JPH0881443A - Extracellular matrix metal protease inhibitor - Google Patents

Abstract

PURPOSE: To obtain a compound useful for treating rheumatoid arthritis disease, having high inhibitory activity against extracellular matrix metal protease, low toxicity, excellent oral absorbability, long duration time, high stability and stability of medicine, shown by a specific formula. CONSTITUTION: This compound of formula I [R<1> is H or AR<1a> (A is a lower alkylene; R<1a> is H, amino, phthalimide, etc.); R<2> is H or a lower alkyl; R<3> is H, OH, a lower alkoxy (lower alkoxy), etc.; R<4> is H, a halogen, OH, a lower alkoxy, etc.; R<5> is H, benzoyl, etc.; R<6> is a 1-12C alkyl, a lower alkoxy lower alkyl, etc.; (n) is 1 or 2], preferably 3S-[4-(N-hydroxyamino)-2R- isobutylsuccinyl]amino-1-methyl-6,7-methylenedioxy-3,4-dihydroxycarbos tyril, etc. For example, preferably a carboxylic acid of formula II is reacted with an alkylhalocarboxylic acid to give a mixed acid anhydride, which is reacted with an amine of formula III.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION This invention relates to extracellular matrix metalloprotease inhibitors.

[0002]

BACKGROUND OF THE INVENTION Extracellular matrix metalloproteases are secreted by mammalian cells and the like and produce extracellular matrix (collagen, type IV collagen, laminin, proteoglycan, fibronectin, elastin, gelatin, etc.). Disassemble. When extracellular matrix metalloproteinase secretion and activity are abnormally increased, metastatic invasion and proliferation of cancer cells, rheumatoid joint disease, periodontal disease, corneal ulcer, bone resorption disease such as osteoporosis, and diseases such as multiple sclerosis It is thought to cause.
Natural products such as TIMP-1, TIMP-2, and α ₂ -macroglobulin are known as substances exhibiting an inhibitory effect on extracellular matrix metalloproteases. Further, JP-A-62-230757, WO-905716 and WO-9217460 also describe compounds having the above-mentioned inhibitory action. That is, JP-A-6
No. 2-230757 discloses a general formula

[0003]

Embedded image

[In the formula, A represents a group HN (OH) -CO- or HCO-NOH-. R ^A represents an alkyl group of C ₂ -C _5. R ^B may be protected at any functional group present, may be acylated at any amino group present, and may also be amidated at any carboxyl group present. The characteristic groups of α-amino acids are shown (excluding hydrogen atom or methyl group). R
^C is a hydrogen atom, amino, hydroxy, mercapto, C ₁
To C ₆ alkyl, C _{1 to} C ₆ alkoxy, C _{1 to} C ₆ alkylamino, C _{1 to} C ₆ alkylthio or aryl-
(C ₁ -C ₆ alkyl) group or amino, hydroxy,
Amino- (C ₁ -C ₁ -mercapto or carboxyl group may be protected, amino group may be acylated or carboxyl group may be amidated
₆ alkyl), hydroxy- (C ₁ -C ₆ alkyl),
A mercapto- (C ₁ -C ₆ alkyl) or carboxyl- (C ₁ -C ₆ alkyl) group is shown. R ^D represents a hydrogen atom or a methyl group. R ^E hydrogen atom or C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, di (C ₁ -C ₆ alkoxy) -methylene, carboxyl,
(C ₁ -C ₆ alkyl) -carbonyl, (C ₁ -C ₆ alkoxy) carbonyl, arylmethoxycarbonyl,
A (C ₁ -C ₆ alkyl) aminocarbonyl or arylaminocarbonyl group is shown. R ^F represents a hydrogen atom or a methyl group. R ^B and R ^D may together represent a-(CH ₂ ) m- group in which p represents a number from 4 to 11. See also R ^D
And R ^F may together represent a trimethylene group. ] The compound represented by these is disclosed.

WO-905716 describes the general formula

[0006]

[Chemical 3]

[Wherein R ^G is a hydrogen atom, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, phenyl, phenyl (C
₁ -C ₆₎ alkyl, C ₁ -C ₆ alkylthiomethyl,
It represents a phenylthiomethyl, substituted phenylthiomethyl, phenyl (C ₁ -C ₆ ) alkylthiomethyl or heterocyclylthiomethyl group. Alternatively, R ^G represents -SR ^X , and R ^X is the following group.

[0008]

[Chemical 4]

Is shown. R ^H is a hydrogen atom, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkenyl, phenyl (C ₁ -C ₆ ).
Alkyl, a cycloalkyl (C ₁ ~C ₆₎ alkyl or cycloalkenyl (C ₁ ~C ₆₎ alkyl group. R
^I is an amino acid side chain, C ₁ -C ₆ alkyl, benzyl,
(C ₁ -C ₆ ) alkoxybenzyl, benzyloxy (C ₁ -C ₆ ) alkyl or benzyloxybenzyl group is shown. R ^J represents a hydrogen atom or a methyl group. q is 1
6 is an integer. B represents a —NH ₂ group, a substituted acyclic amine or a heterocyclic base. ] The compound represented by these is disclosed.

Further, in the specification of WO-9217460,
General formula

[0011]

[Chemical 5]

[In the formula, R ^K represents a hydrogen atom, C ₁ -C ₆ alkyl or-(CH ₂ ) r-D-R ^N group. Here, r is 0 or an integer of 1 to 6, D is a single bond or an oxygen or sulfur atom, and R ^N is an optionally substituted aryl or an optionally substituted heteroaryl group. ^RL
Represents a C ₃ -C ₆ alkyl group. The R ^M - (CH ₂₎ s
-E- shows the (CH ₂₎ t-group. Where s is an integer from 1 to 9, t is 2 to 10 integer, E is -NR ^O - group (R ^O is a hydrogen atom, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkanoyl, C ₁ -C ₆ alkoxycarbonyl, aryl, aralkyl or aralkyloxycarbonyl, each aryl group may have a substituent).
- (CH ₂₎ s- shall bound to carbon atoms of the * in the general formula represented by the chemical formula 5. ] The compound represented by these is disclosed.

However, at present, a compound having low toxicity and a strong inhibitory action has not been found yet.

[0014]

DISCLOSURE OF THE INVENTION It is an object of the present invention to provide a novel compound having excellent extracellular matrix metalloprotease inhibitory activity and low toxicity. The inventors of the present invention have conducted extensive studies to achieve the above object, and as a result, the following general formula (1), which is unpredictable from the above literature, is obtained.

[0015]

[Chemical 6]

[Wherein R ¹ is a hydrogen atom or a group -A-R ^1a
(A represents a lower alkylene group, R ^1a represents a hydrogen atom, an amino group, a phthalimido group, a thienylthio group, a lower alkanoylthio group, a mercapto group, a halogen atom as a substituent, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a carboxy group. , A phenyl group which may have 1 to 3 groups selected from the group consisting of a lower alkoxycarbonyl group and a lower alkylenedioxy group, a carboxy group, a lower alkoxycarbonyl group, a phenylthio group or a lower alkylthio group) . R ² represents a hydrogen atom or a lower alkyl group. R ³ is a hydrogen atom, a hydroxyl group, a lower alkoxy group,
Lower alkoxy lower alkoxy group, lower alkoxy lower alkoxy lower alkoxy group, lower alkoxy lower alkoxy lower alkoxy lower alkoxy group or group -BR
^3a (B represents a lower alkylene group, a lower alkenylene group or a lower alkynylene group, R ^3a represents a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a halogen atom as a substituent, a cyano group, a hydroxyl group, a lower alkyl group. , A phenyl group which may have 1 to 3 groups selected from a lower alkoxy group, a carboxy group and a lower alkoxycarbonyl group, a thienyl group which may have a halogen atom as a substituent, a phthalimido group, a carboxy group, a lower alkoxycarbonyl group. Group or group -CO-N (R
^3b) shows a -R ^3c. Here, R ^3b represents a hydrogen atom or a lower alkyl group, and R ^3c represents a hydrogen atom, a lower alkyl group or a lower alkoxy group. The group -N (R ^3b) -R ^3c is formed a nitrogen atom, an oxygen atom and a saturated 5- or 6-membered heterocycle with further having one more heteroatom selected the group consisting of sulfur atoms Good. ). R ⁴ represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group or a lower alkylenedioxy group. R ⁵
Represents a hydrogen atom, a benzoyl group, a lower alkanoyl group or a phenyl lower alkyl group. R ⁶ represents an alkyl group having 1 to 12 carbon atoms, a lower alkoxy lower alkyl group or a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring. n represents 1 or 2. ] The carbostyril derivative represented by the following formula and its salt have an excellent inhibitory effect on extracellular matrix metalloproteases, especially an inhibitory effect on stromelysin purified from the culture supernatant of mouse colon cancer cells (Colon 26 cells), human fibroblasts (Detroit551 cell)
It has an inhibitory effect on interstitial collagenase purified from culture supernatant, an inhibitory effect on Type IV collagenase purified from human lung fibrosarcoma cell (HT-1080 cells) culture supernatant, and has low toxicity and excellent oral absorption. The present invention has been completed by obtaining new knowledge that it exists.

The carbostyril derivative represented by the above general formula (1) and salts thereof according to the present invention are used in diseases and cases in which extracellular matrix metalloproteases (interstitial collagenase, type IV collagenase, stromelysin, etc.) are involved,
For example, metastatic invasion or proliferation of various cancer cells, rheumatoid joint disease, periodontal disease, corneal ulcer, bone resorption disease such as osteoporosis, multiple sclerosis, treatment of myelin degeneration, diseases associated with angiogenesis, skin and Gastrointestinal ulceration and wound healing, post-operative symptoms such as colonic anastomosis with elevated collagenase levels, increased collagen destruction associated with diabetes,
It is useful in various clinical fields as a prophylactic and therapeutic agent for atherosclerosis, thickening at the time of blood vessel suture, nephritis and the like.

The carbostyril derivatives represented by the above general formula (1) and salts thereof exhibit high inhibitory activity, low toxicity, excellent oral absorption, long duration, high safety and stable drug stability. It has features such as good performance.

Each group shown in the present specification, whether it is independently present or in another group, is more specifically as follows.

Examples of the lower alkylene group include methylene, methylmethylene, ethylene, dimethylmethylene, trimethylene, 1-methyltrimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, tetramethylene, pentamethylene and hexamethylene. Number of carbon atoms such as 1
Examples of the straight chain or branched chain alkylene group of 6

Examples of the thienylthio group include thienylthio groups such as 2-thienylthio and 3-thienylthio groups.

Examples of the lower alkanoylthio group include formylthio, acetylthio, propanoylthio, butanoylthio, isobutanoylthio, pentanoylthio,
Alkanoyl moiety such as hexanoylthio group has 1 to 1 carbon atoms
The alkanoylthio group, which is a linear or branched alkanoyl group of 6, can be exemplified.

As the lower alkyl group, for example, methyl,
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl and hexyl groups.

Examples of the lower alkoxy group include straight-chain or branched-chain alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, pentyloxy, hexyloxy groups. It can be illustrated.

As the lower alkoxycarbonyl group, for example, an alkoxy moiety such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl group has 1 to 10 carbon atoms. Examples thereof include an alkoxycarbonyl group of 6 which is a linear or branched alkoxy group.

Examples of the lower alkylenedioxy group include alkylenedioxy groups having 1 to 3 carbon atoms such as methylenedioxy, ethylenedioxy and trimethylenedioxy groups.

Examples of the lower alkylthio group include linear or branched alkylthio groups having 1 to 6 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, tertiary butylthio, pentylthio and hexylthio groups. .

Examples of lower alkoxy lower alkoxy groups include methoxymethoxy, ethoxymethoxy, propoxymethoxy, hexyloxymethoxy, methoxyethoxy, ethoxyethoxy, propoxyethoxy, isopropoxymethoxy, butoxymethoxy, tertiary butoxymethoxy, pentyloxymethoxy. And a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms, such as a hexyloxymethoxy group, having a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms.

Examples of lower alkoxy lower alkoxy lower alkoxy groups include methoxymethoxymethoxy, ethoxymethoxymethoxy, propoxymethoxymethoxy, hexyloxymethoxymethoxy, methoxymethoxyethoxy, ethoxymethoxyethoxy, propoxymethoxyethoxy, hexyloxymethoxyethoxy, methoxyethoxy. Ethoxy, ethoxy ethoxy ethoxy,
Propoxyethoxyethoxy, isopropoxymethoxyethoxy, butoxymethoxyethoxy, methoxyethoxymethoxy, ethoxyethoxymethoxy, propoxyethoxymethoxy, isopropoxymethoxymethoxy, butoxymethoxymethoxy, tertiary butoxymethoxymethoxy, pentyloxymethoxymethoxy, hexyloxymethoxymethoxy C1-C6 straight or branched chain having a C1-C6 straight-chain or branched-chain alkoxy group substituted with a C1-C6 straight-chain or branched-chain alkoxy group An example is a linear alkoxy group.

Examples of the lower alkoxy lower alkoxy lower alkoxy lower alkoxy group include methoxymethoxymethoxymethoxy, ethoxymethoxymethoxymethoxy, propoxymethoxymethoxymethoxy, hexyloxymethoxymethoxymethoxy, methoxymethoxymethoxyethoxy, ethoxymethoxymethoxyethoxy and propoxymethoxymethoxy. Ethoxy, hexyloxymethoxymethoxyethoxy, methoxyethoxyethoxyethoxy, ethoxyethoxyethoxyethoxy, propoxyethoxyethoxymethoxy, isopropoxyethoxymethoxyethoxy, butoxymethoxyethoxymethoxy, methoxyethoxyethoxymethoxy, ethoxyethoxyethoxymethoxy, propoxymethoxyethoxymethoxy, isopropoxy Number of carbon atoms substituted with a straight or branched chain alkoxy group having 1 to 6 carbon atoms such as simethoxymethoxyethoxy, butoxyethoxymethoxymethoxy, tertiary butoxymethoxyethoxymethoxy, pentyloxymethoxyethoxymethoxy, and hexyloxymethoxyethoxymethoxy group Examples of the straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms having a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms substituted with the straight-chain or branched-chain alkoxy group having 1 to 6 are exemplified. it can.

Examples of the lower alkenylene group include vinylene, arylene, isopropenylene, 2-butenylene,
3-pentenylene, 4-hexenylene, 2-methyl-2
Examples thereof include linear or branched alkenylene groups having 2 to 6 carbon atoms such as butenylene group.

Examples of the lower alkynylene group include ethynylene, 1-propynylene, 2-propynylene, 2-butynylene, 3-pentynylene, 4-hexynylene and 2-.
Examples thereof include linear or branched alkynylene groups having 2 to 6 carbon atoms such as methyl-2-butynylene group.

As the halogen atom, for example, a fluorine atom,
Examples thereof include bromine atom, chlorine atom and iodine atom.

As the thienyl group which may have a halogen atom as a substituent, for example, 5-fluoro-2-thienyl, 5-bromo-2-thienyl, 3-bromo-2-
Thienyl, 5-chloro-2-thienyl, 5-chloro-3
-Thienyl, 4-chloro-2-thienyl, 4-chloro-
Examples thereof include a thienyl group which may have a halogen atom as a substituent such as a 3-thienyl or 5-iodo-2-thienyl group.

Examples of the 5- or 6-membered saturated heterocyclic group which may further have one hetero atom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom include 1-pyrrolidinyl, 1-piperidinyl, Examples thereof include 1-imidazolidinyl, 1-piperazinyl, morpholino and thiomorpholino groups.

The lower alkanoyl group includes, for example, formyl, acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl and hexanoyl groups having 1 to 1 carbon atoms.
The linear or branched alkanoyl group of 6 can be illustrated.

Examples of the phenyl lower alkyl group include benzyl, 2-phenylethyl, 1-phenylethyl,
3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 2-methyl-3
Examples thereof include a phenyl lower alkyl group in which an alkyl moiety such as -phenylpropyl and 2-phenylpropyl group is a linear or branched alkyl group having 1 to 6 carbon atoms.

Examples of the alkyl group having 1 to 12 carbon atoms include linear groups such as methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl groups. Alternatively, a branched chain alkyl group can be exemplified.

As the lower alkoxy lower alkyl group,
For example, methoxymethyl, ethoxymethyl, propoxymethyl, hexyloxymethyl, methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxymethyl,
Directly having 1 to 6 carbon atoms, such as butoxymethyl, tertiary butoxymethyl, pentyloxyethyl, hexyloxyethyl, propoxypropyl, hexyloxyhexyl groups, etc., having a linear or branched alkoxy group having 1 to 6 carbon atoms. A chain or branched alkyl group can be exemplified.

As the phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, for example, in addition to the phenyl lower alkyl group exemplified above, 2,3-methylenedioxybenzyl, 3 ，
4-methylenedioxybenzyl, 3,4-ethylenedioxybenzyl, 3,4-trimethylenedioxybenzyl, 2- (3,4-methylenedioxyphenyl) ethyl, 3- (3,4-methylenedioxy Alkyl moiety such as phenyl) propyl, 4- (3,4-methylenedioxyphenyl) butyl, 5- (3,4-methylenedioxyphenyl) pentyl, 6- (3,4-methylenedioxyphenyl) hexyl group Is a linear or branched alkyl group having 1 to 6 carbon atoms, and may be a phenylalkyl group which may have an alkylenedioxy group having 1 to 3 carbon atoms as a substituent on the phenyl ring.

When n is 2, R ⁴ represents the same group or different groups.

The compounds represented by the general formula (1) of the present invention include the following compounds.

Compounds of the general formula (1) in which R ² and R ⁵ are both hydrogen atoms Compounds of the general formula (1) in which R ⁵ is a benzoyl group, a lower alkanoyl group or a phenyl lower alkyl group R ² and R ⁵ are both hydrogen atoms, R ⁴ is a hydrogen atom,
A halogen atom, a lower alkoxy group or a lower alkylenedioxy group, R ⁶ is an alkyl group having 1 to 12 carbon atoms, R ² and R ⁵ are both hydrogen atoms, and R ⁶ Is a lower alkoxy lower alkyl group or a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring, and the compounds R ² and R ⁵ of the above general formula (1) are both hydrogen atoms, R ⁴ is a hydrogen atom,
A halogen atom, a lower alkoxy group or a lower alkylenedioxy group, R ⁶ is an alkyl group having 1 to 12 carbon atoms, R ¹ is a hydrogen atom or a group —A—R ^1a group, R ^1a
Is selected from the group consisting of a hydrogen atom, a phthalimido group, a thienylthio group, a lower alkanoylthio group or a halogen atom as a substituent, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group. The compound of the general formula (1) R ² and R ^5, which is a phenyl group which may have 1 to 3 groups, are both hydrogen atoms, R ⁴ is a hydrogen atom,
A halogen atom, a lower alkoxy group or a lower alkylenedioxy group, R ⁶ is an alkyl group having 1 to 12 carbon atoms, R ¹ is a group —A—R ^1a group, R ^1a is an amino group,
The compounds R ² and R ⁵ of the above general formula (1) which are mercapto group, carboxy group, lower alkoxycarbonyl group, phenylthio group or lower alkylthio group are both hydrogen atoms, R ⁴ is hydrogen atom,
A halogen atom, a lower alkoxy group or a lower alkylenedioxy group, R ⁶ is an alkyl group having 1 to 12 carbon atoms, R ³ is a hydrogen atom or a group —B—R ^3a , R ^3a is a hydrogen atom, Lower alkoxy group, lower alkoxy lower alkoxy group, carboxy group or group -CO-N ( ^R3b ) ^R3c
R ^3b is a hydrogen atom or a lower alkyl group, and R ^3b
3c is a hydrogen atom, a lower alkyl group or a lower alkoxy group, the compounds R ² and R ^{5 of the} general formula (1) are both hydrogen atoms, R ⁴ is a hydrogen atom,
A halogen atom, a lower alkoxy group or a lower alkylenedioxy group, R ⁶ is an alkyl group having 1 to 12 carbon atoms, R ³ is a hydrogen atom or a group —B—R ^3a , R ^3a is a hydrogen atom, Lower alkoxy group, lower alkoxy lower alkoxy group, carboxy group or group -CO-N ( ^R3b ) ^R3c
R ^3b is a hydrogen atom or a lower alkyl group, and R ^3b
3c is a hydrogen atom, a lower alkyl group or a lower alkoxy group, R ¹ is a hydrogen atom or a group —A—R ^1a group, R ^1a
Is selected from the group consisting of a hydrogen atom, a phthalimido group, a thienylthio group, a lower alkanoylthio group or a halogen atom as a substituent, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group. The compound of the general formula (1) R ² and R ^5, which is a phenyl group which may have 1 to 3 groups, are both hydrogen atoms, R ⁴ is a hydrogen atom,
A halogen atom, a lower alkoxy group or a lower alkylenedioxy group, R ⁶ is an alkyl group having 1 to 12 carbon atoms, R ³ is a hydrogen atom or a group —B—R ^3a , and R ^3a is a lower alkoxy group. Or a lower alkoxy lower alkoxy group, R ¹ is a hydrogen atom or a group —A—R ^1a group, and R ^1
1a is selected from the group consisting of a hydrogen atom, a phthalimido group, a thienylthio group, a lower alkanoylthio group or a halogen atom as a substituent, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group. A compound of the above-mentioned general formula (1) in which B is a lower alkylene group, which is a phenyl group which may have 1 to 3 groups, and R ² and R ⁵ of the above-mentioned general formula (1) are both hydrogen atoms. And R ⁴ is a hydrogen atom,
A halogen atom, a lower alkoxy group or a lower alkylenedioxy group, R ⁶ is an alkyl group having 1 to 12 carbon atoms, R ³ is a hydrogen atom or a group —B—R ^3a , and R ^3a is a lower alkoxy group. Or a lower alkoxy lower alkoxy group, B is a lower alkylene group, R ¹ is a hydrogen atom or a group —A—R ^1a group, and R ^1a is a hydrogen atom, R ² of the above formula (1) And R ⁵ are both hydrogen atoms, R ⁴ is a hydrogen atom,
A halogen atom, a lower alkoxy group or a lower alkylenedioxy group, R ⁶ is an alkyl group having 1 to 12 carbon atoms, R ³ is a hydrogen atom or a group —B—R ^3a , R ^3a is a hydrogen atom, Carboxy group or group -CO-N ( ^R3b ) ^R3c
R ^3b is a hydrogen atom or a lower alkyl group, and R ^3b
3c is a hydrogen atom, a lower alkyl group or a lower alkoxy group, B is a lower alkylene group, R ¹ is a hydrogen atom or a group —A—R ^1a group, R ^1a is a hydrogen atom, a phthalimido group or a thienylthio group. , A lower alkanoylthio group or having 1 to 3 groups selected from the group consisting of a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group as a substituent. A compound of the above general formula (1) R ² and R ^5, which is a phenyl group, is a hydrogen atom, R ⁴ is a hydrogen atom,
A halogen atom, a lower alkoxy group or a lower alkylenedioxy group, R ⁶ is an alkyl group having 1 to 12 carbon atoms, R ³ is a hydrogen atom or a group —B—R ^3a , R ^3a is a hydrogen atom, Carboxy group or group -CO-N ( ^R3b ) ^R3c
R ^3b is a hydrogen atom or a lower alkyl group, and R ^3b
3c is a hydrogen atom, a lower alkyl group or a lower alkoxy group, B is a lower alkylene group, R ¹ is a hydrogen atom or a group —A—R ^1a group, and R ^1a is a hydrogen atom. 1) the compounds R ² and R ⁵ are both hydrogen atoms, R ⁴ is a hydrogen atom,
A halogen atom, a lower alkoxy group or a lower alkylenedioxy group, R ⁶ is an alkyl group having 1 to 12 carbon atoms, R ³ is a hydrogen atom or a group —B—R ^3a , R ^3a is a hydrogen atom, Lower alkoxy group, lower alkoxy lower alkoxy group, carboxy group or group -CO-N ( ^R3b ) ^R3c
R ^3b is a hydrogen atom or a lower alkyl group, and R ^3b
3c is a hydrogen atom, a lower alkyl group or a lower alkoxy group, B is a lower alkenylene group or a lower alkynylene group, R ¹ is a hydrogen atom or a group —A—R ^1a group, and R is
^1a is selected from the group consisting of a hydrogen atom, a phthalimido group, a thienylthio group, a lower alkanoylthio group or a halogen atom as a substituent, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group. The compound of the general formula (1) R ² and R ^5, which is a phenyl group which may have 1 to 3 groups, are both hydrogen atoms, R ⁴ is a hydrogen atom,
A halogen atom, a lower alkoxy group or a lower alkylenedioxy group, R ⁶ is an alkyl group having 1 to 12 carbon atoms, R ³ is a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a lower alkoxy lower alkoxy lower alkoxy A group or a lower alkoxy lower alkoxy lower alkoxy lower alkoxy group represented by the above general formula (1), R ² and R ⁵ are both hydrogen atoms, R ⁴ is a hydrogen atom,
A halogen atom, a lower alkoxy group or a lower alkylenedioxy group, R ⁶ is an alkyl group having 1 to 12 carbon atoms, R ³ is a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a lower alkoxy lower alkoxy lower alkoxy Or a lower alkoxy lower alkoxy lower alkoxy lower alkoxy group, R ¹ is a hydrogen atom or a group -A-R ^1a , and R ^1a is a hydrogen atom, a phthalimido group, a thienylthio group, a lower alkanoylthio group or a halogen atom as a substituent. An atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, and a phenyl group which may have 1 to 3 groups selected from the group consisting of a lower alkylenedioxy group; 1) The compounds R ² and R ⁵ are both hydrogen atoms, and R ⁴ is a hydrogen atom. ,
A halogen atom, a lower alkoxy group or a lower alkylenedioxy group, R ⁶ is an alkyl group having 1 to 12 carbon atoms, R ³ is a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a lower alkoxy lower alkoxy lower alkoxy A group or a lower alkoxy lower alkoxy lower alkoxy lower alkoxy group, R ¹ is a hydrogen atom or a group —A—R ^1a , and R ^1a is a hydrogen atom, the compounds R ² and R ⁵ of the above general formula (1) are Both are hydrogen atoms, R ⁴ is a hydrogen atom,
A halogen atom, a lower alkoxy group or a lower alkylenedioxy group, R ⁶ is an alkyl group having 1 to 12 carbon atoms, R ³ is a lower alkoxy group, R ¹ is a hydrogen atom or a group -A-R ^1a Wherein R ^1a is a hydrogen atom, the compounds R ² and R ^{5 of the} general formula (1) are both hydrogen atoms, R ⁴ is a hydrogen atom,
A halogen atom, a lower alkoxy group or a lower alkylenedioxy group, R ⁶ is an alkyl group having 1 to 12 carbon atoms, R ³ is a group —B—R ^3a , R ^3a is a hydroxyl group, and halogen is a substituent. Atom, cyano group, hydroxyl group, lower alkyl group, lower alkoxy group, phenyl group which may have 1 to 3 groups selected from carboxy group and lower alkoxycarbonyl group, thienyl group which may have halogen atom as a substituent , phthalimide group, lower alkoxycarbonyl group or a group ^{-CO-N (R 3b) -R} 3c, group -N (R ^3b) -R ^3c is selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom 5-membered or compounds R ⁴ is a lower alkylenedioxy group der of the general formula 6-membered and forms a saturated heterocyclic ring (1) which may have further one heteroatom , N is a compound wherein R ⁴ is a lower alkylenedioxy group in the general formula (1) is 1, n is 1, the general formula R ^1, R ² and R ⁵ are all hydrogen atoms (1 Compound R ⁴ is a lower alkylenedioxy group, n is 1, R ¹ , R ² and R ⁵ are all hydrogen atoms, R ³ is a lower alkyl group, and R ⁶ is a lower alkyl group. Wherein the compound R ⁴ of the above general formula (1) is a lower alkylenedioxy group, n is 1, R ¹ , R ² and R ⁵ are all hydrogen atoms, and R ³ is a methyl group or an ethyl group. And the compound represented by the general formula (1) in which R ⁶ is a lower alkyl group includes all stereoisomers, optical isomers, geometric isomers, and the like.

The compound of the present invention and the starting material compound can be produced by various methods. For example, the compound of the present invention can be produced by the method shown in the following reaction process formula-1 or reaction process formula-2. .

Reaction process formula-1

[0046]

[Chemical 7]

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ and n are the same as above. The method shown in the above reaction process formula-1 is a method of reacting the amine compound of the general formula (3) and the carboxylic acid of the general formula (2) in a usual amide bond forming reaction.

Known amide bond formation reaction conditions can be easily applied to the amide bond formation reaction. For example, (a) a mixed acid anhydride method, that is, a method of reacting a carboxylic acid (2) with an alkylhalocarboxylic acid to form a mixed acid anhydride, and reacting this with an amine (3), (b) an active ester method, that is, Carboxylic acid (2) was added to p-nitrophenyl ester, N-
A method of reacting an amine (3) with an active ester such as hydroxysuccinimide ester or 1-hydroxybenzotriazole ester, (c) carbodiimide method, that is, carboxylic acid (2) with amine (3) dicyclohexylcarbodiimide, Condensation reaction in the presence of an activator such as carbonyldiimidazole, (d) Other methods, for example, carboxylic acid (2) is converted to a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and then amine (3) A method of reacting an amine (3) with an ester of a carboxylic acid (2) and a lower alcohol, and a method of reacting an acid halide of a carboxylic acid (2), that is, a carboxylic acid halide with an amine (3). Can be mentioned.
Among these, the active ester method or the mixed acid anhydride method is preferable.

The mixed acid anhydride used in the above mixed acid anhydride method (a) is obtained by a usual Schotten-Baumann reaction, and this is usually reacted with an amine (3) without isolation to give a general formula. The compound of (1) is produced. The Schotten-Baumann reaction is carried out in the presence of a basic compound. Examples of the basic compound used include compounds commonly used in Schotten-Baumann reaction such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4,3,0] nonene-5 (DBN), 1,
8-diazabicyclo [5,4,0] undecene-7 (D
BU), 1,4-diazabicyclo [2,2,2] octane (DABCO), and other organic bases; potassium carbonate, sodium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, and other inorganic bases. The reaction is usually -20 to 10
The reaction is carried out at about 0 ° C, preferably about 0 to 50 ° C, and the reaction time is about 5 minutes to 10 hours, preferably 5 minutes to
It takes about 2 hours. The reaction between the obtained mixed acid anhydride and the amine (3) is usually carried out at about -20 to 150 ° C, preferably about 10 to 50 ° C, and the reaction time is about 5 minutes to 10 hours, preferably 5 minutes to. It takes about 5 hours.
The mixed acid anhydride method is generally performed in a solvent. As the solvent to be used, any solvent commonly used for mixed acid anhydrides can be used, and specifically, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene. Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dimethoxyethane, methyl acetate,
Examples thereof include esters such as ethyl acetate, aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, acetonitrile and hexamethylphosphoric triamide, and mixed solvents thereof. Examples of the alkylhalocarboxylic acid used in the mixed acid anhydride method include methyl chloroformate, methyl bromoformate, ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate and the like. In the method, the carboxylic acid (2) and the alkylhalocarboxylic acid (3) are usually used in equimolar proportions, but the alkylhalocarboxylic acid and the carboxylic acid (2) are used in relation to the amine (3). Each can be used within a range of about 0.5 to 1 times the molar amount.

When the method of reacting the carboxylic acid halide with the amine (3) is adopted among the other methods (d), the reaction is carried out in the presence of a basic compound in an appropriate solvent. As the basic compound used, known compounds can be widely used. For example, in addition to the basic compound used in the Schotten-Baumann reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, etc. It can be illustrated. Examples of the solvent used include, in addition to the solvent used in the mixed acid anhydride method, alcohols such as methanol, ethanol, propanol, butanol, 3-methoxo-1-butanol, ethyl cellosolve, and methyl cellosolve, pyridine, Acetone, water, etc. can be illustrated. The use ratio of the amine (3) and the carboxylic acid halide is not particularly limited and can be appropriately selected within a wide range. Usually, the latter is at least about equimolar amount, preferably about 0.5 to equimolar amount with respect to the former. Good to use. The reaction is usually carried out at about -20 to 180 ° C, preferably about 0 to 150 ° C, and generally 5 minutes to 3 ° C.
The reaction is completed in about 0 hours.

When the method of reacting an amine (3) with an ester of a carboxylic acid (2) and a lower alcohol is adopted, the reaction is carried out in the presence of a basic compound in a suitable solvent. Examples of the basic compound include sodium hydroxide, potassium hydroxide, sodium alcoholate, potassium alcoholate and the like. As the solvent,
Examples thereof include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, and polar solvents such as dimethylformamide. The use ratio of the amine (3) and the carboxylic acid ester is not particularly limited and can be appropriately selected from a wide range, but usually the former is at least about equimolar to the latter, preferably 2
It is preferable to use about 5 times the molar amount. The amount of the basic compound used is preferably about 1 to 3 times the molar amount of the carboxylic acid ester. The reaction is usually performed at about -20 to 180 ° C, preferably about 0 to 40 ° C, and generally the reaction is completed in about 5 minutes to 30 hours.

Further, in the amide bond forming reaction represented by the above reaction process formula-1, carboxylic acid (2) and amine (3) are treated with triphenylphosphine, diphenylphosphinyl chloride and phenyl-N-phenylphosphoramide chloride. , Diethylchlorophosphenate, diethyl cyanophosphate, diphenylphosphoric acid azide, bis (2-oxo-3
It can also be carried out by a method of reacting in the presence of a condensing agent for a phosphorus compound such as -oxazolidinyl) phosphinic chloride.

The reaction is carried out in the presence of a solvent and a basic compound used in the method of reacting the carboxylic acid halide with the amine (3), usually at about -20 to 150 ° C, preferably at about 0 to 100 ° C. Generally 5 minutes ~
The reaction is completed in about 30 hours. The condensing agent and the carboxylic acid (2) are used in an amount of at least about equimolar amounts, preferably about equimolar to about 2 times the molar amount of the amine (3).

Reaction formula-2

[0055]

Embedded image

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n are the same as defined above. R ^{5 ′} represents a benzoyl group, a lower alkanoyl group or a phenyl lower alkyl group. X represents a halogen atom. The reaction for converting the compound of general formula (1-A) into the compound of general formula (1-B) is carried out by subjecting the compound of general formula (1-A) to an ordinary reduction reaction or saponification reaction. Be done.

Known reduction conditions can be easily applied to the above reduction reaction. For example, in the case of (a) catalytic reduction,
It can be carried out in the presence of a catalyst in a suitable solvent. Usual solvents can be widely used, for example, alcohols such as methanol, ethanol and isopropanol, hydrocarbons such as hexane and cyclohexane, ethers such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran and diethyl ether, methyl acetate and ethyl acetate. And the like, polar solvents such as N, N-dimethylformamide, water, acetic acid, and mixed solvents thereof. Palladium as the reduction catalyst,
Palladium-black, palladium-carbon, platinum, platinum oxide,
Examples include copper chromite and Raney nickel. The amount of such a catalyst used is preferably about 0.001 to 2 times the weight of the compound of the general formula (1-A). The reaction may be carried out under pressure, but when it is carried out under normal pressure, the reaction temperature is preferably about 10 to 60 ° C, preferably about 20 to 40 ° C, and the reaction is generally carried out for about 1 hour to 5 days. Complete. When (b) cyclohexene, cyclohexadiene, formic acid, ammonium formate, isopropyl alcohol or the like is used as a hydrogen source, it can be carried out in a suitable solvent in the presence of a catalyst. As the solvent, the same solvent as the above (a) can be used. Examples of the catalyst include palladium, palladium-black, palladium-carbon and the like. The amount of the catalyst used is represented by the general formula (1
The amount of the compound (A) is about 0.01 to 2 times, the reaction temperature is about 10 to 100 ° C., and the reaction time is generally 1
The reaction is completed in about 3 to 3 days.

For the saponification reaction, general conditions for saponification can be widely applied. For example, it can be carried out using a usual basic compound. Examples of the basic compound include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. The amount of such basic compound used is preferably about 1 to 6 mol per 1 mol of the compound of the general formula (1-A). This reaction is usually -1
It is carried out at about 0 to 50 ° C., and the reaction is generally for 30 minutes to 2
It will be finished in about 4 hours.

The compound of the general formula (1-B) is replaced by the compound of the general formula (1-
The conversion reaction to the compound of A) is carried out in the presence of a basic compound in a suitable solvent in the general formula R ^{5 ′} —X or (R ^{5 ′} ) ₂
It is carried out by reacting a compound represented by O [R ^{5 ′} and X are the same as defined above] with a compound represented by the general formula (1-B). Examples of the solvent include polar solvents such as N, N-dimethylformamide and halogenated hydrocarbons such as dichloromethane. Examples of the basic compound include organic bases such as pyridine, triethylamine and N-methylmorpholine. The amount of such a basic compound to be used is preferably about 1 to 3 moles per 1 mole of the compound of the general formula (1-B). The reaction temperature is preferably about -10 to 50 ° C, and generally the reaction is completed in about 10 minutes to 24 hours.

The compound of the general formula (2), which is the starting material in the above reaction process formula-1, can be produced by various methods. For example, the following reaction process formulas -4, -6,
It can be manufactured by the methods shown in -7, -8 and -9.

Reaction formula-3

[0062]

[Chemical 9]

[In the formula, R ² , R ³ , R ⁴ , R ⁶ and n are the same as defined above. R ⁹ and R ¹⁰ each represent a selectively removable ester group such as a phenyl lower alkoxycarbonyl group and a lower alkoxycarbonyl group. The compound of general formula (5) is produced by removing the protective group of the carboxyl group of the compound of general formula (4).
A general method for removing a protective group for a carboxyl group can be widely applied to the removal of the protective group, and examples thereof include (a) a treatment with an acid, (b) a method using catalytic reduction, and (c) a ken. And the like.

When the method of treating with an acid is adopted, the compound of the general formula (5) is treated by treating the compound of the general formula (4) in the presence of an acid in a suitable solvent or without solvent. Manufactured. Examples of the acid include organic acids such as trifluoroacetic acid and inorganic acids such as hydrogen fluoride and hydrogen chloride. The acid is preferably used in a large excess amount with respect to 1 mol of the compound of the general formula (4). Usual solvents can be widely used, and examples thereof include halogenated hydrocarbons such as dichloromethane, ethers such as dioxane, esters such as ethyl acetate, acetic acid and the like. The above reaction is usually -40 to 6
The reaction proceeds at 0 ° C, preferably about -20 to 40 ° C, and the reaction is generally completed in about 1 minute to 5 hours.

When the method using catalytic reduction is adopted, known conditions for reduction reaction can be widely applied. For example, it can be carried out under the same reaction conditions as the reduction reaction shown in the above reaction scheme-2.

When the method by saponification is adopted, ordinary saponification conditions can be widely applied. For example, it can be carried out using a usual basic compound. Examples of the basic compound include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. The amount of such basic compound used is preferably about 1 to 3 mol per 1 mol of the compound of the general formula (4).
This reaction is usually performed at about -10 to 50 ° C, and generally the reaction is completed in about 30 minutes to 24 hours.

The compound of the general formula (7) is produced by reacting the compound of the general formula (5) with the compound of the general formula (6) in a usual amide bond forming reaction. The amide bond formation reaction can be carried out in the same manner as in the method described in the above Reaction scheme-1.

Reaction process formula-4

[0069]

[Chemical 10]

[In the formula, R ² , R ³ , R ⁴ , R ⁶ , R ⁹ and n are the same as defined above. The compound of the general formula (2-A) is obtained by subjecting the compound of the general formula (7) to elimination reaction of a carboxy-protecting group in a suitable solvent, and then reacting the reaction product after the elimination reaction in a suitable solvent. It is manufactured by heating.

For the elimination reaction of the carboxy-protecting group, known conditions for the elimination reaction of the carboxy-protecting group can be widely applied. For example, the elimination reaction of the carboxy-protecting group can be carried out in the same manner as the elimination reaction of the carboxy-protecting group represented by the reaction formula-3.

Examples of the solvent for heating the reaction product after the elimination reaction of the carboxy protecting group include aromatic hydrocarbons such as toluene and benzene. The reaction temperature is 50
It is preferably carried out under reflux at about 120 ° C.
Generally, the reaction is completed in about 1 minute to 3 days.

Reaction process formula-5

[0074]

[Chemical 11]

[In the formula, R ² , R ³ , R ⁴ , R ⁶ , R ⁹ and n are the same as defined above. The compound of the general formula (9) can be prepared by reacting the compound of the general formula (7) in a suitable solvent.
And then subjecting the reaction product after the elimination reaction to the elimination reaction of the carboxy protecting group, the Mannich reaction with the aliphatic secondary amine in the presence of formaldehyde in a suitable solvent,
It is produced by heating the reaction product after the Mannich reaction.

For the elimination reaction of the above-mentioned carboxy protecting group, known conditions for the elimination reaction of a carboxy protecting group can be widely applied. For example, the elimination reaction is performed in the same manner as the elimination reaction of the carboxy protecting group represented by the reaction formula-3. When the reaction product after the elimination reaction of the carboxy protecting group is subjected to the Mannich reaction, for example, water, methanol, ethanol, alcohols such as isopropanol, etc. can be used,
As the aliphatic secondary amine, for example, dimethylamine, diethylamine, piperidine, etc. can be used. The amount of the aliphatic secondary amine used is preferably about 1 to 2 times the molar amount of the compound of the general formula (7). The amount of formaldehyde used is 1-2 with respect to the compound of the general formula (7).
About twice the mole is good. The reaction temperature is 10 to 60 ° C, preferably about 20 to 40 ° C. Generally, the above reaction is 1
It will be completed in about 3 days.

When the reaction product after the Mannich reaction is heated, the reaction liquid after completion of the Mannich reaction is heated at a reaction temperature of 50 to 50 ° C.
It is preferable to heat or reflux at about 120 ° C. Generally, the reaction is completed in about 1 minute to 1 day.

Reaction process formula-6

[0079]

[Chemical 12]

[Wherein, R ² , R ³ , R ⁴ , R ⁶ and n are the same as defined above. R ¹¹ is a thienyl group, a lower alkanoyl group,
A phenyl group or a lower alkyl group is shown. The compound of general formula (2-B) is produced by reacting the compound of general formula (9) with the compound of general formula (10) in a suitable solvent or without solvent. Examples of the solvent include alcohols such as methanol and ethanol.
The amount of the compound of the general formula (10) used is preferably a large excess amount or a solvent amount with respect to 1 mol of the compound of the general formula (9). The above reaction is usually 10 to 120 ° C., preferably 20 to
It is carried out at about 100 ° C., and the reaction is generally completed in about 1 hour to 10 days in the dark.

