JPH08283221A - Production of aldehyde derivative - Google Patents

Abstract

PURPOSE: To profitably obtain the subject compound useful as a bone resorption- inhibiting agent in a good yield under a mild condition without performing a DMSO oxidation generating a malodor by reducing a specific compound. CONSTITUTION: A compound of formula I [R<1> , R<2> , R<3> are each H, a (substituted) hydrocarbon group; R<4> is an acyl; R<5> , R<6> are each a (substituted) hydrocarbon group; (m), (n) are 0, 1] or its salt [e.g. N-(1-naphthalenesulfonyl)-L-isoleucyl-L- tryptophan-N,O-dimethylhydroxylamide] is reduced with a metal aluminum hydride, etc., to obtain a compound of formula II or its salt [e.g. N--(1- naphthalenesulfonyl)-L-isoleucyl-L-tryptophanal].

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an aldehyde derivative or a salt thereof useful as a bone resorption inhibitor and an intermediate thereof.

[0002]

2. Description of the Related Art Conventionally, peptidic aldehyde derivatives are
It is generally synthesized by subjecting the corresponding alcohol derivative to DMSO oxidation. For example, EP-A1
In -0623627 and JP-A-5-163221, an aldehyde derivative is synthesized by DMSO oxidation of a corresponding alcohol derivative. However, in this synthetic method, the odor of dimethyl sulfide generated in DMSO oxidation may be attached to the aldehyde derivative,
It is desirable to eliminate this completely.

[0003]

Therefore, a method for producing an optically active peptidic aldehyde derivative without using DMSO oxidation has been desired.

[0004]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors in order to solve the above problems, the result of the general formula (I)

Embedded image [Wherein R ¹ , R ² and R ³ are the same or different and are hydrogen or an optionally substituted hydrocarbon group, R ⁴ is an acyl group and R ⁵ and R ⁶ are the same or different and are substituted. A hydrocarbon group which may be present, m and n are the same or different and each represents 0 or 1, and a odorless and optically active aldehyde derivative can be obtained by subjecting a compound represented by They have found the present invention and completed the present invention.

That is, the present invention provides (1) general formula (I)

[Chemical 17] [Wherein R ¹ , R ² and R ³ are the same or different and are hydrogen or an optionally substituted hydrocarbon group, R ⁴ is an acyl group and R ⁵ and R ⁶ are the same or different and are substituted. A hydrocarbon group which may be present, m and n are the same or different and represent 0 or 1, and the compound represented by the formula or a salt thereof is subjected to a reduction reaction.

Embedded image [Wherein R ¹ , R ² , R ³ , R ⁴ , m and n have the same meanings as described above], or a method for producing a salt thereof, wherein (2) the reduction reaction is carried out using metal aluminum hydride. (3) R ¹ , R ² and R ³ are the same or different and are hydrogen or C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl. , C _3-12 cycloalkyl, C _5-12 cycloalkenyl, C _5-12 cycloalkadienyl, C _3-7 cycloalkyl-C _1-8 alkyl,
A hydrocarbon group selected from C _5-7 cycloalkenyl-C _1-8 alkyl and C _6-14 aryl, wherein the hydrocarbon group is (i) hydroxyl group, C _1-3 alkoxy, halogen or C ₁ C _6-14 aryl optionally substituted with _-3 alkyl, (ii) hydroxyl group, C _1-3 alkoxy, halogen or C _3-7 cycloalkyl optionally substituted with C _1-3 alkyl or C _{3 -6} cycloalkenyl, (iii) 5- to 7-membered aromatic heterocyclic group containing 1 sulfur atom, nitrogen atom or oxygen atom, which may be substituted with C _1-3 alkyl, 2 to 4 nitrogens 5- or 6-membered aromatic heterocyclic group containing atoms, 5- or 6-membered aromatic heterocyclic group containing 1-2 nitrogen atoms and 1 sulfur atom or oxygen atom,
5- to 7-membered non-aromatic heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom, and 4 to 5 containing one nitrogen atom and a hetero atom selected from 3 or less nitrogen, oxygen and sulfur atoms. A heterocyclic group selected from a 7-membered non-aromatic heterocyclic group, (iv) carboxyl, (lower (C _1-6 ) alkoxy) carbonyl, (C _6-10 aryloxy) carbonyl or (C _7-13 aralkyloxy) ) Carbonyl,
(V) C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl or carbamoyl optionally substituted with C _7-13 aralkyl, (vi) C _1-6 alkyl, C _3-6 cyclo Amino _optionally substituted with alkyl, C _6-10 aryl or C _7-13 aralkyl, (vii) C _1-6 alkyl, C
_A hydroxyl group _optionally substituted by _3-6 cycloalkyl, C _6-10 aryl or C _7-13 aralkyl, (viii) C
_1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl or thiol _optionally substituted with C _7-13 aralkyl, (ix) halogen and (x) C _1-6 alkyl or C _1-6 It may have 1 to 3 substituents selected from phosphono which may be substituted with alkoxy; R
^4, the general formula -CONHR ^7, -CSNHR ^8, -CO
R ^9, -SOR ¹⁰ or -SO ₂ R ¹¹ wherein, R ^7, R ^8,
R ⁹ , R ¹⁰ and R ¹¹ are the same or different and are hydrogen or (A) C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, C _5-12 cycloalkenyl, A hydrocarbon group selected from C _5-12 cycloalkadienyl, C _3-7 cycloalkyl-C _1-8 alkyl, C _5-7 cycloalkenyl-C _1-8 alkyl and C _6-14 aryl or (B ) 5- to 7-membered aromatic heterocyclic group containing 1 sulfur atom, nitrogen atom or oxygen atom, 5- or 6-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms, 1 to 2 nitrogen atoms And a 5- or 6-membered aromatic heterocyclic group containing 1 sulfur atom or oxygen atom, a 5- to 7-membered non-aromatic heterocyclic group containing 1 sulfur atom, nitrogen atom or oxygen atom, and 1 nitrogen Selected from atoms and up to 3 nitrogen, oxygen and sulfur atoms That a heterocyclic group selected from 4-7 membered non-aromatic heterocyclic group containing a hetero atom, hydrocarbon and heterocyclic group, (i) a hydroxyl group, C _1-3
C _6-14 aryl optionally substituted with alkoxy, halogen or C _1-3 alkyl, (ii) hydroxyl group, C _1-3
C _3-7 cycloalkyl or C _3-6 cycloalkenyl optionally substituted with alkoxy, halogen or C _1-3 alkyl, (iii) 1 sulfur optionally substituted with C _1-3 alkyl 5- to 7-membered aromatic heterocyclic group containing atom, nitrogen atom or oxygen atom, 5- or 6-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms, 1 to 2 nitrogen atoms and 1 sulfur 5- or 6-membered aromatic heterocyclic group containing atom or oxygen atom, 5- to 7-membered non-aromatic heterocyclic group containing 1 sulfur atom, nitrogen atom or oxygen atom,
And a heterocyclic group selected from a 4- to 7-membered non-aromatic heterocyclic group containing a hetero atom selected from one nitrogen atom and three or less nitrogen, oxygen and sulfur atoms, (iv) carboxyl, (lower ( C _1-6 ) alkoxy) carbonyl, (C
_6-10 aryloxy) carbonyl or (C _7-13 aralkyloxy) carbonyl, (v) substituted with C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl or C _7-13 aralkyl Carbamoyl, (vi) C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl or amino _optionally substituted with C _7-13 aralkyl,
(Vii) C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10
A hydroxyl group _optionally substituted with aryl or C _7-13 aralkyl, (viii) optionally substituted with C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl or C _7-13 aralkyl Thiol, (ix) halogen, and (x) may have 1 to 3 substituents selected from phosphono optionally substituted with C _1-6 alkyl or C _1-6 alkoxy] R ⁵ and R ⁶ are the same or different and are C _1-10 alkyl, C _2-10
Alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, C _5-12 cycloalkenyl, C _5-12 cycloalkadienyl, C _3-7 cycloalkyl-C _1-8 alkyl, C _5-7 cycloalkenyl A hydrocarbon group selected from -C _1-8 alkyl and C _6-14 aryl, wherein the hydrocarbon group is
(I) hydroxyl group, C _1-3 alkoxy, halogen or C
_1-3 C _6-14 aryl _optionally substituted with alkyl,
(Ii) hydroxyl group, C _1-3 alkoxy, halogen or C
_1-3 alkyl optionally substituted C _3-7 also be cycloalkyl or C _3-6 cycloalkenyl, optionally substituted with (iii) C _1-3 alkyl, 1 sulfur atom or a nitrogen atom 5- to 7-membered aromatic heterocyclic group containing an oxygen atom,
5- or 6-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms, 5- or 6-membered aromatic heterocyclic group containing 1-2 nitrogen atoms and 1 sulfur atom or oxygen atom, 1 5- to 7-membered non-aromatic heterocyclic group containing a sulfur atom, a nitrogen atom or an oxygen atom, and one nitrogen atom and 3
Heterocyclic groups selected from 4- to 7-membered non-aromatic heterocyclic groups containing up to 4 heteroatoms selected from nitrogen, oxygen and sulfur atoms, (iv) carboxyl, (lower (C _1-6 ) alkoxy) carbonyl , (C _6-10 aryloxy) carbonyl or (C _7-13 aralkyloxy) carbonyl, (v) C
_1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl or carbamoyl _optionally substituted with C _7-13 aralkyl, (vi) C _1-6 alkyl, C _3-6 cycloalkyl,
Amino _optionally substituted with C _6-10 aryl or C _7-13 aralkyl, (vii) substituted with C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl or C _7-13 aralkyl Optionally a hydroxyl group, (viii) C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl or C
_7-13 thiol _optionally substituted with aralkyl, (i
x) halogen and (x) 1 to 3 substituents selected from phosphono optionally substituted by C _1-6 alkyl or C _1-6 alkoxy,
The production method according to (1) above, (4) The production method according to (1) above, wherein R ¹ , R ² and R ³ are the same or differently optionally substituted alkyl groups, and (5) R ¹ is The production method according to (1) above, which is a linear or branched C _1-6 alkyl group substituted with an aryl or heterocyclic group, (6) R ² and R ³ are the same or different and are linear or branched. Branched C _1-6
The production method according to (1) above, which is an alkyl group, (7) the production method according to (1) above, wherein the acyl group is derived from carboxylic acid, sulfonic acid, sulfinic acid, carbamic acid or thiocarbamic acid. 8) The acyl group has the formula —SO ₂ R
¹¹ or -COR ⁹ [wherein, R ¹¹ and R ⁹ are the same or different and each is hydrogen or an optionally substituted hydrocarbon or heterocyclic group], and the production method according to (1) above, 9) R ⁴ is of the formula —SO ₂ R ¹¹ ′ [wherein R ¹¹ ′ is C
_6-10 aryl group], wherein (10) R ⁵ and R ⁶ are the same or different and are saturated or unsaturated aliphatic chain hydrocarbon groups; 1)
(11) The saturated aliphatic hydrocarbon group is C _1-10.
The production method according to (10) above, which is an alkyl group, (12)
The production method according to the above (11), wherein the alkyl group is methyl;
(13) The production method according to the above (1), wherein m is 1 and n is 0, and (14) the compound of the general formula (I) has the formula (ι)

[Chemical 19] [In the formula, R ⁵ 'and R ⁶ ' are the same or different and are C _1-6.
An alkyl group] or a salt thereof, the production method according to the above (1), (15) the general formula (I)

Embedded image [Wherein R ¹ , R ² and R ³ are the same or different and are hydrogen or an optionally substituted hydrocarbon group, R ⁴ is an acyl group and R ⁵ and R ⁶ are the same or different and are substituted. A hydrocarbon group which may be present, m and n are the same or different and represent 0 or 1, or a salt thereof, (16) the compound of the general formula (I) is a compound represented by the formula (ι)

