JPH08208462A - Cathepsin l inhibitor - Google Patents

Abstract

PURPOSE: To obtain the subject inhibitor having cathepsin L inhibiting action, directly acting on the bone to exhibit excellent bone resorption suppressing action and useful for the prevention and treatment of osteoporosis of mammals. CONSTITUTION: This cathepsin L inhibitor contains a compound of formula I (Q is a bond or one or two amino acid residues; R<1> is H, a hydrocarbon group or a heterocyclic group; R<4> is an acyl or carboxyl which may be esterified; R<5> and R<6> are each H, a hydrocarbon group or a heterocyclic group; R<5> and R<6> may together form a ring) or its salt, preferably the compound of formula II (R<2> and R<3> are each same as R<1> ; (m) and (n) are each 0 or 1), e.g. N-(quinoline-2-carbonyl)-L-isoleucine-(3S)-3-amino-2-oxo-4-phenylbutanoic acid benzylamide or its salt. The compound of formula I can be produced e.g. by oxidizing a compound of formula III.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a cathepsin L inhibitor containing an α-ketoamide derivative or a salt thereof as an active ingredient and its use.

[0002]

2. Description of the Related Art Osteoporosis is a pathological condition or disease in which the quantity of bone has been reduced to a certain extent or more, which causes some symptoms or danger. Its main symptoms are kyphosis of the spine, lumbar spine and vertebral bodies, femoral neck, lower radius, ribs, upper humerus and other fractures. In bone tissue, bone formation and bone destruction due to bone resorption are constantly repeated in a balanced manner, and osteoblasts play a central role in bone formation and osteoclasts play a central role in bone resorption. The balance between bone formation and bone destruction due to bone resorption is disturbed, and when bone resorption occurs more strongly than bone formation, it is accompanied by a quantitative decrease in bone. Therefore, agents that suppress bone resorption are considered to be useful for the prevention and treatment of osteoporosis, and bone resorption inhibiting substances such as estrogen agents and calcitonin have been administered as therapeutic agents for osteoporosis. However, when these therapeutic agents are administered, the subject to be administered may be limited or the effect may be uncertain, and a sufficient effect has not been obtained. Therefore, the development of a new preventive and therapeutic method for enhancing bone resorption is desired. Recently, it was revealed that cathepsin L, which is a protease secreted by osteoclasts in the process of bone resorption, is greatly involved in the degradation of collagen, which is a bone supporting protein (FEBS Lett. 321).
Vol. 247, 1993). Therefore, by inhibiting the activity of cathepsin L, it is possible to prevent the degradation of bone collagen due to bone resorption, and it is considered to be useful for the preventive treatment of osteoporosis. Conventionally, leupeptin, antipain, and epoxysuccinic acid derivatives (JP-A-2-
304074, JP-A-2-304075, JP-A-2-304085), a cathepsin L inhibitory action is known as one of the inhibitory actions. Conventionally, as a α-ketoamide derivative having a protease inhibitory action, the natural product poststatin (postostati
n) is known, and various compounds have been synthesized as amino acid-derived α-ketoamide derivatives. For example, International Publication WO 94/00095 discloses an α-ketoamide derivative as a Calpain inhibitor.
(Tokuyohei 6-504547) is an α-ketoamide derivative of calpain, papain, cathepsin B.
(Cathepsin B) disclosed as an inhibitor.

[0003]

None of the α-ketoamide derivatives reported so far has disclosed a cathepsin L inhibitory action. Further, most of the synthesized α-ketoamide derivatives convert the carboxyl group of the corresponding amino acid into an α-ketoester by subjecting it to a Dakin-West reaction, so that the α-position of the ketone is racemized. There is.

[0004]

Means for Solving the Problems The present inventors have earnestly studied for the purpose of developing a more general drug having a selective inhibitory action on cathepsin L and directly acting on bone to suppress bone resorption. I went. As a result, they have found that the α-ketoamide derivative has a strong cathepsin L inhibitory action, and directly acts on bone to exhibit an excellent bone resorption inhibitory action, thereby becoming a useful preventive and therapeutic agent for bone diseases, and completed the present invention. did. That is, the present invention provides (1) the general formula (Ia)

Embedded image [Wherein, Q is a bond or an optionally substituted 1 or 2 amino acid residue, R ¹ is hydrogen or an optionally substituted hydrocarbon or heterocyclic group, and R ⁴ is an acyl group or In the optionally esterified carboxyl group, R ⁵ and R ⁶ are the same or different and each represents hydrogen or an optionally substituted hydrocarbon or heterocyclic group. R ⁵ and R ⁶ may be bonded to each other to form a ring] or a compound represented by the formula (I)

[Chemical 6] [Wherein R ¹ , R ² and R ³ are the same or different,
Hydrogen or an optionally substituted hydrocarbon or heterocyclic group, R ⁴ is an acyl group or an optionally esterified carboxyl group, and R ⁵ and R ⁶ are the same or different and are hydrogen or substituted. Represents a hydrocarbon or a heterocyclic group which may be present. R ⁵ and R ⁶ may combine with each other to form a ring. m and n are the same or different and each represents 0 or 1.], The cathepsin L inhibitor according to (1) above, (3) the general formula (I ′)

[Chemical 7] [Wherein R ¹ , R ² and R ³ are the same or different,
Hydrogen or an optionally substituted hydrocarbon or heterocyclic group, R ^4a has the formula —COR ^a or —SO ₂ R ^b (wherein
R ^a and R ^b are the same or different and each represents an optionally substituted aryl or aromatic heterocyclic group), and R ^5a and R ^6a are the same or different and are substituted. An optionally substituted aryl or aromatic heterocyclic group or a linear or branched lower alkyl group optionally substituted with an optionally esterified carboxyl group, m and n are the same or different, and Or 1 is shown. However, when R ^a is an optionally substituted aromatic heterocyclic group, R ^5a and R ^6a are the same or different,
A linear or branched lower alkyl group substituted with an optionally substituted aryl or aromatic heterocyclic group or an optionally esterified carboxyl group]
A compound represented by: or a salt thereof, (4) the compound described in (3) above, wherein the aryl groups of R ^a and R ^b are naphthyl,
(5) The compound described in (3) above, wherein the aromatic heterocyclic group of R ^a and R ^b is quinolyl, (6) The above (3) description wherein one of R ^5a and R ^6a is hydrogen and the other is benzyl. (7) The compound according to (3) above, wherein R ¹ is a phenyl-substituted linear or branched C _1-6 alkyl group,
(8) The compound according to the above (3), wherein R ² and R ³ are the same or different and are a linear or branched C _1-6 alkyl group, (9) N- (quinoline-2-carbonyl) -L-isoleucine- (3S) -3-amino-2-oxo-4-phenylbutanoic acid benzylamide or a salt thereof, (10)
N- [N- (6-oxo-1,4,5,6-tetrahydropyridazine-3-carbonyl) -L-leucyl]-
(3S) -3-Amino-2-oxo-4-phenylbutanoic acid benzylamide or a salt thereof, (11) N-benzyloxycarbonyl-L-leucyl-L-leucyl-
(3S) -3-Amino-2-oxo-4-phenylbutanoic acid benzylamide or a salt thereof, (12) N- (quinoline-2-carbonyl) -L-leucyl-L-leucyl- (3S) -3- Amino-2-oxo-4-phenylbutanoic acid benzylamide or a salt thereof, (13) general formula (I ″)

Embedded image [Wherein R ¹ , R ² and R ³ are the same or different,
Hydrogen or an optionally substituted hydrocarbon or heterocyclic group, R ^4b is represented by the formula —COR ^c (wherein R ^c is a straight chain substituted by an optionally substituted aryl or aromatic heterocyclic group or A group represented by a branched lower alkyl group), R ^5b and R ^6b are the same or different and are substituted with an optionally substituted aryl group or an optionally esterified carboxyl group. A linear or branched lower alkyl group, m and n are the same or different and represent 0 or 1, or a salt thereof, (14) containing the compound according to (3) above. And (15) a composition containing the compound according to (13) above.

