JP2002145848A - Alkenylamino acid derivative and method for manufacturing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new proteasome-inhibiting substance, and thereby to provide an excellent immunosuppressant, antiinflammatory agent, antiallergic agent, treating agent for an autoimmune disease, antitumor agent and treating agent for a neurodegenerative disease. SOLUTION: A new alkenylamino derivative of general formula (1), and a pharmaceutically permissible salt and a hydrate of the derivative. A concrete example is a compound of general formula (2).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to alkenyl amino acid derivatives having proteasome inhibitory activity and useful as immunosuppressants, anti-inflammatory agents, antiallergic agents, therapeutic agents for autoimmune diseases, anticancer agents, and therapeutic agents for neurodegenerative diseases. It relates to the production method thereof.

[0002]

2. Description of the Related Art Proteasome is a huge soluble high molecular weight protein complex having a very complicated molecular structure, mainly present in the nucleus and cytoplasm of eukaryotic cells.
There are two molecular species, ATP-independent type and ATP-dependent type with a sedimentation coefficient of 26S. The 20S proteasome itself has chymotrypsin-like activity, trypsin-like activity and peptidylglutamyl peptide hydrolysis activity, and can degrade short-chain peptides. The 26S proteasome is formed by binding the regulatory subunit complex to the 20S proteasome, which has a catalytic function, and degrades ubiquitinated proteins into peptides and amino acids (Experimental Medicine, vol. 15, 2056, 1997, Science vol.26
8, 533, 1995, Nature 357, 375, 1992).
In addition, studies on the catalytic mechanism of the purified archaeal proteasome have revealed that the proteasome is a threonine protease (Science vol.268, p.579, 1995).
Year).

[0003] As the physiological function of the proteasome,
Inflammatory cytokines such as NF-α, IL-1, IL-2 and ICAM-
1. Plays an important role in the activation of the inflammatory transcription factor NF-κB, which is important for the expression of adhesion molecules such as VCAM-1 (Cell
vol.78, p.773, 1994, Cellvol.80, p.529, 1995
Year). It also functions as an endogenous antigen processing enzyme and plays an important role in the immune response. Furthermore, it is involved in cell cycle control, and is also involved in the degradation of tumor suppressor proteins and apoptosis of nerve cells (Nature vol. 349, p. 132, 1991, Cell vol. 75, 49).
5, 1993, FEBS vol. 304, 57, 1992, tissue culture
Volume 22, page 106, 1996, EMBO Journal vol.15, 3845
P. 1996).

[0004] As described above, it has become clear that the proteasome is deeply involved in various life phenomena such as cell proliferation and control of the immune system. Therefore, drugs that inhibit the proteasome having such various physiological actions are immunosuppressants effective for rejection in organ transplantation, or autoimmune diseases such as rheumatoid arthritis, nephritis, knee osteoarthritis, and systemic lupus erythematosus. It is considered to be effective as a therapeutic agent for chronic inflammatory diseases such as inflammatory bowel disease, allergic diseases such as asthma and dermatitis, a therapeutic agent for cancer and a neurodegenerative disease.

[0005] Proteasome inhibitors reported to date include lactacystin (J. Antibiotic vol.4).
0, page 113, 1991, protein nucleic acid enzyme 41, 327, 199
6 years, Cell Engineering 15, Vol. 929, 1996) and natural products such as TMC-95 (JP-A-11-29595) and peptide aldehydes (WO
95/24914, J. Med.Chem., Vol. 38, p. 2276, 1995, B
ioorganic & Med. Chem. Lett., vol. 6, p. 287, 1996.
Years, JP-A-10-36289, JP-A-11-292833), peptidic ketoamides and ketoaldehydes (Bioorganic & Med. Che.
m. Lett., vol. 9, p. 2603, 1999, Bioorganic & Me
d. Chem. Lett., vol. 8, p. 373, 1998), peptidic epoxy ketone (Tetrahedron Lett., vol. 39, 1343)
Page, 1996, JP-A-11-124397, Chemistry & Biology,
vol.6, 811, 1999, Bioorganic & Med. Chem. Let
t., vol. 9, p. 2283, 1999, Bioorganic & Med. Che
m. Lett., vol. 9, p. 3335, 1999), peptide boric acid (WO96 / 13266, Bioorganic & Med. Chem. Lett., vol.
8, p. 333, 1998).

Further, compounds having a structure similar to a part of the claims of the present invention have been reported to act as cysteine protease inhibitors, but have not been reported as proteasome inhibitors (Bioorganic & Med. Chem. .
Lett., Vol. 6, p. 2477, 1998, J. Med. Chem., Vol.
38, 3193, 1995). Further, as a peptide vinyl sulfone derivative, only a compound having the sequence of Leu-Leu-Leu has been reported as a proteasome inhibitor (Proc. Natl. Acad. Sci. USA, vol. 94, p. 6629, 1997).
Year).

[0007]

DISCLOSURE OF THE INVENTION The present invention provides a substance that inhibits the proteasome to provide excellent immunosuppressants, anti-inflammatory agents, anti-allergic agents, therapeutic agents for autoimmune diseases, anticancer agents, and neurodegenerative diseases. To provide an agent.

[0008]

Means for Solving the Problems The present inventors have conducted intensive studies on compounds having proteasome inhibitory activity, and as a result, have found that a novel alkenyl amino acid having a different structure from the conventionally known proteasome inhibitors. The present inventors have found that the derivative inhibits the proteasome and completed the present invention.

That is, the present invention provides a compound represented by the general formula (1) [Wherein A is a benzyloxycarbonyl group (Z group), t
-Butoxycarbonyl group (Boc group), R-CO-, R- (C
O) ₂ — or R—SO ₂ — (where R is an optionally substituted benzene ring, pyrazine ring, naphthalene ring, indole ring, optionally substituted quinoline ring, coumarin ring, benzofuran ring, Represents an optionally substituted benzyl group, an optionally substituted styryl group or an optionally substituted phenethyl group), R1 represents a hydrogen atom, or R1 and R2 combine to form a pyrrolidine ring R2, R3 and R4 may be the same or different and are each a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cyclohexylmethyl group, an optionally substituted benzyl group, a naphthylmethyl group, R5 represents a hydrogen atom, a fluorine atom, a lower alkoxycarbonyl group having 1 to 4 carbon atoms, and R6 represents a lower alkyl group having 1 to 4 carbon atoms. Alkoxycarbonyl group, carboxyl group, lower alkoxyphosphoryl group having 1 to 4 carbon atoms, cyano group, lower alkylsulfonyl group having 1 to 4 carbon atoms, phenylsulfonyl group, lower alkoxysulfonyl group having 1 to 4 carbon atoms, phenethylaminocarbonyl Group, lower alkylaminocarbonyl group having 1 to 4 carbon atoms, N, O-dimethylhydroxylaminocarbonyl group,
Acetyl group, benzoyl group, 2-thiazolecarbonyl group, 2-benzothiazolecarbonyl group, carbon number 1-4
A lower alkylaminosulfonyl group, an N, O-dimethylhydroxylaminosulfonyl group or a phenethylaminosulfonyl group, and m represents 0 or 1.] and a pharmacologically acceptable amino acid derivative. And proteasome inhibitors comprising at least one of the following salts and hydrates as active ingredients.