The compound of the general formula (2) in which R ¹ represents a lower alkyl group can be produced by subjecting the compound of the general formula (9) to an ordinary reduction reaction. A wide range of reaction conditions for ordinary reduction reaction can be applied to this reduction reaction, and for example, it can be carried out in the same manner as the reduction reaction shown in the above reaction process formula-2.

Reaction process formula-7

[0083]

[Chemical 13]

[In the formula, R ² , R ³ , R ⁴ , R ⁶ , X and n are the same as defined above. R ¹² represents a lower alkanoyl group or a lower alkyl group. The reaction for obtaining the compound of general formula (2-D) from the compound of general formula (2-C) is carried out in the presence of an amine in a suitable solvent or in a suitable solvent. In the case of saponification, the reaction conditions of ordinary saponification reaction can be widely applied, and for example, it can be carried out in the same manner as the saponification reaction shown in the above reaction process formula-3. When the reaction is carried out in the presence of amine, examples of the solvent used include alcohols such as methanol and ethanol. Methylamine as the amine,
Examples thereof include aliphatic amines such as ethylamine. The amount of such amine used is the compound 1 of the general formula (2-C).
It is preferable to use a large excess amount with respect to the mole. The above reaction is usually carried out at about -20 to 100 ° C, and generally the reaction is completed in about 1 minute to 24 hours.

From the compound of the general formula (2-D), the compound of the general formula (2
The reaction for obtaining the compound of the formula (C) is carried out in the presence of a basic compound in a suitable solvent in the presence of the general formula R ¹² —X or (R ¹² ) ₂ O
[R ¹² and X are as defined above. ] It manufactures by making the compound represented by these and the compound of general formula (2-D) react. Examples of the solvent include halogenated hydrocarbons such as chloroform, aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran, esters such as ethyl acetate, and polar solvents such as N, N-dimethylformamide. . Examples of the basic compound include organic bases such as triethylamine and inorganic bases such as potassium carbonate and sodium carbonate. As the amount of the basic compound used,
About 2 to 5 mol is preferable for 1 mol of the compound of the general formula (2-D). The above reaction is usually carried out at about 0 to 100 ° C., and generally the reaction is completed in about 1 minute to 24 hours.

Reaction process formula-8

[0087]

Embedded image

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ ,
R ⁹ , R ¹⁰ , X and n are the same as above. R ¹³ is a group -A-R
^{Shows 1a} . R ¹⁹ represents a lower alkyl group or a phenyl lower alkyl group. The compound of general formula (14) is produced by reacting the compound of general formula (12) with the compound of general formula (13) in a suitable solvent in the presence of a basic compound. As the basic compound, sodium hydride, potassium hydride,
Examples thereof include lithium hydride, sodium methylate, potassium ethylate and the like. Examples of the solvent include ethers such as tetrahydrofuran and polar solvents such as dimethylformamide. The amount of the basic compound used is 1 to 3 times mol, preferably 1 mol, per mol of the compound of the general formula (12). The amount of the compound of the general formula (13) used is 1 to 3 with respect to 1 mol of the compound of the general formula (12).
It is about double mole, preferably equimolar. The reaction temperature is usually about 0 to 120 ° C, preferably about 20 to 60 ° C. Generally, the reaction is completed in about 1 hour to 5 days.

The compound of the general formula (15) can be prepared by
It is produced by subjecting the compound of the general formula (12) or the compound of the general formula (14) to the elimination reaction of the carboxy protecting group, and then heating the reaction product after the elimination reaction in a suitable solvent. A wide range of known conditions for the elimination reaction of a carboxy protecting group can be applied to the elimination reaction of a carboxy protecting group. For example, the elimination reaction is carried out in the same manner as the reaction shown in the reaction formula-3. The heating reaction of the reaction product after the elimination reaction of the carboxy protecting group is carried out in the same manner as the reaction represented by the reaction formula-4.

The compound of the general formula (16) has the general formula (15)
It is produced by reacting the compound of formula (1) with the compound of general formula (6) in a usual amide bond formation reaction. The amide bond-forming reaction can be carried out in the same manner as in the method described in Reaction Scheme-1.

The compound of general formula (2-E) can be produced by subjecting the compound of general formula (16) to a carboxy-protecting group elimination reaction in a suitable solvent. This reaction is carried out in the same manner as the elimination reaction of the carboxy protecting group represented by the reaction scheme-3.

The compound of the general formula (15) used in the above reaction scheme-8 is manufactured by various methods. For example, the general formula R ⁶ CH ₂ COOH [wherein R ⁶
Is the same as above. ] After converting the compound represented by the following formula to an acid halide with a halogenating reagent, the compound is reacted with an optically active oxazolidin-2-one in the presence of n-butyllithium,
Then, a general formula R ⁶ CH ₂ COZ obtained, wherein R ⁶
Is the same as above. Z represents an optically active 2-oxo-oxazolidyl group. ] To the compound represented by the general formula R ¹⁰ CH
₂ X [wherein R ¹⁰ and X are the same as defined above. Represented by] by reacting α- haloacetate of the general formula _{^{R 10 CH 2 CH (R 6}} ) further obtained COZ [wherein R ^6, R ¹⁰ and Z are as defined above. ] In the compound represented by the hydrolysis to optically active 2-oxo - by removing the oxazolidyl group (Z), the general formula _{^{R 10 CH 2 CH (R 6}} ) C
OOH [wherein R ⁶ and R ¹⁰ are the same as defined above]. ] The compound represented by these is manufactured. For each of these reactions, for example, W
The reaction conditions corresponding to each reaction described in O-9309097 can be widely applied.

Reaction process formula-9

[0094]

[Chemical 15]

[Wherein, R ² , R ³ , R ⁴ , R ⁶ and n are the same as defined above. R ¹⁴ represents a lower alkoxycarbonyl group. R ¹⁵ represents an alkylidene group having 1 to 12 carbon atoms, a lower alkoxy lower alkylidene group, or a phenyl lower alkylidene group which may have a lower alkylenedioxy group as a substituent on the phenyl ring. R ¹⁶ represents a lower alkyl group. The compound of the general formula (20) can be obtained by reacting the compound of the general formula (1
It is obtained by reacting the compound of 8) with the compound of general formula (19) in the presence of a basic compound, and then saponifying (alkali hydrolysis). Suitable solvents include methanol, ethanol, isopropyl alcohol, te
Examples thereof include alcohols such as rt-butyl alcohol. Examples of the basic compound include sodium hydride, potassium hydride, lithium hydride, sodium methylate, potassium ethylate and the like. The amount of the compound of the general formula (19) used is preferably about 1 to 1.5 mol per 1 mol of the compound of the general formula (18). The amount of the basic compound used is preferably about 1 to 1.5 mol per mol of the compound of the general formula (18). The above reaction is usually carried out at about 10 to 120 ° C., and generally the reaction is completed in about 1 minute to 24 hours.

Subsequent saponification is carried out, for example, using customary basic compounds. Examples of the basic compound include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. The amount of the basic compound used is preferably about 2 to 6 mol per 1 mol of the compound of the general formula (18). The above reaction is usually 0
It is carried out at about 100 ° C., and the reaction is generally completed in about 1 to 24 hours.

The compound of the general formula (22) has the formula (2)
It is produced by reacting the compound of 0) with a dehydrating condensing agent such as acetic anhydride, N, N'-dicyclohexylcarbodiimide (DCC), and then reacting the reaction product thereof with the compound of the general formula (21). In the reaction of the compound of the general formula (20) with acetic anhydride, DCC, etc., the amount of acetic anhydride, DCC, etc. used is about 1 mol to a large excess amount with respect to 1 mol of the compound of the general formula (20). Is good. The above reaction proceeds at about 20 to 120 ° C., and generally 1 minute to 1
It will be completed in about 0 hours. In the reaction of the reaction product with the compound of the general formula (21), the amount of the compound of the general formula (21) used is preferably a large excess amount with respect to 1 mol of the compound of the general formula (20). The above reaction is usually performed at about 10 to 100 ° C., and generally the reaction is completed in about 1 to 24 hours.

The compound of the general formula (23) has the general formula (22)
It can be obtained by subjecting a compound of 1 to a conventional reduction reaction. Known reduction reaction conditions can be widely applied to this reduction reaction. For example, the reaction is performed in the same manner as the reaction represented by the reaction scheme-2.

The compound of the general formula (24) has the formula (2)
It can be obtained by reacting the compound of 3) with the compound of general formula (6) in a usual amide bond formation reaction. The amide bond formation reaction is carried out in the same manner as the reaction represented by the reaction formula-1.

The compound of general formula (2-A) is produced by treating the compound of general formula (24) in the presence of a basic compound in a suitable solvent. Suitable solvents include
Examples thereof include alcohols such as methanol and ethanol. Examples of the basic compound include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as triethylamine. The amount of the basic compound used is preferably about 1 to 3 mol with respect to 1 mol of the compound of the general formula (24). The above reaction is usually carried out at about 0 to 40 ° C., and generally the reaction is completed in about 1 to 24 hours.

The compound of the general formula (4) used as a starting material in the above reaction process formula-3 can be produced by various methods. For example, it is produced by the method represented by the following reaction process formula-10.

Reaction Process Formula-10

[0103]

Embedded image

[In the formula, R ⁶ , R ⁹ and R ¹⁰ are the same as defined above. R ¹⁷ represents an alkali metal such as sodium or potassium. Y represents a halogen atom. The compound of general formula (28) is produced by subjecting the compound of general formula (26) and the compound of general formula (27) to an ordinary diazo coupling reaction in the presence of nitrite in a suitable solvent.

Examples of nitrites include sodium nitrite and potassium nitrite. The amount of nitrite used is 1 to 1.5 with respect to 1 mol of the compound of the general formula (26).
The amount of the compound of the general formula (27) used is preferably about 1 to 1.5 mol per 1 mol of the compound of the general formula (26). Examples of the solvent include water, an acidic solvent such as hydrochloric acid and sulfuric acid, or a mixed solvent thereof. The above reaction is usually −
It is carried out at about 10 to 100 ° C., and the reaction is generally 1 minute to
It will be completed in about one day.

The compound of the general formula (29) has the general formula (28)
It is prepared by subjecting the compound of 1 to a conventional esterification reaction in a suitable solvent.

The compound of the general formula (4) is produced by reacting the compound of the general formula (29) with the compound of the general formula (30) in the presence of a basic compound in a suitable solvent. As the solvent, a polar solvent such as dimethylformamide,
Halogenated hydrocarbons such as dichloromethane can be exemplified. Examples of the basic compound include sodium hydride and potassium t-butoxy. The amount of the basic compound used is preferably about 1 to 3 mol per 1 mol of the compound of the general formula (29). The above reaction is usually carried out at about -20 to 70 ° C, and generally the reaction is completed in about 1 hour to 10 days.

The compound of the general formula (12) used as a starting material in the above reaction process formula-8 can be produced by various methods. For example, it is produced by the method represented by the following reaction process formula-11.

Reaction Process Formula-11

[0110]

[Chemical 17]

[In the formula, R ⁶ , R ⁹ , R ¹⁰ , R ¹⁹ and Y are the same as defined above. The compound of general formula (32) can be produced by subjecting the compound of general formula (26) to a conventional diazo coupling reaction in the presence of nitrite in a suitable solvent. The diazo coupling reaction is carried out under the same reaction conditions as in the production of the compound of the general formula (28) in the above reaction scheme-10.

The compound of the general formula (34) has the formula (3)
It is produced by reacting the compound of 2) with the compound of general formula (33) in a suitable solvent in the presence of a basic compound. Examples of the solvent include ethers such as tetrahydrofuran and aromatic hydrocarbons such as benzene and toluene. Examples of the basic compound include organic bases such as triethylamine and N-methylmorpholine. The amount of the basic compound used is preferably about 1 to 2 mol per 1 mol of the compound of general formula (32), and the amount of the compound of general formula (33) is used to 1 mol of the compound of general formula (32). 1 to 2
Good molarity. The reaction temperature is preferably about 0 to 100 ° C, and is generally completed in 1 to 24 hours. The compound of the general formula (34) can also be produced by subjecting it to a usual esterification reaction in a suitable solvent.

The compound of the general formula (12) has the general formula (3
It is produced by converting the compound of 4) to a sulfonic acid ester and then reacting the compound of the general formula (35) with a basic compound. The reaction of converting the compound of the general formula (34) into a sulfonic acid ester is carried out by reacting with an acid anhydride such as sulfonic anhydride and an acid halide such as sulfonyl halide in the presence of a basic compound in a suitable solvent. Examples of the solvent include halogenated hydrocarbons such as dichloromethane and ethers such as tetrahydrofuran. Examples of the basic compound include organic bases such as pyridine, triethylamine and N-methylmorpholine.
The amount of the basic compound used is preferably about 1 to 1.5 mol with respect to 1 mol of the compound of the general formula (34).
The amount of the acid anhydride or acid halide used is represented by the general formula (3
About 1 to 1.5 mol is preferable for 1 mol of the compound of 4). The reaction temperature is about -50 to 50 ° C, and generally the reaction is completed in 1 minute to 1 day.

The reaction of the sulfonic acid ester of the compound of general formula (34) with the compound of general formula (35) is carried out in a suitable solvent,
It is carried out in the presence of a basic compound. Examples of the solvent include polar solvents such as dimethylformamide and halogenated hydrocarbons such as dichloromethane. Examples of the basic compound include sodium hydride, potassium hydride, lithium hydride, sodium methylate, potassium ethylate and the like. The amount of the basic compound used is about 1 to 2 mol per mol of the compound of the general formula (34), and the amount of the compound of the general formula (35) is the general formula (34).
1 to 2 mol per 1 mol of the compound is preferable. The reaction temperature is preferably about -10 to 50 ° C, and generally the reaction is completed in 1 hour to 10 days.

The compounds of the general formula (6) used in the above reaction process formulas -3, -8 and -9 are new or known compounds, and are described, for example, in J. Med. Chem. , 197
2, 15, 325, J. Org. Chem. , 198
It is easily manufactured according to the method described in 9, 54, 3394 and the like. Further, the compound of the general formula (6) is produced, for example, by the method shown in the following reaction process formulas -12 and -13.

Reaction Process Formula-12

[0117]

[Chemical 18]

[In the formula, R ² , R ⁴ , R ^3a , B, X and n
Is the same as above. R ²⁰ represents a hydrogen atom, an acyl group or an amino group-protecting group. The reaction of the compound of general formula (36) with the compound of general formula (37) is carried out in a suitable solvent in the presence of a basic compound. Examples of the solvent used include ethers such as dioxane, tetrahydrofuran, diethyl ether, and ethylene glycol dimethyl ether, and polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide. Examples of the basic compound include inorganic bases such as sodium hydride, potassium hydride, lithium hydride, sodium methylate and potassium ethylate. The amount of such a basic compound used is usually 0.5 to 2 times the molar amount of the compound of the general formula (36), preferably an equimolar amount. The compound of the general formula (36) and the general formula (3
The ratio of the compound of 7) to the compound used is usually about 1 to 3 times the molar amount of the former, preferably about equimolar. The reaction temperature is usually about -20 to 120 ° C, preferably about 0 to 60 ° C, and the reaction is generally 10 minutes to 5 ° C.
Complete in days. Reaction process formula-13

[0119]

[Chemical 19]

[In the formula, R ² , R ⁴ , R ²⁰ , X and n are the same as defined above. R ^16a represents a lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy lower alkoxy lower alkyl group or a lower alkoxy lower alkoxy lower alkoxy lower alkyl group. The reaction of the compound of the general formula (39) with the compound of the general formula (40) is carried out by the reaction of the general formula (36) in the above reaction process formula-12.
The reaction conditions similar to those of the compound of formula (37) and the compound of general formula (37) can be used.

The compound of the general formula (38-A) and the compound of the general formula (38-B) are converted to the compound of the general formula (6) by an ordinary deprotection reaction.

The compound of the general formula (15) used in the above reaction process formula-8 can be produced by various methods.
For example, it is produced by the method shown in the following reaction process formula-14.

Reaction Process Formula-14

[0124]

Embedded image

[In the formula, R ⁶ , R ⁹ , R ¹⁰ and R ¹⁹ are the same as defined above. ] The deprotection of the compound of the general formula (12) is carried out by the reaction step formula-
In 3, the reaction can be performed under the same reaction conditions as the reaction for obtaining the compound of the general formula (5) from the compound of the general formula (4). The subsequent Mannich reaction can be carried out under the same reaction conditions as the reaction for obtaining the compound of the general formula (9) from the compound of the general formula (7) in the above-mentioned reaction step formula-5. The hydrogenation reaction of the compound of the general formula (41) is carried out by the above reaction process formula-
In 2, the compound of general formula (1-A) can be reduced and converted into the compound of general formula (1-B) under the same reaction conditions.

Substituents such as amino groups and hydroxyl groups in the intermediate compounds shown in the above reaction schemes can be protected at appropriate times by a usual method that does not affect the reaction, and after the reaction is completed, a usual method can be used. The protecting group can be removed at any time.

Further, the compound of the general formula (1) of the present invention and the intermediate compound shown in each of the above reaction schemes for producing the same have the types of R ¹ , R ³ and R ⁵ mentioned above. Although various changes can be made as described above, the changes are not limited to these, and changes that are normally made can be made.

Examples of the elimination reaction of the protective group for the hydroxyl group include the desilylation reaction for obtaining the compound of the general formula (1-B) from the compound of the general formula (42) in the following reaction process formula-15.

Reaction Process Formula-15

[0130]

[Chemical 21]

[In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and n are the same as defined above. R ²¹ , R ²² and R ²³ each represent a lower alkyl group. The reaction between the compound of the general formula (2) and the compound of the general formula (3 ′) is the same as the reaction between the compound of the general formula (2) and the compound of the general formula (3) in the aforementioned reaction process formula-1. It can be carried out under reaction conditions.

The compound of the general formula (42) is replaced by the compound of the general formula (1-
For the reaction leading to the compound B), any of the usual reaction conditions for desilylation can be applied. For example, the desilylation reaction is a suitable catalyst conventionally used for this type of desilylation reaction,
For example, inorganic acids such as hydrochloric acid, sulfuric acid, perchloric acid, formic acid, acetic acid,
Lower alkanoic acid such as propionic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4
-Usually carried out in a solvent using an appropriate amount of an organic acid such as an organic sulfonic acid such as methylbenzene sulfonic acid. As the solvent, a usual inert solvent such as water, methanol,
Lower alcohols such as ethanol and isopropanol,
Acetone, ketones such as methyl ethyl ketone, ethers such as dioxane, tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, lower alkanoic acids such as acetic acid, propionic acid, etc. These mixed solvents can be used. The catalyst is
It is generally preferable to use a catalyst amount to an excess amount, preferably an excess amount. The reaction temperature is usually 0 to 100 ° C., preferably room temperature to 80 ° C., and the reaction is 3 minutes to
It will be finished in about 20 hours.

Examples of the elimination reaction of the protective group of the amino group include the hydrazine decomposition reaction shown below. For example, when R ¹ is a phthalimido lower alkyl group, R ¹ is subjected to a hydrazine decomposition reaction by reacting with hydrazine or a hydrazine derivative in a solvent-free or inert solvent to give R 1
¹ can be converted to an amino lower alkyl group. Examples of the inert solvent used in this reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, alcohols such as methanol and ethanol, and the like. Examples of the hydrazine derivative include lower alkyl-substituted hydrazine such as methylhydrazine and ethylhydrazine, and aryl-substituted hydrazine such as phenylhydrazine. The amount of hydrazine or hydrazine derivative used with respect to the starting compound in which R ¹ is a phthalimido lower alkyl group is usually at least an equimolar amount, preferably an equimolar to 10-fold molar amount. This reaction is usually 0 to 100 ° C., preferably 0.
The reaction is carried out at -80 ° C, and generally the reaction is completed in about 1 to 40 hours.

In the above reaction scheme-8, the compound of the general formula (13) used as a starting material is, for example, as described in J.
Gen. Chem. , 22 , 267-269 (195
2) and Khim. Geterotsikl. Soedi
n. , 3 , 344-345 (1975) and the like, or compounds easily produced according to the methods described in these documents.

The compounds of the present invention include addition salts of pharmaceutically acceptable acid or base compounds. The salt is easily formed by the action of the acid or base. Examples of the acid used for salt formation include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, and in some cases, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid and citric acid. , Organic acids such as benzoic acid. Examples of the base compound used for the salt formation include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like.

The compound of the general formula (1) and the salt thereof produced by the above-mentioned methods can be isolated by usual separation means such as distillation, recrystallization, column chromatography, preparative thin layer chromatography, solvent extraction and the like. Can be easily isolated and purified from the reaction system.

The extracellular matrix metalloprotease inhibitor of the present invention is usually used in the form of a general pharmaceutical preparation. The formulation is prepared by using a diluent or an excipient such as a filler, a filler, a binder, a moisturizer, a disintegrant, a surface active agent and a lubricant which are usually used. Various forms of this pharmaceutical preparation can be selected according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, and injections ( Liquids, suspensions and the like), ointments and the like. When molded into a tablet form, as a carrier, for example, lactose, sucrose, sodium chloride, glucose,
Excipients such as urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinyl Binders such as pyrrolidone, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, disintegrating agents such as lactose, white sugar , Stearin,
Decay inhibitor for cocoa butter, hydrogenated oil, quaternary ammonium base, absorption promoter for sodium lauryl sulfate, humectant for glycerin, starch, adsorption of starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. Agents, purified talc, stearates, boric acid powder, lubricants such as polyethylene glycol, and the like can be used. Further, the tablet is a tablet coated with a usual coating as necessary, for example, a sugar-coated tablet,
It may be a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multi-layer tablet. When molded into the form of pills, as a carrier, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, tragacanth powder, gelatin, binders such as ethanol, laminaran , Disintegrating agents such as agar and the like can be used. In the case of molding into a suppository, as a carrier, for example, polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, semisynthetic glyceride and the like can be used. The capsules are prepared by a conventional method, usually by mixing the various carriers exemplified above with the compound of the present invention and filling them into hard gelatin capsules, hard capsules or the like. When prepared as an injection, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood. When molding into these forms, water, lactic acid aqueous solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be used as a diluent. In this case, a sufficient amount of salt, glucose or glycerin for preparing an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizer, desiccant, soothing agent, etc. may be added. You may add.
Further, if necessary, a colorant, a preservative, a fragrance, a flavoring agent, a sweetening agent and the like and other pharmaceuticals may be contained in the pharmaceutical preparation.
When formulating in the form of paste, cream and gel, white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like can be used as a diluent.

The amount of the compound of the present invention to be contained in the pharmaceutical preparation of the present invention is not particularly limited and is appropriately selected from a wide range, but it is usually 1 to 70% by weight in the pharmaceutical preparation.

The method of administration of the pharmaceutical preparation of the present invention is not particularly limited and may be variously determined according to the age, sex and other conditions of the patient, the state of disease, various preparation forms, etc., but usually systemically or locally Orally or parenterally. For example, it is orally administered in the form of tablets, pills, solutions, suspensions, emulsions, granules, and capsules, and is intravenously, intramuscularly, or intradermally in the form of injections, optionally mixed with a normal replacement fluid. In addition to being administered subcutaneously or intraperitoneally, it is administered rectally as a suppository or applied as an ointment.

The dose of the pharmaceutical preparation of the present invention to humans is appropriately selected depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but usually it is within the range of about 0.1 to 100 mg per 1 kg of body weight per day. , The formulation is 1 daily
It may be administered in divided doses. Of course, since the dose varies depending on various conditions as described above, a dose smaller than the above dose range may be sufficient in some cases, or a dose exceeding the range may be necessary in some cases.

[0141]

EXAMPLES The production examples of the compounds used in the present invention will be described below as Examples, and then the results of pharmacological tests and formulation examples of these compounds will be shown.

Reference Example 1 (a) Production of 2R-bromo-4-methyl-pentanoic acid D-leucine (50.0 g) was added to sulfuric acid (112 ml) and water (38).
It is dissolved in 0 ml of a mixed solvent, 158 g of potassium bromide is added, and the reaction solution is cooled to -2 ° C. Sodium nitrite 3
A solution prepared by dissolving 4.8 g in 100 ml of water is added dropwise over 1 hour so that the above reaction solution maintains -1 to -2 ° C, and after completion of the dropping, the mixture is stirred for 2 hours in an ice bath. Chloroform (300 ml) is added to the reaction solution, insoluble matter is filtered off, the organic layer is separated, and the aqueous layer is extracted 5 times with 100 ml of chloroform. The chloroform layers were combined, dried over magnesium sulfate, and then evaporated in vacuum to obtain the above target compound as a yellow oil. Yield 58.5g.

(B) tert-butyl-2R-bromo-
Preparation of 4-methyl-pentanoate 2R-Bromo-4-methylpentanoic acid 5
After dissolving 8.5 g in 150 ml of dichloromethane and cooling this solution to -40 ° C, about 50 ml of isobutene is collected. While cooling to -40 ° C, 1.5 ml of concentrated sulfuric acid was added dropwise with stirring, the tube was sealed, and the mixture was stirred overnight at room temperature. The reaction vessel was cooled again to −40 ° C. or lower, the sealed tube was opened, and the mixture was allowed to stand at room temperature. After the reaction solution reached 10 ° C. or higher, it was vacuum evaporated until the reaction solution became about half. Chloroform (200 ml) was added to the residue, and the chloroform layer was added with saturated aqueous sodium hydrogen carbonate solution (100 ml x
(Twice), washed with 100 ml of brine, dried over magnesium sulfate and evaporated in vacuo to give the above-identified compound as a yellow oil. Yield 67.2g.

(C) Preparation of benzyl 2-benzyloxycarbonyl-3R-tert-butoxycarbonyl-5-methylhexanoate 76.2 g of dibenzyl malonate was dissolved in 100 ml of dry dimethylformamide and potassium t-butoxide 3 was added.
Add 0.0 g with ice cooling and stir at room temperature until all potassium t-butoxide is dissolved. Cooled again in an ice bath, tert-butyl 2R-bromo-4-methyl-pentanoate 67.2 g dimethylformamide 120 m.
1 solution was added dropwise over 1 hour, and the mixture was stirred at 4 ° C. for 4 days. The reaction solution was poured into 500 ml of saturated ammonium chloride, extracted with ethyl acetate (300 ml × 3 times), and the organic layer was evaporated in vacuum. Diethyl ether 600 in the residue
After adding ml, washing with saline (500 ml x 2 times),
It was dried over magnesium sulphate and evaporated in vacuo. The oily residue was subjected to column chromatography (silica gel 900
g, hexane / ethyl acetate = 20/1 V / V) to obtain the above target compound as a colorless oil. Yield 7
1.6 g.

Reference Example 2 3S- (4-Benzyloxy-3-benzyloxycarbonyl-2R-isobutylsuccinyl) amino-3,4
-Production of dihydrocarbostyril Benzyl 2-benzyloxycarbonyl-5-methyl-3R-tert-butoxycarbonylhexanoate (4.06 g) was added with trifluoroacetic acid (10 ml) and allowed to stand at room temperature for 1 hour. Evaporated.
Chloroform (35 ml) was added to the residue, and brine (10
ml × 2), dry over anhydrous magnesium sulfate,
Evaporated in vacuo. The obtained residue was dissolved in 15 ml of dimethylformamide, 1.45 g of 3S-amino-3,4-dihydrocarbostyril was added, and the mixture was cooled in a water bath,
1-hydroxybenzotriazole 1.21 g, N, N
After adding 1.84 g of ′ -dicyclohexylcarbodiimide, the pH was adjusted to 8 with N-methylmorpholine, and the mixture was stirred at room temperature for 20 hours. After filtering the precipitate, it was evaporated in vacuo.
100 ml of ethyl acetate was added to the residue, and 1N hydrochloric acid (20
ml × 2 times), saturated aqueous sodium hydrogen carbonate solution (15 m
It was washed with brine (10 ml), dried over anhydrous magnesium sulfate and evaporated in vacuo. The oily residue was purified by column chromatography (silica gel 90 g, eluted with 33% ethyl acetate / hexane and then 40% ethyl acetate / hexane) to give the above-identified compound as a colorless oil. Yield 3.54g.

NMR (270 MHz, CDCl ₃ ) δp
pm: 8.08 (1H, s), 7.31 (10H,
s), 6.96-7.30 (3H, m), 6.74-
6.79 (2H, m), 5.03-5.26 (4H,
m), 4.52 (1H, dt, J ₁ = 14 Hz, J ₂ =
6Hz), 3.85 (1H, dd, J ₁ = 16Hz, J
₂ = 10 Hz), 3.36 (1H, dd, J ₁ = 16H)
z, J ₂ = 6 Hz), 2.92-3.15 (1H,
m), 2.63 (1H, t, J = 15Hz), 1.50
-1.80 (2H, m), 0.95-1.15 (1H,
m), 0.75-1.00 (6H, m).

Reference Example 3 Preparation of 3S- (3-Hydroxycarbonyl-2R-isobutylpropanoyl) amino-3,4-dihydrocarbostyril 3S- (4-Benzyloxy-3-benzyloxycarbonyl-2R-isobutylsuccinyl) Amino-3,4
-Dihydrocarbostyril 3.50 g in methanol 35
It was dissolved in ml, 10% palladium-carbon 35 mg was added, and the mixture was saturated with hydrogen. After stirring under normal pressure for 1 day, the catalyst is filtered off and the filtered solution is concentrated to dryness under reduced pressure. 20 ml of toluene was added to the above residue and heated under reflux for 20 minutes. The reaction solution was concentrated to dryness under reduced pressure, and 10 m of ethyl acetate was added to the residue.
l, heated and dissolved, added 2 ml of hexane,
After standing at room temperature for 1 day, the precipitated crystals were filtered to obtain the above target compound as a white solid. Yield 500 mg.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 8.19 (1H, d, J = 8Hz), 7.1
5-7.30 (1H, m), 7.16 (2H, t, J =
7Hz), 6.90 (2H, dt, J ₁ = 8Hz, J ₂
= 7 Hz), 4.46 ( ₁ H, dt, J ₁ = 12 Hz,
J ₂ = 8 Hz), 2.60-3.00 (3 H, m),
2.43 (1H, dd, J ₁ = 16Hz, J ₂ = 8H
z), 2.24 (1H, dd, J ₁ = 16 Hz, J ₂ =
6Hz), 1.05-1.80 (3H, m), 0.88
(6H, dd, J ₁ = 16 Hz, J ₂ = 6 Hz).

Reference Example 4 Preparation of 3S- (4-hydroxy-2R-isobutyl-3-methylenesuccinyl) amino-3,4-dihydrocarbostyril 3S- (4-benzyloxy-3-benzyloxycarbonyl-2R-isobutyl) Succinyl) amino-3,4
-Dihydrocarbostyril 10.8 g with methanol 10
It was dissolved in 0 ml, 10% palladium-carbon (1.0 g) was added, and the mixture was saturated with hydrogen. After stirring for 1 day under normal pressure, the catalyst is filtered off. To the above reaction solution, 2.2 ml of piperidine was added, and after stirring for 15 minutes, 37% formaldehyde solution 4.9
After adding ml, the mixture was stirred at room temperature for 7 hours and then heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, dissolved in 200 ml of a saturated aqueous solution of potassium carbonate, and added with chloroform (20 ml x 3
Wash). Cool the aqueous layer in a water bath and add concentrated hydrochloric acid to pH 1
After extraction with chloroform (50 ml × 2 times), the extract was washed with brine (20 ml), dried over magnesium sulfate and evaporated in vacuo to give the above-identified compound as a white solid. Yield 1.98g.

NMR (270 MHz, CDCl ₃ ) δp
pm: 8.69 (1H, s), 7.19 (2H, dd,
J ₁ = 14 Hz, J ₂ = 7 Hz), 7.03 (1H,
d, J = 7 Hz), 6.82 (1H, d, J = 7H
z), 6.46 (1H, s), 5.89 (1H, s),
4.58 (1H, dt, J ₁ = 13Hz, J ₂ = 6H
z), 3.61 (1H, t, J = 7Hz), 3.51
(1H, dt, J ₁ = 15 Hz, J ₂ = 6 Hz), 2.
76 (1H, t, J = 15Hz), 1.50-2.00
(3H, m), 0.91 (6H, dd, J ₁ = 10H
z, J ₂ = 6 Hz).

Reference Example 5 Preparation of 3S- (4-hydroxy-2R-isobutyl-3S-acetylthiomethylsuccinyl) amino-3,4-dihydrocarbostyril 3S- (4-hydroxy-2R-isobutyl-3-methylenesuccinyl) ) Amino-3,4-dihydrocarbostyril (840 mg) is dissolved in thioacetic acid (8 ml), and the mixture is stirred at 30 ° C for 4 days in the dark. Diethyl ether was added to the reaction solution, and the precipitated crystals were filtered to obtain the above target compound as a white solid. Yield 330 mg.

NMR (270 MHz, CDCl ₃ ) δp
pm: 8.70 (1H, brs), 6.80-7.30
(4H, m), 4.45-4.60 (1H, m), 3.
59 (1H, dd, J ₁ = 15 Hz, J ₂ = 6 Hz),
2.80-3.40 (4H, m), 2.68 (1H,
t, J = 15 Hz), 2.36 (3H, s), 1.10
-1.80 (3H, m), 0.95 (6H, dd, J ₁
= 13 Hz, J ₂ = 7 Hz).

Reference Example 6 (a) Production of D-leucinic acid 100 ml of an aqueous solution of 14 g of sodium nitrite was heated and stirred at 95 ° C. under heating and stirring, and 25 g of D-leucine 400 of 0.5N sulfuric acid 400 was added.
The ml aqueous solution was added dropwise over 45 minutes. After the completion of dropping, the mixture was stirred for 15 minutes until no bubbles appeared. The reaction solution was concentrated under reduced pressure (200 ml), and the obtained residue was extracted with diethyl ether. The diethyl ether layer was sequentially washed once with 1N hydrochloric acid and twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily residue was left to crystallize to obtain the target compound. Yield 14.50g.

(B) Production of D-leucinic acid benzyl ester D-leucinic acid 14.50 g of tetrahydrofuran 15
Triethylamine (15.2 g) and benzyl bromide (14.4 ml) were added to the 0 ml solution, and the mixture was stirred under reflux for 3 hours. The insoluble matter generated from the reaction solution was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 150 ml of ethyl acetate and extracted. The ethyl acetate layer was washed twice with saturated aqueous sodium hydrogen carbonate, 1
It was washed twice with N hydrochloric acid and twice with saturated saline, respectively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The oily residue obtained was dried to obtain the above-mentioned target compound. Yield 1
8.34 g.

(C) Preparation of 1,2-dibenzyl-1-t-butyl-4-methyl-1,1,2 (R) -pentane-tricarboxylate Benzyl t-butyl malonate 20.65 g of N, N-
3.30 g of sodium hydride (containing 60%) was added to 140 ml of the dimethylformamide solution, and the mixture was stirred at room temperature for 1 hour. On the other hand, D-leucinic acid benzyl ester 18.34
6.66 g of pyridine in 100 ml of dichloromethane.
ml, and under ice-cooling stirring, 13.53 ml of trifluoromethanesulfonic anhydride was added to 100 m of dichloromethane.
1 solution was added dropwise in 30 minutes. After completion of the dropping, the mixture was further stirred for 1 hour under ice cooling. The reaction solution was once with water and 1 with saturated saline solution.
It was washed successively and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was N, N- prepared above.
The solution was added dropwise to the dimethylformamide solution over 30 minutes while stirring with ice cooling. After the dropping was completed, the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was extracted with 300 ml of ethyl acetate. The ethyl acetate layer was washed twice with saturated aqueous sodium hydrogen carbonate and 2 times with 1N hydrochloric acid.
The extract was washed once with saturated saline and twice with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily residue was added to silica gel column chromatography and eluted with ethyl acetate / petroleum ether (1:20) to obtain the above-mentioned target compound as an oily substance. Yield 19.0g.

Reference Example 7 Preparation of 1,2-dibenzyl-1-tert-butyl-1-phthalimidomethyl-4-methyl-1,1,2 (R) -pentane-tricarboxylate 1,2-dibenzyl-1 To a solution of 6.00 g of -tert-butyl-4-methyl-1,1,2 (R) -pentane-tricarboxylate in 50 ml of dimethylformamide,
653 mg (60% content) of sodium hydride under stirring with ice cooling
Was added and stirred for 30 minutes. The reaction solution was returned to room temperature, 4.04 g of N-bromomethylphthalimide was added thereto, and the mixture was stirred at room temperature for 3 days. The reaction solution was neutralized by adding a small amount of acetic acid and then concentrated under reduced pressure. The obtained oily residue was extracted with 100 ml of ethyl acetate, the ethyl acetate layer was washed once with water and twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily residue was added to silica gel column chromatography and eluted with chloroform to obtain the above-mentioned target compound as an oily substance. Yield 4.00g.

Reference Example 8 Preparation of 4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinic acid 1,2-dibenzyl-1-tert-butyl-1-phthalimidomethyl-4-methyl- 1,1,2 (R) -Pentane-tricarboxylate 4.00 g of methanol 3
200 mg of 10% palladium-carbon was added to the 0 ml solution, hydrogen gas was introduced under reduced pressure, and the mixture was stirred for 2 days. The catalyst was filtered off from the reaction solution using Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 30 ml of toluene, 0.70 ml of N-methylmorpholine was added thereto, and the mixture was stirred under reflux for 7 hours. 70 ml of toluene was added to the reaction solution, and the organic layer was washed twice with 1N hydrochloric acid and three times with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily residue was added to silica gel column chromatography and eluted with 2% methanol / chloroform to obtain the above target compound as an oily substance. Yield 1.0
0 g.

Reference Example 9 3S- (4-tert-butoxy-2R-isobutyl-
Preparation of 3 (R or S) -phthalimidomethylsuccinyl) amino-3,4-dihydrocarbostyril 4-tert-butoxy-2R-isobutyl-3 (R or S) -phthalimidomethylsuccinic acid 500 mg and 1-
A suspension of 190 mg of hydroxybenzotriazole and 228 mg of 3S-amino-3,4-dihydrocarbostyril in 10 ml of dimethylformamide was stirred under ice-cooling.
N, N'-dicyclohexylcarbodiimide 290 mg
After adding, the mixture was stirred under ice cooling for 2 hours and at room temperature for 18 hours.
The reaction solution was concentrated under reduced pressure, 60 ml of ethyl acetate was added to the residue, and the insoluble material was filtered off. The ethyl acetate layer of the filtrate was saturated with sodium hydrogen carbonate solution (× 2 times), 1N hydrochloric acid (× 2 times), saturated saline solution (× 2 times).
The extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oily residue was added to silica gel column chromatography and eluted with 0.5% methanol / chloroform to obtain the above target compound as a powder. Yield 390 mg.

NMR (270 MHz, CDCl ₃ ) δp
pm: 8.52 (1H, s), 7.87-7.79 (2
H, m), 7.75-7.69 (2H, m), 7.53
(1H, d, J = 5Hz), 7.24-7.19 (2
H, m), 7.02 (1H, t, J = 7 Hz), 6.8
9 (1H, d, J = 8Hz), 4.66-4.58 (1
H, m), 4.19 (1H, dd, J ₁ = 9 Hz, J ₂
= 14 Hz), 3.80 (1H, dd, J ₁ = 5 Hz,
J ₂ = 14 Hz, 3.63 (1H, dd, J ₁ = 6H
z, J ₂ = 15 Hz), 3.50-3.47 (1H,
m), 2.98-2.80 (2H, m), 1.73-
1.58 (3H, m), 0.92 (6H, dd, J ₁ =
7 Hz, J ₂ = 14 Hz).

Reference Example 10 Production of 3,4-methylenedioxybenzylidene succinic acid 19.14 g of metallic sodium was dissolved in 400 ml of ethanol, and 110.8 ml of diethyl succinate and 100 g of piperonal were added thereto, and the mixture was heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 700 ml of water and washed with 300 ml of diethyl ether. The aqueous layer was stirred under ice cooling,
Adjust the pH to 1 with concentrated hydrochloric acid, and add 300 ml of diethyl ether.
It was extracted with. The diethyl ether layer was washed once with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
181.4 g of the obtained oily residue was added to 350 ml of ethanol.
Was dissolved in the mixture, 400 ml of 5N sodium hydroxide was added thereto, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was washed with 200 ml of diethyl ether. The aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid under ice-cooling stirring and extracted with 400 ml of ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the obtained residue, 300 ml of diethyl ether was added and solidified to obtain the above target compound. Yield 67.34g.

Reference Example 11 Preparation of 4-ethoxy-2- (3,4-methylenedioxybenzylidene) succinic acid 3,4-methylenedioxybenzylidene succinic acid 23.
200 ml of acetic anhydride was added to 5 g, and the mixture was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and 200 ml of ethanol was added to the residue.
Was added and the mixture was heated under reflux overnight. The reaction solution was concentrated under reduced pressure, and the residue was extracted with 300 ml of ethyl acetate. The ethyl acetate layer was washed twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the obtained crystalline residue and washed to obtain the above target compound. Yield 17.76g.

Reference Example 12 Preparation of 4-ethoxy-2-piperonyl succinic acid 10% palladium-carbon (970 mg) was added to a solution of 9.70 g of 4-ethoxy-2- (3,4-methylenedioxybenzylidene) succinic acid in 100 ml of ethanol. Catalytic hydrogenation was carried out overnight at room temperature. The catalyst was filtered off from the reaction solution using Celite, and the filtrate was concentrated under reduced pressure. The oily residue obtained was dried to obtain the above-mentioned target compound. Yield 10.36
g.

Reference Example 13 Preparation of 3- (4-ethoxy-2-piperonylsuccinyl) amino-3,4-dihydrocarbostyril 3-amino-3,4-dihydrocarbostyril 260 m
g of dimethylformamide in 3 ml of solution of 4-ethoxy-
2-Piperonyl succinic acid 500 mg dichloromethane 5
ml solution and 1-hydroxybenzotriazole 240 m
g, 360 g of N, N'-dicyclohexylcarbodiimide was added with stirring under ice cooling, and the mixture was stirred for 3 hours at room temperature under ice cooling for 3 hours.
It was stirred for a day. The insoluble matter was removed from the reaction solution by filtration, and the filtrate was concentrated under reduced pressure. Chloroform (30 ml) was added to the resulting residue for extraction, and the chloroform layer was washed successively with saturated aqueous sodium hydrogen carbonate, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was added to silica gel column chromatography, and ethyl acetate / hexane (1: 1) was added.
The target compound was obtained. Yield 100 mg.

