JP2965599B2 - Dipeptide compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Purpose] The present invention relates to a novel dipeptide compound having an excellent renin inhibitory activity, a good oral absorbability and a novel renin inhibitory activity, and a pharmaceutically acceptable salt thereof. .

As peptide derivatives having a renin inhibitory action, conventionally, tetrapeptide, tripeptide derivatives and the like are known (JP-B-58-39149, JP-A-60-163899, JP-A-61-275256, etc.). .

The present inventors have conducted intensive studies on the synthesis of the dipeptide compound and its renin inhibitory activity over many years, and as a result, a dipeptide compound having a specific structure having the general formula (I) described below specifically binds to renin. They have found that they have excellent inhibitory activity and good oral absorbability, and thus completed the present invention.

〔Constitution〕

The dipeptide compound according to the present invention has the general formula And a pharmacologically acceptable salt thereof.

In the above formula, R ¹ is a 5- to 6-membered cyclic heterocyclyl group or a formula Group (wherein, R ⁷ having represents a C ₁ -C ₄ alkyl group, R ⁸
C ₁ -C ₄ alkyl, a phenyl group which may be substituted by C ₁ -C ₄ alkoxy or halogen; phenyl moiety is C ₁
A phenyl-C ₁ -C ₄ alkyl group which may be substituted with —C ₄ alkyl, C ₁ -C ₄ alkoxy or halogen; or a C ₅ -C ₆ cycloalkyl group. ) Indicates that R ² is C ₁
-C ₄ alkyl, a phenyl group or a naphthyl group which may be substituted with C ₁ -C ₄ alkoxy or halogen,
R ³ represents a thiazolyl group, R ⁴ represents a cyclohexyl group or an isopropyl group, R ⁵ represents a C ₁ -C ₄ alkyl group, and R ⁶ represents a C ₁ -C ₆ alkyl group.

In the above general formula (I), the 5- to 6-membered cyclic heterocyclyl group for R ¹ is, for example, a saturated heterocyclyl having 1-2 nitrogen, oxygen and sulfur atoms such as pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl. represents a group, the nitrogen atom of the ring may be substituted by C ₁ -C ₄ alkyl or phenyl.

C ₁ -C ₄ alkyl group such as R ^7, C ₁ C ₁ -C ₄ alkoxy groups contained in the phenyl -C ₁ -C ₄ alkyl group or R ⁸ or the like of R ⁸
-C ₄ alkyl moiety, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl.

C ₁ -C ₆ alkyl group R ⁶ is, for example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, preferably a C ₁ -C ₄ alkyl group.

Halogen atoms contained in R ^{8 and the} like are, for example, fluorine, chlorine, bromine and iodine atoms, preferably fluorine and chlorine atoms.

C ₅ -C ₆ cycloalkyl group R ⁸ is, for example, cyclopentyl, cyclohexyl.

Suitable groups for R ¹ , R ² , R ⁵ and R ⁶ in compound (I) are, for example, as follows.

R ⁵ : CH ₃ , C ₂ H ₅ , C ₃ H ₇ , i-C ₃ H ₇ , i-C ₄ H ₉ R ⁶ : CH ₃ , C ₂ H ₅ , C ₃ H ₇ , i-C ₃ H ₇ , C ₄ H ₉ , i-C ₄ H ₉ , C ₆ H ₁₃ More preferred groups are as follows.

^{_{R 5: CH 3, C 2}} H 5, i-C 3 H 7 R 6: CH 3, C 2 H 5, C 3 H 7, C 4 H 9, i-C 4 H 9 Compound (I), the When an optical isomer based on an asymmetric carbon is present, it includes an optically active isomer and a racemic isomer. The moiety is in the R configuration, Wherein the moiety is in the S configuration, Wherein the moiety is in the S configuration, Part is an expression Is a compound having a coordination.

The compound having the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt. Such salts include, for example, mineral salts such as hydrochloride, sulfate, phosphate, organic acid salts such as acetic acid, oxalate, maleate, succinate, citrate, and methanesulfonic acid. Acid addition salts such as salts, benzenesulfonates and sulfonates such as p-toluenesulfonate, or alkali metal salts or alkaline earth metal salts such as sodium salts, potassium salts, calcium salts and magnesium salts, dicyclohexyl Organic base salts such as amine salts can be mentioned.

In the compound (I), preferred compounds include: (1) R ¹ is pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 4-methylpiperazinyl, 4-phenylpiperazinyl or a compound represented by the formula Group (wherein having, R ⁷ is C ₁ -C ₄ alkyl group, R ⁸ is a phenyl moiety which is methyl, methoxy, chloro with optionally substituted phenyl -C ₁ -C ₄ alkyl group. (2) a compound wherein R ² is a phenyl, tolyl, methoxyphenyl or naphthyl group; and (3) a compound wherein R ⁶ is a C ₁ -C ₄ alkyl group.

Further preferred compounds include: (4) R ¹ is morpholinyl or (benzyl) (methyl)
A compound which is amino (particularly a compound which is morpholinyl); (5) a compound wherein R ² is phenyl or methoxyphenyl; (6) a compound wherein R ⁴ is cyclohexyl; (7) a compound wherein R ⁵ is methyl, ethyl or isopropyl (8) a compound wherein R ⁶ is methyl, ethyl, propyl, butyl or isobutyl; (9) R ¹ is morpholinyl or (benzyl) (methyl)
Amino, R ² is phenyl or methoxyphenyl, R ⁴ is cyclohexyl, R ⁵ is methyl, ethyl or isopropyl, and R ⁶ is methyl, ethyl, propyl, butyl or isobutyl. Can be.

Specific examples of the compound having the general formula (I) of the present invention include the compounds shown in the following table, 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.

In the above formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meaning as described above.

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

The first step of the present method is a step of producing the compound (I) using the compound (II) or a reactive derivative thereof and the compound (III).
It is carried out by an active ester method, a mixed acid anhydride method or a condensation method.

In the peptide synthesis method described above, the azide method comprises the steps of: converting an amino acid or an ester thereof with hydrazine in an inert solvent (eg, dimethylformamide);
Amino acid hydrazide produced by reacting at around room temperature is reacted with a nitrite compound, converted into an azide compound, and then treated with an amine compound.

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

The reaction is suitably carried out in an inert solvent. Examples of the solvent used include amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and pyrrolidones such as N-methylpyrrolidone. Can be given. The method 2
The two steps are usually performed in one reaction solution, and the reaction temperature in the first stage is −50 ° C. to 0 ° C., and the second stage is −10 ° C. to 10 ° C.
℃, and the time required for the reaction is 5 minutes to 1
The time period is 10 hours to 5 days.

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

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

As the active esterifying agent used, for example, N-
Examples include N-hydroxy compounds such as hydroxysuccinimide, 1-hydroxybenzotriazole, and N-hydroxy-5-norbornene-2,3-dicarboximide, and the active esterification reaction is performed by dicyclohexylcarbodiimide, carbonyldiimidazole In the presence of a condensing agent such as

The reaction temperature is from -10 ° C to 25 ° C for the active esterification reaction.
° C, and the temperature of the reaction between the active ester compound and the amine is around room temperature, and the time required for both reactions is 30 minutes to 10 hours.

The mixed acid anhydride method is performed by producing a mixed acid anhydride of an amino acid and then reacting the mixed acid anhydride with an amine.

The reaction for producing the mixed acid anhydride is carried out in an inert solvent (for example, the amides and ethers described above) in a lower alkyl halide such as ethyl chlorocarbonate or isobutyl chlorocarbonate or a di-lower alkyl halide such as diethyl cyanophosphoric acid. This is achieved by reacting an alkyl cyanophosphoric acid with an amino acid.

The reaction is preferably carried out in the presence of an organic amine such as triethylamine or N-methylmorpholine, the reaction temperature is from -10 ° C to 25 ° C, and the time required for the reaction is from 30 minutes to 5 hours. .

The reaction between the mixed acid anhydride and the amine is preferably performed in an inert solvent (for example, the amides or ethers described above) in the presence of the 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 carbonyldiimidizole. This reaction is carried out in the same manner as the above-mentioned reaction for producing an active ester.

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

In the first step of the method A ', the compound (Ia) is reacted with the compound (II) or a reactive derivative thereof and the compound (XXIIIa).
Is performed in the same manner as in the first step of the method A.

The first step "A" in the method A 'is a step of producing the compound (I), which is achieved by reacting the compound (Ia) with the compound (XXIV) in an inert solvent.

The inert solvent used, for example, ether, tetrahydrofuran, ethers such as dioxane, hexane, benzene, toluene, hydrocarbons such as xylene, methanol, alcohols such as ethanol can be mentioned, Preferably, they are alcohols.
In addition, compound (XXIV) can be used in a large excess also as a solvent.

The reaction temperature varies depending on the type of the compound (XXIV) to be used and the like, but is usually 0 ° C to 150 ° C (preferably 0 ° C
To 100 ° C.), and the time required for the reaction varies depending on the reaction temperature and the like, but is usually 30 minutes to 20 hours.

Compound (Ia) is obtained by converting compound (IV) or a reactive derivative thereof into a compound represented by the general formula Can also be produced by reacting with a compound having

Method B is a method for separately producing compound (I).
The second step of this method is carried out in the same manner as in the first step of Method A using compound (IV) or a reactive derivative thereof and compound (V).

If desired, the compound (III) or (V) in which the amino group is protected can be subjected to removal of the protecting group to produce compound (III) or (V).

The reaction for removing the protecting group depends on the type of the protecting group, but is carried out according to a conventional method.