The α-ketoamide derivative in the present invention is
It is an optically active substance having a S configuration at the β-position, which is synthesized by oxidizing a corresponding optically active α-hydroxyamide derivative under mild DMSO oxidizing conditions. The above formula (I
In a), “optionally substituted 1” represented by Q
To the amino acid residues in the two amino acid residues ", alpha-amino acids, beta-amino acids, such as γ- amino and the like, for example, each formula _{RCH (NH 2) COOH, H} 2 NCH 2 CHRCO 2 H,
It is represented by H ₂ NCH ₂ CH ₂ CHRCO ₂ H [wherein R represents hydrogen or an optionally substituted hydrocarbon group or a heterocyclic group], and α-amino acids are preferable. Here, when Q is a dipeptide residue in which two amino acids are bound, the two amino acids may be of the same type,
Although it may be of a different type, it is preferably one consisting of two α-amino acids. When they are of the same type (for example, an amino acid residue consisting of two α-amino acids), the two amino acids may be the same or different. The hydrocarbon group in the "optionally substituted hydrocarbon group" defined by R is "an optionally substituted hydrocarbon group" defined by the following R ¹ , R ² and R ^3.
The same groups as the hydrocarbon group in are mentioned. The heterocyclic group in the "optionally substituted heterocyclic group" defined by R is a heterocyclic group in the "optionally substituted heterocyclic group" defined by R ¹ , R ² and R ³ below. The same as the group is mentioned. The substituent in the "optionally substituted hydrocarbon group or heterocyclic group" defined by R is "an optionally substituted hydrocarbon group or heterocyclic group defined by the following R ¹ , R ² and R ^3. The same as the substituents in the “heterocyclic group” can be mentioned. Examples of the α-amino acid residue include glycine and natural or unnatural L-type or D-type α-amino acid. For example, glycine, α-L-amino acid or α-D-amino acid (eg, α
-L-form or α-D-form of alanine, valine, leucine, isoleucine, serine, threonine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, cysteine, methionine, phenylalanine, tyrosine, tryptophan, histidine, proline Etc.), preferably glycine, α-L
-Type of alanine, valine, leucine, isoleucine,
Methionine, phenylalanine, tyrosine, tryptophan and the like can be mentioned.

The amino acid residue in the "optionally substituted 1 or 2 amino acid residue" represented by Q may have 1 to 3 substituents at substitutable positions.
Examples of the substituent include the same as those in the "optionally substituted hydrocarbon group or heterocyclic group" defined by R ¹ , R ² and R ³ below. Q is the formula (Ia-Q)

[Chemical 9] [Wherein R ² and R ³ are the same or different and represent hydrogen or an optionally substituted hydrocarbon group or a heterocyclic group, and m and n are the same or different and represent 0 or 1] Is preferred. The above formulas (I) and (Ia
In -Q), the hydrocarbon group in the "optionally substituted hydrocarbon group" represented by R ¹ , R ² and R ³ is a saturated or unsaturated aliphatic chain hydrocarbon group, saturated or unsaturated hydrocarbon group. Examples thereof include unsaturated alicyclic hydrocarbon groups and aryl groups. Examples of the saturated aliphatic hydrocarbon group include a linear or branched saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms (e.g., 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 of 1 to 6 carbon atoms A branched or branched saturated aliphatic hydrocarbon group and the like. 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-
C _2-10 alkenyl groups such as hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl C ₂ such as 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-heptynyl and 1-octynyl _-10 alkynyl group), and preferably has 2 to 6 carbon atoms.
And straight-chain or branched unsaturated aliphatic hydrocarbon groups.

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-, 4-, 5- or 6-azulenyl, acenaphthylenyl and the like can be mentioned, and among them, C _6-10 aryl such as phenyl, 1-naphthyl, 2-naphthyl and the like are preferable.

The hydrocarbon group in the "optionally substituted hydrocarbon group" represented by R ¹ , R ² and R ³ has 1 to 3 arbitrary substituents at substitutable positions. May be. 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 Optionally substituted carbamoyl group, optionally substituted amino group, optionally substituted hydroxyl group, optionally substituted thiol group, halogen (eg, fluorine, chlorine, bromine,
Iodine), an optionally substituted phosphono group, and the like. Examples of the aryl group which may be substituted include C _6-14 aryl such as phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like, and among them, phenyl, 1-naphthyl and 2-naphthyl are preferable. 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,
C _1-3 alkoxy such as methoxy, ethoxy and propoxy), halogen atom (eg, fluorine, chlorine, bromine, iodine), optionally substituted alkyl group (eg, methyl,
C _1-3 alkyl such as 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, dimethoxyphosphoryl, diethoxy). Phosphoryl 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 among them, quinolyl, isoquinolyl, furyl, thienyl, indolyl, isoindolyl, imidazolyl, pyrazinyl, pyridyl, pyrimidinyl and the like are preferable. The non-aromatic heterocyclic group is 5 to 7 containing one sulfur atom, nitrogen atom or oxygen atom.
Membered non-aromatic heterocyclic groups or 4- to 7-membered non-aromatic heterocyclic groups containing one nitrogen atom and up to 3 hetero atoms (eg nitrogen, 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.

Examples of the optionally esterified carboxyl include --COOH and (lower (C _1-6 ) alkoxy).
Carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.-butoxycarbonyl, sec.-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert.-pentyl Oxycarbonyl, 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 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 group (eg,
Benzyl, phenethyl and the like), and these substituents may be the same or different and may be substituted by one or two. Examples of the substituent of the optionally substituted amino 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 groups (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), C _7-13 aralkyl groups (eg, benzyl, phenethyl, etc.) and the like, and these substituents are the same or different and are 1 or 2 It may be replaced.

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 groups (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), C _7-13 aralkyl groups (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.). Examples of the optionally substituted phosphono group include phosphoryl, dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxyphosphoryl, diisopropoxyphosphoryl, ethylenedioxyphosphoryl, trimethylenedioxyphosphoryl or tetramethylenedioxyphosphoryl. . Also, R ¹ , R ² and R ³
When the hydrocarbon group in the “optionally substituted hydrocarbon group” is an alicyclic hydrocarbon group or an aryl group, the substituent may be an optionally substituted aliphatic hydrocarbon group. It may be. The aliphatic hydrocarbon group is the same as the saturated or unsaturated (preferably saturated) aliphatic hydrocarbon group in the “optionally substituted hydrocarbon group” defined for R ¹ , R ² and R ³ above. Examples thereof include alkyl groups (eg, C _1-3 alkyl such as methyl, ethyl, propyl, etc.) 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.

