JPH1171270A - Medicine containing hydroxamic acid derivative as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine having an excellent matrix metaloproteinase inhibitory activity and useful as a suppressing agent for the metastasis, infiltration and propagation of cancer cells by containing bydroxamic acid derivative as an active ingredient. SOLUTION: This suppressing agent for the metastasis, etc., of cancer cells, is obtained by containing a compound of the formula [R<1> is a (substituted) 1-15C alkyl or the like; R<2> is H, OH, or the like; R<3> is a (substituted) 1-6 alkyl or the like; R<4> is H, a 2-5C alkoxycarbonyl or the like; R<5> is H, a 1-4C alkyl or the like; R<6> is H, a (substituted) 1-6C aliphatic acyl or the like], (e.g. 2-[3-(4- chlorophenyl) propyl]-N<4> -hycroxy-N<1> -[1-hydroxymethyl-2,2- dimethylpropyl]succinamide) as an active ingredient. This medicine is administered by 1 mg as a lower limit and 1,000 mg as an upper limit as one time dose in the case of oral administration, by 0.5 mg as a lower limit and 500 mg as an upper limit as one time dose in the case of intravenous administration, and given as divided by one to several times a day.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an agent for inhibiting metastasis, invasion and growth of various cancer cells, a novel hydroxamic acid derivative having excellent matrix metalloproteinase inhibitory activity as an active ingredient, and osteoarthritis and rheumatoid arthritis. The present invention relates to a therapeutic and prophylactic agent for arthritis.

[0002]

BACKGROUND ART Matrix metalloproteinases are
It is an enzyme that degrades protein components that make up connective tissue. Gelatinase belonging to this class degrades type IV collagen which is a main component of the basement membrane. In the process of forming blood vessels in a cancer tissue or in the process of metastasis of a cancer, the expression level of gelatinase is increased or activated.
Therefore, it is said that gelatinase plays an important role in destroying the basement membrane of cells of normal tissues by cancer cells (Annual Review of Cel).
l Biology, vol. 9, 541-573 (1
993)). In addition, in osteoarthritis, the expression level of collagenase belonging to matrix metalloproteinase in tissue cells is increased or their activation is occurring.Furthermore, in rheumatoid arthritis, matrix metalloproteinase in tissue cells is The expression level of the enzyme to which stromelysin belongs is increased or their activation is occurring. Therefore, it is said that collagenase and stromelysin play an important role in joint destruction (J. Clin. Invest. Vol. 9).
7, 761-768 (1996), Lab. Inves
t. vol. 66, 680-690 (1992)). Therefore, from the above findings, it is considered that an agent that inhibits a matrix metalloproteinase is useful as an agent for inhibiting metastasis, invasion and growth of various cancer cells, and as a therapeutic and preventive agent for osteoarthritis and rheumatoid arthritis.

Many compounds have been reported as inhibitors of matrix metalloproteinases (Current Medicinal Chemis).
tryvol. 2,743-762 (1995)), and in particular, hydroxamic acid derivatives, for which a number of patent applications have been filed in recent years (WO94-02446, WO94-0).
2447, WO95-19956, WO95-1995
7, WO95-19961, WO96-06074, W
O96-16931, WO93-24449, WO93
-24475, WO94-25434, WO94-25
435, WO95-04033, WO92-2252
3). Among these inhibitors, N listed in WO94-02447 ² - (4- hydroxy-amino-2-
(R) -Isobutyl-3- (S) -hydroxysuccinyl) -Lt-leucine-N ¹ -methylamide is being clinically tested in Europe and the United States as an anticancer agent (Proceedings of the Ameri).
can Association for Cance
r Research, vol. 37, 633 (199
6)).

[0004]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies on the synthesis of derivatives having excellent matrix metalloproteinase inhibitory activity and their pharmacological activities. And a novel derivative that has good oral absorbability, and is useful as an agent for inhibiting metastasis, invasion and proliferation of various cancer cells, and a therapeutic and prophylactic agent for osteoarthritis and rheumatoid arthritis, and completed the present invention. did.

[0005]

DISCLOSURE OF THE INVENTION The present invention relates to an agent for inhibiting metastasis, invasion and growth of various cancer cells, a novel hydroxamic acid derivative having an excellent matrix metalloproteinase inhibitory activity, and an osteoarthritis. Provided are a therapeutic agent and a preventive agent for rheumatoid arthritis.

The compound which is the active ingredient of the medicament of the present invention is
General formula (1)

[0007]

Embedded image

And a pharmacologically acceptable salt thereof.

The present invention is a medicine containing the above compound (1) as an active ingredient.

The present invention is an agent for inhibiting metastasis of cancer cells, comprising the compound (1) and a pharmacologically acceptable carrier or excipient.

The present invention is a cancer cell invasion inhibitor comprising the above compound (1) and a pharmacologically acceptable carrier or excipient.

The present invention is a cancer cell growth inhibitor comprising the compound (1) and a pharmacologically acceptable carrier or excipient.

The present invention is a therapeutic or preventive agent for osteoarthritis comprising the above compound (1) and a pharmacologically acceptable carrier or excipient.

The present invention is a therapeutic or preventive agent for rheumatoid arthritis, comprising the above compound (1) and a pharmacologically acceptable carrier or excipient.

In the above formula (1), R ¹ is an alkyl group having 1 to 15 carbon atoms which may have a substituent (the substituent is an alkoxy group having 1 to 6 carbon atoms, An aryl group having 6 to 10 carbon atoms (the substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogeno group) which may have An aryloxy group having 6 to 10 carbon atoms which may have a group (the substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogeno group); An aralkyloxy group having 7 to 14 carbon atoms which may have a substituent (the substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogeno group);
A cycloalkyl group having 3 to 8 carbon atoms or an alkoxyalkoxy group having 2 to 8 carbon atoms which may have a substituent (the substituent is a halogeno group);
² represents a hydrogen atom, a hydroxy group or an aliphatic acyloxy group having 1 to 4 carbon atoms, and R ³ represents an alkyl group having 1 to 6 carbon atoms which may have a substituent (the substituent is , A hydroxy group, an alkoxy group having 1 to 4 carbon atoms,
An alkylthio group having 1 to 4 carbon atoms, an aliphatic acyloxy group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms which may have a substituent (the substituent is 1
1 to 4 alkyl groups, hydroxy groups, 1 to 4 carbon atoms
An aliphatic acyloxy group, an alkoxy group having 1 to 4 carbon atoms or a halogeno group), a monocyclic or condensed heterocyclyl group having 5 to 15 atoms (a hetero atom contained in the ring is nitrogen, oxygen or R ⁴ is a hydrogen atom, an alkoxycarbonyl group having 2 to 5 carbon atoms or a carbon atom which may have a substituent. An alkyl group having 1 to 4 carbon atoms (the substituent is a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, an aliphatic acyloxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, An alkylcarbamoyl group having 2 to 5 carbon atoms, a dialkylcarbamoyl group having 3 to 9 carbon atoms, or a dialkylamino group having 2 to 8 carbon atoms), and R ⁵ is a hydrogen atom or a carbon atom having 1 to ⁵ carbon atoms. Shows a 4 alkyl groups, R ⁶ is
A hydrogen atom, an aliphatic acyl group having 1 to 6 carbon atoms which may have a substituent (the substituent may be an amino group, a monoalkylamino group having 1 to 4 carbon atoms, A dialkylamino group, an alkoxycarbonyl group having 2 to 5 carbon atoms, a monocyclic or condensed heterocyclyl group or a carboxy group having 5 to 10 atoms) or a carbamoyl group (optional) The substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxycarbonylalkyl group having 3 to 9 carbon atoms or a carboxyalkyl group having 2 to 5 carbon atoms (provided that R ¹ is a substituent) Is an alkyl group having 1 to 7 carbon atoms which may have R ² is a hydrogen atom, and R ⁴ has an alkoxycarbonyl group or a substituent having 2 to 5 carbon atoms. 1 or more carbon atoms Excluding those having 2 alkyl groups (the substituent is an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkylcarbamoyl group having 2 to 5 carbon atoms, or a dialkylcarbamoyl group having 3 to 9 carbon atoms) .).

In the above formula (1), examples of the “alkyl group having 1 to 15 carbon atoms” of the “alkyl group having 1 to 15 carbon atoms which may have a substituent” for R ¹ include, for example, Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 1-ethylbutyl, -Methylpentyl, 3-methylpentyl, 2-
Methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3
-Methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylhexyl Methylheptyl, 6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 7-methyloctyl , 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl , Undecyl, 4,8-dimethylnonyl, dodecyl, tridecyl , Tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl group and the like. Preferably, when unsubstituted, those having 4 to 10 carbon atoms (particularly, isobutyl, octyl, nonyl, 7-methyl Octyl, decyl and 8-methylnonyl groups), more preferably those having 8 to 10 carbon atoms (especially octyl, 7-methyloctyl, nonyl and 8-methylnonyl groups), and most preferably 9 (especially nonyl and 7-methyloctyl groups), and when having a substituent, those having 1 to 6 carbon atoms (especially methyl,
Propyl, butyl and hexyl groups).

In the above formula (1), when R ¹ is “optionally substituted alkyl group having 1 to 15 carbon atoms”, the number of substitution is preferably 1 to 3 And more preferably one. In the above formula (1), examples of the “C ¹ to C 6 alkoxy group” as a substituent in the “optionally substituted C ¹ to C 15 alkyl group” for R ¹ include: , Methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy,
Isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-
Methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-
Dimethylbutoxy, 1,2-dimethylbutoxy, 1,3
-Dimethylbutoxy, 2,3-dimethylbutoxy, etc., preferably having 2 to 4 carbon atoms (especially ethoxy, isopropoxy and butoxy), and the substituent "substituent 6 to 1 carbon atoms that may be present
Examples of the zero aryl group (the substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogeno group) are, for example, phenyl, naphthyl and the like. Unsubstituted aryl group; 2-methylphenyl, 3
-Methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-propylphenyl, 4-ethylphenyl,
2-butylphenyl, 3-pentylphenyl, 4-pentylphenyl, 3,5-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 2,4-
Dimethylphenyl, 3,5-dibutylphenyl, 2,5
-Dipentylphenyl, 2,6-dipropylphenyl,
2,4-dipropylphenyl, 2,3,6-trimethylphenyl, 2,3,4-trimethylphenyl, 3,4
5-trimethylphenyl, 2,5,6-trimethylphenyl, 2,4,6-trimethylphenyl, 2,3,6-
Tributylphenyl, 2,3,4-tripentylphenyl, 3,4,5-tributylphenyl, 2,5,6-tripropylphenyl, 2,4,6-tripropylphenyl, 1-methyl-2-naphthyl, 2-methyl-1-naphthyl, 3-methyl-1-naphthyl, 1-ethyl-2-naphthyl, 2-propyl-1-naphthyl, 3-butyl-1
-Naphthyl, 3,8-dimethyl-1-naphthyl, 2,3
-Dimethyl-1-naphthyl, 4,8-dimethyl-1-naphthyl, 5,6-dimethyl-1-naphthyl, 3,8-diethyl-1-naphthyl, 2,3-dipropyl-1-naphthyl, 4,8 -Dipentyl-1-naphthyl, 5,6-dibutyl-1-naphthyl, 2,3,6-trimethyl-1-
Naphthyl, 2,3,4-trimethyl-1-naphthyl,
3,4,5-trimethyl-1-naphthyl, 4,5,6-
Trimethyl-1-naphthyl, 2,4,8-trimethyl-
An alkyl-substituted aryl group such as a 1-naphthyl group;
Methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-propoxyphenyl, 4-ethoxyphenyl, 2-butoxyphenyl, 3-pentoxyphenyl, 4-pentoxyphenyl, 3,5-dimethoxy Phenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3,5-dibutoxyphenyl, 2,5
-Dipentoxyphenyl, 2,6-dipropoxyphenyl, 2,4-dipropoxyphenyl, 2,3,6-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 3,4,5-trimethoxy Phenyl, 2,5,6-
Trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2,3,6-tributoxyphenyl, 2,3,4
-Tripentoxyphenyl, 3,4,5-tributoxyphenyl, 2,5,6-tripropoxyphenyl, 2,
4,6-tripropoxyphenyl, 1-methoxy-2-
Naphthyl, 2-methoxy-1-naphthyl, 3-methoxy-1-naphthyl, 1-ethoxy-2-naphthyl, 2-propoxy-1-naphthyl, 3-butoxy-1-naphthyl, 3,8-dimethoxy-1- Naphthyl, 2,3-dimethoxy-1-naphthyl, 4,8-dimethoxy-1-naphthyl, 5,6-dimethoxy-1-naphthyl, 3,8-diethoxy-1-naphthyl, 2,3-dipropoxy-1-
Naphthyl, 4,8-dipentoxy-1-naphthyl, 5,
6-dibutoxy-1-naphthyl, 2,3,6-trimethoxy-1-naphthyl, 2,3,4-trimethoxy-1-
Naphthyl, 3,4,5-trimethoxy-1-naphthyl,
4,5,6-trimethoxy-1-naphthyl, 2,4,8
Alkoxy-substituted aryl groups such as -trimethoxy-1-naphthyl group; 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl,
3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,
3,5-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,5-dibromophenyl, 2,5-dibromophenyl, 2,6-dichlorophenyl, 2, 4-dichlorophenyl, 2,3,6-trifluorophenyl,
2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 2,5,6-trifluorophenyl, 2,4,6-trifluorophenyl, 2,3,6-
Tribromophenyl, 2,3,4-tribromophenyl, 3,4,5-tribromophenyl, 2,5,6-trichlorophenyl, 2,4,6-trichlorophenyl,
1-fluoro-2-naphthyl, 2-fluoro-1-naphthyl, 3-fluoro-1-naphthyl, 1-chloro-2-
Naphthyl, 2-chloro-1-naphthyl, 3-bromo-1
-Naphthyl, 3,8-difluoro-1-naphthyl, 2,
3-difluoro-1-naphthyl, 4,8-difluoro-
1-naphthyl, 5,6-difluoro-1-naphthyl,
3,8-dichloro-1-naphthyl, 2,3-dichloro-
1-naphthyl, 4,8-dibromo-1-naphthyl, 5,
6-dibromo-1-naphthyl, 2,3,6-trifluoro-1-naphthyl, 2,3,4-trifluoro-1-naphthyl, 3,4,5-trifluoro-1-naphthyl,
4,5,6-trifluoro-1-naphthyl, 2,4,8
A halogeno-substituted aryl group such as a trifluoro-1-naphthyl group; 1-methyl-3-methoxyphenyl, 3-
Aryl groups substituted with alkyl and alkoxy groups such as ethyl-4-ethoxyphenyl; 3-methyl-5
Aryl groups substituted with alkyl and halogeno groups such as fluorophenyl and 2-ethyl-4-chlorophenyl; substituted with alkoxy and halogeno groups such as 3-methoxy-6-fluorophenyl and 2-ethoxy-3-chlorophenyl Aryl groups and the like.
A phenyl group which may have a substituent (the number of substituents is
It is preferably 1 to 3, more preferably 1), still more preferably a phenyl group which is unsubstituted or substituted with one methyl, methoxy or chloro group, more preferably Is phenyl, 4-methylphenyl, 4
-Methoxyphenyl and 4-chlorophenyl groups (especially
4-chlorophenyl group), which is an aryloxy group having 6 to 10 carbon atoms which may have a substituent (the substituent is an alkyl group having 1 to 4 carbon atoms, Examples thereof include unsubstituted aryloxy groups such as phenyloxy and naphthyloxy groups; 2-methylphenyloxy, 3-methylphenyloxy, -Methylphenyloxy, 2-ethylphenyloxy, 3-propylphenyloxy, 4-ethylphenyloxy,
-Butylphenyloxy, 3-pentylphenyloxy, 4-pentylphenyloxy, 3,5-dimethylphenyloxy, 2,5-dimethylphenyloxy, 2,
6-dimethylphenyloxy, 2,4-dimethylphenyloxy, 3,5-dibutylphenyloxy, 2,5-
Dipentylphenyloxy, 2,6-dipropylphenyloxy, 2,4-dipropylphenyloxy, 2,
3,6-trimethylphenyloxy, 2,3,4-trimethylphenyloxy, 3,4,5-trimethylphenyloxy, 2,5,6-trimethylphenyloxy,
2,4,6-trimethylphenyloxy, 2,3,6-
Tributylphenyloxy, 2,3,4-tripentylphenyloxy, 3,4,5-tributylphenyloxy, 2,5,6-tripropylphenyloxy, 2,
4,6-tripropylphenyloxy, 1-methyl-2
-Naphthyloxy, 2-methyl-1-naphthyloxy,
3-methyl-1-naphthyloxy, 1-ethyl-2-naphthyloxy, 2-propyl-1-naphthyloxy, 3
-Butyl-1-naphthyloxy, 3,8-dimethyl-1
-Naphthyloxy, 2,3-dimethyl-1-naphthyloxy, 4,8-dimethyl-1-naphthyloxy, 5,6
-Dimethyl-1-naphthyloxy, 3,8-diethyl-
1-naphthyloxy, 2,3-dipropyl-1-naphthyloxy, 4,8-dipentyl-1-naphthyloxy,
5,6-dibutyl-1-naphthyloxy, 2,3,6-
Trimethyl-1-naphthyloxy, 2,3,4-trimethyl-1-naphthyloxy, 3,4,5-trimethyl-
Alkyl-substituted aryloxy groups such as 1-naphthyloxy, 4,5,6-trimethyl-1-naphthyloxy, 2,4,8-trimethyl-1-naphthyloxy;
Methoxyphenyloxy, 3-methoxyphenyloxy, 4-methoxyphenyloxy, 2-ethoxyphenyloxy, 3-propoxyphenyloxy, 4-ethoxyphenyloxy, 2-butoxyphenyloxy, 3-methoxyphenyloxy
Pentoxyphenyloxy, 4-pentoxyphenyloxy, 3,5-dimethoxyphenyloxy, 2,5-dimethoxyphenyloxy, 2,6-dimethoxyphenyloxy, 2,4-dimethoxyphenyloxy, 3,5-
Dibutoxyphenyloxy, 2,5-dipentoxyphenyloxy, 2,6-dipropoxyphenyloxy,
2,4-dipropoxyphenyloxy, 2,3,6-trimethoxyphenyloxy, 2,3,4-trimethoxyphenyloxy, 3,4,5-trimethoxyphenyloxy, 2,5,6-trimethoxy Phenyloxy, 2,
4,6-trimethoxyphenyloxy, 2,3,6-tributoxyphenyloxy, 2,3,4-tripentoxyphenyloxy, 3,4,5-tributoxyphenyloxy, 2,5,6-trioxy Propoxyphenyloxy,
2,4,6-tripropoxyphenyloxy, 1-methoxy-2-naphthyloxy, 2-methoxy-1-naphthyloxy, 3-methoxy-1-naphthyloxy, 1-ethoxy-2-naphthyl, 2-propoxy- 1-naphthyloxy, 3-butoxy-1-naphthyloxy, 3,8-
Dimethoxy-1-naphthyloxy, 2,3-dimethoxy-1-naphthyloxy, 4,8-dimethoxy-1-naphthyloxy, 5,6-dimethoxy-1-naphthyloxy, 3,8-diethoxy-1-naphthyloxy , 2, 3
-Dipropoxy-1-naphthyloxy, 4,8-dipentoxy-1-naphthyl, 5,6-dibutoxy-1-naphthyloxy, 2,3,6-trimethoxy-1-naphthyloxy, 2,3,4-trimethoxy- 1-naphthyloxy, 3,4,5-trimethoxy-1-naphthyloxy,
4,5,6-trimethoxy-1-naphthyloxy, 2,
Alkoxy-substituted aryloxy groups such as 4,8-trimethoxy-1-naphthyloxy group; 2-fluorophenyloxy, 3-fluorophenyloxy, 4-fluorophenyloxy, 2-chlorophenyloxy, 3-chlorophenyloxy, 4- Chlorophenyloxy, 2-bromophenyloxy, 3-bromophenyloxy, 4-
Bromophenyloxy, 3,5-difluorophenyloxy, 2,5-difluorophenyloxy, 2,6-difluorophenyloxy, 2,4-difluorophenyloxy, 3,5-dibromophenyloxy, 2,5-dibromophenyl Oxy, 2,6-dichlorophenyloxy, 2,4-dichlorophenyloxy, 2,3,6-trifluorophenyloxy, 2,3,4-trifluorophenyloxy, 3,4,5-trifluorophenyloxy, , 5,6-trifluorophenyloxy, 2,
4,6-trifluorophenyloxy, 2,3,6-tribromophenyloxy, 2,3,4-tribromophenyloxy, 3,4,5-tribromophenyloxy,
2,5,6-trichlorophenyloxy, 2,4,6-
Trichlorophenyloxy, 1-fluoro-2-naphthyloxy, 2-fluoro-1-naphthyloxy, 3-fluoro-1-naphthyloxy, 1-chloro-2-naphthyloxy, 2-chloro-1-naphthyloxy, 3 -Bromo-1-naphthyloxy, 3,8-difluoro-1-naphthyloxy, 2,3-difluoro-1-naphthyloxy, 4,8-difluoro-1-naphthyloxy, 5,6
-Difluoro-1-naphthyloxy, 3,8-dichloro-1-naphthyloxy, 2,3-dichloro-1-naphthyloxy, 4,8-dibromo-1-naphthyloxy,
5,6-dibromo-1-naphthyloxy, 2,3,6-
Trifluoro-1-naphthyloxy, 2,3,4-trifluoro-1-naphthyloxy, 3,4,5-trifluoro-1-naphthyloxy, 4,5,6-trifluoro-1-naphthyloxy, 2,4,8-trifluoro-1
A halogeno-substituted aryloxy group such as a naphthyloxy group; 1-methyl-3-methoxyphenyloxy,
Aryloxy groups substituted with alkyl and alkoxy groups such as ethyl-4-ethoxyphenyloxy;
Methyl-5-fluorophenyloxy, 2-ethyl-4
Aryloxy groups substituted with alkyl and halogeno groups, such as -chlorophenyloxy; 3-methoxy-6-
And an aryloxy group substituted with an alkoxy or halogeno group such as fluorophenyloxy and 2-ethoxy-3-chlorophenyloxy. A phenyloxy group optionally having a substituent (substituent Is preferably 1 to 3, more preferably 1), and still more preferably phenyloxy which is unsubstituted or substituted with one methyl, methoxy or chloro group. Groups, more preferably phenyloxy, 4-methylphenyloxy, 4-methoxyphenyloxy and 4-
A chlorophenyloxy group, the substituent being an "aralkyloxy group having 7 to 14 carbon atoms which may have a substituent (the substituent is an alkyl group having 1 to 4 carbon atoms;
An alkoxy group having 1 to 4 carbon atoms or a halogeno group) ”includes benzyloxy, α-naphthylmethyloxy, β-naphthylmethyloxy, 2-methylbenzyloxy, 3-methylbenzyloxy, 4-methylbenzyl Oxy, 2,4,6-trimethylbenzyloxy,
3,4,5-trimethylbenzyloxy, 2-methoxybenzyloxy, 3-methoxybenzyloxy, 4-methoxybenzyloxy, 3,4-dimethoxybenzyloxy, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4- Chlorobenzyloxy, 4-bromobenzyloxy, 1-naphthylethyloxy, 2-naphthylethyloxy, 1-phenylpropyloxy, 2-phenylpropyloxy, 3-phenylpropyloxy, 1-
Naphthylpropyloxy, 2-naphthylpropyloxy, 3-naphthylpropyloxy, 1-phenylbutyloxy, 2-phenylbutyloxy, 3-phenylbutyloxy, 4-phenylbutyloxy, 1-naphthylbutyloxy, 2-naphthylbutyl Oxy, 3-naphthylbutyloxy, 4-naphthylbutyloxy, 1-phenylpentyloxy, 2-phenylpentyloxy, 3-
Phenylpentyloxy, 4-phenylpentyloxy, 5-phenylpentyloxy, 1-phenylhexyloxy, 2-phenylhexyloxy, 3-phenylhexyloxy, 4-phenylhexyloxy, 5-phenylhexyloxy, 6-phenylhexyl An oxy group and the like, preferably an unsubstituted one, more preferably an unsubstituted benzyloxy group, and the substituent “cycloalkyl group having 3 to 8 carbon atoms”; Is cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, cycloheptyl and cyclooctyl groups, preferably having 4 to 6 carbon atoms,
More preferably, it is a cyclohexyl group, and as the substituent "an alkoxyalkoxy group having 2 to 8 carbon atoms which may have a substituent (the substituent is a halogeno group)", Methoxymethoxy, ethoxyethoxy, ethoxymethoxy, isopropoxymethoxy, fluoromethoxymethoxy, (2,2,2-trifluoroethoxy) methoxy, trifluoromethoxymethoxy, chloromethoxymethoxy, bromomethoxymethoxy, iodomethoxymethoxy, methoxybutoxy, Butoxybutoxy group and the like, preferably having 3 to 6 carbon atoms, more preferably ethoxyethoxy, isopropoxyethoxy and (2,2,2-trifluoroethoxy) methoxy group. , the number of "carbon which may have a substituent R ¹ 1 to 1 As a whole number alkyl group ",
Preferred are unsubstituted alkyl groups having 4 to 10 carbon atoms, alkyl groups having 1 to 6 carbon atoms substituted with alkoxy groups having 2 to 6 carbon atoms, and methyl, methoxy or chloro groups. An alkyl group having 1 to 6 carbon atoms substituted with a phenyl group, an alkyl group having 1 to 6 carbon atoms substituted with a cycloalkyl group having 4 to 6 carbon atoms, and an alkyl group having 4 to 6 carbon atoms An alkyl group having 1 to 6 carbon atoms substituted with an alkoxyalkoxy group, more preferably octyl, 7-methyloctyl, nonyl, 8-methylnonyl, 3-phenylpropyl,
(4-methylphenyl) propyl, 3- (4-methoxyphenyl) propyl, 3- (4-chlorophenyl) propyl, cyclohexylmethyl, 3- (cyclohexyl)
Propyl, 6-ethoxyhexyl, 6-isopropoxyhexyl and 4-butoxybutyl, most preferably nonyl, 7-methyloctyl and 3- (4-chlorophenyl) propyl.

In the above formula (1), R ² has 1 to 6 carbon atoms.
Examples of the “aliphatic acyloxy group” include formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy group and the like, and preferably an acetoxy group.

In the above formula (1), examples of the “alkyl group having 1 to 6 carbon atoms” of the “alkyl group having 1 to 6 carbon atoms which may have a substituent” for R ³ include, for example, Methyl,
Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl,
Isopentyl, 2-methylbutyl, neopentyl, 1-
Ethylpropyl, n-hexyl, 1-ethylbutyl, 4
-Methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, etc., preferably having 1 to 4 carbon atoms which may have a substituent, and more preferably none. In the case of substitution, isopropyl, isobutyl, s-butyl and t
a ert- butyl group, if having substituents are methyl, ethyl and isopropyl group (especially methyl and ethyl), in the formula (1), have a "substituent R ³ Examples of the “C1 to C4 alkoxy group” that is a substituent in the “good C1 to C6 alkyl group” include, for example, methoxy, ethoxy, n-propoxy,
Examples include isopropoxy, n-butoxy, isobutoxy, s-butoxy, and tert-butoxy groups, which is preferably a methoxy group, and the substituent "an alkylthio group having 1 to 4 carbon atoms" includes, for example, And methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, s-butylthio and tert-butylthio groups, preferably methylthio and ethylthio groups, more preferably methylthio group. Yes,
Examples of the substituent "an aliphatic acyloxy group having 1 to 6 carbon atoms" include formyloxy, acetoxy, propionyloxy, butyryloxy, and pentanoyloxy groups, and preferably an acetoxy group. An aryl group having 6 to 10 carbon atoms which may have a substituent (the substituent is an alkyl group having 1 to 4 carbon atoms, a hydroxy group, 4 aliphatic acyloxy groups, an alkoxy group having 1 to 4 carbon atoms or a halogeno group), for example, aryl groups such as phenyl and naphthyl groups; 2-methylphenyl, 3-methylphenyl , 4-methylphenyl, 2-ethylphenyl, 3-propylphenyl, 4-ethylphenyl, 2-butylphenyl, 3-pentylphenyl,
-Pentylphenyl, 3,5-dimethylphenyl, 2,
5-dimethylphenyl, 2,6-dimethylphenyl,
2,4-dimethylphenyl, 3,5-dibutylphenyl, 2,5-dipentylphenyl, 2,6-dipropylphenyl, 2,4-dipropylphenyl, 2,3,6-
Trimethylphenyl, 2,3,4-trimethylphenyl, 3,4,5-trimethylphenyl, 2,5,6-trimethylphenyl, 2,4,6-trimethylphenyl,
2,3,6-tributylphenyl, 2,3,4-tripentylphenyl, 3,4,5-tributylphenyl,
2,5,6-tripropylphenyl, 2,4,6-tripropylphenyl, 1-methyl-2-naphthyl, 2-methyl-1-naphthyl, 3-methyl-1-naphthyl, 1-
Ethyl-2-naphthyl, 2-propyl-1-naphthyl,
3-butyl-1-naphthyl, 3,8-dimethyl-1-naphthyl, 2,3-dimethyl-1-naphthyl, 4,8-dimethyl-1-naphthyl, 5,6-dimethyl-1-naphthyl, 3, 8-diethyl-1-naphthyl, 2,3-dipropyl-1-naphthyl, 4,8-dipentyl-1-naphthyl, 5,6-dibutyl-1-naphthyl, 2,3,6-trimethyl-1-naphthyl, 2,3,4-trimethyl-1
-Naphthyl, 3,4,5-trimethyl-1-naphthyl,
4,5,6-trimethyl-1-naphthyl, 2,4,8-
Alkyl-substituted aryl groups such as trimethyl-1-naphthyl; hydroxy-substituted aryl groups such as 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl; 2-acetoxyphenyl, 3- Aliphatic acyloxy-substituted aryl groups such as acetoxyphenyl, 4-acetoxyphenyl, 4-propionyloxyphenyl; 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-propoxyphenyl,
4-ethoxyphenyl, 2-butoxyphenyl, 3-pentoxyphenyl, 4-pentoxyphenyl, 3,5-
Dimethoxyphenyl, 2,5-dimethoxyphenyl,
2,6-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3,5-dibutoxyphenyl, 2,5-dipentoxyphenyl, 2,6-dipropoxymethoxyphenyl, 2,4-dipropoxyphenyl, 2, 3,6-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,5,6-
Trimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2,3,6-tributoxyphenyl, 2,3,4
-Tripentoxyphenyl, 3,4,5-tributoxyphenyl, 2,5,6-tripropoxyphenyl, 2,
4,6-tripropoxyphenyl, 1-methoxy-2-
Naphthyl, 2-methoxy-1-naphthyl, 3-methoxy-1-naphthyl, 1-ethoxy-2-naphthyl, 2-propoxy-1-naphthyl, 3-butoxy-1-naphthyl, 3,8-dimethoxy-1- Naphthyl, 2,3-dimethoxy-1-naphthyl, 4,8-dimethoxy-1-naphthyl, 5,6-dimethoxy-1-naphthyl, 3,8-diethoxy-1-naphthyl, 2,3-dipropoxy-1-
Naphthyl, 4,8-dipentoxy-1-naphthyl, 5,
6-dibutoxy-1-naphthyl, 2,3,6-trimethoxy-1-naphthyl, 2,3,4-trimethoxy-1-
Naphthyl, 3,4,5-trimethoxy-1-naphthyl,
4,5,6-trimethoxy-1-naphthyl, 2,4,8
An alkoxy-substituted aryl group such as trimethoxy-1-naphthyl; 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3
-Chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,
3,5-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 2,4-difluorophenyl, 3,5-dibromophenyl, 2,5-dibromophenyl, 2,6-dichlorophenyl, 2, 4-dichlorophenyl, 2,3,6-trifluorophenyl,
2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 2,5,6-trifluorophenyl, 2,4,6-trifluorophenyl, 2,3,6-
Tribromophenyl, 2,3,4-tribromophenyl, 3,4,5-tribromophenyl, 2,5,6-trichlorophenyl, 2,4,6-trichlorophenyl,
1-fluoro-2-naphthyl, 2-fluoro-1-naphthyl, 3-fluoro-1-naphthyl, 1-chloro-2-
Naphthyl, 2-chloro-1-naphthyl, 3-bromo-1
-Naphthyl, 3,8-difluoro-1-naphthyl, 2,
3-difluoro-1-naphthyl, 4,8-difluoro-
1-naphthyl, 5,6-difluoro-1-naphthyl,
3,8-dichloro-1-naphthyl, 2,3-dichloro-
1-naphthyl, 4,8-dibromo-1-naphthyl, 5,
6-dibromo-1-naphthyl, 2,3,6-trifluoro-1-naphthyl, 2,3,4-trifluoro-1-naphthyl, 3,4,5-trifluoro-1-naphthyl,
4,5,6-trifluoro-1-naphthyl, 2,4,8
And halogeno-substituted aryl groups such as -trifluoro-1-naphthyl, and the like. Preferably, it is a phenyl group optionally having 1 to 3 substituents. Examples of the 5 to 10 monocyclic or condensed heterocyclyl groups (hetero atoms contained in the ring are nitrogen, oxygen or sulfur atoms) include 5 to 7 containing 1 to 3 nitrogen atoms, oxygen or / and nitrogen atoms. Membered heterocyclic groups (eg, furyl,
Thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
Isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl,
Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
Morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, etc.)
And a group in which these “5- to 7-membered heterocyclic group” and another cyclic group are condensed (for example, benzofuranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl,
Indolidinyl, isoindolyl, indolyl, indazolyl, prynyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, carbazolyl, carbolinyl, acridinyl, isoindolinyl, etc.
Preferably, it is a furyl, thienyl and benzofuranyl group, more preferably a furyl group, and the substituent "cycloalkyl group having 3 to 8 carbon atoms" is cyclopropyl, cyclobutyl, cyclopentyl, Examples thereof include cyclohexyl, cycloheptyl and cyclooctyl groups, preferably those having 4 to 6 carbon atoms (especially cyclohexyl group), and the R ³ having 1 to 5 carbon atoms which may have a substituent. As the “six alkyl groups” as a whole, preferred are unsubstituted alkyl groups having 1 to 4 carbon atoms, alkyl groups having 1 to 4 carbon atoms substituted with methylthio or ethylthio groups, and 4 to 6 carbon atoms. Methyl and ethyl groups substituted with a cycloalkyl group, an alkyl group having 1 to 4 carbon atoms substituted with an unsubstituted phenyl group, and a hydroxy group. And an alkyl group has been having 1 to 4 carbon substituted by the number 1 to 4 alkyl groups and an acetoxy group carbon, further preferred are isopropyl, t
tert-butyl, 1-methylpropyl, 2-methylpropyl, 1-methylthio-1-methylethyl, cyclohexylmethyl, benzyl, hydroxymethyl and acetoxymethyl groups, most preferably tert-butyl,
1-methylthio-1-methylethyl, cyclohexylmethyl and benzyl groups (particularly tert-butyl and benzyl groups).

In the above formula (1), R ⁴ "C2 to C5"
Examples of the `` alkoxycarbonyl group '' include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl and tert-butoxycarbonyl group. Carbonyl and ethoxycarbonyl groups.

In the above formula (1), the “alkyl group having 1 to 4 carbon atoms” of the “alkyl group having 1 to 4 carbon atoms which may have a substituent” for R ⁴ includes, for example, Methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, tert-butyl groups, preferably methyl, ethyl and propyl groups, more preferably,
Methyl and ethyl groups.

In the above formula (1), R 1 represents a “C 1 to C ⁴ alkoxy group” which is a substituent in the “optionally substituted C 1 to C ⁴ alkyl group”. Is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy and
A tert-butoxy group is preferred, preferably a methoxy or ethoxy group, and examples of the substituent "an aliphatic acyloxy group having 1 to 6 carbon atoms" include acetoxy, propionyloxy, butyryloxy and pentayloxy. A noyloxy group, preferably a group having 2 to 3 carbon atoms (ie, an acetoxy or propionyloxy group), more preferably an acetoxy group, and the substituent “C 2 Examples of the "to 5 alkoxycarbonyl groups" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl groups, and are preferably ethoxycarbonyl groups, and the substituent "C2-C5" Examples of the “five alkylcarbamoyl groups” include methylcarbamoyl, ethylcarbamoyl Yl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, s-butylcarbamoyl and tert-butylcarbamoyl groups, preferably methylcarbamoyl and ethylcarbamoyl groups, more preferably methylcarbamolyl group And the substituent “dialkylcarbamoyl group having 3 to 9 carbon atoms” includes, for example, dimethylcarbamoyl, methyl (ethyl) carbamoyl, diethylcarbamoyl, dipropylcarbamoyl, methyl (propyl) carbamoyl, diisopropylcarbamoyl, Dibutylcarbamoyl, diisobutylcarbamoyl, di (s-butyl) carbamoyl, di (tert-butyl) carbamoyl, and the like.
Preferably, they are a dimethylcarbamoyl group and a diethylcarbamoyl group. More preferably, they are a dimethylcarbamoyl group. Examples of the substituent "dialkylamino group having 2 to 8 carbon atoms" include dimethylamino, methyl (ethyl ) Amino, diethylamino, methyl (propyl) amino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, di (s-butyl) amino, di (tert-butyl) amino, and the like. An amino and diethylamino group, more preferably a dimethylamino group, and R ⁴ "an alkyl group having 1 to 4 carbon atoms which may have a substituent";
As a whole, preferred are unsubstituted alkyl groups having 1 to 4 carbon atoms, alkyl groups having 1 to 4 carbon atoms substituted with a hydroxy group, and 1 to 4 carbon atoms substituted with an ethoxycarbonyl group. An alkyl group having 1 to 4 carbon atoms substituted with an acetoxy group, an alkyl group having 1 to 4 carbon atoms substituted with a methylcarbamoyl group, and 1 to 4 carbon atoms substituted with a dimethylcarbamoyl group And an alkyl group having 1 to 4 carbon atoms substituted with a dimethylamino group, and an alkyl group having 1 to 4 carbon atoms substituted with a dimethylamino group and a hydroxy group, a dimethylamino group and an acetoxy group. Alkyl groups having 1 to 4 carbon atoms (especially methyl, ethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, ethoxyca Bonirumechiru, acetoxymethyl,
2-acetoxyethyl, 3-acetoxypropyl, methylcarbamoylmethyl, dimethylcarbamoylmethyl,
Dimethylaminoethyl, 3-dimethylamino-2-hydroxypropyl and 3-dimethylamino-2-acetoxypropyl groups), more preferably an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group or acetoxy group. An alkyl group having 1 to 4 carbon atoms substituted with a group (particularly, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, acetoxymethyl, 2-acetoxyethyl and 3-acetoxypropyl), more preferably Is an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group (particularly, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl).

In the above formula (1), “C 1 to C 4” of R ⁵
As the `` alkyl group '', for example, methyl, ethyl,
Examples include n-propyl, isopropyl, n-butyl, isobutyl, s-butyl and tert-butyl groups, preferably a methyl group.

In the above formula (1), as the “C 1 -C 6 aliphatic acyl group” of the “optionally substituted C 1 -C 6 aliphatic acyl group” for R ⁶ , Is, for example,
Examples include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl and pivaloyl groups, preferably those having 2 to 3 carbon atoms (that is, acetyl and propionyl groups), and more preferably acetyl group. .

In the above formula (1), a monoalkyl having 1 to 4 carbon atoms which is a substituent of the "optionally substituted aliphatic acyl group having 1 to 6 carbon atoms" for R ⁶ Amino group "
Examples thereof include a methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino and tert-butylamino group, and preferably a methylamino group, The “dialkylamino group having 2 to 8 carbon atoms” is, for example, dimethylamino, methyl (ethyl) amino, diethylamino, methyl (propyl) amino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, diisobutylamino, (S-butyl) amino, di (tert-butyl) amino group and the like, preferably 2 to 4, more preferably dimethylamino group, and the substituent " Examples of the “alkoxycarbonyl group having 2 to 5 carbon atoms” include methoxycarbonyl, ethoxy and the like. Carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl and tert-butoxycarbonyl group, preferably ethoxycarbonyl group; 15 monocyclic or condensed heterocyclyl groups (hetero atoms contained in the ring are nitrogen, oxygen or sulfur atoms) "
Examples of the substituent include the same substituents as those described above as the substituent for the “alkyl group having 1 to 6 carbon atoms which may have a substituent” for R ³ , and preferably morpholino And a pyrrolidino group, and preferred as R ⁶ “optionally substituted aliphatic acyl group having 1 to 6 carbon atoms” are acetyl, propionyl, dimethylaminoacetyl, carboxyacetyl and It is a 3-carboxypropionyl group, more preferably an acetyl and propionyl group (especially an acetyl group).

In the above formula (1), “C 1 -C 1” which is a substituent of “carbamoyl group optionally having substituent (s)” for R ^6.
Examples of the "to 4 alkyl groups" include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl and tert-butyl groups, preferably methyl and ethyl groups. Examples of the substituent “alkoxycarbonylalkyl group having 3 to 9 carbon atoms” include methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl,
Ethoxycarbonylethyl, propoxycarbonylpropyl, butoxycarbonylbutyl groups and the like are preferred. Preferred are methoxycarbonylmethyl and ethoxycarbonylmethyl groups, and the substituent "carboxyalkyl group having 2 to 5 carbon atoms". Is, for example, carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, 2-carboxy-1-methylethyl, 4-carboxybutyl, 3-carboxy-1-methylpropyl, 3
-Carboxy-2-methylpropyl group and the like, preferably carboxymethyl, 2-carboxyethyl, 3
-Carboxypropyl and 4-carboxybutyl groups, and as a whole, the "carbamoyl group optionally having substituent (s)" for R ⁶ , preferred are methylcarbamoyl,
Ethylcarbamoyl, methoxycarbonylmethylcarbamoyl and ethoxycarbonylmethylcarbamoyl groups.

In the above formula (1), R ¹ as a whole is preferably an unsubstituted alkyl group having 4 to 10 carbon atoms or 1 to 6 carbon atoms substituted with an alkoxy group having 2 to 6 carbon atoms. Alkyl group, an alkyl group having 1 to 6 carbon atoms substituted with a phenyl group which may be substituted with one methyl, methoxy or chloro group, and a cycloalkyl group having 4 to 6 carbon atoms. C1 to C6 alkyl group and C1 to C6 alkyl group substituted with C4 to C6 alkoxyalkoxy group, more preferably octyl, 7-methyloctyl, nonyl ,
8-methylnonyl, phenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, 4-chlorophenylpropyl, cyclohexylmethyl, cyclohexylpropyl, 6-ethoxyhexyl, 6-isopropoxyhexyl and 4-butoxybutyl, Preferred are nonyl, 7-methyloctyl and 4-chlorophenylpropyl groups.

In the above formula (1), R ² as a whole is preferably a hydrogen atom, a hydroxy or an acetoxy group, more preferably a hydrogen atom or a hydroxy group.

In the above formula (1), R ³ as a whole is preferably an unsubstituted alkyl group having 1 to 4 carbon atoms, 1 to 4 carbon atoms substituted with one methylthio or ethylthio group. An alkyl group, a methyl or ethyl group substituted with one cycloalkyl group having 4 to 6 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with one unsubstituted phenyl group, Having 1 carbon atom substituted by a hydroxy group
To 4 alkyl groups and an alkyl group having 1 to 4 carbon atoms substituted with one acetoxy group, more preferably isopropyl, tert-butyl, 1-methylpropyl, 2-methylpropyl, -Methylthio-1-
Methylethyl, cyclohexylmethyl, benzyl, hydroxymethyl and acetoxy groups, more preferably,
tert-butyl, 1-methylthio-1-methylethyl, cyclohexylmethyl and benzyl groups (particularly te
rt-butyl and benzyl groups).

In the above formula (1), R ⁴ as a whole is preferably a hydrogen atom, an unsubstituted alkyl group having 1 to 4 carbon atoms, or a carbon atom substituted with 1 hydroxy group having 1 to 4 carbon atoms.
Alkyl group, alkyl group having 1 to 4 carbon atoms substituted with one ethoxycarbonyl group, alkyl group having 1 to 4 carbon atoms substituted with one acetoxy group, 1 methylcarbamoyl group An alkyl group having 1 to 4 carbon atoms substituted with 1, an alkyl group having 1 to 4 carbon atoms substituted with 1 dimethylcarbamoyl group, and 1 to 4 carbon atoms substituted with 1 dimethylamino group An alkyl group having 1 to 4 carbon atoms each substituted with one dimethylamino group and a hydroxy group, and an alkyl group having 1 to 4 carbon atoms each substituted with one dimethylamino group and an acetoxy group Group, more preferably a hydrogen atom and an alkyl group having 1 to 4 carbon atoms, which is substituted with one hydroxy group or one acetoxy group. Child, hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl group, and most preferably a hydrogen atom.

In the above formula (1), a preferable one as R ⁵ as a whole is a hydrogen atom.

In the above formula (1), preferred as R ⁶ as a whole are a hydrogen atom and an unsubstituted aliphatic acyl group having 2 to 3 carbon atoms, and a dialkylamino having 1 to 2 carbon atoms. Or an aliphatic acyl group having 2 or 3 carbon atoms and substituted with one carboxy group, more preferably a hydrogen atom, acetyl and propionyl group, most preferably a hydrogen atom and an acetyl group. It is.

Among the compounds which are the active ingredients of the medicament of the present invention, preferred are those represented by the formula (1): 1) R ¹ is an unsubstituted alkyl group having 4 to 10 carbon atoms,
1 carbon atom substituted by an alkoxy group having 2 to 6 carbon atoms
Substituted with an alkyl group having 1 to 6 carbon atoms, substituted with an alkyl group having 1 to 6 carbon atoms, and a cycloalkyl group having 4 to 6 carbon atoms, which is substituted with a phenyl group which may be substituted with a methyl group, a methoxy group or a chloro group. A compound having an alkyl group having 1 to 6 carbon atoms or an alkyl group having 1 to 6 carbon atoms substituted by an alkoxyalkoxy group having 4 to 6 carbon atoms, 2) R ¹ is octyl, 7-methyloctyl, Nonyl,
A compound which is an 8-methylnonyl, phenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, 4-chlorophenylpropyl, cyclohexylmethyl, cyclohexylpropyl, 6-ethoxyhexyl, 6-isopropoxyhexyl or 4-butoxybutyl group, 3) R ¹ is nonyl, 7-methyloctyl or 3- (4
A compound wherein R ¹ is nonyl or 3- (4-chlorophenyl) propyl; 5) a compound wherein R ² is hydrogen, hydroxy or acetoxy; 6) a compound wherein R ¹ is nonyl or 3- (4-chlorophenyl) propyl; ^A compound wherein ² is a hydrogen atom or a hydroxy group; 7) R ³ is an unsubstituted alkyl group having 1 to 4 carbon atoms;
1 carbon atom substituted with a methylthio or ethylthio group
A methyl or ethyl group substituted with an alkyl group having 4 to 6 carbon atoms, a cycloalkyl group having 4 to 6 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with an unsubstituted phenyl group, or a hydroxy group Compound having 1 to 4 carbon atoms, or 1 carbon atom substituted with an acetoxy group
8) compounds wherein R ³ is isopropyl, tert-butyl, 1-methylpropyl, 2-methylpropyl, 1-methylthio-
1-methylethyl, cyclohexylmethyl, benzyl,
A compound which is a hydroxymethyl or acetoxymethyl group, 9) R ³ is tert-butyl, 1-methylthio-1-
Methyl ethyl, compound cyclohexylmethyl or benzyl group, 10) R ³ is, compounds which are tert- butyl or benzyl group, 11) R ⁴ is a hydrogen atom, unsubstituted C 1 to 4 alkyl groups, 1 to 4 carbon atoms substituted with a hydroxy group
Alkyl groups having 1 to 4 carbon atoms substituted with an ethoxycarbonyl group, alkyl groups having 1 to 4 carbon atoms substituted with an acetoxy group, and 1 to 4 carbon atoms substituted with a methylcarbamoyl group. Alkyl groups, 1 to 4 carbon atoms substituted with a dimethylcarbamoyl group, and 1 to 4 carbon atoms substituted with a dimethylamino group
C1 to C4 alkyl groups substituted with dimethylamino and hydroxy groups or C1 to C4 substituted with dimethylamino and acetoxy groups
12) a compound wherein R ⁴ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group or an acetoxy group; 13) a compound wherein R ⁴ is a hydrogen atom or a hydroxy group 14) a compound wherein R ⁴ is a hydrogen atom, a hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl group, 15) a compound wherein R ⁴ is hydrogen 16) a compound wherein R ⁵ is a hydrogen atom; 17) a compound wherein R ⁶ is a hydrogen atom or an unsubstituted aliphatic acyl group having 2 to 3 carbon atoms, a dialkylamino having 2 to 4 carbon atoms. 2 or 3 carbon atoms substituted with a group or a carboxy group
A compound wherein R ⁶ is a hydrogen atom, an acetyl or propionyl group; 19) a compound wherein R ⁶ is a hydrogen atom or an acetyl group;
Can be mentioned.

Further, R ¹ is selected from ¹ ) to 4),
Select R ² from 5) to 6) and select R ² from 7) to 10)
Select ³ and select R ⁴ from 11) to 15),
Compounds in which R ⁵ is selected from ⁶ ) and R ⁶ is selected from 17) to 19) are also suitable.