For example, when the protecting group is a t-butyloxycarbonyl group, the corresponding compound is converted into an acid (eg, hydrochloric acid, trifluoroacetic acid, trifluoroboron) in an inert solvent (eg, dioxane, methanol, dimethylformamide, etc.). (Etherate etc.) at 0 ° C. to 30 ° C. for 20 minutes to 1 hour.

When the protecting group is an aralkyloxycarbonyl group or a carbonate residue, the corresponding compound is placed in an inert solvent (eg, methanol, ethanol, tetrahydrofuran, etc.) in the presence of a catalytic reduction catalyst (eg, palladium-carbon, palladium black, etc.) The reaction is carried out by reacting with hydrogen at normal pressure to 10 atm near room temperature for 1 to 8 hours.

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, removing excess insoluble matter if present, 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 compounds (II), (III), (IV),
(V), (Va) or (XXIIIa) is known,
It is easily manufactured according to a known method (for example,
63-63649, JP-A-62-53952, etc.). In addition, the compound (I
V) is a compound represented by the following formula (I):
V a) can be selectively produced.

In the above formula, R ¹ and R ² are as defined above. X is
Shows halogen atoms such as chlorine and bromine. R ⁹ represents a phenyl group or a lower alkyl, and R ¹⁰ represents a lower alkyl group. That is, a compound having the formula (VI) is converted to a base (for example, n
-Butyllithium) to give the corresponding alkali metal salt, and then react with an acid halide compound having the formula (VII) (third step). The resulting compound (VIII) is converted to a base (for example, diisopropyllithium amide). ) And then
The halide compound (IX) is reacted stereoselectively (fourth step), and the resulting compound (X) is subjected to catalytic reduction (for example, treatment with hydrogen under a palladium-carbon catalyst) or hydrolysis according to a conventional method (step 4). 5)) reacting the obtained compound (XI) with an amine compound having the formula (XII) in the presence of a condensing agent (for example, diethyl-triethylamine dianophosphate) (6th step), This is a method for producing compound (IVa) by finally hydrolyzing (XIII) (seventh step).

Note that the expression As the amino acid having, a compound which is easily produced according to the following method is used.

In the above formula, R ³ , R ¹⁰ and X are as defined above, and R ¹¹
Represents an aliphatic acyl group such as acetyl, propionyl, and butyryl.

First, a compound having the formula (XV) is treated with a base (eg, an alkali metal hydride compound such as sodium hydride), and then reacted with a compound having the formula (XVI) (eighth step). Compound (XVII) is treated with an acid (eg, a mineral acid such as hydrochloric acid) (Step 9).

In addition, the starting compound (III) can selectively produce a preferred coordination isomer (IIIa) according to the method E, that is, the following method.

In the above formula, R ⁴ , R ⁵ , R ⁶ , R ¹⁰ and X have the same meanings as described above, and R ¹² represents a protecting group for an amino group. That is, the formula (X VII
The compound having (I) is reduced with a reducing agent such as sodium borohydride (tenth step), and the obtained compound (XIX)
Is oxidized using a sulfur trioxide-pyridine complex, and is then mixed with a lithium salt of lower alkyl acetylene carbonate at -78 ° C.
To 0 ° C. (eleventh step) to obtain a compound (XX)
After catalytic reduction in the presence of palladium-barium sulfate, a catalytic amount of acetic acid was added and heated (step 12) to give compound (XX)
I get. Then, in the presence of a base such as lithium diisopropylamide, an alkyl halide (XXII) is reacted (13th step) to produce a compound (XXIII) and reacted with an amine (XXIV) (14th step). , Compound (XX V)
And the starting compound (IIIa) can be produced by removing the amino-protecting group (Step 15).

In the compound (XXIII), the compound (XXIIIa) in which R ⁵ is an isopropyl group can be separately produced from the compound (XXI).

In the above formula, R ⁴ and R ¹² have the same meaning as described above, and R ¹³ represents C ₁ -C ₄ alkyl.

That is, the compound (XXI) is reacted with acetone in the presence of a base such as lithium diisopropylamine (Step 16), and the resulting compound (XXVI) is reacted with methyloxalyl in the presence of a base such as triethylamine. Reaction with a C ₁ -C ₄ alkyl oxalyl halide such as chloride (17th
Step), the target compound (XXIIIa) can be produced by treating the obtained compound (XXVII) with a trialkyltin hydride such as tri-n-butyltin hydride.

(Effect)

The results of a test of the inhibitory activity of the peptides of the present invention having the general formula (I) on human renin are shown below. The test method was the method of Kofu et al. [Hypertension, 5 , 191-1.
97 (1983)], by mixing the peptide of the present invention with a sheep renin substrate in advance, and then adding human renin.

The target compound (I) of the present invention exhibited an excellent inhibitory effect on human renin as shown in the above Test Examples. In addition, compound (I) showed an excellent effect by oral administration using marmoset. Therefore, it is useful as a diagnostic or therapeutic agent for hypertension based on the renin-angiotensin system, particularly for oral use. Examples of the administration form include oral administration by tablets, capsules, granules, powders, syrups and the like, as well as parenteral administration by injections, suppositories and the like. The amount used depends on the purpose of use, symptoms, age, etc., for example, about 0.
The dose is from 01 mg to 100 mg / kg body weight, which 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.

Example 1 (2S, 4S, 5S) -5- {N- [2 (R) -benzyl-3-
(Morpholinocarbonyl) propionyl] -3- (4-
Thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid
Methylamide 1 (a) (2S, 4S, 5S) -5- [N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanyl]
Amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid methylamide Compound 966 mg (2.51 mmol) synthesized in Reference Example 3
Was added to 4N hydrochloric acid / 25 ml of dioxane, followed by stirring at room temperature for 30 minutes. Thereafter, the solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and further the solvent was distilled off under reduced pressure. This operation 3
After repeating this process twice, the resultant was dried under reduced pressure for 8 hours. After drying, the resultant was suspended in 20 ml of anhydrous tetrahydrofuran, and further suspended in N-
(T-butoxycarbonyl) -3- (4-thiazolyl)
752 mg (2.76 mmol) of -L-alanine were added. In this solution, under a nitrogen atmosphere, diethyl cyanophosphate was added under ice cooling.
0.42 ml (2.77 mmol) and 0.77 ml of triethylamine
(5.52 mmol) and further stirred at room temperature for 6 hours. Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (methylene chloride: methanol = 20: 1) to give the title compound as white crystals.
0 mg (71%) was obtained.

Melting point 183-185 ° C ▲ [α] ²⁰ _D ▼ = -40.0 ゜ (C = 0.43, methanol) Elemental analysis: C ₂₇ H ₄₆ N ₄ O ₅ S · 1 / 2H ₂ O Calculated: C, 59.21; H, 8.65; N, 10.23; S, 5.85 Found: C, 58.79; H, 8.22; N, 9.96; S, 5.59 IR spectrum (KBr): 1686, 1640 cm ^-1 Mass spectrum (m / e): 539 ( M ⁺ +1), 381,127 1 (b) (2S, 4S, 5S) -5- {N- [2 (R) -benzyl-3- (morpholinocarbonyl) propionyl]-
3- (4-thiazolyl) -L-alanine {amino-6
Cyclohexyl-4-hydroxy-2-isopropylhexanoic acid methylamide 300 mg (0.56 mmol) of the compound synthesized in Example 1 (a) was added to 4N hydrochloric acid / 25 ml of dioxane, and the mixture was added at room temperature.
Stir for 30 minutes. Thereafter, the solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and further the solvent was distilled off under reduced pressure. After repeating this operation three times, the resultant was dried under reduced pressure for 8 hours. After drying, the residue was suspended in 10 ml of anhydrous tetrahydrofuran, and further suspended in 2 ml.
170 mg (0.61 mmol) of (R) -benzyl-3- (morpholinocarbonyl) propionic acid were added. To this solution, under a nitrogen atmosphere, diethyl cyanophosphate 0.09 with ice cooling.
ml (0.59 mmol) and 0.26 ml of triethylamine (1.
86 mmol), and the mixture was further stirred at room temperature for 8 hours. The solvent was distilled off under reduced pressure, and the residue was purified on a silica gel thin layer plate (methylene chloride: methanol = 10: 1) to obtain 281 mg (72%) of the title compound as white crystals.

Melting point 83-86 ° C ▲ [α] ²⁰ _D ▼ = -38.0 ゜ (C = 0.5, methanol) Elemental analysis: C ₃₇ H ₅₅ N ₅ O ₆ S ・ 1 / 2H ₂ O Calculated: C, 62.86; H, 7.98; N, 9.91; S, 4.54 Found: C, 62.82; H, 8.08; N, 9.80; S, 4.52 Example 2 (2S, 4S, 5S) -5-） N- [2 (R) -Benzyl-3-
(Morpholinocarbonyl) propionyl] -3- (4-
Thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid
n-butylamide 2 (a) (2S, 4S, 5S) -5- {N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanyl}
Amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid n-butylamide 370 mg (0.87 mmol) of the compound synthesized in Reference Example 4
Was added to 4 ml of 4N hydrochloric acid / dioxane and stirred at room temperature for 30 minutes. Thereafter, the solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and further distilled under reduced pressure. This operation was repeated three times, and then dried under reduced pressure for 8 hours. Suspend in 10 ml of anhydrous tetrahydrofuran and further add N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanine
260 mg (0.96 mmol) were added. Under a nitrogen atmosphere, 0.15 ml (0.99 mmol) of diethyl cyanophosphate and 0.27 ml (1.94 mmol) of triethylamine were added to this solution under ice cooling, and the mixture was further stirred for 6 hours. Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (methylene chloride: methanol = 20: 1).
470 mg (93%) of the title compound was obtained as white crystals.

