JPH0662530B2 - Peptide derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Purpose) The present invention relates to a novel peptide derivative having a renin inhibitory action, good oral absorbability and water solubility, and a pharmacologically acceptable salt thereof.

As peptide derivatives having a renin-inhibiting action, tetrapeptides, tripeptide derivatives and the like have hitherto been known (JP-A-52-151166, etc.).

The inventors of the present application, for the synthesis of the peptide derivative and its renin inhibitory activity, as a result of extensive studies over many years, the peptide derivative having a novel structure that has not been known has an excellent renin inhibitory activity, Moreover, they have found that the oral absorbability and water solubility are good, and that they can be important intermediates for synthesizing the derivative, and completed the present invention.

(Structure) The peptide derivative according to the present invention is a compound having the formula (I).

And a pharmacologically acceptable salt thereof.

In the above formula, R ¹ and R ² are the same or different and are represented by the formula —BR ⁷ group (wherein B 1
Is a linear or branched lower alkylene group,
R ⁷ represents an aryl group or a heteroaryl group. ) Or a formula-ER ⁸ group (wherein E represents a lower alkylene group which may be interrupted by one oxygen atom, R ⁸ represents a lower alkoxy group, an aryloxy group, an arylthio group, an aralkyloxy group or a nitrogen atom). Represents a heterocyclyl group containing an atom), R ³ represents a hydrogen atom, an optionally substituted C ₁ -C ₁₀ alkyl group (the substitution may be 1 or 2 and they are a halogen atom). , Trifluoromethyl group, trichloromethyl group, hydroxyl group, lower alkoxy group, aryloxy group,
Aralkyloxy group, lower aliphatic acyloxy group, mercapto group, lower alkylthio group optionally substituted with lower aliphatic acylamino, arylthio group, aralkylthio group, lower alkylsulfinyl group, arylsulfinyl group, lower alkylsulfonyl Group, arylsulfonyl group, amino group, mono- or di-lower alkylamino group, arylamino group, lower aliphatic acylamino group, arylacylamino group, lower alkoxycarbonylamino group, aralkyloxycarbonylamino group, carboxy group, lower alkoxy Carbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, carbamoyl group, mono- or di-lower alkylcarbamoyl group, ureido group, thioureido group, guanidyl group, C ₃
-C ₇ cycloalkyl, C ₅ -C ₈ cycloalkenyl group, an aryl group or a heteroaryl group. ), C ₃
-C ₇ cycloalkyl, C ₅ -C ₈ cycloalkenyl group, an aryl group or a heteroaryl group, R ⁴ represents an isopropyl group, a cycloalkyl group or a phenyl group of C ₃ -C _7, R ⁵ is Represents a straight-chain or branched C ₁ -C ₅ alkyl group, R ⁶ represents a sulfo lower alkyl group, an aryl group, an aralkyl group, a heteroaryl group (including N-oxide) or a heteroaryl (N- (Including oxide) -lower alkyl group (the lower alkyl portion of the aralkyl group or the heteroaryl-lower alkyl group may have a substituent, and the substituent is an amino group, a mono- or di-lower alkylamino group, A guanidino group or a mono- or di-lower alkyl guanidino group).

The linear or branched lower alkylene group for B represents a C ₁ -C ₄ alkylene group, and examples thereof include methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, n-propylmethylene and 2-ethylethylene. Three
-Methyltrimethylene and 2-methyltrimethylene can be mentioned.

The aryl group such as R ³ , R ⁶ , R ⁷ and R ⁸ or the aryl moiety such as aralkyl group, aryloxy group or arylthio group represents optionally substituted phenyl, indenyl or naphthyl. The substituent may be present in the number of 1 to 3, and R ⁶ is, for example, substituted with an amino group, a mono- or di-lower alkylamino group, an amino, a mono-lower alkylamino or a di-lower alkylamino. A lower alkyl group, a guanidino group, a mono- or di-lower alkyl guanidino group, a guanidino, a lower alkyl group substituted with a mono-lower alkyl guanidino or a di-lower alkyl guanidino, and R ³ , R ⁷ and R ⁸ are, for example, A lower alkyl group, a halogen atom such as fluorine, chlorine, bromine and iodine, a lower alkoxy group, a lower alkoxycarbonyl group, a trifluoromethyl group, an amino group, a cyano group or a nitro group. The lower alkyl moiety such as a lower alkyl group, a lower alkylamino group or a lower alkoxy group may be, for example, methyl,
Examples thereof include ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl or t-butyl (the same applies hereinafter).