For example, 20) R ¹ is an unsubstituted alkyl group having 4 to 10 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with an alkoxy group having 2 to 6 carbon atoms, methyl, methoxy or An alkyl group having 1 to 6 carbon atoms substituted with a phenyl group which may be substituted with a chloro group, an alkyl group having 1 to 6 carbon atoms or a carbon group substituted with a cycloalkyl group having 4 to 6 carbon atoms An alkyl group having 1 to 6 carbon atoms, which is substituted by an alkoxy group having 4 to 6 alkoxy groups;
² is a hydrogen atom, a hydroxy or acetoxy group,
R ³ is an unsubstituted alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a methylthio or ethylthio group, or a methyl substituted with a cycloalkyl group having 4 to 6 carbon atoms. Or a compound which is an alkyl group having 1 to 4 carbon atoms substituted with an ethyl group or an unsubstituted phenyl group, an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group, or a carbon number substituted with an acetoxy group R ⁴ is a hydrogen atom, an unsubstituted alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group, or an ethoxycarbonyl group; A substituted alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with an acetoxy group,
An alkyl group having 1 to 4 carbon atoms substituted with a methylcarbamoyl group, an alkyl group having 1 to 4 carbon atoms substituted with a dimethylcarbamoyl group, and an alkyl group having 1 to 4 carbon atoms substituted with a dimethylamino group Is an alkyl group having 1 to 4 carbon atoms substituted with a dimethylamino group and a hydroxy group or an alkyl group having 1 to 4 carbon atoms substituted with a dimethylamino group and an acetoxy group, and R ⁵ is a hydrogen atom R ⁶ is a hydrogen atom or an unsubstituted carbon number 2
A compound having ¹ to 3 aliphatic acyl groups, an aliphatic acyl group having 2 to 3 carbon atoms substituted with a dialkylamino group having 2 to 4 carbon atoms or a carboxy group; 21) R ¹ is nonyl, 7 -Methyloctyl or 3-
A (4-chlorophenyl) propyl group, R ² is a hydrogen atom or a hydroxy group, R ³ is a tert-butyl, 1-methylthio-1-methylethyl, cyclohexylmethyl or benzyl group, and R ⁴ is A compound wherein R ⁵ is a hydrogen atom and R ⁶ is a hydrogen atom or an acetyl group; 22) R ¹ is nonyl or 3- (4-chlorophenyl);
A propyl group, R ² is a hydrogen atom or a hydroxy group, R ³ is a tert-butyl or benzyl group, R ⁴ is a hydrogen atom, R ⁵ is a hydrogen atom, R ⁶ Is a hydrogen atom or an acetyl group.

When the compound (1), which is an active ingredient of the medicament of the present invention, has a carboxy group, it can be converted into a salt, and the salt is also included in the present invention. Are alkali metal salts such as sodium salt, potassium salt, lithium salt, alkaline earth metal salts such as calcium salt, magnesium salt, aluminum salt, iron salt, zinc salt, copper salt, nickel salt, cobalt salt, etc. Metal salts; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts,
Diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) Examples thereof include amine salts such as an organic salt such as an aminomethane salt. When the compound (1), which is an active ingredient of the medicament of the present invention, has an amino group, the compound can be converted into a salt. Included in the present invention, such salts preferably include hydrofluorides, hydrochlorides, hydrobromides, hydrohalides such as hydroiodide, nitrates, perchlorates. Inorganic acid salts such as acid salts, sulfates and phosphates; such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate Arylsulfonates such as lower alkanesulfonate, benzenesulfonate, p-toluenesulfonate, acetic acid, malic acid, fumarate, succinate, citrate, tartrate, oxalic acid Organic acid salts such as salts and maleates; and glycine salts and lysine salts;
Amino acid salts such as arginine salt, ornithine salt, glutamate and aspartate can be mentioned.

The compound (1), which is an active ingredient of the medicament of the present invention, may absorb water and leave adsorbed water or form a hydrate when left in the air,
Such hydrates are also included in the present invention.

Further, the compound (1), which is an active ingredient of the medicament of the present invention, has an asymmetric carbon in the molecule,
There are stereoisomers that are coordinated or S-coordinated, and each of them or any mixture thereof in any proportion is included in the present invention.

Among the compounds (1), which are the active ingredients of the medicament of the present invention, the compounds having a suitable steric configuration include those of the following formulas (wherein R ¹ , R ² , R
³ , R ⁴ , R ⁵ and R ⁶ are as defined above).

[0040]

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The compound which is an active ingredient of the medicament of the present invention includes:
Examples can be shown in Table 1, but the present invention is not limited to these.

In Table 1, Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, i Pr represents an isopropyl group, Bu represents a butyl group, and i Bu represents an isobutyl group. , T Bu represents a t-butyl group, and Bn
Represents a benzyl group, Ac represents an acetyl group, and Oct represents
Represents an octyl group, Non represents a nonyl group, and c Hx
Represents a cyclohexyl group, Ph represents a phenyl group,
Mor represents a morpholino group, and Thi represents a thienyl group.

[0043]

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[0044]

[Table 1] No. R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ ──────────────────────────────────── 0001 i Bu H t Bu HHH 0002 i Bu H t Bu HH Ac 0003 i Bu H Bn HHH 0004 i Bu H c HxCH 2 HHH 0005 i Bu H c HxCH 2 HH Ac 0006 7-Me-Oct H t Bu HHH 0007 7-Me-Oct H t Bu HH Ac 0008 Non H t Bu HHH 0009 Non H t Bu HH Ac 0010 Non H i Pr HHH 0011 Non H i Pr HH Ac 0012 Non H c HxCH 2 HHH 0013 Non H c HxCH 2 HH Ac 0014 Non H Bn HHH 0015 Non H Bn HH Ac 0016 Non H HOCH ₂ HHH 0017 Non H AcOCH ₂ HH Ac 0018 Non H CH ₃ CH (OH) HHH 0019 Non H CH ₃ CH (OAc) HH Ac 0020 Non H MeSC (Me) ₂ HHH 0021 Non H MeSC (Me) _{2 HH Ac 0022 8-Me-} Non H t Bu HHH 0023 8-Me-Non H t Bu HH Ac 0024 4-MeOPh (CH 2) 3 H t Bu HHH 0025 4-MeOPh (CH 2) 3 H t Bu HH _{Ac 0026 4-MeOPh (CH 2} ) 3 H MeSC (Me) 2 HHH 0027 4-MeOPh (CH 2) 3 H MeSC (Me) 2 HH Ac 0028 4-ClPh (CH 2) 3 H t Bu H _{HH 0029 4-ClPh (CH 2} ) 3 H t Bu HH Ac 0030 4-ClPh (CH 2) 3 H MeSC (Me) 2 HHH 0031 4-ClPh (CH 2) 3 H MeSC (Me) 2 HH Ac 0032 4 _{-MePh (CH 2) 3 H t} Bu HHH 0033 4-MePh (CH 2) 3 H t Bu HH Ac 0034 4-MePh (CH 2) 3 H MeSC (Me) 2 HHH 0035 4-MePh (CH 2) 3 _{H MeSC (Me) 2 HH Ac} 0036 c Hx (CH 2) 3 H t Bu HHH 0037 c Hx (CH 2) 3 H t Bu HH Ac 0038 c Hx (CH 2) 3 H MeSC (Me) 2 HHH 0039 c _{Hx (CH 2) 3 H MeSC} (Me) 2 HH Ac 0040 c HxCH 2 H t Bu HHH 0041 c HxCH 2 H t Bu HH Ac 0042 c HxCH 2 H MeSC (Me) 2 HHH 0043 c HxCH 2 H MeSC (Me _{) 2 HH Ac 0044 BuO (CH} 2) 4 H t Bu HHH 0045 BuO (CH 2) 4 H t Bu HH Ac 0046 BuO (CH 2) 4 H MeSC (Me) 2 HHH 0047 BuO (CH 2) 4 H MeSC _{(Me) 2 HH Ac 0048 EtO} (CH 2) 6 H t Bu HHH 0049 EtO (CH 2) 6 H t Bu HH Ac 0050 i PrO (CH 2) 6 H t Bu HHH 0051 i PrO (CH 2) 6 H _{t Bu HH Ac 0052 CF 3 CH} 2 OCH 2 O (CH 4) 2 H t Bu HHH 0053 CF 3 CH 2 OCH 2 O (CH 4) 2 H t Bu HH Ac 0054 Non H t Bu Me HH 0055 Non H t Bu Me H Ac 0056 Non H t Bu Me Me H 0057 Non H i Pr Me Me H 0058 Non H c HxCH ₂ Me Me H 0059 Non H t Bu Et HH 0 060 Non H t Bu Et H Ac 0061 Non H Bn -COOMe HH 0062 Non H Bn -CH ₂ CONHMe HH 0063 Non H Bn -CH ₂ CONMe ₂ HH 0064 Non H t Bu -CH ₂ CONHMe HH 0065 Non H t Bu- _{CH 2 CONMe 2 HH 0066 Non H} t Bu -CH 2 OH HH 0067 Non H t Bu -CH 2 OAc H Ac 0068 Non H i Pr -CH 2 OH HH 0069 Non H i Pr -CH 2 OAc H Ac 0070 Non H _{t Bu -CH 2 CH 2 OH HH} 0071 Non H t Bu -CH 2 CH 2 OAc H Ac 0072 Non H i Pr -CH 2 CH 2 OH HH 0073 Non H i Pr -CH 2 CH 2 OAc H Ac 0074 Non H _{t Bu -CH 2 (CH 2)} 2 OH HH 0076 Non H i Pr -CH 2 (CH 2) 2 OH HH 0077 Non H i Pr -CH 2 (CH 2) 2 OAc H Ac 0078 Non H t Bu -CH ₂ CH ₂ NMe ₂ HH 0079 Non H t Bu -CH ₂ CH ₂ NMe ₂ H Ac 0080 Non H t Bu -CH ₂ CH (OH) CH ₂ NMe ₂ HH 0081 Non H t Bu -CH ₂ CH (OAc) CH ₂ NMe ₂ H Ac 0082 Non H t Bu -CH ₂ CH ₂ NMe (Et) HH 0083 Non H t Bu -CH ₂ CH ₂ NMe (Et) H Ac 0084 Non H t Bu HH -COEt 0085 Non H t Bu HH -COCH ₂ NH ₂ 0086 Non H t Bu HH -COCH ₂ NHMe 0087 Non H t Bu HH -COCH ₂ NMe ₂ 0088 Non H t Bu HH -COCH ₂ CH ₂ NH ₂ 0089 Non H t Bu HH -COCH ₂ CH ₂ CO ₂ Et 0090 Non H t Bu HH -COCH ₂ CH ₂ COOH 0091 Non H t Bu HH -CONHEt 0092 Non H t Bu HH -CONHMe 0093 Non H t Bu HH -CONHCH ₂ CO ₂ Me 0094 Non H t Bu HH -CONHCH ₂ CO ₂ Et 0095 Non H EtCH (Me) HHH 0096 Non H EtCH (Me) HH Ac 0097 Non H (Me) ₂ CHCH ₂ HHH 0098 Non H (Me) ₂ CHCH ₂ HH Ac 0099 Non H ThiCH ₂ HHH 0100 Non H ThiCH ₂ HH Ac 0101 Non H i Pr Et HH 0102 i Bu OH t Bu HHH 0103 i Bu OH t Bu HH Ac 0105 i Bu OH c HxCH ₂ HHH 0106 i Bu OH c HxCH ₂ HH Ac 0107 7-Me-Oct OH t Bu HHH 0108 7- Me-Oct OH t Bu HH Ac 0109 Non OH t Bu HHH 0110 Non OH t Bu HH Ac 0111 Non OH i Pr HHH 0112 Non OH i Pr HH Ac 0113 Non OH c HxCH ₂ HHH 0114 Non OH c HxCH ₂ HH Ac 0115 Non OH Bn HHH 0116 Non OH Bn HH Ac 0117 Non OH HOCH ₂ HHH 0118 Non OH AcOCH ₂ HH Ac 0119 Non OH CH ₃ CH (OH) HHH 0120 Non OH CH ₃ CH (OAc) HH Ac 0121 Non OH MeSC (Me ) ₂ HHH 0122 Non OH MeSC (Me) ₂ HH Ac 0123 8-Me-Non OH t Bu HHH 0124 8-Me-Non OH t Bu HH Ac 0125 4-MeOPh (CH ₂ ) ₃ OH t Bu HHH 0126 4- MeOPh (CH ₂ ) ₃ OH t Bu HH Ac 0127 4-MeOPh (CH ₂ ) ₃ OH MeSC (Me) ₂ HHH 0128 4-Me OPh (CH ₂ ) ₃ OH MeSC (Me) ₂ HH Ac 0129 4-ClPh (CH ₂ ) ₃ OH t Bu HHH 0130 4-ClPh (CH ₂ ) ₃ OH t Bu HH Ac 0131 4-ClPh (CH ₂ ) ₃ OH MeSC (Me) ₂ HHH 0132 4-ClPh (CH ₂ ) ₃ OH MeSC (Me) ₂ HH Ac 0133 4-MePh (CH ₂ ) ₃ OH t Bu HHH 0134 4-MePh (CH ₂ ) ₃ OH t Bu HH Ac 0135 4-MePh (CH ₂ ) ₃ OH MeSC (Me) ₂ HHH 0136 4-MePh (CH ₂ ) ₃ OH MeSC (Me) ₂ HH Ac 0137 c Hx (CH ₂ ) ₃ OH t Bu HHH 0138 c Hx ( CH ₂ ) ₃ OH t Bu HH Ac 0139 c Hx (CH ₂ ) ₃ OH MeSC (Me) ₂ HHH 0140 c Hx (CH ₂ ) ₃ OH MeSC (Me) ₂ HH Ac 0141 c HxCH ₂ OH t Bu HHH 0142 c HxCH ₂ OH t Bu HH Ac 0143 c HxCH ₂ OH MeSC (Me) ₂ HHH 0144 c HxCH ₂ OH MeSC (Me) ₂ HH Ac 0145 BuO (CH ₂ ) ₄ OH t Bu HHH 0146 BuO (CH ₂ ) ₄ OH t Bu HH Ac 0147 BuO (CH ₂ ) ₄ OH MeSC (Me) ₂ HHH 0148 BuO (CH ₂ ) ₄ OH MeSC (Me) ₂ HH Ac 0149 EtO (CH ₂ ) ₆ OH t Bu HHH 0150 EtO (CH ₂ ) ₆ OH t Bu HH Ac 0151 i PrO (CH ₂ ) ₆ OH t Bu HHH 0152 i PrO (CH ₂ ) ₆ OH t Bu HH Ac 0153 CF ₃ CH ₂ OCH ₂ O (CH ₂ ) ₄ OH t Bu HHH 0154 CF ₃ CH ₂ OCH ₂ O (CH ₂ ) ₄ OH t Bu HH Ac 0155 Non OH t Bu Me HH 0156 Non OH t Bu Me H Ac 0157 Non OH t Bu Me Me H 0158 Non OH i Pr Me Me H 0159 Non OH c HxCH ₂ Me Me H 0160 Non OH t Bu Et HH 0161 Non OH t Bu Et H Ac 0162 Non OH Bn -COOMe HH 0163 Non OH Bn- CH ₂ CONHMe HH 0164 Non OH Bn -CH ₂ CONMe ₂ HH 0165 Non OH t Bu -CH ₂ CONHMe HH 0166 Non OH t Bu -CH ₂ CONMe ₂ HH 0167 Non OH t Bu -CH ₂ OH HH 0168 Non OH t Bu -CH ₂ OAc H Ac 0169 Non OH i Pr -CH ₂ OH HH 0170 Non OH i Pr -CH ₂ OAc H Ac 0171 Non OH t Bu -CH ₂ CH ₂ OH HH 0172 Non OH t Bu -CH ₂ CH ₂ OAc H Ac 0173 Non OH i Pr -CH ₂ CH ₂ OH HH 0174 Non OH i Pr -CH ₂ CH ₂ OAc H Ac 0175 Non OH t Bu -CH ₂ (CH ₂ ) ₂ OH HH 0176 Non OH t Bu -CH ₂ (CH ₂ ) ₂ OAc H Ac 0177 Non OH i Pr -CH ₂ (CH ₂ ) ₂ OH HH 0178 Non OH i Pr -CH ₂ (CH ₂ ) ₂ OAc H Ac 0179 Non OH t Bu -CH ₂ CH ₂ NMe ₂ HH 0180 Non OH t Bu -CH ₂ CH ₂ NMe ₂ H Ac 0181 Non OH t Bu -CH ₂ CH (OH) CH ₂ NMe ₂ HH 0182 Non OH t Bu -CH ₂ CH (OAc) CH ₂ NMe ₂ H Ac 0183 Non OH t Bu -CH ₂ CH ₂ NMe (Et) HH 0184 Non OH t Bu -CH ₂ CH ₂ NMe (Et) H Ac 0185 Non OH t Bu HH -COEt 0186 Non OH t Bu HH -COCH ₂ NH ₂ 0187 Non OH t Bu HH -COCH ₂ NHMe 0188 Non OH t Bu HH -COCH ₂ NMe ₂ 0189 Non OH t Bu HH -COCH ₂ CH ₂ NH ₂ 0190 Non OH t Bu HH -COCH ₂ CH ₂ CO ₂ Et 0191 Non OH t Bu HH -COCH ₂ CH ₂ COOH 0192 Non OH t Bu HH -CONHEt 0193 Non OH t Bu HH -CONHMe 0194 Non OH t Bu HH -CONHCH ₂ CO ₂ Me 0195 Non OH t Bu HH -CONHCH ₂ CO ₂ Et 0196 Non OH EtCH (Me) HHH 0197 Non OH EtCH (Me) HH Ac 0198 Non OH (Me) ₂ CHCH ₂ HHH 0199 Non OH (Me) ₂ CHCH ₂ HH Ac 0200 Non OH ThiCH ₂ HHH 0201 Non OH ThiCH ₂ HH Ac 0202 Non OH i Pr Et HH 0203 Non OAc t Bu HH Ac 0204 Non OAc t Bu HH COEt 0205 Oct H t Bu HO (CH ₂ ) ₂ HH 0206 Non H t Bu HO (CH ₂ ) ₂ H -COCH _{2 CH 2 COOH 0207 Non H t Bu} HO (CH 2) 2 H -COCH 2 CH 2 NEt 2 0208 Oct OH t Bu HO (CH 2) 2 HH 0209 Non OH t Bu HO (CH 2) 2 H -COCH 2 CH ₂ COOH 0210 Non OH t Bu HO (CH ₂ ) ₂ H -COCH ₂ CH ₂ NEt ₂ 0211 Oct H t Bu HO (CH ₂ ) ₃ HH 0212 Non H t Bu HO (CH ₂ ) ₃ H -COCH ₂ CH ₂ COOH 0213 Non H t Bu HO ( CH 2) 3 H -COCH 2 CH 2 NEt 2 0214 Oct OH t Bu HO (CH 2) 3 HH 0215 Non OH t Bu HO (CH 2 ) ₃ H -COCH ₂ CH ₂ COOH 0216 Non OH t Bu HO (CH ₂ ) ₃ H -COCH ₂ CH ₂ NEt ₂ 0217 Non H t Bu HO (CH ₂ ) ₄ HH 0218 Non H t Bu HO (CH ₂ ) _{4 H -COCH 2 CH 2 COOH 0219} Non H t Bu HO (CH 2) 4 H -COCH 2 CH 2 NEt 2 0220 Non OH t Bu HO (CH 2) 4 HH 0221 Non OH t Bu HO (CH 2) 4 H -COCH ₂ CH ₂ COOH 0222 Non OH t Bu HO (CH ₂ ) ₄ H -COCH ₂ CH ₂ NEt ₂ 0223 Non H t Bu AcO (CH ₂ ) ₂ HH 0224 Non H t Bu AcO (CH ₂ ) ₂ H -COCH ₂ CH ₂ COOH 0225 Non H t Bu AcO (CH ₂ ) ₂ H -COCH ₂ CH ₂ NEt ₂ 0226 Non OH t Bu AcO (CH ₂ ) ₂ HH 0227 Non OH t Bu AcO (CH ₂ ) ₂ H- COCH ₂ CH ₂ COOH 0228 Non OH t Bu AcO (CH ₂ ) ₂ H -COCH ₂ CH ₂ NEt ₂ 0229 Non H t Bu AcO (CH ₂ ) ₃ HH 0230 Non H t Bu AcO (CH ₂ ) ₃ H -COCH _{2 CH 2 COOH 0231 Non H t} Bu AcO (CH 2) 3 H -COCH 2 CH 2 NEt 2 0232 Non OH t Bu AcO (CH 2) 3 HH 0233 Non OH t Bu AcO (CH 2) 3 H -COCH 2 CH ₂ COOH 0234 Non OH t Bu AcO (CH ₂ ) ₃ H -COCH ₂ CH ₂ NEt ₂ 0235 Non H t Bu AcO (CH ₂ ) ₄ HH 0236 Non H t Bu AcO (CH ₂ ) ₄ H -COCH ₂ CH ₂ COOH 0237 Non H t Bu AcO (CH ₂ ) ₄ H -COCH ₂ CH ₂ NEt ₂ 0238 N on OH t Bu AcO (CH ₂ ) ₄ HH 0239 Non OH t Bu AcO (CH ₂ ) ₄ H -COCH ₂ CH ₂ COOH 0240 Non OH t Bu AcO (CH ₂ ) ₄ H -COCH ₂ CH ₂ NEt ₂ 0241 EtO _{(CH 2) 2 O (CH} 2) 2 H t Bu HO (CH 2) 2 HH 0242 EtO (CH 2) 2 O (CH 2) 2 H t Bu HO (CH 2) 2 H -COCH 2 CH 2 COOH _{0243 EtO (CH 2) 2 O} (CH 2) 2 H t Bu HO (CH 2) 2 H -COCH 2 CH 2 NEt 2 0244 EtO (CH 2) 2 O (CH 2) 2 OH t Bu HO (CH 2 ) ₂ HH 0245 EtO (CH ₂ ) ₂ O (CH ₂ ) ₂ OH t Bu HO (CH ₂ ) ₂ H -COCH ₂ CH ₂ COOH 0246 EtO (CH ₂ ) ₂ O (CH ₂ ) ₂ OH t Bu HO ( CH ₂ ) ₂ H -COCH ₂ CH ₂ NEt ₂ 0247 EtO (CH ₂ ) ₂ O (CH ₂ ) ₄ H t Bu HO (CH ₂ ) ₂ HH 0248 EtO (CH ₂ ) ₂ O (CH ₂ ) ₄ H t _{Bu HO (CH 2) 2 H} -COCH 2 CH 2 COOH 0249 EtO (CH 2) 2 O (CH 2) 4 H t Bu HO (CH 2) 2 H -COCH 2 CH 2 NEt 2 0250 EtO (CH 2) ₂ O (CH ₂ ) ₄ OH t Bu HO (CH ₂ ) ₂ HH 0251 EtO (CH ₂ ) ₂ O (CH ₂ ) ₄ OH t Bu HO (CH ₂ ) ₂ H -COCH ₂ CH ₂ COOH 0252 EtO (CH _{2) 2 O (CH 2)} 4 OH t Bu HO (CH 2) 2 H -COCH 2 CH 2 NEt 2 0253 PrO (CH 2) 2 O (CH 2) 4 H t Bu HO (CH 2) 2 HH 0254 _{PrO (CH 2) 2 O (} CH 2) 4 H t Bu HO (CH 2) 2 H -COCH 2 CH 2 _{COOH 0255 PrO (CH 2) 2} O (CH 2) 4 H t Bu HO (CH 2) 2 H -COCH 2 CH 2 NEt 2 0256 PrO (CH 2) 2 O (CH 2) 4 OH t Bu HO (CH ₂ ) ₂ HH 0257 PrO (CH ₂ ) ₂ O (CH ₂ ) ₄ OH t Bu HO (CH ₂ ) ₂ H -COCH ₂ CH ₂ COOH 0258 PrO (CH ₂ ) ₂ O (CH ₂ ) ₄ OH t Bu HO (CH ₂ ) ₂ H -COCH ₂ CH ₂ NEt ₂ 0259 Non H t Bu HO (CH ₂ ) ₂ H -COCH ₂ NEt ₂ 0260 Non OH t Bu HO (CH ₂ ) ₂ H -COCH ₂ NEt ₂ 0261 EtO ( _{CH 2) 2 O (CH 2} ) 2 H t Bu HO (CH 2) 2 H -COCH 2 NEt 2 0262 EtO (CH 2) 2 O (CH 2) 2 OH t Bu HO (CH 2) 2 H -COCH _{2 NEt 2 0263 EtO (CH 2} ) 2 O (CH 2) 4 H t Bu HO (CH 2) 2 H -COCH 2 NEt 2 0264 EtO (CH 2) 2 O (CH 2) 4 OH t Bu HO (CH _{2) 2 H -COCH 2 NEt 2} 0265 PrO (CH 2) 2 O (CH 2) 4 H t Bu HO (CH 2) 2 H -COCH 2 NEt 2 0266 PrO (CH 2) 2 O (CH 2) 4 OH t Bu HO (CH ₂ ) ₂ H -COCH ₂ NEt ₂ 0267 Non H t Bu HO (CH ₂ ) ₂ H -COCH ₂ COOH 0268 Non OH t Bu HO (CH ₂ ) ₂ H -COCH ₂ COOH 0269 EtO ( _{CH 2) 2 O (CH 2} ) 2 H t Bu HO (CH 2) 2 H -COCH 2 COOH 0270 EtO (CH 2) 2 O (CH 2) 2 OH t Bu HO (CH 2) 2 H -COCH 2 _{COOH 0271 EtO (CH 2) 2} O (CH 2) 4 H t Bu HO (CH 2) _{2 H -COCH 2 COOH 0272 EtO (} CH 2) 2 O (CH 2) 4 OH t Bu HO (CH 2) 2 H -COCH 2 COOH 0273 PrO (CH 2) 2 O (CH 2) 4 H t Bu HO (CH ₂ ) ₂ H -COCH ₂ COOH 0274 PrO (CH ₂ ) ₂ O (CH ₂ ) ₄ OH t Bu HO (CH ₂ ) ₂ H -COCH ₂ COOH 0275 Non H t Bu HO (CH ₂ ) ₂ H- _{COCH 2 NMe 2 0276 Non OH t} Bu HO (CH 2) 2 H -COCH 2 NMe 2 0277 EtO (CH 2) 2 O (CH 2) 2 H t Bu HO (CH 2) 2 H -COCH 2 NMe 2 0278 EtO (CH ₂ ) ₂ O (CH ₂ ) ₂ OH t Bu HO (CH ₂ ) ₂ H -COCH ₂ NMe ₂ 0279 EtO (CH ₂ ) ₂ O (CH ₂ ) ₄ H t Bu HO (CH ₂ ) ₂ H _{-COCH 2 NMe 2 0280 EtO (CH} 2) 2 O (CH 2) 4 OH t Bu HO (CH 2) 2 H -COCH 2 NMe 2 0281 PrO (CH 2) 2 O (CH 2) 4 H t Bu HO (CH ₂ ) ₂ H -COCH ₂ NMe ₂ 0282 PrO (CH ₂ ) ₂ O (CH ₂ ) ₄ OH t Bu HO (CH ₂ ) ₂ H -COCH ₂ NMe ₂ 0283 Non H t Bu HO (CH ₂ ) _{2 H -CO (CH 2) 2 NMe} 2 0284 Non OH t Bu HO (CH 2) 2 H -CO (CH 2) 2 NMe 2 0285 EtO (CH 2) 2 O (CH 2) 2 H t Bu HO (CH ₂ ) ₂ H -CO (CH ₂ ) ₂ NMe ₂ 0286 EtO (CH ₂ ) ₂ O (CH ₂ ) ₂ OH t Bu HO (CH ₂ ) ₂ H -CO (CH ₂ ) ₂ NMe ₂ 0287 EtO (CH _{2 ) 2 O (CH 2) 4} H t Bu HO (CH 2) 2 H -CO (CH 2) 2 NMe 2 0288 EtO _{(CH 2) 2 O (CH} 2) 4 OH t Bu HO (CH 2) 2 H -CO (CH 2) 2 NMe 2 0289 PrO (CH 2) 2 O (CH 2) 4 H t Bu HO (CH 2 ) ₂ H -CO (CH ₂ ) ₂ NMe ₂ 0290 PrO (CH ₂ ) ₂ O (CH ₂ ) ₄ OH t Bu HO (CH ₂ ) ₂ H -CO (CH ₂ ) ₂ NMe ₂ 0291 Non H 4- ( OH) PhCH ₂ HHH 0292 Non H 4- (AcO) PhCH ₂ HH Ac 0293 Non OH 4- (OH) PhCH ₂ HHH 0294 Non OH 4- (AcO) PhCH ₂ HH Ac 0295 Non OAc Me (Me) ₂ SHH Ac 0296 Non OH i Pr Et HH 0297 4-ClPh (CH ₂ ) ₃ OH Bn CH ₂ CONHMe H Ac 0298 4-ClPh (CH ₂ ) ₃ OH Bn CH ₂ CONHMe HH 0299 EtO (CH ₂ ) ₂ O (CH ₂ ) _{3 H t Bu HH Ac 0300 EtO} (CH 2) 2 O (CH 2) 3 H t Bu HHH 0301 4-ClPh (CH 2) 3 H Bn HH Ac 0302 4-ClPh (CH 2) 3 H Bn HHH 0303 4 _{-ClPhO (CH 2) 2 H t} Bu HH Ac 0304 4-ClPhO (CH 2) 2 H t Bu HHH 0305 4-ClPh (CH 2) 3 H HOCH 2 HHH 0306 4-ClPh (CH 2) 3 H AcOCH 2 HH Ac 0307 4-ClPh (CH 2) 3 H c HxCH 2 HHH 0308 4-ClPh (CH 2) 3 H c HxCH 2 HH Ac 0309 Non H AcOCH 2 Me H Ac 0310 Non H HOCH 2 Me HH 0311 Non H t _{Bu HH COCH 2 Mor 0312 Non H} t Bu HH COCH 2 CH 2 CO 2 Na 0313 i Bu OAc t Bu HH Ac 0314 PhCH 2 OCH 2 H t Bu Me Me H 0315 N on H CH ₂ OMe HHH 0316 Non H t Bu CH ₂ CO ₂ Me H Ac 0317 Non H t Bu CH ₂ OMe HH ───────────────────────の う ち Among the above exemplified compounds, preferred are 8, 9,
10, 11, 12, 13, 16, 17, 20, 21, 2
8, 29, 66, 67, 70, 71, 74, 75, 10
2, 107, 108, 109, 110, 167, 16
8, 171, 172, 175, 176, 301, 30
2, 305, 306, 307, 308 and 313, more preferably N ⁴ -hydroxy-
N ¹ - [1-hydroxy-2,2-dimethyl-propyl] -2-nonyl disk Sina bromide (8), acetic acid 2-
[2-(N-hydroxy-carbamoylmethyl) undecanoylamino amino] -3,3-dimethyl-butyl ester (9), N ⁴ - hydroxy -N ¹ - [1-hydroxy-2-methylpropyl] -2-Bruno Nilsuccinamide (10), acetic acid 2- [2- (N-hydroxycarbamoylmethyl) undecanoylamino] -3-methylbutyl ester (11), N ⁴ -hydroxy-N ^1- [2-
Hydroxy-1- (hydroxymethyl) ethyl] -2-
Nonyl succinamide (16), 3-acetoxy acetic acid
2- [2- (N-hydroxycarbamoylmethyl) undecanoylamino] propyl ester (17), N ⁴ −
Hydroxy -N ¹ - [1-hydroxy-2-methyl-2-methylthio propyl] -2-nonyl disk Sina bromide (20), acetic acid 2-[2-(N-hydroxy-carbamoylmethyl) undecanoylamino amino] - 3-methyl-
3-methylthiobutyl ester (21), 2- [3-
(4-chlorophenyl) propyl] -N ⁴ - hydroxy -N ¹ - [1-hydroxy-2,2-dimethylpropyl] succinamide (28), acetic acid 2- [5- (4
- chlorophenyl)-2-(N-hydroxy-carbamoylmethyl) pentanoylamino] -3,3-dimethyl-butyl ester (29), N ⁴ -3- dihydroxy -N ¹
-[1-hydroxymethyl-2,2-dimethylpropyl] -2- (7-methyloctyl) succinamide (10
7), 2- (S)-{2- [acetoxy (hydroxycarbamoyl) methyl] -9-decanoylamino} acetate
-3,3-dimethylbutyl ester (108), N ⁴ −
3-dihydroxy -N ¹ - [1-hydroxy-methyl -
2,2-dimethylpropyl] -2-nonylsuccinamide (109), 2- [5- (4-chlorophenyl) acetic acid
-2- (N-hydroxycarbamoylmethyl) pentanoylamino] -3-phenylpropyl ester (30
^1), N 1 - [1- benzyl-2-hydroxyethyl]
2- [3- (4-chlorophenyl) propyl] -N ⁴
-Hydroxysuccinamide (302), 2- [3- (4
- chlorophenyl) propyl] -N ⁴ - hydroxy -N
¹ - (2-hydroxy-1-hydroxymethyl-ethyl)
Succinamide (305), acetic acid 2- [5- (4-chlorophenyl) -2- (N-hydroxycarbamoylmethyl) pentanoylamino] -3-acetoxypropyl ester (306), 2- [3- (4-chlorophenyl)
Propyl] -N ¹ - [1- cyclohexylmethyl-2
Hydroxyethyl] -N ⁴ - 2-hydroxysuccinimide Sina bromide (307) and acetic acid [5- (4-chlorophenyl)-2-(N-hydroxy-carbamoylmethyl) pentanoylamino] -3-cyclohexyl-propyl ester (308) is And most preferably, 2- [3-
(4-chlorophenyl) propyl] -N ⁴ - hydroxy -N ¹ - [1-hydroxy-2,2-dimethylpropyl] succinamide (28), acetic acid 2- [5- (4
- chlorophenyl)-2-(N-hydroxy-carbamoylmethyl) pentanoylamino] -3,3-dimethyl-butyl ester (29), N ⁴ -3- dihydroxy -N ¹
-[1-hydroxymethyl-2,2-dimethylpropyl] -2-nonylsuccinamide (109), acetic acid 2-
{2- [hydroxy (hydroxycarbamoyl) methyl] undecanoylamino} -3,3-dimethylbutyl ester (110), acetic acid 2- [5- (4-chlorophenyl) -2- (N-hydroxycarbamoylmethyl)
Pentanoylamino] -3-phenylpropyl ester (301) and N ¹ - [1-benzyl-2-hydroxy-ethyl] -2- [3- (4-chlorophenyl) propyl] -N ⁴ - hydroxysuccinimide Sina bromide (302) Is raised.

[0045]

BEST MODE FOR CARRYING OUT THE INVENTION The hydroxamic acid derivative which is an active ingredient of the medicament of the present invention can be produced by the method described below.

[0046]

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[0047]

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[0048]

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[0049]

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[0050]

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[0051]

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[0052]

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[0053]

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[0054]

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[0055]

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[0056]

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[0057]

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[0058]

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In the above process chart, R ¹ , R ² , R ³ , R ⁴ ,
R ⁵ and R ⁶ have the same meaning as described above, and R ^6a is an aliphatic acyl group having 2 to 5 carbon atoms which may have a substituent (the substituent may be protected An amino group, an alkylamino group having 1 to 4 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms or a carboxy group which may be protected) or a substituent A carbamoyl group optionally having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, an alkoxycarbonylalkyl group having 3 to 9 carbon atoms, or a 2
To 5 carboxyalkyl groups), and R ⁷
Represents a “silyl-type” protecting group (preferably a tert-butyldimethylsilyl group) or a benzyl-type protecting group (preferably a benzyl group); R ⁸ represents the same group as R ⁷ ; ⁹ represents an aliphatic or aromatic acyl group, R ¹⁰ represents an isopropyl group or a benzyl group, X represents a halogen atom, R ¹¹ has the formula _{^{R 11a -CH = CH-CH 2}} - (R
^11a is an alkyl group having 1 to 12 carbon atoms which may have a substituent (the substituent is an alkyl group having 1 to 15 carbon atoms which may have a substituent of R ¹ ) And a group capable of reducing the double bond of the formula to R ^1, and R ¹² is a protecting group for an amino group (preferably tert. -Butoxycarbonyl group or benzyloxycarbonyl group);
¹³ , R ¹⁴ and R ¹⁵ are the same or different and represent an alkyl group having 1 to 4 carbon atoms, R ¹⁶ represents an aliphatic or aromatic acyl group, R ¹⁷ represents an alkyl group, and R ¹⁸ represents an aliphatic group. Or an aromatic acyl group; n represents an integer of 1 to 4;
Bu represents a t-butyl group, iPr represents an isopropyl group, TBS represents a t-butyldimethylsilyl group, and T
s represents a p-toluenesulfonyl group.

Hereinafter, each step will be described.

(First Step) Condensation In this step, compound (2) and compound (3) are prepared in an inert solvent.
To produce the compound (4).

The condensation is carried out by a conventional method, for example, an azide method, an active ester method, a mixed acid anhydride method or a condensation method.

In the azide method, compound (2) is treated with hydrazine in an inert solvent (eg, dimethylformamide).
After reacting around room temperature, then reacting the produced acid hydrazide with a nitrite compound to convert it to an azide compound,
It is performed by treating with an amine compound (3). Examples of the nitrite compound used include an alkali metal nitrite such as sodium nitrite and an alkyl nitrite such as isoamyl nitrite. The reaction is preferably carried out in an inert solvent. Examples of the solvent used include amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and pyrrolidone such as N-methylpyrrolidone. You can give a kind. The two steps of the present method are usually performed in one reaction solution. Is 5 minutes to 1 hour in the first stage and 10 hours to 5 days in the second stage.

The active ester method is carried out by reacting the compound (2) with an active esterifying agent to produce an active ester and then reacting with the amine compound (3).
Both reactions are suitably carried out in an inert solvent, examples of solvents used include methylene chloride, halogenated hydrocarbons such as chloroform, ethers, ethers such as tetrahydrofuran, dimethylformamide, Examples thereof include amides such as dimethylacetamide and nitriles such as acetonitrile. Examples of the active esterifying agent used include N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide or dipyridyl disulfide. The active esterification reaction is suitably performed in the presence of a condensing agent such as dicyclohexylcarbodiimide or triphenylphosphine.

In some cases, an organic amine such as triethylamine, N-methylmorpholine, or dimethylaminopyridine may be used as the base catalyst.

In the active esterification reaction, the reaction temperature is-
The temperature is 10 ° C. to 100 ° C., the temperature is around room temperature in the reaction between the active ester compound and the amine (3), and the time required for both reactions is 30 minutes to 80 hours.

The mixed acid anhydride method is carried out by producing a mixed acid anhydride of the compound (2) and then reacting the mixed acid anhydride with an amine. The reaction for producing the mixed anhydride is carried out in an inert solvent (for example, the above-mentioned halogenated hydrocarbons, amides, ethers (preferably tetrahydrofuran)) in a mixed anhydride agent such as ethyl chlorocarbonate. A lower (C ₁ -C ₄ ) alkyl carbonate such as isobutyl chlorocarbonate, a lower alkanoyl halide such as pivaloyl chloride, or a lower alkyl or diaryl cyanophosphoric acid such as diethyl cyanophosphoric acid and diphenyl cyanophosphoric acid; This is achieved by reacting compound (2).

The reaction is preferably carried out with triethylamine, N
Carried out in the presence of an organic amine such as methylmorpholine, dimethylaminopyridine, pyridine, and the reaction temperature is
The temperature is -20 ° C to 50 ° C, and the time required for the reaction is 30 minutes to 20 hours.

The reaction of the mixed acid anhydride with the amine (3) is preferably carried out in an inert solvent (for example, the above-mentioned amides or ethers) in the presence of the above-mentioned organic amine, and the reaction temperature is 0. C. to 80 ° C., and the time required for the reaction is 1 hour to 24 hours. This reaction is also performed in the presence of compound (2), compound (3) and a mixed acid anhydride agent.

The condensation method comprises directly reacting compound (2) with amine (3) in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, 1-methyl-2-chloro-pyridinium iodide-triethylamine. Done by This reaction is carried out in the same manner as the above-mentioned reaction for producing an active ester.

After the completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound can be obtained by a conventional method, for example, recrystallization, reprecipitation, or a method usually used for separation and purification of organic compounds, for example, silica gel, alumina, magnesium-silica gel type florisil. Column chromatography using a suitable carrier; Sephadex LH-20 (manufactured by Pharmacia), Amberlite XAD-11 (Rohm and
Haas), a method using synthetic adsorbents such as distribution column chromatography using a carrier such as Diaion HP-20 (Mitsubishi Kasei), a method using ion exchange chromatography, or silica gel or alkylation. Separation and purification can be achieved by appropriately combining normal phase / reverse phase column chromatography with silica gel (preferably high performance liquid chromatography) and eluting with a suitable eluent.

(Second Step) Condensation In this step, compound (5) and compound (3) are mixed in an inert solvent.
To produce the compound (6).

This step can be performed in the same manner as in the first step.

(Third Step) Condensation In this step, compound (2) and compound (7) are mixed in an inert solvent.
To produce the compound (8).

This step can be performed in the same manner as in the first step.

(Fourth Step) Deprotection In this step, the t-butyl group of compound (8) and the protecting group represented by R ⁷ are removed using an acid in an inert solvent to give compound (9). This is the step of manufacturing.

This step is performed when R ⁷ is a silyl-type protecting group.

The acids used include acetic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid,
An organic acid such as trifluoromethanesulfonic acid or an inorganic acid such as hydrochloric acid, preferably trifluoroacetic acid. The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent, but is preferably a halogenated hydrocarbon such as methylene chloride or chloroform; diethyl ether Ethers such as acetic acid, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; water; organic acids such as acetic acid and mixed solvents thereof. And preferably methylene chloride. The reaction temperature and the reaction time are not particularly limited, but are usually 0 ° C to 100 ° C (preferably 10 ° C).
1 to 72 hours (preferably 1 to 2 hours).
4 hours).

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if an insoluble substance is present, it is removed by filtration. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Fifth Step) Condensation In this step, compound (5) and compound (7) are mixed in an inert solvent.
And the step of producing a compound (10).

This step can be performed in the same manner as in the first step.

(Step 6) Deprotection In this step, the compound (10) is prepared by using an acid in an inert solvent.
In this step, the compound (9) is produced by removing the isopropylidene group and the protecting group represented by R ⁷ .

This step is performed when R ⁷ is a silyl-type protecting group.

This step can be carried out in the same manner as in the fourth step. Preferably, acetic acid is used as the acid and a mixed solution of tetrahydrofuran and water is used as the solvent.

(Step 6a) Deprotection In this step, the compound (10) is prepared by using an acid in an inert solvent.
In this step, the isopropylidene group is removed to produce the compound (6a).

This step is performed when R ⁷ is a benzyl-type protecting group.

This step can be performed in the same manner as in the sixth step.

(Step 7) Deprotection In this step, the t-butyl group of compound (4) is removed with an acid in an inert solvent to produce compound (9).

This step can be performed in the same manner as in the fourth step.

(Eighth Step) Condensation This step is a step of producing compound (12) by reacting compound (9) with alkoxyamine R ⁸ ONH ₂ in an inert solvent.

This step can be performed in the same manner as in the first step.

(Ninth Step) Deprotection This step is a step for producing the target compound (1a) of the present invention by removing the protecting group represented by R ⁸ of the compound (12) in an inert solvent. .

When R ⁸ is a silyl-type protecting group,
The reaction can be performed in the same manner as in the step, but preferably, hydrochloric acid is used as the acid, and a mixed solvent of dioxane and water is used as the solvent.

When R ⁸ is a benzyl-type protecting group, a method of removing by contacting with a reducing agent in a solvent (preferably catalytic reduction at room temperature under a catalyst) is generally suitable. The solvent to be used is not particularly limited as long as it does not participate in the present reaction.
Alcohols such as toluene and isopropanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as toluene, benzene and xylene; aliphatics such as hexane and cyclohexane. Hydrocarbons, esters such as ethyl acetate and propyl acetate, amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphorotriamide, and fatty acids such as formic acid and acetic acid , Water, or a mixed solvent thereof is more preferable, and more preferably, an alcohol (particularly, methanol), a mixed solvent of an alcohol and an ether, or a mixed solvent of an alcohol and water. is there.

The catalyst to be used is not particularly limited as long as it is usually used in a catalytic reduction reaction, but is preferably palladium carbon, palladium black, Raney nickel, platinum oxide, platinum black, Palladium-aluminum oxide, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride and palladium-barium sulfate are used, preferably palladium-aluminum oxide.
The pressure is not particularly limited, but it is usually 1 to 10 atm. The reaction temperature and reaction time vary depending on the type of the starting material, the solvent and the catalyst, but are usually from 0 ° C to 100 ° C.
(Preferably 20 ° C. to 50 ° C.) and 5 minutes to 48 hours (preferably 30 minutes to 10 hours).

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the reduction catalyst is removed by filtration, the solvent is distilled off if necessary, and water such as ethyl acetate is removed. An organic solvent that is immiscible with water is added, washed with water or the like, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 10) Acylation In this step, compound (4) is prepared in an inert solvent in the presence of a base.
Is reacted with an acid halide R ^6a X (X is preferably chloride) or an acid anhydride R ^6a OR ^6a to produce a compound (13).

In the acylation using an acid halide, the solvent used is preferably an ether such as diethyl ether or tetrahydrofuran; a hydrocarbon such as methylene chloride or chloroform; or an amide such as dimethylformamide. .

As the base used, organic amines such as pyridine, dimethylaminopyridine, N-methylmorpholine and triethylamine are preferred.

The reaction temperature is usually from 0 ° C. to room temperature, and the reaction time varies depending on the starting materials, solvent, base and the like used.
Usually 30 minutes to 1 day.

In the acylation using the acid anhydride R ^6a OR ^6a ; the solvents used are ethers such as diethyl ether and tetrahydrofuran; hydrocarbons such as methylene chloride and chloroform; amides such as dimethylformamide. Are preferred.

As the base used, organic amines such as pyridine, dimethylaminopyridine, N-methylmorpholine and triethylamine are preferred.

The reaction temperature is usually from 0 ° C. to room temperature, and the reaction time varies depending on the starting material, solvent, base and the like used.
Usually 30 minutes to 1 day.

When R ^6a is a carbamoyl group, R ^6b NC
O (R ^6b represents a portion of R ^6a except for the carbonyl group)
Can also be used.

As the solvent to be used, aromatic hydrocarbons such as benzene and toluene are preferable, and pyridine and triethylamine are used as bases. The reaction temperature is
The reaction time is usually from room temperature to 60 ° C., and the reaction time is from 30 minutes to 3 days.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Eleventh Step) Deprotection In this step, compound (13) is prepared by using an acid in an inert solvent.
In this step, the t-butyl group is removed to produce a compound (14).

This step can be performed in the same manner as in the fourth step.

(Twelfth Step) Condensation This step is a step of producing compound (15) by reacting compound (14) with alkoxyamine R ⁸ ONH ₂ in an inert solvent.

This step can be performed in the same manner as in the eighth step.

(Thirteenth Step) Deprotection This step is a step of removing the protecting group represented by R ⁸ of compound (15) in an inert solvent to produce the desired compound (1b) of the present invention. .

This step can be performed in the same manner as in the ninth step.

(Step 14) Deacylation In this step, the compound (1) is prepared in an inert solvent in the presence of a base.
This is a step of preparing the target compound (1a) of the present invention by removing the protecting group represented by R ^6a in b).

The base used is not particularly limited as long as it does not affect the other parts of the compound, but is preferably a metal alkoxide such as sodium methoxide; sodium carbonate, potassium carbonate, carbonate Alkali metal carbonates such as lithium; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or ammonia such as ammonia water and concentrated ammonia-methanol are used. However, sodium carbonate and potassium carbonate are preferred. The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction. Water; methanol, ethanol, n-
Organic solvents such as alcohols such as propanol, ethers such as tetrahydrofuran and dioxane, or mixed solvents of water and the above-mentioned organic solvents are preferred, and alcohols (particularly methanol) are more preferred. It is. The reaction temperature and the reaction time are different depending on the starting material, the solvent, the base used and the like, and are not particularly limited.
C) for 1 to 24 hours.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(15th step) Deprotection This step is a step for producing a compound (11) by removing the isopropylidene group of the compound (6) using an acid in an inert solvent.

This step can be performed in the same manner as in the sixth step.

(Sixteenth Step) Condensation This step is a step of producing compound (16) by reacting compound (11) with alkoxyamine R ⁸ ONH ₂ in an inert solvent.

This step can be performed in the same manner as in the eighth step.

(Step 16a) Condensation In this step, compound (11a) is reacted with alkoxyamine R ⁸ ONH ₂ in an inert solvent to give compound (16a).
This is the step of manufacturing a).

This step can be performed in the same manner as in the eighth step.

Further, it is carried out when R ² is a benzyl-type protecting group.

(Step 17) Deprotection This step is a step of removing the protecting group represented by R ⁸ of compound (16) in an inert solvent to produce the desired compound (1c) of the present invention. .

This step can be performed in the same manner as in the ninth step.

(Eighteenth Step) Acylation This step is a step of reacting compound (6) with R ^6a X (described above) in an inert solvent to produce compound (17).

This step can be performed in the same manner as in the tenth step.

(Step 19) Deprotection In this step, compound (17) is prepared by using an acid in an inert solvent.
In this step, the isopropylidene group is removed to produce a compound (18).

This step can be performed in the same manner as in the sixth step.

(Twentieth Step) Condensation This step is a step of reacting compound (18) with alkoxyamine R ⁸ ONH ₂ in an inert solvent to produce compound (19).

This step can be performed in the same manner as in the eighth step.

(Step 21) Deprotection In this step, the protective compound represented by R ⁸ of compound (19) is removed in an inert solvent to give the desired compound (1d) of the present invention.
This is the step of manufacturing.

This step can be performed in the same manner as in the ninth step.

(Step 22) Deacylation In this step, the protecting group represented by R ^6a of compound (1d) is removed in an inert solvent to produce compound (1c) of the present invention. is there.

This step can be performed in the same manner as in the fourteenth step.

(Step 23) Acylation This step is a step of producing compound (20) by reacting compound (19) with R ⁹ X in an inert solvent.

This step can be performed in the same manner as in the tenth step.

(Step 23a) Acylation In this step, compound (16a) is reacted with R ⁹ X in an inert solvent.
Is reacted to produce a compound (47).

This step can be performed in the same manner as in the tenth step.

(Step 24) Deprotection This step is a step of removing the protecting group represented by R ⁸ of compound (20) in an inert solvent to produce target compound (1e) of the present invention. .

This step can be performed in the same manner as in the ninth step.

(Step 24a) Deprotection This step comprises the steps of reacting R ⁸ and R of compound (47) in an inert solvent.
^In this step, the protecting group represented by ⁷ is removed to produce the target compound (1f) of the present invention.

This step can be performed in the same manner as in the ninth step.

(Step 25) Condensation In this step, a compound (21) is prepared by using a base in an inert solvent.
This is a step of producing a compound (22) by reacting the compound (21a) with the compound (22).

As the solvent to be used, ethers such as tetrahydrofuran and diethyl ether are preferable, and as the base to be used, n-butyllithium is preferable.

The reaction is usually carried out at -78 ° C, and the reaction time is 1
0 minutes to 5 hours.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 26) Alkylation This step is a step of reacting compound (22) with t-butyl bromoacetate in an inert solvent to produce compound (23).