[Chemical 21] [In the formula, R ⁵ 'and R ⁶ ' are the same or different and are C _1-6.
An alkyl group] or a salt thereof;

[Chemical formula 22] [Wherein, M represents an amino-protecting group] or a reactive derivative at a carboxyl group thereof or a salt thereof and a compound of formula (β)

[Chemical formula 23] [In the formula, R ⁵ 'and R ⁶ ' are the same or different and are C _1-6.
An alkyl group] or a reactive derivative of the amino group thereof or a salt thereof is reacted to form a compound of formula (γ)

[Chemical formula 24] [In the formula, R ⁵ ', R ⁶ ' and M have the same meanings as described above]
After the compound represented by
The compound of formula (δ)

[Chemical 25] [Wherein R ⁵ 'and R ⁶ ' have the same meanings as described above] or a salt thereof is produced, and (ii) the compound represented by the formula (δ) or its reactivity at the amino group Derivative or salt thereof and formula (ε)

[Chemical formula 26] [Wherein M'represents an amino-protecting group] or a reactive derivative of the carboxyl group thereof or a salt thereof to give a compound of formula (ζ)

[Chemical 27] [Wherein R ⁵ ′, R ⁶ ′ and M ′ have the same meanings as described above], and then a compound represented by the formula (ζ) or a salt thereof is amino-protected. The formula (η) for the elimination reaction of the group

[Chemical 28] [Wherein R ⁵ ′ and R ⁶ ′ are as defined above] or a salt thereof, and (iii) the compound represented by the formula (η) or its reactivity at the amino group Derivative or salt thereof and formula (θ)

[Chemical 29] [Wherein X represents a halogen atom] is reacted with a compound represented by the formula (ι)

Embedded image [Wherein R ⁵ 'and R ⁶ ' are as defined above] or a salt thereof is produced, and (iv) the compound represented by the formula (ι) or a salt thereof is subjected to a reduction reaction. An expression characterized by being attached

[Chemical 31] The present invention relates to a method for producing a compound represented by or a salt thereof.

The following is a description of the above general formulas and the definitions included in the scope of the present invention, and preferable examples thereof. Unless otherwise specified, the constituent amino acids in the present specification mean the L-form, and when indicated by abbreviations, IUPAC (International Union of Pure and Appl) such as Gly: glycine; Leu: leucine; Ile: isoleucine.
ied Chemistry) -IUB (International Union of Bi
ochemistry) naming convention.

In the above formulas (I) and (II), R ¹ ,
The hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R ² and R ³ is a saturated or unsaturated aliphatic chain hydrocarbon group or a saturated or unsaturated alicyclic hydrocarbon. Groups, aryl groups and the like. Examples of the saturated aliphatic hydrocarbon group include linear or branched saturated aliphatic hydrocarbon groups having 1 to 10 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, isopentyl, neopentyl, tert- pentyl, hexyl, isohexyl, heptyl, such as C _1-10 alkyl group such as octyl) and the like, preferably a straight-chain or branched having 1 to 6 carbon atoms Examples thereof include branched saturated aliphatic hydrocarbon groups.
Examples of the unsaturated aliphatic hydrocarbon group include a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 10 carbon atoms (eg, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4 -C _2-10 alkenyl groups such as hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, etc.,
Ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-heptinyl, 1-octynyl, etc. C _2-10 alkynyl group etc.)
And preferably a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms and the like.

Examples of the saturated alicyclic hydrocarbon group include a saturated alicyclic hydrocarbon group having 3 to 12 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.
1) heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] C _3-12 cycloalkyl group such as decyl), and preferably a saturated alicyclic hydrocarbon group having 3 to 6 carbon atoms and the like. Examples of the unsaturated alicyclic hydrocarbon group include an unsaturated alicyclic hydrocarbon group having 5 to 12 carbon atoms (eg, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexene C _5-12 cycloalkenyl groups such as -1-yl and 3-cyclohexen-1-yl, and also 2,4-cyclopentadiene-1-yl, 2,4-cyclohexadiene-1-yl, 2,5 -Cyclohexadiene-1-
C _5-12 cycloalkadienyl group such as yl). Further, the hydrocarbon group of the “optionally substituted hydrocarbon group” represented by R ¹ , R ² and R ³ is a carbon group substituted with the above saturated or unsaturated alicyclic hydrocarbon group. A saturated aliphatic hydrocarbon group of the number 1 to 8 (eg, C _3-7 cycloalkyl-C _1-8 alkyl, etc. or C _5-7 cycloalkenyl-C _1-8 alkyl, etc., specifically, for example, cyclo Propylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl , Cycloheptylethyl, etc.).

Examples of the aryl group include monocyclic or condensed polycyclic aromatic hydrocarbon ring groups having 6 to 14 carbon atoms. Examples of the aromatic hydrocarbon ring group include phenyl, tolyl, xylyl, biphenyl, 1- or 2-
Naphthyl, 1-, 2- or 9-anthryl, 1-, 2
-, 3-, 4- or 9-phenanthryl, 1, -2
Examples thereof include C _6-14 aryl such as-, 4-, 5- or 6-azulenyl and acenaphthylenyl. Among them, C _6-10 aryl such as phenyl, 1-naphthyl and 2-naphthyl is preferable. The hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R ¹ , R ² and R ³ may have 1 to 3 arbitrary substituents at substitutable positions. .
The substituent is an optionally substituted aryl group,
Optionally substituted cycloalkyl group or cycloalkenyl group, optionally substituted heterocyclic group, optionally esterified carboxyl group, optionally substituted carbamoyl group, optionally substituted amino Examples thereof include a group, an optionally substituted hydroxyl group, an optionally substituted thiol group, a halogen (eg, fluorine, chlorine, bromine and iodine), an optionally substituted phosphono group and the like. Examples of the aryl group which may be substituted include phenyl, naphthyl, anthryl, phenanthryl, C _6-14 aryl of acenaphthylenyl and the like, and among them, phenyl, 1-naphthyl and 2-naphthyl are preferable. The aryl may have 1 or 2 arbitrary substituents at substitutable positions, and the substituents are:
Hydroxyl group, optionally substituted alkoxy group (eg, C _1-3 alkoxy such as methoxy, ethoxy, propoxy),
Halogen atom (eg, fluorine, chlorine, bromine, iodine), optionally substituted alkyl group (eg, methyl, ethyl,
C _1-3 alkyl such as propyl) and the like. The alkoxy group and the alkyl group may have 1 to 2 arbitrary substituents at substitutable positions, and as the substituent, an optionally substituted phosphono group (eg, phosphoryl, dimethoxyphosphoryl, Diethoxyphosphoryl, etc.) and the like.

Examples of the cycloalkyl group of the optionally substituted cycloalkyl group include C _3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of the substituent of the optionally substituted cycloalkyl group and the number of substitutions thereof include the same kind and number as the substituents of the optionally substituted aryl group. Examples of the cycloalkenyl group of the optionally substituted cycloalkenyl group include C _3-6 cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. Examples of the substituents of the optionally substituted cycloalkenyl group and the number of substitutions thereof include the same kind and number as the substituents in the optionally substituted aryl group.

The heterocyclic group of the optionally substituted heterocyclic group is an aromatic heterocyclic group having at least one hetero atom of oxygen, sulfur and nitrogen as a ring system atom (ring atom). Examples thereof include a cyclic group and a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group), but an aromatic heterocyclic group is preferable. The aromatic heterocyclic group includes, for example, 5 containing one sulfur atom, nitrogen atom or oxygen atom.
To 7-membered aromatic heterocyclic group, 5- or 6-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms, 5- or 6-membered containing 1 to 2 nitrogen atoms and 1 sulfur atom or oxygen atom Aromatic heterocyclic groups are mentioned, and these aromatic heterocyclic groups are
6-membered ring containing 2 or less nitrogen atoms, benzene ring or 1
It may be condensed with a 5-membered ring containing one sulfur atom. The aromatic heterocyclic group is an aromatic monocyclic heterocyclic group (eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,
Pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-
Oxadiazolyl, 1,3,4-oxadiazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,4-
Thiadiazolyl, 1,3,4-thiadiazolyl, 1,
2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,
Pyrazinyl, triazinyl, etc.) and condensed aromatic heterocyclic groups (eg, benzofuranyl, isobenzofuranyl, benzo [ b ] thienyl, indolyl, isoindolyl, 1H-
Indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, Naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-
Carborinyl, β-carbolinyl, γ-carbolinyl,
Acridinyl, phenoxazinyl, phenothiazinyl,
Phenazinyl, phenoxathinyl, thianthrenyl,
Phenatoridinyl, phenatorolinyl, indoridinyl, pyrrolo [1,2- b ] pyridazinyl, pyrazolo [1,5- a ] pyridyl, imidazo [1,2- a ] pyridyl, imidazo [1,5- a ] pyridyl, imidazo [1, 2- b ] pyridazinyl, imidazo [1,2- a ]
Pyrimidinyl, 1,2,4-triazolo [4,3- a ]
Pyridyl, 1,2,4-triazolo [4,3- b ] pyridazinyl and the like), but furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl and the like are preferable. The non-aromatic heterocyclic group is a 5- to 7-membered non-aromatic heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom or one nitrogen atom and 3 or less hetero atoms (eg, nitrogen, And a 4- to 7-membered non-aromatic heterocyclic group containing oxygen and sulfur atoms). Examples of the non-aromatic heterocyclic group include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. Examples of the substituent of the optionally substituted heterocyclic group include an alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, etc.) and the like. These non-aromatic heterocyclic groups may be condensed with a benzene ring, a 6-membered ring containing 2 or less nitrogen atoms or a 5-membered ring containing 1 sulfur atom, for example, a condensed non-aromatic heterocyclic group. Examples of the ring group include chromanyl, isochromanyl, indolinyl, isoindolinyl, thiochromanyl, isothiochromanyl and the like.

The optionally esterified carboxy
Examples of carboxy include carboxy and (lower C _1-6Alkoxy)
Rubonyl (eg, methoxycarbonyl, ethoxycarbonyl
L, propoxy carbonyl, isopropoxy carbonyl
L, butoxycarbonyl, tert-butoxycarbonyl,
sec-Butoxycarbonyl, pentyloxycarboni
Ru, isopentyloxycarbonyl, neopentyl oki
Sicarbonyl, tert-pentyloxycarbonyl
Do), (C_6-10Aryloxy) carbonyl (eg, fe
Nonoxycarbonyl, 1-naphthoxycarbonyl, etc.),
(C_7-13Aralkyloxy) carbonyl (eg, benzyl
Oxycarbonyl etc.) and the like. Above all
Ruboxyl group, methoxycarbonyl, ethoxycarbonyl
Is preferred. The optionally substituted carbamoyl group
As the substituent of, for example, lower (C_1-6) Alkyl
(Eg, methyl, ethyl, propyl, isopropyl, buty
Ru, isobutyl, sec-butyl, tert-butyl, pliers
Ru, isopentyl, neopentyl, hexyl, isohex
Sill), C_3-6Cycloalkyl group (eg, cyclopro
Pill, cyclobutyl, cyclopentyl, cyclohexyl
Etc.), C_6-10Aryl group (eg, phenyl, 1-naphthyl
Le, 2-naphthyl, etc.), C_7-13Aralkyl groups (eg,
, Phenethyl, etc.)
The substituents may be the same or different and may be substituted by 1 or 2.
Yes. As a substituent of the optionally substituted amino group
Is, for example, lower (C_1-6) Alkyl (eg, methyl, et
Chill, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopenchi
Le, neopentyl, hexyl, isohexyl, etc.), C
_3-6Cycloalkyl group (eg, cyclopropyl, cyclobu
Chill, cyclopentyl, cyclohexyl, etc.), C_6-10
Aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl
, Etc., C_7-13Aralkyl groups (eg benzyl, phenene
Etc., etc., and these substituents are the same or
Differently, 1 or 2 may be substituted.

