KR100551944B1 - Novel epoxysuccinamide derivative or salt thereof - Google Patents

Abstract

The present invention is the following general formula (I)

[Wherein, R ¹ represents a hydrogen atom, an alkyl group or an aminoalkyl group which may have a protecting group, R ² represents an aminoalkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, a substituent A heterocyclic group which may have an alkyl group substituted with a heterocyclic group which may have a substituent, or R ¹ and R ² may be combined with adjacent nitrogen atoms to form a nitrogen-containing heterocyclic group which may have a substituent, R ³ and R ⁴ , which are the same as or different from each other, represent a hydrogen atom, an alkyl group or an aralkyl group], or a salt thereof, a manufacturing process thereof, and a pharmaceutical containing such a derivative or salt as an active ingredient. It is about. The compound has a specific inhibitory activity against cathepsin L and its family enzymes, and is useful as an agent for preventing and treating metabolic bone diseases such as osteoporosis and hypercalcemia.

Description

New Epoxysuccinamide Derivatives or Salts thereof {NOVEL EPOXYSUCCINAMIDE DERIVATIVE OR SALT THEREOF}

The present invention relates to a novel epoxysuccinamide derivative or salt thereof having inhibitory activity against cathepsin and a medicament containing the same.

In the age of aging society, hyperactivity of bone resorption of the elderly is deeply involved in various elderly diseases, and senile osteoporosis has become a major social problem that is widely known. The symptoms of pharmacotherapy for osteoporosis are performed by (1) estrogen, (2) protein anabolic hormone, (3) calcitonin, (4) vitamin D, or (5) bisphosphonate. The only real improvement in subjective symptoms is the fact that there is no definitive treatment.

On the other hand, it has been considered that there are two problems that cause osteoporosis, such as calcium deposition, prolapse and abnormal decomposition of supporting tissue collagen, but the development of drugs focusing on the abnormal enhancement of collagen decomposition is just beginning. It has been reported that cathepsin group, a kind of cysteine protease, is involved in the decomposition of collagen, and that cathepsin L is deeply involved among these cathepsin groups [FEBS Letters, 269 , pp. 189-193 (1990); And FEBS Letters, 280 , pp. 311-315 (1991). Recently, it has been found that cathepsin K, a cathepsin L family, is also involved in bone absorption [J. Biol. Chem., 271 , pp. 12517-12524 (1996). As for compounds that inhibit cysteine protease, for example, Japanese Patent Publication No. 104683/1996 and European Patent Publication No. 655447A1 report similar epoxy succinic acid derivatives, but these are cathepsin L and B enzymes. It inhibits all at about the same time. Cathepsin B is not involved in bone absorption and is described in [FEBS Letters, 321 , pp. 247-250 (1993)], and enzymes related to the immune system, such as antigen presentation. [FEBS Letters, 324 , pp. 325-330 (1993)], inhibition of cathepsin B may cause immunodeficiency. Thus, selective inhibition of bone resorption requires inhibitors that selectively inhibit cathepsin L and its family enzymes, but such inhibitors have not yet been found.

An object of the present invention is to provide a novel compound capable of inhibiting cathepsin L and its family enzymes at a lower concentration than other cysteine proteases. That is, the present invention provides a novel compound useful as an agent for treating and preventing bone metabolic diseases such as osteoporosis, hypercalcemia, Paget's disease, hyperparathyroidism and bone metastasis of cancer.

In order to achieve the above object, the present inventors synthesized a number of epoxy succinamide derivatives and examined the action on cathepsin, and thus, succeeded in the invention of a compound useful as a medicine for treating osteoporosis by specifically inhibiting cathepsin L. The present invention was completed.

That is, the present invention is the following general formula (I)

[Wherein, R ¹ represents a hydrogen atom, an alkyl group or an aminoalkyl group which may have a protecting group, R ² represents an aminoalkyl group which may have a substituent, an aryl group which may have a substituent, an aralkyl group which may have a substituent, a substituent A heterocyclic group which may have an alkyl group substituted with a heterocyclic group which may have a substituent, or R ¹ and R ² may be combined with adjacent nitrogen atoms to form a nitrogen-containing heterocyclic group which may have a substituent, R ³ and R ^4, the same as or different from each other, represent a hydrogen atom, an alkyl group or an aralkyl group.

The present invention also provides a medicament containing the epoxy succinamide derivative represented by the general formula (I) or a salt thereof as an active ingredient.

The present invention also provides a pharmaceutical composition containing an epoxy succinamide derivative represented by the general formula (I) or a salt thereof and a pharmacologically acceptable carrier.

The present invention also provides the use of an epoxy succinamide derivative represented by the general formula (I) or a salt thereof as a medicine.

The present invention also provides a method for treating bone disease, characterized by administering an effective amount of the epoxy succinamide derivative represented by the general formula (I) or a salt thereof.

Best Mode for Carrying Out the Invention

In the general formula (I), the alkyl group represented by R ¹ is preferably an alkyl group having 1 to 6 carbon atoms, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, isopen Tyl group, hexyl group, and isohexyl group are mentioned.

The aminoalkyl group represented by R ¹ is preferably an aminoalkyl group having 1 to 6 carbon atoms, and examples thereof include aminomethyl group, aminoethyl group, aminopropyl group, aminobutyl group, aminopentyl group and aminohexyl group. The amino group of the aminoalkyl group may be protected with an alkyloxycarbonyl group having 2 to 7 carbon atoms as in the tert-butoxycarbonyl group.

Of these, R ¹ is more preferably a hydrogen atom, a C _1-6 alkyl group or a C _1-6 aminoalkyl group, particularly preferably a hydrogen atom, a methyl group or an aminoethyl group.

In the general formula (I), the aminoalkyl group represented by R ² is preferably an aminoalkyl group having 1 to 6 carbon atoms, and examples thereof include aminomethyl group, aminoethyl group, aminopropyl group, aminoisopropyl group, aminobutyl group and aminoiso A butyl group, an aminopentyl group, an aminoisopentyl group, an aminohexyl group, and an aminoisohexyl group are mentioned. Of these, aminoethyl groups are particularly preferred. Such an aminoalkyl group may have a substituent on its amino group, and examples of the substituent include alkyloxycarbonyl groups (methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, tert) having 2 to 7 carbon atoms in total. -Butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group, etc.), aralkyloxycarbonyl group having 8 to 14 carbon atoms (benzyloxycarbonyl group, phenylethyloxycarbonyl group, phenylpropyloxycarbonyl group, naphthylmethoxyoxycarbonyl group, etc.), carbon number 1 Alkyl sulfinyl groups (methyl sulfinyl group, ethyl sulfinyl group, propyl sulfinyl group, butyl sulfinyl group, pentyl sulfonyl group, hexyl sulfinyl group, etc.) of-6, alkyl sulfonyl group of 1 to 6 carbon atoms (methyl sulfonyl group, ethyl sulfonyl group, Propylsulfonyl group, butylsulfonyl group, pentylsulfonyl group, hexylsulfonyl group, etc.), arylsulfinyl group having 6 to 10 carbon atoms (benzenesulfinyl , Toluenesulfinyl, naphthalenesulfinyl, etc.), arylsulfonyl groups having 6 to 10 carbon atoms (benzenesulfonyl group, toluenesulfonyl group, naphthalenesulfonyl group, etc.), and heterocyclic groups which may have an amino group or a nitro group as a substituent (pyridyl group) , Nitropyridyl group, aminopyridyl group, aminopyrimidyl group and the like).

Among the aminoalkyl groups having such a substituent, an alkyloxycarbonyl group having 2 to 7 carbon atoms, an aralkyloxycarbonyl group having 8 to 14 carbon atoms, a benzenesulfonyl group, or a heterocyclic group (which may have an amino group or a nitro group as a substituent) A C _1-6 aminoalkyl group having a substituent is preferable, an aminoethyl group having a heterocyclic group (which may have an amino group or a nitro group as a substituent) as a substituent is more preferred, and a pyridyl group (which may have an amino group or a nitro group as a substituent) Or an aminoethyl group having a pyrimidyl group as a substituent is particularly preferred.

In the general formula (Ⅰ), and the aryl group is an aryl group preferably has 6 to 10 carbon atoms represented by R ^2, His For example a phenyl group and a naphthyl group. Among these, a phenyl group is more preferable, and such an aryl group may have 1 to 3 substituents at arbitrary positions. Examples of the substituent include an aryloxy group having 6 to 10 carbon atoms (phenoxy group, naphthyloxy group, etc.), hydroxyl group, amino group, amidino group, acetoamidino group, guanidino group, cyano group, carboxyl group, Aralkyloxycarbonyl groups having 8 to 14 carbon atoms (benzyloxycarbonyl group, phenylethyloxycarbonyl group, phenylpropyloxycarbonyl group, naphthylethyloxycarbonyl group, etc.), carbamoyl group, acyl group, acylamino group, 1-piperidino group , 1-piperazino group, 5-nitropyridin-2-yl group, alkyloxycarbonylamino group having 2 to 7 carbon atoms (methoxycarbonylamino group, ethoxycarbonylamino group, propoxycarbonylamino group, isopropoxy) Carbonylamino group, butoxycarbonylamino group, tert-butoxycarbonylamino group, pentyloxycarbonylamino group, hexyloxycarbonylamino group, etc., aralkyloxycarbonylamino group having 8 to 14 carbon atoms in total ( Jyloxycarbonylamino group, phenylethyloxycarbonylamino group, phenylpropyloxycarbonylamino group, naphthylmethyloxycarbonylamino group, etc.), alkylthio group having 1 to 6 carbon atoms (methylthio group, ethylthio group, propyl) Thiothio, butylthio group, pentylthio group, hexylthio group, etc.), alkylsulfinyl group having 1 to 6 carbon atoms (methylsulfinyl group, ethylsulfinyl group, propylsulfinyl group, butylsulfinyl group, pentylsulfinyl group, hexylsulpi Nyl groups, etc.), aminosulfonyl groups, alkylsulfonyl groups having 1 to 6 carbon atoms (methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, butylsulfonyl group, pentylsulfonyl group, hexylsulfonyl group, etc.), and 6 to 6 carbon atoms 10-membered arylthio group (phenylthio group, naphthylthio group, etc.), arylsulfinyl group having 6 to 10 carbon atoms (benzenesulfinyl group, toluenesulfinyl group, naphthalenesulfinyl group, etc.), arylsulfo having 6 to 10 carbon atoms Neyl group (benzenesulfonyl group, toluenesulfonyl group, naphthalenesulfonyl group Arylsulfonylamino group having 6 to 10 carbon atoms (benzenesulfonylamino group, toluenesulfonylamino group, naphthalenesulfonylamino group, etc.), alkyl group having 1 to 6 carbon atoms and optionally having a substituent (methyl group, ethyl group) , Propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group, isohexyl group, etc.) and alkenyl group having 2 to 6 carbon atoms ( Ethenyl group, propenyl group, butenyl group, pentenyl group, hexenyl group, etc.) are mentioned. Substituents which may have an alkyl group as a substituent further include hydroxyl group, amino group, acylamino group (acetylamino group, propanoylamino group, benzoylamino group, etc.), alkyloxycarbonylamino group having 2 to 7 carbon atoms, and total carbon number. And protective amino groups such as an aralkyloxycarbonylamino group having 8 to 14 and a C _6-10 arylsulfonylamino group.

Among these aryl groups which may have a substituent, a carboxyl group, an aralkyloxycarbonyl group having 8 to 14 carbon atoms, a C _1-6 alkyl group substituted with an alkyloxycarbonylamino group having 2 to 7 carbon atoms, and acylamino-C _{1 6} - alkyl group, a C _1-6 aminoalkyl group, aminosulfonyl group, an aryloxy group having the carbon number of 6~10, C _2-6 alkenyl group and more preferably is a phenyl group substituted with a group selected from C _1-6 alkyl group. Among these, carboxyl, C _1-6 alkyl group, C _2-6 alkenyl group, benzoylamino group-substituted C _1-6 alkyl group, aryloxy group having 6 to 10 carbon atoms and C _1-6 aminoalkyl group are more preferable, Particularly preferred is a phenyl group substituted with a group selected from aminomethyl group, ethyl group, tert-butyl group, carboxyl group, benzoylaminomethyl group, vinyl group and phenoxy group.

In the general formula (I), the aralkyl group represented by R ² is preferably an aralkyl group having 7 to 12 carbon atoms, and examples thereof include phenyl-C _1-6 such as benzyl group, phenethyl group, phenylpropyl group and phenylbutyl group. -Alkyl group is mentioned. As an example of the substituent of such an aralkyl group, the thing similar to the substituent of the aryl group represented by R <^2> can be mentioned, You may have a substituent. Among these aralkyl groups, a phenyl-C _1-6 -alkyl group which may be substituted with a group selected from acetoamidino group, methylsulfonyl group, aminosulfonyl group, carbamoyl group and amino group is more preferable, and acetoamidino group and aminosulfonyl group And a phenyl-C _1-3 -alkyl group which may be substituted with a group selected from an amino group is more preferable, and a benzyl group or phenethyl group which may be substituted with a group selected from an acetoamidino group, an aminosulfonyl group and an amino group is particularly preferable.

In the general formula (I), the heterocyclic group represented by R ² is preferably a hetero atom or a saturated or unsaturated heterocyclic group having a 5- or 10-membered monocyclic or condensed cyclic group having 1 to 3 atoms selected from nitrogen, oxygen, and sulfur. For example, piperidyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, furyl group, thienyl group, oxazolyl group, isooxazolyl group, thiazolyl group, isothiazolyl group, furazanyl group, And pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl and benzimidazolyl groups. Examples of the substituent of such a heterocyclic group are the same as those of the substituent of the aryl group represented by R ² , and may have a substituent. Among these, a phenyl-C _1-6 -alkyl group or a C _1-6 alkyl group is preferable.

Among the heterocyclic groups which may have these substituents, the piperidyl group, pyridyl group, quinolyl group and isoxazolyl group which may be substituted with a phenyl-C _1-6 -alkyl group or a C _1-6 alkyl group are preferable, and phenyl-C _{1 The} piperidinyl group, pyridyl group, and isoxazolyl group which may be substituted with a _-6 -alkyl group or a C _1-6 alkyl group are more preferable, and the piperidinyl group, pyridyl group, and isoxazolyl group which may be substituted with a benzyl group or a methyl group are particularly preferable. Do.

In the general formula (I), examples of the alkyl group substituted with a heterocyclic group represented by R ² include a C _1-6 alkyl group substituted with a nitrogen-containing saturated heterocyclic group such as morpholino group, piperidinyl group or piperazinyl group, and hetero Examples of the atom include a C _1-6 alkyl group substituted with a 5- or 10-membered monocyclic or condensed ring having 1-3 atoms selected from nitrogen, oxygen, and sulfur. Examples of the aromatic heterocyclic group in the C _1-6 alkyl group substituted with the aromatic heterocyclic group include pyrrolyl group, imidazolyl group, pyrazolyl group, furyl group, thienyl group, oxazolyl group, isoxazolyl group, thiazolyl group, iso Thiazolyl group, furazanyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, triazinyl group, quinolyl group, isoquinolyl group, benzimidazolyl group, naphthyridinyl group, phthalazinyl Group, indolyl group, benzofuranyl group, benzotriazolyl group and benzoxazolyl group. Examples of the C _1-6 alkyl group include methyl group, ethyl group and n-propyl group. Examples of the substituent of such a heterocyclic group are the same as those of the substituent of the aryl group represented by R ² , and these groups may be substituted.

Among such heterocyclic group-substituted alkyl groups, piperidinyl group, morpholino group, thiazolyl group, imidazolyl group, pyrrolyl group, pyridyl group, pyrazinyl group, pyrimidyl group and benzimidazolyl group (these groups have a total carbon number 2-7 alkyl-oxy-carbonyl group, an amino group, a di-alkyl pyrrolyl group, than a C _1-6 alkyl group and a nitro group, a C _1-6 alkyl group substituted by a heterocyclic group selected from 1 to 3 groups may be substituted) is selected from Preferred, morpholino group, thiazolyl group, imidazolyl group, pyridyl group, pyrazinyl group and benzimidazolyl group (these groups are selected from amino group, dimethylpyrrolyl group, C _1-6 alkyl group and nitro group) Particularly preferred are C _1-6 alkyl groups substituted with a heterocyclic group selected from.

In the general formula (I), the nitrogen-containing heterocyclic group which may have a substituent formed by R ¹ and R ² joining with an adjacent nitrogen atom is a hetero atom having 1 to 3 atoms selected from nitrogen, oxygen, and sulfur. 5-, 6- or 7-membered rings are preferable, and examples thereof include a pyrrolidine group, an imidazolidine group, a piperidine group, a piperazine group, and a morpholine group. Examples of the substituent of these heterocyclic groups are the same as the substituents of the aryl group represented by R ² , and may be substituted. Among these, a phenyl group, a phenyl-C _1-6 -alkyl group, an alkyloxycarbonyl group having 2 to 7 carbon atoms, a methylenedioxyphenyl-C _1-6 -alkyl group, a pyrimidinyl group and an aminopyrimidinyl group are more preferable.

Among these nitrogen-containing heterocyclic groups, piperazine rings which may be substituted with a group selected from a phenyl group, a phenyl-C _1-6 -alkyl group, a methylenedioxyphenyl-C _1-6 -alkyl group, a pyrimidinyl group and an aminopyrimidinyl group are preferable, Particularly preferred is a piperazine ring substituted with a group selected from methylenedioxybenzyl group, pyrimidinyl group and aminopyrimidinyl group.

In general formula (I), the C _{1-6 -alkyl} group similar to the example of the alkyl group represented by R <^1> is mentioned as an alkyl group represented by R <^3> and R <^4> . Among these, a methyl group, an ethyl group, and n-propyl group are preferable, and a methyl group is especially preferable.

In general formula (I), as an aralkyl group represented by R <^3> and R <^4> , the same phenyl-C _1-6 -alkyl group as the example of the aralkyl group which may have a substituent represented by R <^2> is mentioned. Among these, benzyl groups and phenethyl groups are particularly preferable.

The epoxysuccinamide derivatives according to the invention may form pharmacologically acceptable salts. Specific examples thereof, when acid groups are present, form alkali and alkaline earth metal salts such as lithium salts, sodium salts, potassium salts, magnesium salts and calcium salts, or ammonium salts such as ammonium salts, methylammonium salts, dimethylammonium salts and trimethylammonium salts. Mineral salts such as hydrochloride, bromate, sulfate, nitrate, phosphate, or acetate, propionate, tartarate, fumarate, maleate, malate, citrate, methanesulfonate and Organic acid salts such as paratoluenesulfonic acid salts.

Regarding the stereochemistry of the epoxy portion of the epoxy succinamide derivative of the present invention represented by the general formula (I), depending on the stereoposition of the epoxy succinic acid as a starting material, (R, R), (S, R), ( Four types of R, S) and (S, S) can be taken, and the present invention includes all three-dimensional arrangements thereof. In addition, the subsidiary carbons other than these include both R and S.

In the compound according to the present invention, R ¹ is a hydrogen atom, or a C _1-6 alkyl group or a C _1-6 aminoalkyl group, and R ² is an amino-C _1-6 -alkyl group which may have a substituent, or may have a substituent. A phenyl group, a phenyl group which may have a substituent, a heterocyclic group which may have a substituent, a phenyl-C _1-6 -alkyl group which may have a substituent, or a C _1-6 alkyl group having a substituent as a substituent, Or R ¹ and R ² together form a nitrogen-containing heterocyclic group in which adjacent nitrogen atoms may have a substituent; R ³ and R ⁴ are each preferably a hydrogen atom or a C _1-6 alkyl group or a phenyl-C _1-6 -alkyl group.