The pharmacologically acceptable salts of the compound represented by the general formula (1) in the present invention include hydrochloride, hydrobromide, methanesulfonate, citrate, and tartrate. Suitable acid addition salts and alkali salts include metal salts such as sodium, potassium and magnesium.

In the general formula (1) of the present invention, a lower alkyl group, a lower alkoxycarbonyl group, a lower alkoxyphosphoryl group, a lower alkylsulfonyl group, a lower alkoxysulfonyl group, a lower alkylaminocarbonyl group, a lower alkylaminosulfonyl group The term "lower alkyl group" as used herein means, for example, a linear or branched hydrocarbon group having 1 to 4 carbon atoms such as methyl, ethyl and isopropyl, and "an optionally substituted lower alkyl group having 1 to 4 carbon atoms". "Means, at any position of a lower alkyl group, a methylthio group, a methylsulfinyl group, a methylsulfonyl group,
A lower alkoxy group having 1 to 4 carbon atoms, a hydroxy group, a carboxyl group, a lower alkoxycarbonyl group having 1 to 4 carbon atoms, an amino group, a carbamoyl group, a benzyloxycarbonylamino group, a t-butoxycarbonylamino group,
Those having a 4-dichlorobenzoylamino group are exemplified. `` An optionally substituted benzene ring, an optionally substituted quinoline ring, an optionally substituted benzyl group, an optionally substituted styryl group, an optionally substituted phenethyl group '' C1-C4 lower alkyl group, C1-C4 lower alkoxy group, benzyloxy group, phenoxy group, hydroxy group, halogen atom such as Cl, Br, I, F, phenyl group , A benzoyl group, a sulfonamide group, or a nitro group.

According to the present invention, the compound represented by the above general formula (1) can be produced by the following route.

In the compound represented by the general formula (1), R5
Is a hydrogen atom or a fluorine atom, and R6 is a lower alkoxycarbonyl group having 1 to 4 carbon atoms, a carboxyl group, and a 1 to 1 carbon atom.
4 lower alkoxyphosphoryl group, cyano group, 1 carbon atom
Lower alkylsulfonyl group, phenylsulfonyl group, lower alkoxysulfonyl group having 1 to 4 carbon atoms, phenethylaminocarbonyl group, lower alkylaminocarbonyl group having 1 to 4 carbon atoms, N, O-dimethylhydroxylaminocarbonyl group Certain compounds, ie, general formula (4) Wherein A is a Z group, a Boc group, R—CO—, R— (CO) ₂ — or R—SO ₂ — (where R is a benzene ring, a pyrazine ring, a naphthalene ring which may be substituted) Ring, indole ring, optionally substituted quinoline ring, coumarin ring, benzofuran ring, optionally substituted benzyl group, optionally substituted styryl group or optionally substituted phenethyl group), R1 represents a hydrogen atom, or R1
And R2 may combine to form a pyrrolidine ring;
R3 and R4 are the same or different and each represent a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cyclohexylmethyl group, an optionally substituted benzyl group, a naphthylmethyl group, an indolylmethyl group, A pyridylmethyl group, R7 is a hydrogen atom or a fluorine atom, and R8 is
4 to lower alkoxycarbonyl groups, carboxyl groups,
C1-C4 lower alkoxyphosphoryl group, cyano group, C1-C4 lower alkylsulfonyl group, phenylsulfonyl group, C1-C4 lower alkoxysulfonyl group, phenethylaminocarbonyl group, C1-C4
Represents a lower alkylaminocarbonyl group or an N, O-dimethylhydroxylaminocarbonyl group, wherein m is 0 or 1
The compound represented by the general formula (2) Wherein A, R1, R2, R3, R4 and m are as described above, and a compound represented by the general formula (3) [Wherein R7 and R8 are as described above].

The reaction is carried out using 1,4-dioxane, dimethylsulfoxide (DMSO), N, N-dimethylformamide (DMF), tetrahydrofuran (THF) or the like as a reaction solvent, an organic base such as triethylamine or pyridine, or hydrogenation. The reaction can be carried out in the presence of an inorganic base such as sodium, potassium hydride, sodium alkoxide, potassium alkoxide, and the like, at a reaction temperature of 0 ° C to room temperature.

Further, among the compounds represented by the general formula (1), compounds wherein R5 and R6 are lower alkoxycarbonyl groups having 1 to 4 carbon atoms, that is, a compound represented by the general formula (6) [Wherein, R9 represents a lower alkoxycarbonyl group having 1 to 4 carbon atoms, Ra represents a lower alkyl group having 1 to 4 carbon atoms, and A, R1, R2, R3, R4 and m are as described above]
The compound represented by the general formula (2) Wherein A, R1, R2, R3, R4 and m are as described above, and a compound represented by the general formula (5): [Wherein, R 9 and Ra are as described above].

The reaction is carried out in the presence of titanium tetrachloride and an organic base such as pyridine, triethylamine, diisopropylethylamine, piperidine and the like, using a solvent such as carbon tetrachloride, methylene chloride and THF at -78 ° C. to room temperature. it can.

Further, among the compounds represented by the above general formula (1), compounds wherein R5 is a hydrogen atom or a fluorine atom and R6 is a carboxyl group, that is, a compound represented by the general formula (8) [Wherein, R10 represents a hydrogen atom or a fluorine atom,
A, R1, R2, R3, R4 and m are as described above], and the compound represented by the general formula (7) [Wherein A, R1, R2, R3, R4, R10, R and m are as described above], and can be produced by alkali hydrolysis.

The reaction is carried out in the presence of an aqueous alkali solution such as sodium hydroxide, potassium hydroxide or lithium hydroxide in the presence of methanol, ethanol, 1,4-dioxane, DMF,
The reaction can be performed at 0 ° C. to room temperature using a solvent such as THF and DMSO.

Further, among the compounds represented by the general formula (1),
A compound in which R5 is a hydrogen atom or a fluorine atom, and R6 is a phenethylaminocarbonyl group, a lower alkylaminocarbonyl group having 1 to 4 carbon atoms or an N, O-dimethylhydroxyaminocarbonyl group, that is, a compound represented by the general formula (10): [Wherein, R11 represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms or a phenethyl group, R12 represents a lower alkyl group having 1 to 4 carbon atoms, a phenethyl group or a methoxy group,
A, R1, R2, R3, R4, R10 and m are as described above], and the compound represented by the general formula (8) Wherein A, R1, R2, R3, R4, R10 and m
Is as described above] and a compound represented by the general formula (9) [Wherein R11 and R12 are as described above].

