyl) -3- (1-pyrrolidinylcarbonyl) propionyl] -2-oxazolidinone The compound 305 mg (0.6 mmol) synthesized in Reference Example 2 was prepared according to the method of Reference Example 3 and pyrrolidine 43 mg (0.6 mmol).
Reacts with 240 mg of the title compound as colorless amorphous
Obtained.

Elemental analysis value: Calculated as C ₂₉ H ₃₀ N ₂ O ₄・ 0.5H ₂ O: C; 72.63, H; 6.52, N; 5.84 Actual value: C; 72.68, H; 6.32, N; 5.81 Mass spectrum m / e: 470 (M ⁺ ) (b) (2R) -2- (1-naphthylmethyl) -3- (1
-Pyrrolidinylcarbonyl) propionic acid 220 mg (0.47 mmol) of the compound synthesized in Reference Example 20 (a) was reacted according to the method of Reference Example 4 to obtain 83 mg of the title compound as a colorless amorphous.

Mass spectrum m / e: 311 (M ⁺ ) Reference Example 21 (2R) -3- (1-naphthyl) -2-piperidinocarbonylmethylpropionic acid (a) (4S) -4-benzyl-3-[( 2R) -3- (1
-Naphthyl) -2-piperidinocarbonylmethylpropionyl] -2-oxazolidinone Compound 610 mg (1.2 mmol) synthesized in Reference Example 2 was used according to the method of Reference Example 3 to give piperidine 250 mg (1.4 mmol).
To give 530 mg of the title compound as a white powder.

(B) (2R) -3- (1-naphthyl) -2-piperidinocarbonylmethylpropionic acid 0.50 g (1.03 mmol) of the compound synthesized in Reference Example 21 (a) was prepared according to the method of Reference Example 4. The reaction was performed to obtain 180 mg of the title compound as a white powder.

Mass spectrum m / e: 325 (M ⁺ ) Elemental analysis value Calculated as C ₂₀ H ₂₃ NO ₃・ 1 / 2H ₂ O: C; 71.83, H; 7.23, N; 4.19 Found: C; 71.60, H; 6.96, N; 4.20 Reference Example 22 (2R) -3- (1-naphthyl) -2-[(propylcarbamoyl) methyl) propionic acid (a) (4S) -4-benzyl-3-[(2R) -3 -(1
-Naphtyl) -2-[(propylcarbamoyl) methyl] propionyl] -2-oxazolidinone The compound 610 mg (1.2 mmol) synthesized in Reference Example 2 was reacted with 83 mg (1.4 mmol) propylamine according to the method of Reference Example 3. Then, 210 mg of the title compound was obtained as a white powder.

(B) (2R) -3- (1-naphthyl) -2-[(propylcarbamoyl) methyl] propionic acid 0.17 g (0.37 mmol) of the compound synthesized in Reference Example 22 (a) was used in the method of Reference Example 4. The reaction was followed in the same manner to obtain 100 mg of the title compound as a white powder.

Mass spectrum ^{m / e: 299 (M +} ) Elemental analysis _{C 18 H 21 NO 3 · 1} / 4H 2 O Calculated: C; 71.14, H; 7.13 , N; 4.61 Found: C; 70.98, H; 7.13, N; 4.59 Reference Example 23 (2R) -3- (1-naphthyl) -2-[(phenethylcarbamoyl) methyl] propionic acid (a) (4S) -4-benzyl-3-[(2R) -3 -1-
Naphthyl) -2-[(phenethylcarbamoyl) methyl] propionyl] -2-oxazolidinone 350 mg (0.84 mmol) of the compound synthesized in Reference Example 2 was prepared according to the method of Reference Example 3 and phenethylamine 125 mg (1.04
390 m of the title compound as a white powder.
g got.

(B) (2R) -3- (1-naphthyl) -2-[(phenethylcarbamoyl) methyl] propionic acid 340 mg (0.65 mmol) of the compound synthesized in Reference Example 23 (a) was prepared according to the method of Reference Example 4. And reacted to give 230 mg of the title compound as a white powder.

