WO1997031892A1

WO1997031892A1 - Hydroxamic acid derivatives

Info

Publication number: WO1997031892A1
Application number: PCT/JP1997/000582
Authority: WO
Inventors: Tomoyuki Shibata; Nobuyuki Ohkawa; Toshiyasu Takemoto; Susumu Sato; Kazuhiko Tamaki; Shinwa Kurihara; Kazuhiko Tanzawa; Tomowo Kobayashi; Shinichi Miura
Original assignee: Sankyo Company, Limited
Priority date: 1996-03-01
Filing date: 1997-02-27
Publication date: 1997-09-04
Also published as: AU1812197A

Abstract

Compounds represented by general formula (1), which have excellent inhibitory activities on matrix metaproteinases and are useful as a cancerous metastasis inhibitor, etc.; wherein R1 represents optionally substituted C¿1-15? alkyl; R?2¿ represents H, hydroxy or C¿1-4? acyloxy; R?3¿ represents optionally substituted C¿1-6? alkyl; R?4¿ represents H, C¿2-5? alkoxycarbonyl or optionally substituted C1-4 alkyl; R?5¿ represents H or C¿1-4? alkyl; and R?6¿ represents H, optionally substituted C¿2-5? acyl or optionally substituted carbamoyl.

Description

Hydroxamic acid derivative

TECHNICAL FIELD The present invention relates to a novel yarn having excellent matrix metallobrotinase inhibitory activity.

The present invention relates to a hydroxamic acid derivative, an agent for inhibiting metastasis, invasion and growth of various cancer cells, and a therapeutic and prophylactic agent for osteoarthritis and rheumatoid arthritis, which contain the derivative as an active ingredient. Background branch surgery Matrix meta-oral proteinase is an enzyme that degrades the protein components that make up connective tissue. Gelatinase, which belongs to this group, degrades type IV collagen, a major component of the basement membrane. In the process of neovascularization and metastasis of cancer in cancer tissues, the expression of gelatinase is increased or activated. Therefore, it is said that gelatinase plays an important role in destroying the basement membrane of cells in normal tissues (Annua 1 Review of Cell Biology, vol. 9). , 541-573 (1993)).

In addition, in osteoarthritis, the expression level of collagenase, which is a function of matrix metallobutinase in tissue cells, is increased or activated, and in rheumatoid arthritis, Expression of stromelysin in the matrix metalob 丄

Sexualization is taking place. For this reason, it is said that collagena zestromelysin plays an important role in joint destruction (J. C1 inn. Inves, vol. 97, 76 1-768 (1996), L. a b. Invest, vol. 66, 680-690 (1992)). Therefore, based on the above findings, agents that inhibit Matrix meta-oral proteinase are useful as agents for inhibiting metastasis, invasion, and growth of various cancer cells, and as agents for treating and preventing osteoarthritis and rheumatoid arthritis. it is conceivable that. Many compounds have been reported to be inhibitors of matrix metallobutin tinase (Currentedicinal Chemistryvol. 2, 743-762 (1959)), and in particular, hydroxamic acid derivatives have recently been developed. Many patent applications have been filed (W 094-02446, W094-02447, W095-19956, W095-1957, W095-19961, W096-06074, W096-16931, W093-24449, W093 -24475, W094- 25434, W094-25435, W09 5-04033, W092-22523). Among these inhibitors, N ² described in WO 94-02447 — (4-Hydroxyamino-12- (R) -isobutyl-3- (S) -hydroxysuccinyl) —L-t-one-isocyanate-N ¹ -Methylamide is undergoing clinical trials in Europe and the United States as an anticancer agent (Proceedings of American As soci at ion for cancer Research, vol. 37, 633 (1996)). The present inventors have conducted intensive studies on the synthesis of a derivative having excellent matrix metallobrotinase inhibitory activity and its pharmacological activity, and as a result, it has excellent enzyme inhibitory activity on matrix metallobulininase. And has good oral absorption, and The present inventors have found novel derivatives useful as agents for inhibiting metastasis, invasion and proliferation of various cancer cells, and as therapeutic and preventive agents for osteoarthritis and rheumatoid arthritis, and completed the present invention. The present invention relates to a novel hydroxamic acid derivative having excellent matrix meta-oral proteinase inhibitory activity, and an agent for inhibiting metastasis, invasion and growth of various cancer cells, and an osteoarthritis containing the derivative as an active ingredient. And a therapeutic and prophylactic agent for rheumatoid arthritis. DISCLOSURE OF THE INVENTION The compound of the present invention has the general formula (1)

And a pharmacologically acceptable salt thereof, 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,

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, an alkoxy group or a halogeno group having 1 to 4 carbon atoms),

Aryloxy group having 6 to 10 carbon atoms which may have a substituent f

An aralkyloxy group having 7 to i4 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) ,

C3-C8 cycloalkyl group

Or

An alkoxyalkoxy group having 2 to 8 carbon atoms which may have a substituent (the substituent is a halogeno group)

Is)

Indicates that

R ² represents a hydrogen atom, a hydroxy group or an aliphatic acyloxy port having 1 to 4 carbon atoms,

R ³ is 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,

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 alkoxy group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or a halogeno group),

A monocyclic or condensed heterocyclyl group having 5 to 15 atoms (hetero atoms contained in the ring are nitrogen, oxygen or sulfur atoms) Or

C3-C8 cycloalkyl group

Is)

Indicates that

R ⁴ is a hydrogen atom,

C2-C5 alkoxycarbonyl group

Or

An alkyl group having 1 to 4 carbon atoms which may have a substituent (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, C2-C5 alkoxyl-rubonyl group, C2-C5 alkyl-rubamyl group, C3-C9 dialkyl-rubamoyl group, or C2-C8 dialkylamino group

Is)

Indicates that

R ⁵ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,

R ^e is a hydrogen atom,

An aliphatic acyl group having 1 to 6 carbon atoms which may have a substituent (an amino group, a monoalkylamino group having 1 to 4 carbon atoms, a dialkylamino having 2 to 8 carbon atoms) Group, an alkoxycarbonyl group having 2 to 5 carbon atoms, a monocyclic or condensed heterocyclyl group having 5 to 10 atoms or a carboxy group)

Or

An optionally substituted carbamoyl group

(The substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxycarbonylalkyl group having 3 to 9 carbon atoms, or a carboxy group having 2 to 5 carbon atoms. b

Is a xyalkyl group)

(Provided that R ¹ is an optionally substituted alkyl group having 1 to 7 carbon atoms, R ² is a hydrogen atom, and R ⁴ is 2 to 5 carbon atoms) An alkoxycarbonyl group or an alkyl group having 1 to 4 carbon atoms which may have a substituent (the substituent is an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkyl group having 2 to 5 carbon atoms) Which is a rubamoyl group or a dialkyl 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, 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, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methyl Tylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1- Bropylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 7-methyloctyl, 1-propylhexyl, 2-ethylethyl, 2-ethylethyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl, 7,7-dimethyloctyl, pendecyl, 4,8-dimethylnonyl, dodecyl, Ridecyl, Tetradecyl, Pencil Decyl, 3, 7, 11-Trimethyldode Preferably, when unsubstituted, those having 4 to 10 carbon atoms (particularly, isobutyl, octyl, nonyl, 7-methyloctyl, decyl and 8-methylnonyl groups), Preferred are those having 8 to 10 carbon atoms (especially octyl, 7-methyloctyl, nonyl and 8-methylnonyl groups), and most preferred are those having 9 carbon atoms (especially nonyl and 7-methyloctyl). And when it has a substituent, it has 1 to 6 carbon atoms (especially methyl, propyl, butyl and hexyl groups). In the above formula (1), R ¹ s s is an integer having 1 to 15 carbon atoms which may have a substituent. When it is an “s-alkyl group”, the number of substitution is preferably 1 to 3, and more preferably 1. In the above formula (1), as the substituent in the “alkyl group having 1 to 15 carbon atoms which may have a substituent” for R ′, the “alkoxy group having 1 to 6 carbon atoms” is For example, 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 group and the like, preferably those having 2 to 4 carbon atoms (especially ethoxy, isopropoxy and butoxy groups). The substituent is an aryl group having 6 to 10 carbon atoms which may have a substituent (the substituent may be an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halogeno group). And the like) are, for example, unsubstituted aryl groups such as phenyl and naphthyl; 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-bromophenyl, 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-diphenylpyruphenyl, 2,4-diphenylbiphenyl, 2,3,6-trimethylphenyl, 2,3,4-trimethylphenyl 2,3,4,5-trimethylphenyl, 2,5,6-trimethylphenyl, 2,4,6-trimethylphenyl.2,3,6-Tributylphenyl, 2,3,4-tripentylphenyl Nyl, 3,4,5-Tributylphenyl, 2,5,6-Tripropylphenyl, 2,4,6—Tribrovirphenyl, 1-Methyl-2-Naphthyl, 2-Methyl-1 Naphthyl 3-Methyl-1-naphthyl, 1-Ethyl-2-naphthyl, 2-Bropropyl-1-naphthyl, 3-Butyl-1-naphthyl, 3,8-Dimethyl-1-naphthyl, 2,3-Dimethyl-1-naphthyl, 4,8-Dimethyl-1-naphthyl, 5,6-Dimethyl-11-naphthyl, 3,8-Jetyl-1-naphthyl, 2,3-Dipropyl-11-naphthyl, 4,8-Dipentyl-11-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 — Alkyl-substituted aryl groups such as trimethyl-1-naphthyl, 2,4,8-trimethyl-1-naphthyl; 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxy Enil, 3-propoxyphenyl , 4-ethoxyphenyl, 2-butoxyphenyl, 3-pentoxyphenyl, 4-pentoxyphenyl, 3,5-dimethylethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 2,4 Dimethoxyphenyl, 3,5-dibutoxyphenyl, 2,5-dipentoxyphenyl, 2,6-dipropoxyphenyl, 2,4-dibromoxyphenyl, 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-triphenyloxyphenyl, 3,4,5-tributoxyphenyl, 2,5,6-tribromoboxyl, 2,4,6-tribromoxyphenyl, 1-methoxy2 —Na Tyl, 2-methoxy-1-naphthyl, 3-methoxy-1-naphthyl, 1-1ethoxy-2-naphthyl, 2-propoxy-1-naphthyl, 3-butoxy-1-naphthyl, 3,8-dimethyl Xyi 1-naphthyl, 2,3-dimethoxy 1-naphthyl, 4,8-dimethyloxy 1-naphthyl, 5,6-dimethoxy 1-naphthyl, 3,8-jetoxy 1-naphthyl, 2,3 —Dibromoxie 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-trimethoxy 1-naphthyl fc

Alkoxy substituted aryl groups such as 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl 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-triphenyl Fluorophenyl, 2,4,6-trifluorophenyl, 2,3,6-tribromophenyl, 2,3,4-tribromophenyl, 3,4,5-tribromophenyl Nyl, 2,5,6—Trichloro mouth phenyl, 2,4,6—Tricyclo mouth phenyl, 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-jib-mouth 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-trifluoro Lifluoro-1 naphthyl group Aryl-substituted aryl groups such as; 1-methyl-3-methoxyphenyl, aryl groups substituted with alkyl and alkoxy groups such as 3-ethyl-4-ethoxyphenyl; 3-methyl-5-fluorophenyl, 2-ethyl-4 —Aryl groups substituted with alkyl and halogeno groups such as chlorophenyl; aryl groups substituted with alkoxy and halogeno groups such as 3-methoxy-6-fluorophenyl and 2-ethoxy-13-chlorophenyl. And preferably a phenyl group which may have a substituent (the number of substituents is preferably 1 to 3, and more preferably 1). Preferably, a phenyl group which is unsubstituted or substituted by one methyl, methoxy or chloro group, I i

Preferable are phenyl, 4-methylphenyl, 4-methoxyphenyl and 4-chlorophenyl (particularly 4-chlorophenyl), and the substituent " A good aryloxy 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) is, for example, phenyloxy. Unsubstituted aryloxy groups such as naphthyloxy group; 2-methylphenyloxy, 3-methylphenyloxy, 4-methylphenyloxy, 2-ethylphenyloxy, 3-propylphenyloxy , 4-ethylphenyloxy, 2-butylphenyloxy, 3-pentylphenyloxy, 4-pentylphenyloxy, 3,5-dimethylphenyloxy, 2,5-dimethylphenyl Niloxy, 2,6-dimethylphenyloxy, 2,4-dimethylphenyloxy, 3,5-dibutylphenyloxy, 2,5-dipentylphenyloxy, 2,6-dibutyl biphenyloxy, 2,4-dipro Bilphenoxy, 2,3,6-trimethylphenyloxy, 2,3,4-trimethylphenyloxy, 3,4,5-trimethylphenyloxy, 2,5,6-trimethyl Limethylphenyloxy, 2,4,6-Trimethylphenyloxy, 2,3,6-Tributylphenyloxy, 2,3,4-Tripentylphenyloxy, 3,4,5- Tributyl phenyloxy, 2, 5, 6-triphenyl bilphenyl, 2, 4, 6-tributyl bilenyl, 1-methyl-2-naphthyloxy, 2-methyl-11-naphthyloxy , 3-methyl-1 -naphthyloxy, 1- Cyl-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-11-naphthyloxy, 3,8-Jetyl-1-1 naphthyloxy, 2,3-dibucchi building-1-1-naphthyloxy, 4,8-dipentyl-1-naphthyloxy, 5,6-dibutyl-1 1-naphthyloxy, 2,3,6-trimethyl-1-naphthyloxy, 2,3,4-trimethyl-1-naphthyloxy, 3,4,5-trimethyl-1-naphthyloxy, 4,5,6-trimethyl I-naphthyloxy, 2,4,8-trimethyl-11-alkyl-substituted aryloxy groups such as naphthyloxy group; 2-methoxyphenyloxy, 3-methoxyphenyloxy, 4-methoxy Siphenyloxy, 2-ethoxyphenyloxy, 3-propoxyphenyloxy, 4-ethoxyphenyloxy, 2-butoxyphenyloxy, 3-pentoxyphenyloxy, 4-pentoxy Xyphenoxy, 3,5-dimethoxyphenoxy, 2,5-dimethoxyphenyloxy, 2,6-dimethoxyphenyloxy, 2,4-dimethoxyphenyloxy, 3,5 —Dibutoxyphenyloxy, 2,5—Dipentoxyphenyloxy, 2,6 1-dibutoxyphenyloxy, 2,4,1-dibutoxyoxyphenyl, 2,3,6 Lime Toxifeniroki 2,3,4-trimethoxyphenyloxy, 3,4,5-trimethoxyphenyloxy, 2,5,6-trimethoxyphenyloxy, 2,4,6-trimethoxyphenyloxy Triethoxyphenyloxy, 2,3,6- Tributoxyphenyloxy, 2,3,4-Tripentoxyphenyloxy, 3,4,5-Tributoxyphenyloxy, 2,5,6— Tribromoboxyloxy, 2, 4, 6-Triphenyloxy-phenyloxy, 1-Methoxy-2-Naphthyloxy, 2-Methoxy-11-Naphthyloxy, 3-Methoxy-11-Naphthyloxy, 1 1-ethoxy 2-naphthyl, 2-propoxy 1 1-naphthyloxy, 3-butoxy 1 1-naphthoxy, 3,8-dimethoxy 1-naphthyloxy, 2,3-dimethoxy 1-naphthoxy, 4,8-dimethoxy 1 1 — naphthyloxy 5, 6-Dimethoxy 1-naphthyloxy, 3,8-Diethoxy 1-naphthyloxy, 2, 3-Dibutoxy 1-naphthyloxy, 4, 8-Dipentoxy 1-naphthyl, 5, 6-Dibutoxy 1— Naphthyloxy, 2,3,6-trimethoxyl-naphthyloxy, 2,3,4-trimethoxyl-l-naphthyloxy, 3,4,5—trimethoxyl-l-l-naphthoxyl, 4,5,6-trimethoxy 1-naphthyloxy, 2,4,8-trimethyloxy-1 Alkoxy-substituted aryloxy group such as 1-naphthyloxy group; 2-fluorophenyloxy, 3-fluorophenyloxy, 4-fluorophenyloxy, 2 —Black mouth phenyloxy—3—Black mouth phenyloxy, 4 Monochrome phenyloxy, 2-Bromophenyl /

Oxy, 3-bromophenyloxy, 4-bromophenyloxy, 3,5-difluorophenyloxy, 2,5-difluorophenyloxy, 2,6-difluoromethylphenyl, 2,2-difluorophenyloxy 4-difluorophenyloxy, 3,5-dibromophenyloxy, 2,5-dibromophenyloxy, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 2,3,6-trifluorophenyl 2,3,4-trifluorophenyloxy, 3,4,5-trifluorophenyloxy, 2,5,6-trifluorophenyloxy, 2,4,6-trifluorophenyloxy Xy, 2,3,6-tribromophenyloxy, 2,3,4-tribromophenyloxy, 3,4,5-tribromophenyloxy, 2,5,6 Phenyloxy, 2, 4, 6-trichloro 1-Fluoro-2-naphthyloxy, 2-fluoro-1-naphthyloxy, 3-fluoro-1-naphthyloxy, 1-naphthyloxy, 2-chloro-naphthyloxy, 2-chloro-1-naphthyloxy, 3-bromo-11 Naphthyloxy, 3,8-difluoro-11-naphthyloxy, 2,3-difluoro-11-naphthyloxy, 4,8-difluoro-1-naphthyloxy, 5,6-difluoro-1-naphthyloxy, 3,8-dichloro-11-naphthyloxy, 2, 3-Dichloro-1-naphthyloxy, 4,8-Jib mouth 1-naphthyloxy, 5,6-Jib mouth 1-naphthyloxy, 2, 3, 6-Trifluoro-1-naphthyloxy, 2,3,4-Trifluoro-1 1-naphthyloxy, 3,4,5-trifluoro-1-naphthyloxy, 4,5,6-trifluoro-1-na Halogeno-substituted aryloxy groups such as tyloxy, 2,4,8-trifluoro-1-naphthyloxy; alkyls and alkoxys such as 1-methyl-3-methoxyphenyloxy, 3-ethyl-4-ethoxyphenyloxy Aryloxy group substituted with alkyl and halogeno groups such as 3-methyl-5-fluorophenyloxy, 2-ethyl-4-chlorophenyl, and ₃ -methoxy-6-fluoro Examples thereof include an aryloxy group substituted with an alkoxy group and a halogeno group, such as phenyloxy and 2-ethoxy-3-chlorophenyloxy. Preferably, a phenyloxy group which may have a substituent (the number of substituents) Is preferably one to three, No

More preferably, it is 1). More preferably, unsubstituted or 1 methyl

A phenyloxy group substituted with a methoxy or chloro group, more preferably a phenyloxy, 4-methylphenyloxy, 4-methoxyphenyloxy or 4-cyclophenyloxy group. And the substituent is 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, and an alkyl group having 1 to 4 carbon atoms, An alkoxy group or a halogeno group)] are benzyloxy, α-naphthylmethyloxy, / 3-naphthylmethyloxy, 2-methylbenzyloxy, 3-methylbenzyloxy, 4-methylbenzyloxy, 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-naphthylethyl, naphthylethyl, 1-naphthylethyloxy, 1 1-phenylpropoxy, 2-phenylpropyl, 3-phenylpropyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylviroxy, 1-phenylbutyroxy, 2-phenylbutyloxy Xy, 3-phenylbutyloxy, 4-phenylbutyloxy, 1-naphthylbutyloxy, 2-naphthylbutyloxy, 3-naphthylbutyloxy, 4-naphthylbutyloxy, 1-phenylpentyloxy Xy, 2-phenylpentyloxy, 3-phenylpentyloxy, 4-phenylpentyloxy, 5-phenylpentyloxy, 1-phenylhexyloxy, 2-phenylhexyloxy, 3-phenylhexyloxy, 4-phenylhexyloxy, 5-phenylhexyloxy, 6-phenylhexyloxy, etc. Preferred is an unsubstituted benzyloxy group, more preferably an unsubstituted benzyloxy group, and the substituent “cycloalkyl group having 3 to 8 carbon atoms” is cyclobutyl / Pill, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl group, preferably 4 to 6 carbon atoms, more preferably cyclohexyl group, The substituent “alkoxyalkoxy group having 2 to 8 carbon atoms which may have a substituent (the substituent is an octalogeno group)” J is methoxymethoxy, ethoxyethoxy, ethoxymethyl or the like. Toxi, isopropoxymethoxy, fluoromethoxime, (2,2,2-trifluoroethoxy) methoxy, trifluoromethoxime, chloromethoxime, promomethoxime, odomethoxime Examples include toxic, methoxybutoxy and butoxybutoxy groups, preferably those having 3 to 6 carbon atoms. Ri, more preferably, Etokishe Bok carboxymethyl, I Sopurobokishe Bok alkoxy and (2, 2, 2-Torifuruoroe Bok carboxymethyl) a main Bok alkoxy group,

Preferred as R ¹ `` an alkyl group having 1 to 15 carbon atoms which may have a substituent '' as a whole,

Even if substituted with 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 methyl group Alkyl groups having 1 to 6 carbon atoms substituted with a good phenyl group, alkyl groups having 1 to 6 carbon atoms substituted with a cycloalkyl group having 4 to 6 carbon atoms, and alkoxy groups having 4 to 6 carbon atoms An alkyl group having 1 to 6 carbon atoms substituted with an alkoxy group; more preferably, octyl, 7-methyloctyl, nonyl, 8-methylnonyl, 3-phenylpropyl, 3- (4-methylphenyl) propyl, 3 — (4-methoxyphenyl) bromo, 3- (4-chlorophenyl) propyl, cyclohexylmethyl, 3- (cyclohexyl) propyl, 6-ethoxyhexyl, 6-isoprop A cyclohexyl and 4 _ butoxybutyl to Bokishi, and most preferably, nonyl, 7-Mechiruokuchiru and 3- (4 one black port phenyl) Buropiru group. In the above formula (I), examples of the “aliphatic acyloxy group having 1 to 6 carbon atoms” for R ² include, for example, formyloxy, acetoxy, propionyloxy, petyriloxy, pentanoyloxy group and the like. Is an acetate group. In the above formula (1), as 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 , for example, methyl, Ethyl, η-propyl, isopropyl, η-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 group, etc., preferably having 1 to 4 carbon atoms which may have a substituent, and more preferably, In the case of substitution, they are isopropyl, isobutyl, s-butyl and tert-butyl, and in the case of having a substituent, they are methyl, ethyl and isopropyl (especially methyl and ethyl). In the formula (1), examples of the “C 1 to C 4 alkoxy group” as a substituent in the “optionally substituted C 1 to C ⁶ alkyl group” for R ³ include, for example, , Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, tert-butoxy groups, and is preferably a methoxy group. Examples of the “to 4 alkylthio groups” include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, s-butylthio, and tert-butyl. And preferably a methylthio and an ethylthio group, more preferably a methylthio group, '

Examples of the substituent "aliphatic acyloxy group having 1 to 6 carbon atoms" include, for example, formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy, and the like. , An ethoxy group, and the substituent, "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 alkoxy group having 1 to 4 carbon atoms, an alkoxy group or a halogeno group having 1 to 4 carbon atoms)), for example, an aryl group such as a phenyl or naphthyl group; Tylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-propylphenyl, 4-ethylphenyl, 2-butylphenyl, 3-pentylphenyl, 4-pentylphenyl Nyl, 3,5-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl, 2,4-dimethylphenyl, 3,5-dibutylphenyl, 2,5-dipentylphenyl, 2,6-dib Mouth pyrphenyl, 2,4-dibu Mouth pyrphenyl, 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-Triprophenyl Bilphenyl, 2,4,6-Triprovirphenyl, 1-Methyl-2-naphthyl, 2-Methyl-1-naphthyl, 3-Methyl-1-naphthyl, 1-Ethyl-2-naphthyl, 2-Provyl-1-naphthyl , 3-butyl-one-naphthyl, 3, 8-Dimethyl-1-naphthyl, 2,3-Dimethyl-1-naphthyl, 4,8-Dimethyl-1-naphthyl, 5,6-Dimethyl-1-naphthyl, 3,8-Jetyl-1-naphthyl, 2,3-Jib mouth Pill-1-1-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 Alkyl-substituted aryl groups such as, 5 — trimethyl- 1-naphthyl, 4,5,6-trimethyl- 1-naphthyl, 2,4,8-trimethyl- 1-naphthyl; 2-hydro Hydroxy-substituted aryl groups such as xyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl; 2-acetoxyphenyl, 3-acetoxyphenyl, 4-acetoxyphenyl, 4 Aliphatic acyloxy-substituted aryl groups such as monopropionyloxyphenyl; 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-propoxyphenyl, 4 1-ethoxyphenyl, 2-butoxyphenyl, 3-pentoxyphenyl, 4-pentoxyphenyl, 3,5-dimethylethoxyphenyl, 2,5-dimethyloxyphenyl, 2,6-dimethyloxyphenyl, 2, 4-dimethoxyphenyl, 3,5-dibutoxyphenyl, 2,5-dipentoxyphenyl, 2,6-dibromoxethoxyphenyl 2,4-dibromoboxyl, 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-Tributyphenyl Xyphenyl, 2,5,6-tripropoxyphenyl, 2,4,6-tripropoxyphenyl, 1-methoxy-2-naphthyl, 2-methoxy-1-naphthyl, 3-methoxy-1-naphthyl, 1 2-ethoxy-naphthyl, 2-propoxy-1-naphthyl, 3-butoxy-1-naphthyl, 3,8-dimethyloxy-naphthyl, 2,3-dimethyloxy-naphthyl, 4,8 —Dimethoxy 1-naphthyl, 5, 6—Dimethoxy 1-naphthyl, 3, 8 Diethoxy 1-naphthyl, 2,3-dibromoboxy-naphthyl, 4,8-dipentoxy 1-naphthyl, 5,6-dibutoxy 1-1-naphthyl, 2,3,6-trimethoxy 1-naphthyl, 2,2 Like 3,4-trimethoxy-1-naphthyl, 3,4,5-trimethoxy-1-naphthyl, 4,5,6-trimethoxy-1-naphthyl, 2,4,8-trimethoxy-1-naphthyl Alkoxy substituted aryl groups; 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-di >?

Fluorophenyl, 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-trichloromethylphenyl, 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—Difluo -1-naphthyl, 5,6-difluoro-l-naphthyl, 3,8-dichloro-l-naphthyl, 2,3-dichloro-l-naphthyl, 4,8-jib-mouth 1-naphthyl, 5,6-jib-mouth Mo 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 Halogeno-substituted aryl groups such as mononaphthyl and 2,4,8-trifluoro-1-naphthyl; and the like, preferably a phenyl group optionally having 1 to 3 substituents; And the substituent “a monocyclic or condensed heterocyclyl group having 5 to 10 atoms (the heteroatom contained in the ring is a nitrogen, oxygen or sulfur atom)” is a nitrogen atom, oxygen or Z And a 5- to 7-membered heterocyclic group containing 1 to 3 nitrogen atoms (for example, , Furyl, thienyl, pyrrolyl, azevinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, viridanyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridyl, pyridinyl Thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, vilazolidinyl, villazolinyl, biperidyl, piperazinyl, and the like; and groups obtained by condensing these “5- to 7-membered heterocyclic groups” with other cyclic groups (for example, benzofuranyl, Benzofuranyl, iO

Romenyl, xanthenyl, pentoxathiinyl, indolizinyl, isoindolinyl, indolyl, indazolyl, prenyl, quinolizinyl, isoquinolyl, quinolyl, phthalazur, naphthyridinyl, quinoxalinyl, quinazolinyl, kyvalzazolyl, carbolinyl, azolidinyl) Preferable are a furyl, phenyl and benzofuranyl group, more preferably a furyl group, and the substituent "the cycloalkyl group having 3 to 8 carbon atoms" is , Cyclobutyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups, preferably having 4 to 6 carbon atoms (especially cyclohexyl group),

As a whole, “an alkyl group having 1 to 6 carbon atoms which may have a substituent” for R ³ is preferably an unsubstituted alkyl group having 1 to 4 carbon atoms, methylthio or ethylthio. Alkyl group substituted with 1 to 4 carbon atoms, methyl and ethyl groups substituted with 4 to 6 cycloalkyl groups, and 1 to 4 carbon atoms substituted with unsubstituted phenyl group And an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group and an alkyl group having 1 to 4 carbon atoms substituted with an acetyl group. Isobrovir, tert-butyl, 1-methylpropyl, 2-methylpropyl, 1-methylthio-1-methylethyl, cyclohexylmethyl, benzyl, hydroxymethyl and acetomethyl groups, most preferably tert-butyl. Le, 1 Mechiruchio one 1 Mechiruechiru, is cyclohexylmethyl cyclohexylene and benzyl groups (especially tert- butyl and downy Njiru group)

In the above formula (1), examples of the “alkoxycarbonyl group having 2 to 5 carbon atoms” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl /

And s-butoxycarbonyl and tert-butoxycarbonyl groups, preferably methoxycarbonyl and ethoxycarbonyl groups. In the above formula (1), examples of 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 include methyl, Examples include ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl and tert-butyl groups, preferably methyl, ethyl and propyl groups, and more preferably methyl and ethyl groups. In the above formula (1), examples of the “C 1 to C 4 alkoxy group” which is a substituent in the “optionally substituted C 1 to C 4 alkyl group” include: Examples include methoxy, ethoxy, propoxy, isobroboxy, butoxy, isobutoxy, s-butoxy and tert-butoxy groups, and are preferably methoxy and ethoxy groups, and the substituents "1 to 1 carbon atoms" Examples of the "six aliphatic radicals" include, for example, acetate, propionyloxy, butyryloxy and pentanoyl radicals, preferably those having 2 to 3 carbon atoms (ie, Acetoxy and propionyloxy groups), and more preferably an acetoxy group, and the substituent “an alkoxycarbonyl group having 2 to 5 carbon atoms j” Examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, and the like. Preferably, it is an ethoxycarbonyl group, and the substituent "alkyl C2-5 alkyl group" is preferred. Examples include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamine, butylcarbamoyl, isobutylcarbamoyl, s-butylcarbamoyl and tert-butylcarbamoyl groups. Rucarbamoyl and ethylcarbamoyl groups, more preferably a methylcarbamolyl group, and the substituent “dialkyl-powered rubamoyl group having 3 to 9 carbon atoms” includes, for example, dimethylcarbamoyl, methyl (ethyl) Power rubamoyl, getylcarbamoyl, dipropyl power rubamoyl, methyl (propyl) power rubamoyl, diisoprovil power rubamoyl, dibutyl carbamoyl, diisobutyl carbamoyl, di (s-butyl) power rubamoyl, di (tert-butyl) power rubamoyl group, etc. And preferably a dimethylcarbamoyl group and a dimethylcarbamoyl group, more preferably a dimethylcarbamoyl group, and the substituent “dialkylamino group having 2 to 8 carbon atoms” is dimethylamino. , Methyl (Ethyl) amino, getylamino, methyl (propyl) amino, dibuviramino, diisopropylamino, dibutylamino, diisobutylamino, di (s-butyl) amino, di (tert-butyl) amino and the like. Is a dimethylamino and getylamino group, more preferably a dimethylamino group,

As a whole, “an alkyl group having 1 to 4 carbon atoms which may have a substituent” for R ⁴ is preferably an unsubstituted alkyl group having 1 to 4 carbon atoms or a hydroxy group. Alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with an ethoxycarbonyl group, an alkyl group having 1 to 4 carbon atoms substituted with an ethoxy group, and a methylcarbamoyl group. A substituted alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with a dimethylcarbamoyl group, an alkyl group having 1 to 4 carbon atoms substituted with a dimethylamino group, and a dimethylamino group. And alkyl groups having 1 to 4 carbon atoms substituted with hydroxy and hydroxy groups, and alkyl groups having 1 to 4 carbon atoms substituted with dimethylamino and acetooxy groups (especially methyl, ethyl, hydroxyme Le, 2 - hydroxy E Chill, 3 - hydroxypropionic building, Ethoxycarbonylmethyl, acetoxymethyl, 2-acetoxitytyl, 3-acetooxypropyl, methylcarbamoylmethyl, dimethylcarbamoylmethyl, dimethylaminoethyl, 3-dimethylamino-2-hydroxypropyl and 3-dimethylamino-2-ace And more preferably an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group or an alkyl group having 1 to 4 carbon atoms substituted with an acetyl group (especially, phenyl group). Hydroxyalkyl, 2-hydroxypropyl, 3-hydroxypropyl, acetomethyl, 2-acetoxethyl, and 3-acetooxypropyl groups), more preferably an alkyl having 1 to 4 carbon atoms substituted with a hydroxy group. Groups (especially hydroxymethyl, 2-hydroxyl, 3-hydroxy It is a Rokishipurobiru). In the above formula (1), the “alkyl group having 1 to 4 carbon atoms” for R ⁵ includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl and tert-butyl groups And preferably a methyl group. In the above formula (1), as "aliphatic Ashiru group having 1 to 6 carbon atoms" in "optionally aliphatic Ashiru group which may having 1 to 6 carbon atoms have a substituent" for R ^e is, for example, And formyl, acetyl, propionyl, butyryl, isoptyryl, pentanoyl, and vivaloyl 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 monoalkylamino group having 1 to 4 carbon atoms” which is a substituent of “an aliphatic acryl group having 1 to 6 carbon atoms which may have a substituent” for R ⁶ Examples thereof include a methylamino, ethylamino, propylamino, isobroviramino, butylamino, isobutylamino, s-butylamino and tert-butylamino group, preferably a methylamino group, and the substituent, "C2 having 2 carbon atoms" Or 8 dialkylamino groups '' , Dimethylamino, methyl (ethyl) amino, getylamino, methyl (propyl) amino, dibutylamino, diisopropylamino, diisopropylamino, dibutylamino, disobutylamino, di (s-butyl) amino, di (tert-butyl) amino and the like. And preferably 2 to 4, more preferably a dimethylamino group, and the substituent “alkoxycarbonyl group having 2 to 5 carbon atoms” is, for example, Toxoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isobroboxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl and tert-butoxycarbonyl groups, preferably ethoxycarbonyl group, Is "5 to 15 atoms Ring or heterocyclyl groups condensed (heteroatom nitrogen contained in the ring, oxygen or sulfur atom) as the "aforementioned alkyl" substituent a good number 1 to 6 carbon atoms which may have R ³ The same substituents as those described above as the substituent of the `` group '' can be mentioned, and are preferably morpholino and pyrrolidino groups,

R ⁶ “optionally substituted aliphatic alkyl group having 1 to 6 carbon atoms” As a whole, preferred are acetyl, bropionyl, dimethylaminoacetyl, carboxyacetyl, and 3-carboxybutionyl group. And more preferably an acetyl and propionyl group (especially an acetyl group). In the above formula (1), examples of the “alkyl group having 1 to 4 carbon atoms” which is a substituent of the “optionally substituted rubamoyl group” of R ⁶ include methyl, ethyl, n —Propyl, isopropyl, n-butyl, isobutyl, s-butyl and tert-butyl groups, preferably methyl and ethyl groups, and the substituent “alkoxycarbonylalkyl having 3 to 9 carbon atoms” Examples of the group include methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, propoxycarbonylpropyl, butoxycarbonylbutyl, and the like. Carbonylmethyl and ethoxycarbonylmethyl groups, wherein the substituent is a carboxyalkyl group having 2 to 5 carbon atoms. Examples of the benzyl group include carboxymethyl, 2-carboxyethyl, 3-carboxybutyl pill, 2-carboxy-1-methylethyl, 4-carboxybutyl, 3-carboxy-1-methylpropyl, and 3-carboxy-2-methylpropyl. And carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and 4-carboxybutyl groups.