The heteroaryl group of R ³ , R ⁶ , R ⁷ or the like or the heteroaryl moiety of the heteroaryl-lower alkyl group may be condensed with a phenyl ring, and has 5 to 6 members containing an oxygen, sulfur or / and nitrogen atom. Indicates a cyclic aromatic group, for example, furyl,
Thienyl, oxazolyl, thiazolyl, pyridyl, benzofuryl, benzothiophenyl, indolyl, benzthiazolyl, benzimidazolyl, quinolyl or isoquinolyl may be mentioned, and the ring may have a substituent, and the substituent may be: Regarding R ⁶ , for example, the above R ⁶
And a group similar to the substituent of the aryl group in R ³ ,
Examples of R ^{7 and the} like include a lower alkyl group, a halogen atom and a lower alkoxy group.

R ⁶ also represents a heteroaryl group having an N-oxide bond such as pyridine-N-oxide and quinoline-N-oxide.

The lower alkylene group which may be interrupted by one oxygen atom is a C ₁ -C ₄ alkylene group, and examples thereof include the above-mentioned B.
C ₁ -C ₄ alkylene in the formula _{-CH 2 -O-CH 2 -,} - CH 2 CH 2
_{-O-CH 2 -, - CH} 2 -O-CH 2 CH 2 -, - CH 2 CH 2 -O-CH 2 CH 2 - can be named group.

The aralkyl group of R ⁶ , R ^{8 and the} like or the aralkyl portion of the aralkyloxy group represents a lower alkyl group substituted with an aryl group, and examples thereof include a benzyl group, a phenethyl group and a 4-phenylbutyl group.

The heterocyclyl group containing a nitrogen atom of R ⁸ contains one or two nitrogen atoms and may contain an oxygen or sulfur atom.
To 6-membered cyclic group, for example, piperidyl, piperidino, pyrrolidyl, pyrrolidino, morpholinyl, morpholino, oxazolidinyl, oxazolidino, thiazolidinyl, thiazolidino, imidazolidino, piperazinyl, piperazino, and also a substituent on the ring. The substituent may have, for example, lower alkyl,
Hydroxy lower alkyl, lower alkoxy, optionally substituted phenyl (substituents are the same as the above-mentioned substituents of the aryl group), heteroaryl, aralkylcarboxy, lower alkoxycarbonyl, pyridyl group or cinnamoyl (the phenyl). The substituent on the ring is the same as the above-mentioned substituent of the aryl group.).

Alkyl C ₁ -C ₁₀ for R ³ is, for example, the aforementioned C ₁ -
In addition to the C ₄ alkyl group, n-pentyl, 1-methylbutyl, isopentyl, 2-methylbutyl, s-pentyl, n-hexyl, s-hexyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, n Examples include -heptyl, n-octyl, 1,5-dimethylhexyl, n-nonyl and n-decyl.

The acyl moiety of R ^{3 such as} a lower aliphatic acylamino group is C ₁
An acyl group -C _4, for example, may be mentioned formyl, acetyl, propionyl, butyryl, isobutyryl.

The C ₃ -C ₇ cycloalkyl group in R ³ or in R ⁴ is
For example, it represents a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

Cycloalkenyl group C ₅ -C ₈ in R ^3, for example, it may be mentioned cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl.

The C ₁ -C ₅ alkyl of R ⁵ is, for example, the above C ₁ -C ₄ alkyl.
In addition to the alkyl group of, n-pentyl and isopentyl groups can be mentioned.

Preferred groups for R ⁶ are substituted aryl, aralkyl, heteroaryl and heteroaryl-lower alkyl groups, more preferably substituted phenyl, benzyl, phenethyl, pyridyl and pyridylmethyl groups. You can

Further, in the compound (I), suitable groups for R ¹ , R ² , R ³ , R ⁵ and R ⁶ are, for example, as follows.