Mass spectrum 361 (M ⁺ ) Reference Example 24 (2R) -3- (4-Methyl-1-piperazinylcarbonyl) -2- (1-naphthylmethyl) propionic acid (a) (4S) -4-benzyl- 3-[(2R) -3- (4
-Methyl-1-piperazinylcarbonyl) -2- (1-
Naphthylmethyl) -propionyl] -2-oxazolidinone Compound 610 mg (1.2 mmol) synthesized in Reference Example 2 was prepared according to the method of Reference Example 3 and N-methylpiperazine 120 mg (1.2
To give 540 mg of the title compound as a colorless amorphous substance.

Elemental _{analysis: C 30 H 33 N 3 O} 4 · 0.5H 2 O Calculated: C; 70.84, H; 6.74 , N; 8.26 Found: C; 70.62, H; 6.44 , N; 8.11 (b) ( 2R) -3- (4-Methyl-1-piperazinylcarbonyl) -2- (1-naphthylmethyl) propionic acid 480 mg (0.96 mmol) of the compound synthesized in Reference Example 24 (a) was used in the method of Reference Example 4. According to the above-mentioned reaction, the title compound was obtained as a colorless oil to obtain 115 mg.

Reference Example 25 (2R) -3- (1-naphthyl) -2-[(4-phenyl-1-piperazinyl) carbonylmethyl] propionic acid (a) (4S) -4-benzyl-3-[(2R)- 3- (1
-Naphthyl) -2-[(4-phenyl-1-piperazinyl) carbonylmethyl] propionyl] -2-oxazolidinone 340 mg (0.67 mmol) of the compound synthesized in Reference Example 2 was prepared according to the method of Reference Example 3 and 1-phenyl 110 mg piperazine
By reacting with (0.67 mmol), 230 mg of the title compound was obtained as a white powder.

(B) (2R) -3- (1-naphthyl) -2-[(4-phenyl-1-piperazinyl) carbonylmethyl] propionic acid 0.21 g (0.37 mmol) of the compound synthesized in Reference Example 25 (a) was added. The reaction was performed according to the method of Reference Example 4 to obtain 103 mg of the title compound as a white powder.

Mass spectrum m / e: 402 (M ⁺ ) Elemental analysis value Calculated as C ₂₅ H ₂₆ N ₂ O ₃ 1 / 2H ₂ O: C; 72.97, H; 6.61, N; 6.81 Actual value: C; 72.68, H; 6.62, N; 6.67 Reference Example 26 (2R) -3- (N, N-diethylcarbamoyl) -2-
(1-Naphthylmethyl) propionic acid (a) (4S) -4-benzyl-3-[(2R) -3- (N,
N-diethylcarbamoyl) -2- (1-naphthylmethyl) propionyl] -2-oxazolidinone Compound 305 mg (0.6 mmol) synthesized in Reference Example 2 was reacted with diethylamine 44 mg (0.6 mmol) according to the method of Reference Example 3. The title compound as colorless amorphous.
0 mg was obtained.

Elemental analysis value: Calculated as C ₂₉ H ₃₂ N ₂ O ₄ 0.25H ₂ O: C; 73.01, H; 6.87, N; 5.87 Actual value: C; 73.08, H; 6.85, N; 5.64 Mass spectrum m / e: 472 (M ⁺ ) (b) (2R) -3- (N, N-diethylcarbamoyl)-
2- (1-Naphthylmethyl) propionic acid 230 mg (0.49 mmol) of the compound synthesized in Reference Example 26 (a) was reacted according to the method of Reference Example 4 to obtain 100 mg of the title compound as a colorless amorphous.