The reaction can be produced by a mixed acid anhydride method or an active ester method used in a usual peptide bond formation reaction, and a method using a condensing agent is preferable. Dicyclohexylcarbodiimide (DCC),
In the presence of a condensing agent such as diisopropylcarbodiimide (DIPC), diphenylphosphoryl azide (DPPA), diethylphosphoryl cyanide (DEPC), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (WSC), and sometimes 4 -Dimethylaminopyridine (DMAP) is added as a catalyst, THF, methylene chloride, DMSO, DMF and the like are used as a reaction solvent, and the reaction can be carried out at a temperature of 0 ° C to room temperature.

Further, among the compounds represented by the general formula (1), compounds wherein R5 is a hydrogen atom or a fluorine atom and R6 is an acetyl group, a benzoyl group, a 2-thiazolecarbonyl group or a 2-benzothiazolecarbonyl group. That is, the general formula (13) [Wherein, R10 represents a hydrogen atom or a fluorine atom;
3 represents a methyl group, a phenyl group, a thiazole ring or a benzothiazole ring, and A, R1, R2, R3, R4, R1
0 and m are as described above], and the compound represented by the general formula (11) Wherein A, R1, R2, R3, R4, R10 and m are as described above, and a compound represented by the general formula (12) [Wherein M represents Li, MgI, MgBr or MgCl, and R13 is as described above], and can also be produced.

The reaction can be carried out in an atmosphere of an inert gas such as argon, using THF or the like as a solvent, and at a reaction temperature of -78 ° C. to room temperature.

Further, among the compounds represented by the general formula (1), R5 is a hydrogen atom or a fluorine atom, and R6 is a lower alkylaminosulfonyl group having 1 to 4 carbon atoms, an N, O-dimethylhydroxylaminosulfonyl group. Or a compound that is a phenethylaminosulfonyl group, that is, [Wherein, A, R1, R2, R3, R4, R10, R1
1, R12, and m are as described above], the compound represented by the general formula (14) [Wherein A, R1, R2, R3, R4, R10, R, m
Is as described above], after dealkoxylation of the compound represented by
Converted to sulfonic acid chloride, general formula (9) [Wherein R11 and R12 are as described above].

The reaction comprises tetramethylammonium chloride,
In the presence of a quaternary ammonium salt such as tetramethylammonium bromide, tetramethylammonium iodide, preferably tetrabutylammonium iodide, DMF, preferably acetone, is used as an organic solvent at room temperature, preferably under reflux with heating. After conversion to a dealkoxylated product, the product can be treated with sulfuryl chloride and carried out at 0 ° C. to room temperature in the presence of an organic base such as triethylamine or pyridine using methylene chloride, DMF, THF or the like as an organic solvent.

Further, the compound represented by the general formula (1) is Wherein A, R1, R2, R3 and m are as described above, and a compound represented by the general formula (17) [Wherein R4, R5 and R6 are as described above], and can also be produced by condensation.

The reaction can be produced by a mixed acid anhydride method or an active ester method used in a usual peptide bond formation reaction, and a method using a condensing agent is preferable. DCC, DIPC, DPPA, DEPC, WS
C. In the presence of a condensing agent such as C, DMAP is optionally added as a catalyst, and THF, methylene chloride, DMSO, DMF, or the like is used as a reaction solvent, and the reaction temperature is 0.
C. to room temperature.

In the compound represented by the general formula (1),
Is 1, that is, a compound represented by the general formula (20) Wherein A, R1, R2, R3, R4, R5 and R6 are as described above, and the compound represented by the general formula (18) Wherein A, R1 and R2 are as described above, and a compound represented by the general formula (19): [Wherein R 3, R 4, R 5 and R 6 are as described above].

The reaction can be produced by a mixed acid anhydride method or an active ester method used in a usual peptide bond formation reaction, and a method using a condensing agent is preferable. DCC, DIPC, DPPA, DEPC, WS
C. In the presence of a condensing agent such as C, DMAP is optionally added as a catalyst, and THF, methylene chloride, DMSO, DMF, or the like is used as a reaction solvent, and the reaction temperature is 0.
C. to room temperature.

[0029]

Next, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples. Further, although the compound of the present invention has an asymmetric carbon, the present invention also includes optical isomers and racemates thereof.

Example 1 N- [N- (benzyloxycarbonyl)-(L) -leucyl- (L) -phenylalanyl]-(3S) -3-
Amino-1-methanesulfonyl-4-phenyl-1-butene Diethyl (methylsulfonylmethyl) phosphonate (15
0 mg) was dissolved in THF (15 mL) and 60% NaH (24
mg), and the mixture was returned to room temperature and stirred for 1 hour. The reaction solution was ice-cooled again, and Z- (L) -Leu- (L) -Ph dissolved in THF (3 mL) was used.
e- (L) -Phe-H (300 mg) was added and the mixture was stirred for 30 minutes. The reaction solution was poured into water, extracted with ethyl acetate, washed with water and saturated saline in that order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1). The desired product (89 mg) was obtained as a colorless powder. 186-188 ° C Hereinafter, various peptide aldehydes and various phosphonates were reacted in the same manner as in Example 1 to obtain compounds shown in Tables 1 and 2. Unless otherwise specified, amino acids in the table indicate L-form.

[0031]

[Table 1]

[0032]

[Table 2]

Example 18 N- [N- (benzyloxycarbonyl)-(L) -prolyl- (L) -phenylalanyl]-(3S) -3-
Amino-1-methanesulfonyl-4-phenyl-1-butene Hydrochloride (40 mg) obtained by treating the compound obtained in Example 17 with a 1 mol / L-HCl-ethyl acetate solution
Dissolve Z-Pro-OH (24 mg) in methylene chloride and add
C-HCl (30 mg) and a small amount of dimethylaminopyridine were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water, extracted with ethyl acetate, and water, dilute aqueous phosphoric acid, water, saturated aqueous sodium hydrogen carbonate, water,
After washing with saturated saline in this order, the extract was dried over anhydrous sodium sulfate and concentrated. The residue was suspended in diisopropyl ether, and the solid was collected by filtration and dried to obtain the desired product (48 mg) as a white powder. FABMS: 604 ([M + H] ⁺ )

Example 19 N- [N- (benzoyl)-(L) -phenylalanyl]-(3S) -3-amino-1-methanesulfonyl-
4-phenyl-1-butene Hydrochloride (40 mg) obtained by treating the compound obtained in Example 17 with a 1 mol / L-HCl-ethyl acetate solution and HOB
Dissolve tH ₂ O (16 mg) and benzoic acid (13 mg) in methylene chloride, and add WSC-HCl (29 mg) and triethylamine (14 μL).
Was added and stirred at room temperature for 3 hours. The reaction solution was poured into water, extracted with ethyl acetate, washed with diluted phosphoric acid aqueous solution, saturated aqueous sodium bicarbonate solution and saturated saline solution in that order, dried over anhydrous sodium sulfate and concentrated. The residue was suspended in diisopropyl ether, and the solid was collected by filtration and dried to give the desired product (29 mg) as a white powder. FABMS: 477 ([M + H] ⁺ )

The compounds shown in Tables 3 and 4 were obtained by condensing with various amino acids and carboxylic acids in the same manner as in Examples 18 and 19.