The heterocyclic group in the "optionally substituted heterocyclic group" represented by R ¹ , R ² and R ³ includes oxygen, sulfur and nitrogen as atoms (ring atoms) constituting the ring system. Among these, an aromatic heterocyclic group having at least one hetero atom and a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group) can be mentioned, but an aromatic heterocyclic group is 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, and a 5- or 6-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms. A 5- or 6-membered aromatic heterocyclic group containing a cyclic group, 1 to 2 nitrogen atoms and 1 sulfur atom or oxygen atom, and these aromatic heterocyclic groups have 2 or less nitrogen atoms. It may be condensed with a 6-membered ring containing it, a benzene ring or a 5-membered ring containing one sulfur atom. Examples of the aromatic heterocyclic group include aromatic monocyclic heterocyclic groups (e.g., 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, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 2-, 4-, 5- or 6-pyrimidinyl, 2-pyrazinyl, triazinyl, etc.) and fused aromatic heterocyclic groups (eg , Benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl,
Isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1
H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenazinyl, phenazinyl. Inyl, thianthrenyl, phenatridinyl, phenatorolinyl, indolizinyl, 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 etc.) and the like, but among them, quinolyl, isoquinolyl, furyl, thienyl, imine Zoriru,
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, , A 4- to 7-membered non-aromatic heterocyclic group containing nitrogen, oxygen and sulfur atoms (eg, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, Homopiperidyl, pyrrolinyl, imidazolidinyl, 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 heterocyclic group in the “optionally substituted heterocyclic group” represented by R ¹ , R ² and R ³ 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 A carbamoyl group which may be substituted, an amino group which may be substituted,
Optionally substituted hydroxyl group, optionally substituted thiol group, halogen (eg, fluorine, chlorine, bromine, iodine), optionally substituted phosphono group, optionally substituted aliphatic hydrocarbon group Etc.

The optionally substituted aryl group, the optionally substituted cycloalkyl group or the cycloalkenyl group, the optionally substituted heterocyclic group, the optionally esterified carboxyl group, the optionally substituted Optionally carbamoyl group, optionally substituted amino group, optionally substituted hydroxyl group, optionally substituted thiol group, halogen (eg, fluorine, chlorine, bromine, iodine), optionally substituted The good phosphono group and the optionally substituted aliphatic hydrocarbon group are the same as those defined for the substituents in the "optionally substituted hydrocarbon group" for R ¹ , R ² and R ³ above. There are many things. 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, especially a straight chain 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. 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. As R ¹ , an alkyl group substituted with an optionally substituted aryl or heterocyclic group is preferable.

More preferably, R ¹ is an alkyl group substituted with an aryl or a heterocycle. Examples of the alkyl substituted with the aryl include a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl) and 1 carbon atom. -6 bonded to lower alkyl (preferably C _1-4 alkyl) (eg, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, α-naphthylmethyl, α) -Naphthylethyl, β-
Naphthylmethyl, β-naphthylethyl, etc.) and the like. Examples of the alkyl substituted with the heterocycle include those in which an aromatic heterocyclic group and a lower alkyl having 1 to 6 carbon atoms (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-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, 1H-imidazo [4,5-c] pyridine- 2-yl, 1H-imidazo [4,5-b] pyrazine-
2-yl and the like can be mentioned, but preferably 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-imidazolyl,
2-thienyl, 2-furyl, indol-3-yl and the like can be mentioned.

Further, R ¹ is more preferably a linear or branched C _1-6 alkyl group substituted with phenyl. As R ² and R ³ , the same or different, and a straight-chain or branched C _1-6 alkyl group is more preferable. R ¹ preferably includes indol-3-ylmethyl, benzyl, methyl, isopropyl, 1-naphthylmethyl and the like. R ² and R ³ are preferably
The same or different, sec.-butyl, benzyl, isobutyl, isopropyl and the like. As R ¹ and R ² , for example, R ¹ is indol-3-ylmethyl, benzyl, methyl, isopropyl or 1-naphthylmethyl, and R ² is sec.-butyl, benzyl, isobutyl or isopropyl. Certain combinations are preferred. As R ¹ , R ² and R ³ , for example, R ¹ is indol-3-ylmethyl, benzyl, methyl, isopropyl or 1-naphthylmethyl, 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 formula (I), the “acyl group” represented by R ⁴ may be an optionally substituted carbamic acid, an optionally substituted thiocarbamic acid, an optionally substituted carboxylic acid, or an optionally substituted carboxylic acid. which may be sulfinic acid, acyl group and the like derived from such good acid substituted, for example, each formula -CONHR ^7, -C
^{SNHR 8, -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 a heterocyclic group. ] And the like. The hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ is the same as defined in R ¹ , R ² and R ³ above. The same as the hydrocarbon group in the “hydrocarbon group which may be substituted” 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. The substituent may have,
The same as the substituents in the “optionally substituted hydrocarbon group” defined for R ¹ , R ² and R 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 thing as the heterocyclic group in the said "optionally substituted heterocyclic group" is mentioned. The heterocyclic group in the “optionally substituted heterocyclic 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, the “optionally substituted heterocyclic group” defined for R ¹ , R ² and R ³ above.
The same groups as the substituents in can be mentioned. Examples of the “acyl group” represented by R ⁴ include alkanoyl groups (eg, formyl, acetyl, propionyl, butyryl,
Isobutyryl, valeryl, isovaleryl, pivaloyl,
(Lower C _1-6 alkyl) carbonyl group such as hexanoyl, alkenoyl group (eg, acryloyl, methacryloyl, crotonoyl, isocrotonoyl (lower C _1-6 alkyl) carbonyl group)
_2-6 alkenyl) carbonyl group), cycloalkanecarbonyl group (eg, (C _3-6 cycloalkyl) carbonyl group such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl), cycloalkenylcarbonyl group (eg, (C _3-7 cycloalkenyl) carbonyl group such as cyclopropenylcarbonyl, cyclobutenylcarbonyl, cyclopentenylcarbonyl, cyclohexenylcarbonyl),
Aliphatic acyl groups such as alkanesulfonyl groups (eg, lower C _1-6 alkylsulfonyl groups such as mesyl, ethanesulfonyl, propanesulfonyl), aroyl groups (eg, benzoyl, p-toluoyl, 1-naphthoyl, 2-naphthoyl, etc.) (C _6-10 aryl) carbonyl group), an arylalkanoyl group (eg, phenylacetyl, phenylpropionyl, hydroatropoyl, phenylbutyryl and the like) substituted with a C _6-10 aryl group (C _1-6 alkyl) ) Carbonyl group), arylalkenoyl group (eg, (C _2-6 alkenyl) carbonyl group substituted with C _6-10 aryl group such as cinnamoyl, atropoyl), arenesulfonyl group (eg, benzenesulfonyl group, p- Aromatic acyl group such as C _6-10 arylsulfonyl group such as toluenesulfonyl group, aromatic heterocyclic group Bonyl group (eg, furoyl, tenoyl, nicotinoyl, isonicotinoyl, pyrrole carbonyl, aromatic heterocyclic carbonyl group such as oxazole carbonyl, imidazole carbonyl, pyrazole carbonyl), aromatic heterocyclic alkanoyl group (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 . The group represented by the formula -COR ⁹ is more preferably the formula -COR ^a [R ^a represents an optionally substituted aryl or aromatic heterocyclic group].
Or a group represented by the formula -COR ^c [wherein R ^c represents a linear or branched lower (C _1-6 ) alkyl group substituted with an optionally substituted aryl or aromatic heterocyclic group] Is mentioned. ^Examples of the aryl group in the “optionally substituted aryl group” for R ^a include C _6-10 aryl such as phenyl, 1-naphthyl and 2-naphthyl. R ^a "optionally substituted aromatic heterocyclic group"
Examples of the aromatic heterocyclic group in: include quinolyl, isoquinolyl, furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl and the like, with preference given to quinolyl and isoquinolyl. The optionally substituted aryl or aromatic heterocyclic group may have a substituent at any substitutable position, and the substituent is a lower (C _1-3 ) alkyl (eg, , Methyl, ethyl, propyl, isopropyl, etc.), lower (C _1-3 ) alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, etc.), halogen (eg, fluorine, chlorine, bromine, etc.) and the like. The “linear or branched lower (C _1-6 ) alkyl” for R ^c is methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec.-
Butyl, tert.-butyl, pentyl, isopentyl, neopentyl, tert.-pentyl, hexyl, isohexyl and the like can be mentioned. R ^c “linear or branched lower (C
" _1-6 ) Alkyl" means at least one (preferably 1)
Or an optionally substituted aryl or aromatic heterocyclic group as the substituent, examples of the optionally substituted aryl or aromatic heterocyclic group defined above in R ^a. The same groups as the group heterocyclic groups can be mentioned. As R ^c , a linear or branched C _1-4 alkyl group substituted with 1 or 2 optionally substituted aryl (eg, phenyl) groups is preferable.