Melting point 201-203 ° C ▲ [α] ²⁰ _D ▼ = -43.7 ゜ (C = 1, methanol) Elemental analysis: C ₃₀ H ₅₂ N ₄ O ₅ S Calculated: C, 62.04; H, 9.02; N, 9.65; S, 5.52 found: C, 62.12; H, 9.07; N, 9.74; S, 5.69 2 (b) (2S, 4S, 5S) -5- {N- [2 (R) -benzyl-3- (Morpholinocarbonyl) propionyl]-
3- (4-thiazolyl) -L-alanyl {amino-6
Cyclohexyl-4-hydroxy-2-isopropylhexanoic acid n-butylamide 150 mg (0.26 mmol) of the compound synthesized in Example 2 (a) was added to 5 ml of 4N hydrochloric acid / dioxane, and the solution was added at room temperature.
Stirred for 0 minutes. Thereafter, the solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and further distilled off under reduced pressure.
After repeating this process twice, the resultant was dried under reduced pressure for 8 hours. The suspension was suspended in 10 ml of anhydrous tetrahydrofuran, and 79 mg of 2 (R) -benzyl-3- (morpholinocarbonyl) propionic acid was further added.
(0.29 mmol) was added. To this solution, under a nitrogen atmosphere, 0.04 ml (0.26 mmol) of diethyl cyanophosphate and 0.12 ml (0.86 mmol) of triethylamine were added under ice cooling, and the mixture was further stirred for 8 hours. The solvent was distilled off under reduced pressure, and the residue was purified on a silica gel thin layer plate (methylene chloride: methanol = 10: 1) to give the title compound as white crystals.
8 mg (72%) were obtained.

Melting point 161-163 ° C ▲ [α] ²⁰ _D ▼ = -40.4 ゜ (C = 0.5, methanol) Elemental analysis: C ₄₀ H ₆₁ N ₅ O ₆ S ・ 1 / 2H ₂ O Calculated: C, 64.14; H, 8.34; N, 9.35; S, 4.28 Found: C, 64.39; H, 8.07; N, 9.35; S, 4.29 Example 3 (2S, 4S, 5S) -5- ｛N- [2 (R) -(4-methoxy) benzyl-3- (morpholinocarbonyl) propionyl] -3- (4-thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid methylamide Example 1 (a 200 mg (0.37 mmol) synthesized in 2) and 2 (R)-(4-methoxy) benzyl-3-
137 mg (0.45 mmol) of (morpholinocarbonyl) propionic acid was reacted according to Example 1 (b) to give 188 mg (70%) of the title compound as white crystals.

Melting point 128-130 ° C ▲ [α] ²⁰ _D ▼ = -37.6 ゜ (C = 0.5, methanol) Elemental analysis: C ₃₈ H ₅₇ N ₅ O ₇ S · H ₂ O Calculated: C, 61.18; H, 7.97; N, 9.39; S, 4.30 Found: C, 61.43; H, 7.83; N, 9.31; S, 4.21 MS spectrum (m / e): 728 (M ⁺⁺ 1), 290, 121 Example 4 (2S, 4S , 5S) -5- {N- [2 (R)-(4-methoxy) benzyl-3- (morpholinocarbonyl) propionyl] -3- (4-thiazolyl) -L-alanyl} amino-6-cyclohexyl-4 -Hydroxy-2-isopropylhexanoic acid n-butylamide 300 mg (0.52 mmol) of the compound synthesized in Example 2 (a) and 2 (R)-(4-methoxy) benzyl-3-
175 mg (0.57 mmol) of (morpholinocarbonyl) propionic acid was reacted according to Example 2 (b) to give 332 mg (83%) of the title compound as white crystals.

Melting point 152-154 ° C ▲ [α] ²⁰ _D ▼ = -37.4 ゜ (C = 0.5, methanol) Elemental analysis: C ₄₁ H ₆₃ N ₅ O ₇ S Calculated: C, 63.95; H, 8.25; N, 9.09; S, 4.16 found: C, 63.66; H, 8.43; N, 9.10; S, 4.22 Example 5 (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3-
(Morpholinocarbonyl) propionyl] -3- (4-
Thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid methylamide 5 (a) (2R, 4S, 5S) -5- {N- (t-butoxycarbonyl) -3- ( 4-thiazolyl) -L-alanyl}
Amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid methylamide (2R, 4S, 5S) -5- (t-butoxycarbonyl) amino-6-cyclohexyl-4-hydroxy-2 synthesized in Reference Example 5. -Methylhexanoic acid methylamide 200mg
(0.56 mmol) in 4 ml of 4N hydrochloric acid / dioxane and stirred at room temperature for 30 minutes. Thereafter, the solvent was distilled off under reduced pressure, benzene was added, and the operation was repeated under reduced pressure. This operation was repeated three times, and then dried under reduced pressure for 8 hours. The suspension was suspended in 10 ml of anhydrous tetrahydrofuran, and N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanine was further added.
150 mg (1.68 mmol) were added. To this solution was added 0.1 ml of 95% diethyl cyanophosphate (0.6
7 mmol) and 0.23 ml (1.68 mmol) of triethylamine were added, and the mixture was further stirred for 15 hours. The reaction mixture was evaporated under reduced pressure, water was added to the residue, and the precipitated crystals were collected, washed with water, dissolved in dichloromethane, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 260 mg as a pale yellow powder.

Melting point 158-160 ° C Elemental analysis: C ₂₅ H ₄₂ N ₄ O ₅ S Calculated: C, 58.80; H, 8.29; N, 10.97; S, 6.28 Found: C, 58.86; H, 8.41; N, 10.67; S, 6.25 5 (b) (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3- (morpholinocarbonyl) propionyl]-
3- (4-thiazolyl) -L-alanyl {amino-6
Cyclohexyl-4-hydroxy-2-methylhexanoic acid methylamide (2R, 4S, 5S) -5- [N synthesized in Example 5 (a)
-(T-butoxycarbonyl) -3- (4-thiazolyl) -L-alanyl] amino-6-cyclohexyl-4
-Hydroxy-2-methylhexanoic acid methylamide 11
0 mg (0.215 mmol) was added to methanol (2 ml) and 4N hydrochloric acid / dioxane (20 ml), followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, benzene was added, the distillation was further performed under reduced pressure, and this operation was repeated three times, followed by drying under reduced pressure for 8 hours. Suspended in 8 ml of anhydrous tetrahydrofuran, and further 2- (R) -benzyl-3- (morpholinocarbonyl)
59.6 mg (0.215 mmol) of propionic acid were added. To this solution, under a nitrogen atmosphere, 0.042 ml (0.258 mmol) of 95% diethyl cyanophosphate and 0.12 ml of triethyl under ice cooling.
(0.86 mmol) was added and the mixture was further stirred for 18 hours. The reaction mixture was distilled off under reduced pressure, and the residue was purified on a silica gel thin layer plate (methylene chloride: methanol = 10: 1) to obtain 50 mg as a white powder.

Elemental analysis: C ₃₅ H ₅₁ N ₅ O ₆ S. 3H ₂ O Calculated: C, 58.07; H, 7.94; N, 9.67; S, 4.43 Found: C, 57.71; H, 7.56; N, 9.19 S, 4.40 Example 6 (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3-
(Morpholinocarbonyl) propionyl] -3- (4-
Thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid n-butylamide 6 (a) (2R, 4S, 5S) -5- {N- (t-butoxycarbonyl) -3 -(4-Thiazolyl) -L-alanyl]
Amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid n-butylamide 220 mg (0.552 mmol) of the compound synthesized in Reference Example 6
Was added to 4 ml of 4N hydrochloric acid / dioxane and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, benzene was added to the residue, and the solvent was further distilled off under reduced pressure. After this operation was repeated three times, the resultant was dried under reduced pressure for 8 hours. Anhydrous tetrahydrofuran
Suspended in 10 ml and further 0.15 g of N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanine
(0.552 mmol) was added. Under a nitrogen atmosphere, 0.11 ml (0.662 mmol) of diethyl cyanophosphate and 0.23 ml of triethylamine were added to this solution under ice-cooling.
Stirred for hours. The reaction solvent was concentrated under reduced pressure, water was added to the residue, the precipitated powder was collected, washed with water, dissolved in methylene chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from isopropyl ether to obtain 243 mg of the title compound as a pale yellow powder.

Melting point 172-174 ° C Elemental analysis: C ₂₈ H ₄₈ N ₄ O ₅ S Calculated: C, 60.84; H, 8.75; N, 10.14; S, 5.80 Found: C, 60.51; H, 8.75; N, 10.13; S, 6.026 (b) (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3- (morpholinocarbonyl) propionyl]-
3- (4-thiazolyl) -L-alanyl {amino-6
N-Butylamide of cyclohexyl-4-hydroxy-2-methylhexanoic acid 230 mg (0.416 mmol) of the compound synthesized in Example 6 (a) was added to 5 ml of 4N hydrochloric acid / dioxane, followed by stirring at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, benzene was added to the residue, and the operation was repeated under reduced pressure. This operation was repeated three times, and then dried under reduced pressure for 8 hours. Anhydrous tetrahydrofuran
The suspension was suspended in 15 ml, and 120 mg (0.416 mmol) of 2- (R) -benzyl-3- (morpholinocarbonyl) propionic acid was further added. Under a nitrogen atmosphere, 82 μl (0.499 mmol) of diethyl cyanophosphate and 0.23 ml (1.664 mmol) of triethylamine were added to this solution under ice cooling, and the mixture was further stirred for 15 hours. The reaction solvent was evaporated under reduced pressure, water was added to the residue, and the precipitated crystals were collected, washed with water, dissolved in methylene chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and isopropyl ether was added to the residue for crystallization to obtain 138 mg of the title compound as a pale yellow powder.