Examples of the substituent of the optionally substituted hydroxyl group include lower (C _1-6 ) alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.), C _3-6 cycloalkyl group (eg, cyclopropyl,
Cyclobutyl, cyclopentyl, cyclohexyl, etc.), a C _6-10 aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), a C _7-13 aralkyl group (eg, benzyl, phenethyl, etc.) and the like. Examples of the substituent of the optionally substituted thiol group include lower (C _1-6 ) alkyl (eg, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec-
Butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.), C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _6-10 aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), a C _7-13 aralkyl group (eg, benzyl, phenethyl, etc.) and the like. Examples of the substituent in the optionally substituted phosphono group include lower (C _1-6 ) alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, Isopentyl, neopentyl, hexyl, isohexyl, etc.), lower (C _1-6 ) alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,
Pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, isohexyloxy, etc.). As the optionally substituted phosphono group,
Examples thereof include phosphoryl, dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxyphosphoryl, diisopropoxyphosphoryl, ethylenedioxyphosphoryl, trimethylenedioxyphosphoryl or tetramethylenedioxyphosphoryl. When the hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R ¹ , R ² and R ³ is an alicyclic hydrocarbon group or an aryl group, the substituent is further substituted. It may be an aliphatic hydrocarbon group. The aliphatic hydrocarbon group is the same as the saturated or unsaturated (preferably saturated) hydrocarbon group in the “optionally substituted hydrocarbon group” defined for R ¹ , R ² and R ³ above. , But preferably an alkyl group (eg, methyl, ethyl,
C _1-3 alkyl such as propyl) and the like. The aliphatic hydrocarbon group may have 1 to 2 arbitrary substituents at substitutable positions, and as the substituents, an optionally substituted phosphono group (eg, phosphoryl, dimethoxyphosphoryl, Diethoxyphosphoryl, etc.) and the like.

Among the above, the hydrocarbon group of the “optionally substituted hydrocarbon group” represented by R ¹ , R ² and R ³ is an alkyl group, preferably C _1-10 alkyl,
In particular, linear or branched lower alkyl having 1 to 6 carbon atoms and the like (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert- (Pentyl, hexyl, isohexyl, 4-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc.)
Are preferred. Further, the substituent of the “optionally substituted hydrocarbon group” is preferably an optionally substituted aryl (preferably phenyl or the like) or an optionally substituted heterocycle.

The "optionally substituted hydrocarbon group" represented by R ¹ , R ² and R ³ is more preferably
Examples thereof include an alkyl group which may be substituted with an aryl or a heterocycle (preferably, a heterocycle). An alkyl group which may be substituted with the aryl or heterocycle (preferably a lower alkyl having 1 to 6 carbon atoms (preferably C _1-4
Alkyl)), the alkyl substituted with aryl includes, for example, a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, etc. ) And C _1-6 alkyl (eg benzyl,
2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, α-naphthylmethyl, α-naphthylethyl, β-naphthylmethyl, β-
Examples of the alkyl substituted with a heterocycle such as naphthylethyl) include those in which an aromatic heterocyclic group and C _1-6 alkyl (preferably C _1-4 alkyl) are bonded. Examples of the aromatic heterocyclic group include 2-furyl,
3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl,
4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4- Pyrazolyl, isothiazolyl, isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-triazol-3-yl, 1,2,3
-Triazol-4-yl, tetrazol-5-yl,
Benzimidazol-2-yl, indol-2-yl, indol-3-yl, 1H-indazolyl, benzo [b] furanyl, isobenzofuranyl, benz [b] thienyl, 1H-pyrrolo [2,3-b] Pyrazin-2-yl, 1H-pyrrolo [2,3-b] pyridin-6-yl,
1H-imidazo [4,5-b] pyridin-2-yl, 1
H-imidazo [4,5-c] pyridin-2-yl, 1H
-Imidazo [4,5-b] pyrazin-2-yl and the like can be mentioned, but preferably 2-pyridyl, 3-pyridyl,
4-pyridyl, 4-imidazolyl, 2-thienyl, 2-
Frill, indol-2-yl, indol-3-yl and the like can be mentioned.

R ¹ is preferably alkyl substituted with a heterocycle, more preferably indol-3-ylmethyl and the like. R ² and R ³ are preferably the same or different and are linear or branched C
_1-6 alkyl groups, more preferably sec-butyl, benzyl, isobutyl, isopropyl and the like can be mentioned. As R ¹ and R ² , for example, a combination in which R ¹ is indol-3-ylmethyl and R ² is sec-butyl, benzyl, isobutyl or isopropyl is preferable. Examples of R ¹ , R ² and R ³ include, for example:
R ¹ is indol-3-ylmethyl and R ² is sec-
Butyl, benzyl, isobutyl, or isopropyl, and R ³ is sec- butyl, benzyl, a combination isobutyl or isopropyl preferred.

In the general formulas (I) and (II), examples of the "acyl group" represented by R ⁴ include an acyl group derived from an organic acid which may be substituted. The acyl group derived from the optionally substituted organic acid includes optionally substituted carbamic acid, optionally substituted thiocarbamic acid, optionally substituted carboxylic acid, and optionally substituted. Examples thereof include an acyl group derived from sulfinic acid, an optionally substituted sulfonic acid, and the like, and examples thereof include the general formulas —CONHR ⁷ , —CSNR ⁸ , and —
COR ⁹ , -SOR ¹⁰ , -SO ₂ R ¹¹ [R ⁷ , R ⁸ , R ⁹ ,
R ¹⁰ and R ¹¹ are the same or different and each represents hydrogen or an optionally substituted hydrocarbon group or heterocyclic group. ] And the like. R ⁷ ,
The hydrocarbon group in the "optionally substituted hydrocarbon group" represented by R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ is "substituted" defined in the above R ¹ , R ² and R ^3. The same as the hydrocarbon group in the “optional hydrocarbon group” can be mentioned. The hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ has 1 to 3 arbitrary substituents at substitutable positions. It may have, and as the substituent, R ¹ , R ² and R
^{The same} as the substituents in the “optionally substituted hydrocarbon group” defined in ³ can be mentioned. .

The heterocyclic group in the "optionally substituted heterocyclic group" represented by R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ is defined as R ¹ , R ² and R ^{3 above} . The same as the heterocyclic group defined as the substituent in the above-mentioned "optionally substituted hydrocarbon group" can be mentioned. R ⁷ ,
The heterocyclic group in the “optionally substituted heterocyclic group” represented by R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ has 1 to 3 arbitrary substituents at substitutable positions. The substituent may be the same as the substituent in the “optionally substituted hydrocarbon group” defined for R ¹ , R ² and R ³ . The "acyl group" represented by R ⁴ includes, for example, an alkanoyl group (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, valproyl (lower C _1-6 alkyl) carbonyl, etc. Group),
Alkenoyl group (eg, acryloyl, methacryloyl,
(Lower C _2-6 alkenyl) carbonyl group such as crotonoyl and isocrotonoyl), cycloalkanecarbonyl group (eg (C _3-6 cycloalkyl) carbonyl group such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl) , A cycloalkenylcarbonyl group (eg, (C _3-7 cycloalkenyl) carbonyl group such as cyclopropenylcarbonyl, cyclobutenylcarbonyl, cyclopentenylcarbonyl, cyclohexenylcarbonyl), an alkanesulfonyl group (eg, mesyl, ethanesulfonyl, propane) aliphatic acyl groups such as a sulfonyl (lower C _1-6 alkyl) sulfonyl group), aroyl group (e.g., benzoyl, p- toluoyl, 1-naphthoyl, and 2-naphthoyl (C _6-10 aryl) Cal Group), an aryl alkanoyl group (e.g., phenylacetyl, phenylpropionyl, hydro atto Ropo yl, C such phenylbutyryl
(C _1-6 alkyl) carbonyl group substituted with _6-10 aryl group), arylalkenoyl group (eg, (C _2-6 alkenyl) carbonyl substituted with C _6-10 aryl group such as cinnamoyl and atropoyl) Group), arylsulfonyl group (eg, benzenesulfonyl group, C _6-10 arylsulfonyl group such as p-toluenesulfonyl group), aromatic acyl group, aromatic heterocyclic carbonyl group (eg, furoyl, tenoyl, nicotinoyl, Aromatic heterocyclic carbonyl groups such as isonicotinoyl, pyrrole carbonyl, oxazole carbonyl, imidazole carbonyl, and pyrazole carbonyl), aromatic heterocyclic alkanoyl groups (eg,
(C _1-6 alkyl) carbonyl group substituted with an aromatic heterocyclic group such as thienylacetyl, thienylpropanoyl, furylacetyl, thiazolylacetyl, 1,2,4-thiadiazolylacetyl, and pyridylacetyl) Examples thereof include aromatic acyl groups.

Among the above, the acyl group represented by R ⁴ is preferably a group represented by the formula —COR ⁹ or a group represented by the formula —SO ₂ R ¹¹ , and more preferably a group represented by the formula —SO ₂
It is a group represented by R ¹¹ . The group represented by the formula —COR ⁹ is more preferably a group represented by the formula —COR ⁹ ′ [R ⁹ ′ represents hydrogen or an optionally substituted alkyl, alkenyl or aromatic group]. Can be mentioned. R ⁹ '
Alkyl in the “optionally substituted alkyl” represented by is a lower (C _1-6 ) alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl). , Isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl and the like). The alkenyl in the “optionally substituted alkenyl” represented by R ⁹ ′ is lower (C _2-6 ) alkenyl (eg, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-
Butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl and the like). The alkyl in the “optionally substituted alkyl” and the alkenyl in the “optionally substituted alkenyl” represented by R ⁹ ′ each have 1 or 2 optional substituents at substitutable positions. The substituent may be an optionally substituted aryl group (preferably phenyl, 1-naphthyl, 2-naphthyl) and the like.
The aryl has 1 to 1 substituent (s) at substitutable position (s).
The substituent may be two, and examples of the substituent include an optionally substituted alkyl group (eg, C _1-3 alkyl such as methyl, ethyl, propyl). The alkyl group may have 1 to 2 arbitrary substituents at substitutable positions, and as the substituent, a phosphono group which may be substituted (eg, phosphoryl, dimethoxyphosphoryl, diethoxyphosphoryl). Etc.) and the like.

The aromatic group in the "optionally substituted aromatic group" represented by R ⁹ 'is preferably furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl and the like. The aromatic in the “optionally substituted aromatic group” represented by R ⁹ ′ may have an arbitrary substituent at a substitutable position, and the substituent has 1 or less carbon atoms. To alkyl (eg, methyl, ethyl, propyl, etc.), halogen and the like. The group represented by the formula —SO ₂ R ¹¹ is more preferably a group represented by the formula —SO ₂ R ¹¹ ′ [R ¹¹ ′
Represents an optionally substituted aryl group]. Examples of the aryl in the “optionally substituted aryl group” represented by R ¹¹ ′ include, for example,
C _6-14 aryl such as phenyl, 1-naphthyl, 2-naphthyl and the like can be mentioned. The aryl group may have 1 to 2 arbitrary substituents at substitutable positions, and as the substituent, an optionally substituted alkyl group (eg, methyl,
C _1-3 alkyl such as ethyl and propyl) and the like. The alkyl group may have 1 to 2 arbitrary substituents at substitutable positions, and as the substituent, a phosphono group which may be substituted (eg, phosphoryl, dimethoxyphosphoryl, diethoxyphosphoryl). Etc.) and the like.