The group represented by the formula -SO ₂ R ¹¹ is more preferably represented by the formula -SO ₂ R ^b [R ^b represents an optionally substituted aryl or aromatic heterocyclic group]. Group. ^Examples of the "optionally substituted aryl or aromatic heterocyclic group" for R ^b include the same as the optionally substituted aryl or aromatic heterocyclic group defined for R ^a. To be As R ^b , an aryl group which may be substituted is particularly preferable. Examples of the “optionally substituted aryl group” represented by R ^b include C _6-14 aryl groups such as phenyl, 1-naphthyl, 2-naphthyl and the like. The aryl group may have 1 to 2 arbitrary substituents at substitutable positions, and the substituent is an alkyl group (eg, C _1-3 alkyl such as methyl, ethyl, propyl). Etc. Examples of the “optionally esterified carboxyl group” represented by R ⁴ include, for example, the general formula —COOR ¹²
And R ¹² represents hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _6-10 aralkyl or 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.)
Examples of such a compound in which a carboxyl group and an alkenyl group having 2 to 6 carbon atoms are bonded to each other include C _2-6 alkenyloxycarbonyl and the like (eg, allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl, 3-hexenyloxycarbonyl etc.) having a carboxyl group and an aralkyl group having a carbon number of 7 to 10 bound thereto include C _7-10 aralkyloxycarbonyl etc. (eg benzyloxycarbonyl, phenethyloxycarbonyl etc.) .

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 a linear or branched saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms (e.g., 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 of 1 to 6 carbon atoms A branched or branched saturated aliphatic hydrocarbon group and the like. 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
-, 4-, 5- or 6-azulenyl, acenaphthylenyl and the like can be mentioned, among which phenyl, 1-naphthyl, 2-
C _6-10 aryl groups such as naphthyl are preferred. “An optionally substituted hydrocarbon group” represented by R ⁵ and R ⁶
The hydrocarbon group in 1 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 Optionally substituted carbamoyl group, optionally substituted amino group, optionally substituted hydroxyl group, optionally substituted thiol group, halogen (eg, fluorine, chlorine, bromine, iodine), substituted And the phosphono group which may be present. Examples of the aryl group of the optionally substituted aryl group include C _6-14 aryl such as phenyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl, and among them, phenyl,
1-naphthyl and 2-naphthyl are preferable. 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). C _1-3 alkoxy), halogen atom (eg fluorine, chlorine, bromine, iodine), optionally substituted alkyl group (eg C _1-3 alkyl such as methyl, ethyl, propyl) and the like. To be 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, dimethoxyphosphoryl, diethoxy). Phosphoryl 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, and a 5- or 6-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms. And 5- or 6-membered aromatic heterocyclic groups containing 1 to 2 nitrogen atoms and 1 sulfur atom or oxygen atom, and these aromatic heterocyclic groups contain 2 or less nitrogen atoms. It may be condensed with a 6-membered ring, a benzene ring or a 5-membered ring containing one sulfur atom. As the aromatic heterocyclic group, 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, 1,3,3 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-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxadinyl. Nyl, thianthrenyl, phenatridinyl, 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-
b ] Pyridazinyl, 1,2,4-triazolo [4,3-
a ] pyridyl and the like), quinolyl,
Isoquinolyl, furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl and the like are preferable. As the non-aromatic heterocyclic group, a 5- to 7-membered non-aromatic heterocyclic group containing one sulfur atom, a nitrogen atom or an 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,
Examples include 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.

Examples of the optionally esterified carboxyl include --COOH, (lower C _1-6 alkoxy) carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.-butoxy). Carbonyl, sec.-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert.-pentyloxycarbonyl, etc.), (C _6-10 aryloxy) carbonyl (eg, phenoxycarbonyl, 1-naphthoxy) Carbonyl, 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, te
rt.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.), an optionally substituted C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
And optionally substituted C _6-10 aryl groups (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), optionally substituted C _7-13 aralkyl groups (eg, benzyl, phenethyl, etc.) and the like. These substituents may be the same or different and may be substituted by 1 or 2. The substituent in the optionally substituted lower (C _1-6 ) alkyl and the optionally substituted C _3-6 cycloalkyl group is an optionally esterified carboxyl group or aromatic heterocyclic group. (Eg, furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl, etc.), amino group, hydroxyl group, phenyl group and the like. Examples of the substituent of the optionally substituted aryl group and the optionally substituted aralkyl group include
Examples thereof include a halogen atom (eg, fluorine, chlorine, bromine, iodine), an optionally esterified 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 a cyclic amino group include 1-azetidinyl, 1
-Pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and the like.

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, te
rt.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.), an optionally substituted C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
And optionally substituted C _6-10 aryl groups (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), optionally substituted C _7-13 aralkyl groups (eg, benzyl, phenethyl, etc.) and the like. These substituents may be the same or different and may be substituted by 1 or 2. The substituent in the optionally substituted lower (C _1-6 ) alkyl and the optionally substituted C _3-6 cycloalkyl group is an optionally esterified carboxyl group or aromatic heterocyclic group. (Eg, furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidyl, imidazolyl, etc.), amino group, hydroxyl group, phenyl group and the like. Examples of the substituent of the optionally substituted aryl group and the optionally substituted aralkyl group include
Examples thereof include a halogen atom (eg, fluorine, chlorine, bromine, iodine), an optionally esterified 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 a cyclic amino group include 1-azetidinyl, 1
-Pyrrolidinyl, piperidino, morpholino, 1-piperazinyl and the like. Examples of the substituent of the optionally substituted hydroxyl group include an optionally substituted lower (C _1-6 ) alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.), optionally substituted C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.), optionally substituted Examples thereof include a C _6-10 aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.) and an optionally substituted C _7-13 aralkyl group (eg, benzyl, phenethyl, etc.).

Examples of the substituent in the optionally substituted thiol group include, for example, optionally substituted lower (C _1-6 ) alkyl (eg, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec.-butyl, te
rt.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.), an optionally substituted C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.),
And optionally substituted C _6-10 aryl groups (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), optionally substituted C _7-13 aralkyl groups (eg, benzyl, phenethyl, etc.) and the like. To be Examples of the substituent of 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, pentoxy, isopentoxy, neopentoxy, Hexyloxy, isohexyloxy, etc.) 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. As the aliphatic hydrocarbon group,
The same as the saturated or unsaturated (preferably saturated) aliphatic hydrocarbon group in the “optionally substituted hydrocarbon group” defined by R ⁵ and R ⁶ above can be mentioned, but an alkyl group is preferable. (Eg, C _1-3 alkyl such as methyl, ethyl and 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. R
^The heterocyclic group in the “optionally substituted heterocyclic group” represented by ⁵ and R ⁶ includes at least one of oxygen, sulfur and nitrogen as an atom (ring atom) constituting the ring system. Examples thereof include an aromatic heterocyclic group having a hetero atom and a saturated or unsaturated non-aromatic heterocyclic group (aliphatic heterocyclic group), but an aromatic heterocyclic group is 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, and 5 or 6 containing 2 to 4 nitrogen atoms.
Membered aromatic heterocyclic groups, 5- or 6-membered aromatic heterocyclic groups containing 1 to 2 nitrogen atoms and 1 sulfur atom or oxygen atom, and these aromatic heterocyclic groups are 2 or less. May be condensed with a 6-membered ring containing a nitrogen atom, a benzene ring or a 5-membered ring containing one sulfur atom. Examples of the aromatic heterocyclic group include aromatic monocyclic heterocyclic groups (e.g., 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, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 2-, 4-, 5- or 6-pyrimidinyl, 2-pyrazinyl, triazinyl, etc.) and fused aromatic heterocyclic groups (eg , Benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl,
Isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1
H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenazinyl, phenazinyl. Inyl, thianthrenyl, phenatridinyl, phenatorolinyl, indolizinyl, 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, etc.) and the like, among which quinolyl, isoquinolyl, furyl, thienyl, Lil, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl are preferred.