R ¹ , R ² : _{^{R 3: H, -CH 3,}} -CH 2 CH 3, -nC 3 H 7, -iC 3 H 7, -nC 4 H 9, -iC 4 H 9, -sC 4 H 9, -nC 5 H 11 , -IC ₅ H ₁₁ , -nC ₆ H ₁₃ , -nC ₇ H ₁₅ , -nC ₈ H ₁₇ , -nC ₉ H ₁₉ , -nC ₁₀ H ₂₁ , -CH ₂ F, -CH ₂ Cl, -CH ₂ CHCl ₂ , -CH ₂ CCl ₃ , -CH ₂ SH, -CH ₂ CH ₂ SH, -CH ₂ -S-CH ₂ NHCOCH ₃ , -CH ₂ -CH ₂ -S-CH ₃ , -CH ₂ -CH ₂ -S-CH ₂ CH ₃ , CH _{2 3} S-CH ₃ , CH _{2 4} S-CH
₃ , _{^{R 5: -nC 3 H 7,}} -iC 3 H 7, -nC 4 H 9, -iC 4 H 9, -sC 4 H 9, -nC 5 H 11, -iC 5 H 11 R 6: In the compound (I), when an optical isomer based on an asymmetric carbon is present, it includes an optically active substance and a racemate, and preferably has the formula: The part is S-coordinate, and the formula Part is S-coordinate, It is a compound in which the moiety is in the S configuration.

The compound having the general formula (I) of the present invention can be converted 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 sulfonates such as benzene sulfonate and P-toluene sulfonate, alkali metal salts or alkaline earth metal salts such as sodium salt, potassium salt, calcium salt, magnesium salt, dicyclohexylamine salt An organic base salt such as

Further, in the compound (I), preferably 1) a compound in which at least one of R ¹ and R ² is a group of formula —B—R ⁷ , and 2) a lower alkyl group which R ³ may be substituted ( The substituent is a lower alkoxy group, a benzyloxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a carbamoyl group, an optionally substituted phenyl group or a heteroaryl group). , 3) a compound in which R ⁴ is an isopropyl group, 4) a compound in which R ⁵ is an isopropyl group, isobutyl group, s-butyl group, 5) R ⁶ is a sulfoethyl group, a substituted phenyl group, a benzyl group, a phenethyl group Or a compound which is a pyridylmethyl group (wherein the substituent represents an amino group, an aminomethyl group or an aminoethyl group), 6) at least one of R ¹ and R ² is a group of formula —B—R ⁷ , R ³ A lower alkyl group which may be substituted (wherein the substituent is a lower alkoxy group, a benzyloxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, a carbamoyl group, an optionally substituted phenyl group). A group or a heteroaryl group), R ⁴ is an isopropyl group, R ⁵ is an isopropyl group, an isobutyl group or a s-butyl group, and R ⁶ is a sulfoethyl group, a substituted phenyl group or a benzyl group. A phenethyl group or a pyridylmethyl group (wherein the substituent represents an amino group, an aminomethyl group or an aminoethyl group), 7) R ¹ and R ² are the same or different, and are represented by the formula -B-R ⁷ A compound which is a group having 8) R ³ is a lower alkyl group or lower alkoxy, lower alkylthio, carbamoyl, optionally substituted phenyl,
A compound which is a C ₁ -C ₂ alkyl group substituted with imidazolyl or optionally substituted thiazolyl, 9) R ¹ and R ² are the same or different, and are groups having the formula —B—R ⁷ , ³ is a lower alkyl group or a lower alkoxy, lower alkylthio, carbamoyl, optionally substituted phenyl, imidazolyl or optionally substituted thiazolyl substituted C ₁ -C ₂ alkyl group, R
⁴ is an isopropyl group, R ⁵ is an isobutyl group or s-
A compound which is a butyl group and R ⁶ is a benzyl group or a phenethyl group substituted with aminomethyl or aminoethyl, 10) a compound wherein R ¹ and R ² are both naphthylmethyl groups, and 11) R ³ is n-propyl. , Isopropyl, n-butyl, isobutyl, imidazolylmethyl, thiazolylmethyl, an optionally substituted benzyl group, a methylthioethyl, a carbamoylmethyl group or a carbamoylethyl group, and further preferably in compound (I), Table 1-
The compounds exemplified in Table 3 can be mentioned.