In the above formula (I), the hydrocarbon group in the "optionally substituted hydrocarbon group" represented by R ⁵ and R ⁶ is a saturated or unsaturated aliphatic chain hydrocarbon group, Examples thereof include saturated or unsaturated alicyclic hydrocarbon groups and aryl groups. Examples of the saturated aliphatic hydrocarbon group include linear or branched saturated aliphatic hydrocarbon groups having 1 to 10 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- Butyl,
(C _1-10 alkyl groups such as tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.), preferably linear or branched having 1 to 6 carbon atoms. And saturated aliphatic hydrocarbon groups thereof. Examples of the unsaturated aliphatic hydrocarbon group include a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 10 carbon atoms (eg, ethenyl, 1-
Propenyl, 2-propenyl, 1-butenyl, 2-butenyl,
3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2
-Pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-
C _2-10 alkenyl groups such as 2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, etc., ethynyl, 1-propynyl, 2-propynyl, 1 -Butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-heptynyl, 1 -C _2-10 alkynyl group such as octynyl) and the like, preferably, a linear or branched unsaturated aliphatic hydrocarbon group having 2 to 6 carbon atoms and the like.

Examples of the saturated alicyclic hydrocarbon group include a saturated alicyclic hydrocarbon group having 3 to 12 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.
1) heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] C _3-12 cycloalkyl group such as decyl), and preferably a saturated alicyclic hydrocarbon group having 3 to 6 carbon atoms and the like. Examples of the unsaturated alicyclic hydrocarbon group include an unsaturated alicyclic hydrocarbon group having 5 to 12 carbon atoms (eg, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadienyl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexene C _5-12 cycloalkenyl groups such as -1-yl and 3-cyclohexen-1-yl, and also 2,4-cyclopentadiene-1-yl, 2,4-cyclohexadiene-1-yl, 2,5 -Cyclohexadiene-1-
C _5-12 cycloalkadienyl group such as yl). Further, the hydrocarbon group of the “optionally substituted hydrocarbon group” represented by R ⁵ and R ⁶ has 1 to 10 carbon atoms substituted with the saturated or unsaturated alicyclic hydrocarbon group described above.
8 saturated aliphatic hydrocarbon groups (eg, C _3-7 cycloalkyl-C _1-8 alkyl, etc., or C _5-7 cycloalkenyl-C _1-8 alkyl, etc., specifically, for example, cyclopropylmethyl, Cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptyl Ethyl, etc.).

Examples of the aryl group include monocyclic or condensed polycyclic aromatic hydrocarbon ring groups having 6 to 14 carbon atoms. Examples of the aromatic hydrocarbon ring group include phenyl, tolyl, xylyl, biphenyl, 1- or 2-
Naphthyl, 1-, 2- or 9-anthryl, 1-, 2
-, 3-, 4- or 9-phenanthryl, 1, -2
Examples thereof include C _6-14 aryl such as-, 4-, 5- or 6-azulenyl and acenaphthylenyl. Among them, C _6-10 aryl such as phenyl, 1-naphthyl and 2-naphthyl is preferable. The hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R ⁵ and R ⁶ may have 1 to 3 arbitrary substituents at substitutable positions. As the substituent, an optionally substituted aryl group, an optionally substituted cycloalkyl group or a cycloalkenyl group, an optionally substituted heterocyclic group, an optionally esterified carboxyl group, a substituent An optionally substituted carbamoyl group, an optionally substituted amino group, an optionally substituted hydroxyl group, an optionally substituted thiol group, a halogen (eg, fluorine, chlorine, bromine, iodine),
Examples thereof include an optionally substituted phosphono group and the like. As the aryl group of the optionally substituted aryl group,
Examples thereof include C _6-14 aryl such as phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl, and among them, C _6-10 such as phenyl, 1-naphthyl and 2-naphthyl.
Aryl is preferred. The aryl may have 1 to 2 arbitrary substituents at substitutable positions, and the substituents include a hydroxyl group and an optionally substituted alkoxy group (eg, methoxy, ethoxy, propoxy). Such as C _1-3 alkoxy), halogen atom (eg, fluorine, chlorine, bromine,
Iodine), an optionally substituted alkyl group (eg, C _1-3 alkyl such as methyl, ethyl and propyl) and the like. The alkoxy group and the alkyl group may have 1 to 2 arbitrary substituents at substitutable positions, and as the substituent, an optionally substituted phosphono group (eg, phosphoryl, dimethoxyphosphoryl, Diethoxyphosphoryl, etc.) and the like.

Examples of the cycloalkyl group of the optionally substituted cycloalkyl group include C _3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Examples of the substituent of the optionally substituted cycloalkyl group and the number of substitutions thereof include the same kind and number as the substituents of the optionally substituted aryl group. Examples of the cycloalkenyl group of the optionally substituted cycloalkenyl group include C _3-6 cycloalkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl. Examples of the substituents of the optionally substituted cycloalkenyl group and the number of substitutions thereof include the same kind and number as the substituents in the optionally substituted aryl group. The heterocyclic group of the optionally substituted heterocyclic group is an aromatic heterocyclic group having at least one hetero atom of oxygen, sulfur and nitrogen as an atom (ring atom) constituting the ring system, Examples thereof include saturated or unsaturated non-aromatic heterocyclic groups (aliphatic heterocyclic groups), but aromatic heterocyclic groups are preferable. Examples of the aromatic heterocyclic group include a 5- to 7-membered aromatic heterocyclic group containing one sulfur atom, a nitrogen atom or an oxygen atom, a 5- or 6-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms. Ring group, 1-2
A 5- or 6-membered aromatic heterocyclic group containing 1 nitrogen atom and 1 sulfur atom or oxygen atom, and these aromatic heterocyclic groups include a 6-membered ring containing 2 or less nitrogen atoms, benzene. It may be fused with a ring or a 5-membered ring containing one sulfur atom. The aromatic heterocyclic group is an aromatic monocyclic heterocyclic group (eg, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2, 4-
Triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like) and an aromatic condensed heterocyclic group (eg: benzofuranyl, isobenzofuranyl, benzo [ b ] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl,
Benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl. , Carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenatridinyl, phenatrollinyl, indoridinyl, pyrrolo [1,2- b ] pyridazinyl, pyrazolo [1]. , 5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyridinium Jiniru, 1,2,4-triazolo [4,3- a] pyridyl, 1,2,4-triazolo [4,3- b] pyridazinyl, etc.). Among them furyl, thienyl, indolyl, isoindolyl,
Pyrazinyl, pyridyl, pyrimidinyl and the like are preferable.
The non-aromatic heterocyclic group is a 5- to 7-membered non-aromatic heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom or one nitrogen atom and 3 or less hetero atoms (eg, nitrogen, And a 4- to 7-membered non-aromatic heterocyclic group containing oxygen and sulfur atoms). Examples of the non-aromatic heterocyclic group include oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl,
Morpholinyl, thiomorpholinyl, piperazinyl and the like can be mentioned. Examples of the substituent of the optionally substituted heterocyclic group include an alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, etc.) and the like. These non-aromatic heterocyclic groups include benzene rings and 2 or less nitrogen atoms.
It may be condensed with a membered ring or a 5-membered ring containing one sulfur atom, and examples of the condensed non-aromatic heterocyclic group include chromanyl, isochromanyl, indolinyl, isoindolinyl, thiochromanyl or isothiochromanyl. .

Examples of the optionally esterified carboxyl include carboxy, (lower C _1-6 alkoxy) carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl,
sec-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, etc.), (C _6-10 aryloxy) carbonyl (eg, phenoxycarbonyl, 1-naphthoxycarbonyl, etc.),
(C _7-13 aralkyloxy) carbonyl (eg, benzyloxycarbonyl etc.) and the like can be mentioned. Of these, a carboxyl group, methoxycarbonyl and ethoxycarbonyl are preferred. Examples of the substituent of the optionally substituted carbamoyl group include, for example, optionally substituted lower (C _1-6 ) alkyl (eg, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, ter
t-butyl, pentyl, isopentyl, neopentyl,
Hexyl, isohexyl, etc.), an optionally substituted C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), an optionally substituted C _6-10 aryl group (eg, phenyl, 1
-Naphthyl, 2-naphthyl, etc.), an optionally substituted C _7-13 aralkyl group (eg, benzyl, phenethyl, etc.), etc., and these substituents are the same or different and are substituted by 1 or 2 substituents. May be. The substituent in the optionally substituted lower (C _1-6 ) alkyl and the optionally substituted C _3-6 cycloalkyl group is
Examples thereof include a carboxyl group, an aromatic heterocyclic group (eg, furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl, etc.), an amino group, a hydroxyl group, and a phenyl group. Examples of the substituent of the optionally substituted aryl group and the optionally substituted aralkyl group include a halogen atom (eg, fluorine, chlorine, bromine, iodine), a carboxyl group and the like. Further, the substituents on two nitrogen atoms may be combined with the nitrogen atom to form a cyclic amino group, and examples of such cyclic amino group include 1-azetidinyl, 1-
Pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and the like can be mentioned.

Examples of the substituent of the optionally substituted amino group include, for example, optionally substituted lower (C _1-6 ) alkyl (eg, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, ter
t-butyl, pentyl, isopentyl, neopentyl,
Hexyl, isohexyl, etc.), an optionally substituted C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), an optionally substituted C _6-10 aryl group (eg, phenyl, 1
-Naphthyl, 2-naphthyl, etc.), an optionally substituted C _7-13 aralkyl group (eg, benzyl, phenethyl, etc.), etc., and these substituents are the same or different and are substituted by 1 or 2 substituents. May be. Examples of the substituent in the optionally substituted lower (C _1-6 ) alkyl and the optionally substituted C _3-6 cycloalkyl group include a carboxyl group and an aromatic heterocyclic group (eg, furyl, thienyl, Indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl, etc.), amino group,
Examples thereof include hydroxyl group and phenyl group. The substituent of the optionally substituted aryl group and the optionally substituted aralkyl group is a halogen atom (eg, fluorine,
Chlorine, bromine, iodine), carboxyl group and the like. Further, the substituents on two nitrogen atoms may be combined with the nitrogen atom to form a cyclic amino group, and examples of such cyclic amino group include 1-azetidinyl, 1-
Pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and the like can be mentioned. Examples of the substituent of the optionally substituted hydroxyl group include lower (C _1-6 ) alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl). , Neopentyl, hexyl, isohexyl, etc.), C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.), C _6-10 aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl etc.) , C _7-13 aralkyl groups (eg, benzyl, phenethyl, etc.) and the like.

Examples of the substituent of the optionally substituted thiol group include lower (C _1-6 ) alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl). , Pentyl, isopentyl, neopentyl, hexyl, isohexyl etc.), C _3-6 cycloalkyl group (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.), C _6-10 aryl group (eg phenyl, 1-naphthyl, 2 -Naphthyl etc.), a C _7-13 aralkyl group (eg benzyl, phenethyl etc.) and the like. Examples of the substituent in the optionally substituted phosphono group include lower (C _1-6 ) alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, Isopentyl, neopentyl, hexyl, isohexyl, etc., lower (C _1-6 ) alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, se)
c-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy,
Isohexyloxy and the like). Examples of the optionally substituted phosphono group include phosphoryl, dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxyphosphoryl, diisopropoxyphosphoryl, ethylenedioxyphosphoryl, trimethylenedioxyphosphoryl or tetramethylenedioxyphosphoryl. . When the hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R ⁵ and R ⁶ is an alicyclic hydrocarbon group or an aryl group, the substituent may be further substituted. It may be a good aliphatic hydrocarbon group. Examples of the aliphatic hydrocarbon group include R ⁵ and R ⁶ described above.
Examples of the saturated or unsaturated (preferably saturated) hydrocarbon group in the "optionally substituted hydrocarbon group" defined in are, but preferably an alkyl group (eg, methyl, ethyl, propyl C _1-3 alkyl) and the like. The aliphatic hydrocarbon group may have 1 or 2 arbitrary substituents at substitutable positions,
Examples of the substituent include an optionally substituted phosphono group (eg, phosphoryl, dimethoxyphosphoryl, diethoxyphosphoryl, etc.) and the like.