As the non-aromatic heterocyclic group, 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, oxygen and sulfur atoms), and 4- to 7-membered non-aromatic heterocyclic groups. Examples of the non-aromatic heterocyclic group include oxiranyl, azetidinyl,
Examples include oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidyl, pyrrolinyl or imidazolidinyl. 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. R
^The heterocyclic group in the “optionally substituted heterocyclic group” represented by ⁵ and R ⁶ may have 1 to 3 arbitrary substituents at substitutable positions. As the substituent,
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 group, optionally substituted hydroxyl group, optionally substituted thiol group, halogen (eg, fluorine, chlorine, bromine, iodine), optionally substituted phosphono group, Examples thereof include an optionally substituted aliphatic hydrocarbon group and the like. The optionally substituted aryl group, optionally substituted cycloalkyl group or cycloalkenyl group, optionally substituted heterocyclic group,
Carboxyl group which may be esterified, carbamoyl group which may be substituted, amino group which may be substituted, hydroxyl group which may be substituted, thiol group which may be substituted, halogen (eg, fluorine , Chlorine, bromine, iodine), an optionally substituted phosphono group, and an optionally substituted aliphatic hydrocarbon group are the above-mentioned “optionally substituted hydrocarbon group” for R ⁵ and R ⁶ , respectively. The same as those defined for the substituent in

R ⁵ and R ⁶ may be bonded to each other to form a heterocycle which may further contain another hetero atom (eg, oxygen, nitrogen, sulfur) together with the adjacent nitrogen atom. Well, for example, 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, 1-piperazinyl, 1
-Homopiperazinyl and the like. The heterocycle may have 1 to 2 substituents at substitutable positions, and examples of the substituent include alkyl (eg, C _1-3 alkyl etc.), carboxyl group, hydroxyl group 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, and particularly linear or branched. -Like 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. Further, the substituent of the "optionally substituted hydrocarbon group" includes optionally substituted aryl (preferably phenyl etc.), optionally substituted heterocycle, and optionally esterified carboxyl. Groups are preferred.

The "optionally substituted hydrocarbon group" represented by R ⁵ and R ⁶ is more preferably an alkyl group substituted with an aryl or a heterocycle.
Examples of the alkyl substituted with the aryl include a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl) and 1 carbon atom. -6 bonded to lower alkyl (preferably C _1-4 alkyl) (eg, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl, α-naphthylmethyl, α) -Naphthylethyl, β
-Naphthylmethyl, β-naphthylethyl, etc.) and the like. Examples of the alkyl substituted with the heterocycle include those in which an aromatic heterocyclic group and a lower alkyl having 1 to 6 carbon atoms (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-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, 1H-imidazo [4,5-c] pyridine- 2-yl, 1H-imidazo [4,5-b] pyrazine-
2-yl and the like can be mentioned, but preferably 2-furyl,
3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 4-imidazolyl and the like can be mentioned.

As R ⁵ and R ⁶ , preferably one is hydrogen and the other is sec.-butyl, benzyl, isobutyl or isopropyl (preferably benzyl). As R ⁵ and R ⁶ , when one is hydrogen, the other is represented by the formula (Ia-aa)

[Chemical 10] [In the formula, R ^d represents hydrogen, an optionally substituted hydrocarbon group or a heterocyclic group, and R ^e represents an optionally esterified carboxyl group or an optionally substituted carbamoyl group] And the groups mentioned above. Expression (Ia
-Aa), the hydrocarbon group in the “optionally substituted hydrocarbon group” represented by R ^d is the “optionally substituted hydrocarbon group” defined for R ¹ , R ² and R ³ above. The same as the hydrocarbon group in the "hydrogen group" can be mentioned. R
^The hydrocarbon group in the “optionally substituted hydrocarbon group” represented by ^d has an arbitrary substituent at the substitutable position of 1
To 3 may be present, and examples of the substituent include those similar to the substituents in the “optionally substituted hydrocarbon group” defined for R ¹ , R ² and R ³ above. . In the formula (Ia-aa), the heterocyclic group in the "optionally substituted heterocyclic group" represented by R ^d is "substituted or unsubstituted" as defined in the above R ¹ , R ² and R ^3. The same as the heterocyclic group in "may be heterocyclic group" can be mentioned. "A heterocyclic group which may be substituted" represented by R ^d
The heterocyclic group in 1 may have 1 to 3 arbitrary substituents at substitutable positions, and the substituent may be the above R.
^{The same} as the substituents in the “optionally substituted heterocyclic group” defined by ¹ , R ² and R ³ can be mentioned.

The hydrocarbon group of the "optionally substituted hydrocarbon group" represented by R ^d is an alkyl group, preferably C _1-10 alkyl, especially a linear or branched carbon number. 1-6 lower alkyl, etc. (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
c.-butyl, tert.-butyl, pentyl, isopentyl,
Neopentyl, tert.-pentyl, hexyl, isohexyl, 4-methylpentyl, 1,1-dimethylbutyl,
2,2-dimethylbutyl, 3,3-dimethylbutyl, 2
-Ethylbutyl and the like) are preferred. Further, the substituent of the “optionally substituted hydrocarbon group” includes optionally substituted aryl (preferably phenyl etc.), optionally substituted heterocycle, and optionally esterified carboxyl. Groups are preferred. Formula (Ia−a
In a), the "optionally esterified carboxyl group" represented by R ^e is carboxyl, (lower C _1-6
Alkoxy) carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.-butoxycarbonyl, sec.-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert. -Pentyloxycarbonyl etc.), ( _C6-10 aryloxy) carbonyl (eg phenoxycarbonyl, 1-naphthoxycarbonyl etc.), ( _C7-13 aralkyloxy) carbonyl (eg benzyloxycarbonyl etc.) and the like. To be Of these, a carboxyl group, methoxycarbonyl and ethoxycarbonyl are preferred.

In the formula (Ia-aa), the substituent of the "optionally substituted carbamoyl group" represented by R ^b is, for example, optionally substituted lower (C _1-6 ) alkyl ( Examples, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, etc.), 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.) and the like, and these substituents may be the same or different and may be substituted by one or two. The optionally substituted lower (C
_1-6 ) Alkyl and optionally substituted C _3-6 cycloalkyl group include, as substituents, optionally esterified carboxyl group, aromatic heterocyclic group (eg, furyl, thienyl, indolyl, isoindolyl). , Pyrazinyl, pyridyl, pyrimidyl, imidazolyl, etc.), amino group, hydroxyl group, phenyl group and the like. 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), an optionally esterified carboxyl group and the like. To be Further, the substituents on two nitrogen atoms may be combined with the nitrogen atom to form a cyclic amino group, and examples of such a cyclic amino group include 1-azetidinyl, 1-pyrrolidinyl and piperidino. , Morpholino, 1-piperazinyl and the like.