As the combination of the reagent and the solvent to be used, a combination of lithium diisopropylamide (LDA) and ethers such as tetrahydrofuran and diethyl ether, or a combination of dibutyl boron triflate-
Preferred are combinations of triethylamine and halogenated hydrocarbons such as methylene chloride, chloroform.

The reaction temperature is usually -78.degree. C. when LDA is used, and the temperature is gradually raised from -78.degree. C. to room temperature when dibutylboron triflate is used. The reaction time varies depending on the reagents and raw materials, but is 30 minutes to 1 day.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 27) Hydrolysis In this step, a compound (23) is prepared by using a base in an inert solvent.
Is a step of producing compound (2) by hydrolysis of

As a solvent to be used, a mixed solvent of tetrahydrofuran and water is preferable, and as a base to be used, an alkali metal hydroxide such as lithium hydroxide is preferable. The reaction can be performed efficiently.

The reaction temperature is usually from 0 to 50 ° C., and the reaction time is usually from 30 minutes to 5 hours, depending on the starting materials and reagents.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 28) Alkylation In this step, a known compound (2) is prepared by using a base in an inert solvent.
This is a step of producing compound (25) by reacting 4) with allyl halide R ¹¹ X (X represents a halogen atom, preferably bromine or chlorine).

As the solvent to be used, ethers such as tetrahydrofuran and diethyl ether are preferable.

The base used is preferably a disilazide such as lithium hexamethyldisilazide or potassium hexamethyldisilazide, or lithium diisopropylamide, and more preferably a disilazide.

The reaction temperature is usually gradually raised from -78 ° C to room temperature. The reaction time varies depending on the reagents and raw materials, but is 1 to 20 hours.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 29) Reduction of Double Bond This step is a step of producing a compound (26) by reducing the double bond of the compound (25) in an inert solvent.

The solvent to be used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol, ethanol and isopropanol, diethyl ether, tetrahydrofuran, Ethers such as dioxane, aromatic hydrocarbons such as toluene, benzene and xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, formamide, dimethylformamide , Dimethylacetamide, N-methyl-2-pyrrolidone, amides such as hexamethylphosphorotriamide, formic acid, fatty acids such as acetic acid, water, and a mixed solvent thereof are more preferable. -Esters (especially methanol) and esters (especially ethyl acetate).

The catalyst to be used is not particularly limited as long as it is usually used in a catalytic reduction reaction, but is preferably palladium carbon, palladium black, Raney nickel, platinum oxide, platinum black, Palladium-aluminum oxide, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride and palladium-barium sulfate are used, preferably palladium carbon. The pressure is not particularly limited, but it is usually 1 to 10 atm. The reaction temperature and the reaction time vary depending on the type of the starting material, the solvent, the catalyst and the like, but are usually 0 ° C to 100 ° C (preferably
0 ° C to 50 ° C), 5 minutes to 48 hours (preferably 30
Minutes to 10 hours).

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, after the reduction catalyst is removed by filtration, the solvent is distilled off if necessary, and water such as ethyl acetate is added. It is obtained by adding an organic solvent immiscible with water, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 30) Hydrolysis In this step, a compound (26) is prepared by using a base in an inert solvent.
Is a step of producing a compound (27) by hydrolysis of

The base used is preferably an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide, and the solvent used is a mixed solvent of ethers such as dioxane or tetrahydrofuran and water. It is.

The reaction temperature is usually from 60 to 100 ° C.
The reaction time varies depending on the starting material, base and the like, but is usually 5 hours to 1 day.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture by a conventional method. For example, if necessary, the solvent is distilled off, and a water-immiscible organic solvent such as ethyl acetate is added. And the like, and then the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off. If necessary, the obtained target compound can be obtained by a conventional method, for example, recrystallization, reprecipitation, or, usually,
Methods commonly used for separation and purification of organic compounds, for example,
This can be performed by the method described in the first step.

(Step 31) Protection In this step, the hydroxyl group and carboxylic acid of compound (27) are simultaneously protected by removing the generated water by azeotropic distillation in an inert solvent using an acid catalyst. This is the step of manufacturing (5).

As a reagent to be used, usually, 2,2-dimethoxypropane or acetone is used.

The solvent is not particularly limited as long as it does not inhibit the reaction, but preferably includes aromatic hydrocarbons such as benzene and toluene.

The acid catalyst to be used is not particularly limited as long as it is usually used as an acid, but is preferably an organic catalyst such as p-toluenesulfonic acid, camphorsulfonic acid or pyridinium = p-toluenesulfonate. Mention may be made of acids or inorganic acids such as hydrochloric acid. The reaction temperature varies depending on the acid catalyst used, the starting compound, and the like.
The reaction is carried out at a temperature of from 80 to 100 ° C., and the reaction time is usually from 30 minutes to 10 hours, although it depends mainly on the reaction temperature, the starting compound and the kind of the solvent used.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 32) Alkylation In this step, compound (28) is treated with Grignard reagent R ⁵ MgX ^a (X ^a represents a halogeno group, preferably bromide or chloride) in an inert solvent. Reacting to produce compound (32a).

As the solvent to be used, ethers such as tetrahydrofuran and diethyl ether are preferable.

The reaction temperature is -78 ° C to 0 ° C, and the reaction time varies depending on the raw materials, but is usually 10 minutes to 10 hours.

If necessary, the reaction can be efficiently carried out by using a copper salt such as copper iodide.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 33) Introduction of methoxymethylamino group This step is a step of producing compound (34) by reacting methoxymethylamine with compound (28) in an inert solvent.

This step is performed when R ¹⁷ is hydrogen, and is performed according to the active ester method and the condensation method described in the first step.

(Step 34) The ester reduction (alcohol formation) step is a step of producing a compound (29) by reducing the compound (28) in an inert solvent.

As a solvent to be used, a mixed solvent of tetrahydrofuran and ethyl alcohol is preferable.

As the reducing agent to be used, lithium borohydride or a combination of sodium borohydride and lithium chloride is preferable.

The reaction temperature is usually 0 to 40 ° C., and the reaction time is usually 10 hours to 3 days.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture by a conventional method. For example, the remaining reducing agent is decomposed and appropriately neutralized, and if insoluble matters are present, filtration is performed. After removal, an organic solvent immiscible with water such as ethyl acetate is added, washed with water or the like, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off. Can be If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation,
Alternatively, it can be performed by a method usually used for separation and purification of an organic compound, for example, the method described in the first step.

(35th Step) Oxidation of Alcohol (Formation of Aldehyde) In this step, compound (29) is oxidized in an inert solvent to give
This is a step of producing a compound (30).

In this step, Moffatt oxidation, Swer
It can be performed by a method called n-oxidation.

The reaction temperature is usually 10 to 50 ° C., and the reaction time is usually 30 minutes to 5 hours.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the remaining oxidizing agent is decomposed and appropriately neutralized. After removal, an organic solvent immiscible with water such as ethyl acetate is added, washed with water or the like, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off. Can be If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation,
Alternatively, it can be performed by a method usually used for separation and purification of an organic compound, for example, the method described in the first step.

[0189] (36 step) Alkylation In this step, in an inert solvent, compound (30) to be reacted with an alkylating agent R ⁴ MgX ^a, is a step for preparing a compound (31).

This step can be performed in the same manner as in the thirty-second step.

(Step 37) Alkylation This step is a step of preparing compound (32) by alkylating compound (34) in an inert solvent.

This step can be performed in the same manner as in the thirty-second step.

(Step 37a) Introduction of CN Group This step is a step of producing compound (35) by reacting compound (30) with a cyanating agent in an inert solvent.

As the solvent to be used, a mixed solvent of halogenated hydrocarbons such as methylene chloride and water is preferable.

As the cyanating agent to be used, an alkali metal cyanide such as sodium cyanide and potassium cyanide and hydrochloric acid are used.

The reaction temperature is usually from 0 to 40 ° C., and the reaction time is usually from 5 hours to 1 day, varying based on raw materials, reagents and the like.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 38) Hydrolysis In this step, compound (35) is hydrolyzed under acidic conditions to produce compound (36).

This reaction is performed when R ¹² is a group which can be removed by an acid such as a tert-butoxycarbonyl group.

As the solvent used, water is preferred.

The acid to be used is not particularly limited as long as it is usually used, but hydrochloric acid is preferred.

The reaction temperature is usually from 60 to 100 ° C.
The reaction time varies depending on the raw materials, reagents, etc.
4 hours.

After completion of the reaction, the target compound of this reaction is obtained from the reaction mixture by a conventional method, and can be obtained, for example, by filtering off the crystals formed by concentrating the reaction mixture. If necessary, the obtained target compound can be obtained by a conventional method,
For example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, a method described in the first step can be used.

(Step 39) Hydrolysis In this step, a compound (36) is prepared by using a base in an inert solvent.
Is a step of producing a compound (37) by hydrolysis of

This is performed when R ¹² is an acid-stable group such as a benzyloxycarbonyl group.

This step can be performed in the same manner as in the thirty-eighth step.

(Step 40) Condensation This step is a step of preparing a compound (38) by condensing the compound (37) with a desired amine R ¹⁴ R ¹⁵ NH in an inert solvent.

This step can be performed in the same manner as in the first step.

(Step 41) Aldol condensation In this step, compound (30) is prepared using a base in an inert solvent.
Is reacted with CH ₃ CO ₂ R ¹³ to produce a compound (39). This step can be performed in the same manner as in the 26th step.

(Step 42) Hydrolysis In this step, a compound (39) is prepared by using a base in an inert solvent.
Is a step of producing a compound (40) by hydrolysis.

This step can be performed in the same manner as in the thirtieth step.

(Step 43) Condensation This step is a step of condensing compound (40) with a desired amine in an inert solvent to produce compound (41).

This step can be performed in the same manner as in the first step.

(Step 44) Alkylation In this step, first, compound (42) was prepared in an inert solvent.
This is a step of synthesizing a mixed acid anhydride and then reacting diazomethane to produce a compound (43).

The reaction for producing the mixed acid anhydride is carried out by using an inert solvent (for example, the above-mentioned halogenated hydrocarbons, amides,
Ethers (preferably diethyl ether)), mixed acid anhydride agents, for example, lower (C ₁ -C ₄ ) alkyl halides such as ethyl chlorocarbonate and isobutyl chlorocarbonate, and lower such as pivaloyl chloride. It is achieved by reacting the compound (42) with an alkanoyl halide or a lower alkyl or diaryl cyanophosphoric acid such as diethyl cyanophosphoric acid or diphenyl cyanophosphoric acid.

The reaction is preferably carried out with triethylamine, N
Carried out in the presence of an organic amine such as methylmorpholine, dimethylaminopyridine, pyridine, and the reaction temperature is
The temperature is from -20 ° C to 0 ° C, and the time required for the reaction is from 30 minutes to 1 hour.

The reaction between the mixed acid anhydride and diazomethane is preferably performed in an inert solvent (for example, the above-mentioned ethers) at a reaction temperature of 0 ° C. to 50 ° C., and the time required for the reaction is 1 hour.
10 to 10 hours. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, in the case where insolubles are present, they are obtained by removing by filtration and then distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 45) Alkoxylation or acyloxylation In this step, compound (4) was prepared in an inert solvent in the presence of a catalyst.
This is a step of producing a compound (44) by reacting 3) with an alcohol or an acid R ¹⁸ OH.

As a solvent to be used, a desired alcohol or acid is used, or ethers such as dioxane and tetrahydrofuran are preferable.

As the catalyst to be used, copper salts such as cupric acetate, cupric chloride and copper oxide are preferred.

The reaction temperature is usually from 20 to 100 ° C.
The reaction time varies depending on the raw materials and the like;
Time.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 46) Reduction In this step, compound (44) is reduced in an inert solvent to give
This is a step of producing a compound (45).

This step is performed when R ¹⁸ is an acyl group.

This step can be carried out in the same manner as in the thirty-fourth step.

[0226] Furthermore, compounds reducing the ketone with sodium borohydride (44), followed by methanol, is reacted with potassium carbonate, it can also be carried out in a stepwise method of removing R ^18.

When R ¹⁸ is an alkyl group, R ¹⁸ is not removed, and a compound corresponding to compound (53) can be obtained.

(Step 47) Reduction In this step, compound (39) is reduced in an inert solvent to give
This is a step of producing a compound (46).

This step can be carried out in the same manner as in the thirty-fourth step.

[0230] (48 step) Alkylation In this step, in an inert solvent, compound (32) is reacted with an alkylating agent R ⁴ MgX ^a, is a step for preparing a compound (33).

This step can be performed in the same manner as in the thirty-second step.

(Step 49) Alkylation This step is a step of reacting compound (34) with an allyl Grignard reagent in an inert solvent to produce compound (48).

This step can be performed in the same manner as in the thirty-seventh step.

(50th Step) Oxidation This step is a step of producing compound (49) from compound (48) in an inert solvent. This step can be performed by a method called hydroboration-hydrogen peroxide oxidation method.

As the solvent to be used, ethers such as diethyl ether and tetrahydrofuran, and aromatic hydrocarbons such as benzene and toluene are preferable.

As the borating reagent to be used, 9-
Borabicyclo [3,3,1] nonane, borane-dimethylthioether complex and the like are preferred. The reaction temperature for boration is usually 10 to 50 ° C., and the reaction time is usually 1 to 10 hours. The subsequent oxidation is performed by using hydrogen peroxide in water in the presence of sodium hydroxide. The reaction temperature is usually 0 to 40 ° C,
The reaction time is usually from 10 minutes to 5 hours.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the remaining oxidizing agent is decomposed to appropriately neutralize the reaction mixture, After removal by filtration, add an organic solvent that is immiscible with water such as ethyl acetate, wash with water, etc.
An organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then obtained by distilling off the solvent.
If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 51) Ketone reduction This step is a step of producing compound (50) by reacting compound (49) with a reducing agent in an inert solvent. As the solvent used, alcohols such as methanol and ethanol are preferable.

As a reducing agent to be used, sodium borohydride is preferable.

The reaction temperature is usually from 0 ° C. to 40 ° C. The reaction time varies depending on the starting material and the reducing agent, but is usually from 1 hour to 1 hour.
Day.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the remaining reducing agent is decomposed, the reaction mixture is appropriately neutralized, and when an insoluble substance is present, After removal by filtration, add an organic solvent that is immiscible with water such as ethyl acetate, wash with water and the like,
An organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then obtained by distilling off the solvent.
If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 52) Protection In this step, compound (51) is prepared using a base in an inert solvent.
Is reacted with t-butyldimethylsilyl halide,
This is a step of producing a compound (52). Suitable solvents used are halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as diethyl ether and tetrahydrofuran; and amides such as dimethylformamide.

As the base to be used, organic amines such as triethylamine, 4,4-dimethylaminopyridine and imidazole are preferable.

The reaction temperature is usually 0 to 40 ° C., and the reaction time is 30 minutes to 5 hours, depending on the raw materials and the like.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 53) Acylation In this step, compound (51) is reacted with acyl halide R ¹⁶ X or R ¹⁶ OR ¹⁶ in an inert solvent to give compound (5).
This is the step of manufacturing 3).

This step can be performed in the same manner as in the tenth step.

(Step 54) Tosylation In this step, compound (51) is reacted with p-toluenesulfonyl halide (or anhydride) in an inert solvent to give
This is a step of producing a compound (54).

As the solvent used, halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as diethyl ether and tetrahydrofuran; and amides such as dimethylformamide are preferable.

As the base to be used, organic amines such as triethylamine, 4,4-dimethylaminopyridine and imidazole are preferable.

The reaction temperature is usually 0 to 40 ° C., and the reaction time is 30 minutes to 24 hours, depending on the raw materials and the like.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 55) Amination This step is a step of producing compound (55) by reacting compound (54) with desired amine R ¹⁴ R ¹⁵ NH in an inert solvent.

Suitable solvents used are halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as diethyl ether and tetrahydrofuran; and amides such as dimethylformamide.

As the base to be used, organic amines such as triethylamine and 4,4-dimethylaminopyridine are preferable.

The reaction temperature is usually from 20 to 100 ° C.
The reaction time varies depending on the raw materials and the like, but is 30 minutes to 24 hours.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 56) Alkoxylation This step is a step of reacting compound (54) with a desired alcohol R ¹⁷ OH in an inert solvent to produce compound (56).

As the solvent to be used, ethers such as diethyl ether and tetrahydrofuran are preferable.

As the base to be used, alkali metal hydrides such as sodium hydride and potassium hydride, n
Alkyl lithium, such as -butyl lithium, is preferred. The reaction temperature is usually 20 to 60 ° C., and the reaction time varies depending on the raw materials and the like, but is 30 minutes to 24 hours.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

In some cases, immediately before the 55th step and the 56th step, the hydroxyl group of compound (54) is protected,
Immediately after the fifty-fifth step and the fifty-sixth step, deprotection of the hydroxyl group is carried out to obtain the desired compounds (55) and (56).
To manufacture. As the protecting group for the hydroxyl group, a tetrahydropyranyl group or a methoxymethyl group is preferable, and protection and deprotection are performed by a conventional method.

(Step 57) Alcohol Oxidation This step is a step of reacting compound (51) with an oxidizing agent in an inert solvent to produce compound (57).

As the solvent to be used, amides such as dimethylformamide are preferable, and as the oxidizing agent to be used, pyridinium chlorochromate and pyridinium dichromate are preferable.

In some cases, the reaction can be carried out efficiently by using the molecular sieve 4A.

The reaction temperature is usually from 10 to 40 ° C., and the reaction time is from 30 minutes to 5 hours, depending on the raw materials and the like.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the remaining oxidizing agent is decomposed to appropriately neutralize the reaction mixture. After removal by filtration, add an organic solvent that is immiscible with water, such as ethyl acetate, wash with water
An organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then obtained by distilling off the solvent.
If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 58) Condensation This step is a step of producing compound (58) by reacting compound (57) with alcohol in an inert solvent.

This step is carried out according to the active ester method or the condensation method in the first step.

(Step 59) Reduction This step is a step of producing compound (59) by reacting compound (58) with a reducing agent in an inert solvent.

This step can be performed in the same manner as in the fifty-first step.

(Step 60) Amidation In this step, compound (59) is reacted with desired amine R ¹⁴ R ¹⁵ NH in an inert solvent to produce compound (60).

Suitable solvents used are halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as diethyl ether and tetrahydrofuran; and amides such as dimethylformamide.

The reaction temperature is usually from 20 to 100 ° C.
The time varies depending on the raw material and the like, but is usually 1 hour to 3 days.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

Compound (60) can also be produced by reducing the ketone of compound (57) according to the fifty-ninth step, and then condensing it with an amine according to the active ester method or condensation method in the first step. .

(Step 61) Alkylation In this step, compound (30) is prepared using a base in an inert solvent.
Is reacted with allyl magnesium halide (preferably, bromide or chloride) to produce compound (61).

This step can be carried out according to the thirty-sixth step.

(Step 62) Silylation In this step, compound (61) is reacted with t-butyldimethylsilyl halide in an inert solvent to give compound (6).
This is the step of manufacturing 2).

This step can be performed in the same manner as in the 52nd step.

(Step 63) Oxidative Cleavage This step is a step of producing compound (63) by reacting compound (62) with an oxidizing agent in an inert solvent.

This step is performed by oxidizing with sodium periodate after the dihydroxylation reaction. Alternatively, the dihydroxylation reaction and the oxidation of sodium periodate can be performed simultaneously.

As the solvent used in the dihydroxylation reaction, ethers such as diethyl ether and tetrahydrofuran, and aromatic hydrocarbons such as benzene and toluene are preferable.

The dihydroxylating reagent used includes:
Preference is given to osmium tetroxide or a combination of osmium tetroxide with a co-oxidant such as N-methylmorpholine N-oxide. The reaction temperature for boration is usually 0 to 50 ° C., and the reaction time is usually 1 to 10 hours.

The subsequent oxidation is carried out by using sodium periodate in a mixed solvent of water and an alcohol such as methanol. The reaction temperature is usually from 0 to 40 ° C, and the reaction time is usually from 10 minutes to 3 hours.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the remaining oxidizing agent is decomposed to neutralize the reaction mixture appropriately, After removal by filtration, add an organic solvent that is immiscible with water such as ethyl acetate, wash with water and the like,
An organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then obtained by distilling off the solvent.
If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 64) Wittig Reaction In this step, compound (6) is prepared in an inert solvent in the presence of a base.
This is a step of producing compound (64) by reacting 3) with ethyl diethylphosphonoacetate.

The solvent used in the Wittig reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Such ethers.

The reaction temperature is usually from 0 to 40 ° C., and the reaction time is usually from 30 minutes to 20 hours, depending on the raw materials and the like.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized. It is obtained by adding an organic solvent immiscible with water such as ethyl, washing with water or the like, separating an organic layer containing the target compound, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent. If necessary, the obtained target compound is subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separation and purification of an organic compound, for example, the method described in the first step described above. Can be.

(Step 65) Reduction of Double Bond This step is a step of producing compound (65) by reacting compound (64) with a reducing agent in an inert solvent.

This step can be performed in the same manner as in the twenty-ninth step.

(Step 66) Ester reduction (alcohol production) This step is a step of producing compound (66) by reacting compound (65) with a reducing agent in an inert solvent.

This step can be carried out in the same manner as in the forty-seventh step.

(Step 67) Desilylation In this step, compound (66) is reacted with a deprotecting agent in an inert solvent to produce compound (67).

Compound (3) and compound (7) are compound (33), compound (31), compound (32a), compound (38), compound (39), compound (41), compound (45), compound (45) (46), R of compound (50), compound (51), compound (52), compound (53), compound (55), compound (56), compound (59), compound (60) and compound (67) It can be obtained by removing the protecting group represented by ¹² by an ordinary method. The present invention relates to an agent for inhibiting metastasis, invasion and proliferation of various cancer cells, and a therapeutic and prophylactic agent for osteoarthritis and rheumatoid arthritis, comprising as an active ingredient a novel hydroxamic acid derivative having excellent matrix metalloproteinase inhibitory activity I will provide a.

Examples of the dosage form of the medicament of the present invention include oral administration such as tablets, capsules, granules, powders or syrups, and parenteral administration such as injections or suppositories. Formulations may contain excipients (eg, sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, low substitution) Cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally crosslinked sodium carboxymethylcellulose; gum arabic; dextran; organic excipients such as pullulan: Inorganic excipients such as silicate derivatives such as low-grade silicic anhydride, synthetic aluminum silicate and magnesium metasilicate aluminate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate. Lubricating agents (eg, stearic acid, metal salts of stearic acid such as calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as veegum, gay wax; boric acid; adipic acid) Sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate;
Leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; and the above-mentioned starch derivatives. ), Binders (for example, polyvinylpyrrolidone, macrogol, and the same compounds as the above-mentioned excipients), disintegrants (for example, the same compounds as the above-mentioned excipients, and croscarmellose) Sodium, sodium carboxymethyl starch, chemically modified starch and cellulose such as polyvinylpyrrolidone, and stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; chlorobutanol, benzyl alcohol) Alcohols such as phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal;
Dehydroacetic acid; and sorbic acid. ), Flavoring agents (for example, commonly used sweeteners, sour agents, flavors, etc.) and diluents can be used in a well-known method. The amount used depends on the symptoms, age, administration method, etc., for example,
In the case of oral administration, the lower limit is 1 mg (preferably 10 mg) and the upper limit is 1000 mg (preferably 500 mg).
It is desirable to administer 0.5 mg (preferably 5 mg) as the lower limit and 500 mg (preferably 250 mg) as the upper limit once or several times a day depending on the symptoms.

[0298]

【Example】

(Example 1) N ¹ - [1-(S)-t-butyl-2-
(R) -hydroxy-3- (N-methylcarbamoyl)
Propyl] -N ⁴ - hydroxy -2- (R) - Nonirusu
Xinamide (Exemplified Compound No. 64) 1-a) [1- (S) -t-butyl-2- (R) -H
Droxy-3- (N-methylcarbamoyl) propyl]
Carbamic acid benzyl ester 4- (S) -benzyloxycarbonylamino-3-
To a solution of (R) -hydroxy-5,5-dimethylhexanoic acid (5.3 g) in tetrahydrofuran (80 ml) was added N-methylmorpholine (2.1 ml) and isopropyl chloroformate (2.4 ml) at -10 ° C. After stirring for 1 hour, a methanol solution of methylamine (9.4 m
1, 2.0 M) and stirred at 0 ° C. for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and then the solvent was removed. The residue was purified by flash column chromatography (ethyl acetate: hexane = 5: 1) to give the desired compound (3.7 g, 66%) as a colorless oil.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δ ppm: 1.01 (4H, s), 2.21-2.43 (2H, m), 2.78 (3H,
d, J = 4.8Hz), 3.48 (1H, dd, J = 9.3, 5.9Hz), 3.96-4.0
9 (1H, m), 4.20 (1H, d, J = 4.8Hz), 4.75 (1H, d, J = 9.3H
z), 5.08 (1H, d, J = 12.2Hz), 5.13 (1H, d, J = 12.2Hz),
6.04-6.17 (1H, m), 7.31-7.44 (5H, m) 1-b) 3- (R)-[1- (S) -t-butyl-2
-(R) -hydroxy-3- (N-methylcarbamoy
Le) -propylcarbamoyl] dodecanoic acid t- butyl S.
Ter [1- (S) -tert-butyl-2- (R) -hydroxy-
3- (N-methylcarbamoyl) propyl] carbamic acid benzyl ester (1.79 g) in methanol (15
ml) solution, 10% palladium carbon (165 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. After the reaction solution was filtered, the solvent was removed, and tetrahydrofuran (1
5 ml). 2- (R)-at 0 ° C.
t-butoxycarbonylmethylundecanoic acid (2.0
g), triethylamine (1.2 ml) and diethyl cyanophosphonate (1.3 ml) were added, and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, extracted with ethyl acetate,
After washing with saturated saline and drying over anhydrous sodium sulfate, the solvent was removed. The residue was purified by flash column chromatography (ethyl acetate: hexane = 2: 1) to give the desired compound (888 mg, 34%) as a colorless oil.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δ ppm: 0.88 (3H, t, J = 6.8Hz), 1.02 (9H, s), 1.17
-1.36 (16H, m), 1.43 (9H, s), 2.16-2.77 (5H, m), 2.81
(3H, d, J = 4.8Hz), 3.69 (1H, dd, J = 7.8, 4.0Hz), 4.01
-4.14 (1H, m), 4.78-4.89 (1H, m), 6.28 (1H, d, J = 7.8H
z), 6.72-6.83 (1H, m ) 1-c) N 1 - [1- (S) - butyl -2- (R) -
Hydroxy-3- (N-methylcarbamoyl) propyl
Le] -N ⁴ - hydroxy -2- (R) - Nonirusukushina
Mid 3- (R)-[1- (S) -t-butyl-2- (R)-
Hydroxy-3- (N-methylcarbamoyl) propylcarbamoyl] dodecanoic acid t-butyl ester (440
mg) in methylene chloride (12 ml) was added at 0 ° C. with trifluoroacetic acid (3.6 ml), and the mixture was stirred at room temperature for 2 hours.
Melted into. After cooling the solution to 0 ° C., N-methylmorpholine (0.90 ml), O- (t-butyldimethylsilyl) hydroxylamine (146 mg), 1-
(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (190 mg) was added, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate,
The solvent was removed. The residue was dissolved in a 1N hydrochloric acid (1 ml) -dioxane (1 ml) mixed solvent and stirred at room temperature for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate, and then the solvent was removed. The residue was purified by preparative thin-layer chromatography (ethyl acetate: methanol = 20: 1) to give the desired compound (19 mg, 5%).
Was obtained as a colorless oil.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ ) δ ppm: 0.88 (3H, t, J = 7.0Hz), 1.01 (9H, s), 1.24
-1.85 (16H, m), 2.41-2.54 (4H, m), 2.63 (1H, m), 2.80
(3H, d, J = 4.6Hz), 3.78 (1H, m), 4.16 (1H, m), 4.72-
4.85 (1H, m), 7.18 (1H, brs), 7.58 (1H, d, J = 7.2Hz),
10.43 (1H, brs) (Example 2) 2- (S), N ¹ -dihydroxy-N ⁴ −
[1- (S) -t-butyl-2- (R) -hydroxy-
3- (N-methylcarbamoyl) propyl] -3-
(R) -Nonylsuccinamide (Exemplary Compound No. 165) 2-a) 2- (R)-(2,2-dimethyl-5-oxo
So- [1,3] -dioxolan-4- (S) -yl)
N-decanoic acid [1- (S) -t-butyl-2- (R ) -H
Droxy-3- (N-methylcarbamoyl) propyl]
Amide [1- (S) -tert-butyl-2- (R) -hydroxy-
3- (N-methylcarbamoyl) propyl] carbamic acid benzyl ester (967 mg) in methanol (10
ml) solution, 10% palladium carbon (100 mg) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. After the reaction solution was filtered, the solvent was removed and methylene chloride (40 ml)
Melted into. At 0 ° C., 2- (R)-(2,2
-Dimethyl-5-oxo- [1,3] -dioxolane-
4- (S) -yl) undecanoic acid (991 mg), N-
Methylmorpholine (0.362 ml) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (633 mg) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and then the solvent was removed. The residue was purified by flash column chromatography (ethyl acetate), and the target compound (540 mg, 42
%) As a colorless oil.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ ) δ ppm: 0.88 (3H, t, J = 6.8Hz), 1.03 (9H, s), 1.16
-1.43 (14H, m), 1.58 (3H, m), 1.59 (3H, s), 1.64-1.82
(2H, m), 2.22 (1H, dd, J = 15.2, 8.3Hz), 2.31 (1H, dd,
J = 15.2, 2.8Hz), 2.71-2.78 (1H, m), 2.81 (3H, d, J =
4.8Hz), 3.73 (1H, dd, J = 8.1, 4.7Hz), 3.96-4.07 (1H,
m), 4.60 (1H, d, J = 4.4Hz), 4.74 (1H, d, J = 7.4Hz), 6.5
3 (1H, d, J = 8.1Hz), 6.63 (1H, q, J = 4.8Hz) 2-b) N 1 - benzyloxy -N ⁴ - [1-(S)
-T-butyl-2- (R) -hydroxy-3- (N-meth
Tylcarbamoyl) propyl] -2- (S) -hydroxy
C-3- (R) -nonylsuccinamide 2- (R)-(2,2-dimethyl-5-oxo- [1,
3] -Dioxolan-4- (S) -yl) undecanoic acid [1- (S) -tert-butyl-2- (R) -hydroxy-
3- (N-methylcarbamoyl) propyl] amide (5
40 mg) in acetic acid (10 ml) was added to water (3.3 m).
After l) was added and the mixture was stirred at 30 ° C. for 10 hours, the solvent was removed. Tetrahydrofuran (5 ml) and water (0.5
ml) and O-benzylhydroxylamine hydrochloride (394 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (474 m) at 0 ° C.
g) was added and stirred at room temperature for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and then the solvent was removed. The residue was purified by recrystallization (ethyl acetate: hexane) to give the desired compound (400 mg, 60%) as a white solid.

The ¹ H-nuclear magnetic resonance spectrum (270 Hz, CDC
l ₃ ) δ ppm: 0.87 (3H, t, J = 7.0Hz), 0.99 (9H, s), 1.13
-1.38 (14H, m), 1.53-1.82 (2H, m), 2.16-2.43 (2H, m),
2.63 (3H, d, J = 4.7Hz), 2.88-2.98 (1H, m), 3.78 (1H,
dd, J = 9.4, 4.7Hz), 4.13 (1H, brs), 4.24 (1H, m), 4.56
-4.64 (1H, m), 4.84 (1H, d, J = 10.7Hz), 4.89 (1H, d, J
= 10.7Hz), 5.21 (1H, brs), 6.64 (1H, q, J = 4.7Hz), 7.13
(1H, d, J = 9.4 Hz), 7.35-7.40 (5H, m), 10.24 (1H, s) 2-c) 2- (S), N ¹ -dihydroxy-N ⁴ −
[1- (S) -t-butyl-2- (R) -hydroxy-
3- (N-methylcarbamoyl) propyl] -3-
(R) - nonyl disk Sina bromide N ¹ - benzyloxy -N ⁴ - [1-(S)-t-butyl-2- (R) - hydroxy-3-(N-methylcarbamoyl) propyl] -2- ( S) -Hydroxy-3-
5% palladium-alumina (4%) was added to a solution of (R) -nonylsuccinamide (400 mg) in methanol (20 ml).
0 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours.
After filtering the reaction solution, the solvent was removed. The residue was purified by recrystallization (ethyl acetate: hexane) to give the desired compound (205 mg, 62%) as a white solid.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δ ppm: 0.89 (3H, t, J = 7.1Hz), 1.01 (9H, s), 1.18
-1.43 (14H, m), 1.47-1.73 (2H, m), 2.17 (1H, dd, J = 1
4.2, 9.9Hz), 2.40 (1H, dd, J = 14.2, 2.5Hz), 2.67-2.8
2 (1H, m), 2.72 (3H, s), 3.71 (1H, d, J = 7.2Hz), 4.07-
4.14 (1H, m), 4.11 (1H, d, J = 5.8Hz) ( Example 3) N ⁴ - [1- (S) -t- butyl-2-
(R), 4-dihydroxybutyl] -2- (S), N ¹
-Dihydroxy-3- (R) -nonylsuccinamide (Exemplary Compound No. 171) 3-a) [1- (S) -t-butyl-2- (R), 4
-Dihydroxybutyl] carbamic acid benzyl ester 4- (S)-(benzyloxycarbonyl) amino-3
-(R) -Hydroxy-5,5-dimethylhexanoic acid ethyl ester (4.74 g) in ethanol (30 ml)
Sodium borohydride (1.1 g), lithium chloride (1.2 g) in a solution of tetrahydrofuran (20 ml) at 0 ° C.
A suspension of g) in ethanol (30 ml) -tetrahydrofuran (20 ml) was added, and the mixture was stirred at room temperature for 15 hours.
Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and then the solvent was removed. The residue was purified by flash column chromatography (ethyl acetate: hexane = 1: 1) to give the desired compound (3.7 g, 89%) as a colorless oil.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δ ppm: 0.99 (9H, s), 1.57-1.71 (2H, m), 2.79 (1H,
brs), 3.52-3.64 (2H, m), 3.77-3.92 (2H, m), 4.06 (1
H, brs), 4.88 (1H, d, J = 8.9Hz), 5.12 (2H, s), 7.29-
7.42 (5H, m) 3-b) [1- (S) -t-butyl-4- (t-butyl
Dimethylsilyloxy) -2- (R) -hydroxybu
Butyl ] carbamic acid benzyl ester [1- (S) -t-butyl-2- (R), 4-dihydroxybutyl] carbamic acid benzyl ester in methylene chloride (100 ml) solution at 0 ° C. with triethylamine (3.8 ml). , 4-dimethylaminopyridine (151
mg), t-butyldimethylsilyl chloride (2.1
g) was added and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and then the solvent was removed. The residue was purified by flash column chromatography (ethyl acetate:
Purification with hexane = 1: 2) gave the desired compound (2.7 g,
53%) as a colorless oil.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δ ppm: 0.07 (6H, s), 0.89 (9H, s), 1.00 (9H, s),
1.53-1.82 (2H, m), 3.76 (1H, d, J = 5.3Hz), 3.58 (1H, d
d, J = 9.9, 4.8Hz), 3.72-3.98 (3H, m), 4.77 (1H, d, J =
9.9Hz), 5.11 (2H, s), 7.28-7.43 (5H, m) 3-c) 2- (R)-[2,2-dimethyl-5-oxo
So- [1,3] -dioxolan-4- (S) -yl]
Ndekan acid [1- (S) -t- butyl-4-(t - butyl
Dimethylsilyloxy) -2- (R) -hydroxybu
Example 2-a) was prepared from benzyl ] amide [1- (S) -t-butyl-4- (t-butyldimethylsilyloxy) -2- (R) -hydroxybutyl] carbamic acid benzyl ester (480 mg). The target compound (385 mg,
59%) as a white solid.

A ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δ ppm: 0.06 (3H, s), 0.07 (3H, s), 0.85-0.92 (12
H, m), 1.01 (9H, s), 1.12-1.41 (14H, m), 1.44-1.82 (4
H, m), 1.55 (3H, s), 1.62 (3H, s), 2.65 (1H, m), 3.71
-4.04 (4H, m), 4.55 (1H, d, J = 5.0Hz), 6.26 (1H, d, J =
^{8.3Hz) 3-d) N 1} - benzyloxy -N ⁴ - [1-(S)
-T-butyl-2- (R), 4-dihydroxybutyl]
-2- (S) -hydroxy-3- (R) -nonylsuccine
Namide 2- (R)-[2,2-dimethyl-5-oxo- [1,
3] -Dioxolan-4- (S) -yl] undecanoic acid [1- (S) -t-butyl-4- (t-butyldimethylsilyloxy) -2- (R) -hydroxybutyl] amide (730 mg) Thus, the target compound (255 mg, 39%) was obtained as a white solid in the same manner as in Example 2-b).

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δ ppm: 0.88 (3H, t, J = 7.1Hz), 1.01 (9H, s), 1.16
-1.43 (14H, m), 1.56-1.88 (4H, m), 2.64 (1H, brs), 2.
91-3.01 (1H, m), 3.52-3.63 (1H, m), 3.77-3.92 (2H, m
m), 4.01-4.23 (2H, m), 4.78 (2H, s), 4.88-4.98 (1H,
m), 6.31 (1H, brs ), 7.32-7.92 (5H, m), 9.34 (1H, brs) 3-e) N 4 - [1- (S) -t- butyl-2-
(R), 4-dihydroxybutyl] -2- (S), N ¹
- dihydroxy-3-(R) - nonyl disk Sina bromide N ¹ - benzyloxy -N ⁴ - [1- (S) -t- butyl-2- (R), 4-dihydroxy-butyl] -2-
From (S) -hydroxy-3- (R) -nonylsuccinamide (255 mg), the target compound (146 mg, 70%) was obtained as a white solid in the same manner as in Example 2-c).

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δ ppm: 0.89 (3H, t, J = 7.0Hz), 1.00 (9H, s), 1.19-
1.86 (18H, m), 2.72-2.77 (1H, m), 3.70-3.78 (3H, m),
3.88-3.92 (1H, m), 4.08 (1H, d, J = 5.9Hz) ( Example 4) N ¹ - [1- (S) - benzyl-2-
(R) -hydroxy-3- (N-methylcarbamoyl)
Propyl] -N ⁴ - hydroxy -2- (R) - Nonirusu
Xinamide (Exemplified Compound No. 62) 4-a) 4- (S) -t-butoxycarbonylamino
-3- (R) -Hydroxy-5-phenylpentanoic acid
Cylamide 4- (S) -t-butoxycarbonylamino-3-
(R) -hydroxy-5-phenylpentanoic acid (310
mg) in tetrahydrofuran (6 ml) and a 30% -methylamine methanol solution (0.13
ml), diethyl cyanophosphonate (0.18 ml),
Add triethylamine (0.33 ml) and add 3 under ice-cooling.
Stirred for 0 minutes. After completion of the reaction, the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the target compound (235 mg, 7
2.9%) as a white powder.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ + CD ₃ OD) δppm: 1.01 (9H, s), 2.22-2.45 (2H, m), 2.
60-2.80 (1H, m), 2.77 (3H, s), 3.00-3.10 (1H, m), 3.6
5-3.80 (1H, m), 3.80-3.95 (1H, m), 7.12-7.35 (5H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3319, 168
3, 1648, 1531 Mass spectrum (FAB): m / z [M + H] ⁺ = 323 4-b) 4- (S) -amino-3- (R) -hydroxy
Ci-5-phenylpentanoic acid methylamide hydrochloride 4- (S) -t-butoxycarbonylamino-3-
(R) -Hydroxy-5-phenylpentanoic acid methylamide (650 mg) was dissolved in ethanol (13 ml), 4N hydrochloric acid / dioxane was added under ice-cooling, the mixture was returned to room temperature, stirred for 15 hours, and then heated to 40 ° C. Stir for 2 hours. The solvent was distilled off under reduced pressure, and the target compound (520 mg, 100
%) As a white powder.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ + CD ₃ OD) δppm: 2.50-2.70 (2H, m), 2.79 (3H, s), 2.
95-3.15 (2H, m), 3.60-3.75 (1H, m), 4.20-4.40 (1H,
m), 7.20-7.50 (5H, m) Mass spectrum (EI): m / z [M] ⁺ = 223 4-c) 3- (R)-[1- (S) -benzyl-2-
(R) -hydroxy-3- (N-methylcarbamoyl)
Propylcarbamoyl] dodecanoic acid t- Buchirue ester 4- (S) - Amino -3- (R) - from hydroxy-5-phenyl-pentanoic acid methylamide hydrochloride (500 mg), in the same manner as in Example 1-b) desired compound (500m
g, 61.5%) as a white powder.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm ： 0.88 (3H, t, J = 6.7Hz), 1.10-1.40 (16H,
m), 1.42 (9H, s), 2.25-2.50 (5H, m), 2.80 (3H, d, J =
4.74Hz), 2.85-3.10 (2H, m), 3.90-4.08 (2H, m), 6.25-
6.35 (1H, m), 6.77-6.87 (1H, m), 7.15-7.35 (5H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3314, 173
0, 1645, 1553 Mass spectrum (FAB): m / z [M + H] ⁺ = 505 Melting point 204-205 ° C 4-d) 3- (R)-[1- (S) -benzyl-2-
(R) -hydroxy-3- (N-methylcarbamoyl)
Propylcarbamoyl] dodecanoic acid 3- (R)-[1- (S) -benzyl-2- (R) -hydroxy-3- (N-methylcarbamoyl) propylcarbamoyl] dodecanoic acid t-butyl ester (450 m
g) was suspended in methylene chloride (9 ml), trifluoroacetic acid (2.08 ml) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the target compound (390 mg, 10
0%) as a white powder.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ + CD ₃ OD) δppm ： 0.88 (3H, t, J = 6.7Hz), 1.10-1.50 (1
6H, m), 2.25-2.50 (5H, m), 2.78 (3H, s), 2.86 (1H, d
d, J = 14.3, 9.1Hz), 3.04 (1H, dd, J = 14.3, 4.7Hz), 3.
90-4.10 (2H, m), 7.15-7.38 (5H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3316, 32
86, 1731, 1645, 1549 Mass spectrum (FAB): m / z [ M + H] + = 449 mp ^{202-204 ℃ 4-e) N 1} - [1- (S) - benzyl-2-(R)
-Hydroxy-3- (N-methylcarbamoyl) propyl
Le] -N ⁴ - hydroxy -2- (R) - Nonirusukushina
Mido 3- (R)-[1- (S) -benzyl-2- (R) -hydroxy-3- (N-methylcarbamoyl) propylcarbamoyl] dodecanoic acid (390 mg) was dissolved in tetrahydrofuran (10 ml), and ice was added. O- (t-butyldimethylsilyl) hydroxyamine (158 mg) under cooling,
Diethyl cyanophosphonate (0.16 ml) and triethylamine (0.37 ml) were added, and the mixture was stirred under ice cooling for 2 hours. Pour the reaction solution into saturated aqueous sodium bicarbonate,
Extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was washed with ether and dissolved in ethanol.
After adding 1N-hydrochloric acid and stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The residue was washed with ether, added with methanol-water and recrystallized to give the desired compound (70 mg, 17.4%).
Was obtained as white crystals. ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ + CD ₃ OD) δp
pm: 0.89 (3H, t, J = 6.9Hz), 1.05-1.50 (16H, m), 1.91
(1H, dd, J = 14.6, 7.1Hz), 1.96 (1H, dd, J = 14.6, 7.4H
z), 2.29 (1H, dd, J = 14.6, 9.1Hz), 2.46 (1H, dd, J = 1
4.6, 2.4Hz), 2.49-2.51 (1H, m), 2.76 (3H, s), 2.75 (1
H, dd, J = 14.0, 9.9Hz), 3.14 (1H, dd, J = 14.0, 3.6H
z), 3.94-4.03 (2H, m), 7.13-7.26 (5H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3289, 16
43, 1550 Mass spectrum (FAB): m / z [ M + H] + = 464 mp 220-222 ° C. (Example 5) N ¹ - [1- (S) - benzyl-2-
(S) -hydroxy-3- (N-methylcarbamoyl)
Propyl] -N ⁴ - hydroxy -2- (R) - Nonirusu
Cucinamide (Exemplified Compound No. 62) 5-a) 4- (S) -t-butoxycarbonylamino
-3- (S) -hydroxy-5-phenylpentanoic acid
Cylamide 4- (S) -t-butoxycarbonylamino-3-
(S) -hydroxy-5-phenylpentanoic acid (31 m
g) In the same manner as in Example 4-a), the target compound (26)
mg, 80.6%) as a white powder.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 1.40 (9H, s), 2.16 (1H, dd, J = 14.9, 2.4H
z), 2.43 (1H, dd, J = 14.9, 9.6Hz), 2.78 (3H, d, J = 4.9H
z), 2.91 (2H, d, J = 7.6Hz), 3.60-3.80 (1H, m), 3.90-
4.02 (1H, m), 4.57 (1H, brs), 4.98 (1H, d, J = 9.6Hz),
5.65-5.82 (1H, m), 7.16-7.40 (5H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3369, 168
8, 1654, 1639, 1522 Mass spectrum (EI): m / z [M] ⁺ = 323 Melting point 134-135 ° C 5-b) 4- (S) -amino-3- (S) -hydroxy
Ci-5-phenylpentanoic acid methylamide hydrochloride 4- (S) -t-butoxycarbonylamino-3-
The target compound (16 mg, quant.) Was obtained as a white powder from (S) -hydroxy-5-phenylpentanoic acid methylamide (20 mg) in the same manner as in Example 4-b).

Mass spectrum (FAB): m / z [M + H] ⁺ = 22
35 -c) 3- (R)-[1- (S) -benzyl-2-
(S) -hydroxy-3- (N-methylcarbamoyl)
Propylcarbamoyl] dodecanoic acid t- Buchirue ester 4- (S) - Amino -3- (S) - from the hydroxy-5-phenyl-pentanoic acid methylamide hydrochloride (440 mg), Example 1-b) with the desired compound in the same manner (540m
g, 76.4%) as a white powder.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm ： 0.88 (3H, t, J = 6.6Hz), 1.15-1.37 (16H,
m), 1.43 (9H, s), 2.09-2.57 (5H, m), 2.77 (3H, d, J =
4.9Hz), 2.94 (2H, m), 3.88-4.03 (2H, m), 4.67-4.73 (1
H, m), 5.89-5.98 (1H, m), 6.17 (1H, d, J = 9.5Hz), 7.13
-7.34 (5H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3333, 173
1, 1700, 1661, 1530 Mass spectrum (FAB): m / z [M + H] ⁺ = 505 Melting point 104-105 ° C 5-d) 3- (R)-[1- (S) -benzyl-2-
(S) -hydroxy-3- (N-methylcarbamoyl)
Propylcarbamoyl] dodecanoic acid 3- (R)-[1- (S) -benzyl-2- (S) -hydroxy-3- (N-methylcarbamoyl) propylcarbamoyl] dodecanoic acid t-butyl ester (500 m
g) In the same manner as in Example 4-d), the target compound (4
00 mg, 89.2%) as a white powder.

Mass spectrum (FAB): m / z [M + H] ⁺ = 44
9 5-e) N ¹ - [1- (S) - benzyl-2-(S)
-Hydroxy-3- (N-methylcarbamoyl) propyl
Le] -N ⁴ - hydroxy -2- (R) - Nonirusukushina
Example 4 from mido 3- (R)-[1- (S) -benzyl-2- (S) -hydroxy-3- (N-methylcarbamoyl) propylcarbamoyl] dodecanoic acid (350 mg)
-E) and the target compound (140 mg, 38.7).
%) As a white powder.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm ： 0.89 (3H, t, J = 6.9Hz), 1.13-1.59 (16H,
m), 2.01 (1H, dd, J = 14.6, 7.6Hz), 2.05 (1H, dd, J = 14.
6, 7.0Hz), 2.25 (1H, dd, J = 14.3, 4.2Hz), 2.32 (1H, d
d, J = 14.3, 8.8Hz), 2.59-2.69 (1H, m), 2.71 (3H, s),
2.84 (1H, dd, J = 13.7, 8.9Hz), 2.94 (1H, dd, J = 13.7,
6.1Hz), 3.92-4.09 (2H, m), 7.10-7.30 (5H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3305, 16
38, 1539 Mass spectrum (FAB): m / z [M + H] ⁺ = 464 Melting point 166-167 ° C (Example 6) 2- (R) -hydroxy-3- (S)-
[2- (R)-(N-hydroxycarbamoylmethyl)
Undecanoylamino amino] -4-phenylbutane Sanme Chill
Ester (Exemplified Compound No. 61) 6-a) 3- (S) -Dibenzylamino-2- (R)
- hydroxy-4-Fe Nirubutan acid methyl ester 3- (S) - dibenzylamino-2-(R) - hydroxy-4-phenyl butanoic acid (1.5 g) was dissolved in methanol, diazomethane yellow clear solution Added until it was. Acetic acid was added to decompose excess diazomethane, and the solvent was distilled off. Purification by silica gel column chromatography gave the target compound (1.55 g, 99.5%) as a colorless oil.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 2.81 (1H, dd, J = 14.0, 7.3Hz), 3.03 (1H, d
d, J = 14.0, 7.3Hz), 3.09 (1H, d, J = 6.3Hz), 3.42 (1H, d
t, J = 2.6, 7.3Hz), 3.53 (3H, s), 3.66 (2H, d, J = 14.0H
z), 3.82 (2H, d, J = 14.0Hz), 4.49 (1H, dd, J = 6.3, 2.6
Hz), 7.02-7.33 (15H, m) Mass spectrum (FAB): m / z [M + H] ⁺ = 390 6-b) 3- (S) -amino-2- (R) -hydroxy
Methyl 4-phenylbutanoate 3- (S) -dibenzylamino-2- (R) -hydroxy-4-phenylbutanoate methyl ester (700 m
g) was dissolved in methanol (13.44 ml), and after purging with nitrogen, 10% palladium-carbon catalyst (350 mg) was added, and formic acid (0.56 ml) was further added, followed by stirring at room temperature for 3 hours. After filtering the catalyst, the solvent was distilled off under reduced pressure to obtain the target compound (408 mg, quant.) As a colorless oily substance.