Among the above, the hydrocarbon group of the "optionally substituted hydrocarbon group" represented by R ⁵ and R ⁶ is an alkyl group, preferably C _1-10 alkyl, especially a straight chain group. Or branched lower alkyl having 1 to 6 carbon atoms (eg, methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl,
Hexyl, isohexyl, 4-methylpentyl, 1,1
-Dimethylbutyl, 2,2-dimethylbutyl, 3,3-
(Dimethylbutyl, 2-ethylbutyl, etc.) are preferred. R ⁵ and R ⁶ may be the same or different, but are preferably the same. R ⁵ and R ⁶ are preferably unsubstituted alkyl groups (preferably methyl and ethyl). In the general formulas (I) and (II), m and n are i)
m is 1 and n is 1, ii) m is 1 and n is 0, or
iii) m is 0 and n is preferably 0, and more preferably m is 1 and n is 0.

The general formula (I) is represented by the general formula (I ')

Embedded image [In the formula, R ¹ 'is indol-3-ylmethyl and R ⁴ ″ is
Represents an acyl group or an optionally esterified carboxyl group. Other symbols have the same meaning as above]. Further, the general formula (II) is represented by the general formula (II ′)

[Chemical 33] [In the formula, R ¹ 'is indol-3-ylmethyl and R ⁴ ″ is
Represents an acyl group or an optionally esterified carboxyl group. Other symbols have the same meaning as above].

Examples of the "optionally esterified carboxyl group" include the general formula --COOR ¹² [R ¹²
Is hydrogen, C _1-6 alkyl, C _2-6 alkenyl or C _6-10
And groups such as aralkyl and the like]. For example, a bond of a carboxyl group and an alkyl group having 1 to 6 carbon atoms includes C _1-6 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec. -Butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.) is a combination of a carboxyl group and an alkenyl group having 2 to 6 carbon atoms, such as C _2-6 alkenyloxycarbonyl (eg, Allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl,
3-hexenyloxycarbonyl etc.) having a carboxyl group and an aralkyl group having 6 to 10 carbon atoms bonded thereto include C _6-10 aralkyloxycarbonyl etc. (eg benzyloxycarbonyl, phenethyloxycarbonyl etc.) .

In the present invention, the general formula (II) produced is used.
Examples of the compound represented by are as follows. -N- (4-toluenesulfonyl)-(L) -isoleucyl- (L) -tryptophanal-N- (t-butoxycarbonyl)-(L) -isoleucyl- (L) -tryptophanal-N- ( 1-naphthylsulfonyl)-(L) -isoleucyl- (L) -tryptophanalN- (1-naphthylsulfonyl)-(L) -isoleucyl- (L) -isoleucyl- (L) -tryptophanalN -Benzylcarbamoyl- (L) -isoleucyl-
(L) -Tryptophanal

N-[(2-cyclohexylethyl) carbamoyl]-(L) -isoleucyl- (L) -tryptophanal N- (3-trifluoromethylphenylcarbamoyl)-(L) -isoleucyl- (L ) -Tryptophanal N- (2-propylpentanoyl)-(L) -tryptophanal N-dibenzylacetyl- (L) -tryptophanal N-dibenzylacetyl- (L) -phenylalani Nal-N- (1-naphthylsulfonyl)-(L) -isoleucyl- (L) -phenylalaninal-N- (1-naphthylsulfonyl)-(L) -isoleucyl- (L) -alaninal-N- (2 -Propylpentanoyl)-(L) -alanyl- (L) -tryptophanal N- (2-propylpentanoyl)-(L) -valyl -(L) -Tryptophanal

The general formulas (I), (I '), and
The salt of the compound of (II) and (II ′) is preferably a physiologically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, Examples thereof include salts with basic or acidic amino acids. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt. Preferable examples of the salt with an organic base include, for example, ammonium salt, trimethylamine, triethylamine, pyridine, picoline, ethanolamine,
Examples thereof include salts with diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p. -Salts such as toluene sulfonic acid are included. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. To be

The production method of compound (II) is described in detail below. [Process A]

Embedded image [In the formula, each symbol has the same meaning as described above. ]

This reduction reaction is carried out by using an aluminum hydride-based reducing agent, Synthesis page 676 (1983) and Journal of Medicinal Chemistry, 33rd.
Vol., Pp. 11-13 (1990). The reducing agent preferably includes metal aluminum hydride (eg, diisobutylaluminum hydride, lithium aluminum hydride, bis (2-methoxyethoxy) sodium aluminum hydride, etc.) and the like. The reducing agent is used in an amount of about 3 to 10 times mol, preferably about 4 to 5 times mol, relative to 1 mol of the compound represented by the general formula (I). The reaction time is about 10 minutes to 24 hours, preferably about 30 minutes to 5 hours, and the reaction temperature is about -10.
It is 0 to 100 ° C, preferably about -70 to 60 ° C. As the solvent used, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran and dioxane are used. To be These solvents may be used alone, or may be used by mixing two or more kinds of them, if necessary. The aldehyde derivative (II) thus obtained can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization,
It can be isolated and purified by phase transfer, chromatography and the like.

The starting compound of step A can be produced, for example, by the following method. [Process B]

Embedded image Wherein, R ⁴ 'represents an optionally substituted carboxylic acid or unsubstituted or derived good acid have the acyl group. Other symbols have the same meanings as described above. However, R
^{When 1} is indol-3-ylmethyl, R ⁴ ′ may be an optionally esterified carboxyl group. ]

In this step, compound (III) or its reactive derivative at the carboxyl group or its salt is
Compound (IV) or its reactive derivative at the amino group or its salt is reacted to give compound (I-
1) is manufactured. Suitable reactive derivative at the amino group of compound (IV) includes compound (IV) and aldehyde,
Schiff base type imino or its enamine type tautomer formed by reaction with a carbonyl compound such as a ketone; Compound (IV) and bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea Examples thereof include silyl derivatives produced by the reaction with such silyl compounds; derivatives produced by the reaction of compound (IV) with phosphorus trichloride or phosgene. For suitable salts of the compound (IV) and its reactive derivative, the acid addition salts exemplified for the compound (I) may be referred to. Examples thereof include salts with inorganic acids and salts with organic acids. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p. -Salts such as toluene sulfonic acid are included.

Suitable reactive derivative at the carboxyl group of the compound (III) includes acid halide, acid anhydride, activated amide, activated ester and the like. Suitable examples of the reactive derivative include acid chloride; acid azide; substituted phosphoric acid such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acid and the like. , Sulfite, thiosulfate, sulfuric acid, sulfonic acids such as methanesulfonic acid,
Mixed acid anhydride with an aliphatic carboxylic acid such as acetic acid, propionic acid, butyric acid, isobutyric acid pivalic acid, pentanoic acid, isopentanoic acid, trichloroacetic acid or the like such as aromatic carboxylic acid such as benzoic acid; symmetrical acid Anhydride; imidazole, 4-substituted imidazole, dimethylpyrazo-
Or an activated amide with triazole or tetrazole; or for example cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, Activated ester such as mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenyl ester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthioester, or for example. N, N-dimethylhydroxyamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole Bruno esters with N- hydroxy compound. These reactive derivatives can be arbitrarily selected depending on the type of compound (III) used. Suitable salts of the compound (III) or its reactive derivative are, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt such as trimethylamine salt and triethylamine. Examples thereof include basic salts such as salts, pyridine salts, picoline salts, dicyclohexylamine salts, and organic base salts such as N, N-dibenzylethylenediamine salt.

The reaction in this step is usually carried out with water such as methanol.
Alcohol, alcohols such as ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, in a conventional solvent such as pyridine. The reaction can be carried out in any other organic solvent as long as it does not adversely affect the reaction. These conventional solvents may be used as a mixture with water. In this reaction, when compound (III) is used in the form of a free acid or a salt thereof, N, N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N ' -(Four-
Diethylaminocyclohexyl) carbodiimide; N, N '
-Diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N '-(3-dimethylaminopropyl)
Carbodiimide; N, N'-carbonylbis (2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine;
1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride; diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; eg ethyl chloroformate; isopropyl chloroformate, etc. Lower alkyl haloformate; triphenylphosphine; 2-ethyl-7-
Hydroxybenzisoxazolium salt, 2-ethyl-5-
(M-Sulfophenyl) isoxazolium hydroxide inner salt; N-hydroxybenzotriazole; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; N, N'- It is desirable to carry out the reaction in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent prepared by the reaction of dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride and the like. The reaction is also carried out in the presence of an inorganic or organic base such as an alkali metal hydrogencarbonate tri (lower) alkylamine, pyridine, N- (lower) -alkylmorpholine, N, N-di (lower) alkylbenzylamine, etc. You can go. The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating (eg, about -100 ° C to 100 ° C). The reaction time is usually about 30 minutes to 72 hours.

[Step C]

Embedded image [In the formula, L represents a carboxy group-protecting group, and other symbols have the same meanings as described above] Examples of the carboxy-protecting group represented by L include a protecting group usually used in the field of peptide synthesis, for example, an ester derivative. Can be mentioned. In this step, R ⁴ may be an optionally esterified carboxyl group.
Examples of the optionally esterified carboxyl group include groups represented by the formula —COOR ¹² [wherein R ¹² has the same meaning as described above].

In this step, the compound (V) or the reactive derivative at the carboxyl group or its salt is treated with the compound (V).
After producing (VII) by reacting (VI) or its reactive derivative at the amino group or its salt,
Compound (III-1) was subjected to elimination reaction of carboxy protecting group.
To manufacture. The reaction of the compound (V) or its reactive derivative at the carboxyl group or its salt with the compound (VI) or its reactive derivative at its amino group or its salt is carried out in the same manner as in step B. The carboxy-protecting group elimination reaction of compound (VII) can be carried out by any conventional method used for the carboxy-protecting group elimination reaction, for example, hydrolysis,
Reduction, elimination using a Lewis acid, or the like can be applied. When the carboxy protecting group is an ester, it can be eliminated by hydrolysis or elimination with a Lewis acid. The hydrolysis is preferably carried out in the presence of a base or an acid. Suitable bases include, for example, alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (eg magnesium hydroxide,
Calcium hydroxide, etc., alkali metal carbonates (eg sodium carbonate, potassium carbonate etc.), alkaline earth metal carbonates (eg magnesium carbonate, calcium carbonate etc.), alkali metal bicarbonates (sodium bicarbonate, etc.)
Potassium bicarbonate), alkali metal acetates (eg sodium acetate, potassium acetate etc.), alkaline earth metal phosphates (eg magnesium phosphate, calcium phosphate etc.), alkali metal hydrogen phosphates (eg disodium hydrogen phosphate) , Dibasic hydrogen phosphate, etc.), trialkylamines (eg, trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] non-5- Ene, 1,4-diazabicyclo (2.2.2)
Examples include organic bases such as non-5-ene and 1,8-diazabicyclo [5.4.0] -7-undecene. Hydrolysis with a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent. Suitable acids may include organic or inorganic acids such as formic acid, hydrobromic acid, sulfuric acid and the like.