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

For example, the target compound has the general formula (Wherein R ¹ , R ² and R ³ have the same meanings as described above) and a general formula of a carvone having (In the formula, R ⁴ and R ⁵ have the same meanings as described above,
⁶ ', in addition to an amino group, mono-substituted amino group is protected, as defined for R ^6. ) Is used to produce a peptide derivative by a conventional method in a peptide synthesis method, for example, an azide method, an active ester method, a mixed acid anhydride method, a carbodiimide method, or a condensation method using a redox system, and R ⁶ It can be produced by removing protection such as amino group contained in '.

Also, the general formula (Wherein R ³ , R ⁴ , R ⁵ and R ⁶ ′ have the same meanings as described above) and a general formula (Wherein R ¹ and R ² have the same meanings as defined above), or a reactive derivative thereof is used to produce a peptide derivative according to the above-mentioned peptide synthesis method,
The target compound (I) can also be produced by removing a protecting group such as an amino group contained in R ⁶ ′.

In the peptide synthesis method, the azide method is a method in which an amino acid or an ester thereof is mixed with hydrazine in an inert solvent (for example, dimethylformamide),
It is carried out by reacting the amino acid hydrazide produced by reacting at around room temperature with a nitrite compound to convert it 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 ilamyl 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, and the latter is -10 ° C to 1
The reaction time is 0 ° C., and the time required for the reaction is 5 minutes to 1 hour in the first step and 10 hours to 15 days in the second step.

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, and examples of the solvent used include, for example, methylene chloride, halogenated hydrogen halides 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 1 in the active esterification reaction.
The temperature is 0 ° C., the reaction between the active ester compound and the amine is near room temperature, and the time required for the reaction is 30
Minutes to 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 achieved by reacting the amino acid with a lower carbonic acid carbonate such as isobutyl chlorocarbonate or a dilower alkylcyanophosphoric acid such as diethyl cyanophosphoric acid.

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 time required for the reaction is 3
It is from 0 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.

When carrying out each of the above methods, the amino group of the amino acid can be protected or deprotected as necessary.

The amino group contained in R ⁶ ′ or the amino acid-protecting group contained in the amino acid is not particularly limited as long as it is a protecting group used in the field of amino acid chemistry, and examples thereof include a benzyloxycarbonyl group and p-methoxybenzyloxy group. Examples of the acyl group include a carbonyl group, a t-butyloxycarbonyl group, and a 9-fluorenylmethyloxycarbonyl group.

For protection of amino groups and the like, an acyl halide (for example, benzyloxycarbonyl chloride) or dialkyldicarbonate (for example, di-t-butyldicarbonate) is added to a corresponding compound in an inert solvent (for example, benzene) at 0 ° C to 0 ° C. It is achieved by reacting at 30 ° C. for 2 to 5 hours.

The reaction for removing the protecting group differs depending on the type of the protecting group such as amino group.

For example, when the protecting group is an aralkyloxycarbonyl group such as a benzyloxycarbonyl group, the corresponding compound is added in the presence of a catalytic reduction catalyst (for example, palladium-
Carbon) in an inert solvent and hydrogen at atmospheric pressure to 3 atm at around room temperature for 3 hours to 10 hours. When the protecting group is a t-butoxycarbonyl group, it is achieved by reacting the corresponding compound with an acid (for example, hydrochloric acid-dioxane) at 0 ° C to 30 ° C for 20 minutes to 1 hour.

Further, if desired, the amino group contained in R ⁶ can be converted into a guanidino group.

Conversion of an amino group to a guanidino group is carried out by reacting 1-guanyl-3,5-dimethylpyrazole nitrate in an inert solvent (for example, dimethylformamide) in the presence of a base such as triethylamine at 10 ° C. to 25 ° C. for 1 day to 7 days. Achieved by reacting for days [eg RABBannard et.a.
l, Can. J. Chem, 36 , 1541 (1958)].

〔effect〕

The results of the test for the inhibitory effect of the peptides having the general formula (I) of the present invention on human renin are shown below. In addition,
The test method is that of Kokufu et al. [Hypertension, 5 , 191-197 (1
983)], followed by mixing human renin and a renin inhibitor, and then adding a sheep renin substrate. 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 by oral administration using marmosets 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 not only oral administration by tablets, capsules, granules, powders, syrups and the like, but also parenteral administration by injections, suppositories and the like. 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 it can be administered once or in several divided doses.