The “optionally substituted carbamoyl group” for R ^{6 As} a whole, preferred are methylcarbamoyl, ethylcarbamoyl, methoxycarbonylmethylcarbamoyl and ethoxycarbonylmethylcarbamoyl. In the above formula (1), R ¹ as a whole is preferably a non-substituted alkyl group having 4 to 10 carbon atoms, or a carbon atom having 1 to 6 carbon atoms substituted with an alkoxy group having 2 to 6 carbon atoms. An alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 1 to 6 carbon atoms, and a cycloalkyl group having 4 to 6 carbon atoms, which may be substituted with one methyl, methoxy, Substituted alkyl group having 1 to 6 carbon atoms and 4 to 4 carbon atoms -it,

An alkyl group having 1 to 6 carbon atoms substituted with 6 alkoxyalkoxy groups, more preferably octyl, 7-methyloctyl, nonyl, 8-methylnonyl, phenylpropyl, 4-methylphenyl Propyl, 4-methoxyphenylphenyl, 4-cyclophenylphenyl, cyclohexylmethyl, cyclohexylpropyl, 6-ethoxyhexyl, 6-isopropoxyhexyl and 4-butoxybutyl, more preferably Is a nonyl, 7-methyloctyl and 4-cyclophenylphenylpropyl group. In the above formula (1), R ² as a whole is preferably a hydrogen atom, a hydroxy or an acetyl group, and 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 or an alkyl group having 1 to 4 carbon atoms substituted with one methylthio or ethylthio 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, one hydroxy group An alkyl group having 1 to 4 carbon atoms substituted by a group; and an alkyl group having 1 to 4 carbon atoms substituted by one acetyloxy group. More preferably, isopropyl, tert-butyl , 1-methylpropyl, 2-methylpropyl, 1-methylthio-1-methylethyl, cyclohexylmethyl, benzyl, hydroxymethyl and acetooxy groups, more preferably tert-butyl, 1-methylthio-1-methyl Echiru, cyclohexylmethyl cyclohexane and benzyl group (particularly, tert- butyl and downy Njiru group).

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 an alkyl group having 1 to 4 carbon atoms substituted with one hydroxy group. Group, an alkyl group having 1 to 4 carbon atoms substituted with one ethoxycarbonyl group, an alkyl group having 1 to 4 carbon atoms substituted with one acetyloxy group, 1 ιΠ

1 to 4 carbon atoms substituted with 1 dimethylcarbamoyl group, 1 to 4 carbon atoms substituted with 1 dimethylcarbamoyl group, and 1 carbon atom substituted with 1 dimethylamino group An alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms each substituted by one dimethylamino group and hydroxy group, and a dimethylamino group and acetooxy group each substituted by 1 And more preferably an alkyl group having 1 to 4 carbon atoms, more preferably an alkyl group having 1 to 4 carbon atoms, which is substituted with a hydrogen atom and one hydroxy group or one acetyl group. More preferably, they are a hydrogen atom, a hydroxymethyl, a 2-hydroxyl and a 3-hydroxypropyl group, and most preferably a hydrogen atom. In the above formula (1), a preferable example of 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, a dialkylamino group having 1 to 2 carbon atoms or 1 Aliphatic carbonyl group having 2 to 3 carbon atoms, more preferably a hydrogen atom, acetyl and propionyl group, most preferably a hydrogen atom and acetyl group . Among the compounds 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, an alkyl group having 1 to 6 carbon atoms substituted by an alkoxy group having 2 to 6 carbon atoms, methyl, methoxy or Or an alkyl group having 1 to 6 carbon atoms substituted by a phenyl group which may be substituted by a chloro group, or an alkyl group having 1 to 6 carbon atoms substituted by a cycloalkyl group having 4 to 6 carbon atoms A compound having 1 to 6 carbon atoms, which is substituted by a group or an alkoxyalkoxy group having 4 to 6 carbon atoms,

2) R ¹ is octyl, 7-methyloctyl, nonyl, 8-methylnonyl, Phenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, 4-chlorophenylpropyl, cyclohexylmethyl, cyclohexylpropyl, 6-ethoxyhexyl, 6-isopropoxyhexyl Or a compound that is a 4_butoxybutyl group,

3) compounds wherein R ¹ is Noel, 7-methyloctyl or 3- (4-chlorophenyl) butylpyr;

4) compounds wherein R ¹ is nonyl or 3- (4-monophenyl) propyl group

5) a compound wherein R ² is a hydrogen atom, a hydroxy or acetyl group;

6) R ² force a compound which is a hydrogen atom or a hydroxy group,

7) 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 cycloalkyl group having 4 to 6 carbon atoms. A substituted or unsubstituted phenyl-substituted phenyl group-substituted alkyl group having 1 to 4 carbon atoms, a hydroxy-substituted alkyl group having 1 to 4 carbon atoms, or an acetoxy group A compound which is a substituted alkyl group having 1 to 4 carbon atoms,

8) R ³ force A compound that is an isobrovir, tert-butyl, 1-methylbrovir, 2-methylbutyl, 1-methylthio-11-methylethyl, cyclohexylmethyl, benzyl, hydroxymethyl or acetyloxymethyl group,

9) R ³ compound which is tert-butyl, 1-methylthio-1-methylethyl, cyclohexylmethyl or benzyl group, 10) a compound that is an R ³ tert-butyl or benzyl group;

11) 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, 1 to 4 carbon atoms substituted with an acetyloxy group, 1 to 4 carbon atoms substituted with a methylcarbamoyl group, and carbon 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, a dimethylamino group or an alkyl group having 1 to 4 carbon atoms or a dimethylamino group substituted with a hydroxy group; A compound which is an alkyl group having 1 to 4 carbon atoms and is substituted by an acetoxy group,

1 2) R ⁴ force A compound which 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 having 1 to 4 carbon atoms substituted with a hydrogen atom or a hydroxy group,

14) A compound which is a hydrogen atom, a hydroxymethyl, a 2-hydroxyl or a 3-hydroxypropyl group,

1 5) Force A compound that is a hydrogen atom,

1 6) R ⁵ force A compound that is a hydrogen atom,

1 7) R ⁶ force Hydrogen atom or unsubstituted aliphatic carbon group having 2 to 3 carbon atoms, carbon atom substituted by dialkylamino group having 2 to 4 carbon atoms or carboxy group A compound that is 2 to 3 aliphatic acyl groups,

18) compounds wherein R ⁶ is a hydrogen atom, acetyl or propionyl group,

1 9) R ⁶ force A compound which is a hydrogen atom or an acetyl group,

Can be mentioned. Further, 1) to 4) selects the R ¹ from 5) to 6) to select the R ² from 7) to 1 0) to select the R ³ from a 1 1) to 1 5) from R ⁴ selected, select R ⁵ 1 6), 1 7) to 1 9) select the R ^6, compound combination is also good 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 chloro. An alkyl group having 1 to 6 carbon atoms, which is substituted by a phenyl group which may be substituted by an alkyl group, an alkyl group having 1 to 6 carbon atoms, which is substituted by a cycloalkyl group having 4 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,

R ² force, a hydrogen atom, a hydroxy or acetyl group,

R ³ is substituted with 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 cycloalkyl group having 4 to 6 carbon atoms Substituted with methyl or ethyl, unsubstituted phenyl-substituted alkyl group having 1 to 4 carbon atoms, hydroxy-substituted alkyl group having 1 to 4 carbon atoms or substituted with acetyl group Alkyl group having 1 to 4 carbon atoms,

R ⁴ , 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, and an ethoxycarbonyl group Alkyl group having 1 to 4 carbon atoms, alkyl group having 1 to 4 carbon atoms substituted with acetooxy group, alkyl group having 1 to 4 carbon atoms substituted with methylcarbamoyl group, substituted with 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 or a dimethylamino group substituted with a dimethylamino group and a hydroxy group, and An alkyl group having 1 to 4 carbon atoms, which is substituted with an acetoxy group;

R ⁵ force ⁵ , hydrogen atom,

R ⁶ is a hydrogen atom or an unsubstituted aliphatic C2 to C3 aliphatic acyl group, a C2 to C3 aliphatic C2 to C4 dialkylamino group or a carboxy group A compound that is

2 1) R 'force nonyl, 7-methyloctyl or 3- (4-monophenyl) propyl group;

R ² is a hydrogen atom or a hydroxy group,

R ^{3 is} tert-butyl, 1-methylthio-1-methylethyl, cyclohexylmethyl or benzyl group,

R ⁴ is a hydrogen atom,

R ⁵ is a hydrogen atom,

A compound wherein R ⁶ is a hydrogen atom or an acetyl group;

22) R ^{1 is a} nonyl or 3- (4-monophenyl) 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,

A compound wherein R ^e is a hydrogen atom or an acetyl group Can be given. When the compound (1) of the present invention has a carboxy group, it can be converted into a salt.

, And salts thereof are also included in the present invention,

Such salts are preferably 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, Metal salts such as copper salts, 2'-sokel salts, and cobalt salts; inorganic salts such as ammonium salts, octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N —Methylglucamine salt, guanidine salt, getylamine salt, triethylamine salt, dicyclohexylamine salt, N, N '—dibenzylethylenediamine salt, chlorobrocaine salt, pro-forcein salt, diethanolamine salt, N-benzyldiene Tilamine salt, biradine salt, tetramethylammonium Salts and amine salts such as organic salts such as tris (hydroxymethyl) aminomethane salt can be mentioned. When the compound (1) of the present invention has an amino group, it can be converted into a salt. Salts are also included in the present invention,

Such salts preferably include hydrofluorides, hydrochlorides, hydrobromides, hydrohalides such as hydroiodide, nitrates, perchlorates, sulfates, and the like. Inorganic acid salts such as phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; benzenesulfonates; and salts such as P-toluenesulfonate. Sulfonic acid, acetic acid, malic acid, fumarate, succinate, citrate, tartrate, oxalate, maleate, and other organic acid salts; and glycine salt, lysine salt, arginine salt, orditin Salts, amino acids such as glutamate and aspartate can be mentioned. The compound (1) of the present invention absorbs moisture when left in the air. In some cases, water may be collected and adsorbed water may be formed, or may be hydrated. Such a hydrate is also included in the present invention. Furthermore, the compound (1) of the present invention has an asymmetric carbon atom in the molecule, and there are stereoisomers each of which is in the R or S configuration. Any of the mixtures are included in the present invention. Among the compounds (1) of the present invention, examples of the compound having a suitable configuration include those of the following formula (wherein, R ¹ , R ² , R ³ , R ⁴ , R ^s and R ^s are Same meaning as above).

39- The compounds included in the present invention have the following powers as exemplified in Table 1. The present invention is not limited to these.

In Table 1, Me represents a methyl group, Et represents an ethyl group, Pr represents a bromo group, 丄 Pr represents an isopropyl group, Bu represents a butyl group, and 丄 Bu represents isobutyl group. Represents a tyl group, Bu represents a t-butyl group, Bn represents a benzyl group, Ac represents an acetyl group, ct represents an octyl group, Non represents a nonyl group, and HX represents cyclo. Ph represents a hexyl group, Ph represents a phenyl group, Mor represents a morpholino group, and T hi represents a chelyl group.

Table 1 χΰ c = i

½ ^ R ¹ R ^z R ³ R ⁴ R ⁵ R ⁶

0001 iBu H tBu H H H

0002 iBu H tBu H H Ac

0003 iBu H Bn H H H

0004 iBu H cHxCH ₂ HHH

0005 iBu H cHxCH ₂ HH Ac

0006 7- e-0ct H tBu H H H

0007 7-Me-0ct H tBu H H Ac

0008 Non H tBu H H H

0009 Non H tBu HH Ac 0010 Non H iPr HHH

0011 Non H iPr H H Ac

0012 Non H cHxCH ₂ HHH

0013 Non H cHxCH ₂ HH Ac

0014 Non H Bn H H H

0015 Non H Bn H H Ac

0016 Non H H0CH ₂ HHH

0017 Non H AcOCH ₂ HH Ac

0018 Non H CH ₃ CH (0H) HHH

0019 Non H CH ₃ CH (0Ac) HH Ac

0020 Non H MeSC (Me) ₂ HHH

0021 Non H MeSC (Me) ₂ HH Ac

0022 8-Me-Non H tBu H H H

0023 8-Me-Non H tBu H H Ac

0024 4-MeOPh (CH ₂ ) ₃ H tBu HHH

0025 4-MeOPh (CH ₂ ) ₃ H tBu HH Ac

002 & 4-MeOPh (CH ₂ ) ₃ H MeSC (Me) ₂ HHH

0027 4-MeOPh (CH _z ) ₃ H MeSC (Me) _z HH Ac

0028 4-ClPh (CH ₂ ) a H tBu HHH

0029 4-ClPh (CH ₂ ) a H tBu HH Ac

0030 4-ClPh (CH ₂ ) a H MeSC (Me) ₂ HHH

0031 4-ClPh (CH ₂ ) a H MeSC (Me) ₂ HH Ac

0032 4- ePh (CH ₂ ) ₃ H tBu HHH

0033 4-MePh (CH ₂ ) ₃ H tBu 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 cHx (CH ₂ ) a H tBu HHH

0037 cHx (CH ₂ ) a H tBu HH Ac

Five

3 5 KC ¾ as 3: ¾ o 32 O as

5 ¾ 3 33

£ S 0039X2HH (r H MeSCMe HH one 003 H8x one Hr MeS MCe HH ?ヮ

0066 on H tBu -CH ₂ 0H HH

0067 Non H tBu -CH ₂ 0Ac H Ac

0068 Non H iPr -CH ₂ 0H HH

0069 Non H iPr -CHzOAc H Ac

0070 Non H tBu -CH ₂ CH ₂ 0H HH

0071 Non H tBu -CH ₂ CH ₂ 0Ac H Ac

0072 Non H iPr -CH ₂ CH ₂ 0H HH

0073 Non H iPr-CH ₂ CH ₂ 0Ac H Ac

0074 Non H tBu -CH ₂ (CH ₂ ) ₂ 0H HH

0075 Non H tBu -CH ₂ (CH ₂ ) ₂ 0Ac H Ac

0076 Non H iPr-CH ₂ (CH ₂ ) ₂ OH HH

0077 Non H iPr -CH ₂ (CH ₂ ) ₂ 0Ac H Ac

0078 Non H tBu -CH ₂ CH ₂ Ne ₂ HH

0079 Non H tBu -CH ₂ CH ₂ NMe ₂ H Ac

0080 Non H tBu -CH ₂ CH (OH) CH ₂ NMe ₂ HH

0081 Non H tBu -CH ₂ CH (0Ac) CH ₂ NMe ₂ H Ac

0082 Non H tBu -CH ₂ CH ₂ NMe (Et) HH

0083 Non H tBu -CH ₂ CH ₂ NMe (Et) H Ac

0084 Non H tBu H H -COEt

0085 Non H tBu HH -C0CH ₂ NH ₂

0086 Non H tBu HH -C0CH _z NHMe

0087 Non H tBu HH -C0CH ₂ NMe ₂

0088 Non H tBu HH -C0CH ₂ CH ₂ NH ₂

0089 Non H tBu HH -COCH ₂ CH ₂ C0 ₂ Et

0090 Non H tBu HH -C0CH ₂ CH ₂ C00H

0091 Non H tBu H H -CO HEt

0092 Non H tBu H H -CO HMe

0093 Non H tBu HH -C0NHCH ₂ C0 ₂ Me 0094 Non H tBu HH -CONHCH ₂ CO _z Et

0095 Non H EtCH (Me) H H H

0096 Non H EtCH (Me) H H Ac

0097 Non H (Me) ₂ CHCH ₂ HHH

0098 Non H (Me) ₂ CHCH ₂ HH Ac

0099 Non H ThiCH 2 H H H

0100 Non H ThiCH _z HH Ac

0101 Non H iPr Et H H

0102 iBu OH tBu H H H

0103 iBu OH tBu H H Ac

0104 iBu OH Bn H H H

0105 iBu OH cHxCH _z HHH

0106 iBu OH cHxCH ₂ HH Ac

0107 7- Me- Oct OH tBu H H H

0108 7-Me-Oct OH tBu H H Ac

0109 Non OH tBu H H H

01 10 Non OH tBu H H Ac

0111 Non OH iPr H H H

0112 Non OH iPr H H Ac

0113 Non OH cHxCH ₂ HHH

0114 Non OH cHxCH ₂ HH Ac

0115 Non OH Bn H H H

0116 Non OH Bn H H Ac

0117 Non OH H0CH ₂ HHH

0118 Non OH AcOCHa H H Ac

0119 Non OH CH ₃ CH (OH) HHH

0120 Non OH CH ₃ CH (0Ac) HH Ac

0121 Non OH eSC (Me) _z HHH 0122 on OH MeSC (Me) ₂ HH Ac

0123 8-Me-Non OH tBu H H H

0124 8-Me-Non OH tBu H H Ac

0125 4-Me0Ph (CH ₂ ) ₃ OH tBu HHH

0126 4-MeOPh (CH ₂ ) ₃ OH tBu HH Ac

0127 4- e0Ph (CH ₂ ) ₃ OH MeSC (Me) _z HHH

0128 4-Me0Ph (CH ₂ ) ₃ OH MeSC (Me) ₂ HH Ac

0129 4-ClPh (CH ₂ ) a OH tBu HHH

0130 4-ClPh (CH ₂ ) a OH tBu HH Ac

0131 4-ClPh (CH ₂ ) a OH MeSC (Me) ₂ HHH

0132 4-ClPh (CH ₂ ) a OH MeSC (Me) ₂ HH Ac

0133 4- ePh (CH ₂ ) ₃ OH tBu HHH

0134 4- ePh (CH ₂ ) ₃ OH tBu HH Ac

0135 4- ePh (CH ₂ ) ₃ OH MeSC (Me) ₂ HHH

0136 4- ePh (CH ₂ ) ₃ OH MeSC (Me) ₂ HH Ac

0137 cHx (CH ₂ ) a OH tBu HHH

0138 cHx (CH ₂ ) 3 OH tBu HH Ac

0139 cHx (CH ₂ ) 3 OH MeSC (Me) 2 HHH

0140 cHx (CH ₂ ) a OH MeSC (Me) ₂ HH Ac

0141 cHxCHa OH tBu H H H

0142 cHxCH ₂ OH tBu HH Ac

0143 cHxCH ₂ OH MeSC (Me) ₂ HHH

0144 cHxCH ₂ OH MeSC (Me) ₂ HH Ac

0145 BuO (CH ₂ ) 4 OH tBu HHH

0146 BuO (CH ₂ ) 4 OH tBu HH Ac

0147 BuO (CH ₂ ) ^ OH MeSC (Me) ₂ HHH

0148 BuO (CH ₂ )-OH MeSC (Me) ₂ HH Ac

0149 EtO (CH ₂ ) 6 OH tBu HHH

s s s ¾ 3: 3: a; ac rc c ■>. S 3 5 »· 5>>

OXO ¾ EC ¾ 3: 33 3S 3S O ¾ SC 35 ¾ O 3S O 33 O 32 O

V /

0178 Non OH iPr-CH ₂ (CH ₂ ) ₂ 0Ac H Ac

0179 on OH tBu-CH ₂ CH ₂ NMe ₂ HH

0180 Non OH tBu-Cli ₂ CH ₂ NMe ₂ H Ac

0181 Non OH tBu -CH ₂ CH (OH) CH ₂ NMe ₂ HH

0182 Non OH tBu-CH ₂ CH (0A c) CH ₂ Ne ₂ H Ac

0183 Non OH tBu -CH ₂ CH ₂ NMe (Et) HH

0184 Non OH tBu -CH ₂ CH ₂ Ne (Et) H Ac

0185 Non OH tBu H H -COEt

0186 Non OH tBu HH -C0CH ₂ NH ₂

0187 Non OH tBu HH -C0CH ₂ NHMe

0188 Non OH tBu HH -C0CH ₂ NMe _z

0189 Non OH tBu HH -COCH _z CH ₂ NH _z

0190 Non OH tBu HH-COCH ₂ CH ₂ C0 ₂ Et

0191 Non OH tBu H H -COCH2CH2COOH

0192 Non OH tBu H H -CONHEt

0193 Non OH tBu H H -CONHMe

0194 Non OH tBu HH -CONHCH ₂ C0 ₂ e

0195 Non OH tBu HH -C0NHCH ₂ C0 ₂ Et

0196 Non OH EtCH (Me) H H H

0197 Non OH EtCH (Me) H H Ac

0198 Non OH (Me) a CHCH ₂ HHH

0199 Non OH (Me) ₂ CHCH ₂ HH Ac

0200 Non OH ThiCH 2 H H H

0201 Non OH ThiCH Z H H Ac

0202 Non OH iPr Et H H

0203 Non OAc tBu H H Ac

0204 Non OAc tBu H H COEt

0205 Oct H tBu H0 (CH ₂ ) ₂ HH 0206 Non H tBu H0 (CH _z ) H -C0CH ₂ CH _Z C00H

0207 Non H tBu H0 (CH ₂ ) H -COCH ₂ CH ₂ NEt ₂

0208 Oct OH tBu H0 (CH ₂ ) HH

0209 Non OH tBu H0 (CH ₂ ) H -COCH ₂ CH ₂ COOH

0210 Non OH tBu H0 (CH ₂ ) H -COCH ₂ CH ₂ NEt ₂

0211 Oct H tBu H0 (CH ₂ ) HH

0212 Non H tBu H0 (CH ₂ ) H -C0CH ₂ CH ₂ C00H

0213 Non H tBu H0 (CH ₂ ) H -COCH ₂ CH ₂ NEt ₂

0214 Oct OH tBu HO (CHz) H H

0215 Non OH tBu H0 (CH ₂ ) H-C0CH ₂ CH ₂ C00H

0216 Non OH tBu H0 (CH ₂ ) H -COCH ₂ CH ₂ NEt ₂

0217 Non H tBu H0 (CH ₂ ) HH

0218 Non H tBu H0 (CH ₂ ) H -C0CH ₂ CH ₂ C00H

0219 Non H tBu H0 (CH ₂ ) H -COCH ₂ CH ₂ NEt ₂

0220 Non OH tBu HO (CHa) H H

0221 Non OH tBu H0 (CH ₂ ) H -COCH ₂ CH ₂ COOH

0222 Non OH tBu H0 (CH _z ) H -COCH ₂ CH ₂ NEt ₂

0223 Non H tBu Ac0 (CH ₂ ) HH

0224 Non H tBu AcO (CH ₂ ) H -C0CH ₂ CH ₂ C00H

0225 Non H tBu AcO (CH ₂ ) H -COCH ₂ CH ₂ NEt ₂

0226 Non OH tBu AcO (CH ₂ ) HH

0227 Non OH tBu AcO (CH ₂ ) H -C0CH ₂ CH ₂ C00H

0228 Non OH tBu AcO (CH ₂ ) H -COCH ₂ CH ₂ NEt ₂

0229 Non H tBu AcO (CH ₂ HH

0230 Non H tBu AcO (CH ₂ H -C0CH ₂ CH _z C00H

0231 Non H tBu AcO (CH ₂ H -COCHaCHaNEtz

0232 Non OH tBu AcO (CH ₂ 1 HH

0233 Non OH tBu AcO (CH ₂ 1 H -C0CHzCH ₂ C00H ^ 2

0234 Non OH tBu AcO (CH ₂ ) 3 H -COCHa CH _z NEt _z

0235 Non H tBu AcO (CH ₂ ) 4 HH

0236 Non H tBu AcO (CH ₂ ) 4 H -COCHs CH ₂ COOH

0237 Non H tBu AcO (CH ₂ ) 4 H -C0CH ₂ CH ₂ NEt ₂

0238 Non OH tBu Ac0 (CH ₂ ) 4 HH

0239 Non OH tBu Ac0 (CH ₂ ) 4 H-C0CH ₂ CH ₂ C00H

0240 Non OH tBu AcO (CH ₂ ) 4 H -C0CH ₅ CH ₂ NEt ₂

0241 EtO (CH ₂ ) ₂ 0 (CH ₂ ) 2 H tBu H0 (CH ₂ ) 2 HH

0242 Et0 (CH ₂ ) 2O (CHz) 2 H tBu H0 (CH ₂ ) 2 H -COCH2 CH ₂ COOH

0243 EtO (CH ₂ ) 2O (CH2) 2 H tBu HO (CH ₂ ) ₂ H -C0CH _∑ CH ₂ NEt ₂

0244 Et0 (CH ₂ ) 2O (CH ₂ ) 2 OH tBu H0 (CH ₂ ) 2 HH

0245 Et0 (CH ₂ ) 2O (CH ₂ ) 2 OH tBu H0 (CH ₂ ) 2 H-COCH: .CH ₂ COOH

0246 EtO (CH ₂ ) 2O (CH2) 2 OH tBu H0 (CH ₂ ) a H -C0CH: CH _z NEt ₂

0247 Et0 (CH ₂ ) ₂ 0 (CH ₂ ) 4 H tBu H0 (CH ₂ ) ₂ HH

0248 Et0 (CH ₂ ) ₂₀ (CH ₂ ) H tBu H0 (CH ₂ ) 2 H-COCH: .CH ₂ COOH

0249 Et0 (CH ₂ ) ₂₀ (CH ₂ ) 4 H tBu H0 (CH ₂ ) ₂ H -COCH; .CH ₂ NEt ₂

0250 EtO (CH ₂ ) ₂₀ (CH ₂ ) OH tBu H0 (CH ₂ ) 2 HH

0251 EtO (CH ₂ ) ₂₀ (CH ₂ ) 4 OH tBu H0 (CH ₂ ) 2 H-COCH: .CHzCOOH

0252 EtO (CH ₂ ) ₂₀ (CH ₂ ) OH tBu H0 (CH _z ) ₂ H-COCH: iCHz Etz

0253 PrO (CH ₂ ₂₀ (CH ₂ ), H tBu HO (CH ₂ ) 2 HH

0254 Pr0 (CH ₂ ) ₂₀ (CH ₂ ) 4 H tBu H0 (CH ₂ ) 2 H-COCH: ₅ CH ₂ C00H

0255 PrO (CH ₂ ) ₂₀ (CH ₂ ) ^ H tBu H0 (CH ₂ ) z H -COCH; .CH _z NEt ₂

0256 PrO (CH ₂ ) ₂₀ (CH ₂ ), OH tBu HO (CH ₂ ) z HH

0257 Pr0 (CH ₂ ) ₂₀ (CH ₂ ) 4 OH tBu H0 (CH ₂ ) ₂ H -COCH; j CHzCOOH

0258 PrO (CH ₂ ) ₂₀ (CH ₂ ) 4 OH tBu HO (CH ₂ ) a H -COCH ₂ CH ₂ NEt ₂

0259 Non H tBu H0 (CH ₂ ) 2 H -COCH ₂ NEt ₂

0260 Non OH tBu H0 (CH ₂ ) 2 H -COCH ₂ NEt ₂

0261 EtO (CH ₂ ) ₂₀ (CH ₂ ) 2 H tBu HO (CH ₂ ) a H -COCH ₂ NEt3 _{0262 EtO (CH 2 .0 (CH} : z OH tBu H0 (CH 2 H -C0CH 2 NEt z

_{0263 EtO (CH 2 .0 (CH} : 4 H tBu H0 (CH 2 H -C0CH 2 NEt 2

_{0264 EtO (CH 2 .0 (CH} : OH tBu H0 (CH 2 H -COCH 2 NEta

0265 PrO (CH _2: 0 (CH: 4 H tBu H0 (CH ₂ H -COCH ₂ NEt ₂

0266 PrO (CH _2: 0 (CH _: 4 OH tBu H0 (CH ₂ H -COCH ₂ NEt ₂

0267 Non H tBu H0 (CH _z H -COCH ₂ COOH

0268 Non OH tBu H0 (CH ₂ H-COCH ₂ COOH

0269 EtO (CH ₂ ! 0 (CH: 2 H tBu HO (CH ₂ H -C0CH ₂ C00H

_{0270 EtO (CH 2 .0 (CH} : 2 OH tBu H0 (CH 2 H -COCH 2 COOH

0271 EtO (CH ₂ ! 0 (CH: H tBu H0 (CH ₂ H -COCH _z COOH

0272 Et0 (CH ₂ ! 0 (CH: OH tBu H0 (CH ₃ H -C0CH ₂ C00H

0273 Pr0 (CH ₂ ! 0 (CH: H tBu HO (CH ₂ H -C0CH ₂ C00H

0274 PrO (CH _{2 s} 0 (CHi OH tBu HO (CH ₂ H -COCH ₂ COOH

0275 Non H tBu H0 (CH ₂ H -C0CH ₂ NMe _z

0276 Non OH tBu HO (CH ₂ H -C0CH ₂ NMe ₂

0277 EtO (CH ₂ > 0 (CH _: 2 H tBu H0 (CH ₂ H -COCH ₂ NMe ₂

_{0278 EtO (CH 2 .0 (CH} ; 2 OH tBu HO (CH 2 H -COCH 2 NMe 2

0279 EtO (CH _z »0 (CH _; 4 H tBu HO (CH = H-C0CH ₂删 e ₂

0280 EtO (CH ₂ ! 0 (CH: 4 OH tBu H0 (CH: H -COCH _z NMe _z

0281 PrO (CH _{2 s} 0 (CH: 4 H tBu H0 (CH: H -COCH ₂ Me ₂

0282 PrO (CH _{2 20} (CH: ₄ OH tBu HOlCHi H -C0CH ₂ Ne ₂

0283 Non H tBu H0 (CH: H -C0 (CH _z ) _z NMe _z

0284 Non OH tBu HO (CH _: H -C0 (CH ₂ ) ₂ NMe ₂

0285 EtO (CH ₂ > 0 (CH; 2 H tBu HO (CH: H -CO (CH ₂ ) ₂ NMe ₂

_{0286 EtO (CH 2: 0 (} CH: z OH tBu H0 (CH; H -CO (CHz) 2 N e 2

0287 EtO (CH: ₂₀ (CH ₄ H tBu HO (CH _; H -C0 (CH ₂ ) ₂ NMe ₂

0288 EtO (CH _{s 20} (CH, OH tBu H0 (CH: H -CO (CH ₂ ) ₂ NMe ₂

_{0289 PrO (CH 5 2 0 (} CH * H tBu H0 (CH H -CO (CH 2) 2 NMe 2 0290 PrO (CH ₂ ) ₂₀ (CH ₂ :) 4 OH tBu H0 (CH ₂ ) z H -C0 (CH ₂ ) ₂ Γ

0291 Non H 4-(0H) PhCH ₂ HHH

0292 Non H 4- (AcO) PhCH _z 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 iPr Et H H

0297 4-ClPh (CH ₂ ) ₃ OH Bn CH ₂ CO fraction e H Ac

0298 4-ClPh (CH ₂ ) 3 OH Bn CH ₂ CONH e HH

0299 Et0 (CH ₂ ) ₂ 0 (CH ₅ i) 3 H tBu HH Ac

0300 EtO (CH _z ) ₂ 0 (CH:!) 3 H tBu HHH

0301 4-ClPh (CH ₂ ) 3 H Bn HH Ac

0302 4-ClPh (CH ₂ ) 3 H Bn HHH

0303 4-ClPh0 (CH ₂ ) 2 H tBu HH Ac

0304 4-ClPhO (CH ₂ ) 2 H tBu HHH

0305 4-ClPh (CH ₂ ) a H H0CH ₂ HHH

0306 4-ClPh (CH ₂ ) 3 H Ac0CH ₂ HH Ac

0307 4-ClPh (CH ₂ ) a H cHxCH ₂ HHH

0308 4-ClPh (CH ₂ ) a H cHxCH ₂ HH Ac

0309 Non H AcOCH ₂ Me H Ac

0310 Non H HOCHa Me H H

0311 Non H tBu H H COCHaMor

0312 Non H tBu HH C0CH ₂ CH ₂ i

0313 iBu OAc tBu H H Ac

0314 PhCH ₂ 0CH ₂ H tBu Me Me H

0315 Non H CH ₂ O e HHH

_{_{0316 Non H tBu CH 2 C0 2}} Me H Ac

0317 Non H tBu CH ₂ 0Me HH Among the above exemplified compounds, preferred ones are 8, 9, 10, 10, 11, 12, 13, 16, 17, 17, 20, 21, 28, 29, 66, 67, 70, 7 1, 74, 75, 102, 107, 108, 109, 110, 167, 168, 171, 1 72, 1 75, 1 76, 30 1, 302, 305, 306, 307, 308 and 313, and more preferably,

N ⁴ -Hydroxy N '-[1-Hydroxymethyl-12,2-dimethylpropyl] -12-nonylsuccinamide (8),

Acetic acid 2- [2- (N-hydroxycarbamoylmethyl) pentadecylamino) 1,3-dimethylbutyl ester (9)

N ⁴ over human Dorokishi one N 'i (1-arsenide Dorokishimechiru one 2-methylpropyl] one 2- Nonirusukushinami de (1 0),

Acetic acid 2- [2- (N-hydroxycarbamoylmethyl) pentadecylamino] -3-methylbutyl ester (11),

N ⁴ - arsenide Dorokishi N ¹ - [2- arsenide Dorokishi one 1- (human Dorokishimechiru) E Chi le] - 2- Nonirusukushinami de (16),

Acetic acid 3-acetoxy 2- [2- (N-hydroxycarbamoylmethyl) ゥ decanoylamino] propyl ester (17)

N-Hydroxy N '-[1-Hydroxymethyl-12-methyl-2-methylthiop mouth pill] -12-Nonylsuccinamide (20),

Acetic acid 2- [2- (N-hydroxycarbamoylmethyl) pentadecylamino] -3-methyl-3-methylthiobutyl ester (21),

2- (3- (4-chlorophenyl) brovir) 1-Hydroxy-1-N ¹ — [1-Hydroxymethyl-2,2-dimethylpropyl] succinamide (28), acetic acid 2— [5— (4— 1,2- (N-hydroxycarbamoylmethyl) pentanoylamino] -1,3-dimethylbutyl ester (29)

New one 3- dihydric Dorokishi one New ¹ - [1-arsenide Dorokishimechiru 2, 2-dimethylpropyl] one 2- (7-Mechiruokuchiru) Sukushinami de (1 07), One

Acetic acid 2- (S) -1- {2-acetoxy (hydroxycarbamoyl) methyl] -19-decanoylamino-1,3-dimethylbutyl ester (108),

New ⁴ one 3- dihydric Dorokishi N '- [1 over human Dorokishimechiru 2, 2 - dimethyl Buropiru] one 2- Nonirusukushinami de (1 09),

Acetic acid 2- [5- (4-chlorophenyl) -2- (Ν-hydroxycarbamoylmethyl) pentanoylamino] -3-phenylpropyl ester (301),

Ν ^1- [1 Benzyl 2-Hydroxicetil] — 2-[3- (4-chlorophenyl) propyl] 1 Ν ^4- Hydroxyscinamide (302),

2 - [3 - (4 one black port phenyl) propyl] one New ⁴ - heat Dorokishi one N '- (2-heat Dorokishi -1-hydroxycarboxylic methyl E chill) Sukushinami de (305), acetic acid 2- [5- (4-chlorophenyl) 1-2- (Ν-hydroxycarbamoylmethyl) pentanoylamino] -13-acetoxypropyl ester (306)

2- [3-((4-chlorophenyl) propyl] -N '-[1-cyclohexylmethyl-l-hydroxy-l-hydroxyl] ^4- Ν-hydroxysuccinamide (307) and

Diacid 2- [5- (4-chlorophenyl) -12- (Νhydroxycarbamoylmethyl) pentanoylamino] -13-cyclohexylpropyl ester (308)

Most preferably,

2-[3-(4-Chlorophenyl) provyl] —Ν ⁴ —Hydroxyl — ¹ [1-Hydroxymethyl-2,2-dimethylprovyl] succinamide (28), acetic acid 2 — [5-(4 Phenyl)-2- (Ν-hydroxycarbamoylmethyl) bentanoylamino] 1,3-dimethylbutyl ester (29),

Ν ⁴ — 3-dihydroxy Ν ¹ — [1-Hydroxymethyl-2,2-dimethylpropyl] -1-nonylsuccinamide (109),

Acetic acid 2— ■! 2— [Hydroxy (hydroxycarbamoyl) methyl] benzylamide 1,3-dimethylbutyl ester (1 10) Acetic acid 2- [5- (4-chlorophenyl) -12- (N-hydroxycarbamoylmethyl) pentanoylamino] -13-phenylpropyl ester (301) and

N ^1- [1 Benzyl 2-Hydroxicetyl]-2-[3-(4-Chlorophenyl) propyl]-N ^4- Hydroxysuccinamide (302).

The hydroxamic acid derivative of the present invention can be produced by the method described in the following!

(3)

(3)

Γ /

f .