Reference Example 14 Preparation of 4-t-butoxy-3-methylene-2R-isobutylsuccinic acid 1,2-dibenzyl-1-t-butyl-4-methyl-
1,1,2 (R) -pentane-tricarboxylate 4
3.50 g of 10% palladium-carbon was added to a 200 ml solution of 0.0 g of isopropanol, hydrogen gas was introduced under reduced pressure, and the mixture was stirred overnight at room temperature. The catalyst was filtered off from the reaction solution using Celite. Piperidine 23.
72 ml and 37% aqueous formaldehyde solution 108.2 m
1 was added and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in 350 ml of ethyl acetate and extracted. The ethyl acetate layer was mixed with 1N hydrochloric acid (300 ml × 1, 2).
(00 ml × 1), washed twice with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oily residue was subjected to silica gel column chromatography (2
% Elution with methanol / chloroform) to obtain an oily target compound. Yield 13.81g.

NMR (270 MHz, CDCl ₃ ) δp
pm: 11.00 (1H, bs), 6.29 (1H,
s), 5.67 (1H, s), 3.55 (1H, t, J
= 8 Hz), 1.76 ( ₁ H, dd, J ₁ = 6 Hz, J
₂ = 14 Hz), 1.63 to 1.49 (2H, m),
1.49 (9H, s), 0.92 (6H, dd, J ₁ =
6 Hz, J ₂ = 9 Hz).

Reference Example 15 Preparation of 4-t-butoxy-2R-isobutyl-3S-methylsuccinic acid 4-T-butoxy-3-methylene-2R-isobutylsuccinic acid 13.81 g of ethyl acetate in 100 ml of a solution of 10
% Palladium-carbon (970 mg) was added, hydrogen gas was introduced under reduced pressure, and the mixture was stirred overnight at room temperature. The catalyst was filtered off from the reaction solution using Celite, and 11.35 ml of dicyclohexylamine was added to the filtrate while stirring with ice cooling. A white precipitate formed immediately and was collected by filtration and washed with a small amount of diethyl ether. The white precipitate obtained was recrystallized from 150 ml of ethyl acetate to obtain 13.50 g of a white solid.

8.20 g of the compound obtained above was suspended in 200 ml of ethyl acetate, and the ethyl acetate layer was washed with 0.5 M sulfuric acid (100 ml × 2 times) and saturated saline (100 ml × 3).
Each time), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dried to obtain the target compound as an oil. Yield 4.60g.

NMR (270 MHz, CDCl ₃ ) δp
pm: 10.00 (1H, bs), 2.73-2.68
(1H, m), 2.61-2.55 (1H, m), 1.
72-1.63 (2H, m), 1.45 (9H, s),
1.29-1.19 (1H, m), 1.17 (3H,
d, J = 7 Hz), 0.91 (6H, dd, J ₁ = 2H
z, J ₂ = 7 Hz).

Reference Example 16 Preparation of 3S-t-butoxycarbonylamino-3,4-dihydrocarbostyril 10 g of 3S-amino-3,4-dihydrocarbostyril
Was dissolved in 100 ml of N, N-dimethylformamide,
After cooling with ice, 14.8 g of t-butoxycarboxylic acid anhydride was added, and the pH was adjusted to 8 with triethylamine. After stirring at 0 ° C. for 1 hour, the temperature was returned to room temperature, the pH was adjusted to 8 again with triethylamine, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, 300 ml of ethyl acetate was added to the residue, and 1N
Hydrochloric acid (100 ml x 2 times), saturated aqueous sodium hydrogen carbonate solution (100 ml x 2 times), saturated saline solution (100 ml)
Washed with, dried over anhydrous magnesium sulfate and evaporated in vacuo. The oily residue was purified by column chromatography (silica gel 200 g, eluted with 33% ethyl acetate / hexane), and the obtained oily substance was vacuum dried to crystallize to obtain the above-mentioned target compound. Yield 14.38g.

NMR (270 MHz, CDCl ₃ ) δp
pm: 8.20 (1H, brs), 7.18-7.26
(2H, m), 7.02 (1H, dt, J ₁ = 1 Hz,
J ₂ = 7 Hz), 6.80 (1H, d, J = 8 Hz),
5.62 (1H, brs), 4.36 (1H, dt, J
_{1 = 15Hz, J 2 = 6Hz} ), 3.49 (1H, d
d, J ₁ = 15 Hz, J ₂ = 6 Hz), 2.85 (1
H, t, J = 15 Hz), 1.53 (9H, s).

Reference Example 17 Preparation of 3S-benzyloxycarbonylamino-3,4-dihydrocarbostyril 10 g of 3S-amino-3,4-dihydrocarbostyril
Was suspended in 100 ml of N, N-dimethylformamide, 17.6 ml of benzyloxycarbonyl chloride was added dropwise under stirring with ice cooling, and the pH was adjusted to 8 with triethylamine. After stirring at 0 ° C for 1 hour, return to room temperature,
The pH was adjusted to 8 again with triethylamine, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure and ethyl acetate was added to the residue.
After adding 0 ml and filtering off the insoluble matter, the filtrate was washed with 1N hydrochloric acid (100 ml × 2 times), saturated aqueous sodium hydrogen carbonate solution (100 ml × 2 times) and saturated saline solution (100 ml), and dried over anhydrous magnesium sulfate. . The organic layer was evaporated in vacuo, 5 ml of ethyl acetate was added to the obtained oily residue, 50 ml of hexane was added, and the precipitated crystals were filtered to obtain the above target compound. Yield 7.2g.

NMR (270 MHz, CDCl ₃ ) δp
pm: 8.16 (1H, brs), 7.30-7.40
(5H, m), 7.18-7.24 (2H, m), 7.
03 (1H, dt, J ₁ = 1 Hz, J ₂ = 7 Hz),
6.80 (1H, dd, J ₁ = 1 Hz, J ₂ = 8H
z), 5.88 (1H, brs), 5.16 (2H,
s), 4.42 (1H, dt, J ₁ = 15 Hz, J ₂ =
6Hz), 3.52 (1H, dd, J ₁ = 15Hz, J
₂ = 6 Hz), 2.87 (1 H, t, J = 15 Hz).

Reference Example 18 3S-t-butoxycarbonylamino-7-chloro-
Production of 3,4-dihydrocarbostyril The above target compound was obtained in the same manner as in Reference Example 16 using the corresponding starting materials.

NMR (270 MHz, CDCl ₃ ) δp
pm: 8.04 (1H, bs), 7.13 (1H, d,
J = 8 Hz), 7.00 ( ₁ H, dd, J ₁ = 2 Hz,
J ₂ = 8 Hz), 6.81 (1H, d, J = 2 Hz),
5.56 (1H, bs), 4.38-4.29 (1H,
m), 3.48 (1H, dd, J ₁ = 6 Hz, J ₂ = 1)
5 Hz), 2.80 (1 H, t, J = 15 Hz), 1.
48 (9H, s).

Reference Example 19 3S-t-butoxycarbonylamino-7-chloro-1
Preparation of 3-Hydroxy-3,4-dihydrocarbostyril 3S-Amino-7-chloro-1-hydroxy-3,4-
To a solution of 4.00 g of dihydrocarbostyryl hydrochloride in 30 ml of dimethylformamide, 1.64 ml of N-methylmorpholine was added with stirring under ice cooling, and subsequently 3.90 g of dimethylformamide in di-t-butyldicarbonate 10 was added.
The ml solution was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, 50 ml of water was added to the residue, solidified and collected by filtration. The crude product was washed with diethyl ether to obtain the above target compound. Yield 1.84g.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.63 (1H, s), 7.27 (1H,
d, J = 8 Hz), 7.25 (1H, d, J = 9H
z), 7.16 (1H, d, J = 2Hz), 7.06
(1H, dd, J ₁ = 2 Hz, J ₂ = 8 Hz) 4.2
8-4.24 (1H, m), 3.00 (1H, s),
2.97 (1H, d, J = 4Hz), 1.41 (9H,
s).

Reference Example 20 Production of 3S-t-butoxycarbonylamino-1-hydroxy-3,4-dihydrocarbostyril Using the corresponding starting materials, the above target compound was obtained in the same manner as in Reference Example 19.

NMR (270 MHz, CDCl ₃ ) δp
pm: 8.85 (1H, bs), 7.20 (2H, t,
J = 8 Hz), 7.01 (1H, dt, J ₁ = 1 Hz,
J ₂ = 8 Hz), 6.85 (1H, d, J = 8 Hz),
5.66 (1H, d, J = 5Hz), 4.39-4.3
1 (1H, m), 3.48 (1H, dd, J ₁ = 6H
z, J ₂ = 15 Hz), 2.85 (1H, t, J = 15)
Hz), 1.49 (9H, s).

Reference Example 21 Preparation of 3S-t-butoxycarbonylamino-1-hexyloxy-3,4-dihydrocarbostyril 3S-t-butoxycarbonylamino-1-hydroxy-3,4-dihydrocarbostyril 700 mg of dimethyl To the 5 ml solution of formamide, 111 mg of sodium hydride (containing 60%) was added under ice-cooling stirring, 15 minutes later, 641 mg of iodohexane was added, and then the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was extracted with 30 ml of ethyl acetate. The ethyl acetate layer was washed twice with 1N hydrochloric acid,
The extract was washed twice with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily residue was added to silica gel column chromatography and eluted with chloroform to obtain the above target compound. Yield 630 mg.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.30 (1H, t, J = 8Hz), 7.21
(2H, d, J = 9Hz), 7.07 (1H, td, J
_{1 = 1Hz, J 2 = 7Hz} ), 5.60 (1H, b
s), 4.37-4.32 (1H, m), 4.12 (1)
H, q, J = 7 Hz), 4.02 (1H, q, J = 7H)
z) 3.43 (1H, dd, J ₁ = 5 Hz, J ₂ = 1)
5 Hz), 2.80 (1 H, t, J = 15 Hz), 1.
82-1.70 (2H, m), 1,48 (9H, s),
1.54 to 1.30 (6H, m), 0.90 (3H,
t, J = 7 Hz).

Reference Example 22 3S- (4-t-butoxy-2R-isobutyl-3S-
Methylsuccinyl) amino-1-hexyloxy-3,
Preparation of 4-dihydrocarbostyril 3S-t-butoxycarbonylamino-1-hexyloxy-3,4-dihydrocarbostyril 630 mg was dissolved by adding 5 ml of trifluoroacetic acid, and left at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in 10 ml of tetrahydrofuran. To this solution was added triethylamine under ice-cooling stirring to neutralize, and then 247 mg of 1-hydroxybenzotriazole and 4-t-butoxy-2R-isobutyl-3S-methylsuccinic acid 446.
After adding a solution of 10 mg of tetrahydrofuran in 130 ml, triethylamine (130 μl) and dicyclohexylcarbodiimide (377 mg) were added, and the mixture was stirred under ice-cooling for 2 hours and at room temperature overnight. The insoluble matter generated from the reaction solution was filtered off, and the filtrate was concentrated under reduced pressure. The oily residue obtained was dissolved in 50 ml of ethyl acetate and extracted. The ethyl acetate layer was washed twice with saturated aqueous sodium hydrogen carbonate, 1
The extract was washed twice with N hydrochloric acid and twice with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting oily residue was added to silica gel column chromatography,
The target compound was obtained by eluting with chloroform. Yield 740 mg.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.30 (1H, t, J = 8Hz), 7.21
(2H, d, J = 9Hz), 7.07 (1H, dt, J
₁ = 1 Hz, J ₂ = 8 Hz), 6.70 (1H, d, J
= 5 Hz), 4.63-4.50 (1 H, m), 4.1
3 (1H, q, J = 8Hz), 4.02 (1H, q, J
= 8 Hz), 3.51 (1H, dd, J ₁ = 6 Hz, J
₂ = 15Hz), 2.73 (1H, t, J = 15H)
z), 2.56-2.53 (2H, m), 1.81-
1.69 (4H, m), 1.52-1.30 (6H,
m), 1.46 (9H, s), 1.18-1.09 (4
H, m), 0.95-0.86 (9H, m).

Reference Example 23 Preparation of 3S- (4-benzyloxyamino-2R-isobutyl-3S-methylsuccinyl) amino-1-hexyloxy-3,4-dihydrocarbostyril 3S- (4-t-butoxy-2R -Isobutyl-3S-
Methylsuccinyl) amino-1-hexyloxy-3,
To 740 mg of 4-dihydrocarbostyril, 5 ml of trifluoroacetic acid was added and dissolved, and the mixture was allowed to stand at room temperature for 1 hour and 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained oily residue was dissolved in 50 ml of ethyl acetate and extracted. The ethyl acetate layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate,
It was concentrated under reduced pressure. The oily residue thus obtained was dried and then dissolved in 10 ml of dimethylformamide, which was then stirred for 1 hour under ice cooling.
-Hydroxybenzotriazole (306 mg) and benzyloxyamine hydrochloride (362 mg) were added with N-methylmorpholine (231 μl) in dimethylformamide (5 ml), and then N-methylmorpholine (120 μl) and 1-ethyl-3- (3-dimethylaminopropyl). ) Carbodiimide hydrochloride (434 mg) was added, and the mixture was stirred under ice cooling for 2 hours and at room temperature overnight. The reaction solution was concentrated under reduced pressure, and 50 ml of ethyl acetate was added to the obtained oily residue for extraction. The ethyl acetate layer was washed twice with saturated aqueous sodium hydrogen carbonate, twice with 1N hydrochloric acid and twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the obtained crystalline residue, which was collected by filtration and dried to obtain the target compound. Yield 4
30 mg.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 11.10 (1H, s), 8.57 (1H,
d, J = 8 Hz), 7.40-7.35 (6H, m),
7.30 (1H, t, J = 8Hz), 7.14 (1H,
d, J = 7 Hz), 7.06 (1H, t, J = 7H
z), 4.79 (2H, s), 4.63-4.54 (1
H, m), 4.01-3.95 (2H, m), 3.05
(1H, t, J = 13Hz), 2.93 (1H, dd,
J ₁ = 7 Hz, J ₂ = 15 Hz), 2.52-2.49
(1H, m), 2.17-2.13 (1H, m), 1.
71-1.29 (10H, m), 0.97 (3H, d,
J = 7 Hz), 0.90-0.79 (10H, m).

Reference Example 24 Preparation of 3S-t-butoxycarbonylamino-1- (4-cyanobenzyl) -3,4-dihydrocarbostyril 3S-t-butoxycarbonylamino-3,4-dihydrocarbostyril 600 mg of dimethyl Formamide 5
To the ml solution, 96 mg of sodium hydride (containing 60%) was added under ice-cooling stirring, 15 minutes later, 494 mg of α-bromo-p-tolunitrile was added, and the mixture was stirred at room temperature for 2 hours. 30 ml of ethyl acetate was added to the reaction solution for extraction. The ethyl acetate layer was washed once with 1N hydrochloric acid and three times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (eluted with chloroform) to obtain the above target compound. Yield 760 mg.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.62 (2H, d, J = 8Hz), 7.32
(2H, d, J = 9 Hz), 7.25 (1H, d, J =
8 Hz), 7.17 (1H, t, J = 8 Hz), 7.0
5 (1H, td, J ₁ = 1 Hz, J ₂ = 7 Hz), 6.
77 (1H, dd, J ₁ = 1 Hz, J ₂ = 8 Hz),
5.71 (1H, bs), 5.46 (1H, d, J = 1
7 Hz), 4.97 (1 H, d, J = 16 Hz), 4.
50-4.40 (1H, m), 3.48 (1H, dd,
J ₁ = 6 Hz, J ₂ = 15 Hz), 2.88 (1H,
t, J = 15 Hz), 1.48 (9H, s).

Reference Example 25 Preparation of 3S-t-butoxycarbonylamino-1- (5-chloro-2-thienylmethyl) -3,4-dihydrocarbostyril 5-chloro-2-chloromethylthiophene and the corresponding starting material Were reacted and in the same manner as in Reference Example 24 to obtain the above target compound.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.28-7.20 (2H, m), 7.11-
7.02 (2H, m), 6.79 (1H, d, J = 4H
z), 6.72 (1H, d, J = 4Hz), 5.75
(1H, bs) 5.32 (1H, d, J = 16H
z), 5.03 (1H, d, J = 16Hz), 4.34
-4.29 (1H, m), 3.43 (1H, dd, J ₁
= 5 Hz, J ₂ = 15 Hz), 2.80 (1H, t, J
= 15 Hz), 1.48 (9H, s).

Reference Example 26 Preparation of 1-benzyloxy-3S-t-butoxycarbonylamino-3,4-dihydrocarbostyril Benzyl bromide was reacted with the corresponding starting material, and in the same manner as in Reference Example 24, the above target compound was prepared. Got

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.52-7.47 (2H, m), 7.40-
7.35 (3H, m), 7.31-7.18 (3H,
m), 7.06 (1H, td, J ₁ = 2 Hz, J ₂ = 7
Hz), 5.59 (1H, bs), 5.13 (1H,
d, J = 10 Hz), 5.03 (1H, d, J = 9H
z), 4.40-4.35 (1H, m), 3.42 (1
H, dd, J ₁ = 6 Hz, J ₂ = 15 Hz), 2.78
(1H, t, J = 15Hz), 1.48 (9H, s).

Reference Example 27 3S-t-butoxycarbonylamino-7-chloro-1
-Production of ethoxy-3,4-dihydrocarbostyril Iodoethane was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Reference Example 21.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.21 (1H, d, J = 2Hz), 7.13
(1H, d, J = 8Hz), 7.04 (1H, dd, J
_{1 = 2Hz, J 2 = 8Hz} ), 5.56 (1H, b
s), 4.35-4.29 (1H, m), 4.18 (2
H, qd, J ₁ = 7 Hz, J ₂ = 16 Hz), 3.42
(1H, dd, J ₁ = 5 Hz, J ₂ = 15 Hz), 2.
76 (1H, t, J = 15Hz), 1.47 (9H,
s), 1.40 (3H, t, J = 7Hz).

Reference Example 28 Preparation of 3S-amino-1-isobutoxy-3,4-dihydrocarbostyril Using isobutoxyamine, J. Org. Chem. 1
According to the method described in 989, 54, 3394, the above target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.15-7.35 (3H, m), 7.05 (1
H, t, J = 7Hz), 3.93 (1H, t, J = 7H
z), 3.78 (1H, t, J = 7Hz), 3.62
(1H, dd, J ₁ = 13 Hz, J ₂ = 6 Hz), 3.
10 (1H, dd, J ₁ = 15Hz, J ₂ = 6Hz),
2.83 (1H, t, J = 15 Hz), 2.05-2.
25 (1H, m), 1.08 (3H, d, J = 5H
z), 1.05 (3H, d, J = 5Hz).

Reference Example 29 3S-t-butoxycarbonylamino-1-ethoxy-
Production of 3,4-dihydrocarbostyril Iodoethane was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Reference Example 21.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.20-7.23 (3H, m), 7.07 (1
H, dt, J ₁ = 1 Hz, J ₂ = 7 Hz), 5.59
(1H, brs), 4.34 (1H, dt, J ₁ = 14
Hz, J ₂ = 6 Hz), 4.16 (1H, q, J = 7H
z), 4.13 (1H, q, J = 7Hz), 3.42
(1H, dd, J ₁ = 6 Hz, J ₂ = 14 Hz), 2.
81 (1H, t, J = 14Hz), 1.48 (9H,
s), 1.39 (3H, t, J = 7Hz).

Reference Example 30 Production of 3S-benzyloxycarbonylamino-1-ethoxymethyl-3,4-dihydrocarbostyryl ethoxymethyl chloride was reacted with the corresponding starting material, and in the same manner as in Reference Example 24, the above target compound was prepared. Got

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.39-7.28 (7H, m), 7.21 (1
H, d, J = 7 Hz), 7.09 (1H, td, J ₁ =
1 Hz, J ₂ = 7 Hz), 5.95 (1 H, bs),
5.78 (1H, d, J = 11Hz), 5.15 (2
H, s), 4.95 (1H, d, J = 11 Hz), 4.
42-4.37 (1H, m), 3.61 (2H, qd,
J ₁ = 7 Hz, J ₂ = 3 Hz), 3.46 (1H, d
d, J ₁ = 5 Hz, J ₂ = 14 Hz), 2.82 (1
H, t, J = 15Hz), 1.21 (3H, t, J = 7)
Hz).

Reference Example 31 Preparation of 3S-benzyloxycarbonylamino-1-hexyloxymethyl-3,4-dihydrocarbostyril Hexyloxymethyl chloride was reacted with the corresponding starting material, and in the same manner as in Reference Example 24, The target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.39-7.28 (7H, m), 7.21 (1
H, d, J = 7 Hz), 7.09 (1H, td, J ₁ =
1 Hz, J ₂ = 7 Hz), 5.96 (1 H, bs),
5.77 (1H, d, J = 11Hz), 5.15 (2
H, s), 4.95 (1H, d, J = 11 Hz), 4.
42-4.37 (1H, m), 3.57-3.42 (3
H, m), 2.82 (1H, t, J = 15Hz), 1.
58-1.51 (2H, m), 1.33-1.21 (6
H, m), 0.85 (3H, t, J = 7Hz).

Reference Example 32 Preparation of 3S-benzyloxycarbonylamino-1-methoxymethyl-3,4-dihydrocarbostyryl methoxymethyl chloride was reacted with the corresponding starting material, and in the same manner as in Reference Example 24, the above target compound was prepared. Got

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.15-7.50 (8H, m), 7.09 (1
H, t, J = 7 Hz), 5.95 (1H, brs),
5.70 (1H, d, J = 10Hz), 5.15 (2
H, s), 4.95 (1H, d, J = 10 Hz), 4.
41 (1H, dt, J ₁ = 14 Hz, J ₂ = 5 Hz),
3.46 (1H, dd, J ₁ = 14Hz, J ₂ = 5H
z), 3.39 (3H, s), 2.83 (1H, t, J
= 14 Hz).

Reference Example 33 1-Benzyl-3S-t-butoxycarbonylamino-
Production of 3,4-dihydrocarbostyril Benzyl bromide was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Reference Example 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.36-7.12 (7H, m), 7.01 (1
H, td, J ₁ = 7 Hz, J ₂ = 1 Hz), 6.90
(1H, d, J = 8Hz), 5.81 (1H, bs),
5.44 (1H, d, J = 16Hz), 4.91 (1
H, d, J = 16 Hz), 4.44-4.39 (1H,
m), 3.48 (1H, dd, J ₁ = 6 Hz, J ₂ = 1)
5Hz), 2.86 (1H, t, J = 15Hz), 1.
48 (9H, s).

Reference Example 34 Preparation of 3S-t-butoxycarbonylamino-1- (4-methoxycarbonylbenzyl) -3,4-dihydrocarbostyril 4-methoxycarbonylbenzyl bromide was reacted with the corresponding starting material to prepare a reference. The target compound was obtained in the same manner as in Example 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.99 (2H ,, d, J = 8Hz), 7.27
(2H, d, J = 7 Hz), 7.23 (1H, d, J =
7 Hz), 7.14 (1H, t, J = 7 Hz), 7.0
2 (1H, td, J ₁ = 1 Hz, J ₂ = 8 Hz), 6.
82 (1H, d, J = 8 Hz), 5.77 (1H, b
s), 5.48 (1H, d, J = 17 Hz), 4.97
(1H, d, J = 17 Hz), 4.48-4.39 (1
H, m), 3.90 (3H, s), 3.49 (1H, d)
d, J ₁ = 5 Hz, J ₂ = 14 Hz), 2.88 (1
H, t, J = 15 Hz), 1.49 (9H, s).

Reference Example 35 Preparation of 3S-t-butoxycarbonylamino-1- (4-methoxybenzyl) -3,4-dihydrocarbostyril 4-methoxybenzyl chloride was reacted with the corresponding starting material to give Reference Example 24. The target compound was obtained in the same manner as.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.28-7.13 (4H, m), 7.03-
6.91 (2H, m), 6.84 (2H, d, J = 9H
z), 5.81 (1H, bs), 5.34 (1H, d,
J = 16Hz), 4.88 (1H, d, J = 16H)
z), 4.41-4.36 (1H, m), 3.77 (3
H, s), 3.46 (1H, dd, J ₁ = 7 Hz, J ₂
= 16 Hz), 2.84 (1H, t, J = 15 Hz),
1.48 (9H, s).

Reference Example 36 Preparation of 3S-t-butoxycarbonylamino-1-phthalimidomethyl-3,4-dihydrocarbostyril N-bromomethylphthalimide was reacted with the corresponding starting material, and in the same manner as in Reference Example 24. The above target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.81 (2H, dd, J ₁ = 6 Hz, J ₂ = 3
Hz), 7.01 (2H, dd, J = 6.J ₁ = 14H
z, J ₂ = 3 Hz), 7.10-7.35 (3H,
m), 7.02 (1H, t, J = 7Hz), 6.24
(1H, d, J = 14 Hz), 5.75-5.90 (1
H, m), 5.74 (1H, d, J = 14 Hz), 4.
31 (1H, dt, J ₁ = 14 Hz, J ₂ = 5 Hz),
3.37 (1H, dd, J ₁ = 14Hz, J ₂ = 5H
z), 2.81 (1H, t, J = 14Hz), 1.47
(9H, s).

Reference Example 37 Preparation of 3S-t-butoxycarbonylamino-1-ethoxycarbonylmethyl-3,4-dihydrocarbostyryl Ethyl iodoacetate or ethyl bromoacetate was reacted with the corresponding starting material to give Reference Example 24. Similarly, the above target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.23 (2H, d, J = 8Hz), 7.06
(1H, t, J = 8Hz), 6.79 (1H, d, J =
8 Hz), 5.68 (1 H, brs), 4.88 (1
H, d, J = 17Hz), 4,47 (1H, d, J = 1)
7 Hz), 4.36 ( ₁ H, dt, J ₁ = 14 Hz, J
₂ = 5Hz), 4.21 (2H, q, J = 7Hz),
3.44 (1H, dd, J ₁ = 14Hz, J ₂ = 5H
z), 2.81 (1H, t, J = 14Hz), 1.47
(9H, s), 1.26 (3H, t, J = 7Hz).

Reference Example 38 3S-t-butoxycarbonylamino-7-chloro-1
-Production of ethoxycarbonylmethyl-3,4-dihydrocarbostyryl Ethyl bromoacetate was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Reference Example 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.16 (1H, d, J = 8Hz), 7.04
(1H, dd, J ₁ = 8 Hz, J ₂ = 2 Hz), 6.7
8 (1H, d, J = 2Hz), 5.64 (1H, br
s), 4.82 (1H, d, J = 18Hz), 4.45
(1H, d, J = 18Hz), 4.25-4.45 (1
H, m), 4.24 (2H, q, J = 7Hz), 3.4
3 (1H, dd, J ₁ = 15Hz, J ₂ = 5Hz),
2.82 (1H, t, J = 15Hz), 1.47 (9
H, s), 1.28 (3H, t, J = 7Hz).

Reference Example 39 Preparation of 1-benzyloxycarbonylmethyl-3S-t-butoxycarbonylamino-3,4-dihydrocarbostyril Reaction of benzyl bromoacetate with the corresponding starting material,
The target compound was obtained in the same manner as in Reference Example 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.10-7.40 (7H, m), 7.05 (1
H, t, J = 8Hz, 6.75 (1H, d, J = 8H)
z), 5.67 (1H, brs), 5.18 (2H,
s), 4.90 (1H, d, J = 18Hz), 4.56
(1H, d, J = 18Hz), 4.36 (1H, dt,
J ₁ = 14 Hz, J ₂ = 5 Hz), 3.42 (1 H, d
d, J ₁ = 14 Hz, J ₂ = 5 Hz), 2.83 (1
H, t, J = 14 Hz), 1.47 (9H, s).

Reference Example 40 Preparation of 3S-t-butoxycarbonylamino-1-carboxymethyl-3,4-dihydrocarbostyril 1-Benzyloxycarbonylmethyl-3S-t-butoxycarbonylamino-obtained in Reference Example 39 3,4-
2.98 g of dihydrocarbostyril was added to 10 m of methanol.
A solution obtained by dissolving 200 mg of 10% palladium-carbon in 10 ml of methanol was added, and the mixture was saturated with hydrogen. After stirring under atmospheric pressure for 1 day, the catalyst was filtered off and the filtrate was evaporated in vacuo to give the above-mentioned target compound as a white solid. Yield 2.0g.

NMR (270 MHz, CDCl ₃ ) δ
ppm: 7.20-7.26 (2H, m), 7.05
(1H, t, J = 7Hz), 6.81 (1H, d, J =
8 Hz), 5.69 (1 H, brs), 4.89 (1
H, d, J = 18Hz), 4.45 (1H, d, J = 1)
8 Hz), 4.31-4.38 (1 H, m), 3.37.
-3.43 (1H, m), 2.86 (1H, t, J = 1
5 Hz), 1.46 (9H, s).

Reference Example 41 Production of 3S-t-butoxycarbonylamino-1-propoxycarbonylmethyl-3,4-dihydrocarbostyril 3S-t-butoxycarbonylamino-1-carboxy-3, obtained in Reference Example 40 600 mg of 4-dihydrocarbostyril was dissolved in 10 ml of dichloromethane, 420 μl of propanol was added, the mixture was cooled in an ice bath, 247 μl of N-methylmorpholine, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride 430
mg and dimethylaminopyridine 11 mg,
Stir at room temperature for 20 hours. Evaporate the reaction solution in vacuo,
To the residue was added 40 ml of ethyl acetate and 1m hydrochloric acid 15m.
1, washed with 15 ml of a saturated sodium hydrogen carbonate aqueous solution and 10 ml of a saturated saline solution, dried over magnesium sulfate,
Evaporation in vacuo gave the desired compound as a colorless oil. Yield 600 mg.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.23 (2H, d, J = 7Hz), 7.06
(1H, t, J = 7 Hz), 6.79 (1H, d, J =
7Hz), 5.68 (1H, brs), 4.87 (1
H, d, J = 17 Hz), 4.50 (1 H, d, J = 1)
7 Hz), 4.35 ( ₁ H, dt, J ₁ = 14 Hz, J
₂ = 5Hz), 4.11 (2H, t, J = 7Hz),
3.45 (1H, dd, J ₁ = 14Hz, J ₂ = 5H
z), 2.86 (1H, t, J = 14Hz), 1.63
(2H, dq, J ₁ = 7Hz, J ₂ = 7Hz), 1.4
8 (9H, s), 0.86 (3H, t, J = 7Hz).

Reference Example 42 Production of 3S-t-butoxycarbonylamino-1-isopropoxycarbonylmethyl-3,4-dihydrocarbostyril 2-Propanol was reacted with the corresponding starting material, and in the same manner as in Reference Example 41. The above target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.23 (2H, d, J = 8Hz), 7.06
(1H, t, J = 8Hz), 6.78 (1H, d, J =
8 Hz), 5.69 (1H, brs), 4.95-5.
15 (1H, m), 4.81 (1H, d, J = 17H
z), 4.47 (1H, d, J = 17 Hz), 4.35
(1H, dt, J ₁ = 14 Hz, J ₂ = 5 Hz), 3.
45 (1H, dd, J ₁ = 14 Hz, J ₂ = 5 Hz),
2.86 (1H, t, J = 14Hz), 1.47 (9
H, s), 1.20-1.30 (6H, m).

Reference Example 43 Preparation of 3S-benzyloxycarbonylamino-1-t-butoxycarbonylmethyl-3,4-dihydrocarbostyril Reaction of t-butyl bromoacetate with the corresponding starting material was carried out in the same manner as in Reference Example 24. To obtain the above target compound.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.23-7.39 (5H, m), 7.07 (2
H, t, J = 8 Hz), 6.79 (2H, d, J = 8H)
z), 5.97 (1H, brs), 5.14 (2H,
s), 4.74 (1H, d, J = 17Hz), 4.34
-4.45 (2H, m), 3.47 (1H, dd, J ₁
= 14 Hz, J ₂ = 6 Hz), 2.88 (1H, t, J
= 14 Hz), 1.42 (9H, s).

Reference Example 44 Preparation of 1-aminocarbonylmethyl-3S-t-butoxycarbonylamino-3,4-dihydrocarbostyril Iodoacetamide was reacted with the corresponding starting material, and in the same manner as in Reference Example 24, the above target compound was prepared. Got

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.15-7.35 (2H, m), 7.05-
7.15 (2H, m), 6.13 (1H, brs),
5.60 (1H, brs), 5.44 (1H, br
s), 4.95 (1H, d, J = 16Hz), 4.38
(1H, dt, J ₁ = 14 Hz, J ₂ = 6 Hz), 4.
19 (1H, d, J = 16Hz), 3.30-3.50
(1H, m), 2.88 (1H, t, J = 14Hz),
1.47 (9H, s).

Reference Example 45 Preparation of 3S-t-butoxycarbonylamino-1- (N-methylaminocarbonylmethyl) -3,4-dihydrocarbostyril 3S-t-butoxycarbonylamino-1-carboxymethyl-3,4 -Dissolve 500 mg of dihydrocarbostyril in 10 ml of dichloromethane, and under stirring with ice cooling, 240 mg of 1-hydroxybenzotriazole, 0.21 ml of N-methylmorpholine and 358 mg of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride.
Was added and stirred for 10 minutes, and N-methylmorpholine 0.3
4 ml and 210 mg of methylamine hydrochloride were added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to give a residue.
Dichloromethane (30 ml) was added, 1N hydrochloric acid (15 ml), saturated aqueous sodium hydrogencarbonate solution (15 ml), saturated saline solution (15 ml).
It was washed with ml and dried over anhydrous magnesium sulfate. Evaporation in vacuo gave the desired compound as a white solid. Yield 5
40 mg.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.06-7.32 (4H, m), 6.12 (1
H, brs), 5.59 (1H, brs), 4.94
(1H, d, J = 16Hz), 4.34-4.44 (1
H, m), 4.10 (1H, d, J = 16 Hz), 3.
41 (1H, dd, J ₁ = 15 Hz, J ₂ = 8 Hz),
2.87 (1H, t, J = 15Hz), 2.82 (3
H, d, J = 5 Hz), 1.48 (9 H, m).

Reference Example 46 Preparation of 3S-t-butoxycarbonylamino-1- (N-propylaminocarbonylmethyl) -3,4-dihydrocarbostyril 1-Propylamine was reacted with the corresponding starting material,
The above target compound was obtained in the same manner as in Reference Example 45.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.06-7.32 (4H, m), 6.01 (1
H, brs), 5.60 (1H, brs), 4.92
(1H, d, J = 16Hz), 4.34-4.42 (1
H, m), 4.14 (1H, d, J = 16 Hz), 3.
43 (1H, dd, J ₁ = 15 Hz, J ₂ = 8 Hz),
3.22 (2H, dq, J ₁ = 2Hz, J ₂ = 7H
z), 2.86 (1H, t, J = 15Hz), 1.42
-1.53 (11H, m), 0.86 (3H, t, J =
7 Hz).

Reference Example 47 Preparation of 3S-t-butoxycarbonylamino-1- (N-methoxyaminocarbonylmethyl) -3,4-dihydrocarbostyryl methoxyamine was reacted with the corresponding starting material to give Reference Example 45. Similarly, the above target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 9.06 (1H, s), 7.15-7.40 (3
H, m), 7.09 (1H, t, J = 8 Hz), 5.5
5 (1H, brs), 4.75-4.95 (1H,
m), 4.36 (1H, dt, J ₁ = 14 Hz, J ₂ =
6 Hz), 4.00-4.20 (1 H, m), 3.78
(3H, s), 3.39 (1H, dd, J ₁ = 14H
z, J ₂ = 5 Hz), 2.86 (1H, t, J = 14H
z), 1.48 (9H, s).

Reference Example 48 3S-t-butoxycarbonylamino-1- (N, N-
Production of dimethylaminocarbonylmethyl) -3,4-dihydrocarbostyryl Dimethylamine was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Reference Example 45.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.20-7.26 (2H, m), 7.03 (1
H, t, J = 8Hz), 6.78 (1H, d, J = 8H)
z), 5.78 (1H, brs), 4.93 (1H, br)
d, J = 17 Hz), 4.50 (1H, d, J = 17H)
z), 4.34-4.43 (1H, m), 3.39-
3.46 (1H, m), 3.13 (3H, s), 2.9
9 (3H, s), 2.90 (1H, t, J = 14H
z), 1.47 (9H, s).

Reference Example 49 Preparation of 3S-t-Butoxycarbonylamino-1-morpholinocarbonylmethyl-3,4-dihydrocarbostyryl Morpholine was reacted with the corresponding starting material to prepare Reference Example 4
The above target compound was obtained in the same manner as in 5.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.22 (2H, d, J = 7Hz), 7.05
(1H, t, J = 7Hz), 6.80 (1H, d, J =
7 Hz), 5.66 (1 H, brs), 4.92 (1
H, d, J = 16Hz), 4.52 (1H, d, J = 1)
6 Hz), 4.39 ( ₁ H, dt, J ₁ = 14 Hz, J
₂ = 5 Hz), 3.73 (4H, dd, J ₁ = 15H)
z, J ₂ = 4 Hz), 3.61 (4H, dd, J ₁ = 1)
5 Hz, J ₂ = 4 Hz), 3.43 ( ₁ H, dd, J ₁
= 14 Hz, J ₂ = 5 Hz), 2.90 (1H, t, J
= 14 Hz), 1.47 (9H, s).

Reference Example 50 1-allyl-3S-t-butoxycarbonylamino-
Production of 3,4-dihydrocarbostyril Allyl bromide was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Reference Example 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.23 (1H, d, J = 8Hz), 7.21
(1H, d, J = 7 Hz), 7.06-6.99 (2
H, m), 5.94-5.82 (1H, m), 5.75
(1H, bs), 5.23-5.12 (2H, m),
4.88-4.78 (1H, m), 4.35-4.26
(2H, m) 3.44 (1H, dd, J ₁ = 5 Hz,
J ₂ = 15Hz), 2.81 (1H, t, J = 15H
z), 1.48 (9H, s).

Reference Example 51 Production of 3S-t-butoxycarbonylamino-1-cinnamyl-3,4-dihydrocarbostyril Reaction of cinnamyl bromide with the corresponding starting material,
The target compound was obtained in the same manner as in Reference Example 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.36-7.19 (7H, m), 7.10-
7.01 (2H, m), 6.54 (1H, d, J = 16
Hz), 6.24 (1H, td, J ₁ = 16 Hz, J ₂
= 6 Hz), 5.76 (1H, bs), 4.99 (1
H, ddd, J ₁ = 2 Hz, J ₂ = 5 Hz, J ₃ = 17
Hz), 4.46 (1H, ddd, J ₁ = 1 Hz, J ₂
= 6 Hz, J ₃ = 16 Hz), 4.37-4.31 (1
H, m) 3.45 (1H, dd, J ₁ = 5 Hz, J ₂
= 15 Hz), 2.83 (1H, t, J = 15 Hz),
1.48 (9H, s).

Reference Example 52 3S-t-butoxycarbonylamino-1-methyl-
Production of 3,4-dihydrocarbostyril Iodomethane was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Reference Example 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.20-7.32 (2H, m), 6.98-
7.08 (2H, m), 5.71 (1H, brs),
4.19-4.28 (1H, m), 3.48-3.50
(1H, m), 2.78 (1H, t, J = 15Hz),
1.48 (9H, s).

Reference Example 53 3S-t-butoxycarbonylamino-1-ethyl-
Production of 3,4-dihydrocarbostyril Iodoethane was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Reference Example 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.15-7.35 (2H, m), 7.03 (2
H, t, J = 7 Hz), 5.74 (1H, brs),
4.24 (1H, dt, J ₁ = 14Hz, J ₂ = 5H
z), 3.85-4.20 (2H, m), 3.41 (1
H, dd, J ₁ = 14 Hz, J ₂ = 5 Hz), 2.75
(1H, t, J = 14Hz), 1.47 (9H, s),
1.26 (3H, t, J = 7Hz).

Reference Example 54 Preparation of 1-benzyloxyethyl-3S-t-butoxycarbonylamino-3,4-dihydrocarbostyril 1-Benzyloxy-2-iodoethane was reacted with the corresponding starting material to prepare Reference Example 24. The target compound was obtained in the same manner as.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.15-7.40 (8H, m), 6.95-
7.10 (1H, m), 5.71 (1H, brs),
4.52 (2H, s), 4.15-4.35 (2H,
m), 3.95-4.15 (1H, m), 3.73 (2
H, t, J = 6 Hz), 3.39 (1H, dd, J ₁ =
14 Hz, J ₂ = 6 Hz), 2.76 (1 H, t, J =
14 Hz), 1.47 (9H, s).

Reference Example 55 Preparation of 3S-t-butoxycarbonylamino-1- (2-hydroxyethyl) -3,4-dihydrocarbostyril 1-Benzyloxyethyl-3S-t-butoxycarbonylamino-3,4- Dihydrocarbostyril 1.50
g was dissolved in 10 ml of ethanol and 20% palladium hydroxide-on-carbon (wet) 100 was added.
mg was added and saturated with hydrogen. After stirring under normal pressure for 1 day, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain the above target compound. 1.05 g.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.00-7.40 (4H, m), 5.70 (1
H, brs), 4.15-4.40 (2H, m), 3.
80-4.15 (3H, m), 3.40 (1H, dd,
J ₁ = 15Hz, J ₂ = 7Hz, 2.81 (1H,
t, J = 15 Hz), 2.23 (1H, brs), 1.
47 (9H, s).

Reference Example 56 Preparation of 3S-t-butoxycarbonylamino-1- (2-propynyl) -3,4-dihydrocarbostyril Propargyl bromide was reacted with the corresponding starting material, and in the same manner as in Reference Example 24. The above target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.21-7.35 (3H, m), 7.08 (1
H, dt, J ₁ = 1 Hz, J ₂ = 7 Hz), 5.68
(1H, brs), 4.95 (1H, dd, J ₁ = 17
Hz, J ₂ = 2 Hz), 4.47 (1H, dd, J ₁ =
17 Hz, J ₂ = 2 Hz), 4.25-4.44 (1
H, m) 3.42 (1H, dd, J ₁ = 15 Hz, J
₂ = 5Hz), 2.80 (1H, t, J = 15Hz),
2.24 (1H, t, J = 2Hz), 1.47 (9H,
s).