Mass spectrum: m / z [M + H] ⁺ = 210 6-c) 3- (R)-[1- (S) -benzyl-2-
(R) -hydroxy-2-methoxycarbonylethylca
Rubamoyl] dodecanoic acid t-butyl ester 3- (S) -amino-2- (R) -hydroxy-4-phenylbutanoic acid methyl ester (15 mg) in the same manner as in Example 1-b) to give the desired compound (18 mg, 73.2
%) As a colorless oil.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm ： 0.88 (3H, t, J = 6.9Hz), 1.18-1.39 (16H,
m), 1.41 (9H, s), 2.27-2.50 (3H, m), 2.85 (2H, d, J =
7.4Hz), 3.53 (3H, s), 3.62 (1H, d, J = 5.5Hz), 4.30 (1
H, dd, J = 5.5, 2.7Hz), 4.57-4.69 (1H, m), 6.15 (1H, d,
J = 8.6 Hz), 7.15-7.37 (5H, m) Mass spectrum (FAB): m / z [M + H] ⁺ = 492 6-d) 3- (R)-[1- (S) -benzyl-2 −
(R) -hydroxy-2-methoxycarbonylethylca
Lubamoyl] dodecanoic acid 3- (R)-[1- (S) -Benzyl- 2- (R) -hydroxy-2-methoxycarbonylethylcarbamoyl] dodecanoic acid t-butyl ester (140 mg) to give Example 4-d The target compound (110m
g, 90.2%) as a colorless oil.

Mass spectrum (FAB): m / z [M + H] ⁺ = 43
6 6-e) 2- (R) -hydroxy-3- (S)-[2
-(R)-(N-hydroxycarbamoylmethyl) un
-Decanoylamino] -4-phenyl-butanoic acid methylcarbamoyl Ruesu
From 3- (R)-[1- (S) -benzyl-2- (R) -hydroxy-2-methoxycarbonylethylcarbamoyl] dodecanoic acid (100 mg), the desired compound was obtained in the same manner as in Example 4-e). (63 mg, 60.8%) was obtained as white crystals. ¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD) δ ppm:
0.89 (3H, t, J = 7.1Hz), 1.10-1.55 (16H, m), 1.93 (2H,
d, J = 7.2Hz), 2.55-2.62 (1H, m), 2.77 (1H, dd, J = 14.
0, 9.6Hz), 2.91 (1H, dd, J = 14.0, 5.0Hz), 3.65 (3H,
s), 4.18 (1H, d, J = 5.0Hz), 4.45-4.50 (1H, m), 7.13-
7.30 (5H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3300, 17
45, 1645, 1544 Mass spectrum (FAB): m / z [ M + H] + = 451 mp 143-145 ° C. (Example 7) 2- (S), N 1 - dihydroxy -N ⁴ -
[1- (S) -t-butyl-2- (R) -hydroxy-
3- (N, N-dimethylcarbamoyl) propyl] -3
-(R) -nonylsuccinamide (Exemplary Compound No. 16
6) 7-a) [1- (S) -t-butyl-2- (R) -H
Droxy-3- (N, N -dimethylcarbamoyl) pro
Pyl] carbamic acid benzyl ester 4- (S) -benzyloxycarbonylamino-3-
(R) -hydroxy-5,5-dimethylhexanoic acid (3
10 mg) and N, N-dimethylformamide (6 ml)
From the dimethylamine hydrochloride (163 mg) dissolved in the same manner as in Example 1-a).
7.2%) as a white powder.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 1.03 (9H, s), 2.37-2.56 (2H, m), 2.84 (3H,
s), 2.92 (3H, s), 3.53 (1H, dd, J = 10.6, 8.0Hz), 3.97
-4.10 (1H, m), 4.28 (1H, d, J = 4.4Hz), 4.67 (1H, d, J =
10.6Hz), 5.05 (1H, d, J = 12.4Hz), 5.16 (1H, d, J = 12.4
Hz), 7.30-7.40 (5H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3361, 17
09, 1624, 1543 Mass spectrum (EI): m / z [M] ⁺ = 336 7-b) 2- (R)-(2,2-dimethyl-5-oxo
So- [1,3] -dioxolan-4- (S) -yl)
N-decanoic acid [1- (S) -t-butyl-2- (R ) -H
Droxy-3- (N, N-dimethylcarbamoyl) pro
Pyl] amide [1- (S) -tert-butyl-2- (R) -hydroxy-
Example 2 from 3- (N, N-dimethylcarbamoyl) propyl] carbamic acid benzyl ester (1.64 g)
Compound (630 mg, 26.5) in the same manner as in -a)
%) As a colorless oil.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.88 (3H, t, J = 7.1Hz), 1.04 (9H, s), 1.20
-1.40 (16H, m), 1.55 (3H, s), 1.63 (3H, s), 2.49 (2H,
d, J = 5.7Hz), 2.60-2.70 (1H, m), 2.95 (3H, s), 2.97 (3H
H, s), 3.88 (1H, dd, J = 9.6, 7.3Hz), 4.03-4.15 (1H,
m), 4.20 (1H, d, J = 5.0Hz), 4.55 (1H, d, J = 5.5Hz), 6.2
8 (1H, d, J = 9.6Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3409, 17
87, 1672, 1629 Mass spectrum (FAB): m / z [ M + H] + = 485 7-c) N 1 - benzyloxy -N ⁴ - [1- (S) -t-
Butyl-2- (R) -hydroxy-3- (N, N-dimethyl
Tylcarbamoyl) propyl] -2- (S) -hydroxy
C-3- (R) -nonylsuccinamide 2- (R)-(2,2-dimethyl-5-oxo- [1,
3] -Dioxolan-4- (S) -yl) undecanoic acid [1- (S) -tert-butyl-2- (R) -hydroxy-
From 3- (N, N-dimethylcarbamoyl) propyl] amide (630 mg), the target compound (574 mg, 80.3%) was obtained as a white powder in the same manner as in Example 2-b).

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm ： 0.88 (3H, t, J = 6.8Hz), 1.03 (9H, s), 1.20
-1.45 (14H, m), 1.73 (2H, m), 2.37-2.55 (2H, m), 2.86
-3.00 (1H, m), 2.95 (6H, s), 3.85 (1H, dd, J = 10.0, 6.
7Hz), 4.10-4.20 (3H, m), 4.82 (1H, d, J = 11.2Hz), 4.8
9 (1H, d, J = 11.2Hz), 5.23 (1H, d, J = 8.4Hz), 6.09 (1H,
d, J = 10.0Hz), 7.28 (5H, brs), 9.35 (1H, brs) Infrared absorption spectrum (CDCl ₃ , cm ⁻¹ ): 3402, 1687, 16
33 Mass spectrum (FAB): m / z [M + H] ⁺ = 550 7-d) 2- (S), N ¹ -dihydroxy-N ⁴ −
[1- (S) -t-butyl-2- (R) -hydroxy-
3- (N, N-dimethylcarbamoyl) propyl] -3
- (R) - nonyl disk Sina bromide N ¹ - benzyloxy -N ⁴ - [1- (S) -t- butyl -2- (R) - hydroxy-3-dimethylcarbamoyl-propyl] -2- (S) - Hydroxy-3- (R)-
Example 2-c) from nonylsuccinamide (550 mg)
In the same manner as in the above, the target compound (340 mg, 74.0%) was obtained as a white compound.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm ： 0.89 (3H, t, J = 6.9Hz), 1.02 (9H, s), 1.20
-1.40 (14H, m), 1.42-1.55 (1H, m), 1.60-1.70 (1H, m),
2.39 (1H, dd, J = 15.2, 2.7Hz), 2.61 (1H, dd, J = 15.2,
9.4Hz), 2.72 (1H, dt, J = 9.5, 5.9Hz), 2.94 (3H, s),
3.07 (3H, s), 3.79 (1H, d, J = 6.9Hz), 4.08 (1H, d, J = 5.
9Hz), 4.18 (1H, ddd, J = 9.4, 6.9, 2.7Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3279, 32
04, 1648, 1632 Mass spectrum (FAB): m / z [M + H] ⁺ = 460 Melting point 167-169 ° C (Example 8) Acetic acid 2- (S)-[2- (R)-(N-
Hydroxycarbamoylmethyl) undecanoylamido
No] -3,3-dimethylbutyl ester (Exemplary Compound No. 9) 8-a) 2- (R) -t-butoxycarbonylmethyl
4- (S) -isopropyl-3- undecanoic acid -3- (2- (R) -tert-butoxycarbonylmethyl-1-oxoundecyl) -2
-Oxazolidinone (12.00 g) was dissolved in tetrahydrofuran-water (3: 1,600 ml) and cooled to 0 ° C. Lithium hydroxide monohydrate (2.45 g), 30%
Aqueous hydrogen peroxide (14.4 ml) was sequentially added, and the mixture was stirred for 3.5 hours. After adding a 1.5 N aqueous sodium sulfite solution (112 ml) at the same temperature, the reaction solution was poured into 0.5 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 7.83 g (89%) of the desired compound.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δppm ： 0.88 (3H, t, J = 6.6Hz), 1.16-1.75 (16H,
m), 1.47 (9H, s), 2.38 (1H, dd, J = 16.3, 5.2Hz), 2.63
(1H, dd, J = 16.3, 9.2Hz), 2.80 (1H, m) Infrared absorption spectrum (liquid film, cm ^-1 ) 1734, 1709 High resolution mass spectrum m / z [M + H] ⁺ = 301.2354 Calculated value: 301.2379 (C ₁₇ H ₃₃ O ₄ ) Specific rotation: [α] _D ²⁵ = + 14.1 ° (C: 1.07, EtOH) 8-b) 3- (R)-[1- (S) -hydroxymethyl
Le-2,2-Jimechirupu Ropi carbamoyl] dodecane
Acid t-butyl ester 2- (R) -t-butoxycarbonylmethylundecanoic acid (1.92 g) obtained in Example 8-a) was dissolved in tetrahydrofuran (40.0 ml) under a nitrogen atmosphere.
Cooled to 20 ° C. Then triethylamine (0.94
ml) and isobutyl chloroformate (0.88 ml) were added dropwise, followed by stirring at -20 ° C for 25 minutes. Next, a solution of (S) -t-leucinol (845 mg) in N, N-dimethylformamide (8 ml) was added, and the mixture was stirred overnight while warming to room temperature. Pour the reaction solution into a 5% aqueous solution of potassium hydrogen sulfate,
The mixture was extracted with ethyl acetate, and the organic layer was washed with a 5% aqueous sodium hydrogen carbonate solution, water, and saturated saline in this order, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
3: 1) to give 1.51 g (59%) of the desired compound
Was obtained as a white solid. 63-65 ° C ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δppm
： 0.88 (3H, t), 0.95 (9H, s), 1.10-1.50 (14H, m), 1.
43 (9H, s), 1.47-1.90 (2H, m), 2.39 (1H, m), 2.50-2.7
0 (2H, m), 3.54 (1H, m), 3.73-3.91 (2H, m), 6.09 (1H,
d, J = 8.9Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3328, 1732, 1645, 1544 Mass spectrum (FAB) m / z [M + H] ⁺ = 400 High-resolution mass spectrum (FAB) m / z [ M ⁺ H] + = 400.3419 _{calculated: 400.3427 (C 23 H 46 O} 4 N) 8-c) 3- (R) - [1- (S) - Asetokishimechi
-2,2-dimethylpropylcarbamoyl] dodecane
Acid t-butyl ester 3- (R)-[1- (S)-obtained in Example 8-b).
Hydroxymethyl-2,2-dimethylpropylcarbamoyl] dodecanoic acid t-butyl ester (704 mg) was dissolved in tetrahydrofuran (5 ml) and cooled to 0 ° C. Then, pyridine (160 μl) and acetyl chloride (1
(35 μl) was added in sequence, and the mixture was stirred at 0 ° C. for 1.3 hours. The reaction solution was poured into a 5% aqueous potassium hydrogen sulfate solution and extracted with ethyl acetate. The organic layer was washed with a 5% aqueous sodium hydrogen carbonate solution, water,
After sequentially washing with a saturated saline solution, the resultant was dried with sodium sulfate.
After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 768 mg (99%) of the desired compound as a colorless oil.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ ) δppm ： 0.87 (3H, t, J = 6.8Hz), 0.94 (9H, s), 1.
15-1.50 (15H, m), 1.42 (9H, s), 1.67 (1H, m), 2.03 (3
H, s), 2.32 (1H, dd, J = 16.7, 3.5Hz), 2.53 (1H, m),
2.63 (1H, dd, J = 16.7, 9.8Hz), 4.01-4.13 (2H, m), 4.2
1 (1H, m), 5.83 (1H, d, J = 8.8Hz) Infrared absorption spectrum (liquid film, cm ^-1 ) 3320, 1732, 1648, 1545 Mass spectrum (FAB) m / z [M + H] ⁺ = 442 High-resolution mass spectrum (FAB) m / z [M + H] ⁺ = 442.3506 Calculated: 442.3533 (C ₂₅ H ₄₈ NO ₅ ) 8-d) 3- (R)-[1- (S) -acetoxymethyl
-2,2-dimethylpropylcarbamoyl] dodecane
3- (R)-[1- (S)-obtained in Acid Example 8-c).
Trifluoroacetic acid (2.5 ml) was added to a solution of t-butyl acetoxymethyl-2,2-dimethylpropylcarbamoyl] dodecanoate (690 mg) in methylene chloride (25 ml), and the mixture was stirred at room temperature for 3.7 hours.
After toluene (30 ml) was added to the reaction solution, volatiles were distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (methylene chloride: methanol = 30:
Purification according to 1) gave 584 mg (97%) of the desired compound as a colorless oil.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ ), δppm ： 0.88 (3H, t, J = 6.8Hz), 0.95 (9H, s), 1.
13-1.38 (14H, m), 1.48 (1H, m), 1.67 (1H, m), 2.03 (3
H, s), 2.46-2.61 (2H, m), 2.77 (1H, dd, J = 17.2, 9.5H
z), 4.01-4.16 (2H, m), 4.22 (1H, m), 5.73 (1H, d, J =
9.4Hz) Infrared absorption spectrum (liquid film, cm ^-1 ) 3320, 1742, 1727, 1500 Mass spectrum (FAB) m / z [M + H] ⁺ = 386 High resolution mass spectrum (FAB) m / z [M + H] ⁺ = 386.2889 _{calculated: 386.2906 (C 21 H 40 NO} 5) 8-e) acetic acid 2- (S) - [2- (R) - (N- hydrate
Roxycarbamoylmethyl) undecanoylamino]-
3,3-dimethylbutyl ester 3- (R)-[1- (S) -obtained in Example 8-d).
Acetoxymethyl-2,2-dimethylpropylcarbamoyl] dodecanoic acid (2.55 g) was dissolved in N, N-dimethylformamide (56 ml) and cooled to 0 ° C. Then, 1-hydroxybenzotriazole (1.34)
g), N-methylmorpholine (1.20 ml), 1-
(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.03 g) and O- (t-butyldimethylsilyl) hydroxylamine (1.85 g) were sequentially added, and the mixture was stirred while warming to room temperature. The reaction solution was poured into a 5% aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was washed with a 5% aqueous solution of potassium hydrogen sulfate, water and saturated brine in that order, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride: methanol = 20: 1), and the obtained white solid was recrystallized from methanol-water to give 1.71 g (65%) of the desired compound. Was obtained as white crystals.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ ) δppm ： 0.88 (3H, t, J = 6.9Hz), 0.89 (9H, s), 1.
17-1.53 (15H, m), 1.65 (1H, m), 2.02 (3H, s), 2.29 (1
H, m), 2.49 (1H, m), 2.75 (1H, m), 3.95-4.13 (2H, m),
4.24 (1H, d, J = 8.4 Hz), 6.18 (1H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3299, 1745, 1643, 1550 Mass spectrum (FAB) m / z [M + H] ⁺ = 401 High-resolution mass spectrum (FAB) m / z [M + H] ⁺ = 401.3022 Calculated value: 401.3016 (C ₂₁ H ₄₁ N ₂ O ₅ ) Specific rotation: [α] _D ²⁵ = + 8.8 ° (C: 0.34, MeOH) (example 9) N ⁴ - hydroxy -N ¹ - [1-(S) -
Hydroxymethyl-2,2-dimethylpropyl] -2-
(R) -Nonylsuccinamide (Exemplary Compound No. 8) 2- (S)-(2-acetic acid) obtained in Example 8-e)
Potassium carbonate (186 mg) was added to a methanol (10 ml) solution of (R)-(N-hydroxycarbamoylmethyl) undecanoylamino) -3,3-dimethylbutyl ester (258 mg), and the mixture was stirred at room temperature for 2.3 hours. did. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate, extracted with ethyl acetate, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained white solid was recrystallized from ethyl acetate-methanol to give 183 mg of the desired compound (7 mg).
9%) as white crystals.

Nuclear magnetic resonance spectrum (400 MHz, DMSO-d ₆ )
δppm ： 0.84 (9H, s), 0.86 (3H, t, J = 6.6Hz), 1.10-
1.35 (15H, m), 1.42 (1H, m), 2.01 (1H, dd, J = 14.3, 7.
8Hz), 2.15 (1H, dd, J = 14.3, 6.5Hz), 2.65 (1H, m), 3.
30-3.45 (1H, overlapped with solvent peak), 3.46-3.
65 (2H, m), 4.25 (1H, t, J = 5.4Hz), 7.41 (1H, d, J = 9.3
Hz), 8.65 (1H, d, J = 1.4Hz), 10.36 (1H, d, J = 1.4Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3401, 3254, 1666, 1613, 1532 Mass spectrum (FAB ) m / z [M + H] ⁺ = 359 High-resolution mass spectrum (FAB) m / z [M + H] ⁺ = 359.2923 Calculated: 359.2910 (C ₁₉ H ₃₉ N ₂ O ₄ ) Specific rotation: [α] _D ²⁵ = + 2.9 ° (C: 0.38, MeOH) Melting point 162 to 164 ° C. (Example 10) Acetic acid 2- (S)-{2- (R)-
[(S) -hydroxy (hydroxycarbamoyl) methyl
Le] undecanoylamino amino} -3,3 Jimechirubuchi Le
Ester (Exemplified Compound No. 110) 10-a) 2- (R)-[2,2-dimethyl-5-o
Oxo- [1,3] -dioxolan-4- (S) -yl]
Undecanoic acid [1- (S) -hydroxymethyl- 2,2
-Dimethylpropyl] amide According to the method of Example 8-b), 2- (R)-[2,2-
Dimethyl-5-oxo- [1,3] -dioxolan-4
-(S) -yl] undecanoic acid (518 mg) and (S) -t-leucinol (250 mg) as starting materials and 361 mg (52
%, Conversion yield 72%) as a white solid. On this occasion,
Starting material 2- (R)-[2,2-dimethyl-5-
140 mg (27%) of oxo- [1,3] -dioxolan-4- (S) -yl] undecanoic acid was recovered.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δppm ： 0.88 (3H, t, J = 6.6Hz), 0.96 (9H, s), 1.
15-1.50 (14H, m), 1.55 (3H, s), 1.60-1.90 (2H, m), 1.
63 (3H, s), 2.69 (1H, dt, J = 5.2, 10.2Hz), 2.85-3.45
(1H, br), 3.54 (1H, dd, J = 12.0, 8.7Hz), 3.80-3.94 (2
H, m), 4.62 (1H, d, J = 5.2Hz), 6.38 (1H, d, J = 8.7Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3259, 3093, 1798, 1646, 1571 Mass spectrum (FAB) m / z [M + H] ⁺ = 400 High-resolution mass spectrum (FAB) m / z [M + H] ⁺ = 400.3088 Calculated: 400.3053 (C ₂₂ H ₄₂ NO ₅ ) Melting point 110-112 ° C. 10-b) Acetic acid 2- (S)-｛2- (R)-[2,2
-Dimethyl-5-oxo- [1,3] -dioxolane-
4- (S) - yl] undecanoylamino amino} -3, 3-
Dimethyl butyl ester 2- (R)-[2,2-dimethyl-5-oxo- [1,3] -dioxolan-4- obtained in Example 10-a).
(S) -yl] undecanoic acid [1- (S) -hydroxymethyl-2,2-dimethylpropylamide (350 m
g) in a solution of tetrahydrofuran (10 ml), pyridine (105 μl), acetic anhydride (125 μl), and 4-dimethylaminopyridine (10 mg) were sequentially added.
Stirred for hours. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate. The organic layer was washed sequentially with a 5% aqueous sodium hydrogen carbonate solution, water and saturated saline, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain 370 mg of the desired compound
(96%) as a white solid.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δppm ： 0.88 (3H, t, J = 6.6Hz), 0.97 (9H, s), 1.15
-1.45 (14H, m), 1.54 (3H, s), 1.61 (3H, s), 1.70-1.88
(2H, m), 2.03 (3H, s), 2.57 (1H, dt, J = 5.9, 8.8Hz),
4.00-4.16 (2H, m), 4.26 (1H, m), 4.52 (1H, d, J = 5.9H
z), 6.07 (1H, br d, J = 9.3Hz) Infrared absorption spectrum (KBr pellet) 3335, 1792, 1741, 1651 Mass spectrum (FAB) m / z [M + H] ⁺ = 442 High resolution mass spectrum (FAB) m / z [M + H] ⁺ = 442.3176 Calculated: 442.3169 (C ₂₄ H ₄₄ NO ₆ ) 10-c) Acetic acid 2- (S)-｛2- (R)-[(S)
-Benzyloxycarbamoyl (hydroxy) methyl]
Undecanoylamino amino} -3,3 Jimechirubuchi Ruesu
Acetic acid 2- (S)-{2-} obtained in Tell Example 10-b)
(R)-[2,2-dimethyl-5-oxo- [1,3]
-Dioxolan-4-yl] undecanoylamino}-
3,3-Dimethylbutyl ester (367 mg) was dissolved in acetic acid-water (2: 1, 15 ml) and stirred at room temperature for 27 hours. Toluene (50 ml) was added to the reaction solution, and acetic acid and the solvent were distilled off under reduced pressure. The obtained white solid was further dried under reduced pressure for 8 hours, and then dissolved in tetrahydrofuran-water (1: 1, 15 ml). At room temperature, O-benzylhydroxylamine hydrochloride (233 mg), 1- (3
-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (355 mg) was added and stirred overnight. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride: methanol = 40: 1) to obtain the desired compound 268.
mg (2 steps, 64%) was obtained as a foam.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ ) δppm ： 0.88 (3H, t, J = 6.9Hz), 0.97 (9H, s), 1.20
-1.43 (14H, m), 1.65 (1H, m), 1.79 (1H, m), 2.03 (3H, m
s), 2.88 (1H, m), 3.95-4.10 (2H, m), 4.15 (1H, dd, J =
8.7, 2.2Hz), 4.36 (1H, m), 4.83 (1H, d, J = 11.2Hz),
4.89 (1H, d, J = 11.2Hz), 5.17 (1H, d, J = 8.7Hz), 5.82
(1H, d, J = 9.3Hz), 7.30-7.45 (5H, m), 9.30 (1H, s) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3338, 3275, 3199, 1744, 1642, 1554 Mass spectrum (FAB) m / z [M + H] ⁺ = 507 High-resolution mass spectrum (FAB) m / z [M + H] ⁺ = 507.3417 Calculated: 507.3434 (C ₂₈ H ₄₇ N ₂ O ₆ ) 10-d) acetic acid 2- ( S)-｛2- (R)-[(S)
-Hydroxy (hydroxycarbamoyl) methyl] un
Decanoylamino} -3,3-dimethylbutyl an ester Example 10-c) obtained in acetic acid 2- (S) - {2-
5% palladium-alumina (40%) was added to a solution of (R)-[(S) -benzyloxycarbamoyl (hydroxy) methyl] undecanoylamino} -3,3-dimethylbutyl ester (260 mg) in methanol (4.0 ml).
mg), and hydrolyzed under a hydrogen atmosphere for 2 hours.
The catalyst was removed by celite filtration, the obtained filtrate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 40: 1) to obtain 110 mg (51%) of the desired compound as a foam-like substance. As obtained.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ ) δppm ： 0.88 (3H, t, J = 6.8Hz), 0.92 (9H, s), 1.
15-1.48 (14H, m), 1.65 (1H, m), 1.86 (1H, m), 2.03 (3
H, s), 2.93 (1H, m), 4.01 (1H, m), 4.74 (1H, m), 4.15
-4.30 (2H, m), 5.25 (1H, m), 6.18 (1H, d, J = 9.8Hz),
7.43 (1H, br), 9.46 (1H, br s) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3351, 3305, 3215, 1716, 1639, 1564 Mass spectrum (FAB) m / z [M + H] ⁺ = 417 High resolution mass spectrum (FAB) m / z [M + H] ⁺ = 417.2956 Calculated: 417.2965 (C ₂₁ H ₄₁ N ₂ O ₆ ) Specific rotation: [α] _D ²⁵ = + 5.7 ° (C: 0.56, MeOH) Example 11 2 (S), N ¹ -dihydroxy-N ⁴
-[1- (S) -hydroxymethyl-2,2-dimethyl
[Propyl] -3- (R) -nonylsuccinamide (Exemplified Compound No. 109) Acetic acid 2- (S)-{2-} obtained in Example 10-d)
(R)-[(S) -hydroxy (hydroxycarbamoyl) methyl] undecanoylamino} -3,3-dimethylbutyl ester (68.0 mg) in methanol (3.
0 ml) solution, potassium carbonate (70.1 mg) was added,
Stir at room temperature for 3 hours. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the obtained white solid was recrystallized from methanol-water to obtain 47.9 mg (78%) of the target compound as white crystals. ¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD), δ ppm
: 0.89 (3H, t, J = 6.8 Hz),
0.94 (9H, s), 1.17-1.54 (15
H, m), 1.65 (1H, m), 2.68
(1H, m), 3.48 (1H, dd, J = 1
2.1, 9.2 Hz), 3.70-3.81 (2
H, m), 4.06 (1H, d, J = 6.5H
z) Infrared absorption spectrum (KBr pellet, c
m ^-1 ) 3385, 3327, 3152, 3066, 1
670, 1618, 1575 Mass spectrum (FAB) m / z [M + H] ⁺ = 375 Elemental analysis Calculated: C ₁₉ H ₃₈ N ₂ O ₅ : C, 60.93%; H, 10.23%; N, 7.48% Measured: : C, 60.92%; H, 10.48%; N, 7.37% Specific rotation: [α] _D ²⁵ = -1 ° (C: 0.38, MeOH) (Example 12) N ⁴ -hydroxy-N ^1- [1 -(S)
-Hydroxymethyl-2-phenylethyl] -2-
(R) -Nonylsuccinamide (Exemplary Compound No. 14) 12-a) 3- (R)-[1- (S) -Hydroxyme
Tyl-2-phenylethylcarbamoyl] dodecanoic acid t
-Butyl ester According to the method of Example 8-b), 2- (R) -tert-butoxycarbonylmethylundecanoic acid (1.50 g) obtained in Example 8-a) and L-phenylalaninol (798 mg) Was used as a starting material, and 1.65 g (76%) of the target compound was obtained as a white solid by the same reaction treatment.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ), δppm ： 0.88 (3H, t, J = 6.6Hz), 1.13-1.80 (16H,
m), 1.43 (9H, s), 2.33 (1H, dd, J = 15.3, 3.5Hz), 2.40
-2.63 (2H, m), 2.78-3.00 (2H, m), 3.66 (2H, d, J = 4.6H
z), 4.04 (1H, m), 6.00 (1H, d, J = 7.4Hz), 7.17-7.37 (5
H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3360, 1709, 1645, 1531 Mass spectrum (FAB) m / z [M + H] ⁺ = 434 High-resolution mass spectrum (FAB) m / z [M + H] ⁺ = 434.3259 _{calculated: 434.3271 (C 26 H 44 NO} 4) mp: 70~72 ℃ 12-b) N 4 - hydroxy -N ¹ - [1- (S) -
Hydroxymethyl-2-phenylethyl] -2- (R)
-Nonylsuccinamide 3- (R)-[1- (S) obtained in Example 12-a)
-Hydroxymethyl-2-phenylethylcarbamoyl] dodecanoic acid t-butyl ester (1.60 g) in methylene chloride (55 ml) was treated with trifluoroacetic acid (5.
5 ml) and stirred at room temperature for 3.3 hours. After toluene (100 ml) was added to the reaction solution, the volatiles were distilled off under reduced pressure, and the obtained white solid was recrystallized from hexane-ethyl acetate to obtain 1.41 g of white crystals. A part (708 mg) of the obtained crystals was dissolved in N, N-dimethylformamide (20 ml) and cooled to 0 ° C. Then 1-
Hydroxybenzotriazole (353 mg), N-methylmorpholine (350 μl), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5
39 mg) and O- (t-butyldimethylsilyl) hydroxylamine (496 mg) were sequentially added, and the mixture was stirred overnight while warming to room temperature. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate and extracted with ethyl acetate. The organic layer was washed successively with a 5% aqueous solution of sodium hydrogen carbonate, water and saturated saline, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained white solid was recrystallized twice using chloroform-methanol to obtain 256 mg (35%) of the target compound as white crystals.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, DMS
Od ₆ ), δppm ： 0.85 (3H, t, J = 6.8Hz), 1.05-1.40 (16
H, m), 1.80-1.98 (2H, m), 2.45-2.60 (1H, m, overlapp
ed with solvent peak), 2.60 (1H, dd, J = 13.7, 8.6H
z), 2.85 (1H, dd, J = 13.7, 5.3Hz), 3.22-3.35 (2H, m),
3.88 (1H, m), 4.71 (1H, t, J = 5.5Hz), 7.10-7.33 (5H,
m), 8.44 (1H, d, J = 7.7Hz), 8.69 (1H, d, J = 1.3Hz), 1
0.34 (1H, d, J = 1.3Hz) Infrared absorption spectrum ^{(KBr pellet, cm -1) 3443} , 1658, 1641, 1551 Mass spectrum (FAB) m / z [M + H] + = 393 Analysis Calculated: C ₂₂ H ₃₆ N ₂ O ₄・ 0.2H ₂ O: C, 66.70%; H, 9.26%; N, 7.07% Measurement value: C, 66.50%; H, 9.14%; N, 7.03% Specific rotation: [α] _D ²⁵ = -16.9 ° (C: 0.16, M
MeOH) Melting point: 161-163 ° C. (Example 13) 3-Cyclohexyl acetate-2- (S) —
[2- (R)-(N-hydroxycarbamoylmethyl)
Undecanoylamino] propyl ester (Exemplified Compound No. 13) 13-a) 3- (R)-[2-cyclohexyl-1-
(S)-(hydroxymethyl) ethylcarbamoyl] do
Decanoic acid t-butyl ester According to the method of Example 8-b), 2- (R) -t-butoxycarbonylmethylundecanoic acid (5.93 g) and 2- (S) obtained in Example 8-a). -Amino-3-cyclohexyl-1-propanol (7.03 g) was used as a starting material and subjected to the same reaction treatment to give the desired compound (7.27).
g) was obtained as a white solid.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD
Cl ₃ ), δppm: 0.87-1.03 (2H, m), 0.88 (3H, t, J = 6.9H
z), 1.05-1.85 (27H, m), 1.43 (9H, s), 2.35 (1H, dd, J
= 16.3, 3.9Hz), 2.50 (1H, m), 2.51 (1H, dd, J = 16.3,
9.5Hz), 2.94 (1H, dd, J = 6.3, 5.3Hz), 3.56 (1H, ddd, J
= 11.1, 6.4, 5.3Hz), 3.64 (1H, ddd, J = 11.1, 6.3, 3.5H
z), 3.96 (1H, m), 5.83 (1H, d, J = 7.3Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3535, 3270, 1727, 1717, 1628, 1562 High resolution mass spectrum (FAB) m / z [M + H] + = 440.3740 _{calculated: 440.3740 (C 26 H 50 NO} 4) 13-b) 3- (R) - [1- (S) - Asetokishime
Tyl-2-cyclohexylethylcarbamoyl] dodeca
Acid t-butyl ester According to the method of Example 8-c), 3- (R)-[2-cyclohexyl-1- (S)-obtained in Example 13-a).
(Hydroxymethyl) ethylcarbamoyl] dodecanoic acid t-butyl ester (1.53 g) was used as a starting material and subjected to the same reaction treatment to give 1.67 g (99%) of the target compound as a colorless oily substance.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ), δppm: 0.88 (3H, t, J = 6.7Hz), 0.72-1.50 (23H,
m), 1.44 (9H, s), 1.52-1.86 (6H, m), 2.06 (3H, s), 2.
30 (1H, dd, J = 16.5, 4.0Hz), 2.47 (1H, m), 2.63 (1H, d
d, J = 16.5, 9.2Hz), 4.04 (2H, d, J = 4.7Hz), 4.29 (1H,
m), 5.71 (1H, d, J = 8.9Hz) Infrared absorption spectrum (liquid film, cm ^-1 ) 3302, 1746, 1733, 1645 High resolution mass spectrum (FAB) m / z [M + H] ⁺ = 482.3846 Calculated value _{: 482.3846 (C 28 H 52 NO} 5) 13-c) 3- (R) - [1- (S) - Asetokishime
Tyl-2-cyclohexylethylcarbamoyl] dodeca
According to the method of phosphate Example 8-d), obtained in Example 13-c) 3- (R) - [1- (S) - acetoxymethyl -2
-Cyclohexylethylcarbamoyl] dodecanoic acid t-
The same reaction was carried out using butyl ester (1.66 g) as a starting material to obtain 1.36 g (93%) of the target compound as a white solid.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ ), δppm: 0.76-1.03 (2H, m), 0.88 (3H, t, J = 6.9H
z), 1.05-1.55 (21H, m), 1.57-1.85 (6H, m), 2.06 (3H,
s), 2.41-2.58 (2H, m), 2.75 (1H, dd, J = 17.0, 8.9Hz),
4.00-4.13 (2H, m), 4.32 (1H, m), 5.71 (1H, d, J = 8.8H
z) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3311, 1745, 1729, 1640, 1547 High resolution mass spectrum (FAB) m / z [M + H] ⁺ = 426.3201 Calculated value: 426.3219 (C ₂₄ H ₄₄ NO ₅ ) 13-d) 3-Cyclohexyl acetate-2- (S)-
[[2- (R)-(N-hydroxycarbamoylmethyl)
L) Undecanoylamino] propyl ester 3- (R)-[1- (S) -acetoxymethyl-2 obtained in Example 13-c) according to the method of Example 8-e).
-Cyclohexylethylcarbamoyl] dodecanoic acid (1.31 g) and O- (t-butyldimethylsilyl)
The same reaction was carried out using hydroxylamine (1.00 g) as a starting material to obtain 756 mg (56%) of the target compound as white crystals. For recrystallization of this compound, hexane was used instead of methanol-water used in Example 8-e).
Performed using ethyl acetate.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, DMS
Od ₆ ), δppm: 0.65-0.98 (2H, m), 0.85 (3H, t, J = 6.6
Hz), 1.00-1.50 (22H, m), 1.50-1.78 (5H, m), 1.95 (3H,
s), 1.99 (1H, dd, J = 14.4, 8.4Hz), 2.10 (1H, dd, J = 1
4.4, 6.0Hz), 2.57 (1H, m), 3.74 (1H, dd, J = 10.7, 7.0
Hz), 3.97 (1H, dd, J = 10.7, 4.8Hz), 4.05 (1H, m), 7.7
6 (1H, d, J = 8.7Hz), 8.67 (1H, d, J = 1.4Hz), 10.37 (1H,
d, J = 1.4Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3287, 1745, 1644, 1549 Mass spectrum (FAB) m / z [M + H] ⁺ = 441 Elemental analysis Calculated value: C ₂₄ H ₄₄ N ₂ O ₅ : C, 65.42%; H, 10.07%; N, 6.36% Measurement value:: C, 65.31%; H, 9.78%; N, 6.32% Specific rotation: [α] _D ²⁵ = -7.4 ° (C : 0.37, MeOH) mp: 109-111 ° C. (example 14) N ¹ - [2-cyclohexyl-1-
(S) - (hydroxymethyl) ethyl] -N ⁴ - hydro
Xy-2- (R) -nonylsuccinamide (Exemplified Compound No. 12) According to the method of Example 9, 3-cyclohexyl acetate-2- (S)-[2- ( R)-
(N-Hydroxycarbamoylmethyl) undecanoylamino] propyl ester (195 mg) was used as a starting material, and 150 mg (85%) of the target compound was obtained by the same reaction treatment.
%) As white crystals.

¹ H-nuclear magnetic resonance spectrum (400 MHz, DMS
Od ₆ ), δppm ： 0.74 (1H, m), 0.85 (3H, t, J = 6.8Hz),
0.80-0.97 (1H, m, overlapped with δ0.85), 1.00-1.4
5 (22H, m), 1.51-1.68 (4H, m), 1.73 (1H, m), 1.99 (1H,
dd, J = 14.3, 8.4Hz), 2.10 (1H, dd, J = 14.3, 6.1Hz),
2.53 (1H, m), 3.13 (1H, m), 3.25-3.40 (1H, m, overlap
ped with solvent peak), 3.76 (1H, m), 4.54 (1H, t, J
= 5.5Hz), 7.52 (1H, d, J = 6.7Hz), 8.67 (1H, d, J = 1.1H
z), 10.37 (1H, d, J = 1.1Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3365, 3261, 3113, 1663, 1612 Mass spectrum (FAB) m / z [M + H] ⁺ = 399 Elemental analysis _{calculated: C 22 H 42 N 2 O} 4: C, 66.30%; H, 10.62%; N, 7.03% measured value:: C, 66.26%; H , 10.44%; N, 7.00% specific rotation: [alpha _D ²⁵ = -16.0 ° (C: 0.19, MeOH) Melting point: 155 to 157 ° C. (Example 15) Acetic acid 2- (S)-[2- (R)-(N-
Hydroxycarbamoylmethyl) undecanoylamido
No] -3-methylbutyl ester (Exemplary Compound No. 1
1) 15-a) 3- (R)-[1- (S) -hydroxyme
Tyl-2-methylpropylcarbamoyl] dodecanoic acid t
- butyl ester in Example 8-a) obtained in 2- (R) -t- butoxycarbonylamino-methylumbelliferone methylene chloride decanoic acid (47.6mg) (1.5ml) was added 1-hydroxybenzotriazole (26.5 mg ), N-methylmorpholine (2
1.0 μl), 1- (3-dimethylaminopropyl)-
3-Ethylcarbodiimide hydrochloride (37.9 mg) was added, and the mixture was stirred at room temperature for 5 minutes. Then, L-valinol (21.8 mg) in methylene chloride (0.5 ml) was added to the reaction solution.
The solution was added and stirred at room temperature overnight. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate. The organic layer was washed sequentially with a 5% aqueous sodium hydrogen carbonate solution, water and saturated saline, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue is purified by silica gel preparative thin-layer chromatography (20 cm × 20 cm, 0.5 mm thick, 2 sheets, developing solvent: methylene chloride: methanol = 15: 1) to obtain the desired compound 54.4 mg (89%) were obtained as a white solid.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ), δppm ： 0.88 (3H, t, J = 6.6Hz), 0.93 (3H, d, J =
2.9Hz), 0.96 (3H, d, J = 2.8Hz), 1.10-1.50 (15H, m),
1.43 (9H, s), 1.67 (1H, m), 1.91 (1H, m), 2.37 (1H,
m), 2.48-2.70 (2H, m), 3.57-3.77 (3H, m), 6.03 (1H,
m) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3316, 1732, 1643, 1546 Mass spectrum (FAB) m / z [M + H] ⁺ = 386 High-resolution mass spectrum (FAB) m / z [M + H] ⁺ = 386.3273 _{calculated: 386.3270 (C 22 H 44 NO} 4) 15-b) 3- (R) - [1- (S) - Asetokishime
Tyl-2-methylpropylcarbamoyl] dodecanoic acid t
-Butyl ester The 3- (R)-[1- (S) -hydroxymethyl-2 obtained in Example 15-a) according to the method of Example 8-c).
[Methylpropylcarbamoyl] dodecanoic acid t-butyl ester (607 mg) was used as a starting material to give the target compound (607 mg, 90%) as a colorless oily substance.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ ), δppm ： 0.88 (3H, t, J = 6.9Hz), 0.92 (3H, d, J =
2.2Hz), 0.94 (3H, d, J = 2.2Hz), 1.16-1.47 (15H, m),
1.42 (9H, s), 1.65 (1H, m), 1.81 (1H, m), 2.05 (3H,
s), 2.31 (1H, dd, J = 16.9, 3.7Hz), 2.51 (1H, m), 2.63
(1H, dd, J = 16.9, 9.6Hz), 3.97-4.10 (2H, m), 4.15 (1
H, dd, J = 11.2, 6.4Hz), 5.82 (1H, d, J = 9.3Hz) Infrared absorption spectrum (liquid film, cm ^-1 ) 3308, 1745, 1732, 1645, 1545 Mass spectrum (FAB) m / z [M + H] ⁺ = 428 High resolution mass spectrum (FAB) m / z [M + H] ⁺ = 428.3402 Calculated: 428.3376 (C ₂₄ H ₅₆ NO ₅ ) 15-c) 3- (R)-[1- (S) -acetoxime
Tyl-2-methylpropylcarbamoyl] dodecanoic acid 3- (R)-[1- (S) -acetoxymethyl-2 obtained in Example 15-b) according to the method of Example 8-d).
[Methylpropylcarbamoyl] dodecanoic acid t-butyl ester (598 mg) was used in a similar reaction. After azeotropic distillation with toluene, the obtained white solid was recrystallized from hexane-ethyl acetate to give the desired compound 45.
3 mg (87%) were obtained as white crystals.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CD
Cl ₃ ), δppm ： 0.88 (3H, t, J = 6.6Hz), 0.93 (3H, d, J =
4.0Hz), 0.95 (3H, d, J = 3.9Hz), 1.15-1.40 (14H, m),
1.48 (1H, m), 1.65 (1H, m), 1.82 (1H, m), 2.05 (3H, m
s), 2.42-2.59 (2H, m), 2.78 (1H, dd, J = 17.6, 9.8Hz),
3.97-4.12 (2H, m), 4.18 (1H, dd, J = 11.4, 6.9Hz), 5.8
0 (1H, d, J = 9.1Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3300, 1746, 1731, 1698, 1644, 1553 Mass spectrum (FAB) m / z [M + H] ⁺ = 372 High resolution mass Spectrum (FAB) m / z [M + H] ⁺ = 372.2740 Calculated: 372.2750 (C ₂₀ H ₃₈ NO ₅ ) Melting point: 91-92 ° C. 15-d) Acetic acid 2- (S)-[2- (R)-( N-hi
Droxycarbamoylmethyl) undecanoylamino]
-3-Methylbutyl ester 3- (R)-[1- (S) -acetoxymethyl-2 obtained in Example 15-c) according to the method of Example 8-e).
-Methylpropylcarbamoyl] dodecanoic acid (443 m
g) and O- (t-butyldimethylsilyl) hydroxylamine (334 mg) as starting materials to give 261 mg (57%) of the desired compound as white crystals by the same reaction treatment.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃
OD), δppm ： 0.89 (3H, t, J = 6.8Hz), 0.93 (3H, d, J =
6.7Hz), 0.95 (3H, d, J = 6.7Hz), 1.18-1.48 (15H, m),
1.56 (1H, m), 1.82 (1H, m), 2.01 (3H, s), 2.16 (1H, d
d, J = 14.4, 6.9Hz), 2.32 (1H, dd, J = 14.4, 7.7Hz), 2.
78 (1H, m), 3.89 (1H, dt, J = 3.6,7.3Hz), 3.97 (1H, dd,
J = 11.1, 7.3Hz), 4.23 (1H, dd, J = 11.1, 3.6Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3276, 1745, 1645, 1549 Mass spectrum (FAB) m / z [M + H] ⁺ = 387 analysis _{calculated: C 20 H 38 N 2 O} 5: C, 62.15%; H, 9.91%; N, 7.25% measured value:: C, 62.14%; H , 9.62%; N, 7.17% ratio Optical ^{_{rotation: [α] D 25 = -6.1}} ° (C: 0.44, MeOH) mp: 149-150 ° C. (example 16) N ⁴ - hydroxy -N ¹ - [1-
(S) -hydroxymethyl-2-methylpropyl] -2
-(R) -Nonylsuccinamide (Exemplary Compound No. 10) According to the method of Example 9, 2- (S)-[2- (R)-(N-hydroxy) acetic acid obtained in Example 15-d) Carbamoylmethyl) undecanoylamino] -3-methylbutyl ester (61.6 mg) was used as a starting material and subjected to the same reaction treatment to give 45.0 mg (82%) of the desired compound as white crystals. The recrystallization of this compound was performed using water-methanol instead of ethyl acetate-methanol used in Example 9. ¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD), δ ppm
： 0.89 (3H, t, J = 6.8Hz), 0.91 (3H, d, J = 6.9Hz), 0.9
4 (3H, d, J = 6.9Hz), 1.20-1.50 (15H, m), 1.58 (1H, m),
1.88 (1H, m), 2.18 (1H, dd, J = 14.5, 6.8Hz), 2.33 (1
H, dd, J = 14.5, 7.9Hz), 2.73 (1H, m), 3.51-3.61 (2H,
m), 3.68 (1H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3291, 1663, 1633, 1557 Mass spectrum (FAB) m / z [M + H] ⁺ = 345 Elemental analysis Calculated value: C ₁₈ H ₃₆ N ₂ O ₄ .0.2H ₂ O: C, 62.11%; H, 10.54%; N, 8.05% Measurement value:: C, 62.14%; H, 10.38%; N, 8.10% Specific rotation: [α] _D ²⁵ = -10.3 ° (C: 0.32, MeOH) Melting point: 129 to 130 ° C. (Example 17) 3- (R) -acetoxy- 2-acetic acid
(R)-[2- (R)-(N-hydroxycarbamoyl
Methyl) undecanoylamino] butyl ester (Exemplified Compound No. 19) 17-a) 3- (R)-[2- (R) -hydroxy-
1- (R)-(hydroxymethyl) propylcarbamoy
L] Dodecanoic acid t-butyl ester According to the method of Example 8-b), 2- (R) -t-butoxycarbonylmethylundecanoic acid (712 mg) and 2- (R) obtained in Example 8-a) -Amino-1,3
Using (R) -butanediol (252 mg) as a starting material, 531 mg (58 mg) of the target compound was obtained by the same reaction treatment.
%) As a colorless oil.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ ), δppm ： 0.88 (3H, t, J = 6.8Hz), 1.15-1.50 (14H,
m), 1.21 (3H, d, J = 6.4Hz), 1.43 (9H, s), 1.55-1.80 (2
H, m), 2.40 (1H, dd, J = 16.3, 3.6Hz), 2.55 (1H, m),
2.66 (1H, dd, J = 16.3, 10.0Hz), 2.85 (1H, m), 3.19 (1
H, m), 3.70-3.82 (2H, m), 3.88 (1H, m), 4.12 (1H, dq,
J = 2.7, 6.4Hz), 6.35 (1H, d, J = 8.1Hz) Infrared absorption spectrum (liquid film, cm ^-1 ) 3347, 1731, 1649, 1540 Mass spectrum (FAB) m / z [M + H] ⁺ = 388 High-resolution mass spectrum (FAB) m / z [M + H] ⁺ = 388.3068 Calculated: 388.3063 (C ₂₁ H ₄₂ NO ₅ ) 17-b) 3- (R)-[2- (R) -acetoxy-
1- (R)-(acetoxymethyl) propylcarbamoy
L] dodecanoic acid t-butyl ester 3- (R)-[2- (R) obtained in Example 17-a)
-Hydroxy-1- (R)-(hydroxymethyl) propylcarbamoyl] dodecanoic acid t-butyl ester (5
Pyridine (280 μl) and acetic anhydride (330 μl) were added to a solution of 30 mg) in tetrahydrofuran (7.0 ml).
l) and 4-dimethylaminopyridine (11 mg) were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate, extracted with ethyl acetate, and the organic layer was washed with a 5% aqueous solution of sodium hydrogen carbonate, water, and saturated saline in that order, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride: methanol = 40: 1) to obtain 632 mg (98%) of the desired compound as a colorless oily substance. ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ), δ ppm
： 0.88 (3H, t, J = 6.8Hz), 1.15-1.50 (15H, m), 1.23 (3
H, d, J = 6.4Hz), 1.42 (9H, s), 1.64 (1H, m), 2.04 (3H,
s), 2.09 (3H, s), 2.34 (1H, dd, J = 16.7, 3.8Hz), 2.5
0 (1H, m), 2.65 (1H, dd, J = 16.7, 9.6Hz), 4.00 (1H, d
d, J = 11.1, 6.6Hz), 4.08 (1H, dd, J = 11.1, 6.5Hz), 4.3
5 (1H, m), 5.12 (1H, dq, J = 3.0, 6.4Hz), 5.98 (1H, d,
J = 9.4Hz) Infrared absorption spectrum (liquid film, cm ^-1 ) 3326, 1745, 1732, 1680, 1655 Mass spectrum (FAB) m / z [M + H] ⁺ = 472 High-resolution mass spectrum (FAB) m / z [ M ⁺ H] + = 472.3276 _{calculated: 472.3275 (C 25 H 46 NO} 5) 17-c) 3- (R) - [2-(R) - acetoxy -
1- (R)-(acetoxymethyl) propylcarbamoy
L] dodecanoic acid 3- (R)-[2- (R) -acetoxy-1- obtained in Example 17-b) according to the method of Example 8-d).
(R)-(acetoxymethyl) propylcarbamoyl]
Dodecanoic acid t-butyl ester (630 mg) was used as a starting material and subjected to the same reaction treatment to obtain 464 mg (8
4%) as a white solid.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ), δppm ： 0.88 (3H, t, J = 6.6Hz), 1.10-1.40 (14H,
m), 1.22 (3H, d, J = 6.4Hz), 1.45 (1H, m), 1.64 (1H,
m), 2.05 (3H, s), 2.07 (3H, s), 2.39-2.65 (2H, m), 2.
81 (1H, dd, J = 16.5, 9.0Hz), 3.95-4.15 (2H, m), 4.35 (1
H, m), 5.11 (1H, dq, J = 3.6, 6.4Hz), 5.95 (1H, d, J =
9.4Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3224, 1743, 1651, 1544 Mass spectrum (FAB) m / z [M + H] ⁺ = 416 High-resolution mass spectrum (FAB) m / z [M + H] ⁺ = 416.2674 _{calculated: 416.2648 3- (C 21 H 38} NO 7) 17-d) acetic acid (R) - acetoxy-2-(R)
-[2- (R)-(N-hydroxycarbamoylmethyl)
L) Undecanoylamino] butyl ester 3- (R)-[2- (R) -acetoxy-1- obtained in Example 17-c) according to the method of Example 8-e).
(R)-(acetoxymethyl) propylcarbamoyl]
Using dodecanoic acid (460 mg) and O- (t-butyldimethylsilyl) hydroxylamine (216 mg) as starting materials, 206 mg of the target compound was obtained by the same reaction treatment.
(43%) as a foam. The final purification of this compound was not the recrystallization from methanol-water used in Example 8-e), but was performed by silica gel preparative thin-layer chromatography (20 cm × 20 cm, 1.0 mm thick, 3 sheets,
Developing solvent: methylene chloride: methanol = 10: 1).