Evening.i

16a

24a

twenty four

〇 R ³

HONH

ir6

37 36

(40)

(St)

Z8S00 / L6dT / ∑D Z68IC / Z.6 OAV

52

55

53 56

60

(30) (61)

(62)

63

(67)

ίλ In the above process chart,

R ′, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the same meanings as described above, and R ^6a is an optionally substituted C 2-5 aliphatic acyl group. (The substituent may be an amino group which may be protected, an alkylamino group having 1 to 4 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, or an alkoxycarbonyl group having 2 to 5 carbon atoms. Or a protected carboxy group) or an optionally substituted rubamoyl group (the substituent is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 3 to 9 carbon atoms) A carbonylalkyl group or a carboxyalkyl group having 2 to 5 carbon atoms)

R ⁷ represents a “silyl-type” protecting group (preferably a tert-butyldimethylsilyl group) or a benzyl-type protecting group (preferably a benzyl group), and R ⁸ represents the same group as R ^7. R ⁹ represents an aliphatic or aromatic acyl group; ^{Represents an} isopropyl group or a benzyl group, X represents a halogen atom, and R ¹¹ represents a group represented by the formula R ^lla -CH = CH—CH ₂ — (R ^{1, 3} represents an ^optionally substituted carbon atom 1 To 12 alkyl groups (the substituents are the same as the substituents of the “alkyl group having 1 to 15 carbon atoms which may have a substituent of R ′”) And R ¹² represents a group that becomes R ′ by reducing the double bond of the formula, and R ¹² is a protecting group for an amino group (preferably, a tert-butoxycarbonyl group or a benzyloxycarbonyl group). R 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, and R ¹⁷ represents an alkyl group , R ^ie represents a fat aliphatic or aromatic Ashiru radical, n represents 1 to 4 integers, t B u represents a t-Bed butyl group, i P r is Indicates an isopropyl group, TBS represents a t one heptyl dimethyl silyl group, T s is. Below showing the p- toluenesulfonyl group, will be described for each step.

(Step 1) Condensation

In this step, the compound (2) and the compound (3) are condensed in an inert solvent to give a compound This is the step of manufacturing (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 reacted with hydrazine in an inert solvent (eg, dimethylformamide) at around room temperature, and then the produced acid hydrazide is reacted with a nitrite compound to convert the compound to an azide compound. After that, it is performed by treating with an amine compound (3).

Examples of the nitrite compound to be used include an alkali metal nitrite such as sodium nitrite or an alkyl nitrite such as isoamyl nitrite.

The reaction is preferably carried out in an inert solvent, and examples of the solvent used include amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and N-methylvilolid. And pyrrolidones such as don.

The two steps of the present method are usually performed in one reaction solution, and the reaction temperature is −50 to 0 ° C. in the first stage, and 110 ° C. to 10 ° C. in the second stage. The time required for the reaction 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 it with the amine compound (3). Both reactions are preferably carried out in an inert solvent and the solvents used are, for example, halogenated hydrocarbons such as methylene chloride, chloroform, ethers and tetrahydrofuran. Examples thereof include amides such as ethers, dimethylformamide and dimethylacetamide, and nitriles such as acetonitrile.

Examples of the active esterifying agent used include N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene and the like. Shi-

Examples thereof include N-hydroxy compounds such as 2,3-dicarboximide and disulfide compounds such as dipyridyl disulfide. The active esterification reaction is carried out by dicyclohexylcarbodiimide or triphenylphosphine. It is suitably carried out in the presence of a condensing agent such as

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

The reaction temperature is between 110 ° C. and 100 ° C. for the active esterification reaction, and is around room temperature for the reaction of the active ester compound with the amine (3). 30 minutes to 80 hours. The mixed acid anhydride method is carried out by producing a mixed acid anhydride of the compound (2) and reacting the mixed acid anhydride with an amine.

The reaction for producing the mixed acid anhydride is carried out in an inert solvent (for example, the above-mentioned halogenated hydrocarbons, amides, ethers (preferably tetrahydrofuran)) in a mixed acid dehydrating agent such as chlorocarbonic acid. Ethyl, lower alkanol halides such as pivaloyl chloride or lower (C, -C 4) alkyl halides such as isobutyl chlorocarbonate or lower alkyls or diarylcyanos such as getylcyanophosphate, diphenylcyanophosphate. This can be achieved by reacting compound (2) with phosphoric acid or the like.

The reaction is preferably carried out in the presence of an organic amine such as triethylamine, N-methylmorpholine, dimethylaminoviridine, pyridine, and the reaction temperature is 120 to 50, and the time required for the reaction is 30. Minutes to 20 hours. The reaction of the mixed anhydride with the amine (3) is preferably carried out in an inert solvent (for example, the amides or ethers described above) in the presence of the organic amine! ^The reaction is performed at a temperature of 0 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-forming agent. In the condensation method, the compound (2) and the amine (3) can be obtained by diluting the compound (2) in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, ^ -methyl-2-chloro-pyridinyl-m-zidotriethylamine. It is done by reacting directly. This reaction is carried out in the same manner as the above-mentioned reaction for producing an active ester.

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 insoluble matter is present, it is removed by filtration. Such an organic solvent 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 the solvent is distilled off.

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 simple carrier; Sephadex LH-20 (Pharmacia), Amber-Light XAD-11 (Rohm and Haas), Diaion HP-20 ( Synthesis such as partition column chromatography using a carrier such as Mitsubishi Kasei Co., Ltd. Method using adsorbent, method using ion exchange chromatography, or normal / reverse phase column chromatography using silica gel or alkylated silica gel Elution with an appropriate eluent by appropriately combining a chromatography method (preferably high performance liquid chromatography) It can isolate and purify by the.

(2nd step) Condensation

This step is a step of condensing compound (5) and compound (3) in an inert solvent to produce compound (6).

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

(Step 3) Condensation

This step is a step of producing compound (8) by condensing compound (2) and compound (7) in an inert solvent. This step can be performed in the same manner as in the first step.

(Fourth step) Deprotection In this step, in an inert solvent, with an acid to remove the t one-butyl group and the protecting group represented by R ⁷ of the compound (8) to produce the compound (9) It is a process.

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

The acid used is an organic acid such as acetic acid, methanesulfonic acid, para-toluenesulfonic acid, trifluoroacetic acid, or trifluoromethanesulfonic acid, or an inorganic acid such as hydrochloric acid, and preferably trifluoroacetic acid. .

The solvent to be 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. Ethers such as tyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethyloxetane and diethylene glycol dimethyl ether; And organic solvents and mixed solvents thereof. Methylene chloride is preferred.

The reaction temperature and the reaction time are not particularly limited, but are usually 0 to 100 (preferably 10 ° C. to 30 ° C.) and 1 to 72 hours (preferably 1 to 24 hours). Time) Implemented.

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. Add an organic solvent that is immiscible with water and wash with water etc.

The organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.

The obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, or

It can be performed by a method used for separation and purification of organic compounds, for example, the method described in the first step. (Fifth step) Condensation

This step is a step of condensing compound (5) and compound (7) in an inert solvent to produce compound (10).

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

(Step 6) Deprotection

In this step, in an inert solvent, with an acid to remove the isopropylidene group and the protective group represented by R ⁷ of the compound (10) is a step for preparing a compound (9). This step is performed when R ⁷ is a silyl-type protecting group.

This step can be performed 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

This step is a step of removing the isopropylidene group of compound (10) using an acid in an inert solvent to produce 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

This step is a step of producing a compound (9) by removing the t-butyl group of the compound (4) using an acid in an inert solvent.

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

(Eighth step) Condensation

In this step, in an inert solvent, the compound (9) is reacted with Arukokishiamin R ^e 0 nH _2, is a step for preparing Compound (1 2).

This step can be performed in the same manner as in the first step. 6?

(9th step) Deprotection

In this step, in an inert solvent, to remove the protecting group represented by R ⁸ in the compound (1 2), a step for preparing the object compound (1 a) of the present invention.

When R ⁸ is a silyl-type protecting group, the ability to carry out in the same manner as in the fourth step. 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 used is not particularly limited as long as it does not take part in the reaction, but includes alcohols such as methanol, ethanol and isopropanol, ethers such as getyl ether, tetrahydrofuran and dioxane, toluene, benzene, Aromatic hydrocarbons such as xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, formamide, dimethylformamide, dimethylacetamide, Amides such as N-methyl-2-virolidone and hexamethyl phosphorotriamide, fatty acids such as formic acid and acetic acid, water, and a mixed solvent thereof are more preferable, and alcohol is more preferable. (Especially methanol), mixed solvents of alcohols and ethers, alcohol Is a mixed solvent of water and water.

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 monoxide, rhodium aluminum monoxide, 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 starting material, solvent and type of catalyst, but are usually 0. C to 100 (preferably 20 to 5 CTC), 5 minutes to 48 hours (preferably 30 minutes to 10 hours). έ? 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 removing the reduction catalyst by filtration, the solvent is distilled off if necessary, and the mixture is mixed with water such as ethyl acetate. An organic solvent containing no target compound 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 may be subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separating and purifying an organic compound, for example, the method described in the first step described above. Can be.

no

(Step l0) Acylation

In this step, the compound (4) is reacted with an acid halide R ^6a X (X is preferably chloride) or an acid anhydride R ^6a 0 R ^6a in an inert solvent in the presence of a base to give a compound This is the process of manufacturing (13). In acylation using acid halides;

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

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

The reaction temperature is usually from 0 ° C. to room temperature, and the reaction time is usually from 30 minutes to 1 day, depending on the starting material, solvent, base and the like used. In acylation with the acid anhydride R ^6a 0 R ^6a ;

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

Suitable bases used are organic amines such as pyridine, dimethylamino pyridine, N-methylmorpholine and triethylamine.

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

R ^e when R ^6a is a carbamoyl group. NCO (R ⁶ represents the portion of ^Rea excluding 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 usually from room temperature to 60, 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. A water-immiscible organic solvent such as that described above 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.

The method can be performed by a method commonly used for separating and purifying an organic compound, for example, the method described in the first step.

(Step 1) Deprotection

This step is a step of producing a compound (14) by removing the t-butyl group of the compound (13) using an acid in an inert solvent.

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

(Step 12) Condensation

In this step, in an inert solvent, compound (14) is reacted with Arukokishiamin R ⁸ 0 NH _2, it is a step for preparing a compound (15).

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

(Step 13) 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 target compound (lb) of the present invention.

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

(Step 14) Deacylation

In this step, in an inert solvent in the presence of a base to remove the coercive Mamorumoto represented by R ^ea compound (lb), a step for preparing the object compound (1 a) of the present invention. 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, carbon dioxide Alkali metal carbonates such as lime and lithium carbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or ammonia water, ammonia such as concentrated ammonia-methanol , But are preferably sodium carbonate and potassium carbonate.

The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction. Water; alcohols such as methanol, ethanol and n-propanol; ethers such as tetrahydrofuran and dioxane Preferred are organic solvents such as alcohols and mixed solvents of water and the above-mentioned organic solvents, and more preferred are alcohols (particularly methanol).

The reaction temperature and reaction time vary depending on the starting material, the solvent, the base used, and the like, and are not particularly limited.However, in order to suppress a side reaction, the reaction is usually performed at 0 to 150 ° C (preferably at 20 to 150 ° C). Performed at 30 ° 0 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, and then ethyl acetate is added. Such an organic solvent 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 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 organic compounds, for example, the method described in the first step described above. Can be.

(Step 15) Deprotection

This step is a step of removing the isopropylidene group of compound (6) using an acid in an inert solvent to produce compound (11).

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

(Step 16) Condensation

In this step, in an inert solvent, the compound (1 1), by reacting Arukokishiamin R ^a 0 NH _2, is a step for preparing Compound (1-6).

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

(Step 16a) Condensation

In this step, in an inert solvent, the compound (1 1 a), by reacting an alkoxyamine R ^beta ONH _2, is a step for preparing a compound (16 a).

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

It is performed when R ^{2 is a} benzyl-type protecting group.

(Step 17) Deprotection

This step is a step for producing the target compound (lc) of the present invention by removing the protecting group represented by R ⁸ of the compound (16) in an inert solvent.

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

(Step 18) Acylation

In this step, compound (6) is reacted 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

This step is a step of producing compound (18) by removing the isopropylidene group of compound (17) using an acid in an inert solvent.

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

(Step 20) Condensation K

In this step, in an inert solvent, the compound (1 8) is reacted with Arukokishiami emissions R ⁸ 0 NH _z, it is a step for preparing Compound (1-9).

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

C

(Step 2) Deprotection

This step is a step of removing the protecting group represented by ^Ra of compound (19) in an inert solvent to produce the target compound (Id) of the present invention.

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

(Step 22) Deacylation

In this step, in an inert solvent, to remove the protecting group represented by R ^ea compound (I d), a step for preparing the object compound (lc) of the present invention.

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

(Step 23) Acylation

In this step, compound (20) is produced 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 to produce compound (47).

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

(Step 24) Deprotection

In this step, in an inert solvent, to remove the protecting group represented by R ^e of the compound (20), it is a step for preparing the objective compound of the present invention (le).

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

(Step 24a) Deprotection

In this step, in an inert solvent, to remove the protecting group represented by R ⁸ and R ⁷ of the compound (47), is a step for preparing the objective compound of the present invention (I f). This step can be performed in the same manner as in the ninth step.

(Step 25) Condensation

This step is a step of reacting compound (21) with compound (21a) using a base in an inert solvent to produce compound (22).

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

The reaction is usually performed at 178 ° C, and the reaction time is 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 reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Add water-immiscible organic solvent and wash with water

(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 an ether such as tetrahydrofuran and getyl ether, or a mixture of dibutylboron triflate-triethylamine and methylene chloride, and methylform Combinations of such halogenated hydrocarbons are preferred.

The reaction temperature, when using the LDA is usually one 7 8 gradually warmed to room temperature from a Ί 8 ^e C in the case of using dibutyl boron tri frame Bok. Anti The reaction time varies from 30 minutes to 1 day depending on the reagents and raw materials.

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. Add an organic solvent that is immiscible with clean water and wash with water etc.

(Step 27) Hydrolysis

This step is a step of producing compound (2) by hydrolyzing compound (23) in an inert solvent using a base.

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, and the reaction is carried out by adding hydrogen peroxide. Can be performed efficiently. The reaction temperature is usually from 0 to 5 CTC, and the reaction time is usually from 30 minutes to 5 hours, varying depending on a raw material and a reagent.

After the reaction, the desired compound of this reaction according to a conventional method, collected from the reaction mixture, for example, the reaction mixture was appropriately neutralized, and, after removing by據過if insoluble materials exist, acetic E ¹ A water-immiscible organic solvent, such as toluene, is added, the organic layer containing the target compound is separated after washing with water or the like, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.

(Step 28) Alkylation In this step, a known compound (24) is reacted with an arylhalide R′′X (X represents a halogen atom, preferably bromine or chlorine) using a base in an inert solvent to give a compound. This is the process of manufacturing (25).

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

As the base to be used, disilazides such as lithium hexamethyldisilazide and potassium hexamethyldisilazide, and lithium disoproviramide are preferable, and disilazides are more preferable.

The reaction temperature is usually raised gradually from 18 C to room temperature. The reaction time varies depending on the reagents and raw materials, and 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, and if insolubles are present, they are removed by filtration. Such an organic solvent 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 the solvent is distilled off.

(Step 29) Double bond reduction

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 the reaction. Examples of the solvent include alcohols such as methanol, ethanol, and isopropanol; ethers such as dimethyl ether, tetrahydrofuran, and dioxane; Aromatic hydrocarbons such as toluene, benzene, xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, formamide, dimethylformamide, Dimethylacetamide, N-methyl-2-viroli Amides such as methacrylic acid and hexane methyl phosphorotriamide, fatty acids such as formic acid and acetic acid, water, and a mixed solvent thereof are more preferable. Alcohols (particularly methanol) ), 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 monoxide Rhodium aluminum monoxide, triphenylphosphine-rhodium chloride and palladium barium monosulfate are used, preferably palladium carbon.

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 0 ° C to 10 CTC (preferably 20 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 removing the reduction catalyst by filtration, the solvent is distilled off if necessary, and the mixture is mixed with water such as ethyl acetate. An organic solvent containing no target compound 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.

(Step 30) Hydrolysis

This step is a step of producing a compound (27) by hydrolyzing the compound (26) using a base in an inert solvent.

Alkali metal hydroxides such as potassium hydroxide and sodium hydroxide are suitable as the base used, and a mixed solvent of ethers and water such as dioxane and tetrahydrofuran is used as the solvent. It is.

The reaction temperature is usually 60 to 100 ° C, and the reaction time varies depending on the raw material, base, etc. But usually 5 hours to 1 day.

After the completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. Thereafter, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off.

(Step 3) Protection

This step is a step of producing a compound (5) by simultaneously protecting the hydroxyl group and the carboxylic acid of the compound (27) by removing the generated water by azeotropic distillation in an inert solvent using an acid catalyst. It is.

Usually, 2,2-dimethyloxypropane 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 acid such as p-toluenesulfonic acid, camphorsulfonic acid, or pyridium-P-toluenesulfonate. Or an inorganic acid such as hydrochloric acid.

The reaction temperature varies depending on the acid catalyst used, the starting compound, etc., but is usually from 80 to 100, and the reaction time is mainly determined by the reaction temperature, the starting compound, and the type of solvent used. It usually varies from 30 minutes to 10 hours, depending on the situation.

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 insoluble substances are present, they are removed by filtration. 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 usually used for separating and purifying an organic compound, for example, the method described in the first step described above. be able to.

(Step 32) Alkylation

In this step, in an inert solvent, Compound (28), a Grignard reagent ^{^{R s M g X a (X}} a represents a halogeno group, preferably a Buromi de a Kurori de) by reacting the compound This is the step of manufacturing (32a). ^ Top

The reaction temperature is -78 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 carried out efficiently 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, and if insoluble substances are present, they are removed by permeation. Add an organic solvent that is immiscible with water and wash with water, etc.

It can be performed by a method used for separation and purification of organic compounds, for example, the method described in the first step.

(Step 33) Introduction of methoxymethylamino group

This step is a step of producing compound (34) by reacting compound (28) with methoxymethylamine 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) Ester reduction (alcohol production)

The step is a step of reducing compound (28) in an inert solvent to produce compound (29).

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 suitable. 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 according to a conventional method, for example, to reduce residual After decomposing the agent, neutralizing it as appropriate, and removing any insoluble matter by filtration, adding a water-immiscible organic solvent such as ethyl acetate, washing with water, etc., and containing the target compound The organic layer is separated, dried over anhydrous magnesium sulfate and the like, and then the solvent is distilled off.

(Step 35) Alcohol oxidation (aldehyde formation)

This step is a step of oxidizing compound (29) in an inert solvent to produce compound (30).

This step can be performed by a method called Moffatt oxidation or Swern 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 neutralized as appropriate, and if insolubles are present, they are removed by filtration. Then, an organic solvent immiscible with water, such as ethyl acetate, is added, washed with water, etc., the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate, etc., and the solvent is distilled off. .

The method can be carried out by a method that has been used for separation and purification of organic compounds, for example, the method described in the first step.

(Step 36) Alkylation In this step, in an inert solvent, Compound (3 0) the alkylating agent R ⁴ M g X ^a are reacted in a step of producing the compound (3 1).

This step can be performed in the same manner as in the 32nd step.

(Step 37) Alkylation

This step is a step of producing a compound (32) by alkylating the compound (34) in an inert solvent.

This step can be performed in the same manner as in the 32nd step.

(Step 37a) Introduction of CN group

This step is a step of reacting compound (30) with a cyanating agent in an inert solvent to produce compound (35).

As a solvent to be used, a mixed solvent of a halogenated hydrocarbon such as methylene chloride and water is suitable.

As the cyanating agent to be used, an alkali metal cyanide such as sodium cyanide or 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 depending on a raw material, a reagent and the like.

(Step 38) Hydrolysis This step is a step of hydrolyzing compound (35) under acidic conditions to produce compound (36).

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

Water is preferred as the solvent used.

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, and the reaction time is usually from 5 to 24 hours, depending on the starting 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, and can be obtained, for example, by filtering off the crystals generated by concentrating the reaction mixture.

(Step 39) Hydrolysis

This step is a step of hydrolyzing compound (36) using a base in an inert solvent to produce compound (37).

This is performed when R ′ ^{2 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

In this step, in an inert solvent, compound (37) and by condensing the desired Amin R "R ^'S NH, is a step for preparing a compound (38).

This step can be performed in the same manner as in the first step. (Step 41) Aldol condensation

In this step, in an inert solvent, with a base, the compound (30) is reacted with CH ₃ C0 ₂ R ^13, it is a step for preparing a compound (39).

This step can be performed in the same manner as in the 26th step.

(Step 42) Hydrolysis

This step is a step of producing a compound (40) by hydrolyzing the compound (39) using a base in an inert solvent.

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

(Step 43) Condensation

This step is a step of producing compound (41) by condensing compound (40) and a desired amine in an inert solvent.

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

(Step 44) Alkylation

In this step, first, a mixed acid anhydride is synthesized from compound (42) in an inert solvent and then reacted with diazomethane to produce compound (43). The reaction for producing the mixed acid anhydride is carried out in an inert solvent (for example, the above-mentioned halogenated hydrocarbons, amides, and ethers (preferably, ethyl ether)) in a mixed acid anhydride agent such as chloro. Ethyl carbonate, lower (C,-) alkyl halides such as isobutyl chlorocarbonate, lower alkanol halides such as vivacyl chloride, or lower alkyls or phenyls such as getylcyanophosphate, diphenylcyanophosphate. This is achieved by reacting compound (42) with lucyanophosphoric acid or the like.

The reaction is preferably performed in the presence of an organic amine such as triethylamine, N-methylmorpholine, dimethylaminoviridine, pyridine, and the reaction temperature is 120 ° C to 0 ° C, and the time required for the reaction is 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 to 10 hours. It is.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, when insolubles are present, they are removed by filtration and then the solvent is distilled off.

(Step 45) Alkoxylation or acyloxylation

In this step, in an inert solvent in the presence of a catalyst, the compound (4 3), the alcohol or by reacting the acid R ^{1 beta} Omicron H, is a process for preparing a compound (4 4).

As the solvent to be used, a solvent using a desired alcohol or acid, or an ether such as dioxane or tetrahydrofuran is preferable.

Suitable catalysts are copper salts such as cupric acetate, cupric chloride and copper oxide.

The reaction temperature is usually from 20 to 100 ° C., and the reaction time is usually from 10 minutes to 3 hours, depending on raw materials and the like.

(Step 46) Reduction In this step, compound (44) is reduced in an inert solvent to produce compound (45).

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

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

Also, reducing the Ke Bokun using borohydride sodium compound (44), and have continued, in methanol, is reacted with potassium carbonate, it can also be carried out 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 produce compound (46).

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

(Step 48) Alkylation

This step is a step of producing compound (33) by reacting compound (32) with alkylating agent R ⁴ MgX ⁸ in an inert solvent.

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

(Step 49) Alkylation

This step is a step of producing a compound (48) by reacting the compound (34) with an aryl Grignard reagent in an inert solvent.

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

(Step 50) Oxidation

This step is a step of producing compound (49) from compound (48) in an inert solvent. This step can be carried out by a method called hydroboration-hydrogen peroxide oxidation method.

As the solvent used, ethers such as getyl 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 suitable. The reaction temperature for volatilization is usually 10 to 50 ° C, and the reaction time is usually 1 to 10 hours. 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, and the reaction time is usually 10 minutes to 5 hours.

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 remaining oxidizing agent is decomposed, the reaction mixture is appropriately neutralized, and if there is an insoluble substance, the compound is renatured. After removal by filtration, add an organic solvent that is immiscible with water, such as ethyl acetate, wash with water, etc., separate the organic layer containing the target compound, dry with anhydrous magnesium sulfate, etc., and evaporate the solvent Obtained by:

(Step 51) Ketone reduction

This step is a step of reacting compound (49) with a reducing agent in an inert solvent to produce compound (50).

As the solvent to be used, alcohols such as methanol and ethanol are suitable.

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

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

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 if an insoluble substance is present, the reaction is performed. After removal by filtration, add an organic solvent that is immiscible with water, such as ethyl acetate, wash with water, etc., separate the organic layer containing the target compound, dry with anhydrous magnesium sulfate, etc., and evaporate the solvent Obtained by:

(Step 52) Protection

In this step, compound (51) is reacted with t-butyldimethylsilyl halide in an inert solvent using a base to produce compound (52).

As the solvent to be used, halogenated hydrocarbons such as methylene chloride and black form; ethers such as getyl ether and tetrahydrofuran; and amides such as dimethylformamide are preferable.

Suitable bases used are organic amines such as triethylamine, 4,4-dimethylaminopyridine and imidazole.

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, Ή For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, a water-immiscible organic solvent such as ethyl acetate is added, and the target compound is washed with water or the like. It is obtained by separating the organic layer containing, drying over anhydrous magnesium sulfate or the like, and distilling off the solvent.

(Step 53) Acylation

In this step, in an inert solvent, Compound (5 1), by reacting Ashiruharai de R ^{1 6} X or R ^{1 6} OR ^{1 6,} is a step for preparing a compound (5 3).

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

(Step 54) Tosylation

This step is a step of reacting compound (51) with p-toluenesulfonyl halide (or anhydride) in an inert solvent to produce compound (54).

As the solvent to be used, halogenated hydrocarbons such as methylene chloride and black form; ethers such as getyl ether and tetrahydrofuran; amides such as dimethylformamide are preferable. is there.

As the base to be used, organic amines such as triethylamine, 4,4-dimethylaminopyridin 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. Such an organic solvent 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 the solvent is distilled off. The obtained target compound may be used in a conventional manner, for example, recrystallization, reprecipitation, or

(Step 55) Amination

In this step, in an inert solvent, Compound (4), the desired Amin R ^{1 4} R ^{1 5} NH by reaction, to produce compound (5 5).

As the solvent to be used, halogenated hydrocarbons such as methylene chloride and black form; ethers such as getyl ether and tetrahydrofuran; amides such as dimethylformamide are preferable. .

Suitable bases to be used are organic amines such as triethylamine and 4,4-dimethylaminopyridin.

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

(Step 56) Alkoxylation

In this step, in an inert solvent, Compound (4), the desired alcohol R ^{1 7} 0 H by reaction, to produce compound (5 6).

As the solvent to be used, ethers such as getyl ether and tetrahydrofuran are preferable. 9.1 Suitable bases used are alkali metal hydrides such as sodium hydride and potassium hydride, and alkyllithiums such as n-butyllithium. The reaction temperature is usually 20 to 60 ° C, and the reaction time is 30 minutes to 24 hours, depending on the raw materials and the like.

If necessary, the obtained target compound may be subjected to a conventional method, for example, recrystallization, reprecipitation, or a method generally used for separating and purifying an organic compound, for example, the method described in the first step described above. Can be. In some cases, the hydroxyl group of compound (54) is protected immediately before Steps 55 and 56, and the hydroxyl group is deprotected immediately after Steps 55 and 56. To produce the desired compounds (55) and (56). As the protecting group for the hydroxyl group, a tetrahydrobiranyl group and a methoxymethyl group are suitable, 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).

Amides such as dimethylformamide are suitable as the solvent to be used, and pyridinum chromatochromate and pyridinium dichromate are suitable as the oxidizing agent to be used.

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

The reaction temperature is usually 10 to 40 ° C, and the reaction time varies depending on the raw materials and the like. o 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, the reaction mixture is appropriately neutralized, and, if insoluble matters are present, filtration is performed. After removing by water, add an organic solvent that is immiscible with water, such as ethyl acetate, wash with water, etc., separate the organic layer containing the target compound, dry with anhydrous magnesium sulfate, and distill off the solvent. Obtained by

(Step 58) Condensation

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

This step is performed according to the active ester method or the condensation method of the first step. (Step 59) Reduction

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

This step can be performed in the same manner as in the 51st step.

(Step 60) Amidation

In this step, in an inert solvent, the compound (5 9), the desired Amin R "R ^{1 5} NH by reaction, to produce compound (6 0).

As the solvent to be used, halogenated hydrocarbons such as methylene chloride and chloroform are preferred; ethers such as dimethyl ether and tetrahydrofuran; and amides such as dimethylformamide are suitable.

The reaction temperature is usually 20 to 100 ° C, and the time varies depending on the raw materials 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, and if insolubles are present, they are removed by filtration. 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 the solvent is distilled off.

The compound (60) is produced by reducing the ketone of the compound (57) according to the 59th step, and then condensing it with an amine according to the active ester method or the condensation method of the 1st step. You can also.

¾

(Step 61) Alkylation

In this step, compound (30) is reacted with arylmagnesium halide (preferably, promide or chloride) using a base in an inert solvent to produce compound (61). is there.

This step can be performed according to step 36.

(Step 62) Silylation

In this step, compound (61) is reacted with t-butyldimethylsilyl halide in an inert solvent to produce compound (62).

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 a compound (63) by reacting the 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 sodium periodate oxidation can be performed simultaneously.

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

As the dihydroxylating reagent to be used, a combination of osmium tetroxide or smear oxide and a co-oxidant such as N-methylmorpholine N-oxide is preferable. The reaction temperature for boration is usually 0 to 5 crc, and the reaction time is usually 1 to 10 hours.

The subsequent oxidation takes place in a mixed solvent of water and alcohols such as methanol.

The reaction is carried out by using sodium periodate. The reaction temperature is usually 0 to 40 ° C, and the reaction time is usually 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, 9?

For example, the remaining oxidizing agent is decomposed, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an organic solvent immiscible with water, such as ethyl acetate, is added. The organic layer containing the target compound is separated after washing with, for example, and dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off.

(Step 64) Hui's Sotihi reaction

This step is a step of producing a compound (64) by reacting the compound (63) with ethyl ethylphosphonoacetate in an inert solvent in the presence of a base.

The solvent used in the Wittig reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. Preferably, it is dimethyl ether, disopropyl ether, or tetraethyl ether. These are ethers such as lahydrofuran. The reaction temperature is usually 0 to 4 (TC), and the reaction time is usually 30 minutes to 20 hours, depending on the raw materials and the like.

(Step 65) Double bond reduction

This step is a step of producing a compound (65) by reacting the compound (64) with a reducing agent in an inert solvent. This step can be performed in the same manner as in the 29th step.

(Step 66) Ester reduction (alcohol production)

In this step, compound (65) is reacted with compound (65) in an inert solvent to produce compound (66).

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

(Step 67) Desilylation

This step is a step of reacting compound (66) 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 (46), compound (50), compound (51), compound (52), compound (53), compound (55), compound (56), compound (59), compound (60), and compound (67) the protective group represented by the R ^12, by conventional method carried out, obtained by divided.

9?

The present invention relates to a novel hydroxamic acid derivative having an excellent matrix metalloproteinase inhibitory activity, and an agent for suppressing metastasis, invasion and growth of various cancer cells, and an osteoarthritis and rheumatism containing the derivative as an active ingredient. Provided are a therapeutic agent and a preventive agent for rheumatoid arthritis. Examples of the dosage form of the compound (1) of the present invention include oral administration such as tablets, capsules, granules, powders or syrups, and parenteral administration such as injections or suppositories.

These preparations may contain excipients (eg, lactose, sucrose, dextrose, saccharides such as mannitol, sorbitol; corn starch, potato starch, α-starch, dextrin, starch such as carboxymethyl starch). Derivatives; Cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, and internally crosslinked carboxymethylcellulose sodium; arabia gum; dextran Organic excipients such as pullulan: and silicate derivatives such as light silicic anhydride, synthetic aluminum silicate, magnesium metasilicate aluminate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; Sulfuric acid Inorganic excipients such as sulfates such as sodium chloride, etc.), lubricants (for example, metal stearates such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal silica) Waxes such as veegum and gay; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; sodium salt of fatty acids; sodium lauryl sulfate; magnesium lauryl sulfate Lauryl sulfate such as silicic acid, silicic acid such as silicic acid hydrate; and the above-mentioned starch derivative.), Binder (for example, polyvinyl virolidone, macrogol, and The same compounds as the excipients can be mentioned.), Disintegrants (for example, the excipients) Similar compounds and agents, and croscarmellose sodium, carboxymethyl starch isocyanatomethyl Riumu, chemically modified starches and cellulose such as cross-linked polyvinyl pyrrolidone Can be mentioned. ), Stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and 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.), diluents and the like. It is manufactured in a known manner using additives. The dosage varies depending 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 10 OO mg ( In the case of intravenous administration, the lower limit is preferably 0.5 mg (preferably 5 mg) and the upper limit is 500 mg (preferably 25 mg). Omg) is preferably administered once or several times daily depending on the symptoms.

BEST MODE FOR CARRYING OUT THE INVENTION

(Example ^{1) N 1 - [1 -} (S) - t- Puchiru 2-(R) over human Dorokishi three to (N- methylcarbamoyl) propyl! - N ⁴ over arsenide Dorokishi 2-(R) over Bruno Nirusukushinami de (Compound No. 64)

1-a) [1-(S) 1 -1: 1-butyl-2-(R) -hydroxy 3-(N-methylcarbamoyl) propyl]

4- (S) -benzyloxycarbonylamino-3- (R) -hydroxy-5,5-dimethylhexanoic acid (5.3 g) in tetrahydrofuran (8 Om 1) solution At 0 ° C, N-methylmorpholine (2.1 ml) and isopropyl chloroformate

After adding (2.4 ml) and stirring for 1 hour, a methanol solution of methylamine (9.4 ml, 2.0 M) was added, and the mixture was 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 obtain the desired compound (3.7 g, 66%) as a colorless oil.

'.Eta. nuclear magnetic resonance scan Bae spectrum _{(270MHz, CDC1 3) ό ppm} :

1.01 (4H, s), 2.21-2.43 (2H, ra), 2.78 (3H, d, J = 4.8Hz), 3.48 (1H, dd, J = 9.3, 5.9Hz), 3.96-4.09 (1H, m), 4.20 (1H, d, J = 4.8Hz), 4.75 (1H, d, J-9.3Hz), 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-methylcarbamoyl) broviryl rubamoyl〗 dodecanoic acid t-butyl ester

[11- (S) -t-butyl-2- (R) -hydroxy-3-((N-methylcarbamoyl) provyl]] A solution of benzyl benzyl ester (1.79 g) in methanol (15 ml) was prepared by adding 10% Add palladium carbon (165 mg) and add hydrogen atmosphere The mixture was stirred at room temperature under CO. For 1 hour. After the reaction mixture was filtered, the solvent was removed and the residue was dissolved in tetrahydrofuran (15 ml). At 0 ° C, add 2-(R) -t-butoxycarbonylmethyl decanoic acid (2.0 g), triethylamine (1.2 ml), and getyl cyanophosphonate (1.3 ml) at 0 ° C. ) And 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 = 2: 1) to give the desired compound (888m S, 34%) as a colorless oil.

'11 over nuclear magnetic resonance scan Bae-vector (27011 «12, 0 (1 3) 5 ppm:

0.88 (3H, t, J = 6.8Hz), 1.02 (9Η, s), 1.17-1.36 (16H, m), 1.43 (9H, s), 2.1 6-2.77 (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 (lH, m), 6.28 (1H, d, J = 7.8 Hz), 6.72-6.83 (1H, tn)

1-c) N ¹ [1 — (S) -butyl-2- (R) -hydroxy-3- (N-methylcarbamoyl) propyl] 1—hydroxy-1 2— (R) -nonylskcinamide

3- (R)-[1- (S) -t-butyl-2- (R) -hydroxy-3-((N-methylcarbamoyl) propyl-capsulebamoyl] dodecanoic acid t-butyl ester

To a solution of (44 O mg) in methylene chloride (12 ml) was added trifluoroacetic acid (3.6 ml) at 0 C, and the mixture was stirred at room temperature for 2 hours. The solvent was removed, and the residue was treated with methylene chloride (1 ml). 0 ml). After cooling the solution to 0, N-methylmorpholine (0.90 ml), 0- (t-butyldimethylsilyl) hydroxylamine (146 mg), 1- (3-dimethylaminobutyryl) One 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 saturated saline, dried over anhydrous sodium sulfate, and then the solvent was removed. The residue was dissolved in a mixed solvent of 1 N hydrochloric acid (1 ml) and dioxane (1 ml) and stirred at room temperature for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline, and then dried over anhydrous sodium sulfate. After drying, 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%) as a colorless oil.