Melting point 162-163 ° C Elemental analysis: C ₃₈ H ₅₇ N ₅ O ₆ S ・ 0.5H ₂ O Calculated: C, 63.31; H, 8.11; N, 9.71; S, 4.45 Found: C, 63.30; H , 8.06; N, 9.92; S, 4.65 Example 7 (2R, 4S, 5S) -5- {N- [2 (R)-(4-methoxy) benzyl-3- (morpholinocarbonyl) propionyl] -3- (4-thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid n-butylamide 200 mg (0.36 mmol) of the compound synthesized in Example 6 (a) and 2 (R)- (4-methoxybenzyl) -3-
110 mg (0.36 mmol) of (morpholinocarbonyl) propionic acid was reacted according to Example 6 (b) to give 158 mg of the title compound as a white powder.

Melting point 130-132 ° C Elemental analysis: C ₃₉ H ₅₉ N ₅ O ₇ S Calculated: C, 63.13; H, 8.02; N, 9.44; S, 4.32 Found: C, 62.81; H, 8.11; N, 9.29; S, 5.06 Example 8 (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3-
(N-benzyl-N-methylaminocarbonyl) propionyl] -3- (4-thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid n-butylamide Example 6 (a) 170 mg (0.308 mmol) of 2 (R) -benzyl-3- (N-benzyl-N
-Methylaminocarbonyl) propionic acid 96 mg (0.308
Was reacted according to Example 6 (b) to give 148 mg of the title compound as a white powder.

Melting point 111-113 ° C Elemental analysis: C ₄₂ H ₅₉ N ₅ O ₅ S Calculated: C, 67.62; H, 7.97; N, 9.39; S, 4.30 Found: C, 67.33; H, 8.04; N, 9.53; S, 4.30 Example 9 (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3-
(N-cyclohexyl-N-methylaminocarbonyl)
Propionyl] -3- (4-thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2
-Methylhexanoic acid n-butylamide 170 mg (0.31 mmol) of the compound synthesized in Example 6 (a) and 94 mg of 2 (R) -benzyl-3- (N-cyclohexyl-N-methylaminocarbonyl) propionic acid
(0.308 mmol) was reacted according to Example 6 (b) to give 149 mg of the title compound as a white powder.

Melting point: 116-118 ° C Elemental analysis: C ₄₁ H ₆₃ N ₅ O ₅ S Calculated: C, 66.72; H, 8.60; N, 9.49; S, 4.34 Found: C, 66.10; H, 8.59; N, 9.57; S, 4.84 Example 10 (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3-
(Morpholinocarbonyl) propionyl] -3- (4-
Thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid n-hexaneamide 10 (a) (2R, 4S, 5S) -5- [N- (t-butoxycarbonyl)- 3- (4-thiazolyl) -L-alanyl]
Amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid n-hexaneamide 412 mg (0.96 mmol) of the compound synthesized in Reference Example 7
In 4N hydrochloric acid / 8.0 ml of dioxane, and
Stirred for minutes. The solvent was distilled off under reduced pressure, benzene was added to the residue, and the solvent was distilled off under reduced pressure.
Dry under reduced pressure for hours. The suspension was suspended in 50 ml of anhydrous tetrahydrofuran, and N- (t-butoxycarbonyl) -3 was further added.
289 mg (1.06 mmol) of-(4-thiazolyl) -L-alanine were added. Under a nitrogen atmosphere, 0.17 ml (1.06 mmol) of diethyl cyanophosphate and 0.6 ml (4.3 mmol) of triethylamine were added to the solution under ice cooling, and the mixture was further stirred for 15 hours. The reaction solvent was concentrated under reduced pressure, water was added to the residue,
The precipitated crystals were collected, dissolved in methylene chloride, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and isopropyl ether was added to the residue for crystallization to obtain 465 mg of the title compound as a white powder.

156-158 ° C 10 (b) (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3- (morpholinocarbonyl) propionyl]-
3- (4-thiazolyl) -L-alanyl {amino-6
Cyclohexyl-4-hydroxy-2-methylhexanoic acid n-hexaneamide 200 mg (0.344 mmol) of the compound synthesized in Example 10 (a) and 105 mg (0.38 mmol) of 2 (R) -benzyl-3- (morpholinocarbonyl) propionic acid Mmol) was reacted according to Example 6 (b) to give the title compound as a white powder.
110 mg were obtained.

Elemental analysis: C ₄₀ H ₆₁ N ₅ O ₆ S Calculated: C, 64.92; H, 8.31; N, 9.46; S, 4.33 Found: C, 64.26; H, 8.31; N, 9.50; S, 4.55 Example 11 (2R, 4S, 5S) -5- {N- [2 (R)-(4-methoxy) benzyl-3- (N-benzyl-N-methylaminocarbonyl) propionyl] -3- (4- Thiazolyl)
-L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid n-butylamide 150 mg (0.27 mmol) of the compound synthesized in Example 6 (a) and 2 (R)-(4-methoxybenzyl) ) -3-
9.2 mg (0.27 mmol) of (N-benzyl-N-methylaminocarbonyl) propionic acid was reacted according to Example 6 (b) to give 146 mg of the title compound as a white powder.

Melting point 112-114 ° C Elemental analysis: C ₄₃ H ₆₁ N ₅ O ₆ S Calculated: C, 66.55; H, 7.92; N, 9.02; S, 4.13 Found: C, 66.31; H, 7.74; N, 9.16; S, 4.01 Example 12 (2R, 4S, 5S) -5- {N- [2 (R)-(4-methoxy) benzyl-3- (4-methylpiperazinocarbonyl) propionyl] -3- (4-Thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid n-butylamide 150 mg (0.27 mmol) of the compound synthesized in Example 6 (a) and 2 (R)- (4-methoxybenzyl) -3-
93 mg of (4-methylpiperazinocarbonyl) propionic acid
(0.27 mmol) was reacted according to Example 6 (b) to give 32 mg of the title compound as a white powder.

Melting point 125-126 ° C Elemental analysis: C ₄₀ H ₆₂ N ₆ O ₆ S Calculated: C, 63.63; H, 8.28; N, 11.13; S, 4.25 Found: C, 63.29; H, 8.01; N, 10.98; S, 3.98 Example 13 (2R, 4S, 5S) -5- {N- [2 (R)-(4-methoxy) benzyl-3- (piperidinocarbonyl) propionyl] -3- (4- Thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid n-butylamide 150 mg (0.27 mmol) of the compound synthesized in Example 6 (a) and 2 (R)-(4- Methoxybenzyl) -3-
86 mg (0.28 mmol) of (piperidinocarbonyl) propionic acid was reacted according to Example 6 (b) to give 47 mg of the title compound as a white powder.

Melting point: 120-122 ° C Elemental analysis: C ₄₀ H ₆₁ N ₅ O ₆ S Calculated: C, 64.93; H, 8.31; N, 9.46; S, 4.33 Found: C, 64.75; H, 8.56; N, 9.23; S, 4.19 Example 14 (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3-
(N-benzyl-N-methylaminocarbonyl) propionyl] -3- (4-thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid methylamide In Example 5 (a) 250 mg (0.49 mmol) of the synthesized compound and 2 (R) -benzyl-3- (N-benzyl-N
-Methylaminocarbonyl) propionic acid (156 mg, 0.5 mmol) was reacted according to Example 5 (b) to give 172 mg of the title compound as white crystals.

Melting point 121-123 ° C Elemental analysis: C ₃₉ H ₅₃ N ₅ O ₅ S ・ 1 / 2H ₂ O Calculated: C, 65.74; H, 7.64; N, 9.83; S, 4.50 Found: C, 65.77; H, 7.47; N, 9.90; S, 4.24 Example 15 (2S, 4S, 5S) -5- {N- [2 (R) -benzyl-3-
(N-benzyl-N-methylaminocarbonyl) propionyl] -3- (4-thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid methylamide In Example 1 (a) 260 mg (0.48 mmol) of the synthesized compound and 2 (R) -benzyl-3- (N-benzyl-N
-Methylaminocarbonyl) propionic acid 150 mg (0.48
Was reacted according to Example 1 (b) to give 190 mg of the title compound as a white powder.

Melting point 125-127 ° C Elemental analysis: C ₄₁ H ₅₇ N ₅ O ₅ S Calculated: C, 67.27; H, 7.85; N, 9.57; S, 4.38 Found: C, 67.02; H, 7.92; N, 9.48; S, 4.17 Example 16 (2S, 4S, 5S) -5- {N- [2 (R) -benzyl-3-
(N-benzyl-N-methylaminocarbonyl) propionyl] -3- (4-thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid n-butylamide Example 2 (a) 280 mg (0.48 mmol) of the compound synthesized in 2) and 2 (R) -benzyl-3- (N-benzyl-N
-Methylaminocarbonyl) propionic acid 150 mg (0.48
Was reacted according to Example 2 (b) to give 187 mg of the title compound as a white powder.

Melting point: 155-156 ° C Elemental analysis: C ₄₄ H ₆₃ N ₅ O ₅ S ・ 1 / 2H ₂ O Calculated: C, 67.49; H, 8.24; N, 8.94; S, 4.09 Found: C, 67.74; H, 8.17; N, 8.93; S, 4.08 Example 17 (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3-
(N-benzyl-N-methylaminocarbonyl) propionyl] -3- (4-thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid isobutylamide 17 (a) (2R, 4S, 5S) -5- [N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanyl]
Amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid isobutylamide 300 mg (0.753 mmol) of the compound synthesized in Reference Example 17
And N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanine (210 mg, 0.753 mmol) was reacted according to Example 5 (a) to give 320 mg of the title compound as a colorless powder.