In the case of R ^2, R ² is (1) a small number of the bullet alkyloxycarbonyl 2 to 7, the aralkyloxycarbonyl group, a benzene sulfonyl group, a small number of bullets 8-14, or (which may be substituted an amino group or a nitro good) heterocyclic C _1-6 aminoalkyl group substituted with; (2) carboxyl group, aralkyloxycarbonyl group having 8 to 14 carbon atoms, C _1-6 alkyl group substituted with alkyloxycarbonylamino group having 2 to 7 carbon atoms, alkylamino-C _1-6 -alkyl group, C ₁ A phenyl group substituted with a group selected from _-6 aminoalkyl group, aminosulfonyl group, aryloxy group having 6 to 10 carbon atoms, C _2-6 alkenyl group and C _1-6 alkyl group; (3) a phenyl-C _1-6 -alkyl group which may be substituted with a group selected from acetoamidino group, methylsulfonyl group, aminosulfonyl group, carbamoyl group and amino group; (4) Saturated having a 5- to 10-membered monocyclic or condensed cyclic group having 1 to 3 atoms selected from nitrogen, oxygen and sulfur as a hetero atom, which may be substituted with a phenyl-C _1-6 -alkyl group or a C _1-6 alkyl group Or unsaturated heterocyclic groups; And (5) a C _1-6 alkyl group substituted with a nitrogen-containing saturated heterocyclic group or an aromatic heterocyclic group composed of 5 to 10 membered monocyclic or condensed cyclic groups having 1 to 3 atoms selected from nitrogen, oxygen and sulfur as hetero atoms ( The aromatic heterocyclic group may have a substituent selected from alkoxycarbonylamino group having 2 to 7 carbon atoms, amino group, dialkylpyrrolyl group, C _1-6 alkyl group and nitro group; Or R ¹ and R ² may be substituted with a group selected from a phenyl group, a phenyl-C _1-6 -alkyl group, a methylenedioxyphenyl-C _1-6 -alkyl group, a pyrimidinyl group and an aminopyrimidinyl group together with an adjacent nitrogen atom. The compound which forms a piperazine ring is more preferable.

In the case of R ³ and R ^4, R ³ and R ⁴ or both the C _1-6 alkyl group, or R ³ is a hydrogen atom, R ⁴ is C _1-6 alkyl or phenyl -C _1-6 - alkyl group is a compound desirable.

Preferred embodiments according to the present invention are shown in the following Tables 1-8.

TABLE 1

TABLE 2

TABLE 3

TABLE 4

TABLE 5

TABLE 6

TABLE 7

TABLE 8

Among the compounds shown in the above table, Compounds 8, 11, 13, 18, 25, 27, 29, 31, 32, 35, 37, 39, 40, 41, 43, 44, 46-50, 53, 56, 62- 65, 69, 73, 75-79, 82-88, 90, and 93 are preferred in view of selectivity of inhibitory activity against cathepsin L and its family enzymes, bone resorption inhibitory activity, and known stability. More preferred are compounds 8, 11, 13, 27, 29, 31, 32, 49, 53, 56, 65, 69, 73, 75, 77, 79, 90 and 93, 56, 65, 75, 79 and 90 This is particularly preferred.

The epoxy succinic acid derivative according to the present invention can be synthesized by, for example, the following process.

[The same as the electric wherein R, R ^1, R ^2, R ³ and R ^4, R ⁵ is a protected R ² to be used, if necessary, be a substituent of R ² protection, to R ² by a deprotection Is switched. Provided that when the compound does not require deprotection of the fourth step, R ² and R ⁵ are the same substituent]

More specifically, the epoxy succinic acid monoethyl ester (II) is condensed with phenylalanylamide (III) to obtain compound (IV), and the ester portion of the compound is hydrolyzed to give compound (V), where it is condensed. In the presence of the agent, the amine derivative (VI) is condensed with compound (V) and deprotected as necessary to obtain compound (I) of the present invention.

Each process is demonstrated below.

<Process 1>

Literature known methods [Chemical and Pharmaceutical Bulletin, Vol. 35, p. 1098, (1987)] is condensed with compound (III) in a suitable solvent to obtain an amide derivative (IV). As the condensing agent used in the present reaction, it is also preferable to be commonly used in organic synthesis, and examples thereof include N, N-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydro Chloride, 1,1-carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolinium chloride, ethyl chloroformate, isobutyl chloroformate, pivaloyl chloride, thionyl chloride, oxychloride And trifluoroacetic anhydride. This reaction can be carried out via an active ester. Examples of the active ester used at this time include 4-nitrophenyl ester, 1-benzotriazolyl ester and N-hydroxysuccinimide ester. The produced active ester can be used as it is or without being separated. The reaction can be carried out even in the presence of a suitable base, and examples of the base include organic amines such as pyridine, triethylamine, 2,6-lutidine, N, N-dimethylaminopyridine and diisopropylethylamine. . The solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, benzene and toluene , N, N-dimethylformamide and dimethyl sulfoxide, and these can be used alone or in combination.

Compound (III) used in Step 1 is synthesized according to the following method.

[Wherein R ⁶ represents a protecting group of an amino group, R ⁷ represents a hydrogen atom or an ester residue, and R ³ and R ⁴ are the same as described above]

In other words, the phenylalanine derivative and the amine compound are condensed in a suitable solvent to obtain a condensate ( ) (Step 5), and then R ⁶ is removed therefrom to obtain compound (III) (step 6). And when R ⁷ is a hydrogen atom, a suitable condensing agent is required.

Moreover, as a condensing agent used for reaction of a compound (VII) and an amine compound, the general condensing agent used for organic synthesis reaction is mentioned, For example, N, N- dicyclohexyl carbodiimide, 1 -Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1,1-carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolinium chloride, ethyl chloroformate, isobutyl chloro Formate, pivaloyl chloride, thionyl chloride, oxyphosphoric chloride and trifluoroacetic anhydride.

This reaction can be carried out in the presence of a suitable base, and examples of the base include organic amines such as pyridine, triethylamine, 2,6-lutidine, N, N-dimethylaminopyridine and diisopropylethylamine. Can be.

When R ⁷ is p-nitrophenyl group, succinylimide group, 1-benzotriazolyl group, or the like and forms an active carboxyl group with an active ester, compound (IX) is used as an amine compound (X) without using a condensing agent. ) And a condensate can be obtained by mixing in a suitable solvent.

The solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, benzene, toluene, N And N-dimethylformamide and dimethyl sulfoxide, and these can be used alone or in combination.

Condensate obtained in step 5 ( When R ⁶ is removed in accordance with a suitable method, an amine derivative (III) can be obtained.

The conditions of the reaction depend on R ⁶ , and when R ⁶ is a C _2-5 alkyloxycarbonyl group, it can be carried out by treating the condensate with an acid or a base in a suitable solvent. The solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, benzene and toluene , N, N-dimethylformamide and dimethyl sulfoxide, and these can be used alone or in combination. Examples of the acid include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid and organic acids such as trifluoroacetic acid, p-toluenesulfonic acid and methanesulfonic acid.

Examples of bases include sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide. The reaction can be carried out by mixing a sulfur-containing compound with an acid, examples of the sulfur-containing compound include thioanisole, dimethylsulfide and methionine, and examples of the acid include mineral acid such as hydrochloric acid, bromic acid, sulfuric acid and nitric acid, Organic acids such as sulfonic acid, p-toluenesulfonic acid and trifluoroacetic acid.

Moreover, when R <^6> is a benzyloxycarbonyl group, the objective can be achieved by contact hydrogenation, As a catalyst, Palladium on carbon, Palladium on alumina, Palladium black, Platinum oxide, Platinum oxide, Alumina platinum, and Platinum black These are preferable, The usage-amount is preferably 10% to 200% of the substrate weight. Examples of the solvent include methanol, ethanol, water, acetic acid, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, ethyl acetate, dichloromethane and chloroform, which can be used alone or in combination.

The amine derivative can be synthesized via anhydrous cyclic N-carboxylic acid.

[Wherein R ⁸ represents a protecting group of a carbamate type of a hydrogen atom or an amino group, and R ³ and R ⁴ are as described above]

Phenylalanine Derivatives ( ) Is treated with an activator in a suitable solvent to give anhydrous cyclic N-carboxylic acid ( ) Can be converted to (step 7). Examples of carbamate type protecting groups for amino groups include methoxycarbonyl groups, ethoxycarbonyl groups and benzyloxycarbonyl groups, and examples of active agents include phosgene, phosgene dimers, triphosgene, phosphorus tribromide, phosphorus trichloride, phosphorus pentachloride and Thionyl chloride. There is no particular limitation on the solvent used in the reaction, as long as it does not affect the reaction, for example, dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, benzene , Toluene, N, N-dimethylformamide and dimethyl sulfoxide. These may be used alone or in combination. Mountain anhydrides ) May be used as is in the next step without or separated.

The anhydrous N-carboxylic acid obtained in step 7 is converted into phenylalanine amide derivative (III) by reaction with an amine compound (iii) in a suitable solvent (step 8). The solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, benzene, toluene and methanol , Ethanol and water, and these can be used alone or in combination.

<Process 2>

The amide derivative (IV) obtained in step 1 can be hydrolyzed to obtain carboxylic acid (V). Inorganic bases are used as the reaction reagent, and examples thereof include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, lithium carbonate, sodium carbonate and potassium carbonate. The solvent is not particularly limited as long as it does not affect the reaction. Examples thereof include tetrahydrofuran, dioxane, diethyl ether, isopropyl ether, benzene, toluene, N, N-dimethylformamide, and dimethyl sulfoxide. , Methanol, ethanol, n-propanol, 2-propanol and water, and these may be used alone or in combination.

<Process 3>

When the carboxylic acid (V) and the amine derivative (VI) obtained in Step 2 are reacted in the presence of a condensing agent in a suitable solvent, a condensate can be obtained. Examples of the solvent used for this reaction include dichloromethane, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, benzene, toluene, N, N-dimethylformamide and dimethyl sulfoxide. These can be used individually or in mixture. Moreover, as a condensing agent, the general condensing agent used for organic synthesis reaction can be mentioned, For example, N, N- dicyclohexyl carbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1,1-carbonyldiimidazole, 2-chloro-1,3-dimethylimidazolinium chloride, ethyl chloroformate, isobutyl chloroformate, fibaroylchloride, thionyl chloride, phosphorus oxychloride and anhydrous Trifluoroacetic acid is mentioned.

This reaction can be carried out in the presence of a suitable base, and examples of the base include organic amines such as pyridine, triethylamine, 2,6-lutidine, N, N-dimethylaminopyridine and diisopropylethylamine. Can be.

In addition, this reaction can be carried out using an active ester, and examples of the active ester include 4-nitrophenyl ester, 1-benzotriazolyl ester and N-hydroxysuccinimide ester. After the reaction, the active ester can be used as it is or without being separated. In addition, compound (i) can be obtained even if the condensation order of compound (III) and compound (VI) changes.

<Step 4>

The condensate obtained in step 3 can be converted into compound (I) through deprotection or subsequent functional group conversion, if necessary. The conditions of deprotection can use the method illustrated at the process 6. The functional group conversion following such deprotection refers to functional group conversion such as acylation, and can be carried out by reacting with an acylating agent in the presence of a basic compound in an appropriate solvent or with an acid in the presence of a condensing agent. Suitable solvents include, for example, those mentioned in Process 1. The basic compound is preferably an organic base, and examples thereof include triethylamine, pyridine, N, N-dimethylaminopyridine, diisopropylethylamine, 1,8-diazabicyclo- [5,4,0]- 7-undecene. Examples of the acylating agent include acid anhydrides such as acetic anhydride, propionic anhydride, trifluoroacetic anhydride and benzoic anhydride or acid chlorides such as acetyl chloride, propionyl chloride, trifluoroacetyl chloride and benzoyl chloride. Examples of the condensing agent include those mentioned in Step 3. As the acid, an organic acid having 1 to 7 carbon atoms is preferable, and examples thereof include formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, bareric acid, isovaleric acid, pivalic acid, heptanoic acid, and benzoic acid.

The production intermediate thus obtained and the compound of the present invention can be purified by conventional separation means in synthetic chemistry such as recrystallization, distillation, column chromatography.

The compounds of the present invention have inhibitory activity against cysteine proteases such as cathepsin L, B and H, as evident in later pharmacological studies. More preferably, the IC ₅₀ of the compound of the present invention on cathepsin L is about 1/100 or less of the IC ₅₀ of cathepsin B, with inhibition of cathepsin L being selective. The compounds according to the invention also strongly inhibit cathepsin K, its family enzyme of cathepsin L. J. Clin. In the inhibition of pit formation by bone resorption using ivory slices according to the methods described in Invest., 80 , 425-429 (1981) and FEBS Letters, 321 , 247-250 (1993), the compounds according to the invention Pit formation was strongly suppressed at a concentration of 10 ⁻⁹ to 10 ⁻⁷ . J. Jpn. Soc. In accordance with the method disclosed in Cancer Ther., 28 , 1671-1676 (1993), for a bone resorption model prepared by inoculating subcutaneous calvaria cells of mouse colon cancer colon 26 cells according to the present invention, Compounds were administered intraperitoneally, intravenously or orally at a dose of 3-50 mg / kg / day for 5 days at tumor implantation. As a result, the compound significantly inhibited bone resorption without toxicity. The compounds according to the present invention exhibited known stability and high safety and inhibitory activity against cathepsin L and its family enzymes, and also against bone resorption. Therefore, the compounds of the present invention are a disease derived from cysteine protease, such as muscle dystrophy, myotrophic atrophy, myocardial infarction, stroke, Alzheimer's disease, conscious disorder or exercise disorder during head trauma, multiple sclerosis, neurofuge of peripheral nerve, cataract Can be used as a prophylaxis and treatment for inflammation, allergy, extreme hepatitis, osteoporosis, hypercalcemia, breast cancer, prostate cancer, enlarged prostate, or as a proliferation inhibitor, metastasis prevention agent, platelet prevention and treatment, but not cathepsin L It is useful as a prophylactic and therapeutic agent for bone diseases, in particular, a prophylactic and therapeutic agent for osteoporosis, by inhibiting the absorption of bone by inhibiting bone resorption.

The compounds of the present invention and salts thereof are usually administered orally or parenterally for the treatment of such diseases, including osteoporosis in mammals, including humans. The dosage is not constant depending on age, sex, weight, symptoms, etc., but is usually 0.1 to 1000 mg, preferably 1 to 1000 mg per day per adult, more preferably 5 to 500 mg 2-3 times. Divided orally or parenterally.

The compound of the present invention may be administered orally or parenterally in combination with a physiologically acceptable carrier, and as a solid preparation such as tablets, capsules, granules or powders, or liquid preparations such as syrups or injections.

As the pharmaceutically acceptable carrier, various organic or inorganic carrier materials which are conventionally used are used as materials for the preparation, and excipients, lubricants, binders and disintegrating agents in solid preparations, solvents in solvent preparations, dissolution aids and suspensions are used. As a topical agent, isotonicity agent, buffer, painless agent, and the like. Moreover, preparation additives, such as a preservative, antioxidant, a coloring agent, and a sweetening agent, can be used as needed. Suitable examples of excipients include lactose, D-mannitol, starch, crystalline cellulose and hard silicic anhydride. Suitable examples of glidants include magnesium stearate, calcium stearate, talc and colloidal silica. Further suitable examples of the binder include crystalline cellulose, white sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone. Suitable examples of disintegrants include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium and carboxymethyl starch sodium.

Further suitable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil. Suitable examples of dissolution aids include polyethylene glycol, propylene glycol, D-mannitol, benzyl succinate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate. Suitable examples of suspending agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride and glycerin monostearate, and polyvinyl alcohol, polyvinylpyrrolidone, carboxy Hydrophilic polymers such as methyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose. Suitable examples of buffers also include phosphates, acetates, carbonates and citrates. In addition, a suitable example of the non-solvent agent is benzyl alcohol. Further suitable examples of the preservative include p-oxysuccinic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dihydroacetic acid and sorbic acid. Suitable examples of antioxidants include sulfite and ascorbate.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to these Examples.

Preparation Example 1:

L-phenylalanine dimethylamide hydrochloride:

50% aqueous dimethylamine solution (1.0 mL, 11.11 mmol) was added to an ethyl acetate solution (50 mL) of Nt-butoxycarbonyl-L-phenylalanine 4-nitrophenyl ester (3.0 g, 7.77 mmol) at room temperature for 9 hours. Was stirred. After completion of the reaction, the mixture was washed with dilute aqueous sodium hydroxide solution until discoloration of the reactant, followed by washing with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was deprotected with 4N hydrochloric acid / ethyl acetate to obtain 1.5 g of the title compound.

Melting Point: 216-217 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.60 (3H, s), 2.79 (3H, s), 2.90 (1H, dd, J = 8.2, 13.4 Hz),

3.10 (1H, doublet of doublets, J = 6.1, 13.4 Hz), 4.53 (1H, broad doublet, J = 7.1 Hz),

7.20-7.34 (5H, m).

Mass (FAB (+)) m / e: 193 (M−H) ⁺ .

Preparation Example 2:

L-3-trans-[(S) -l-dimethylcarbamoyl-2-phenylethylcarbamoyl] oxirane-2-carboxylic acid:

Tetrahydrofuran solution of triethylamine (7.7 mL, 55.0 mmol) in ethyl 4-nitrophenyl-L-trans-epoxysuccinate (14.0 g, 49.8 mmol) and the compound obtained in Preparation Example 1 (12.0 g, 52.3 mmol) (160 mL) was added and stirred at room temperature for 2.5 hours. After the precipitated solid was separated by filtration, the condensate obtained by column chromatography (isopropyl ether: chloroform = 3: 1-methanol: chloroform = 1:10) with silica gel was dissolved in ethanol (100 mL) and ice-cold. Potassium hydroxide (3.1 g, 55.6 mmol) / water (3 mL) was added and stirred for 3.5 h. The solvent was distilled off under reduced pressure, and a small amount of water was added, followed by washing with tetrahydrofuran-ethyl acetate. The aqueous phase was acidified with 1N hydrochloric acid, extracted three times with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 12.0 g of the title compound as a foam.

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.80-2.86 (1H, m), 2.87 (3H, s),

2.95 (1H, doublet of doublets, J = 6.1, 13.2 Hz), 3.38 (1H, doubled, J = 1.7 Hz),

3.62 (1H, doublet, J = 1.7 Hz), 4.93 (1H, dt, J = 6.4, 14.6 Hz),

7.20-7.30 (5H, m), 8.80 (1H, doublet, J = 8.3 Hz), 13.38 (1H, br.s).

Mass (FAB (−)) m / e: 305 (M ⁻ H) ⁻ .

Preparation Example 3:

L-phenylalanine propylamide hydrochloride:

Deprotection of condensates (6.0 g) obtained using Nt-butoxycarbonyl-L-phenylalanine (15.0 g, 56.5 mmol) and n-propylamine (3.5 g, 58.4 mmol) in a similar manner to Preparation Example 1 4.7 g of the title compound was obtained.

Melting Point: 154 -155 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

0.74 (3H, t, J = 11.2 Hz), 1.26-1.38 (2H, m),

2.86-2.97 (1H, m), 2.98-3.13 (3H, m), 3.95 (1H, t, J = 6.4 Hz),

7.20-7.40 (5H, m), 8.32 (2H, broad singlet), 8.44 (1H, t, J = 5.6 Hz).

Mass (FAB (+)) m / e: 207 (M−H) ⁺ .

Preparation Example 4:

L-3-trans-[(S) -l-propylcarbamoyl-2-phenylethylcarbamoyl] oxirane-2-carboxylic acid:

In a similar manner to Preparation Example 2, 1.8 g of the title compound was obtained using the compound (2.0 g, 8.2 mmol) obtained in Preparation Example 3.

Melting Point: 184-186 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

0.79 (3H, t, J = 7.3 Hz), 1.31-1.41 (2H, m),

2.80 (1H, doublet of doublets, J = 9.5, 13.6 Hz), 2.92-3.08 (3H, m),

3.29 (1H, d, J = 1.7 Hz), 3.59 (1H, d, J = 1.7 Hz),

4.48-4.55 (1H, m), 7.17-7.30 (5H, m), 8.06 (1H, t, J = 5.6 Hz),

8.58 (1H, doublet, J = 8.6 Hz).

Mass (FAB (+)) m / e: 321 (M−H) ⁺ .

Preparation Example 5

L-phenylalanine-2-phenylethylamide hydrochloride:

To the ethyl acetate solution (50 mL) of N-benzyloxycarbonyl-L-phenylalanine 4-nitrophenyl ester (2.0 g, 4.8 mmol) was added 2-phenylethylamine (577 mg, 4.8 mmol), followed by room temperature. Stir for 9 hours. After completion of the reaction, the mixture was washed with dilute aqueous sodium hydroxide solution until discoloration of the reactant, followed by washing with water and saturated brine, and dried over anhydrous magnesium sulfate. 1.9 g of a condensate obtained by distilling off the solvent under reduced pressure was obtained. The condensate thus obtained (1.65 g, 4.3 mmol) was dissolved in a methanol-chloroform mixture (100: 1), and then 10% palladium / carbon (1.65 g) was added, followed by stirring at room temperature under hydrogen stream for 1 hour. After completion of the reaction, the catalyst was filtered off and the filtrate was condensed under reduced pressure to give 1.13 g of the title compound.