[Table 3]

[0036]

[Table 4]

Example 96 Ethyl N- [N- (benzyloxycarbonyl)-(L) -phenylalanyl]-(4S) -4-amino-2-ethoxycarbonyl-6-methyl-2-heptenoate Under argon, THF (3 ml) was cooled to -78 ° C, and a solution of titanium tetrachloride (0.17 ml) in carbon tetrachloride (1 ml) was added dropwise. Then, a solution of Z- (L) -Phe- (L) -Leu-H (310 mg) and ethyl malonate (0.12 mL) in THF (1 mL) was added dropwise, and pyridine (0.25 mL) was added. After stirring to room temperature for one day, water was added, and the mixture was extracted with ethyl acetate. After washing with a saturated saline solution, the solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the desired product (320 m
g) was obtained as a colorless powder. MS: 538 (M ⁺ )

Example 97 N- [N- (benzyloxycarbonyl)-(L) -leucyl- (L) -phenylalanyl]-(4S) -4-
Amino-2-ethoxycarbonyl-6-phenyl-2-
Ethyl pentenoate The same procedure as in Example 96 was carried out except that Z- (L) -Leu- (L) -Phe- (L) -Phe-H was used as a raw material, to obtain the desired product as a pale yellow amorphous substance. FABMS: 686 ([M + H] ⁺ )

Example 98 N- [N- (benzyloxycarbonyl)-(L) -leucyl- (L) -leucyl]-(4S) -4-amino-
6-methyl-2-heptenoic acid The compound of Example 2 (720 mg) was dissolved in ethanol (20 mL), 1 mol / L-NaOH (2 mL) was added, and the mixture was stirred at 0 ° C for 1 hour. After distilling off ethanol under reduced pressure, add water and dilute hydrochloric acid.
The mixture was adjusted to pH 2 and extracted with ethyl acetate. After washing with a saturated saline solution, the solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
The desired product (450 mg) was obtained as a colorless amorphous. FABMS: 518 ([M + H] ⁺ )

Example 99 N- [N- (benzyloxycarbonyl)-(L) -phenylalanyl]-(4S) -4-amino-6-methyl-2-heptenoic acid The same procedures used in Example 98 were carried out except for using the compound prepared in Example 11 to give a desired product as a pale yellow amorphous substance. FABMS: 439 ([M + H] ⁺ )

Example 100 N- [N- (benzyloxycarbonyl)-(L) -leucyl]-(4S) -4-amino-6-methyl-2-heptenoic acid The same procedures as in Example 98 were carried out except for using the compound of Example 12 to give a desired product as a pale brown amorphous. MS: 404 (M ^<+> )

Example 101 N- [N- (benzyloxycarbonyl)-(L) -phenylalanyl]-(4S) -4-amino-1- (2-
Benzothiazolyl) -5-phenyl-2-pentene-1
-ON Benzothiazole (0.11 mL) T under argon gas flow
The HF (5 mL) solution was cooled to −78 ° C., and 1.6 mol / L-BuLi (hexane solution 0.7 mL) was added dropwise. One hour later, a solution of the compound of Example 14 (140 mg) in THF (2 mL) was added dropwise. The mixture was stirred for 5 hours while slowly warming to room temperature. Dilute hydrochloric acid was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain the desired product (60 m
g) was obtained as a yellow powder. MS: 589 (M ^<+> )

Example 102 N- [N- (benzyloxycarbonyl)-(L) -phenylalanyl]-(4S) -4-amino-1- (2-
Thiazolyl) -5-phenyl-2-penten-1-one The same procedures as in Example 101 were carried out except that the compound of Example 14 was used (thiazole was used instead of benzothiazole) to give the desired product as a pale brown powder. MS: 539 (M ⁺ )

Example 103 N- [N- (benzyloxycarbonyl)-(L) -leucyl- (L) -phenylalanyl]-(4S) -4-
Amino-1- (2-thiazolyl) -5-phenyl-2-
Penten-1-one The same procedures used in Example 102 were carried out except for using the compound prepared in Example 50 to give a desired product as a pale yellow amorphous substance. MS: 652 (M ⁺ )

Example 104 N- [N- (benzyloxycarbonyl)-(L) -phenylalanyl]-(5S) -5-amino-6-phenyl-3-hexen-2-one The same procedures as in Example 101 were carried out except that the compound of Example 14 was used (methyllithium was used instead of lithiobenzothiazole) to give the desired product as a colorless powder. FABMS: 471 ([M + H] ⁺ )

Example 105 N- [N- (benzyloxycarbonyl)-(L) -phenylalanyl]-(4S) -4-amino-1,5-diphenyl-2-penten-1-one The same procedures as in Example 101 were carried out except that the compound of Example 14 was used (phenyllithium was used instead of lithiobenzothiazole) to give the desired product as a colorless powder. MS: 532 (M ⁺ )

Example 106 N- [N- (benzyloxycarbonyl)-(L) -leucyl- (L) -phenylalanyl]-(3S) -3
-Amino-1-[(N'-methoxy-N'-methyl) aminosulfonyl] -4-phenyl-1-butene Literature (J. Am. Chem. Soc., Vol. 120, 1998, 10994
N-Boc- (3S) -3-
Amino-1-chlorosulfonyl-4-phenyl-1-butene (50 mg) was dissolved in methylene chloride (2 mL), and N, O-dimethylhydroxyamine hydrochloride (20 mg) and diisopropylethylamine (25 μL) were added under ice-cooling. Stir for 30 minutes. The reaction solution was poured into water, extracted with ethyl acetate, washed with diluted phosphoric acid, water, saturated aqueous sodium bicarbonate, water and saturated saline in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: diethyl ether = 20: 1) to give N-Boc- (3S) -3-amino-1-.
[(N-methoxy-N-methyl) aminosulfonyl]-
4-Phenyl-1-butene (20 mg) was obtained as a pale yellow oil. It was dissolved in methylene chloride (1 mL) and cooled on ice. A mixture of methylene chloride (1 mL) and trifluoroacetic acid (1 mL) was added, and the mixture was returned to room temperature and stirred for 30 minutes. The reaction solution was concentrated and dried, and the residue was redissolved in a mixed solvent of methylene chloride and dimethylformamide. There, Z-Leu-Phe-OH (3
0 mg), HOBt. H ₂ O (11 mg), WSC (20 mg), and diisopropylethylamine (15 mL) were sequentially added, and the mixture was allowed to stand at room temperature for 2 days. The reaction solution was poured into water, extracted with ethyl acetate, washed with water, dilute aqueous phosphoric acid, water, saturated aqueous sodium bicarbonate, water and saturated brine in that order, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired product (25 mg) as a pale yellow amorphous. FABMS: 665 ([M + H] ⁺ )