'Eta - nuclear magnetic resonance scan Bae-vector _{(400MHz, CDC1 3) δ ppm} :

0.88 (3H, t, J = 7.0Hz), 1.01 (9H, s), 1.24-1.85 (16H, ra), 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-1-N ⁴ — [1- (S) -t-butyl 2- (R) -hydroxy-3 -— (N-methylcarbamoyl) propyl] -1-3- ( R) -Nonylsuccinamide (Exemplary Compound No. 1 65)

2-a) 2-(R)-(2, 2-dimethyl-5-oxo-[1, 3]-dioxolan-1-(S)-yl) decanoic acid [11-(S)-t-butyl-2 — (R) -Hydroxy— 3- (N-methylcarbamoyl) propyl] amide

(1-(S)-t-butyl-2-(R)-hydroxy-3-(N-methylcarbamoyl) propyl benzylamine (967 mg) in methanol (10 ml) solution with 10% palladium carbon (10 O mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour.The reaction mixture was filtered, the solvent was removed, and the residue was dissolved in methylene chloride (40 ml). C at 2— (R)-(2,2-dimethyl-1-5- [1,3] -dioxolan-14-1 (S) —yl) pentadecanoic acid

(991 mg), N-methylmorpholine (0.362 ml), 11- (3-dimethylaminofuran pill) -13-ethylcarposimid hydrochloride (633 mg) were added, and the mixture was added at room temperature. Stir for 1 hour. Water was added to the 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 flash column chromatography (ethyl acetate) to obtain the desired compound (540 mS, 42%) as a colorless oil.

¹ H- nuclear magnetic resonance scan Bae spectrum _{(400MHz, CDC1 3) δ ppm} :

0.88 (3H, t, J = 6.8Hz), 1.03 (9H, s), 1.16-1.43 (14H, ra), 1.58 (3H, in), 1.5 / c 9-

9 (3H, s), 1.64-1.82 (2H, m), 2.22 (1H, dd, J = 15.2, 8.3 Hz), 2.31 (1H, dd, J = 15.2, 2.8 Hz), 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 (lH, m), 4.60 (1H, d, J-4.4Hz), 4.74 (1H, d, J = 7.4Hz), 6.53 (1H, d, J = 8.1Hz), 6.63 (1H, q, J = 4.8Hz)

2 - b) N ¹ one Benjiruokishi ^{N 4 - [1 - (S} ) one t one-butyl - 2- (R) - arsenide Dorokishi 3- (N- methylcarbamoyl) propyl] one 2-(S) over human Dorokishi one 3— (R) -nonylsuccinamide

2- (R) 1 (2,2-Dimethyl-1-5-oxo-1U, 3] dioxolan-1 41- (S) -yldecandenoic acid [1- (S) -t-butyl-2 (R) —Hydroxoxy 3— (N-methylcarbamoyl) propyl] amide (540 mg) in acetic acid (10 ml) was added with water (3.3 ml), and then added. After stirring at C for 10 hours, the solvent was removed. Tetrahydrofuran (5 ml) and water (0.5 ml) were added to the residue, and at 0 ° C, 0-benzylhydroxylamine hydrochloride (394 mg) and 1- (3-dimethylaminobutyryl) 13 —Ethylcarbodiimid hydrochloride (474 mg) was added, and the mixture was 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 obtain the desired compound (400 mg, 60%) as a white solid.

'H-nuclear magnetic resonance spectrum (270HMz, CDCl 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 = 9.4Hz), 7.35-7.40 (5H, m), 10.24 (1H, s)

2 - c) 2- (S) , N 1 Jihi Dorokishi ^{-N 4 - [1 - (S} ) - t one-butyl - 2- (R) _- heat Dorokishi 3 - (N-methylcarbamoyl) Burobiru 1 one 3 — /

(R) -Nonylsuccinamide

N ¹ monobenzyloxy — — [1 — (S) — t-butyl-2- (R) — hydroxy 3 — (N-methylcarbamoyl) propyl] 1 2 — (S) -hydroxy-3-(R) To a solution of -nonylsuccinamide (400 mg) in methanol (20 ml) was added 5% palladium-alumina (40 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. Recrystallize the residue (ethyl acetate

: Hexane) to give the desired compound (205 mg, 62%) as a white solid.

¹ H-nuclear magnetic resonance spectrum (400MHz, CDsOD) 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 = 14.2, 9.9Hz) , 2.40 (1H, dd, J = 14.2, 2.5Hz), 2.67-2.82 (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 one [1 - (S) one t- Puchiru 2- (R), 4 Jihidoroki Shibuchiru] one 2- (S), Ν ¹ Jihi Dorokishi 3- (R) - on Nonirusukushinami (Compound Number 1 7 1)

3-a) (1-(S) 1 t-1-butyl-2- (R), 4-dihydroxybutyl 1 carbamic acid benzyl ester

4- (S)-(benzyloxycarbonyl) amino-3- (R) -hydroxy-5,5-dimethylhexanoic acid ethyl ester (4.74 g) in ethanol (3Oml) -tetrahydrofuran (20ml) At 0 ° C, a suspension of sodium borohydride (1.1 g) and lithium chloride (1.2 g) in ethanol (30 ml) —tetrahydrofuran (2 Om 1) was added to the solution, and the mixture was added at room temperature. Stir 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 obtain the desired compound (3.7 g, 89%) as a colorless oil. ¹ H- nuclear magnetic resonance scan Bae click Bokuru _{(270MHz, CDC1 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 (1H, brs), 4.88 (1H, d, J = 8.9Hz), 5.12 (2H, s), 7.29-7.42 (5H, m)

3-b) [1-(S) 1 t-1 -butyl-4-(t -butyldimethylsilyloxy)-2-(R)-hydroxybutyl] Benzyl ester of rubamate

[11 (S) -t-butyl-2- (R), 4-dihydroxybutyl] carbenyl benzyl ester in methylene chloride (100 ml) at 0 ° C at 0 ° C. ml), 4-dimethylaminopyridine (151 mg) and t-butyldimethylsilyl chloride (2.1 g) were 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: 2) to give the desired compound (2.7 g, 53%) as a colorless oil.

'H - NMR Supekubokuru _{(270MHz, CDC1 3) 5 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, dd, J = 9.9, 4.8Hz), 3.72-3.98 (3H, m), 4.77 (1H, d, J = 9.9 Hz), 5.11 (2H, s), 7.28-7.43 (5H, m)

3—c) 2— (R) — [2,2-Dimethyl-5-oxo-1 [1,3] —dioxolan-1 41- (S) —yl] Pindecanoic acid [111—S—t-butyl-4 — (T-butyldimethylsilyloxy) — 2— (R) -hydroxybutyl] amide

[1-(S) 1 t-butyl-41- (t-butyldimethylsilyloxy) 1 2—

(R) -Hydroxybutyl] benzyl rubinate (480 mg) to give the desired compound (385 mg, 59%) as a white solid in the same manner as in Example 2-a).

'Eta - nuclear magnetic resonance scan Bae spectrum _{(270MHz, CDC1 3) δ ppm} : Q.0613H, s), 0.07 (3H, s), 0.85-0.92 (12H, m), 1.01 (9H, s), 1.12-1.41 is 4 H, m), 1.44-1.82 (4H, m), 1.55 (3H, s), 1.62 (3H, s), 2.65 (1H, m), 3.71-4.0 4 (4H, m), 4.55 (1H, d, J = 5.0 Hz), 6.26 (1H, d, J = (8.3Hz)

3 - d) N ¹ one Benjiruokishi N ⁴ one [1 one (S) - t-butyl-2- (R), 4- dihydric Dorokishibuchiru] one 2 - (S) over human Dorokishi one 3 - (R) - Noel Sukushinami de

2 — (R) 1 [2,2-dimethyl-5-oxo 1 [1, 3] — dioxolan 1

4- (S) -yl] decanoic acid [1- (S) -t-butyl-4- (t-butyldimethylsilyloxy) 1-2- (R) -hydroxybutyl] amide (730 mg )) To give the target compound (255 mg, 39%) as a white solid in the same manner as in Example 2-b).

- nuclear magnetic resonance scan base click Bokuru _{(270MHz, CDC1 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), 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, in), 9.34 (1H, brs)

^{3 - e) N 4 - [} 1 - (S) one t one-butyl - 2- (R), 4 Jihi Dorokishibu chill] one 2- (S), Ν over dihydroxy chromatography 3- (R) over Bruno succinate cyanamide

Ν ^1- benzyloxy Ν ⁴ — [1 — (S) 1 "t-butyl-2 — (R), 4-dihydroxylbutyl) 1 2 — (S) -hydroxy-3 — (R) -nonylsuccinamide (255 mg) Thus, the target compound (146 mg, 70%) was obtained as a white solid in the same manner as in Example 2-c).

Nuclear magnetic resonance scan Bae spectrum _{(400MHz, CD 3 0D) S} 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) ¹ [1-(S) -benzyl-2- (R) -hydroxy-3- (N-methylcarbamoyl) propyl; - N ⁴ over arsenide Dorokishi 2-(R) - nonyl Sukushinami de (Compound No. 62)

4- (a) 4- (S) 1-t-butoxycarbonylamino-3- (R) -hydroxy-5-phenylpentanoic acid methylamide

4- (S) -t-Butoxycarbonylamino-3- (R) -hydroxy-15-phenylpentanoic acid (310 mg) is dissolved in tetrahydrofuran (6 ml) and cooled on ice. Then, a 30% methylamine methanol solution (0.13 ml), getyl cyanophosphonate (0.18 ml), and triethylamine (0.33 ml) were added, and the mixture was stirred for 30 minutes under ice-cooling. After the 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 a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the target compound (235 mg, 72.9%) as a white powder.

'H—nuclear magnetic resonance spectrum (270MHz, CDCI3 + CD3OD) δ ppm:

1.01 (9H, s), 2.22-2.45 (2Η, m), 2.60-2.80 (1Η, m), 2.77 (3Η, s), 3.00-3.1 0 (1Η, m), 3.65-3.80 (1H, πι) , 3.80-3.95 (1Η, m), 7.12-7.35 (5Η, m)

Infrared absorption spectrum (KBr pellet, cm "'):

3319, 1683, 1648, 1531

Mass spectrum (FAB): m / z [+ H] ⁺ = 323

4-b) 4- (S) -Amino-3- (R) -hydroxy-5-phenylpentanoic acid methylamide hydrochloride

4- (S) -t-Butoxycarbonylamino-3- (R) -hydroxy-5-phenylpentanoic acid methylamide (650 mg) is dissolved in ethanol (13 ml) and cooled under ice-cooling. After adding 4N-hydrochloric acid / dioxane and returning to room temperature and stirring for 15 hours, the temperature was raised to 40 ° C. and stirred for 2 hours. The solvent was distilled off under reduced pressure to obtain the target compound (520 mg, 100%) as a white powder.

'H—nuclear magnetic resonance spectrum (270MHz, CDCI3 + CD3OD) δρριπ: /?

2.50-2.70 (2H, m), 2.79 (3H, s), 2.95-3.15 (2H, m), 3.60-3.75 (1H, m), 4.2 0-4.40 (lH, m), 7.20-7.50 (5H, m)

Mass spectrum (EI): m / z [M] + = 223

4-c) 3-(R)-1-(S) 1-benzyl-2- (R)-hydroxy 3-(N-methylcarbamoyl) propyl-rubamoyl t-butyl ester dodecanoate

From 4-methylmethylamide 4- (S) -amino-3- (R) -hydroxy-5-phenylpentanoate hydrochloride (500 mg) in the same manner as in Example 1-b), the target compound (

50 O mg, 61.5%) as a white powder.

'.Eta. Nuclear magnetic resonance spectrum _{(270MHz, CDC1 3) δ ppm} :

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 (1 H, m), 6.77-6.87 (lH, m), 7.15-7.35 (5H, m)

Infrared absorption spectrum (KBr pellet, cm ' ¹ ):

3314, 1730, 1645, 1553

Mass spectrum (FAB): m / z [M + H] ⁺ = 505

204-205. C

4-d) 3- (R) -I- [1- (S) -benzyl-2- (R) -hydroxy-31- (N-methylcarbamoyl) bromopyruvamoyl-dodecanoic acid

3- (R) -1- [S- (S) -benzyl-1-2- (R) -hydroxy-13- (N-methylcarbamoyl) propyl rubamoyl] Dodecanoic acid t-butyl ester (45 O mg) The suspension was suspended in methylene (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 to obtain the target compound (39 O mg, 100%) as a white powder.

'Η—nuclear magnetic resonance spectrum (270MHz, CDCI3 + CD3OD) 5ppm:

0.88 (3H, t, J = 6.7Hz), 1.10-1.50 (16H, m), 2.25-2.50 (5H, m), 2.78 (3H, s) , 2.86 (1H, dd, 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, 3286, 1731, 1645, 1549

Mass spectrum (FAB): m / z [M + H] ⁺ = 449

Melting point 202-204 ° C

4-e) N '1 [1-(S)-benzyl-2-(R)-hydroxy-3-(N-methylcarbamoyl) brovir] 1 N ^4- hydroxy 2-(R)-nonyls cincinamide

3- (R)-[1— (S) -Benzyl-1- (R) -hydroxy-3- (N-methylcarbamoyl) brovir-ylrubamoyl] Dodecanoic acid (390 mg) in tetrahydrofuran (10 ml) ), And 0- ("t-butyldimethylsilyl) hydroxyamine (158 mg), getyl cyanophosphonate (0.16 m1), and triethylamine (0.37 m1) were dissolved on ice. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and 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 washed with ether and dissolved in ethanol IN-hydrochloric acid was added, the mixture was stirred at room temperature for 2 hours, the solvent was distilled off under reduced pressure, the residue was washed with ether, and methanol was added. Add water and recrystallize to give the desired compound (70 mg, 17.4) %) Was obtained as white crystals.

'H- NMR spectrum _{_{(400MHz, CDC1 3 + CD 3}} 0D) δ ppra:

0.89OH, 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, 7.4Hz), 2.29 ( 1H, dd, J = 14.6, 9.1Hz), 2.46 (1H, dd, J = 14.6, 2.4Hz), 2.49-2.51 (1H, m), 2.76 (3H, s), 2.75 (1H, dd, J = 14.0, 9.9Hz), 3.14 (1H, dd, J = 14.0, 3.6Hz), 3.94-4.03 (2H, in), 7.13-7.26 (5H, m) Infrared absorption spectrum (KBr pellet, cnT ') ):

3289, 1643, 1550

Mass spectrum (FAB): m / z [M + H] ⁺ = 464 'Li

220-222 ° C

(Example 5) N ¹ one [1 - (S) - benzyl-2 - (S) over human Dorokishi 3- (N- methylcarbamoyl) propyl] one N ⁴ - heat Dorokishi 2-(R) - nonyl Sukushinami de ( Exemplified compound number 62)

5-a) 4-(S) 1-t-butoxycarbonylamino-3- (S) -hydroxy-5-phenyl penic acid methyl amide

4-I- (S) -t-butoxycarbonylamino 3- (S) -hydroxy-5-phenylpentanoic acid (31 mg) In the same manner as in Example 41a), the desired compound (26 mg, 80 . 6%) as a white powder.

'H—nuclear magnetic resonance spectrum (270MHz, CDCI3) δρρηι:

1.40OH, s), 2.16 (1H, dd, J = 14.9, 2.4Hz), 2.43 (1H, dd, J = 14.9, 9.6Hz), 2.78 (3H, d, J = 4.9Hz), 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), 7.16-7.4 0 (5H, m)

Infrared absorption spectrum (KBr pellet, cm— ¹ ):

3369, 1688, 1654, 1639, 1522

Mass spectrum (EI): m / z [M] ⁺ = 323

134-135 ° C

5- (b) 4- (S) -Amino-3- (S) -hydroxy-5-phenylmethyl benzoate methylamide hydrochloride

4- (S) -t-butoxycarbonylamino-3- (S) -hydroxy-5-phenylpentanoic acid methylamide (20 mg) In the same manner as in Example 41-b), the desired compound (16 mg, quant.) was obtained as a white powder.

Mass spectrum (FAB): m / z [M + H] ⁺ = 223

5-c) 3-_ (RJ-[_1-shi S]--Benjiru 2-shi S) _-hydroxy _3 Menu

-(N-Methylcarbamoyl) propyl sorbamoyl t-butyl ester dodecanoate

From 4-(S)-amino-3-(S)-hydroxy-1-phenylpentanoic acid methylamide hydrochloride (440 mg), the desired compound (54 Omg, 76.4%) as a white powder.

'.Eta. Nuclear magnetic resonance spectrum _{(270MHz, CDC1 3) δ ppm} :

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 (1H, 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, 1731, 1700, 1661, 1530

Mass spectrum (FAB): m / z (+ H) ⁺ = 505

Melting point 104-105 ° C

5-d) 3-(R)-[1-(S) Benzyl 2-(S)-Hydroxy-1-1 (N-methylcarbamoyl) propyl-sulfuryl] Dodecanoic acid

3- (R) -I (1- (S) -benzyl-1- (S) -Hydroxy-3- (N-methylcarbamoyl) -propyl-l-bamoyl] dodecanoic acid "t-butyl ester (50 Omg) Example 41 In a similar manner to d), the desired compound (400 mg, 89-2%) was obtained as a white powder.

Mass spectrum (FAB): m / z [Μ + Η] ⁺ = 449

5-e) N ¹ [1-(S)-benzyl-2-(S)-hydroxy 3-(N-methylcarbamoyl) propyl]--hydroxy 2-(R)-nonyls xinamide

3- (R)-[1- (S) -Benzyl-1- (S) -hydroxy-3-((N-methylcarbamoyl) propyl] rubamoyl] Dodecanoic acid (35 Omg) from Example 41-e) Similarly, target compound (140 mg, 38.7%) was obtained as white powder // 3

As obtained.

'Η—Nuclear magnetic resonance spectrum (400MHz, CDsOD) δ ppm:

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, dd, 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, 1638, 1539

Mass spectrum (FAB): m / z [M + H] ⁺ = 464

Melting point 166-167 ° C

Example 6 2- (R) -Hydroxy 3- (S)-[2 (R) -I- (N-Hydroxyoxycarbamoylmethyl) pentacanylamino] 4-phenylbutyric acid Cyl ester (Exemplary Compound No. 6 1)

6-a) 3- (S) dibenzylamino-1- (R) -hydroxy-4-phenylphenylbutanoic acid methyl ester

3- (S) Dibenzylamino-2- (R) -hydroxy-4-phenylbutanoic acid (1.5 g) was dissolved in methanol, and diazomethane was added until a yellow transparent solution was obtained. 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.

'Η—Nuclear magnetic resonance spectrum (270MHz, CDCla) δ ppm:

2.81 (1H, dd, J = 14.0, 7.3Hz), 3.03 (1H, dd, J = 14.0, 7.3Hz), 3.09 (1H, d, J = 6.3Hz), 3.42 (1H, dt, J = 2.6, 7.3Hz), 3.53 (3H, s), 3.66 (2H, d, J = 14.0Hz), 3.82 (2H, d, J = 14.0Hz), 4.49 (1H, dd, J = 6.3, 2.6Hz), 7.02 -7.33 (15H, m) Mass spectrum (FAB): m / ζίΜ + H] ⁺ = 390

6— b) 3-(S) — 1-amino 2-[R) _-1-hydroxyl 4-phenylbutane /

Acid methyl ester

3- (S) -Dibenzylamino-2- (R) -hydroxy-4-phenylbutanoic acid methyl ester (700 mg) was dissolved in methanol (13.44 ml), and the solution was replaced with nitrogen. % 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 filtration of the catalyst, the solvent was distilled off under reduced pressure to obtain the target compound (408 mg, QUANT.) As a colorless oily substance.

Mass vector: m / z [M + H] +-210

6-c) 3-(R)-[1-(S)-benzyl-2-(R)-hydroxy-12-methoxycarborletylcarbamoyl] dodecanoic acid t-butyl ester

3- (S) -Amino-2- (R) -hydroxy-14-phenylbutanoic acid methyl ester (15 mg) was obtained in the same manner as in Example 11-b) to obtain the desired compound (18 mg,

73.2%) as a colorless oil.

'.Eta. Nuclear magnetic resonance spectrum (270MHz, CDC1 ₃₎ δρρπι:

0.88 (3H, t, J = 6.9Hz), 1.18-1.39 (16H, in), 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 (1H, 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) 1-benzyl-1-2- (R) -hydroxy-2-methoxycarbenylethylcarbamoyl-dodecanoic acid

3-(R)-[1-(S) 1-Benzyl 1-2-(R)-Hydroxy-1-2-methoxycarbenylethylcarbamoyl] Dodecanoic acid "b-butyl ester (140 mg). The desired compound (110 mg, 90.2%) was obtained as a colorless oil in the same manner as in Example 4 d).

Mass spectrum (FAB): m / z [+ H] ⁺ = 436

6-e) 2-(_R) -Hydroxy 3-(SJ-1 [2-(R)-N-H 〃

Xycarbamoylmethyl) decanoylamino] methyl 4- (4-phenylbutanoate)

3-(R)-[1-(S) 1-Benzyl 2-(R)-Hydroxy-1-methoxycarborletylcarbamoyl] From dodecanoic acid (100 mg), Example 41-e) . purpose in the same manner ^ (匕合product (63 mg, 60. give 8%) as white crystals 1 H - NMR spectrum _{(400MHz, CD 3 0D) 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) '3.6 5 (3H, s), 4.18 (1H, d, J = 5.0Hz), 4.45-4.50 (1H, m) , 7.13-7.30 (5H, ra) Infrared absorption spectrum (KBr pellet, cm " ¹ ):

3300, 1745, 1645, 1544

Mass spectrum (FAB): m / z [M + H] ⁺ = 451

143-145 ° C

(Example 7) 2- (S), N 1 - dihydric Dorokishi ^{N 4 - (1 - (S} ) - t - Petit Lu 2-(R) over human Dorokishi 3- (N, N-dimethylcarbamoyl) Buropiru] — 3— (R) —Nonylsuccinamide

7-a) [1-(S)-t-butyl-2-(R)-hydroxy-3-(N, N-dimethylcarbamoyl) propyl benzyl benzyl ester

4- (S) 1-benzyloxycarbonylamino-3- (R) -hydroxy-1,5,5-dimethylhexanoic acid (31 Omg) and N, N-dimethylformamide (6 m1 )) To give the desired compound (226 mg, 67.2%) as a white powder from dimethylamine hydrochloride (163 mg) in the same manner as in Example 11a).

—Nuclear magnetic resonance spectrum (270MHz, CDC) δ ppm:

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), δ.05 (1Η, d, J = 12.4Hz), 5.16 (1H, d, J = 12.4Hz), 7.30-7.40 (5H, m) Infrared absorption spectrum (KBr pellet, cm " ¹ ): 3361, 1709, 1624, 1543

Mass spectrum (EI): m / z [M] ⁺ = 336

7-b) 2-(R)-(2,2-Dimethyl-1-5-oxo [1,3] -dioxolan-41- (S) -yl) -Pindecanoic acid [1-1 (S) -t- Butyl 2- (R) -hydroxy-3- (N, N-dimethylcarbamoyl) propyl] amide

[1- (S) -t-butyl-2- (R) -hydroxy-3- (N, N-dimethylcarbamoyl) propyl] benzyl carbamic acid ester (1.64 g) Same as Example 2-a) The target compound (630 mg, 26.5%) was obtained as a colorless oily substance.

lH- NMR spectrum _{(270MHz, CDC1 3) δ ppm} :

0.88 (3H, t, J = 7.1Hz), 1.04 (9H, s), 1.20-1.40 (16H, m), 1.55 (3H, s), 1.6

3 (3H, s), 2.49 (2H, d, J = 5.7 Hz), 2.60-2.70 (1H, m), 2.95 (3H, s), 2.97 (3H, s), 3.88 (1H, dd, J = 9.6, 7.3Hz), 4.03-4.15 (1H, ra), 4.20 (1H, d, J = 5.0Hz), 4.55 (1H, d, J = 5.5Hz), 6.28 (1H, d, J = 9.6Hz)

Infrared absorption spectrum (KBr pellet, cm- ¹ ):

3409, 1787, 1672, 1629

Mass spectrum (FAB): ra / z [+ H] ⁺ = 485

7-c) N '1-benzyloxy-N *-[1-(S) 1-t-butyl-2-(R)-hydroxy-3-(N, N-dimethylcarbamoyl) propyl]-2-(S)- Hydroxy-3- (R) -nonylsuccinamide

2- (R) -I (2,2-Dimethyl-I 5-Oxo-I [1, 3] -Dioxolan-I

4- (S) -yl) pentadecanoic acid [1- (S) -t-butyl-2- (R) -hydroxy-13- (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, CDCla) 5 ppm: Ί

0.8813H, t, J = 6.8Hz), 1.03 (9H, s), 1.20-1.45 (14H, m), 1.73 (2H, m), 2.3 7-2.55I2H, 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), 4.89 (1H, d, J = ll.2Hz), 5.23 (1H , d, J = 8.4Hz), 6.09 (1H, d, J = 10.0Hz), 7.28 (5H, brs), 9.35 (1H, brs) IR spectrum (CDC1 ₃ , CnT Li:

3402, 1687, 1633

Mass spectrum (FAB): m / z [M + H] ⁺ = 550

7 - d) 2 - (S ), N 1 - dihydric Dorokishi one ^{N 4 - (1 - (S} ) one t one-butyl - 2- (R) - heat Dorokishi - 3- (N, N- dimethylcarbamoyl) propyl ] I 3— (R) — Nonylsuccinamide

N ¹ —benzyloxy N ⁴ — [11- (S) -tert-butyl- 2 _ (R) -hydroxy-3--3-dimethylcarbamoylpropyl] 1-2- (S) -hydroxy-3-

The target compound (340 mg, 74.0%) was obtained as a white compound from (R) -nonylsuccinamide (550 mg) in the same manner as in Example 2-c).

'Η—nuclear magnetic resonance spectrum (400MHz, CDaOD) δ ppm:

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 "):

3279, 3204, 1648, 1632

Mass spectrum (FAB): m / z [+ H] ⁺ = 460

Mp 167-169 "C (Example 8) Acetic acid 2- (S)-[2- (R) -I- (N-hydroxycarbamoylmethyl) pandecanoylamino] -1,3-dimethylbutyl ester (Exemplified Compound No. 9)

8-a) 2— (R) — t-Butoxycarbonylmethylpandecanoic acid

4- (S) -Isopropyl-1- (2- (R) -t-Butoxycarbonylmethyl-1-oxoxodecyl) -1-2-oxazolidinone (1.2.00 g) in tetrahydrofuran-water (3: 1 , 600 ml) and cooled to 0 ° C. Lithium hydroxide monohydrate (2.45 g) and 30% aqueous hydrogen peroxide (14.4 ml) were 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 successively 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.

—Nuclear magnetic resonance spectrum (270MHz, CDCls) δρρηι ：

0.88 (3H, t, J = 6.6Hz), 1.16-1.75 (16H, m), 1.47 (9H, s), 2.38 (1H, dd, J = l 6.3, 5.2Hz), 2.63 (1H, dd, J = 16.3, 9.2Hz), 2.80 (1H, m)

Infrared absorption spectrum (liquid film, cm- ')

1734, 1709

High-resolution mass spectrum

m / z [M + H] ⁺ = 301.2354

_{_{Calculated: 301.2379 (C l7 H 33 0}} 4)

Specific rotation: [α] 0 ²⁵ = + 14.Γ (C: 1.07, EtOH)

8-b) 3-(R)-[1-(S) -Hydroxymethyl-2,2-dimethylpropyl rubamoyl] Dodecanoic acid t-butyl ester

2- (R) 1-t-butoxycarbonylmethylpandecanoic acid (1.92 g) obtained in Example 8-a) was dissolved in tetrahydrofuran (40. Oml) under a nitrogen atmosphere. -Cooled to 20. Next, triethylamine (0.94ml) ί /

Isobutyl formate (0.88 ml) was added dropwise and the mixture was stirred at 120 ° C for 25 minutes. Then, a solution of (S) 1 t-leucinol (845 mg) in N, N-dimethylformamide (8 ml) was added, and the mixture was stirred overnight while warming to room temperature. The reaction solution was poured into a 5% aqueous sodium hydrogen sulfate solution, extracted with ethyl acetate, and the organic layer was washed successively 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 = 3: 1) to obtain 1.51 g (59%) of the desired compound as a white solid. Melting point 63-65 ° C

1 H - NMR spectrum _{(270MHz, CDC1 3) δ ppm} :

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), 2.50-2.70 ( 2H, m), 3.54 (1H, m), 3.73-3.91 (2H, ra), 6.09 (1H, d, J = 8.9Hz)

Infrared absorption spectrum (KBr pellet, cm ")

3328, 1732, 1645, 1544

Mass spectrum (FAB) m / z [M + H] ⁺ = 400

High resolution mass spectrum (FAB)

m / z [+ H] ⁺ = 400.3419

Calculated value: 400.3427 (C ₂₃ H "(N)

8-c) 3-(R)-[1-(S)-Acetoxymethyl-2, 2-dimethylbutyl rubamoyl] Dodecanoic acid t-butyl ester

3- (R) -I- (1- (S) -hydroxymethyl-2,2-dimethylpropylrubumoyyl) -dodecanoic acid t-butyl ester (704 mg) obtained in Example 8-b) was added to tetrahydrofuran (5 m l) and cooled to 0 ° C. Next, pyridine (1601) and acetyl chloride (135w1) were added in that order, and the mixture was stirred at 0 ° C for 1.3 hours. The reaction solution was poured into a 5% aqueous sodium hydrogen sulfate solution and extracted with ethyl acetate. The organic layer was washed with a 5% aqueous sodium hydrogen carbonate solution, 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. /

Purification by chromatography (hexane: ethyl acetate = 5: 1) gave the desired compound (768 mg, 9.9%) as a colorless oil.

'H—nuclear magnetic resonance spectrum (400MHz, CDC) δ ppm:

0.87 (3H, t, J = 6.8Hz), 0.94 (9H, s), 1.15-1.50 (15H, m), 1.42 (9H, s), 1.6

7 (1H, m), 2.03 (3H, s), 2.32 (1H, dd, J = 15.7, 3.5Hz), 2.53 (1H, m), 2.63 (1H, dd, J = 16.7, 9.8Hz), 4.01 -4.13 (2H, m), 4.21 (1H, m), 5.83 (1H, d, J = 8.8Hz Infrared absorption spectrum (liquid film, cm- ¹ )

3320, 1732, 1648, 1545

Mass vector (FAB) m / z [M + H] ⁺ = 442

High resolution mass spectrum (FAB)

m / z [Μ + Η] ⁺ = 442.3506

_{_{Calculated: 442.3533 (C 25 H 48 N0}} 5)

8-d) 3-(R)-[1-(S) -acetoxymethyl-2,2-dimethylbutyruvamoyl] Dodecanoic acid

3- (R) — [1- (S) -acetoxymethyl-2,2-dimethylpropyl-l-rubamoyl] dodecanoic acid t-butyl ester (690 mg) obtained in Example 8—c) in methylene chloride ( Trifluoroacetic acid (2.5 ml) was added to the solution (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 was purified by silica gel column chromatography (methylene chloride: methanol = 30: 1) to obtain 584 mg (97%) of the target compound as a colorless oily substance.

'Η—nuclear magnetic resonance spectrum (400MHz, CDCU), δ ppm:

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 (3H, s), 2.46-2.61 (2H, in), 2.77 (1H, dd, J = 17.2, 9.5Hz), 4.01-4.16 (2H, m), 4.22 (1H, m), 5.73 (1H, d, J = 9.4 Hz)

Infrared absorption spectrum (liquid film, era "') /

3320, 1742, 1727, 1500

Mass spectrum (FAB) m / z [Μ + ΗΓ = 386

High resolution mass spectrum (FAB)

m / z [M + H] ⁺ = 386.2889

Calculated value: 386.2906 (C ₂₁ H ₄ oN0 ₅ )

8-e) Acid 2- (S)-[2- (R)-(Hydroxycarbamoylmethyl) decanoylamino] -3,3-dimethylbutyl ester

Example 8-3- (R)-[1- (S) -acetoxymethyl-2,2-dimethylprovyl-rubamoyl-dodecanoic acid (2.55 g) obtained in d) was added to N, N-diamine. It was dissolved in methylformamide (56 ml) and cooled to 0 ° C. Next, 1-hydroxybenzotriazole (1.34 g), N-methylmorpholine (1.20 ml), 1- (3-dimethylaminopropyl) -13-ethylcarposimimid hydrochloride (2. 03 g) and 0- (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 sodium hydrogen carbonate solution, extracted with ethyl acetate, and the organic layer was washed successively with a 5% aqueous potassium hydrogen sulfate solution, water, and a saturated saline solution, 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 = 20: 1), and the white solid obtained was recrystallized from methanol-water to obtain the desired compound 1.7. 1 g (65%) was obtained as white crystals.

'.Eta. Nuclear magnetic resonance spectrum _{(400MHz, CDC1 3) δ ppm} :

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 (1H, m), 2.49 (1H, m), 2.75 (1H, m), 3.95-4.13 (2H, m), 4.24 (1H, d, J = 8.4Hz), 6.18 (1H, m)

Infrared absorption spectrum (KBr pellet, cm " ¹ )

3299, 1745, 1643, 1550

Mass spectrum (FAB) ra / z [M + H] ⁺ = 401

High resolution mass spectrum (FAB) m / z [+ H] * = 401.3022

_{Calculated: 401.3016 (C, N 2 0} 5)

Specific rotation: [a] + 8.8 ° (C-.0.34, MeOH)

(Example 9) N ⁴ over human Dorokishi one N '- [1 - (S) over human Dorokishimechiru 2, 2 - dimethylpropyl] - 2-(R) over Bruno succinate cyanamide (Compound No. 8)

2- (S) -acetic acid obtained in Example 8-e) 2- (S)-(2- (R)-(N-hydroxylrubamoylmethyl) undecanoylamino) -1,3-dimethylbutylester (2 To a solution of 58 mg) in methanol (10 ml) was added lithium carbonate (186 mg) and the mixture was stirred at room temperature for 2.3 hours. 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 evaporated under reduced pressure, and the obtained white solid was recrystallized from ethyl acetate-methanol to give 183 mg (79%) of the desired compound as white crystals.

Nuclear magnetic resonance spectrum (400MHz, DMSO-de) δρρηι:

0.84 (9H, s), 0.86 (3H, t, J = 6.6Hz), 1.10-1.35 (15H, m), 1.42 (1H, m), 2.0 1 (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 = 9.3Hz), 8.65 (1H, d, J = 1.4Hz), 10.36 (1H, d, J = 1.4Hz)

Infrared absorption spectrum (KBr pellet, cm "')

3401, 3254, 1666, 1613, 1532

Mass vector (FAB) m / z [M + H] + = 359

High Resolution Mass Vector (FAB)

m / z [M + H] = 359.2923

_{Calculated: 359.2910 (0, 9Η 39 Ν} 2 θ)

Specific rotation: [a] ²⁵ = + 2.9 ° (C: 0.38, MeOH)

Melting point 16 2 to 1 64 ° C / 3

(Example 10) Acetic acid 2— (S) — {2— (R) — [(S) —hydroxy (hydroxoxycarbamoyl) methyl] indecanoylamino amino-1,3-dimethylbutyl ester ( (Exemplary Compound No. 110)

1 0-a) 2-(R) 1 [2,2-dimethyl- 1-5-oxo- 1 [1, 3]-dioxolane 1-4 (S)-yl] didecanoic acid U-(S) Droxymethyl-2,2-dimethylpropyl] amide

According to the method of Example 8-b), 2- (R)-(2,2-dimethyl-5-oxo-1- [1,3] -dioxolan-1- (S) -yl) pentadecanoic acid (518 mg) ) And (S) -t one-port isinol (250 mg) as starting materials to give 36 mg (52%, conversion yield 72%) of the target compound as a white solid by the same reaction treatment. At this time, 40 mg (27%) of 2- (R) -1- [2,2-dimethyl-5-oxo-5- [1,3] -dioxolan-1-4- (S) -yl] pentadecanoic acid as a starting material Collected.

'.Eta. Nuclear magnetic resonance spectrum _{(270MHz, CDC1 3) δ ppm} :

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 (2H, m), 4.62 ( 1H, d, J = 5.2Hz), 6.38UH, 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 value: 400.3053 (C ₂₂ H "N0 _s )

Melting point 110-112 ° C

1 0-b) M 2-(SJ one {2-() _ one _ 2 丄 2-dimethyl one 5- / U

-[1,3] dioxolan-1 41 (S) -yl) ndecanoylamino-3 2- (R) -1- [2,2-dimethyl-5- obtained in Example 10-a) Oxo—

[1,3] dioxolan-1-41- (S) yl] pentadecanoic acid [1- (S) -hydroxymethyl-2,2-dimethylpropylamide (35 Omg) tetrahydrofuran (10 ml) Pyridine (105 u1), acetic anhydride (125 u1), and 4-dimethylaminopyridine (10 mg) were sequentially added to the solution, 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, and extracted with ethyl acetate. The organic layer was washed successively 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 (96%) of the desired compound as a white solid.