Melting Point: 64-67 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

1.91 (2H, broad singlet), 2.58 (1H, doublet of doublets, J = 8.2, 13.3 Hz),

2.66 (2H, t, J = 7.3 Hz), 2.88 (1H, dd, J = 5.1, 13.3 Hz),

3.25-3.41 (1H, m), 7.15-7.28 (10H, m),

7.90 (1H, broad doublet, J = 6.0 Hz).

Mass (FAB (+)) m / e: 269 (M−H) ⁺ .

Preparation Example 6:

L-3-trans-[(S) -l- (2-phenylethylcarbamoyl) -2-phenylethylcarbamoyl] oxirane-2-carboxylic acid:

In a similar manner to Preparation Example 2, 1.10 g of the title compound was obtained using the compound (1.0 g, 3.90 mmol) obtained in Preparation Example 5.

Melting Point: 154-155.5 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.67 (2H, t, J = 7.3 Hz), 2.75 (1H, dd, J = 9.8, 13.2 Hz),

2.94 (1H, doublet of doublets, J = 4.9, 13.7 Hz), 3.21-3.28 (2H, m),

3.29 (1H, d, J = 2.0 Hz), 3.58 (1H, d, J = 1.3 Hz),

4.47-4.52 (1H, m), 7.18-7.30 (10H, m),

8.25 (1H, broad doublet, J = 5.4 Hz), 8.66 (1H, doublet, J = 8.8 Hz).

Mass (FAB (+)) m / e: 381 (M−H) ⁺ .

Preparation Example 7:

2- (t-butoxycarbonylaminomethyl) aniline:

2-aminobenzylamine (5.0 g, 40.9 mmol) and triethylamine (4.1 g, 40.9 mmol) were dissolved in a mixture of dioxane-water (2: 1) (50 mL), and then di-t-butyl under ice-cooling. Dioxane solution of carbonate (8.9 g / 10 mL) was added dropwise and stirred for 2 hours. After diluting the reaction with ethyl acetate, the aqueous phase was removed, and the organic liquid phase was washed three times with water and once with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from diisopropylether-hexane to give 6.70 g of the title compound.

Melting Point: 94-95 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

1.38 (9H, s), 3.94 (2H, d, J = 6.l Hz), 4.97 (2H, s),

6.48 (1H, doublet of doublets, J = 6.5, 6.5 Hz), 6.58 (1H, doublet, J = 7.3 Hz),

6.91 (1H, doublet, J = 7.l Hz), 6.92 (1H, doublet, J = 6.8, 6.8 Hz),

7.22 (1H, broad doublet, J = 6.l Hz).

Mass (EI (+)) m / e: 222 (M) ⁺ .

Preparation Example 8

3- (t-butoxycarbonylaminomethyl) aniline:

Sodium azide (10.0 g, 153.8 mmol) was added to an N, N-dimethylformamide solution (100 mL) of 3-nitrobenzyl bromide (5.0 g, 23.14 mmol) and stirred at room temperature for 5 hours. The reaction was diluted with ethyl acetate, washed five times with water and once with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 5: 1) to dissolve the azide compound in dioxane (100 mL), and 10% palladium / carbon (500 mg). Was added and stirred for 4 hours at room temperature under a hydrogen stream. After completion of the reaction, the catalyst was separated by filtration, and water (50 mL) and triethylamine (2.8 mL, 20.0 mmol) were added to the filtrate, and further di-t-butylcarbonate (4.4 g, 20 mmol) was cooled on ice. ) Was added dropwise and stirred for 24 hours. The reaction was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, washed again with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 2: 1) to give 652 mg of the titled compound as an oil.

¹ H-NMR (DMSO-d ₆ ) δ:

1.38 (9H, s), 3.95 (2H, d, J = 6.l Hz), 4.98 (2H, s),

6.39-6.41 (3H, m), 6.90 (1H, doublet of doublets, J = 7.6, 7.6 Hz), 8.38 (1H, s).

Mass (EI (+)) m / e: 222 (M) ⁺ .

Preparation Example 9:

4- (t-butoxycarbonylaminomethyl) aniline:

In a similar manner to Preparation Example 7, 7.2 g of the title compound was obtained using 4- (aminomethyl) aniline (5.0 g, 40.9 mmol).

Melting Point: 88-90 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

1.36 (9H, s), 3.91 (2H, d, J = 6.1 Hz), 4.90 (2H, s),

6.47 (1H, d, J = 8.3 Hz), 6.87 (1H, d, J = 8.3 Hz),

7.12 (1H, broad doublet, J = 5.8 Hz).

Mass (EI (+)) m / e: 222 (M) ⁺ .

Preparation Example 10

N-t-butoxycarbonyl-N'-phenylethylenediamine:

In a similar manner to Preparation Example 7, 2.1 g of the title compound was obtained using N-phenylethylenediamine (2.0 g, 14.7 mmol).

Melting Point: 84-85 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

1.37 (9H, s), 3.02-3.08 (4H, m), 5.54 (1H, br.t, J = 5.1 Hz),

6.50 (1H, doublet of doublets, J = 7.3, 7.3 Hz), 6.54 (2H, doubled, J = 7.8 Hz),

6.87 (1H, broad doublet, J = 5.6 Hz), 7.05 (2H, doublet of doublets, J = 7.3, 8.3 Hz).

Mass (FAB (+)) m / e: 381 (M−H) ⁺ .

Preparation Example 11

N-benzenesulfonylethylenediamine:

Hoppe-Seyler's, Z. Physiol. N-benzyloxycarbonylethylenediamine hydrochloride (2.3 g, 10.0 mmol) and benzenesulfonyl chloride (1.2 mL, 0.95 mmol) according to the process described in Chem., 349 , 251 (1968) in water (100 mL) After suspension, triethylamine (1.4 mL) was added and 1N aqueous sodium hydroxide solution (10 mL) was added in portions for 10 minutes and stirred at 70 ° C. for 30 minutes. Toluene was added to the reaction, the condensate obtained by distilling off the solvent under reduced pressure was dissolved in methanol, and then 10% palladium / carbon (1.3 g) was added, followed by stirring for 3 hours under hydrogen stream. After filtration of the catalyst, the solvent was distilled off under reduced pressure to give 727 mg of the titled compound as an oil.

¹ H-NMR (CDCl ₃ ) δ:

2.77-2.85 (2H, m), 2.95-3.03 (2H, m), 7.49-7.70 (3H, m),

7.85-8.00 (2H, m).

Mass (FAB (+)) m / e: 201 (M−H) ⁺ .

Preparation Example 12

2-t-butoxycarbonylamino-4- (2-hydroxyethyl) thiazole:

Ethyl 2-amino-4-thiazole-acetate (5.0 g, 26.8 mmol) and triethylamine (3.8 mL, 26.8 mmol) were dissolved in dichloromethane (20 mL) and then di-t-butylcarbonate under ice cooling (7.0 g, 32.2 mmol) was added and stirred at rt overnight. After 18 h, di-t-butylcarbonate (1.4 g, 13.4 mmol) was added and stirred at rt for 6 h. After completion of the reaction, the solvent was distilled off under reduced pressure, dissolved in ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 3: 1) to obtain 3.1 g of ethyl 2-t-butoxycarbonylamino-4-thiazole-acetate. Some of these (2.0 g, 7.0 mmol) were dissolved in an ethanol-tetrahydrofuran (3: 2) mixture (50 mL), followed by lithium chloride (592 mg, 14.0 mmol) and sodium hydrogen boride (528 mg, 14.0 mmol). Add at room temperature and stir for 6 hours. Then sodium hydrogen boride (530 mg, 14.1 mmol) and lithium chloride (592 mg, 14.0 mmol) were added and stirred at room temperature for 3 hours. The reaction was diluted with ethyl acetate, washed with water, diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 1: 1 to 2: 3) to give 959 mg of the titled compound as an oil.

¹ H-NMR (DMSO-d ₆ ) δ:

1.46 (9H, s), 2.68 (2H, t, J = 6.8 Hz),

3.62 (2H, doublet of doublets, J = 7.1, 12.4 Hz), 4.58 (1H, high t, J = 5.4 Hz),

6.71 (1 H, s), 11.30 (1 H, br. S).

Mass (FAB (+)) m / e: 245 (M−H) ⁺ .

Preparation Example 13

2-t-butoxycarbonylamino-4- (2-aminoethyl) thiazole:

The compound obtained in Preparation 12 (949 mg, 3.88 mmol) was dissolved in dichloromethane (50 mL), and triethylamine (432 mg, 4.27 mmol) and 4-chlorobenzenesulfonyl chloride (982 mg, 4.66 mmol) under ice-cooling. ) Was added, followed by stirring at room temperature. After 3 hours, N, N-dimethylaminopyridine (47 mg, 0.39 mmol) was added and stirred. After 3.5 hours 4-chlorobenzenesulfonyl chloride (491 mg, 2.33 mmol) was added and after 23 hours 45 minutes 4-chlorobenzenesulfonyl chloride (819 mg, 3.88 mmol) and triethylamine (393 mg, 3.88 mmol) was added and stirred for 5 days. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, the mixture was washed with water, diluted hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 1) to obtain 1.18 g of a sulfone derivative. Partially (1.15 g, 2.75 mmol) was taken to obtain N, It was dissolved in N-dimethylformamide (30 mL), sodium azide (1.78 g, 27.45 mmol) was added, followed by stirring at 60 ° C. for 3 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, washed several times with water and once with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 2: 1) to give 739 mg of an azide compound. (730 mg, 2.71 mmol) was taken and dissolved in ethanol (50 mL), 10% palladium / carbon (146 mg) was added, and the mixture was stirred under a hydrogen stream for 1.5 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 652 mg of the title compound as an oil.

¹ H-NMR (DMSO-d ₆ ) δ:

1.45 (9H, s), 2.59 (2H, t, J = 7.l Hz), 2.77 (2H, t, J = 6.8 Hz),

4.73 (2H, broad singlet), 6.68 (1H, singlet).

Mass (FAB (+)) m / e: 244 (M−H) ⁺ .

Preparation Example 14

Benzyl 4-Aminobenzoate Hydrochloride:

4-aminobenzoic acid (5.0 g, 36.46 mmol) was dissolved in a 1,4-dioxane / lN sodium hydroxide (1/1) mixture (50 mL), and then 1,4 of di-t-butylcarbonate under ice-cooling. Dioxane solution (9.5 g, 43.75 mmol / 25 mL) was added dropwise and stirred at room temperature. After 7.5 hours, di-t-butylcarbonate (1.5 g) was added during stirring. After 24 hours, 6N hydrochloric acid was added to acidify the reaction, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed four times with water and once with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 9.28 g (39.10 mmol) of 4-butoxycarbonylaminobenzoic acid, which was benzyl alcohol (4.23 g, 39.10 mmol) and N, N- in 100 mL of N, N-dimethylformamide. After dissolving in dimethylaminopyridine (478 mg, 3.91 mmol), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (8.99 g, 46.92 mmol) was added under ice cooling for 8 hours at room temperature. Stirred. The reaction was diluted with ethyl acetate, washed with water (twice), 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (toluene: ethyl acetate = 20: 1) to obtain 4.09 g (12.5 mmol) of benzyl ester, which was dissolved in ethyl acetate (70 mL) and then 4N hydrochloric acid. 70 ml of ethyl acetate was added and stirred at room temperature. After 1.5 hours, 4N hydrochloric acid / ethyl acetate (70 mL) was added while stirring, and after 1 hour, the reaction was stopped. The filtered precipitate was suspended in ethyl acetate, the suspension was ultrasonically washed and filtered to obtain 2.86 g of the title compound.

Melting Point: 108-110 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

5.27 (2H, s), 6.81 (2H, d, J = 8.3 Hz), 7.32-7.45 (5H, m),

7.78 (2H, doublet, J = 8.8 Hz), 8.56 (2H, br.s).

Mass (FAB (+)) m / e: 228 (M−H) ⁺ .

Preparation Example 15

N-methyl-4-ethylaniline:

4-ethylaniline (2.4 g, 20 mmol) was dissolved in dichloromethane (150 mL), triethylamine (8.4 mL, 60 mmol) and ethylchloroformate (5.8 mL, 60 mmol) were added for 2 hours. Stirred. The reaction was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was dissolved in diethyl ether (20 mL), and then added dropwise to a suspension of lithium aluminum hydride (2.4 g, 63.2 mmol) in diethyl ether under a nitrogen stream under ice-cooling, followed by stirring for 1 hour. And again stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, tetrahydrofuran (20 mL) was added to the residue, and the mixture was heated to reflux for 1 hour 40 minutes. Ice water was slowly added to the reaction, and potassium sulfate was further added, followed by extraction with ethyl acetate. The extract was extracted again with 1N hydrochloric acid, basified with 4N aqueous sodium hydroxide solution, extracted with ethyl acetate (twice) and diethyl ether (once), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 20: 1) to give 1.8 g of the titled compound as an oil.

¹ H-NMR (DMSO-d ₆ ) δ:

1.10 (3H, t, J = 7.6 Hz), 2.44 (2H, q, J = 7.6 Hz),

2.63 (3H, d, J = 5.4 Hz), 6.45 (2H, d, J = 8.3 Hz),

6.91 (2H, doublet, J = 8.3 Hz).

Mass (EI (+)) m / e: 135 (M) ⁺ .

Preparation Example 16

D-3-trans-[(S) -l-dimethylcarbamoyl-2-phenylethyl-carbamoyl] oxirane-2-carboxylic acid:

3.0 g (18.7 mmol) of monoethyl D-trans-epoxysuccinate, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.95 g, 21.0 mmol) and 1-hydroxybenzotriazole ( 2.8 g, 21.0 mmol) was dissolved in N, N-dimethylformamide (50 mL), the compound obtained in Preparation Example 1 (5.6 g, 24.4 mmol) was added, and triethylamine (2.9 mL, 21 mmol) was added. It dripped at the mixture. After stirring for 2 hours at room temperature, the reaction was poured into water and extracted twice with ethyl acetate. The extract was collected, washed with a saturated aqueous sodium hydrogen carbonate solution, saturated brine, 1N hydrochloric acid, and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 1: 2) to obtain 2.75 g of a condensate and hydrolyzed in the same manner as in Preparation Example 2 to obtain 2.43 g of the title compound. .

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.75-2.90 (1H, m), 2.85 (3H, s),

2.95 (1H, doublet of doublets, J = 6.6, 13.2 Hz), 3.27-3.35 (1H, m),

3.63 (1H, d, J = 1.7 Hz), 4.86-4.96 (1H, m), 7.17-7.31 (5H, m),

8.88 (1H, doublet, J = 8.l Hz).

Mass (FAB (+)) m / e: 307 (M−H) ⁺ .

Preparation Example 17

N-t-butoxycarbonyl-L-phenylalanine methylamide:

Nt-butoxycarbonyl-L-phenylalanine (2.65 g, 10.0 mmol) is dissolved in N, N-dimethylformamide (20 mL) and 40% aqueous methylamine solution (0.8 mL, 10.3 mmol), 1- under ice-cooling Hydroxybenzotriazole (1.48 g, 11.0 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.30 g, 12.0 mmol) were added, followed by stirring at room temperature for 2.5 hours The mixture was diluted with ethyl acetate, washed twice with water, once with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The dried product was filtered off, the solvent was distilled off under reduced pressure, and the residue was washed with diisopropyl ether to obtain 2.41 g of the title compound.

Melting Point: 143.5-145 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

1.30 (9H, s), 2.57 (3H, d, J = 4.6 Hz),

2.71 (1H, dd, J = 10.2, 13.7 Hz), 2.91 (1H, dd, J = 4.6, 13.7 Hz),

4.09 (1H, ddd, J = 4.6, 9.5, 9.5 Hz), 6.89 (1H, d, J = 8.6 Hz),

7.12-7.28 (5H, m), 7.83 (1H, broad doublet, J = 4.6 Hz).

Mass (FAB (+)) m / e: 279 (M−H) ⁺ .

Preparation Example 18

L-phenylalanine methylamide hydrochloride:

The compound (2.40 g, 8.62 mmol) obtained in Preparation Example 17 was dissolved in 4N hydrochloric acid / ethyl acetate mixture, and stirred at room temperature for 30 minutes. The precipitated solid was filtered and washed with ethyl acetate to give 1.62 g of the title compound.

Melting Point: 205-208 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.58 (3H, doublet, J = 4.6 Hz), 3.01-3.07 (2H, m), 3.93 (1H, broad s),

7.22-7.35 (5H, m), 8.32 (2H, br.s), 8.46 (1H, br.s).

Mass (FAB (+)) m / e: 179 (M−H) ⁺ .

Preparation Example 19

Ethyl L-3-trans-[(S) -l-methylcarbamoyl-2-phenylethylcarbamoyl] oxirane-2-carboxylate:

The compound obtained in Preparation Example 18 (1.50 g, 6.99 mmol) and ethyl L-trans-epoxysuccinate (1.12 g, 6.99 mmol) were dissolved in N, N-dimethylformamide (20 mL) and then triethylamine under ice-cooling. (974 μl, 6.99 mmol), 1-hydroxybenzotriazole (1.04 g, 7.69 mmol), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.61 g, 8.39 mmol) Was added and stirred at room temperature for 2 hours. The reaction was diluted with ethyl acetate, and then washed twice with water, once with 10% aqueous citric acid solution, saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The dried product was filtered off, the filtrate was concentrated under reduced pressure, and the remaining solid was washed with diisopropyl ether to obtain 1.88 g of the title compound.

Melting Point: 184.5-186.5 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

1.21 (3H, t, J = 7.l Hz), 2.58 (3H, d, J = 4.6 Hz),

2.78 (1H, dd, J = 10.0, 13.7 Hz), 3.02 (1H, dd, J = 4.6, 13.7 Hz),

3.41 (1H, doublet, J = 1.9 Hz), 3.62 (1H, dd, J = 1.7 Hz),

4.14-4.20 (2H, m), 4.47 (1H, double doublet of doublets, J = 5.2, 9.3, 9.3 Hz),

7.18-7.30 (5H, m), 8.05 (1H, broad doublet, J = 4.6 Hz),

8.68 (1H, doublet, J = 8.6 Hz).

Mass (FAB (+)) m / e: 321 (M−H) ⁺ .

Preparation Example 20

L-3-trans-[(S) -l-methylcarbamoyl-2-phenylethylcarbamoyl] oxirane-2-carboxylic acid:

The compound (1.86 g, 5.81 mmol) obtained in Production Example 19 was dissolved in ethanol (10 mL), and 1N aqueous sodium hydroxide solution (6.1 mL) was added dropwise under ice cooling, followed by stirring at room temperature for 20 minutes. The reaction was diluted with water and extracted twice with ethyl acetate, the aqueous phase was acidified with 1N hydrochloric acid, extracted twice with ethyl acetate, washed twice with saturated brine and dried over anhydrous magnesium sulfate. The dried product was filtered off and the solvent was distilled off to obtain 1.39 g of the title compound.

Melting Point: 193-196 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

1.17 (3H, t, J = 7.1 Hz), 2.58 (3H, d, J = 4.6 Hz),

2.79 (1H, dd, J = 10.0, 13.7 Hz), 3.02 (1H, dd, J = 4.9, 13.6 Hz),

3.28 (1H, d, J = 2.0 Hz), 3.57 (1H, d, J = 1.7 Hz),

4.47 (1H, double doublet of doublets, J = 4.9, 8.5, 10.0 Hz), 7.18-7.29 (5H, m),

8.04 (1H, doublet, J = 11.7 Hz), 8.63 (1H, doublet, J = 8.5 Hz).

Mass (FAB (+)) m / e: 293 (M−H) ⁺ .

Preparation Example 21

N- {L-3-trans-[(4-nitrophenoxy) carbonyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide:

Ethyl acetate solution (20 mL) of N, N-dicyclohexylcarbodiimide (10.1 g, 49 mmol) was added to an ethyl acetate solution (50 mL) of the compound (15.0 g, 49 mmol) obtained in Preparation Example 2 under ice-cooling. After dropwise addition, 30 minutes later, ethyl acetate solution (20 mL) of 4-nitrophenol (6.8 g, 49 mmol) was added thereto, followed by stirring for 2.5 hours. The insoluble substance obtained here was filtered off, the solvent was distilled off, and the residue was purified by column chromatography on silica gel (hexane: ethyl acetate = 1: 1 to 1: 2) to obtain 13.5 g of the title compound as a foam.