Next, the present invention will be described more specifically with reference to examples.

Example 1. N- [bis (1-naphthylmethyl) acetyl] -L-histidyl-statyl-L-leucyl- (m-aminomethyl) benzylamide dihydrochloride.

(a) N- [bis (1-naphthylmethyl) acetyl] -L
-Histidyl-statin hydrazide N-t-butyroxycarbonyl-statin ethyl ester 2.0 g (6.6 mmol) in 20 ml of 4N hydrochloric acid / dioxane solution at room temperature.
Treatment was carried out for 0 minutes to remove the t-butyroxycarbonyl group. The reaction mixture was concentrated under reduced pressure to dryness, the residue was dissolved in 10 ml of dimethylformamide, and then neutralized with 0.67 g (6.6 mmol) of triethylamine under ice cooling. In addition, N ^α −
2.18 g (5.2 mmol) of t-butyroxycarbonyl-N ^im -2,4-dinitrophenyl-L-histidine isopropanol, N-hydroxy-5-norbornene-2,3-
Methylene chloride solution (40 ml) of the active ester prepared from 1.18 g (6.6 mmol) dicarboximide and 1.48 g (7.2 mmol) dicyclohexylcarbodiimide.
Was added, and the mixture was stirred at room temperature for 8 hours. The precipitated dicyclohexylurea was removed, and the liquid was concentrated under reduced pressure. 10 for residue
% Aqueous citric acid solution was added, and the precipitated oily substance was extracted with ethyl acetate. The ethyl acetate layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether-n-hexane (1: 1) was added to the oily residue for solidification, and the solvent was decanted off. Add diethyl ether to the solid residue
I took it. 3.4 g (5.6 mmol) of N was obtained as a yellow powder.
The -t-butyroxycarbonyl group was removed by treating with 20 ml of a 4N hydrochloric acid / dioxane solution, concentrated under reduced pressure and dried.
The residue was dissolved in 20 ml of dimethylformamide, 1.9 g (5.6 mmol) of bis (1-naphthylmethyl) acetic acid and 0.96 g (5.6 mmol) of 90% diethyl cyanophosphate were added thereto, and the mixture was ice-cooled. Triethylamine (1.13 g, 11.2 mmol) was added, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added 3-fold amount of ethyl acetate, and the mixture was washed with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and diethyl ether-n-hexane (1: 1) was added to the residue to solidify it. This was carefully dropped to obtain 3.84 g of a yellow powder. Next, the total amount of this compound (4.4 mmol) was dissolved in 40 ml of methanol, 3.44 g (44 mmol) of 2-mercaptoethanol was added, and further saturated aqueous sodium hydrogen carbonate solution was added to adjust the pH to 8, and then 2.
Stir for 5 hours. The solvent was evaporated under reduced pressure, water was added to the residue, and the precipitated oily substance was extracted with ethyl acetate. The organic layer was washed with water, further washed with saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:
Elution with methanol: acetic acid = 95: 5: 3, followed by elution with methylene chloride: methanol = 10: 1).
2.12 g of pale yellow powder was obtained. This was dissolved in 10 ml of dimethylformamide, 3.2 g (32 mmol) of hydrazine hydrate was added, and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the deposited precipitate was collected and washed with water and diethyl ether to give N- [bis (1-naphthylmethyl) acetyl] -L-histidyl- as a pale yellow powder.
1.06 g of statin hydrazide was obtained.