Reference Example 57 Preparation of 7-chloro-3S-phthalimido-3,4-dihydrocarbostyril 2.82 g of 3S-amino-7-chloro-3,4-dihydrocarbostyril was suspended in 40 ml of dimethylformamide, N-carboethoxyphthalimide (3.46 g) and sodium carbonate (1.52 g) were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, 50 ml of water was added to the residue, and the precipitate was collected by filtration. 30 ml of crude purified product
And washed with 30 ml of methanol to obtain the above-mentioned desired product as a light brown solid. Yield 4.02g.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.69 (1H, brs), 7.89-
7.97 (4H, m), 7.25 (1H, d, J = 8H
z), 7.04 (1H, dd, J ₁ = 8 Hz, J ₂ = 2
Hz), 6.95 (1H, d, J = 2Hz), 5.06
(1H, dd, J ₁ = 15 Hz, J ₂ = 7 Hz), 3.
66 (1H, t, J = 15Hz), 3.15 (1H, d
d, J ₁ = 15 Hz, J ₂ = 7 Hz).

Reference Example 58 Preparation of 3S-triphenylmethylamino-3,4-dihydrocarbostyril 2.2 S-Amino-3,4-dihydrocarbostyril 2.2
6 g was suspended in 40 ml of dimethylformamide, 5.03 g of triphenylmethyl chloride was added under stirring with ice cooling, and the pH was adjusted to 8 with triethylamine. After stirring at 0 ° C for 1 hour, the temperature was returned to room temperature, the pH was adjusted to 8 again with triethylamine, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, 100 ml of ethyl acetate was added to the residue, 1N hydrochloric acid (80 ml) and saturated aqueous sodium hydrogen carbonate solution (50
ml × 2 times), washed with saturated saline (50 ml × 2 times),
It was dried over anhydrous magnesium sulfate and evaporated in vacuo. N-Hexane was added to the residue, and the precipitate was collected by filtration to obtain the desired product. Yield 5.34g.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.52-7.57 (6H, m), 7.44 (1
H, br), 7.19-7.32 (9H, m), 7.1
0 (1H, t, J = 8Hz), 6.87 (1H, t, J
= 8 Hz), 6.69 (1H, d, J = 8 Hz), 6.
64 (1H, d, J = 8Hz), 3.41 (1H, d
d, J ₁ = 6 Hz, J ₂ = 15 Hz), 2.46 (1
H, t, J = 15 Hz), 1.65 (1H, dd, J ₁
= 6 Hz, J ₂ = 15 Hz).

Reference Example 59 Preparation of 3S- (t-butoxycarbonyl) amino-7-chloro-1-methoxy-3,4-dihydrocarbostyril Iodomethane was reacted with the corresponding starting material in the same manner as in Reference Example 21. The above target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.22 (1H, d, J = 2Hz), 7.14
(1H, d, J = 8Hz), 7.05 (1H, dd, J
_{1 = 2Hz, J 2 = 8Hz} ), 5.55 (1H, b
r), 4.34 (1H, dt, J ₁ = 14 Hz, J ₂ =
6Hz), 3.94 (3H, s), 3.42 (1H, d)
d, J ₁ = 14 Hz, J ₂ = 6 Hz), 2.77 (1
H, t, J = 14 Hz), 1.48 (9H, s).

Reference Example 60 3S- (4-hydroxy-2R-isobutyl-3S-methylsuccinyl) amino-1-methoxymethyl-3,4
-Preparation of dihydrocarbostyril 3 obtained in the same manner as in Reference Example 4 using the corresponding starting material.
S- (4-hydroxy-2R-isobutyl-3-methylenesuccinyl) amino-1-methoxymethyl-3,4-
Dihydrocarbostyril (800 mg) was dissolved in ethanol (10 ml) and 10% palladium-carbon (10 mg) was added.
0 mg) was added and saturated with hydrogen. After stirring under normal pressure for 1 day, the catalyst was filtered off and the solvent was distilled off under reduced pressure.
The above target compound was obtained. Yield 790 mg.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 8.50 (1H, d, J = 8Hz), 7.1
5-7.35 (3H, m), 7.06 (1H, t, J =
7 Hz), 5.48 (1H, d, J = 10 Hz), 5.
02 (1H, d, J = 10 Hz), 4.57 (1H, d
t, J ₁ = 14 Hz, J ₂ = 7 Hz), 3.26 (3
H, s), 3.05 (1H, t, J = 14 Hz), 2.
94 (1H, dd, J = J ₁ = 14Hz, J ₂ = 7H
z), 2.80-3.20 (1H, m), 2.20-
2.45 (1H, m), 1.40-1.70 (2H,
m), 0.90-1.20 (1H, m), 1.04 (3
H, d, J = 7Hz), 0.90 (3H, d, J = 7H
z), 0.83 (3H, d, J = 7Hz).

Reference Example 61 Preparation of 3S-benzyloxycarbonylamino-1-methoxyethoxymethyl-3,4-dihydrocarbostyryl Methoxyethoxymethyl chloride was reacted with the corresponding starting material, and the same procedure as in Reference Example 24 was repeated. The target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.20-7.50 (7H, m), 7.20 (1
H, d, J = 7 Hz), 7.09 (1H, t, J = 7H)
z), 5.92 (1H, brs), 5.82 (1H,
d, J = 11 Hz), 5.15 (2H, s), 5.01
(1H, d, J = 11 Hz), 4.40 (1H, dt,
J ₁ = 14 Hz, J ₂ = 6 Hz), 3.72 (2H, d
d, J ₁ = 5 Hz, J ₂ = 3 Hz), 3.53 (2H,
t, J = 5 Hz), 3.41 (1H, dd, J ₁ = 14)
Hz, J ₂ = 6 Hz), 3.37 (3H, s), 2.8
3 (1H, t, J = 14Hz).

Reference Example 62 Preparation of 4-t-butoxy-2R-isobutyl-3-propylsuccinic acid The aryl bromide was reacted with the corresponding starting material, and in the same manner as in Reference Example 8 the above target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 2.68 (1H, dt, J ₁ = 3 Hz, J ₂ = 9
Hz), 2.50 (1H, dt, J ₁ = 2 Hz, J ₂ =
10 Hz), 1.74-1.12 (16 H, m), 1.
45 (9H, s), 0.96-0.87 (9H, m).

Reference Example 63 Preparation of 3-benzyl-4-t-butoxy-2R-isobutylsuccinic acid Benzyl bromide was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Reference Example 8.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.26-7.16 (5H, m), 2.91-
2.74 (4H, m), 1.77-1.60 (2H,
m), 1.29-1.18 (10H, m), 1.26
(9H, s), 0.91 (6H, dd, J ₁ = 3Hz,
J ₂ = 7 Hz).

Reference Example 64 Preparation of 4-t-butoxy-2R-isobutyl-3- (4-methoxybenzyl) succinic acid 4-Methoxybenzyl chloride was reacted with the corresponding starting material in the same manner as in Reference Example 8. The above target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.09 (2H, d, J = 9Hz), 6.79
(2H, d, J = 9Hz), 3.77 (3H, s),
2.87-2.72 (4H, m), 1.72-1.59
(2H, m), 1.33-1.21 (10H, m),
1.28 (9H, s), 0.90 (6H, dd, J ₁ =
3 Hz, J ₂ = 7 Hz).

Reference Example 65 Benzyl 2-benzyloxycarbonyl-3S-t-
Production of butoxycarbonyl-5-methylhexanoate Using L-leucine, the above target compound was obtained in the same manner as in Reference Example 1.

Reference Example 66 Preparation of 3S-benzyloxycarbonylamino-1-methoxymethoxyethyl-3,4-dihydrocarbostyril 1-Iodo-2-methoxymethoxyethane was reacted with the corresponding starting material to prepare Reference Example 24. The target compound was obtained in the same manner as.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.15-7.45 (8H, m), 7.06 (1
H, t, J = 7 Hz), 6.01 (1H, brs),
5.15 (2H, s), 4.59 (2H, q, J = 6H
z), 4.25-4.40 (1H, m), 4.25 (1
H, dt, J ₁ = 14 Hz, J ₂ = 5 Hz), 4.08
(1H, dt, J ₁ = 14 Hz, J ₂ = 7 Hz), 3.
78 (2H, t, J = 5Hz), 3.44 (1H, d
d, J ₁ = 15 Hz, J ₂ = 6 Hz), 3.29 (3
H, s), 2.81 (1H, t, J = 15Hz).

Reference Example 67 Preparation of 4-t-butoxy-2R-isobutyl-3- (3-phenylpropyl) succinic acid Cinnamyl bromide was reacted with the corresponding starting material,
The target compound was obtained in the same manner as in Reference Example 8.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.29-7.13 (5H, m), 2.71-
2.50 (4H, m), 1.74-1.42 (15H,
m), 1.43 (9H, s), 1.20-1.12 (1
H, m), 0.90 (6H, d, J = 7 Hz).

Reference Example 68 Preparation of 4-t-butoxy-2R-isobutyl-3- (2-methylbenzyl) succinic acid α-Bromo-o-xylene was reacted with the corresponding starting material, and the same as in Reference Example 8 To obtain the above target compound.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.12-7.06 (4H, m), 2.91-
2.79 (4H, m), 2.29 (3H, s), 1.7
7-1.60 (2H, m), 1.29-1.17 (10
H, m), 1.25 (9H, s), 0.92 (6H, d
d, J ₁ = 1 Hz, J ₂ = 6 Hz).

Reference Example 69 Preparation of 4-t-butoxy-2R-isobutyl-3- (3-methylbenzyl) succinic acid α-Bromo-m-xylene was reacted with the corresponding starting material, and the same as in Reference Example 8 To obtain the above target compound.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.17-6.95 (4H, m), 2.89-
2.73 (4H, m), 2.29 (3H, s), 1.7
9-1.54 (2H, m), 1.31-1.20 (10
H, m), 1.27 (9H, s), 0.91 (6H, d)
d, J ₁ = 3 Hz, J ₂ = 7 Hz).

Reference Example 70 Preparation of 4-t-butoxy-2R-isobutyl-3- (4-methylbenzyl) succinic acid α-Bromo-p-xylene was reacted with the corresponding starting material, and the same as in Reference Example 8 To obtain the above target compound.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.05 (4H, s), 2.88-2.70 (4
H, m), 2.29 (3H, s), 1.76-1.59.
(2H, m), 1.33-1.17 (10H, m),
1.28 (9H, s), 0.90 (6H, dd, J ₁ =
4 Hz, J ₂ = 7 Hz).

Reference Example 71 4S-isopropyl-3- (1-oxononyl) -2-
Production of oxazolidinone 4S-isopropyl-2-oxazolidinone (1.02
g) under a nitrogen atmosphere, tetrahydrofuran (25 ml)
And was cooled to -78 ° C. n-Butyllithium (1.63M hexane solution) (5.09 ml) was added dropwise, and the mixture was stirred for 30 minutes. Next, pelargonyl chloride (5.09 ml) was added, and the mixture was stirred at -78 ° C for 1.5 hr. The reaction solution was 5% ammonium chloride aqueous solution (30 ml)
And extracted with ethyl acetate (30 ml × 2). The organic layer was washed with water (10 ml) and saturated saline (20 ml), and dried over magnesium sulfate. After evaporating the solvent, the target compound was obtained as a colorless oil. Yield 2.10g.

NMR (270 MHz, CDCl ₃ ) δp
pm: 4.40 (1H, dt, J ₁ = 8 Hz, J ₂ = 4
Hz), 4.26 (1H, t, J = 9 Hz), 4.19
(1H, dd, J ₁ = 9 Hz, J ₂ = 3 Hz) 2.7
5-3.05 (2H, m), 2.25-2.50 (1
H, m), 1.50-1.75 (2H, m), 1.15
-1.50 (10H, m), 0.91 (3H, d, J =
7Hz), 0.86 (3H, d, J = 7Hz), 0.8
0-1.00 (3H, m).

Reference Example 72 Preparation of 4S-isopropyl-3- (2R-t-butoxycarbonylmethyl-1-oxononyl) -2-oxazolidinone Diisopropylamine (1.38 ml) under a nitrogen atmosphere.
Tetrahydrofuran (25 ml) was added to
-Butyl lithium (1.63M hexane solution) (5.5
(0 ml) was added dropwise and the mixture was stirred for 15 minutes, then cooled to -78 ° C and 4S-isopropyl-3- (1-oxononyl).
A solution of 2-oxazolidinone (2.30 g) in tetrahydrofuran (5 ml) was added dropwise, and the mixture was stirred at -78 ° C for 30 minutes. Then t-butyl bromoacetate (1.66 ml)
Was added, and the temperature was gradually raised to −5 ° C. while stirring for 7 hours. The reaction mixture was poured into 5% aqueous ammonium chloride solution, extracted with ethyl acetate (20 ml × 2), and the organic layer was washed with water (20 m).
l) and a saturated saline solution (20 ml) were sequentially washed, and then dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel chromatography (eluting with hexane: ethyl acetate = 14: 1) to obtain the target compound. Yield 2.19g.

NMR (270 MHz, CDCl ₃ ) δp
pm: 4.43 (1H, dt, J ₁ = 8 Hz, J ₂ = 4
Hz), 4.10-4.35 (3H, m), 2.74.
(1H, dd, J ₁ = 16Hz, J ₂ = 10Hz),
2.42 (1H, dd, J ₁ = 16Hz, J ₂ = 4H
z), 2.30-2.55 (1H, m), 1.41 (9
H, s), 1.10-1.75 (12H, m), 0.9
3 (3H, d, J = 6Hz), 0.88 (3H, d, J
= 6 Hz), 0.80-1.10 (3H, m).

Reference Example 73 Preparation of 3S- (2R-t-butoxycarbonylmethyl-1-oxononyl) amino-1-methoxy-3,4-dihydrocarbostyril 4S-isopropyl-3- (2R-t-butoxycarbonylmethyl) -1-Oxononyl) -2-oxazolidinone (2.19 g) was added to tetrahydrofuran-water (3: 1,
It was dissolved in a mixed solvent (120 ml) and cooled to 0 ° C. Next, lithium hydroxide hydrate (479 mg) and a 30% aqueous hydrogen peroxide solution (2.94 ml) were sequentially added, and the mixture was added at 1.degree.
Stir for 5 hours. 1.5N sodium sulfite aqueous solution (2
(1.5 ml) was added, the mixture was stirred for several minutes, poured into methylene chloride (150 ml), washed successively with 1N hydrochloric acid (50 ml) and saturated brine (20 ml), and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, dimethylformamide (10 ml) was added, and the mixture was cooled with water and 3S-amino-1-
Methoxy-3,4-dihydrocarbostyryl hydrochloride (1.30 g), N-methylmorpholine (628 μ
l), 1-hydroxybenzotriazole (873m
g), dicyclohexylcarbodiimide (1.18 g)
Were sequentially added, and the mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure, ethyl acetate (50 ml) was added, and 1N hydrochloric acid (20 ml) was added.
ml), saturated aqueous sodium hydrogen carbonate solution (20 ml x
2), washed successively with saturated saline (30 ml), and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, silica gel chromatography (hexane: ethyl acetate =
The target compound was obtained by purification with 3: 1 elution). Yield 2.70g.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.15-7.40 (3H, m), 7.08 (1
H, t, J = 7 Hz, 6.63 (1H, d, J = 6H)
z), 4.60 (1H, dt, J ₁ = 14 Hz, J ₂ =
6 Hz), 3.94 (3H, s), 3.49 (1H, d
d, J ₁ = 15 Hz, J ₂ = 6 Hz), 2.76 (1
H, t, J = 15 Hz), 2.55-2.80 (2H,
m), 2.30-2.50 (1H, m), 1.45 (9
H, s), 1.20-1.80 (12H, m), 0.8
7 (3H, t, J = 7Hz).

Reference Example 74 Preparation of 7-chloro-1-methoxymethyl-3s-phthalimido-3,4-dihydrocarbostyril methoxymethyl chloride was reacted with the corresponding starting material, and in the same manner as in Reference Example 24, the above-mentioned object was carried out. The compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.86-7.93 (2H, m), 7.73-
7.79 (2H, m), 7.39 (1H, d, J = 2H
z), 7.06-7.14 (2H, m), 5.68 (1
H, d, J = 11 Hz), 5.15 (1H, dd, J ₁
= 15 Hz, J ₂ = 6 Hz), 4.99 (1H, d, J
= 11 Hz), 4.02 (1H, t, J = 6 Hz),
3.41 (3H, s), 2.97 (1H, dd, J ₁ =
14 Hz, J ₂ = 6 Hz).

Reference Example 75 3 (R, S) -benzyloxycarbonylamino-1-
Production of t-butoxyethyl-3,4-dihydrocarbostyril 1-Iodo-2-t-butoxyethane was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Reference Example 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 6.99-7.40 (9H, m), 6.00 (1
H, br), 5.12-5.17 (2H, m), 4.0.
8-4.35 (2H, m), 3.87 (1H, dt, J
_{1 = 14Hz, J 2 = 7Hz} ), 3.55-3.64
(3H, m), 2.80 (1H, t, J = 14Hz),
1.12 (9H, s).

Reference Example 76 Preparation of 1-methoxyethyl-3S-triphenylmethylamino-3,4-dihydrocarbostyryl 1-iodo-2-methoxyethane was reacted with the corresponding starting material, and the same as in Reference Example 24 To obtain the above target compound.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.49-7.54 (6H, m), 7.08-
7.31 (11H, m), 6.88 (1H, dt, J ₁
= 2 Hz, J ₂ = 8 Hz), 6.66 (1 H, d, J =
8Hz), 4.20 (1H, dt, J ₁ = 14Hz, J
₂ = 5 Hz), 3.98 (1H, dt, J ₁ = 14H
z, J ₂ = 7 Hz), 3.59 (1H, dd, J ₁ = 7)
Hz, J ₂ = 5 Hz), 3.37 (1H, dd, J ₁ =
14 Hz, J ₂ = 5 Hz), 3.34 (3 H, s),
2.36 (1H, t, J = 14Hz), 1.56 (1
H, dd, J ₁ = 14 Hz, J ₂ = 5 Hz).

Reference Example 77 Preparation of 3 (R, S) -benzyloxyamino-1-methoxyethyl-3,4-dihydrocarbostyril 1-Iodo-2-methoxyethane was reacted with the corresponding starting material to prepare a reference. The target compound was obtained in the same manner as in Example 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.19-7.40 (8H, m), 7.05 (1
H, t, J = 7 Hz), 5.99 (1H, br), 5.
15 (2H, s), 4.33 (1H, dt, J ₁ = 14
Hz, J ₂ = 5 Hz), 4.25 (1H, dt, J ₁ =
14 Hz, J ₂ = 5 Hz), 4.00 (1H, dt, J
_{1 = 14Hz, J 2 = 7Hz} ), 3.59-3.68
(2H, m) 3.44 (1H, dd, J ₁ = 14H
z, J ₂ = 5 Hz), 3.35 (1 H, s), 2.81
(1H, t, J = 14Hz).

Reference Example 78 Preparation of 4-t-butoxy-2R-isobutyl-3- (4-methoxycarbonylbenzyl) succinic acid 4-Methoxycarbonylbenzyl bromide was reacted with the corresponding starting material, and the same as in Reference Example 8 To obtain the above target compound.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.94 (2H, d, J = 8Hz), 7.25
(2H, d, J = 8Hz), 3.90 (3H, s),
2.97-2.74 (4H, m), 1.78-1.60
(2H, m), 1.29-1.18 (10H, m),
1.26 (9H, s), 0.91 (6H, dd, J ₁ =
3 Hz, J ₂ = 6 Hz).

Reference Example 79 Preparation of 4-t-butoxy-3-hexyl-2R-isobutylsuccinic acid 1-Iodohexane was reacted with the corresponding starting material,
The target compound was obtained in the same manner as in Reference Example 8.

NMR (270 MHz, CDCl ₃ ) δp
pm: 2.71 (1H, dt, J ₁ = 4 Hz, J ₂ = 9
Hz), 2.52 (1H, dt, J ₁ = 4 Hz, J ₂ =
9 Hz), 1.76-1.55 (2H, m), 1.49
(9H, s), 1.30-1.15 (11H, m),
0.99-0.88 (9H, m).

Reference Example 80 Benzyl 2-benzyloxycarbonyl-3R-t-
Production of butoxycarbonyl-heptanoate D-norleucine was reacted with the corresponding starting material to obtain the target compound in the same manner as in Reference Example 1.

Reference Example 81 4-t-butoxy-2R-isobutyl-3- (3,4-
Production of methylenedioxybenzyl) succinic acid 3,4-methylenedioxybenzyl chloride was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Reference Example 8.

NMR (270 MHz, CDCl ₃ ) δp
pm: 6.71-6.60 (3H, m), 5.91 (2
H, s), 2.83-2.69 (4H, m), 1.75.
-1.56 (2H, m), 1.32 (9H, s), 1.
25-1.16 (1H, m), 0.90 (6H, dd,
J ₁ = 3 Hz, J ₂ = 7 Hz).

Reference Example 82 Preparation of 4-t-butoxy-3- (3-ethoxycarbonylpropyl) -2R-isoptylsuccinic acid Ethyl 4-bromocrotonate was reacted with the corresponding starting material, and in the same manner as in Reference Example 8. The above target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 4.12 (2H, q, J = 7Hz), 2.73-
2.63 (1H, m), 2.53-2.46 (1H,
m), 2.34-2.29 (2H, m), 1.73-
1.51 (6H, m), 1.46 (9H, s), 1.2
8-1.16 (4H, m), 1.25 (3H, t, J =
7Hz), 0.90 (6H, d, J = 6Hz).

Reference Example 83 Preparation of 1-Ethoxymethyl-3S-triphenylmethylamino-3,4-dihydrocarbostyryl ethoxymethyl chloride was reacted with the corresponding starting material, and in the same manner as in Reference Example 24, the above target compound was prepared. Got

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.52 (6H, d, J = 7Hz), 7.10-
7.40 (11H, m), 6.93 (1H, dt, J ₁
= 1 Hz, J ₂ = 7 Hz), 6.68 (1 H, d, J =
7 Hz), 5.76 (1 H, d, J = 10 Hz), 4.
94 (1H, d, J = 10 Hz), 3.45-3.60
(2H, m) 3.43 (1H, dd, J ₁ = 14H
z, J ₂ = 5 Hz), 2.44 (1H, t, J = 14H
z), 1.67 (1H, dd, J ₁ = 14 Hz, J ₂ =
5Hz), 1.19 (3H, t, J = 7Hz).

Reference Example 84 Preparation of O-butyl-D-serine 60% sodium hydride (28.8 g), imidazole (1.08 g) and dry tetrahydrofuran (270 m)
l) to the mixed solution at -15 ° C, N-trityl-D-serine (25.0 g) and dry tetrahydrofuran (150 m).
The mixed solution of l) was added dropwise over 15 minutes, and the mixture was stirred at -15 ° C for 45 minutes. Butyl iodide (65.5 ml) was added thereto, and the mixture was stirred at -15 ° C for 2 hours. Furthermore, 60 at -15 ° C
% Sodium hydride (12.0 g) and butyl iodide (129 ml) were added, and the mixture was stirred at -20 ° C for 1 day. Water (1 liter) was added to the reaction solution, and diethyl ether (3
The organic layer was washed with 5% aqueous citric acid solution (200 ml) and saturated saline (100 ml), and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained oily product was added with a 50% acetic acid-ethanol solution (1
(00 ml) was added, and the mixture was stirred at room temperature for 15 hours. The precipitate is collected by filtration, washed with ethanol and diethyl ether,
6.11 g of the above target compound was obtained.

NMR (270 MHz, D ₂ O) δpp
m: 3.75-4.00 (3H, m), 3.50-3.
70 (2H, m), 1.57 (2H, dt, J ₁ = 14
Hz, J ₂ = 7 Hz), 1.33 (2H, dt, J ₁ =
14 Hz, J ₂ = 7 Hz), 0.90 (3H, t, J =
7 Hz).

Reference Example 85 Benzyl 2-benzyloxycarbonyl-3S-t-
Production of butoxycarbonyl-4-butoxy-butyrate O-butyl-D-serine was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Reference Example 1.

Reference Example 86 Synthesis of O-nitrophenyl-L-alanine N-acetyl-O-nitrophenyl-DL-alanine (324 g) was added to a 1N sodium hydroxide aqueous solution (1.8 g).
1 liter) was added and dissolved, and the acylase (9.0
g) and cobalt (II) chloride hexahydrate (100 mg) were sequentially added, and the mixture was stirred at 37 ° C. at 2. After filtering the insoluble matter, the filtrate was evaporated under reduced pressure, and the precipitated crystals were filtered and washed with a small amount of water to give the above target compound 99.6.
g was obtained.

Reference Example 87 Preparation of 3S- (4-hydroxy-2-isobutyl-3-methylthiomethylsuccinyl) amino-3,4-dihydrocarbostyril 3S- (4-Hydroxy-2-isobutyl-3-acetylthiomethyl) Succinyl) amino-3,4-dihydrocarbostyril (800 mg) and methanol (10 m
The mixture of 1) was ice-cooled, 1N aqueous sodium hydroxide solution (8 ml) was added, and the mixture was stirred under ice-cooling for 40 minutes. Methyl iodide (430 μl) was added, and the mixture was further stirred under ice cooling for 2 hours. 1N Hydrochloric acid (10 ml) was added, and the precipitated crystals were collected by filtration to give the target compound as a yellow solid (330 mg).

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.22 (1H, s), 8.47 (1H,
d, J = 8 Hz, 7.18 (2H, q, J = 8H)
z), 6.89 (2H, dd, J ₁ = 11 Hz, J ₂ =
8 Hz), 4.43 ( ₁ H, dt, J ₁ = 14 Hz, J
₂ = 7 Hz), 2.80-3.20 (3H, m), 2.
40-2.80 (3H, m), 2.04 (3H, s),
1.35-1.70 (2H, m), 0.90-1.05
(1H, m), 0.87 (3H, d, J = 7Hz),
0.83 (3H, d, J = 7Hz).

Reference Example 88 Preparation of 3S-amino-1-ethoxyethoxy-3,4-dihydrocarbostyril Sodium hydride (oil, 186 mg) was added to hexane (2
ml) and washed twice, dimethylformamide (14m
l) and suspended under ice-cooling, 3S-amino-1-hydroxy-3,4-dihydrocarbostyryl hydrochloride (500
mg) was added, and the mixture was stirred under ice cooling for 20 minutes and at room temperature for 1 hour. Ice-cooling again, and 2-iodoethyl ethyl ether (5
13 mg) was added, and the mixture was stirred under ice cooling for 20 minutes and at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was mixed with water (30
ml) was added, the mixture was extracted twice with dichloromethane (30 ml), the organic layers were combined, washed with saturated brine (30 ml), and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the above target compound (522 mg).

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.40 (1H, t, J = 8Hz), 7.10-
7.35 (2H, m), 7.05 (1H, t, J = 8H
z), 4.20-4.35 (2H, m), 3.60-
3.80 (2H, m), 3.65 (1H, dd, J ₁ =
13 Hz, J ₂ = 6 Hz), 3.53 (2H, q, J =
7 Hz), 3.10 ( ₁ H, dd, J ₁ = 15 Hz, J
₂ = 6Hz), 2.86 (1H, t, J = 15Hz),
1.23 (3H, t, J = 7Hz).

Reference Example 89 3S-amino-1-methoxymethoxyethoxy-3,4
-Production of dihydrocarbostyril Using 1-iodo-2-methoxymethoxyethane, the above target compound was obtained in the same manner as in Reference Example 88.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.37 (1H, d, J = 7Hz), 7.33
(1H, d, J = 7Hz), 7.20 (1H, d, J =
7 Hz), 7.05 ( ₁ H, td, J ₁ = 7 Hz, J ₂
= 1 Hz), 4.68 (2H, s), 4.20-4.4
0 (2H, m), 3.75-3.95 (2H, m),
3.64 (1H, dd, J ₁ = 13Hz, J ₂ = 6H
z), 3.38 (3H, s), 3.11 (1H, dd,
J ₁ = 15 Hz, J ₂ = 6 Hz), 2.85 (1H,
t, J = 15 Hz).

Reference Example 90 3S-t-butoxycarbonylamino-1-methoxy-
Production of 7-methoxy-3,4-dihydrocarbostyril Using the corresponding starting material, the above target compound was obtained in the same manner as in Reference Example 21.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.11 (1H, d, J = 8Hz), 6.79
(1H, d, J = 2Hz), 6.60 (1H, dd, J
_{1 = 8Hz, J 2 = 2Hz} ), 5.57 (1H, br
s), 4.33 (1H, dt, J ₁ = 14 Hz, J ₂ =
6 Hz), 3.92 (3H, s), 3.82 (3H,
s), 3.36 (1H, dd, J ₁ = 14 Hz, J ₂ =
4Hz), 2.73 (1H, t, J = 14Hz), 1.
48 (9H, s).

Reference Example 91 3S-t-butoxycarbonylamino-1-ethoxy-
Production of 7-methoxy-3,4-dihydrocarbostyril Ethyl iodide was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Reference Example 21.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.11 (1H, d, J = 8Hz), 6.79
(1H, d, J = 3Hz), 6.59 (1H, dd, J
_{1 = 8Hz, J 2 = 3Hz} ), 5.57 (1H, br
s), 4.31 (1H, dt, J ₁ = 14 Hz, J ₂ =
6 Hz), 4.05-4.25 (2H, m), 3.82
(3H, s), 3.37 (1H, dd, J ₁ = 15H
z, J ₂ = 6 Hz), 2.72 (1H, t, J = 15H)
z), 1.49 (9H, s), 1.38 (3H, t, J
= 7 Hz).

Reference Example 92 Preparation of 3-t-butoxycarbonylamino-1-methoxyethyl-6,7-methylenedioxy-3,4-dihydrocarbostyril 1-Iodo-2-methoxyethane and corresponding starting materials Was reacted in the same manner as in Reference Example 24 to obtain the above target compound.

NMR (270 MHz, CDCl ₃ ) δp
pm: 6.89 (1H, s), 6.65 (1H, s),
5.94 (2H, dd, J ₁ = 1 Hz, J ₂ = 2H
z), 5.70 (1H, bs), 4.25-4.14.
(2H, m), 3.93-3.82 (1H, m), 3.
62-3.60 (2H, m), 3.34 (3H, s),
_{3.29-3.23 (1H, dd, J 1} = 5Hz, J 2
= 14 Hz), 2.67 (1 H, t, J = 15 Hz),
1.47 (9H, s).

Reference Example 93 Preparation of 3-benzyloxycarbonylamino-6,7-dimethoxy-1-methoxymethyl-3,4-dihydrocarbostyril Reaction of methoxymethyl chloride with the corresponding starting material gave Reference Example 24 and Similarly, the above target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.30-7.34 (5H, m), 6.96 (1
H, s), 6.71 (1H, s), 5.96 (1H, b)
rs), 5.71 (1H, d, J = 11 Hz), 5.1
5 (2H, s), 4.89 (1H, d, J = 11H
z), 4.38 (1H, dt, J ₁ = 14 Hz, J ₂ =
5 Hz), 3.88 (3H, s), 3.86 (3H,
s), 3.40 (3H, s), 3.36 (1H, dd,
J ₁ = 14 Hz, J ₂ = 5 Hz), 2.76 (1H,
t, J = 14 Hz).

Reference Example 94 Preparation of 3-amino-6,7-dimethoxy-3,4-dihydrocarbostyryl hydrochloride Using 2-nitro-4.5-dimethoxybenzyl chloride, J. Med, Chem. , 1972, 15, 325
The above target compound was produced according to the method described in 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.49 (1H, s), 8.52 (3H,
s), 6.92 (1H, s), 6.56 (1H, s),
4.06-4.16 (1H, m), 3.72 (3H,
s), 3.70 (3H, s), 3.12 (1H, dd,
J ₁ = 14 Hz, J ₂ = 7 Hz), 2.98 (1H,
t, J = 14 Hz).

Reference Example 95 Preparation of 8-methoxy-1-methoxyethyl-3S-tritylamino-3,4-dihydrocarbostyril 1-iodo-2-methoxyethane was reacted with the corresponding starting material, and Reference Example 24. The target compound was obtained in the same manner as.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.49-7.45 (6H, m), 7.30-
7.18 (9H, m), 6.90 (1H, t, J = 8H
z), 6.74 (1H, d, J = 8 Hz), 6.25
(1H, d, J = 8Hz), 4.45 (2H, m),
4.14-4.09 (1H, m), 3.80 (3H,
s), 3.49-3.41 (2H, m), 3.28 (1
H, dd, J ₁ = 5 Hz, J ₂ = 14 Hz) 3.23
(3H, s), 2.36 (1H, t, J = 14Hz),
1.28 (1H, dd, J ₁ = 5Hz, J ₂ = 15H
z).

Reference Example 96 Preparation of 1-methoxyethoxy-3S-triphenylmethylamino-3,4-dihydrocarbostyril 1-iodo-2-methoxyethane was reacted with the corresponding starting material and the same as in Reference Example 24. To obtain the above target compound.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.51-7.56 (6H, m), 7.22-
7.32 (11H, m), 6.91 (1H, dt, J ₁
= 2 Hz, J ₂ = 7 Hz), 6.66 (1 H, d, J =
7 Hz), 4.23-4.30 (1 H, m), 4.08
-4.20 (1H, m), 3.95 (1H, d, J = 3)
Hz), 3.63-3.76 (2H, m), 3.44
(1H, ddd, J ₁ = 14 Hz, J ₂ = 5 Hz, J ₃
= 3 Hz), 3.39 (3H, s), 2.33 (1H,
t, J = 14 Hz), 1.56 (1H, dd, J ₁ = 1)
4 Hz, J ₂ = 5 Hz).

Reference Example 97 Preparation of 3S-amino-1-methoxyethoxymethoxyethoxy-3,4-dihydrocarbostyril 1-Iodo-2-methoxyethoxymethoxyethane was reacted with the corresponding starting material to give Reference Example 88. Similarly, the above target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.10-7.45 (3H, m), 7.06 (1
H, td, J ₁ = 7 Hz, J ₂ = 2 Hz), 4.77
(2H, s), 4.20-4.40 (2H, m), 3.
75-3.95 (2H, m), 3.45-3.75 (5
H, m), 3.38 (3H, s), 3.11 (1H, d)
d, J ₁ = 15 Hz, J ₂ = 6 Hz), 2.86 (1
H, t, J = 15 Hz).

Reference Example 98 3S-amino-1-methoxyethoxyethoxy-3,4
-Production of Dihydrocarbostyril 1-Iodo-2-methoxyethoxyethane was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Reference Example 88.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.39 (1H, t, J = 7Hz), 7.10-
7.35 (2H, m), 7.05 (1H, t, J = 7H
z), 4.20-4.40 (2H, m), 3.70-
3.90 (2H, m), 3.50-3.70 (5H,
m), 3.40 (3H, s), 3.10 (1H, dd,
J ₁ = 15 Hz, J ₂ = 6 Hz), 2.86 (1H,
t, J = 15 Hz).

Reference Example 99 Preparation of 6,7-methylenedioxy-3S-triphenylmethylamino-3,4-dihydrocarbostyril Using triphenylmethyl chloride and the corresponding starting material, the same procedure as in Reference Example 58 was repeated. The target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.63 (1H, brs), 7.56-7.52
(6H, m), 7.32-7.19 (9H, m), 6.
24 (1H, s), 6.15 (1H, s), 5.85
(2H, s), 3.98 (1H, brs), 3.35
(1H, dd, J ₁ = 5 Hz, J ₂ = 14 Hz), 2.
33 (1H, t, J = 14Hz), 1.47 (1H, d
d, J ₁ = 6 Hz, J ₂ = 15 Hz).

Reference Example 100 Preparation of 1-methoxymethyl-3S-triphenylmethylamino-6,7-methylenedioxy-3,4-dihydrocarbostyril Using chloromethyl methyl ether and the corresponding starting material, Reference Example 24 The target compound was obtained in the same manner as.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.50-7.54 (6H, m), 7.15-
7.29 (9H, m), 6.82 (1H, s), 6.1
3 (1H, s), 5.86 (2H, s), 5.61 (1
H, d, J = 11 Hz), 4.84 (1H, d, J = 1)
1Hz), 3.39 (1H, dd, J ₁ = 5Hz, J ₂
= 15 Hz), 3.31 (3 H, s), 2.30 (1
H, t, J = 15 Hz), 1.48 (1H, dd, J =
5.15 Hz).

Reference Example 101 Preparation of 1-hexyloxymethyl-6,7-methylenedioxy-3S-triphenylmethylamino-3,4-dihydrocarbostyril Using chloromethylhexyl ether and the corresponding starting material, Reference Example The above target compound was obtained in the same manner as in 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.53-7.50 (6H, m), 7.29-
7.19 (9H, m), 6.90 (1H, s), 6.1
3 (1H, s), 5.87 (2H, s), 5.70 (1
H, d, J = 11 Hz), 4.86 (1H, d, J = 1)
1 Hz), 4.10 (1H, brs), 3.51-3.
34 (3H, m), 2.28 (1H, t, J = 14H
z), 1.56-1.27 (9H, m), 0.87 (3
H, t, J = 5 Hz).

Reference Example 102 Preparation of 1-methoxyethoxymethyl-3S-triphenylmethylamino-6,7-methylenedioxy-3,4-dihydrocarbostyril Using methyl methoxyethyl iodide and the corresponding starting material. And reacted to obtain the above target compound in the same manner as in Reference Example 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.49-7.53 (6H, m), 7.18-
7.31 (9H, m), 6.92 (1H, s), 6.1
4 (1H, s), 5.87 (1H, d, J = 1Hz),
5.86 (1H, d, J = 1 Hz), 5.75 (1H,
d, J = 11 Hz), 4.91 (1H, d, J = 11H)
z), 4.04 (1H, brs), 3.49-3.72.
(4H, m), 3.38 (3H, s), 3.36 (1
H, dd, J ₁ = 5 Hz, J ₂ = 15 Hz), 2.31
(1H, t, J = 15Hz), 1.49 (1H, dd,
J ₁ = 5 Hz, J ₂ = 15 Hz).

Reference Example 103 Preparation of 1-methoxymethoxyethyl-3S-triphenylmethylamino-6,7-methylenedioxy-3,4-dihydrocarbostyril Using methyl iodide methylmethoxymethyl ether and the corresponding starting material, The target compound was obtained in the same manner as in Reference Example 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.48-7.55 (6H, m), 7.18-
7.36 (9H, m), 6.75 (1H, s), 6.1
2 (1H, s), 5.88 (1H, d, J = 2Hz),
5.86 (1H, d, J = 2Hz), 4.54-4.6
2 (2H, m), 4.16-4.21 (1H, m),
3.93-4.03 (1H, m), 3.70-3.77
(2H, m) 3.31 (1H, dd, J ₁ = 5Hz,
J ₂ = 15 Hz), 3.26 (3H, s), 2.27
(1H, t, J = 15Hz), 1.35 (1H, dd,
J ₁ = 5 Hz, J ₂ = 15 Hz).

Reference Example 104 Preparation of 1- (4-methoxybenzyl) -3S-triphenylmethylamino-6,7-methylenedioxy-3,4-dihydrocarbostyril 4-methoxybenzyl chloride and the corresponding starting materials were prepared. Using, in the same manner as in Reference Example 24, the above target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.53-7.56 (6H, m), 7.20-
7.33 (9H, m), 7.04-7.08 (2H,
m), 6.80-6.85 (2H, m), 6.38 (1
H, s), 6.13 (1H, s), 5.82 (1H,
d, J = 2 Hz), 5.79 (1H, d, J = 2H)
z), 4.22 (1H, brs), 3.79 (3H,
s), 3.45 (1H, dd, J ₁ = 5 Hz, J ₂ = 1)
5 Hz), 2.32 (1 H, t, J = 15 Hz), 1.
46 (1H, dd, J ₁ = 5 Hz, J ₂ = 15 Hz).

Reference Example 105 1-Ethoxyethyl-6,7-methylenedioxy-3S
-Manufacture of triphenylmethylamino-3,4-dihydrocarbostyril Using ethyl ethyl iodide and the corresponding starting material, the above target compound was obtained in the same manner as in Reference Example 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.52-7.48 (6H, m), 7.31-
7.18 (9H, m), 6.81 (1H, s), 6.1
1 (1H, s), 5.87 (2H, d, J = 3Hz),
4.18-4.09 (2H, m), 3.92-3.84
(1H, m), 3.62 (2H, dd, J ₁ = 5Hz,
J ₂ = 7 Hz), 3.54-3.43 (2H, m),
3.30 (1H, dd, J ₁ = 5Hz, J ₂ = 14H
z), 2.27 (1H, t, J = 14Hz), 1.37
(1H, dd, J ₁ = 5 Hz, J ₂ = 15 Hz), 1.
16 (3H, t, J = 7Hz).

Reference Example 106 Preparation of 1-hexyl-6,7-methylenedioxy-3S-triphenylmethylamino-3,4-dihydrocarbostyril Using hexane iodide and the corresponding starting material, Reference Example 24
The target compound was obtained in the same manner as.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.57-7.48 (6H, m), 7.31-
7.18 (9H, m), 6.49 (1H, s), 6.1
1 (1H, s), 5.87 (2H, d, J = 4Hz),
4.27 (1H, brs), 3.99-3.90 (1
H, m), 3.82-3.74 (1H, m), 3.27.
(1H, dd, J ₁ = 5 Hz, J ₂ = 14 Hz), 2.
22 (1H, t, J = 15Hz), 1.56-1.50
(2H, m), 1.36-1.24 (7H, m), 0.
88 (3H, t, J = 6Hz).