Mass spectrum m / e: 313 (M ⁺ ) Reference Example 27 (2R) -3- (benzylcarbamoyl) -2- (1-naphthylmethyl) propionic acid (a) (4S) -4-benzyl-3-[( 2R) -3- (Benzylcarbamoyl) -2- (1-naphthylmethyl) propionyl] -2-oxazolidinone 610 mg (1.2 mmol) of the compound synthesized in Reference Example 2 was used according to the method of Reference Example 3 to obtain benzylamine 130 mg ( 1.2 mmol) to give 530 mg of the title compound as a colorless oil.

Elemental analysis value: Calculated as C ₃₂ H ₃₀ N ₂ O ₄ : C; 75.87, H; 5.97, N; 5.53 Actual value: C; 75.72, H; 6.07, N; 5.66 ▲ [α] ²⁵ _D ▼: +152 .7 (C = 1.5, MeOH) (b) (2R) -3- (benzylcarbamoyl) -2-
(1-Naphthylmethyl) propionic acid 450 mg (0.92 mmol) of the compound synthesized in Reference Example 27 (a) was reacted according to the method of Reference Example 4 to obtain 270 mg of the title compound as colorless amorphous.

Elemental _{analysis: C 22 H 21 NO 3 ·} 0.25H 2 O Calculated: C; 75.09, H; 6.16 , N; 3.98 Found: C; 74.85, H; 6.16 , N; 3.97 ▲ [α] ²⁵ _D ▼: + 30 ° (C = 1, MeOH) Mass spectrum m / e: 347 (M ⁺ ) Reference Example 28 4-morpholinocarbonyl-2- (1-naphthyl) butyric acid Dimethyl glutarate 25 g (0.16 mol) and 1-naphtho Laldehyde 23.4g (0.16mol) is dissolved in anhydrous methanol 200ml, 55% sodium hydride 8.17g (0.19mol) under ice cooling
After adding, the mixture was heated under reflux for 30 minutes. To this solution was added 190 ml (0.19 mol) of 1N aqueous sodium hydroxide solution, and the mixture was heated under reflux for 1 hour. After the solvent was distilled off under reduced pressure, water was added to the residue and the mixture was washed with ether. The aqueous layer was acidified and extracted with ether. The ether layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, isopropyl ether was added to the residue, and the precipitated crystals were collected by filtration.
18.5 g of (1-naphthylmethylene) glutaric acid was obtained.

100 ml of acetic anhydride was added to 10 g (37 mmol) of 2- (1-naphthylmethylene) glutaric acid, and the mixture was stirred at 60 ° C. for 1 hour. After distilling off the solvent under reduced pressure, benzene / hexane (1:
The mixed solution of 1) was added, and the precipitated crystals were collected by filtration, and 2- (1-
8.1 g of glutaric anhydride was obtained.

7.5 g of 2- (1-naphthylmethylene) glutaric anhydride
(Mmol) was dissolved in 70 ml of methylene chloride, 2.85 ml (33 mmol) of morpholine was added thereto, and the mixture was stirred at room temperature for 4 hours. The reaction solution was washed with a 5% citric acid solution and saturated saline,
It was dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 10.0 g (30 mmol) of 4-morpholinocarbonyl-2- (1-naphthylmethylene) butyric acid.

5.0 g (14.8 mmol) of this butyric acid was dissolved in 50 ml of methanol, 1.0 g of 10% palladium carbon was added, and the mixture was hydrogenated under normal pressure.
After removing the catalyst by filtration, the solvent was evaporated under reduced pressure, ether was added to the residue, and the precipitated crystals were collected by filtration to obtain 4.5 g of 4-morpholinocarbonyl-2- (1-naphthylmethyl) butyric acid as white crystals.

Mp: 130-135 ° C. Elemental analysis C ₂₀ H ₂₃ NO ₄ Calculated: C; 70.36, H; 6.79 , N; 4.10 Found: C; 70.06, H; 6.90 , N; 3.98 Reference Example 29 t-Butyl 5 -(N-benzyl-N-methyl) amino-4-hydroxy-2- (1-naphthylmethyl) pentanoate t-butyl 3,5-epoxy-2- (1-naphthylmethyl) pentanoate (Reference Example 11) 2.39 g (7.65 mmol) and N-methylbenzylamine 1.39 g (11.5 mmol) were reacted in 20 ml of methanol for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (5% methanol / dichloromethane) to give a pale brown oil (3.13 g).