'.Eta. Nuclear magnetic resonance spectrum (270MHz, CDC1 ₃₎ δρριη:

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), 4.0 0-4.16 (2H, m), 4.26 (1H, m), 4.52 (1H, d, J = 5.9Hz) ), 6.07 (1H, br d, J = 9.3Hz infrared absorption spectrum (KBr pellet)

3335, 1792, 1741, 1651

Mass vector (FAB) m / z [+ H] ⁺ = 442

High resolution mass spectrum (FAB)

m / z [+ H] ⁺ = 442.3176

_{Calculated: 442.3169 (C 2 ^ H ^} N0 6)

10-c) Acetic acid 2- (S) -1- {2- (R) -1-[(S) -1-benzyloxycarbamoyl (hydroxy) methyl] decanoylamino} -3,3-dimethylbutyl ester

Acetic acid 2- (S) -1- {2- (R)-[2,2-dimethyl) obtained in Example 10-b) / Γ

Chill-5-oxo-1 [1,3] -dioxolan-4yl] decanoylamino} 13,3-dimethylbutyl ester (366 mg) in acetic acid-water (2:15 ml), and the mixture was stirred in a room 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 dried under reduced pressure for further 8 hours, and then dissolved in tetrahydrofuran monohydrate (1: 1, 15 ml). At room temperature, 0-benzylhydroxylamine hydrochloride (233 mg) and 1- (3-dimethylaminobutyral pill) -13-ethylcarposimid hydrochloride (355 mg) were added overnight. Stirred. The reaction solution was poured into a 5% aqueous potassium hydrogen sulfate solution and extracted with ethyl acetate. The organic layer was washed successively 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 (2 68 mg, 2 steps, 64%) as a foam-like substance. .

'H—nuclear magnetic resonance spectrum (400 MHz, CDCla) δ pm:

0.88 (3H, t, J = 6.9Hz), 0.97 (9H, s), 1.20-1.43 (14H, ra), 1.65 (1H, m), 1.79 (1H, m), 2.03 (3H, 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 vector (FAB) m / z [M + H] ⁺ = 507

High resolution mass spectrum (FAB)

m / z (M + H) ⁺ = 507.3417

_{_{Calculated: 507.3434 (C 28 H47N Z 0}} 6)

1 O-d) Acetic acid 2- (S) -1-2- (R) — [(S) -Hydroxy (hydroxycarbamoyl) methyl} decanecanylamino} 1-3,3-Dimethylylbutyl ^ ster

Acetic acid 2- (S) -1-i2- (R) -1-[(S) -benzene obtained in Example 10-c) 5% palladium-alumina (40 mg) was added to a solution of 1,3-dimethylbutyl ester (260 mg) in methanol (4.O ml). In addition, hydrogen decomposition was performed for 2 hours in a hydrogen atmosphere. The catalyst was removed by filtration through celite, and the obtained filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride: methanol = 40: 1) to obtain 11 Omg (51%) of the desired compound. ) Was obtained as a foam-like substance.

'Η—nuclear magnetic resonance spectrum (400MHz, CDCla) δ ppm:

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 (3H, 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 = 9.8 Hz), 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 value: 417.2965 (C _{2 l} HN ₂ 0 ₆ )

Specific rotation: [a] D ²⁵ = + 5.Γ (C: 0.56, MeOH)

(Example 11) 2 (S), N ¹ -dihydroxy-N ⁴ — [1- (S) -hydroxymethyl-2,2-dimethylpropyl] — 3- (R) -nonylsuccinamide (Exemplified Compound No. 1 09)

Acetic acid 2— (S) — {2- (R) — [(S) —hydroxy (hydroxycarbamoyl) methyl] indecanoylamino} obtained in Example 10-d) To a solution of 3,3-dimethylbutyl ester (68. Omg) in methanol (3. Oml) was added potassium carbonate (70.1 mg), and the mixture was stirred at room temperature for 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 water and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the obtained white solid was methanol /

The crystals were recrystallized from Draft water to obtain 47.9 mg (78%) of the target compound as white crystals.

1 H—nuclear magnetic resonance spectrum (400 MHz, CD ₃₀ D), δ ppm:

0.89 (3H, t, J = 6.8Hz), 0.94 (9H, s), 1.17- 1 · 54 (15H, m), 1.65 (1H, m), 2.68 (1H, m), 3.48 (1H, dd) , J = 12.1, 9.2Hz), 3.70-3.81 (2H, m), 4.06 (1H, d, J = 6-5Hz)

Infrared absorption spectrum (KBr pellet, cm " ¹ )

3385, 3327, 3152, 3066, 1670, 1618, 1575

Mass vector (FAB) ra / z [M + H] ⁺ = 375

Elemental analysis

Calculated _{_{_{_{Ci 9 H 3 8 2 0 5}}}} : C, 60.93¾; H, 10.23%; N, 7.48%

Measured value: C, 60.92¾; H, 10.48%; N, 7.37¾

Specific rotation [a] D ²⁵ = -Γ (C-.0.38, MeOH)

(Example 1 2) N ⁴ -Hydroxy N ¹ — (1-(S) -Hydroxymethyl- 1 -2-phenylethyl)-2-(R) -nonylsuccinamide (Exemplary Compound No. 14) 12 -a) 3 — (R)-[1- (S) -Hydroxymethyl 1-2-phenylcarbamoyl] dodecanoic acid t-butyl ester

According to the method of Example 8-b), 2- (R) -t-butoxycarbonylmethyl-decaneic acid (1.50 g) obtained in Example 8-a) and L-phenylalani The same compound was treated in the same manner as described above, using ethanol (798 mg) as a starting material, to obtain 1.65 g (76%) of the target compound as a white solid.

—Nuclear magnetic resonance spectrum (270MHz, CDCla), δ ppm:

0.88 {3H, t, J = 6.6Hz), 1.13-1.80 (16H, m), 1.43 (9H, s), 2.33 (1H, dd, J = l 5.3, 3.5Hz), 2.40-2.63 (2H, m ), 2.78-3.00 (2H, m), 3.66 (2H, d, J = 4.6Hz), 4 • 04 (1H, m), 6.00 (1H, d, J = 7.4Hz), 7.17-7.37 (5H, m)

Infrared absorption spectrum (KBr pellet, cm " ¹ )

3360, 1709, 1645, 1531

Mass vector (FAB) m / z [+ H] ⁺ = 434 High resolution mass spectrum (FAB)

m / z [M + H] ⁺ = 434.3259

Calculated value: 434.3271 (0 ₂₆ Η ₄ ΛΝ0)

Melting point: 70-72 ° C

1 2-b) ⁴ —Hydroxy N ^1- [1 — (S) —Hydroxymethyl 1 2 —Phenylethyl 2 — (R) —Nonylsuccinamide

Example 12 3- (R)-[1— (S) -hydroxymethyl-2-phenylphenylcarbamoyl] dodecanoic acid "t-butyl ester (1.60 g) obtained in 2a) Trifluoroacetic acid (5.5 ml) was added to the methylene chloride (55 ml) solution, and the mixture was stirred for 3.3 hours at room temperature.Toluene (100 ml) was added to the reaction solution, and then the mixture was evaporated under reduced pressure. The white solid obtained by distilling off the substance was recrystallized from hexane-ethyl acetate to obtain 1.41 g of a white crystal. It was dissolved in dimethylformamide (20 ml) and cooled to 0 ° C. Then, 1-hydroxybenzotriazole (353 mg), N-methylmorpholine (355 Li 1), —Dimethylaminobutyl pill) — 3-Ethyl carbodiimide hydrochloride (539 mg), 0— (t-butyldimethylsilyl) hydroxy (496 mg) was sequentially added, and the mixture was stirred overnight while the temperature was raised to room temperature.The reaction solution was poured into a 5% aqueous solution of hydrogen sulfate and extracted with ethyl acetate, and the organic layer was extracted with 5% aqueous sodium hydrogen carbonate solution. After washing with water and saturated brine in that order, drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting white solid was recrystallized twice from chloroform-methanol to give the desired compound 256. mg (35%) as white crystals.

'Η—nuclear magnetic resonance spectrum (400MHz, DMSO-c), δ ppm:

0.85 (3H, t, J = 6.8Hz), 1.05-1.40 (16H, m), 1.80-1.98 (2H, m), 2.45-2.60 (1H, m, overlapped with solvent peak), 2.60 (1H, dd , J = 13.7, 8.6Hz), 2.85 (1H, dd, J = 13.7, 5.3Hz), 3.22-3.35 (2H, m), 3.88 (1H, m), 4.71 (1H, t, J = 5.5H z), 7.10-7.33 (5H, m), 8.44 (1H, d, J = 7.7Hz), 8.69 (1H, d, J = 1.3Hz), 10.34 (1H, d, J = 1.3Hz) Infrared absorption spectrum (KBr pellet, cm " ¹ )

3443, 1658, 1641, 1551

Mass vector (FAB) m / z [+ H] ⁺ = 393

Elemental analysis

_{_{_{Calculated: C 22 H 36 N 2 (}}} K * Q.2H 2 0: C, 66.70¾; H, 9.26%; N, 7.07%

Measured value: C, 66.50%; H, 9.14%; N, 7.03¾

Specific rotation: [a] D ^Z5 = -16.9 ° (C: 0.16, MeOH)

Melting point: 16 1-163 ° C

(Example 13) Enzymatic acid 3-cyclohexyl-1- (S)-[2- (R)-(N-hydroxycarbamoylmethyl) undecanoylamino] propyl ester (exemplary compound number 13 )

13-a) 3- (R) -I- [2-cyclohexyl-1-1 (S)-(hydroxymethyl) ethylcarbamoyl] dodecanoic acid t-butyl ester

According to the method of Example 8-b), 2- (R) -i-t-butoxycarbonylmethylpandecanoic acid (5.993 g) and 2- (S) obtained in Example 8-a) The target compound (7.27 g) was obtained as a white solid by a similar reaction treatment using -amino-13-cyclohexyl-11-propanol (7.03 g) as a starting material.

—Nuclear magnetic resonance spectrum (400MHz, CDC), δ ppm:

0.87-1.03 (2H, m), 0.88 (3H, t, J = 6.9Hz), 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 = ll.l, 6.4, 5.3Hz), 3.64 (1H, ddd, J = ll.1, 6.3, 3.5Hz), 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 [+ H] ⁺ = 440.3740

_{_{Calculated: 440.3740 (C 26 H 5O N0}} 4) /. c

1 3-b) 3— (R)-[1-(S) -acetoxymethyl-2-cyclohexylethylcarbamoyl] dodecanoic acid t-butyl ester

According to the method of Example 8-c), 3- (R)-[2-cyclohexyl-1-1 (S)-(hydroxymethyl) ethylcarbamoyl] dodecanoic acid obtained in Example 13-a) The same reaction was carried out using b-butyl ester (1.53 g) as a starting material to obtain 1.67 g (9.9%) of the target compound as a colorless oily substance.

lH—nuclear magnetic resonance spectrum (270MHz, CDCla), δ ppm:

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 (IH, dd, J = 16.5, 9.2Hz), 4.04 (2H, d, J = 4.7Hz), 4.29 (1H, m), 5.71 ( IH, d, J-8.9Hz) Infrared absorption spectrum (liquid film, cm " ¹ )

3302, 1746, 1733, 1645

High resolution mass spectrum (FAB)

m / z [+ H] ⁺ = 482.3846

Calculated value: 482.3846 (0 _Ζ 8 ΗΒ ₂ Ν 0 ₅ )

1 3-c) 3-(R)-[1-(S)-acetoxymethyl-2-cyclohexylethylcarbamoyl-dodecanoic acid

According to the method of Example 8-d), 3- (R)-[1- (S) -acetoxymethyl-2-cyclohexylethylcarbamoyl] dodecanoic acid obtained in Example 13-c) The same reaction was carried out using t-butyl ester (1.66 g) as a starting material to obtain 1.36 g (93%) of the target compound as a white solid.

'H—nuclear magnetic resonance spectrum (400MHz, CDCla), δ ppm:

0.76-1.03 (2H, m), 0.88 (3H, t, J = 6.9Hz), 1.05-1.55 (21H, m), 1.57-1.85 (6H, m), 2.06 (3H, s), 2.41-2.58 (2H, in), 2.75 (1H, dd, J = 17.0, 8.9Hz), 4.00- 4.13 (2H, m), 4.32 (IH, m), 5.71 (IH, d, J = 8.8Hz)

Infrared absorption spectrum (KBr pellet, cm ") 3311, 1745, 1729, 1640, 1547

High resolution mass spectrum (FAB)

m / z [+ H] ⁺ = 426.3201

_{Calculated: 426.3219 (. C 2, H4} 0 5)

13-d) Acetic acid 3-cyclohexyl 2- (S)-[(2- (R)-(N-hydroxycarbamoylmethyl) pentacanylamino] propyl ester

According to the method of Example 8-e), 3- (R)-[1- (S) -acetoxymethyl-2-cyclohexylethylcarbamoyl] dodecanoic acid obtained in Example 13-c) (1.31 g) and 0- (t-butyldimethylsilyl) hydroxylamine (1.00 g) were subjected to the same reaction treatment to obtain 756 mg (56%) of the target compound as white crystals. . The recrystallization of this compound was performed using hexane: ethyl acetate instead of the methanol-water used in Example 8-e).

—Nuclear magnetic resonance spectrum (400MHz, DMSO-de), δ ppm:

0.65-0.98 (2H, m), 0.85 (3H, t, J = 6.6Hz), 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 = 14.4, 6.0Hz), 2.57 (1H, m), 3.74 (1H, dd, J = 10.7, 7.0Hz), 3.97 (1H , dd, J = 10.7, 4.8 Hz), 4.05 (1H, m), 7.76 (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 ")

3287, 1745, 1644, 1549

Mass vector (FAB) m / z [M + H] ⁺ = 441

Elemental analysis

_{_{_{Calculated: C 24 H 44 N 2 0}}} 5: C, 65.42%; H, 10.07%; N, 6.36¾

Measurements: C, 65.31¾; H, 9.78%; N, 6.32¾

Specific rotation: [α] ₀ ²⁵ = -7.4 ° (C: 0.37, MeOH)

Melting point: 109-111 ° C (Example 1 4) N '- [2- ethylhexyl one 1 one to cyclo (S) - (arsenate Dorokishimechi Le) Echiru] - N ⁴ - heat Dorokishi 2-(R) - Nonirusukushinami de (Compound No. 1 2 )

According to the method of Example 9, 3-cyclohexyl acetate 1-2- (S) -1- [2- (R)-(N-hydroxycarbamoylmethyl) acetate obtained in Example 13-d) Using propyl ester (195 mg) as a starting material, 150 mg (85%) of the target compound was obtained as white crystals by the same reaction treatment.

— Nuclear magnetic resonance spectrum (400MHz, DMSO-de), δ ppm:

0.74 (1H, m), 0.85 (3H, t, J = 6.8Hz), 0.80-0.97 (1H, m, overlapped with δ 0.85), 1.00-1.45 (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, ra), 3.13 (1H, m), 3.2 5-3.40 (1H, m, overlapped 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 = l.1Hz), 10.37 (1H, d, J = l.1Hz Infrared absorption spectrum (KBr pellet, cm- ¹ )

3365, 3261, 3113, 1663, 1612

Mass spectrum (FAB) ra / z [+ H] ⁺ = 399

Elemental analysis

_{_{_{Calculated: C 22 1 2 N 2 0}}} 4: C, 66.30%; H, 10.62%; N, 7.03%

Measurements: C, 66.26%; H, 10.44¾; N, 7.00¾

Specific rotation: [a] D ²⁵ = -16.0 ° (0.19, MeOH)

Melting point: 155 ~ 157 ° C (Example 15) Acetic acid 2- (S)-(2- (R)-(N-hydroxycarbamoylmethyl) undecanoylamino-13-methylbutyl ester (Exemplified Compound No. 11)

15-a) 3- (R) mono (1- (S) -hydroxymethyl-2-methylpropylcarbamoyl] dodecanoic acid t-butyl ester

1-Hydroxybenzotriazole (47.6 mg) in methylene chloride (1.5 ml) solution obtained in Example 8-a) was added to 1-hydroxybenzotriazole (47.6 mg). 26.5 mg), N-methylmorpholine (21.01), 1- (3-dimethylaminopropyl) -13-ethylcarbodiimid hydrochloride (37.9 mg) were added, and 5 Stirred at room temperature for minutes. Next, a solution of L-valinol (21.8 _mg ) in methylene chloride (0.5 ml) was added to the reaction solution, and the mixture was stirred overnight at room temperature. The reaction solution was poured into a 5% aqueous potassium hydrogen sulfate solution, and extracted with ethyl acetate. The organic layer was washed successively 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 separated by silica gel preparative thin-layer chromatography (20 cm x 20 cm, 0.5 mm thick, 2 sheets, developing solvent: methylene chloride: methanol = 15: Purification using 1) yielded 54.4 mg (89%) of the desired compound as a white solid.

—Nuclear magnetic resonance spectrum (270MHz, CDCla), δ ppm:

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, ra), 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, ra), 6.03 (1H, m)

Infrared absorption spectrum (KBr pellet, cm "')

3316, 1732, 1643, 1546

Mass vector (FAB) ra no z [M + H] ⁺ = 386

High resolution mass spectrum (FAB)

m / z [M + H] * = 386.3273

_{Calculated: 386.3270 (C 22 H "N0} 4) 1 5-b) 3-(R) 1 [1-(S)-acetomethyl-2-methylpropylcarbamoyl] dodecanoic acid t-butyl ester

According to the method of Example 8-c), 3-i- (R)-(1- (S) -hydroxymethyl-2-hydroxypropyl rubamoyl] dodecanoic acid t-butyl ester obtained in Example i 5-a) (607 mg) as a starting material and 607 mg (90%) of the target compound were obtained as a colorless oily substance by the same reaction treatment.

1 H - NMR spectrum _{(400MHz, CDC1 3), δ} ppm:

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 (1H, dd, J = 11.2, 6.4Hz), 5.82 (1H, d, J = 9.3Hz)

Infrared absorption spectrum (liquid film, cm "')

3308, 1745, 1732, 1645, 1545

Mass spectrum (FAB) m / z [M + H] ⁺ = 428

High resolution mass spectrum (FAB)

ra / z [M + H] ⁺ = 428.3402

_{_{Calculated: 428.3376 (C 2 4H 5e 0}} 5)

1 5-c) 3— (R)-[1-(S) acetoxymethyl-2-methylpropylcarbamoyl] dodecanoic acid

According to the method of Example 8—d), 3- (R) — [1- (S) —acetoxymethyl-2-methylpropyl-potamoyl] dodecanoic acid “b-one” obtained in Example 15-b) A similar reaction was carried out using butyl ester (598 mg) as a starting material.After azeotropic distillation with toluene, the obtained white solid was recrystallized from ethyl hexane monoacetate to obtain 45 53 mg (87%) of the desired compound. Was obtained as white crystals.

'Eta - nuclear magnetic resonance spectrum _{(270MHz, CDC1 3), δ} ppm:

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, s), 2.42- "

.59 (211, 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), 5.80 (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 [+ H] ⁺ = 372.2740

Calculated value: 372.2750 (C ₂ oH ₃₈ NO _s )

Melting point: 9 1 ~ 9 2 ° C

15-d) Acetic acid 2- (S)-[2- (R) -I- (N-hydroxycarbamoylmethyl) decanoylamino] — 3-methylbutyl ester

According to the method of Example 8-e), 3- (R)-[1- (S) -acetoxymethyl-2-methylpropylpyrumomoyl] dodecanoic acid obtained in Example 15-c) (443 mg) ) And 0- (t-butyldimethylsilyl) hydroxylamine (334 mg) as starting materials to give 26 lmg (57%) of the target compound as white crystals by the same reaction treatment.

- nuclear magnetic resonance spectrum (400 thigh _{z, CD 3 0D), δ} ppm:

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, in), 1.56 (1H, m ), 1.82 (1H, m), 2.01 (3H, s), 2.16 (1H, dd, 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 = ll.1, 7.3Hz), 4.23 (1H, dd, J = ll.l, 3.6Hz)

Infrared absorption spectrum (KBr pellet, cm " ¹ )

3276, 1745, 1645, 1549

Mass vector (FAB) ra / z [M + H] ⁺ = 387

Elemental analysis

Calculated: C _2. _{_{_{H 3e N 2 0 5: C}}} , 62.15%; H, 9.91%;, 7.25%

Measured value: 62.14¾; H, 9.62¾; N, 7.17% Specific rotation: [a] D ²⁵ = -6. Γ (C: 0.44, MeOH)

Melting point: 149-150 ° C

(Example 16) -Hydroxy-1-N '-[1- (S) -hydroxymethyl-

2-Methylpropyl] -1- (R) -nonylsuccinamide (Exemplified Compound No. 10 Acetic acid 2- (S) -1- [2— (R) obtained in Example 15-d) according to the method of Example 9 ) — (N-Hydroxycarbamoylmethyl) Pandecanoylamino :! The same reaction was carried out using 1-3-methylbutyl ester (61.6 mg) as a starting material to obtain 4.5 mg (82%) of the target compound as white crystals. The recrystallization of this compound was performed using water-methanol instead of ethyl acetate-methanol used in Example 9.

'H - NMR spectrum _{(400MHz, CD 3 0D),} 5 pm:

0 ・ 89 (3Η, t, J = 6.8Hz), 0.91 (3H, d, J = 6.9Hz), 0.94 (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, 6.8 Hz), 2.33 (1H, dd, J = 14.5, 7.9 Hz), 2.73 (lH, m), 3.51- 3.61 (2H, m), 3.68 (1H, m) Infrared absorption spectrum (KBr pellet, cnT ¹ )

3291, 1663, 1633, 1557

Mass vector (FAB) m / z [M + H] ⁺ = 345

Elemental analysis

_{_{_{Calculated: C ie H 36 N 2 0}}} 4 · 0.2H 2 O: C, 62.11%; H, 10.54%; N, 8.05%

Measured values: C, 62.14%; H, 10.38¾; N, 8.10%

Specific rotation: [α] _D ²⁵ = -10.3 ° (C: 0.32, MeOH)

Melting point: 12.9 ~ 130 ° C

(Example 17) Acetic acid 3- (R) -acetoxy 2- (R)-[2- (R)-(N-hydroxycarbamoylmethyl) undecanoylamino] butyl ester (Exemplary Compound No. 19) /}?

1 7-a) 3-(R)-(2-(R) —hydroxyl 1 (R) — (hydroxymethyl) propyl sorbamoyl〗 dodecanoic acid t-butyl ester

According to the method of Example 8-b), 2- (R) 1 t-butyl carboxymethylmethyldecanoic acid (71 2 mg) and 2- (R) obtained in Example 8-a) The same reaction was carried out using amino-1,3 (R) -butanediol (252 mg) as a starting material to obtain 53 l mg (58%) of the target compound as a colorless oily substance.

'Η—Nuclear magnetic resonance spectrum (400MHz, CDCla), δ ppm:

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 (2H, 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 (1H, 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 ")

3347, 1731, 1649, 1540

Mass vector (FAB) m / z [M + H] ⁺ = 388

High resolution mass spectrum (FAB)

m / z [M + H] ⁺ = 388.3068

Calculated value: 388.3063 (C ₂₁ H, ₂ N0 _S )

1 7-b) 3- (R) -I [2-(R) -acetoxy 11- (R)-(acetoximemethyl) provil-power-rubamoyl] Dodecanoic acid t-butyl ester

Example 17 of 3- (R)-[2- (R) -hydroxy-11- (R)-(hydroxymethyl) propyl-l-rubamoyl] dodecanoic acid t-butyl ester obtained in 7-a) (530 mg) To a solution of tetrahydrofuran (7. Oml), pyridine (280 u1), acetic anhydride (330 w1) and 4-dimethylaminopyridine (1 lmg) were sequentially added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into a 5% aqueous potassium hydrogen sulfate solution, extracted with ethyl acetate, and the organic layer was washed successively with a 5% aqueous sodium hydrogen carbonate solution, water and saturated saline, and then dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (methylene chloride: methanol = 40: C

Purification according to 1) gave 63 2 mg (98%) of the desired compound as a colorless oil.

1 H—nuclear magnetic resonance spectrum (400 MHz, CDCla), 0 ppm:

0.88 (3H, t, J = 6.8Hz), 1.15-1.50 (15H, m), 1.23 (3H, 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), 2.50 (1H, m), 2.65 (1H, dd, J = 16.7, 9.6Hz), 4.00 {1H, dd, J = ll.l, 6.6Hz), 4.08 (1H, dd, J = ll.1, 6.5Hz), 4.35 (1H, m), 5.12 (1H, dq, J = 3.0, 6.4Hz), 5 .98 (1H, d, J = 9.4Hz)

Infrared absorption spectrum (liquid film, era "')

3326, 1745, 1732, 1680, 1655

Mass spectrum (FAB) tn / z [M + H] ⁺ = 472

High Resolution Mass Vector (FAB)

m / z {+ H] ⁺ = 472.3276

Calculated value: 472.3275 (C ₂₅ H4 ₆ N0 ₅ )

1 7-c) 3-(R)-f 2-(R) Acetoxy 1-(R)-(Acetoxymethyl) propyl-rubamoyl) Dodecanoic acid

According to the method of Example 8—d), the 3- (R)-[2- (R) -acetoxy-1-1 (R)-(acetoxymethyl) propyl force obtained in Example 17-b) was obtained. Lubamoyl] Dodecanoic acid: Monobutyl ester (630 mg) was used as a starting material, and the same reaction was carried out to give 464 mg (84%) of the target compound as a white solid.

-Nuclear magnetic resonance spectrum (270MHz, CDCla), δ ppm:

0.88 (3H, t, J = 6.6Hz), 1.10-1.40 (14H, ra), 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, ra), 4.35 (1H, m), 5.11 (1H, dq, J = 3.6, 6.4Hz), 5.95 (1H, d, J = 9.4Hz)

Infrared absorption spectrum (KBr pellet, era "')

3224, 1743, 1651, 1544

Mass vector (FAB) m / z [+ H] ⁺ = 416 n?

High Resolution Mass Vector (FAB)

m / z [M + H] ⁺ = 416.2674

Calculated value: 416.2648 (C ₂₁ H ₃₈ N07)

1 7-d) Acetic acid 3-(R)-acetoxy 2-(R)-[2-(R)-(N-hydroxycarbamoylmethyl) dedecanolylaminobutyl ester

According to the method of Example 8-e), 3- (R)-[21 (R) -acetoxy-11- (R)-(acetoxymethyl) propylcaptamyl) obtained in Example 17-c) Using dodecanoic acid (46 mg) and 0- (t-butyldimethylsilyl) hydroxylamine (216 mg) as starting materials, 206 mg (43%) of the target compound was obtained in the form of a foam by the same reaction treatment. Obtained as material. 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 x 20 cm, 1.0 mm thick, 3 sheets). The developing solvent was methylene chloride: methanol = 10: 1).

H—nuclear magnetic resonance spectrum (400MHz, CDaOD), δ ppm:

0.89 (3H, t, J = 6.7Hz), 1.15-1.50 (15H, m), 1.21 (3H, d, J = 6.5Hz), 1.56 (1H, ra), 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 = ll.1 , 7.5Hz), 4.2Q (1H, dd, J = ll.l, 5.5Hz), 4.28 (1H, m), 5.06 (1H, dq, J = 3.6, 6.5Hz)

Infrared absorption spectrum (KBr pellet, cm- ')

3289, 1740, 1648, 1551

Mass spectrum (FAB) m / z [M + H] ⁺ = 431

Elemental analysis

_{_{_{Calculated: C 2 l H 3e N 2}}} 0 7 · 0.1H 2 0: C, 58.34¾; H, 8.91%;, 6.48¾

Measurements:: C, 58.26¾; H, 8.83%; N, 6.55¾

Specific rotation: [a] D ²⁵ = + 20. Γ (C: 0.53, eOH)

(Example 1 8) New - hydroxy-N ¹ - tooth 2 - hydroxy-1 one R)-(Hydroxoxymethyl) propyl) -12- (R) -nonylsuccinamide (Example compound No. 18)

Example 17 3- (R) -Acetoxy-2- (R)-[21- (R)-(Ν-Hydroxycarbamoylmethyl) pentadecylua obtained from 7-d) To a solution of [mino] butyl ester (92.3 mg) in methanol (3.5 ml) was added potassium carbonate (108 mg), and the mixture was stirred at room temperature for 45 minutes. The reaction solution was poured into a 5% aqueous hydrogen sulfate aqueous solution, 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-phase preparative thin-layer chromatography (silica gel 60 silanized RP—2 Merck, Art. 5 74 7, 20 cmx 20 cm, 0.25 mm thickness x The resulting white solid was further recrystallized from methanol-water to obtain 33.3 mg (45%) of the target compound as white crystals. (2 sheets, methanol: water = 3: 2).

'Η—nuclear magnetic resonance spectrum (400MHz, CDaOD), δ ppm:

0.89 (3H, t, J = 6.9Hz), 1.15 (3H, d, J = 6.5Hz), 1.20-1.48 (15H, m), 1.58 (1H, ra), 2.18 (1H, dd, 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, dd, J = 10.9, 6.2 Hz), 3.80 (1H, ddd, J = 6.2, 6.0, 3.5Hz), 3.99 (1H, dq, J = 3.5, 6.5Hz)

Infrared absorption spectrum (KBr pellet, cm "')

3447, 3392, 3317, 3221, 1664, 1635, 1532

Mass spectrum (FAB) m / z [M + H] ⁺ = 347

Elemental analysis

_{_{_{Calculated: CH 34 N 2 0 5:}}} C, 58.93¾; H, 9.89¾; N, 8.09¾

Measurements: C, 58.93%; H, 9.68¾; N, 7.98¾

Specific rotation: [a] D ^2S = + 4 ° (C: 0.17, MeOH)

Melting point: 1 19 to 120 ° C

(Example 19) Sulfuric acid 3-acetoxy 2- [2- (R)-(N-hydroxycarbamoylmethyl) _ndecanoylamino "L propyl ester (Exemplary compound number 1 7)

191-a) 3- (R)-[2-Hydroxy-11- (hydroxymethyl) ethyl

Example 8— Dissolve 2- (R) -t-butoxycarbonylmethylpandecanoic acid (57 mg) obtained in a) in dichloromethane (2 ml) under a nitrogen atmosphere, and cool to 0 ° C. did. Hydroxybenzotriazole (37 mg), 2-amino-1,3-propanediol (27 mg), N-methylmorpholine (601), pyridine (4Ou1), 1- (3- Dimethylaminopropyl) -13-ethylcarbodiimid 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 a saturated saline solution, and then dried with 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 thick, dichloromethane: methanol = 8: 1 development, ethyl acetate: methanol = 1/10). : 1 elution) to obtain the desired compound (52 mg) as a colorless oily substance.

1 H—nuclear magnetic resonance spectrum (270 MHz, CDCla), δ ppm:

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 (1H, 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 ")

3322, 1730, 1650

High resolution mass spectrum (FAB)

m / z [+ H] ⁺ = 374.2900

Calculated value: 374.2906 (C ₂₀ H4oNO _s )

1 9-b) 3-(R)-(2-acetoxy 11- (acetoxymethyl) ethyl ethyl rubamoyl) Dodecanoic acid t-butyl ester 1 According to the method of Example 17-b), 3- (R)-(2-hydroxyl- (hydroxymethyl) ethylethylcarbamoyl) 3- (R)-(2-hydroxymethyl) ethylcarbamoyl) obtained in Example 19-a) 1-tert-butyl dodecanoate The target compound (699 mg) was obtained as a white solid by a similar reaction treatment using the ester (643 mg) as a starting material.

— Nuclear magnetic resonance spectrum (270MHz, CDCla), δ ppm:

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 (3H, 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), 4.04-4.25 (4H, m) , 4.47 (1H, m), 6.13 (1H, d, J = 8.6Hz)

Infrared absorption spectrum (KBr pellet, cm "')

3376, 1746, 1727, 1656

Mass spectrum (FAB) m / z [M + H] + = 458

Elemental analysis

_{_{_{Calculated: C 24 H 43 0 7 N}}} : C, 62.99¾; H, 9.47%; N, 3.06¾

Measured values: C, 62.70¾; H, 9.47¾; N, 3.06¾

1 9— c) 3-(R) 1- (2-acetoxy 1- (acetoxymethyl) ethyl ethyl rubamoyl) dodecanoic acid

According to the method of Example 8-d), 3- (R)-(2-acetoxy-11- (acetoxymethyl) ethylcarbamoyl) dodecanoic acid t-butyl ester (697 mg) obtained in Example 19-b) Starting compound as starting material

(553 mg) was obtained as a white solid.

'H—Nuclear magnetic resonance spectrum (270MHz, CDC), δ ppm:

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), 2.45UH, 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 3 Mass vector (FAB) m / z [+ H] ⁺ = 402

Elemental analysis

_{_{_{Calculated: C 2O H 3 5N0 7 -}}} 0.25H 2 0: C, 59.17%; H, 8.80%; N, 3.45%

Measured value: :( :, 59.00%; H, 8.82%; N, 3.50¾

1 9— d) Acetic acid 3-acetoxy 2 -— [[2- (R)-(N-hydroxybamoylmethyl) pentacanylamino] propyl ester

According to the method of Example 8-e), 3- (R)-(2-acetoxy-11- (acetoxymethyl) ethylethylcarbamoyl) dodecanoic acid obtained in Example 199-1c) (555 m) ) And 0- (t-butyldimethylsilyl) hydroxylamine (476 mg) as starting materials, and the same reaction treatment was carried out to obtain 371 mg (65%) of the target compound as a white powder. The purification of the present compound was carried out by using only one of the methods described in 8-e), Siri gel gel column chromatography.

- nuclear magnetic resonance spectrum _{(270MHz, CDC1 3), δ} ppm:

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 (3H, 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 [+ H] ⁺ = 417.2593

Calcd _{_{_{417.2600 (C 2O H 37 N 2}}} 0 7)

Specific rotation: [] D ^zs = + 5.00 ° (C: 0.33, MeOH)

(Example 2 0) New ^{lambda-hydroxy-New} ¹ - [2-arsenide Dorokishi 1 i (human Proxy methyl) Echiru] one 2-(R) over Bruno succinate cyanamide method (Compound No. 1 6) Example 1 8 According to the procedure, 3-acetoxoxyacetic acid 2- [2- (R)-(N-hydroxycarbamoylmethyl) pentadecanoylamino obtained in Example 19-1 d) No.] propyl ester (192 mg) was used as a starting material, and 30 mg (20%) of the target compound was obtained as a white powder by the same reaction treatment.

'H- NMR spectrum _{(400MHz, CD 3 0D),} δ ppm:

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 vector (FAB) m / z [M + H] + = 333

Elemental analysis

_{_{_{Calculated: C, 6 H 32 N 2}}} 0 s * 0.25H 2 0: C, 57.03%; H, 9.71%; N, 8.31%

Measured values:: C, 57.08%; H, 9.44¾; N, 8.33¾

Specific rotation: [a] D ²⁵ = + 5.6 ° (C: 0.1, eOH)

(Example 21) Ethylcarbamic acid 2- (S) — [2- (R)-(N-hydroxycarbamoylmethyl) pentacanylamino] 13,3-dimethylbutylester (exemplary compound Number 9 1)

2 1-a) 3- (R)-[1- (S) -Ethylcarbamoyloxymethyl—2,2-dimethylbromopyruvamoyl] dodecanoic acid t-butyl ester

3- (R) — [1— (S) —Hydroxymethyl-2,2-dimethylpropylhydrorubamoyl] dodecanoic acid t-butyl ester (86 mg) obtained in Example 8—b) was added to benzene (5 ml). ) And heated to 60 ° C. Ethyl isocyanate (20 μl) was added to this solution, and the mixture was stirred at 60 ° for 1.3 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was separated by silica gel preparative thin-layer chromatography (20 cm x 20 cni, 0.5 mm thick x 2, hexane: ethyl acetate = 2: 1 development, The target compound (90 mg) was obtained as a white powder by purifying with ethyl acetate: methanol = 10: 1. 'Η—nuclear magnetic resonance spectrum (270MHz, CDCla), δ ppm:

0.88 (3H, t, J = B.9Hz), 0.94 (9H, s), 1.12 (3H, t, J = 7.3Hz), 1.18-1.30 (14H, m), 1.420H, s), 1.63-1.66 (2H,), 2.32 (1H, dd, J = 15.8, 9.6Hz), 2.55 (1H, m), 2.62 (1H, dd, J = 15.8, 2.6Hz), 3.14-3.24 (2H, m), 4.05 (1H, m), 4.10-4.14 (2H, m), 4.75 (1H, m), 5.89 (1H, d, 2Hz)

Infrared absorption spectrum (KBr pellet, cm " ¹ )

3332, 3289, 1735, 1702, 1662

High-resolution mass spectrum

m / z [M + H] ⁺ = 471.3794

_{_{Calculated: 471.3798 (C 2 6H 51 N}} 2 0s)

Specific rotation: [a] ²⁵ = -6.6 ° (C: 1.06, MeOH)

2 1-b) 3-(R)-[1-(S) -Ethylcarbamoyloxymethyl-2,2-dimethylpropylrubamoyl〗 dodecanoic acid

According to the method of Example 8-d), 3- (R)-[1- (S) -ethylethylcarbamoyloxymethyl-2,2-dimethylpropylpothamoyl] obtained in Example 21-a) Dodecanoic acid 1: monobutyl ester (43 mg) was used as a starting material, and the target compound (33 mg) was obtained as a colorless oil by a similar reaction treatment.