¹ H-NMR (DMSO-d ₆ ) δ:

2.80 (3H, s), 2.85 (1H, dd, J = 8.3, 13.4 Hz), 2.88 (3H, s),

2.98 (1H, doublet of doublets, J = 6.4, 13.4 Hz), 3.85 (1H, s), 3.93 (1H, s),

4.97 (1H, double doublet of doublets, J = 6.4, 8.0, 8.3 Hz), 7.19-7.34 (5H, m),

7.54 (2H, d, J = 8.3 Hz), 8.34 (2H, d, J = 8.3 Hz),

8.93 (1H, doublet, J = 8.0 Hz).

Mass (FAB (+)) m / e: 428 (M−H) ⁺ .

Preparation Example 22

1- (2-cyanoethyl) -4-nitroimidazole:

4-nitroimidazole (6.87 g, 60 mmol), triethylamine (18.2 g, 180 mmol) and acrylonitrile (9.55 g, 180 mmol) are dissolved in N, N-dimethylformamide (100 mL), Stir at 100 ° C. for 5 hours. The reaction was concentrated under reduced pressure and chloroform was added. The precipitated solid was filtered and dried to give 9.2 g of the title compound.

Melting Point: 112-113 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

7.94 (1H, doublet, J = 1.2 Hz), 8.52 (1H, doublet, J = 1.2 Hz),

3.20 (2H, t, J = 7.2 Hz), 4.46 (2H, t, J = 7.2 Hz).

Mass (FAB (+)) m / e: 167 (M−H) ⁺ .

Preparation Example 23

1- (2-cyanoethyl) -4-aminoimidazole:

1- (2-cyanoethyl) -4-nitroimidazole (3.32 g, 20 mmol) was dissolved in methanol (100 mL), platinum oxide (50 mg) was added and stirred for 12 hours under hydrogen stream. . The catalyst was filtered off with celite, the filtrate was concentrated under reduced pressure, and the residue was then chromatographed with silica gel (chloroform: methanol = 10: 1 to 5: 1) to give 2.31 g of the titled compound as an oil.

¹ H-NMR (DMSO-d ₆ ) δ:

2.94 (2H, t, J = 7.9 Hz), 4.11 (2H, t, J = 7.9 Hz), 6.22 (1H, s),

7.19 (1 H, s).

Mass (FAB (+)) m / e: 137 (M−H) ⁺ .

Preparation Example 24

1- (3-aminopropyl) -4-aminoimidazole:

1- (2-cyanoethyl) -4-aminoimidazole (1 g, 6 mmol) was suspended in a 3% ammonia / ethanol mixture (50 mL), and Raney nickel was added thereto at 80 ° C under hydrogen stream. Stir for 5 hours. The catalyst was filtered off with celite, the filtrate was concentrated under reduced pressure, and the residue was then subjected to column chromatography on silica gel (chloroform: methanol: aqueous ammonia solution = 5: 1: 0.5) to give 620 mg of the title compound as an oil.

¹ H-NMR (DMSO-d ₆ ) δ:

1.85 (2H, s), 1.92 (2H, quintet, J = 6.6 Hz),

2.51 (2H, t, J = 6.6 Hz), 4.00 (2H, t, J = 6.6 Hz), 4.82 (2H, s),

6.21 (1 H, s), 7.19 (1 H, s).

Mass (FAB (+)) m / e: 141 (M−H) ⁺ .

Preparation Example 25

5-amino-2- (2-aminoethyl) pyridine:

Tin chloride dihydrate (11.65 g, 51.6 mmol) was dissolved in ice-cold Synthesis, p. 5-nitropyridylacetonitrile (2.55 g, 15.9 mmol) was added to a concentrated hydrochloric acid / ethanol (1/1) mixture (32 mL) according to the method described in 314 (1989), and stirred at room temperature for 2 hours. Ethanol was distilled off under reduced pressure, the residue was diluted with ethyl acetate, washed with an aqueous sodium carbonate solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform: methanol = 19: 1) to give 1.14 g of a yellow oily substance. The oily material thus obtained was dissolved in ammonia-containing methanol (3.6 mL), Raney nickel (550 mg) was added, and shaken for 3 hours under hydrogen stream (3 kg / cm 2). The catalyst was filtered off with celite, the filtrate was concentrated under reduced pressure, and the residue was column chromatographed with chromatography Rex NH silica (Chloroform: Methanol: = 20: 1) to give the title compound 450 mg. Got.

Melting Point: 42-45 ℃

¹ H-NMR (CDCl ₃ ) δ:

2.80 (2H, t, J = 6.4 Hz), 3.02 (2H, t, J = 6.4 Hz), 6.96 (2H, s),

8.01 (1 H, s).

Mass (FAB (+)) m / e: 138 (M−H) ⁺ .

Preparation Example 26

2- (2-Methyl-5-nitro-l-imidazolyl) ethyl methanesulfonate:

Metronidazole (5.0 g, 29.2 mmol) was dissolved in pyridine (10 mL), a pyridine solution (10 mL) of methanesulfonyl chloride (3.5 g, 30.7 mmol) was added dropwise, and stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the residue was washed with a water-ethanol mixture and dried to obtain 6.4 g of the title compound.

Melting Point: 152-153 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.46 (3H, s), 3.15 (3H, s), 4.56 (2H, t, J = 4.9 Hz),

4.66 (2H, t, J = 4.9 Hz), 8.07 (1H, s).

Mass (FAB (+)) m / e: 250 (M−H) ⁺ .

Preparation Example 27

(2-Methyl-5-nitro-l-imidazolyl) ethyl azide:

The compound obtained in Preparation 26 (1.99 g, 7.9 mmol) was suspended in acetone (10 mL), and an aqueous solution of sodium azide (2.0 g, 31.5 mmol) and sodium iodide (110 mg, 0.7 mmol) (2 mL) ) And refluxed for 3 days. The solvent was distilled off under reduced pressure, 1N aqueous sodium hydroxide solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was purified by column chromatography on silica gel (chloroform: methanol: = 20: 1) to obtain 1.5 g of the title compound.

Melting Point: 51.0 -51.5 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.48 (3H, s), 3.79 (2H, t, J = 5.8 Hz), 4.48 (2H, t, J = 5.8 Hz),

8.06 (1 H, s).

Mass (FAB (+)) m / e: 197 (M−H) ⁺ .

Preparation Example 28

1- (2-Aminoethyl) -2-methyl-5-nitroimidazole:

After the compound (1.5 g, 7.6 mmol) obtained in Preparation Example 27 was hydrogenated with a catalyst according to Preparation Example 11, the catalyst was filtered off with celite, and the filtrate was purified by column chromatography with silica gel (chloroform: methanol = 10: 1. ), 450 mg of the title compound in the foam was obtained.

¹ H-NMR (DMSO-d ₆ ) δ:

2.47 (3H, s), 2.88 (2H, t, J = 6.4 Hz), 3.34 (2H, br.s),

4.27 (2H, t, J = 6.4 Hz), 8.02 (1H, s).

Mass (FAB (+)) m / e: 171 (M−H) ⁺ .

Preparation Example 29

2- (2-aminoethylamino) -4-aminopyrimidine:

4-benzoylamino-2-chloropyrimidine (2.34 g, 10.0 mmol) obtained by the method disclosed in Japanese Patent Application Laid-Open No. 81375/1987 was stirred at 100 ° C. in ethylenediamine (12.1 g, 200.0 mmol) for 1 hour. . After completion of the reaction, ethylenediamine was distilled off under reduced pressure, and the residue was column chromatographed with CHP-20P gel (manufactured by Mitsubishi Chemical Industries Ltd .; acetonitrile: water = 10:90 to 15:85) to give 410 mg of the title compound. Got it.

¹ H-NMR (DMSO-d ₆ ) δ:

2.61 (2H, t, J = 6.2 Hz), 3.17 (2H, dt, J = 6.2, 12.2 Hz),

2.0-3.6 (2H, br.s), 5.66 (1H, d, J = 5.8 Hz), 6.23 (3H, br.s),

7.65 (1H, doublet, J = 5.8 Hz).

Mass (FAB (+)) m / e: 154 (M−H) ⁺ .

Preparation Example 30

N- {N-[(2S, 3S) -3-trans-carboxyoxirane-2-carbonyl] -L-phenylalanyl} -1,8-diaminooctane:

The title compound was synthesized by the method disclosed in European Patent Application No. 0655447A1.

Melting point:> 210 ° C. (decomposition).

¹ H-NMR (DMSO) -d ₆ ) δ:

1.20-1.36 (11H, m), 1.50-1.53 (1H, m),

2.72 (2H, t, J = 7.3 Hz), 2.78 (1H, dd, J = 9.5, 13.4 Hz),

2.89 (1H, d, J = 2.0 Hz), 2.92-2.96 (2H, m), 3.09-3.16 (1H, m),

3.23 (1H, doublet, J = 1.7 Hz), 4.42 (1H, doublet of doublets, J = 5.4, 9.3 Hz),

7.16-7.27 (5H, m), 7.92 (1H, br.s).

Mass (FAB (+)) m / e: 406 (M−H) ⁺ .

Example 1:

N- {L-3-trans-[(4-phenylpiperazin-1-yl) carbonyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 1):

1-hydroxybenzotriazole (149 mg, 1.1 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (230 mg, 1.2 mmol) were obtained in Preparation Example 2 (306 mg , 1.0 mmol) and N-phenylpiperazine (162 mg, 1.0 mmol) were added successively to a mixture of ethyl acetate-tetrahydrofuran (1: 1) and stirred at room temperature for 3 hours. The reaction was washed with water, diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was chromatographed (ethyl acetate) with silica gel to give 334 mg of the titled compound.

Melting Point: 72-74 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.80 (3H, s), 2.83 (1H, dd, J = 8.6, 13.7 Hz), 2.89 (3H, s),

2.96 (1H, dd, J = 6.4, 13.4 Hz), 3.12 (2H, t, J = 5.0 Hz),

3.19 (2H, t, J = 4.9 Hz), 3.55-3.70 (4H, m),

3.59 (1H, d, J = 1.9 Hz), 3.88 (1H, d, J = 2.0 Hz),

4.93-5.02 (1H, m), 6.82 (1H, t, J = 7.2 Hz), 6.93-7.00 (2H, m),

7.22-7.30 (7H, m), 8.67 (1H, doublet, J = 8.3 Hz).

Mass (FAB (+)) m / e: 451 (M−H) ⁺ .

Example 2:

N- {L-3-trans- [2- (benzenesulfonylamino) ethylcarbamoyl] -oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 2)

In a similar manner as in Example 1, using the compound obtained in Preparation Example 2 (1.1 g, 3.6 mmol) and the compound obtained in Preparation Example 11 (720 mg, 3.6 mmol), 1.1 g of the title compound in the foam was obtained.

¹ H-NMR (DMSO-d ₆ ) δ:

2.75-2.85 (3H, m), 2.78 (3H, s), 2.88 (3H, s),

2.94 (1H, doublet of doublets, J = 6.1, 13.4 Hz), 3.08-3.16 (2H, m),

3.36 (1H, d, J = 1.7 Hz), 3.55 (1H, d, J = 1.7 Hz),

4.85-4.98 (1H, m), 7.19-7.32 (5H, m), 7.57-7.82 (6H, m),

8.33 (1H, t, J = 5.6 Hz), 8.84 (1H, d, J = 8.3 Hz).

Mass (FAB (+)) m / e: 489 (M−H) ⁺ .

Example 3:

N- {L-3-trans- [2- (t-butoxycarbonylaminomethyl) phenylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 3):

In a similar manner to Example 1, 780 mg of the title compound in the foam was obtained using the compound obtained in Preparation Example 2 (500 mg, 1.63 mmol) and the compound obtained in Preparation Example 7 (363 mg, 1.63 mmol).

¹ H-NMR (DMSO-d ₆ ) δ:

1.38 (9H, s), 2.78 (3H, m), 2.83 (1H, doublet of doublets, J = 8.0, 13.4 Hz),

2.87 (3H, s), 2.96 (1H, dd, J = 6.1, 13.2 Hz),

3.68 (1H, d, J = l.0 Hz), 3.75 (1H, d, J = 1.7 Hz),

4.08 (2H, doublet, J = 5.9 Hz), 4.95 (1H, doublet of doublets, J = 8.3, 14.6 Hz),

7.12-7.43 (10H, m), 8.99 (1H, d, J = 8.3 Hz), 9.94 (1H, s).

Mass (FAB (+)) m / e: 549 (M + K) ⁺ .

Example 4:

N- {L-3-trans- [2- (aminomethyl) phenylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide hydrochloride (Compound No. 4)

The compound (200 mg, 0.39 mmol) obtained in Example 3 was suspended in chloroform (4 mL), and then 2 mL of trifluoroacetic acid was added under ice-cooling, and stirred at room temperature for 40 minutes. 4N hydrochloric acid / ethyl acetate mixed solution (0.1 mL) was added under ice-cooling, and the solvent was distilled off under reduced pressure. Chloroform and toluene were added to the residue, and the solvent was distilled off under reduced pressure to obtain 188 mg of the title compound.

Melting Point: 102-107 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.80 (3H, s), 2.85 (1H, dd, J = 8.5, 13.6 Hz), 2.89 (3H, s),

2.98 (1H, doublet of doublets, J = 6.4, 13.7 Hz), 3.76 (1H, high d, J = 2.0 Hz),

3.78 (2H, doublet, J = 1.7 Hz), 4.00 (2H, broad doublet, J = 5.6 Hz),

4.97 (1H, doublet of doublets, J = 8.0, 14.6 Hz), 7.23-7.51 (9H, m),

8.07 (2H, broad doublet), 8.98 (1H, doublet, J = 8.0 Hz), 10.11 (1H, slow).

Mass (FAB (+)) m / e: 411 (M−H) ⁺ .

Example 5:

N- {L-3-trans- [3- (t-butoxycarbonylaminomethyl) phenylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 5):

In a similar manner to Example 1, 740 mg of the title compound in the foam was obtained using the compound obtained in Preparation Example 2 (500 mg, 1.63 mmol) and the compound obtained in Preparation Example 8 (363 mg, 1.63 mmol).

¹ H-NMR (DMSO-d ₆ ) δ:

1.40 (9H, s), 2.79 (3H, s), 2.83 (1H, dd, J = 8.3, 13.4 Hz),

2.88 (3H, s), 2.97 (1H, doublet of doublets, J = 6.1, 13.4 Hz),

3.67 (1H, d, J = 1.7 Hz), 3.70 (1H, d, J = 2.0 Hz),

4.09 (2H, broad doublet, J = 6.3 Hz), 4.95 (1H, doublet of doublets, J = 8.3, 14.6 Hz),

6.97 (1H, doublet, J = 7.6 Hz), 7.21-7.50 (9H, m),

8.99 (1H, doublet, J = 8.3 Hz), 10.43 (1H, s).

Mass (FAB (+)) m / e: 549 (M + K) ⁺ .

Example 6:

N- {L-3-trans- [3- (aminomethyl) phenylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide hydrochloride (Compound No. 6)

In a similar manner to Example 4, 195 mg of the title compound was obtained using the compound (200 mg, 0.39 mmol) obtained in Example 5.

Melting Point: 107-112 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.84 (1H, dd, J = 8.6, 13.4 Hz), 2.88 (3H, s),

2.97 (1H, doublet of doublets, J = 6.1, 13.4 Hz), 3.70 (1H, doubled, J = 1.7 Hz),

3.72 (1H, doublet, J = 1.7 Hz), 4.02 (2H, broad doublet, J = 3.0 Hz),

4.95 (1H, doublet of doublets, J = 8.3, 14.6 Hz), 7.19-7.53 (8H, m),

7.79 (1 H, s), 8.15 (2 H, br. S), 8.99 (1 H, d, J = 8.1 Hz),

10.55 (1 H, s).

Mass (FAB (+)) m / e: 411 (M−H) ⁺ .

Example 7:

N- {L-3-trans- [4- (t-butoxycarbonylaminomethyl) phenylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 7):

In a similar manner to Example 1, 774 mg of the title compound in the foam was obtained using the compound obtained in Preparation Example 2 (500 mg, 1.63 mmol) and the compound obtained in Preparation Example 9 (363 mg, 1.63 mmol).

¹ H-NMR (DMSO-d ₆ ) δ:

1.39 (9H, s), 2.79 (3H, s), 2.83 (1H, dd, J = 8.2, 13.4 Hz),

2.88 (3H, s), 2.96 (1H, dd, J = 6.1, 13.4 Hz),

3.65 (1H, d, J = 1.7 Hz), 3.70 (1H, d, J = 1.7 Hz),

4.07 (2H, doublet, J = 6.l Hz), 4.94 (1H, dd, J = 8.3, 14.6 Hz),

7.13-7.36 (7H, m), 7.53 (2H, d, J = 8.3 Hz),

8.99 (1 H, d, J = 8.0 Hz), 10.40 (1 H, s).

Mass (FAB (+)) m / e: 549 (M + K) ⁺ .

Example 8:

N- {L-3-trans- [4- (aminomethyl) phenylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide hydrochloride (Compound No. 8)

In a similar manner to Example 4, using the compound (200 mg, 0.39 mmol) obtained in Example 7, 175 mg of the title compound was obtained.

Melting Point: 115-120 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.78 (3H, s), 2.83 (1H, dd, J = 8.3, 13.6 Hz), 2.88 (3H, s),

2.97 (1H, doublet of doublets, J = 6.1, 13.4 Hz), 3.68 (1H, doublet, J = 1.4 Hz),

3.72 (1H, doublet, J = 1.7 Hz), 3.99 (2H, broad s),

4.95 (1H, doublet of doublets, J = 8.3, 14.6 Hz), 7.23-7.32 (5H, m),

7.41 (2H, d, J = 8.5 Hz), 7.65 (2H, d, J = 8.8 Hz),

8.15 (2H, broad s), 8.98 (1H, d, J = 8.3 Hz), 10.55 (1H, s).

Mass (FAB (+)) m / e: 411 (M−H) ⁺ .

Example 9:

N- [L-3-trans- (4-benzylpiperazin-1-yl-carbonyl) oxirane-2-carbonyl] -L-phenylalanine dimethylamide (Compound No. 9):

In a similar manner to Example 1, the compound (306 mg, 1.0 mmol) and 1-benzylpiperazine (176 mg, 1.0 mmol) obtained in Preparation Example 2 were used to obtain 155 mg of the title compound in the foam.

¹ H-NMR (DMSO-d ₆ ) δ:

2.33 (2H, t, J = 4.9 Hz), 2.40 (2H, t, J = 4.9 Hz),

2.82 (1H, doublet of doublets, J = 8.6, 13.4 Hz), 2.87 (3H, s), 2.89 (3H, s),

2.94 (1H, doublet of doublets, J = 6.3, 13.4 Hz), 3.38-3.48 (4H, m),

3.50 (2H, s), 3.55 (1H, d, J = 1.9 Hz), 3.80 (1H, d, J = 2.0 Hz),

4.90-4.98 (1 H, m), 7.13-7.35 (10 H, m),

8.13 (1H, doublet, J = 8.0 Hz).

Mass (FAB (+)) m / e: 465 (M−H) ⁺ .

Example 10

N- {L-3-trans- [N- (2-t-butoxycarbonylaminoethyl) -N-phenylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 10 ):

In a similar manner to Example 1, 206 mg of the title compound in the foam was obtained using the compound obtained in Preparation Example 2 (500 mg, 1.63 mmol) and the compound obtained in Preparation Example 10 (385 mg, 1.63 mmol).

¹ H-NMR (DMSO-d ₆ ) δ:

1.32 (9H, s), 2.76 (1H, dd, J = 7.8, 13.4 Hz), 2.80 (3H, s),

2.81 (3H, s), 2.89 (1H, dd, J = 6.1, 13.4 Hz),

3.04 (1H, doublet, J = 1.7 Hz), 3.07 (2H, broad doublet, J = 6.l Hz),

3.61 (1H, doublet, J = 1.7 Hz), 3.64-3.74 (2H, m),

4.82 (1H, doublet of doublets, J = 7.8, 14.6 Hz), 6.94 (1H, broad doublet, J = 5.4 Hz),

7.10 (2H, doublet, J = 7.8 Hz), 7.17-7.46 (8H, m),

8.68 (1H, doublet, J = 8.6 Hz).