Reference Example 107 1-phenethyl-3S-triphenylmethylamino-
Preparation of 6,7-methylenedioxy-3,4-dihydrocarbostyril Using phenethyl iodide and the corresponding starting material, Reference Example 2
The target compound was obtained in the same manner as in 4.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.49-7.53 (6H, m), 7.19-
7.32 (14H, m), 6.44 (1H, s), 6.
12 (1H, s), 5.89 (1H, d, J = 1H
z), 5.87 (1H, d, J = 1 Hz), 4.11-
4.22 (2H, m), 3.94-4.05 (1H,
m), 3.27 (1H, dd, J ₁ = 5 Hz, J ₂ = 1)
5Hz), 2.83-2.92 (2H, m), 2.16
(1H, t, J = 15Hz), 1.32 (1H, dd,
J ₁ = 5 Hz, J ₂ = 15 Hz).

Reference Example 108 1-Ethoxymethyl-6,7-methylenedioxy-3S
-Production of triphenylmethylamino-3,4-dihydrocarbostyril Using chloromethyl ethyl ether and the corresponding starting material, the above target compound was obtained in the same manner as in Reference Example 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.53-7.49 (6H, m), 7.31-
7.18 (9H, m), 6.90 (1H, s), 6.1
3 (1H, s), 5.87 (2H, dd, J ₁ = 1H
z, J ₂ = 3 Hz), 5.71 (1H, d, J = 11H)
z), 4.85 (1H, d, J = 11 Hz), 4.10
(1H, brs), 3.53 (2H, qd, J ₁ = 4H
z, J ₂ = 7 Hz), 3.36 (1H, dd, J ₁ = 5)
Hz, J ₂ = 14 Hz), 2.30 (1H, t, J = 1)
5 Hz), 1.46 ( ₁ H, dd, J ₁ = 5 Hz, J ₂
= 15 Hz), 1.20 (3H, t, J = 7Hz).

Reference Example 109 Preparation of 3S-Amino-6,7-methylenedioxy-1-propyl-3,4-dihydrocarbostyril Using propyl iodide and the corresponding starting material, Reference Example 88.
The target compound was obtained in the same manner as.

NMR (270 MHz, CDCl ₃ ) δp
pm: 6.68 (1H, s), 6.57 (1H, s),
5.94 (2H, s), 3.70-4.00 (2H,
m), 3.62 (1H, dd, J ₁ = 6 Hz, J ₂ = 1)
4 Hz), 2.99 ( ₁ H, dd, J ₁ = 6 Hz, J ₂
= 14 Hz), 2.84 (1H, t, J = 14 Hz),
1.50-1.90 (2H, m), 0.94 (3H,
t, J = 7 Hz).

Reference Example 110 1-carbamoylmethyl-6,7-methylenedioxy-
Production of 3S-triphenylmethylamino-3,4-dihydrocarbostyril Using 2-iodoacetamide and the corresponding starting material, the above target compound was obtained in the same manner as in Reference Example 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.52 (6H, d, J = 7Hz), 7.10-
7.40 (9H, m), 6.64 (1H, s), 6.1
9 (1H, s), 5.96 (1H, brs), 5.88
(1H, s), 5.86 (1H, s), 5.36 (1
H, brs), 4.78 (1H, d, J = 16Hz),
4.10 (1H, d, J = 16Hz), 3.82 (1
H, brs), 3.39 (1H, dd, J ₁ = 5 Hz,
J ₂ = 14Hz, 2.32 (1H, t, J = 14H)
z), 1.65 (1H, dd, J ₁ = 5 Hz, J ₂ = 1
5 Hz).

Reference Example 111 1-t-Butoxycarbonylmethyl-6,7-methylenedioxy-3S-triphenylmethylamino-3,4-
Production of Dihydrocarbostyril Using t-butyl bromoacetate and the corresponding starting material, the above target compound was obtained in the same manner as in Reference Example 24.

NMR (270 MHz, CDCl ₃ ) δp
pm: 7.51 (6H, d, J = 7Hz), 7.10-
7.40 (9H, m), 6.29 (1H, s), 6.1
4 (1H, s), 5.87 (1H, s), 5.85 (1
H, s), 4.62 (1H, d, J = 17 Hz), 4.
35 (1H, d, J = 17 Hz), 4.10 (1H,
s), 3.35 (1H, dd, J ₁ = 5 Hz, J ₂ = 1)
4 Hz), 2.32 (1 H, t, J = 14 Hz), 1.
42 (9H, s), 1.30-1.60 (1H, m).

Reference Example 112 Preparation of 3S-Amino-1-methyl-6,7-methylenedioxy-3,4-dihydrocarbostyril Using methyl iodide and the corresponding starting material, the same procedure as in Reference Example 88 was repeated. The target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 6.68 (1H, s), 6.57 (1H, s),
5.95 (2H, s), 3.49 (1H, dd, J ₁ =
6 Hz, J ₂ = 13 Hz), 3.34 (3 H, s),
2.80-3.00 (1H, m), 2.75 (1H, m
t, J = 13 Hz).

Reference Example 113 Preparation of 3S-amino-1-ethyl-6,7-methylenedioxy-3,4-dihydrocarbostyril Using ethyl iodide and the corresponding starting material, the same procedure as in Reference Example 88 was repeated. The target compound was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 6.67 (1H, s), 6.60 (1H, s),
5.94 (2H, s), 3.80-4.10 (2H,
m), 3.48 (1H, dd, J ₁ = 6 Hz, J ₂ = 1)
4 Hz), 2.91 ( ₁ H, dd, J ₁ = 7 Hz, J ₂
= 14 Hz), 2.72 (1H, t, J = 14 Hz),
1.26 (3H, t, J = 7Hz).

Example 1 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-3,4-dihydrocarbostyril 3S- [4- (N-benzyloxyamino) -2R-isobutyl Succinyl] amino-3,4-dihydrocarbostyril 240 mg was dissolved in ethanol 10.8 ml, cyclohexene 1.2 ml and 10% palladium-
Carbon (60 mg) was added, and the mixture was stirred under reflux for 20 minutes. The catalyst is filtered off and the filtrate is concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica gel 20 g, chloroform / methanol = 20/1 V / V) to obtain the above target compound as a white solid. Yield 110 mg.

[Α] _D = −49 ° (c = 1, methanol) NMR (270 MHz, DMSO-d ₆ ) δppm: 1
0.38 (1H, brs), 10.20 (1H, s),
8.70 (1H, brs), 8.15 (1H, d, J =
8 Hz), 7.16 (2H, t, J = 7 Hz), 6.9
0 (2H, dd, J ₁ = 16Hz, J ₂ = 8Hz),
4.44 (1H, dt, J ₁ = 12Hz, J ₂ = 8H
z), 2.70-3.00 (3H, m), 2.17 (1
H, dd, J ₁ = 14 Hz, J ₂ = 6 Hz), 2.04
(1H, dd, J ₁ = 14 Hz, J ₂ = 7 Hz), 1.
40-1.70 (2H, m), 1.00-1.30 (1
H, m), 0.86 (6H, dd, J ₁ = 12Hz, J
₂ = 6 Hz).

Example 2 3S-was carried out in the same manner as in Example 1 using the corresponding starting materials.
[4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-7-methoxy-3,4-dihydrocarbostyril was obtained.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.36 (1H, brs), 10.14
(1H, s), 8.70 (1H, s), 8.13 (1
H, d, J = 8Hz), 7.08 (1H, d, J = 8H
z), 6.51 (1H, dd, J ₁ = 8 Hz, J ₂ = 2
Hz), 6.46 (1H, d, J = 2Hz), 4.42
(1H, dt, J ₁ = 13 Hz, J ₂ = 8 Hz), 3.
70 (3H, s), 2.65-3.00 (3H, m),
2.17 (1H, dd, J ₁ = 14Hz, J ₂ = 6H
z), 2.01 (1H, dd, J ₁ = 14 Hz, J ₂ =
7 Hz), 1.20-1.70 (2H, m), 1.00
-1.20 (1H, m), 0.86 (6H, dd, J 1
= 13 Hz, J ₂ = 6 Hz).

Example 3 3S-was carried out in the same manner as in Example 1 using the corresponding starting materials.
[4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril was obtained.

[Α] _D = −19 ° (c = 1, methanol) NMR (270 MHz, DMSO-d ₆ ) δppm: 1
0.40 (1H, brs), 8.71 (1H, br)
s), 8.36 (1H, d, J = 8Hz), 7.31
(2H, dd, J ₁ = 16 Hz, J ₂ = 8 Hz), 7.
16 (1H, d, J = 8Hz), 7.07 (1H, t,
J = 8 Hz), 4.60 (1H, dt, J ₁ = 13H
z, J ₂ = 8 Hz), 3.82 (3H, s), 2.85
-3.15 (2H, m), 2.70-2.85 (1H,
m), 2.18 (1H, dd, J ₁ = 14 Hz, J ₂ =
6Hz), 2.01 (1H, dd, J ₁ = 14Hz, J
₂ = 8 Hz), 1.40 to 1.75 (2H, m), 1.
00-1.15 (1H, m), 0.87 (6H, dd,
J ₁ = 13 Hz, J ₂ = 6 Hz).

Example 4 3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-acetylthiomethylsuccinyl] amino-
Production of 3,4-dihydrocarbostyril 330 mg of 3S- (4-hydroxy-2R-isobutyl-3S-acetylthiomethylsuccinyl) amino-3,4-dihydrocarbostyril, a mixed solvent of 1 ml of dimethylformamide and 3.5 ml of dichloromethane. Dissolved in water, cooled in an ice bath, 110 mg of 1-hydroxybenzotriazole, 107 μl of N-methylmorpholine, 1
-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (186 mg) was added, and the mixture was stirred in an ice bath for 1 hour.
Add the solution dissolved in. After stirring for 1 hour in an ice bath, the reaction solution is concentrated under reduced pressure. Butanol 10 ml
The residue was dissolved in, washed with 5 ml of water and evaporated in vacuo. The residue was subjected to column chromatography (silica gel 20 g, chloroform / methanol = 20/1 V /
Purification according to V) gave the above target compound as a white solid. Yield 45 mg.

[Α] _D = −49 ° (c = 1, methanol) NMR (270 MHz, DMSO-d ₆ ) δppm: 1
0.61 (1H, s), 10.23 (1H, s), 8.
92 (1H, s), 8.51 (1H, d, J = 8H
z), 7.10-7.20 (2H, m), 6.91 (2
H, dd, J ₁ = 15 Hz, J ₂ = 8 Hz), 4.51
(1H, q, J = 9Hz), 2.80-3.20 (4
H, m), 1.40 to 1.60 (2H, m), 0.80
-1.00 (1H, m), 0.83 (6H, dd, J ₁
= 12 Hz, J ₂ = 6 Hz).

Example 5 3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-mercaptomethylsuccinyl] amino-
Preparation of 3,4-dihydrocarbostyril 3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-acetylthiomethylsuccinyl] amino-
14 mg of 3,4-dihydrocarbostyril was dissolved in 1 ml of methanol, and 200 μl of a 40% methylamine / methanol solution was added dropwise. After stirring at room temperature for 1 hour, the precipitated crystals were filtered to obtain the above target compound as a white solid. Yield 4 mg.

NMR (270 MHz, DMSO-d ₆ ).
δ ppm: 10.59 (1 H, s), 10.11 (1
H, s), 8.95 (1H, s), 8.54 (1H,
d, J = 8 Hz), 7.05-7.25 (2H, m),
6.82 (2H, dd, J ₁ = 16Hz, J ₂ = 8H
z), 4.40-4.60 (1H, m), 2.60-
3.30 (4H, m), 1.45 to 1.70 (2H,
m), 0.80-1.10 (1H, m), 0.84 (6
H, dd, J ₁ = 12 Hz, J ₂ = 6 Hz).

Example 6 3S-was carried out in the same manner as in Example 4 using the corresponding starting materials.
[4- (N-hydroxyamino) -2R-isobutyl-
3S- (2-thienylthiomethyl) succinyl] amino-3,4-dihydrocarbostyril was obtained.

[Α] _D = −52 ° (c = 1, methanol) NMR (270 MHz, DMSO-d ₆ ) δppm: 1
0.70 (1H, s), 10.22 (1H, s), 8.
95 (1H, s), 8.47 (1H, d, J = 7H
z), 7.60 (1H, d, J = 4Hz), 7.10-
7.20 (3H, m), 7.05 (1H, dd, J ₁ =
3 Hz, J ₂ = 5 Hz), 6.90 (2H, dd, J ₁
= 17 Hz, J ₂ = 8 Hz), 4.37 (1 H, dt,
J ₁ = 14 Hz, J ₂ = 7 Hz), 2.80-3.20
(4H, m), 1.40-1.60 (2H, m), 0.
80-1.00 (1H, m), 0.82 (6H, dd,
J ₁ = 10 Hz, J ₂ = 6 Hz).

Example 7 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl] amino-3,4-dihydrocarbostyril 3S- [4- ( N-benzyloxyamino) -2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl] amino-3,4-dihydrocarbostyril 320
200 mg of 10% palladium-carbon was added to a 20 ml suspension of dimethylformamide, and hydrogen gas was introduced under reduced pressure, followed by stirring for 2 days. The catalyst was filtered off from the reaction solution using Celite, and the filtrate was concentrated under reduced pressure. 200 ml of methanol was added to the crystalline residue and dissolved by heating, and the remaining catalyst was filtered off using Celite. The filtrate was concentrated under reduced pressure, and the deposited precipitate was filtered and dried to obtain a white solid of the above target compound. Yield 172 mg.

NMR (270 MHz, DMSO-d ₆ ).
δ ppm: 10.47 (1 H, s), 10.12 (1
H, s), 8.68 (1H, s), 8.50 (1H,
d, J = 8 Hz), 7.88-7.80 (4H, m),
7.16 (2H, t, J = 8Hz), 6.90 (2H,
dd, J ₁ = 8 Hz, J ₂ = 13 Hz), 4.46−
4.43 (1H, m), 3.90-3.85 (1H,
m), 3.50-3.43 (1H, m), 2.97 (2
H, d, J = 11 Hz), 2.63-2.59 (2H,
m), 1.62-1.53 (2H, m), 0.95-
0.81 (7H, m).

Example 8 3S- [4- (N-benzoyloxyamino) -2R-
Preparation of isobutylsuccinyl] amino-3,4-dihydrocarbostyril 180 mg of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-3,4-dihydrocarbostyril was mixed with 2 ml of dimethylformamide and 2 ml of dichloromethane. Dissolved in solvent, cooled in water bath, 220 μl pyridine and benzoyl chloride 88
μl was added, and the mixture was stirred in an ice bath for 30 minutes. The reaction solution was evaporated in vacuo, 30 ml of chloroform was added, and 1N hydrochloric acid 1
It was washed with 0 ml, water 10 ml, dried over magnesium sulfate and evaporated in vacuo. 10m of diethyl ether on the residue
l was added, and the precipitated crystals were filtered to obtain the above target compound as a white solid. Yield 110 mg.

NMR (270 MHz, CDCl ₃ ) δp
pm: 10.48 (1H, brs), 8.08 (2H,
d, J = 7 Hz), 7.74 (1H, s), 7.62
(1H, t, J = 7Hz), 7.46 (2H, t, J =
7 Hz), 7.10-7.25 (2H, m), 7.01
(2H, t, J = 7Hz), 6.74 (1H, d, J =
7Hz), 4.55 (1H, dt, J ₁ = 14Hz, J
₂ = 7 Hz), 3.40 (1H, dd, J ₁ = 15H)
z, J ₂ = 6 Hz), 2.65-3.30 (3H,
m), 2.49 (1H, dd, J ₁ = 15 Hz, J ₂ =
3Hz), 1.00-1.80 (3H, m), 0.96
(6H, dd, J ₁ = 12 Hz, J ₂ = 6 Hz).

Example 9 Preparation of 3- [4- (N-hydroxyamino) -2-piperonylsuccinyl] amino-3,4-dihydrocarbostyril 49 mg of hydroxylamine hydrochloride in methanol 10
10 ml of a methanol solution of 66 mg of potassium hydroxide was added to ml under ice-cooling stirring, and the mixture was stirred for 5 minutes, and then 3- (4-ethoxy-2-piperonylsuccinyl) amino-3,4-
A solution of 100 mg of dihydrocarbostyril in 3 ml of dimethylformamide was added, and the mixture was stirred at room temperature overnight. The reaction solution was neutralized with acetic acid, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was extracted with 20 ml of n-butanol. The organic layer was washed with water three times and then concentrated under reduced pressure. The residue was purified by silica gel preparation (chloroform: methanol = 7:
1), the above target compound was obtained. Yield 4.47 mg.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.40 (1H, brs), 10.29
(1H, brs), 8.70 (1H, brs), 8.1
7 (1H, d, J = 8Hz), 7.17 (2H, t, J
= 7 Hz), 6.96-6.61 (5H, m), 5.9.
7 (2H, s), 4.51 to 4.42 (1H, m),
3.10-2.62 (4H, m), 2.49-1.93
(3H, m).

Example 10 Preparation of 3S- [4- (N-benzyloxyamino) -2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl] amino-3,4-dihydrocarbostyril 3S- (4- tert-butoxy-2R-isobutyl-
990 mg of 3 (R or S) -phthalimidomethylsuccinyl) amino-3,4-dihydrocarbostyryl was dissolved in 5 ml of dichloromethane, 10 ml of 4N hydrogen chloride / dioxane was added thereto, and the mixture was allowed to stand at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 50 ml of ethyl acetate. The ethyl acetate layer was washed with saturated brine (× 2 times), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dried to give a powder (660 mg). This powder 660
190 μl of N-methylmorpholine was added to a solution of 10 mg of tetrahydrofuran in ice / salt under cooling and stirring, and then 240 μl of isobutyl chloroformate was added and stirred for 5 minutes. Then, a solution of 573 mg of benzyloxyamine in 10 ml of dimethylformamide was added, and the mixture was stirred at room temperature for 1 hour while keeping the pH at 8. The reaction solution was concentrated under reduced pressure, 20 ml of water was added to the residue, and the mixture was solidified and filtered. The crude product was washed with ethyl acetate / diethyl ether to obtain a white solid of the above target compound. Yield 330 mg.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 11.18 (1H, s), 10.24 (1
H, s), 8.57 (1H, d, J = 8 Hz), 7.9
2-7.84 (4H, m), 7.32-7.15 (7
H, m), 6.97-6.91 (2H, m), 4.67.
-4.37 (3H, m), 4.00-3.85 (1H,
m), 3.60-3.50 (1H, m), 3.03 (2
H, d, J = 10 Hz), 2.72-2.69 (2H,
m), 1.59-1.54 (2H, m), 0.98-
0.83 (7H, m).

Example 11 Preparation of 3S- [4- (N-benzyloxyamino) -2R-isobutylsuccinyl] amino-3,4-dihydrocarbostyril 3S- (3-Carboxy-2R-isobutylpropionyl) amino-3 , 4-dihydrocarbostyril 500 m
g was dissolved in 5 ml of dimethylformamide, 329 mg of O-benzylhydroxylamine was added, and the mixture was cooled in an ice bath to give 213 mg of 1-hydroxybenzotriazole,
259 μl of N-methylmorpholine, 1-ethyl-3-
368 mg of (3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred in an ice bath for 3 hours and at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, 50 ml of ethyl acetate was added to the residue, 10 ml of water, 10 ml of 1N hydrochloric acid,
It was washed with saturated aqueous sodium hydrogen carbonate solution (10 ml × 3 times), brine 10 ml, dried over magnesium sulfate and evaporated in vacuo. Column chromatography of the residue (silica gel 50 g, chloroform / methanol = 40/1
V / V) to give the above-mentioned target compound as a white solid. Yield 300 mg.

NMR (270 MHz, CDCl ₃ ) δp
pm: 8.57 (1H, brs), 7.79 (1H, b)
rs), 7.38 (5H, s), 7.18 (2H, d)
d, J ₁ = 14 Hz, J ₂ = 7 Hz), 7.01 (1
H, t, J = 7Hz), 6.78 (1H, d, J = 7H)
z), 4.90 (2H, s), 4.45-4.60 (1
H, m), 3.35-3.50 (1H, m), 2.80.
-2.98 (1H, m), 2.80 (1H, t, J = 1
4 Hz), 2.20-2.50 (2H, m), 1.20
-1.40 (3H, m), 0.94 (6H, dd, J ₁
= 16 Hz, J ₂ = 6 Hz).

Example 12 3S was prepared in the same manner as in Example 11 using the corresponding starting materials.
-[4- (N-benzyloxyamino) -2R-isobutylsuccinyl] amino-7-methoxy-3,4-dihydrocarbostyril was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 8.90 (1H, s), 8.49 (1H, s),
7.34 (5H, s), 7.05-7.15 (1H,
m), 6.99 (1H, d, J = 8Hz), 6.51
(1H, dd, J ₁ = 8 Hz, J ₂ = 2 Hz), 6.4
1 (1H, s), 4.88 (2H, s), 4.40-
4.55 (1H, m), 3.73 (3H, s), 3.2
5-3.45 (1H, m), 2.90-3.10 (1
H, m), 2.66 (1H, t, J = 14Hz), 2.
15-2.50 (2H, m), 1.50-1.80 (2
H, m), 1.20-1.40 (1H, m), 0.94
(6H, dd, J ₁ = 19 Hz, J ₂ = 6 Hz).

Example 13 3S was prepared in the same manner as in Example 11 using the corresponding starting materials.
-[4- (N-benzyloxyamino) -2R-isobutylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril was obtained.

NMR (270 MHz, CDCl ₃ ) δp
pm: 8.69 (1H, s), 7.37 (5H, s),
7.15-7.35 (3H, m), 7.07 (1H,
t, J = 7 Hz), 6.67 (1H, d, J = 6H)
z), 4.90 (2H, s), 4.40-4.60 (1
H, m), 3.92 (3H, s), 3.25-3.45.
(1H, m), 2.75-2.95 (2H, m), 2.
20-2.50 (2H, m), 1.50-1.80 (2
H, m), 1.20-1.35 (2H, m), 0.93
(6H, dd, J ₁ = 16 Hz, J ₂ = 6 Hz).

Example 14 1-Hexyloxy-3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl]
Preparation of amino-3,4-dihydrocarbostyril 3S-
[4- (N-benzyloxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-1-hexyloxy-3,4-dihydrocarbostyril 400 mg in a tetrahydrofuran 15 ml solution, 10% palladium-carbon 150 mg and cyclohexene 1. 0 ml was added and the mixture was stirred for 30 minutes while refluxing. The catalyst was filtered off from the reaction solution using Celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with 3% methanol / chloroform) to obtain the above target compound. Yield 250 mg.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.48 (1H, s), 8.76 (1H, s)
s), 8.55 (1H, d, J = 8Hz), 7.35-
7.27 (2H, m), 7.14 (1H, d, J = 7H
z), 7.06 (1H, t, J = 7 Hz), 4.63-
4.58 (1H, m), 4.00 (1H, d, J = 7H
z), 3.97 (1H, d, J = 7Hz), 3.06
(1H, t, J = 13Hz), 2.94 (1H, dd,
J ₁ = 7 Hz, J ₂ = 16 Hz), 2.51-2.45
(1H, m), 2.20-2.13 (1H, m), 1.
71-1.27 (10H, m), 0.97 (3H, d,
J = 7 Hz), 0.92-0.80 (10H, m).

Example 15 Preparation of 1- (4-cyanobenzyl) -3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-3,4-dihydrocarbostyril Reference Example 24 And corresponding starting materials are reacted to give Example 1
The above target compound was obtained in the same manner as in 6.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.49 (1H, s), 8.77 (1H,
s), 8.54 (1H, d, J = 9Hz), 7.80
(2H, d, J = 8 Hz), 7.43 (2H, d, J =
8 Hz), 7.29 (1H, d, J = 7 Hz), 7.1
7 (1H, t, J = 8Hz), 7.00 (1H, t, J
= 7 Hz), 6.90 (1H, d, J = 8 Hz), 5.
30 (1H, d, J = 17Hz), 5.19 (1H,
d, J = 17 Hz), 4.75-4.70 (1H,
m), 3.15 (1H, t, J = 15Hz), 3.00
(1H, dd, J ₁ = 6 Hz, J ₂ = 15 Hz), 2.
55-2.49 (1H, m), 2.21-2.15 (1
H, m), 1.58-1.43 (2H, m), 0.99
(3H, d, J = 7Hz), 1.01-0.79 (1
H, m), 0.83 (6H, dd, J ₁ = 7 Hz, J ₂
= 18 Hz).

Example 16 1- (5-chloro-2-thienylmethyl) -3S- [4
-(N-hydroxyamino) -2R-isobutyl-3S
Preparation of -Methylsuccinyl] amino-3,4-dihydrocarbostyril 3S- (4-t-Butoxy-2R-isobutyl-3, obtained in the same manner as in Reference Example 22 using the corresponding starting materials.
S-methylsuccinyl) amino-1- (5-chloro-2
To 920 mg of -thienylmethyl) -3,4-dihydrocarbostyril, 5 ml of trifluoroacetic acid was added and dissolved, and the mixture was left at room temperature for 1 hour and 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained oily residue was extracted with 30 ml of ethyl acetate. The ethyl acetate layer was washed 3 times with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was dried (790 mg). Compound 39 obtained above
To a solution of 0 mg of tetrahydrofuran in ice (10 ml) was added N-methylmorpholine (126 µl) and then isobutyl chloroformate (111 µl) under ice / salt cooling, and the mixture was stirred for 15 minutes. O- (t-butyldimethylsilyl) in the reaction solution
Hydroxyamine (195 mg) was added, and the mixture was stirred at room temperature overnight. The insoluble material was filtered off from the reaction solution, 4 ml of acetic acid and 4 ml of water were added to the filtrate, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in 50 ml of ethyl acetate and extracted. The ethyl acetate layer was washed 3 times with saturated brine and twice with water, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with 3% methanol / chloroform) to obtain the above target compound as a white solid. Yield 170 mg.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.48 (1H, s), 8.76 (1H, s)
s), 8.52 (1H, d, J = 8Hz), 7.29-
7.25 (3H, m), 7.06 to 7.00 (2H,
m), 6.94 (1H, d, J = 4Hz), 5.23
(2H, d, J = 3Hz), 4.62-4.57 (1
H, m), 3.04 (1H, t, J = 14 Hz), 2.
93 (1H, dd, J ₁ = 6 Hz, J ₂ = 15 Hz),
2.54-2.47 (1H, m), 2.20-2.14
(1H, m), 1.60-1.42 (2H, m), 0.
98 (3H, d, J = 7Hz), 1.00-0.80
(1H, m), 0.85 (6H, dd, J ₁ = 6Hz,
J ₂ = 17 Hz).

Example 17 Preparation of 3S- [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-3,4-dihydrocarbostyril In analogy to Example 14 using the corresponding starting materials. The above target compound was obtained.

NMR (270 MHz, DMSO-d ₆ ).
δ ppm: 10.48 (1 H, s), 10.18 (1
H, s), 8.75 (1H, s), 8.37 (1H,
d, J = 8 Hz), 7.20-7.13 (2H, m),
6.95-6.86 (2H, m), 4.51-4.46
(1H, m), 2.99-2.93 (2H, m), 2.
51-2.44 (1H, m), 2.20-2.14 (1
H, m), 1.60-1.40 (2H, m), 0.97
(3H, d, J = 7Hz), 0.98-0.80 (1
H, m), 0,84 (6H, dd, J ₁ = 6Hz, J ₂
= 15 Hz).

Example 18 Preparation of 1-hydroxy-3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-3,4-dihydrocarbostyril Reference Example 26 and the corresponding starting material Example 1
The target compound was obtained in the same manner as in 4.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.49 (2H, bs), 8.76 (1
H, s), 8.54 (1H, d, J = 8 Hz), 7.3
2-7.20 (3H, m), 7.01 (1H, td, J
_{1 = 2Hz, J 2 = 7Hz} ), 4.64-4.54 (1
H, m), 3.06 (1H, t, J = 15 Hz), 2.
93 (1H, dd, J ₁ = 7 Hz, J ₂ = 16 Hz),
2.51-2.45 (1H, m), 2.20-2.14
(1H, m), 1.65-1.42 (2H, m), 0.
98 (3H, d, J = 7Hz), 1.00-0.80
(1H, m), 0.85 (6H, dd, J ₁ = 7Hz,
J ₂ = 16 Hz).

Example 19 Preparation of 3S- [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril Carried out using the corresponding starting materials. The target compound was obtained in the same manner as in Example 14.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.48 (1H, s), 8.76 (1H, s)
s), 8.55 (1H, d, J = 8Hz), 7.36-
7.28 (2H, m), 7.16 (1H, d, J = 8H
z), 7.07 (1H, t, J = 7 Hz), 4.66-
4.61 (1H, m), 3.83 (3H, s), 3.0
6-2.93 (2H, m), 2.52-2.44 (1
H, m), 2.20-2.13 (1H, m), 1.57
-1.42 (2H, m), 0.97 (3H, d, J = 7
Hz), 0.98-0.81 (1H, m), 0.84
(6H, dd, J ₁ = 6 Hz, J ₂ = 14 Hz).

Example 20 Preparation of 7-chloro-1-ethoxy-3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-3,4-dihydrocarbostyril Reference Example 27 and Reaction of the corresponding starting materials, Example 1
The target compound was obtained in the same manner as in 4.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.48 (1H, s), 8.77 (1H,
s), 8.58 (1H, d, J = 8Hz), 7.32
(1H, d, J = 8 Hz), 7.13-7.09 (2
H, m), 4.63-4.59 (1H, m), 4.06.
(2H, q, J = 7 Hz), 3.04-2.95 (2
H, m), 2.51-2.43 (1H, m), 2.19
-2.12 (1H, m), 1.69-1.41 (2H,
m), 1.28 (3H, t, J = 7Hz), 0.97
(3H, d, J = 7Hz), 0.98-0.80 (1
H, m), 0.83 (6H, dd, J ₁ = 7 Hz, J ₂
= 12 Hz).

Example 21 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-isobutoxy-3,4-
Preparation of dihydrocarbostyril Reference Example 28 and the corresponding starting materials were reacted to give Example 1
The target compound was obtained in the same manner as.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.71 (1H,
s), 8.35 (1H, d, J = 8Hz), 7.25-
7.40 (2H, m), 7.15 (1H, d, J = 7H
z), 7.06 (1H, t, J = 7Hz), 4.50-
4.70 (1H, m), 3.78 (2H, dt, J ₁ =
12 Hz, J ₂ = 7 Hz), 2.70-3.10 (3
H, m), 2.17 (1H, dd, J ₁ = 14 Hz, J
₂ = 6 Hz), 1.90-2.15 (2H, m), 1.
40-1.75 (2H, m), 1.00-1.20 (1
H, m), 0.99 (6H, dd, J ₁ = 6 Hz, J ₂
= 3 Hz), 0.87 (6H, dd, J ₁ = 12 Hz,
J ₂ = 6 Hz).

Example 22 1-Ethoxy-3S- [4- (N-hydroxyamino)
Preparation of -2R-isobutyl-3S-methylsuccinyl] amino-3,4-dihydrocarbostyril Reference Example 29 and the corresponding starting material were reacted to give Example 1
The target compound was obtained in the same manner as in 4.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.49 (1H, s), 8.77 (1H,
s), 8.57 (1H, d, J = 8Hz), 7.31
(2H, t, J = 8Hz), 7.16 (1H, d, J =
8Hz), 7.06 (1H, t, J = 8Hz), 4.5
4-4.66 (1H, m), 4.05 (2H, q, J =
7 Hz), 2.96-3.07 (2H, m), 2.49
-2.52 (1H, m), 2.12-2.20 (1H,
m), 1.40-1.58 (2H, m), 1.28 (3
H, t, J = 7 Hz), 0.98 (3H, d, J = 7H
z), 0.98-0.84 (1H, m), 0.84 (6
H, dd, J ₁ = 13 Hz, J ₂ = 6 Hz).

Example 23 Preparation of 3R- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril Similar to Example 1 using the corresponding starting materials. To obtain the above target compound.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.42 (1H, s), 8.76 (1H, s)
s), 8.51 (1H, d, J = 8Hz), 7.32
(2H, dd, J ₁ = 16 Hz, J ₂ = 8 Hz), 7.
16 (1H, d, J = 8Hz), 7.07 (1H, t,
J = 8 Hz), 4.58 (1H, q, J = 8 Hz),
3.83 (3H, s), 2.70-3.10 (3H,
m), 2.22 (1H, dd, J ₁ = 15 Hz, J ₂ =
5Hz), 2.02 (1H, dd, J ₁ = 15Hz, J
₂ = 9 Hz), 1.40 to 1.60 (2H, m), 0.
95-1.20 (1H, m), 0.84 (6H, d, J
= 6 Hz).

Example 24 Preparation of 3R- [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril.

The target compound was obtained in the same manner as in Example 14 using the corresponding starting materials.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.48 (1H, s), 8.76 (1H, s)
s), 8.61 (1H, d, J = 8Hz), 7.25-
7.40 (2H, m), 7.16 (1H, d, J = 8H
z), 7.07 (1H, t, J = 8Hz), 4.66
(1H, dt, J ₁ = 13 Hz, J ₂ = 8 Hz), 2.
80-3.10 (2H, m), 2.40-2.60 (1
H, m), 2.05-2.30 (1H, m), 1.30
-1.60 (2H, m), 1.07 (3H, d, J = 7
Hz), 0.75-1.05 (1H, m), 0.81
(6H, dd, J ₁ = 6 Hz, J ₂ = 4 Hz).

Example 25 Preparation of 1-ethoxymethyl-3 (R or S)-[4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-3,4-dihydrocarbostyril The compound of Reference Example 30 was prepared. The target compound (diastereomer 1: 1 mixture) was obtained in the same manner as in Example 1 by reacting the compound subjected to catalytic reduction treatment with the corresponding starting material.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.40 (1H, bs), 8.76 + 8.
72 (1H, s), 8.44 + 8.28 (1H, d, J
= 8 Hz), 7.29-7.26 (3H, m), 7.0
9-7.03 (1H, m), 5.56 + 5.54 (1
H, d, J = 11 Hz), 5.02 + 5.01 (1H,
d, J = 11 Hz), 4.53-4.48 (1H,
m), 3.51 (2H, q, J = 7Hz), 3.00-
2.82 (3H, m), 2.25-1.98 (2H,
m), 1.70-1.45 (2H, m), 1.11 (3
H, t, J = 7 Hz), 1.14 to 1.07 (1H,
m), 0.91-0.83 (6H, m).

Example 26 1-Hexyloxymethyl-3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-
Production of 3,4-dihydrocarbostyril The compound of Reference Example 31 was reacted with the compound obtained by catalytic reduction treatment and the corresponding starting material to give the desired compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.71 (1H,
s), 8.28 (1H, d, J = 8Hz), 7.27
(3H, t, J = 6Hz), 7.06 (1H, td, J
₁ = 2Hz, J ₂ = 8Hz), 5.54 (1H, d, J
= 11 Hz), 5.02 (1H, d, J = 11 Hz),
4.56-4.45 (1H, m), 3.45 (2H, m
t, J = 6 Hz), 3.00-2.80 (3H, m),
2.18 (1H, dd, J ₁ = 6Hz, J ₂ = 14H
z), 2.02 (1H, dd, J ₁ = 8 Hz, J ₂ = 1
5 Hz), 1.75-1.55 (1 H, m), 1.54
-1.45 (3H, m), 1.20-1.07 (7H,
m), 0.91-0.78 (9H, m).

Example 27 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxymethyl-3,4
-Production of dihydrocarbostyril The compound of Reference Example 32 was subjected to catalytic reduction treatment and the corresponding starting material was reacted to obtain the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.39 (1H, brs), 8.71 (1
H, brs), 8.29 (1H, d, J = 7 Hz),
7.15-7.35 (3H, m), 7.07 (1H,
t, J = 7 Hz), 5.49 (1H, d, J = 10H
z), 5.00 (1H, d, J = 10Hz), 4.52
(1H, dt, J ₁ = 14 Hz, J ₂ = 7 Hz), 3.
26 (3H, s), 2.70-3.10 (3H, m),
2.18 (1H, dd, J ₁ = 14Hz, J ₂ = 6H
z), 2.02 (1H, dd, J ₁ = 14 Hz, J ₂ =
8 Hz), 1.35 to 1.75 (2 H, m), 1.00
-1.20 (1H, m), 0.88 (6H, dd, J ₁
= 14 Hz, J ₂ = 6 Hz).

Example 28 1-Benzyl-3S- [4- (N-hydroxyamino)
Production of -2R-isobutylsuccinyl] amino-3,4-dihydrocarbostyril The compound of Reference Example 33 was treated with a trifluoroacetic acid-treated compound and the corresponding starting material to give the above target compound in the same manner as in Example 1. It was

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.39 (1H, s), 8.72 (1H,
s), 8.31 (1H, d, J = 8Hz), 7.34-
7.14 (8H, m), 6.98 (1H, t, J = 8H
z), 5.22 (1H, d, J = 16 Hz), 5.10.
(1H, d, J = 16Hz), 4.69-4.59 (1
H, m), 3.07-2.97 (2H, m), 2.81
-2.75 (1H, m), 2.20 (1H, dd, J ₁
= 7 Hz, J ₂ = 15 Hz), 2.03 (1H, dd,
J ₁ = 8 Hz, J ₂ = 15 Hz), 1.65 to 1.45
(2H, m), 1.14 to 1.07 (1H, m), 0.
871 (6H, dd, J ₁ = 7Hz, J ₂ = 16H
z).

Example 29 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1- (4-methoxycarbonylbenzyl) -3,4-dihydrocarbostyril The compound of Reference Example 34 was prepared. The compound treated with trifluoroacetic acid was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.39 (1H, s), 8.72 (1H,
s), 8.33 (1H, d, J = 7 Hz), 7.91
(2H, d, J = 8 Hz), 7.37 (2H, d, J =
8 Hz), 7.27 (1H, d, J = 7 Hz), 7.1
6 (1H, t, J = 7Hz), 7.00 (1H, t, J
= 7 Hz), 6.91 (1H, d, J = 8 Hz), 5.
30 (1H, d, J = 17Hz), 5.17 (1H,
d, J = 17 Hz), 4.73-4.63 (1H,
m), 3.83 (3H, s), 3.09-2.99 (2
H, m), 2.88-2.73 (1H, m), 2.20.
(1H, dd, J ₁ = 7 Hz, J ₂ = 15 Hz), 2.
03 (1H, dd, J ₁ = 8 Hz, J ₂ = 15 Hz),
1.65-1.46 (2H, m), 1.13-1.07
(1H, m), 0.87 (6H, dd, J ₁ = 6Hz,
J ₂ = 15 Hz).

Example 30 1- (4-Carboxybenzyl) -3 (R or S)-
Preparation of [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-3,4-dihydrocarbostyril 3S- [4- (N-benzyloxyamino) -2R-isobutylsuccinyl] amino-1- (4 -Methoxycarbonylbenzyl) -3,4-dihydrocarbostyryl 2
00 mg of methanol 5 ml and tetrahydrofuran 5
To a mixed solution of ml, at room temperature, 1N sodium hydroxide 2.0
ml was added and the mixture was stirred overnight. The reaction mixture was neutralized with 1N hydrochloric acid and concentrated under reduced pressure. 20 ml of ethyl acetate to the obtained residue
And 20 ml of water were added, and the mixture was shaken to separate the aqueous layer, and the ethyl acetate layer was washed once with saturated aqueous sodium hydrogen carbonate. The aqueous layer and saturated aqueous sodium hydrogen carbonate were combined, pH was adjusted to 2 with 1N hydrochloric acid under ice-cooling stirring, and the mixture was extracted with 30 ml of ethyl acetate. The ethyl acetate layer was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the obtained crystalline residue, filtered and dried. Yield 110 mg.

The compound obtained above was treated in the same manner as in Example 1 to obtain the desired compound (mixture of diastereomers 1: 1).
I got

NMR (270 MHz, DMSO-d ₆ ).
δppm: 12.85 (1H, bs), 10.41 + 1
0.39 (1H, s), 8.75 + 8.72 (1H,
s), 8.49 + 8.33 (1H, d, J = 8Hz),
7.88 (2H, d, J = 8Hz), 7.34 (2H,
d, J = 7 Hz), 7.28 (1H, d, J = 8H
z), 7.17 (1H, t, J = 7 Hz), 7.02-
6.91 (2H, m), 5.31 (1H, d, J = 17
Hz), 5.16 (1H, d, J = 17 Hz), 4.7
0-4.62 (1H, m), 3.08-2.81 (3
H, m), 2.22 (1H, dd, J ₁ = 5 Hz, J ₂
= 15 Hz), 2.03 ( ₁ H, dd, J ₁ = 9 Hz,
J ₂ = 15 Hz), 1.54-1.44 (2H, m),
1.12-1.03 (1H, m), 0.90-0.82
(6H, m).

Example 31 Production of 3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-1- (4-methoxybenzyl) -3,4-dihydrocarbostyril Reference Example 35 And corresponding starting materials are reacted to give Example 1
The target compound was obtained in the same manner as in 4.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.48 (1H, s), 8.76 (1H, s)
s), 8.51 (1H, d, J = 8Hz), 7.26
(1H, d, J = 8Hz), 7.19-7.14 (3
H, m), 7.01-6.95 (2H, m), 6.87.
(2H, d, J = 9 Hz), 5.10 (2H, bs),
4.68-4.63 (1H, m), 3.70 (3H,
s), 3.09 (1H, t, J = 15Hz), 2.96
(1H, dd, J ₁ = 6 Hz, J ₂ = 15 Hz), 2.
56-2.49 (1H, m), 2.22-2.16 (1
H, m), 1.58-1.44 (2H, m), 1.01
-0.80 (1H, m), 0.99 (3H, d, J = 7
Hz), 0.85 (6H, dd, J ₁ = 6 Hz, J ₂ =
19 Hz).

Example 32 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-phthalimidomethyl-
Production of 3,4-dihydrocarbostyril The compound of Reference Example 36 was reacted with the compound treated with trifluoroacetic acid and the corresponding starting material to give the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.36 (1H, s), 8.71 (1H,
s), 8.36 (1H, d, J = 8Hz), 7.84
(4H, s), 7.25 (3H, s), 6.90-7.
10 (1H, m), 6.05 (1H, d, J = 14H
z), 6.66 (1H, d, J = 14 Hz), 4.47
(1H, q, J = 8Hz), 2.70-3.00 (3
H, m), 2.18 (1H, dd, J ₁ = 14Hz, J
₂ = 7 Hz), 2.01 (1H, dd, J ₁ = 14H
z, J ₂ = 7 Hz), 1.40 to 1.80 (2H,
m), 1.00-1.25 (1H, m), 0.88 (6
H, dd, J ₁ = 17 Hz, J ₂ = 6 Hz).