In the general formula (I), as m and n, i) m is 1 and n is 1, ii) m is 1 and n is 0, or iii) m is 0 and n is 0. preferable. The salts of the compounds of the general formulas (Ia), (I), (I ′) and (I ″) in the present invention are preferably physiologically acceptable salts, for example salts with inorganic bases and organic bases. Examples thereof include salts, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Preferable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts. Alkaline earth metal salts such as calcium salts and magnesium salts; and aluminum salts.
Suitable examples of salts with organic bases include ammonium salts, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,
Salts with N, N'-dibenzylethylenediamine and the like can be mentioned. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid,
Tartaric acid, maleic acid, citric acid, succinic acid, malic acid,
Salts with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned. 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 compounds (I), (Ia), and
The production methods of (I ′) and (I ″) will be described in detail. Further, in each reaction of the present invention and each reaction of the raw material compound synthesis described below,
A raw material compound has a substituent such as an amino group, a carboxyl group,
In the case of having a hydroxyl group, a protecting group generally used in peptide chemistry or the like may be introduced into these groups, and the target compound may be removed by removing the protecting group as necessary after the reaction. Obtainable. The amino-protecting group includes, for example, formyl, optionally substituted C _1-6 alkylcarbonyl (eg,
Acetyl, ethylcarbonyl, etc.), phenylcarbonyl, C _1-6 alkyl-oxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl, C _7-10 aralkyl-carbonyl (eg, benzylcarbonyl, etc.), trityl, Phthaloyl or N, N-dimethylaminomethylene is used. As these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), a nitro group, etc. are used. The number of substituents is about 1 to 3. Examples of the protective group for the carboxyl group include C _1-6 alkyl which may have a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl, etc.), phenyl, trityl, silyl, etc. Is used. As these substituents, a halogen atom (for example,
Fluorine, chlorine, bromine, iodine, etc.), formyl, C _1-6
Alkyl-carbonyl (eg, acetyl, ethylcarbonyl, butylcarbonyl, etc.), nitro group and the like are used, and the number of substituents is about 1 to 3. Examples of the hydroxyl-protecting group include C _1-6 alkyl optionally having a substituent (eg, methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl, etc.),
Phenyl, C _7-10 aralkyl (eg benzyl etc.), formyl, C _1-6 alkyl-carbonyl (eg acetyl, ethylcarbonyl etc.), phenyloxycarbonyl, benzoyl, (C _7-10 aralkyl) carbonyl (eg Benzylcarbonyl), pyranyl,
Furanyl or silyl is used. As these substituents, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl (eg, methyl,
Ethyl, propyl etc.), phenyl, C _7-10 aralkyl (eg benzyl etc.), nitro group etc. are used,
The number of substituents is about 1 to 4. As a method for removing the protective group, a method known per se or a method analogous thereto can be used, and examples thereof include acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, and tetrabutylammonium fluoride. A method of treating with palladium acetate or the like is used.

The compound (Ia) has the general formula (IIa)

[Chemical 11] [In the formula, Q is a bond or 1 or 2 optionally substituted amino acid residues, R ¹ is hydrogen or an optionally substituted hydrocarbon group or heterocyclic group, and R ⁴ is an esterification group. And an optionally substituted carboxyl group or an acyl group, and R ⁵ and R ⁶ are the same or different and represent hydrogen or an optionally substituted hydrocarbon group or a heterocyclic group. R ⁵ and R ⁶ may combine with each other to form a ring], and can be produced by subjecting the compound to an oxidation reaction as described in detail below. Also,
The compound (I) has the general formula (II)

[Chemical 12] [In the formula, R ¹ , R ² and R ³ are the same or different and each is hydrogen or an optionally substituted hydrocarbon group or a heterocyclic group, and R ⁴ is an optionally esterified carboxyl group or an acyl group. , R ⁵ and R ⁶ are the same or different and each represents hydrogen or an optionally substituted hydrocarbon group or heterocyclic group. R ⁵ and R ⁶ may combine with each other to form a ring. m and n are the same or different and each represents 0 or 1, and can be produced by subjecting it to an oxidation reaction, as described in detail below. Compounds (I ′) and (I ″) can be produced by a method similar to the method for producing compounds (I) and (Ia). [Method A]

[Chemical 13] [In the formula, each symbol has the same meaning as described above. The main oxidation reaction is carried out according to a known oxidation reaction.
For example, Jones oxidation consisting of chromium oxide-sulfate-pyridine, Collins oxidation using a chromium oxide-pyridine complex, oxidation with pyridinium chlorochromate (PCC), pyridinium dichromate (PD
Chromic acid oxidation such as oxidation by C), oxidation by activated DMSO described in detail in Method B below, oxidation by oxoammonium salt, etc. are used.

In the case of an optically active substance, it is preferably carried out by activated dimethyl sulfoxide (DMSO) oxidation. Activated DMSO oxidation is performed in a solvent in the coexistence of DMSO and an electrophilic reagent. Examples of the solvent include ethers such as ethyl ether, isopropyl ether, tetrahydrofuran and hexane, aromatic hydrocarbons such as benzene, toluene and xylene, N, N-dimethylformamide (DMF), chloroform and dichloromethane. And halogenated hydrocarbons such as pyridine, dimethylsulfoxide and the like, which are appropriately selected depending on the type of electrophilic reagent to be used. Activated DMS
For O-oxidation, depending on the electrophilic reagent used, the dicyclohexylcarbodiimide (DCC) method, acetic anhydride method, phosphorus pentoxide method, chlorine method, sulfur trioxide-pyridine method, keteneimine-enamine method, mercury (II) acetate method, etc. There is something called. This oxidation reaction is advantageously carried out by an improved method of the dicyclohexylcarbodiimide (DCC) method. That is, it is an oxidation reaction using 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD.HCl) as a DMSO activation reagent using trifluoroacetic acid / pyridine salt as a catalyst. This reaction is also carried out using dimethyl sulfoxide as a solvent. The amount of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD.HCl) used is 1 to 10 molar equivalents, preferably 2 to 5 molar equivalents, relative to compound (II). The amount of trifluoroacetic acid / pyridine salt used is 0.1 to 2 equivalents. Reaction temperature is -7
It is carried out at 0 ° C to 80 ° C, preferably -20 ° C to 40 ° C. The reaction time is 0.5 to 10 hours.

The ketoamide derivatives (Ia) and (I) thus obtained can be isolated and purified by known separation and purification means such as concentration,
It can be isolated and purified by concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. The compound (II) in the present invention can be produced, for example, by the following method. [Method B]

Embedded image [In the formula, each symbol has the same meaning as described above. In this method, (II) is produced by reacting compound (III) 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. Suitable reactive derivative at the amino group of compound (IV) includes compound (I
Schiff base type imino or its enamine type tautomer formed by the reaction of V) with a carbonyl compound such as an aldehyde or ketone; Compound (IV) and bis (trimethylsilyl) acetamide, mono (trimethylsilyl)
Examples thereof include silyl derivatives formed by reaction with silyl compounds such as acetamide, bis (trimethylsilyl) urea, etc .; derivatives formed by reaction of compound (IV) with phosphorus trichloride or phosgene. Compound (IV)
For suitable salts of the compound and its reactive derivative, the acid addition salts exemplified for the compound (I) may be referred to.

Suitable reactive derivatives of the compound (III) at the carboxyl group include acid halides, acid anhydrides, activated amides and activated esters. 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, Mesyl phenyl ester, phenyl azophenyl ester, phenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester,
Activated esters such as 8-quinolyl thioesters, or eg N, N-dimethylhydroxyamine, 1-hydroxy-2-
Examples thereof include esters with N-hydroxy compounds such as (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, and 1-hydroxy-1H-benzotriazole. These reactive derivatives are compounds (III) used
It can be arbitrarily selected according to the type. Suitable salts of the reactive derivative of the compound (III) include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt,
Examples thereof include basic salts such as ammonium salts, trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, and organic base salts such as N, N-dibenzylethylenediamine salts. The reaction is usually
Water, for example, alcohols such as methanol and ethanol,
It is carried out in a conventional solvent such as acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine, etc., as long as it does not adversely affect the reaction The reaction can be carried out in any organic solvent. 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 '-(4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide; N, N'-carbonylbis (2-methylimidazole); pentamethylene ketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;
Isopropyl polyphosphate; Phosphorus oxychloride; Diphenylphosphoryl azide; Thionyl chloride; Oxalyl chloride; For example, ethyl chloroformate; Lower alkyl haloformates such as isopropyl chloroformate; Triphenylphosphine; 2-Ethyl-7-hydroxybenzisoxazolium salt 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt; N-hydroxybenzotriazole; 1-
(p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by reaction of N, N'-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc. It is desirable to carry out the reaction in the presence of a conventional condensing agent such as 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.