Mass (FAB (+)) m / e: 563 (M + K) ⁺ .

Example 11:

N- {L-3-trans- [N- (2-aminoethyl) -N-phenylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide hydrochloride (Compound No. 11):

In a similar manner to Example 4, 127 mg of the title compound was obtained using the compound (200 mg, 0.38 mmol) obtained in Example 10.

¹ H-NMR (DMSO-d ₆ ) δ:

2.76 (1H, doublet of doublets, J = 8.0, 13.4 Hz), 2.80 (3H, s), 2.81 (3H, s),

2.86-2.94 (2H, m), 3.10 (1H, d, J = 2.0 Hz),

3.65 (1H, d, J = 1.7 Hz), 3.90 (2H, br.t, J = 5.6 Hz),

4.82 (1H, doublet of doublets, J = 8.0, 14.6 Hz), 7.08-7.49 (10H, m),

7.82 (2H, broad singlet), 8.61 (1H, doublet, J = 8.3 Hz).

Mass (FAB (+)) m / e: 425 (M−H) ⁺ .

Example 12:

N- {L-3-trans- [4- (t-butoxycarbonylaminomethyl) phenylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine-2-phenylethylamide (Compound No. 12) :

In a similar manner to Example 1, 275 mg of the title compound was obtained using the compound obtained in Preparation Example 6 (200 mg, 0.55 mmol) and the compound obtained in Preparation Example 9 (122 mg, 0.55 mmol).

Melting Point: 152.5-156 ℃

¹ H-NMR (DMSO-d ₆ )

1.39 (9H, s), 2.67 (2H, t, J = 7.1 Hz),

2.76 (1H, dd, J = 10.0, 13.9 Hz), 2.94 (1H, dd, J = 4.9, 13.9 Hz),

3.19-3.32 (2H, m), 3.63 (1H, d, J = 1.7 Hz),

3.69 (1H, doublet, J = 1.7 Hz), 4.06 (2H, d, J = 5.8 Hz),

4.47-4.45 (1H, m), 7.13-7.33 (12H, m),

7.35 (1H, t, J = 7.0 Hz), 7.54 (2H, d, J = 8.6 Hz),

8.24 (1H, d, J = 5.6 Hz), 8.81 (1H, d, J = 8.5 Hz), 10.39 (1H, s).

Mass (FAB (+)) m / e: 625 (M + K) ⁺ .

Example 13:

N- {L-3-trans- [4- (aminomethyl) phenylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine-2-phenylethylamide hydrochloride (Compound No. 13):

In a similar manner to Example 4, 69 mg of the title compound was obtained using the compound (130 mg, 0.23 mmol) obtained in Preparation Example 12.

Melting Point: 152-154 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.68 (2H, t, J = 7.3 Hz), 2.77 (1H, dd, J = 10.0, 13.7 Hz),

2.95 (1H, doublet of doublets, J = 4.9, 13.7 Hz), 3.18-3.40 (2H, m),

3.70 (1H, s), 3.71 (1H, s), 3.96 (2H, s), 4.48-4.57 (1H, m),

7.15-7.33 (10H, m), 7.45 (2H, d, J = 8.3 Hz),

7.66 (2H, doublet, J = 8.3 Hz), 8.23-8.37 (4H, m),

8.84 (1 H, d, J = 8.5 Hz), 10.67 (1 H, s).

Mass (FAB (+)) m / e: 487 (M−H) ⁺ .

Example 14

N- [L-3-trans- (4-t-butoxycarbonylpiperazin-1-yl-carbonyl) oxirane-2-carbonyl] -L-phenylalanine dimethylamide (Compound No. 15):

In a similar manner to Example 1, 240 mg of the title compound was obtained using compound (306 mg, 1.0 mmol) and 1-t-butoxycarbonylpiperazine (186 mg, 1.0 mmol) obtained in Preparation Example 2.

Melting Point: 159-160 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

1.41 (9H, s), 2.79 (3H, s), 2.82 (1H, dd, J = 4.9, 13.4 Hz),

2.88 (3H, s), 2.97 (1H, doublet of doublets, J = 7.0, 13.2 Hz),

3.30-3.55 (8H, m), 3.58 (1H, d, J = 1.9 Hz),

3.85 (1H, d, J = 1.6 Hz), 4.95 (1H, ddd, J = 6.4, 8.4, 8.5 Hz),

7.20-7.30 (5H, m), 8.68 (1H, doublet, J = 8.3 Hz).

Mass (FAB (+)) m / e: 513 (M + K) ⁺

(FAB (−)) m / e: 473 (M ⁻ H) ⁻ .

Example 15:

N- [L-3-trans- (piperazin-1-yl-carbonyl) oxirane-2-carbonyl] -L-phenylalanine dimethylamide hydrochloride (Compound No. 16):

In a similar manner to Example 4, 86 mg of the title compound was obtained using the compound (100 mg, 0.21 mmol) obtained in Preparation Example 14.

Melting Point: 150-155 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.86 (3H, s), 2.72-2.88 (1H, m),

2.95 (1H, doublet of doublets, J = 6.4, 13.6 Hz), 3.02-3.50 (4H, m),

3.63 (1H, doublet, J = 2.0 Hz), 3.65-3.85 (4H, m),

3.91 (1H, doublet, J = 2.0 Hz), 4.88-5.00 (1H, m), 7.21-7.31 (5H, m),

8.04 (1H, doublet, J = 8.0 Hz).

Mass (FAB (+)) m / e: 375 (M−H) ⁺ .

Example 16:

N- {L-3-trans-[(l-benzylpiperidin-4-yl) carbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide hydrochloride (Compound No. 18):

In a similar manner to Example 1, 244 mg of the title compound was obtained using compound (306 mg, 1.0 mmol) and 1-benzyl-4-aminopiperidine (190 mg, 1.0 mmol) obtained in Preparation Example 2.

Melting Point: 120-122 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

1.37-1.49 (2H, m), 1.63-1.74 (2H, m), 1.95-2.05 (2H, m),

2.69-2.77 (2H, m), 2.78 (3H, s),

2.80 (1H, doublet of doublets, J = 8.5, 13.4 Hz), 2.87 (3H, s),

2.93 (1H, doublet of doublets, J = 6.1, 13.4 Hz), 3.41 (1H, doublet, J = 1.7 Hz),

3.47 (2H, s), 3.50-3.62 (1H, m), 3.57 (1H, d, J = 1.7 Hz),

4.85-4.95 (1H, m), 7.22-7.33 (10H, m),

8.33 (1H, doublet, J = 9.0 Hz), 8.92 (1H, doublet, J = 8.0 Hz).

Mass (FAB (+)) m / e: 479 (M−H) ⁺ .

Example 17:

N- {L-3-trans- [2- (piperidin-1-yl) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide hydrochloride (Compound No. 19):

In a similar manner to Example 1, 270 mg of the title compound was obtained using compound (306 mg, 1.0 mmol) and 1- (2-aminoethyl) piperidine (128 mg, 1.0 mmol) obtained in Preparation Example 2.

Melting Point: 99-101 ℃

¹ H-NMR (DMSO-d ₆ )

1.31-1.54 (6H, m), 2.23-2.43 (6H, m), 2.78 (3H, s),

2.81 (1H, doublet of doublets, J = 8.3, 13.4 Hz), 2.87 (3H, s),

2.94 (1H, dd, J = 6.2, 13.4 Hz), 3.18 (2H, dt, J = 6.3, 6.4 Hz),

3.43 (1H, d, J = 2.0 Hz), 3.55 (1H, d, J = 1.7 Hz),

4.91 (1H, double doublet of doublets, J = 6.1, 6.3, 8.3 Hz), 7.22-7.30 (5H, m),

8.23 (1H, t, J = 5.5 Hz), 8.87 (1H, d, J = 8.l Hz).

Mass (FAB (+)) m / e: 417 (M−H) ⁺ .

Example 18:

N- [L-3-trans- (4-aminobenzylcarbamoyl) oxirane-2-carbonyl] -L-phenylalanine dimethylamide hydrochloride (Compound No. 20):

In a similar manner to Example 1, 232 mg of the title compound was obtained using the compound (500 mg, 1.63 mmol) and 4-aminobenzylamine (199 mg, 1.63 mmol) obtained in Preparation Example 2.

Melting Point: 118-123 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.81-2.84 (1H, m), 2.88 (3H, s),

2.95 (1H, doublet of doublets, J = 6.1, 13.4 Hz), 3.47 (1H, high d, J = 2.0 Hz),

3.62 (1H, doublet, J = 2.0 Hz), 4.26 (1H, doublet of doublets, J = 5.9, 15.2 Hz),

4.32 (1H, doublet of doublets, J = 6.6, 15.0 Hz), 4.91 (1H, doublet of doublets, J = 8.3, 14.4 Hz),

7.20-7.34 (9H, m), 8.92-8.94 (2H, m), 9.92 (2H, br.s).

Mass (FAB (+)) m / e: 411 (M−H) ⁺ .

Example 19:

N- {L-3-trans- [4- (aminosulfonyl) phenylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 21):

In a similar manner to Example 1, 322 mg of the title compound was obtained using the compound (500 mg, 1.63 mmol) and 4-aminobenzenesulfonamide (281 mg, 1.63 mmol) obtained in Preparation Example 2.

Melting Point: 163-175 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

1.89 (3H, s), 2.72 (1H, dd, J = 8.6, 13.7 Hz), 2.36 (3H, s),

2.96 (1H, doublet of doublets, J = 6.3, 13.4 Hz), 3.69 (1H, high d, J = 1.7 Hz),

3.72 (1H, doublet, J = 1.7 Hz), 4.94 (1H, doublet of doublets, J = 8.0, 14.6 Hz),

7.17-7.31 (9H, m), 9.00 (1H, d, J = 8.0 Hz), 10.73 (1H, s).

Mass (FAB (+)) m / e: 461 (M−H) ⁺ .

Example 20:

N- {L-3-trans- [2- (benzyloxycarbonylamino) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 22):

In a similar manner to Example 1, the compound obtained in Preparation Example 2 (306 mg, 1.0 mmol) and Hoppe-Seyler's, Z. Physiol. 280 mg of the title compound in the foam was obtained using N-benzyloxycarbonylethylenediaminehydrochloride (254 mg, 1.1 mmol) prepared according to the method described in Chem., 349 , 251 (1968).

¹ H-NMR (DMSO-d ₆ ) δ:

2.78 (3H. S), 2.82 (1H, dd, J = 8.8, 13.4 Hz), 2.88 (3H, s),

2.94 (1H, doublet of doublets, J = 6.1, 13.4 Hz), 3.03-3.12 (2H, m),

3.12-3.11 (2H, m), 3.39 (1H, d, J = 1.4 Hz),

3.58 (1H, doublet, J = 1.4 Hz), 4.80-4.95 (1H, m), 5.01 (2H, s),

7.23-7.60 (11H, m), 8.37 (1H, t, J = 5.4 Hz),

8.84 (1H, doublet, J = 8.5 Hz).

Mass (FAB (+)) m / e: 483 (M−H) ⁺ .

Example 21:

N- {L-3-trans- [2- (t-butoxycarbonylamino) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 23):

In a similar manner to Example 1, 100 mg of the title compound in the foam was obtained using the compound (306 mg, 1.0 mmol) and N-t-butoxycarbonylethylenediamine (176 mg, 1.1 mmol) obtained in Preparation Example 2.

¹ H-NMR (DMSO-d ₆ ) δ:

1.37 (9H, s), 2.79 (3H, s), 2.82 (1H, dd, J = 8.6, 13.7 Hz),

2.88 (3H, s), 2.93 (1H, doublet of doublets, J = 6.1, 13.7 Hz),

2.98 (2H, dt, J = 6.1, 6.4 Hz), 3.11 (dt, J = 5.8, 6.l Hz),

3.39 (1H, d, J = 1.7 Hz), 3.58 (1H, d, J = 1.7 Hz),

4.91 (1H, double doublet of doublets, J = 6.1, 8.3, 8.6 Hz), 6.86 (1H, t, J = 5.8 Hz),

7.20-7.40 (5H, m), 8.32 (1H, t, J = 6.4 Hz),

8.84 (1H, doublet, J = 8.3 Hz).

Mass (FAB (+)) m / e: 487 (M + K) ⁺ .

Example 22:

N- {L-3-trans-[(2-aminoethyl) carbamoyl] oxirane-2-carbonyl] -L-phenylalanine dimethylamide hydrochloride (Compound No. 24):

In a similar manner to Example 4, 30 mg of the title compound on the foam was obtained using the compound (100 mg, 0.22 mmol) obtained in Example 21.

¹ H-NMR (DMSO-d ₆ ) δ:

2.75-2.93 (3H, m), 2.79 (3H, s), 2.88 (3H, s),

2.95 (1H, doublet of doublets, J = 6.1, 13.4 Hz), 3.15-3.42 (2H, m),

3.42 (1H, doublet, J = 1.3 Hz), 3.63 (1H, doublet, J = 1.3 Hz),

4.85-4.96 (1H, m), 7.10-7.40 (5H, m), 7.86 (3H, br.s),

8.50 (1H, t, J = 5.6 Hz), 8.82 (1H, d, J = 8.3 Hz).

Mass (FAB (+)) m / e: 349 (M−H) ⁺ .

Example 23:

N- [L-3-trans- (4-piperonylpiperazin-1-yl-carbonyl) oxirane-2-carbonyl] -L-phenylalanine dimethylamide (Compound No. 25):

In a similar manner as in Example 1, 300 mg of the title compound in the foam was obtained using the compound (306 mg, 1.0 mmol) and 1-piperonylpiperazine (242 mg, 1.1 mmol) obtained in Preparation Example 2.

¹ H-NMR (DMSO-d ₆ ) δ:

2.31 (2H, doublet of doublets, J = 4.6, 4.9 Hz), 2.38 (2H, doubled of doublets, J = 4.6, 4.9 Hz),

2.79 (3H, s), 2.82 (1H, dt, J = 8.6, 13.4 Hz), 2.87 (3H, s),

2.95 (1H, dt, J = 6.1, 13.4 Hz), 3.34 (2H, s),

3.32-3.59 (4H, m), 3.56 (1H, d, J = 1.9 Hz),

3.80 (1H, d, J = 1.9 Hz), 4.95 (1H, ddd, J = 6.1, 8.3, 8.6 Hz),

5.99 (2H, s), 6.72-6.78 (1H, m), 6.80-6.88 (2H, m),

7.18-7.28 (5H, m), 8.65 (1H, doublet, J = 8.3 Hz).

Mass (FAB (+)) m / e: 509 (M−H) ⁺ .

Example 24:

N- {L-3-trans- [4- (t-butoxycarbonylaminomethyl) phenylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine propylamide (Compound No. 26):

In a similar manner as in Example 1, 112 mg of the title compound was obtained using the compound (336 mg, 1.1 mmol) obtained in Preparation Example 4 and the compound (222 mg, 1.0 mmol) obtained in Preparation Example 9.

Melting Point: 219-221 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

0.79 (3H, t, J = 7.6 Hz), 1.28-1.44 (2H, m), 1.39 (9H, s),

2.81 (1H, doublet of doublets, J = 9.5, 13.7 Hz), 2.90-3.09 (3H, m),

3.63 (1H, d, J = 1.7 Hz), 3.69 (1H, d, J = 1.7 Hz),

4.07 (2H, doublet, J = 6.l Hz), 4.47-4.57 (1H, m), 7.12-7.32 (7H, m),

7.35 (1H, t, J = 6.l Hz), 7.53 (2H, d, J = 8.5 Hz),

8.11 (1H, d, J = 5.6 Hz), 8.21 (1H, d, J = 8.5 Hz), 10.39 (1H, s).

Mass (FAB (+)) m / e: 565 (M + K) ⁺ .

Example 25:

N- {L-3-trans-[(4-aminomethyl) phenylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine propylamide hydrochloride (Compound No. 27):

In a similar manner as in Example 4, 47 mg of the title compound was obtained using the compound (100 mg, 0.19 mmol) obtained in Example 24.

Melting Point: 149-152 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

0.79 (3H, t, J = 7.3 Hz), 1.26-1.42 (2H, m),

2.82 (1H, doublet of doublets, J = 9.5, 13.7 Hz), 2.90-3.05 (3H, m),

3.67 (1H, d, J = 1.7 Hz), 3.72 (1H, d, J = 1.7 Hz), 3.97 (2H, s),

4.45-4.59 (1H, m), 7.16-7.34 (5H, m), 7.43 (2H, d, J = 8.6 Hz),

7.65 (2H, d, J = 8.6 Hz), 8.12 (1H, t, J = 5.6 Hz),

8.25 (2H, broad singlet), 8.80 (1H, d, J = 8.6 Hz), 10.59 (1H, single).

Mass (FAB (+)) m / e: 425 (M−H) ⁺ .

Example 26:

N- [L-3-trans- (4-ethylphenylcarbamoyl) oxirane-2-carbonyl] -L-phenylalanine dimethylamide (Compound No. 29):

In a similar manner to Example 1, 250 mg of the title compound was obtained using compound (200 mg, 0.65 mmol) and 4-ethylaniline (79 mg, 0.65 mmol) obtained in Preparation Example 2.

Melting Point: 89-94 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

1.15 (3H, t, J = 7.6 Hz), 2.56 (2H, dd, J = 7.6, 15.l Hz),

2.79 (3H, s), 2.88 (3H, s), 2.83 (1H, dd, J = 8.3, 13.7 Hz),

2.96 (1H, doublet of doublets, J = 6.4, 13.4 Hz), 3.64 (1H, high d, J = 1.7 Hz),

3.70 (1H, d, J = 1.7 Hz), 4.94 (1H, m), 7.16 (2H, d, J = 8.6 Hz),

7.21-7.32 (5H, m), 7.51 (2H, d, J = 8.5 Hz),

8.99 (1H, doublet, J = 8.3 Hz), 10.34 (1H, s).

Mass (FAB (+)) m / e: 410 (M−H) ⁺ .

Example 27:

N- [L-3-trans- (phenylcarbamoyl) oxirane-2-carbonyl] -L-phenylalanine dimethylamide (Compound No. 35):

In a similar manner to Example 1, 392 mg of the title compound was obtained using compound (306 mg, 1.0 mmol) and aniline (93 mg, 1.0 mmol) obtained in Preparation Example 2.

Melting Point: 86-89 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.83 (1H, dd, J = 8.3, 13.3 Hz),

3.66 (1H, d, J = 1.7 Hz), 7.32 (1H, d, J = 1.7 Hz), 4.95 (1H, m),

7.21-7.35 (8H, m), 7.61 (2H, d, J = 7.6 Hz),

8.99 (1H, doublet, J = 8.3 Hz), 10.41 (1H, s).

Mass (FAB (+)) m / e: 382 (M−H) ⁺ .

Example 28:

N- [L-3-trans- (pyridin-3-yl-carbamoyl) oxirane-2-carbonyl] -L-phenylalanine dimethylamide hydrochloride (Compound No. 36):

In a similar manner to Example 1, 70 mg of the title compound was obtained using compound (306 mg, 1.0 mmol) and 3-aminopyridine (94 mg, 1.0 mmol) obtained in Preparation Example 2.

Melting point: 140-147 ° C (decomposition).

¹ H-NMR (DMSO-d ₆ ) δ:

2.78 (3H, s), 2.83 (1H, dd, J = 5.8, 11.2 Hz), 2.87 (3H, s),

2.96 (1H, doublet of doublets, J = 6.4, 13.7 Hz), 3.78 (1H, high d, J = 1.9 Hz),

3.80 (1H, J = 1.7 Hz), 4.95 (1H, m), 7.13-7.30 (5H, m).

8.01 (2H, d, J = 7.l Hz), 8.68 (1H, d, J = 7.l Hz),

9.01 (1H, doublet, J = 7.8 Hz), 11.63 (1H, s).

Mass (FAB (+)) m / e: 383 (M−H) ⁺ .

Example 29:

N- [L-3-trans- (4-t-butylphenylcarbamoyl) oxirane-2-carbonyl] -L-phenylalanine dimethylamide (Compound No. 37):

In a similar manner to Example 1, 357 mg of the title compound was obtained using compound (308 mg, 1.0 mmol) and 4-t-butylaniline (179 mg, 1.2 mmol) obtained in Preparation Example 2.