178-180 ° C 17 (b) (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3- (N-benzyl-N-methylaminocarbonyl) propionyl] -3- (4 -Thiazolyl) -L-alanyl} amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid isobutylamide 300 mg (0.543 mmol) of the compound synthesized in Example 17 (a) and 2 (R) -benzyl-3 -(N-benzyl-N
-Methylaminocarbonyl) propionic acid 170 mg (0.543
(Mmol) was reacted according to Example 6 (b) to give 216 mg of the title compound as a colorless powder.

Melting point 118-120 ° C Elemental analysis: C ₄₂ H ₅₉ N ₅ O ₅ S Calculated: C, 67.62; H, 7.97; N, 9.39; S, 4.30 Found: C, 67.50; H, 8.16; N, 9.18; S, 4.13 Example 18 (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3-
(N-benzyl-N-methylaminocarbonyl) propionyl] -3- (4-thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid n-propylamide 18 (a) ( 2R, 4S, 5S) -5- [N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanyl]
Amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid n-propylamide 280 mg (0.728 mmol) of the compound synthesized in Reference Example 18
And 204 mg (0.75 mmol) of N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanine were reacted according to Example 5 (a) to obtain 306 mg of the title compound as colorless crystals.

18 (b) (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3- (N-benzyl-N-methylaminocarbonyl) propionyl] -3- (4 -Thiazolyl) -L-alanyl diamino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid n-propylamide 252 mg (0.468 mmol) of the compound synthesized in Example 18 (a) and 2 (R) -benzyl -3- (N-benzyl-N
-Methylaminocarbonyl) propionic acid 152 mg (0.488
(Mmol) was reacted according to Example 6 (b) to give 111 mg of the title compound as a colorless powder.

Melting point: 115-118 ° C Elemental analysis: C ₄₁ H ₅₇ N ₅ O ₅ S Calculated: C, 67.27; H, 7.85; N, 9.57; S, 4.38 Found: C, 66.97; H, 8.10; N, 9.30; S, 4.42 Example 19 (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3-
(N-benzyl-N-methylaminocarbonyl) propionyl] -3- (4-thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid ethylamide 19 (a) (2R, 4S , 5S) -5- [N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanyl]
Amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid ethylamide 321 mg (0.87 mmol) of the compound synthesized in Reference Example 19
And 242 mg (0.89 mmol) of N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanine according to Example 5 (a) to give 344 mg of the title compound as white crystals. .

179-181 ° C 19 (b) (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3- (N-benzyl-N-methylaminocarbonyl) propionyl] -3- (4 -Thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid ethylamide 325 mg (0.62 mmol) of the compound synthesized in Example 19 (a) and 2 (R) -benzyl-3- (N-benzyl-N
-Methylaminocarbonyl) propionic acid 200 mg (0.64
Was reacted according to Example 6 (b) to give 129 mg of the title compound as white crystals.

Melting point 148-150 ° C Elemental analysis: C ₄₀ H ₅₅ N ₅ O ₅ S Calculated: C, 66.92; H, 7.72; N, 9.75; S, 4.47 Found: C, 66.74; H, 7.64; N, 9.68; S, 4.30 Example 20 (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3-
(N-benzyl-N-methylaminocarbonyl) propionyl] -3- (4-thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid isopropylamide 20 (a) (2R, 4S, 5S) -5- [N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L-alanyl]
Amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid isopropylamide (2R, 4S, 5S) -5- () obtained by reacting the compound of Reference Example 2 with isopropylamine according to Reference Example 19. t-
(Butoxycarbonyl) amino-6-cyclohexyl-4
180 mg (0.47 mmol) of isopropylamide of -hydroxy-2-methylhexanoic acid was reacted according to Example 5 (a) to obtain 185 mg of the title compound.

185-187 ° C 20 (b) (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3- (N-benzyl-N-methylaminocarbonyl) propionyl] -3- (4 -Thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid isopropylamide 170 mg (0.32 mmol) of the compound of Example 20 (a);
98.4 mg (0.32 mmol) of 2 (R) -benzyl-3- (N-benzyl-N-methylaminocarbonyl) propionic acid was reacted according to Example 6 (b) to give the title compound 10
8 mg were obtained.

Melting point 142-144 ° C Elemental analysis: C ₄₁ H ₅₇ N ₅ O ₅ S Calculated: C, 67.27; H, 7.85; N, 9.57; S, 4.38 Found: C, 67.08; H, 7.90; N, 9.44; S, 4.22 Example 21 (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3-
(Morpholinocarbonyl) propionyl] -3- (4-
Thiazolyl) -L-alanyl {amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid methylamide 21 (a) (3R, 5S) -5-[(1S) -1- {N- [2
(R) -benzyl-3- (morpholinocarbonyl) propionyl] -3- (4-thiazolyl) -L-alanyl}
Amino-2-cyclohexylethyl] -3-methyldihydrofuran-2 (3H) -one 1.7 g (3.64 mmol) of the compound synthesized in Reference Example 26 was added to 20 ml of 4N hydrochloric acid / dioxane, and the mixture was added at room temperature for 60 minutes. Stirred. Thereafter, the solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and further the solvent was distilled off under reduced pressure. After repeating this operation three times, the resultant was dried under reduced pressure for 8 hours. After drying, the resultant was suspended in 30 ml of anhydrous tetrahydrofuran, and further suspended in (2R)-
Benzyl-3- (morphonylcarbonyl) propionic acid
1.11 g (4.0 mmol) was added. 0.71 ml (4.37 mmol) of diethyl cyanophosphate and 2.0 ml (14.56 mmol) of triethylamine were added to this solution under ice cooling under ice cooling, and the mixture was further stirred at room temperature for 15 hours. Thereafter, the solvent was distilled off under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (ethyl acetate) to obtain 1.43 g of the title compound as a colorless foam.

Elemental analysis: C ₃₄ H ₄₆ N ₄ O ₆ S ・ 1 / 2H ₂ O Calculated: C, 63.04; H, 7.31; N, 8.65; S, 4.95 Found: C, 63.28; H, 7.38; N , 8.54; S, 4.70 21 (b) (2R, 4S, 5S) -5- {N- [2 (R) -benzyl-3- (morpholinocarbonyl) propionyl]-
3- (4-thiazolyl) -L-alanyl {amino-6
Cyclohexyl-4-hydroxy-2-methylhexanoic acid methylamide 200 mg (0.313 mmol) of the compound synthesized in Example 21 (a) was dissolved in 2 ml of methanol, and 40% methylamine
2.5 ml (25.3 mmol) of a methanol solution was added and left at room temperature for 1 hour. After excess amine and methanol were distilled off under reduced pressure, 4 ml of ethyl acetate was added to the residue, and the mixture was allowed to stand after dissolution. The precipitated crystals were collected, and the title compound was converted to white crystals by 150 m.
g obtained.

Melting point 130-132 ° C Elemental analysis: C ₃₅ H ₅₁ N ₅ O ₆ S Calculated: C, 62.75; H, 7.67; N, 10.45; S, 4.79 Found: C, 62.74; H, 7.78; N, 10.25; S, 4.79 Reference Example 1 (3S, 5S) -5-[(1S) -1- (t-butoxycarbonyl) amino-2-cyclohexylethyl] -3-isopropyldihydrofuran-2 (3H) -one 1 (A) (3S, 5S) -5-[(1S) -1- (t-butoxycarbonyl) amino-2-cyclohexylethyl]
-3- (1-Hydroxy-1-methylethyl) dihydrofuran-2 (3H) -one Dissolve 3.55 ml (25.3 mmol) of diisopropylamine in 30 ml of anhydrous tetrahydrofuran, and add-under a nitrogen atmosphere.
At 78 ° C., 15.81 ml (25.3 mmol) of n-butyllithium (1.6 M, n-hexane solution) was added, and the mixture was stirred for 30 minutes.
A solution obtained by dissolving 3.58 g (11.5 mmol) of (5S) -5-[(1S) -1- (t-butoxycarbonyl) amino-2-cyclohexylethyl] dihydrofuran-2 (3H) -one in 10 ml of anhydrous tetrahydrofuran was used. In addition, after stirring at -78 ° C for an additional hour, 1.86 ml (25.3 mmol) of distilled acetone was added, and the mixture was stirred for 2 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous citric acid solution, water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by medium-pressure silica gel column chromatography (n-hexane: diethyl ether = 1: 1) to give 3.65 g (86%) of the title compound as white crystals from the less polar compound. Obtained.

Melting point 123-125 ° C ▲ [α] ²⁰ _D ▼ -20.6 ゜ (C = 1, methanol) Elemental analysis: As C ₂₀ H ₃₅ NO ₅ Calculated: C, 65.01; H, 9.55; N, 3.79 Actual: C, 65.01; H, 9.62; N, 3.91 Mass spectrometry spectrum (m / e): 369 (M ⁺ ), 226, 170, 126 On the other hand, diastereomers of the title compound from the most polar compound: (3R) form 290 mg (7%) Was obtained as white crystals.