'H- NMR spectrum _{(270MHz, CDC1 3), δ} ppm:

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 (lH, 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, era ' ¹ )

3339, 3287, 3074, 1714, 1702, 1663

High-resolution mass spectrum

m / z [M + H] ⁺ = 415.3193

Calculated value: 415.3172 (C ₂ N ₂ 0 _S ) I "

Specific ^{rotation: [a] D 25 = -2.0} . (C: 1.08, eOH)

21-c) Ethylcarbamic acid 2- (S)-[2- (R)-(N-hydroxylrubamoylmethyl) pentadecylamino] 13,3-dimethylbutylester Example 8-e) 3-(R)-[1- (S) -Ethylcarbamoyloxymethyl-2,2-dimethylpropylpotassium) obtained in Example 21-b) dodecanoic acid (50 mg) Using 0 and (0- (t-butyldimethylsilyl) hydroxylamine (28 mg) as starting materials, 36 mg (69%) of the target compound was obtained as a colorless oily substance.

1 H- nuclear magnetic resonance spectrum _{(270MHz, CDC1 3), δ} ppra:

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 (lH, m), 2.88 (lH, 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 H4 N 3}} 0 5)

Specific rotation: [a] D ²⁵ = -7.3 ° (C: 0.95, MeOH)

(Example 22) ί 2- (S)-(2- (R)-(N-hydroxycarbamoylmethyl) ゥ decanoylamino) 1,3,3-dimethylbutoxycarbonylamino] acetic acid methyl ester (exemplary) Compound No. 9 3)

2 2-a) 3-(_R) ^-f 1-(S) 1- (ethoxycarbonylmethyl) rubamoyloxymethyl—2,2-dimethylpropyl rubamoyl〗 dodecanoic acid t-butyl ester

3- (R)-[1- (S) -Hydroxymethyl-2,2-dimethylpropyl-l-rubamoyl] dodecanoic acid t-butyl ester (75 mg) obtained in Example 8-b) in benzene (5 ml ) Isocyanatoethyl acetate (301) and viridin (2Owl) were sequentially added to the solution, and the mixture was stirred at room temperature for 16 hours. Thereafter, the mixture was stirred for 6.8 hours while heating to 40 ° C. The reaction solution was poured into 5% potassium hydrogen sulfate, extracted with ethyl acetate, and 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 oil.

¹ H—nuclear magnetic resonance spectrum (270MHz, CDCla), δρρπι:

0.88 (3H, t, J = 6.6Hz), 0.94 (9H, s), 1.18-1.24 (14H, in), 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, ra), 2.65 (1H, dd, J = 15.3, 6.2Hz), 3.92 (2H, q, J = S.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 value: 529.3853 (C ₂₈ H ₅₃ N ₂ 07)

2 2-b) 3-(R1-[1-(S)-(Ethoxycarbonylmethyl) carbamoyloxymethyl-2,2-dimethylpropyl rubamoyl〗 dodecanoic acid

According to the method of Example 8-d), the 3- (R)-[1- (S)-(ethoxycarbonylmethyl) -potassium obtained from Example 22-a) is rubamoyloxymethyl-2,2-. Dimethylpropyl-l-rubamoyl-dodecanoic acid t-butyl ester (76 mg) was used as a starting material, and the same reaction was carried out to give the desired compound (61 mg) as a colorless oil.

'H-nuclear magnetic resonance spectrum (270MHz, CDCla), 5 ppm:

0.88 (3H, t, J = 7.0Hz), 0.95 (9H, s), 118-18.27 (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, cnT ')

3395, 3362, 1746, 1709, 1631

High-resolution mass vector

m / z [M + H] ⁺ = 473.3255

Calculated value: 473.3226 (C "H ₄₅ N ₂ 0 ₇ )

2 2-c) [2-(S) 1-(2-(R)-(N-hydroxycarbamoylmethyl) decanoylamino)-3,3-dimethylbutoxycarbonylamino] acetic acid methyl ester

3- (R)-[1- (S)-(ethoxycarbylmethyl) potassium 2-hydroxypropyl-2- (2,2-dimethylpropyl) -rubamoyl) dodecanoic acid (56 mg) obtained in Example 22-c) was used. Dissolve in dimethylformamide (3 ml) under a nitrogen atmosphere, and at 0 ° C, 1-hydroxybenzotriazole (44 mg), N-methylmorpholine (20 ul), 11- (3-dimethylaminopropyl) ) 13-Ethylcar pozimid hydrochloride (50 mg) and 0- (t-butyldimethylsilyl) hydroxyamine (44 mg) were sequentially added, and the mixture was stirred in a room 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 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 obtained residue was subjected to reverse phase preparative thin-layer chromatography (silica gel 60 silanized RP-2 Merck Art. 5747, 20 cm × 20 cm) 1 la

, 0.25 mm thick x 2 pieces, methanol: water = 3: 1 developed, eluted with methanol), dissolved in methanol, and left 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, CDCla), δ ppm:

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 (1H, 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

ra / z [M + H] ⁺ = 474.3163

_{_{Calculated: 474.3147 (C 23 H44N 3 0}} 7)

Specific rotation: [a] D ²⁵ = -10.8 ° (C.-0.85, eOH)

(Example 23) 2- (S)-(2- (R)-(N-hydroxycarbamoylmethyl) undecanoylamino-1,3,3-dimethylbutyloxycarbonyl bromoethyl ester (Exemplified Compound No. 89)

23-a) 2- (S) -I [2-(R)-(t-butoxycarbonylmethyl) ゥ decanoylamino〗 1,3-Dimethylbutyloxycarbonylpropionic acid ethyl ester

Example 8— (R) — (1- (S) -Hydroxymethyl-2,2-dimethylpropyirubamoyl) dodecanoic acid t-butyl ester (549′2 ms) obtained in b) Ethyl succinyl chloride (0.24 ml) and pyridine (0.15 ml) were sequentially added to a solution of trihydrohydrofuran (THF, 16.Oml) and stirred for 2 to 0 hours at 0. The reaction solution was 5%. The mixture was poured into an aqueous solution of potassium hydrogen sulfate, extracted with ethyl acetate, the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Purified by ethyl acetate = 3: 1), 559.1 mg of the target compound (77.1%) Was obtained as a colorless oil.

'H- nuclear magnetic resonance spectrum _{(270MHz, CDC1 3), δ} ppm:

0.87 (3H, t, J = 6.8Hz), 0.94 (9H, s), 1.23-1.38 (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, mi, 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 value: 528.3900 (C29H54O7N)

Specific rotation: [] D ²⁵ = -10.4 ° (C: 1.00, CHCI3)

2 3-b) 2-(S) 1-(2-(R)-(benzyloxycarbamoylmethyl) undecanoylamino] 1, 3,3-dimethylbutyloxycarbonylpropionic acid ethyl ester

Example 2 2- (S)-[2- (R)-(t-butoxycarbonylmethyl) ndecanoylamino] 1-3,3-dimethylbutyloxycarbonyl ethyl ester obtained from 3-a) To a solution of (443.6 mg) in methylene chloride (12.0 ml) was added trifluoroacetic acid (4. Oml), and the mixture was stirred at room temperature for 2.0 hours. After the reaction solution was distilled off under reduced pressure and dried, the residue was dissolved in methylene chloride (15. Oml) and cooled to 0 ° C. To this solution was added 1-hydroxybenzotriazole (193.0 mg), 0-benzylhydroxylamine hydrochloride (234.lmg), and then 1- (3-dimethylaminopropyl) -3-ethyl. Carbodiimide hydrochloride (276.9 mg) and N-methylmorpholine (0.47 ml) were sequentially added, and the mixture was heated to room temperature and stirred overnight. 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 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 24.4 mg (66. If!

%).

¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCla, δ ppm):

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), 2.37 (1H, m), 2.58 (4H, s), 2.72 (1H, m), 4.03 (2H, 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 "')

3313, 3194, 1736, 1674, 1646, 1557

High-resolution mass spectrum

m / z [+ H] ⁺ = 577.3872

_{_{Calculated: 577.3853 (C 32 H 53 07N}} 2)

Specific ^{rotation: [a] D 25 = -} 23.7 ° (C: 1.00, CHC1 3)

2 3-c) 2-(S) 1-[2-(R)-(N-hydroxycarbamoylmethyl) undecanoylamino] 1, 3, 3-dimethylbutyloxycarbonylpropionic acid ethyl ester

Example 23 2- (S) -1- [2- (R) -1- (benzyloxycarbamoylmethyl) ndecanoylamino] 1-3,3-dimethylbutyloxypropylonylpropionate ethyl ester obtained in 3-b) (324.4 mg) was dissolved in methanol (12. Oml) 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. The reaction solution was washed with methanol and washed with methanol, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1) to obtain 600.5 mg (95.2%) of the target compound 26 as a white powder.

'Eta - nuclear magnetic resonance spectrum _{(270MHz, CD 3 0D, δ} ppm):

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, ra), 2.77 (1H, m), 3.94 (2H, m), 4.12 (2H, q, J = 7.2Hz), 4.43 (1H, m) / ίΓ

Infrared absorption spectrum (liquid film, cnT ')

3217, 1738, 1642, 1542

High-resolution mass vector

m / z [+ H] ⁺ = 487.3399

_{_{Calculated: 487.3384 (C 2S H 47 0}} 7 N 2)

Specific ^{rotation: [a] D 25 = -} 16.3 ° (C: 1.00, CHC1 3)

(Example 24) Dimethylaminoacetic acid 2- (S) -1- [2- (R) -1- (N-hydroxycarbamoylmethyl) undecanoylamino] —3,3-dimethylbutylester (Exemplified Compound No. 87 )

24— a) 3- (R)-(1- (S) -dimethylaminoacetoxymethyl-2,2-dimethylpropyl-lubamoyl] dodecanoic acid t-butyl ester

Example 8—Chlorination of 3- (R)-[1- (S) -hydroxymethyl-2,2-dimethylpropyl-rubumoyl] dodecanoic acid t-butyl ester (601-8 mg) obtained in d) 0 in methylene (18 Oml) solution. At C, N, N-dimethylglycine (239.5 mg), 1-hydroxybenzotriazole (307.7 mg), 1- (3-dimethylaminopropyl) — 3-ethylcarbodiimid hydrochloride Salt (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. 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 evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 469.6 mg (64.3%) of the desired compound as a colorless oil.

¹ H- nuclear magnetic resonance spectrum _{(270MHz, CDC1 3, δ ριη} ):

0.87 (3Η, t, J = 6.9Hz), 0.95 (9Η, s), 1.18-1-39 (15H, m), 1.42 (9Η, s), 1.66 (1Η, m), 2.32UH, m) , 2.34 (6Η, s), 2.48-2.67 (2Η, m), 3.14 (2Η, s), 4.08 (2Η, ra), 4.31 (1Η, m), 5.92 (1Η, 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 value: 485.3955 (C ₂₇ H ₅₃ 0 _s N ₂ )

Specific rotation: [a] D ²⁵ = — 16.2 ° (Crl.OO, CHC)

24-b) Dimethylaminoacetic acid 2- (S)-[2- (R)-(N-hydroxyl-rubamoylmethyl) decanoylamino-3,3-dimethylbutyl ester Obtained in Example 24-a) 3- (R)-(1- (S) -dimethylaminoacetoxymethyl-2,2-dimethylpropyl-l-rubamoyl] dodecanoic acid t-butyl ester (342.3 mg) in methylene chloride (15. To the solution was added trifluoroacetic acid (5.0 ml), and the mixture was stirred at room temperature for 3.0 hours.The reaction solution was distilled off under reduced pressure, dried, and the residue was washed with N, N-dimethylformamide (1 ml). 2.0 ml) and cooled to 0 ° C. To this was added 1-hydroxybenzotriazole (147.0 mg), 0- (t-butyldimethylsilyl) hydroxylamine (21.8 ms) ), Followed by 1- (3-dimethylaminopropyl) -1-ethylcarbodiimid hydrochloride (25 1. N-methylmorpholine (0.30 ml) was added sequentially, and the mixture was heated to room temperature, stirred overnight, poured into a 10% aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, and saturated with an organic layer. After washing with brine and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 20 _: 1) to give the desired compound (68.1 mg, 21.7%) as a colorless oil.

'Η—Nuclear magnetic resonance spectrum (270MHz, CDaOD, δ ppm):

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 tank (liquid film, cm " ¹ ) 3248, 1746, 1646, 1548

High-resolution mass vector

m / z [+ H] + = 444.3434

_{_{Calculated: 444.3438 (C 23 H 46 0}} s N 3)

Specific rotation: [a] D ^{2 S} = + 9.3 ° (C: 1.00, MeOH)

(Example 25) Acetic acid 2- (S)-{2- (R)-[(S) -hydroxy (hydroxycarbamoyl) methyl] -14-methylpentanoylamino 1-3,3-dimethyl Butyl ester (Exemplary Compound No. 103)

25-a) 2- (R)-[2,2-Dimethyl-5-oxo [1,31-dioxolan-1-4- (S) -yl] —4-Methylpentanoic acid [1-1 (S) —Hydroxymethyl-2,2-dimethylpropyl] amide

2- (R)-(2,2-dimethyl-5-oxo-1,1,3-dioxolan-1- (S) yl) solution of 1,4-methylpentanoic acid (105 mg) in methylene chloride (1.5 m 1) One one ten. C, and then 1-hydroxybenzotriazole (74 mg), N-methylmorpholine (60 ul), 1- (3-dimethylaminobu pill)-3-ethylcarbodimid hydrochloride (105 mg ) Was added in sequence, and the mixture was stirred at the same temperature for 1 hour under a nitrogen atmosphere. Next, a solution of L-t-one-port isinol (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.

— Nuclear magnetic resonance spectrum (270MHz, CDCla, 5ppm):

0.95 (5H, 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 = 4.7Hz), 6.29 (1H, d, J = 8.2Hz) )

25-b) g¾2-LSJ 1 2-(R _-2,2-dimethyl-5-oxo I one

According to the method of Example 10—b), 2— (R) 1 [2,2-dimethyl-5-oxo-1 [shi 3] —di-sixisolan 1-41 (obtained in Example 25—a) S) -yl] -4-Methylpentanoic acid [1- (S) -hydroxymethyl-2,2-dimethylpropyl] amide (137 mg) was used as a starting material, and 87 mg of the target compound was obtained by the same reaction treatment. 56%).

¹ H—nuclear magnetic resonance spectrum (270 MHz, CDCla, δ ppm):

0.90-1.00 (15H, m), 1.58 (3H, s), 1.58 (2H, 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] -1-methylpentanoylamino-1,3,3-dimethyl Butyl ester

According to the method of Example 10-c), acetic acid 2- (S) -1- {2- (R)-[2,2-dimethyl-1-5-acetic acid obtained in Example 25-b) was obtained. , 3] 1-dioxolan-14- (S) yl] -14-methylpentanoylamino] 1,3,3-dimethylbutyl ester (87 mg) as a starting material in the same reaction treatment as above.

3 mg (62%) were obtained.

'Η-nuclear magnetic resonance spectrum (270MHz, CDCla, δ ppm):

0.93-0.96 (15H, m), 0.96 (9H, s), 1.44 (1H, m), 1.63 (1H, in), 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, 2.1 Hz), 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 / Τέ

25-d) Shaoic acid 2- (S)-{2- (R) -1-[(S) -hydroxy (hydroxycarbamoyl) methyl] -1-4-methylpentanoylamino ί-3,3-dimethyi Rubutyl ester

According to the method of Example 10-d), 2- (S) -1- {2- (R) -acetic acid obtained in Example 25-c)-[(S) -benzyloxycarbamoyl (hydroxy) methyl [14-Methylpentanoylamino] Using 1,3,3-dimethylbutyl ester (60 mg) as a starting material, 28 mg (57%) of the target compound was obtained by the same reaction treatment.

¹ H - NMR spectrum _{(270MHz, CDC1 3, δ ppm} ):

0.87-1.00 (15H, m), 1.37 (1H, m), 1.60 (1H, m), 1.85 (1H, m), 2.02 (3H, s), 3.03 (1H, m), 4.01-4.28 (4H, m), 6.63 (1H, m)

(Example 2 6) 2 - (S) , N 1 - dihydric Dorokishi ^{N 4 - [1 - (S} ) - arsenide de port Kishimechiru one 2, 2-dimethylpropyl] one 3- (R) one isobutyl disk Sina Mi (Exemplary Compound No. 102)

According to the method of Example 9, acetic acid 2- (S) — {2-

(R) mono ((S) -hydroxy (hydroxycarbamoyl) methyl] —4-methylpentanoylamino} 13,3-dimethylbutyl ester (23 mg) as a starting material 5 mg (25%) of the target compound was obtained.

'Eta - nuclear magnetic resonance spectrum _{(270MHz, CD 3 0D, δ} ppm):

0.90-1.00 (15H, m), 1.26 (1H, m), 1.67 (2H, m), 2.81 (1H, m), 3.50 (1H, m), 3.77 (2H, m), 4.06 (1H, d, (J-5.3Hz)

(Example 27)

2-(S), N ¹ Dihydroxy N ^A- [2-(R)-hydroxy 1-(S)-isopropylbutyl] 1 3-(R)-nonylsuccinamide (Exemplified Compound No. 202)

2 7-a) 2-shi R) _— ί 2 2 2-dimethyl-5-oxo [1.3. · ；;: ^ ¾ ¾% (% ε 8 '3 ui in) eye, ci τ2 ί¾¾: ο> pair (gi (oz m T (s ^ gg S)

? 1 ^^ / ^ (--(H) — S— ί ^^ ί ^ ^-(S)-I-J ^ n ii ^-(H)-Z]-^ H-^^ ^-(S ) —K, ^^ K, Be, N

(-r-(a) — ε— ί ^-^ ^ (? ij r. y- (s)-i-

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(S)-T-^ n ^-(H)-Z)-^ ^ ζ, [(y-(S)-

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ZSS00 / L6dT / ± Dd Z68WL6 O

° (ZHZ 'Γ'Ρ'Ηΐ) Β6 · ε'(ΖΗλ'ε'· 8 = Γ'ΡΡ'ΗΙ) 9 · £' (ZJ · 8 = Γ P 'Ηΐ) · Ε'("<'Ηΐ ) U ΗΓ ")-80 ·"'HZ) U · Ί' (· "'Η9ΐ) 9 ^ Ί-ΤΖΤ (""ΉΖΐ) 86 · 0-88" 0 ^ dd g (αθ ^Ε 03' ΖΗΜΟΟ ^ ) Γ Μ ^ ^ I'dif-Η,

Z8S00 / 16df / XDd Z68IC / .6 ΟΛ (Example 28)

Acetic acid 2- (S) -1- [2- (R)-((S) -hydroxy (hydroxycarbamoyl) methyl) -1-9-methyldecanoylamino] -1,3-dimethylbutylester (exemplified compound (Number 1 08)

28- a) 2- (S) -Hydroxy-3- (R)-(7-methyl-12-octyl) succinic acid diisopropyl ester

2- (S) -Hydroxysuccinic acid diisopropyl ester (10.43 g) was dissolved in tetrahydrofuran (200 ml) under a nitrogen atmosphere and cooled to 178 ° 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-hydroxy-7-methyl-2-octene (13.26 g) in tetrahydrofuran (100 ml) was added, and the mixture was stirred at 178 ° C for 2 hours, and then heated to room temperature and further heated for 2 hours. Stirred for hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off 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. Obtained.

¹ H—nuclear magnetic resonance spectrum (400 MHz, CDCla, δ ppm): 0.86 (6H, d, J = 6.6 Hz), 1.1 2 —1.39 (4H, m), 1.22 (6H, d, J = 6.4 Hz) , 1.28 (6H, d, J = 6.4Hz), 1.52 (1H, m), 1.98 (2H, ra), 2.36 (1H, in), 2.54 (lH, m), 2.84 (lH, m), 3.18 ( lH, d, J = 7.4Hz), 4.21 (lH, dd, J = 3.1,7.4Hz), 5.01 (lH, m), 5.11 (lH, m), 5.40 (ΙΗ, πι), 5.57 (lH, m ).

Infrared absorption spectrum (Liquid film, cm- ¹ ): 3515, 1738

Mass spectrum (FAB): m / z [M + H] ⁺ = 343

28-b) 2- (R) 1- (2,2-dimethyl-5-oxo-1 一, 3] -dioxolan-14-1 (S) yl-1-19-methyldecanoic acid

The 2- (S) -hydroxy-3- (R)-(7-methyl-2-octenyl) succinate diisopropyl ester (7.46 g) obtained in Example 28-a) was meta- It was dissolved in I-nor (75 ml), 10% palladium-carbon (0.75 g) was added, and hydrogenation was performed 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. Then, the obtained residue was dissolved in dioxane (40 ml), and an aqueous solution (80 ml) of potassium hydroxide (4.24 g) was added thereto under ice-cooling, followed by heating and stirring at 90 ° C for 16 hours. The reaction solution was neutralized by adding Amberlyst 15E, and then 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-dimethylmethoxypropane (1.3.17 ml) and pyridinium p-toluenesulfonate (0.54 g) were added. The mixture was added successively and heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 4: 1 to 1: 1) to give 4.28 g (65%) of the desired compound as white Obtained as crystals.

¹ H—nuclear magnetic resonance spectrum (400MHz, CDCla, δριη): 0.86 (6Η, d, J = 6.6Ηζ), 1.1 0 —1.47 (10H, m), 1.51 (lH, m), 1.55 (3Η, s ), 1.60 (3H, s), 1.74 -1.83 (2H, m), 2.93 (lH, m), 4.50 (lH, d, J = 5.0Hz).

Infrared absorption spectrum (KBr pellet, cm " ¹ ): 1799,1716

Mass spectrum (FAB): m / e [M + H] ⁺ = 301

Elemental analysis

_{_{_{Calculated: C 16 H 28 0 5:}}} C 63.97%; H, 9.40%

Measured value: C, 63.76%; H, 9.29%

28-c) 2- (R)-(2,2-Dimethyl-1-5-oxo-1 [1,3] -Dioxolan-1-4- (S) -yl) -1-9-Methyldecanoic acid (1- (S) —Hydroxymethyl 2,2—dimethyl propyl) amide

2- (R)-(2,2-dimethyl-5-year-old oxo) obtained in Example 28-b)

Example 1 using [1,3] -dioxolan-1-4- (S) -yl) -19-methyldecanoic acid (1,0000 g) and (S) -tert-mouth isinol (468mg) as starting materials 5- 27 g (85%) of the target compound was obtained in the same manner as in 5) a). α> ΐ6〜68 ： ψ m 9 ΐ'6 9ΐ'0 ΐ '96 Γΐεεε ：

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1 'S)-(H)-S]-(S)-2¾iS ^ ¾¾a (P-82 [ΐίίδϊΙ 1' C-[ί i ^ (Two 6-{(-((^^ η .Η ~ Ά) Λ (y V ^ ^ ^^ /: ー (S) \ one (H)-Z} one (S) Wei ^ (9-8 S

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Melting point: 107-109. C

(Example 29)

2 - (S), N ¹ Jihi Dorokishi one N ⁴ - (1 - (S) over human Dorokishimechiru 2, 2-dimethylpropyl) Single 3- (R) i (7- Mechiruokuchiru) Sukushinami _ (Compound No. 1 07 )

2- (S) -acetic acid obtained in Example 28-f) 2- (S)-[2- (R)-((S) -hydroxy (hydroxycarbamoyl) methyl) -1 9-methyldecanoylamino] 1

In a similar manner to Example 11, 70 mg (76%) of the target compound 1 was obtained as white crystals from 3,3-dimethylbutyl ester (25 Omg).

¹ H—nuclear magnetic resonance spectrum (400 MHz, CDsOD, δ ppm): 0.87 (6H, d, J = 6.6 Hz), 0.9

4 (9H, s), 1.13 to 1.55 (llH'm), 1.51 (lH, m), 1.60 (lH, m), 2.68 (lH, m), 3.48 (lH, dd, J = 9.2, 12.3Hz) , 3.73 to 3.79 (2H, m), 4.06 (1H, d, J = 6.5Hz).

Infrared absorption spectrum (KBr pellet, cm- ¹ ): 3277,3124, 1669, 1469

Mass spectrum (FAB): m / z [M + H] ⁺ = 375

Melting point: 156-158 ° C

Three

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32— a) 3— (R)-“1-1 (S) —acetoxymethyl-1,2,2-propylamine”! One 6- (4-chlorophenyl) hexanoic acid

2- (R) -t-Butoxycarbonylmethyl-5- (4-chlorophenyl) pentanoic acid (1.000 g) in methylene chloride (30 ml) solution 1- (3-dimethylaminopropyl) Ethylcarbodiimide hydrochloride (704 mg), 1-hydroxybenzotriazole (496 mg), and N-methylmorpholine (0.40 ml) were sequentially added, and the mixture was cooled to 0 ° C. Next, a solution of (S) -t-mouth isinol (43 Omg) in methylene chloride (10 ml) was added to the solution, and the mixture was stirred at room temperature for 18 hours. The reaction solution was poured into 1N hydrochloric acid and extracted with methylene chloride. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated saline solution, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was redissolved in methylene chloride (25 ml) and cooled to 0 ° C. Then, pyridine (0.49 ml), 4-dimethylaminopyridine (37 mg), and acetic anhydride (0.58 ml) were sequentially added to the solution, 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 1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was redissolved in methylene chloride (30 ml) and cooled to 0. Then, trifluoroacetic acid (4.71 ml) was added to the solution, and the mixture was stirred at room temperature for 16 hours. After toluene was added to the reaction solution, volatiles were distilled off under reduced pressure. The resulting 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.

— Nuclear magnetic resonance spectrum (400MHz, CD ₃ OD) δ ppm: 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 (2H, m), 2.60 (lH, dd, J = 16.7,9.4Hz), 2.80 (lH, m), 3.88 (lH, dd, J = 10.9,10.2Hz), 3.96 (lH, dd, J = 10.2,2.6Hz), 4.37 (lH, dd, J = 10.9,2.6Hz), 7.16 (2H, m), 7.24 (2H, m)

Infrared absorption spectrum (KBr pellet, cm ' ¹ ): 3318, 2964, 1737, 1648, 1549, 1238. Mass spectrum (FAB): m / z [M + H] + = 412 s zsoiduvDxJ OM

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No. 1 — 3-Methyl-3-methylthiobutyl ester (Exemplary Compound No. 21) 38—a) 3- (R)-[1- (S) -hydroxymethyl-2-methyl-1--2-methylthiopropyl rubamoyl 1 dodecane Acid t-butyl ester

To a solution of 2- (R) -t-butoxycarbonylmethyldecanoic acid (667mg) and N-methylmorpholine (250 til) in tetrahydrofuran (6ml) was added dropwise isobutyl chloroformate (2901). The mixture was stirred at room temperature for 30 minutes. Next, a solution of N, N-dimethylformamide (2 ml) of N-methylmorpholine (500 ju1) and 1- (S) -hydroxymethyl-2-methyl-2-methylthiopropylamine hydrochloride (412 mg) was sequentially added. The mixture was left overnight at room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 5: 1) to give the desired compound (373 mg, 39%) as a colorless oil As obtained.

'Η—nuclear magnetic resonance spectrum (270MHz, CDCl ₃ ) δ ppm:

0.88 (3H, t, J = 6.6Hz), 1.20-1.36 (14H, complex), 1.31 (3H, s), 1.36 (3H, s), 1.43 (9 H, s), 1.48-1.76 (3H, complex ), 2.08 (3H, s), 2.37 (lH, m), 2.56-2.70 (2H, complex), 3.75 (1H, dd, J = 6.4, 11.3Hz), 3.82-3.97 (2H, complex), 6.47 (1H, d, J = 7.2Hz)

38-b) 3— (R)-[1- (S) -acetoxymethyl-2-methyl-2-methylthiopropyl-rubumoyl] dodecanoic acid t-butyl ester

Example 38— 3- (R)-[1- (S) -hydroxymethyl-2-methyl-2-methylthioprovyl-l-rubamoyl] dodecanoic acid t-butyl ester (369 mg) obtained in methylene chloride (369 mg) Acetic anhydride (881), pyridine (76 μΐ) and 4-dimethylaminoaminopyridine (1 Omg) were sequentially added to the solution, 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 then dried over anhydrous magnesium sulfate. The solvent was distilled off 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 (313 rag, 77%) as a colorless oil. Obtained as quality.

'H—nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ ppm:

0.88 (3H, t, J = 6.7Hz), 1.20-1.40 (17H, complex), 1.34 (3H, s), 1.43 (9H, s), 2.55-2.75 (2H, complex), 2.03 (3H, s), 2.09 (3H, s), 2.31 (IH, dd, J = 3.2, 16.OHz), 2.55 (lH, m), 2.65 (lH, dd, J = 9.5,16.0Hz), 4.18 (IH, dd, J = 9.6, 11.OHz), 4.34 (IH, dt, J = 3.4, 9.6 Hz), 4.47 (lH, dd, J = 3.4,11.0Hz), 6.02 (lH, d, J = 9.6Hz)

38-c) 3-(R)-“1- (S) —acetoxymethyl-2-methyl-2-methylthiopropyl pyruvamoyl] dodecanoic acid

Chlorination of 3- (R)-[1- (S) -acetoxymethyl-2-methyl-2-methylthiopropyl-pyruvamoyl] dodecanoate t-butylester (31 mg) obtained in Example 38-b) Trifluoroacetic acid (1.6 ml) was added to the methylene (3.2 ml) solution, and the mixture was stirred at room temperature for 1.5 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 1: 1) to give the desired compound (273 mg, 99%) as a colorless oil.

lH—nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) 5 ppm:

0.88 (3H, t, J = 6.6Hz), 1.18-1.43 (17H, complex), 1.37 (3H, s), 1.51 (lH, m), 1.67 (1 H, m), 2.03 (3H, s), 2.09 (3H, s), 2, 49-2.60 (2H, complex), 2.79 (IH, dd, J = 9.6, 17.4Hz), 4.17 (IH, dd, J = 9.6, 11.OHz), 4.33 (IH , dt, J = 3.3, 9.6Hz), 4.46 (lH, dd, J-3.3,11.0 Hz), 5.98 (lH, d, J = 9.6Hz)

38-d) Acetic acid 2- [2- (N-Hydroxycarbamoylmethyl) pentacanylamino] — 3-methyl-3-methylthiobutyl ester

3- (R)-[1- (S) -acetoxymethyl-2-methyl-2-methylthiopropylcaproluvamoyl] obtained in Example 38-c) dodecanoic acid (273 mg) and N-methylmorpholine (1 To a solution of 801) in tetrahydrofuran (2 ml) was added isobutyl chloroformate (901) under ice-cooling, followed by stirring for 30 minutes. There, 0— (t-butyldimethylsilyl) hydroxylamine (1 16 mg) in tetrahydrofuran (1 ml) was added and stirred overnight. The reaction solution was poured into water, and 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) and stirred at room temperature for 30 minutes. After distilling off under reduced pressure with methanol, extraction was performed 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 (21 Omg, 74%) as a white powder.

'Η—Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ ) δ ppm:

0.88 (3H, t, J = 6.6Hz), 1.20-1.37 (14H, complex), 1.34 (3H, s), 1.44 (1H, m), 1.59 (3H, s), 1.64 (lH, m), 2.03 (3H, s), 2.08 (3H, s), 2.33 (lH, dd, J = 4.0, 14.4Hz), 2.51 (1H, dd, J = 10.2, 14.4Hz), 2.69 (lH, m), 4.14 (lH, 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 (lH, d, J = 9.4Hz), 7.18 (lH, brs), 9.19 (lH, brs)

Infrared absorption spectrum (KBr pellet, cm " ¹ ):

3345, 3244, 1 728, 1653, 1 550, 1 238, 1 040 Mass spectrum (FAB): m / e [M + H] ⁺ = 433

(Example 39)

N ⁴ - hydroxy-N ¹ - obtained in - [1-hydroxy methyl one 2-methyl-2 menu Le Chiopuropiru] one 2- (R) over Bruno succinate cyanamide (Compound No. 20) Example 38- d), Acetic acid 2- [2- (N-hydroxycarbamoylmethyl) indecanoylamino] 13-methyl-13-methylthiobutyl ester (108 mg) was prepared in the same manner as in Example 9 (but The resulting powder was washed with ethyl acetate without crystallization, and the target compound (71 mg, 73%) was obtained as a white powder.

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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 0 7)

(Example 4 1)

2- (R) - [3- (2-ethoxyethoxy) Purobiru] one N ⁴ - heat Dorokishi - N ¹ one [1 one (S) over human Dorokishimechiru 2, 2-dimethylpropyl] Sukushi cyanamide (Compound No. 300)

Acetic acid obtained in Example 40-e) 2- (S)-[5- (2-ethoxyxetoxy) -1 2- (R)-(N-hydroxycarbamoylmethyl) pentanylamino] 13 The desired compound 11 I mg (36%) was obtained as a white powder from, 3-dimethylbutyl ester (345 mg) in the same manner as in Example 9.

'.Eta. Nuclear magnetic resonance spectrum _{(400MHz, CD 3 0D) 5} ppm: 0.93 (9H, s), 1.19 (3H, t, J = 7 • 2Hz), 1.45-1.71 (4H, m), 2.19 (IH , dd, J = 14.6, 6.6Hz), 2.35 (IH, dd, J = 14.6, 7.7Hz), 2.83 (lH, 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, 1669, 1647, 1549, 1101. Mass spectrum (FAB): m / z [+ H] ⁺ = 363

High resolution mass spectrum (FAB): m / z [M + H] ⁺ = 363.2509

_{_{Calculated: 363.2496 (C l 7 H 3S}} N 2 0 6)

Melting point: 127-129 ° C

(Example 42)

Acetic acid 3-acetoxy 2- (S)-[2- (R)-(N-hydroxycarbamoylmethyl) undecanoylamino] 1-1 (S) -methylpropyl ester (Exemplary Compound No. 309)

42-a) _3-IR)-"1 (S) _-Hydroxy 1-(SJ-Hydroxy _

1- (S) -acetoxy-1 1- (S) -acetoxymethylpropyl sorbamoyl] Dodecanoic acid t-butyl ester (81 13 mg) was used as a starting material and subjected to the same reaction treatment to obtain the desired compound 716 mg (1 00%) as a colorless oil.

¹ H- nuclear magnetic resonance spectrum _{(270MHz, CDC1 3) δ ppm} : 0.88 (3H, t, J = 6.6Hz), 1.22 (1H, d, J = 6.4Hz), 1.24-1.37 (14H, m), 1.47 (lH, m), 1.63 (lH, m), 2.05 (3H, s), 2.07 (3H, s), 2.48 (lH, m), 2.58 (lH, m), 2.80 (1H, in), 4.08 ( 2H, m), 4.35 (lH, m), 5.12 (1H, m), 5.99 (lH, d, J = 8.8Hz).

Infrared absorption spectrum (Liquid film, cm "): 3439,2930,1737,1679,1511.