Example 33 Preparation of 1-ethoxycarbonylmethyl-3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-3,4-dihydrocarbostyril The compound of Reference Example 37 was treated with trifluoroacetic acid. The treated compound was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, s), 8.71 (1H, s)
s), 8.29 (1H, d, J = 8Hz), 7.26
(2H, t, J = 7Hz), 7.06 (1H, t, J =
7 Hz), 6.97 (1H, d, J = 7 Hz), 4.8
0 (1H, d, J = 17Hz), 4.56 (1H, d,
J = 17 Hz), 4.42-4.65 (1H, m),
4.14 (2H, q, J = 7Hz), 2.70-3.1
0 (3H, m), 2.19 (1H, dd, J ₁ = 14H
z, J ₂ = 7 Hz), 2.01 (1H, dd, J ₁ = 1)
4 Hz, J ₂ = 7 Hz), 1.40 to 1.78 (2H,
m), 1.20 (3H, t, J = 7Hz), 1.00-
1.25 (1H, m), 0.87 (6H, dd, J ₁ =
15 Hz, J ₂ = 6 Hz).

Example 34 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-carboxymethyl-3,
Preparation of 4-dihydrocarbostyril 3S- [4- (N-benzyloxyamino) -2R-isobutylsuccinyl] amino-1-ethoxycarbonylmethyl-3 obtained in a similar manner to Example 11 using the corresponding starting materials. , 4-Dihydrocarbostyril was used as a starting material, and the target compound was obtained in the same manner as in Example 30.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.40 (1H, s), 8.75 (1H, s)
brs), 8.21 (1H, d, J = 7Hz), 7.2
1 (2H, t, J = 7Hz), 6.98 (1H, t, J
= 7 Hz), 6.88 (1H, d, J = 7 Hz), 4.
56 (1H, d, J = 17 Hz), 4.47 (1H, d
t, J ₁ = 14 Hz, J ₂ = 7 Hz), 4.06 (1
H, d, J = 17 Hz), 2.65-3.05 (3H,
m), 2.18 (1H, dd, J ₁ = 14 Hz, J ₂ =
7Hz), 2.01 (1H, dd, J ₁ = 14Hz, J
₂ = 8 Hz), 1.40 to 1.75 (2H, m), 1.
00-1.20 (1H, m), 0.87 (6H, dd,
J ₁ = 16 Hz, J ₂ = 7 Hz).

Example 35 7-Chloro-1-ethoxycarbonylmethyl-3S-
Production of [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-3,4-dihydrocarbostyryl The compound of Reference Example 38 was treated with trifluoroacetic acid and the corresponding starting material was reacted to give an example. The above target compound was obtained in the same manner as in 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.71 (1H,
s), 8.33 (1H, d, J = 8Hz), 7.31
(1H, d, J = 7Hz), 7.10-7.20 (2
H, m), 4.79 (1H, d, J = 18 Hz), 4.
63 (1H, d, J = 18 Hz), 4.45-4.60
(1H, m), 4.14 (2H, q, J = 7Hz),
2.60-3.10 (3H, m), 2.17 (1H, d
d, J ₁ = 14 Hz, J ₂ = 6 Hz), 2.01 (1
H, dd, J ₁ = 14 Hz, J ₂ = 7 Hz), 1.20
-1.75 (2H, m), 1.21 (3H, t, J = 7
Hz), 1.00-1.20 (1H, m), 0.86
(6H, dd, J ₁ = 14 Hz, J ₂ = 6 Hz).

Example 36 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-propoxycarbonylmethyl-3,4-dihydrocarbostyril The compound of Reference Example 41 was treated with trifluoroacetic acid. The treated compound was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.71 (1H,
s), 8.31 (1H, d, J = 8Hz), 7.27
(2H, t, J = 8Hz), 7.05 (1H, t, J =
8 Hz), 6.98 (1H, d, J = 8 Hz), 4.8
1 (1H, d, J = 17Hz), 4.59 (1H, d,
J = 17 Hz), 4.40-4.55 (1H, m),
4.04 (2H, t, J = 7Hz), 2.65-3.1
0 (3H, m), 2.18 (1H, dd, J ₁ = 14H
z, J ₂ = 6 Hz), 2.01 (1H, dd, J ₁ = 1)
4 Hz, J ₂ = 7 Hz), 1.40 to 1.75 (4H,
m), 1.00-1.20 (1H, m), 0.75-
1.00 (9H, m).

Example 37 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-isopropoxycarbonylmethyl-3,4-dihydrocarbostyril The compound of Reference Example 42 was treated with trifluoroacetic acid. The compound treated in step (4) was reacted with the corresponding starting material to obtain the desired compound as described in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.71 (1H,
s), 8.31 (1H, d, J = 8Hz), 7.27
(2H, t, J = 8Hz), 7.05 (1H, t, J =
8 Hz), 6.94 (1H, d, J = 8 Hz), 4.9
3 (1H, tt, J ₁ = 7Hz, J ₂ = 7Hz), 4.
77 (1H, d, J = 18Hz), 4.54 (1H,
d, J = 18 Hz), 4.45-4.65 (1H,
m), 2.70-3.15 (3H, m), 2.18 (1
H, dd, J ₁ = 14 Hz, J ₂ = 6 Hz), 2.01
(1H, dd, J ₁ = 14 Hz, J ₂ = 7 Hz), 1.
40-1.75 (2H, m), 1.21 (3H, d, J
= 2 Hz), 1.19 (3H, d, J = 2 Hz), 1.
00-1.20 (1H, m), 0.87 (6H, dd,
J ₁ = 15 Hz, J ₂ = 6 Hz).

Example 38 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-t-butoxycarbonylmethyl-3,4-dihydrocarbostyril The compound of Reference Example 43 was catalytically reduced. The target compound was obtained in the same manner as in Example 1 by reacting the compound treated in step 1 with the corresponding starting material.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, brs), 8.71 (1
H, brs), 8.30 (1H, d, J = 8Hz),
7.25-7.30 (2H, m), 7.06 (1H,
t, J = 7 Hz), 6.93 (1H, d, J = 7H)
z), 4.70 (1H, d, J = 17Hz), 4.44
-4.54 (2H, m), 2.75-3.02 (3H,
m), 1.98-2.26 (2H, m), 1.61-
1.71 (1H, m), 1.42-1.51 (1H,
m), 1.39 (9H, s), 1.01-1.11 (1
H, m), 0.87 (6H, dd, J ₁ = 15Hz, J
₂ = 7 Hz).

Example 39 Preparation of 1-aminocarbonylmethyl-3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-3,4-dihydrocarbostyril The compound of Reference Example 44 was treated with trifluoroacetic acid. The treated compound was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.39 (1H, s), 8.73 (1H,
s), 8.24 (1H, d, J = 8Hz), 7.58
(1H, s), 7.10-7.30 (3H, m), 7.
02 (1H, t, J = 8Hz), 6.84 (1H, d,
J = 8 Hz), 4.64 (1H, d, J = 17 Hz),
4.50-4.70 (1H, m), 4.19 (1H, m
d, J = 17 Hz), 2.70-3.10 (3H,
m), 2.18 (1H, dd, J ₁ = 14 Hz, J ₂ =
6Hz), 2.01 (1H, dd, J ₁ = 14Hz, J
₂ = 8 Hz), 1.40 to 1.75 (2H, m), 0.
95-1.20 (1H, m), 0.87 (6H, dd,
J ₁ = 15 Hz, J ₂ = 6 Hz).

Example 40 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1- (N-methylaminocarbonylmethyl) -3,4-dihydrocarbostyril Compound of Reference Example 45 Was reacted with trifluoroacetic acid and the corresponding starting material was reacted to obtain the desired compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, brs), 8.71 (1
H, brs), 8.24 (1H, d, J = 8Hz),
8.00 (1H, d, J = 5Hz), 7.23-7.2
7 (2H, m), 7.03 (1H, t, J = 7Hz),
6.84 (1H, d, J = 8Hz), 4.57-4.6
9 (2H, m), 4.20 (1H, d, J = 17H
z), 2.92-3.05 (2H, m), 2.74-
2.80 (1H, m), 2.60 (3H, d, J = 5H
z), 1.98-2.25 (2H, m), 1.42-
1.68 (2H, m), 1.01-1.12 (1H,
m), 0.87 (6H, dd, J ₁ = 15 Hz, J ₂ =
7 Hz).

Example 41 Production of 3S- [4- (N-Hydroxyamino) -2R-isobutylsuccinyl] amino-1- (N-propylaminocarbonylmethyl) -3,4-dihydrocarbostyril Compound of Reference Example 46 Was reacted with trifluoroacetic acid and the corresponding starting material was reacted to obtain the desired compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, brs), 8.72 (1
H, brs), 8.24 (1H, d, J = 8Hz),
8.08 (1H, brs), 7.22-7.27 (2
H, m), 7.02 (1H, t, J = 7 Hz), 6.8
4 (1H, d, J = 8Hz), 4.54-4.68 (2
H, m), 4.25 (1H, d, J = 17 Hz), 2.
94-3.05 (3H, m), 2.75-2.80 (1
H, m), 1.96-2.25 (2H, m), 1.42
-1.68 (2H, m), 1.01-1.12 (1H,
m), 0.80-0.91 (9H, m).

Example 42 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1- (N-methoxyaminocarbonylmethyl) -3,4-dihydrocarbostyril Compound of Reference Example 47 Was reacted with trifluoroacetic acid and the corresponding starting material was reacted to obtain the desired compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 11.40 (1H, s), 10.39 (1
H, s), 8.72 (1H, s), 8.27 (1H,
d, J = 8 Hz), 7.20-7.40 (2H, m),
7.04 (1H, t, J = 8Hz), 6.91 (1H,
d, J = 8 Hz), 4.59 (1H, d, J = 16H
z), 4.40-4.70 (1H, m), 4.25 (1
H, d, J = 16 Hz), 3.59 (3H, s), 2.
70-3.10 (3H, m), 2.19 (1H, dd,
J ₁ = 14 Hz, J ₂ = 7 Hz), 2.02 (1 H, d
d, J ₁ = 14 Hz, J ₂ = 7 Hz), 1.30-1.
80 (2H, m), 0.90-1.20 (1H, m),
0.87 (6H, dd, J ₁ = 15Hz, J ₂ = 6H
z).

Example 43 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1- (N, N-dimethylaminocarbonylmethyl) -3,4-dihydrocarbostyril Reference Example 48 The above compound was treated with trifluoroacetic acid and the corresponding starting material was reacted to obtain the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, brs), 8.72 (1
H, brs), 8.26 (1H, d, J = 8Hz),
7.20-7.26 (2H, m), 7.00 (1H,
t, J = 8 Hz), 6.84 (1H, d, J = 8H)
z), 4.93 (1H, d, J = 17Hz), 4.46
-4.56 (2H, m), 3.09 (3H, s), 2.
73-3.02 (6H, m), 1.95-2.25 (2
H, m), 1.42-1.70 (2H, m), 1.01
-1.12 (1H, m), 0.87 (6H, dd, J ₁
= 15 Hz, J ₂ = 7 Hz).

Example 44 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-morpholinocarbonylmethyl-3,4-dihydrocarbostyril The compound of Reference Example 49 was treated with trifluoroacetic acid. The treated compound was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.71 (1H,
s), 8.27 (1H, d, J = 8Hz), 7.24
(2H, t, J = 8Hz), 7.01 (1H, t, J =
8 Hz), 6.86 (1H, d, J = 8 Hz), 4.9
7 (1H, d, J = 17Hz), 4.57 (1H, d,
J = 17 Hz), 4.40-4.60 (1H, m),
3.50-3.75 (8H, m), 2.70-3.20
(3H, m), 2.19 (1H, dd, J ₁ = 14H
z, J ₂ = 7 Hz), 2.01 (1H, dd, J ₁ = 1)
4 Hz, J ₂ = 7 Hz), 1.40-1.80 (2H,
m), 0.95-1.20 (1H, m), 0.87 (6
H, dd, J ₁ = 15 Hz, J ₂ = 6 Hz).

Example 45 1-allyl-3S- [4- (N-hydroxyamino)-
2R-isobutyl-3S-methylsuccinyl] amino-
3.4 Production of 4-dihydrocarbostyril The compound of Reference Example 50 and the corresponding starting material are reacted,
The target compound was obtained in the same manner as in Example 16.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.48 (1H, s), 8.77 (1H,
s), 8.45 (1H, d, J = 8Hz), 7.25
(2H, t, J = 7Hz), 7.06-6.99 (2
H, m), 5.90-5.80 (1H, m), 5.15
-5.06 (2H, m), 4.69-4.53 (2H,
m), 4.41 (1H, d, J = 17Hz), 3.04
(1H, t, J = 15Hz), 2.93 (1H, dd,
J ₁ = 6 Hz, J ₂ = 15 Hz), 2.54-2.47
(1H, m), 2.20-2.14 (1H, m), 1.
60-1.42 (2H, m), 0.97 (3H, d, J
= 7 Hz), 0.98-0.80 (1H, m), 0.8
4 (6H, dd, J ₁ = 6 Hz, J ₂ = 17 Hz).

Example 46 Preparation of 1-Cinnamyl-3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-3,4-dihydrocarbostyril Compound of Reference Example 51 and corresponding React the starting materials,
The target compound was obtained in the same manner as in Example 16.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.49 (1H, s), 8.77 (1H,
s), 8.47 (1H, d, J = 8Hz), 7.40
(2H, d, J = 7 Hz), 7.32-7.21 (5
H, m), 7.16 (1H, t, J = 8 Hz), 7.0
2 (1H, t, J = 8Hz), 6.52 (1H, d, J
= 16 Hz), 6.30 ( ₁ H, dt, J ₁ = 5 Hz,
J ₂ = 16 Hz), 4.82 (1H, dd, J ₁ = 4H
z, J ₂ = 17 Hz), 4.67-1.52 (2H,
m), 3.07 (1H, t, J = 15Hz), 2.96
(1H, dd, J ₁ = 6 Hz, J ₂ = 15 Hz), 2.
56-2.49 (1H, m), 2.21-2.15 (1
H, m), 1.61-1.43 (2H, m), 0.98
(3H, d, J = 7 Hz), 0.99-0.79 (1
H, m), 0.84 (6H, dd, J ₁ = 6Hz, J ₂
= 18 Hz).

Example 47 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methyl-3,4-dihydrocarbostyril The compound of Reference Example 52 was treated with trifluoroacetic acid. The compound was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, s), 8.71 (1H, s)
s), 8.20 (1H, d, J = 8Hz), 7.33-
7.24 (2H, m), 7.11 (1H, d, J = 8H
z), 7.04 (1H, t, J = 8 Hz), 4.49-
4.39 (1H, m), 3.28 (3H, s), 2.9
7-2.89 (2H, m), 2.85-2.73 (1
H, m), 2.17 (1H, dd, J ₁ = 6 Hz, J ₂
= 14 Hz), 2.01 (1H, dd, J ₁ = 7 Hz,
J ₂ = 14 Hz), 1.73-1.62 (1 H, m),
1.54-1.42 (1H, m), 1.15-1.00
(1H, m), 0.87 (6H, dd, J ₁ = 6Hz,
J ₂ = 15 Hz).

Example 48 1-Ethyl-3S- [4- (N-hydroxyamino)-
Production of 2R-isobutylsuccinyl] amino-3,4-dihydrocarbostyril A compound obtained by treating the compound of Reference Example 53 with trifluoroacetic acid was reacted with the corresponding starting material to give the above target compound in the same manner as in Example 1. It was

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, s), 8.71 (1H, s)
s), 8.20 (1H, d, J = 8Hz), 7.20-
7.35 (2H, m), 7.15 (1H, d, J = 8H
z), 7.03 (1H, t, J = 8Hz), 4.35-
4.50 (1H, m), 3.80-4.10 (2H,
m), 2.91 (2H, d, J = 9Hz), 2.70-
2.90 (1H, m), 2.17 (1H, dd, J ₁ =
14 Hz, J ₂ = 7 Hz), 2.01 (1 H, dd, J
_{1 = 14Hz, J 2 = 8Hz} ), 1.40-1.80
(2H, m), 1.13 (3H, t, J = 7Hz),
1.00-1.25 (1H, m), 0.87 (6H, d
d, J ₁ = 14 Hz, J ₂ = 6 Hz).

Example 49 Preparation of 3S- [4- (N-Hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-1-propyl-3,4-dihydrocarbostyril The compound of Reference Example 50 and the corresponding React the starting materials,
The above target compound was obtained in the same manner as in Example 14.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.47 (1H, s), 8.76 (1H, s)
s), 8.41 (1H, d, J = 8Hz), 7.28-
7.25 (2H, m), 7.14 (1H, d, J = 8H
z), 7.02 (1H, t, J = 7Hz), 4.52-
4.47 (1H, m), 3.84 (2H, t, J = 8H
z), 3.05-2.80 (2H, m), 2.51-
2.46 (1H, m), 2.20-2.16 (1H,
m), 1.59-1.46 (4H, m), 0.96 (3
H, d, J = 7 Hz), 0.91-0.80 (10H,
m).

Example 50 Production of 3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-1- (3-phenylpropyl) -3,4-dihydrocarbostyril Reference Example 51 And the corresponding starting materials are reacted,
The above target compound was obtained in the same manner as in Example 14.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.47 (1H, s), 8.76 (1H, s)
s), 8.41 (1H, d, J = 8Hz), 7.30-
7.15 (7H, m), 7.07-6.98 (2H,
m), 4.51-4.46 (1H, m), 3.92 (2
H, t), 2.98-2.88 (2H, m), 2.64.
(2H, t, J = 8Hz), 2.51-2.46 (1
H, m), 2.20-2.13 (1H, m), 1.87.
-1.78 (2H, m), 1.65-1.38 (2H,
m), 0.96 (3H, d, J = 7Hz), 0.98-
0.80 (1H, m), 0.84 (6H, dd, J ₁ =
6 Hz, J ₂ = 17 Hz).

Example 51 Preparation of 3S- [4- (N-Hydroxyamino) -2R-isobutylsuccinyl] amino-1- (2-hydroxyethyl) -3.4-dihydrocarbostyril The compound treated with fluoroacetic acid was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.49 (1H, s), 8.70 (1H,
s), 8.19 (1H, d, J = 8Hz), 7.15-
7.35 (3H, m), 6.90-7.10 (1H,
m), 4.85 (1H, t, J = 6Hz), 4.46
(1H, dt, J ₁ = 13 Hz, J ₂ = 8 Hz), 3.
90-4.05 (1H, m), 3.84 (1H, dt,
J ₁ = 14 Hz, J ₂ = 7 Hz), 3.45-3.65
(2H, m), 2.70-3.00 (3H, m), 2.
18 (1H, dd, J ₁ = 14 Hz, J ₂ = 7 Hz),
2.04 (1H, dd, J ₁ = 14Hz, J ₂ = 7H
z), 1.35-1.75 (2H, m), 0.95-
1.20 (1H, m), 0.87 (6H, dd, J ₁ =
15 Hz, J ₂ = 7 Hz).

Example 52 3S- [4- (N-Hydroxyamino) -2R-isobutyl-3-methylsuccinyl] amino-1-methyl-
Production of 3,4-dihydrocarbostyril The compound of Reference Example 52 and the corresponding starting material are reacted,
The target compound was obtained in the same manner as in Example 16.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.48 (1H, brs), 8.76 (1
H, brs), 8.41 (1H, d, J = 8Hz),
7.25-7.33 (2H, m), 7.11 (1H,
d, J = 8 Hz), 7.03 (1H, d, J = 7H
z), 4.44-4.54 (1H, m), 3.28 (3
H, s), 2.89-3.07 (2H, m), 2.49.
-2.53 (1H, m), 2.16 (1H, dd, J ₁
= 11 Hz, J ₂ = 7 Hz), 1.41-1.62 (2
H, m), 0.96 (3H, d, J = 7Hz), 0.8
4-0.96 (1H, m), 0.84 (6H, dd, J
_{1 = 17Hz, J 2 = 6Hz} ).

Example 53 Preparation of 3S- [4- (N-acetoxyamino) -2R-isobutylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril Reaction was carried out by reacting acetic anhydride with the corresponding starting material. The target compound was obtained in the same manner as in Example 8.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 11.60 (1H, s), 8.34 (1H,
d, J = 8 Hz), 7.20-7.40 (2H, m),
7.16 (1H, d, J = 8Hz), 7.07 (1H,
t, J = 8 Hz), 4.61 (1H, dt, J ₁ = 12)
Hz, J ₂ = 8 Hz), 3.82 (3H, s), 2.6
0-3.10 (3H, m), 2.34 (1H, dd, J
_{1 = 15Hz, J 2 = 7Hz} ), 2.17 (1H, d
d, J ₁ = 15 Hz, J ₂ = 7 Hz), 2.15 (3
H, s), 1.40 to 1.80 (2H, m), 1.05
-1.40 (1H, m), 0.87 (6H, dd, J ₁
= 15 Hz, J ₂ = 6 Hz).

Example 54 3S- [4- (N-benzoyloxyamino) -2R-
Production of isobutyl-3S-methylsuccinyl] amino-1-methoxy-3.4-dihydrocarbostyril The above target compound was obtained in the same manner as in Example 8 using the corresponding starting materials.

NMR (270 MHz, DMSO-d ₆ ).
δ ppm: 12.08 (1H, s), 8.64 (1H,
d, J = 8 Hz), 8.04 (2H, d, J = 7H
z), 7.76 (1H, t, J = 8Hz), 7.60
(2H, t, J = 8Hz), 7.37-7.29 (2
H, m), 7.16 (1H, d, J = 7 Hz), 7.0
7 (1H, t, J = 8Hz), 4.68-4.63 (1
H, m), 3.83 (3H, s), 3.08 (1H,
t, J = 13 Hz), 2.97 (1H, dd, J ₁ = 7)
Hz, J ₂ = 16 Hz), 2.55-2.41 (2H,
m), 1.60-1.53 (2H, m), 1.21-
1.15 (1H, m), 1.10 (3H, d, J = 6H
z), 0.87 (6H, t, J = 7Hz).

Example 55 Preparation of 3S- [4- (N-Hydroxyamino) -2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril Corresponding The above target compound was obtained in the same manner as in Example 7 using the starting materials.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.47 (1H, s), 8.68 (1H,
s), 8.65 (1H, d, J = 9 Hz), 7.88-
7.80 (4H, m), 7.33 (1H, t, J = 8H
z), 7.26 (1H, d, J = 7 Hz), 7.16
(1H, d, J = 7Hz), 7.06 (1H, t, J =
7 Hz), 4.61-1.56 (1 H, m), 3.89
(1H, dd, J ₁ = 3 Hz, J ₂ = 15 Hz), 3.
82 (3H, s), 3.48 (1H, dd, J ₁ = 5H
z, J ₂ = 14 Hz), 3.06-2.89 (2H,
m), 2.79-2.63 (2H, m), 1.67-
1.54 (3H, m), 0.86 (6H, dd, J ₁ =
6 Hz, J ₂ = 15 Hz).

Example 56 3- [4- (N-hydroxyamino) -2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl]
Production of Amino-1-methyl-3.4-dihydrocarbostyril The compound of Reference Example 52 was treated with trifluoroacetic acid and the corresponding starting material was reacted to give the above-mentioned target compound (diastereomer) in the same manner as in Example 7. Mar 1: 1 mixture) was obtained.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.50 + 10.45 (1H, s), 8.
71 + 8.68 (1H, s), 8.66 + 8.53 (1
H, d, J = 8 Hz), 7.88-7.80 (4H,
m), 7.32-7.20 (2H, m), 7.14-
6.99 (2H, m), 4.56-4.40 (1H,
m), 4,05 + 3.89 (1H, dd, J ₁ = 10H
z, J ₂ = 13 Hz), 3.70 + 3.47 (1H, d
d, J ₁ = 4 Hz, J ₂ = 13 Hz), 3.28 (3
H, s), 3.01-2.89 (2H, m), 2.82.
-2.65 (2H, m), 1.70-1.49 (3H,
m), 0.91-0.82 (6H, m).

Example 57 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-1- (2-propynyl) -3.4-dihydrocarbostyril Reference Example 56 and Reaction of the corresponding starting materials, Example 1
The above target compound was obtained in the same manner as in 6.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.49 (1H, brs), 8.77 (1
H, brs), 8.48 (1H, d, J = 8Hz),
7.20-7.36 (3H, m), 7.07 (1H,
t, J = 8 Hz), 4.79 (1H, dd, J ₁ = 18)
Hz, J ₂ = 2 Hz), 4.62 (1H, dd, J ₁ =
18 Hz, J ₂ = 2 Hz), 4.48-4.58 (1
H, m), 3.00 (1H, t, J = 15 Hz), 2.
91 (1H, dd, J ₁ = 15 Hz, J ₂ = 6 Hz),
2.46-2.54 (2H, m), 2.14-2.20
(1H, m), 1.58-1.66 (1H, m), 1.
46 (1H, dt, J ₁ = 3 Hz, J ₂ = 15 Hz),
0.97 (3H, d, J = 7Hz), 0.97-0.8
5 (1H, m), 0.85 (6H, dd, J ₁ = 14H
z, J ₂ = 7 Hz).

Example 58 Preparation of 3S- [4- (N-hydroxyamino) -3S-aminomethyl-2R-isobutylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril 3S- [4- (N -Hydroxyamino) -2R-isobutyl-3S-phthalimidomethylsuccinyl] amino-
1-methoxy-3.4-dihydrocarbostyril 50m
g was dissolved in 3 ml of dimethylformamide, 19 μl of hydrazine monohydrate was added, and the mixture was stirred at room temperature for 1 hour.
The reaction solution was concentrated under reduced pressure, 1 ml of methanol was added,
After separating the insoluble matter by filtration, the filtrate was evaporated in vacuo, 3 ml of diethyl ether was added to the precipitated crystals, and the crystals were collected by filtration.
The above target compound was obtained as a white solid. Yield 7 mg.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.56 (1H, brs), 9.56 (1
H, s), 8.60 (1H, d, J = 8 Hz), 7.3
2 (2H, dd, J ₁ = 15 Hz, J ₂ = 7 Hz),
7.16 (1H, d, J = 7Hz), 7.07 (1H,
t, J = 7 Hz), 4.68 (1H, dt, J ₁ = 12)
Hz, J ₂ = 8 Hz), 3.82 (3H, s), 2.4
0-3.20 (6H, m), 0.90-1.80 (3
H, m), 0.87 (6H, dd, J ₁ = 18Hz, J
₂ = 6 Hz).

Example 59 Preparation of 1-aminocarbonylmethyl-3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-acetylthiomethylsuccinyl] amino-3,4-dihydrocarbostyril In Reference Example 44 The obtained compound was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Example 4.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.62 (1H, s), 8.92 (1H,
s), 8.55 (1H, d, J = 8Hz), 7.57
(1H, s), 7.10-7.35 (3H, m), 7.
03 (1H, t, J = 7Hz), 6.86 (1H, d,
J = 7 Hz), 4.55-4.75 (1 H, m), 4.
66 (1H, d, J = 17Hz), 4.20 (1H,
d, J = 17 Hz), 2.80-3.20 (4H,
m), 2.40-2.65 (1H, m), 2.31 (3)
H, s), 2.20-2.40 (1H, m), 1.40.
-1.70 (2H, m), 0.80-1.00 (1H,
m), 0.87 (3H, d, J = 7Hz), 0.81
(3H, d, J = 7Hz).

Example 60 7-Chloro-3S- [4- (N-hydroxyamino)-
2R-isobutylsuccinyl] amino-1-methoxy-
Production of 3,4-dihydrocarbostyril The compound of Reference Example 59 was reacted with the compound treated with trifluoroacetic acid and the corresponding starting material to obtain the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, brs), 8.72 (1
H, brs), 8.38 (1H, d, J = 8Hz),
7.31 (1H, d, J = 8Hz), 7.11-7.1
6 (2H, m), 4, 63 (1H, dt, J ₁ = 11H
z, J ₂ = 8 Hz), 3.84 (3H, s), 2.98
(1H, d, J = 11Hz), 2.97 (1H, d, J
= 8 Hz), 2.75-2.76 (1H, m), 2.1
6 (1H, dd, J ₁ = 6 Hz, J ₂ = 14 Hz),
2.01 (1H, dd, J ₁ = 8Hz, J ₂ = 14H
z), 1.60-1.65 (1H, m), 1.42-
1.49 (1H, m), 1.02-1.12 (1H,
m), 0.87 (6H, dd, J ₁ = 6 Hz, J ₂ = 1
2 Hz).

Example 61 Preparation of 1-carboxymethyl-3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-3,4-dihydrocarbostyril Obtained in Reference Example 39. The target compound was obtained by reacting the compound with a corresponding starting material in the same manner as in Example 14.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.49 (1H, s), 8.75 (1H,
bs), 8.46 (1H, d, J = 8 Hz), 7.28
-7.22 (2H, m), 7.02 (1H, t, J = 8
Hz), 6.93 (1H, d, J = 8 Hz), 4.69
(1H, d, J = 17 Hz), 4.57-4.52 (1
H, m), 4.34 (1H, d, J = 17 Hz), 3.
05 (1H, t, J = 15Hz), 2.91 (1H, d
d, J ₁ = 6 Hz, J ₂ = 15 Hz), 2.51-2.
47 (1H, m), 2.21-2.15 (1H, m),
1.63-1.42 (2H, m), 0.99-0.80
(10H, m), 0.98 (3H, d, J = 8Hz),
0.85 (6H, dd, J ₁ = 6Hz, J ₂ = 18H
z).

Example 62 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-1-methoxymethyl-3,4-dihydrocarbostyril Obtained in Reference Example 60. The target compound was obtained by reacting the compound with a corresponding starting material in the same manner as in Example 14.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.49 (1H, s), 8.77 (1H,
s), 8.49 (1H, d, J = 8Hz), 7.15-
7.35 (3H, m), 7.06 (1H, t, J = 7H
z), 5.47 (1H, d, J = 10Hz), 5.02
(1H, d, J = 10 Hz), 4.57 (1H, dt,
J ₁ = 14 Hz, J ₂ = 7 Hz), 3.27 (3H,
s), 3.07 (1H, t, J = 14Hz), 2.91
(1H, dd, J ₁ = 14 Hz, J ₂ = 6 Hz), 2.
40-2.60 (1H, m), 2.10-2.30 (1
H, m), 1.50-1.70 (1H, m), 1.46
(1H, t, J = 11 Hz), 0.80-1.00 (1
H, m), 0.98 (3H, d, J = 7Hz), 0.8
8 (3H, d, J = 7Hz), 0.81 (3H, d, J
= 7 Hz).

Example 63 3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-acetylthiomethylsuccinyl] amino-
Production of 1-methoxymethyl-3,4-dihydrocarbostyril The compound obtained in Reference Example 32 was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Example 4.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.61 (1H, s), 8.91 (1H,
s), 8.60 (1H, d, J = 8Hz), 7.15-
7.35 (3H, m), 7.07 (1H, t, J = 7H
z), 5.47 (1H, d, J = 10 Hz), 5.03
(1H, d, J = 10 Hz), 4.60 (1H, dt,
J ₁ = 13 Hz, J ₂ = 7 Hz), 3.27 (3H,
s), 2.80-3.20 (4H, m), 2.40-
2.70 (1H, m), 2.20-2.40 (1H,
m), 2.30 (3H, s), 1.40-1.70 (2
H, m), 0.80-1.00 (1H, m), 0.87
(3H, d, J = 6Hz), 0.81 (3H, d, J =
6 Hz).

Example 64 3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-mercaptomethylsuccinyl] amino-1
Production of -methoxymethyl-3,4-dihydrocarbostyril Using the corresponding starting materials, the above target compound was obtained in the same manner as in Example 5.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 8.55 (1H, d, J = 8Hz), 7.1
5-7.30 (3H, m), 7.06 (1H, t, J =
8 Hz), 5.47 (1H, d, J = 10 Hz), 5.
01 (1H, d, J = 10 Hz), 4.53 (1H, d
t, J ₁ = 14 Hz, J ₂ = 7 Hz), 3.27 (3
H, s), 3.09 (1H, t, J = 15 Hz), 2.
97 (1H, dd, J ₁ = 15 Hz, J ₂ = 7 Hz),
2.40-2.70 (3H, m), 2.20-2.40
(1H, m), 1.40-1.70 (2H, m), 0.
80-1.00 (1H, m), 0.86 (3H, d, J
= 7 Hz), 0.82 (3H, d, J = 7 Hz).

Example 65 1-Ethoxy-3S- [4- (N-hydroxyamino)
Preparation of -2R-isobutylsuccinyl] amino-3,4-dihydrocarbostyril The compound of Reference Example 29 was reacted with the compound treated with trifluoroacetic acid and the corresponding starting material, and the above target compound was prepared in the same manner as in Example 1. Got

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, s), 8.71 (1H, s)
s), 8.35 (1H, d, J = 8Hz), 7.35-
7.26 (2H, m), 7.16 (1H, d, J = 8H
z), 7.06 (1H, t, J = 7 Hz), 4.63-
4.53 (1H, m), 4.04 (2H, q, J = 7H
z), 3.01-2.92 (2H, m), 2.80-
2.72 (1H, m), 2.17 (1H, dd, J ₁ =
6 Hz, J ₂ = 14 Hz), 2.01 (1 H, dd, J
_{1 = 8Hz, J 2 = 15Hz} ), 1.64-1.43
(2H, m), 1.28 (3H, t, J = 7Hz),
1.12-1.04 (1H, m), 0.87 (6H, d
d, J ₁ = 6 Hz, J ₂ = 12 Hz).

Example 66 Production of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxyethoxymethyl-3,4-dihydrocarbostyril Compound obtained by catalytically reducing the compound of Reference Example 61. Was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.41 (1H, s), 8.73 (1H,
s), 8.29 (1H, d, J = 8Hz), 7.25-
7.40 (3H, m), 7.00-7.15 (1H,
m), 5.57 (1H, d, J = 10Hz), 5.02
(1H, d, J = 10 Hz), 4.51 (1H, dt,
J ₁ = 14 Hz, J ₂ = 7 Hz), 3.60 (2H,
t, J = 4 Hz), 3.44 (2H, t, J = 4H)
z), 3.22 (3H, s), 2.70-3.10 (3
H, m), 2.18 (1H, dd, J ₁ = 14Hz, J
₂ = 7 Hz), 2.02 (1H, dd, J ₁ = 14H
z, J ₂ = 7 Hz), 1.40 to 1.80 (2H,
m), 1.00-1.30 (1H, m), 0.90 (3
H, d, J = 7Hz), 0.85 (3H, d, J = 7H
z).

Example 67 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutyl-3-propylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril Compound obtained in Reference Example 62 Was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Example 14.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.49 (1H, s), 8.78 (1H,
s), 8.52 (1H, d, J = 8Hz), 7.36-
7.29 (2H, m), 7.16 (1H, d, J = 8H
z), 7.07 (1H, t, J = 7Hz), 4.67-
4.62 (1H, m), 3.83 (3H, s), 3.0
4 (1H, t, J = 16Hz), 2.94 (1H, d
d, J ₁ = 7 Hz, J ₂ = 16 Hz), 2.52-2.
43 (1H, m), 2.11-2.09 (1H, m),
1.58-1.41 (2H, m), 1.24-1.03
(4H, m), 0.96-0.80 (10H, m).

Example 68 3S- [3-Benzyl-4- (N-hydroxyamino)]
Production of -2R-isobutylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 63 was reacted with the corresponding starting material to give the above target compound in the same manner as in Example 14. Obtained.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.28 (1H, s), 8.69-8.6
5 (2H, m), 7.36-7.03 (9H, m),
4.68-4.63 (1H, m), 3.84 (3H,
s), 3.12 (1H, t, J = 15Hz), 2.98
(1H, dd, J ₁ = 7 Hz, J ₂ = 16 Hz), 2.
75-2.71 (2H, m), 2.58-2.55 (1
H, m), 2.45-2.39 (1H, m), 1.62
-1.48 (2H, m), 1.03 to 0.97 (1H,
m), 0.87 (6H, dd, J ₁ = 6 Hz, J ₂ = 1
6 Hz).

Example 69 Production of 3S- [4- (N-hydroxyamino) -2R-isobutyl-3- (4-methoxybenzyl) succinyl] amino-1-methoxy-3,4-dihydrocarbostyril Reference Example 64 The target compound was obtained in the same manner as in Example 14 by reacting the compound obtained in (4) with the corresponding starting material.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.25 (1H, s), 8.65 (1H,
d, J = 8 Hz), 8.64 (1H, s), 7.36-
7.27 (2H, m), 7.16 (1H, d, J = 7H
z), 7.05 (1H, dt, J ₁ = 1 Hz, J ₂ = 7
Hz), 6.99 (2H, d, J = 9 Hz), 6.79
(2H, d, J = 9 Hz), 4.68-4.63 (1
H, m), 3.84 (3H, s), 3.71 (3H,
s), 3.11 (1H, t, J = 15Hz), 2.98
(1H, dd, J ₁ = 7 Hz, J ₂ = 16 Hz), 2.
68-2.56 (3H, m), 2.39-2.34 (1
H, m), 1.64-1.51 (2H, m), 1.00
-0.96 (1H, m), 0.86 (6H, dd, J ₁
= 7 Hz, J ₂ = 16 Hz).

Example 70 Preparation of 1-carboxymethyl-3S- [4- (N-hydroxyamino) -2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl] amino-3,4-dihydrocarbostyril Reference The target compound was obtained in the same manner as in Example 14 by reacting Example 39 and the corresponding starting material.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.50 (1H, s), 8.70 (1H, s)
bs), 8.57 (1H, d, J = 8 Hz), 7.88
-7.80 (4H, m), 7.28-7.23 (2H,
m), 7.02 (1H, t, J = 7Hz), 6.94
(1H, d, J = 8Hz), 4.71 (1H, d, J =
18Hz), 4.50-4.37 (2H, m), 3.9.
0 (1H, dd, J ₁ = 10 Hz, J ₂ = 14 Hz),
3.48 (1H, dd, J ₁ = 5Hz, J ₂ = 14H
z), 3.17-2.92 (2H, m), 2.84-
2.65 (2H, m), 1.71-1.54 (2H, m
m), 1.00-0.96 (1H, m), 0.86 (6
H, dd, J ₁ = 7 Hz, J ₂ = 19 Hz).

Example 71 Production of 3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-1-methoxyethoxymethyl-3,4-dihydrocarbostyril The compound of Reference Example 61 was prepared. The catalytically reduced compound was reacted with the corresponding starting material to obtain the target compound in the same manner as in Example 62.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.49 (1H, s), 8.78 (1H,
s), 8.48 (1H, d, J = 8Hz), 7.20-
7.35 (3H, m), 7.00-7.10 (1H,
m), 5.56 (1H, d, J = 10Hz), 5.04
(1H, d, J = 10 Hz), 4.55 (1H, dt,
J ₁ = 14 Hz, J ₂ = 7 Hz), 3.60 (2H, d
d, J ₁ = 6 Hz, J ₂ = 3 Hz), 3.44 (2H,
dd, J ₁ = 6 Hz, J ₂ = 3 Hz), 3.22 (3
H, s), 3.06 (1H, t, J = 14 Hz), 2.
91 (1H, dd, J ₁ = 14 Hz, J ₂ = 6 Hz),
2.45-2.60 (1H, m), 2.10-2.30
(1H, m), 1.50-1.70 (1H, m), 1.
47 (1H, t, J = 13Hz), 0.80-1.10
(1H, m), 0.98 (3H, d, J = 7Hz),
0.88 (3H, d, J = 7Hz), 0.81 (3H,
d, J = 7 Hz).

Example 72 Preparation of 3S- [4- (N-hydroxyamino) -2S-isobutylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril Starting compound corresponding to the compound obtained in Reference Example 65 The starting material was reacted to obtain the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.41 (1H, brs), 8.75 (1
H, brs), 8.50 (1H, d, J = 8Hz),
7.32 (2H, t, J = 8Hz), 7.16 (1H,
d, J = 8 Hz), 7.07 (1H, t, J = 8H
z), 4.60 (1H, dt, J ₁ = 11 Hz, J ₂ =
8Hz), 3.83 (3H, s), 2.98 (1H,
d, J = 11 Hz), 2.97 (1H, d, J = 8H
z), 2.79-2.84 (1H, m), 2.21 (1
H, dd, J ₁ = 5 Hz, J ₂ = 14 Hz), 2.02
(1H, dd, J ₁ = 9 Hz, J ₂ = 14 Hz), 1.
42-1.51 (2H, m), 1.02-1.12 (1
H, m), 0.84 (6H, d, J = 6Hz).

Example 73 Production of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxymethoxyethyl-3,4-dihydrocarbostyril Compound obtained by catalytically reducing the compound of Reference Example 66. Was reacted with a corresponding starting material to obtain the above-mentioned target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, s), 8.70 (1H,
s), 8.23 (1H, d, J = 8Hz), 7.20-
7.35 (3H, m), 7.03 (1H, t, J = 8H
z), 4.52 (2H, q, J = 6Hz), 4.40-
4.60 (1H, m), 4.09 (2H, t, J = 6H
z), 3.63 (2H, t, J = 6Hz), 3.17.
(3H, s), 2.70-3.00 (3H, m), 2.
18 (1H, dd, J ₁ = 15 Hz, J ₂ = 6 Hz),
2.01 (1H, dd, J ₁ = 15Hz, J ₂ = 7H
z), 1.40-1.80 (2H, m), 1.00-
1.20 (1H, m), 0.90 (3H, d, J = 7H
z), 0.84 (3H, d, J = 7Hz).

Example 74 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutyl-3- (3-phenylpropyl) succinyl] amino-1-methoxy-3,4-dihydrocarbostyril Reference Example 67 The target compound was obtained in the same manner as in Example 14 by reacting the compound obtained in (4) with the corresponding starting material.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.52 (1H, s), 8.80 (1H, s)
s), 8.52 (1H, d, J = 8Hz), 7.35
(1H, t, J = 7Hz), 7.30-7.15 (7
H, m), 7.10 (1H, t, J = 7 Hz), 4.6
6-4.61 (1H, m), 3.83 (3H, s),
2.96 (1H, t, J = 16Hz), 2.82 (1
H, dd, J ₁ = 6 Hz, J ₂ = 16 Hz), 2.56
-2.43 (3H, m), 2.14-2.09 (1H,
m), 1.57-1.29 (6H, m), 0.95-
0.92 (1H, m), 0.83 (6H, dd, J ₁ =
6 Hz, J ₂ = 12 Hz).