The starting compound (III) of Method B is produced by the following Method C to Method J. [C method]

[Chemical 15] [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. In this method, (VII) is produced by reacting compound (V) or a reactive derivative at a carboxyl group or a salt thereof with compound (VI) or a reactive derivative at an amino group or a salt thereof,
A compound (III) is produced by subjecting a carboxy protecting group to elimination reaction. 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 Method B. For the carboxy-protecting group elimination reaction of compound (VII), all the conventional methods used for the carboxy-protecting group elimination reaction, such as hydrolysis, reduction, elimination using Lewis acid and 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 carbonates). Sodium, potassium carbonate, etc., alkaline earth metal carbonates (eg magnesium carbonate, calcium carbonate etc.), alkali metal bicarbonates (sodium bicarbonate, potassium bicarbonate etc.), alkali metal acetates (eg sodium acetate, potassium acetate) Etc.), inorganic bases such as alkaline earth metal phosphates (eg magnesium phosphate, calcium phosphate etc.), alkali metal hydrogen phosphates (eg disodium hydrogen phosphate, dipotassium hydrogen phosphate etc.), trialkylamines ( For example, trimethylamine, triethyl Amines, etc.), picoline, N- methylpyrrolidine, N- methylmorpholine, 1,5-diazabicyclo [4.
3.0] Non-5-ene, 1,4-diazabicyclo [2.2.2] non-5-
Organic bases such as ene and 1,8-diazabicyclo [5.4.0] -7-undecene are mentioned. Hydrolysis with a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent. Suitable acids include organic acids such as formic acid,
And acetic acid), and inorganic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, etc.). This hydrolysis is usually carried out in an organic solvent, water or a mixed solvent composed of these. 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. The elimination using Lewis acid is
Compound (VII) or a salt thereof can be converted into a Lewis acid such as boron trihalide (eg, boron trichloride, boron trifluoride, etc.), titanium tetrahalide (eg, titanium tetrachloride, titanium tetrabromide, 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 elimination by reduction is preferably applied to elimination of a protecting group such as haloalkyl (eg 2-iodoethyl, 2,2,2-trichloroethyl etc.) ester, 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.)
And a conventional catalytic reduction in the presence of a conventional metal catalyst (for example, 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. [D method]

Embedded image [Each symbol in the formula has the same meaning as described above. In this method, compound (IX) or a reactive derivative at a carboxyl group or a salt thereof is reacted with compound (VIII) or a reactive derivative at an amino group or a salt thereof to prepare (X), and then carboxy is prepared. The compound (III-1) is produced by subjecting the protective group to elimination reaction. This method is performed in the same manner as the C method. [E method]

[Chemical 17] [Each symbol in the formula has the same meaning as described above. In this method, compound (XI) or a salt thereof is treated with compound (VII)
After producing (XII) by reacting with I) or a salt thereof, a compound (III-2) is produced by subjecting it to a carboxy-protecting group elimination reaction. The reaction of (VIII) and (XI) 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, alcohols such as methanol, ethanol and propanol, and ethyl acetate. , Acetonitrile, pyridine, N, N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetone, 2-butanone and mixed solvents thereof. The reaction of (VIII) and (XI) is carried out by alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and sodium hydrogen carbonate, amines such as pyridine, triethylamine and N, N-dimethylaniline, hydrogenation. It is carried out in the presence of an appropriate base such as sodium or potassium hydride, and the amount of these bases to be used is preferably about 1 to 5 mol relative to compound (VIII). This reaction is usually -20 ° C.
~ 150 ° C, preferably about -10 ° C to 100 ° C. The compound (XII) thus obtained is subjected to a deprotecting group reaction to produce a compound (III-2). This deprotection group reaction is performed in the same manner as the deprotection group reaction in Method C.

[F method]

Embedded image [Each symbol in the formula has the same meaning as described above. In this method, compound (XIII) or a salt thereof is treated with compound (XIII)
I) or a salt thereof to give a compound (III-
2) is manufactured. This sulfonylation reaction is usually carried out under the so-called Schotten Baumann condition in which the amino acid derivative (XIII) is used as a sodium salt aqueous solution, and the compound (XI) is reacted and then acidified. [G method]

[Chemical 19] [Each symbol in the formula has the same meaning as described above. In this method, compound (XIII) or a salt thereof is treated with compound (XI
V) or a salt thereof to give a compound (III-
1) is manufactured. This acylation reaction is performed in the same manner as in Method F. [H method]

Embedded image [Each symbol in the formula has the same meaning as described above. In this method, compound (XIII) or a salt thereof is treated with compound (XIII)
V) or a salt thereof to give a compound (III-
4) is manufactured. This method is performed in the same manner as the G method. [I
Law]

[Chemical 21] [Each symbol in the formula has the same meaning as described above. ]

In this method, compound (VIII) or a salt thereof is reacted with compound (XVI) to give (XVII), which is then subjected to elimination reaction of carboxy protecting group to give compound (III-5). To manufacture. The reaction between compound (VIII) or a salt thereof and compound (XVI) 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,
Acetonitrile, pyridine, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetone, 2-butanone and mixed solvents thereof can be mentioned. The amount of compound (XVI) used is preferably about 1 to 5 mol relative to compound (VIII). This reaction is generally -20 ° C to 150 ° C, preferably about -10 ° C to 1
It is carried out at 00 ° C. Compound (XVII) thus obtained
Produces a compound (III-5) by subjecting it to a deprotecting group reaction. This deprotection group reaction is performed in the same manner as the deprotection group reaction in Method C. [J method]

[Chemical formula 22] [Each symbol in the formula has the same meaning as described above. In this method, compound (VIII) or a salt thereof is treated with compound (XV
After producing (XIX) by reacting with III), a compound (III-6) is produced by subjecting it to elimination reaction of a carboxy protecting group. This reaction is performed in the same manner as in Method I. The starting compound (II) for Method A is also produced by the following method.

[K method]

[Chemical formula 23] [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 a protecting group usually used in the field of peptide synthesis, for example, an oxycarbonyl derivative, and preferably benzyloxycarbonyl is used. In this method, compound (XX) or a reactive derivative at a carboxyl group or a salt thereof is reacted with compound (XXI) or a reactive derivative at an amino group or a salt thereof to produce (XXII), and then carboxyl protection is performed. The compound (XX
III) is manufactured. Compound (XX) or a reactive derivative at a carboxyl group or a salt thereof, and compound (XXI)
Alternatively, the reaction of the amino group with its reactive derivative or its salt is carried out in the same manner as in Method B. Compound (XXI
The carboxyl protecting group elimination reaction of I) can be carried out using the method described in Method C. A compound (XXIII) or a reactive derivative at a carboxyl group or a salt thereof is reacted with an amine derivative or a salt thereof to produce a compound (XXIV), which is then subjected to an elimination reaction of an amino protecting group to give a compound (XXV). To manufacture. The reaction of the compound (XXIII) or the reactive derivative at the carboxyl group or its salt with the amine derivative or its salt is carried out in the same manner as in Method B. The amino protecting group elimination reaction of compound (XXIV) 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). The reaction temperature is not particularly limited, and the reaction is usually performed under cooling, at room temperature or under heating. Then, the compound (XXV) is acylated in the same manner as in the reaction between the compound (VIII) and the compound (IX) in the method D or the reaction between the compound (XIII) and the compound (XIV) in the method G, and the compound (VIII) in the method E is used. ) And the compound (XI) in the same manner as in the reaction of the compound (VIII) and the compound (XV) in the H method, and the compound (VIII) and the compound (XV in the method I in the same manner as the reaction of the compound (VIII).
Carbamoylation is carried out in the same manner as in the reaction of I), and thiocarbamoylation is carried out in the same manner as in the reaction of the compound (VIII) and the compound (XVIII) in the J method to produce the compound (II).