Reference Example 30 5- (N-benzyl-N-methyl) amino-2- (1-
Naphthylmethyl) -4-oxopentanoic acid t-butyl 5- (N-benzyl-N-methyl) amino-4-hydroxy-2- (1-naphthylmethyl) pentanoate (Reference Example 29) 3.13 g (7.22 mmol) ) And 5 ml of triethylamine were dissolved in 20 ml of dimethyl sulfoxide, and 5.64 g of sulfur trioxide / pyridine complex was added at room temperature and stirred for 2 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added 4N hydrochloric acid / dioxane (20 ml), the mixture was stirred for 2 hours, and concentrated under reduced pressure. Dissolve the residue in water, neutralize with 1N sodium hydroxide, and concentrate under reduced pressure. Dissolve the residue in dichloromethane and separate the insolubles,
The liquid was concentrated under reduced pressure to obtain 1.94 g of the title compound as a colorless amorphous substance.

Rf = 0.55 (20% methanol / dichloromethane) Reference Example 31 (2R) -3- (N-cyclohexyl-N-methylcarbamoyl) -2- (1-naphthylmethyl) propionic acid (a) (4S) -4-isopropyl -3-[(2R) -3-
(N-cyclohexyl-N-methylcarbamoyl) -2
-(1-Naphthylmethyl) propionyl] -2-oxazolidinone benzyl (3R) -4- (1-naphthyl) -3-[(4S)
-2-oxo-4-isopropyloxazolidine-3-
Yl] butyrate 174 mg (0.38 mmol) according to the method of Reference Example 3 N-hexyl-N-methylamine 52 mg
By reacting with (0.46 mmol), 170 mg of the title compound was obtained as a white powder.

(B) (2R) -3- (N-cyclohexyl-N-methylcarbamoyl) -2- (1-naphthylmethyl) propionic acid 150 mg of the above compound was reacted according to the method of Reference Example 4 to give the title compound as a white powder. As 70 mg was obtained.

Mass spectrum 353 (M ⁺ ) Reference Example 32 (2R) -3- (N-benzyl-N-methylcarbamoyl) -2- (1-naphthylmethyl) propionic acid (a) (4S) -4-isopropyl-3- [(3- (1-
Naphthyl) propionyl] -2-oxazolidinone (S)-(−)-4-benzyl-2-oxazolidinone (S)-(−)-4-isopropyl-2-oxazolidinone 1.9 g (14.8 mmol) and 1- 2.95 g (13.5 mmol) of naphthylpropionyl chloride was used as a reference example 1.
According to the above procedure, 3.2 g of the title compound was obtained as a white powder.

(B) (4S) -4-isopropyl-3-[(2R) -3-
(N-benzyl-N-methylcarbamoyl) -2- (1
-Naphthylmethyl) propionyl] -2-oxazolidinone (4S) -3- [3- (1-naphthyl) propionyl]-
384 mg (1.3 mmol) of 4-isopropyl-2-oxazolidinone and 613 ml of bromacetic acid benzyl ester (3.87
(Mmol) in the same manner as in Reference Example 2 and then in Reference Example 3
The reaction was conducted according to the procedure described above to obtain 297 mg of the title compound as a white powder.

(C) (2R) -3- (N-benzyl-N-methylcarbamoyl) -2- (1-naphthylmethyl) propionic acid 1.42 g (3.0 mmol) of the compound synthesized in Reference Example 32 (b) was used as a reference example. The reaction was performed according to the method of 4 to give 825 mg of the title compound as a white powder.