Melting Point: 127.5-130 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

1.26 (9H, s), 2.79 (3H, s), 2.83 (1H, dd, J = 8.4, 13.2 Hz),

2.88 (3H, s), 2.97 (1H, doublet of doublets, J = 6.4, 13.2 Hz),

3.64 (1H, d, J = 2.0 Hz), 3.71 (1H, d, J = 2.0 Hz),

4.89-5.00 (1H, m), 7.21-7.53 (9H, m), 9.00 (1H, d, J = 8.l Hz),

10.36 (1 H, s).

Mass (FAB (+)) m / e: 438 (M−H) ⁺ .

Example 30:

N- {L-3-trans- [2- (2-t-butoxycarbonylaminothiazol-4-yl) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (compound Number 38):

In a similar manner to Example 1, 1.29 g of the title compound in the foam was obtained using the compound obtained in Preparation Example 2 (806 mg, 2.63 mmol) and the compound obtained in Preparation Example 13 (640 mg, 2.63 mmol).

¹ H-NMR (DMSO-d ₆ ) δ:

1.40 (9H, s), 2.69 (2H, dt, J = 7.3, 14.6 Hz), 2.77 (3H, s),

2.80 (1H, doublet of doublets, J = 8.6, 13.6 Hz). 2.86 (3H, s),

2.93 (1H, doublet of doublets, J = 6.1, 13.4 Hz), 3.32-3.80 (2H, m),

3.39 (1H, d, J = 1.4 Hz), 3.55 (1H, d, J = 1.5 Hz), 4.90 (1H, m),

6.76 (1H, s), 7.11-7.27 (5H, m), 8.37 (1H, t, J = 5.8 Hz),

8.87 (1H, doublet, J = 8.3 Hz), 11.36 (1H, br.s).

Mass (FAB (+)) m / e: 532 (M−H) ⁺ .

Example 31:

N- {L-3-trans- [2- (2-aminothiazol-4-yl) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide hydrochloride (Compound No. 39):

In a similar manner to Example 4, 783 mg of the title compound was obtained using the compound (1.28 g, 2.41 mmol) obtained in Example 30.

Melting Point: 127.5-129 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.63 (2H, t, J = 2.6 Hz), 2.77 (3H, s),

2.81 (1H, doublet of doublets, J = 8.3, 12.9 Hz), 2.86 (3H, s),

2.94 (1H, doublet of doublets, J = 6.4, 13.4 Hz), 3.30-3.37 (2H, m),

3.38 (1H, doublet, J = 1.7 Hz), 3.54 (1H, doublet, J = 2.0 Hz),

4.88-4.93 (1H, m), 6.50 (1H, s), 7.19-7.29 (5H, m),

8.42 (1H, t, J = 5.8 Hz), 8.84 (1H, d, J = 8.3 Hz),

8.88 (2H, broad singlet).

Mass (FAB (+)) m / e: 432 (M−H) ⁺ .

Example 32:

N- [L-3-trans- (quinolin-6-yl-carbamoyl) oxirane-2-carbonyl] -L-phenylalanine dimethylamide hydrochloride (Compound No. 40):

In a similar manner to Example 1, 285 mg of the title compound was obtained using compound (306 mg, 1.0 mmol) and 6-aminoquinoline (114 mg, 1.0 mmol) obtained in Preparation Example 2.

Melting point: 155 ° C (decomposition).

¹ H-NMR (DMSO-d ₆ ) δ:

2.73 (3H, s), 2.80 (3H, s), 2.85 (1H, dd, J = 8.6, 14.0 Hz),

2.98 (1H, doublet of doublets, J = 6.4, 13.4 Hz), 3.75 (1H, s), 3.77 (1H, s),

4.92-5.02 (1H, m), 7.28-7.34 (5H, m),

7.50 (1H, doublet of doublets, J = 4.2, 4.2 Hz), 7.84 (1H, doublet, J = 9.8 Hz),

7.95 (1H, s), 7.99 (1H, d, J = 9.3 Hz), 8.32 (1H, d, J = 8.3 Hz),

8.39 (1H, s), 8.81 (1H, d, J = 4.4 Hz), 9.03 (1H, d, J = 8.3 Hz),

10.8 (1 H, s).

Mass (FAB (+)) m / e: 433 (M−H) ⁺ .

Example 33:

N- {L-3-trans-[(2-methylisoxazol-4-yl) carbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 41):

In a similar manner to Example 1, 320 mg of the title compound was obtained using the compound (2.0 g, 6.5 mmol) and 2-methyl-4-aminoisoxazole (640 mg, 6.5 mmol) obtained in Preparation Example 2.

Melting Point: 80-82 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.38 (3H, s), 2.79 (3H, s), 2.82 (1H, dd, J = 8.5, 13.2 Hz),

2.87 (3H, s), 2.96 (1H, dd, J = 6.8, 13.2 Hz), 3.70 (2H, br.s),

4.89-4.98 (1H, m), 6.61 (1H, s), 7.19-7.34 (5H, m),

8.95 (1H, doublet, J = 8.3 Hz), 11.53 (1H, s).

Mass (FAB (+)) m / e: 387 (M−H) ⁺ .

Example 34:

N- {L-3-trans-[(4-benzyloxycarbonylphenyl) carbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 42):

In a similar manner to Example 1, using the compound obtained in Preparation Example 2 (632 mg, 2.06 mmol) and the compound obtained in Preparation Example 14 (543 mg, 2.06 mmol), 606 mg of the title compound in the foam was obtained.

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.83 (1H, dd, J = 8.3, 13.4 Hz), 2.88 (3H, s),

2.97 (1H, doublet of doublets, J = 6.6, 13.4 Hz), 3.70 (1H, doublet, J = 1.7 Hz),

3.73 (1H, d, J = 1.7 Hz), 4.29-4.98 (1H, m), 5.33 (2H, s),

7.21-7.47 (10H, m), 7.77 (2H, d, J = 8.8 Hz),

7.98 (2H, doublet, J = 8.8 Hz), 8.99 (1H, d, J = 8.3 Hz), 10.75 (1H, s).

Mass (FAB (+)) m / e: 516 (M−H) ⁺ .

Example 35:

N- [L-3-trans- (4-carboxyphenylcarbamoyl) oxirane-2-carbonyl] -L-phenylalanine dimethylamide (Compound No. 43):

10% palladium / carbon (200 mg) was added to a methanol solution (50 mL) of the compound (606 mg, 1.18 mmol) obtained in Example 34, and stirred for 1.5 hours at room temperature under hydrogen stream. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 474 mg of the title compound.

Melting Point: 105-107 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.83 (1H, dd, J = 10.0, 15.1 Hz), 2.88 (3H, s),

2.97 (1H, doublet of doublets, J = 6.3, 13.6 Hz), 3.70 (1H, doublet, J = 1.7 Hz),

3.73 (1H, doublet, J = 1.7 Hz), 4.29-4.98 (1H, m), 7.23-7.32 (5H, m),

7.73 (2H, doublet, J = 8.8 Hz), 7.91 (2H, doublet, J = 8.8 Hz),

9.01 (1 H, d, J = 8.3 Hz), 10.71 (1 H, s).

Mass (FAB (−)) m / e: 424 (M ⁻ H) ⁻ .

Example 36:

N- {L-3-trans- [4- (benzoylaminomethyl) phenylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 44):

The compound obtained in Example 8 (200 mg, 0.45 mmol) and triethylamine (91 mg, 0.89 mmol) were dissolved in dichloromethane (10 mL), benzoyl chloride (69 mg, 0.49 mmol) was added under ice cooling, 2.5 Stirred for hours. The reaction was diluted with chloroform, washed with water, diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform: methanol = 20: 1) to give the title compound (146 mg).

Melting Point: 104-107 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.82 (1H, dd, J = 8.5, 13.6 Hz), 2.88 (3H, s),

2.96 (1H, doublet of doublets, J = 6.3, 13.4 Hz), 3.65 (1H, high d, J = 1.4 Hz),

3.71 (1H, doublet, J = 1.7 Hz), 4.44 (2H, doublet, J = 5.9 Hz),

4.91-4.97 (1H, m), 7.21-7.31 (7H, m), 7.45-7.54 (5H, m),

7.89 (2H, doublet, J = 7.l Hz), 8.97-9.02 (2H, m), 10.41 (1H, s).

Mass (FAB (+)) m / e: 515 (M−H) ⁺ .

Example 37:

N- {L-3-trans- [2- (5-nitropyridin-2-yl) aminoethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 46):

In a similar manner to Example 1, 1.55 g of the title compound using the compound (1.22 g, 4.0 mmol) and 2- (2-aminoethylamino) -5-nitropyridine (729 mg, 4.0 mmol) obtained in Preparation Example 2 Got.

Melting Point: 77-79 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.81 (1H, dd, J = 8.4, 13.4 Hz), 2.88 (3H, s),

2.94 (1H, doublet of doublets, J = 6.3, 13.6 Hz), 3.25-3.35 (2H, m),

3.41 (1H, doublet, J = 1.7 Hz), 3.47 (2H, broad square meter),

3.59 (1H, doublet, J = 1.7 Hz), 4.91 (1H, dt, J = 6.4, 8.2 Hz),

6.56 (1H, doublet, J = 9.5 Hz), 7.18-7.32 (5H, m), 8.05-8.15 (1H, m),

8.15-8.25 (1H, m), 8.47 (1H, t, J = 5.6 Hz),

8.83 (1H, doublet, J = 8.0 Hz), 8.92 (1H, doublet, J = 2.7 Hz).

Mass (FAB (+)) m / e: 471 (M−H) ⁺ .

Example 38:

N- {L-3-trans-[(4-ethenylphenyl) carbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 47):

In a similar manner to Example 1, 397 mg of the title compound was obtained using compound (306 mg, 1.0 mmol) and 4-aminostyrene (119 mg, 1.0 mmol) obtained in Preparation Example 2.

Melting Point: 78-80 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.83 (1H, dd, J = 8.6, 13.7 Hz), 2.88 (1H, s),

2.97 (1H, doublet of doublets, J = 6.4, 13.4 Hz), 3.66 (1H, high d, J = 1.7 Hz),

3.71 (1H, doublet, J = 2.0 Hz), 4.95 (1H, doublet, J = 8.3, 14.6 Hz),

5.20 (1H, d, J = 11.7 Hz), 5.76 (1H, d, J = 17.8 Hz),

6.68 (1H, doublet of doublets, J = 11.0, 17.8 Hz), 7.14-7.32 (5H, m),

7.44 (2H, doublet, J = 8.5 Hz), 7.60 (2H, doublet, J = 8.6 Hz),

8.99 (1 H, d, J = 8.3 Hz), 10.47 (1 H, s).

Mass (FAB (+)) m / e: 408 (M−H) ⁺ .

Example 39:

N- [L-3-trans- (4-phenoxyphenylcarbamoyl) oxirane-2-carbonyl] -L-phenylalanine dimethylamide (Compound No. 48):

In a similar manner to Example 1, 295 mg of the title compound was obtained using the compound (200 mg, 0.65 mmol) and 4-phenoxyaniline (121 mg, 0.65 mmol) obtained in Preparation Example 2.

Melting Point: 107-109 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.83 (1H, dd, J = 5.1, 13.6 Hz), 2.88 (3H, s),

2.97 (1H, doublet of doublets, J = 6.1, 13.4 Hz), 3.65 (1H, doublet, J = 1.7 Hz),

3.72 (1H, doublet, J = 1.7 Hz), 4.92-4.98 (1H, m),

6.96-4.40 (12H, m), 7.62 (2H, d, J = 9.0 Hz),

8.99 (2H, doublet, J = 8.3 Hz), 10.44 (1H, s).

Mass (FAB (+)) m / e: 474 (M−H).

Example 40:

N- {L-3-trans- [N- (4-ethylphenyl) -N-methylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 31):

In a similar manner to Example 1, 420 mg of the title compound in the foam was obtained using the compound obtained in Preparation Example 2 (306 mg, 1.0 mmol) and the compound obtained in Preparation Example 15 (142 mg, 1.05 mmol).

¹ H-NMR (DMSO-d ₆ ) δ:

1.17 (3H, t, J = 7.6 Hz), 2.61 (2H, q, J = 7.6 Hz),

2.77 (1H, doublet of doublets, J = 8.1, 13.4 Hz), 2.81 (6H, s),

2.90 (1H, doublet of doublets, J = 6.4, 13.4 Hz), 3.20 (3H, s), 3.32 (2H, br.s),

4.79-4.89 (1H, m), 7.09-7.31 (9H, m), 8.74 (1H, d, J = 8.3 Hz).

Mass (FAB (+)) m / e: 424 (M−H) ⁺ .

Example 41:

N- [L-3-trans- (4-ethylphenylcarbamoyl) oxirane-2-carbonyl] -L-phenylalanine propylamide (Compound No. 32):

In a similar manner to Example 1, 588 mg of the title compound was obtained using the compound (500 mg, 1.56 mmol) and 4-ethylaniline (189 mg, 1.56 mmol) obtained in Preparation Example 4.

Melting Point: 224-226 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

0.79 (3H, t, J = 7.3 Hz), 1.15 (3H, t, J = 7.6 Hz),

1.31-1.39 (2H, m), 2.56 (1H, doublet of doublets, J = 7.3, 14.9 Hz),

2.81 (1H, doublet of doublets, J = 9.5, 13.4 Hz), 3.62 (1H, doublet, J = 1.7 Hz),

3.69 (1H, doublet, J = 1.4 Hz), 4.50-4.55 (1H, m),

7.16 (2H, doublet, J = 8.3 Hz), 7.20-7.31 (5H, m),

7.51 (2H, d, J = 8.3 Hz), 8.1 (1H, t, J = 5.6 Hz),

8.81 (2H, doublet, J = 8.3 Hz), 10.34 (1H, s).

Mass (FAB (+)) m / e: 424 (M−H) ⁺ .

Example 42:

N- [D-3-trans- (4-ethylphenylcarbamoyl) oxirane-2-carbonyl] -L-phenylalanine dimethylamide (Compound No. 49):

In a similar manner to Example 1, 2.5 g of the title compound was obtained using the compound (2.4 g, 7.9 mmol) and 4-ethylaniline (1.06 g, 8.7 mmol) obtained in Preparation Example 16.

Melting point: 143-145 ° C.

¹ H-NMR (DMSO-d ₆ ) δ:

1.16 (3H, t, J = 7.8 Hz), 2.56 (1H, q, J = 7.8 Hz), 2.80 (3H, s),

2.82 (1H, doublet of doublets, J = 8.3, 13.7 Hz), 2.87 (3H, s),

2.97 (1H, doublet of doublets, J = 6.8, 13.7 Hz), 3.63 (1H, s), 3.71 (1H, s),

4.88-4.98 (1H, m), 7.14-7.31 (7H, m), 7.51 (2H, d, J = 8.0 Hz),

8.91 (1H, doublet, J = 8.3 Hz), 10.35 (1H, s).

Mass (FAB (+)) m / e: 410 (M−H) ⁺ .

Example 43:

N- [L-3-trans- (benzylcarbamoyl) oxirane-2-carbonyl] -L-phenylalanine dimethylamide (Compound No. 50):

In a similar manner to Example 1, 220 mg of the amorphous title compound was obtained using the compound (200 mg, 0.65 mmol) and benzylamine (70 mg, 0.65 mmol) obtained in Preparation Example 2.

¹ H-NMR (DMSO-d ₆ ) δ:

2.78 (3H, s), 2.81 (1H, dd, J = 8.6, 13.4 Hz), 2.88 (3H, s),

2.95 (1H, doublet of doublets, J = 6.1, 13.4 Hz), 3.47 (1H, doubled, J = 1.7 Hz),

3.62 (1H, doublet, J = 2.0 Hz), 4.27 (1H, doublet of doublets, J = 5.8, 14.9 Hz),

4.32 (1H, doublet of doublets, J = 6.6, 15.4 Hz), 4.89-4.95 (1H, m),

7.20-7.35 (10H, m), 8.86 (1H, t, J = 6.4 Hz),

8.92 (1H, doublet, J = 8.3 Hz).

Mass (FAB (+)) m / e: 396 (M−H) ⁺ .

Example 44:

N- [L-3-trans- (2-phenylethylcarbamoyl) oxirane-2-carbonyl] -L-phenylalanine dimethylamide (Compound No. 53):

In a similar manner to Example 1, 272 mg of the amorphous title compound was obtained using the compound (612 mg, 2.0 mmol) and 2-phenylethylamine (254 mg, 2.0 mmol) obtained in Preparation Example 2.

¹ H-NMR (DMSO-d ₆ ) δ:

2.73 (2H, t, J = 7.4 Hz), 2.79 (3H, s),

2.81 (1H, doublet of doublets, J = 8.6, 13.4 Hz), 2.87 (3H, s),

2.95 (1H, doublet of doublets, J = 6.2, 13.5 Hz), 3.28-3.35 (2H, m),

3.39 (1H, d, J = 2.0 Hz), 3.55 (1H, d, J = 1.7 Hz),

4.88-4.95 (1H, m), 7.16-7.35 (10H, m),

8.41 (1H, t, J = 5.4 Hz), 8.86 (1H, d, J = 8.3 Hz).

Mass (FAB (+)) m / e: 410 (M−H) ⁺ .

Example 45:

N- {L-3-trans- [2- (pyridin-2-yl) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 56):

In a similar manner as in Example 1, the title compound 650 mg was obtained using the compound (1.22 g, 4.0 mmol) and 2- (2-aminoethyl) pyridine (538 mg, 4.0 mmol) obtained in Preparation Example 2.

Melting Point: 123-124 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.81 (1H, dd, J = 8.3, 13.4 Hz), 2.87 (3H, s),

2.88 (2H, t, J = 7.6 Hz), 2.94 (1H, dd, J = 6.1, 13.4 Hz),

3.39 (1H, doublet, J = 0.8 Hz), 3.45 (2H, dt, J = 6.6, 6.9 Hz),

3.55 (1H, doublet, J = 1.2 Hz), 4.87-4.95 (1H, m),

7.08-7.33 (7H, m), 7.71 (1H, doublet of doublets, J = 7.6, 7.8 Hz),

8.42 (1H, t, J = 5.8 Hz), 8.50 (1H, d, J = 4.6 Hz),

8.86 (1H, doublet, J = 8.3 Hz).

Mass (FAB (+)) m / e: 411 (M−H) ⁺ .

Example 46:

N- {D-3-trans-[(2-phenylethyl) carbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 60):

In a similar manner to Example 1, 1.04 g of the title compound was obtained using compound (1.02 g, 3.3 mmol) and 2-phenylethylamine (427 mg, 3.3 mmol) obtained in Preparation Example 16.

Melting point: 140-147 ° C. (decomposition).

¹ H-NMR (DMSO-d ₆ ) δ:

2.73 (2H, t, J = 7.3 Hz), 2.78 (3H, s),

2.80 (1H, doublet of doublets, J = 5.1, 13.7 Hz), 2.85 (3H, s),

2.95 (1H, doublet of doublets, J = 6.5, 13.7 Hz), 3.29-3.35 (2H, m),

3.38 (1H, d, J = 1.7 Hz), 3.55 (1H, d, J = 1.7 Hz),

4.86-4.92 (1 H, m), 7.15-7.34 (10 H, m),

8.41 (2H, t, J = 5.6 Hz), 8.85 (1H, d, J = 8.0 Hz).

Mass (FAB (+)) m / e: 410 (M−H) ⁺ .

Example 47:

N- {D-3-trans- [2- (pyridin-2-yl) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 61):

In a similar manner to Example 1, 630 mg of the title compound was obtained using the compound (1.02 g, 3.3 mmol) and 2- (2-aminoethyl) pyridine (428 mg, 3.3 mmol) obtained in Preparation Example 16.

Melting Point: 143-144 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.78 (3H, s), 2.81 (1H, dd, J = 5.4, 13.7 Hz), 2.85 (3H, s),

2.88 (2H, t, J = 7.2 Hz), 2.94 (1H, dd, J = 6.6, 13.7 Hz),

3.37 (1H, s), 3.43-3.48 (2H, m), 3.55 (1H, s),

4.87-4.92 (1 H, m), 7.18-7.30 (7 H, m),

7.71 (1H, doublet of doublets, J = 7.3, 8.0 Hz), 8.42 (1H, high t, J = 5.6 Hz),

8.50 (1H, doublet, J = 4.6 Hz), 8.85 (1H, doublet, J = 8.1 Hz).

Mass (FAB (+)) m / e: 411 (M−H) ⁺ .