Example 75 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutyl-3- (2-methylbenzyl) succinyl] amino-1-methoxy-3,4-dihydrocarbostyril Reference Example 68 The target compound was obtained in the same manner as in Example 14 by reacting the compound obtained in (4) with the corresponding starting material.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.21 (1H, s), 8.70 (1H,
d, J = 8 Hz), 8.60 (1H, s), 7.33
(1H, t, J = 8Hz), 7.28 (1H, d, J =
7 Hz), 7.16 (1H, d, J = 8 Hz), 7.0
7-6.96 (5H, m), 4.68-4.62 (1
H, m), 3.84 (3H, s), 3.15 (1H,
t, J = 15 Hz), 2.98 (1H, dd, J ₁ = 6)
Hz, J ₂ = 16 Hz), 2.75-2.71 (2H,
m), 2.61-2.56 (1H, m), 2.42-
2.37 (1H, m), 2.22 (3H, s), 1.6
3-1.47 (2H, m), 1.00-0.96 (1
H, m), 0.87 (6H, dd, J ₁ = 6Hz, J ₂
= 17 Hz).

Example 76 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutyl-3- (3-methylbenzyl) succinyl] amino-1-methoxy-3,4-dihydrocarbostyril Reference Example 69 The target compound was obtained in the same manner as in Example 14 by reacting the compound obtained in (4) with the corresponding starting material.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.27 (1H, s), 8.67-8.6
4 (2H, m), 7.36-7.27 (2H, m),
7.18-6.85 (6H, m), 4.68-4.63
(1H, m), 3.84 (3H, s), 3.12 (1
H, t, J = 15 Hz), 2.98 (1H, dd, J ₁
= 7 Hz, J ₂ = 16 Hz), 2.75-2.49 (3
H, m), 2.44-2.38 (1H, m), 2.26.
(3H, s), 1.64-1.47 (2H, m), 1.
01-0.97 (1H, m), 0.87 (6H, dd,
J ₁ = 6 Hz, J ₂ = 16 Hz).

Example 77 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutyl-3- (4-methylbenzyl) succinyl] amino-1-methoxy-3,4-dihydrocarbostyril Reference Example 70 The target compound was obtained in the same manner as in Example 14 by reacting the compound obtained in (4) with the corresponding starting material.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.25 (1H, s), 8.66-8.6
3 (2H, m), 7.36-7.27 (2H, m),
7.16 (1H, d, J = 8Hz), 7.08-7.0
2 (3H, m), 6.96 (2H, d, J = 8Hz),
4.68-4.63 (1H, m), 3.84 (3H,
s), 3.11 (1H, t, J = 13Hz), 2.98
(1H, dd, J ₁ = 6 Hz, J ₂ = 15 Hz), 2.
75-2.49 (3H, m), 2.41-2.35 (1
H, m), 2.25 (3H, s), 1.61-1.47
(2H, m), 1.00-0.82 (7H, m), 0.
86 (6H, dd, J ₁ = 6 Hz, J ₂ = 15 Hz).

Example 78 Preparation of 3S- [4- (N-Hydroxyamino) -2R-heptylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril Starting compound corresponding to the compound obtained in Reference Example 73 The starting materials were reacted to obtain the above target compound in the same manner as in Example 14.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.71 (1H,
s), 8.32 (1H, d, J = 8Hz), 7.32
(2H, dd, J ₁ = 16 Hz, J ₂ = 8 Hz), 7.
16 (1H, d, J = 8Hz), 7.07 (1H, t,
J = 8 Hz), 4.61 (1H, dt, J ₁ = 12H
z, J ₂ = 8 Hz), 3.82 (3H, s), 2.85
-3.10 (2H, m), 2.55-2.80 (1H,
m), 2.20 (1H, dd, J ₁ = 14 Hz, J ₂ =
7Hz), 2.02 (1H, dd, J ₁ = 14Hz, J
₂ = 7 Hz), 1.05-1.60 (12H, m),
0.87 (3H, t, J = 6Hz).

Example 79 3S- [4- (N-acetoxyamino) -2R-isobutylsuccinyl] amino-1-methoxymethyl-3,4
-Production of dihydrocarbostyril Acetic anhydride was reacted with the corresponding starting material to obtain the above-mentioned target compound in the same manner as in Example 8.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 11.63 (1H, s), 8.33 (1H,
d, J = 8 Hz), 7.20-7.35 (3H, m),
7.07 (1H, t, J = 7Hz), 5.49 (1H,
d, J = 10 Hz), 5.00 (1H, d, J = 10H
z), 4.53 (1H, dt, J ₁ = 13 Hz, J ₂ =
8 Hz), 3.26 (3 H, s), 2.90-3.10
(2H, m), 2.70-2.90 (1H, m), 2.
35 (1H, dd, J ₁ = 15Hz, J ₂ = 6Hz),
2.18 (1H, dd, J ₁ = 15Hz, J ₂ = 8H
z), 2.15 (3H, s), 1.40-1.80 (2
H, m), 1.10-1.35 (1H, m), 0.90
(3H, d, J = 7Hz), 0.85 (3H, d, J =
7 Hz).

Example 80 7-chloro-3S- [4- (N-hydroxyamino)-
Production of 2R-isobutylsuccinyl] amino-1-methoxymethyl-3,4-dihydrocarbostyril The compound of Reference Example 74 was reacted with the compound treated with hydrazine and the corresponding starting material, and the same procedure as in Example 1 was performed. The target compound was obtained.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, brs), 8.72 (1
H, brs), 8.32 (1H, d, J = 8Hz),
7.30 (1H, d, J = 8Hz), 7.28 (1H,
d, J = 2 Hz), 7.13 (1H, dd, J ₁ = 2H)
z, J ₂ = 8 Hz), 5.47 (1H, d, J = 11H)
z), 5.06 (1H, d, J = 11Hz), 4.55
(1H, dt, J ₁ = 11 Hz, J ₂ = 8 Hz), 3.
26 (3H, s), 2.98 (1H, d, J = 11H
z), 2.97 (1H, d, J = 8Hz), 2.75-
2.84 (1H, m), 2.17 (1H, dd, J ₁ =
7Hz, J ₂ = 15Hz), 2.01 (1H, dd, J
_{1 = 8Hz, J 2 = 15Hz} ), 1.51-1.59
(1H, m), 1.43-1.53 (1H, m), 1.
02-1.12 (1H, m), 0.87 (6H, dd,
J ₁ = 6 Hz, J ₂ = 13 Hz).

Example 81 1-t-Butoxyethyl-3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-
Production of 3,4-dihydrocarbostyryl The compound of Reference Example 75 was reacted with the compound treated by catalytic reduction and the corresponding starting material to give the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, brs), 8.70 (1
H, brs), 8.20 (1H, d, J = 8 Hz),
7.22-7.31 (3H, m), 6.99-7.05
(1H, m), 4.43 (1H, dt, J ₁ = 11H
z, J ₂ = 8 Hz), 4.04 (1H, dt, J ₁ = 1)
4Hz, J ₂ = 6Hz), 3.85 (1H, dt, J ₁
= 14 Hz, J ₂ = 7 Hz), 3.45-3.50 (1
H, m), 2.92 (1H, d, J = 11 Hz), 2.
91 (1H, d, J = 8Hz), 2.76-2.82
(1H, m), 2.18 (1H, dd, J ₁ = 7 Hz,
J ₂ = 15 Hz), 2.01 (1H, dd, J ₁ = 8H
z, J ₂ = 15 Hz), 1.59-1.67 (1H,
m), 1.45-1.54 (1H, m), 1.06-
1.13 (1H, m), 1.06 (9H, s), 0.8
7 (6H, dd, J ₁ = 7 Hz, J ₂ = 14 Hz).

Example 82 3S- [4- (N-Hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxyethyl-3,4
-Production of dihydrocarbostyril The compound of Reference Example 76 was reacted with the compound treated with trifluoroacetic acid and the corresponding starting material to obtain the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, brs), 8.71 (1
H, brs), 8.23 (1H, d, J = 8Hz),
7.23-7.31 (3H, m), 7.00-7.06
(1H, m), 4.45 (1H, dt, J ₁ = 11H
z, J ₂ = 8 Hz), 4.01-4.11 (2H,
m), 3.45-3.54 (2H, m), 3.23 (3
H, s), 2.92 (1H, d, J = 11 Hz), 2.
91 (1H, d, J = 8 Hz), 2.75-2.79
(1H, m), 2.17 (1H, dd, J ₁ = 7 Hz,
J ₂ = 14 Hz), 2.01 (1H, dd, J ₁ = 8H
z, J ₂ = 14 Hz), 1.62-1.66 (1H,
m), 1.43-1.54 (1H, m), 1.08-
1.15 (1H, m), 0.87 (6H, dd, J ₁ =
7 Hz, J ₂ = 14 Hz).

Example 83 3R- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxyethyl-3,4
-Production of dihydrocarbostyril The compound of Reference Example 77 was reacted with the compound treated by catalytic reduction and the corresponding starting material to give the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.40 (1H, brs), 8.74 (1
H, brs), 8.39 (1H, d, J = 8Hz),
7.22-7.31 (3H, m), 7.00-7.05
(1H, m), 4.43 (1H, dt, J ₁ = 8Hz,
J ₂ = 11 Hz), 4.02-4.12 (2H, m),
3.49-3.53 (2H, m), 3.24 (3H,
s), 2.91 (1H, d, J = 8Hz), 2.90
(1H, d, J = 11 Hz), 2.83-2.88 (1
H, m), 2.11 (1H, dd, J ₁ = 5 Hz, J ₂
= 14 Hz), 2.01 (1H, dd, J ₁ = 9 Hz,
J ₂ = 14 Hz), 1.44 to 1.47 (2H, m),
1.05-1.07 (1H, m), 0.84 (6H, d
d, J ₁ = 6 Hz, J ₂ = 2 Hz).

Example 84 3S- [4- (N-hydroxyamino) -2R-ethoxyethylsuccinyl] amino-1-methoxy-3,4-
Preparation of dihydrocarbostyril 4-Ethoxypropionic acid (Vlado Prelo
g, Ber. , 72B, 11036 (1939)) was reacted with oxalyl chloride to convert it to 4-ethoxypropionyl chloride, and the corresponding starting material was reacted to give the above target compound in the same manner as in Example 78.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.39 (1H, s), 8.71 (1H,
s), 8.30 (1H, d, J = 8Hz), 7.32
(2H, dd, J ₁ = 16 Hz, J ₂ = 8 Hz), 7.
16 (1H, d, J = 8Hz), 7.08 (1H, t,
J = 8 Hz), 4.61 (1H, dt, J ₁ = 12H
z, J ₂ = 8 Hz), 3.82 (3H, s), 3.41
(2H, q, J = 8Hz), 3.25-3.50 (2
H, m), 2.90-3.10 (2H, m), 2.70.
-2.90 (1H, m), 2.23 (1H, dd, J ₁
= 15 Hz, J ₂ = 7 Hz), 1.50-1.80 (2
H, m), 1.11 (3H, t, J = 7Hz).

Example 85 3R- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxymethyl-3,4
-Preparation of dihydrocarbostyril J. Med. Chem. , 1972, 15, 325, and the corresponding starting materials, and in the same manner as in Example 27, the above target compound was obtained.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.41 (1H, s), 8.75 (1H,
s), 8.44 (2H, d, J = 8Hz), 7.20-
7.35 (3H, m), 7.06 (1H, t, J = 7H
z), 5.50 (1H, d, J = 10Hz), 5.01
(1H, d, J = 10 Hz), 4.51 (1H, dt,
J ₁ = 12 Hz, J ₂ = 8 Hz), 3.26 (3H,
s), 2.75-3.10 (3H, m), 2.22 (1
H, dd, J ₁ = 15 Hz, J ₂ = 5 Hz), 2.02
(1H, dd, J ₁ = 15 Hz, J ₂ = 9 Hz), 1.
40-1.60 (1H, m), 0.95-1.35 (2
H, m), 0.85 (6H, t, J = 5Hz).

Example 86 3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-acetylthiomethylsuccinyl] amino-
Production of 1-methoxy-3,4-dihydrocarbostyril Using the corresponding starting materials, the above target compound was obtained in the same manner as in Example 4.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.61 (1H, s), 8.91 (1H,
s), 8.67 (1H, d, J = 8Hz), 7.34
(1H, t, J = 8Hz), 7.27 (1H, d, J =
8 Hz), 7.17 (1H, d, J = 8 Hz), 7.0
7 (1H, t, J = 7Hz), 4.67 (1H, dt,
J ₁ = 12 Hz, J ₂ = 8 Hz, 3.83 (3H,
s), 2.80-3.15 (4H, m), 2.25-
2.65 (1H, m), 2.20-2.40 (1H,
m), 2.30 (3H, s), 1.50-1.70 (1
H, m), 1.51 (1H, t, J = 11 Hz), 0.
93 (1H, t, J = 11Hz), 0.86 (3H,
t, J = 7Hz), 0.82 (3H, d, J = 7H)
z).

Example 87 3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-mercaptomethylsuccinyl] amino-1
Preparation of -methoxy-3,4-dihydrocarbostyril Using the corresponding starting materials, the above target compound was obtained in the same manner as in Example 5.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 8.62 (1H, d, J = 8Hz), 7.3
2 (2H, dd, J ₁ = 14 Hz, J ₂ = 7 Hz),
7.15 (1H, d, J = 8Hz), 7.07 (1H,
t, J = 7 Hz), 4.58 (1H, dt, J ₁ = 14
Hz, J ₂ = 7 Hz), 3.82 (3H, s), 3.1
0 (1H, t, J = 15Hz), 2.98 (1H, d
d, J ₁ = 15 Hz, J ₂ = 7 Hz), 2.40-2.
65 (3H, m), 2.20-2.40 (1H, m),
1.45-1.70 (1H, m), 1.50 (1H, m
t, J = 12 Hz), 0.94 (1H, t, J = 12H)
z), 0.86 (3H, d, J = 7Hz), 0.82
(3H, d, J = 7Hz).

Example 88 Production of 3S- [4- (N-Hydroxyamino) -2R-isobutyl-3- (4-methoxycarbonylbenzyl) succinyl] amino-1-methoxy-3,4-dihydrocarbostyril Reference Example The compound obtained in 78 was reacted with the corresponding starting material to obtain the target compound in the same manner as in Example 14.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.29 (1H, s), 8.70 (1H,
d, J = 8 Hz), 8.66 (1H, s), 7.85
(2H, d, J = 8 Hz), 7.36-7.27 (2
H, m), 7.22 (2H, d, J = 8 Hz), 7.1
6 (1H, d, J = 7Hz), 7.05 (1H, t, J
= 7 Hz), 4.66-4.61 (1H, m), 3.8
4 (6H, s), 3.14 (1H, t, J = 15H
z), 2.99 (1H, dd, J ₁ = 7 Hz, J ₂ = 1)
6 Hz), 2.81-2.78 (2H, m), 2.60
-2.57 (1H, m), 2.46-2.40 (1H,
m), 1.62-1.48 (2H, m), 1.01-
0.97 (1H, m), 0.87 (6H, dd, J ₁ =
6 Hz, J ₂ = 16 Hz).

Example 89 3S- [3-hexyl-4- (N-hydroxyamino)]
Production of −2R-isobutylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 79 was reacted with the corresponding starting material, and the above target compound was obtained in the same manner as in Example 14. Obtained.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.48 (1H, s), 8.77 (1H,
s), 8.53 (1H, d, J = 8Hz), 7.34
(1H, t, J = 8Hz), 7.28 (1H, d, J =
7 Hz), 7.16 (1H, d, J = 8 Hz), 7.0
6 (1H, t, J = 8Hz), 4.66-4.61 (1
H, m), 3.83 (3H, s), 2.99 (1H,
t, J = 13 Hz), 2.90 (1H, dd, J ₁ = 9)
Hz, J ₂ = 12 Hz), 2.51-2.42 (1H,
m), 2.09-2.05 (1H, m), 1.57-
1.41 (2H, m), 1.22-1.09 (10H,
m), 0.95-0.80 (10H, m).

Example 90 3S- [4- (N-hydroxyamino) -2R-butyl-3S-methylsuccinyl] amino-1-methoxy-
Production of 3,4-dihydrocarbostyril The compound obtained in Reference Example 80 was reacted with the corresponding starting material to obtain the desired compound as described in Example 62.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.49 (1H, s), 8.76 (1H,
s), 8.52 (1H, d, J = 8Hz), 7.32
(2H, dd, J ₁ = 16 Hz, J ₂ = 8 Hz), 7.
16 (1H, d, J = 8Hz), 7.07 (1H, t,
J = 8 Hz), 4.62 (1H, dt, J ₁ = 14H
z, J ₂ = 7 Hz), 3.83 (3H, s), 2.30
-2.50 (1H, m), 2.10-2.30 (1H,
m), 1.00-1.50 (6H, m), 0.95 (3
H, d, J = 7Hz), 0.85 (3H, t, J = 7H)
z).

Example 91 Preparation of 3S- [4- (N-Hydroxyamino) -2R-butylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 80 and the corresponding starting material The starting material was reacted to obtain the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.70 (1H,
s), 8.31 (1H, d, J = 7Hz), 7.32
(2H, dd, J ₁ = 16 Hz, J ₂ = 8 Hz), 7.
16 (1H, d, J = 8Hz), 7.07 (1H, t,
J = 8 Hz), 4.61 (1H, dt, J ₁ = 13H
z, J ₂ = 8 Hz), 3.82 (3H, s), 2.80
-3.10 (2H, m), 2.55-2.80 (1H,
m), 2.20 (1H, dd, J ₁ = 14 Hz, J ₂ =
7Hz), 2.03 (1H, dd, J ₁ = 14Hz, J
₂ = 8 Hz), 1.10-1.60 (6H, m), 0.
87 (3H, t, J = 7Hz).

Example 92 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutyl-3- (3,4-methylenedioxybenzyl) succinyl] amino-1-methoxy-3,4-dihydrocarbostyril Production The target compound was obtained in the same manner as in Example 14 by reacting the compound obtained in Reference Example 81 with the corresponding starting material.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.28 (1H, s), 8.68 (1H,
s), 8.65 (1H, d, J = 8Hz), 7.36-
7.27 (2H, m), 7.16 (1H, d, J = 7H
z), 7.05 (1H, dt, J ₁ = 1 Hz, J ₂ = 7
Hz), 6.77 (1H, d, J = 8 Hz), 6.60
(1H, d, J = 2Hz), 6.52 (1H, dd, J
_{1 = 2Hz, J 2 = 8Hz} ), 5.95 (2H, s),
4.66-4.61 (1H, m), 3.84 (3H,
s), 3.12 (1H, t, J = 15Hz), 2.98
(1H, dd, J ₁ = 7 Hz, J ₂ = 16 Hz), 2.
66-2.49 (3H, m), 2.38-2.32 (1
H, m), 1.60-1.46 (2H, m), 0.99
-0.95 (1H, m), 0.86 (6H, dd, J ₁
= 6 Hz, J ₂ = 15 Hz).

Example 93 3S- [3- (3-ethoxycarbonylpropyl) -4
Preparation of-(N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 82 was reacted with the corresponding starting material to give Example 14 and Similarly, the above target compound was obtained.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.53 (1H, s), 8.83 (1H,
s), 8.54 (1H, d, J = 8Hz), 7.34
(1H, t, J = 8Hz), 7.28 (1H, d, J =
8 Hz), 7.16 (1H, d, J = 8 Hz), 7.0
7 (1H, t, J = 8Hz), 4.69-4.59 (1
H, m), 4.05 (2H, q, J = 7Hz), 3.8
3 (3H, s), 3.08-2.93 (2H, m),
2.51-2.43 (1H, m), 2.32-2.22
(2H, m), 2.10-2.06 (1H, m), 1.
56-1.31 (6H, m), 1.18 (3H, t, J
= 7 Hz), 0.95-0.80 (7H, m), 0.8
4 (6H, dd, J ₁ = 6 Hz, J ₂ = 12 Hz).

Example 94 1-Ethoxymethyl-3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-3,4
-Preparation of dihydrocarbostyril The compound of Reference Example 83 was reacted with the compound treated by catalytic reduction and the corresponding starting material to give the above target compound as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.39 (1H, s), 8.72 (1H,
s), 8.28 (1H, d, J = 8Hz), 7.20-
7.35 (3H, m), 7.06 (1H, t, J = 7H
z), 5.54 (1H, d, J = 10 Hz), 5.00
(1H, d, J = 10 Hz), 4.50 (1H, dt,
J ₁ = 14 Hz, J ₂ = 7 Hz), 3.51 (2H,
q, J = 7 Hz), 2.70-3.10 (3H, m),
2.15 (1H, dd, J ₁ = 14Hz, J ₂ = 7H
z), 2.01 (1H, dd, J ₁ = 14 Hz, J ₂ =
7 Hz), 1.40 to 1.80 (2H, m), 1.10
(3H, t, J = 7Hz), 1.00-1.20 (1
H, m), 0.90 (3H, d, J = 7Hz), 0.8
5 (3H, d, J = 7 Hz).

Example 95 3S- [4- (N-hydroxyamino) -2S-butoxymethylsuccinyl] amino-1-methoxy-3,4-
Production of Dihydrocarbostyril The compound obtained in Reference Example 85 was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, s), 8.69 (1H,
s), 8.34 (1H, d, J = 8Hz), 7.34
(1H, t, J = 8Hz), 7.28 (1H, d, J =
8 Hz), 7.16 (1H, d, J = 8 Hz), 7.0
8 (1H, t, J = 8Hz), 4.58 (1H, dt,
J ₁ = 12 Hz, J ₂ = 8 Hz, 3.83 (3H,
s), 3.30-3.60 (4H, m), 2.90-
3.10 (3H, m), 2.27 (1H, dd, J ₁ =
15Hz, J ₂ = 8Hz), 2.11 (1H, dd, J
_{1 = 15Hz, J 2 = 6Hz} ), 1.20-1.60
(4H, m), 0.88 (3H, t, J = 7Hz).

Example 96 3S- [4- (N-hydroxyamino) -2-isobutyl-3-methylthiomethylsuccinyl] amino-3,4
-Production of dihydrocarbostyril The compound obtained in Reference Example 87 was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Example 4.

NMR (270 MHz, DMSO-d ₆ ).
δ ppm: 10.61 (1 H, s), 10.19 (1
H, s), 8.87 (1H, s), 8.45 (1H,
d, J = 8 Hz), 7.18 (2H, dd, J ₁ = 16)
Hz, J ₂ = 8 Hz), 6.90 (2H, dd, J ₁ =
16Hz, J ₂ = 8Hz, 4.41 (1H, dt, J
_{1 = 14Hz, J 2 = 7Hz} ), 2.80-3.30
(3H, m), 2.25-2.70 (3H, m), 2.
00 (3H, s), 1.30-1.70 (2H, m),
0.80-1.10 (1H, m), 0.86 (3H,
d, J = 7Hz), 0.82 (3H, d, J = 7H
z).

Example 97 3S- [4- (N-hydroxyamino) -2R-isobutyl-3S- (2-thienylthiomethyl) succinyl]
Production of amino-1-methoxy-3,4-dihydrocarbostyril After reacting the corresponding starting materials, the above target compound was obtained in the same manner as in Example 4.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.70 (1H, s), 8.96 (1H,
s), 8.64 (1H, d, J = 8Hz), 7.60
(1H, dd, J ₁ = 5 Hz, J ₂ = 1 Hz), 7.3
3 (1H, t, J = 8Hz), 7.00-7.30 (5
H, m), 4.54 (1H, dt, J ₁ = 14Hz, J
₂ = 7 Hz), 3.81 (3H, s), 2.80-3.
20 (5H, m), 2.30-2.50 (1H, m),
1.40-1.65 (2H, m), 0.80-1.00
(1H, m), 0.84 (3H, d, J = 6Hz),
0.81 (3H, d, J = 6Hz).

Example 98 3S- [4- (N-hydroxyamino) -2S-butoxymethyl-3S-methylsuccinyl] amino-3,4-
Preparation of dihydrocarbostyril After the reaction using the corresponding starting materials, the above target compound was obtained in the same manner as in Example 62.

NMR (270 MHz, DMSO-d ₆ ).
δ ppm: 10.48 (1 H, s), 10.26 (1
H, s), 8.77 (1H, s), 8.35 (1H,
d, J = 7 Hz), 7.16 (2H, t, J = 8H)
z), 6.93 (1H, d, J = 8 Hz), 6.87
(1H, d, J = 8Hz), 4.40 (1H, dt, J
_{1 = 12Hz, J 2 = 7Hz} ), 3.10-3.50
(4H, m), 2.80-3.10 (2H, m), 2.
74 (1H, dt, J ₁ = 4 Hz, J ₂ = 10 Hz),
2.10-2.30 (1H, m), 1.20-1.50
(4H, m), 0.98 (3H, d, J = 7Hz),
0.85 (3H, t, J = 7Hz).

Example 99 1-Ethoxyethoxy-3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-3,
Production of 4-dihydrocarbostyril After reacting the compound obtained in Reference Example 88 with the corresponding starting material, the above target compound was obtained in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.72 (1H,
s), 8.36 (1H, d, J = 8Hz), 7.32
(2H, d, J = 3Hz), 7.27 (1H, d, J =
7 Hz), 7.00-7.10 (1 H, m), 4.60
(1H, dt, J ₁ = 13 Hz, J ₂ = 7 Hz), 4.
15 (2H, t, J = 4Hz), 3.63 (2H, d
d, J ₁ = 7 Hz, J ₂ = 4 Hz), 3.44 (2H,
q, J = 7 Hz), 2.85-3.10 (2H, m),
2.65-2.85 (1H, m), 2.17 (1H, d
d, J ₁ = 14 Hz, J ₂ = 7 Hz), 2.01 (1
H, dd, J ₁ = 14 Hz, J ₂ = 8 Hz), 1.40
-1.75 (2H, m), 1.00-1.20 (1H,
m), 1.13 (3H, t, J = 7Hz), 0.89
(3H, d, J = 6Hz), 0.84 (3H, d, J =
6 Hz).

Example 100 1-Ethoxy-3R- [4- (N-hydroxyamino)
Production of -2R-isobutylsuccinyl] amino-3,4-dihydrocarbostyril The above target compound was obtained in the same manner as in Example 1 using the corresponding starting materials.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.42 (1H, s), 8.76 (1H, s)
s), 8.51 (1H, d, J = 8Hz), 7.31
(2H, dd, J ₁ = 16 Hz, J ₂ = 8 Hz), 7.
16 (1H, d, J = 8Hz), 7.06 (1H, t,
J = 8 Hz), 4.56 (1H, q, J = 9 Hz),
4.05 (2H, q, J = 7Hz), 2.90-3.1
0 (2H, m), 2.70-2.95 (1H, m),
2.20 (1H, dd, J ₁ = 14Hz, J ₂ = 5H
z), 2.02 (1H, dd, J ₁ = 14 Hz, J ₂ =
9Hz), 1.35-1.60 (2H, m), 1.28
(3H, t, J = 7Hz), 0.95-1.20 (1
H, m), 0.85 (3H, s), 0.83 (3H,
s).

Example 101 Preparation of 3S- [4- (N-Hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxymethoxyethoxy-3,4-dihydrocarbostyril Starting compound corresponding to the compound of Reference Example 89 After reacting with, the above target compound was obtained in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.70 (1H,
brs), 8.37 (1H, d, J = 8Hz), 7.2
0-7.40 (3H, m), 7.06 (1H, td, J
₁ = 7 Hz, J ₂ = 2 Hz), 4.62 (2H, s),
4.50-4.70 (1H, m), 4.15-4.25
(2H, m), 3.60-3.80 (2H, m), 3.
28 (3H, s), 2.85-3.15 (2H, m),
2.70-2.90 (1H, m), 2.17 (1H, d
d, J ₁ = 14 Hz, J ₂ = 6 Hz), 2.01 (1
H, dd, J ₁ = 14 Hz, J ₂ = 8 Hz), 1.40
-1.75 (2H, m), 0.95-1.20 (1H,
m), 0.89 (3H, d, J = 6Hz), 0.85
(3H, d, J = 6Hz).

Example 102 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1,7-dimethoxy-3,4
-Production of dihydrocarbostyril After reacting the compound of Reference Example 90 with the corresponding starting material, the above target compound was obtained in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.39 (1H, s), 8.73 (1H,
s), 8.36 (1H, d, J = 8Hz), 7.19
(1H, d, J = 8Hz), 6.60-6.70 (2
H, m), 4.57 (1H, q, J = 10 Hz), 3.
82 (3H, s), 3.77 (3H, s), 2.89
(2H, d, J = 9 Hz), 2.70-2.90 (1
H, m), 2.16 (1H, dd, J ₁ = 14Hz, J
₂ = 7 Hz), 2.01 (1H, dd, J ₁ = 14H
z, J ₂ = 8 Hz), 1.40 to 1.75 (2H,
m), 1.00-1.20 (1H, m), 0.89 (3
H, d, J = 6Hz), 0.85 (3H, d, J = 6H
z).

Example 103 1-Ethoxy-3S- [4- (N-hydroxyamino)
Preparation of -2R-isobutylsuccinyl] amino-7-methoxy-3,4-dihydrocarbostyril After reacting the compound obtained in Reference Example 91 with the corresponding starting material, the above-mentioned object was obtained in the same manner as in Example 1. The compound was obtained.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, s), 8.71 (1H, s)
s), 8.32 (1H, d, J = 5 Hz), 7.19
(1H, d, J = 8Hz), 6.55-6.70 (2
H, m), 4.54 (1H, q, J = 10 Hz), 4.
04 (2H, q, J = 7Hz), 3.77 (3H,
s), 2.70-3.00 (3H, m), 2.16 (1
H, dd, J ₁ = 14 Hz, J ₂ = 7 Hz), 2.01
(1H, dd, J ₁ = 14 Hz, J ₂ = 8 Hz), 1.
35-1.70 (2H, m), 1.28 (3H, t, J
= 7 Hz), 1.00-1.20 (1H, m), 0.8
9 (3H, d, J = 7Hz), 0.85 (3H, d, J
= 7 Hz).

Example 104 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxyethyl-6,7
-Preparation of methylenedioxy-3,4-dihydrocarbostyryl The compound of Reference Example 92 was reacted with the compound treated with trifluoroacetic acid and the corresponding starting material, and the reaction was carried out in the same manner as in Example 1, followed by purification by HPLC. Then, the above target compound was obtained.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, s), 8.71 (1H, s)
s), 8.17 (1H, d, J = 8Hz), 6.98
(1H, s), 6.87 (1H, s), 5.99 (2
H, s), 4.40-4.37 (1H, m), 4.00.
(2H, t, J = 6Hz), 3.48 (2H, t, J =
6 Hz), 3.23 (3 H, s), 2.80-2.75
(3H, m), 2.17 (1H, dd, J ₁ = 7Hz,
J ₂ = 15 Hz), 2.00 ( ₁ H, dd, J ₁ = 8 H
z, J ₂ = 14 Hz), 1.63 to 1.61 (1H,
m), 1.47-1.44 (1H, m), 1.12
1.06 (1H, m), 0.87 (6H, dd, J ₁ =
6 Hz, J ₂ = 14 Hz).

Example 105 3R- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxyethyl-6,7
-Preparation of methylenedioxy-3,4-dihydrocarbostyril The compound of Reference Example 92 was reacted with the compound treated with trifluoroacetic acid and the corresponding starting material, and the reaction was carried out in the same manner as in Example 1, followed by purification by HPLC. The above target compound was obtained.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.40 (1H, s), 8.74 (1H,
s), 8.35 (1H, d, J = 8Hz), 6.98
(1H, s), 6.88 (1H, s), 5.99 (2
H, s), 4.40-4.32 (1H, m), 4.01.
(2H, t, J = 5Hz), 3.48 (2H, t, J =
5 Hz), 3.23 (3 H, s), 2.83-2.75
(3H, m), 2.20 (1H, dd, J ₁ = 5Hz,
J ₂ = 15 Hz), 2.01 (1H, dd, J ₁ = 9H
z, J ₂ = 14 Hz), 1.50-1.43 (2H,
m), 1.09-1.05 (1H, m), 0.83 (6
H, dd, J ₁ = 3 Hz, J ₂ = 6 Hz).

Example 106 3S- [4- (N-benzoyloxyamino) -2R-
Production of isobutylsuccinyl] amino-1-methoxyethoxymethyl-3,4-dihydrocarbostyril The above target compound was obtained in the same manner as in Example 8 using the corresponding starting materials.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 11.95 (1H, bs), 8.35 (1
H, d, J = 8 Hz), 8.03 (2H, d, J = 7H
z), 7.76 (1H, t, J = 7Hz), 7.60
(2H, t, J = 8Hz), 7.30-7.25 (3
H, m), 7.07 (1H, dt, J ₁ = 2 Hz, J ₂
= 8 Hz), 5.57 (1H, d, J = 11 Hz),
5.03 (1H, d, J = 11 Hz), 4.59-4.
49 (1H, m), 3.60 (2H, dd, J ₁ = 4H
z, J ₂ = 6 Hz), 3.44 (2H, dd, J ₁ = 4)
Hz, J ₂ = 6 Hz), 3.22 (3H, s), 3.0
1-2.93 (2H, m), 2.87-2.82 (1
H, m), 2.44 (1H, dd, J ₁ = 7 Hz, J ₂
= 15 Hz), 2.27 ( ₁ H, dd, J ₁ = 7 Hz,
J ₂ = 15 Hz), 1.71-1.53 (2H, m),
1.27-1.21 (1H, m), 0.90 (6H, d
d, J ₁ = 6 Hz, J ₂ = 13 Hz).

Example 107 3S- [4- (N-benzoyloxyamino) -2R-
Isobutylsuccinyl] amino-1-methoxymethyl-
Production of 3,4-dihydrocarbostyril The above target compound was obtained in the same manner as in Example 8 using the corresponding starting materials.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 11.95 (1H, bs), 8.36 (1
H, d, J = 8 Hz), 8.03 (2H, d, J = 7H
z), 7.76 (1H, t, J = 7Hz), 7.60
(2H, t, J = 8Hz), 7.32-7.22 (3
H, m), 7.07 (1H, t, J = 7 Hz), 5.4
9 (1H, d, J = 11Hz), 5.01 (1H, d,
J = 10 Hz), 4.58-4.50 (1H, m),
3.27 (3H, s), 3.02-2.94 (2H,
m), 2.87-2.82 (1H, m), 2.44 (1
H, dd, J ₁ = 7 Hz, J ₂ = 15 Hz), 2.27
(1H, dd, J ₁ = 7 Hz, J ₂ = 15 Hz), 1.
69-1.53 (2H, m), 1.27-1.17 (1
H, m), 0.902 (6H, dd, J ₁ = 6Hz, J
₂ = 13 Hz).

Example 108 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-6,7-dimethoxy-1-methoxymethyl-3,4-dihydrocarbostyril Obtained in Reference Example 93. After reacting the obtained compound with the corresponding starting material, the above target compound was obtained in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.71 (1H,
s), 8.25 (1H, d, J = 8 Hz), 6.91
(1H, s), 6.86 (1H, s), 5.48 (1
H, d, J = 10 Hz), 5.01 (1 H, d, J = 1
0 Hz), 4.48 ( ₁ H, dt, J ₁ = 11 Hz, J
₂ = 8 Hz), 3.75 (3 H, s), 3.74 (3
H, s), 3.26 (3H, s), 2.80-2.91.
(3H, m), 2.18 (1H, dd, J ₁ = 7Hz,
J ₂ = 8 Hz, 2.02 ( ₁ H, dd, J ₁ = 7 H
z, J ₂ = 8 Hz), 1.60-1.67 (1H,
m), 1.43-1.54 (1H, m), 1.03-
1.13 (1H, m), 0.87 (6H, dd, J ₁ =
14 Hz, J ₂ = 7 Hz).

Example 109 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-6,7-dimethoxy-3,4
-Production of dihydrocarbostyril After reacting the compound obtained in Reference Example 94 with the corresponding starting material, the above target compound was obtained in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 9.97 (1H,
s), 8.74 (1H, s), 8.12 (1H, d, J
= 8 Hz), 6.83 (1H, s), 6.53 (1H, s)
s), 4.41 (1H, dt, J ₁ = 11 Hz, J ₂ =
8 Hz), 3.70 (6 H, s), 2.76-2.89
(3H, m), 2.17 (1H, dd, J ₁ = 8Hz,
J ₂ = 7 Hz), 2.01 ( ₁ H, dd, J ₁ = 8 H
z, J ₂ = 7 Hz), 1.57-1.65 (1H,
m), 1.42-1.52 (1H, m), 1.03-
1.13 (1H, m), 0.86 (6H, dd, J ₁ =
14 Hz, J ₂ = 7 Hz).

Example 110 Preparation of 3S- [4- (N-Hydroxyamino) -2R-isobutylsuccinyl] amino-8-methoxy-1-methoxyethyl-3,4-dihydrocarbostyril Obtained in Reference Example 95. After reacting the compound with the corresponding starting material, the above target compound was obtained in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.35 (1H, s), 8.69 (1H, s)
s), 8.16 (1H, d, J = 8Hz), 7.12-
7.01 (2H, m), 6.88 (1H, d, J = 7H
z), 4.34-4.21 (2H, m), 4.01-
3.94 (1H, m), 3.84 (3H, s), 3.4
5-3.26 (2H, m), 3.11 (3H, s),
2.85-2.74 (3H, m), 2.16 (1H, d
d, J ₁ = 7 Hz, J ₂ = 15 Hz), 2.00 (1
H, dd, J ₁ = 8 Hz, J ₂ = 14 Hz), 1.64
-1.59 (1H, m), 1.52-1.42 (1H,
m), 1.13-1.03 (1H, m), 0.87 (6
H, dd, J ₁ = 6 Hz, J ₂ = 16 Hz).

Example 111 3S- [4- (N-benzoyloxyamino) -2R-
Isobutylsuccinyl] amino-1-methoxy-3,4
-Production of dihydrocarbostyril Using the corresponding starting material, the above target compound was obtained in the same manner as in Example 8.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 12.00 (1H, brs), 8.46 (1
H, d, J = 8 Hz), 8.02 (2H, d, J = 7H
z), 7.75 (1H, t, J = 7Hz), 7.60
(2H, t, J = 7Hz), 7.35 (1H, d, J =
7 Hz), 7.28 (1H, d, J = 7 Hz), 7.1
6 (1H, d, J = 7Hz), 7.07 (1H, t, J
= 7 Hz), 4.64 (1H, q, J = 10 Hz),
3.83 (3H, s), 2.90-3.10 (2H,
m), 2.70-2.95 (1H, m), 2.41 (1
H, dd, J ₁ = 15 Hz, J ₂ = 7 Hz), 2.26
(1H, dd, J ₁ = 15 Hz, J ₂ = 7 Hz), 1.
40-1.80 (2H, m), 1.10-1.35 (1
H, m), 0.92 (3H, d, J = 6Hz), 0.8
8 (3H, d, J = 6Hz).

Example 112 3- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxyethyl-6,7-
Production of Methylenedioxy-3,4-dihydrocarbostyril After reacting the compound of Reference Example 92 with the compound treated with trifluoroacetic acid and the corresponding starting material, the above target compound (dia A stereomeric 1: 1 mixture) was obtained.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.39 + 10.36 (1H, s), 8.
73 + 8.70 (1H, s), 8.35 + 8.16 (1
H, d, J = 8 Hz), 6.98 (1H, s), 6.8
8 + 6.86 (1H, s), 5.99 (2H, s),
4.40-4.35 (1H, m), 4.01-4.00
(2H, m), 3.48 (2H, t, J = 6Hz),
3.31 + 3.23 (3H, s), 2.80-2.75
(3H, m), 2.24-2.13 (1H, m), 2.
05-1.97 (1H, m), 1.73-1.40 (2
H, m), 1.07-1.05 (1H, m), 0.91
-0.82 (6H, m).

Example 113 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxyethoxy-3,
Production of 4-dihydrocarbostyril After reacting the compound obtained in Reference Example 96 and the corresponding starting material, the above target compound was obtained in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, brs), 8.72 (1
H, brs), 8.37 (1H, d, J = 8Hz),
7.26-7.36 (3H, m), 7.06 (1H,
t, J = 7 Hz), 4.61 (1H, dt, J ₁ = 11)
Hz, J ₂ = 8 Hz), 4.13-4.16 (2H,
m), 3.60-3.61 (2H, m), 3.29 (3
H, s), 2.99 (1H, d, J = 11 Hz), 2.
92 (1H, d, J = 8 Hz), 2.73-2.77
(1H, m), 2.17 (1H, dd, J ₁ = 14H
z, J ₂ = 6 Hz), 2.01 (1H, dd, J ₁ = 1)
4 Hz, J ₂ = 8 Hz), 1.61-1.67 (1H,
m), 1.43-1.53 (1H, m), 1.06-
1.15 (1H, m), 0.87 (6H, dd, J ₁ =
13 Hz, J ₂ = 7 Hz).

Example 114 Preparation of 3S- [4- (N-Hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxyethoxymethoxyethoxy-3,4-dihydrocarbostyril With the compound obtained in Reference Example 97 After reacting the corresponding starting materials, the above target compound was obtained in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.72 (1H,
s), 8.37 (1H, d, J = 8Hz), 7.20-
7.40 (3H, m), 7.06 (1H, td, J ₁ =
7 Hz, J ₂ = 2 Hz), 4.68 (2H, s), 4.
50-4.80 (1H, m), 4.18 (2H, t, J
= 4 Hz), 3.76 (2H, m), 3.60 (2H, m)
m), 3.47 (2H, m), 3.24 (3H, s),
2.85-3.10 (2H, m), 2.70-2.85
(1H, m), 2.17 (1H, dd, J ₁ = 14H
z, J ₂ = 7 Hz), 2.01 (1H, dd, J ₁ = 1)
0 Hz, J ₂ = 8 Hz), 1.35-1.75 (2H,
m), 1.00-1.20 (1H, m), 0.89 (3
H, d, J = 7Hz), 0.85 (3H, d, J = 7H
z).