Example 107 N- [N- (benzyloxycarbonyl)-(L) -leucyl- (L) -phenylalanyl]-(3S) -3
-Amino-1-[(N'-ethyl) aminosulfonyl]
-4-phenyl-1-butene This was carried out in the same manner as in Example 106 (using ethylamine instead of N, O-dimethylhydroxyamine) to obtain the desired product as a yellow amorphous substance. FABMS: 649 ([M + H] ⁺ )

Example 108 N- [N- (benzyloxycarbonyl)-(L) -leucyl- (L) -phenylalanyl]-(3S) -3
-Amino-1-[(N'-phenethyl) aminosulfonyl] -4-phenyl-1-butene In the same manner as in Example 106 (using phenethylamine instead of N, O-dimethylhydroxyamine), the target product was obtained as a yellow amorphous substance. FABMS: 725 ([M + H] ⁺ )

Example 109 N- [N- (benzyloxycarbonyl)-(L) -phenylalanyl]-(3S) -3-amino-1-
[(N'-methoxy-N'-methyl) aminosulfonyl] -4-phenyl-1-butene The same conversion as in Example 106 was carried out using the compound of Example 86 to give the desired product as a yellow powder. FABMS: 552 ([M + H] ⁺ )

Example 110 N- [N- (2,4-dichloro-5-aminosulfonylbenzoyl)-(L) -phenylalanyl]-(3
S) -3-Amino-1-[(N'-methoxy-N'-methyl) aminosulfonyl] -4-phenyl-1-butene Using the compound of Example 88, the same conversion as in Example 106 was performed to obtain the desired product as a pale yellow powder. FABMS: 669 ([M + H] ⁺ )

Example 111 N- [N- (benzoyl)-(L) -lysyl- (L)-
Phenylalanyl]-(3S) -3-amino-1-methanesulfonyl-4-phenyl-1-butene Dissolve the compound of Example 44 (50 mg) in ethyl acetate (5 mL),
A 3 mol / L-HCl ethyl acetate solution (5 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated and suspended in diisopropyl ether. The solid was collected by filtration and dried to give the desired product (38 mg) as a pale brown powder solid. FABMS: 605 ([M + H] ⁺ )

Example 112 N- [N- (benzoyl)-(L) -α-glutamyl-
(L) -phenylalanyl]-(3S) -3-amino-
1-methanesulfonyl-4-phenyl-1-butene Dissolve the compound of Example 45 (50 mg) in ethyl acetate (5 mL) and add 3
A mol / L-HCl ethyl acetate solution (5 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was concentrated and suspended in diisopropyl ether. The solid was collected by filtration and dried to give the desired product (39 mg) as a pale brown powder solid. FABMS: 606 ([M + H] ⁺ )

Next, the results supporting the usefulness of the compound of the present invention are shown by experimental examples.

<Experimental Example 1> Proteasome Inhibition Test Proteasome was purified from bovine kidney and used. Purification of proteasome and measurement of its activity are described in Tanaka et al.
Of Biological Chemistry, 263, 31
No., 16209-16217, 1988). Specifically, the centrifugal supernatant homogenized by adding Tris buffer (pH 7.5) to bovine kidney was
The proteasome was purified by fractionation using ammonium sulfate precipitation, ion exchange chromatography (Q Sepharose FF), and gel filtration chromatography (High Road Superdex 200). Proteasome activity was determined by Suc-Leu.
-Leu-Val-Tyr-MCA The degradation was measured using the substrate as an index. DMS of test compound was placed in a 96-well plate.
1 μL of the O solution and 89 μL of a proteasome solution of about 1 U / mL were added and mixed, and incubated at 37 ° C. for 30 minutes. Subsequently, 200 μmol / L of Suc-Leu-
Add 10 μL of Leu-Val-Tyr-MCA substrate
Mix and incubate at 37 ° C. for 1 hour. 10% S
After 100 μL of DS solution was added to stop the reaction, the fluorescence intensity of aminomethylcoumarin released from the substrate was measured at an excitation wavelength of 355 nm and a fluorescence wavelength of 460 nm, and the value was defined as proteasome activity. Based on the proteasome activity when the test compound was not added, the concentration (IC ₅₀ ) of the compound that inhibited the activity by 50% was calculated. It is shown in Table 5.

[0056]

[Table 5]

<Experimental Example 2> Luciferase reporter gene assay The NF-κB activation inhibitory action of the test compound based on the proteasome inhibitory action was measured by a reporter gene assay using firefly luciferase as a reporter gene. Thymidine kinase (TK) promoter upstream of the firefly luciferase (Luc) gene, which is a reporter gene, and
Further, a plasmid (pNFkB-LUC: Stratagene) having a κB sequence repeated 5 times further upstream was used as a reporter vector. Also, for internal standard,
A plasmid (pRL-TK: Stratagene) in which a reporter gene, Renilla luciferase gene (RL), was linked upstream of a TK promoter was used. Human histiocytic lymphoma cells U937 (ATCC No. 1) maintained and cultured in RPMI-1640 medium (Gibco) containing 10% fetal bovine serum (FBS).
CRL1593), these plasmids were simultaneously co-transfected (Co-transfection) using Lipofectamine reagent (Gibco). Cells transiently transfected with the gene were suspended in the above medium, dispensed into a 24-well plate at 7 × 10 ⁵ cells / well, and cultured overnight. Test compounds were diluted in the above medium, added to a 24-well plate, and pretreated for 45 minutes. Then the final concentration
HTNF-α (human tumor necrosis factor, Boehringer Mannheim) was added to 3 ng / mL, and the cells were further cultured for 5 hours to stimulate the cells. After completion of the culture, the cells were collected to obtain a cell lysate. The firefly luciferase activity in the cell lysate was measured using a dual luciferase reporter assay system (Promega). At the same time, Renilla luciferase activity was measured using the same assay kit. The NF-κB transcription activity detected by firefly luciferase activity was normalized from the internal standard Renilla luciferase activity. Test compound NF-
The κB activation inhibitory effect was observed by a decrease in NF-κB transcription activity, and the inhibition rate (%) was calculated by the following equation. Inhibition rate (%) = (1-(Test-Blank) / (Control-B
lank)) × 100 (Test: Transcriptional activity of cells stimulated with TNF-α with addition of compound, Blank: Transcriptional activity of cells without stimulation with TNF-α without addition of compound, Control: Addition of compound Without, T
Table 6 shows the results of the transcriptional activity of cells stimulated with NF-α.