Mass spectrum (FAB): m / z [M + H] + = 416

42-d) Acetic acid 3-acetoxyl-1- (S) -methyl-2- (S)-[2- (R) -I- (N-benzylcarbamoylmethyl) pentadecylylamino] propyl ester

3- (R) -I- [2- (S) -acetoxy-l- (S) -acetoxymethylpropyl-pyrvamoyl] obtained in Example 42-c) was salted with dodecanoic acid (573 mg). Dissolved in methylene chloride (15 ml), and at room temperature, 0-benzylhydroxylamine hydrochloride (396 mg), 1- (3-dimethylaminobutyryl) —3-ethylcarbodiimid hydrochloride (529 mg) , 1-hydroxybenzotriazole (280 mg) and N-methylmorpholine (0.27 ml) were added, and the mixture was 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 successively 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.

'Η—Nuclear magnetic resonance spectrum (270MHz, CDC1) δ ppm: 0.88 (3H, t, J = 6.8Hz), 1.23 (3H, d, J = 6.7Hz), 1.24-1.30 (14H, ra), 1.42 ( lH, m), 1.60 (lH, m), 2.04 (3H, s), 2.08 (3H, s), 2.22 (lH, m), 2.36 (lH, m), 2.69 (lH, m), 4.05 (2H , m), 4.31 (lH, m), 4.86 (2H, s), 5.09 (lH.m), 6.00 (1H, d, J = 8.6Hz), 7.37 (5H, m), 8.41 (lH, brs ) · 42-e) Acetic acid 3-acetoxy 2- (S)-[2- (R)-(N [-hydroxycarbamoylmethyl) undecanoylamino] — 1- (S) -methyl propyl ester

According to the method of Example 10-d), 3-acetoxy-1-acetic acid 1- (S) -methyl-2- (S) -1- [2- (R) -acetate obtained in Example 42-d) 475 mg (82%) of the target compound was obtained as a white solid by the same reaction treatment using (N-benzylcarbamoylmethyl) pentadecylamino] propyl ester (697 mg) as a starting material.

¹ H—nuclear magnetic resonance spectrum (400 MHz, CDC) δ ppm: 0.88 (3H, t, J = 6.7 Hz), 1.21 (3H, d, J = 6.5 Hz), 1.23-1.32 (14H, m), 1.43 (lH, m), 1.63 (lH, m), 1.77 (lH, m), 2.05 (3H, s), 2.08 (3H, s), 2.31 (1H, dd, J = 4.3,14.4Hz), 2.51 ( lH, m), 2.73 (lH, m), 4.02 (1H, dd, J = 6.9, 11.2Hz), 4.10 (lH, dd, J = 5.8, 11.2Hz), 4.3 (ΙΗ, πι), 5.09 (lH , m), 6.19 (lH, d, J = 9.8Hz), 7.86 (lH, brs), 9.57 (lH, brs).

Infrared absorption spectrum (KBr pellet, ^ ' ¹ ): 3291,2923,1737,1649,1553.

Mass vector (FAB): m / z [M + H] + = 431

High resolution mass spectrum (FAB): m / z [+ H] ⁺ = 431.2728

_{_{Calculated: 431.2757 (C 21 H 39 0}} T N 2)

Specific rotation: [] D ²⁵

(Example 43)

Ν ^Λ —Hydroxy Ν ^1- [2-(S) -Hydroxyl 11-(S) -Hydroxymethylpropyl) — 2-(R) -Nonylsuccinamide (Exemplified Compound No. 310)

3-Acetoxyacetic acid 2- (S)-[2- (R) -I (N-hydroxycarbamoylmethyl) ndecanoylamino] -1 obtained in Example 42-e) Potassium carbonate (305 mg) was added to a solution of (S) monomethylpropyl ester (315 mg) in methanol (5 ml), 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. Wash the organic layer with saturated saline After the purification, the extract was 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 x 20 cm 1 mm thick, 3 sheets, developing solvent: methylene chloride: methanol = 10: 1) to obtain the desired compound. 94 mg (37%) of the product were obtained as a white solid.

'.Eta. Nuclear magnetic resonance spectrum _{(400MHz, CD 3 0D) δ} ppm: 0.89 (3Η, t, J = 6.3Hz), 1.15 (3H, d, J = 6.3Hz), 1.22-1.36 (14H, m), 1.43 (lH, m), 1.59 (lH, 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 (lH, m), 3.62 (lH, m), 3.80 (1H, m), 3.99 (lH, m). Infrared absorption spectrum (Liquid film, cm " ¹ ): 3293, 2926, 1650, 1548.

Mass spectrum (FAB): m / z [+ H] ⁺ = 347

Specific rotation: [α] D ²⁵ = + 2.46 (C: 0.61, CHCl ₃ )

(Example 44)

Morpholine 1-4-ylacetic acid 2- (S)-{2- (R) -1-[(S) -hydroxy (hydroxycarbamoyl) methyl 1-decanoylamino] 1-3,3-dimethylbutyl ester (exemplified compound number 3 1 1)

44-a) Morpholine-1-yl-acetic acid 2- (S)-{2- (R) -1- [2,2-dimethyl-5-oxo-1- [1,31-dioxolan-1-4-1 (S) -yl ] Decanoylamino] 1,3-dimethylbutyl ester

Dissolve 2- (4-morpholinyl) acetic acid (300 mg) in methylene chloride (6 ml), add DMF (30 u1) and oxalyl chloride (0.22 ml) under water cooling, and stir for 1 hour under nitrogen atmosphere did. After distilling off the reaction solution under reduced pressure, 2- (R)-[2,2-dimethyl-5-oxo-1- [1,3] -dioxolan-1- (S) obtained in Example 10-a) was obtained. 1) [yl] decanoic acid [1- (S) -hydroxymethyl-2,2-dimethylpropyl] amide (300 mg) in THF (10 ml) and pyridine (80 wl) were added sequentially, and the mixture was added under a nitrogen atmosphere. — Stirred at 20 ° C for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. After washing the organic layer with saturated saline, sulfuric anhydride

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Z8S00 / .6dT / XDJ Z6SWL6 OAV 47-b) 3-(R) — “1 — (S) —acetoxymethyl-2,2-dimethylpropyl-l-rubamoyl 16- (4-methoxyphenyl) hexanoic acid t-butyl ester

According to the method of Example 10-b), 3- (R) -1- [1- (S) -hydroxymethyl-2,2-dimethylpropyl-l-bamoyl] 1-6- (R) obtained in Example 47-a) Methoxyphenyl) hexanoic acid t-butyl ester (1.26 g) gave 1.34 g (96%) of the desired compound as a white solid.

'Η—nuclear magnetic resonance spectrum (270MHz, CDC1a) δ ppm: 0.93 (9H, s), 1.41 (9H, s), 1.45-1.81 (4H, m), 1.84 (3H, s), 2.27 -2.68 (5H, m), 3.77 (3H, s), 4.03-4.21 (3H, m), 5.83 (lH, d, J = 9.2Hz), 6.80 (2H, d, J = 8.5Hz), 7.06 ( (2H, d, J = 8.5Hz).

Infrared absorption spectrum (KBr pellet, cm— '): 3315,2967,2937,2867,1735,1666,1647,1612,1582,1559.

Mass spectrum (Fab): [M + H] + = 464

47-c) 3-(R)-[1-(S)-acetoxmethyl-2, 2-dimethylpropyl-rubamoyl] 1-6-(4-methoxyphenyl) hexanoic acid

According to the method of Example 8—d), 3— (R)-[1- (S) -acetoxymethyl-2,2-dimethylprovyl-rubamoyl] obtained in Example 47—b) 1.1 g (quant.) Of the desired compound was obtained as an oily substance from t-butyl ester of (methoxyxyphenyl) hexanoic acid (1.24 g).

Mass spectrum (Fab): [M + H] + = 408

47-d) 2- (S) acetic acid 2- (R)-(Ν-hydroxycarbamoylmethyl) -5- (4-methoxyphenyl) pentanoylamino] — 3,3-dim. Butyl ester

According to the method of Example 8-e), 3- (R) -1- [1- (S) -acetoxymethyl-2,2-dimethylpropylpyrumoyl] -1-6- (4-) obtained in Example 47-c) From methoxyphenyl) hexanoic acid (1.1 g), 598 mg of the target compound ( ^ Y

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Z8S00 / L6df / X3d Z68I £ //. 6 OAV [1-(S)-(methoxy (methyl) potassium rubamoyl)-1-Methylpropyl] Benzyl ester of potassium rubinate (3.0 g) was added to a solution of tetrahydrofuran (100 ml). At 0 ° C, a 0 M arylmagnesium bromide THF solution (30.6 ml) was added, and the mixture was stirred at 0 ° C for 2 hours. 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: 5) to give the desired compound (2.0 s, 72%) as a colorless oil.

¹ H- nuclear magnetic resonance spectrum _{(270MHz, CDC1 3) δ ppm} : 0.89 (d, J = 6.6Hz, 3H), 1.08 (d, J = 6.6Hz, 3H), 1.64-1.66 (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 [+ H] ⁺ = 276

49-b) (2- (R), 5-dihydroxyl- (S) -isopropylpropyl) Benzyl ester

(1 — (S)-isopropyl-2-oxopento-4-enyl) To a solution of benzyl carbamic acid ester (2.0 g) in tetrahydrofuran (50 ml) was added 0. C, a 1.0 M solution of a borane-tetrahydrofuran complex in tetrahydrofuran (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 1 N aqueous solution of sodium hydroxide (50 ml) and a 30% aqueous hydrogen peroxide solution (5. Om 1) were added, and the mixture was stirred for 1 hour. Water was added to the 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.

lH-nuclear magnetic resonance spectrum (270MHz, CDCla) δ ppm: 0.97 (d, J = 6.8Hz, 1H), 1.02 (d, J = 6.8Hz, 1H), 1.40-2.10 (m, 5H), 3.43- 3.90 (m, 5H), 4.84-4.87 (m, 1H), 5.11-5.23 (m, 3H), 7.34-7.46 (m, 5H).

Mass spectrum (FAB): m / z [M + H] + = 296 49-c) [5- (t-butyldimethylsilyloxy) -1-2- (R) -hydroxyl-l- (S) -isopropylpentyl] benzyl ester of rubamate

(2- (R), 5-dihydroxyl-l- (S) -isopropylpentyl) carbamic acid benzyl ester (1.15 g) was obtained in the same manner as in Example 3-b). .21 g, 76%) as a colorless oil.

'Η—Nuclear magnetic resonance spectrum (270MHz, CDC1a) δ ppm: 0.10 (s, 6H), 0.87-0.92 (m, 15H), 1.37-1.52 (m, IH), 1.59-1.87 (m, 4H) , 3.30-3.33 (m, IH), 3.47-3.82 (m, 4H), 4.67 -4.74 (m, IH), 5.11 (s, 2H), 7.29-7.36 (m, 5H).

Mass spectrum (FAB): m / z [M + H] + = 410

4 9-d) 2-(R)-"2,2-Dimethyl-5-oxo-1 [1,3] -dioxolan-1 41- (S) -yl] pandecanoic acid [5- (t-butyldimethyl (Silyloxy) 1 2— (R) —hydroxy 1 1— (S) —isobromovirpentyl]

[5- (t-Butyldimethylsilyloxy) -1- (R) -hydroxyl-1- (S) -isopropylpentyl] Benzyl ester of rubamate (1.21 g) Example 2-a) In a similar manner to the above, the target compound (1.25 g, 78%) was obtained as a white solid.

'H—nuclear magnetic resonance spectrum (CDCla, 270MHz) δ ppni: 0.07 (s, 6H), 0.78-0.99 (m, 18H), 1.32-1.46 (in, 14H), 1.54 (s, 3H), 1.62 ( s, 3H), 1.62-1.73 (m, 7H), 2.51-2.61 (m, 1H), 3.59-3.89 (m, 4H), 4.53 (d, J = 6. lHz, IH), 5.94 (d, J = 4.5Hz, IH)-Mass spectrum (FAB): m / z [M + H] + = 558

49 - e) N 'one Benjiruokishi N ⁴ one [2 - (R), 5- dihydroxy-1 one (S) - iso blow building pentyl 1 one 2-(S) over human Dorokishi 3- (R) - Nonirusukushinami de

2- (R)-[2,2-Dimethyl-5-oxo-1 [1,3] —Dioxolan-1 4- (S) -yl] pentadecanoic acid [5- (t-butyldimethylsilyloxy) 1-2— (R) —hydroxy-11- (S) —isopropylpentyl] amide (1.2

From 5 g), the desired compound (188 _mg , 16 _mg ) was obtained in the same manner as in Example 2-b).

%) Was obtained as a white solid.

¹ H—nuclear magnetic resonance spectrum (CDCl ₃ , 270 MHz) δ ppm: 0.77-0.96 (m, 9H), 1.19-1.42 (m, 14H), 1.62-2.11 (m, 7H), 2.53-2.64 (m , IH), 3.57-3.79 (m, 4H), 4.73-4.89 (m, 5H), 6.09 (d, J = 1.3Hz, IH), 7.32-7.48 (m, 5H), 8.07 (bs, IH).

Mass spectrum (FAB): m / z [M + H] ⁺ = 508

4 9-f) N ⁴ 1 2-(R), 5-dihydroxy 1-1 (S)-isopropylpentyl]-2-(S), N ^1- dihydroxy 1 3-(R)-nonylsuccinamide

N ¹ one base Njiruokishi one ^{N 4 - [2 - (R} ), 5- dihydroxy over 1 - (S) - isopropyl pentyl] - 2- (S) over human Dorokishi 3- (R) Nonirusuku Shinami de (1 88m g )) To give the desired compound (117 mg, 76%) as a white solid in the same manner as in Example 2-c).

'H—nuclear magnetic resonance spectrum (CDCl ₃ , 400 Hz) δ ppm: 0.86-0.94 (m, 9H), 1.25-1.47 (m, 17H), 1.53-1.80 (m, 4H), 2.09-2.17 ( ra, IH), 2.63-2.72 (m, IH), 3.49-3.58 (m, 3H), 3.72-3.79 (m, IH), 4.02 (d, J = 2.8Hz, IH).

Mass spectrum (FAB): m / z [M + Hl + = 419

(Example 50)

3-cyclohexyl acetate 2- (S)-{2- (R)-[(S) -hydroxy (hydroxycarbamoyl) methyl] -l-decanoylamino-bromopyrylester (Example Compound No. 1) 14)

5 0-a) 2-(R) 1- (2,2-dimethyl-5-oxo-1 [1,3] dioxolan-1 4- (S) -yl) pentadecanoic acid [1- (S) -cyclohexylme Lou 2—Hydroxyshetil "L According to the method of Example 8—b), 2— (R) — [2,2-dimethyl-5-oxo— [1,3] dioxolan-1 4- (S) —yl] pentadecanoic acid (1.08 g) And Cyclohexylalaninol (◦.622 g) as starting materials, and 707 mg (44.7%) of the target compound was obtained as a white solid by the same reaction treatment.

'H—nuclear magnetic resonance spectrum (270MHz, CDCla) δ ppm: 0.81-1.87 (29Η, m), 0.88 (3Η, t, J = 6.6Hz), 1.55 (3H, s), 1.63 (3H, s), 2.60 (IH, m), 3.52 (lH, dd, J = ll.1, 1Hz), 3.68 (IH, dd, 11.1,3.4Hz), 4.09 (lH, m), 4.56 (1H, d, J = 5.3Hz), 5.98 (1H, d, J = 7.7Hz). Infrared absorption spectrum (KBr pellet, cm " ¹ ): 3247, 1799, 1646,1571.

High resolution mass spectrometer (FAB): m / z [+ H] ⁺ = 440.3381

Calculated value: 440.3369 (C ₂₅ H ₄₆ 0 _s N)

50-b) 3-cyclohexyl acetate—2— (S) — [2— (R) — (2,2

—Dimethyl-5—Kizo 1 [1,3] —Dioxolan 4— (S) —Ir) didecanoylamino] propyl ester

According to the method of Example 10-b), 2- (R) — (2,2-dimethyl-5-oxo-1 [1,3] —dioxolan-1 4-— (S) obtained in Example 50-a) ) —Yl) pentadecanoic acid [1 — (S) —cyclohexylmethyl-2-cyclohydricyl

Using the amide (632 mg) as the starting material, the target compound 68

2 mg (quant) was obtained as a colorless solid.

'Η—nuclear magnetic resonance spectrum (270MHz, CDC1 a) δ ppm: 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 (lH, m), 3.99 (lH, dd, J = ll.

2,5.4Hz), 4.11 (lH, dd, 11.2,4.1Hz), 4.33 (1H, m), 4.52 (1H, d, J = 5.4Hz), 5.91 (lH, d,

J = 8.9Hz).

Infrared absorption spectrum (KBr pellet, cm " ¹ ): 1787, 1741,1653,1533.

High resolution mass spectrum (FAB): m / z [+ H] ⁺ = 482.3481

_{_{Calculated: 482.3483 (C 27 H 48 0}} 6 N)

50-c) g¾ 2-i S)-{_2-s R) 1 "(S)-benzyloxyl

50-d) Acetic acid 3-cyclohexyl-2- (S)-{2- (R) -1-[(S) -hydroxy (hydroxycarbamoyl) methyl] decanoylamino} propyl ester

According to the method of Example 10-d), 2- (S) -1- {2- (R) -1-[(S) -benzyloxycarbamoyl (hydroxy)] acetic acid obtained in Example 50-c) was obtained. The same reaction was carried out using tyl [indecanoylamino] -13-cyclohexylpropyl ester (308 mg) as a starting material, to obtain 21.9 mg (85.2%) of the target compound as a white solid. However, in this case, purification was performed by thin-layer preparative chromatography (20 x 20 cm, 0.5 mm thick, 5 sheets, chromate form: methanol: developed with 40: 3, ethyl acetate: methanol = 10: 1). I went in.

Nuclear magnetic resonance spectrum (270MHz, CDaOD) δ ppm: 0.73-1.88 (29H, m), 0.88 (3H, t, J = 6.6Hz), 2.03 (3H, s), 2.59 (1H, m), 3.87 (1H , Dd, J = 10.1,6.9Hz), 4.00 (1H, d, J = 7.4Hz), 4.13 (lH, dd, J = ll.0,4.3Hz), 4.26 (lH, m).

'H—Infrared absorption spectrum (KBr pellet, cm " ¹ ): 3370,3294,3208,3099, 1747, 16 68,1643,1580.

High resolution mass spectrometer (FAB): m / z [+ H] ⁺ = 457.3246

_{_{Calculated: 457.3315 (C 2 4H 5 0}} 6 N 2)

Specific rotation: [a] n ^zs = -12 ° (C: 0.59, EtOH)

(Example 5 1)

NJ- [11- (S) -cycloxylmethyl-2-hydroxethyl] 1-2- (S), ^1- dihydroxy 3- (R) -nonylsuccinamide (Exemplary Compound No. 113)

According to the method of Example 11 1), 3-cyclohexyl acetate 2- (S)-{2- (R) -1-[(S) -hydroxy (hydroxycarbamoyl) methyl acetate obtained in Example 50-d) 86 mg (86%) of the target compound was obtained as a white solid by the same reaction treatment using decanoylamino} propyl ester (11 Omg) as a starting material. However, the purification at this time was performed by thin-layer preparative chromatography (20 x 2 i "

O cm, 0.5 mm thickness, 4 gel gel plates, developed with 7: 1 mouth-form: methanol, and eluted with ethyl acetate: methanol-10: 1).

¹ H - NMR spectrum _{(270MHz, CD 3 0D) δ} ppm: 0.72-1.90 (29H, m), 0.89 (3H, t, J = 6.6Hz), 2.59 (lH, m), 3.39-3.53 ( 2H, m), 4.01 (1H, m), 4.03 (1H, d, J = 6.7Hz) .Infrared absorption spectrum (KBr pellet, cm- ¹ ): 3412,3371, 3261,3112, 1672, 1606. High Resolution Mass Vector (FAB): m / z [+ H], 415.3173

_{_{Calculated: 415.3171 (C 22 H. 3 0sN}} 2)

Specific rotation: [a] D ²⁵ = -22. Γ (C: 1.03, Et0H)

(Example 52)

Acetic acid 2 — (S)-{2 — (R)-[(S)-hydroxy (hydroxycarbamoyl) methyl] decanoylamino »13-methylbutyl ester (Ex. Compound No. 112)

5 2-a) 2 — (R)-(2, 2 -dimethyl 5-oxo-1 [1, 3] — dioxolan 1 4 — (S) yl) pentadecanoic acid [1-1 (S)-( tert-Butyl dimethylsilanyloxymethyl) — 2-methylpropyl] amide

2- (R)-(2,2-dimethyl-5-oxo [1,3] -dioxolan-41- (S) yl) pentadecanoic acid (1.OO g) tetrahydrofuran (15 m 1) The solution contains 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (760 mg), 1-hydroxybenzotriazole (450 mg), N-methylmorpholine ( A solution of N, N'-dimethylformamide (15 ml) of 440 itl) and 11- (S)-(t-butyldimethylsilanyloxymethyl) -l-methylpropylamine (866 mg) in sequence In addition, the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction solution was poured into a 5% aqueous potassium hydrogen sulfate solution, and the organic layer extracted and extracted 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 purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 1.18 g (71.0%) of the desired compound as a white solid. At this time, the diastereomer of the target compound is also 3 2 4

{Νο

8 (lH, m), 4.05-4.19 (3H, m), 4.87 (2H, m), 5.17 (1H, d, J = 8.6 Hz), 5.96 (1H, d, 4 Hz), 7.38 (5H, m) , 9.33 (lH, s).

Infrared absorption spectrum (KBr pellet, cm- ¹ ): 3401, 3290, 3217, 1721, 1666, 1641, 1559.

High resolution mass spectrum (FAB): m / z [+ H] ⁺ = 493.3288

_{_{Calculated: 493.3266 (C 2 7H4 0 6}} N 2)

5 2-e) Acetic acid 2-(S)-1-(2-(R)-1-[(S)-hydroxy (hydroxycarbamoyl) methyl] decanoylamino}-3-methylbutyl ester

2k

According to the method of Example 10-d), 2- (S) -1- {2- (R) -1-[(S) -1-benzyloxycarbamoyl (hydroxy) acetate) obtained in Example 52-d) was obtained. The same reaction was carried out using, as a starting material, [methyl] decanoylamino} -3-methylbutyl ester (296 mg) 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.

'Η—Nuclear magnetic resonance spectrum (270MHz, CDsOD) δ ppm: 0.89 (3H, t, J = 6.6Hz), 0.95 (3H, d, J = 6.6Hz), 0.96 (3H, d, J = 6.6Hz) 1.17-1.69 (16H, m), 1.82 (lH, m), 2.02 (3H, s), 2.66 (1H, m), 3.87-4.03 (3H, m), 4.24 (1H, m).

Infrared absorption spectrum (KBr pellet, cm- ¹ ): 3384,3281,3217,3105,1747, 1669,1644,1561.

High resolution mass spectrum (FAB): m / z [M + H] = 403.2786

_{_{Calculated: 403.2840 (C 2 .H 39 0}} 6 N 2)

Specific rotation [a] D ^{2 S} = -8.8 ° (C: 1.07, EtOH)

(Example 53)

2-(S), N ¹ Dihydroxy N ⁴ -Γ 1-(S) -Hydroxymethyl-2-methylpropyl 1-3-(BJ-nonylsuccinamide (Exemplified Compound No. 11 1)

According to the method of Example 11 1), 2- (S)-{2- (R)-[(S) -hydroxy (hydroxycarbamoyl) methyl] pentacacetate obtained in Example 52-e) The same reaction was carried out using Nylamino} 13-methylbutyl ester (104 mg) 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 x 20 cm, Cloth form: methanol = 10: 1, developed 3 times, ethyl acetate: methanol = 5: 1) ) To purify the target compound.

'' Η- nuclear magnetic resonance spectrum (270MHz, CD ₃ OD) δ ppm: 0.83-0.98 (9H, m), 1.14-1.73 (16H, ra), 1.88 (lH, m), 2.66 (1H, in), 3.57 (2H, d, J = 5.4Hz), 3.70 (lH, m), 4.05 (lH, d, J = 6.2Hz).

Infrared absorption spectrum (KBr pellet, cm "): 3384, 3283, 3222, 3106, 1668, 1642, 1630, 1560.

High resolution mass spectrum (FAB) IN-Nalaq addition

m / z [M + Na] ⁺ = 383.2510

Calculated value: 383.2542 (CaHaeOs aNa)

Specific rotation [] _D ²⁵ = -19.5 ° (C: 1.02, EtOH)

(Example 54)

Acetic acid 2 — (S)-1-[2-(R) -hydroxycarbamoylmethyl-10-methyldidecanoylamino] 1,3-dimethylbutyl ester (Exemplary Compound No. 124)

54-a) 3 (R) 1-[1-(S)-hydroxymethyl-2, 2-dimethylbutyl rubamoyl〗 1-1-methyl dodecanoic acid t-butyl ester

According to the method of Example 5 2-a), 2- (R) -t-butoxycarbonylmethyl-1-10-methylpandecanoic acid (1.52 g) and (S) —t-one-isinol (

(68 O mg) as a starting material, and 1.76 g (88.0%) of the target compound was obtained as a colorless oily substance. However, at this time, silica gel column chromatography

The same reaction treatment was carried out using 1- (S) -acetoxymethyl-2,2-dimethylpropyl-l-bamoyl--11-methyldodecanoic acid t-butyl ester (1.93 g) as a starting material to obtain the target compound 1.7. 3 g (quant) were obtained as a colorless oil. However, at this time, the target compound was purified by silica gel chromatography (cloth form: methanol = 20: 1).

¹ H- nuclear magnetic resonance spectrum _{(270MHz, CDC1 3) δ ppm} : 0.86 (6H, d, J = 6.6Hz), 0.95 (9H, s), 1.07-1.77 (15H, m), 2.03 (3H, s ), 2.45-2.62 (2H, m), 2.78 (lH, m), 4.03-4.28 (3 H, m), 5.77 (lH, m).

Infrared absorption spectrum (liquid film, cm "): 3321, 1741, 1728, 1650, 1549.

High resolution mass spectrum (FAB): m / z [M + H] ⁺ = 400.3083

_{_{Calculated: 400.3034 (C Z 2 H4 2}} 0 5 N)

5 4-d) Acetic acid 2 — (S)-[2-(R) 1-(benzyloxycarbamoylmethyl) 1 10-Methyldecanoylamino]-3,3-dimethylbutylester

Example 5 3- (R) -1- [1- (S) -acetoxymethyl-2,2-dimethylbromopyruvamoyl] 1-11-methyldodecanoic acid (1.71 g) obtained in 4-c) Was dissolved in methylene chloride (25 ml), and under a nitrogen atmosphere, 11- (3-dimethylaminobutyral pill) -13-ethylcarbodiimide hydrochloride (972 mg), 1-hydroxybenzotriazole ( 572 mg) and N-methylmorpholine (560 jLt 1) were sequentially added, and the mixture was stirred at room temperature for 10 minutes. Then, 0-benzylhydroxyamine hydrochloride (809 mg) and N-methylmorpholine (5001) 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 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: 2) to obtain 1.81 g (84.7%) of the desired compound as a white solid.

'' H—nuclear magnetic resonance spectrum (270MHz, CDCla) 5 ppm: 0.86 (6H, d, J = 6.6Hz), 0.95 ( ^^) 1 (H) 1 1 ΪΛ (7 a l-ir ^ 1 τ ⁴ Ζ-(-^ ^ α ^--(S)-Τ] 1, Ν-^ η ^-Ν

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According to the method of Example 11 1), 2- (S) -acetic acid 2-[(R) -hydroxycarbamoylmethyl) -1-10-methyl-decanoylamino obtained in Example 54-e) The same reaction was carried out using 1,3-dimethylbutyl ester (670 mg) as a starting material to obtain 527 mg (87.5%) of the target compound as colorless crystals. However, at this time, the target compound was purified by recrystallization from methanol-ethyl acetate-hexane.

'' H--nuclear magnetic resonance spectrum (270MHz, CDaOD) δ ppm: 0.87 (6Η, d, J = 6.6Hz), 0.93 (9H, s), 1.07-1.69 | 15H, m), 2.20 (lH, dd, J = 14.4,6.8Hz), 2.35 (lH, dd, J = 14.4,7.7Hz), 2.76 (lH, m), 3.46 (lH, dd, J = 12.1,9.7Hz), 3.78 (2H, m).

Infrared absorption spectrum (KBr pellet, ^ " ¹ ): 3405, 3255, 3115, 1667, 1613, 1590. Elemental analysis (C ₂₀ HJ) + 1 / 8H ₂ 0:

Analytical value C; 64.13, H; 11.03, N; 7.51

Theory C; 64.09, H; 10.82, N; 7.47

Specific rotation [a]

(C: 0.980, eOH)

Melting point: 166.4-167.4 ° C

(Example 56)

Acetic acid 2- (S)-[2- (R)-(N-hydroxycarbamoylmethyl) ゥ decanoylamino] 13- (S) -methylpentyl ester (Exemplified Compound No. 96)

56-a) 3- (R)-[1- (S) -Hydroxymethyl-l2- (S) -Methylbutylcarbamoyl〗 dodecanoic acid t-butyl ester

2- (R) 1-t-butoxycarbonylmethylpandecanoic acid (773 mg) obtained in Example 8-a) was dissolved in dichloromethane (23. Oml) under a nitrogen atmosphere. Then, hydroxybenzotriazole (417 mg), N-methylmorpholine (340 μl), 1- (3-dimethylaminopropyl) -13-ethylcarbodiimid hydrochloride (593 mg) were sequentially added. Cool to 0, (S)-(+) Soleucinol (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 with a 5% aqueous solution of potassium hydrogen sulfate, water and a saturated saline solution 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 (hexane: ethyl acetate = 3: 1) to obtain 91 mg (90%) of the desired compound as a colorless oily substance.

¹ H- nuclear magnetic resonance spectrum _{(270MHz, CDC1 3) δ ppm} : 0.84-0.94 (9H, complex), 1. 15-1.37 (14H, complex), 1.43 (9H, s), 1.46-1.52 (2H, complex), 1.61-1.73 (3H, compl ex), 2.36 (ΙΗ, ιπ), 2.53-2.67 (2H, complex), 2.89 (1H, m), 3.61-3.88 (3H, complex), 6.02 (lH , d, J = 7.1Hz}.

Infrared absorption spectrum (Liquid film, cm- '): 3313, 2927, 1732, 1637.

High resolution mass spectrometer (FAB): m / z [+ H] ⁺ = 400.3426

Calculated value: 400.3427

5 6-b) 3-(R) 1-(S)-Acetoxymethyl-2-(S)-methylbutylcarbamoyl 1 dodecanoic acid t-butyl ester

3- (R)-[1- (S) -hydroxymethyl-2- (S) -methylbutylcarbamoyl] dodecanoic acid obtained in Example 56-a) according to the method of Example 10-b) The same reaction was carried out using t-butyl ester (907 mg) as a starting material to give the desired compound (925 mg, 92%) as a colorless oil.

¹ H- nuclear magnetic resonance spectrum _{(270MHz, CDC1 3) δ ppm} : 0.85-0.93 (9H, complex), 1. 12-1.37 (14H, complex), 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 (lH, m), 2.63 (1H, dd, J = 16.5, 9.4Hz), 4.02-4.21 (3H, compl ex), 5.85 (lH, 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 value: 442.3533 (C ₂₅ H ₄ e0sN) w

5 6-c) 3 — (R)-f 1-(S) —acetoxymethyl-1- 2 — (S) -methylbutylcarbamoyl] dodecanoic acid

According to the method of Example 8-d), 3- (R)-[1- (S) -acetoxymethyl-2- (S) -methylbutylcarbamoyl] dodecane obtained in Example 56-b) The same reaction was carried out using t-butyl acid ester (925 rng) as a starting material to obtain 722 mg (89%) of the target compound as a white solid.

'H—nuclear magnetic resonance spectrum (270MHz, CDCla) δ ppm: 0.84-0.93 (9Η, complex), 1.08-1.29 (15H, complex), 1.40-1.49 (2H, complex), 1.60-1.67 (2H, complex), 2.05 (3H, s), 2.44-2.56 (2H, complex), 2.78 (lH, dd, J = 17.8,9.5Hz), 4.06-4.20 (3H, complex), 5.92 (lH, d, J = 8.6Hz), 8.01 (lH, ra).

Infrared absorption spectrum (Br pellet, cm- ¹ ): 3290, 2924, 1745, 1701, 1644.

Mass spectrum (FAB): m / z [M + H] ⁺ = 385

Elemental analysis (as C ₂₁ H ₃₉ N0 ₅ '1 / 8H ₂₀ )

Calculated () C; 65.04, H; 10.19, N; 3.G1

Obtained value (%) C; 64.77, H; 10.24, N; 3.60

5 6-d) Acetic acid 2- (S)-[2- (R)-(N-hydroxycarbamoylmethyl) ndecanoylamino 13- (S) -Methylpentyl ester

According to the method of Example 8-e), 3- (R)-[111 (S) -acetoxymethyl-2- (S) -methylbutylcarbamoyl] dodecanoic acid obtained in Example 56-c) 434 mg (59%) of the target compound was obtained as white crystals by the same reaction treatment using (722 mg) as a starting material.

Melting point: 148-150. C

'.Eta. Nuclear magnetic resonance spectrum _{(270MHz, CD 3 0D) δ} ppm:. 0.89 (9H, complex), 1.11-1 45 (17H, complex), 1-53-1.60 (2H, complex), 2.02 (3H, s), 2.19 (lH, m), 2.32 (lH, m), 2 • 71 (1H, m), 3.97 (2H, d, J = 6.5Hz), 4.25 (lH, m), 4.58 (lH, m ), 8.01 (lH, m).

Infrared absorption spectrum (KBr pellet, cm " ¹ ): 3289, 2924, 1746, 1642.

Mass spectrum (FAB): m / z [M + H] ⁺ = 401 XI c

Elemental analysis (as C ₂₁ H _4n 0 ₅ N ₂ 'l / 10H ₂₀ )

Calculated value (%) C; 62.69, H; 10.06, N; 6.96

Found (%) C; 62.52, H; 10.29, N; 6.96

Specific rotation [] _D ^2S =-4.6 ° (C: 0.55, eOH)

(Example 5 7)

4-arsenide Dorokishi one ^{N 1 - [1 - (S} ) - human Dorokishimechiru one 2-(S) over main Chirubuchiru 1 one 2-(R) - Nonirusukushinami de (Compound No. 9 5)

According to the method of Example 9), 2- (S)-[2- (R)-(N-hydroxycarbamoylmethyl) pentadecylamino] acetic acid obtained in Example 56-d) The same reaction was carried out using 3- (S) -methylpentyl ester (239 mg) as a starting material to obtain 174 mg (81%) of the target compound as white crystals.

Melting point: 138-140 ° C

'H- NMR spectrum _{(270MHz, CD 3 0D) δ} ppm: 0.85-0.94 (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 = 14.4,6.8Hz), 2.33 (lH, dd, J = 14.4,7.7Hz), 2.70 (lH, m), 3.55-3.63 (2H, compl ex) , 3.73 (1H, m), 7.76 (1H, d, J = 8.6Hz).

Infrared absorption spectrum (KBr pellet, cm " ¹ ): 3280, 2925, 1643.

High resolution mass spectrum (FAB): m / z [M + H] ⁺ = 359.2898

_{_{Calculated: 359.2910 (C 19 H 33 0}} 4 N 2)

Specific rotation [a]

. (C: 0.76, MeOH)

(Example 58)

Acetic acid 2- (S) — [2- (R) — (N-Hydroxycarbamoylmethyl) ゥ decanoylamino] 13- (2-Chenyl) propyl ester (Exemplary Compound No. 100)

58-a) N-t-butoxycarbone 3- (2-Chenyl) -L-alanine You

3- (2-Chenyl) -l-alanine (502 mg) was dissolved in dioxane (7 ml) and water (3.5 ml) and cooled to 0 ° C. Next, di-t-butyl dicarbonate (0.7 ml) and a 1N aqueous solution of sodium hydroxide (3 ml) were sequentially added, and the mixture was stirred overnight while the temperature was raised to room temperature. The reaction solution was poured into a 5% aqueous hydrogen sulfate aqueous solution, extracted with ethyl acetate, and the organic layer was washed successively with water and saturated saline, and then dried over sodium sulfate. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 5: 1) to obtain 574 mg (72%) of the target compound as a white solid.

'.Eta. Nuclear magnetic resonance spectrum _{(270MHz, CD 3 0D) δ} ppm:. 1.42 (9Η, s), 3.22 (lH, m), 3 35 (lH, m), 4.27 (lH, m), 6.84- 6.93 (2H, complex), 7.18 (lH, m).