Example 115 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxyethoxyethoxy-3,4-dihydrocarbostyril Corresponds to the compound obtained in Reference Example 98. After reacting the starting materials described above, the above target compound was obtained in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.71 (1H,
s), 8.35 (1H, d, J = 8Hz), 7.20-
7.45 (3H, m), 7.06 (1H, t, J = 7H
z), 4.61 (1H, dt, J ₁ = 13 Hz, J ₂ =
8 Hz), 4.15 (2 H, dd, J ₁ = 5 Hz, J ₂
= 3 Hz), 3.68 (2H, d, J = 3 Hz), 3.
40-3.60 (4H, m), 3.28 (3H, s),
2.85-3.15 (2H, m), 2.65-2.85
(1H, m), 2.17 (1H, dd, J ₁ = 15H
z, J ₂ = 6 Hz), 2.01 (1H, dd, J ₁ = 1)
5 Hz, J ₂ = 8 Hz), 1.35-1.75 (2H,
m), 0.95-1.20 (1H, m), 0.89 (3
H, d, J = 7Hz), 0.85 (3H, d, J = 7H
z).

Example 116 Preparation of 3S- [4- (N-hydroxyamino) -2R-hexylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril After reacting the corresponding starting materials, the Example The above target compound was obtained in the same manner as in 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, s), 8.70 (1H,
s), 8.32 (1H, d, J = 8Hz), 7.35
(1H, d, J = 8 Hz), 7.29 (1H, d, J =
8 Hz), 7.16 (1H, d, J = 8 Hz), 7.0
7 (1H, t, J = 8Hz), 4.61 (1H, dt,
J ₁ = 11 Hz, J ₂ = 8 Hz, 3.82 (3H,
s), 2.85-3.10 (2H, m), 2.55-
2.80 (1H, m), 2.19 (1H, dd, J ₁ =
14 Hz, J ₂ = 7 Hz), 2.02 (1 H, dd, J
_{1 = 14Hz, J 2 = 8Hz} ), 1.10-1.60
(10H, m), 0.87 (3H, t, J = 7Hz).

Example 117 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methyl-6,7-methylenedioxy-3,4-dihydrocarbostyril Reference Example 112 The obtained compound was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.71 (1H,
s), 8.17 (1H, d, J = 8Hz), 6.88
(1H, s), 6.86 (1H, s), 5.99 (2
H, s), 4.37 (1H, dt, J ₁ = 8 Hz, J ₂
= 17 Hz), 3.23 (3H, s), 2.65-2.
90 (3H, m), 2.16 (1H, dd, J ₁ = 6H
z, J ₂ = 14 Hz), 2.00 (1H, dd, J ₁ =
7 Hz, J ₂ = 14 Hz), 1.35-1.80 (2
H, m), 0.95-1.20 (1H, m), 0.89
(3H, d, J = 7 Hz), 0.84 (3H, d, J =
7 Hz).

Example 118 1-Ethyl-3S- [4- (N-hydroxyamino)-
Production of 2R-isobutylsuccinyl] amino-6,7-methylenedioxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 113 was reacted with the corresponding starting material, and in the same manner as in Example 1 above. The target compound was obtained.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, s), 8.70 (1H,
s), 8.14 (1H, d, J = 8Hz), 6.89
(1H, s), 6.87 (1H, s), 5.99 (2
H, s), 4.36 (1H, q, J = 9 Hz), 3.8
4 (2H, q, J = 7Hz), 2.70-2.85 (3
H, m), 2.17 (1H, dd, J ₁ = 7 Hz, J ₂
= 14 Hz), 2.01 (1H, dd, J ₁ = 7 Hz,
J ₂ = 14 Hz), 1.40 to 1.75 (2H, m),
0.89 (3H, d, J = 7Hz), 0.84 (3H,
d, J = 7 Hz).

Example 119 1-Carboxymethyl-3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-6
Production of 7-methylenedioxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 111 was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.71 (1H,
s), 8.23 (1H, d, J = 8Hz), 6.88
(1H, s), 6.71 (1H, s), 5.98 (2
H, s), 4.61 (1H, d, J = 17 Hz), 4.
30-4.50 (1H, m), 4.40 (1H, d, J
= 17 Hz), 2.70-3.00 (3H, m), 2.
18 (1H, dd, J ₁ = 7 Hz, J ₂ = 14 Hz),
2.01 (1H, dd, J ₁ = 7Hz, J ₂ = 14H
z), 1.35-1.80 (2H, m), 0.95-
1.25 (1H, m), 0.89 (3H, d, J = 6H
z), 0.84 (3H, d, J = 6Hz).

Example 120 1-carbamoylmethyl-3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-
Production of 6,7-methylenedioxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 110 was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.73 (1H,
s), 8.19 (1H, d, J = 8 Hz), 7.54
(1H, s), 7.18 (1H, s), 6.88 (1
H, s), 6.56 (1H, s), 5.98 (2H,
s), 4.56 (1H, d, J = 7Hz), 4.45-
4.60 (1H, m), 4.23 (1H, d, J = 7H
z), 2.70-2.95 (3H, m), 2.17 (1
H, dd, J ₁ = 7 Hz, J ₂ = 14 Hz), 2.01
(1H, dd, J ₁ = 8 Hz, J ₂ = 14 Hz), 1.
35-1.80 (2H, m), 0.95-1.20 (1
H, m), 0.89 (3H, d, J = 6Hz), 0.8
4 (3H, d, J = 6Hz).

Example 121 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxymethyl-6,7
-Production of methylenedioxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 100 was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, brs), 8.71 (1
H, brs), 8.24 (1H, d, J = 8Hz),
6.89 (2H, s), 5.99 (2H, d, J = 3H
z), 5.42 (1H, d, J = 10 Hz), 4.98
(1H, d, J = 10 Hz), 4.46 (1H, dt,
J ₁ = 8 Hz, J ₂ = 16 Hz), 3.24 (3H,
s), 2.73-2.84 (3H, m), 2.17 (1
H, dd, J ₁ = 7 Hz, J ₂ = 15 Hz), 2.01
(1H, dd, J ₁ = 8 Hz, J ₂ = 15 Hz), 1.
60-1.70 (1H, m), 1.43-1.53 (1
H, m), 1.07-1.16 (1H, m), 0.89
(3H, d, J = 7 Hz), 0.84 (3H, d, J =
7 Hz).

Example 122 1-Ethyl-3S- [4- (N-hydroxyamino)-
3S-methyl-2R-isobutylsuccinyl] amino-
Production of 6,7-methylenedioxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 113 was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Example 14.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.48 (1H, s), 8.76 (1H, s)
s), 8.34 (1H, d, J = 8Hz), 6.89
(2H, s), 5.99 (2H, s), 4.43 (1
H, dt, J ₁ = 6 Hz, J ₂ = 13 Hz), 3.87
(2H, q, J = 7Hz), 2.70-2.90 (2
H, m), 2.40-2.60 (1H, m), 2.16
(1H, dd, J ₁ = 7 Hz, J ₂ = 10 Hz), 1.
45-1.70 (1H, m), 1.45 (1H, t, J
= 12 Hz), 1.09 (3H, t, J = 7 Hz),
0.95 (3H, d, J = 7Hz), 0.75-1.0
0 (1H, m), 0.87 (3H, d, J = 6Hz),
0.81 (3H, d, J = 6Hz).

Example 123 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-6,7-methylenedioxy-
Production of 1-Propyl-3,4-dihydrocarbostyril The compound obtained in Reference Example 109 was reacted with the corresponding starting material to obtain the target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.73 (1H,
s), 8.16 (1H, d, J = 8Hz), 6.90
(1H, s), 6.88 (1H, s), 5.99 (2
H, s), 4.37 (1H, q, J = 9 Hz), 3.6
5-4.00 (2H, m), 2.70-2.90 (3
H, m), 2.16 (1H, dd, J ₁ = 7 Hz, J ₂
= 14 Hz), 2.00 ( ₁ H, dd, J ₁ = 7 Hz,
J ₂ = 14 Hz), 1.00-1.75 (5H, m),
0.80-0.95 (9H, m).

Example 124 1-Hexyloxymethyl-3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-
Production of 6,7-methylenedioxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 101 was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, brs), 8.71 (1
H, brs), 8.23 (1H, d, J = 8Hz),
6.91 (1H, s), 6.88 (1H, s), 5.9
9 (2H, d, J = 2Hz), 5.47 (1H, d, J
= 11 Hz), 4.99 (1H, d, J = 11 Hz),
4.47-4.42 (1H, m), 3.42 (2H,
t, J = 6 Hz), 2.87-2.79 (3H, m),
2.17 (1H, dd, J ₁ = 7Hz, J ₂ = 15H
z), 2.01 (1H, dd, J ₁ = 8 Hz, J ₂ = 1
5 Hz), 1.64-1.44 (4 H, m), 1.26
-1.07 (7H, m), 0.90-0.79 (9H,
m).

Example 125 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-6,7-methylenedioxy-
Production of 3,4-dihydrocarbostyril The compound obtained in Reference Example 99 was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, brs), 10.01
(1H, brs), 8.71 (1H, brs), 8.1
1 (1H, d, J = 8Hz), 6.81 (1H, s),
6.48 (1H, s), 5.94 (2H, d, J = 3H
z), 4.44-4.33 (1H, m), 2.83-.
2.79 (3H, m), 2.17 (1H, dd, J ₁ =
6 Hz, J ₂ = 14 Hz), 2.01 (1 H, dd, J
_{1 = 8Hz, J 2 = 14Hz} ), 1.62-1.44
(2H, m), 1.12-1.07 (1H, m), 0.
88 (3H, d, J = 6Hz), 0.84 (3H, d,
J = 6 Hz).

Example 126 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxyethoxymethyl-6,7-methylenedioxy-3,4-dihydrocarbostyril Reference Example The compound obtained in 102 was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, brs), 8.71 (1
H, brs), 8.23 (1H, d, J = 8Hz),
6.93 (1H, s), 6.88 (1H, s), 6.0
0 (2H, d, J = 2Hz), 5.51 (1H, d, J
= 11 Hz), 4.97 (1H, d, J = 11 Hz),
4.44 (1H, dt, J ₁ = 8Hz, J ₂ = 16H
z), 3.57 (2H, dd, J ₁ = 4 Hz, J ₂ = 7)
Hz), 3.44 (2H, dd, J ₁ = 4 Hz, J ₂ =
7 Hz), 3.23 (3 H, s), 2.75-2.86
(3H, m), 2.17 (1H, dd, J ₁ = 7Hz,
J ₂ = 15 Hz), 2.01 (1H, dd, J ₁ = 8H
z, J ₂ = 15 Hz), 1.59-1.65 (1H,
m), 1.43-1.53 (1H, m), 1.02-
1.12 (1H, m), 0.89 (1H, d, J = 7H
z), 0.84 (1H, d, J = 7Hz).

Example 127 Preparation of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxymethoxyethyl-6,7-methylenedioxy-3,4-dihydrocarbostyril Reference Example The compound obtained in 103 was reacted with the corresponding starting material to obtain the desired compound as described in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, brs), 8.71 (1
H, brs), 8.18 (1H, d, J = 8Hz),
6.99 (1H, s), 6.87 (1H, s), 6.0
0 (2H, s), 4.52 (2H, d, J = 6Hz),
4.39 (1H, dt, J ₁ = 8Hz, J ₂ = 16H
z), 4.01-4.11 (2H, m), 3.58-
3.62 (2H, m), 3.17 (3H, s), 2.7
7-2.81 (3H, m), 2.16 (1H, dd, J
_{1 = 7Hz, J 2 = 15Hz} ), 2.00 (1H, d
d, J ₁ = 8 Hz, J ₂ = 15 Hz), 1.59-1.
64 (1H, m), 1.42-1.48 (1H, m),
1.02-1.12 (1H, m), 0.89 (1H, m
d, J = 7Hz), 0.84 (1H, d, J = 7H
z).

Example 128 Of 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1- (4-methoxybenzyl) -6,7-methylenedioxy-3,4-dihydrocarbostyril The target compound was obtained in the same manner as in Example 1 by reacting the compound obtained in Production Reference Example 104 with the corresponding starting material.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, brs), 8.72 (1
H, brs), 8.26 (1H, d, J = 8Hz),
7.14 (2H, d, J = 9Hz), 6.88 (1H,
s), 6.87 (2H, d, J = 9Hz), 6.74
(1H, s), 5.93 (2H, s), 5.13 (1
H, d, J = 17 Hz, 4.98 (1H, d, J = 1)
7 Hz), 4.53 ( ₁ H, dt, J ₁ = 8 Hz, J ₂
= 12 Hz), 3.71 (3 H, s), 2.84 (3
H, m), 2.19 (1H, dd, J ₁ = 7 Hz, J ₂
= 15 Hz), 2.02 ( ₁ H, dd, J ₁ = 8 Hz,
J ₂ = 15 Hz), 1.59-1.69 (1 H, m),
1.44-1.54 (1H, m), 1.03-1.13
(1H, m), 0.90 (1H, d, J = 7Hz),
0.84 (1H, d, J = 7Hz).

Example 129 3S- [3-benzyl-4- (N-hydroxyamino)]
-2R-isobutylsuccinyl] amino-1-ethyl-
Production of 6,7-methylenedioxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 113 was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Example 14.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.28 (1H, brs), 8.64 (1
H, brs), 8.46 (1H, d, J = 8Hz),
7.27-7.05 (5H, m), 6.90 (2H,
s), 5.98 (2H, d, J = 3Hz), 4.51-
4.41 (1H, m), 3.88 (2H, q, J = 7H
z), 2.95-2.70 (3H, m), 2.62-
2.40 (3H, m), 1.63 to 1.47 (2H,
m), 1.10 (3H, t, J = 7Hz), 1.01-
0.96 (1H, m), 0.89 (3H, d, J = 6H
z), 0.82 (3H, d, J = 7Hz).

Example 130 1-Ethoxyethyl-3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-6,7
-Production of methylenedioxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 105 was reacted with the corresponding starting material to obtain the above-mentioned target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, brs), 8.72 (1
H, brs), 8.18 (1H, d, J = 8Hz),
7.01 (1H, s), 6.87 (1H, s), 5.9
9 (2H, s), 4.40-4.36 (1H, m),
4.02-3.93 (2H, m), 3.53-3.39
(4H, m), 2.80-2.77 (3H, m), 2.
17 (1H, dd, J ₁ = 6 Hz, J ₂ = 14 Hz),
2.00 (1H, dd, J ₁ = 8Hz, J ₂ = 15H
z), 1.65 to 1.48 (2H, m), 1.06 (3
H, t, J = 7 Hz), 1.12-1.03 (1H,
m), 0.89 (3H, d, J = 7Hz), 0.84
(3H, d, J = 7Hz).

Example 131 1-Hexyl-3S- [4- (N-hydroxyamino)
Production of −2R-isobutylsuccinyl] amino-6,7-methylenedioxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 106 was reacted with the corresponding starting material, and the same procedure as in Example 1 was conducted. The above target compound was obtained.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, brs), 8.72 (1
H, brs), 8.16 (1H, d, J = 8 Hz),
6.88 (2H, d, J = 2Hz), 6.00 (2H,
s), 4.38-4.31 (1H, m), 3.92-
3.89 (1H, m), 3.77-3.74 (1H,
m), 2.80-2.77 (3H, m), 2.16 (1
H, dd, J ₁ = 6 Hz, J ₂ = 14 Hz), 2.00
(1H, dd, J ₁ = 8 Hz, J ₂ = 15 Hz), 1.
63-1.45 (4H, m), 1.26-1.25 (6
H, m), 1.12 to 1.07 (1H, m), 0.90
-0.83 (9H, m).

Example 132 Preparation of 3S- [4- (N-Hydroxyamino) -2R-isobutylsuccinyl] amino-1-phenethyl-6,7-methylenedioxy-3,4-dihydrocarbostyril In Reference Example 107 The obtained compound was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, brs), 8.71 (1
H, brs), 8.14 (1H, d, J = 8Hz),
7.18-7.32 (5H, m), 6.94 (1H,
s), 6.88 (1H, s), 6.00 (2H, s),
4.38 (1H, dt, J ₁ = 8Hz, J ₂ = 16H
z), 4.00-4.13 (2H, m), 2.72-
2.83 (5H, m), 2.17 (1H, dd, J ₁ =
7Hz, J ₂ = 15Hz), 2.01 (1H, dd, J
_{1 = 8Hz, J 2 = 15Hz} ), 1.57-1.63
(1H, m), 1.42-1.48 (1H, m), 1.
03-1.13 (1H, m), 0.89 (1H, d, J
= 7 Hz), 0.84 (1H, d, J = 7 Hz).

Example 133 1-Ethyl-3S- [4- (N-hydroxyamino)-
Production of 2R-hexylsuccinyl] amino-6,7-methylenedioxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 113 was reacted with the corresponding starting material, and in the same manner as in Example 78, The target compound was obtained.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.36 (1H, s), 8.69 (1H,
s), 8.11 (1H, d, J = 8Hz), 6.89
(1H, s), 6.88 (1H, s), 5.99 (2
H, s), 4.36 (1H, dt, J ₁ = 8 Hz, J ₂
= 12 Hz), 3.87 (2H, q, J = 7 Hz),
2.60-2.85 (3H, m), 2.19 (1H, d
d, J ₁ = 7 Hz, J ₂ = 14 Hz), 2.02 (1
H, dd, J ₁ = 7 Hz, J ₂ = 14 Hz), 1.15
-1.60 (10H, m), 1.09 (3H, t, J =
7Hz), 0.86 (3H, t, J = 7Hz).

Example 134 3S- [4- (N-hydroxyamino) -2R-hexylsuccinyl] amino-1-methoxyethyl-6,7-
Production of methylenedioxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 92 was reacted with the corresponding starting material to obtain the desired compound as described in Example 78.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, s), 8.70 (1H,
s), 8.15 (1H, d, J = 8Hz), 6.98
(1H, s), 6.87 (1H, s), 5.99 (2
H, s), 4.38 (1H, q, J = 10 Hz), 3.
90-4.10 (2H, m), 3.40-3.55 (2
H, m), 3.23 (3H, s), 2.78 (2H,
d, J = 10 Hz), 2.60-2.75 (1H,
m), 2.19 (1H, dd, J ₁ = 7 Hz, J ₂ = 1)
4 Hz), 2.04 ( ₁ H, dd, J ₁ = 7 Hz, J ₂
= 14 Hz), 1.15 to 1.60 (10 H, m),
0.86 (3H, t, J = 6Hz).

Example 135 1-Ethyl-3S- [4- (N-hydroxyamino)-
Production of 2R-heptylsuccinyl] amino-6,7-methylenedioxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 113 was reacted with the corresponding starting material, and in the same manner as in Example 78 above. The target compound was obtained.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, s), 8.70 (1H,
s), 8.11 (1H, d, J = 8Hz), 6.90
(1H, s), 6.88 (1H, s), 6.00 (2
H, s), 4.37 (1H, dt, J ₁ = 8 Hz, J ₂
= 12 Hz), 3.87 (2H, q, J = 7 Hz),
2.60-2.90 (3H, m), 2.19 (1H, d
d, J ₁ = 7 Hz, J ₂ = 14 Hz), 2.02 (1
H, dd, J ₁ = 8 Hz, J ₂ = 14 Hz), 1.15
-1.60 (12H, m), 1.09 (3H, t, J =
7Hz), 0.86 (3H, t, J = 7Hz).

Example 136 1-Ethyl-3S- [4- (N-hydroxyamino)-
Production of 2R-pentylsuccinyl] amino-6,7-methylenedioxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 113 was reacted with the corresponding starting material, and in the same manner as in Example 78, The target compound was obtained.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, s), 8.70 (1H,
s), 8.11 (1H, d, J = 8Hz), 6.90
(1H, s), 6.88 (1H, s), 6.00 (2
H, s), 4.37 (1H, dt, J ₁ = 8 Hz, J ₂
= 12 Hz), 3.87 (2H, q, J = 7 Hz),
2.60-2.90 (3H, m), 2.19 (1H, d
d, J ₁ = 7 Hz, J ₂ = 14 Hz), 2.02 (1
H, dd, J ₁ = 8 Hz, J ₂ = 14 Hz), 1.15
-1.60 (8H, m), 1.09 (3H, t, J = 7
Hz), 0.87 (3H, t, J = 7Hz).

Example 137 1-Ethoxy-3S- [4- (N-hydroxyamino)
Production of -2R-hexylsuccinyl] amino-3,4-dihydrocarbostyryl The compound obtained in Reference Example 29 was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Example 78.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, s), 8.70 (1H,
s), 8.32 (1H, d, J = 8Hz), 7.31
(2H, dd, J ₁ = 8 Hz, J ₂ = 16 Hz), 7.
17 (1H, d, J = 8Hz), 7.06 (1H, t,
J = 8 Hz), 4.59 (1H, dt, J ₁ = 8 Hz,
J ₂ = 12 Hz), 4.05 (2H, q, J = 7H
z), 2.85-3.10 (2H, m), 2.60-
2.80 (1H, m), 2.19 (1H, dd, J ₁ =
7Hz, J ₂ = 14Hz), 2.05 (1H, dd, J
_{1 = 7Hz, J 2 = 14Hz} ), 1.20-1.60
(13H, m), 0.87 (3H, t, J = 7Hz).

Example 138 3S- [4- (N-hydroxyamino) -2R-heptylsuccinyl] amino-1-methoxymethyl-3,4-
Production of dihydrocarbostyril After reacting the compound obtained in Reference Example 32 with the corresponding starting material, the above target compound was obtained in the same manner as in Example 78.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, s), 8.70 (1H,
s), 8.26 (1H, d, J = 8Hz), 7.15-
7.30 (3H, m), 7.07 (1H, t, J = 8H
z), 5.49 (1H, d, J = 10 Hz), 5.00
(1H, d, J = 10 Hz), 4.52 (1H, dt,
J ₁ = 7 Hz, J ₂ = 13 Hz), 3.26 (3H,
s), 2.80-3.10 (2H, m), 2.60-
2.80 (1H, m), 2.20 (1H, dd, J ₁ = 7H
z, J ₂ = 14 Hz), 2.03 (1H, dd, J ₁ = 7
Hz, J ₂ = 14 Hz), 1.15 to 1.60 (12
H, m), 0.86 (3H, t, J = 6Hz).

Example 139 Preparation of 3S- [4- (N-hydroxyamino) -2R-pentylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril After reaction with the corresponding starting materials, Example 78
The target compound was obtained in the same manner as.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.37 (1H, s), 8.70 (1H,
s), 8.32 (1H, d, J = 8Hz), 7.32
(2H, dd, J ₁ = 8 Hz, J ₂ = 16 Hz), 7.
16 (1H, d, J = 8Hz), 7.07 (1H, t,
J = 8 Hz), 4.61 (1H, dt, J ₁ = 8 Hz,
J ₂ = 12 Hz), 3.82 (3H, s), 2.85-
3.10 (2H, m), 2.60-2.80 (1H,
m), 2.20 (1H, dd, J ₁ = 7 Hz, J ₂ = 1)
4 Hz), 2.03 ( ₁ H, dd, J ₁ = 7 Hz, J ₂
= 14 Hz), 1.20-1.60 (8H, m), 0.
87 (3H, t, J = 7Hz).

Example 140 1-Ethoxy-3S- [4- (N-hydroxyamino)
Production of -2R-Pentylsuccinyl] amino-3,4-dihydrocarbostyril The compound obtained in Reference Example 29 was reacted with the corresponding starting material to obtain the desired compound in the same manner as in Example 78.

NMR (270 MHz, DMSO-d₆)
δppm: 10.38 (1H, s), 8.73 (1H,
s), 8.33 (1H, d, J = 8Hz), 7.31
(2H, dd, J₁= 8Hz, J₂= 16 Hz), 7.
17 (1H, d, J = 8Hz), 7.07 (1H, t,
J = 8 Hz), 4.59 (1H, dt, J₁= 8Hz,
J ₂= 12 Hz), 4.05 (2H, q, J = 7H
z), 2.90-3.10 (2H, m), 2.60-
2.80 (1H, m), 2.19 (1H, dd, J₁=
7Hz, J₂= 14 Hz), 2.05 (1H, dd, J
₁= 7Hz, J₂= 14 Hz), 1.28 (3H, t,
J = 7 Hz), 1.20-1.60 (8H, m), 0.
87 (3H, t, J = 7Hz).

Example 141 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxymethoxy-3,
Preparation of 4-dihydrocarbostyril After the reaction using the corresponding starting materials, the above target compound was obtained in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, s), 8.72 (1H,
s), 8.40 (1H, d, J = 8Hz), 7.15-
7.40 (3H, m), 7.07 (1H, t, J = 7H
z), 5.07 (1H, d, J = 7Hz), 5.03
(1H, d, J = 7Hz), 4.56 (1H, dt, J
= J ₁ = 7 Hz, J ₂ = 12 Hz), 3.49 (3H,
s), 2.65-3.15 (3H, m), 2.17 (1
H, dd, J ₁ = 6 Hz, J ₂ = 14 Hz), 2.01
(1H, dd, J ₁ = 8 Hz, J ₂ = 14 Hz), 1.
00-1.70 (3H, m), 0.89 (3H, d, J
= 6 Hz), 0.84 (3H, d, J = 6 Hz).

Example 142 1-Ethoxymethyl-3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-6,7
-Production of methylenedioxy-3,4-dihydrocarbostyril The compound obtained in Reference Example 108 was reacted with the corresponding starting material to obtain the above target compound in the same manner as in Example 1.

NMR (270 MHz, DMSO-d ₆ ).
δppm: 10.38 (1H, brs), 8.71 (1
H, brs), 8.23 (1H, d, J = 8Hz),
6.92 (1H, s), 6.88 (1H, s), 6.0
0 (2H, s), 5.48 (1H, d, J = 10H
z), 4.98 (1H, d, J = 11 Hz), 4.50
-4.39 (1H, m), 3.48 (2H, q, J = 7)
Hz), 2.93-2.75 (3H, m), 2.17
(1H, dd, J ₁ = 7 Hz, J ₂ = 15 Hz), 2.
01 (1H, dd, J ₁ = 8 Hz, J ₂ = 15 Hz),
1.64-1.43 (2H, m), 1.10 (3H, m
t, J = 7 Hz), 1.13-1.08 (1H, m),
0.89 (3H, d, J = 7Hz), 0.84 (3H,
d, J = 7 Hz).

Pharmacological Test 1 (1) Method for Measuring Stromelysin Inhibitory Activity Inhibition of stromelysin purified from the culture supernatant of mouse colon cancer cells (Colon 26 cells) was inhibited by the method of Miyazaki et al. [J. Biochem. , 108 , 537-543 (1
990)] and towing (Twining.SS).
Method [Fed. Proc. , 42 , 1951 (198
4)] and the measurement was performed using fluorescence-labeled casein.

Activation of the enzyme was carried out by incubation in 1 mM mercuric p-aminophenylacetate at 37 ° C. for 2 hours. The test compound was used after being dissolved in dimethyl sulfoxide. 50 mM Tris-hydrochloric acid (pH 7.5) containing 0.25% (W / V) of a test compound and a fluorescent labeled casein which is a substrate, 10 mM CaCl ₂ , 0.
The enzyme reaction was started by adding the enzyme activated by the above method to a 1% (V / V) dimethyl sulfoxide solution. The reaction was carried out at 37 ° C for 3 hours, and an equal amount of 5% (W
/ V) It was stopped by adding a solution of trichloroacetic acid. Then, the undegraded substrate was precipitated by centrifugation at 3000 rpm at 4 ° C. for 15 minutes, and 4 volumes of 0.3 M phosphate buffer (pH 8.5) was added to 1 volume of the resulting supernatant.
Was added, and the fluorescence intensity was changed to 520 nm (Em) / 495n.
The amount of degradation products was quantified by measuring m (Ex).

Enzyme inhibitory activity is the activity of a known amount of enzyme
It was expressed as the concentration (IC ₅₀ ) of the test compound that inhibits up to%. The results are shown in Table 1 below.

(2) Method for measuring interstitial collagenase inhibitory activity Inhibition of interstitial collagenase purified from human fibroblast (Detroit551 cell) culture supernatant was performed by the method of Nagai et al. [Inflammation, 4 (2), 123 (1984). )] And using fluorescently labeled collagen.

Enzyme activation was carried out by incubation in 1 mM mercuric p-aminophenylacetate at 37 ° C for 3 hours. The test compound was used after being dissolved in dimethyl sulfoxide. 50 mM containing 0.025% (W / V) of the test compound and the fluorescence-labeled collagen that is the substrate
Tris-hydrochloric acid (pH 7.5), 0.2M NaCl,
5 mM CaCl ₂ , 0.02% (W / V) NaN ₃ ,
The enzyme reaction was started by adding the enzyme activated by the above method to a solution of 2.5 mM acetic acid and 0.1% (V / V) dimethyl sulfoxide. The reaction was carried out at 35 ° C. for 2 hours and ice-cooled 80 mM O-phenanthroline, 5
It was stopped by adding 1/20 volume of 0% (V / V) ethanol solution. An equal amount of 50 mM Tris-hydrochloric acid (pH 7.5), 0.2 M NaCl, 5 mM Ca was added to this.
Cl ₂ and 0.02% (W / V) NaN ₃ solution were added and further incubated at 35 ° C. for 1 hour to specifically denature only the degradation product, and an equal amount of 70% (V / V) was added.
0.17 M Tris-hydrochloric acid containing ethanol (pH 9.
5), 0.67 M NaCl solution was added to extract the decomposed product, and then the undecomposed substrate was precipitated by centrifugation at 3000 rpm at 4 ° C. for 15 minutes. The fluorescence intensity in the obtained supernatant was determined to be 520 nm (Em) / 495 nm (E
x) to measure the amount of degradation products.

Enzyme inhibitory activity is the activity of a known amount of enzyme
It was expressed as the concentration (IC ₅₀ ) of the test compound that inhibits up to%. The results are shown in Table 2 below.

(3) Method for measuring type IV collagenase inhibitory activity Inhibition of type IV collagenase purified from culture supernatant of human lung fibrosarcoma cells (HT-1080 cells) was inhibited by the method of Harris et al. [Haris, E. et al. D. and Kran
e, S. M. , Biochim. Biophys. Ac
ta. , 258, 566-576 (1972)].

Activation of the enzyme was carried out by incubation in 1 mM mercuric p-aminophenylacetate at 37 ° C for 22 hours. The test compound was used after being dissolved in dimethyl sulfoxide. 50 mM Tris-hydrochloric acid (pH 7.5) containing 10% (W / V) of a test compound and fluorescence-labeled gelatin as a substrate, 10 mM CaCl ₂ ,
0.01% (W / V) Bridge 35 [trade name, manufactured by Wako Pure Chemical Industries, Ltd.], 0.1% (V / V) dimethyl sulfoxide solution to which the enzyme activated by the above method is added The enzymatic reaction was started by. The reaction was carried out at 37 ° C. for 6 hours, and was stopped by adding 1/2 volume of a 30% (W / V) trichloroacetic acid solution. After standing at 4 ° C. for 30 minutes, the undecomposed substrate was precipitated by centrifugation at 10,000 rpm, 4 ° C. for 10 minutes. 1 of the obtained supernatant
To the volume, add 50 volumes of 0.3M phosphate buffer pH 8.5,
The fluorescence intensity is set to 520 nm (Em) / 495 nm (E
x) to measure the amount of degradation products.

Enzyme inhibitory activity is the activity of a known amount of enzyme
It was expressed as the concentration (IC ₅₀ ) of the test compound that inhibits up to%. The results are shown in Table 3 below.

The test compounds are as follows.

1.3 S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-3,4-
Dihydrocarbostyril 2.3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-7-methoxy-3,4-
Dihydrocarbostyril 3.3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxy-3,4-
Dihydrocarbostyryl 4.3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-acetylthiomethylsuccinyl] amino-3,4-dihydrocarbostyryl 5.3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-mercaptomethylsuccinyl] amino-3,4-dihydrocarbostyryl 6.3S- [4- (N-hydroxyamino) -2R-isobutyl-3S- (2-thienylthiomethyl) succinyl] amino -3,4-Dihydrocarbostyril 7.3S- [4- (N-Hydroxyamino) -2R-isobutyl-3 (R or S) -phthalimidomethylsuccinyl] amino-3,4-dihydrocarbostyril 8.1- Ethoxycarbonylmethyl-3S- [4- (N
-Hydroxyamino) -2R-isobutylsuccinyl]
Amino-3,4-dihydrocarbostyril 9.3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril 10.1-amino Carbonylmethyl-3S- [4- (N-
Hydroxyamino) -2R-isobutylsuccinyl] amino-3,4-dihydrocarbostyril 11.3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1- (4-methoxycarbonylbenzyl) -3 , 4-Dihydrocarbostyril 12.1-ethyl-3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-3,4-
Dihydrocarbostyril 13.1-allyl-3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-3.4-dihydrocarbostyril 14.3S- [4- (N-hydroxy Amino) -2R-isobutylsuccinyl] amino-1-methoxymethyl-
3,4-Dihydrocarbostyril 15.3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-1- (2
15.-Propinyl) -3.4-dihydrocarbostyril 16.1-Carboxymethyl-3S- [4- (N-hydroxyamino) -2R-isobutyl-3S-methylsuccinyl] amino-3,4-dihydrocarbostyril 17. 1-ethoxy-3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-3,4-
Dihydrocarbostyril 18.3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxyethoxymethyl-3,4-dihydrocarbostyril 19.3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxymethoxyethyl-3,4-dihydrocarbostyril 20.3S- [4- (N-hydroxyamino) -2R-heptylsuccinyl] amino-1-methoxy-3,4- Dihydrocarbostyril 21.3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxyethyl-
3,4-dihydrocarbostyril 22.3 S- [4- (N-hydroxyamino) -2R-ethoxyethylsuccinyl] amino-1-methoxy-3,
4-Dihydrocarbostyril 23.3S- [4- (N-hydroxyamino) -2R-isobutyl-3- (3,4-methylenedioxybenzyl)
Succinyl] amino-1-methoxy-3,4-dihydrocarbostyril 24.3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxyethyl-
6,7-Methylenedioxy-3,4-dihydrocarbostyril 25.3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxyethyl-
6,7-Methylenedioxy-3,4-dihydrocarbostyril 26.3- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methoxyethyl-6,6
7-Methylenedioxy-3,4-dihydrocarbostyril 27.3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-methyl-6,7-methylenedioxy-3,4- Dihydrocarbostyril 28.1-ethyl-3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-6,7-
Methylenedioxy-3,4-dihydrocarbostyril 29.1-Ethyl-3S- [4- (N-hydroxyamino) -2R-pentylsuccinyl] amino-6,7-methylenedioxy-3,4-dihydrocarboyl Styryl 30.3S- [4- (N-hydroxyamino) -2R-pentylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril 31.3S- [4- (N-hydroxyamino) -2R-isobutyl Succinyl] amino-1-methoxymethoxy-
3,4-dihydrocarbostyryl

[0658]

[Table 1]

[0659]

[Table 2]

[0660]

[Table 3]

Pharmacological test 2 Motoyama et al.'S method (Cancer and Chemotherapy, 21 (8): 1209-
1214, 1994). That is,
Colons 26 PMF15 tumor cells were transplanted at 5 × 10 ⁵ cells / individual in the footprints of the left hind limbs of 7 male CDF ₁ mice per group. On the 14th day of transplantation, under pentobarbital anesthesia, the left hind limb was cut from above the knee joint with an electric knife to remove the primary lesion. On the 28th day after transplantation, the lungs were removed, and the number of metastatic nodules on the surface was measured to be used as an index of the effect. The test compound was orally administered once a day from the day after tumor transplantation to the 27th day after transplantation excluding the day of primary tumor resection. The results are shown in Table 4 below.

[0662]

[Table 4]

Formulation Example 1 The following components were admixed in a conventional method and punched out to give 100 tablets each having 50 mg of active ingredient.

3S- [4- (N-Hydroxyamino) -2R-isobutyl-3S-acetylthiomethylsuccinyl] amino-3,4-dihydrocarbostyril 5 g Sodium lauryl sulphate 0.2 g Magnesium stearate 0.2 g Crystalline cellulose 4 Formulation Example 2 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-1-carboxymethyl-3,4-dihydrocarbostyril 1 g Polyethylene glycol (molecular weight: 4000) 0.3 g Sodium chloride 0 9.9 g Polyoxyethylene-sorbitan monooleate 0.4 g Sodium metabisulfite 0.1 g Methyl-paraben 0.18 g Propyl-paraben 0.02 g Distilled water for injection 10.0 ml The above-mentioned parabens, sodium metabisulfite and sodium chloride. Dissolve the barium at 80 ° C. in about half of the above distilled water with stirring. The resulting solution is cooled to 40 ° C., and the active ingredient compound of the present invention, followed by polyethylene glycol and polyoxyethylene sorbitan monooleate, are dissolved in the above solution. Next, distilled water for injection is added to the solution to adjust the final volume, and the solution is sterilized by sterilizing with an appropriate filter paper to prepare an injection.

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] October 4, 1995

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Correction content]

[Claims]

Embedded image [In the formula, R ¹ represents a hydrogen atom or a group -A-R ^1a (A represents a lower alkylene group, R ^1a represents a hydrogen atom, an amino group, a phthalimido group, a thienylthio group, a lower alkanoylthio group,
Phenyl which may have 1 to 3 groups selected from the group consisting of a mercapto group, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group as a substituent. Group, a carboxy group, a lower alkoxycarbonyl group, a phenylthio group or a lower alkylthio group). R ² represents a hydrogen atom or a lower alkyl group. R ³ is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a lower alkoxy lower alkoxy lower alkoxy group, a lower alkoxy lower alkoxy lower alkoxy lower alkoxy group or a group —B—R ^3a (B is a lower alkylene group, a lower Represents an alkenylene group or a lower alkynylene group, and R ^3a represents a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a halogen atom as a substituent, a cyano group, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a carboxy group and a lower group. A phenyl group which may have 1 to 3 groups selected from alkoxycarbonyl groups, a thienyl group which may have a halogen atom as a substituent, a phthalimido group, a carboxy group, a lower alkoxycarbonyl group or a group -CO-N (R ^3b ) -R ^3c , where R ^3b represents a hydrogen atom or a lower alkyl group, R ^3c represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and the group —N (R ^3b ) —R ^3c comprises a nitrogen atom, an oxygen atom and a sulfur atom. And may form a 5- or 6-membered saturated heterocycle which may further have one heteroatom selected from the group). R ⁴ represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group or a lower alkylenedioxy group. R ⁵ represents a hydrogen atom, a benzoyl group, a lower alkanoyl group or a phenyl lower alkyl group. R ⁶ represents an alkyl group having 1 to 12 carbon atoms, a lower alkoxy lower alkyl group or a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring. n represents 1 or 2. ] An extracellular matrix metalloprotease inhibitor containing, as an active ingredient, at least one selected from the carbostyril derivative represented by the formula and a salt thereof.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location C07D 405/12 215 409/12 215 491/056 7019-4C // C12N 9/99 (C07D 405 / 12 215: 38 317: 48) (C07D 409/12 215: 38 333: 10) (C07D 409/12 215: 38 333: 28)

Claims (4)

[Claims] 1. A compound of the general formula [In the formula, R ¹ represents a hydrogen atom or a group -A-R ^1a (A represents a lower alkylene group, R ^1a represents a hydrogen atom, an amino group, a phthalimido group, a thienylthio group, a lower alkanoylthio group,
Phenyl which may have 1 to 3 groups selected from the group consisting of a mercapto group, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group and a lower alkylenedioxy group as a substituent. Group, a carboxy group, a lower alkoxycarbonyl group, a phenylthio group or a lower alkylthio group). R ² represents a hydrogen atom or a lower alkyl group. R ³ is a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a lower alkoxy lower alkoxy lower alkoxy group, a lower alkoxy lower alkoxy lower alkoxy lower alkoxy group or a group —B—R ^3a (B is a lower alkylene group, a lower Represents an alkenylene group or a lower alkynylene group, and R ^3a represents a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a halogen atom as a substituent, a cyano group, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a carboxy group and a lower group. A phenyl group which may have 1 to 3 groups selected from alkoxycarbonyl groups, a thienyl group which may have a halogen atom as a substituent, a phthalimido group, a carboxy group, a lower alkoxycarbonyl group or a group -CO-N (R ^3b ) -R ^3c , where R ^3b represents a hydrogen atom or a lower alkyl group, R ^3c represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and the group —N (R ^3b ) —R ^3c comprises a nitrogen atom, an oxygen atom and a sulfur atom. And may form a 5- or 6-membered saturated heterocycle which may further have one heteroatom selected from the group). R ⁴ represents a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group or a lower alkylenedioxy group. R ⁵ represents a hydrogen atom, a benzoyl group, a lower alkanoyl group or a phenyl lower alkyl group. R ⁶ represents an alkyl group having 1 to 12 carbon atoms, a lower alkoxy lower alkyl group or a phenyl lower alkyl group which may have a lower alkylenedioxy group as a substituent on the phenyl ring. n represents 1 or 2. ] An extracellular matrix metalloprotease inhibitor containing, as an active ingredient, at least one selected from the carbostyril derivative represented by the formula and a salt thereof. 2. R ¹ is a hydrogen atom, R ² is a hydrogen atom, R ³
Is a lower alkyl group, R ⁴ is a lower alkylenedioxy group,
R ⁵ is a hydrogen atom, R ⁶ is an alkyl group having 1 to 12 carbon atoms,
The carbostyril derivative or a salt thereof according to claim 1, wherein n is 1. 3. 3S- [4- (N-hydroxyamino)
-2R-isobutylsuccinyl] amino-1-methyl-
6,7-Methylenedioxy-3,4-dihydrocarbostyril, 1-ethyl-3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-6,7
-Methylenedioxy-3,4-dihydrocarbostyryl, 1-ethyl-3S- [4- (N-hydroxyamino) -2R-pentylsuccinyl] amino-6,7-methylenedioxy-3,4-dihydrocarboyl Styryl, 3
S- [4- (N-hydroxyamino) -2R-pentylsuccinyl] amino-1-methoxy-3,4-dihydrocarbostyril and 3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino- A carbostyril derivative selected from the group consisting of 1-methoxymethoxy-3,4-dihydrocarbostyril or a salt thereof. 4. 1-Ethyl-3S- [4- (N-hydroxyamino) -2R-isobutylsuccinyl] amino-
6,7-Methylenedioxy-3,4-dihydrocarbostyril or a salt thereof.