Melting point 129-131 ° C ▲ [α] ²³ _D ▼ -54.7 ° (C = 0.3, methanol) Elemental analysis value C ₃₈ H ₄₄ N ₆ O ₄ Calculated value: C, 70.35; H, 6.84; N, 12.95 Measured value: C, 70.12; H, 7.02; N, 12.74 (b) L-leucyl- (m-N-benzyloxycarbonylaminomethyl) benzylamide Nα-t-butyroxycarbonyl-L-leucine N-hydroxysuccinimide 3.28 g (10 M-m)
A solution of 20.4 g (150 mmol) of xylylenediamine in 50 ml of dimethylformamide was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the precipitated oil was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the oily residue was purified by silica gel column chromatography (developing solvent: methylene chloride: methanol = 5: 1). The obtained oily substance was dissolved in dimethylformamide, and 1.01 g of triethylamine (1
0 mmol) was added, and 1.71 g (10 mmol) of benzyloxycarbonyl chloride was added dropwise under ice cooling. After stirring for 3 hours, the reaction solution was concentrated under reduced pressure, water was added to the residue, and the precipitated oily matter was extracted with ethyl acetate. The organic layer was washed with 1N sulfuric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine in this order,
After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The oily residue was treated with 30 ml of 4N hydrochloric acid / dioxane solution to remove the t-butyloxycarbonyl group, concentrated under reduced pressure and dried. Saturated aqueous sodium hydrogen carbonate was added to the residue to give a colorless precipitate. Take this, wash it thoroughly with water, and use L- as a colorless powder.
2.5 g of leucyl- (m-N-benzyloxycarbonylaminomethyl) -benzylamide was obtained.

Melting point 75-77 ° C ▲ [α] ²³ _D ▼ + 5.3 ° (C = 0.3, methanol) Elemental analysis value C ₂₂ H ₂₈ N ₃ O ₃ Calculated value: C, 68.90; H, 7.62; N, 10.96 Measured value : C, 68.71; H, 7.85; N, 10.74 (c) N- [bis (1-naphthylmethyl) acetyl] -L
-Histidyl-statyl-L-leucyl- (m-aminomethyl) benzylamide dihydrochloride 320 mg N- [bis (1-naphthylmethyl) acetyl] -L-histidyl-statin hydrazide synthesized in Example 1 (a). (0.5 mmol) 3 ml of dimethylformamide
While being cooled with dry ice-acetone, 0.42 ml of 4.0N hydrogen chloride / dioxane is added, and the mixture is cooled to -60 ° C. After adding 0.1 ml of isoamyl nitrite to this, the reaction temperature was raised to -20 ° C and stirred for 15 minutes. After confirming that the hydrazide had disappeared, 0.17 g of N-methylmorpholine was added to neutralize the mixture. L-leucyl-synthesized in 1 (b)
0.19 g (0.5 mmol) of (m-N-benzyloxycarbonylaminomethyl) benzylamide was dissolved in 3 ml of dimethylformamide, and the mixture was stirred at 4 ° C. for 21 hours. 5%
The ethyl acetate layer was washed with aqueous sodium hydrogen carbonate, water and saturated brine, dried over anhydrous sodium sulfate, and the ethyl acetate was evaporated under reduced pressure.

The residue was purified by silica gel column chromatography (developing solvent; methylene chloride; methanol = 25: 1) and ether was added to the residue to give 216 mg of pale yellow crystals. The crystals were dissolved in 5 ml of methanol and suspended in 0.4 ml of 1N hydrochloric acid to prepare 10% palladium-
Add 20 mg of carbonic acid catalyst, and add hydrogen gas at room temperature for 4
Reacted for hours. After removing the catalyst, the liquid was concentrated under reduced pressure,
Further, benzene was added and azeotropically distilled to remove water. The obtained residue was crystallized by adding a mixed solvent of ethyl acetate and ether (1: 1) to obtain 158 mg of the title compound as pale yellow crystals.

Melting point 168-172 ° C ▲ [α] ²³ _D ▼ -40.3 ° [C = 0.3, methanol] Elemental analysis value C ₅₂ H ₆₃ O ₅ N ₇・ 2HCl ・ 21 / 2H ₂ O Calculated value C% 63.46 H% 7.17 N % 9.96 Measured value C% 63.33 H% 7.20 N% 9.61

Continuation of the front page (51) Int.Cl. ⁵ Identification code Reference number within the agency FI Technical display location C07C 279/04 7188-4H 317/50 7419-4H 323/60 7419-4H C07D 209/18 9284-4C 215 / 14 235/16 277/30 295/14 Z 307/54 333/24 521/00 8314-4C C12N 9/99 9359-4B // A61K 31/16 AED 31/165 AEQ 31/185 ABU 31/195 31 / 215 31/22 31/33 31/445 (72) Inventor Yasuki Iijima 1-25-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Eiho Takahagi 1-2-2 Hiromachi, Shinagawa-ku, Tokyo No. 58 Sankyo Co., Ltd. (72) Inventor Hiroyuki Koike 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Tatsuro Koufu 2310-7 Shigetsugu Town, Onsen-gun, Ehime Prefecture 72) Inventor Kunio Hiwada 2108-6 Takubo, Shigenobu-cho, Onsen-gun, Ehime Prefecture