Melting point 141-143 ° C ▲ [α] ²⁰ _D ▼ -30.4 ゜ (C = 1, methanol) Elemental analysis: Calculated as C ₂₀ H ₃₅ NO ₅ Calculated: C, 65.01; H, 9.55; N, 3.79 Actual: C, 64.99; H, 9.66; N, 3.91 Mass spectrum (m / e): 369 (M ⁺ ), 226,170,126 1 (b) (3S, 5S) -5-[(1S) -1- (t-butoxycarbonyl) ) Amino-2-cyclohexylethyl]
-3-Isopropyldihydrofuran-2 (3H) -one (3S, 5S) -5-[(1S) -1- (t-butoxycarbonyl) amino-2-cyclohexylethyl] -3-
2.15 g (5.82 mmol) of (1-hydroxy-1-methylethyl) dihydrofuran-2 (3H) -one was dissolved in 20 ml of anhydrous tetrahydrofuran, and 1.62 ml of triethylamine was dissolved.
(1.16 mmol) and 5 mg of 4-N, N-dimethylaminopyridine were added, and under ice cooling, 1.07 ml (11.6 mmol) of methyloxalyl chloride was added dropwise under a nitrogen atmosphere, and the mixture was further stirred for 2 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with brine and dried over anhydrous magnesium sulfate. After evaporation under reduced pressure, the residue was subjected to medium pressure silica gel column chromatography (ethyl acetate: n-hexane =
1: 4) and 2.61 g of oxalyl ester compound (99
%)Obtained. 2.37 g (5.20 mmol) of this ester was dissolved in 30 ml of toluene, and 2.61 g (8.97 mmol) of tri-n-butyltin hydride and 427 mg (2.60 mmol) of azobis (isobutyronitrile) were added to the solution. The mixture was heated under reflux for 2 hours under an atmosphere. The solvent was distilled off under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) and recrystallized from n-hexane to give 1.39 of the title compound as white crystals.
g (76%).

Melting point 114-116 ° C ▲ [α] ²⁰ _D ▼ -25.0 ゜ (C = 1, methanol) Elemental analysis: Calculated as C ₂₀ H ₃₅ NO ₄ Calculated: C, 67.95; H, 9.98; N, 3.96 Actual: C, 67.63; H, 9.92; N, 4.07 Mass spectrum (m / e): 353 (M ⁺ ), 170, 126 Reference Example 2 (3S, 5S) -5-[(1S) -1- (t-butoxycarbonyl) Amino-2-cyclohexylethyl] -3-methyldihydrofuran-2 (3H) -one Dissolve 0.99 ml (7.07 mmol) of diisopropylamine in 20 ml of anhydrous tetrahydrofuran, and add-under a nitrogen atmosphere.
At 78 ° C., 2.83 ml (7.07 mmol) of n-butyllithium (2.5 M n-hexane solution) was added, and the mixture was stirred for 30 minutes.
A solution prepared by dissolving 1.0 g (3.2 mmol) of (5S) -5-[(1S) -1- (t-butoxycarbonyl) amino-2-cyclohexylethyl] dihydrofuran-2 (3H) -one in 10 ml of anhydrous tetrahydrofuran was used. After stirring at −78 ° C. for another 30 minutes, 0.44 ml (7.07 mmol) of methyl iodide was added dropwise. After reacting at the same temperature for 1.5 hours, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 8: 1) to obtain a colorless oil. To this was added n-hexane, and after crystallization, the solvent was distilled off to obtain 0.69 g of white crystals.

Melting point 80-82 ° C Elemental analysis: C ₁₈ H ₃₁ NO ₄ Calculated: C, 66.43; H, 9.60; N, 4.30 Found: C, 66.24; H, 9.67; N, 4.38 Reference Example 3 (2S, (4S, 5S) -5- (t-butoxycarbonyl) amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid methylamide (3S, 5S) -5-[(1S) -1 synthesized in Reference Example 1.
-(T-butoxycarbonyl) amino-2-cyclohexylethyl] -3-isopropyldihydrofuran-2
1.33 g (3.76 mmol) of (3H) -one in 10 ml of methanol
The solution was dissolved in the solution, and methylamine gas was blown into the solution under ice cooling to saturate the solution, sealed, and allowed to stand overnight. The solvent was distilled off under reduced pressure, and the residue was recrystallized from n-hexane to obtain 1.32 g (91%) of the title compound as white crystals.

Melting point 154-157 ° C ▲ [α] ²⁰ _D ▼ = -42.0 ゜ (C = 0.75, methanol) Elemental analysis: C ₂₁ H ₄₀ N ₂ O ₄ Calculated: C, 65.59; H, 10.48; N, 7.28 Found: C, 65.88; H, 10.28; N, 7.24 IR spectrum (KBr): 1666, 1629 cm ^-1 Mass spectrum (m / e): 385 (M ⁺⁺ 1), 158 Reference example 4 (2S, 4S, 5S ) -5- (t-Butoxycarbonyl) amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid butylamide (3S, 5S) -5-[(1S) -1 synthesized in Reference Example 1.
-(T-butoxycarbonyl) amino-2-cyclohexylethyl] -3-isopropyldihydrofuran-2
890 mg (2.52 mmol) of (3H) -one was dissolved in 2.5 ml (25.3 mmol) of n-butylamine and heated at 100 ° C. for 4 hours. After the excess amine was distilled off under reduced pressure, the residue was purified by medium pressure silica gel column chromatography (methylene chloride: methanol = 20: 1) and recrystallized from diisopropyl ether to give 1.05 g (98%) of the title compound as white crystals.
%)Obtained.

Melting point 115-118 ° C ▲ [α] ²⁰ _D ▼ = -34.9 ゜ (C = 1, methanol) Elemental analysis: Calculated as C ₂₄ H ₄₆ N ₂ O ₄ Calculated: C, 67.57; H, 10.87; N, 6.57 Found: C, 67.22; H, 10.88; N, 6.73 IR spectrum (KBr): 1678,1620 cm ^-1 Mass spectrum (m / e): 427 (M ⁺⁺ 1), 200 Reference example 5 (2R, 4S, 5S ) -5- (t-Butoxycarbonyl) amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid methylamide (3R, 5S) -5-[(1S) -1 synthesized in Reference Example 2.
-(T-butoxycarbonyl) amino-2-cyclohexylethyl] -3-methyldihydrofuran-2 (3H)-
Dissolve 0.2 g (0.615 mmol) of ON in 6 ml of methanol,
Methylamine gas was introduced for 3 minutes and left for 3 hours.
The reaction mixture was concentrated under reduced pressure, n-hexane was added to the residue,
0.23 g was obtained as white crystals.

Melting point: 144-145 ° C Elemental analysis: C ₁₉ H ₃₆ N ₂ O ₄ Calculated: C, 63.21; H, 10.19; N, 7.76 Found: C, 63.28; H, 10.36; N, 7.72 Reference Example 6 ( 2R, 4S, 5S) -5- (t-butoxycarbonyl) amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid n-butylamide (3R, 5S) -5-[(( 1S) -1
-(T-butoxycarbonyl) amino-2-cyclohexylethyl] -3-methyldihydrofuran-2 (3H)-
To 0.4 g (1.23 mmol) of ON was added 6 ml of n-butylamine, and the mixture was refluxed for 3.0 hours with stirring. The reaction mixture was concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate) to obtain 0.48 g of the title compound as a white powder.

Reference Example 7 (2R, 4S, 5S) -5- (t-butoxycarbonyl) amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid n-hexylamide Synthesized in Reference Example 2 (3R, 5S) −5-[(1S) -1
-(T-butoxycarbonyl) amino-2-cyclohexylethyl] -3-methyldihydrofuran-2 (3H)-
450 mg (1.38 mmol) of n-hexylamine in 10 ml
Was added and refluxed for 2.2 hours with stirring. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (cyclohexane: ethyl acetate = 1: 2),
443 mg of the title compound were obtained as white crystals.

Reference Example 8 N-3-phenylpropionyl- (S)-(-)-4-
Benzyl-2-oxazolidinone (4S)-(-)-in 200 ml of anhydrous tetrahydrofuran
12.41 g (70 mmol) of 4-benzyl-2-oxazolidinone was dissolved, and 48.1 ml (77 mmol) of a 1.6 M n-butyllithium / hexane solution was added dropwise at -78 ° C under a nitrogen atmosphere. After stirring for 30 minutes, 13.0 g (77 mmol) of 3-phenylpropionyl chloride was added to 100 ml of anhydrous tetrahydrofuran.
The solution dissolved therein was slowly dropped at the same temperature and stirred for 1 hour. One hour later, saturated saline was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / n-hexane = 1/4) and recrystallized (ethyl acetate-hexane). Was carried out to obtain 16.8 g (78%) of the title compound as white crystals.

Melting point: 92-95 ° C Elemental analysis: C ₁₉ H ₁₉ NO ₃ Calculated: C, 73.77; H, 6.19; N, 4.53 Found: C, 73.57; H, 6.28; N, 4.41 Mass spectrum (m / e ): 309 (M ⁺ ) Reference Example 9 (4S)-(-)-4-benzyl-N-[(2R)-(benzyloxycarbonyl) propionyl] -2-oxazolidinone In 50 ml of anhydrous tetrahydrofuran, at -78 ° C. 2.91 ml (20.8 mmol) of diisopropylamine in a nitrogen atmosphere
And 13.40 ml of 1.6 M n-butyllithium-hexane solution
(21.4 mmol was added and stirred for 30 minutes. In this solution, the (4S)-(−)-4-benzyl- obtained in Reference Example 8 was added.
5.35 g (17.3 mmol) of N- (3-phenylpropionyl) -2-oxazolidinone was added to anhydrous tetrahydrofuran 2
A solution dissolved in 0 ml was added, and the mixture was further stirred at the same temperature for 1 hour. After completion of the reaction, bromoacetic acid benzyl ester 5.74
A solution of 10 ml (36.2 mmol) in 10 ml of anhydrous tetrahydrofuran was added dropwise, and the mixture was further stirred for 3 hours. After completion of the reaction, a saturated saline solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/5) to give the title compound as a colorless oil. , 5.47g (69
%)Obtained.