Example 48:

N- {L-3-trans- [2- (pyridin-2-yl) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine methylamide (Compound No. 62):

Compound (500 mg, 1.71 mmol) and 2- (2-aminoethyl) pyridine (209 mg, 1.17 mmol) obtained in Preparation Example 20 were diluted with N, N-dimethylformamide (10 ml) and 1-hydroxybenzotriazole. (254 mg, 1.88 mmol), and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.96 mg, 2.05 mmol) was added under ice cooling, followed by stirring at room temperature for 2 hours. The reaction was diluted with ethyl acetate, washed with water and saturated aqueous sodium hydrogen carbonate solution, collected, saturated with sodium chloride, and extracted twice with ethyl acetate. The organic liquid phase was collected and dried over anhydrous magnesium sulfate. The dried product was filtered off, the filtrate was concentrated under reduced pressure, and the remaining solid was washed with diisopropyl ether to obtain 217 mg of the title compound.

Melting Point: 204-208 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.58 (3H, d, J = 4.3 Hz), 2.78 (1H, dd, J = 9.8, 13.4 Hz),

2.86-2.90 (2H, m), 3.00 (1H, dd, J = 4.6, 13.6 Hz),

3.45 (2H, doublet of doublets, J = 7.3, 13.7 Hz), 3.53 (1H, doubled, J = 1.9 Hz),

4.46 (1H, double doublet of doublets, J = 4.9, 9.3, 9.3 Hz), 7.18-7.30 (9H, m),

7.71 (1H, double doublet of doublets, J = 1.9, 7.8, 7.8 Hz), 8.06 (1H, doubled, J = 4.9 Hz).

8.42 (1H, dd, J = 8.4, 8.4 Hz), 8.50 (1H, dd, J = 0.8, 4.9 Hz),

8.71 (1H, doublet, J = 8.6 Hz).

Mass (FAB (+)) m / e: 397 (M−H) ⁺ .

Example 49:

N- {L-3-trans- [2- (1H-imidazol-4-yl) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 63)

The compound (1.5 g, 4.9 mmol) obtained in Preparation Example 2 was dissolved in acetonitrile (10 mL), triethylamine (0.55 g, 5.4 mmol) was added, and then phosphorus oxychloride (0.83 g, 5.4 mmol) under ice-cooling. ) Was added dropwise and stirred for 15 minutes. Histamine dihydrochloride (850 mg, 4.7 mmol) was added little by little, stirred for 4 hours at room temperature, the reaction was concentrated under reduced pressure, 1N aqueous sodium hydroxide solution was added, and the pH was made basic to pH 9. The residue was extracted with ethyl acetate, the solvent was distilled off, and the residue was purified by column chromatography on silica gel (chloroform: methanol = 3: 1 to 1: 1) to obtain 150 mg of the title compound.

Melting point: 170 ° C (decomposition).

¹ H-NMR (DMSO-d ₆ ) δ:

2.51-2.55 (2H, m), 2.79 (3H, s),

2.81 (1H, doublet of doublets, J = 8.1, 13.4 Hz), 2.88 (3H, s),

2.95 (1H, doublet of doublets, J = 6.1, 13.4 Hz), 3.20-3.45 (2H, m),

3.40 (1H, d, J = 1.2 Hz), 3.57 (1H, d, J = 1.2 Hz),

4.91 (1H, double doublet of doublets, J = 6.1, 8.1, 8.3 Hz), 6.81 (1H, s),

7.17-7.31 (5H, m), 7.54 (1H, s), 8.40 (1H, t, J = 5.8 Hz),

8.87 (1H, doublet, J = 8.3 Hz), 11.85 (1H, brs).

Mass (FAB (+)) m / e: 400 (MH) ⁺ .

Example 50:

N- {L-3-trans- {N- [2- (pyridin-2-yl) ethyl] N-methyl-carbamoyl} oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 64 ):

In a similar manner to Example 49, 450 mg of the title compound on the foam was obtained using the compound (1.0 g, 3.26 mmol) and betahistin dimethanesulfonate (1.0 g, 3.10 mmol) obtained in Preparation Example 2.

¹ H-NMR (DMSO-d ₆ ) δ:

2.77-3.10 (13H, m), 3.33 (0.5H, d, J = 1.7 Hz),

3.46 (0.5H, d, J = 1.7 Hz), 2.60-3.90 (2H, m),

3.73 (0.5H, d, J = 1.7 Hz), 3.75 (0.5H, d, J = 1.7 Hz),

4.90-5.05 (1H, m), 7.18-7.34 (7H, m), 7.65-7.74 (1H, m),

8.46 (0.5H, d, J = 4.6 Hz), 8.49 (0.5H, d, J = 4.6 Hz),

8.66 (0.5H, d, J = 8.3 Hz), 8.73 (0.5H, d, J = 8.3 Hz).

Mass (FAB (+)) m / e: 425 (M−H) ⁺ .

Example 51:

N- {L-3-trans- [3- (imidazol-1-yl) propylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 65):

In a similar manner as in Example 49, the compound (766 mg, 2.5 mmol) and 1- (3-aminopropyl) imidazole obtained in Preparation Example 2 were used to obtain 644 mg of the title compound in the foam.

¹ H-NMR (DMSO-d ₆ ) δ:

1.82-1.85 (2H, m), 2.78 (3H, s),

2.80 (1H, doublet of doublets, J = 8.1, 13.l Hz), 2.87 (1H, s),

2.94 (1H, doublet of doublets, J = 6.1, 13.l Hz), 3.00-3.10 (2H, m),

3.97 (2H, t, J = 7.2 Hz), 3.40 (1H, d, J = 2.0 Hz),

3.58 (1H, doublet, J = 2.0 Hz), 4.92 (1H, ddd, J = 6.1, 8.1, 8.2 Hz),

6.88 (1H, d, J = 1.0 Hz), 7.17 (1H, d, J = l.0 Hz),

7.20-7.30 (5H, m), 7.61 (1H, s), 8.38 (1H, t, J = 5.6 Hz),

8.89 (1H, doublet, J = 8.3 Hz).

Mass (FAB (+)) m / e: 414 (M−H) ⁺ .

Example 52:

N- {L-3-trans- [2- (6-aminopyridin-2-yl) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 69):

In a similar manner to Example 49, the compound obtained in Preparation 2 (1.19 g, 3.89 mmol) and 6-amino-2- (2-aminoethyl) pyridine (535 prepared by the method disclosed in International Application WO97-09982) Mg, 3.89 mmol) was used to give 680 mg of the title compound in the foam.

¹ H-NMR (CDCl ₃ ) δ:

2.69 (3H, s), 2.72-2.78 (2H, m), 2.88 (3H, s), 2.98 (1H, m),

3.36 (1H, d, J = 2.0 Hz), 3.43 (1H, d, J = 2.0 Hz),

3.45-3.55 (1H, m), 3.56-3.66 (1H, m), 4.54 (2H, s),

5.12 (1H, ddd, J = 6.2, 8.4, 8.6 Hz), 6.35 (1H, d, J = 8.4 Hz),

6.47 (1H, doublet, J = 8.4 Hz), 7.15 (1H, br.s), 7.25-7.35 (5H, m),

7.49 (1 H, broad singlet).

Mass (FAB (+)) m / e: 426 (M−H) ⁺ .

Example 53:

N- {L-3-trans- [2- (4-aminophenyl) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 73):

2- (4-aminophenyl) ethylamine (454 mg, 3.3 mmol) was dissolved in ethyl acetate (20 mL) and ethyl acetate (5 mL) of compound (1.37 g, 3.3 mmol) obtained in Preparation Example 21 under ice-cooling. The solution was added dropwise. After completion of the reaction, the solvent was distilled off and the residue was purified by column chromatography on silica gel (chloroform: methanol = 30: 1) to give 650 mg of the title compound as a foam.

¹ H-NMR (DMSO-d ₆ ) δ:

2.45-2.55 (2H, m), 2.79 (3H, s),

2.81 (1H, doublet of doublets, J = 8.5, 13.4 Hz), 2.87 (3H, s),

2.94 (1H, doublet of doublets, J = 6.1, 13.4 Hz), 3.05-3.25 (2H, m),

3.39 (1H, d, J = 1.7 Hz), 3.55 (1H, d, J = 1.7 Hz), 4.86 (2H, brs),

4.89 (1H, double doublet of doublets, J = 6.1, 8.1, 8.5 Hz), 6.49 (2H, doublet, J = 8.3 Hz),

6.84 (2H, doublet, J = 8.3 Hz), 7.20-7.30 (5H, m),

8.35 (1H, doublet, J = 5.6 Hz), 8.86 (1H, doublet, J = 8.l Hz).

Mass (FAB (+)) m / e: 425 (M−H) ⁺ .

Example 54:

N- {L-3-trans- [2- (imidazol-1-yl) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 75):

In a similar manner to Example 53, the compound obtained in Preparation 21 (1.39 g, 3.23 mmol) and 1- (2-aminoethyl)-prepared according to the method described in J. Heterocyclic Chem., 14 , 1279 (1977). Imidazole (300 mg, 2.69 mmol) was used to obtain 1.02 g of the title compound in the foam.

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.82 (1H, doublet of doublets, J = 8.8, 13.4 Hz), 2.87 (3H, s),

2.95 (1H, doublet of doublets, J = 6.1, 13.4 Hz), 3.26-3.41 (2H, broad s),

3.40 (1H, s), 3.54 (1H, s), 4.04 (2H, t, J = 6.l Hz),

4.92 (1H, double doublet of doublets, J = 6.1, 8.3, 8.8 Hz), 6.88 (1H, s), 7.14 (1H, s),

7.17-7.33 (5H, m), 7.57 (1H, s), 8.44 (1H, t, J = 6.4 Hz),

8.88 (1H, doublet, J = 8.3 Hz).

Mass (FAB (+)) m / e: 400 (MH) ⁺ .

Example 55:

N- {L-3-trans- [3- (4-aminoimidazol-1-yl) propylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 76):

In a similar manner to Example 49, 180 mg of the title compound on the foam was obtained using the compound obtained in Preparation Example 2 (1.0 g, 3.28 mmol) and the compound obtained in Preparation Example 24 (460 mg, 3.28 mmol).

¹ H-NMR (DMSO-d ₆ ) δ:

1.85-2.0 (2H, m), 2.79 (3H, s), 2.83 (1H, dd, J = 8.1, 13.l Hz),

2.88 (3H, s), 2.96 (1H, dd, J = 6.2, 13.4 Hz),

3.02-3.09 (2H, m), 3.91-3.99 (2H, m), 3.43 (1H, d, J = 2.0 Hz),

3.58 (1H, d, J = 2.0 Hz), 4.95 (1H, ddd, J = 6.2, 8.1, 8.3 Hz),

5.60 (2H, s), 6.99 (1H, s), 7.21-7.31 (5H, m), 7.82 (1H, s),

8.90 (1H, doublet, J = 8.2 Hz).

Mass (FAB (+)) m / e: 429 (M−H) ⁺ .

Example 56:

N- {L-3-trans- [2- (5-aminopyridin-2-yl) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 77):

The compound (446 mg, 1.45 mmol) obtained in Preparation Example 2 was dissolved in acetonitrile (50 mL) and 4-nitrophenol (202 mg, 1.45 mmol), and 1-ethyl-3- (dimethylaminopropyl) carbodiimide Hydrochloride (307 mg, 1.60 mmol) was added. Compound (200 mg, 1.45 mmol) obtained in Preparation Example 25 was added thereto, stirred at room temperature for 4 hours, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. did. The solvent was distilled off and the residue was purified by column chromatography on silica gel (chloroform: methanol = 10: 1) to give 480 mg of the title compound as a foam.

¹ H-NMR (DMSO-d ₆ ) δ:

2.67 (2H, t, J = 7.9 Hz), 2.79 (3H, s),

2.85 (1H, doublet of doublets, J = 8.4, 13.3 Hz), 2.87 (3H, s),

2.95 (1H, doublet of doublets, J = 6.2, 13.3 Hz), 3.39 (1H, doubled, J = 1.9 Hz),

3.55 (1H, d, J = 1.9 Hz), 4.91 (1H, ddd, J = 6.2, 8.4, 8.6 Hz),

5.20 (2H, s), 6.83-6.89 (2H, m), 7.20-7.30 (5H, m),

7.80 (1 H, s), 8.34 (1 H, br. S), 8.85 (1 H, d, J = 8.l Hz).

Mass (FAB (+)) m / e: 426 (M−H) ⁺ .

Example 57:

N- {L-3-trans-[(1H-benzimidazol-2-yl) methylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 78):

In a similar manner to Example 1, 1.2 g of the title compound in the foam was obtained using the compound (1.0 g, 3.3 mmol) and 2-aminomethylbenzimidazole dihydrochloride (720 mg, 3.3 mmol) obtained in Preparation Example 2. .

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.83 (1H, dd, J = 8.6, 13.3 Hz), 2.89 (3H, s),

2.95 (1H, doublet of doublets, J = 6.4, 13.3 Hz), 3.55 (1H, doubled, J = 1.2 Hz),

3.66 (1H, d, J = 1.2 Hz), 4.53 (2H, d, J = 5.8 Hz),

4.93 (1H, double doublet of doublets, J = 6.4, 8.3, 8.6 Hz), 7.10-7.65 (9H, m),

8.91 (1H, d, J = 8.3 Hz) 9.06 (1H, t, J = 5.8 Hz), 12.31 (1H, s).

Mass (FAB (+)) m / e: 436 (M−H) ⁺ .

Example 58:

N- {L-3-trans-{[4- (pyrimidin-2-yl) piperazin-1-yl] carbonyl} oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 79) :

In a similar manner to Example 1, 900 mg of the title compound using the compound (1.0 g, 3.3 mmol) and 1- (2-pyrimidinyl) piperazine dihydrochloride (773 mg, 3.3 mmol) obtained in Preparation Example 2 Got.

Melting Point: 167-168.5 ℃

¹ H-NMR (DMSO-d ₆ ) δ:

2.80 (3H, s), 2.84 (1H, dd, J = 8.3, 13.4 Hz), 2.89 (3H, s),

2.96 (1H, doublet of doublets, J = 6.3, 13.4 Hz), 3.49-3.62 (4H, m),

3.61 (1H, doublet, J = 2.0 Hz), 3.68-3.87 (4H, m),

3.89 (1H, d, J = 2.0 Hz), 4.97 (1H, ddd, J = 6.3, 8.3, 8.3 Hz),

6.68 (1H, doublet of doublets, J = 4.6, 4.6 Hz), 7.18-7.34 (5H, m),

8.40 (2H, doublet, J = 4.6 Hz), 8.71 (1H, doublet, J = 8.3 Hz).

Mass (FAB (+)) m / e: 453 (M−H) ⁺ .

Example 59:

N- {L-3-trans- (2- [6- (2,5-dimethylpyrrole-1-yl) pyridin-2-yl] ethylcarbamoyl} oxirane-2-carbonyl} -L-phenylalanine Dimethylamide (Compound No. 82):

In a similar manner to Example 49, the compound obtained in Preparation 2 (868 mg, 2.24 mmol) and 6- (2,5-dimethyl-pyrrole-1- prepared according to the method disclosed in International Application WO97-09982. Il) -2- (2-aminoethyl) pyridine (460 mg, 2.14 mmol) was used to give 520 mg of the title compound in the foam.

¹ H-NMR (DMSO-d ₆ ) δ:

2.13 (6H, s), 2.67 (3H, s), 2.88 (3H, s),

2.94 (1H, doublet of doublets, J = 8.2, 13.2 Hz), 3.03 (1H, doublet of doublets, J = 6.2, 13.2 Hz),

3.23 (1H, d, J = l.0 Hz), 3.26 (1H, d, J = l.0 Hz), 3.70 (2H, m),

5.09 (1H, double doublet of doublets, J = 6.2, 8.2, 8.3 Hz), 5.91 (2H, s),

6.82 (1H, doublet, J = 8.0 Hz), 7.08-7.16 (3H, m), 7.24-7.30 (5H, m),

7.76 (1H, t, J = 7.0 Hz).

Mass (FAB (+)) m / e: 504 (M−H) ⁺ .

Example 60:

N- {L-3-trans- [2- (4-aminosulfonylphenyl) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 83):

In a similar manner to Example 49, 564 mg of the title compound on the foam was obtained using the compound (919 mg, 3.0 mmol) and 4- (2-aminoethyl) benzenesulfonamide (571 mg, 2.85 mmol) obtained in Preparation Example 2. Got it.

¹ H-NMR (DMSO-d ₆ ) δ:

2.78 (3H, s), 2.87 (3H, s), 2.76-2.84 (3H, m),

2.90-2.97 (3H, m), 3.39 (1H, d, J = 2.0 Hz),

3.55 (1H, d, J = 2.0 Hz), 4.91 (1H, ddd, J = 6.1, 8.1, 8.2 Hz),

7.17-7.36 (5H, m), 7.39 (2H, d, J = 8.0 Hz),

7.75 (2H, doublet, J = 8.0 Hz), 8.44 (1H, t, J = 4.0 Hz),

8.87 (1H, doublet, J = 8.1 Hz).

Mass (FAB (+)) m / e: 489 (M−H) ⁺ .

Example 61:

N- {L-3-trans- [2- (5-aminopyridin-2-yl) aminoethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 84):

In a similar manner to Example 35, the compound (300 mg, 0.64 mmol) obtained in Example 37 was catalytically hydrogenated to obtain 130 mg of the title compound in the foam.

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.82 (1H, dd, J = 8.3, 13.2 Hz), 2.88 (3H, s),

2.95 (1H, doublet of doublets, J = 6.1, 13.2 Hz), 3.16-3.26 (4H, m),

3.41 (1H, d, J = l.0 Hz), 3.59 (1H, d, J = l.0 Hz),

4.33 (2H, broad singlet), 4.91 (1H, double doublet of doublets, J = 6.1, 8.2, 8.3 Hz),

5.73 (1H, broad singlet), 6.30 (1H, doublet, J = 8.6 Hz),

6.83 (1H, doublet of doublets, J = 2.4, 8.6 Hz), 7.16-7.33 (5H, m),

7.46 (1H, doublet, J = 2.4 Hz), 8.54 (1H, t, J = 5.1 Hz),

8.87 (1H, doublet, J = 8.2 Hz).

Mass (FAB (+)) m / e: 441 (M−H) ⁺ .

Example 62:

N- {L-3-trans- [3-morpholinopropylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 85):

In a similar manner to Example 49, 1.5 g of the title compound on the foam was obtained using the compound (2.14 g, 7.0 mmol) and 4- (3-aminopropyl) morpholine (959 mg, 6.65 mmol) obtained in Preparation Example 2. .

¹ H-NMR (CDCl ₃ ) δ:

1.65 (4H, br.s), 2.67 (3H, s), 2.89 (3H, s),

2.43-2.49 (2H, m), 2.97 (2H, br.s), 3.35 (1H, d, J = 2.0 Hz),

3.38 (1H, doublet, J = 2.0 Hz), 3.26-3.45 (3H, m), 3.67-3.78 (5H, m),

5.10-5.12 (1H, m), 6.91 (1H, d, J = 8.0 Hz), 7.13-7.30 (5H, m),

7.73 (1 H, broad singlet).

Mass (FAB (+)) m / e: 433 (M−H) ⁺ .

Example 63:

N- {L-3-trans- [2- (4-acetoamidinophenyl) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide hydrobromide (Compound No. 86):

In a similar manner to Example 49, the compound obtained in Preparation Example 2 (1.78 g, 5.81 mmol) and N- [4- (2-aminoethyl) phenyl prepared according to the method disclosed in International Application WO 97-19440. ] Acetamidine hydrobromide (1.5 g, 5.81 mmol) gave 1.8 g of the title compound in the foam.

¹ H-NMR (DMSO-d6) δ:

2.51 (3H, s), 2.78 (3H, s), 2.87 (3H, s), 2.75-2.80 (1H, m),

2.90-2.94 (2H, m), 2.94-2.98 (1H, m), 3.04-3.07 (2H, m),

3.40 (1H, d, J = 2.0 Hz), 3.56 (1H, d, J = 2.0 Hz),

4.91-4.93 (1 H, m), 6.92-6.97 (1 H, m), 7.14-7.38 (9 H, m),

8.85 (1H, doublet, J = 8.l Hz).

Mass (FAB (+)) m / e: 466 (M−H) ⁺ .

Example 64:

N- {L-3-trans- [2- (2-methyl-5-nitroimidazol-1-yl) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 87 ):

In a similar manner as in Example 53, 450 mg of the title compound in the foam was obtained using the compound obtained in Preparation Example 21 (1.13 g, 2.65 mmol) and the compound obtained in Preparation Example 28 (450 mg, 2.65 mmol).