Mass spectrum 361 (M ⁺ ) Reference Example 33 N-[(2R) -3-morpholinocarbonyl-2- (1-
Naphthylmethyl) propionyl] -3- (4-thiazolyl) -DL-alanine (a) N-[(2R) -3-morpholinocarbonyl-2-
(1-Naphthylmethyl) propionyl] -3- (4-thiazolyl) -DL-alanine methyl ester N- (t-butoxycarbonyl) -3- (4-thiazolyl) -DL-alanine methyl ester dihydrochloride 263.4 mg
(0.92 mmol) was dissolved in 10 ml of a dioxane solution containing 4N hydrogen chloride, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was completely dried. The residue was dissolved in 10 ml of methylene chloride, and (2R) -3-morpholinocarbonyl-2- (1-naphthylmethyl) propionic acid 300 mg (0.9
2 mmol) was added. Diethyl cyanophosphonate 224
mg (1.37 mmol) and triethylamine 557 mg (5.5 mmol) were added under ice-cold nitrogen atmosphere. The mixture was stirred at room temperature for 3 hours, the solvent was evaporated under reduced pressure, and the residue was extracted with methylene chloride. The extract was washed successively with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow oily substance.

(B) N-[(2R) -3-morpholinocarbonyl-2-
(1-Naphthylmethyl) propionyl-3- (4-thiazolyl) -DL-alanine The oily substance synthesized in Reference Example 33 (b) was dissolved in 5 ml of methanol, and 10 ml of 1N aqueous sodium hydroxide solution (10 ml
Mmol) was added. After stirring at room temperature for 3 hours, the mixture was neutralized with a 10% aqueous citric acid solution. The solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Add hexane to the residue,
400 mg of the title compound was obtained as white crystals.

Reference Example 34 N- (t-butoxycarbonyl) -cyclostatin-
(2-morpholinoethyl) amide N- (t-butoxycarbonyl)-in 20 ml of methanol
5.0 g of (3S, 4S) -4-amino-3-hydroxy-5-phenylpentanoic acid-2-morpholinoethylamide (11.9
(5 mmol) was dissolved and 500 mg of 5% rhodium / alumina was used as a catalyst, and hydrogenation was carried out for 18 hours at medium pressure. After removing the catalyst, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (developing solvent: methylene chloride: methanol =
Purification by 10: 1) gave 4.9 g of white crystals of the title compound.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location C07D 233/64 106 295/18 Z 333/24 403/12 207 409/12 207 413/12 207 / / A61K 31/16 AED 31/38 ABU 31/40 31/415 31/42 31/535 C07D 261/08 417/12 207 213 265 (72) Inventor Yasuki Iijima 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock Company (72) Inventor Eikuni Takahagi 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock Company (72) Hiroyuki Koike 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Incorporated company (72) Inventor Tatsuro Kokufu 2310-7 Shigetsugu Town, Ehime Prefecture Takunoku Shigenobu-cho, Ehime Prefecture (72) Inventor Kunio Hiwada 2108-6 Takuma, Shigenobu Town, Onsen-gun, Ehime Prefecture

Claims (1)

[Claims] 1. A general formula [Wherein, m represents an integer of 0 to 2 and n represents 1 to 3
R ¹ is an alkyl group having 1 to 8 carbon atoms,
An optionally substituted heterocyclyl group bonded by a nitrogen atom or a group having the formula -N (R ⁵ ) (R ⁶ ) (in the formula, R ⁵ and R
⁶ is the same or different and represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an optionally substituted aralkyl group or a cycloalkyl group. ), R ² represents an optionally substituted phenyl group, an optionally substituted naphthyl group or a cyclohexyl group, R ³ represents an optionally substituted heteroaryl group, or an optionally substituted Represents a good phenyl group or an alkyl group having 1 to 8 carbon atoms, and R ⁴ has, as a substituent, an optionally substituted heterocyclyl group, imidazolyl, pyridyl, or a formula —N (R ⁷ ) (R ⁸ ). A group (in the formula, R ⁷ and R ⁸ are the same or different and represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms) or an alkyl group having 1 to 8 carbon atoms which may have a hydroxyl group. Shows,
R ⁴ ′ represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms. ] The peptide analog represented by these, and its salt.