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃
OD), δppm ： 0.89 (3H, t, J = 6.7Hz), 1.15-1.50 (15H,
m), 1.21 (3H, d, J = 6.5Hz), 1.56 (1H, m), 2.01 (3H,
s), 2.06 (3H, s), 2.17 (1H, dd, J = 14.6, 6.6Hz), 2.35
(1H, dd, J = 14.6, 8.0Hz), 2.80 (1H, m), 3.95 (1H, dd,
J = 11.1, 7.5Hz), 4.20 (1H, dd, J = 11.1, 5.5Hz), 4.28
(1H, m), 5.06 (1H, dq, J = 3.6, 6.5Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3289, 1740, 1648, 1551 Mass spectrum (FAB) m / z [M + H] ⁺ = 431 Elemental analysis Calculated: C ₂₁ H ₃₈ N ₂ O ₇ .0.1H ₂ O: C, 58.34%; H, 8.91%;
N, 6.48% Found: C, 58.26%; H, 8.83%;
N, 6.55% Specific rotation: [α] _D ²⁵ = + 20.1 ° (C: 0.53, MeOH) (Example 18) N ⁴ -hydroxy-N ^1- [2-
(R) -hydroxy-1- (R)-(hydroxymethyl
L) Propyl] -2- (R) -nonylsuccinamide (Exemplified Compound No. 18) 3- (R) -acetoxy-2- (R)-[2- (acetic acid) obtained in Example 17-d) Potassium carbonate (108 mg) was added to a methanol (3.5 ml) solution of (R)-(N-hydroxycarbamoylmethyl) undecanoylamino] butyl ester (92.3 mg), and the mixture was stirred at room temperature for 45 minutes. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate, extracted with ethyl acetate, and the organic layer was washed with water and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to reverse-layer preparative thin-layer chromatography (silica gel 60, silanized RP-2, Merck Art. 5747, 20c).
m × 20 cm, 0.25 mm thickness × 2, methanol: water = 3: 2 development), and the obtained white solid was further recrystallized from methanol-water to obtain the desired compound 3
3.3 mg (45%) were obtained as white crystals.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃
OD), δppm ： 0.89 (3H, t, J = 6.9Hz), 1.15 (3H, d, J =
6.5Hz), 1.20-1.48 (15H, m), 1.58 (1H, m), 2.18 (1H, d
d, J = 14.5, 6.4Hz), 2.37 (1H, dd, J = 14.5, 8.1Hz), 2.
74 (1H, m), 3.56 (1H, dd, J = 10.9, 6.0Hz), 3.64 (1H, d
d, J = 10.9, 6.2Hz), 3.80 (1H, ddd, J = 6.2, 6.0, 3.5H
z), 3.99 (1H, dq, J = 3.5, 6.5Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3447, 3392, 3317, 3221, 1664, 1635, 1532 Mass spectrum (FAB) m / z [M + H ] ⁺ = 347 analysis _{calculated: C 17 H 34 N 2 O} 5: C, 58.93%; H, 9.89%; N, 8.09% measured value:: C, 58.93%; H , 9.68%; N, 7.98% Specific rotation: [α] _D ²⁵ = + 4 ° (C: 0.17, MeOH) Melting point: 119-120 ° C. (Example 19) 3-acetoxy-2-acetic acid [ 2-
(R) - (N-hydroxycarboxylic Rubamoirumechiru) undec
Canoylamino] propyl ester (Exemplary Compound No. 1
7) 19-a) 3- (R)-[2-hydroxy-1- (H
Droxymethyl) ethylcarbamoyldodecanoate
Cyl ester 2- (R) -tert-butoxycarbonylmethylundecanoic acid (57 mg) obtained in Example 8-a) was dissolved in dichloromethane (2 ml) under a nitrogen atmosphere, and cooled to 0 ° C. To this solution was added hydroxybenzotriazole (37 m
g), 2-amino-1,3-propanediol (27 m
g), N-methylmorpholine (60 μl), pyridine (40 μl), 1- (3-dimethylaminopropyl)-
3-Ethylcarbodiimide hydrochloride (54 mg) was sequentially added, and the mixture was stirred at room temperature for 4.7 hours. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate, extracted with ethyl acetate, and the organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, and then dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was separated by silica gel preparative thin layer chromatography (20 cm × 20 cm, 0.5 mm thickness, dichloromethane: methanol = 8: 1 development, ethyl acetate: methanol = 10: 1 elution). To give the desired compound (52 mg) as a colorless oil.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ), δppm ： 0.88 (3H, t, J = 6.3Hz), 0.16-1.34 (14H,
m), 1.42 (9H, s), 1.61 (1H, m), 1.87 (1H, m), 2.37 (1
H, dd, J = 16.5, 4.0Hz), 2.49 (1H, m), 2.98 (1H, dd, J
= 16.5,9.9Hz), 3.10 (1H, m), 3.48 (1H, m), 3.70-3.78
(2H, m), 3.83-3.97 (3H, m), 6.44 (1H, d, J = 7.3Hz) Infrared absorption spectrum (liquid film, cm ^-1 ) 3322, 1730, 1650 High resolution mass spectrum (FAB) m ^{/ z [M + H] +} = 374.2900 _{calculated: 374.2906 (C 20 H 40 NO} 5) 19-b) 3- (R) - (2- acetoxy-1- (A
Cetoxymethyl) ethylcarbamoyl ) dodecanoic acid t-
Butyl ester According to the method of Example 17-b), 3- (R)-(2-hydroxy-1- (hydroxymethyl) ethylcarbamoyl) dodecanoic acid-t-butyl ester obtained in Example 19-a) ( 643 mg) as a starting material, and the same reaction treatment was carried out to give the desired compound (697 mg) as a white solid.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ), δppm: 0.88 (3H, t, J = 6.6Hz), 1.17-1.33 (14H,
m), 1.39 (1H, m), 1.43 (9H, s), 1.62 (1H, m), 2.08 (3
H, s), 2.09 (3H, s), 2.33 (1H, dd, J = 16.0, 3.5Hz),
2.52 (1H, m), 2.61 (1H, dd, J = 16.0, 9.3Hz), 4.04-4.2
5 (4H, m), 4.47 (1H, m), 6.13 (1H, d, J = 8.6Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3376, 1746, 1727, 1656 Mass spectrum (FAB) m / z [M + H] ⁺ = 458 Elemental analysis Calculated: C ₂₄ H ₄₃ O ₇ N: C, 62.99%; H, 9.47%; N, 3.06% Measured :: C, 62.70%; H, 9.47%; N, 3.06% 19-c) 3- (R)-(2-acetoxy-1- (A
Cetoxymethyl) ethylcarbamoyl) dodecanoic acid According to the method of Example 8-d), 3- (R)-(2-acetoxy-1- (acetoxymethyl) ethylcarbamoyl) dodecanoic acid obtained in Example 19-b) The same reaction was carried out using -butyl ester (697 mg) as a starting material to obtain the desired compound (553 mg) as a white solid.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ), δppm: 0.88 (3H, t, J = 6.6Hz), 1.17-1.37 (14H,
m), 1.44 (1H, m), 1.63 (1H, m), 2.08 (6H, s), 2.45 (1
H, dd, J = 16.1, 4.1Hz), 2.51 (1H, m), 2.75 (1H, dd, J
= 16.1,9.1Hz), 4.05-4.26 (4H, m), 4.47 (1H, m), 6.32
(1H, d, J = 8.8Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3300, 1741, 1695, 1645 Mass spectrum (FAB) m / z [M + H] ⁺ = 402 Elemental analysis Calculated value: C ₂₀ H _{35 NO 7 · 0.25H 2 O:} C, 59.17%; H, 8.80%; N, 3.45% measured value:: C, 59.00%; H , 8.82%; N, 3.50% 19-d) acetic acid 3-acetoxy - 2-[[2- (R)
-(N-hydroxycarbamoylmethyl) undecanoy
[Ruamino] propyl ester According to the method of Example 8-e), 3- (R)-(2-acetoxy-1- (acetoxymethyl) ethylcarbamoyl) dodecanoic acid (553m) obtained in Example 19-c).
g) and O- (t-butyldimethylsilyl) hydroxylamine (476 mg) as starting materials, and the same reaction treatment was performed to obtain 371 mg (65%) of the desired compound as a white powder. The purification of the present compound was performed using only silica gel column chromatography among the methods shown in 8-e).

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ), δppm ： 0.88 (3H, t, J = 6.6Hz), 1.11-1.37 (14H,
m), 1.42 (1H, m), 1.61 (1H, m), 2.07 (3H, s), 2.10 (3
H, s), 2.30 (1H, m), 2.46 (1H, m), 2.69 (1H, m), 4.07
-4.31 (4H, m), 4.43 (1H, m), 7.78 (1H, d, J = 8.1Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3294, 1744, 1704, 1645, 1616 High-resolution mass spectrum m / z [M + H] ⁺ = 417.2593 Calculated 417.2600 (C ₂₀ H ₃₇ N ₂ O ₇ ) Specific rotation: [α] _D ²⁵ = + 5.00 ° (C: 0.33, MeOH) (Example 20) N ⁴ -Hydroxy-N ^1- [2-hydro
Xy-1- (hydroxymethyl) ethyl] -2- (R)
-Nonylsuccinamide (Exemplified Compound No. 16) According to the method of Example 18, 3-acetoxy-2- [2- (R)-(N-hydroxycarbamoylmethyl) unacetate obtained in Example 19-d). The same reaction treatment was carried out using decanoylamino] propyl ester (192 mg) as a starting material to obtain 30 mg (20%) of the target compound as a white powder.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃
OD), δppm: 0.89 (3H, t, J = 6.8Hz), 1.17-1.39 (14H,
m), 1.42 (1H, m), 1.57 (1H, m), 2.17 (1H, dd, J = 14.5,
6.5Hz), 2.35 (1H, dd, J = 14.5, 8.1Hz), 2.67 (1H, m),
3.28-3.32 (4H, m), 3.92 (1H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3288, 1644 Mass spectrum (FAB) m / z [M + H] ⁺ = 333 Elemental analysis Calculated value: C ₁₆ H ₃₂ N ₂ O ₅ .0.25 H ₂ O: C, 57.03%; H, 9.71%; N, 8.31% Measurements: C, 57.08%; H, 9.44%; N, 8.33% Specific rotation: [α _D ²⁵ = + 5.6 ° (C: 0.1, MeOH) (Example 21) Ethylcarbamic acid 2- (S)-[2
-(R)-(N-hydroxycarbamoylmethyl) un
-Decanoylamino] -3,3-dimethylbutyl an ester (Compound No. 91) 21-a) 3- ( R) - [1-(S) - Echirukaruba
Moyloxymethyl-2,2-dimethylpropylcarba
Moyl] dodecanoic acid t-butyl ester 3- (R)-[1- (S) -obtained in Example 8-b)
Hydroxymethyl-2,2-dimethylpropylcarbamoyl] dodecanoic acid t-butyl ester (86 mg) was dissolved in benzene (5 ml) and heated to 60 ° C. Ethyl isocyanate (20 μl) was added to this solution, and the mixture was stirred at 60 ° C. for 1.3 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was separated by silica gel preparative thin-layer chromatography (20 cm × 20 cm).
cm, 0.5 mm thickness x 2, hexane: ethyl acetate =
(2: 1 development, elution with ethyl acetate: methanol = 10: 1).
Was obtained as a white powder.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ), δppm ： 0.88 (3H, t, J = 6.9Hz), 0.94 (9H, s), 1.
12 (3H, t, J = 7.3Hz), 1.18-1.30 (14H, m), 1.42 (9H,
s), 1.63-1.66 (2H, m), 2.32 (1H, dd, J = 15.8, 9.6Hz),
2.55 (1H, m), 2.62 (1H, dd, J = 15.8, 2.6Hz), 3.14-3.2
4 (2H, m), 4.05 (1H, m), 4.10-4.14 (2H, m), 4.75 (1H,
m), 5.89 (1H, d, J = 9.2Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3332, 3289, 1735, 1702, 1662 High-resolution mass spectrum m / z [M + H] ⁺ = 471.3794 Calculated value: _{471.3798 (C 26 H 51 N 2} O 5) specific ^{_{rotation: [α] D 25 = -6.6}} ° (C: 1.06, MeOH) 21-b) 3- (R) - [1- (S) - Echirukaruba
Moyloxymethyl-2,2-dimethylpropylcarba
Moyl] dodecanoic acid 3- (R)-[1- (S) -ethylcarbamoyloxymethyl-2,2-dimethylpropylcarbamoyl] obtained in Example 21-a) according to the method of Example 8-d).
The same reaction treatment was carried out using t-butyl dodecanoate (43 mg) as a starting material to obtain the desired compound (33 mg) as a colorless oily substance.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ), δppm ： 0.88 (3H, t, J = 7.1Hz), 0.94 (9H, s), 1.
12 (3H, t, J = 7.2Hz), 1.17-1.37 (14H, m), 1.45 (1H,
m), 1.64 (1H, m), 2.49 (1H, dd, J = 16.1, 3.3Hz), 2.59
(1H, m), 2.74 (1H, dd, J = 16.1,8.2Hz), 3.06-3.28 (2H,
m), 4.00-4.10 (2H, m), 4.24 (1H, m), 4.97 (1H, m), 6.
17 (1H, d, J = 9.8Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3339, 3287, 3074, 1714, 1702, 1663 High-resolution mass spectrum m / z [M + H] ⁺ = 415.3193 Calculated value: 415.3172 (C ₂₂ H ₄₂ N ₂ O ₅ ) Specific rotation: [α] _D ²⁵ = −2.0 ° (C: 1.08, MeOH) 21-c) Ethylcarbamic acid 2- (S)-[2-
(R)-(N-hydroxycarbamoylmethyl ) unde
Canoylamino] -3,3-dimethylbutyl ester According to the method of Example 8-e), the 3- (R)-[1- (S) -ethylcarbamoyloxymethyl-2, obtained in Example 21-b). 2-dimethylpropylcarbamoyl]
Dodecanoic acid (50 mg) and O- (t-butyldimethylsilyl) hydroxylamine (28 mg) were used as starting materials and subjected to the same reaction treatment to obtain 36 mg (69%) of the desired compound.
Was obtained as a colorless oil.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ), δppm ： 0.88 (3H, t, J = 6.8Hz), 0.92 (9H, s), 1.
11 (3H, t, J = 7.2Hz), 1.15-1.29 (14H, m), 1.39 (1H,
m), 1.61 (1H, m), 2.29 (1H, dd, J = 13.7, 4.5Hz), 2.46
(1H, m), 2.88 (1H, m), 3.06-3.27 (2H, m), 3.98-4.28 (3H,
m), 5.43 (1H, m), 6.96 (1H, d, J = 9.1Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3297, 1701, 1648 High-resolution mass spectrum m / z [M + H] ⁺ = 430.3286 _{calculated: 430.3281 (C 22 H 44 N} 3 O 5) specific ^{_{rotation: [α] D 25 = -7.3}} ° (C: 0.95, MeOH) ( example 22) [2- (S) - (2- ( R)-(N-hi
Droxycarbamoylmethyl) undecanoylamino)
-3,3-dimethylbutoxycarbonylamino] acetic acid
Cyl ester (Exemplified Compound No. 93) 22-a) 3- (R)-[1- (S)-(ethoxyca
Rubonylmethyl) carbamoyloxymethyl-2,2-
Dimethylpropylcarbamoyl] t -butyl dodecanoate
Ester 3- (R)-[1- (S)-obtained in Example 8-b).
Hydroxymethyl-2,2-dimethylpropylcarbamoyl] dodecanoic acid t-butyl ester (75 mg) in benzene (5 ml) was dissolved in ethyl isocyanatoacetate (30 ml).
μl) and pyridine (20 μl) are sequentially added, and the mixture is added at room temperature for 16 hours.
Stirred for hours. Thereafter, the mixture was stirred at 40 ° C. for 6.8 hours while heating. The reaction solution was poured into 5% potassium hydrogen sulfate and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was subjected to silica gel column chromatography (eluted with hexane: ethyl acetate = 4: 1) to obtain the desired compound (79 mg) as a colorless oily substance.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ), δppm ： 0.88 (3H, t, J = 6.6Hz), 0.94 (9H, s), 1.
18-1.24 (14H, m), 1.28 (3H, t, J = 6.3Hz), 1.42 (9H,
s), 1.61-1.70 (2H, m), 2.32 (1H, dd, J = 15.3, 2.3Hz),
2.57 (1H, m), 2.65 (1H, dd, J = 15.3, 6.2Hz), 3.92 (2
H, q, J = 6.3Hz), 4.02-4.09 (2H, m), 4.16-4.25 (3H, m),
5.26 (1H, t, J = 5.1Hz), 5.91 (1H, d, J = 9.7Hz) High resolution mass spectrum (FAB) m / z [M + H] + = 529.3839 _{Calculated: 529.3853 (C 28 H 53 N} 2 O ₇ ) 22-b) 3- (R)-[1- (S)-(ethoxyca
Rubonylmethyl) carbamoyloxymethyl-2,2-
Dimethylpropylcarbamoyl] dodecanoic acid According to the method of Example 8-d), 3- (R)-[1- (S)-(ethoxycarbonylmethyl) carbamoyloxymethyl-2, obtained in Example 22-a). 2-Dimethylpropylcarbamoyl] dodecanoic acid t-butyl ester (76 mg) was used as a starting material, and the target compound (61 mg) was obtained as a colorless oil by the same reaction treatment.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ), δppm ： 0.88 (3H, t, J = 7.0Hz), 0.95 (9H, s), 1.
18-1.27 (14H, m), 1.29 (3H, t, J = 7.2Hz), 1.50 (1H,
m), 1.66 (1H, m), 2.49-2.80 (3H, m), 3.93 (2H, d, J =
5.7Hz), 4.07 (1H, m), 4.16-4.26 (4H, m), 5.60 (1H, t,
J = 5.7Hz), 5.98 (1H, d, J = 8.5Hz) Infrared absorption spectrum (liquid film, cm ^-1 ) 3395, 3362, 1746, 1709, 1
631 High-resolution mass spectrum m / z [M + H] ⁺ = 473.3255 Calculated value: 473.3226 (C ₂₄ H ₄₅ N ₂ O ₇ ) 22-c) [2- (S)-(2- (R)-(N -Hydro )
Roxycarbamoylmethyl) undecanoylamino)-
3,3-dimethyl-butoxycarbonylamino] acetic acid methylate
Glycol ester obtained in Example 22-c) 3- (R) - [1-(S)
-(Ethoxycarbonylmethyl) carbamoyloxymethyl-2,2-dimethylpropylcarbamoyl] dodecanoic acid (56 mg) was dissolved in dimethylformamide (3 ml) under a nitrogen atmosphere, and 1-hydroxybenzotriazole (44 mg) was added at 0 ° C. -Methylmorpholine (20
μl), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (50 mg) and O- (t-butyldimethylsilyl) hydroxyamine (44 mg) were sequentially added, and the mixture was stirred at room temperature for 3 days. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was washed with a 5% aqueous solution of potassium hydrogen sulfate, water and saturated saline in that order, and then dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was subjected to reverse-phase preparative thin-layer chromatography (silica gel 60, silanized RP-2, Merck, Art. 5747, 20 cm × 20 cm, 0.25 mm).
(thickness: 2 mm, methanol: water = 3: 1 developed, eluted with methanol), the compound obtained by dissolution was dissolved in methanol and allowed to stand for 8 days. The solvent was distilled off under reduced pressure to obtain 13 mg (23%) of the target compound as a colorless oily substance.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ), δppm ： 0.87 (3H, t, J = 6.7Hz), 0.92 (9H, s), 1.
10-1.37 (14H, m), 1.38 (1H, m), 1.59 (1H, m), 2.29 (1
H, m), 2.40 (1H, m), 2.76 (1H, m), 3.73 (3H, s), 3.80
-4.22 (5H, m), 6.80 (1H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3305, 1748, 1728, 1709, 1651 High-resolution mass spectrum m / z [M + H] ⁺ = 474.3163 Calculation Value: 474.3147 (C ₂₃ H ₄₄ N ₃ O ₇ ) Specific rotation: [α] _D ²⁵ = -10.8 ° (C: 0.85, MeOH) (Example 23) 2- (S)-[2- ( R)-(N-hi
Droxycarbamoylmethyl) undecanoylamino]
3,3-dimethyl-butyloxycarbonyl-propionic
Acid ethyl ester (Exemplified Compound No. 89) 23-a) 2- (S)-[2- (R)-(t-butoxy)
[Cicarbonylmethyl) undecanoylamino] -3,3
- dimethyl-butyloxycarbonyl-propionic acid ethyl
Ester 3- (R)-[1- (S)-obtained in Example 8-b).
Hydroxymethyl-2,2-dimethylpropylcarbamoyl] dodecanoic acid t-butyl ester (549.2 m
Ethyl succinyl chloride (0.24 ml) and pyridine (0.15 ml) were sequentially added to a solution of g) in tetrahydrofuran (THF, 16.0 ml), and the mixture was stirred at 0 ° C. for 2.0 hours. Pour the reaction solution into a 5% aqueous solution of potassium hydrogen sulfate,
After extraction with ethyl acetate, the organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 559.1 mg (77.1%) of the desired compound as a colorless oil.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ), δppm: 0.87 (3H, t, J = 6.8Hz), 0.94 (9H, s), 1.2
3-1.38 (18H, m), 1.42 (9H, s), 1.65 (1H, m), 2.33 (1H,
m), 2.54-2.67 (6H, m), 4.06 (2H, m), 4.15 (2H, q, J =
7.2Hz), 4.31 (1H, m), 5.98 (1H, d, J = 8.6Hz) Infrared absorption spectrum (liquid film, cm ^-1 ) 3323, 1736, 1678, 1651, 1538 High resolution mass spectrum m / z [ M + H] ⁺ = 528.3892 Calculated: 528.3900 (C ₂₉ H ₅₄ O ₇ N) Specific rotation: [α] _D ²⁵ = -10.4 ° (C: 1.00, CHCl ₃ ) 23-b) 2- (S)-[ 2- (R)-(benzylo
Xycarbamoylmethyl ) undecanoylamino]-
3,3-dimethylbutyloxycarbonylpropionic acid
Ethyl ester 2- (S)-[2- (R) obtained in Example 23-a)
-(T-butoxycarbonylmethyl) undecanoylamino] -3,3-dimethylbutyloxycarbonylpropionic acid ethyl ester (443.6 mg) in methylene chloride (12.0 ml) was treated with trifluoroacetic acid (4.0).
ml) and stirred at room temperature for 2.0 hours. After the reaction solution was distilled off under reduced pressure and dried, the residue was purified with methylene chloride (15.
0 ml) and cooled to 0 ° C. To this solution was added 1-hydroxybenzotriazole (193.0 mg), O-
Benzylhydroxylamine hydrochloride (234.1m
g), then 1- (3-dimethylaminopropyl) -3
-Ethylcarbodiimide hydrochloride (276.9 mg), N
-Methylmorpholine (0.47 ml) was sequentially added, and the mixture was heated to room temperature and stirred overnight. The reaction solution was poured into a 5% aqueous potassium hydrogen sulfate solution, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 324.4 mg (66.9%) of the desired compound.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ , δppm): 0.87 (3H, t, J = 6.9Hz), 0.94 (9H, s), 1.23-
1.28 (17H, m), 1.40 (1H, m), 1.60 (1H, m), 2.21 (1H, m
m), 2.37 (1H, m), 2.58 (4H, s), 2.72 (1H, m), 4.03 (2
H, m), 4.14 (2H, q, J = 7.2Hz), 4.34 (1H, m), 4.86 (2H,
s), 6.15 (1H, m), 7.36 (5H, s), 9.10 (1H, br s) Infrared absorption spectrum (liquid film, cm ^-1 ) 3313, 3194, 1736, 1674, 1646, 1557 High-resolution mass spectrum m / z [M + H] ⁺ = 577.3872 Calculated: 577.3853 (C ₃₂ H ₅₃ O ₇ N ₂ ) Specific rotation: [α] _D ²⁵ = −23.7 ° (C: 1.00, CHCl ₃ ) 23-c) 2- (S)-[2- (R)-(N-hydro
Xycarbamoylmethyl ) undecanoylamino]-
3,3-dimethylbutyloxycarbonylpropionic acid
Ethyl ester 2- (S)-[2- (R) obtained in Example 23-b)
-(Benzyloxycarbamoylmethyl) undecanoylamino] -3,3-dimethylbutyloxycarbonylpropionic acid ethyl ester (324.4 mg) was dissolved in methanol (12.0 ml) under a nitrogen atmosphere. To this was added 5% palladium-alumina (80.5 mg), and after hydrogen replacement, the mixture was stirred at room temperature for 2.5 hours. After the reaction solution was filtered through celite and washed with methanol, the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1) to obtain 260.5 mg (95.2%) of the target compound as a white powder.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CD ₃
OD, δppm): 0.89 (3H, t, J = 7.0Hz), 0.96 (9H, s), 1.22-
1.41 (18H, m), 1.59 (1H, m), 2.17 (1H, dd, J = 6.8, 14.
5Hz), 2.33 (1H, dd, J = 7.7, 14.5Hz), 2.58 (4H, m), 2.
77 (1H, m), 3.94 (2H, m), 4.12 (2H, q, J = 7.2Hz), 4.43
(1H, m) Infrared absorption spectrum ^{(liquid film, cm -1) 3217} , 1738, 1642, 1542 High resolution mass spectrum m / z [M + H] + = 487.3399 _{Calculated: 487.3384 (C 25 H 47 O} 7 N 2) Specific rotation: [α] _D ²⁵ = -16.3 ° (C: 1.00, CHCl ₃ ) (Example 24) Dimethylaminoacetic acid 2- (S)-[2
-(R)-(N-hydroxycarbamoylmethyl) un
-Decanoylamino] -3,3-dimethylbutyl an ester (Compound No. 87) 24-a) 3- ( R) - [1-(S) - dimethylaminopyridine
Noacetoxymethyl-2,2-dimethylpropylcarba
Moyl] dodecanoic acid t-butyl ester 3- (R)-[1- (S) -obtained in Example 8-d).
[Hydroxymethyl-2,2-dimethylpropylcarbamoyl] dodecanoic acid t-butyl ester (601.8 m
g) in methylene chloride (18.0 ml) solution at 0 ° C. with N, N-dimethylglycine (239.5 mg), 1-hydroxybenzotriazole (307.7 mg),
(3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (438.0 mg), N-methylmorpholine (0.34 ml) and pyridine (0.37 ml) were sequentially added, and the mixture was heated to room temperature and stirred for 24 hours. . Reaction solution 1
The mixture was poured into a 0% aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
1) to give 469.6 mg of the desired compound (64.
3%) as a colorless oil.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
_{l 3, δppm): 0.87 (} 3H, t, J = 6.9Hz), 0.95 (9H, s), 1.18
-1.39 (15H, m), 1.42 (9H, s), 1.66 (1H, m), 2.32 (1H,
m), 2.34 (6H, s), 2.48-2.67 (2H, m), 3.14 (2H, s), 4.
08 (2H, m), 4.31 (1H, m), 5.92 (1H, d, J = 8.9Hz) Infrared absorption spectrum (liquid film, cm ^-1 ) 3321, 1732, 1649, 1545 High-resolution mass spectrum m / z [M + H] ⁺ = 485.3976 Calculated: 485.3955 (C ₂₇ H ₅₃ O ₅ N ₂ ) Specific rotation: [α] _D ²⁵ = -16.2 ° (C: 1.00, CHCl ₃ ) 24-b) dimethylaminoacetic acid 2- (S)-[2-
(R)-(N-hydroxycarbamoylmethyl) unde
Kanoiruamino] -3,3-dimethyl-butyl ester le Example was obtained in 24-a) 3- (R) - [1-(S)
-Dimethylaminoacetoxymethyl-2,2-dimethylpropylcarbamoyl] dodecanoic acid t-butyl ester (342.3 mg) in methylene chloride (15.0 ml) was added with trifluoroacetic acid (5.0 ml). Stirred for 0.0 hours. After distilling off the reaction solution under reduced pressure and drying,
The residue was treated with N, N-dimethylformamide (12.0 m
1) and cooled to 0 ° C. 1-Hydroxybenzotriazole (147.0 mg) and O- (t-butyldimethylsilyl) hydroxylamine (218.3) were added thereto.
mg), then 1- (3-dimethylaminopropyl)
-3-Ethylcarbodiimide hydrochloride (251.7m
g) and N-methylmorpholine (0.30 ml) were sequentially added, and the mixture was heated to room temperature and stirred overnight. The reaction solution was poured into a 10% aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform: methanol = 20:
1) to give 68.1 mg of the desired compound (21.7 mg).
%) As a colorless oil.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CD ₃
OD, δppm): 0.89 (3H, t, J = 7.0Hz), 0.96 (9H, s), 1.22
-1.40 (14H, m), 1.41 (1H, m), 1.57 (1H, m), 2.17 (1H,
dd, J = 6.7, 14.5Hz), 2.29-2.37 (8H, m), 2.77 (1H, m),
3.16 (2H, s), 3.96 (2H, m), 4.49 (1H, m) Infrared absorption spectrum (liquid film, cm ^-1 ) 3248, 1746, 1646, 1548 High-resolution mass spectrum m / z [M + H] ⁺ = 444.3434 _{calculated: 444.3438 (C 23 H 46 O} 5 N 3) specific ^{_{rotation: [α] D 25 = +}} 9.3 ° (C: 1.00, MeOH) ( example 25) acetic acid 2- (S) - {2- (R)-
[(S) -hydroxy (hydroxycarbamoyl) methyl
4-Methylpentanoylamino} -3,3-dimethyl
Butyl ester (Exemplified Compound No. 103) 25-a) 2- (R)-[2,2-dimethyl-5-o
Oxo- [1,3] -dioxolan-4- (S) -yl]
4-methylpentanoic acid [1- (S) - hydroxy Shimechi
-2,2-dimethylpropyl] amide 2- (R)-(2,2-dimethyl-5-oxo-1,3
-Dioxolan-4- (S) -yl) -4-methylpentanoic acid (105 mg) in methylene chloride (1.5 m
1) was cooled to -10 ° C, then 1-hydroxybenzotriazole (74 mg), N-methylmorpholine (60 μl), 1- (3-dimethylaminopropyl)-
3-Ethylcarbodiimide hydrochloride (105 mg) was sequentially added, and the mixture was stirred at the same temperature for 1 hour under a nitrogen atmosphere. Next, a solution of Lt-leucinol (80 mg) in methylene chloride (2.5 ml) was added, and the mixture was stirred for 2 hours. The reaction solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (eluted with hexane: ethyl acetate = 1: 1) gave 46 mg (31%) of the desired compound.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
_{l 3, δppm): 0.95 (} 6H, d, J = 4.3Hz), 0.96 (3H, s), 0.97
(9H, s), 1.50-1.80 (3H, m), 1.55 (3H, s), 1.63 (3H,
s), 2.43 (1H, br s), 2.81 (1H, m), 3.55 (1H, m), 3.85
(2H, m), 4.60 (1H, d, J = 4.7 Hz), 6.29 (1H, d, J = 8.2 Hz) 25-b) Acetic acid 2- (S)-｛2- (R)-[2 2
-Dimethyl-5-oxo- [1,3] -dioxolane-
4- (S) - yl] -4-methyl pentanoyl amino]
-3,3-Dimethylbutyl ester According to the method of Example 10-b), 2- (R)-[2,2-dimethyl-5-oxo- obtained in Example 25-a).
[1,3] -Dioxolan-4- (S) -yl] -4-
Methylpentanoic acid [1- (S) -hydroxymethyl-
Using 2,2-dimethylpropyl] amide (137 mg) as a starting material, 87 mg of the desired compound was obtained by the same reaction treatment.
(56%).

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ , δppm): 0.90-1.00 (15H, m), 1.58 (3H, s), 1.58 (2
H, m), 1.62 (3H, s), 1.81 (1H, m), 2.02 (3H, s), 2.67
(1H, m), 4.06 (2H, m), 4.22 (1H, m), 4.50 (1H, d, J =
5.6Hz), 6.01 (1H, d, J = 8.0Hz) 25-c) Acetic acid 2- (S)-｛2- (R)-[(S)
-Benzyloxycarbamoyl (hydroxy) methyl]
4-methylpentanoylamino} -3,3-di methyl
Butyl ester According to the method of Example 10-c), 2- (S)-{2- (R)-[2,2-dimethyl-5-oxo- [1,2 3] -Dioxolan-4-
(S) -yl] -4-methylpentanoylamino]-
Using 3,3-dimethylbutyl ester (87 mg) as a starting material, 63 mg of the desired compound (6
2%).

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ , δppm): 0.93-0.96 (15H, m), 0.96 (9H, s), 1.44 (1
H, m), 1.63 (1H, m), 1.80 (1H, m), 2.02 (3H, s), 3.06
(1H, m), 4.03 (2H, d, J = 8.3Hz), 4.09 (1H, dd, J = 8.6,
2.1Hz), 4.25 (1H, m), 4.82 (1H, d, J = 11.2Hz), 4.89
(1H, d, J = 11.2Hz), 5.22 (1H, d, J = 8.6Hz), 6.25 (1H,
d, J = 8.4Hz), 7.37 (5H, s), 9.34 (1H, br s) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3302, 3202, 1742, 1645 25-d) Acetic acid 2- (S) -｛2- (R)-[(S)
-Hydroxy (hydroxycarbamoyl) methyl] -4
- methylpentanoylamino} -3,3-dimethylcarbamoyl Rubuchi
According to the method of glycol ester Example 10-d), acetic acid obtained in Example 25-c) 2- (S) - {2- (R) - [(S) - benzyloxy carbamoyl (hydroxy) methyl] -4 −
Methylpentanoylamino} -3,3-dimethylbutyl ester (60 mg) was used as a starting material and subjected to the same reaction treatment to obtain 28 mg (57%) of the target compound.

[0370]¹H-nuclear magnetic resonance spectrum (270MHz, CDC
l_Three, δppm): 0.87-1.00 (15H, m), 1.37 (1H, m), 1.60 (1
H, m), 1.85 (1H, m), 2.02 (3H, s), 3.03 (1H, m), 4.01-
4.28 (4H, m), 6.63 (1H, m) (Example 26)2- (S), N ¹ -dihydroxy-N
⁴ - [1-(S) - hydroxymethyl-2,2-dimethylol
Propyl] -3- (R) -isobutylsuccinamide
(Exemplified Compound No. 102) According to the method of Example 9, the vinegar obtained in Example 25-d)
Acid 2- (S)-{2- (R)-[(S) -hydroxy
(Hydroxycarbamoyl) methyl] -4-methylpen
Tanoylamino｝ -3,3-dimethylbutyl ester
(23 mg) as a starting material by the same reaction treatment.
5 mg (25%) of the target compound were obtained.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CD ₃
OD, δ ppm): 0.90-1.00 (15H, m), 1.26 (1H, m), 1.67 (2
H, m), 2.81 (1H, m), 3.50 (1H, m), 3.77 (2H, m), 4.06
(1H, d, J = 5.3 Hz) (Example 27) 2- (S), N ¹ -dihydroxy-N ⁴
-[2- (R) -hydroxy-1- (S) -isopropyl
Rubutyl] -3- (R) -nonylsuccinamide (Exemplary Compound No. 202) 27-a) 2- (R)-[2,2-dimethyl-5-oxo
So- [1.3] -dioxolan-4- (S) -yl]
Ndecanoic acid [2- (R) -hydroxy-1- (S ) -i
Sopropylbutyl] amide 4- (S) -benzyloxycarbonylamino-5-methylhexane-3- (R) -ol (1.13 g) in the same manner as in Example 2-a) and the target compound ( 1.28 g, 72%) as a white solid.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl ₃
) δppm: 0.76-1.03 (12H, m), 1.03-1.52 (16H, m), 1.53 (3
H, s), 1.62 (3H, s), 17.2-1.93 (3H, m), 2.55-2.63 (1H, m), 3.
59-3.71 (2H, m), 4.08-4.16 (1H, m), 4.52 (1H, d, J = 4.6Hz),
6.08 (1H, d, J = 9.9Hz) 27-b) N ¹ -benzyloxy-2- (S) -hydro
Carboxymethyl ^{-N 4 - [2- (R)} - hydroxy -1- (S) -
Isopropylbutyl] -3- (R) -nonylsuccinami
Do 2- (R)-[2,2-dimethyl-5-oxo- [1.
3] -Dioxolan-4- (S) -yl] undecanoic acid [2- (R) -hydroxy-1- (S) -isopropylbutyl] amide (773 mg) in the same manner as in Example 2-b). , Target compound (260 mg, 29%)
Was obtained as a white solid.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ ) δppm: 0.88 (3H, t, J = 7.2Hz), 0.93 (3H, d, J = 6.3Hz),
0.95 (3H, d, J = 6.3Hz), 1.00 (3H, t, J = 7.4Hz), 1.12-1.43 (14
H, m), 1.46-2.01 (5H, m), 2.04 (1H, brs), 2.91 (1H, m), 3.59
(1H, m), 3.80 (1H, m), 4.15 (1H, m), 4.84 (1H, d, J = 11.2Hz),
4.90 (1H, d, J = 11.2Hz), 5.14 (1H, d, J = 8.3Hz), 6.00 (1H, d, J
= 9.5Hz), 7.32-7.43 (5H, m), 9.35 (1H, s). 27-c) 2- (S) , N 1 - dihydroxy -N ⁴ -
[2- (R) -hydroxy-1- (S) -isopropyl
Butyl] -3- (R) -nonylsuccinamide N ¹ -benzyloxy-2- (S) -hydroxy-N ⁴
-[2- (R) -hydroxy-1- (S) -isopropylbutyl] -3- (R) -nonylsuccinamide (255
mg) to give the target compound (171 mg, 83%) as a white solid in the same manner as in Example 2-c).

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 0.88-0.98 (12H, m), 1.21-1.46 (16H, m), 1.56-1.
71 (2H, m), 2.08-2.22 (m, 1H), 2.63-2.71 (1H, m), 3.44 (1H, d
t, J = 8.7,2.7Hz), 3.76 (1H, dd, J = 8.7,3.7Hz), 3.99 (1H, d, J
= 7.2Hz). (Example 28) Acetic acid 2- (S)-[2- (R)-
((S) -hydroxy (hydroxycarbamoyl) methyl
Ru) -9-Methyldecanoylamino] -3,3-dimethyl
Rubutyl ester (Exemplified Compound No. 108) 28-a) 2- (S) -hydroxy-3- (R)-(7
-Methyl-2-octenyl) diisopropyl succinate
Ester 2- (S) - hydroxy acid diisopropyl ester (10.43 g) was dissolved in a nitrogen atmosphere tetrahydrofuran (200 ml), cooled to -78 ° C.. Lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 115 ml) was added dropwise thereto, and the mixture was stirred for 30 minutes. Then, a solution of trans-1-iodo-7-methyl-2-octene (13.26 g) in tetrahydrofuran (100 ml) was added, and the mixture was stirred at -78 ° C for 2 hours, then warmed to room temperature and further stirred for 2 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 19: 1) to give 7.48 g (46%) of the desired compound as a colorless oil. .

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ , δppm): 0.86 (6H, d, J = 6.6Hz), 1.12 ~ 1.39 (4H, m), 1.
22 (6H, d, J = 6.4Hz), 1.28 (6H, d, J = 6.4Hz), 1.52 (1H, m), 1.9
8 (2H, m), 2.36 (1H, m), 2.54 (1H, m), 2.84 (1H, m), 3.18 (1H, m
d, J = 7.4Hz), 4.21 (1H, dd, J = 3.1,7.4Hz), 5.01 (1H, m), 5.11
(1H, m), 5.40 (1H, m), 5.57 (1H, m). Infrared absorption spectrum (Liquid film, cm ^-1 ): 3515,173
8 Mass spectrum (FAB): m / z [M + H] ⁺ = 343 28-b) 2- (R)-(2,2-dimethyl-5-oxo
So- [1,3] -dioxolan-4- (S) -yl)-
9-Methyldecanoic acid 2- (S) -hydroxy- obtained in Example 28-a)
3- (R)-(7-Methyl-2-octenyl) succinic acid diisopropyl ester (7.46 g) was dissolved in methanol (75 ml), and 10% palladium-carbon (0.
75 g) and hydrogenated at room temperature for 5 hours. The catalyst was filtered off using celite, and the filtrate obtained by washing with methanol was concentrated under reduced pressure. Next, the obtained residue was dissolved in dioxane (40 ml), an aqueous solution of potassium hydroxide (4.24 g) (80 ml) was added under ice-cooling, and the mixture was heated with stirring at 90 ° C. for 16 hours. Amberlyst 15E for reaction solution
, And the mixture was neutralized, and the resin was filtered off using Celite. Further, the filtrate obtained by washing with dioxane was concentrated under reduced pressure. Next, the obtained residue was dissolved in benzene (120 ml), and at room temperature, 2,2-dimethoxypropane (13.
17 ml) and pyridinium p-toluenesulfonate (0.54 g) were sequentially added, and the mixture was heated under reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 1: 1).
(Eluted with 1: 1) to give 4.28 g of the desired compound
(65%) as white crystals.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ , δppm): 0.86 (6H, d, J = 6.6Hz), 1.10-1.47 (10H, m),
1.51 (1H, m), 1.55 (3H, s), 1.60 (3H, s), 1.74 ~ 1.83 (2H,
m), 2.93 (1H, m), 4.50 (1H, d, J = 5.0 Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 1799,1716 Mass spectrum (FAB): m / e [M + H] ⁺
= 301 Analysis _{Calculated: C 16 H 28 O 5:} C, 63.97%;
H, 9.40% Measurement value: C, 63.76%; H, 9.29% 28-c) 2- (R)-(2,2-dimethyl-5-oxo)
So- [1,3] -dioxolan-4- (S) -yl)-
9- methyldecanoic acid (1- (S) - hydroxy methyltransferase -
2,2-Dimethylpropyl) amide 2- (R)-(2,2-dimethyl-5-oxo- [1,3] -dioxolan-4-) obtained in Example 28-b).
(S) -yl) -9-methyldecanoic acid (1,000 g)
And (S) -tert-leucinol (468 mg)
Was used as a starting material to obtain 1.127 g (85%) of the target compound as white crystals in the same manner as in Example 15-a).

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ , δppm): 0.85 (6H, d, J = 6.6Hz), 0.97 (9H, s), 1.09 ~ 1.4
7 (10H, m), 1.50 (1H, m), 1.55 (3H, s), 1.63 (3H, s), 1.64 ~
1.85 (2H, m), 2.39 (1H, t, J = 5.6Hz), 2.69 (1H, dt, J = 5.1,10.
1Hz), 3.55 (1H, m), 3.82 ~ 3.90 (2H, m), 4.62 (1H, d, J = 5.1H
z), 6.25 (1H, d, J = 8.6Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3262,179
8,1646 Mass spectrum (FAB): m / z [M + H] ⁺ = 400 Elemental analysis Theoretical value: C ₂₂ H ₄₁ NO ₅ : C, 66.13%; H, 10.34%; N, 3.51% Analysis value: C , 66.34%; H, 10.64%; N, 3.52% Melting point: 108-110 ° C 28-d) Acetic acid 2- (S)-[2- (R)-(2,2-
Dimethyl-5-oxo- [1,3] -dioxolan-4
-(S) -yl) -9-methyldecanoylamino ]-
3,3-Dimethylbutyl ester 2- (R)-(2,2-dimethyl-5-oxo [1,3] -dioxolan-4-) obtained in Example 28-c)
(S) -yl) -9-Methyldecanoic acid (1- (S) -hydroxymethyl-2,2-dimethylpropyl) amide (1.111 g) was obtained in the same manner as in Example 10-b) to obtain the desired compound 1. 028 g (84%) were obtained as white crystals.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ , δppm): 0.85 (6H, d, J = 6.6Hz), 0.97 (9H, s), 1.10 ~ 1.4
2 (10H, m), 1.50 (1H, m), 1.54 (3H, s), 1.62 (3H, s), 1.73 〜
1.83 (2H, m), 2.03 (3H, s), 2.57 (1H, dt, J = 5.8,9.1Hz), 4.02
~ 4.12 (2H, m), 4.25 (1H, m), 4.52 (1H, d, J = 5.8Hz), 6.03 (1
H, brd, J = 9.2Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3331,179
6,1740,1649,1556 Mass spectrum (FAB): m / z [M + H] ⁺ = 442 Melting point: 89-91 ° C 28-e) Acetic acid 2- (S)-[2- (R)-｛ (S)-
Benzyloxycarbamoyl (hydroxy) methyl}-
9-methyl decanoyl amino] -3,3-dimethylcarbamoyl Rubuchi
Glycol ester Example 28-d) obtained in acetic acid 2- (S) - [2-
(R)-(2,2-dimethyl-5-oxo- [1,3]
-Dioxolan-4- (S) -yl) -9-methyldecanoylamino] -3,3-dimethylbutyl ester (1.013 g) in the same manner as in Example 10-c), 678 mg (58% ) Was obtained as white crystals.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ , δppm): 0.86 (6H, d, J = 6.6Hz), 0.96 (9H, s), 1.10 ~ 1.4
1 (10H, m), 1.51 (1H, m), 1.65 (1H, m), 1.80 (1H, m), 2.03 (3H,
s), 2.90 (1H, m), 3.99 to 4.07 (2H, m), 4.15 (1H, dd, J = 2.1,
8.7Hz), 4.26 (1H, m), 4.83 (1H, d, J = 11.1Hz), 4.89 (1H, d, J =
11.1Hz), 5.20 (1H, d, J = 8.7Hz), 5.91 (1H, d, J = 9.2Hz), 7.33
7.47.42 (5H, m), 9.31 (1H, s). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3307,319
9,1744,1642 Mass spectrum (FAB): m / z [M + H] ⁺ = 507 Melting point: 78-80 ° C 28-f) Acetic acid 2- (S)-[2- (R)-((S )-
Hydroxy (hydroxycarbamoyl) methyl) -9-
Methyl decanoylamino] -3,3 Jimechirubu Chirue
The acetic acid 2- (S)-[2-
(R)-{(S) -benzyloxycarbamoyl (hydroxy) methyl} -9-methyldecanoylamino]-
The target compound 468m was obtained from 3,3-dimethylbutyl ester (664mg) in the same manner as in Example 10-d).
g (86%) were obtained as crystals.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃
OD, δppm): 0.87 (6H, d, J = 6.6Hz), 0.97 (9H, s), 1.11-1.4
4 (11H, m), 1.51 (1H, m), 1.61 (1H, m), 2.00 (3H, s), 2.69 (1H, m
m), 3.87 ~ 4.03 (2H, m), 4.00 (1H, d, J = 7.4Hz), 4.40 (1H, dd,
J = 2.8,11.0Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3310,322
3,1743,1719,1641 Mass spectrum (FAB): m / z [M + H] ⁺ = 417 Melting point: 107-109 ° C (Example 29) 2- (S), N ¹ -dihydroxy-N ⁴
-(1- (S) -hydroxymethyl-2,2-dimethyl
Propyl) -3- (R)-(7-methyloctyl)
Cinamide (Exemplified Compound No. 107) 2- (S)-[2- (acetic acid) obtained in Example 28-f)
(R)-((S) -hydroxy (hydroxycarbamoyl) methyl) -9-methyldecanoylamino] -3,3
Example 1 from dimethyl butyl ester (250 mg)
170 mg (76%) of the target compound by the same method as in 1.
Was obtained as white crystals.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃
OD, δppm): 0.87 (6H, d, J = 6.6Hz), 0.94 (9H, s), 1.13-1.5
5 (11H, m), 1.51 (1H, m), 1.60 (1H, m), 2.68 (1H, m), 3.48 (1H, m
dd, J = 9.2,12.3Hz), 3.73-3.79 (2H, m), 4.06 (1H, d, J = 6.5H
z). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3277,312
4,1669,1469 Mass spectrum (FAB): m / z [M + H] ⁺ = 375 Melting point: 156-158 ° C (Example 30) Acetic acid 2- (S)-[4- (4-chloroacetic acid)
Phenoxy) -2- (R)-(N-hydroxycarbamo
Ylmethyl) butyrylamino] -3,3-dimethylbuty
Glycol ester (Compound No. 303) 30-a) 5- ( 4- chlorophenoxy) -3
(R)-[1- (S) -hydroxymethyl-2,2-di
Methylpropylcarbamoyl] pentanoic acid t- butyl Le
Ester 2- (R) -tert-butoxycarbonylmethyl-4- (4
-Chlorophenoxy) butanoic acid (1.500 g) and (S) -t-leucinol (642 mg) were used as starting materials in the same manner as in Example 15-a).
571 g (81%) were obtained as white crystals.