[0058]

[Table 6]

Experimental Example 3 Inhibitory Effect of Test Compound on Delayed Type Hypersensitivity Reaction in Mouse Methods in Enz
ymology), vol. 300, pp. 345-363, 1999. 1-fluoro-2, so that it becomes 1%
4: 1 4-dinitrobenzene (DNFB, Nacalai Tesque)
Acetone: dissolved in olive oil. Antigen sensitization was performed by applying 10 μL of the 1% DNFB solution to the foot pads of the left and right hind limbs at the age of 8 or 9 weeks of BALB / c male mice (CLEA Japan). This antigen sensitization was performed for two consecutive days, which were designated as day 0 and day 1. Five
On the day, the ear was challenged with the same antigen to elicit a delayed type hypersensitivity reaction. First, the left and right ear thickness before the antigen challenge was measured using a dial thickness gauge G (0.01-10 mm, Ozaki Seisakusho). Next, the test compound was administered. 30 minutes later, 4: 1
Acetone: A 0.2% DNFB solution dissolved in olive oil was applied to each of the right and left ears in an amount of 10 μL each to perform antigen challenge. Twenty-four hours later, the increase in ear thickness was measured, and the average value of the left and right ears was used as data for each individual. The test compound was dissolved in dimethylsulfoxide (DMSO), and then added to 1: 5 polyethylene glycol 400: 0.5% bovine albumin, sonicated and suspended (final concentration of DMSO 5%). This was intraperitoneally administered in 0.1 mL per 10 g of mouse body weight.
The control group received a solvent having the same composition as that used for preparing the test compound. Table 7 shows the results.

[0060]

[Table 7]

Experimental Example 4 Inhibitory Effect of Test Compound on Mouse Host Vs. Graft Rejection Transplantation, No. 55
Vol. 3, No. 3, pp. 578-591, 1993. A spleen of a BALB / c male mouse (CLEA Japan) at 8 or 10 weeks of age was taken out into phosphate buffered saline (PBS (-)) and passed through a stainless steel mesh to obtain a spleen cell suspension. The spleen cell suspension was centrifuged to remove the supernatant, and an ammonium chloride-Tris isotonic buffer was added to lyse erythrocytes. After washing three times with PBS (-), RPMI
-1640 medium (Kifuko). The final concentration is 25μ
g / mL of mitomycin C (Kyowa Hakko) was added, and the cells were cultured at 37 ° C under 5% CO ₂ for 30 minutes. After washing three times by centrifugation with PBS (-), the cells were suspended in RPMI-1640 medium at 2.5 × 10 ⁸ cells / mL, and this was used as a stimulated cell suspension. 20 μL of the stimulated cell suspension (5 × 10 ⁶ cells / animal) was subcutaneously injected into the right hind footpad of 8 or 10-week-old C3H / HeN male mouse (CLEA Japan) using a 27G needle and a micro syringe (Hamilton). Injected. The normal control group was injected with only RPMI-1640 medium. Four days later, the lymph node below the right knee was removed, and METTLER AT201 was used.
The weight was measured using an electronic balance (Mettler Toledo). The test compound was dissolved or suspended in 50% v / v EtOH / DMSO, and then uniformly mixed with olive oil (EtOH and DMSO
2.5% or less of final concentration). This was intraperitoneally administered in 0.1 mL per 10 g of mouse body weight. The administration was performed once a day for a total of four times from the day of stimulating cell injection to three days later. In the control group,
A solvent having the same composition as that used for preparing the test compound was administered. Table 8 shows the results.

[0062]

[Table 8] As described above, the compound of the present invention represented by the general formula (1) was confirmed to have a proteasome inhibitory effect, and was also confirmed to suppress NF-κB transcription activity. Its effectiveness was also confirmed in animal experimental models.

Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat II (Reference) A61K 31/428 A61K 31/428 4C086 31/47 31/47 4C204 38/00 A61P 29/00 4H006 A61P 29/00 35 / 00 4H045 35/00 37/00 37/00 43/00 111 43/00 111 C07C 269/06 C07C 269/06 303/40 303/40 311/16 311/16 311/48 311/48 315/04 315 / 04 317/28 317/28 C07D 209/18 C07D 209/18 209/20 209/20 209/42 209/42 215/48 215/48 241/24 241/24 277/24 277/24 277/64 277 / 64 307/85 307/85 311/12 311/12 C07K 5/062 C07K 5/062 5/065 5/065 5/068 5/068 5/072 5/072 5/078 5/078 C12N 9/99 C12N 9/99 A61K 37/02 (72) Inventor Kazuhiko Kuriyama 1-7-16 Otome, Oyama City, Tochigi Prefecture (72) Inventor Tetsu Iwanami 67-1 Junjima Nogicho, Shimotsuga-gun, Tochigi F-term (reference) 4C031 MA01 4C033 AD08 AD17 AD18 AD20 AE05 AE17 AE18 AE20 4C037 QA13 4C062 EE12 4C084 AA02 BA01 BA14 BA15 BA16 CA59 NA14 ZA962 ZB072 ZB082 ZB112 ZB132 ZB152 ZB262 ZC202 4C086 AA01 AA02 AA03 AA04 BA08 BC13 BC14 BC28 BC82 BC84 MA01 NA14 ZA02 ZA59 ZA68 ZA89 ZB08 ZB11 ZB13 ZB15 ZB26 ZC20 ZC80 4C02 AB01 AB01 AB02 AB01 AB02 AB01 AB01 AC53 AC61 RA04 4H045 AA10 AA20 AA30 BA11 DA56 EA21 EA22 EA28 FA40 FA50 GA01

Claims (10)