Infrared absorption spectrum (KBr pellet, cm- ¹ ): 3334,2978, 1713,1673.

58-b) N-t-butoxycarbone 3-(2-chenyl)-1-L-alanine methyl ester

Example 58—N-t-butoxycarbonyl-3- (2-cell) -l-alanine (574 mg) obtained in a) was converted to N, N-dimethylformamide (4.5 ml). Was dissolved. Then, hydrogen bicarbonate (382 mg) and methyl iodide (190 u1) were sequentially added, and the mixture was stirred at room temperature for 7.3 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was washed successively 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 the desired compound (514 mg, 94%) as a colorless oil.

'H- NMR spectrum _{(270MHz, CDC1 3) δ ppm} : 1.44 (9H, s), 3.35 (2H, d, J = 4 - 7Hz), 3.75 (3H, s), 4.58 (lH, m) , 5.12 (lH, d, J = 6.8Hz), 6.80 (1H, d, J = 3.3Hz), 6.93 (1H.dd, J = 5.3, 3.3Hz), 7.17 (lH, d, J = 5.3Hz) ).

Infrared absorption vector (Liquid film, cm "'): 3371,2978, 1747, 1717.

Mass tank (FAB): m / ziM + H) + = 286 1 ,. 丄

58-c) N-t-butoxycarbonyl 3-(2-cenyl)-L-alaninol

N-t-butoxycarbonyl 3- (2-cell) -1-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), and ethanol (8 ml) were sequentially added, and the mixture was 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 sequentially 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 (83%) of the desired compound as a white solid.

'H- NMR spectrum _{(270MHz, CDC1 3) δ ppm} :. 1.43 (9H, s), 2.73 (lH, m), 3 08 (2H, d, J = 6.6Hz), 3.62-3.66 (2H , complex), 3.85 (lH, m), 4.92 (lH, m), 6.86 (lH, d, J = 3.3 Hz), 6.94 (lH, dd, J = 5.2, 3.3 Hz), 7.16 (lH, d, J = 5.2Hz).

Infrared absorption spectrum (KBr pellet, cm " ¹ ): 3358,2982, 1686.

Mass spectrum (FAB): m / z [M + H] + = 258

Elemental analysis (as C ₁₂ H ₁₉ 0 ₃ NS)

Calculated (%) 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-Chenyl) -L-alaninol

Example 58—N-t-butoxycarbone 3- (2-cell) -1-L-araninol (331 mg) obtained in c) was dissolved in 4 N monohydroxane hydrochloride (6 ml). Then, the mixture was 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 [1-(S)-hydroxymethyl-2-(2-phenyl) ethyl carbamoyl dodecane drunk_ t-butyl ester OO "i S / df /; x Z6 £ SI / L6 O n

-M8 jp l Jedu

14 One

One

{HN Nu

, 7.20 (lH, d, J = 5.3 Hz), 8.21 (IH, d, J = 8.6 Hz).

Infrared absorption tank (KBr pellet, cm- ¹ ): 3281, 2923, 1738, 1645.

Mass spectrum (FAB): m / z [M + Hj + = 441

Elemental analysis (as _{_{_{_{C 22 H 36 N 2 0 5}}}} S-1 / 4H 2 0)

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 [a]

(C: 0.64, eOH)

(Example 59)

New ^lambda over arsenide Dorokishi N '-' 1 - (S) - human Dorokishimechiru one 2 - (2 - Choi sulfonyl) Echiru] - 2 - (R) over Bruno succinate cyanamide (Compound No. 9 9)

According to the method of Example 9, 2- (S)-[2- (R)-(N-hydroxycarbamoylmethyl) pentadecylylamino] acetic acid obtained in Example 58-h) —Chenyl) propyl ester (44 mg) was used as a starting material and subjected to the same reaction treatment to give the desired compound (40 mg).

Melting point: 154-155 ° C

'H - NMR spectrum _{(400MHz, CD 3 0D) δ} ppm: 0.89 (3H, t, J = 6.7Hz), 1.26- 1.32 (14H, complex), 1.36 (lH, m), 1.52 (lH, m ), 2.09 (IH, dd, J = 14.5, 7.9 Hz), 2.20 (IH, dd, J = 14.5, 6.7 Hz), 2.65 (lH, m), 2.97 (lH, dd, J = 14.8, 8.1 Hz) , 3.14 (IH, dd, J = 14.8, 8.1Hz), 3.51 (lH, dd, J = 11.0, 5.5Hz), 3.56 (lH, dd, J-ll.0,5.3Hz), 4.07 (lH, m ), 6.86 -6.92 (2H, complex), 7.18 (1H, d, J = 5.2Hz).

Infrared absorption spectrum (KBr pellet, cm " ¹ ): 3443,3291,2923,1642.

Mass spectrum (FAB): m / z [+ H] ⁺ = 399

Elemental analysis (C _2O H "N ₂ (as hS'l / 3H ₂ 0)

Calculated value (%) C; 59.37, H; 8.63, N; 6.92, S; 7.92

Found (%) C; 59.25, H; 8.72, N; 6.92, S; 7.76

Specific rotation [α] _D ²⁵ = -9.87 (C: 0.63, eOH) (Example 60)

Mono-succinic acid 2- (S) — [2- (R) — (N-hydroxycarbamoylmethyl) ndecanoylamino] 1,3,3-dimethylbutyl] ester (Ex. Compound No. 90)

60-a) N ⁴ -benzyloxy N '-[1-(S) -hydroxymethyl-2,2-dimethylpropyl] -2- (R) -nonylsuccinamide

3- (R)-[1- (S) -Hydroxymethyl—2,2-dimethylpropyl rubamoyl] Dodecanoic acid “t-Butyl ester (112 mg) in methylene chloride (4-Oml) solution Trifluoroacetic acid (2. Oml) was added, and the mixture was stirred at room temperature for 3 hours.Toluene (20 ml) was added to the reaction solution, and then volatiles were distilled off under reduced pressure. Dissolved in methylene (4. Oml), 1-hydroxybenzotriazole (61.4 mg), N-methylmorpholine (110 ul), and 1- (3-dimethylaminobutyric) — 3— Ethyl carposimid hydrochloride (89.3 mg) and 0-benzylhydroxylamine hydrochloride (80.2 mg) were sequentially added, and the mixture was stirred at room temperature for 10 minutes. The mixture was poured and extracted with ethyl acetate, and the organic layer was washed successively with saturated saline and then extracted with sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by preparative thin-layer chromatography (silica gel 0.5 mm thick, 20 cm x 20 cm, 5 sheets, dichloromethane: methanol = 15: 1), and the target compound was purified. 6 mg (67% in two steps) was obtained as a white solid.

'.Eta. Nuclear magnetic resonance spectrum _{(270MHz, CDC1 3) δ pm} : 0.87 (3H, t, J = 6.5Hz), 0.9 3 (9H, s), 1.10-1.52 (15H, complex), 1.62 (lH, m), 2.10-2.52 (2H, complex), 2.58-3.2 0 (2H, complex), 3.57 (lH, m), 3.69-3.89 (2H, complex), 4.85 (2H, s), 6.58 (1H, br) d, J = 8.5Hz), 7.20-7.50 (5H, complex), 9.68 (lH, s)

Infrared absorption spectrum (Kbr pellet, cnr ¹ )

3318, 3187, 1675, 1639, 1556, 1530

High Resolution Mass Vector (FAB)

m / z [M + H] ⁺ = 449.3375

/ y

1,3,3-Dimethylbutylester Mono-succinic acid 2- (S) obtained in Example 60-b) according to the method of Example 10-d) Starting from 2-(R) 1 (N-benzyloxycarbamoylmethyl) didecanoylamino] 1,3,3-dimethylbutyl] ester (574 mg), the same reaction treatment was carried out, and the desired product 31 Omg (65 %) Was obtained as a colorless oil.

'Η—Nuclear magnetic resonance spectrum (270MHz, CD ₃ OD) 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 (IH, dd, J = 14.4,7.6Hz), 2.44-2.63 (4H, complex),

2.79 (lH.m), 3.86-4.05 (2H, complex), 4.44 (1H, d, J = 8.2Hz), 7.92 (lH, 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 0 7)

(Example 6 1)

Koha ^ _ mono 2-(S) 1-[2-(R)-(N-hydroxycarbamoylmethyl) didecanoylamino]-3,3-dimethylbutyl ester sodium salt (Exemplified compound 3 1 2)

Mono-succinic acid 2- (S) obtained in Example 60-c) 2- (S)-[2- (R)-(N-hydroxycarbamoylmethyl) undecanoylamino] -3,3-dimethylbutyl 159 mg of the ester was treated with DIAI • N WK-20 and then freeze-dried to obtain 166 mg (100%) of the desired compound.

'Η-Nuclear magnetic resonance spectrum (270 MHz, CD3OD) 5 ppm:

0.89 (3H, t, J = 6.6Hz), 0.95 (9H, s), 1.10-1.70 (16H, complex),

2.19 (lH, dd, J = 14.5,6.8Hz), 2.35 (lH, dd, J = 14.5,7.6Hz), ?

2.35-2.62 (4H, complex), 2.78 (lH, m), 3.96 (2H, complex), 4.41 (lH, m)

Infrared absorption spectrum (Kbr pellet, cnT ')

3373, 3231, 1725, 1651, 1632, 1580

(Example 62)

Brobionic acid 2- (S)-[2- (R)-(N-hydroxycarbamoylmethyl-p-decanoylamino) -1,3,3-dimethylbutyl] ester (Ex. Compound No. 84)

62-a) Propionic acid 2- (S) — “2- (R)-(N-benzyloxycarbamoylmethyl) pentacanylamino] 1-3,3-dimethylbutyl] ester

Example 60—N ⁴ —benzyloxy N ^1- [1- (S) -hydroxymethyl-2,2-dimethylpropyl] —2- (R) —nonylsuccinamide (208 mg) obtained in a) was obtained under a nitrogen atmosphere. Dissolve in lower tetrahydrofuran (7. Oml), 0. Cooled to C. Then, pyridine (43 ul) and propionyl chloride (45 ul) were added, and 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 ethyl acetate was added for extraction. 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 preparative thin-layer chromatography (silica gel 0.5 mm thick, 20 cm x 20 cm, 6 sheets, dichloromethane: methanol = 20 _: 1) to obtain 21.6 mg of the desired compound ( 92%).

'Η—nuclear magnetic resonance spectrum (270MHz, CDC) 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 (lH, 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, cnT ¹ )

3319, 3196, 1735, 1676, 1648, 1561, 1531

High resolution mass spectrum (FAB)

m / z (M + Hl ⁺ = 505.3663

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(Example 63)

Acetic acid 2- (S) -2- (R) -1-[(S) acetoxy (hydroxycarbamoyl) methyl] —4-methylpentanoylamino] -1,3-dimethylbutyl ester (Exemplified Compound No. 313 )

63-a) 2- (S) -acetoxy 3- (R)-[11- (S) -acetoxydityl-2,2-dimethylbromovir-rubamoyl] -5-methylhexanoic acid

2- (R) — [2,2-dimethyl-5-oxo-1-one obtained in Example 25—a)

[1.3] -Dioxolan-1-41- (S) yl] -4-methylpentanoic acid [1- (S) -hydroxymethyl-2,2-dimethylpropyl] amide (2.10 g) (2 _: 1, 60 ml) and stirred at room temperature for 65 hours. Toluene (200 ml) was added to the reaction solution, and acetic acid and the solvent were distilled off under reduced pressure. The obtained foam was dried under reduced pressure for further 4 hours, and then 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 1 N aqueous solution of hydrochloric acid, and the solution was dissolved in methylene chloride. The organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, diisopropyl ether was added to the residue. The precipitate was collected by filtration, and dried under reduced pressure to obtain the desired compound (2.13 g, 89%).

'Η—nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ ) δ ppm:

0.90-1.00 (6H, m), 0.99 (9H, s), 1.26 (lH, m), 1.68 (2H, m), 2.04 (3H, s), 2.13 (3H, s), 2.86 (lH, ra) , 4.10 (2H, m), 4.24 (1H, ra), 5.14 (1H, d, J = 5.5HZ), 6.29 (1H, d, J = 9.3HZ), 8.71 (lH, br s)

Infrared absorption spectrum (Liquid film, cm- ')

3435, 2966, 1 740, 1 62 1

Mass spectrum (FAB> m / z [+ H] ⁺ = 374

63 -b) Acetic acid 2- (S)-{2- (R) -I-((S) -acetoxy (benziik ^ xycarbamoyl) -methyl-j-I-4-methylpentanoylamino-3_f 3— Dimethyl butyl ester

2- (S) -acetoxy 3- (R)-[1- (S) -acetoxymethyl-2,2-dimethylpropyl-caproluvamoyl] -1-5- (meth) obtained in Example 63-a) To a solution of ruhexanoic acid (2.13 g) in tetrahydrofuran-water (1: 1.100 ml) was added o-benzylhydroxylamine hydrochloride (1.64 g) and 1- (3-dimethylaminobutyryl) 1) -Ethylcarposimid hydrochloride (2.19 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, CDCl ₃ ) δ ppm:

0.85-0.96 (15H, m), 1.49-1.80 (3H, m), 2.02 (3Η, s), 2.05 (3Η, s), 2.91 (lH, m), 4.08-4.16 (2H, m), 4.26 ( lH, m), 4.85 (1H, d, J = 9.4HZ), 4.93 (2H, s), 6.29 (1H, d, J = 8.OHZ), 7.34-7.52 (5H, m), 9.78 (lH, br s)

Infrared absorption spectrum (KBr pellet, cm "')

3323, 32 1 2, 2958, 1 747, 1 649, 1 556

Mass spectrum (FAB) m / z [M + H] = 479

63-c) Acid 2- (S)-{2- (R)-[(S) -acetoxy (hydroxycarbamoyl) methyl] -14-methyl-pentanoylamino-3,3-dimethylbutyl ester

According to the method of Example 10-d), 2- (S) -acetic acid 2- (R)-[(S) -acetoxy (benzyloxycarbamoyl) obtained in Example 63-b) Methyl] 1-4-methylpentanoylamino} 1,3-dimethylbutyl ester (1.3

The same reaction was carried out using 7 g) as a starting material to obtain 884 mg (79%) of the target compound as a white solid.

'Eta - nuclear magnetic resonance spectrum _{(40 OMHz, CD 3 0D)} 0 ppm: 0.93 (6H, m), 0.99 (9H, s), 1.04 (lH, m), 1.55-1.65 (2H, m), 1.99 (3H, s), 2.00 (3H, s), 2.96 (lH, m) , 3.90 (lH, m), 4.02 (lH, m), 4.41 (lH, m), 4.76 (1H, d, J = 10.3Hz)

Infrared absorption spectrum (KBr pel let, cm- ')

2959, 1 75 1, 1 649, 1 537

Mass spectrum (FAB) m / z [+ H] ⁺ = 389

High resolution mass tank (FAB)

m / zlM + H] ⁺ = 389, 2308

_{Calculated: 389, 2288 (C 18 H} 33 N 2 0 7)

Specific rotation: [a] _D ²⁵ = +55. 38 ° (c: 0.80, MeOH)

(Example 64)

Acetic acid 2- (S)-[5- (4-chlorophenyl) -1-2- (R)-(N-hydroxycarbamoylmethyl) pentanoylamino] —3-cyclohexylpropyl ester (Exemplary Compound No. 308)

64— a) 3- (R)-[2-Acetoxy-1- (S) -cyclohexylmethylethylcarbamoyl] -1- (4-chlorophenyl) hexanoic acid

2- (R) -t-butoxycarbonylmethyl-5- (4-chlorophenyl) pentanoic acid (1.50 g) and N-methylmorpholine (0.6 1 ml) in tetrahydrofuran (3 Ond) To the mixture was added dropwise isobutyl chloroformate (0.71 ml) under ice cooling, and the mixture was stirred at 0 for 0.5 hour. Next, a solution of (S) -cyclohexylalaninol (722 mg) in N, N-dimethylformamide (30 ml) was added, and the mixture was stirred at 0 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 sequentially with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and saturated saline, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained residue was dissolved in methylene chloride (30 ml) and cooled to 0 ° C. Next, pyridine (0.74 ml), 4-dimethylaminopyridine (56 mg), and acetic anhydride (0.87 ml) were sequentially added to the solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water and extracted with methylene chloride. The organic layer is treated with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and saturated saline. After washing sequentially, the extract was 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, and the mixture was stirred at room temperature for 17 hours. After toluene was added to the reaction solution, volatiles were distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with methylene chloride: methanol: 49: 1) to give 1.431 g (69%) of the target compound as white crystals.

1 H- nuclear magnetic resonance spectra _{(40 OMHz, CD 3 0D)} δ ppm:

0.75-1.02 (2H, m), 1.09-1.75 (14H, m), 1.75-1.85 (lH, m), 1.86 (3H, s), 2.35 (lH, dd, J = 16.3, 5.1Hz), 2.52- 2.74 (3H, m), 2.70 (lH, m), 3.83 (lH, dd, J = 11.0,7.0Hz), 4.10 (IH.dd, J = ll.0,4.2Hz), 4.22 (lH, m) , 7.15 (2H, tn), 7.23 (2H, m)

Infrared absorption spectrum (KBr pellet, cm— '):

3307, 2924, 2854, 1 741, 1 643, 1 548, 1493, 1 232

Mass spectrum (FAB): m / z [M + H] ⁺ = 452

Melting point: 88-89

64-b) Acetic acid 2- (S)-[5- (4-chlorophenyl) -2- (R)-(N-hydroxycarbamoylmethyl) pentanoylamino] -3-cyclohexylpropyl Ester

3- (R) 1- [2-acetoxy 11- (S) -cyclohexylmethylethylcarbamoyl] 1-6- (4-cyclophenyl) hexene obtained in Example 64-a) To a solution of acetic acid (1.412 g) and N-methylmorpholine in tetrahydrofuran (30 ml) was added ice-cooled isobutyl chloroformate (0.49 ml), and the mixture was stirred for 30 minutes. (t-butyldimethylsilyl) hydroxylamine (92 mg) was added, and the mixture was stirred for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid, 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. Two

¹ H- nuclear magnetic resonance spectra _{(40 OMHz, CD 3 0D)} δ ppm:

0.78-1.01 (2H, m), 1.09-1.72 (14H, m), 1.75-1.83 (1H, πι), 1.86 (3H, s), 2.15 (lH, dd, J = 14.4,7.3Hz), 2.30 (1Η, dd, J = 14.4, 7.2Hz), 2.50-2.67 (2Η, m), 2.74 (1Η, in), 3.83 (lH, dd, J = ll.1,7.ΟΗζ), 4.12 (IH , dd, J = ll .1, 4.1Hz), 4.21 (lH, m), 7.15 (2H, m), 7.23 (2H, m)

Infrared absorption spectrum (KBr pellet, cm- ¹ ):

3279, 2925, 2853, 1 743, 1 643, 1 544 1 493, 1 234

Mass spectrum (FAB): m / z [M + H] ⁺ = 467

High resolution mass spectrum (FAB):

m / z [M + H] + = 467, 2295

Calculated value: 467, 23 1 3 (C ₂ H ₃₆ C1N ₂ 0 ₅ )

Elemental analysis (C ₂ , H ₃₅ C1N _Z 0 ₅ ):

Calculated value: C, 61.73; H, 7.56; N600; CI, 759 Measured value: C, 61.71; H, 7.53; N610; CI, 7 69 Melting point: 1 18-1 20 ° C

(Example 65)

2- (R) Single [3- (4 one black port phenyl) Purobiru) one ^{N 1 - [1 - (S} ) - Kishirumechiru cycloheptane 2-hydroxy E chill] one T - heat Dorokishisukushina Mi (Compound No. 307)

2- (S) -acetic acid 2- [5- (4-chlorophenyl) -2- (R)-(N-hydroxycarbamoylmethyl) pentanoylamino] acetic acid obtained in Example 64-b) The desired compound, 437 rag (97%), was obtained from xylpropyl ester (494 mg) in the same manner as in Example 9 (without recrystallization, but washing the obtained powder with ethyl acetate). As obtained.

'.Eta. Nuclear magnetic resonance spectrum _{(40 OMHz, CD 3 0D)} δ ppm:

0.77-1.02 (2H, m), 1.09-1.72 (14H, m), 1.78-1.87 (lH, ra), 2.16 (lH, dd, J = 14.3,7.3 Hz), 2.31 (lH, dd, J = 14.3,7.2Hz), 2.50-2.67 (2H, m), 2.72 (lH, m), 3.39-3.50 (2H, tn), 3.97 (lH, m), 7.15 (2H, m), 7.23 (2H, m)

Infrared absorption spectrum (KBr pellet, cm— '):

3373, 3254, 3 1 09, 2926, 2846, 1 662, 1 6 1 5, 1 493

Mass spectrum (FAB): m / z [M + H] ⁺ = 425

IM + Na] ⁺ = 447

High-resolution mass spectrum (FAB):

m / z [+ Na] ⁺ = 447, 2043

_{Calculated: 447, 2027 (C 22 H} 33 ClNaN 2 0 4)

Melting point: 1 97-1 99 ° C

(Example 66)

Acetic acid 3-acetoxy 2-— “5- (4-chlorophenyl) — 2- (R) — (N-hydroxycarbamoylmethyl) pentanoylamino] propyl ester (Exemplary Compound No. 306)

66-a) 3-(R)-(2-acetoxy 1-acetooxymethylethylcarbamoyl) 1-6-(4-phenyl) hexanoic acid

2- (R) -t-butoxycarbonylmethyl-5- (4-chlorophenyl) pentanoic acid (1.50 g) and serinol (627 mg) as starting materials In the same manner as in Example 64-a) 1.161 g (59%) of the target compound was obtained as white crystals.

'H- NMR spectrum _{(40 OMHz, CD 3 0D)} δ ppm:

1.42-1.67 (4H, m), 1.90 (3H, s), 2.03 (3H, s), 2.37 (lH'dd, J = 16.3, 5.1Hz), 2.52-2.67 (3H, m), 2.72 ( lH, m), 4.02-4.21 (4H, m), 4.36 (lH, m), 7.16 (2H, m), 7.24 (2H, m) Infrared absorption spectrum (KBr pellet, cm- ¹ ):

3305, 292 1, 1 740, 1 70 1, 1659, 1 652, 1 545, 1 24 1 -D. |-..-j (-T Otsu _α α One Factory-ΓΗ-ζ

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3-Acetoxyacetic acid 2- [5- (4-chlorophenyl) -12- (R) -1- (N-hydroxycarbamoylmethyl) pentanoylamino] propyl ester obtained in Example 66-b) To a solution of (224 mg) in methanol (15 ml) was added sodium methoxide (about 28.0% methanol solution, 0.5 ml), and the mixture was stirred at room temperature for 1 hour. After the reaction solution was neutralized by adding Amberlite CG-5 OTypel, the resin was separated using celite. Further, the filtrate obtained by washing with methanol was concentrated under reduced pressure. The obtained residue was purified by washing with ether to give 118 mg (65%) of the desired compound as a powder.

'H- nuclear magnetic resonance spectrum _{(40 OMHz, CD 3 0D)} δ ρπι:

1.38-1.68 (4Η, πι), 2.16 (1Η, dd, J = 14.5, 6.5Hz), 2.35 (1Η, dd, J = 14.5, 8.1Hz), 2.52 -2.67 (2H, m), 2.72 (lH, m), 3.55-3.66 (4H, m), 3.92 (lH, m), 7.16 (2H, m), 7.23 (2H, m) Infrared absorption spectrum (KBr pellet, cm— ¹ ):

35 1 0, 3298, 3 1 99, 3095, 2935, 1 660, 1 652, 1 55 1, 1 492

Mass spectrum (FAB): m / z [+ H] ⁺ = 359

High resolution Mass Vector (FAB):

m / z [M + H] ⁺ = 359, 1 38 1

_{Calculated: 359, 1 374 (C 16} H 24 C1N 2 0 5)

Melting point: 132-134. C

(Reference example 1)

Acetic acid 2- (S) -1- [5- (4-chlorophenyl) 1-2- (R)-(N-hydroxycarbamoylmethyl) pentanoylamino] -1- (R) -methylcarbamoylmethyl-3- Phenyl propyl ester

1 a) 3— (R) 1 2— (R) Acetoxy 1 1 1 1 (S) 1 benzyl 1 3 1-Methylcarbamoylpropyl-l-bamoyl]-6- (4-chlorophenyl) hexanoic acid t-butyl ester

2- (R) -t-butoxycarbonylmethyl-5- (4-chlorophenyl) pentanoic acid (500mg) in methylene chloride (15ml) solution is 1- (3-dimethylaminobutyl) -3 —Ethyl carbodiimide hydrochloride (352 mg), 1-hydrid xybenzotriazole (248 mg), and N-methylmorpholine (0.45 ml) were added in that order, and the mixture was cooled to 0. Then, add this solution to the solution.

A solution of (R) -hydroxy-5-phenylpentanoic acid methylamide hydrochloride (594 mg) in N, N-dimethylformamide (4 ml) was added, followed by stirring at room temperature for 23 hours. The reaction solution was poured into 1N hydrochloric acid and extracted with methylene chloride-tetrahydrofuran. The organic layer was washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate 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). Next, pyridine (0.62 ml), 4-dimethylaminoviridine (19 mg), and acetic anhydride (0.72 ml) were sequentially added to this solution, and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with 1 N 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 residue was purified by silica gel gel chromatography (eluted with hexane: ethyl acetate = 2: 3–ethyl acetate only) to obtain 587 mg (67%) of the desired compound as a foam-like substance. I got it.

— Nuclear magnetic resonance spectrum (400MHz, CDaOD) δ ppm: 1.28-1.58 (4H, m), 1.36 (9H, s), 1.95 (3H, s), 2.02-2.15 (2H, m), 2.44 (1H, m) dd, J = 14.5, 9.3Hz), 2.48-2.62 (4H, m), 2.68 (lH, m), 2.69 (3H, s), 2.93 (lH, dd, J = 14.2,4.6Hz), 4.43 (lH, m), 5.28 (lH, m), 7.10 -7.28 (9H, m).

Infrared absorption spectrum (KBr pellet, cm "'): 3303, 1735, 1645, 1542, 1237, 1159. Mass spectrum (FAB): m / z [M + H] ⁺ = 573

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In a conventional manner, 100 mg of the compound of Example 1, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98 mg Produced using 8 mg lactose.

(Test Example 1) Inhibitory activity on gelatinase B

The sex of the gelatin was measured according to the method of Tanzawa et al. (J. Antibiotics, Vo1.45 1733-1737).

That is, gelatinase B was prepared from a serum-free culture of TFα of human fibrosarcoma cells, and as a substrate, type I collagen prepared from rat tail was labeled with a radioisotope and then heat denatured. It was measured by measuring the cleavage of gelatin using a gelatinized product.

The compound Α is N ² — (4-hydroxyamino-2- (R) -isobutyl—3- (S) —hydroxysuccinyl) -L-t-one-isocyanate-N ¹ -methylamide, and W094- 02447.

(Results) Gelatinase B inhibitory activity (IC ₅₀ (nM)) 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, a test compound (SomgZkgZSm1PEG400: DMA9: 1) was orally administered to male mice (20 g) (3 mice per group), and at 15, 30, and 60 minutes after administration. Blood was collected from the heart.

The collected blood is centrifuged (ll OOO rpm, 5 minutes), 501 of the plasma is deproteinized with 1501 of acetonitrile, and the plasma concentration of the test compound is measured using LCZMS. did.

(Results) Maximum blood concentration (Cmax (ng / ml)) Compound of Example 11 Compound 950 Compound A 165

(Test Example 3) Inhibitory activity on collagenase-3

The activity of collagenase 13 was measured by a modification of the method of Knight et al. (FEBS Lett, vol. 296, No. 3, 263-266, (1992)). That is, mRNA was isolated according to the conventional method of Human condrosarcoma HCS-2 / 8, and cDNA of collagenase-3 was obtained by RT-PCR. This cDNA was incorporated into an expression vector, and the gene was introduced into C0S-1 cells to express collagenase-3, and the serum-free culture was used as an enzyme solution. Further, using OCAc-Pro-Leu-Gly- Leu-Dpa-Ala-Arg-NH 2 as substrate.

The enzyme solution and substrate, 0.15 NaCl, 10 mM CaC, 0.05¾ Brij 35, was added to 50 mM Tris-HCl buffer containing 0.02¾ N aN _3, 1 hour at 37 ° C for a final volume as 0.1 ml reaction I let it. The reaction was stopped by adding 0.1 ml of 3% acetic acid, and a fluorometer (Labsys Fluorescence of free MOCAc-Pro-Leu-Gly was measured with excitation light 330 πηκ emission light 390 nm using terns Fluoroskanll).

(Results: Lagenase-3 inhibitory activity (IC _S0 (nM)) Compound of Example 37 0.69 Compound A 2.1

INDUSTRIAL APPLICABILITY The hydroxamic acid derivative of the present invention has an excellent matrix meta-oral proteinase inhibitory activity, and has good oral absorbability, so that metastasis, invasion and proliferation of various cancer cells can be achieved. It is useful as an inhibitor or a therapeutic or prophylactic agent for osteoarthritis and rheumatoid arthritis.

Claims

2?>-Scope of request. General formula (1

In the above equation (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 which may have a substituent

Aryloxy group having 6 to 10 carbon atoms which may have a substituent

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) ,

C3-C8 cycloalkyl group

Or

An alkoxyalkoxy group having 2 to 8 carbon atoms which may have a substituent (the substituent is a halogeno group) Is)

Indicates that

R ² represents a hydrogen atom, a hydroxy group or an aliphatic alkoxy group having 1 to 4 carbon atoms,

R ³ is 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,

Aryl group having 6 to 10 carbon atoms which may have a substituent

(The substituent is

A monocyclic or condensed heterocyclyl group having 5 to 15 atoms (hetero atoms contained in the ring are nitrogen, oxygen or sulfur atoms)

Or

C3-C8 cycloalkyl group

Is)

Indicates that

R ⁴ is a hydrogen atom,

C2-C5 alkoxycarbonyl group

Or

An alkyl group having 1 to 4 carbon atoms which may have a substituent (the substituent is a hydroxy group, an alkoxy group having 1 to 4 carbon atoms, C1 to C6 aliphatic acyloxy group, C2 to C5 alkoxycarbonyl group, C2 to C5 alkylcarbamoyl group, C3 to C9 dialkyl carbamoyl group Or a dialkylamino group having 2 to 8 carbon atoms

Is)

Indicates that

R ⁵ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms,

R ⁶ is a hydrogen atom,

Or

An optionally substituted carbamoyl group

(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.)

And a pharmacologically acceptable salt thereof. S

2.R 'force Unsubstituted alkyl group having 4 to 10 carbon atoms, alkyl group having 1 to 6 carbon atoms substituted by alkoxy group having 2 to 6 carbon atoms, methyl, methoxy or An alkyl group having 1 to 6 carbon atoms, which is substituted by a phenyl group which may be substituted by a cyclo group, an alkyl group having 1 to 6 carbon atoms, which is substituted by a cycloalkyl group having 4 to 6 carbon atoms, or The compound according to claim 1, which is an alkyl group having 1 to 6 carbon atoms substituted with an alkoxyalkoxy group having 4 to 6 carbon atoms.

3. R ¹ is octyl, 7-methyloctyl, nonyl, 8-methylnoel, phenylpropyl, 4-methylphenyl, 4-methoxyphenylpropyl, 4-methylphenylpropyl, cyclohexylmethyl, cyclo 2. The compound according to claim 1, which is a hexyl propyl, 6-ethoxy hexyl, 6-isopropoxy hexyl or 4-butoxy butyl group.

4. The compound according to claim 1, wherein R ¹ is nonyl, 7-methyloctyl or 3- (4-cyclophenyl) propyl.

5. The compound according to claim 1, wherein R ¹ is a nonyl or a 3- (4-chlorophenyl) propyl group.

6. R ² forces a hydrogen atom, hydroxy or a compound of claim 1 which is Asetokishi group.

7. A compound according to claim 1 which is R ² forces a hydrogen atom or a hydroxy group.

8. 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 cycloalkyl group having 4 to 6 carbon atoms. A substituted methyl or ethyl group, an unsubstituted phenyl group-substituted alkyl group having 1 to 4 carbon atoms, a hydroxy group substituted with 1 to 4 carbon atoms ?

2. The compound according to claim 1, wherein the compound is an alkyl group having 1 to 4 carbon atoms or an alkyl group having 1 to 4 carbon atoms substituted with an acetyl group.

9. R ³ force Claim 1 which is an isopropyl, tert-butyl, 1-methylpropyl, 2-methylpropyl, 1-methylthio-11-methylethyl, cyclohexylmethyl, benzyl, hydroxymethyl or acetomethyl group. The compound described.

1 0. R ³ force tert- butyl, 1 Mechiruchio one 1- Mechiruechiru A compound according to claim 1 is a cyclohexylmethyl or base Njiru group to consequent opening.

1 1. A compound according to claim 1 which is R ³ force tert- butyl or base Njiru group.

1 2.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 atom substituted with an ethoxycarbonyl group 1 to 4 alkyl groups, 1 to 4 carbon atoms substituted with an acetyl group, 1 to 4 carbon atoms substituted with a methylcarbamoyl group, and carbon substituted with a dimethylcarbamoyl group An alkyl group having 1 to 4 alkyl groups, an alkyl group having 1 to 4 carbon atoms substituted with a dimethylamino group, an alkyl group having 1 to 4 carbon atoms or a dimethylamino group substituted with a dimethylamino group or a hydroxy group The compound according to claim 1, which is an alkyl group having 1 to 4 carbon atoms and substituted with a ethoxy group.

1 3. A compound according to claim 1 R is ⁴ forces hydrogen atom or a hydroxy group or Asetokishi substituted having 1 to 4 alkyl group having a carbon in the group.

14. R ⁴ is a C 1 -C 4 carbon atom substituted with a hydrogen atom or a hydroxy group 2. The compound according to claim 1, which is a alkyl group.

1 5 · R ⁴ forces a hydrogen atom, arsenic Dorokishimechiru compound of claim 1 which is 2-arsenide Dorokishechiru or 3 hydroxycarboxylic propyl.

1 6. A compound according to claim 1 which is R ⁴ force ^ hydrogen atom.

1 7. A compound according to claim 1 which is R ⁵ forces a hydrogen atom.

1 8.R ⁶ force Hydrogen atom or unsubstituted aliphatic 2 to 3 carbon atoms, aliphatic 2 to 3 carbon atoms dialkylamino group or 2 to 3 carbon atoms substituted by carboxy group 2. The compound according to claim 1, which is a acyl group.

1 9. R ⁶ forces a hydrogen atom A compound according to claim 1 which is Asechiru or propionyl group.

20. A compound according to claim 1 which is R ⁶ forces a hydrogen atom or a Asechiru group.

2 1. Compounds shown below:

2— [3 -— (4-chlorophenyl) propyl] —N ⁴ —hydroxy-N ′-[1-hydroxymethyl-2,2-dimethylpropyl] succinamide,

Acetic acid 2- [5- (4-chlorophenyl) -1-2- (N-hydroxycarbamoylmethyl) pentanoylamino] -1,3-dimethylbutyl ester

N ⁴ — 3-dihydroxy N ′ — [1-hydroxymethyl-1,2,2-dimethylpropyl] -12-nonylsuccinamide,

Acetic acid 2- {2- [hydroxy (hydroxycarbamoyl) methyl] indole force aminoamino-3,3-dimethylbutyl ester

Diacid 2- [5- (4-chlorophenyl) -1-2- (N-hydroxycarbamoy) Methyl) pentanoylamino] — 3-phenylpropyl ester or

1 one [1- benzyl-2-arsenide Dorokishechiru] one 2- [3- (4-chlorophyll Eniru) propyl] one New ⁴ - arsenide de roxithromycin comb cyanamide.

22. A cancer metastasis, invasion or proliferation comprising an effective amount of a compound selected from the compounds described in claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or excipient. Pharmaceutical compositions for inhibition.

23. An osteoarthritis or rheumatic disease comprising an effective amount of a compound selected from the compounds described in claim 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or excipient. A pharmaceutical composition for treating or preventing rheumatoid arthritis.

24. Use of a compound according to claim 1 for the manufacture of a pharmaceutical composition according to claims 22 to 23.