This hydrolysis is usually carried out with water such as methanol.
Alcohol, alcohols such as ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, in a conventional solvent such as pyridine. The reaction can be carried out in any other organic solvent as long as it does not adversely affect the reaction. These conventional solvents may be used as a mixture with water. The reaction temperature is not particularly limited and is appropriately selected depending on the type of the carboxy protecting group and the method of elimination. For example, it is performed at about −100 ° C. to 100 ° C. The reaction time is
It is usually performed in about 30 minutes to 72 hours. For elimination using a Lewis acid, a compound (VII) or a salt thereof is treated with a Lewis acid such as boron trihalide (eg boron trichloride, boron trifluoride), titanium halide (eg titanium tetrachloride, tetrabromide). Titanium, etc.), aluminum halide (eg, aluminum chloride, aluminum bromide, etc.), trihaloacetic acid (eg, trichloroacetic acid, trifluoroacetic acid, etc.) and the like. This elimination reaction is preferably carried out in the presence of a cation scavenger (eg, anisole, phenol, etc.), and is usually a nitroalkane (eg, nitromethane, nitroethane, etc.), an alkylene halide (eg, methylene chloride, chloride). Ethylene, etc.), diethyl ether, carbon disulfide, and other solvents that do not adversely influence the reaction. These solvents may be used as a mixture thereof. The reaction time is usually about 30 minutes
The reaction temperature is usually about -100 to 100 ° C. for 48 hours. The elimination by reduction is preferably applied to elimination of a protecting group such as an alkyl halide (eg 2-iodoethyl, 2,2,2-trichloroethyl etc.) ester, an aralkyl (eg benzyl etc.) ester and the like. The reduction method used in this elimination reaction includes, for example, a metal (eg, zinc, zinc amalgam, etc.) or a salt of a chromium compound (eg, chromium chloride, chromium acetate) and an organic or inorganic acid (eg, acetic acid, propionic acid). , Hydrochloric acid, etc.); conventional catalytic reduction in the presence of a conventional metal catalyst (eg, palladium carbon, Raney-nickel, etc.) and the like. The reaction temperature is not particularly limited and is usually under cooling, at room temperature or under heating (eg, about −
The reaction is carried out at 100 ° C to 100 ° C. The reaction time is
It is usually carried out for 30 minutes to 72 hours. As the solvent used, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran and dioxane are used. To be These solvents may be used alone, or may be used by mixing two or more kinds of them, if necessary.

[Process D]

Embedded image [Each symbol in the formula has the same meaning as described above. In this step, (X) is produced by reacting compound (IX) or a reactive derivative at a carboxyl group or a salt thereof with compound (VIII) or a reactive derivative at an amino group or a salt thereof, and then reacting with carboxy The compound (III-2) is produced by subjecting the protective group to elimination reaction. This step is performed in the same manner as the step C.

[Step E]

[Chemical 38] [In the formula, X represents a halogen atom (eg, chlorine, bromine), and other symbols have the same meanings as described above. In this step, compound (XI) or a salt thereof is treated with compound (VI)
(XII) is produced by reacting II) or a reactive derivative of its amino group or a salt thereof, and then subjected to elimination reaction of a carboxy protecting group to produce compound (III-3). The reaction of (VIII) and (XI) is carried out in a suitable solvent. Examples of the solvent include benzene, toluene,
Aromatic hydrocarbons such as xylene, dioxane, tetrahydrofuran, ethers such as dimethoxyethane, ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide, dimethyl sulfoxide, chloroform,
Dichloromethane, 1,2-dichloroethane, 1,1,
2,2-Tetrachloroethane, acetone, 2-butanone and a mixed solvent thereof can be used. (VIII) and (XI)
The reaction of is an alkali metal salt such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, pyridine, triethylamine, N, N-.
It is carried out in the presence of an amine such as dimethylaniline or the like, and an appropriate base such as sodium hydride or potassium hydride, and the amount of these bases to be used is preferably about 1 to 5 mol relative to the compound (VIII). This reaction is generally carried out at -20 ° C to 150 ° C, preferably about -10 ° C to 100 ° C. The reaction time is usually about 30 minutes to 72 hours. For the preferable salt of the compound (VIII), the acid addition salts exemplified for the compound (I) may be referred to. Examples thereof include salts with inorganic acids and salts with organic acids. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p. -Salts such as toluene sulfonic acid are included. The compound (XII) thus obtained is subjected to a deprotecting group reaction to produce a compound (III-3). This deprotection group reaction is performed in the same manner as the deprotection group reaction in step C.

[Step F]

[Chemical Formula 39] [Each symbol in the formula has the same meaning as described above. In this step, compound (XIII) or a salt thereof is treated with compound
(XI) or its salt to react with the compound (III
-3) is manufactured. This sulfonylation reaction is usually carried out by converting the amino acid derivative (XIII) into a sodium salt, and then converting the compound (XI)
The reaction is carried out under the condition of so-called Schotten Baumann, which is acidification. For the preferable salt of the compound (XIII), the acid addition salts exemplified for the compound (VIII) may be referred to.

[Step G]

[Chemical 40] [In the formula, X represents a halogen atom (eg, chlorine, bromine), and other symbols have the same meanings as described above. In this step, compound (XIII) or a salt thereof is treated with compound
(XIV) or a salt thereof to give a compound (II
I-2) is manufactured. This acylation reaction is performed in the same manner as in step F.

[Step H]

Embedded image [Each symbol in the formula has the same meaning as described above. In this step, compound (VIII) or a salt thereof is converted to compound
After producing (XVI) by reacting with (XV), the compound (III-4) is produced by subjecting it to elimination reaction of the carboxy protecting group. Compound (VIII) or its salt and compound (XV)
The reaction with is carried out in a suitable solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, ethyl acetate and acetonitrile,
Pyridine, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-
Examples thereof include dichloroethane, 1,1,2,2-tetrachloroethane, acetone, 2-butanone and a mixed solvent thereof. The amount of the compound (XV) used is preferably about 1 to 5 mol based on the compound (VIII). This reaction is usually from -20 ° C.
It is carried out at 150 ° C, preferably about -10 ° C to 100 ° C. The reaction temperature is usually about 30 minutes to 72 hours. The compound (XVI) thus obtained is subjected to a deprotecting group reaction to produce a compound (III-4). This deprotection group reaction is performed in the same manner as the deprotection group reaction in step C.

[Step I]

Embedded image [Each symbol in the formula has the same meaning as described above. In this step, compound (VIII) or a salt thereof is converted to compound
After producing (XVIII) by reacting with (XVII), the compound (III-
5) is manufactured. This reaction is performed in the same manner as in step H.

[Step J]

[Chemical 43] [In the formula, M represents an amino-protecting group, and other symbols have the same meanings as described above. Examples of the amino group-protecting group represented by M include a protecting group usually used in the field of peptide synthesis, such as acetyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, t-butoxycarbonyl, and formyl. Preferably benzyloxycarbonyl, t-
Butoxycarbonyl is used. In this step, compound (XIX) or a reactive derivative at a carboxyl group or a salt thereof is reacted with compound (XX) or a reactive derivative at an amino group or a salt thereof to produce (XXI), followed by amino protection. Compound (IV) is produced by subjecting the group to elimination reaction. The amino-protecting group elimination reaction of compound (XXI) can be eliminated by all the conventional methods used for the amino-protecting group elimination reaction.
For example, elimination of the benzyloxycarbonyl group is carried out by catalytic reduction in the presence of a conventional metal catalyst (eg palladium carbon, Raney nickel, etc.). The reaction temperature is not particularly limited, and the reaction is usually performed under cooling, at room temperature or under heating (eg, about −100 to 100 ° C.). The reaction time is usually about 30 minutes to 72 hours. The reaction of the compound (XIX) or its reactive derivative at the carboxyl group or its salt with the compound (XX) or its reactive derivative at its amino group or its salt is performed in the same manner as in step C.

The starting compound (I) in step A can be produced by the following method. [Step K]

[Chemical 44] [In the formula, M represents an amino-protecting group, and other symbols have the same meanings as described above. Examples of the amino-protecting group represented by M include the same ones as described above.

In this step, compound (XXIII) was prepared by reacting compound (XXII) or a reactive derivative at a carboxyl group or a salt thereof with compound (IV) or a reactive derivative at an amino group or a salt thereof. After that, the amino protecting group is subjected to elimination reaction to give the compound (XXI
V) is manufactured. The reaction of the compound (XXII) or its reactive derivative at the carboxyl group or its salt with the compound (IV) or its reactive derivative at its amino group or its salt is carried out in the same manner as in step B. Compound (XXII
The amino protecting group elimination reaction of I) can be eliminated by all the conventional methods used for the elimination reaction of amino protecting groups. For the specific method, refer to Process J. Then, the compound (XXIV) is acylated in the same manner as the reaction between the compound (VIII) and the compound (IX) in the step D or the reaction between the compound (XIII) and the compound (XIV) in the step G, and the compound in the step E is used. (VIII) and compound (II)
Sulfonylation in the same manner as in the reaction of step 1, Carbamoylation in the same manner as in the reaction between compound (VIII) and compound (XV) in the step H, and in the same manner as in the reaction between compound (VIII) and compound (XVII) in the step I Thiocarbamoylation is carried out to produce compound (I).

[Process L]

Embedded image [In the formula, each symbol has the same meaning as described above. In this step, compound (V) or a reactive derivative at a carboxyl group or a salt thereof is reacted with compound (XXIV ′) or a reactive derivative at an amino group or a salt thereof to produce (I-2). . This step is C
The process is performed in the same manner.

General formula (II-1)

Embedded image The compound represented by the formula [wherein each symbol has the same meaning as defined above] is preferably produced as follows. (I) Formula (a)

[Chemical 47] [Wherein R ¹ and M have the same meanings as defined above] or a reactive derivative at the carboxyl group thereof or a salt thereof and a compound represented by the formula (b)

Embedded image [Wherein R ⁵ and R ⁶ have the same meanings as defined above] or by reacting with a reactive derivative at the amino group thereof or a salt thereof, the formula (c)

[Chemical 49] [Wherein R ¹ , R ⁵ , R ⁶ and M have the same meanings as defined above] or a salt thereof is prepared, and then the compound of the formula (c) or a salt thereof is amino-protected. Formula (d)

Embedded image [Wherein R ¹ , R ⁵ and R ⁶ have the same meanings as described above] or a salt thereof is prepared, and (ii) the formula (d)
A compound represented by or a reactive derivative at the amino group or a salt thereof and the formula (e)

[Chemical 51] [Wherein R ² has the same meaning as described above and M ′ represents an amino-group-protecting group] or a reactive derivative of the carboxyl group thereof or a salt thereof to give a compound of the formula ( f)

Embedded image [Wherein R ¹ , R ² , R ⁵ , R ⁶ and M ′ have the same meanings as described above] or after producing a salt thereof,
A compound represented by the formula (f) or a salt thereof is subjected to an elimination reaction of an amino protecting group to give a formula (g)

Embedded image [Wherein R ¹ , R ² , R ⁵ , and R ⁶ have the same meanings as described above] or a salt thereof is produced, and (iii) the formula (g)
A compound represented by or a reactive derivative at an amino group thereof or a salt thereof and formula (h) R ¹¹ SO ₂ X [wherein, R ¹¹ has the same meaning as described above, and X is a halogen atom (eg, chlorine, bromine). A compound represented by the formula (i)

[Chemical 54] [Wherein each symbol has the same meaning as defined above] or a salt thereof is produced, and (iv) the compound represented by the formula (i) or a salt thereof is subjected to a reduction reaction. Is a method for producing a compound represented by formula (II-1) or a salt thereof.

Examples of the amino-protecting group represented by M'include the same as those defined for the amino-protecting group represented by M above. In this step, the reaction between the compound (a) or the reactive derivative at the carboxyl group or the salt thereof and the compound (b) or the reactive derivative at the amino group or the salt thereof is performed in the same manner as in the step J. For the amino protecting group elimination reaction of compound (c), refer to Process J. The reaction of the compound (d) or the reactive derivative of the amino group or its salt with the compound (e) or its reactive derivative of the carboxyl group or its salt is carried out in the same manner as in Step K. Compound (f)
The amino protecting group elimination reaction of is performed in the same manner as in step K. The reaction of the compound (g) or the reactive derivative at the amino group or a salt thereof with the compound (h) or a salt thereof is performed in the same manner as in step E. The elimination reaction of compound (i) is performed in the same manner as in step A.