NMR spectrum (400 MHz, CDCl ₃ ) δ ppm: 0.
90 (9H, s), 1.43 (9H, s), 1.93 (1H, m), 2.08 (1H, m), 2.18 (1H,
m), 2.40 (1H, dd, J = 17.4, 3.8Hz), 2.73 (1H, dd, 17.4, 10.1H
z), 3.00 (1H, m), 3.33 (1H, m), 3.73-3.84 (2H, m), 3.97-4.07
(2H, m), 6.05 (1H, brd, J = 8.9Hz), 6.84 (2H, m), 7.23 (2H, m). IR spectrum (KBr pellet, cm ^-1 ): 3365,2961,1704,165
1,1544,1496,1241. Mass spectrum (FAB): m / z [M + H] ⁺ = 428 Melting point: 130-132 ° C 30-b) 3- (R)-[1- (S) -acetoxyme
Tyl-2,2-dimethylpropylcarbamoyl] -5
(4-chlorophenoxy) t-pentanoic acid butyl Ruesu
5- (4-chlorophenoxy) -3- (R)-[1- (S) -hydroxymethyl- obtained in Tell Example 30-a).
2,2-Dimethylpropylcarbamoyl] pentanoic acid
Example 10-from t-butyl ester (1.547 g)
In the same manner as in b), 1.600 g of the target compound (94
%) As white crystals.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl
₃ ) δppm: 0.93 (9H, s), 1.43 (9H, s), 1.85 (3H, s), 1.87 (1H,
m), 2.12 (1H, m), 2.38 (1H, dd, J = 17.5, 3.7 Hz), 2.72 (1H, dd,
J = 17.5,10.2Hz), 2.95 (1H, m), 3.88-4.08 (4H, m), 4.19 (1H,
dd, J = 11.2,3.2Hz), 6.03 (1H, brd, J = 10.1Hz), 6.81 (2H, m),
7.22 (2H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3412,2958,1
738,1724,1669,1246,1233. Mass spectrum (FAB): m / z [M + H] ⁺ = 470 Melting point: 86-88 ° C 30-c) 3- (R)-[1- (S)- Acetoxime
Tyl-2,2-dimethylpropylcarbamoyl] -5
(4-Chlorophenoxy) pentanoic acid 3- (R)-[1- (S) obtained in Example 30-b).
-Acetoxymethyl-2,2-dimethylpropylcarbamoyl] -5- (4-chlorophenoxy) pentanoic acid
Example 8 from t-butyl ester (1.584 g)
1.255 g of the desired compound (90
%) As a foam.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 0.96 (9H, s), 1.85 (3H, s), 1.96 (1H, m), 2.04 (1H,
m), 2.48 (1H, dd, J = 16.7,5.0Hz), 2.71 (1H, dd, J = 16.7,9.6H
z), 3.04 (1H, m), 3.85 (1H, m), 3.95-4.07 (3H, m), 4.39 (1H, d
d, J = 11.3,3.1Hz), 6.90 (2H, m), 7.23 (2H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 2965,1736,1
646,1493,1244. Mass spectrum (FAB): m / z [M + H] ⁺ = 414 30-d) Acetic acid 2- (S)-[4- (4-chlorof
Enoxy) -2- (R)-(N-hydroxycarbamoy
Rumechiru) butyrylamino] -3,3-dimethyl-butyl
Ester 3- (R)-[1- (S) obtained in Example 30-c)
Example 8 starting from -acetoxymethyl-2,2-dimethylpropylcarbamoyl] -5- (4-chlorophenoxy) pentanoic acid (1.240 g) and 0- (t-butyldimethylsilyl) hydroxyamine (883 mg). The target compound 498m in the same manner as in -e).
g (39%) was obtained as a foam.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 0.95 (9H, s), 1.83 (3H, s), 1.93 (1H, m), 2.03 (1H,
m), 2.26 (1H, dd, J = 14.6,6.7Hz), 2.42 (1H, dd, J = 14.6,7.9H
z), 3.07 (1H, m), 3.84 (1H, m), 3.91-4.06 (3H, m), 4.38 (1H, d
d, J = 11.1,3.0Hz), 6.90 (2H, m), 7.23 (2H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3249,2965,1
740,1649,1545,1493,1244. Mass spectrum (FAB): m / z [M + H] ⁺ = 429 (Example 31) 2- (R)-[2- (4-chloropheno)
) Ethyl] -N ⁴ - hydroxy -N ¹ - [1-
(S) -hydroxymethyl-2,2-dimethylpropyl
Succinamide (Exemplified Compound No. 304) Acetic acid 2- (S)-[4-] obtained in Example 30-d)
(4-Chlorophenoxy) -2- (R)-(N-hydroxycarbamoylmethyl) butyrylamino] -3,3-
186 mg (83%) of the target compound was obtained as white crystals from dimethylbutyl ester (250 mg) in the same manner as in Example 9.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 0.92 (9H, s), 1.91 (1H, m), 2.06 (1H, m), 2.28 (1H,
dd, J = 14.6,6.7Hz), 2.43 (1H, dd, J = 14.6,8.0Hz), 3.04 (1H,
m), 3.40 (1H, dd, J = 11.7,9.9Hz), 3.75-3.81 (2H, m), 3.95-
4.07 (2H, m), 6.89 (2H, m), 7.21 (2H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3292,1656,1
618,1569,1493,1232. Mass spectrum (FAB): m / z [M + H] ⁺ = 387 Melting point: 171-173 ° C. (Example 32) Acetic acid 2- (S)-[5- (4-chloroacetic acid)
Phenyl) -2- (R)-(N-hydroxycarbamoy
Rumethyl) pentanoylamino] -3,3-dimethylbutane
Tyl ester (exemplified compound No. 29) 32-a) 3- (R)-[1- (S) -acetoxime
Tyl-2,2-dimethylpropylcarbamoyl] -6
(4-Chlorophenyl) hexanoic acid 2- (R) -t-butoxycarbonylmethyl-5- (4
1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (704) was added to a solution of -chlorophenyl) pentanoic acid (1.000 g) in methylene chloride (30 ml).
mg), 1-hydroxybenzotriazole (496 m
g) and N-methylmorpholine (0.40 ml) were sequentially added, and the mixture was cooled to 0 ° C. Next, (S) -t-leucinol (430 mg) in methylene chloride (10 ml) was added to this solution.
The solution was added and stirred at room temperature for 18 hours. 1N reaction solution
Poured into hydrochloric acid and extracted with methylene chloride. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was redissolved in methylene chloride (25 ml) and cooled to 0 ° C. Next, pyridine (0.49 ml) and 4-dimethylaminopyridine (37
mg) and acetic anhydride (0.58 ml) were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water and extracted with methylene chloride. The organic layer was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was redissolved in methylene chloride (30 ml) and cooled to 0 ° C. The solution was then added to trifluoroacetic acid (4.71).
ml) and stirred at room temperature for 16 hours. After toluene was added to the reaction solution, volatiles were distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with methylene chloride: methanol = 99: 1 to 49: 1) to obtain 846 mg (67%) of the desired compound as a foam.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 0.95 (9H, s), 1.40-1.52 (1H, m), 1.57-1.69 (3H,
m), 1.76 (3H, s), 2.37 (1H, dd, J = 16.7, 5.1Hz), 2.53-2.69 (2
H, m), 2.60 (1H, dd, J = 16.7,9.4Hz), 2.80 (1H, m), 3.88 (1H, d
d, J = 10.9,10.2Hz), 3.96 (1H, dd, J = 10.2,2.6Hz), 4.37 (1H,
dd, J = 10.9,2.6Hz), 7.16 (2H, m), 7.24 (2H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3318,2964,1
737, 1648, 1549, 1238. Mass spectrum (FAB): m / z [M + H] ⁺ = 412 32-b) Acetic acid 2- (S)-[5- (4-chlorof
Enyl) -2- (R)-(N-hydroxycarbamoyl
Methyl) pentanoyl amino] -3,3-dimethylcarbamoyl Rubuchi
Obtained in glycol ester Example 32-a) 3- (R) - [1- (S)
-Acetoxymethyl-2,2-dimethylpropylcarbamoyl] -6- (4-chlorophenyl) hexanoic acid (8
46 mg) and N-methylmorpholine (0.27 m
l) To a solution of l) in tetrahydrofuran (20 ml) was added isobutyl chloroformate (0.32 ml) under ice-cooling, and the mixture was stirred for 0.5 hours. 3 at ℃
Stirred for hours. The reaction solution was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (methylene chloride: methanol = 49: 1 to 1: 1).
19: 1), and 766 mg of the desired compound was obtained.
(87%) as a foam.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 0.94 (9H, s), 1.39-1.51 (1H, m), 1.56-1.68 (3H,
m), 1.74 (3H, s), 2.16 (1H, dd, J = 14.6,6.9Hz), 2.32 (1H, dd,
J = 14.6,7.7Hz), 2.58 (1H, m), 2.63 (1H, m), 2.82 (1H, m), 3.8
8 (1H, dd, J = 10.8,10.2Hz), 3.96 (1H, dd, J = 10.2,2.5Hz), 4.
37 (2H, dd, J = 10.8,2.5Hz), 7.12 (2H, m), 7.23 (2H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3275,2964,2
943,1741,1648,1545,1493,1239. Mass spectrum (FAB): m / z [M + H] ⁺ = 427 Specific rotation: [α] _D ²⁵ = + 10.7 ° (C: 1.06, MeOH) ( Example 33) 2- (R)-[3- (4-chlorophenyl)
) Propyl] -N ⁴ - hydroxy -N ¹ - [1-
(S) -hydroxymethyl-2,2-dimethylpropyl
Ru] succinamide (Exemplified Compound No. 28) 2- (S)-[5- (acetic acid) obtained in Example 32-b)
(4-Chlorophenyl) -2- (R)-(N-hydroxycarbamoylmethyl) pentanoylamino] -3,3
Example 9 from dimethyl butyl ester (190 mg)
132 mg of the desired compound was obtained in the same manner as in the above (however, the obtained powder was washed with ethyl acetate without recrystallization).
(77%) as a white powder.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 0.92 (9H, s), 1.38-1.50 (1H, m), 1.56-1.76 (3H,
m), 2.17 (1H, dd, J = 14.6,6.8Hz), 2.33 (1H, dd, J = 14.6,7.7H
z), 2.52-2.66 (2H, m), 2.81 (1H, m), 3.44 (1H, m), 3.74-3.81
(2H, m), 7.15 (2H, m), 7.22 (2H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3296,2965,1
655,1565,1493. Mass spectrum (FAB): m / z [M + H] ⁺ = 385 Specific rotation: [α] _D ²⁵ = + 6.9 ° (C: 1.04, MeOH) Melting point: 175 to 176 ° C. Example 34) Acetic acid 2- (S)-[2- (R) -sic
Rohexylmethyl-3- (N-hydroxycarbamoy
L) propionylamino] -3,3-dimethylbutyle
Ster (Exemplified Compound No. 41) 34-a) 4-Cyclohexyl-3- (R)-[1-
(S) -hydroxymethyl-2,2-dimethylpropyl
Carbamoyl] butanoic acid t-butyl ester 2- (R) -t-butoxycarbonylmethyl-3-cyclohexylpropanoic acid (1.500 g) and (S)-
The target compound 1.690 was prepared in the same manner as in Example 15-a) using t-leucinol (780 mg) as a starting material.
g (82%) were obtained as white crystals.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl
₃ ) δppm: 0.83-1.02 (2H, m), 0.95 (9H, s), 1.07-1.34 (5H,
m), 1.43 (9H, s), 1.57-1.82 (6H, m), 2.36 (1H, dd, J = 17.3,4.
0Hz), 2.52 (1H, brs), 2.58 (1H, dd, J = 17.3,9.5Hz), 2.75 (1H
H, m), 3.55 (1H, m), 3.76-3.88 (2H, m), 6.05 (1H, brd, J = 8.5H
z). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3367,2922,1
726,1635,1550,1366,1152. Mass spectrum (FAB): m / z [M + H] ⁺ = 370 Melting point: 119-121 ° C 34-b) 3- (R)-[1- (S)- Acetoxime
Tyl-2,2-dimethylpropylcarbamoyl] -4-
Cyclohexylbutanoic acid t-butyl ester 4-cyclohexyl-3- obtained in Example 34-a)
1.799 g of the desired compound from t-butyl (R)-[1- (S) -hydroxymethyl-2,2-dimethylpropylcarbamoyl] butanoate (1.678 g) in the same manner as in Example 10-b). (96%) as white crystals.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl
₃ ) δppm: 0.82-0.97 (2H, m), 0.94 (9H, s), 1.08-1.31 (5H,
m), 1.43 (9H, s), 1.58-1.78 (6H, m), 2.05 (3H, s), 2.29 (1H, d
d, J = 16.9,3.5Hz), 2.61 (1H, dd, J = 16.9,9.6Hz), 2.69 (1H,
m), 4.02-4.10 (2H, m), 4.18-4.26 (1H, m), 5.88 (1H, brd, J =
8.7Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3312,2923,1
739, 1647, 1547, 1368, 1250, 1159. Mass spectrum (FAB): m / z [M + H] ⁺ = 412 Melting point: 84-86 ° C 34-c) 3- (R)-[1- (S ) -Acetoxime
Tyl-2,2-dimethylpropylcarbamoyl] -4-
Cyclohexylbutanoic acid 3- (R)-[1- (S) obtained in Example 34-b)
-Acetoxymethyl-2,2-dimethylpropylcarbamoyl] -4-cyclohexylbutanoic acid t-butyl ester (1.783 g) in the same manner as in Example 8-d) to give 1.291 g (84%) of the target compound in white. Obtained as crystals.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 0.83-1.02 (2H, m), 0.96 (9H, s), 1.10-1.36 (5H,
m), 1.51-1.60 (1H, m), 1.61-1.76 (4H, m), 1.87-1.95 (1H,
m), 2.01 (3H, s), 2.35 (1H, dd, J = 16.3,5.2Hz), 2.56 (1H, dd,
J = 16.3,9.0Hz), 2.91 (1H, m), 3.90 (1H, dd, J = 10.9,9.7Hz),
3.98 (1H, dd, J = 9.7,2.6Hz), 4.42 (1H, dd, J = 10.9,2.6Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3373,2922,1
727,1646,1544,1248. Mass spectrum (FAB): m / z [M + H] ⁺ = 356 Melting point: 163-165 ° C 34-d) Acetic acid 2- (S)-[2- (R) -cyclo
Hexylmethyl-3- (N-hydroxycarbamoyl)
Propionylamino] -3,3-dimethylbutyl ester
Obtained in Le Example 34-c) 3- (R) - [1- (S)
-Acetoxymethyl-2,2-dimethylpropylcarbamoyl] -4-cyclohexylbutanoic acid (1.274)
g) and O- (t-butyldimethylsilyl) hydroxylamine (1.056 g) as starting materials in Example 8
-E) 112 mg of the target compound (8
%) As crystals.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 0.79-1.04 (2H, m), 0.96 (9H, s), 1.10-1.34 (5H,
m), 1.52-1.75 (5H, m), 1.87-1.94 (1H, m), 2.02 (3H, s), 2.13
(1H, dd, J = 14.4,6.9Hz), 2.29 (1H, dd, J = 14.4,7.6Hz), 2.93
(1H, m), 3.89 (1H, dd, J = 11.0,9.5Hz), 3.97 (1H, dd, J = 9.5,
2.8Hz), 4.43 (1H, dd, J = 11.0,2.8Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3302,3249,2
924,1716,1676,1648,1240. Mass spectrum (FAB): m / z [M + H] ⁺ = 371 High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 371.2531 Calculated value: 371.2546 (C ₁₉ H ₃₅ N ₂ O ₅ ) Elemental analysis (C ₁₉ H ₃₄ N ₂ O ₅ ): Calculated: C, 61.60; H, 9.25; N, 7.56 Measured: C, 61.61; H, 9.06; N, 7.60 Melting point: 180-182 ° C (Example 35) 2- (R) -cyclohexylmethyl-N
⁴ - hydroxy ^{-N 1 - [1- (S)} - hydroxymethyl
2- (2 -Dimethylpropyl) succinamide (Exemplified Compound No. 40) 2- (S)-[2- (acetic acid) obtained in Example 34-d)
185 mg (74%) of the target compound was obtained as a white powder from (R) -cyclohexylmethyl-3- (N-hydroxycarbamoyl) propionylamino] -3,3-dimethylbutyl ester (284 mg) in the same manner as in Example 9. Was.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 0.79-1.00 (2H, m), 0.93 (9H, s), 1.07-1.38 (5H,
m), 1.52-1.74 (5H, m), 1.85-1.93 (1H, m), 2.16 (1H, dd, J = 1
4.4,6.9Hz), 2.31 (1H, dd, J = 14.4,7.5Hz), 2.90 (1H, m), 3.4
6 (1H, m), 3.73-3.80 (2H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3306,2924,1
. 652,1560 mass spectrum (FAB): m / z [ M + H] + = 329 High resolution mass spectrum (FAB): m / z [ M + H] + = 329.2439 Calculated: 329.2441 (C ₁₇ H ₃₃ N ₂ O ₄ ) Elemental analysis (C ₁₇ H ₃₂ N ₂ O ₄ ): Calculated: C, 62.17; H, 9.82; N, 8.53 Measured: C, 62.07; H, 9.63; N, 8.59 Specific rotation: α] _D ²⁵ = + 14.9 ° (C: 1.06, MeOH) Melting point: 196-198 ° C. (Example 36) Acetic acid 2- (S)-[5- (4-chloro)
Phenyl) -2- (R)-(N-hydroxycarbamoy
Rumethyl) pentanoylamino] -3-phenylpropy
Glycol ester (Compound No. 301) 36-a) 3- ( R) - [2- acetoxy-1
(S) -benzylethylcarbamoyl] -6- (4-h
( Rolophenyl) hexanoic acid 2- (R) -tert-butoxycarbonylmethyl-5- (4
-Chlorophenyl) pentanoic acid (10.00 g) and (S) -phenylalaninol (5.55 g) as starting materials in the same manner as in Example 32-a), except that
Without recrystallization, wash the resulting powder with ether)
10.95 g (80%) of the target compound was obtained as white crystals.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 1.40-1.60 (4H, m), 1.87 (3H, s), 2.27 (1H, dd, J = 1
6.6,6.5Hz), 2.42 (1H, dd, J = 16.6,8.0Hz), 2.49-2.70 (3H,
m), 2.81 (2H, d, J = 7.4Hz), 3.89 (1H, dd, J = 11.4, 7.2Hz), 4.1
1 (1H, dd, J = 11.4,4.2Hz), 4.34 (1H, m), 7.10-7.30 (9H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3298,2929,1
735,1699,1648,1546,1255. Mass spectrum (FAB): m / z [M + H] ⁺ = 446 Melting point: 133-135 ° C 36-b) Acetic acid 2- (S)-[5- (4- Chlorov
Enyl) -2- (R)-(N-hydroxycarbamoyl
Methyl) pentanoyl amino] -3- Fenirupu propyl
Ester 3- (R)-[2-acetoxy-1- (S) -benzylethylcarbamoyl] -6 obtained in Example 36-a).
-(4-Chlorophenyl) hexanoic acid (10.95 g)
And starting with O- (t-butyldimethylsilyl) hydroxylamine (7.23 g) as the starting material.
10.16 g of the target compound (90
%) As a white powder.

[0396]¹H-nuclear magnetic resonance spectrum (400MHz, CD_ThreeO
D) δppm: 1.34-1.60 (4H, m), 1.86 (3H, s), 2.02 (1H, dd, J = 1
4.5,7.9Hz), 2.10 (1H, dd, J = 14.5,6.6Hz), 2.48-2.73 (3H,
m), 2.75-2.87 (2H, m), 3.90 (1H, dd, J = 11.2,7.0Hz), 4.13 (1H
H, dd, J = 11.2,4.1Hz), 4.34 (1H, m), 7.10-7.29 (9H, m). Infrared absorption spectrum (KBr pellet, cm^-1): 3286,1740,1
645, 1548, 1235. Mass spectrum (FAB): m / z [M + H]⁺= 461 High resolution mass spectrum (FAB): m / z [M + H]⁺= 461.1854 Calculated value: 461.1843 (C_{twenty four}H₃₀ClN_TwoO_Five) Elemental analysis (C_{twenty four}H₂₉ClN_TwoO_Five): Calculated: C, 62.54; H, 6.34; N, 6.08; Cl, 7.69 Measured: C, 62.32; H, 6.24; N, 6.13; Cl, 7.48 Specific rotation: [α]_D ^{twenty five} = -0.9 ° (C: 1.07, MeOH) Melting point: 175-177 ° C (Example 37) ^{N 1 - [1- (S)} - benzyl-2-arsenide
Droxyethyl] -2- (R)-(3- (4-chlorofu
Eniru) propyl] -N ⁴ - hydroxysuccinimide Sina bromide
(Exemplified Compound No. 302) 2- (S)-[5-acetic acid obtained in Example 36-b)
(4-chlorophenyl) -2- (R)-(N-hydroxy
Sicarbamoylmethyl) pentanoylamino] -3-f
Example 9 from phenylpropyl ester (3.00 g)
The same method (however, without recrystallization,
2.31 g of the desired compound (8
5%) as a white powder.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 1.32-1.60 (4H, m), 2.02 (1H, dd, J = 14.6,7.8Hz),
2.09 (1H, dd, J = 14.6,6.6Hz), 2.48-2.62 (2H, m), 2.66 (1H,
m), 2.73 (1H, dd, J = 13.8,8.3Hz), 2.89 (1H, dd, J = 13.8,6.4H
z), 3.51 (2H, d, J = 5.6Hz), 4.10 (1H, m), 7.10-7.27 (9H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3440,3294,1
. 641,1551 mass spectrum (FAB): m / z [ M + H] + = 419 High resolution mass spectrum (FAB): m / z [ M + H] + = 419.1723 Calculated: 419.1737 (C ₂₂ H ₂₈ ClN ₂ O ₄ ) Elemental analysis (C ₂₂ H ₂₇ ClN ₂ O ₄ ): Calculated: C, 63.08; H, 6.50; N, 6.69; Cl, 8.46 Measured: C, 62.82; H, 6.48; N, 6.61; Cl, 8.47 Melting point: 180-182 ° C (Example 38) Acetic acid 2- [2- (N-hydroxycal )
Bamoylmethyl) undecanoylamino] -3-methyl
-3-methylthiobutyl ester (Exemplary Compound No. 2
1) 38-a) 3- (R)-[1- (S) -hydroxyme
Tyl-2-methyl-2-methylthiopropylcarbamoy
L ] dodecanoic acid t-butyl ester 2- (R) -t-butoxycarbonylmethylundecanoic acid (667 mg) and N-methylmorpholine (250 μl)
To a solution of l) in tetrahydrofuran (6 ml) was added dropwise isobutyl chloroformate (290 μl), and the mixture was stirred at room temperature for 30 minutes. Then N-methylmorpholine (500 μl) and 1- (S) -hydroxymethyl-2-methyl-2-
N, N of methylthiopropylamine hydrochloride (412 mg)
-Dimethylformamide (2 ml) solution was sequentially added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was subjected to silica gel column chromatography (hexane:
Purification by elution with ethyl acetate = 5: 1) gave the target compound (373 mg, 39%) as a colorless oil.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δppm ： 0.88 (3H, t, J = 6.6Hz), 1.20-1.36 (14H, co
mplex), 1.31 (3H, s), 1.36 (3H, s), 1.43 (9H, s), 1.48-1.76
(3H, complex), 2.08 (3H, s), 2.37 (1H, m), 2.56-2.70 (2H, co
mplex), 3.75 (1H, dd, J = 6.4,11.3Hz), 3.82-3.97 (2H, compl
ex), 6.47 (1H, d, J = 7.2 Hz) 38-b) 3- (R)-[1- (S) -acetoxime
Tyl-2-methyl-2-methylthiopropylcarbamoy
Ru] dodecanoic acid t-butyl ester 3- (R)-[1- (S) obtained in Example 38-a)
-Hydroxymethyl-2-methyl-2-methylthiopropylcarbamoyl] dodecanoic acid In a solution of t-butyl ester (369 mg) in methylene chloride (4 ml) was added acetic anhydride (88 µl), pyridine (76 µl) and 4-dimethylaminopyridine (10 mg). ) Was added in sequence, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate.
The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 8: 1) to give the desired compound (31
(3 mg, 77%) as a colorless oil.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δppm ： 0.88 (3H, t, J = 6.7Hz), 1.20-1.40 (17H, co
mplex), 1.34 (3H, s), 1.43 (9H, s), 2.55-2.75 (2H, comple
x), 2.03 (3H, s), 2.09 (3H, s), 2.31 (1H, dd, J = 3.2,16.0Hz),
2.55 (1H, m), 2.65 (1H, dd, J = 9.5,16.0Hz), 4.18 (1H, dd, J =
9.6,11.0Hz), 4.34 (1H, dt, J = 3.4,9.6Hz), 4.47 (1H, dd, J =
3.4, 11.0Hz), 6.02 (1H, d, J = 9.6Hz) 38-c) 3- (R)-[1- (S) -acetoxime
Tyl-2-methyl-2-methylthiopropylcarbamoy
L ] dodecanoic acid 3- (R)-[1- (S) obtained in Example 38-b)
-Acetoxymethyl-2-methyl-2-methylthiopropylcarbamoyl] dodecanoic acid To a solution of t-butyl ester (313 mg) in methylene chloride (3.2 ml) was added trifluoroacetic acid (1.6 ml), and the mixture was stirred at room temperature for 1.5 hours. did. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
And eluted with 1) to give the desired compound (273 mg, 99%)
Was obtained as a colorless oil.

¹ H-nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δppm: 0.88 (3H, t, J = 6.6Hz), 1.18-1.43 (17H, co
mplex), 1.37 (3H, s), 1.51 (1H, m), 1.67 (1H, m), 2.03 (3H,
s), 2.09 (3H, s), 2.49-2.60 (2H, complex), 2.79 (1H, dd, J =
9.6, 17.4Hz), 4.17 (1H, dd, J = 9.6, 11.0Hz), 4.33 (1H, dt, J =
3.3,9.6Hz), 4.46 (1H, dd, J = 3.3,11.0Hz), 5.98 (1H, d, J = 9.
6-Hz) 38-d) Acetic acid 2- [2- (N-hydroxycarba )
Moylmethyl) undecanoylamino] -3-methyl-
3-Methylthiobutyl ester 3- (R)-[1- (S) obtained in Example 38-c)
-Acetoxymethyl-2-methyl-2-methylthiopropylcarbamoyl] dodecanoic acid (273 mg) and N-
Isobutyl chloroformate (90 μl) was added to a solution of methylmorpholine (180 μl) in tetrahydrofuran (2 ml) under ice-cooling, followed by stirring for 30 minutes. There,
A solution of O- (t-butyldimethylsilyl) hydroxylamine (116 mg) in tetrahydrofuran (1 ml) was added, and the mixture was stirred overnight. The reaction solution was poured into water, the organic layer extracted with ethyl acetate was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in methanol (6 ml), and 1N hydrochloric acid (1 ml) was added. And stirred at room temperature for 30 minutes. After distilling off with methanol under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated saline, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluted with ethyl acetate) to obtain the desired compound (210 mg, 74 mg).
%) As a white powder.

¹ H-nuclear magnetic resonance spectrum (400 MHz, C
DCl ₃ ) δppm: 0.88 (3H, t, J = 6.6Hz), 1.20-1.37 (14H, co
mplex), 1.34 (3H, s), 1.44 (1H, m), 1.59 (3H, s), 1.64 (1H,
m), 2.03 (3H, s), 2.08 (3H, s), 2.33 (1H, dd, J = 4.0,14.4Hz),
2.51 (1H, dd, J = 10.2,14.4Hz), 2.69 (1H, m), 4.14 (1H, dd, J =
9.4,11.4Hz), 4.31 (1H, dt, J = 3.4,9.4Hz), 4.46 (1H, dd, J =
3.4,11.4Hz), 6.05 (1H, d, J = 9.4Hz), 7.18 (1H, br s), 9.19
(1H, brs) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 334
5,3244,1728,1653,1550,123
8,1040 mass spectrum (FAB): m / e [ M + H] + = 433 ( Example 39) N ⁴ - hydroxy -N ¹ - [1-hydro
Xymethyl-2-methyl-2-methylthiopropyl]-
2- (R) -nonylsuccinamide (Exemplary Compound No. 2
0) 2- [2- (N-Hydroxycarbamoylmethyl) undecanoylamino] acetate obtained in Example 38-d)
-3-methyl-3-methylthiobutyl ester (108
mg) in the same manner as in Example 9 (without recrystallization, but washing the obtained powder with ethyl acetate) to obtain the desired compound (71 mg, 73%) as a white powder.

¹ H-nuclear magnetic resonance spectrum (400 MHz, C
D ₃ OD) δppm: 0.89 (3H, t, J = 6.6Hz), 1.21 (3H, s), 1.24-
1.34 (17H, complex), 1.38 (1H, m), 1.60 (1H, m), 2.07 (3H,
s), 2.19 (1H, dd, J = 6.7,14.4Hz), 2.37 (1H, dd, J = 7.8,14.4H
z), 2.76 (1H, m), 3.55 (1H, dd, J = 8.2,11.0Hz), 4.03 (1H, dd,
J = 3.4,11.0Hz), 4.08 (1H, dd, J = 3.4,8.2Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 339
7,3251,1667,1612,1530,103
5 Mass spectrum (FAB): m / e [M + H] ⁺ = 391 (Example 40) Acetic acid 2- (S)-[5- (2-ethoxy)
Siethoxy) -2- (R)-(N-hydroxycarbamo
Ylmethyl) pentanoylamino] -3,3-dimethyl
Butyl ester (Exemplified Compound No. 299) 40-a) 6- (2-ethoxyethoxy) -3-
(R)-[1- (S) -hydroxymethyl-2,2-di
Methylpropylcarbamoyl] hexanoic acid t- butyl Le
Ester 2- (R) -t-butoxycarbonylmethyl-5- (2
-Ethoxyethoxy) pentanoic acid (1.000 g) and (S) -t-leucinol (462 mg) as starting materials and 1.202 g (91%) of the target compound as an oily substance in the same manner as in Example 15-a). Obtained.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl
₃ ) δppm: 0.94 (9H, s), 1.25 (3H, t, J = 7.3Hz), 1.40-1.51 (1
H, m), 1.43 (9H, s), 1.55-1.70 (2H, m), 1.75-1.89 (1H, m), 2.
33 (1H, dd, J = 16.9,5.7Hz), 2.60 (1H, dd, J = 16.9,8.7Hz), 2.
82 (1H, m), 3.10 (1H, m), 3.41 (1H, m), 3.48-3.70 (8H, m), 3.7
6-3.89 (2H, m), 6.40 (1H, d, J = 9.2Hz). Infrared absorption spectrum (Liquid film, cm ^-1 ): 3329,2972,
2870,1731,1650,1542,1368,1155. Mass spectrum (FAB): m / z [M + H] ⁺ = 404 40-b) 3- (R)-[1- (S) -acetoxyme
Tyl-2,2-dimethylpropylcarbamoyl] -6
T-(2-ethoxyethoxy) hexanoic acid butyl Ruesu
6- (2-Ethoxyethoxy) -3- (R)-[1- (S) -hydroxymethyl- obtained in Tell Example 40-a).
2,2-Dimethylpropylcarbamoyl] hexanoic acid
Example 10- from t-butyl ester (1.185 g)
In the same manner as in b), 1.260 g (96
%) As an oil.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl
₃ ) δppm: 0.94 (9H, s), 1.21 (3H, t, J = 7.3Hz), 1.35-1.52 (1
H, m), 1.42 (9H, s), 1.55-1.80 (3H, m), 2.03 (3H, s), 2.26-2.
37 (1H, m), 2.59-2.71 (2H, m), 3.40-3.61 (8H, m), 3.99-4.11
(2H, m), 4.24 (1H, dd, J = 10.2,2.4Hz), 6.09 (1H, d, J = 9.3H
z). Infrared absorption spectrum (Liquid film, cm ^-1 ): 3320,2974,
2869,1733,1650,1546,1368,1240,1155. Mass spectrum (FAB): m / z [M + H] ⁺ = 445 40-c) 3- (R)-[1- (S) -acetoxime
Tyl-2,2-dimethylpropylcarbamoyl] -6
(2-ethoxyethoxy) hexanoic acid 3- (R)-[1- (S) obtained in Example 40-b).
-Acetoxymethyl-2,2-dimethylpropylcarbamoyl] -6- (2-ethoxyethoxy) hexanoic acid
Example 8- from t-butyl ester (1.244 g)
In the same manner as in d), 1.087 g of the target compound (10
0%) as an oil.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl
₃ ) δppm: 0.96 (9H, s), 1.20 (3H, t, J = 7.2Hz), 1.54-1.92 (4
H, m), 2.03 (3H, s), 2.60 (1H, dd, J = 16.6,3.6Hz), 2.71 (1H, d
d, J = 16.6,8.0Hz), 2.90 (1H, m), 3.42-3.66 (8H, m), 3.98 (1
H, dd, J = 11.3,9.5Hz), 4.08 (1H, ddd, J = 9.8,9.5,3.0Hz), 4.
32 (1H, dd, J = 11.3,3.0Hz), 6.09 (1H, br), 6.72 (1H, d, J = 9.8
Hz). Infrared absorption spectrum (Liquid film, cm ^-1 ): 3315,2966,
2872,1737,1652,1552,1371,1240,1173. Mass spectrum (FAB): m / z [M + H] ⁺ = 390 40-d) Acetic acid 2- (S)-[2- (R)-( Ben
Ziroxycarbamoylmethyl) -5- (2-ethoxy
Ethoxy) pentanoylamino] -3,3-dimethyl Chirubu
Cyl ester 3- (R)-[1- (S) obtained in Example 40-c)
-Acetoxymethyl-2,2-dimethylpropylcarbamoyl] -6- (2-ethoxyethoxy) hexanoic acid (1.074 g) and O-benzylhydroxylamine hydrochloride (880 mg) as starting materials.
In a similar manner to e), 959 mg of the desired compound (70 mg
%) As white crystals.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl
₃ ) δppm: 0.95 (9H, s), 1.20 (3H, t, J = 7.3Hz), 1.44-1.78 (4
H, m), 2.02 (3H, s), 2.20 (1H, m), 2.39 (1H, m), 2.86 (1H, m),
3.39-3.60 (8H, m), 3.94-4.09 (2H, m), 4.28 (1H, m), 4.86 (2
H, s), 6.38 (1H, brd, J = 8.8Hz), 7.31-7.41 (5H, m), 8.72 (1H,
s). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3203,1737,1
641,1242. Mass spectrum (FAB): m / z [M + H] ⁺ = 495 Melting point: 84-86 ° C 40-e) Acetic acid 2- (S)-[5- (2-ethoxy)
Ethoxy) -2- (R) -(N-hydroxycarbamoy
Rumethyl) pentanoylamino] -3,3-dimethylbutane
Cyl ester Acetic acid obtained in Example 40-d) 2- (S)-[2-
(R)-(benzyloxycarbamoylmethyl) -5
(2-ethoxyethoxy) pentanoylamino] -3,
648 mg of the desired compound was obtained from 3-dimethylbutyl ester (946 mg) in the same manner as in Example 23-c).
(84%) was obtained as a solid.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 0.95 (9H, s), 1.18 (3H, t, J = 7.3Hz), 1.44-1.69 (4
H, m), 2.01 (3H, s), 2.17 (1H, dd, J = 14.6,6.7Hz), 2.34 (1H, d
d, J = 14.6,8.0Hz), 2.82 (1H, m), 3.46 (2H, t, J = 6.2Hz), 3.51
(2H, q, J = 7.3Hz), 3.55 (4H, s), 3.91 (1H, dd, J = 10.9,10.2H
z), 3.98 (1H, dd, J = 10.2,2.7Hz), 4.38 (1H, dd, J = 10.9,2.7H
z). Infrared absorption spectrum (Liquid film, cm ^-1 ): 3214,2945,
2870,1740,1726,1645,1553,1242,1113. Mass spectrum (FAB): m / z [M + H] ⁺ = 405 High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 405.2605 _{calculated: 405.2600 (C 19 H 37 N} 2 O 7) ( example 41) 2- (R) - [ 3- (2- Etokishieto
Alkoxy) propyl] -N ⁴ - hydroxy -N ¹ - [1-
(S) -hydroxymethyl-2,2-dimethylpropyl
Ru] succinamide (Exemplified Compound No. 300) 2- (S)-[5-acetic acid obtained in Example 40-e)
(2-ethoxyethoxy) -2- (R)-(N-hydroxycarbamoylmethyl) pentannoylamino]-
111 mg (36 mg) of the target compound was obtained from 3,3-dimethylbutyl ester (345 mg) in the same manner as in Example 9.
%) As a white powder.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 0.93 (9H, s), 1.19 (3H, t, J = 7.2Hz), 1.45-1.71 (4
H, m), 2.19 (1H, dd, J = 14.6,6.6Hz), 2.35 (1H, dd, J = 14.6,7.
7Hz), 2.83 (1H, m), 3.41-3.59 (5H, m), 3.56 (4H, s), 3.74-3.
80 (2H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3220,2927,1
669,1647,1549,1101. Mass spectrum (FAB): m / z [M + H] ⁺ = 363 High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 363.2509 Calculated value: 363.2496 (C ₁₇ H ₃₅ N ₂ O ₆ ) Melting point: 127-129 ° C. (Example 42) Acetic acid 3-acetoxy-2- (S)-
[2- (R)-(N-hydroxycarbamoylmethyl)
Undecanoylamino] -1- (S) -methylpropyl
Ester (Exemplified Compound No. 309) 42-a) 3- (R)-[2- (S) -hydroxy-
1- (S) -hydroxymethyl-propylcarbamoy
Ru] dodecanoic acid t-butyl ester According to the method of Example 8-b), 2- (R) -t-butoxycarbonylmethylundecanoic acid (795 mg) obtained in Example 8-a) and 2- (S) -Amino-1,3
-(S) -Butanediol (334 mg) was used as a starting material, and 750 mg (73 mg) of the target compound was obtained by the same reaction treatment.
%).

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.88 (3H, t, J = 6.7Hz), 1.20 (3H, d, J = 6.4Hz), 1.2
3-1.31 (14H, m), 1.43 (9H, s), 1.66 (1H, m), 1.80 (1H, m), 2.3
9 (1H, dd, J = 3.2,15.7Hz), 2.55 (1H, m), 2.64 (1H, dd, J = 9.7,
15.7Hz), 2.97 (1H, brs), 3.28 (1H, brs), 3.76 (2H, d, J = 7.7H
z), 3.87 (1H, m), 4.11 (1H, m), 6.40 (1H, d, J = 7.7Hz). Infrared absorption spectrum (Liquid film, cm ^-1 ): 3436,2930,
2857, 1714, 1668, 1511. Mass spectrum (FAB): m / z [M + H] ⁺ = 388 42-b) 3- (R)-[2- (S) -acetoxy-
1- (S) -acetoxymethylpropylcarbamoyl]
Dodecanoic acid t-butyl ester According to the method of Example 10-b), the 3- (R)-[2- (S) -hydroxy-1- obtained in Example 42-a).
(S) -Hydroxymethylpropylcarbamoyl] dodecanoic acid t-butyl ester (750 mg) was used as a starting material, and subjected to the same reaction treatment to give 813 mg (8
9%) as a colorless oil.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.88 (3H, t, J = 6.6Hz), 1.22-1.30 (17H, m), 1.43
(9H, s), 1.67 (1H, m), 2.04 (3H, s), 2.09 (3H, s), 2.33 (1H, d
d, J = 3.3,16.0Hz), 2.56 (1H, m), 2.65 (1H, dd, J = 9.4,16.0H
z), 4.07 (2H, m), 4.35 (1H, m), 5.12 (1H, m), 5.99 (1H, d, J = 9.
3Hz). Infrared absorption spectrum (Liquid film, cm ^-1 ): 3440,2930,
2857,1737,1677. Mass spectrum (FAB): m / z [M + H] ⁺ = 472 42-c) 3- (R)-[2- (S) -acetoxy-
1- (S) -acetoxymethylpropylcarbamoyl]
Dodecanoic acid According to the method of Example 8-d), 3- (R)-[2- (S) -acetoxy-1- obtained in Example 42-b).
(S) -acetoxymethylpropylcarbamoyl] dodecanoic acid t-butyl ester (813 mg) was used as a starting material and subjected to the same reaction treatment to obtain 716 mg of the desired compound (1
00%) as a colorless oil.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.88 (3H, t, J = 6.6Hz), 1.22 (1H, d, J = 6.4Hz), 1.2
4-1.37 (14H, m), 1.47 (1H, m), 1.63 (1H, m), 2.05 (3H, s), 2.0
7 (3H, s), 2.48 (1H, m), 2.58 (1H, m), 2.80 (1H, m), 4.08 (2H, m
m), 4.35 (1H, m), 5.12 (1H, m), 5.99 (1H, d, J = 8.8Hz). Infrared absorption spectrum (Liquid film, cm ^-1 ): 3439,2930,
1737,1679,1511. Mass spectrum (FAB): m / z [M + H] ⁺ = 416 42-d) Acetic acid 3-acetoxy-1- (S) -methyl
2- (S)-[2- (R)-(N-benzylcarba
Moirumechiru) undecanoylamino amino] propyl ester
Obtained in Le Example 42-c) 3- (R) - [2- (S)
-Acetoxy-1- (S) -acetoxymethylpropylcarbamoyl] dodecanoic acid (573 mg) in methylene chloride (15 ml) was dissolved at room temperature in O-benzylhydroxylamine hydrochloride (396 mg) and 1- (3-dimethylamino). Propyl) -3-ethylcarbodiimide hydrochloride (529 mg), 1-hydroxybenzotriazole (280 mg), N-methylmorpholine (0.27 m
l) was added and stirred overnight. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate and extracted with methylene chloride. The organic layer was washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain 537 mg (75%) of the desired compound as a foam.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.88 (3H, t, J = 6.8Hz), 1.23 (3H, d, J = 6.7Hz), 1.2
4-1.30 (14H, m), 1.42 (1H, m), 1.60 (1H, m), 2.04 (3H, s), 2.0
8 (3H, s), 2.22 (1H, m), 2.36 (1H, m), 2.69 (1H, m), 4.05 (2H,
m), 4.31 (1H, m), 4.86 (2H, s), 5.09 (1H, m), 6.00 (1H, d, J = 8.
6-Hz), 7.37 (5H, m), 8.41 (1H, brs). 42-e) Acetic acid 3-acetoxy-2- (S)-[2
-(R)-(N-hydroxycarbamoylmethyl) un
-Decanoylamino] -1- (S) - Mechirupuropi Ruesu
According to the method of example 10-d), 3-acetoxy-1- (S) -methyl-2 acetate obtained in example 42-d).
-(S)-[2- (R)-(N-benzylcarbamoylmethyl) undecanoylamino] propyl ester (6
475 mg (82%) of the target compound was obtained as a white solid by the same reaction treatment using 97 mg) as a starting material.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl
₃ ) δppm: 0.88 (3H, t, J = 6.7Hz), 1.21 (3H, d, J = 6.5Hz), 1.2
3-1.32 (14H, m), 1.43 (1H, m), 1.63 (1H, m), 1.77 (1H, m), 2.0
5 (3H, s), 2.08 (3H, s), 2.31 (1H, dd, J = 4.3,14.4Hz), 2.51 (1
H, m), 2.73 (1H, m), 4.02 (1H, dd, J = 6.9,11.2Hz), 4.10 (1H, d
d, J = 5.8,11.2Hz), 4.3 (1H, m), 5.09 (1H, m), 6.19 (1H, d, J =
9.8Hz), 7.86 (1H, brs), 9.57 (1H, brs). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3291,2923,1
737,1649,1553. Mass spectrum (FAB): m / z [M + H] ⁺ = 431 High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 431.2728 Calculated value: 431.2757 (C ₂₁ H ₃₉ O ₇ N ₂ ) Specific rotation: [α] _D ²⁵ = + 5.64 (C: 0.815, CHCl ₃ ) (Example 43) N ⁴ -hydroxy-N ^1- [2- (S)
-Hydroxy-1- (S) -hydroxymethyl propyl
3) -2- (R) -Nonylsuccinamide (Exemplified Compound No. 310) 3-acetoxyacetic acid obtained in Example 42-e)
2- (S)-[2- (R)-(N-hydroxycarbamoylmethyl) undecanoylamino] -1- (S) -methylpropyl ester (315 mg) in methanol (5
potassium carbonate (305 mg) was added to the solution, and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel preparative thin-layer chromatography (20 cm × 20 cm 1 mm thick, 3 sheets, developing solvent: methylene chloride: methanol = 10: 1) to obtain 94 mg of the desired compound (37 mg). %) As a white solid.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 0.89 (3H, t, J = 6.3Hz), 1.15 (3H, d, J = 6.3Hz), 1.2
2-1.36 (14H, m), 1.43 (1H, m), 1.59 (1H, m), 2.19 (1H, dd, J =
6.5,14.5Hz), 2.37 (1H, dd, J = 8.1,14.5Hz), 2.73 (1H, m), 3.
56 (1H, m), 3.62 (1H, m), 3.80 (1H, m), 3.99 (1H, m). Infrared absorption spectrum (Liquid film, cm ^-1 ): 3293,2926,
1650, 1548. Mass spectrum (FAB): m / z [M + H] ⁺ = 347 Specific rotation: [α] _D ²⁵ = + 2.46 (C: 0.61, CHCl ₃ ) (Example 44) Morpholine-4- Il-acetic acid 2- (S)
-｛2- (R)-[(S) -hydroxy (hydroxyca
Rubamoyl) methyl] undecanoylamino} -3,3
-Dimethylbutyl ester (Exemplified Compound No. 311) 44-a) Morpholin-4-yl-acetic acid 2- (S)-
{2- (R)-[2,2-dimethyl-5-oxo-
[1,3] - dioxolan-4-(S) - yl] undecane
[Canoylamino] -3,3-dimethylbutyl ester 2- (4-morpholinyl) acetic acid (300 mg) was dissolved in methylene chloride (6 ml), and DMF (30 μm) was added under ice-cooling.
l) and oxalyl chloride (0.22 ml)
The mixture was stirred for 1 hour under a nitrogen atmosphere. After the reaction solution was distilled off under reduced pressure, the 2- (R)-[2,2) obtained in Example 10-a) was obtained.
-Dimethyl-5-oxo- [1,3] -dioxolane-
4- (S) -yl] undecanoic acid [1- (S) -hydroxymethyl-2,2-dimethylpropyl] amide (30
0 mg) THF (10 ml), pyridine (80 μl)
, And the mixture was stirred at −20 ° C. for 3 hours under a nitrogen atmosphere. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 2) to obtain 257 mg (65%) of the desired compound as a white solid.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.88 (3H, t, J = 6.6Hz), 0.97 (9H, s), 1.24-1.30 (1
4H, m), 1.55 (3H, s), 1.62 (3H, s), 1.70-1.83 (2H, m), 2.52-
2.63 (5H, m), 3.18 (2H, s), 3.74 (4H, t, J = 4.6Hz), 3.97-4.14
(2H, m), 4.48 (1H, m), 4.55 (1H, d, J = 5.3Hz), 6.17 (1H, d, J =
9.9Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3340,1789,1
752,1658,1551. Mass spectrum (FAB): m / z [M + H] ⁺ = 527 44-b) Morpholin-4-yl-acetic acid 2- (S)-
{2- (R)-[(S) -benzyloxycarbamoyl
(Hydroxy) methyl] undecanoylamino} -3
3-Dimethylbutyl ester Morpholin-4-yl-acetic acid 2- (S)-{2-} obtained in Example 44-a) according to the method of Example 10-c).
(R)-[2,2-dimethyl-5-oxo- [1,3]
-Dioxolan-4- (S) -yl] undecanoylamino} -3,3-dimethylbutyl ester (67 mg)
Starting compound is used as a starting material,
mg (53%) was obtained as a white solid.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.88 (3H, t, J = 6.6Hz), 0.95 (9H, s), 1.19-1.30 (1
4H, m), 1.56-1.82 (2H, m), 2.49-2.63 (4H, m), 2.89 (1H, m),
3.15 (2H, s), 3.73 (4H, t, J = 4.6Hz), 3.95-4.16 (3H, m), 4.35
(1H, m), 4.81 (1H, d, J = 11.4Hz), 4.87 (1H, d, J = 11.4Hz), 5.2
7 (1H, m), 6.21 (1H, d, J = 8.8Hz), 7.32-7.43 (5H, m), 9.40 (1
H, brs). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3308,3207,2
926,2856,1751,1647. Mass spectrum (FAB): m / z [M + H] ⁺ = 592 44-c) Morpholin-4-yl-acetic acid 2- (S)-
{2- (R)-[(S) -hydroxy (hydroxycal
Bamoiru) methyl] undecanoylamino amino} -3, 3-
Dimethylbutyl ester Morpholin-4-yl-acetic acid 2- (S)-{2-} obtained in Example 44-b) according to the method of Example 10-d).
Starting from (R)-[(S) -benzyloxycarbamoyl (hydroxy) methyl] undecanoylamino} -3,3-dimethylbutyl ester (120 mg), 69 mg (68%) of the target compound was obtained by the same reaction treatment. Obtained as a white solid.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 0.89 (3H, t, J = 6.8Hz), 0.97 (9H, s), 1.25-1.42 (1
4H, m), 1.47 (1H, m), 1.66 (1H, m), 2.57 (4H, t, J = 3.9Hz), 2.7
1 (1H, m), 3.15 (1H, d, J = 6.7Hz), 3.23 (1H, d, J = 6.7Hz), 3.71
(4H, t, J = 3.9Hz), 3.92-4.08 (3H, m), 4.50 (1H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3294,2926,2
856, 1746, 1649, 1542. Mass spectrum (FAB): m / z [M + H] ⁺ = 502 Specific rotation: [α] _D ²⁵ = -13.33 (C: 0.48, CHCl ₃ ) (Example 45) Acetic acid 2- (S)-{6-butoxy-2
-(R)-[(S) -hydroxy (hydroxycarbamo)
Yl) methyl] hexanoylamino} -3,3-dimethyl
Rubutyl ester (Exemplified Compound No. 146) 45-a) 6-butoxy-2- (R)-[2,2-di
Methyl-5-oxo- [1,3] -dioxolan-4-
(S) - yl] hexane acid [1- (S) - hydro Kishime
Tyl-2,2-dimethylpropyl] amide 6-butoxy-2- according to the method of Example 15-a).
(R)-(2,2-dimethyl-5-oxo- [1,3]
-Dioxolan-4-yl) hexanoic acid (1.5 g) and (S) -t-leucinol (0.7 g) were used as starting materials, and 1.53 g (7
6%) as a white solid.