Mass spectrum (m / e): 457 (M ⁺ ) Reference example 10 (4S)-(-)-4-benzyl-N- [2 (R) -benzyl-3- (morpholinocarbonyl) propionyl]-
2-Oxazolidinone 5.10 g (11.1 mmol) of the compound obtained in Reference Example 9 was dissolved in 100 ml of ethanol, and 10% palladium-carbon 500% was dissolved.
The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours.
After completion of the reaction, the catalyst was removed, and the solution was concentrated under reduced pressure. The residue was dissolved in 50 ml of anhydrous tetrahydrofuran, and 1.16 ml (13.3 mmol) of morpholine, 2.02 ml (13.3 mmol) of diethyl cyanophosphate and 1.86 ml (13.3 mmol) of triethylamine were successively added under ice-cooling under a nitrogen atmosphere, and further added for 2 hours. Stirred. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was
Medium pressure silica gel column chromatography (Developing solvent:
Purification was performed using ethyl acetate / n-hexane = 1/1) to obtain 3.90 g (80%) of the title compound as white crystals.

Melting point 56-59 ° C Elemental analysis: C ₂₅ H ₂₈ N ₂ O ₅ Calculated: C, 68.79; H, 6.47; N, 6.42 Found: C, 68.59; H, 6.75; N, 6.50 Reference Example 11 2 (R) -benzyl-3- (morpholinocarbonyl)-
Propionic acid 3.70 g (8.5 mmol) of the compound obtained in Reference Example 10 was dissolved in 80 ml of tetrahydrofuran and 30 ml of water, and cooled under ice-cooling.
711 mg (16.9 mmol) of lithium hydroxide monohydrate was added, and the mixture was stirred at the same temperature for 3 hours. After completion of the reaction, tetrahydrofuran was distilled off under reduced pressure, 10% aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with methylene chloride. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid under ice-cooling, and extracted with methylene chloride. .
After drying over magnesium sulfate, the residue was distilled off under reduced pressure to give 1.75 g (75%) of the title compound as a white oil.

Mass spectrum (m / e): 277 (M ⁺ ) Reference Example 12 4 (S) -isopropyl-3- (3-phenylpropionyl) -2-oxazolidinone 4 (S) -isopropyl-2-oxazolidinone 11.7
5 g (91.0 mmol) was dissolved in 200 ml of anhydrous tetrahydrofuran, 68.3 ml (0.11 mol) of n-butyllithium (1.6 M hexane solution) was added dropwise at -78 ° C under a nitrogen atmosphere, and the mixture was stirred for 30 minutes. After 30 minutes, a solution of 18.41 g (0.11 mol) of 3-phenylpropionic chloride in 100 ml of anhydrous tetrahydrofuran was added dropwise over 10 minutes. After further stirring for 1 hour, saturated aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 1).
After purification in 3), recrystallization from diisopropyl ether gave the title compound as white crystals in 20.12 g (85
%)Obtained.

Melting point 62-63 ° C ▲ [α] ²⁰ _D ▼ = +71.4 ゜ (C = 1, chloroform) Elemental analysis: C ₁₅ H ₁₉ NO ₃ Calculated: C, 68.94; H, 7.33; N, 5.36 Value: C, 68.89; H, 7.12; N, 5.43 Mass spectrum (m / e): 261 (M ⁺ ), 130 104,91 Reference Example 13 3- [2 (R) -benzyl-3- (benzyloxycarbonyl) ) Propionyl] -4 (S) -isopropyl-2
Dissolve 5.05 ml (36.0 mmol) of oxazolidinone diisopropylamine in 100 ml of anhydrous tetrahydrofuran and under nitrogen atmosphere,
N-Butyllithium (1.6M hexane solution) at -78 ° C
2.50 ml (36.0 mmol) was added dropwise, and the mixture was stirred for 30 minutes, and then synthesized in Reference Example 12, (4S) -isopropyl-3- (3-
Phenyl-1-oxopropyl) -2-oxazolidinone 7.84 g (30.0 mmol) was added to anhydrous tetrahydrofuran 50m.
The solution dissolved in l was added dropwise, and the mixture was further stirred for 1 hour. 1
After an hour, 14.26 ml (90.0 mmol) of benzyl bromoacetate
And stirred for 6 hours while gradually returning to room temperature. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate.
After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (ethyl acetate: n-hexane = 1: 3) and recrystallized from diisopropyl ether. As a result, 9.05 g (74%) of the title compound was obtained as white crystals.

Melting point 118-120 ° C ▲ [α] ²⁰ _D ▼ = + 86.6 ゜ (C = 1, chloroform) Elemental analysis: C ₂₄ H ₂₇ NO ₅ Calculated: C, 70.40; H, 6.65; N, 3.42 Value: C, 70.78; H, 6.71; N, 3.54 Mass spectrometry (m / e): 409 (M ⁺ ), 318 130,91 Reference Example 14 3- {2 (R) -benzyl-3- (N- Benzyl-N-
Methylaminocarbonyl) propionyl {-4 (S)-
Isopropyl-2-oxazolidinone 1.03 g of the benzyl ester synthesized in Reference Example 13 (2.5
(2 mmol) was dissolved in 20 ml of ethanol, 100 mg of 10% palladium-carbon was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 4 hours. Four hours later, the catalyst was removed, the solvent was distilled off under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (50 ml). Under a nitrogen atmosphere, N-benzyl-N-methylamine (0.39 ml, 3.02 mmol) was added under ice-cooling. Diethyl acid 0.
46 ml and 0.42 ml of triethylamine were added and stirred for 6 hours. The solvent was distilled off under reduced pressure, and the residue was purified by medium pressure silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) and recrystallized from isopropyl ether to give 1.04 g of the title compound as white crystals. (98%).

Melting point 60-62 ° C ▲ [α] ²⁰ _D ▼ = + 107.1 ゜ (C = 1, chloroform) Elemental analysis: C ₂₅ H ₃₀ N ₂ O ₄ Calculated: C, 71.07; H, 7.16; N, 6.63 found: C, 70.59; H, 7.14; N, 6.51 Reference Example 15 2 (R) -benzyl-3- (N-benzyl-N-methylaminocarbonyl) propionic acid 400 mg of the compound synthesized in Reference Example 14 (0.95 (Mmol) was dissolved in a mixture of 10 ml of tetrahydrofuran and 4 ml of water, 80 mg (1.89 mmol) of lithium hydroxide was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, methylene chloride was added to the residue, and the mixture was extracted with a 10% aqueous sodium hydroxide solution. The aqueous layer was adjusted to pH 2.0 with citric acid and extracted with methylene chloride. The extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain a colorless oil. N-Hexane was added to the obtained oil, powdered, collected, and recrystallized from isopropyl ether to obtain 84 mg of the title compound as needle crystals.

Melting point: 119-121 ° C Elemental analysis: C ₁₉ H ₂₁ NO ₃ Calculated: C, 73.29; H, 6.80; N, 4.50 Found: C, 72.74; H, 7.10; N, 4.29 Reference Example 16 2 (R )-(4-Methoxybenzyl) -3- (morpholinocarbonyl) propionic acid Starting from 3- (4-methoxyphenyl) propionic acid chloride and using morpholine as an amine,
The same operation as in Reference Example 12-14 was performed to synthesize 2 (R).
Dissolve 1.62 g (4.08 mmol) of-(4-methoxybenzyl) -3- (morpholinocarbonyl) propionic acid benzyl ester in 50 ml of ethanol, add 160 mg of 10% palladium-carbon, and add a hydrogen atmosphere at room temperature for 4 hours. Stirred. After 4 hours, the catalyst was removed, and the solution was concentrated under reduced pressure.
1.25 g of the title compound was obtained as a colorless oil.

Mass spectrometry spectrum (m / e): 307 (M ⁺ ) Reference Example 17 (2R, 4S, 5S) -5- (t-butoxycarbonyl) amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid isobutylamide 290 mg (0.93 mmol) of the compound synthesized in Reference Example 2
Was dissolved in 3 ml of methanol, 3 ml of isobutylamine was added, and the mixture was allowed to stand at room temperature overnight. The reaction mixture was concentrated under reduced pressure,
To the residue was added n-hexane to obtain 340 mg of the title compound as colorless crystals.

Melting point 125-126 ° C Reference Example 18 (2R, 4S, 5S) -5- (t-butoxycarbonyl) amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid isopropylamide Compound 293 mg synthesized in Reference Example 2 (0.9 mmol)
It was dissolved in 3 ml of methanol, 3 ml of n-propylamine was added under ice cooling, and the mixture was left overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and n-hexane was added to the residue to give 315 mg of the title compound as white crystals.

Melting point 115-116 ° C Reference Example 19 (2R, 4S, 5S) -5- (t-butoxycarbonyl) amino-6-cyclohexyl-4-hydroxy-2-methylhexanoic acid ethylamide 325 mg of the compound synthesized in Reference Example 2 ( 1.0 mmol)
It was dissolved in 10 ml of a 23% ethylamine-methanol solution, left at room temperature for 3 hours and 55 minutes, and the solvent was distilled off under reduced pressure. The obtained crystals were recrystallized from isopropyl ether to give 321 mg of the title compound as white crystals.

126-127 ° C Reference Example 20 2 (R) -benzyl-3- (N-cyclohexyl-N-
Methylaminocarbonyl) propionic acid The same operation as in Reference Example 12-14 was performed to synthesize 3- [4
-Oxo-2 (R) -benzyl-4- (N-cyclohexyl-N-methylamino) butyryl] -4 (S) -isopropyl-2-oxazolidinone 500 mg (1.21 mmol) is dissolved in a mixture of 10 ml of tetrahydrofuran and 4 ml of water. Then, 100 mg (2.42 mmol) of lithium hydroxide was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, aqueous sodium bicarbonate was added to the residue, and the mixture was extracted with methylene chloride. The aqueous layer was adjusted to pH 2 with aqueous citric acid and extracted with methylene chloride. The extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain 130 mg of the title compound as amorphous.