The compound represented by the general formula (II-1) is preferably a compound represented by the formula:

[Chemical 55] Is a compound represented by. formula

[Chemical 56] The compound represented by the formula (i) is represented by the formula (α)

[Chemical 57] [Wherein, M represents an amino-protecting group] or a reactive derivative at a carboxyl group thereof or a salt thereof and a compound of formula (β)

Embedded image [In the formula, R ⁵ 'and R ⁶ ' are the same or different and are C _1-6.
An alkyl group] or a reactive derivative of the amino group thereof or a salt thereof is reacted to form a compound of formula (γ)

Embedded image [In the formula, R ⁵ ', R ⁶ ' and M have the same meanings as described above]
After the compound represented by
The compound of formula (δ)

Embedded image [Wherein R ⁵ 'and R ⁶ ' have the same meanings as described above] or a salt thereof is produced, and (ii) the compound represented by the formula (δ) or its reactivity at the amino group Derivative or salt thereof and formula (ε)

[Chemical formula 61] [Wherein M'represents an amino-protecting group] or a reactive derivative of the carboxyl group thereof or a salt thereof to give a compound of formula (ζ)

Embedded image [Wherein R ⁵ ′, R ⁶ ′ and M ′ have the same meanings as described above], and then a compound represented by the formula (ζ) or a salt thereof is amino-protected. The formula (η) for the elimination reaction of the group

[Chemical formula 63] [Wherein R ⁵ ′ and R ⁶ ′ are as defined above] or a salt thereof, and (iii) the compound represented by the formula (η) or its reactivity at the amino group Derivative or salt thereof and formula (θ ')

[Chemical 64] By reacting with a compound represented by

Embedded image [Wherein R ⁵ ′ and R ⁶ ′ have the same meanings as described above], and (iv) the compound represented by the formula (ι) or a salt thereof is subjected to a reduction reaction. It is manufactured by a method characterized by being attached.

According to the production method of the present invention, the optically active compound (II) can be produced from the compound (I) in a good yield under mild conditions, and the DMSO oxidation reaction causing a malodor is not performed. This is an industrially advantageous method. General formula (I
The compound represented by I) or a salt thereof is blended in an effective amount with a physiologically acceptable carrier to give tablets, capsules,
It can be administered orally or parenterally as solid preparations such as granules and powders; or liquid preparations such as syrups and injections. The compound represented by the general formula (II) or a salt thereof has a strong cathepsin L inhibitory action as well as an excellent bone resorption inhibiting action and low toxicity, as described in EP0611756, for example. Therefore,
The compound represented by the general formula (II) or a salt thereof is a mammal (eg, mouse, rat, rabbit, dog, cat, cow, pig,
It can be used for the prevention or treatment of osteoporosis in humans).

[0057]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in detail below with reference to Reference Examples and Examples, but the present invention is not limited thereto. The room temperature is about 20 to 30 ° C.

[0058]

【Example】

Reference Example 1 N-benzyloxycarbonyl-L-tryptophan (40 g),
N, O-dimethylhydroxylamine hydrochloride (12 g) and triethylamine (17.6 ml) were added to dimethylformamide (DMF) (300 m
l), and 1-hydroxybenzotriazole (H
OBt) (20 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD.HCl) (24.8 g) were added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The ethyl acetate layer was washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried (MgSO ₄ ). The solvent was evaporated, the obtained residue was washed with ethyl acetate-hexane, and N
-Benzyloxycarbonyl-L-tryptophan N, O-dimethylhydroxylamide (42g, 93%) was obtained as a white solid. Melting point 131-132 ° C. [α] _D = -21.0 ° (c 0.56, MeOH) (2
0 ° C). Calculated elemental analysis _{C 21 H 23 N 3 O 4} :. C, 66.13; H, 6.08; N, 11.02 analysis: C, 66.38; H, 6.28 ; N, 11.25.

Reference Example 2 In the same manner as in Reference Example 1, N-benzyloxycarbonyl-L
-Alanine N, O-dimethylhydroxylamide was obtained as colorless prism crystals. Melting point 88-89 ° C. [α] _D = -16.6 ° (c 0.
89, MeOH) (20 ° C). Elemental analysis Calculated as C ₁₃ H ₁₈ N ₂ O ₄ : C, 58.63; H, 6.81; N, 10.52. Analytical value: C, 58.59; H, 6.71; N, 10.51. Reference Example 3 N-benzyloxycarbonyl- L-Tryptophan N, O-dimethylhydroxylamide (35 g) and palladium-carbon (5%,
18 g) with methanol (200 ml) and tetrahydrofuran (THF) (2
00 ml) was added to the mixed solvent, and catalytic reduction was performed at 1 atm and room temperature. Palladium-carbon was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dimethylformamide (DMF) (250 ml) and N-benzyloxycarbonyl-L-isoleucine (25.5 ml) was added.
g) was added. Under ice cooling, 1-hydroxybenzotriazole (HOBt) (15.4 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCDHCl) (1
9.3 g) was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The ethyl acetate layer was washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried (MgSO ₄ ). The solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography. Ethyl acetate-hexane (3:
From the part eluted in 1), N-benzyloxycarbonyl-L-
Isoleucyl-L-tryptophan N, O-dimethylhydroxylamide (42 g, 92%) was obtained as a colorless powder. [α] _D = -3
6.6 ° (c 0.55, MeOH) (20 ° C). Elemental analysis Calculated as C ₂₇ H ₃₄ N ₄ O ₅ 1 / 2H ₂ O: C, 64.40; H, 7.01; N, 11.13. Analytical value: C, 64.49; H, 6.77; N, 11.30.

Reference Example 4 N-benzyloxycarbonyl-L-isoleucyl-L-tryptophan N, O-dimethylhydroxylamide (42 g) and palladium-carbon (5%, 18 g) were added to methanol (150 ml) and tetrahydrofuran (THF) ( 150 ml) of the mixed solvent, and catalytic reduction was carried out at 1 atm and room temperature. Palladium-carbon was filtered off, and the filtrate was concentrated under reduced pressure. The residue was treated with dimethylformamide (D
MF) (300 ml), and under ice-cooling 1-naphthalenesulfonyl chloride (20.2 g) and N, N-dimethylaminopyridine (1
0.9 g) was added and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The ethyl acetate layer was washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine in this order, and dried (MgSO ₄ ). The solvent was distilled off, and the obtained residue was subjected to silica gel column chromatography. Ethyl acetate-hexane (3:
N-1-naphthalenesulfonyl-L-isoleucyl-L-tryptophan N, O-dimethylhydroxylamide (42 g, 83%) was obtained as a pale yellow powder from the portion eluted in 1). Toluene was added to the obtained powder and the mixture was concentrated under reduced pressure to completely remove ethyl acetate. [α] _D = + 30.2 ° (c 0.75, MeOH) (20 ° C). Elemental analysis _{C 29 H 34 N 4 O 5} S · 1 / 2tolue
Calculated as ne: C, 65.41; H, 6.42; N, 9.39. Analytical value: C, 65.44; H, 6.43; N, 9.26.

Reference Example 5 In the same manner as in Reference Example 3, N-benzyloxycarbonyl-L
-Valyl-L-phenylalanine N, O-dimethylhydroxylamide was obtained as colorless crystals. Melting point 101-102 ° C. [α]
_D = -36.9 ° (c 0.76, MeOH) (20 ° C). Elemental analysis Calculated as C ₂₄ H ₃₁ N ₃ O ₅ : C, 65.29; H, 7.08; N, 9.52. Analytical value: C, 65.08; H, 7.05; N, 9.41. Next, from the obtained compound, N-valproyl-L-valyl-L-phenylalanine N, O-dimethylhydroxylamide was obtained as colorless needles. Melting point 157-158 [deg.] C. [α] _D = -5
4.6 ° (c 0.66, MeOH) (20 ° C.). Calculated elemental analysis _{C 24 H 39 N 3 O 4} :. C, 66.48; H, 9.07; N, 9.69 Analytical values: C, 66.43; H, 9.04 ; N, in the same manner as 9.86 Reference Example 6 Reference Example 3. , N-α-t-butoxycarbonyl-N-
ε-benzyloxycarbonyl-L-lysyl-L-alanine N,
O-dimethylhydroxylamide was obtained as a colorless oil. ¹ H-NMR (δ ppm in CDCl ₃ ): 1.33 (3H, d, J = 7.0Hz), 1.44
(9H, s), 1.5-1.9 (6H, m), 3.13, (3H, s), 3.1-3.3 (2H, m),
3.75 (3H, s), 4.0-4.2 (1H, m), 4.8-5.0 (1H, m), 5.09 (2H,
s), 5.1-5.3 (1H, m), 6.63 (1H, d, J = 7.4Hz), 7.35 (5H, s). Reference Example 7 In the same manner as in Reference Example 4, N-α- (p-toluene). Sulfonyl)-
N- (ε-benzyloxycarbonyl) -L-lysyl-L-alanine N, O-dimethylhydroxylamide was obtained as colorless needle crystals. Melting point 102-103 ° C. [α] _D = -25.5 ° (c 0.55, MeOH)
(20 ° C). Elemental analysis Calculated as C ₂₆ H ₃₆ N ₄ O ₇ S: C, 56.92; H, 6.61; N, 10.21. Analytical value: C, 57.05; H, 6.54; N, 10.19.

Example 1 N- (1-naphthalenesulfonyl) -L-isoleucyl-L-tryptophan N, O-dimethylhydroxylamide (21 g) was dissolved in anhydrous tetrahydrofuran (THF) (200 ml), and the mixture was dissolved in N ₂ stream. 6
Cooled to 0 ° C. To this solution, a 1.5 M diisobutylaluminum hydride toluene solution (107 ml) was added dropwise over 25 minutes. After stirring at -50 ° C for 4 hours, the reaction solution was added to an aqueous citric acid solution. The mixture was extracted with ethyl acetate, washed with an aqueous citric acid solution, water, a saturated aqueous solution of sodium hydrogencarbonate, and saturated saline in this order, and dried (MgSO ₄ ). The solvent was distilled off, the residue was crystallized from ethyl acetate-hexane, N- (1-naphthalenesulfonyl) -L-isoleucyl-L-tryptophanal (9.0 g, 58%)
Was obtained as colorless crystals. Melting point 156-157 ° C. [α] _D = -54.4
° (c 0.50, CHCl ₃ ) (20 ° C.). Elemental analysis Calculated as C ₂₇ H ₂₉ N ₃ O ₄ S: C, 65.97; H, 5.95; N, 8.55. Analytical value: C, 65.95; H, 6.16; N, 8.36. Example 2 Same as Example 1 Then, N- (valproil) -L-valyl-L-
Phenylalaninal was obtained as colorless crystals. Melting point 161
-162 ° C. [α] _D = -59.3 ° (c 0.84, DMSO) (20 ° C). Elemental analysis
Calculated as C ₂₂ H ₃₄ N ₂ O ₃ : C, 70.55; H, 9.15; N, 7.48. Analytical value: C, 70.16; H, 9.13; N, 7.76. Example 3 In the same manner as in Example 1, N-α- (p-toluenesulfonyl)-
N- (ε-benzyloxycarbonyl) -L-lysyl-L-alaninal was obtained as colorless crystals. Melting point 161-162 ° C. [α] _D =-
9.2 ° (c 0.53, MeOH). Elemental analysis calculated as C ₂₄ H ₃₁ N ₃ O ₆ S: C, 58.88; H, 6.38; N, 8.58. Analytical value: C, 58.46; H, 6.36;
N, 8.61.