[0418]¹H-nuclear magnetic resonance spectrum (270 MHz, CDCl
_Three) Δppm: 0.91 (3H, t, J = 7.3Hz), 0.97 (9H, s), 1.26-1.89 (1
6H, m), 2.62-2.72 (2H, m), 3.33-3.46 (4H, m), 3.57 (1H, m),
3.80-3.89 (2H, m), 4.60 (1H, d, J = 5.9Hz), 6.17 (1H, m). Infrared absorption spectrum (CHCl_Three solution, cm^-1): 3439,29
64,2939,2871,1783,1669,1602. Mass spectrum (Fab): [M + H]⁺= 402 Melting point: 70-72 ° C 45-b)Acetic acid 2- (S)-{6-butoxy-
[2,2-dimethyl-5-oxo- [1,3] -dioxo
Solan-4- (S) -yl] hexanoylamino}-
3,3-dimethylbutyl ester According to the method of Example 10-b), obtained in Example 45-a).
6-butoxy-2- (R)-[2,2-dimethyl
-5-oxo- [1,3] -dioxolan-4- (S)
-Yl] hexanoic acid [1- (S) -hydroxymethyl-
2,2-dimethylpropyl] amide (1.5 g)
910 mg (55%) of the target compound were obtained as a white solid.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.91 (3H, t, J = 7.3Hz), 0.96 (9H, s), 1.26-1.61 (1
4H, m), 1.76-1.86 (2H, m), 2.04 (3H, s), 2.59 (1H, m), 3.32-
3.42 (4H, m), 4.01-4.03 (2H, m), 4.24 (1H, m), 4.52 (1H, d, J =
5.8Hz), 6.03 (1H, m). Infrared absorption spectrum (CHCl ₃ solution, cm ^-1 ): 2964,29
39,2870,1785,1736,1682,1602. Mass spectrum (Fab): [M + H] ⁺ = 444 Melting point: 68-69 ° C 45-c) Acetic acid 2- (S)-｛2- (R)-
[(S) -benzyloxycarbamoyl (hydroxy)
Methyl] -6-butoxy-hexanoylamino} -3,
3-dimethylbutyl ester Acetic acid 2- (S)-{6-butoxy- [2,2-) obtained in Example 45-b) according to the method of Example 10-c).
Dimethyl-5-oxo- [1,3] -dioxolan-4
-(S) -yl] hexanoylamino} -3,3-dimethylbutyl ester (900 mg) to give the desired compound 93
5 mg (88%) were obtained as a glass.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.92 (3H, t, J = 7.4Hz), 0.96 (9H, s), 1.20-1.88 (1
0H, m), 2.03 (3H, s), 2.92 (1H, m), 3.34-3.41 (4H, m), 3.97-
4.28 (4H, m), 4.82 (1H, d, J = 11.2Hz), 4.89 (1H, d, J = 11.2H
z), 5.17 (1H, d, J = 8.6Hz), 5.90 (1H, m), 7.38 (5H, s), 9.31 (1
H, s). Infrared absorption spectrum (CHCl ₃ solution, cm ^-1 ): 3430,34
02,2964,2938,2869,1738,1687,1648,1603,1530. Mass spectrum (Fab): [M + H] ⁺ = 509 45-d) Acetic acid 2- (S)-｛6-butoxy-2-
(R)-[(S) -hydroxy (hydroxycarbamoy
) Methyl] hexanoyl amino} -3,3-di methyl
Butyl ester 2- (S)-{2- (R)-[(S) -benzyloxycarbamoyl (hydroxy) methyl] -acetic acid obtained in Example 45-c) according to the method of Example 10-d). 6
-Butoxyhexanoylamino} -3,3-dimethylbutyl ester (930 mg) from 450 mg of the desired compound
(60%) as a foam.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.89-0.96 (12H, m), 1.26-1.97 (10H, m), 2.03 (3
H, s), 2.94 (1H, m), 3.35-3.43 (4H, m), 3.97-4.10 (2H, m), 4.
18-4.26 (2H, m), 5.24 (1H, d, J = 8.2Hz), 6.20 (1H, m), 7.32 (1
H, m), 9.45 (1H, s). Infrared absorption spectrum (CHCl ₃ solution, cm ^-1 ): 3432,32
96, 2964, 2937, 2869, 1737, 1656, 1603, 1530. Mass spectrum (Fab): [M + H] ⁺ = 419 (Example 46) 2- (R)-(4-butoxybutyl)-
3 (S), N ⁴ - dihydroxy -N ¹ - (1-hydroxy
Cimethyl-2,2-dimethylpropyl) succinylami
De according to the method of (Compound No. 145) Example 9, acetate obtained in Example 45-d) 2- (S) - {6- butoxy-2-(R) -
From [(S) -hydroxy (hydroxycarbamoyl) methyl] hexanoylamino} -3,3-dimethylbutyl ester (150 mg), 15 mg of the target compound (11 mg)
%) As a foam.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl
₃ ) δppm: 0.80-1.00 (12H, m), 1.20-1.95 (10H, m), 2.71 (1
H, m), 3.30-3.50 (4H, m), 3.54 (1H, m), 3.70-3.95 (2H, m), 4.
29 (1H, m), 6.95 (1H, m). Infrared absorption spectrum (CHCl ₃ solution, cm ^-1 ): 3429,33
10,2963,2937,2869,1652,1603,1541. Mass spectrum (Fab): [M + H] ⁺ = 377 (Example 47) Acetic acid 2- (S)-[2- (R)-(N
-Hydroxycarbamoylmethyl) -5- (4-methoxy
Ciphenyl) pentanoylamino] -3,3-dimethyl
Butyl ester (Exemplified Compound No. 25) 47-a) 3- (R)-[1- (S) -hydroxyme
Tyl-2,2-dimethylpropylcarbamoyl] -6
T-(4-methoxyphenyl) hexanoic acid butyl Ruesu
According to the method of Tell Example 15-a), 2- (R) -tert-butoxycarbonyl-5- (4-methoxyphenyl) pentanoic acid (1.60 g) and (S) -tert-leucinol (0.7 g) Was used as a starting material, and 1.47 g (70%) of the target compound was obtained as a white solid by the same reaction treatment.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.94 (9H, s), 1.41 (9H, s), 1.55-1.75 (4H, m), 2.3
4-2.42 (2H, m), 2.52-2.62 (4H, m), 3.53 (1H, m), 3.78 (3H,
s), 3.80-3.86 (2H, m), 6.01 (1H, d, J = 8.8Hz), 6.81 (2H, d, J =
8.5Hz), 7.07 (2H, d, J = 8.5Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3364,2968,2
950, 1703, 1652, 1610, 1583. Mass spectrum (Fab): [M + H] ⁺ = 422 47-b) 3- (R)-[1- (S) -acetoxime
Tyl-2,2-dimethylpropylcarbamoyl] -6
T-(4-methoxyphenyl) hexanoic acid butyl Ruesu
According to the method of Example 10-b), 3- (R)-[1- (S) -hydroxymethyl- obtained in Example 47-a).
2,2-dimethylpropylcarbamoyl] -6- (4-
1.34 g (96%) of the target compound was obtained as a white solid from t-butyl (methoxyphenyl) hexanoate (1.26 g).

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.93 (9H, s), 1.41 (9H, s), 1.45-1.81 (4H, m), 1.8
4 (3H, s), 2.27-2.68 (5H, m), 3.77 (3H, s), 4.03-4.21 (3H,
m), 5.83 (1H, d, J = 9.2Hz), 6.80 (2H, d, J = 8.5Hz), 7.06 (2H,
d, J = 8.5Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3315,2967,2
937,2867,1735,1666,1647,1612,1582,1559. Mass spectrum (Fab): [M + H] ⁺ = 464 47-c) 3- (R)-[1- (S) -acetoxime
Tyl-2,2-dimethylpropylcarbamoyl] -6
(4-Methoxyphenyl) hexanoic acid According to the method of Example 8-d), 3- (R)-[1- (S) -acetoxymethyl- obtained in Example 47-b).
2,2-dimethylpropylcarbamoyl] -6- (4-
From methoxyphenyl) hexanoic acid t-butyl ester (1.24 g), 1.1 g of the desired compound (quan)
t. ) Was obtained as an oil.

Mass spectrum (Fab): [M + H] ⁺ = 408 47-d) Acetic acid 2- (S)-[2- (R)-(N-
Hydroxycarbamoylmethyl) -5- (4-methoxy
Phenyl) pentanoylamino] -3,3-dimethyl Chirubu
Cyl ester According to the method of Example 8-e), 3- (R)-[1- (S) -acetoxymethyl- obtained in Example 47-c).
2,2-dimethylpropylcarbamoyl] -6- (4-
From methoxyphenyl) hexanoic acid (1.1 g), 598 mg (52%) of the target compound was obtained as a foam.

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl
₃ ) δppm: 0.90 (9H, s), 1.42-1.74 (5H, m), 1.82 (3H, s), 2.2
8 (1H, dd, J = 14.5,4.3Hz), 2.49 (1H, dd, J = 14.5,10.3Hz), 2.
53-2.59 (2H, m), 2.73 (1H, m), 3.77 (3H, s), 3.98-4.07 (2H, m
m), 4.21 (1H, m), 5.92 (1H, d, J = 8.5Hz), 6.80 (2H, d, J = 8.5H
z), 7.05 (2H, d , J = 8.5Hz), 9.58 (1H, s) ( Example 48) N ⁴ -. hydroxy -N ¹ - [1- (S)
-Hydroxymethyl-2,2-dimethylpropyl] -2
-(R)-[3- (4-methoxyphenyl) propyl]
Succinamide (Exemplified Compound No. 24) 2- (S)-[2- (R)-(N-hydroxycarbamoylmethyl) -5- (4) -acetic acid obtained in Example 47-d) according to the method of Example 9. -Methoxyphenyl) pentanoylamino] -3,3-dimethylbutyl ester (320 mg) gave 154 mg (53%) of the desired compound as a white solid.

[0427]¹H-nuclear magnetic resonance spectrum (400MHz, CD_ThreeO
D) δppm: 0.92 (9H, s), 1.40-1.72 (4H, m), 2.17 (1H, dd, J = 1
4.6,6.6Hz), 2.33 (1H, dd, J = 14.6,7.8Hz), 2.48-2.60 (2H,
m), 2.80 (1H, m), 3.44 (1H, dd, J = 12.1,9.7Hz), 3.74 (3H, s),
3.75-3.79 (2H, m), 6.79 (2H, d, J = 8.5Hz), 7.07 (2H, d, J = 8.5
Hz). Infrared absorption spectrum (KBr pellet, cm^-1): 3297,3217,2
963,1645,1545,1513. Mass spectrum (Fab): [M + H]⁺= 381 Melting point: 159-160 ° C (Example 49) ^{N 4 - (2- (R)} , 5- dihydroxy
-1- (S) isopropylpentyl) -2- (S), N
¹ -dihydroxy-3- (R) -nonylsuccinamide
(Exemplified Compound No. 177) 49-a)(1- (S) -isopropyl-2-oxo
Pent-4-enyl) carbamic acid benzyl ester [1- (S)-(methoxy (methyl) carbamoyl)-
2-Methylpropyl] carbamic acid benzyl ester
(3.0 g) in tetrahydrofuran (100 ml)
At −78 ° C., 1.0 M allylmagnesium bromide TH
Add F solution (30.6 ml) and stir at 0 ° C. for 2 hours.
Was. Water was added to the reaction solution, extracted with ethyl acetate, and saturated.
Wash with brine, dry over anhydrous sodium sulfate and evaporate the solvent.
Removed. The residue was purified by silica gel flash column chromatography.
Purified by chromatography (ethyl acetate: hexane = 1: 5)
To give the target compound (2.0 g, 72%) as a colorless oil.
I got it.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.89 (d, J = 6.6Hz, 3H), 1.08 (d, J = 6.6Hz, 3H), 1.6
4-1.66 (m, 1H), 3.32-3.34 (m, 2H), 4.45-4.50 (m, 1H), 5.12-
5.29 (m, 4H), 5.41-5.44 (m, 1H), 6.05-5.86 (m, 1H), 7.37-7.
52 (m, 5H). Mass spectrum (FAB): m / z [M + H] ⁺ = 276 49-b) (2- (R), 5-dihydroxy-1-
(S) -isopropylpentyl) benzyl carbamate
Ester (1- (S) -isopropyl-2-oxopent-4-
In a tetrahydrofuran (50 ml) solution of enyl) carbamic acid benzyl ester (2.0 g) at 0 ° C., 1.
A tetrahydrofuran solution of a 0 M borane-tetrahydrofuran complex (21.9 ml) was slowly added, and the mixture was stirred at room temperature for 3 hours. After the temperature of the reaction solution was returned to 0 ° C., a 1N aqueous solution of sodium hydroxide (50 ml) and a 30% aqueous hydrogen peroxide solution (5.0 ml) were added, and the mixture was stirred for 1 hour. Water was added to this reaction solution, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by silica gel flash column chromatography (ethyl acetate: hexane = 1: 2) to give the desired compound (1.15 g, 53%) as a colorless oil.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.97 (d, J = 6.8Hz, 1H), 1.02 (d, J = 6.8Hz, 1H), 1.4
0-2.10 (m, 5H), 3.43-3.90 (m, 5H), 4.84-4.87 (m, 1H), 5.11-
5.23 (m, 3H), 7.34 to 7.46 (m, 5H). Mass spectrum (FAB): m / z [M + H] ⁺ = 296 49-c) [5- (t-butyldimethylsilyloxy )
Shi) -2- (R) - hydro carboxymethyl -1- (S) - isoproterenol
Pyrpentyl] carbamic acid benzyl ester (2- (R), 5-dihydroxy-1- (S) -isopropylpentyl ) carbamic acid benzyl ester (1.
From 15 g), the target compound (1.21 g, 76%) was obtained as a colorless oily substance in the same manner as in Example 3-b).

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.10 (s, 6H), 0.87-0.92 (m, 15H), 1.37-1.52 (m, 1
H), 1.59-1.87 (m, 4H), 3.30-3.33 (m, 1H), 3.47-3.82 (m, 4
H), 4.67-4.74 (m, 1H), 5.11 (s, 2H), 7.29-7.36 (m, 5H). Mass spectrum (FAB): m / z [M + H] ⁺ = 410 49-d) 2 -(R)-[2,2-dimethyl-5-o
Oxo- [1,3] -dioxolan-4- (S) -yl]
Undecanoic acid [5-(t-butyldimethylsilyl Oki
B) -2- (R) -hydroxy-1- (S) -isopro
Pyrpentyl] amide [5- (t-butyldimethylsilyloxy) -2-
(R) -Hydroxy-1- (S) -isopropylpentyl] carbamic acid benzyl ester (1.21 g) was converted to the target compound (1.25 g, 78%) as a white solid in the same manner as in Example 2-a). As obtained.

The ¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 270 MH
z) δppm: 0.07 (s, 6H), 0.78-0.99 (m, 18H), 1.32-1.46 (m, 1
4H), 1.54 (s, 3H), 1.62 (s, 3H), 1.62-1.73 (m, 7H), 2.51-2.6
1 (m, 1H), 3.59-3.89 (m, 4H), 4.53 (d, J = 6.1Hz, 1H), 5.94 (d,
. J = 4.5Hz, 1H) Mass spectrum (FAB): m / z [ M + H] + = 558 49-e) N 1 - benzyloxy -N ⁴ - [2-
(R), 5-dihydroxy-1- (S) -isopropyl
Pentyl] -2- (S) -hydroxy-3- (R) -no
Nilsuccinamide 2- (R)-[2,2-dimethyl-5-oxo- [1,
3] -Dioxolan-4- (S) -yl] undecanoic acid [5- (t-butyldimethylsilyloxy) -2-
From (R) -hydroxy-1- (S) -isopropylpentyl] amide (1.25 g), the target compound (188 mg, 16%) was obtained as a white solid in the same manner as in Example 2-b).

¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 270 MH
z) δppm: 0.77-0.96 (m, 9H), 1.19-1.42 (m, 14H), 1.62-2.1
1 (m, 7H), 2.53-2.64 (m, 1H), 3.57-3.79 (m, 4H), 4.73-4.89
(m, 5H), 6.09 (d, J = 1.3Hz, 1H), 7.32-7.48 (m, 5H), 8.07 (bs,
. IH) Mass spectrum (FAB): m / z [ M + H] + = 508 49-f) N 4 - [2- (R), 5- dihydroxy -
1- (S) -isopropylpentyl] -2- (S), N
¹ - dihydroxy-3-(R) - nonyl disk Sina bromide N ¹ - benzyloxy ^{-N 4 - [2- (R)} , 5- dihydroxy-1-(S) - isopropyl pentyl] -2-
From (S) -hydroxy-3- (R) -nonylsuccinamide (188 mg), the target compound (117 mg, 76%) was obtained as a white solid in the same manner as in Example 2-c).

¹ H-nuclear magnetic resonance spectrum (CDCl ₃ , 400 MH
z) δppm: 0.86-0.94 (m, 9H), 1.25-1.47 (m, 17H), 1.53-1.8
0 (m, 4H), 2.09-2.17 (m, 1H), 2.63-2.72 (m, 1H), 3.49-3.58
(m, 3H), 3.72-3.79 (m, 1H), 4.02 (d, J = 2.8Hz, 1H). Mass spectrum (FAB): m / z [M + H] ⁺ = 419 (Example 50) Acetic acid 3-cyclohexyl-2- (S)
-｛2- (R)-[(S) -hydroxy (hydroxyca
Rubamoyl) methyl] -undecanoylamino} -pro
Pill ester (Exemplary Compound No. 114) 50-a) 2- (R)-(2,2-dimethyl-5-o)
Oxo- [1,3] -dioxolan-4- (S) -yl)
Undecanoic acid [1- (S) - cyclohexyl methylation -2
-Hydroxyethyl] amide 2- (R)-[2,2-dimethyl-5-oxo- [1,3] -dioxolan-4- according to the method of Example 8-b).
(S) -yl] undecanoic acid (1.08 g) and cyclohexylalaninol (0.622 g) were used as starting materials, and 707 mg (4
4.7%) as a white solid.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.81-1.87 (29H, m), 0.88 (3H, t, J = 6.6Hz), 1.55
(3H, s), 1.63 (3H, s), 2.60 (1H, m), 3.52 (1H, dd, J = 11.1,6.1
Hz), 3.68 (1H, dd, 11.1, 3.4Hz), 4.09 (1H, m), 4.56 (1H, d, J =
5.3Hz), 5.98 (1H, d, J = 7.7Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3247,1799,1
646,1571. High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 440.3381 Calculated: 440.3369 (C ₂₅ H ₄₆ O ₅ N) 50-b) 3-Cyclohexyl-2- (S) acetate −
[2- (R)-(2,2-dimethyl-5-oxo-
[1,3] - dioxolan-4-(S) - yl) undecane
Canoylamino] propyl ester 2- (R)-(2,2-dimethyl-5-oxo- [1,3] -dioxolane ) obtained in Example 50-a) according to the method of Example 10-b). 682 mg (qua) of 4- (S) -yl) undecanoic acid [1- (S) -cyclohexylmethyl-2-hydroxyethyl] amide (632 mg) as a starting material by the same reaction treatment.
nt) was obtained as a colorless solid.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.76-1.87 (29H, m), 0.88 (3H, t, J = 6.6Hz), 1.55
(3H, s), 1.62 (3H, s), 2.06 (3H, s), 2.53 (1H, m), 3.99 (1H, d
d, J = 11.2,5.4Hz), 4.11 (1H, dd, 11.2,4.1Hz), 4.33 (1H, m),
4.52 (1H, d, J = 5.4Hz), 5.91 (1H, d, J = 8.9Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 1787,1741,1
653,1533. High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 482.3481 Calculated: 482.3483 (C ₂₇ H ₄₈ O ₆ N) 50-c) Acetic acid 2- (S)-｛2- (R)-
[(S) -benzyloxycarbamoyl (hydroxy)
Methyl] undecanoylamino} -3-cyclohexyl
Propyl ester According to the method of Example 10-c), 3-cyclohexyl acetate-2- (S)-[2) obtained in Example 50-b).
-(R)-(2,2-dimethyl-5-oxo- [1,
3] -Dioxolan-4- (S) -yl) undecanoylamino] propyl ester (658 mg) was used as a starting material and subjected to the same reaction treatment to obtain 308 mg (4
1.2%) as a colorless oil. However, purification at this time was performed by silica gel column chromatography (hexane: ethyl acetate = 2: 1). ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.7
0-1.89 (29H, m), 0.80 (3H, t, J = 6.6Hz), 2.05 (3H, s), 2.80 (1
H, m), 3.99 (1H, dd, J = 11.4,6.1Hz), 4.07 (1H, dd, 11.4,3.8H
z), 4.14 (1H, dd, J = 8.4,2.2Hz), 4.27 (1H, m), 4.89 (2H, s),
5.14 (1H, d, J = 8.4Hz), 5.96 (1H, d, J = 8.9Hz), 7.31-7.46 (5
H, m), 9.41 (1H, s). Infrared absorption spectrum (liquid film, cm ^-1 ): 3288,1746,
1645,1553. 50-d) 3-cyclohexyl-2- (S) -acetic acid
{2- (R)-[(S) -hydroxy (hydroxycal
Bamoiru) methyl] undecanoylamino amino} pro Pirue
Stell Acetic acid 2- (S)-{2- (R)-[(S)-] obtained in Example 50-c) according to the method of Example 10-d).
By the same reaction treatment using benzyloxycarbamoyl (hydroxy) methyl] undecanoylamino] -3-cyclohexylpropyl ester (308 mg) as a starting material, 219 mg (85.2%) of the target compound was obtained as a white solid. However, the purification at this time was carried out by thin-layer preparative chromatography (20 × 20 cm, 0.5 mm thick, 5 sheets, developed with chloroform: methanol = 40: 3, eluted with ethyl acetate: methanol = 10: 1).

Nuclear magnetic resonance spectrum (270 MHz, CD ₃ OD) δ
ppm: 0.73-1.88 (29H, m), 0.88 (3H, t, J = 6.6Hz), 2.03 (3H, m
s), 2.59 (1H, m), 3.87 (1H, dd, J = 10.1,6.9Hz), 4.00 (1H, d, J
= 7.4Hz), 4.13 (1H, dd, J = 11.0,4.3Hz), 4.26 (1H, m) 1 H- Infrared absorption spectrum ^{(KBr pellet, cm -1):} . 3370,3
294,3208,3099,1747,1668,1643,1580. High resolution mass spectrum (FAB): m / z [M + H] ⁺ = 457.3246 Calculated value: 457.3315 (C ₂₄ H ₄₅ O ₆ N ₂ ) Specific rotation ^{_{: [α] D 25 = -12}} ° (C: 0.59, EtOH) ( example ^{51) N 4 - [1- (} S) - cyclohexyl main
Tyl-2-hydroxyethyl] -2- (S), N ¹ -di
Hydroxy-3- (R) -nonylsuccinamide (Exemplified Compound No. 113) According to the method of Example 11), 3-cyclohexyl acetate-2- (S)-{2-} 2-acetate obtained in Example 50-d).
By the same reaction treatment using (R)-[(S) -hydroxy (hydroxycarbamoyl) methyl] undecanoylamino} propyl ester (110 mg) as a starting material, 86 mg (86%) of the target compound was obtained as a white solid. However, the purification at this time was performed by thin-layer preparative chromatography (20 × 20 cm, 0.5 mm thick, silica gel plate 4).
And developed with chloroform: methanol = 7: 1 and eluted with ethyl acetate: methanol = 10: 1).

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CD
₃ OD) δppm: 0.72-1.90 (29H, m), 0.89 (3H, t, J = 6.6Hz), 2.5
9 (1H, m), 3.39-3.53 (2H, m), 4.01 (1H, m), 4.03 (1H, d, J = 6.7
Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3412,3371,3
261,3112,1672,1606. High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 415.3173 Calculated value: 415.3171 (C ₂₂ H ₄₃ O ₅ N ₂ ) Specific rotation: [α] _D ²⁵ = -22.1 ° (C: 1.03, EtOH) (Example 52) Acetic acid 2- (S)-｛2- (R)-
[(S) -hydroxy (hydroxycarbamoyl) methyl
Ru] undecanoylamino} -3-methylbutyl ester
Le (Compound No. 112) 52-a) 2- ( R) - (2,2- dimethyl-5- O
Oxo- [1,3] -dioxolan-4- (S) -yl)
Undecanoic acid [1- (S) - (tert- butyl-dimethylcarbamoyl
Rusilanyloxymethyl) -2-methylpropyl] ami
De 2- (R)-(2,2-dimethyl-5-oxo- [1,
3] -Dioxolan-4- (S) -yl) undecanoic acid (1.00 g) in tetrahydrofuran (15 ml) was treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (760 mg), 1-hydroxy Benzotriazole (450 mg), N-methylmorpholine (440 μl), 1- (S)-(t-butyldimethylsilanyloxymethyl) -2-methylpropylamine (866 mg) of N, N′-dimethylformamide (1
5 ml) solution was added in sequence and stirred overnight at room temperature under a nitrogen atmosphere. Pour the reaction solution into a 5% aqueous solution of potassium hydrogen sulfate,
The organic layer extracted and collected with ethyl acetate was washed successively with saturated sodium hydrogen carbonate, water and saturated saline, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1).
To give 1.18 g (71.0%) of the desired compound as a white solid. At this time, 324 mg of a diastereomer of the target compound was obtained.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.04 (3H, s), 0.05 (3H, s), 0.77-0.97 (9H, m), 0.9
0 (9H, s), 1.08-1.45 (14H, m), 1.53 (3H, s), 1.60 (3H, s), 1.6
7-1.97 (3H, m), 2.50 (1H, m), 3.55 (1H, dd, J = 10.8,4.5Hz),
3.68-3.82 (2H, m), 4.51 (1H, d, J = 6.4Hz), 5.98 (1H, d, J = 9.0
Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3306,1792,1
666,1645,1555. High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 500.3772 Calculated value: 500.3771 (C ₂₇ H ₅₄ O ₅ NSi) 52-b) 2- (R) − [2 , 2-dimethyl-5-o
Oxo- [1,3] -dioxolan-4- (S) -yl]
Undecanoic acid [1- (S) -hydroxymethyl- 2-meth
2- (R)-(2,2-Dimethyl-5-oxo- [1,3] -dioxolan-4- ) obtained in Example 52-a)
(S) -yl) undecanoic acid [1- (S)-(t-butyldimethylsilanyloxymethyl) -2-methylpropyl] amide (869 mg) was dissolved in acetone-water (= 18 ml).
After stirring at room temperature for 2 hours, the reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The collected organic layer was washed with water and saturated saline, and dried with sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane:
Purification by ethyl acetate = 1: 1) yielded the title compound 507
mg (75.7%) was obtained as a white solid.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.88 (3H, t, J = 6.7Hz), 0.95 (3H, d, J = 6.5Hz), 0.9
7 (1H, d, J = 6.5Hz), 1.10-1.45 (14H, m), 1.55 (3H, s), 1.62 (3
H, s), 1.65-1.98 (3H, m), 2.53 (1H, m), 2.64 (1H, m), 3.58-3.
83 (3H, m), 4.57 (1H, d, J = 5.3Hz), 6.11 (1H, d, J = 8.0Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3253,1798,1
647,1571. High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 386.2907 Calculated value: 386.2905 (C ₂₁ H ₄₀ O ₅ N) 52-c) Acetic acid 2- (S)-[2- (R)-[2,
2-dimethyl-5-oxo- [1,3] -dioxolane
-4- (S) -yl) undecanoylamino] -3-
According to the method of the chill-butyl ester le Example 10-b), obtained in Example 52-b) 2- (R) - [2,2- dimethyl-5-oxo -
[1,3] -Dioxolan-4- (S) -yl] undecanoic acid [1- (S) -hydroxymethyl-2-methylpropyl] amide (447 mg) was subjected to the same reaction treatment as a starting material to give the target compound 583 mg (Yield: 100
%) As a white solid. However, at this time, silica gel column chromatography (hexane: ethyl acetate = 3:
Purification was performed in 1).

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.88 (3H, t, J = 6.6Hz), 0.94 (3H, d, J = 6.7Hz), 0.9
6 (3H, d, J = 6.7Hz), 1.15-1.44 (14H, m), 1.54 (3H, s), 1.61 (3
H, s), 1.70-1.96 (3H, m), 2.05 (3H, s), 2.56 (1H, m), 3.97-4.
22 (3H, m), 4.52 (1H, d, J = 5.8Hz), 6.03 (1H, d, J = 8.9Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 1788,1746,1
650,1548. High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 428.3011 Calculated: 428.3013 (C ₂₃ H ₄₂ O ₆ N) 52-d) Acetic acid 2- (S)-｛2- (R)-
[(S) -benzyloxycarbamoyl (hydroxy)
Methyl] undecanoylamino {-3-methylbutyle
According to the method of Example 10-c), 2- (S)-[2- (R)-(2,2-dimethyl-5-oxo- [1,3] -acetic acid obtained in Example 52-c). ] -Dioxolan-4-
The same reaction treatment was carried out using (S) -yl) undecanoylamino] -3-methylbutyl ester (583 mg) as a starting material to obtain 296 mg (51.9%) of the target compound as a white solid. However, at this time, the target compound was purified by recrystallization from hexane-ethyl acetate.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.88 (3H, t, J = 6.6Hz), 0.95 (6H, d, J = 6.7Hz), 1.1
5-1.43 (14H, m), 1.52-1.91 (3H, m), 2.05 (3H, s), 2.87 (1H,
m), 3.98 (1H, m), 4.05-4.19 (3H, m), 4.87 (2H, m), 5.17 (1H,
d, J = 8.6Hz), 5.96 (1H, d, J = 9.4Hz), 7.38 (5H, m), 9.33 (1H,
s). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3401,3290,3
217,1721,1666,1641,1559. High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 493.3288 Calculated: 493.3266 (C ₂₇ H ₄₄ O ₆ N ₂ ) 52-e) Acetic acid 2- (S)-｛2- (R)-
[(S) -hydroxy (hydroxycarbamoyl) methyl
Ru] undecanoylamino} -3-methylbutyl ester
According to the method of Le Example 10-d), obtained in Example 52-d), acetic acid 2- (S) - {2- ( R) - [(S) -
Benzyloxycarbamoyl (hydroxy) methyl] undecanoylamino} -3-methylbutyl ester (2
The same reaction treatment was carried out using 96 mg) as a starting material to obtain 113 mg (47%) of the target compound as a white solid.
However, at this time, the target compound was purified by recrystallization from methanol-isopropyl ether.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CD ₃ O
D) δppm: 0.89 (3H, t, J = 6.6Hz), 0.95 (3H, d, J = 6.6Hz), 0.9
6 (3H, d, J = 6.6Hz) 1.17-1.69 (16H, m), 1.82 (1H, m), 2.02 (3
H, s), 2.66 (1H, m), 3.87-4.03 (3H, m), 4.24 (1H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3384,3281,3
217,3105,1747,1669,1644,1561. High resolution mass spectrum (FAB): m / z [M + H] = 403.2786 Calculated value: 403.2840 (C ₂₀ H ₃₉ O ₆ N ₂ ) Specific rotation [α] _D ²⁵ = −8.8 ° (C: 1.07, EtOH) (Example 53) 2- (S), N ¹ -dihydroxy-N ⁴
-[1- (S) -hydroxymethyl-2-methylpropyl
2--3- (R) -nonylsuccinamide (Exemplified Compound No. 111) Acetic acid 2- (S)-{2- (R) obtained in Example 52-e) according to the method of Example 11). )-[(S) -hydroxy (hydroxycarbamoyl) methyl] undecanoylamino} -3-methylbutyl ester (104 m
The same reaction was carried out using g) as a starting material to obtain 66 mg (71%) of the target compound as a white solid. However, at this time, thin-layer preparative chromatography (0.5 mm thickness,
20 × 20 cm, chloroform: methanol = 10: 1
3 times, eluted with ethyl acetate: methanol = 5: 1)
To purify the target compound.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CD ₃ O
D) δppm: 0.83-0.98 (9H, m), 1.14-1.73 (16H, m), 1.88 (1H,
m), 2.66 (1H, m), 3.57 (2H, d, J = 5.4Hz), 3.70 (1H, m), 4.05 (1
H, d, J = 6.2Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3384,3283,3
222,3106,1668,1642,1630,1560. High resolution mass spectrum (FAB) 1N-NaIaq added m / z [M + Na] ⁺ = 383.2510 Calculated value: 383.2542 (C ₁₈ H ₃₆ O ₅ N ₂ Na) ratio Optical rotation [α] _D ²⁵ = -19.5 ° (C: 1.02, EtOH) (Example 54) Acetic acid 2- (S)-[2- (R) -hydrid
Roxycarbamoylmethyl-10-methylundecanoy
Ruamino] -3,3-dimethylbutyl ester (Exemplary Compound No. 124) 54-a) 3 (R)-[1- (S) -hydroxymethyl
Le-2,2-Jimechirupu Ropi carbamoyl] -11-
Methyl dodecanoic acid t-butyl ester According to the method of Example 52-a), 2- (R) -t-butoxycarbonylmethyl-10-methylundecanoic acid (1.52 g) and (S) -t-leucinol (68).
0 mg) as a starting material, to give 1.76 g (88.0%) of the target compound as a colorless oil. However, at this time, the target compound was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1).

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.86 (6H, d, J = 6.6Hz), 0.95 (9H, s), 1.05-1.78 (1
5H, m), 1.43 (9H, s), 2.32-2.67 (4H, m), 3.55 (1H, m), 3.76-
3.90 (2H, m), 6.03 (1H, d, J = 8.4Hz). Infrared absorption spectrum (liquid film, cm ^-1 ): 3327,1731,
1645,1542. High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 414.3551 Calculated: 414.3629 (C ₂₄ H ₄₈ O ₄ N) 54-b) 3- (R)-[1- ( S) -acetoxime
Tyl-2,2-dimethylpropylcarbamoyl] -11
-Methyldodecanoic acid t-butyl ester 3 (R)-[1- (S) -hydroxymethyl- obtained in Example 54-a) according to the method of Example 10-b).
2,2-Dimethylpropylcarbamoyl] -11-methyldodecanoic acid t-butyl ester (1.76 g) was used as a starting material, and subjected to the same reaction treatment to obtain the target compound 1.94.
g (quant) was obtained as a colorless oil. However, at this time, the target compound was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1).

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.86 (6H, d, J = 6.6Hz), 0.94 (9H, s), 1.06-1.78 (1
5H, m), 1.43 (9H, s), 2.03 (3H, s), 2.32 (1H, dd, J = 16.2,3.0H
z), 2.54 (1H, m), 2.63 (1H, dd, J = 16.2,9.5Hz), 4.01-4.13 (2
H, m), 4.22 (1H, m), 5.85 (1H, d, J = 8.6Hz). Infrared absorption spectrum (liquid film, cm ^-1 ): 3322,1732,
1649, 1545. High-resolution mass spectrum (FAB): m / z [M + H]
⁺ = 456.3718 _{Calculated: 456.3655 (C 26 H 50 O} 5 N) 54-c) 3- (R) - [1- (S) - Asetokishime
Tyl-2,2-dimethylpropylcarbamoyl] -11
-Methyldodecanoic acid 3- (R)-[1- (S) -acetoxymethyl- obtained in Example 54-b) according to the method of Example 8-d).
2,2-Dimethylpropylcarbamoyl] -11-methyldodecanoic acid t-butyl ester (1.93 g) was used as a starting material to carry out a similar reaction treatment to obtain 1.73 of the target compound.
g (quant) was obtained as a colorless oil. However, at this time, the target compound was purified by silica gel column chromatography (chloroform: methanol = 20: 1).

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.86 (6H, d, J = 6.6Hz), 0.95 (9H, s), 1.07-1.77 (1
5H, m), 2.03 (3H, s), 2.45-2.62 (2H, m), 2.78 (1H, m), 4.03-
4.28 (3H, m), 5.77 (1H, m). Infrared absorption spectrum (liquid film, cm ^-1 ): 3321,1741,
1728, 1650, 1549. High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 400.3083 Calculated value: 400.3034 (C ₂₂ H ₄₂ O ₅ N) 54-d) Acetic acid 2- (S)-[ 2- (R)-(Ben
(Diloxycarbamoylmethyl) -10-methylunde
Kanoiruamino] -3,3-dimethyl-butyl es ether obtained in Example 54-c) 3- (R) - [1- (S)
-Acetoxymethyl-2,2-dimethylpropylcarbamoyl] -11-methyldodecanoic acid (1.71 g) in methylene chloride (25 ml),
(3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (972 mg), 1-hydroxybenzotriazole (572 mg), N-methylmorpholine (5
60 μl) was added in sequence, and the mixture was stirred at room temperature for 10 minutes. Then O-benzylhydroxyamine hydrochloride (809 mg)
And N-methylmorpholine (500 μl) were added, and the mixture was further stirred for 2 hours. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate, extracted with ethyl acetate, and the organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and brine, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to obtain 1.81 g of the desired compound (8
4.7%) as a white solid.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.86 (6H, d, J = 6.6Hz), 0.95 (9H, s), 1.05-1.74 (1
5H, m), 2.02 (3H, s), 2.11-2.47 (2H, m), 2.68 (1H, m), 4.05 (2
H, m), 4.23 (1H, m), 4.86 (2H, m), 5.83 (1H, m), 7.37 (5H, m),
8.48 (1H, br.s). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3299,3191,1
731,1676,1641,1564. High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 505.3658 Calculated value: 505.3624 (C ₂₉ H ₄₉ O ₅ N ₂ ) 54-e) Acetic acid 2- (S )-[2- (R) -hydro
Xycarbamoylmethyl) -10-methylundecanoy
L-amino] -3,3-dimethylbutyl ester 2- (S)-[2- (R)-(benzyloxycarbamoylmethyl acetate) obtained in Example 54-d) according to the method of Example 10-d). ) -10-Methylundecanoylamino] -3,3-dimethylbutyl ester (1.
A similar reaction treatment was carried out using 80 g) as a starting material to obtain 1.39 g (94.0%) of the target compound as colorless crystals. However, at this time, the target compound was purified by recrystallization from hexane-ethyl acetate.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.86 (6H, d, J = 6.6Hz), 0.92 (9H, s), 1.05-1.86 (1
5H, m), 2.02 (3H, s), 2.30 (1H, dd, J = 14.3,4.5Hz), 2.52 (1H,
(dd, J = 14.3,10.0Hz), 2.77 (1H, m), 3.97-4.14 (2H, m), 4.24
(1H, m), 6.18 (1H, m), 7.87 (1H, br.s), 9.99 (1H, br.s). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3360,3223,1
. 721,1682,1641,1565 Elemental analysis _{(C 22 H 42 O 5 N} 2): analysis C; 63.51, H; 10.09, N; 6.66 theory C; 63.74, H; 10.21, N; 6.76 Specific rotation degree ^{_{[α] D 25 = + 8.8}} ° (C: 1.06, MeOH) mp: 163.5 ~164.5 ℃ (example 55) N ⁴ - hydroxy -N ¹ - [1- (S)
-Hydroxymethyl-2,2-dimethylpropyl] -2
-(R)-(8-Methylnonyl) succinamide (Exemplary Compound No. 123) Acetic acid 2- (S)-[2- (R) -obtained in Example 54-e) according to the method of Example 11). [Hydroxycarbamoylmethyl) -10-methylundecanoylamino] -3,3-dimethylbutyl ester (670 mg)
The same reaction treatment was carried out using
27 mg (87.5%) were obtained as colorless crystals. However, at this time, the target compound was purified by recrystallization from methanol-ethyl acetate-hexane.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CD ₃ O
D) δppm: 0.87 (6H, d, J = 6.6Hz), 0.93 (9H, s), 1.07-1.69 (1
5H, m), 2.20 (1H, dd, J = 14.4,6.8Hz), 2.35 (1H, dd, J = 14.4,
7.7Hz), 2.76 (1H, m), 3.46 (1H, dd, J = 12.1,9.7Hz), 3.78 (2
H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3405, 3255, 3
. 115,1667,1613,1590 Elemental analysis _{(C 20 H 40 O 4 N} 2) + 1 / 8H 2 O: analysis C; 64.13, H; 11.03, N; 7.51 theory C; 64.09, H; 10.82 , N; 7.47 Specific rotation [α] _D ²⁵ = + 4.3 ° (C: 0.980, MeOH) Melting point: 166.4-167.4 ° C. (Example 56) Acetic acid 2- (S)-[2- (R)-(N
-Hydroxycarbamoylmethyl) undecanoylamido
No] -3- (S) -Methylpentyl ester (Exemplified Compound No. 96) 56-a) 3- (R)-[1- (S) -Hydroxymethyl
Tyl-2- (S) -methylbutylcarbamoyl] dodeca
Phosphate t- butyl ester Example 8-a) obtained in 2- (R) -t- butoxycarbonylamino-methyl undecanoic acid (773 mg) was dissolved in a nitrogen atmosphere in dichloromethane (23.0 ml). Then, hydroxybenzotriazole (417 mg), N-
Methylmorpholine (340 μl) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (593 mg) were sequentially added, and the mixture was cooled to 0 ° C., and (S)-
(+)-Isoleucinol (374 mg) was added, and the mixture was stirred overnight while warming to room temperature. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was washed successively with a 5% aqueous solution of potassium hydrogen sulfate, water and saturated saline, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 921 mg (90%) of the desired compound as a colorless oil.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.84-0.94 (9H, complex), 1.15-1.37 (14H, compl
ex), 1.43 (9H, s), 1.46-1.52 (2H, complex), 1.61-1.73 (3H,
complex), 2.36 (1H, m), 2.53-2.67 (2H, complex), 2.89 (1H,
m), 3.61-3.88 (3H, complex), 6.02 (1H, d, J = 7.1Hz). Infrared absorption spectrum (Liquid film, cm ^-1 ): 3313,2927,
1732, 1637. High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 400.3426 Calculated: 400.3427 (C ₂₃ H ₄₆ O ₄ N) 56-b) 3- (R)-[1- ( S) -acetoxime
Tyl-2- (S) -methylbutylcarbamoyl] dodeca
Acid t-butyl ester According to the method of Example 10-b), 3- (R)-[1- (S) -hydroxymethyl- obtained in Example 56-a).
2- (S) -methylbutylcarbamoyl] dodecanoic acid t
The same reaction was carried out using -butyl ester (907 mg) as a starting material to obtain 925 mg (92%) of the target compound as a colorless oily substance.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.85-0.93 (9H, complex), 1.12-1.37 (14H, compl
ex), 1.43 (9H, s), 1.50-1.71 (3H, complex), 2.05 (3H, s), 2.
31 (1H, dd, J = 16.5,3.5Hz), 2.51 (1H, m), 2.63 (1H, dd, J = 16.
5,9.4Hz), 4.02-4.21 (3H, complex), 5.85 (1H, d, J = 8.5Hz). Infrared absorption spectrum (Liquid film, cm ^-1 ): 3307,2928,
1744, 1645. High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 442.3510 Calculated: 442.3533 (C ₂₅ H ₄₈ O ₅ N) 56-c) 3- (R)-[1 -(S) -acetoxime
Tyl-2- (S) -methylbutylcarbamoyl] dodeca
According to the method of phosphate Example 8-d), obtained in Example 56-b) 3- (R) - [1- (S) - acetoxymethyl -2
-(S) -methylbutylcarbamoyl] dodecanoic acid t-
The same reaction was carried out using butyl ester (925 mg) as a starting material to obtain 722 mg (89%) of the target compound as a white solid.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δppm: 0.84-0.93 (9H, complex), 1.08-1.29 (15H, comp
lex), 1.40-1.49 (2H, complex), 1.60-1.67 (2H, complex),
2.05 (3H, s), 2.44-2.56 (2H, complex), 2.78 (1H, dd, J = 17.
8,9.5Hz), 4.06-4.20 (3H, complex), 5.92 (1H, d, J = 8.6Hz),
8.01 (1H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3290,2924,1
. 745,1701,1644 mass spectrum (FAB): m / z [ M + H] + = 385 Elemental analysis _{(C 21 H 39 NO 5 ·} 1 / 8H 2 as O) Calculated (%) C; 65.04, H ; 10.19, N; 3.61 actual value (%) C; 64.77, H; 10.24, N; 3.60 56-d) acetic acid 2- (S)-[2- (R)-(N-
Hydroxycarbamoylmethyl) undecanoylamido
No] -3- (S) -methylpentyl ester 3- (R)-[1- (S) -acetoxymethyl-2 obtained in Example 56-c) according to the method of Example 8-e).
-(S) -methylbutylcarbamoyl] dodecanoic acid (7
434 mg (59%) of the target compound was obtained as white crystals by the same reaction treatment using 22 mg) as a starting material.

Melting point: 148 to 150 ° C. ¹ H-nuclear magnetic resonance spectrum (270 MHz, CD ₃ OD) δ ppm: 0.8
9 (9H, complex), 1.11-1.45 (17H, complex), 1.53-1.60 (2H,
complex), 2.02 (3H, s), 2.19 (1H, m), 2.32 (1H, m), 2.71 (1H,
m), 3.97 (2H, d, J = 6.5Hz), 4.25 (1H, m), 4.58 (1H, m), 8.01 (1
H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3289,2924,1
. 746,1642 mass spectrum (FAB): m / z [ M + H] + = 401 Elemental analysis _{(C 21 H 40 O 5 N} 2 · 1 / 10H 2 O ) Calculated value (%) C; 62.69, H ; 10.06, N; 6.96 actual value (%) C; 62.52, H; 10.29, N; 6.96 specific rotation [α] _D ²⁵ = -4.6 ° (C: 0.55, MeOH) (Example 57) N ⁴ -hydroxy -N ¹ - [1- (S)
-Hydroxymethyl-2- (S) -methylbutyl] -2
-(R) -Nonylsuccinamide (Exemplified Compound No. 95) Acetic acid 2- (S)-[2- (R)-(N-) obtained in Example 56-d) according to the method of Example 9). Hydroxycarbamoylmethyl) undecanoylamino] -3-
Using (S) -methylpentyl ester (239 mg) as a starting material, 174 mg of the target compound was obtained by the same reaction treatment.
(81%) as white crystals.

Melting point: 138 to 140 ° C. ¹ H-nuclear magnetic resonance spectrum (270 MHz, CD ₃ OD) δ ppm: 0.8
5-0.94 (9H, complex), 1.07-1.23 (2H, complex), 1.24-1.32
(14H, complex), 1.41-1.70 (4H, complex), 2.18 (1H, dd, J = 1
4.4,6.8Hz), 2.33 (1H, dd, J = 14.4,7.7Hz), 2.70 (1H, m), 3.5
5-3.63 (2H, complex), 3.73 (1H, m), 7.76 (1H, d, J = 8.6Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3280,2925,1
643. High resolution mass spectrum (FAB): m / z [M + H] ⁺ = 359.2898 Calculated: 359.2910 (C ₁₉ H ₃₉ O ₄ N ₂ ) Specific rotation [α] _D ²⁵ = -14.6 ° (C: (Example 0.758) Acetic acid 2- (S)-[2- (R)-(N
-Hydroxycarbamoylmethyl) undecanoylamido
No] -3- (2-thienyl) propyl ester (Exemplary Compound No. 100) 58-a) Nt-butoxycarbonyl-3- (2-
Thienyl) -L -alanine 3- (2-thienyl) -L-alanine (502 mg) was dissolved in dioxane (7 ml) -water (3.5 ml).
Cooled to ° C. Then, di-t-butyl dicarbonate (0.7 ml), 1N aqueous sodium hydroxide solution (3 m
l) were added in sequence, and the mixture was stirred overnight while being heated to room temperature.
The reaction solution was poured into a 5% aqueous potassium hydrogen sulfate solution, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline in this order, and then dried over sodium sulfate. The residue was subjected to silica gel column chromatography (dichloromethane: methanol = 5:
Purification according to 1) gave 574 mg (72%) of the desired compound as a white solid.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CD ₃ O
D) δppm: 1.42 (9H, s), 3.22 (1H, m), 3.35 (1H, m), 4.27 (1H,
m), 6.84-6.93 (2H, complex), 7.18 (1H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3334,2978,1
713,1673. 58-b) Nt-butoxycarbonyl-3- (2-
Thienyl) -L-alanine methyl ester Nt-butoxycarbonyl-3- (2-thienyl) -L-alanine obtained in Example 58-a) (574 m
g) was dissolved in N, N-dimethylformamide (4.5 ml). Then, potassium hydrogen carbonate (382 mg) and methyl iodide (190 μl) were added in that order, and the mixture was stirred at room temperature for 7.3 hours. The reaction solution was poured into water and extracted with ethyl acetate,
The organic layer was washed sequentially with a 5% aqueous potassium hydrogen sulfate solution and saturated saline, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 514 mg (94%) of the desired compound as a colorless oil.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 1.44 (9H, s), 3.35 (2H, d, J = 4.7Hz), 3.75 (3H, s),
4.58 (1H, m), 5.12 (1H, d, J = 6.8Hz), 6.80 (1H, d, J = 3.3Hz),
6.93 (1H, dd, J = 5.3,3.3Hz), 7.17 (1H, d, J = 5.3Hz). Infrared absorption spectrum (Liquid film, cm ^-1 ): 3371,2978,
1747, 1717. Mass spectrum (FAB): m / z [M + H] ⁺ = 286 58-c) Nt-butoxycarbonyl-3- (2-
(Thienyl) -L-alaninol Nt-butoxycarbonyl-3- (2-thienyl) -L-alanine methyl ester (432 mg) obtained in Example 58-b) was dissolved in tetrahydrofuran (4 ml). Then lithium chloride (307 mg), sodium borohydride (263 mg), ethanol (8 ml)
Were sequentially added and stirred at room temperature overnight. The reaction solution was cooled with ice water, water was added dropwise, extracted with ethyl acetate, and the organic layer was washed successively with 5% sodium hydrogen sulfate, water and saturated saline, and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 341 mg of the desired compound.
(83%) was obtained as a white solid.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 1.43 (9H, s), 2.73 (1H, m), 3.08 (2H, d, J = 6.6Hz),
3.62-3.66 (2H, complex), 3.85 (1H, m), 4.92 (1H, m), 6.86 (1
H, d, J = 3.3Hz), 6.94 (1H, dd, J = 5.2,3.3Hz), 7.16 (1H, d, J =
5.2Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3358,2982,1
686. Mass spectrum (FAB): m / z [M + H] ⁺ = 258 Elemental analysis (as C ₁₂ H ₁₉ O ₃ NS) Calculated value (%) C; 56.01, H; 7.43, N; 5.44, S; 12.46 Found (%) C; 56.08, H; 7.55, N; 5.44, S; 12.76 58-d) 3- (2-thienyl) -L-alaninol Nt- obtained in Example 58-c). Butoxycarbonyl-3- (2-thienyl) -L-alaninol (331
mg) was dissolved in 4N hydrochloric acid-dioxane (6 ml) and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained target compound was used for the next reaction without purification.