¹ H-NMR (DMSO-d ₆ ) δ:

2.39 (3H, s), 2.79 (3H, s), 2.81 (1H, dd, J = 8.3, 13.4 Hz),

2.87 (3H, s), 2.94 (1H, dd, J = 6.1, 13.4 Hz), 3.35 (1H, s),

3.41-3.53 (2H, m), 3.48 (1H, s), 4.33 (1H, t, J = 5.8 Hz),

4.91 (1H, double doublet of doublets, J = 6.1, 8.3, 8.3 Hz), 7.19-7.30 (5H, m),

8.04 (1H, s), 8.51 (1H, t, J = 6.1 Hz), 8.85 (1H, d, J = 8.3 Hz).

Mass (FAB (+)) m / e: 459 (M−H) ⁺ .

Example 65:

N- {L-3-trans- [2- (pyrazin-2-yl) ethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 88):

In a similar manner to Example 53, the compound obtained in Preparation 21 (1.41 g, 3.3 mmol) and J. Org. 1.0 g of the title compound in the foam was obtained using 2- (2-aminoethyl) pyrazine (400 mg, 3.25 mmol) prepared according to the method described in Chem., 30 , 4379 (1965).

¹ H-NMR (DMSO-d ₆ ) δ:

2.78 (3H, s), 2.81 (1H, dd, J = 8.5, 13.6 Hz), 2.87 (3H, s),

2.89-2.98 (1H, m), 2.93 (2H, t, J = 7.l Hz),

3.38 (1H, doublet, J = 1.8 Hz), 3.45-3.52 (2H, m),

3.54 (1H, d, J = 1.8 Hz), 4.90 (1H, m), 7.17-7.31 (5H, m),

8.43 (1H, t, J = 5.6 Hz), 8.47-8.62 (3H, m),

8.87 (1H, doublet, J = 8.0 Hz).

Mass (FAB (+)) m / e: 412 (M−H) ⁺ .

Example 66:

N- {L-3-trans-[[4- (4-aminopyrimidin-2-yl) piperazin-1-yl] carbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide ( Compound number 90):

In a similar manner to Example 56, the compound (171 mg, 0.55 mmol) obtained in Preparation Example 2 and 2- (l-piperazinyl)-prepared according to the method disclosed in Japanese Patent Application No. 81375/1987. 4-aminopyrimidine (100 mg, 0.55 mmol) was used to give 216 mg of the title compound in the foam.

¹ H-NMR (DMSO-d ₆ ) δ:

2.80 (3H, s), 2.88 (3H, ms), 2.85 (1H, dd, J = 8.2, 13.3 Hz),

2.96 (1H, doublet of doublets, J = 6.2, 13.3 Hz), 3.45-3.58 (4H, m),

3.60 (1H, d, J = 2.0 Hz), 3.62-3.68 (2H, m), 3.69-3.75 (2H, m),

3.87 (1H, doublet, J = 2.0 Hz), 4.96 (1H, ddd, J = 6.2, 8.2, 8.2 Hz),

5.76 (1H, doublet, J = 5.6 Hz), 6.48 (2H, s), 7.22-7.31 (5H, m),

7.76 (1H, doublet, J = 5.6 Hz), 8.71 (1H, doublet, J = 8.3 Hz).

Mass (FAB (+)) m / e: 468 (M−H) ⁺ .

Example 67:

N- {L-3-trans- [2- (4-aminopyrimidin-2-yl) aminoethylcarbamoyl] oxirane-2-carbonyl} -L-phenylalanine dimethylamide (Compound No. 93):

In a similar manner to Example 53, 1.0 g of the title compound was obtained using the compound obtained in Preparation Example 21 (1.28 g, 3.0 mmol) and the compound obtained in Preparation Example 29 (410 mg, 2.67 mmol).

Melting point: 190 ° C. (decomposition).

¹ H-NMR (DMSO-d ₆ ) δ:

2.79 (3H, s), 2.81 (1H, dd, J = 8.6, 13.4 Hz), 2.88 (3H, s),

2.94 (1H, doublet of doublets, J = 6.1, 13.4 Hz), 3.17-3.48 (4H, m),

3.39 (1H, s), 3.58 (1H, s), 4.91 (1H, ddd, J = 6.1, 8.6, 8.7 Hz),

5.70 (1H, d, J = 5.6 Hz), 6.29 (2H, br.s), 6.35 (1H, br.s),

7.18-7.33 (5H, m), 7.66 (1H, d, J = 5.6 Hz),

8.44 (1H, t, J = 5.4 Hz), 8.86 (1H, d, J = 8.7 Hz).

Mass (FAB (+)) m / e: 442 (M−H) ⁺ .

Test Example 1:

Determination of Inhibitory Activity on Cathepsin L and Cathepsin B

Cathepsin L was extracted from rat liver and completely purified according to the method described in J. Biochem., 84 , 650-671 (1978), and Z-Phe-Arg-MCA was used as its substrate. did.

Cathepsin B was extracted from rat liver and biochem. Biophys. Res. Completely purified according to the method disclosed in Commun., 83 , 513-520 (1978), and Z-Arg-Arg-MCA was used as its substrate.

Each cathepsin was diluted with a diluent (0.1% Brij 35) and the concentration was adjusted to 0.3 U (0.1 U: concentration at which 1.0 nmol of MCA was released per minute at 37 ° C). To 500 µl of this solution, 250 µl of the active solution / buffer (340 mM sodium acetate, 60 mM acetic acid, 4 mM EDTA 2 sodium; pH 5.5) was added and placed in an incubator at 30 ° C. for 1 minute, followed by a sample solution of a predetermined concentration and 20 ml of substrate solution was added and reacted for 10 minutes. After stopping the reaction with 1 ml of reaction stopper (100 mM sodium monochloride, 30 ml of sodium acetate, 70 ml of acetic acid; pH 4.3), the fluorescence of the released aminomethylcoumarin was 370 nm using a fluorometer. It measured by the fluorescence of 460 nm wavelength obtained by excitation at a wavelength. As a result, as shown in Table 9, it can be seen that each of the compounds of the present invention shows a stronger inhibitory activity against cathepsin L than cathepsin B.

TABLE 9

Epoxysuccinamide derivatives or salts thereof according to the present invention have inhibitory activity against cysteine proteases such as cathepsin L, B, and H, and in particular, have specific inhibitory activity against cathepsin L, and thus, muscle dystrophy, muscle Atrophy, myocardial infarction, stroke, Alzheimer's disease, conscious or sports disorders during head trauma, multiple sclerosis, neurofuge of peripheral nerves, cataracts, inflammation, allergies, extreme hepatitis, osteoporosis, hypercalcemia, breast cancer, prostate cancer and prostatic hyperplasia It is used as a prophylactic and therapeutic agent of or as an antiproliferative agent of cancer, and an agent for preventing metastasis and platelet coagulation. In particular, it is useful as a preventive and therapeutic agent for bone diseases, especially osteoporosis.

Claims (4)

General formula (Ⅰ) [Wherein, R ¹ represents a hydrogen atom, a C _1-6 alkyl group, an amino-C _1-6 -alkyl group or a C _2-7 alkyloxycarbonylamino-C _1-6 -alkyl group, R ² represents a group selected from the following (1) to (5), or (1) alkyloxycarbonyl groups having 2 to 7 carbon atoms, aralkyloxycarbonyl groups having 8 to 14 carbon atoms, C _6-10 arylsulfonyl groups, or pyridyl or pyrimidyl (which may be substituted with amino or nitro groups); C _1-6 aminoalkyl group which may be substituted by group; (2) C _1-6 alkyl group, acetylamino-C _1-6 alkyl group, benzoylamino having a carboxyl group, an aralkyloxycarbonyl group having 8 to 14 carbon atoms, an alkyloxycarbonylamino group having 2 to 7 carbon atoms as a substituent -C _1-6 alkyl group, a C _1-6 aminoalkyl group, aminosulfonyl group, an aryloxy group having the carbon number of 6~10, C _2-6 alkenyl groups and may be substituted by a group selected from the group consisting of C _1-6 alkyl good C _6-10 aryl group; (3) a C _7-12 aralkyl group which may be substituted by a group selected from acetoamidino group, C _1-6 alkylsulfonyl group, aminosulfonyl group, carbamoyl group and amino group; (4) a heterocyclic group selected from piperidinyl, pyridyl, quinolyl and isoxazolyl which may be substituted with a phenyl-C _1-6 -alkyl group or a C _1-6 -alkyl group; And (5) selected from a piperidinyl group and a morpholino group which may be substituted with 1 to 3 groups selected from alkoxycarbonylamino group having 2 to 7 carbon atoms, amino group, dialkylpyrrolyl group, C _1-6 alkyl group and nitro group; A C _1-6 alkyl group substituted with a heterocyclic group selected from a nitrogen-saturated heterocyclic group or a pyrrolyl group, a pyrimidinyl group, a thiazolyl group, an imidazolyl group, a pyridyl group, a pyrazinyl group and a benzimidazolyl group; or R ¹ and R ² together with adjacent nitrogen atoms are phenyl group, phenyl-C _1-6 -alkyl group, alkyloxycarbonyl group having 2 to 7 carbon atoms, methylenedioxyphenyl-C _1-6 -alkyl group, pyrimidinyl group and amino You may form the piperazine ring or the morpholine ring which may be substituted by the group chosen from the pyrimidinyl group. R ³ and R ^4, the same as or different from each other, represent a hydrogen atom, a C _1-6 alkyl group, or a C _7-12 aralkyl group]. General formula (V) Wherein R ³ and R ⁴ are the same as or different from each other and represent a hydrogen atom, a C _1-6 alkyl group or a C _7-12 aralkyl group] An amine derivative of the following general formula (VI) as a compound represented by [Wherein, R ¹ represents a hydrogen atom, a C _1-6 alkyl group, an amino-C _1-6 -alkyl group or a C _2-7 alkyloxycarbonylamino-C _1-6 -alkyl group, R ⁵ represents a group selected from the following (1) to (5), or (1) alkyloxycarbonyl groups having 2 to 7 carbon atoms, aralkyloxycarbonyl groups having 8 to 14 carbon atoms, C _6-10 arylsulfonyl groups, or pyridyl or pyrimidyl (which may be substituted with amino or nitro groups); C _1-6 aminoalkyl group which may be substituted by group; (2) C _1-6 alkyl group, acetylamino-C _1-6 alkyl group, benzoylamino having a carboxyl group, an aralkyloxycarbonyl group having 8 to 14 carbon atoms, an alkyloxycarbonylamino group having 2 to 7 carbon atoms as a substituent -C _1-6 alkyl group, a C _1-6 aminoalkyl group, aminosulfonyl group, an aryloxy group having the carbon number of 6~10, C _2-6 alkenyl groups and may be substituted by a group selected from the group consisting of C _1-6 alkyl good C _6-10 aryl group; (3) a C _7-12 aralkyl group which may be substituted by a group selected from acetoamidino group, C _1-6 alkylsulfonyl group, aminosulfonyl group, carbamoyl group and amino group; (4) a heterocyclic group selected from piperidinyl, pyridyl, quinolyl and isoxazolyl which may be substituted with a phenyl-C _1-6 -alkyl group or a C _1-6 -alkyl group; And (5) selected from a piperidinyl group and a morpholino group which may be substituted with 1 to 3 groups selected from alkoxycarbonylamino group having 2 to 7 carbon atoms, amino group, dialkylpyrrolyl group, C _1-6 alkyl group and nitro group; A C _1-6 alkyl group substituted with a heterocyclic group selected from a nitrogen-saturated heterocyclic group or a pyrrolyl group, a pyrimidinyl group, a thiazolyl group, an imidazolyl group, a pyridyl group, a pyrazinyl group and a benzimidazolyl group; or R ¹ and R ² together with adjacent nitrogen atoms are phenyl group, phenyl-C _1-6 -alkyl group, alkyloxycarbonyl group having 2 to 7 carbon atoms, methylenedioxyphenyl-C _1-6 -alkyl group, pyrimidinyl group and amino A piperazine ring or a morpholine ring which may be substituted with a group selected from pyrimidinyl groups may be formed.] Formula (I) characterized by reacting with [Wherein, R ¹ is as defined above, R ² represents a group selected from the following (1) to (5), or (1) alkyloxycarbonyl groups having 2 to 7 carbon atoms, aralkyloxycarbonyl groups having 8 to 14 carbon atoms, C _6-10 arylsulfonyl groups, or pyridyl or pyrimidyl (which may be substituted with amino or nitro groups); C _1-6 aminoalkyl group which may be substituted by group; (2) C _1-6 alkyl group, acetylamino-C _1-6 alkyl group, benzoylamino having a carboxyl group, an aralkyloxycarbonyl group having 8 to 14 carbon atoms, an alkyloxycarbonylamino group having 2 to 7 carbon atoms as a substituent -C _1-6 alkyl group, a C _1-6 aminoalkyl group, aminosulfonyl group, an aryloxy group having the carbon number of 6~10, C _2-6 alkenyl groups and may be substituted by a group selected from the group consisting of C _1-6 alkyl good C _6-10 aryl group; (3) a C _7-12 aralkyl group which may be substituted by a group selected from acetoamidino group, C _1-6 alkylsulfonyl group, aminosulfonyl group, carbamoyl group and amino group; (4) a heterocyclic group selected from piperidinyl, pyridyl, quinolyl and isoxazolyl which may be substituted with a phenyl-C _1-6 -alkyl group or a C _1-6 -alkyl group; And (5) selected from a piperidinyl group and a morpholino group which may be substituted with 1 to 3 groups selected from alkoxycarbonylamino group having 2 to 7 carbon atoms, amino group, dialkylpyrrolyl group, C _1-6 alkyl group and nitro group; A C _1-6 alkyl group substituted with a heterocyclic group selected from a nitrogen-saturated heterocyclic group or a pyrrolyl group, a pyrimidinyl group, a thiazolyl group, an imidazolyl group, a pyridyl group, a pyrazinyl group and a benzimidazolyl group; or R ¹ and R ² together with adjacent nitrogen atoms are phenyl group, phenyl-C _1-6 -alkyl group, alkyloxycarbonyl group having 2 to 7 carbon atoms, methylenedioxyphenyl-C _1-6 -alkyl group, pyrimidinyl group and amino A piperazine ring or a morpholine ring which may be substituted with a group selected from pyrimidinyl groups may be formed. R ³ and R ^4, the same as or different from each other, represent a hydrogen atom, a C _1-6 alkyl group or a C _7-12 aralkyl group] Method for producing an epoxy succinamide represented by. Osteoporosis, hypercalcemia, Paget's disease, hyperparathyroidism, bone metastasis of cancer, muscle dystrophy, muscular atrophy, myocardial infarction, Alzheimer's disease containing the compound of claim 1 or a salt thereof and a pharmacologically acceptable carrier as an active ingredient A pharmaceutical composition for treating or preventing a disease selected from the group consisting of multiple sclerosis, neuronal purge of peripheral nerve, cataract, inflammation, allergy, breast cancer, prostate cancer, prostatic hyperplasia, cancer proliferation, metastasis of cancer or platelet aggregation. General formula (V) Wherein R ³ and R ⁴ are the same as or different from each other and represent a hydrogen atom, a C _1-6 alkyl group or a C _7-12 aralkyl group] An amine derivative of the following general formula (VI) as a compound represented by [Wherein, R ¹ represents a hydrogen atom, a C _1-6 alkyl group, an amino-C _1-6 -alkyl group or a C _2-7 alkyloxycarbonylamino-C _1-6 -alkyl group, R ⁵ represents a group selected from the following (1) to (5), or (1) alkyloxycarbonyl groups having 2 to 7 carbon atoms, aralkyloxycarbonyl groups having 8 to 14 carbon atoms, C _6-10 arylsulfonyl groups, or pyridyl or pyrimidyl (which may be substituted with amino or nitro groups); C _1-6 aminoalkyl group which may be substituted by group; (2) C _1-6 alkyl group, acetylamino-C _1-6 alkyl group, benzoylamino having a carboxyl group, an aralkyloxycarbonyl group having 8 to 14 carbon atoms, an alkyloxycarbonylamino group having 2 to 7 carbon atoms as a substituent -C _1-6 alkyl group, a C _1-6 aminoalkyl group, aminosulfonyl group, an aryloxy group having the carbon number of 6~10, C _2-6 alkenyl groups and may be substituted by a group selected from the group consisting of C _1-6 alkyl good C _6-10 aryl group; (3) a C _7-12 aralkyl group which may be substituted by a group selected from acetoamidino group, C _1-6 alkylsulfonyl group, aminosulfonyl group, carbamoyl group and amino group; (4) a heterocyclic group selected from piperidinyl, pyridyl, quinolyl and isoxazolyl which may be substituted with a phenyl-C _1-6 -alkyl group or a C _1-6 -alkyl group; And (5) selected from a piperidinyl group and a morpholino group which may be substituted with 1 to 3 groups selected from alkoxycarbonylamino group having 2 to 7 carbon atoms, amino group, dialkylpyrrolyl group, C _1-6 alkyl group and nitro group; A C _1-6 alkyl group substituted with a heterocyclic group selected from a nitrogen-saturated heterocyclic group or a pyrrolyl group, a pyrimidinyl group, a thiazolyl group, an imidazolyl group, a pyridyl group, a pyrazinyl group and a benzimidazolyl group; or R ¹ and R ² together with adjacent nitrogen atoms are phenyl group, phenyl-C _1-6 -alkyl group, alkyloxycarbonyl group having 2 to 7 carbon atoms, methylenedioxyphenyl-C _1-6 -alkyl group, pyrimidinyl group and amino You may form the piperazine ring or the morpholine ring which may be substituted by the group chosen from the pyrimidinyl group. When the substituent of R ₅ is a substituent involved in the reaction, the substituent has a substituent selected from a C _2-5 alkyloxycarbonyl group and a benzyloxycarbonyl group.] And reacted with, to remove the protecting group of R ₅ [Wherein, R ¹ is as defined above, R ² represents a group selected from the following (1) to (5), or (1) alkyloxycarbonyl groups having 2 to 7 carbon atoms, aralkyloxycarbonyl groups having 8 to 14 carbon atoms, C _6-10 arylsulfonyl groups, or pyridyl or pyrimidyl (which may be substituted with amino or nitro groups); C _1-6 aminoalkyl group which may be substituted by group; (2) C _1-6 alkyl group, acetylamino-C _1-6 alkyl group, benzoylamino having a carboxyl group, an aralkyloxycarbonyl group having 8 to 14 carbon atoms, an alkyloxycarbonylamino group having 2 to 7 carbon atoms as a substituent -C _1-6 alkyl group, a C _1-6 aminoalkyl group, aminosulfonyl group, an aryloxy group having the carbon number of 6~10, C _2-6 alkenyl groups and may be substituted by a group selected from the group consisting of C _1-6 alkyl good C _6-10 aryl group; (3) a C _7-12 aralkyl group which may be substituted by a group selected from acetoamidino group, C _1-6 alkylsulfonyl group, aminosulfonyl group, carbamoyl group and amino group; (4) a heterocyclic group selected from piperidinyl, pyridyl, quinolyl and isoxazolyl which may be substituted with a phenyl-C _1-6 -alkyl group or a C _1-6 -alkyl group; And (5) selected from a piperidinyl group and a morpholino group which may be substituted with 1 to 3 groups selected from alkoxycarbonylamino group having 2 to 7 carbon atoms, amino group, dialkylpyrrolyl group, C _1-6 alkyl group and nitro group; A C _1-6 alkyl group substituted with a heterocyclic group selected from a nitrogen-saturated heterocyclic group or a pyrrolyl group, a pyrimidinyl group, a thiazolyl group, an imidazolyl group, a pyridyl group, a pyrazinyl group and a benzimidazolyl group; or R ¹ and R ² together with adjacent nitrogen atoms are phenyl group, phenyl-C _1-6 -alkyl group, alkyloxycarbonyl group having 2 to 7 carbon atoms, methylenedioxyphenyl-C _1-6 -alkyl group, pyrimidinyl group and amino A piperazine ring or a morpholine ring which may be substituted with a group selected from pyrimidinyl groups may be formed. R ³ and R ^4, the same as or different from each other, represent a hydrogen atom, a C _1-6 alkyl group or a C _7-12 aralkyl group] Method for producing an epoxy succinamide represented by.