[0063]

According to the production method of the present invention, the optically active target compound (II) is converted from the compound (I) in a good yield under mild conditions.
Can be produced, and the DMSO oxidation reaction that produces a foul odor is not performed, which is an industrially advantageous method.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area C07K 5/068 8517-4H C07K 5/068

Claims (17)

[Claims] 1. A compound represented by the general formula (I): [Wherein R ¹ , R ² and R ³ are the same or different and are hydrogen or an optionally substituted hydrocarbon group, R ⁴ is an acyl group and R ⁵ and R ⁶ are the same or different and are substituted. A hydrocarbon group which may be present, m and n being the same or different and each representing 0 or 1] or a salt thereof is subjected to a reduction reaction. [Wherein R ¹ , R ² , R ³ , R ⁴ , m and n are the same as defined above] or a method for producing a salt thereof. 2. The production method according to claim 1, wherein the reduction reaction is carried out using metal aluminum hydride. 3. R ¹ , R ² and R ³ are the same or different and are hydrogen or C _1-10 alkyl, C _2-10 alkenyl, C
_2-10 alkynyl, C _3-12 cycloalkyl, C _5-12 cycloalkenyl, C _5-12 cycloalkadienyl, C _3-7 cycloalkyl-C _1-8 alkyl, C _5-7 cycloalkenyl-
A hydrocarbon group selected from C _1-8 alkyl and C _6-14 aryl, wherein the hydrocarbon group is (i) a hydroxyl group, C
C _6-14 aryl optionally substituted by _1-3 alkoxy, halogen or C _1-3 alkyl, (ii) hydroxyl group, C
_1-3 alkoxy, halogen or C _1-3 optionally substituted by alkyl C _3-7 cycloalkyl or C _3-6 cycloalkenyl, optionally substituted with (iii) C _1-3 alkyl, 1 5- or 7-membered aromatic heterocyclic group containing 1 sulfur atom, nitrogen atom or oxygen atom, 5- or 6-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms, 1-2 nitrogen atoms and 1 5- or 6-membered aromatic heterocyclic group containing 1 sulfur atom or oxygen atom, 5-membered to 7-membered non-aromatic heterocyclic group containing 1 sulfur atom, nitrogen atom or oxygen atom, and 1 nitrogen atom and A heterocyclic group selected from a 4- to 7-membered non-aromatic heterocyclic group containing a hetero atom selected from 3 or less nitrogen, oxygen and sulfur atoms, (iv)
Carboxyl, (lower (C _1-6 ) alkoxy) carbonyl,
(C _6-10 aryloxy) carbonyl or (C _7-13 aralkyloxy) carbonyl, (v) C _1-6 alkyl, C _3-6
Carbamoyl optionally substituted with cycloalkyl, C _6-10 aryl or C _7-13 aralkyl, (vi) C
_1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl or amino _optionally substituted with C _7-13 aralkyl, (vii) C _1-6 alkyl, C _3-6 cycloalkyl, C
Hydroxyl group _optionally substituted with _6-10 aryl or C _7-13 aralkyl, (viii) C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl or C _7-13 aralkyl substituted Optionally have 1 to 3 substituents selected from thiol, (ix) halogen and (x) phosphono optionally substituted with C _1-6 alkyl or C _1-6 alkoxy; R ⁴ is a general formula —CONH
^{R 7, -CSNHR 8, -COR 9} , -SOR 10 or -
SO ₂ R ¹¹ [wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ are the same or different and are hydrogen or (A) C _1-10 alkyl, C
_2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, C _5-12 cycloalkenyl, C _5-12 cycloalkadienyl, C _3-7 cycloalkyl-C _1-8 alkyl, C _{5- 7}
A hydrocarbon group selected from cycloalkenyl-C _1-8 alkyl and C _6-14 aryl or (B) a 5- to 7-membered aromatic heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom, 2 to 5 or 6 containing 4 nitrogen atoms
5- or 6-membered aromatic heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur atom or oxygen atom, 5 to 6 containing 1 sulfur atom, nitrogen atom or oxygen atom 7-membered non-aromatic heterocyclic group, and heterocyclic group selected from 4- to 7-membered non-aromatic heterocyclic group containing one nitrogen atom and 3 or less nitrogen, oxygen and sulfur atom-containing heteroatoms Wherein the hydrocarbon and the heterocyclic group are (i) a hydroxyl group, C _1-3 alkoxy, C _6-14 aryl optionally substituted with halogen or C _1-3 alkyl, (ii) a hydroxyl group, C _1-3 alkoxy, halogen or C _3-7 cycloalkyl optionally substituted with C _1-3 alkyl or C _3-6 cycloalkenyl, (iii) C _1-3
Alkyl-substituted 5- to 7-membered aromatic heterocyclic group containing 1 sulfur atom, nitrogen atom or oxygen atom, 5- or 6-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms A 5- or 6-membered aromatic heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur atom or oxygen atom,
5- to 7-membered non-aromatic heterocyclic group containing one sulfur atom, nitrogen atom or oxygen atom, and 4 to 5 containing one nitrogen atom and a hetero atom selected from 3 or less nitrogen, oxygen and sulfur atoms. A heterocyclic group selected from a 7-membered non-aromatic heterocyclic group, (iv) carboxyl, (lower (C _1-6 ) alkoxy) carbonyl, (C _6-10 aryloxy) carbonyl or (C _7-13 aralkyloxy) ) Carbonyl,
(V) C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl or carbamoyl optionally substituted with C _7-13 aralkyl, (vi) C _1-6 alkyl, C _3-6 cyclo Amino _optionally substituted with alkyl, C _6-10 aryl or C _7-13 aralkyl, (vii) C _1-6 alkyl, C
_A hydroxyl group _optionally substituted by _3-6 cycloalkyl, C _6-10 aryl or C _7-13 aralkyl, (viii) C
_1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl or thiol _optionally substituted with C _7-13 aralkyl, (ix) halogen and (x) C _1-6 alkyl or C _1-6 Optionally having 1 to 3 substituents selected from phosphono which may be substituted with alkoxy]; R ⁵ and R ⁶ are the same or different;
C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, C _5-12 cycloalkenyl,
C _5-12 cycloalkadienyl, C _3-7 cycloalkyl-
A hydrocarbon group selected from C _1-8 alkyl, C _5-7 cycloalkenyl-C _1-8 alkyl and C _6-14 aryl, wherein the hydrocarbon group is (i) hydroxyl group, C _1-3 alkoxy, halogen or C _1-3 alkyl optionally substituted C _6-14 aryl, optionally substituted with (ii) hydroxyl, C _1-3 alkoxy, halogen or C _1-3 alkyl C _{3- 7} cycloalkyl or C _3-6 cycloalkenyl, (iii) optionally substituted with C _1-3 alkyl, 1
5- or 7-membered aromatic heterocyclic group containing 1 sulfur atom, nitrogen atom or oxygen atom, 5- or 6-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms, 1-2 nitrogen atoms and 1 5 or 6 containing 4 sulfur or oxygen atoms
Membered aromatic heterocyclic groups, 5- to 7-membered non-aromatic heterocyclic groups containing one sulfur atom, nitrogen atom or oxygen atom, and one nitrogen atom and 3 or less nitrogen, oxygen and sulfur atoms A heterocyclic group selected from a 4- to 7-membered non-aromatic heterocyclic group containing a hetero atom, (iv) carboxyl, (lower (C _1-6 ) alkoxy) carbonyl, (C _6-10 aryloxy) carbonyl or (C _7-13 aralkyloxy) carbonyl, (v) C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl or carbamoyl optionally substituted with C _7-13 aralkyl, (vi) C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl or C
_7-13 amino _optionally substituted with aralkyl, (vi
i) C _1-6 alkyl, C _3-6 cycloalkyl, C _6-10 aryl or C _7-13 aralkyl-substituted hydroxyl group, (viii) C _1-6 alkyl, C _3-6 cycloalkyl , _Thiols optionally substituted with C _6-10 aryl or C _7-13 aralkyl, (ix) halogen and (x)
The production method according to claim 1, which may have 1 to 3 substituents selected from phosphono which may be substituted with C _1-6 alkyl or C _1-6 alkoxy. 4. The method according to claim ¹ , wherein R ¹ , R ² and R ³ are the same or differently substituted alkyl groups. 5. R ¹ is a linear or branched C _1-6 alkyl group substituted with an aryl or heterocyclic group.
The manufacturing method described. 6. The process according to claim 1, wherein R ² and R ³ are the same or different and each is a linear or branched C _1-6 alkyl group. 7. The method according to claim 1, wherein the acyl group is derived from carboxylic acid, sulfonic acid, sulfinic acid, carbamic acid or thiocarbamic acid. 8. The acyl group has the formula --SO ₂ R ¹¹ or --CO.
The process according to claim 1, which is represented by R ⁹ [wherein R ¹¹ and R ⁹ are the same or different and each is hydrogen or an optionally substituted hydrocarbon or heterocyclic group]. 9. R ⁴ is of the formula --SO ₂ R ¹¹ 'wherein R ¹¹ ' is C
_6-10 aryl group]. 10. The process according to claim 1, wherein R ⁵ and R ⁶ are the same or different and each is a saturated or unsaturated aliphatic chain hydrocarbon group. 11. The method according to claim _10, wherein the saturated aliphatic hydrocarbon group is a C _1-10 alkyl group. 12. The method according to claim 11, wherein the alkyl group is methyl. 13. The method according to claim 1, wherein m is 1 and n is 0. 14. A compound of the general formula (I) is represented by the formula (ι): [In the formula, R ⁵ 'and R ⁶ ' are the same or different and are C _1-6.
The compound according to claim 1, which is an alkyl group] or a salt thereof. 15. General formula (I): [Wherein R ¹ , R ² and R ³ are the same or different and are hydrogen or an optionally substituted hydrocarbon group, R ⁴ is an acyl group and R ⁵ and R ⁶ are the same or different and are substituted. A hydrocarbon group that may be present, m and n are the same or different and represent 0 or 1, or a salt thereof. 16. A compound of the general formula (I) is represented by the formula (ι): [In the formula, R ⁵ 'and R ⁶ ' are the same or different and are C _1-6.
The compound according to claim 15, which is a compound represented by an alkyl group] or a salt thereof. 17. (i) Formula (α): [Wherein, M represents an amino-protecting group] or a reactive derivative of the carboxyl group thereof or a salt thereof and a compound represented by the formula (β): [In the formula, R ⁵ 'and R ⁶ ' are the same or different and are C _1-6.
An alkyl group] or a reactive derivative of the amino group thereof or a salt thereof is reacted to give a compound of formula (γ) [In the formula, R ⁵ ', R ⁶ ' and M have the same meanings as described above]
After the compound represented by
A compound represented by the following formula or a salt thereof is subjected to elimination reaction of an amino protecting group to give a compound represented by the formula (δ): [Wherein R ⁵ ′ and R ⁶ ′ have the same meanings as defined above] or a salt thereof, and (ii) the compound represented by the formula (δ) or its reactivity at the amino group Derivatives or salts thereof and formula (ε) [Wherein M'represents an amino-protecting group] or a reactive derivative of the carboxyl group thereof or a salt thereof is reacted to give a compound of formula (ζ) [Wherein R ⁵ ′, R ⁶ ′ and M ′ are as defined above] or a salt thereof is prepared, and then the compound represented by the formula (ζ) or a salt thereof is amino-protected. A group of formula (η) [Wherein R ⁵ ′ and R ⁶ ′ have the same meanings as described above] or a salt thereof is produced, and (iii) the compound represented by the formula (η) or its reactivity at the amino group Derivatives or salts thereof and formula (θ) [Wherein X represents a halogen atom] or a salt thereof is reacted to give a compound of the formula (ι) [Wherein R ⁵ 'and R ⁶ ' are as defined above] or a salt thereof is produced, and (iv) the compound represented by the formula (ι) or a salt thereof is subjected to a reduction reaction. An equation characterized by: The manufacturing method of the compound or its salt represented by.