58-e) 3- (R)-[1- (S)-
Hydroxymethyl-2- (2-thienyl) ethylcarba
[Moyl] dodecanoic acid t-butyl ester According to the method of Example 56-a), 2- (R) -t-butoxycarbonylmethylundecanoic acid (352 mg) obtained in Example 8-a) and Example 58-d. 3) obtained in
-(2-thienyl) -L-alaninol was used as a starting material, and 439 mg (85%) of the target compound was obtained by the same reaction treatment.
%) As a colorless oil.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.88 (3H, t, J = 6.6Hz), 1.10-1.31 (14H, comple
x), 1.41 (1H, m), 1.43 (9H, s), 1.59 (1H, m), 2.34 (2H, dd, J = 1
5.5,9.0Hz), 2.93 (1H, t, J = 5.6Hz), 3.09 (1H, dd, J = 14.8,7.
0Hz), 3.18 (1H, dd, J = 14.8,7.1Hz), 3.61-3.73 (2H, comple
x), 4.03 (1H, m), 6.10 (1H, d, J = 7.4Hz), 6.89 (1H, d, J = 3.2H
z), 6.94 (1H, dd, J = 5.0,3.2Hz), 7.16 (1H, d, J = 5.0Hz). Infrared absorption spectrum (Liquid film, cm ^-1 ): 3307,2927,
1730, 1646. High-resolution mass spectrum (FAB): m / z [M + Na] ⁺ = 462.2643 calculated: 462.2654 58-f) 3- (R)-[1- (S) -acetoxyme
Tyl-2- (2-thienyl) ethylcarbamoyl] dode
According to the method of Example 10-b), 3- (R)-[1- (S) -hydroxymethyl- cyanic acid t-butyl ester obtained in Example 58-e).
2- (2-thienyl) ethylcarbamoyl] dodecanoic acid t-butyl ester was used as a starting material to give 447 mg (96%) of the target compound as a white solid.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.87 (3H, t, J = 6.6Hz), 1.16-1.29 (14H, comple
x), 1.30 (1H, m), 1.44 (9H, s), 1.64 (1H, m), 2.09 (3H, s), 2.3
2 (1H, dd, J = 15.8,3.9Hz), 2.49 (1H, m), 2.59 (1H, dd, J = 15.
8,8.8Hz), 3.02 (1H, dd, J = 14.8,7.5Hz), 3.11 (1H, dd, J = 14.
8,5.8Hz), 4.00-4.17 (2H, complex), 4.43 (1H, m), 6.00 (1H,
d, J = 8.5Hz), 6.88 (1H, d, J = 3.2Hz), 6.94 (1H, dd, J = 4.2,3.2
Hz), 7.15 (1H, d, J = 4.2Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3360,2924,1
742,1722,1649. High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 482.2928 calculated: 482.2940 58-g) 3- (R)-[1- (S) -acetoxime
Tyl-2- (2-thienyl) ethylcarbamoyl] dode
According to the method of Example 8-d), 3- (R)-[1- (S) -acetoxymethyl-2 obtained in Example 58-f).
-(2-thienyl) ethylcarbamoyl] dodecanoic acid t
372 mg (98%) of the target compound was obtained as a white solid by the same reaction treatment using -butyl ester as a starting material.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δppm: 0.87 (3H, t, J = 6.6Hz), 1.22-1.32 (14H, comple
x), 1.45 (1H, m), 1.61 (1H, m), 2.08 (3H, s), 2.46 (1H, dd, J = 1
8.0,4.0Hz), 2.52 (1H, m), 2.71 (1H, dd, J = 18.0,10.3Hz), 3.
03 (1H, dd, J = 15.0,6.1Hz), 3.09 (1H, dd, J = 15.0,4.3Hz), 4.
05 (1H, dd, J = 11.4,4.7Hz), 4.12 (1H, dd, J = 11.4,5.0Hz), 4.
42 (1H, m), 6.09 (1H, d, J = 8.5Hz), 6.85 (1H, d, J = 3.6Hz), 6.9
3 (1H, dd, J = 5.2,3.4Hz), 7.16 (1H, d, J = 4.1Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3283,2923,1
746, 1737, 1696. High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 426.2293 Calculated: 426.2314 58-h) Acetic acid 2- (S)-[2- (R)-(N-
Hydroxycarbamoylmethyl) undecanoylamido
No] -3- (2-thienyl) propyl ester 3- (R)-[1- (S) -acetoxymethyl-2 obtained in Example 58-g) according to the method of Example 8-e).
The same reaction treatment was carried out using-(2-thienyl) ethylcarbamoyl] dodecanoic acid (350 mg) as a starting material to obtain 209 mg (58%) of the target compound as white crystals.

Melting point: 150-151 ° C. ¹ H-nuclear magnetic resonance spectrum (270 MHz, CD ₃ OD) δ ppm: 0.8
9 (3H, t, J = 6.6Hz), 1.14-1.33 (14H, complex), 1.39 (1H, m),
1.51 (1H, m), 2.04 (3H, s), 2.09 (1H, dd, J = 14.4,7.9Hz), 2.2
2 (1H, dd, J = 14.4,6.6Hz), 2.66 (1H, m), 2.99-3.14 (2H, comp
lex), 3.96 (1H, dd, J = 11.2,6.7Hz), 4.17 (1H, dd, J = 11.2,4.
3Hz), 4.32 (1H, m), 6.87-6.94 (2H, complex), 7.20 (1H, d, J =
5.3Hz), 8.21 (1H, d, J = 8.6Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3281,2923,1
. 738,1645 mass spectrum (FAB): m / z [ M + H] + = 441 Elemental analysis _{(C 22 H 36 N 2 O} 5 S · 1 / 4H 2 O ) Calculated value (%) C; 59.37, H; 8.28, N; 6.29, S; 7.20 Found (%) C; 59.20, H; 8.39, N; 6.
42, S; 7.29 Specific rotation [α] _D ²⁵ = + 1.48 (C: 0.64
MeOH) (Example 59) N ⁴ - hydroxy -N ¹ - [1- (S)
-Hydroxymethyl-2- (2-thienyl) ethyl]-
2- (R) -nonylsuccinamide (Exemplary Compound No. 9
9) According to the method of Example 9, 2- (S)-[2- (R)-(N-hydroxycarbamoylmethyl) undecanoylamino] acetate obtained in Example 58-h). −
The same reaction was carried out using thienyl) propyl ester (44 mg) as a starting material to obtain the desired compound (40 mg).

Melting point: 154 to 155 ° C. ¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD) δ ppm: 0.8
9 (3H, t, J = 6.7Hz), 1.26-1.32 (14H, complex), 1.36 (1H, m),
1.52 (1H, m), 2.09 (1H, dd, J = 14.5,7.9Hz), 2.20 (1H, dd, J = 1
4.5,6.7Hz), 2.65 (1H, m), 2.97 (1H, dd, J = 14.8,8.1Hz), 3.1
4 (1H, dd, J = 14.8,8.1Hz), 3.51 (1H, dd, J = 11.0,5.5Hz), 3.5
6 (1H, dd, J = 11.0,5.3Hz), 4.07 (1H, m), 6.86-6.92 (2H, comp
lex), 7.18 (1H, d, J = 5.2Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3443,3291,2
923,1642. Mass spectrum (FAB): m / z [M + H] ⁺ = 399 elemental analysis (as C ₂₀ H ₃₄ N ₂ O ₄ S / 1 / 3H ₂ O) Calculated value (%) C; 59.37, H; 8.63, N; 6.92, S; 7.92 Actual value (%) C; 59.25, H; 8.72, N; 6.92, S; 7.76 Specific rotation [α] _D ²⁵ = -9.87 (C: 0.63, MeOH) ( Example 60) Succinic acid mono-2- (S)-[2-
(R)-(N-hydroxycarbamoylmethyl) unde
Kanoiruamino] -3,3-dimethyl-butyl] ester (Compound No. ^{90) 60-a) N 4} - benzyloxy -N ¹ - [1-
(S) -hydroxymethyl-2,2-dimethylpropyl
2- (R) -Nonylsuccinamide 3- (R)-[1- (S) -hydroxymethyl-2,2
-Dimethylpropylcarbamoyl] dodecanoic acid t-butyl ester (112 mg) in methylene chloride (4.0 m
l) To the solution was added trifluoroacetic acid (2.0 ml)
The mixture was stirred at room temperature for 3 hours. Toluene (20m
After l) was added, volatiles were distilled off under reduced pressure. The obtained residue was dissolved in methylene chloride (4.0 ml), 1-hydroxybenzotriazole (61.4 mg), N-methylmorpholine (110 μl), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide Hydrochloride (8
9.3 mg) and O-benzylhydroxylamine hydrochloride (80.2 mg) were sequentially added, and the mixture was stirred overnight at room temperature.
The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate. The organic layer was washed successively with saturated saline and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was separated by preparative thin-layer chromatography (silica gel 0.5 m).
m, 20 cm × 20 cm, 5 sheets, dichloromethane: methanol = 15: 1) to purify the target compound, 84.6.
mg (67% over two steps) was obtained as a white solid.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δ ppm: 0.87 (3H, t, J = 6.5Hz), 0.93 (9H, s), 1.10-1.52
(15H, complex), 1.62 (1H, m), 2.10-2.52 (2H, complex), 2.5
8-3.20 (2H, complex), 3.57 (1H, m), 3.69-3.89 (2H, comple
x), 4.85 (2H, s), 6.58 (1H, br.d, J = 8.5Hz), 7.20-7.50 (5H, c
omplex), 9.68 (1H, s) Infrared absorption spectrum (Kbr pellet, cm ^-1 ) 3318, 3187, 1675, 1639, 1556, 1530 High-resolution mass spectrum (FAB) m / z [M + H] ⁺ = 449.3375 Calculation _{value: 449.3379 (C 26 H 45 N} 2 O 4) 60-b) succinic acid mono -2- (S) - [2-
(R) - (N-Benjiruo carboxymethyl carbamoylmethyl) c
Ndecanoylamino] -3,3-dimethylbutyl] S
N ⁴ -Benzyloxy-N obtained in Tell Example 60-a)
¹ - [1- (S) - hydroxy-2,2-dimethylpropyl] -2- (R) - nonyl disk Sina bromide (55
4 mg) was dissolved in methylene chloride (15 ml) under a nitrogen atmosphere and cooled to 0 ° C. Then, diisopropylamine (550 μl) and succinic anhydride (314 mg) were added.
The mixture was stirred overnight while raising the temperature to room temperature. At room temperature, diisopropylamine (300 (μl)) and succinic anhydride (1
28 mg) and further stirred overnight. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate. The organic layer was washed successively with saturated saline and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane: methanol = 40: 1) to obtain the desired compound (589 m).
g (87%) was obtained as a white solid.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CD ₃ O
D) δ ppm: 0.89 (3H, t, J = 6.5Hz), 0.96 (9H, s), 1.11-1.48
(15H, complex), 1.55 (1H, m), 2.14 (1H, dd, J = 14.6,4.6Hz),
2.32 (1H, dd, J = 14.6,8.0Hz), 2.41-2.65 (4H, complex), 2.7
9 (1H, m), 3.80-4.07 (2H, complex), 4.42 (1H, m), 4.81 (2H,
s), 7.20-7.48 (5H, complex), 7.91 (1H, m) Infrared absorption spectrum (liquid film, cm ^-1 ) 3306, 3214, 1739, 1717, 1644, 1550 High-resolution mass spectrum (FAB) m / z [M ⁺ H] + = 549.3558 _{calculated: 549.3540 (C 30 H 40 N} 2 O 7) 60-c) succinic acid mono -2- (S) - [2-
(R)-(N-hydroxycarbamoylmethyl ) unde
Canoylamino] -3,3-dimethylbutyl ester Mono-2- (S)-[2- (R) -succinate obtained in Example 60-b) according to the method of Example 10-d).
(N-benzyloxycarbamoylmethyl) undecanoylamino] -3,3-dimethylbutyl] ester (5
The same reaction was carried out using 74 mg) as a starting material to obtain 310 mg (65%) of the desired product as a colorless oil.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CD ₃ O
D) δ ppm: 0.89 (3H, t, J = 6.6Hz), 0.95 (9H, s), 1.17-1.49
(15H, complex), 1.58 (1H, m), 2.16 (1H, dd, J = 14.4,6.8Hz),
2.33 (1H, dd, J = 14.4,7.6Hz), 2.44-2.63 (4H, complex), 2.7
9 (1H, m), 3.86-4.05 (2H, complex), 4.44 (1H, d, J = 8.2Hz),
7.92 (1H, d, J = 8.8Hz) Infrared absorption spectrum (liquid film, cm ^-1 ) 3235, 1739, 1716, 1651, 1644, 1549 High resolution mass spectrum (FAB) m / z [M + H] ⁺ = 459.3047 _{calculated: 459.3070 (C 23 H 43 N} 2 O 7) ( example 61) succinic acid mono -2- (S) - [2-
(R)-(N-hydroxycarbamoylmethyl) unde
Canoylamino] -3,3-dimethylbutyl ester
Sodium salt (Exemplified compound 312) Mono-2-succinic acid obtained in Example 60-c)
159 mg of (S)-[2- (R)-(N-hydroxycarbamoylmethyl) undecanoylamino] -3,3-dimethylbutyl ester was added to DIAION WK-20.
After the treatment, the target compound 166 is freeze-dried.
mg (100%).

¹ H-nuclear magnetic resonance spectrum (270 MHz, CD ₃ O
D) δ ppm: 0.89 (3H, t, J = 6.6Hz), 0.96 (9H, s), 1.10-1.70
(16H, complex), 2.19 (1H, dd, J = 14.5,6.8Hz), 2.35 (1H, dd,
J = 14.5,7.6Hz), 2.35-2.62 (4H, complex), 2.78 (1H, m), 3.9
6 (2H, complex), 4.41 (1 H, m) Infrared absorption spectrum (Kbr pellet, cm ^-1 ) 3373, 3231, 1725, 1651, 1632, 1580 (Example 62) Propionic acid 2- (S)-[2 −
(R)-(N-hydroxycarbamoylmethyl-unde
(Canoylamino) -3,3-dimethylbutyl] ester (Exemplified Compound No. 84) 62-a) Propionic acid 2- (S)-[2- (R)
- (N-Benjiruoki shea carbamoylmethyl) undec
Noylamino] -3,3-dimethylbutyl] ester N ⁴ -benzyloxy-N obtained in Example 60-a)
¹ - [1- (S) - hydroxy-2,2-dimethylpropyl] -2- (R) - nonyl disk Sina bromide (20
8 mg) in tetrahydrofuran (7.0 m) under a nitrogen atmosphere.
1) and cooled to 0 ° C. Then, pyridine (4
3 μl) and propionyl chloride (45 μl)
The mixture was stirred at the same temperature for 1 hour. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate. The organic layer was washed successively with saturated saline and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was separated by preparative thin-layer chromatography (silica gel 0.5 mm thick, 20 cm × 20 cm,
Six plates were purified by dichloromethane: methanol = 20: 1) to obtain 216 mg (92%) of the target compound.

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δ ppm: 0.87 (3H, t, J = 6.6Hz), 0.94 (9H, s), 1.11 (3H,
t, J = 7.5Hz), 1.12-1.48 (15H, complex), 1.59 (1H, m), 2.10-
2.48 (4H, complex), 2.71 (1H, m), 4.02 (2H, m), 4.12 (2H, s),
4.86 (2H, s), 6.04 (1H, br.d, J = 7.7Hz), 7.76 (5H, s), 9.12
(1H, s) Infrared absorption spectrum (Kbr pellet, cm ^-1 ) 3319, 3196, 1735, 1676, 1648, 1561, 1531 High resolution mass spectrum (FAB) m / z [M + H] ⁺ = 505.3663 Calculated value: _{505.3641 2- (C 29 H 49 N} 2 O 5) 62-b) propionic acid (S) - [2- (R )
- (N-hydroxycarboxylic Rubamoirumechiru) Undekanoi
L-amino] -3,3-dimethylbutyl] ester 2- (S)-[2- (R)-(N-propionic acid) obtained in Example 62-a) according to the method of Example 10-d).
Benzyloxycarbamoylmethyl) -undecanoylamino] -3,3-dimethylbutyl ester (191 m
g) was used as a starting material, and 147 mg (94%) of the target compound was obtained as a colorless oily substance by the same reaction treatment.

The ¹ H-nuclear magnetic resonance spectrum (270 MHz, CD ₃ O
D) δ ppm: 0.89 (3H, t, J = 6.6Hz), 0.96 (9H, s), 1.10 (3H,
t, J = 7.6Hz), 1.15-1.48 (15H, complex), 1.58 (1H, m), 2.17
(1H, dd, J = 14.4,6.7Hz), 2.30 (1H, q, J = 7.6Hz), 2.31 (1H, ov
erlapped with δ 2.30), 2.78 (1H, m), 3.84-4.08 (2H, com
plex), 4.42 (1H, d, J = 8.6Hz), 7.90 (1H, br.d, J = 8.6Hz) Infrared absorption spectrum (liquid film, cm ^-1 ) 3297, 1743, 1642, 1552 High resolution mass spectrum (FAB) m / z [M + H] + = 415.3172 _{calculated: 415.3172 (C 22 H 43 N} 2 O 5) ( example 63) acetic acid 2- (S) - {2- ( R) -
[(S) -acetoxy (hydroxycarbamoyl) methyl]
L] -4-Methylpentanoylamino] -3,3-dim
Tylbutyl ester (Exemplary Compound No. 313) 63-a) 2- (S) -acetoxy-3- (R)-
[1- (S) -acetoxymethyl-2,2-dimethylp
Ropyrcarbamoyl] -5-methylhexanoic acid 2- (R)-[2,2-dimethyl-5-oxo- [1.3] -dioxolan-4- obtained in Example 25-a).
(S) -yl] -4-methylpentanoic acid [1- (S)-
Hydroxymethyl-2,2-dimethylpropyl] amide (2.10 g) was dissolved in acetic acid-water (2: 1, 60 ml) and stirred at room temperature for 65 hours. Toluene (2
Acetic acid and the solvent were distilled off under reduced pressure. The resulting foam was dried under reduced pressure for another 4 hours and dissolved in methylene chloride (50 ml). Acetic anhydride (1.8 ml), pyridine (1.55 ml) and 4-dimethylaminopyridine (78 mg) were sequentially added, and the mixture was stirred at 0 ° C for 1.5 hours. The reaction solution was poured into a 1N-hydrochloric acid aqueous solution and extracted with methylene chloride. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure,
Diisopropyl ether was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to give the desired compound (2.13 g, 89
%).

¹ H-nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δppm: 0.90-1.00 (6H, m), 0.99 (9H, s), 1.26 (1H,
m), 1.68 (2H, m), 2.04 (3H, s), 2.13 (3H, s), 2.86 (1H, m), 4.1
0 (2H, m), 4.24 (1H, m), 5.14 (1H, d, J = 5.5HZ), 6.29 (1H, d, J =
9.3HZ), 8.71 (1H, brs) Infrared absorption spectrum (Liquid film, cm ^-1 ) 3435,2966,1740,1621 Mass spectrum (FAB) m / z [M + H] ⁺ = 374 63-b) Acetic acid 2- (S)-｛2- (R)-
[(S) -acetoxy (benzyloxycarbamoyl)
Methyl] -4-methylpentanoylamino} -3,3-
Dimethyl butyl ester 2- (S) -acetoxy- obtained in Example 63-a)
3- (R)-[1- (S) -acetoxymethyl-2,2
-Dimethylpropylcarbamoyl] -5-methyl-hexanoic acid (2.13 g) in tetrahydrofuran-water (1:
1.100 ml) solution, o-benzylhydroxylamine hydrochloride (1.64 g), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.19 g).
g) was added and the mixture was stirred at room temperature overnight. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to obtain 1.37 g (50%) of the desired compound as a foam.

¹ H-nuclear magnetic resonance spectrum (270 MHz, C
DCl ₃ ) δppm: 0.85-0.96 (15H, m), 1.49-1.80 (3H, m), 2.
02 (3H, s), 2.05 (3H, s), 2.91 (1H, m), 4.08-4.16 (2H, m), 4.2
6 (1H, m), 4.85 (1H, d, J = 9.4HZ), 4.93 (2H, s), 6.29 (1H, d, J =
8.0HZ), 7.34-7.52 (5H, m), 9.78 (1H, brs) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 3323,3212,2958,1747,1649,
1556 Mass spectrum (FAB) m / z [M + H] = 479 63-c) Acetic acid 2- (S)-{2- (R)-
[(S) -acetoxy (hydroxycarbamoyl) methyl]
L] -4-methyl-pentanoylamino] -3,3-di
Methyl butyl ester 2- (S)-{2- (R)-[(S) -acetoxy (benzyloxycarbamoyl) methyl] acetate obtained in Example 63-b) according to the method of Example 10-d). The same reaction was carried out using -4-methylpentanoylamino} -3,3-dimethylbutyl ester (1.37 g) as a starting material to obtain 884 mg (79%) of the target compound as a white solid.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, C
D ₃ OD) δppm: 0.93 (6H, m), 0.99 (9H, s), 1.04 (1H, m), 1.
55-1.65 (2H, m), 1.99 (3H, s), 2.00 (3H, s), 2.96 (1H, m), 3.9
0 (1H, m), 4.02 (1H, m), 4.41 (1H, m), 4.76 (1H, d, J = 10.3Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ) 2959,1751,1649,1537 Mass spectrum (FAB) m / z [M + H] ⁺ = 389 High-resolution mass spectrum (FAB) m / z [M + H] ⁺ = 389,2308 Calculated: 389,2288 (C ₁₈ H ₃₃ N ₂ O) ₇ ) Specific rotation: [α] _D ²⁵ = + 55.38 ° (c: 0.80, MeO
H) (Example 64) Acetic acid 2- (S)-[5- (4-chloro)
Phenyl) -2- (R)-(N-hydroxycarbamoy
Rumethyl) pentanoylamino] -3-cyclohexyl
Propyl ester (Exemplified Compound No. 308) 64-a) 3- (R)-[2-acetoxy-1-
(S) -cyclohexylmethylethylcarbamoyl]-
6- (4-chlorophenyl) hexanoic acid 2- (R) -tert-butoxycarbonylmethyl-5- (4
Isobutyl chloroformate (0.71 ml) was added dropwise to a solution of (-chlorophenyl) pentanoic acid (1.500 g) and N-methylmorpholine (0.61 ml) in tetrahydrofuran (30 ml) under ice cooling, and the mixture was stirred at 0 ° C for 0.5 hour. Stirred.
Then, (S) -cyclohexylalaninol (722 m
A solution of g) in N, N-dimethylformamide (30 ml) was added, and the mixture was stirred at 0 ° C. for 3 hours and further at room temperature for 5 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by methylene chloride (30 ml).
And cooled to 0 ° C. Then, pyridine (0.74 ml) and 4-dimethylaminopyridine (56 m
g) and acetic anhydride (0.87 ml) were sequentially added, and the mixture was added at room temperature for 3 hours.
Stirred for hours. The reaction solution was poured into ice water and extracted with methylene chloride. The organic layer was washed successively with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was redissolved in methylene chloride (40 ml) and cooled to 0 ° C. Then trifluoroacetic acid (6.94 ml) was added to the solution.
Was added and stirred at room temperature for 17 hours. After toluene was added to the reaction solution, volatiles were distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with methylene chloride: methanol = 49: 1) to obtain 1.431 g (69%) of the target compound as white crystals.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, C
_{D 3 OD) δppm: 0.75-1.02 (} 2H, m), 1.09-1.75 (14H, m), 1.
75-1.85 (1H, m), 1.86 (3H, s), 2.35 (1H, dd, J = 16.3,5.1Hz),
2.52-2.74 (3H, m), 2.70 (1H, m), 3.83 (1H, dd, J = 11.0,7.0H
z), 4.10 (1H, dd, J = 11.0,4.2Hz), 4.22 (1H, m), 7.15 (2H, m),
7.23 (2H, m) infrared absorption spectrum (KBr pellet, cm ^-1 ): 330
7, 2924, 2854, 1741, 1643, 154
8,1493,1232 Mass spectrum (FAB): m / z [M + H] ⁺ = 452 Melting point: 88-89 ° C 64-b) Acetic acid 2- (S)-[5- (4-chlorof
Enyl) -2- (R)-(N-hydroxycarbamoyl
Methyl) pentanoyl amino] -3-cyclohex Shirupu
Ropyl ester 3- (R)-[2-Acetoxy-1- (S) -cyclohexylmethylethylcarbamoyl] -6- (4-chlorophenyl) hexanoic acid (1.412 g) obtained in Example 64-a) and N To a solution of -methylmorpholine in tetrahydrofuran (30 ml) was added ice-cooled isobutyl chloroformate (0.49 ml), stirred for 30 minutes, and then added O- (t-butyldimethylsilyl) hydroxylamine (920 mg). Stir for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was diluted with hydrochloric acid,
The extract was washed with water, saturated sodium bicarbonate, water and saturated saline, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was washed with ether to obtain the desired compound (1.039 g, 71%) as a white powder.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, C
D ₃ OD) δppm: 0.78-1.01 (2H, m), 1.09-1.72 (14H, m), 1.
75-1.83 (1H, m), 1.86 (3H, s), 2.15 (1H, dd, J = 14.4,7.3Hz),
2.30 (1H, dd, J = 14.4,7.2Hz), 2.50-2.67 (2H, m), 2.74 (1H,
m), 3.83 (1H, dd, J = 11.1,7.0Hz), 4.12 (1H, dd, J = 11.1,4.1H
z), 4.21 (1H, m), 7.15 (2H, m), 7.23 (2H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 327
9,2925,2853,1743,1643,154
4,1493,1234 Mass spectrum (FAB): m / z [M + H] ⁺ = 467 High-resolution mass spectrum (FAB): m / z [M + H] ⁺ = 467,
2295 _{Calculated: 467,2313 (C 24 H 36 ClN} 2 O 5) Elementary analysis _{(C 24 H 35 ClN 2 O} 5): Calculated: C, 61.73; H, 7.56 ; N, 6.0
0; Cl, 7.59 Found: C, 61.71; H, 7.53; N, 6.1
0; Cl, 7.69 Melting point: 118-120 ° C (Example 65) 2- (R)-[3- (4-chlorophenyl)
) ^{Propyl) -N 1 - [1- (S} ) - cyclohexyl
Methyl-2-hydroxyethyl] -N ⁴ - hydroxysuccinimide
Cusinamide (Exemplified Compound No. 307) 2- (S)-[5- (acetic acid) obtained in Example 64-b)
From (4-chlorophenyl) -2- (R)-(N-hydroxycarbamoylmethyl) pentanoylamino] -3-cyclohexylpropyl ester (494 mg) in the same manner as in Example 9 (however, no recrystallization was carried out. The obtained powder was washed with ethyl acetate) 437 mg of the desired compound
(97%) as a white powder.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, C
D ₃ OD) δppm: 0.77-1.02 (2H, m), 1.09-1.72 (14H, m), 1.
78-1.87 (1H, m), 2.16 (1H, dd, J = 14.3,7.3Hz), 2.31 (1H, dd,
J = 14.3,7.2Hz), 2.50-2.67 (2H, m), 2.72 (1H, m), 3.39-3.50
(2H, m), 3.97 (1H, m), 7.15 (2H, m), 7.23 (2H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 337
3,3254,3109,2926,2846,166
2,1615,1493 High resolution mass spectrum (FAB): m / z [M + Na] ⁺ = 447,
2043 _{Calculated: 447,2027 (C 22 H 33 ClNaN} 2 O 4) mp: 197-199 ° C. (Example 66) Acetic acid 3-acetoxy-2- [5- (4
-Chlorophenyl) -2- (R)-(N-hydroxyca
Rubamoylmethyl) pentanoylamino] propyles
Ter (Exemplified Compound No. 306) 66-a) 3- (R)-(2-acetoxy-1-acetate)
Toximethylethylcarbamoyl) -6- (4-chloro
Phenyl) hexanoic acid 2- (R) -tert-butoxycarbonylmethyl-5- (4
Example 64 starting from -chlorophenyl) pentanoic acid (1.500 g) and serinol (627 mg)
1.161 g of the desired compound (59) was obtained in the same manner as in a).
%) As white crystals.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, C
D ₃ OD) δppm: 1.42-1.67 (4H, m), 1.90 (3H, s), 2.03 (3H,
s), 2.37 (1H, dd, J = 16.3, 5.1 Hz), 2.52-2.67 (3H, m), 2.72 (1
H, m), 4.02-4.21 (4H, m), 4.36 (1H, m), 7.16 (2H, m), 7.24 (2
H, m) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 330
5,2921,1740,1701,1659,165
2,1545,1241 Mass spectrum (FAB): m / z [M + H] ⁺ = 428 Melting point: 99-100 ° C 66-b) Acetic acid 3-acetoxy-2- [5- (4-
Chlorophenyl) -2- (R)-(N-hydroxycal
Bamoirumechiru) pentanoylamino] propyl ester
Obtained in Le Example 66-a) 3- (R) - (2- acetoxy-1 acetoxymethyl ethylcarbamoyl) -6
-(4-chlorophenyl) hexanoic acid (1.143 g)
Example 64-b) and O- (t-butyldimethylsilyl) hydroxylamine (787 mg) as starting material
1.011 g (86%) of the target compound by the same method as described above.
Was obtained as a white powder.

[0477]¹H-nuclear magnetic resonance spectrum (400 MHz, C
D_ThreeOD) δ ppm: 1.39-1.66 (4H, m), 1.89 (3H, s), 2.05 (3H,
s), 2.15 (1H, dd, J = 14.6,7.0Hz), 2.34 (1H, dd, J = 14.6,7.9H
z), 2.51-2.67 (2H, m), 2.75 (1H, m), 4.02-4.22 (4H, m), 4.35
(1H, m), 7.15 (2H, m), 7.24 (2H, m) Infrared absorption spectrum (KBr pellet, cm^-1 ): 329
7, 1737, 1644, 1618, 1550, 123
9 Mass spectrum (FAB): m / z [M + H]⁺= 443 High resolution mass spectrum (FAB): m / z [M + H]⁺ = 443
1589 Calculated: 443, 1585 (C₂₀H₂₈ClN_TwoO₇) Elemental analysis (C₂₀H₂₇ClN_TwoO₇): Calculated: C, 54.24; H, 6.15; N, 6.3.
3: Cl, 8.01 Found: C, 54.17; H, 6.15; N, 6.4.
4: Cl, 8.09 Melting point: 134-136 ° C (Example 67)2- (R)-[3- (4-chlorophenyi
) Propyl] -N ⁴ - hydroxy -N ¹ - (2-hydrate
Roxy-1-hydroxymethylethyl) succinamide
(Exemplified Compound No. 305) Acetic acid 3-acetoxy-2 obtained in Example 66-b)
-[5- (4-chlorophenyl) -2- (R)-(N-
Hydroxycarbamoylmethyl) pentanoylamino]
Propyl ester (224mg) in methanol (15ml)
Add sodium methoxide (about 28.0% methanol
Solution, 0.5 ml) and stirred at room temperature for 1 hour.
Amberlite CG-50 Type 1 was added to the reaction solution to neutralize it.
After that, the resin was separated by filtration using Celite. Methane
The filtrate obtained by washing with water was concentrated under reduced pressure. Obtained residue
The distillate is purified by washing with ether to give the desired compound
118 mg (65%) were obtained as a powder.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, C
D ₃ OD) δppm: 1.38-1.68 (4H, m), 2.16 (1H, dd, J = 14.5,
6.5Hz), 2.35 (1H, dd, J = 14.5,8.1Hz), 2.52-2.67 (2H, m), 2.
72 (1H, m), 3.55-3.66 (4H, m), 3.92 (1H, m), 7.16 (2H, m), 7.2
3 (2H, m) infrared absorption spectrum (KBr pellet, cm ^-1 ): 351
0,3298,3199,3095,2935,166
0, 1652, 1551, 1492 Mass spectrum (FAB): m / z [M + H] ⁺ = 359 High-resolution Mass spectrum (FAB): m / z [M + H] ⁺ = 359,
1381 _{Calculated: 359,1374 (C 16 H 24 ClN} 2 O 5) mp: 132-134 ° C. (Reference Example 1) acetic acid 2- (S) - [5- ( 4- chlorophyll
Enyl) -2- (R)-(N-hydroxycarbamoyl
Methyl) pentanoylamino] -1- (R) -methylca
Rubamoylmethyl-3-phenylpropyl ester 1-a) 3- (R)-[2- (R) -acetoxy- 1
-(S) -benzyl-3 -methylcarbamoylpropyl
Carbamoyl] -6- (4-chlorophenyl) hexane
Acid t-butyl ester 2- (R) -t-butoxycarbonylmethyl-5- (4
1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (352 m) was added to a solution of -chlorophenyl) pentanoic acid (500 mg) in methylene chloride (15 ml).
g), 1-hydroxybenzotriazole (248 m
g) and N-methylmorpholine (0.45 ml) were sequentially added, and the mixture was cooled to 0 ° C. Next, to this solution was added a solution of 4- (S) -amino-3- (R) -hydroxy-5-phenylpentanoic acid methylamide hydrochloride (594 mg) in N, N-dimethylformamide (4 ml), and the mixture was allowed to stand at room temperature for 23 hours. Agitated. The reaction solution was poured into 1N hydrochloric acid, and methylene chloride-
Extracted with tetrahydrofuran. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was dissolved in tetrahydrofuran (50 ml). Then pyridine (0.62 ml), 4-
Dimethylaminopyridine (19 mg), acetic anhydride (0.
72 ml), and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. 1 organic layer
The extract was washed successively with N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 3-eluted only with ethyl acetate) to obtain 587 mg of the desired compound (6 mg).
7%) as a foam.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 1.28-1.58 (4H, m), 1.36 (9H, s), 1.95 (3H, s), 2.0
2-2.15 (2H, m), 2.44 (1H, dd, J = 14.5,9.3Hz), 2.48-2.62 (4
H, m), 2.68 (1H, m), 2.69 (3H, s), 2.93 (1H, dd, J = 14.2,4.6H
z), 4.43 (1H, m), 5.28 (1H, m), 7.10-7.28 (9H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3303,1735,1
645,1542,1237,1159. Mass spectrum (FAB): m / z [M + H] ⁺ = 573 1-b) 3- (R)-[2- (R) -acetoxy-1
-(S) -benzyl-3-methylcarbamoylpropyl
Carbamoyl] -6- (4-chlorophenyl) hexane
3- (R)-[2- (R)-obtained in Acid Reference Example 1-a)
Acetoxy-1- (S) -benzyl-3-methylcarbamoylpropylcarbamoyl] -6- (4-chlorophenyl) hexanoic acid t-butyl ester (1.090
Using g), 886 mg (90%) of the target compound was obtained as white crystals in the same manner as in Example 8-d).

¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ O
D) δppm: 1.35-1.55 (4H, m), 1.95 (3H, s), 2.13-2.27 (2H,
m), 2.39-2.74 (5H, m), 2.43 (1H, dd, J = 14.6,9.4Hz), 2.69 (3
H, s), 2.92 (1H, dd, J = 14.2,4.6Hz), 4.41 (1H, m), 5.28 (1H,
m), 7.10-7.27 (9H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3289,2943,1
734, 1645, 1549, 1208. Mass spectrum (FAB): m / z [M + H] ⁺ = 517 Melting point: 183-185 ° C 1-c) Acetic acid 2- (S)-[5- (4-chlorophene)
Nil) -2- (R)-(N-hydroxycarbamoylmeth
Chill) pentanoylamino] -1- (R) - methylcarbamoyl Rukaru
Bamoylmethyl-3-phenylpropyl ester 3- (R)-[2- (R) -obtained in Reference Example 1-b).
Acetoxy-1- (S) -benzyl-3-methylcarbamoylpropylcarbamoyl] -6- (4-chlorophenyl) hexanoic acid (874 mg) and O- (t-butyldimethylsilyl) hydroxylamine (373 mg)
Using as a starting material, 318 mg (35%) of the target compound was obtained as a white powder in the same manner as in Example 32-b). ¹ H-nuclear magnetic resonance spectrum (400 MHz, CD ₃ OD) δ ppm: 1.2
8-1.56 (4H, m), 1.83-1.98 (2H, m), 1.95 (3H, s), 2.40-2.74
(5H, m), 2.44 (1H, dd, J = 14.6,9.6Hz), 2.69 (3H, s), 2.93 (1
H, dd, J = 14.1,4.5Hz), 4.40 (1H, m), 5.31 (1H, m), 7.10-7.27
(9H, m). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3311,3270,1
733,1653,1638,1541,1237. Mass spectrum (FAB): m / z [M + H] ⁺ = 532 High-resolution Mass spectrum (FAB): m / z [M + H] ⁺ = 532.2206 Calculated value: 532 .241 (C ₂₇ H ₃₅ ClN
₃ O ₆ ) Specific rotation: [α] _D ²⁵ = −0.7 ° (C: 1.03, MeO
H) mp:. 198 ~200 ℃ (dec) ( Reference Example ^{2) N 1 - [1- (} S) - benzyl-2-
(R) -hydroxy-3- (N-methylcarbamoyl)
Propyl] -2- (R)-[3- (4-chlorophenyl
) Propyl] -N ⁴ - hydroxysuccinimide Sina bromide (Compound No. 298) obtained in Reference Example 1-c) acetic acid 2- (S) - [5-
(4-Chlorophenyl) -2- (R)-(N-hydroxycarbamoylmethyl) pentanoylamino] -1-
Using (R) -methylcarbamoylmethyl-3-phenylpropyl ester (180 mg), 150 mg (91%) of the target compound was obtained as a white powder in the same manner as in Example 9.

The ¹ H-nuclear magnetic resonance spectrum (400 MHz, DMSO
-d ₆ ) δppm: 1.12-1.45 (4H, m), 1.69 (1H, dd, J = 14.4,5.1H
z), 1.78 (1H, dd, J = 14.4,9.4Hz), 2.08 (1H, m), 2.25 (1H, m),
2.36-2.64 (4H, m), 2.58 (3H, d, J = 4.5Hz), 3.02 (1H, m), 3.73
-3.85 (2H, m), 5.04 (1H, d, J = 5.5Hz), 7.08-7.30 (9H, m), 7.7
1 (1H, q, J = 4.5Hz), 7.80 (1H, d, J = 8.5Hz), 8.71 (1H, d, J = 1.2
Hz), 1.033 (1H, d, J = 1.2Hz). Infrared absorption spectrum (KBr pellet, cm ^-1 ): 3276,2940,1
. 645,1549,1493 mass spectrum (FAB): m / z [ M + H] + = 490 High resolution mass spectrum (FAB): m / z [ M + H] + = 490.2102 Calculated: 490.2108 (C ₂₅ H ₃₃ ClN ₃ O ₅ ) Melting point: 215 to 217 ° C (dec.) Formulation examples and test examples are shown below.

(Formulation Example 1) (Tablets) According to a conventional method, 100 mg of the compound of Example 1 was added in an amount of 0.2 mg.
mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 m
Produced using g starch and 98.8 mg lactose.

(Test Example 1) Inhibitory activity on gelatinase B
biotics, Vol. 45 1733-1737)
Was measured according to the method described above.

Specifically, gelatinase B was prepared from a serum-free culture of human fibrosarcoma cells supplemented with TNFα, and as a substrate, type I collagen prepared from rat tail was labeled with a radioisotope and then gelatinized by heat denaturation. The measurement was performed by measuring the cleavage of gelatin using the resulting gel.

[0485] Incidentally, Compound A, N ² - (4-hydroxy-amino -2- (R) - isobutyl -3- (S) - hydroxy succinyl) -L-t-leucine -N ¹ - is methylamide, WO94 -02447.

[0486]

[Table 2] Gelatinase B inhibitory activity (IC ₅₀ (nM))化合物 Compound of Example 11 4.2 Compound of Example 37 4.0 Compound A 2.1 ──────────────── (Test Example 2) Blood Concentration at Oral Administration The compound of the present invention was orally administered to experimental animals, and the plasma concentration was measured over time. That is, male mice (20 g) (1
Test compound (30 mg / kg / 2 ml PE)
G400: DMA 9: 1) was orally administered, and 15,
Blood was collected from the heart at 30, and 60 minutes.

The collected blood was centrifuged (11,000 rpm).
m, 5 minutes), 50 μl of plasma was deproteinized with 150 μl of acetonitrile, and the plasma concentration of the test compound was determined by LC
/ MS.

[0488]

[Table 3] ───────────────────────────────── Maximum blood concentration (Cmax (ng / ml)) ─化合物 Compound 950 of Example 11 Compound A 165 ───────── (Test Example 3) Inhibitory activity on collagenase-3 The activity of collagenase-3 was determined by the method of Knight et al.
tt. vol. 296, No. 3, 263-266, (1992)). That is, mRNA was isolated according to a conventional method using Human condrosarcoma HCS-2 / 8, and collagenase was isolated using RT-PCR.
3 cDNAs were obtained. This cDNA was incorporated into an expression vector, gene was introduced into COS-1 cells to express collagenase-3, and the serum-free culture was used as an enzyme solution. Further, using MOCAc-Pro-Leu-Gly- Leu-Dpa-Ala-Arg-NH 2 as substrate.

The enzyme solution and the substrate were mixed with 0.15 M NaCl, 10
mM CaCl ₂ , 0.05% Brij 35, 0.02% NaN ₃
For 1 hour. The reaction was stopped by adding 0.1 ml of 3% acetic acid, and the free MOCAc-Pro-Leu-Gl
The fluorescence of y was measured.

[0490]

Table 4 Collagenase-3 inhibitory activity (IC ₅₀ (nM))化合物 Compound of Example 37 0.69 Compound A 2.1 ─────────────────────── ───

[0490]

The hydroxamic acid derivative of the present invention has excellent matrix metalloproteinase inhibitory activity and good oral absorbability, so it is an agent for inhibiting metastasis, invasion and growth of various cancer cells or osteoarthritis. And a therapeutic or prophylactic agent for rheumatoid arthritis.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 333/36 C07D 333/36 (72) Inventor Susumu Suto 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Kazuhiko Tamaki 1-58 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Nobuka Kurihara 1-258 Hiromachi, Shinagawa-ku, Tokyo Sanko Co., Ltd. (72 ) Inventor Wanko Tanzawa 1-58, Hiromachi, Shinagawa-ku, Tokyo, Japan Sankyo Co., Ltd. (72) Inventor Tomoo Kobayashi 1-2-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Invention Person Shinichi Miura 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Inside Sankyo Co., Ltd.

Claims (26)

[Claims] 1. A compound of the general formula (1) In the above formula (1), R ¹ is an alkyl group having 1 to 15 carbon atoms which may have a substituent (the substituent is an alkoxy group having 1 to 6 carbon atoms, An aryl group having 6 to 10 carbon atoms (the substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxy group or a halogeno group having 1 to 4 carbon atoms), An aryloxy group having 6 to 10 carbon atoms (the substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogeno group) which may be possessed; An aralkyloxy group having 7 to 14 carbon atoms (the substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogeno group), which may have 3 to 8 cycloalkyl groups or 2 to 8 carbon atoms which may have a substituent Shows the alkoxyalkoxy group (said substituent is a halogeno group)), R ² represents a hydrogen atom, hydroxyl group or having 1 to 4 aliphatic acyloxy group having a carbon, R ³ is a substituted group An alkyl group having 1 to 6 carbon atoms which may have a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, and an alkyl group having 1 to 6 carbon atoms; Aliphatic acyloxy groups, an aryl group having 6 to 10 carbon atoms which may have a substituent,
(The substituent is an alkyl group having 1 to 4 carbon atoms, a hydroxy group, an aliphatic acyloxy group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halogeno group.) to indicate the 15 monocyclic or condensed heterocyclyl group is a (hetero atom contained within the ring nitrogen, oxygen or sulfur atom) or a cycloalkyl group having 3 to 8 carbon), R ⁴ is Hydrogen atom, alkoxycarbonyl group having 2 to 5 carbon atoms or carbon atom having 1 to 4 carbon atoms which may have a substituent;
Alkyl groups (the substituent is a hydroxy group,
1 to 4 alkoxy groups, an aliphatic acyloxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkylcarbamoyl group having 2 to 5 carbon atoms, and a dialkylcarbamoyl having 3 to 9 carbon atoms R ⁵ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ⁶ has a hydrogen atom or a substituent. Carbon number 1
To 6 aliphatic acyl groups (the substituents include an amino group, a monoalkylamino group having 1 to 4 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, and an alkoxycarbonyl group having 2 to 5 carbon atoms) A monocyclic or condensed heterocyclyl group or a carboxy group having 5 to 10 atoms or a carbamoyl group which may have a substituent (the substituent is an alkyl group having 1 to 4 carbon atoms; Which is an alkoxycarbonylalkyl group having 3 to 9 carbon atoms or a carboxyalkyl group having 2 to 5 carbon atoms (provided that R ¹ is an alkyl having 1 to 7 carbon atoms which may have a substituent). R ² is a hydrogen atom, and R ⁴ is an alkoxycarbonyl group having 2 to 5 carbon atoms or an alkyl group having 1 to 4 carbon atoms which may have a substituent (the The substituent has 2 to 2 carbon atoms. Number alkoxycarbonyl group, 2 to 5 amino alkylcarbamoyl group or a C 3 carbon atoms
To 9 dialkylcarbamoyl groups). ) A medicament comprising, as an active ingredient, a compound represented by (1) or a pharmacologically acceptable salt thereof. 2. R ¹ is an unsubstituted alkyl group having 4 to 10 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with an alkoxy group having 2 to 6 carbon atoms, a methyl, methoxy or chloro group. An alkyl group having 1 to 6 carbon atoms substituted with a phenyl group which may be substituted with 4 to 6 carbon atoms;
The alkyl group having 1 to 6 carbon atoms substituted with 1 to 6 cycloalkyl groups or the 1 to 6 carbon atoms substituted with 4 to 6 carbon alkoxyalkoxy groups. Medicine. (3) R ¹ is octyl, 7-methyloctyl,
Nonyl, 8-methylnonyl, phenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, 4-chlorophenylpropyl, cyclohexylmethyl, cyclohexylpropyl, 6-ethoxyhexyl,
The medicament according to claim 1, which is a 6-isopropoxyhexyl or 4-butoxybutyl group. 4. The method according to claim 1, wherein R ¹ is a nonyl, 7-methyloctyl or 3- (4-chlorophenyl) propyl group.
The medicament according to item 1. 5. The medicament according to claim 1, wherein R ¹ is a nonyl or 3- (4-chlorophenyl) propyl group. 6. The medicament according to claim 1, wherein R ² is a hydrogen atom, a hydroxy or an acetoxy group. 7. The medicament according to claim 1, wherein R ² is a hydrogen atom or a hydroxy group. Is 8. R ^3, unsubstituted C 1 to 4 alkyl groups, methylthio or C 1 to carbon atoms substituted by an ethylthio group 4 alkyl group, having 4 to 6 cycloalkyl group having a carbon A compound having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms, substituted with an unsubstituted phenyl group, or an acetoxy group. The medicament according to claim 1, which is a substituted alkyl group having 1 to 4 carbon atoms. Is 9. R ^3, isopropyl, tert- butyl, 1-methylpropyl, 2-methylpropyl, 1-methylthio-1-methylethyl, cyclohexyl methyl,
The medicament according to claim 1, which is a benzyl, hydroxymethyl or acetoxymethyl group. 10. The medicament according to claim 1, wherein R ³ is tert-butyl, 1-methylthio-1-methylethyl, cyclohexylmethyl or benzyl group. 11. The medicament according to claim 1, wherein R ³ is a tert-butyl or benzyl group. 12. R ⁴ is a hydrogen atom, an unsubstituted alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group, or a carbon number substituted with an ethoxycarbonyl group. 1 to 4 alkyl groups, an alkyl group having 1 to 4 carbon atoms substituted with an acetoxy group, an alkyl group having 1 to 4 carbon atoms substituted with a methylcarbamoyl group, and a carbon number substituted with a dimethylcarbamoyl group An alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a dimethylamino group, an alkyl group having 1 to 4 carbon atoms substituted with a dimethylamino group and a hydroxy group, or a dimethylamino group and acetoxy. The medicament according to claim 1, which is an alkyl group having 1 to 4 carbon atoms substituted with a group. 13. The medicament according to claim 1, wherein R ⁴ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group or an acetoxy group. 14. The method according to claim 1, wherein R ⁴ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group.
The medicament according to item 1. 15. R ⁴ is a hydrogen atom, hydroxymethyl,
The medicament according to claim 1, which is a 2-hydroxyethyl or 3-hydroxypropyl group. 16. The medicament according to claim 1, wherein R ⁴ is a hydrogen atom. 17. The medicament according to claim 1, wherein R ⁵ is a hydrogen atom. 18. R ⁶ is a hydrogen atom or an unsubstituted carbon number 2
The medicament according to claim 1, which is a C3 to C3 aliphatic acyl group, a C2 to C4 dialkylamino group or a C2 to C3 aliphatic acyl group substituted with a carboxy group. 19. The medicament according to claim 1, wherein R ⁶ is a hydrogen atom, acetyl or propionyl group. 20. The pharmaceutical according to claim 1, wherein R ⁶ is a hydrogen atom or an acetyl group. 21. A medicine containing as an active ingredient a compound represented by the following: 2- [3- (4-chlorophenyl) propyl] -N ⁴ - hydroxy -N ¹ - [1-hydroxy-2,2-dimethyl Propyl] succinamide, 2- [5- (4-chlorophenyl) acetic acid-2- (N-acetate)
Hydroxycarbamoylmethyl) pentanoylamino]
3,3-dimethyl-butyl ester, N ^{4-3-dihydroxy} -N ¹ - [1-hydroxy-2,2-dimethylpropyl] -2-nonyl disk Sina bromide, acetate 2- {2- [hydroxy (hydroxy Carbamoyl) methyl] undecanoylamino {-3,3-dimethylbutyl ester, acetic acid 2- [5- (4-chlorophenyl) -2- (N-
Hydroxycarbamoylmethyl) pentanoylamino]
3-phenylpropyl ester or N ¹ - [1-benzyl-2-hydroxy-ethyl] -2- [3- (4-chlorophenyl) propyl] -N ⁴ - hydroxysuccinimide Sina bromide. 22. An agent for inhibiting metastasis of cancer cells, comprising the compound as an active ingredient of the medicament according to any one of claims 1 to 21 and a pharmacologically acceptable carrier or excipient. 23. A cancer cell invasion inhibitor comprising the compound as an active ingredient of the medicament according to any one of claims 1 to 21 and a pharmacologically acceptable carrier or excipient. 24. A cancer cell growth inhibitor comprising the compound as an active ingredient of the medicament according to claim 1 and a pharmaceutically acceptable carrier or excipient. 25. A therapeutic or prophylactic agent for osteoarthritis comprising the compound as an active ingredient of the medicament according to any one of claims 1 to 21 and a pharmacologically acceptable carrier or excipient. 26. A therapeutic or prophylactic agent for rheumatoid arthritis, comprising a compound as an active ingredient of the medicament according to any one of claims 1 to 21 and a pharmacologically acceptable carrier or excipient.