Claims (1)

[Claims] 1. A formula And a pharmacologically acceptable salt thereof. In the above formula, R ¹ and R ² are the same or different and have the formula —B—R ⁷ group (wherein B represents a linear or branched C ₁ -C ₄ alkylene group, and R ⁷ is It may be condensed with an aryl group or a phenyl ring, and contains 5 to 6 containing an oxygen, sulfur or / and nitrogen atom.
It shows a membered cyclic heteroaryl group. ) Or the formula -E-R ⁸
Group (in the formula, E represents a C ₁ -C ₄ alkylene group which may be interrupted by one oxygen atom, R ⁸ represents a C ₁ -C ₄ alkoxy group, an aryloxy group, an arylthio group, an aralkyloxy group) Or a 5- to 6-membered cyclic heterocyclyl group containing a nitrogen atom and optionally an oxygen or sulfur atom), R ³ is a hydrogen atom, or an optionally substituted C ₁ -C ₁₀ alkyl group ( The substituent may be one or two, and they may be a halogen atom, a trifluoromethyl group, a trichloromethyl group, a hydroxyl group, a C ₁ -C ₄ alkoxy group, an aryloxy group, an aralkyloxy group, a C ₁ -C ₄ fatty acid. family acyloxy group, a mercapto group, C ₁ -C ₄ aliphatic acylamino which may be substituted, C ₁ -C ₄ alkylthio group, an arylthio group, aralkylthio group, C ₁ -C ₄ alkylsulfinyl group , An arylsulfinyl group, a C ₁ -C ₄ alkylsulfonyl group, an arylsulfonyl group, an amino group, a mono- or di-C ₁ -C ₄ alkylamino group, an arylamino group,
C ₁ -C ₄ aliphatic acylamino groups, aryl acyl amino group, C ₁ -C ₄ alkoxycarbonylamino group, an aralkyloxycarbonyl group, a carboxy group, C ₁ -C ₄
Alkoxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, carbamoyl group,
Fused with a mono- or di-C ₁ -C ₄ alkylcarbamoyl group, ureido group, thioureido group, guanidyl group, C ₃ -C ₇ cycloalkyl group, C ₅ -C ₈ cycloalkenyl group, aryl group or phenyl ring Also, a 5- to 6-membered cyclic heteroaryl group containing an oxygen, sulfur or / and nitrogen atom is also preferable. ), A C ₃ -C ₇ cycloalkyl group, a C ₅ -C ₈ cycloalkenyl group, an aryl group or a phenyl ring, which may be condensed with 5 to 6 containing an oxygen, sulfur or / and nitrogen atom.
A membered cyclic heteroaryl group, R ⁴ represents an isopropyl group, a C ₃ -C ₇ cycloalkyl group or a phenyl group, and R ⁵ represents a linear or branched C ₁ -C ₅ alkyl group. R ⁶ may be a sulfo-C ₁ -C ₄ alkyl group, an aryl group, an aralkyl group, or a phenyl ring and may be condensed with a 5- to 6-membered cyclic heteroaryl group containing an oxygen, sulfur or / and nitrogen atom. 5 to 6 containing an oxygen, sulfur or / and nitrogen atom (which may include an N-oxide) or a condensed ring with a phenyl ring.
Membered (including the N- oxide) cyclic heteroaryl -C ₁ -
A C ₄ alkyl group (which may be condensed with the above aralkyl group or a phenyl ring and contains an oxygen, sulfur or / and nitrogen atom;
To an alkyl portion of the 6-membered cyclic heteroaryl-C ₁ -C ₄ alkyl group may have a substituent, and the substituent is an amino group, a mono- or di-C ₁ -C ₄ alkylamino group,
A guanidino group or a mono- or di-C ₁ -C ₄ alkylguanidino group is shown. ) Is shown.