Elemental analysis: C ₁₈ H ₂₅ NO ₃ Calculated: C, 71.26; H, 8.31; N, 4.62 Observed: C, 71.41; H, 8.20; N, 4.78 Reference Example 212 (R)-(4- Methoxybenzyl) -3- (piperidinocarbonyl) propionic acid Starting from 3- (4-methoxyphenyl) propionic chloride and using piperidine as an amine,
The same operation as in Reference Example 12-14 was performed, and synthesized 3- ｛4
-Oxo-2 (R)-(4-methoxybenzyl) -4-
(Piperidino) butyryl｝ -4 (S) -isopropyl-
1.0 g (2.4 mmol) of 2-oxazolidinone was dissolved in a mixture of 25 ml of tetrahydrofuran and 15 ml of water, and 200 mg (4.8 mmol) of lithium hydroxide was added, followed by stirring at room temperature overnight. The solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue.
Further, it was extracted with aqueous sodium bicarbonate. The aqueous layer was acidified with 10% aqueous hydrochloric acid and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as an oil (443m).
g obtained.

▲ [α] ²⁰ _D ▼ = +6.0 (C = 1, methanol) Elemental analysis: C ₁₇ H ₂₃ NO ₄ Calculated: C, 66.86; H, 7.59; N, 4.59 Actual: C, 66.62; H, 7.67; N, 4.35 Reference Example 22 Starting from 2- (R)-(4-methoxybenzyl) -3- (N-benzyl-N-methylaminocarbonyl) propionic acid 3- (4-methoxyphenyl) propionic chloride The same operation as in Reference Example 12-14 was carried out using N-benzyl-N-methylamine as the amine as a raw material to synthesize 3- [4-oxo-2 (R)-(4-methoxybenzyl)-. 4- (N-benzyl-N-methylamino) butyryl] -4 (S) -isopropyl-2-oxazolidinone 1.0 g (2.35 mmol) in tetrahydrofuran
Dissolve in a mixture of 25 ml and water 10 ml, lithium hydroxide 200 mg
(4.8 mmol) and stirred at room temperature for 23 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was extracted with aqueous sodium hydrogen carbonate. The aqueous layer was adjusted to pH 2 with aqueous citric acid,
Extracted with methylene chloride. The extract was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as an oil.
g obtained.

Elemental analysis: C ₂₀ H ₂₃ NO ₄ Calculated: C, 70.36; H, 6.79 ; N, 4.10 Found: C, 70.52; H, 6.48 ; N, 4.25 Reference Example 23 2 (R) - (4- Methoxybenzyl) -3- (N-methylpiperazinocarbonyl) propionic acid benzyl ester hydrochloride Using 3- (4-methoxyphenyl) propionic acid chloride as a starting material and N-methylpiperazine as an amine, Reference Example The same operation as that of 12-14 was performed to synthesize 3- [4-oxo-2 (R)-(4-methoxybenzyl) -4- (N-methylpiperazino) butyryl] -4.
1.0 g of (S) -isopropyl-2-oxazolidinone (2.
3 mmol) in a solution of benzyl alcohol (0.48 ml, 4.6 mmol) in tetrahydrofuran (35 ml) under a nitrogen atmosphere under ice-cooling at 2.5 N-n-.
The solution was added dropwise to 1.38 ml (3.45 mmol) of butyllithium and stirred for 1 hour under the same conditions. Aluminium chloride water was added, and the mixture was extracted with ethyl acetate. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (5% methanol-methylene chloride) to obtain 0.58 g of an oil. Dissolve in dioxane, 4
After adjusting the pH to 1 by adding N-hydrochloric acid / dioxane, the solvent was distilled off under reduced pressure. Acetone was added to the resulting residue, and the mixture was allowed to stand.

Mp 188-190 ° C. Elemental _{analysis: C 24 H 30 N 2 O} 4 · HCl · 1 / 2H 2 O Calculated: C, 63.22; H, 7.07 ; N, 6.14; Cl, 7.78 Found: C, 63.60 ; H, 7.01; N, 6.19; Cl, 7.56 REFERENCE EXAMPLE 24 2 (R)-(4-methoxybenzyl) -3- (N-methylpiperazinocarbonyl) propionic acid hydrochloride synthesized in Reference Example 23. 0.55 g of benzyl (2R)-(4-methoxybenzyl) -3- (N-methylpiperazinocarbonyl) propionate hydrochloride in ethanol 2
The suspension was suspended in 0 ml, and 0.2 g of 10% palladium-carbon was added, followed by stirring at room temperature for 4 hours under a hydrogen atmosphere. Remove the catalyst,
The solution was concentrated under reduced pressure, and ethanol was added to the obtained residue.
On standing, 0.25 g of the title compound was obtained as colorless powder crystals.

Melting point 117-118 ° C (dec.) Elemental analysis: C ₁₇ H ₂₄ N ₂ O ₄ · HCl · 2H ₂ O Calculated: C, 52.34; H, 7.38; N, 7.08; Cl, 8.96 Actual: C , 52.79; H, 6.88; N, 6.98; Cl, 8.97 Reference Example 25 (3R, 5S) -5-{(1S) -1-N- (t-butoxycarbonyl) -3- (4-thiazolyl) -L -Alanil｝
Amino-2-cyclohexylethyl-3-methyldihydrofuran-2 (3H) -one The compound synthesized in Reference Example 2 was 513 mg (1.58 mmol).
Was added to 4N hydrochloric acid / dioxane (20 ml), and the mixture was stirred at room temperature for 65 minutes. Thereafter, the solvent was distilled off under reduced pressure, diethyl ether was added to the residue, and further the solvent was distilled off under reduced pressure. This operation 3
After repeating this process twice, the resultant was dried under reduced pressure for 8 hours. After drying, the residue was suspended in 30 ml of anhydrous tetrahydrofuran,
(T-butoxycarbonyl) -3- (4-thiazolyl)
-460 mg (1.69 mmol) of L-alanine were added. In this solution, under a nitrogen atmosphere, diethyl cyanophosphate was added under ice cooling.
0.27 ml (1.69 mmol) and triethylamine 0.88 ml
(6.34 mmol), and the mixture was further stirred at room temperature for 6 hours. Thereafter, the solvent was distilled off under reduced pressure, 50 ml of water was added to the residue, and the mixture was stirred. The water was separated.The resulting gum was dissolved in methylene chloride, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. I left. Recrystallized from isopropyl ether,
532 mg of the title compound was obtained as white crystals.

Melting point 118-120 ° C Elemental analysis: C ₂₄ H ₃₇ N ₃ O ₅ S Calculated: C, 60.10; H, 7.78; N, 8.76; S, 6.69 Found: C, 60.17; H, 7.77; N, 8.69; S, 6.86 Reference Example 26 (2R, 4S, 5S) -5- [N- (t-butoxycarbonyl)
-3- (4-Thiazolyl) -L-alanyl] -amino-
6-Cyclohexyl-4-hydroxy-2-methylhexanoic acid methylamide 500 mg (1.04 mmol) of the compound synthesized in Reference Example 25
Was dissolved in 2.5 ml of 40% methylamine-methanol and left at room temperature for 1 hour. After removing excess amine and methanol under reduced pressure, the residue was recrystallized from ethyl acetate to obtain 405 mg of the title compound as white crystals.

Melting point 158-160 ° C Elemental analysis: C ₂₅ H ₄₂ N ₄ O ₅ S Calculated: C, 58.80; H, 8.29; N, 10.97; S, 6.28 Found: C, 58.68; H, 8.12; N, 10.93; S, 6.04

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/495 601 A61K 31/495 601 31/535 606 31/535 606 C12N 9/99 C12N 9/99 (72) Inventor Koike Hiroyuki 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Eikun Takahagi 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Yasuki Iijima Shinagawa Tokyo 1-258, Hiromachi, Ward Sankyo Co., Ltd. (72) Inventor Tatsuro Kokufu 1-20-8 Nishiyamadai, Osaka Sayama-shi, Osaka (72) Inventor Kunio Hiwada 2108-6, Takubo, Shigenobu-cho, Ehime Prefecture 56) References JP-A-64-63559 (JP, A) JP-A-63-63649 (JP, A) JP-A-62-142145 (JP, A) JP-A-61-186397 (JP, A) (58) ) investigated the field (Int.Cl. ^6, D Name) C07D 277/30 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] (1) General formula [Wherein, R ¹ is a 5- to 6-membered cyclic heterocyclyl group or a formula Group (wherein, R ⁷ having represents a C ₁ -C ₄ alkyl group, R ⁸
C ₁ -C ₄ alkyl, a phenyl group which may be substituted by C ₁ -C ₄ alkoxy or halogen; phenyl moiety is C ₁
A phenyl-C ₁ -C ₄ alkyl group which may be substituted with —C ₄ alkyl, C ₁ -C ₄ alkoxy or halogen; or a C ₅ -C ₆ cycloalkyl group. ) Indicates that R ² is C ₁
-C ₄ alkyl, a phenyl group or a naphthyl group which may be substituted with C ₁ -C ₄ alkoxy or halogen,
R ³ represents a thiazolyl group, R ⁴ represents a cyclohexyl group or an isopropyl group, R ⁵ represents a C ₁ -C ₄ alkyl group, and R ⁶ represents a C ₁ -C ₆ alkyl group. And a pharmacologically acceptable salt thereof.