[Claims] 1. General formula (1) [Wherein A is a benzyloxycarbonyl group (Z group), t
-Butoxycarbonyl group (Boc group), R-CO-, R- (C
O) ₂ — or R—SO ₂ — (where R is an optionally substituted benzene ring, pyrazine ring, naphthalene ring, indole ring, optionally substituted quinoline ring, coumarin ring, benzofuran ring, Represents an optionally substituted benzyl group, an optionally substituted styryl group or an optionally substituted phenethyl group), R1 represents a hydrogen atom, or R1 and R2 combine to form a pyrrolidine ring R2, R3 and R4 may be the same or different and are each a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cyclohexylmethyl group, an optionally substituted benzyl group, a naphthylmethyl group, R5 represents a hydrogen atom, a fluorine atom, a lower alkoxycarbonyl group having 1 to 4 carbon atoms, and R6 represents a lower alkyl group having 1 to 4 carbon atoms. Alkoxycarbonyl group, carboxyl group, lower alkoxyphosphoryl group having 1 to 4 carbon atoms, cyano group, lower alkylsulfonyl group having 1 to 4 carbon atoms, phenylsulfonyl group, lower alkoxysulfonyl group having 1 to 4 carbon atoms, phenethylaminocarbonyl Group, lower alkylaminocarbonyl group having 1 to 4 carbon atoms, N, O-dimethylhydroxylaminocarbonyl group,
Acetyl group, benzoyl group, 2-thiazolecarbonyl group, 2-benzothiazolecarbonyl group, carbon number 1-4
A lower alkylaminosulfonyl group, an N, O-dimethylhydroxylaminosulfonyl group or a phenethylaminosulfonyl group, and m represents 0 or 1.] Salts and hydrates thereof. 2. General formula (1) Wherein A is a Z group, a Boc group, R—CO—, R— (CO) ₂ — or R—SO ₂ — (where R is an optionally substituted benzene ring, a pyrazine ring, a naphthalene Ring, indole ring,
An optionally substituted quinoline ring, a coumarin ring, a benzofuran ring, an optionally substituted benzyl group, an optionally substituted styryl group or an optionally substituted phenethyl group), and R1 represents a hydrogen atom Show or R1 and R
2 may combine to form a pyrrolidine ring;
3, R4 are the same or different and are each a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cyclohexylmethyl group, an optionally substituted benzyl group, a naphthylmethyl group, an indolylmethyl group or A pyridylmethyl group, wherein R5 is a hydrogen atom, a fluorine atom,
R6 represents a lower alkoxycarbonyl group of
4 to lower alkoxycarbonyl groups, carboxyl groups,
C1-C4 lower alkoxyphosphoryl group, cyano group, C1-C4 lower alkylsulfonyl group, phenylsulfonyl group, C1-C4 lower alkoxysulfonyl group, phenethylaminocarbonyl group, C1-C4
Lower alkylaminocarbonyl group, N, O-dimethylhydroxylaminocarbonyl group, acetyl group, benzoyl group, 2-thiazolecarbonyl group, 2-benzothiazolecarbonyl group, lower alkylaminosulfonyl group having 1 to 4 carbon atoms, N, Represents an O-dimethylhydroxylaminosulfonyl group or a phenethylaminosulfonyl group,
Represents 0 or 1.] The proteasome inhibitor comprising at least one of an alkenyl amino acid derivative and a pharmacologically acceptable salt and hydrate as an active ingredient. 3. General formula (2) Wherein A is a Z group, a Boc group, R—CO—, R— (CO) ₂ — or R—SO ₂ — (where R is an optionally substituted benzene ring, pyrazine ring, naphthalene Ring, indole ring, optionally substituted quinoline ring, coumarin ring, benzofuran ring, optionally substituted benzyl group, optionally substituted styryl group or optionally substituted phenethyl group), R1 represents a hydrogen atom, or R1
And R2 may combine to form a pyrrolidine ring;
R3 and R4 are the same or different and each represent a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cyclohexylmethyl group, an optionally substituted benzyl group, a naphthylmethyl group, an indolylmethyl group, or Represents a pyridylmethyl group, and m represents an integer of 0 or 1.] to a compound represented by the general formula (3) [Wherein, R 7 represents a hydrogen atom or a fluorine atom, R 8 represents a lower alkoxycarbonyl group having 1 to 4 carbon atoms, a carboxyl group, a lower alkoxyphosphoryl group having 1 to 4 carbon atoms,
A cyano group, a lower alkylsulfonyl group having 1 to 4 carbon atoms,
A phenylsulfonyl group, a lower alkoxysulfonyl group having 1 to 4 carbon atoms, a phenethylaminocarbonyl group, a lower alkylaminocarbonyl group having 1 to 4 carbon atoms or an N, O-dimethylhydroxylaminocarbonyl group]. General formula (4) characterized by reacting Wherein A, R1, R2, R3, R4, R5, R6, R
7, R8 and m are as defined above]. 4. General formula (2) Wherein A is a Z group, a Boc group, R—CO—, R— (CO) ₂ — or R—SO ₂ — (where R is an optionally substituted benzene ring, pyrazine ring, naphthalene Ring, indole ring, optionally substituted quinoline ring, coumarin ring, benzofuran ring, optionally substituted benzyl group, optionally substituted styryl group or optionally substituted phenethyl group), R1 represents a hydrogen atom, or R1
And R2 may combine to form a pyrrolidine ring;
R3 and R4 are the same or different and each represent a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cyclohexylmethyl group, an optionally substituted benzyl group, a naphthylmethyl group, an indolylmethyl group, or A pyridylmethyl group, m represents an integer of 0 or 1], and a compound represented by the general formula (5): [Wherein R 9 represents a lower alkoxycarbonyl group having 1 to 4 carbon atoms, and Ra represents a lower alkyl group having 1 to 4 carbon atoms]. ) The method of claim 1, wherein A, R1, R2, R3, R4, R9, Ra and m are as defined above. 5. General formula (7) Wherein A is a Z group, a Boc group, R—CO—, R— (CO) ₂ — or R—SO ₂ — (where R is an optionally substituted benzene ring, pyrazine ring, naphthalene Ring, indole ring, optionally substituted quinoline ring, coumarin ring, benzofuran ring, optionally substituted benzyl group, optionally substituted styryl group or optionally substituted phenethyl group), R1 represents a hydrogen atom, or R1
And R2 may combine to form a pyrrolidine ring;
R3 and R4 are the same or different and each represent a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cyclohexylmethyl group, an optionally substituted benzyl group, a naphthylmethyl group, an indolylmethyl group, or A pyridylmethyl group, R10 represents a hydrogen atom or a fluorine atom, Ra represents a lower alkyl group having 1 to 4 carbon atoms, and m represents an integer of 0 or 1.]. The general formula (8) Wherein A, R1, R2, R3, R4, R10 and m
Is as described above]. 6. The general formula (8) Wherein A is a Z group, a Boc group, R—CO—, R— (CO) ₂ — or R—SO ₂ — (where R is an optionally substituted benzene ring, pyrazine ring, naphthalene Ring, indole ring, optionally substituted quinoline ring, coumarin ring, benzofuran ring, optionally substituted benzyl group, optionally substituted styryl group or optionally substituted phenethyl group), R1 represents a hydrogen atom, or R1
And R2 may combine to form a pyrrolidine ring;
R3 and R4 are the same or different and each represent a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cyclohexylmethyl group, an optionally substituted benzyl group, a naphthylmethyl group, an indolylmethyl group, or A pyridylmethyl group, R10 represents a hydrogen atom or a fluorine atom, m represents an integer of 0 or 1, and a compound represented by the general formula (9) [Wherein, R11 represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms or a phenethyl group, and R12 represents a lower alkyl group having 1 to 4 carbon atoms, a phenethyl group or a methoxy group]
Wherein the compound represented by the formula is condensed: [Wherein A, R1, R2, R3, R4, R10, R1
1, R12 and m are as defined above]. 7. General formula (11) Wherein A is a Z group, a Boc group, R—CO—, R— (CO) ₂ — or R—SO ₂ — (where R is an optionally substituted benzene ring, pyrazine ring, naphthalene Ring, indole ring, optionally substituted quinoline ring, coumarin ring, benzofuran ring, optionally substituted benzyl group, optionally substituted styryl group or optionally substituted phenethyl group), R1 represents a hydrogen atom, or R1
And R2 may combine to form a pyrrolidine ring;
R3 and R4 are the same or different and each represent a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cyclohexylmethyl group, an optionally substituted benzyl group, a naphthylmethyl group, an indolylmethyl group, or Represents a pyridylmethyl group, R10 represents a hydrogen atom or a fluorine atom, and m represents an integer of 0 or 1.]
General formula (12) Wherein R13 represents a methyl group, a phenyl group, a thiazole ring or a benzothiazole ring, and M represents Li, MgI, MgBr or MgCl. ) [Wherein A, R1, R2, R3, R4, R10, R13
And m are as defined above]. 8. The general formula (14) Wherein A is a Z group, a Boc group, R—CO—, R— (CO) ₂ — or R—SO ₂ — (where R is an optionally substituted benzene ring, pyrazine ring, naphthalene Ring, indole ring, optionally substituted quinoline ring, coumarin ring, benzofuran ring, optionally substituted benzyl group, optionally substituted styryl group or optionally substituted phenethyl group), R1 represents a hydrogen atom, or R1
And R2 may combine to form a pyrrolidine ring;
R3 and R4 are the same or different and each represent a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cyclohexylmethyl group, an optionally substituted benzyl group, a naphthylmethyl group, an indolylmethyl group, or Represents a pyridylmethyl group, R10 represents a hydrogen atom or a fluorine atom, Ra represents a lower alkyl group having 1 to 4 carbon atoms, and m represents an integer of 0 or 1.] Is converted to sulfonic acid chloride by the general formula (9) [Wherein, R11 represents a hydrogen atom, a lower alkyl group having 1 to 4 carbon atoms or a phenethyl group, and R12 represents a lower alkyl group having 1 to 4 carbon atoms, a phenethyl group or a methoxy group]
Wherein the compound represented by the formula is condensed: [Wherein A, R1, R2, R3, R4, R10, R1
1, R12 and m are as defined above]. 9. The general formula (16) Wherein A is a Z group, a Boc group, R—CO—, R— (CO) ₂ — or R—SO ₂ — (where R is an optionally substituted benzene ring, pyrazine ring, naphthalene Ring, indole ring, optionally substituted quinoline ring, coumarin ring, benzofuran ring, optionally substituted benzyl group, optionally substituted styryl group or optionally substituted phenethyl group), R1 represents a hydrogen atom, or R1
And R2 may combine to form a pyrrolidine ring;
R3 is the same or different and is a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cyclohexylmethyl group, an optionally substituted benzyl group, a naphthylmethyl group, an indolylmethyl group or a pyridyl group; A methyl group, m represents an integer of 0 or 1], and a compound represented by the general formula (17) [In the formula, R4 represents a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cyclohexylmethyl group,
An optionally substituted benzyl group, a naphthylmethyl group,
R represents an indolylmethyl group or a pyridylmethyl group;
5 represents a hydrogen atom, a fluorine atom or a lower alkoxycarbonyl group having 1 to 4 carbon atoms, and R6 represents a lower alkoxycarbonyl group having 1 to 4 carbon atoms, a carboxyl group, and 1 to 1 carbon atoms.
4 lower alkoxyphosphoryl group, cyano group, 1 carbon atom
Lower alkylsulfonyl group, phenylsulfonyl group, lower alkoxysulfonyl group having 1 to 4 carbon atoms, phenethylaminocarbonyl group, lower alkylaminocarbonyl group having 1 to 4 carbon atoms, N, O-dimethylhydroxylaminocarbonyl group, Acetyl group, benzoyl group, 2-thiazolecarbonyl group, 2-benzothiazolecarbonyl group, lower alkylaminosulfonyl group having 1 to 4 carbon atoms, N, O-dimethylhydroxylaminosulfonyl group or phenethylaminosulfonyl group] General formula (1) characterized by condensing the compound to be prepared The method for producing a compound according to claim 1, wherein A, R1, R2, R3, R4, R5, R6 and m are as defined above. 10. The general formula (18) Wherein A is a Z group, a Boc group, R—CO—, R— (CO) ₂ — or R—SO ₂ — (where R is an optionally substituted benzene ring, pyrazine ring, naphthalene Ring, indole ring, optionally substituted quinoline ring, coumarin ring, benzofuran ring, optionally substituted benzyl group, optionally substituted styryl group or optionally substituted phenethyl group), R1 represents a hydrogen atom, or R1
And R2 may combine to form a pyrrolidine ring;
R3 is the same or different and is a hydrogen atom, an optionally substituted lower alkyl group having 1 to 4 carbon atoms, a cyclohexylmethyl group, an optionally substituted benzyl group, a naphthylmethyl group, an indolylmethyl group or a pyridyl group; A compound represented by the general formula (19): [Wherein, R3 and R4 are the same or different and each represent a hydrogen atom,
An optionally substituted lower alkyl group having 1 to 4 carbon atoms,
A cyclohexylmethyl group, an optionally substituted benzyl group, a naphthylmethyl group, an indolylmethyl group or a pyridylmethyl group; R5 represents a hydrogen atom, a fluorine atom or a lower alkoxycarbonyl group having 1 to 4 carbon atoms;
6 is a lower alkoxycarbonyl group having 1 to 4 carbon atoms, a carboxyl group, a lower alkoxyphosphoryl group having 1 to 4 carbon atoms, a cyano group, a lower alkylsulfonyl group having 1 to 4 carbon atoms, a phenylsulfonyl group, and a 1 to 4 carbon atoms. A lower alkoxysulfonyl group, a phenethylaminocarbonyl group, a lower alkylaminocarbonyl group having 1 to 4 carbon atoms, N, O-
Dimethylhydroxylaminocarbonyl, acetyl, benzoyl, 2-thiazolecarbonyl, 2-
A benzothiazole carbonyl group, a lower alkylaminosulfonyl group having 1 to 4 carbon atoms, an N, O-dimethylhydroxylaminosulfonyl group or a phenethylaminosulfonyl group]. 20) The method according to claim 1, wherein A, R1, R2, R3, R4, R5 and R6 are as defined above.