In the present invention, the compound of the general formula (Ia) or (I) is blended in an effective amount with a physiologically acceptable carrier to give a solid preparation such as tablets, capsules, granules and powders; or It can be orally or parenterally administered as a liquid preparation such as a syrup or an injection. As the pharmaceutically acceptable carrier, various organic or inorganic carrier substances that are commonly used as a formulation material are used. Excipients, lubricants, binders, disintegrants in solid formulations; solvents and solubilizing agents in liquid formulations , A suspending agent, a tonicity agent, a buffering agent, a soothing agent, etc. If necessary, formulation additives such as antiseptics, antioxidants, coloring agents and sweeteners can also be used. Preferable examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D
-Mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.

Preferable examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glyceryl monostearate; Examples thereof include hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose. Preferable examples of the isotonicity agent include sodium chloride, glycerin, D-mannitol and the like. Preferable examples of the buffer include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Preferred examples of the soothing agent include benzyl alcohol and the like. As a preferable example of the preservative,
Examples thereof include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfite, ascorbic acid and the like. The compounds represented by the general formulas (I), (Ia), (I ′) and (I ″) or salts thereof may be used orally, parenterally, by inhalation method, rectal injection or topical administration. And can be used as a pharmaceutical composition or formulation (for example, powder, granules, tablets, pills, capsules, injections, syrups, emulsions, elixirs, suspensions, solutions, etc.). At least one compound of the present invention can be used alone or in combination with a pharmaceutically acceptable carrier (adjuvant, excipient, excipient and / or diluent, etc.).

The pharmaceutical composition can be formulated according to a conventional method. As used herein, parenteral refers to
It includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection or infusion. Injectable preparations, for example,
Sterile injectable aqueous or oleaginous suspensions may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally administrable diluent or solvent, such as an aqueous solution. As the vehicles or solvents that can be used, water,
Examples thereof include Ringer's solution and isotonic saline solution. Further, aseptic non-volatile oil may be used as a solvent or suspending solvent. Any non-volatile oil or fatty acid can be used for this purpose, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural or synthetic or semi-synthetic mono-, di- or triglycerides. A suppository for rectal administration is a drug and a suitable non-irritating excipient such as cocoa butter and polyethylene glycols, which are solid at room temperature but liquid at the temperature of the intestinal tract and melt in the rectum. It can be manufactured by mixing with a substance that emits. Examples of solid dosage forms for oral administration include powders, granules, tablets, pills, capsules and the like described above. In such dosage forms, the active ingredient compound is at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectin. , Tragacanth gums, gum arabic, gelatins, collagens,
It can be mixed with casein, albumin, synthetic or semi-synthetic polymers or glycerides. Such dosage forms can also, as usual, contain further additives, for example inert diluents, lubricants such as magnesium stearate, parabens, preservatives such as sorbic acid,
Examples thereof include antioxidants such as ascorbic acid, α-tocopherol and cysteine, disintegrating agents, binding agents, thickening agents, buffering agents, sweetening agents, flavoring agents and perfume agents. Tablets and pills can also be manufactured with enteric coating. Liquid preparations for oral administration include pharmaceutically acceptable emulsion preparations, syrup preparations, elixir preparations, suspension preparations, solution preparations and the like, which contain an inert diluent commonly used in the art, such as water. You can stay.

The dose for a particular patient depends on age, weight,
These factors and other factors are taken into consideration depending on the general health condition, sex, diet, administration time, administration method, excretion rate, drug combination, and the degree of the medical condition being treated by the patient at that time or other factors. The compounds represented by the general formulas (I), (Ia), (I ') and (I ") or salts thereof have a strong cathepsin L inhibitory action and therefore have an excellent bone resorption inhibitory action and low toxicity. Therefore, the compounds (I), (Ia), (I ') and (I ") of the present invention can be used in mammals (eg, mouse, rat, rabbit,
It can be advantageously used for prevention or treatment of osteoporosis in dogs, cats, cattle, pigs, humans, etc.). This compound (I), (I
When a), (I ') and (I ") or a salt thereof is used as a prophylactic / therapeutic agent for osteoporosis, the daily dose varies depending on the patient's condition, body weight, type of compound, administration route, etc. , Adult (50 kg) daily dose is
In the case of oral administration, about 1 to about 500 mg, preferably about 10
About 500 mg, about 1 to about 300 for parenteral administration
mg, preferably about 5 to about 100 mg.

[0050]

BEST MODE FOR CARRYING OUT THE INVENTION Next, the effects of the compounds (Ia) and (I) will be described with reference to experimental examples. Experimental Example 1 (Measurement of human cathepsin L inhibitory activity) Purified recombinant human cathepsin L was diluted with Diluent [0.1% B
rij35 (manufactured by Sigma)] and adjusted to a concentration of 1 μg / ml. Diluent 46 μl, 0.1M DTT 2 in 1 μl of this enzyme dilution
μl and 25 μl activator / buffer (340 mM sodium acetate, 60 mM acetic acid, 4 mM EDTA disodium salt, pH
5.5) was added and mixed. To this, 1 μl of the sample diluted to 10 ^-2 M with dimethyl sulfoxide (DMSO), 20 μM ZP
Add 25 μl of he-Arg-NHMec (enzyme substrate solution) and add 10 at 30 ℃.
After incubating for minutes, 100 μl of a reaction stop solution (100 mM sodium monochloroacetate, 30 mM sodium acetate, pH 4.3) was added. The above reaction was performed on a 96-well fluoro plate (manufactured by Lab Systems). After stopping the reaction, fluorescence measuring instrument F
Free amino-methylc using CA (Baxter)
oumarin fluorescence at wavelength 450 obtained by excitation at wavelength 365 nm
The fluorescence at nm was measured. In addition, 1 DMSO containing no sample
What added μl was used as a control of the experiment, and the fluorescence measurement value obtained in this reaction was defined as 100% activity. When the residual activity is 10% or less, the diluted sample solution is used to measure the residual activity according to the above procedure, and the IC ₅₀ value is calculated.
The results are shown in [Table 1].

[0051]

[Table 1] Experimental Example 2 (Bone resorption inhibitory effect) The bone resorption effect was measured by Royce's method [Journal of
Clinical Investigation (J.Clin.Inves
t.), 44 , 103-116 (1965)]. Ie pregnancy 1
On day 8, one Sprague-Dawley rat was subcutaneously injected with 50 μCi of ⁴⁵ Ca (isotope of calcium, CaCl ₂ solution),
On the next day, the abdomen was opened and the fetal rat was taken out aseptically, and the left and right forearm bones (radius and ulna) of the fetal rat were cut off from the trunk under a dissecting microscope, and further, connective tissue and cartilage were removed as much as possible to obtain a bone culture sample. Fitton-Jackson modification
(BGJb medium; GIBCO Laboratories, USA) 0.6 ml medium supplemented with bovine serum albumin (final concentration 2 mg / ml)
Bone was added to each of the cells and cultured at 37 ° C for 24 hours. The bone was cultured for 2 days in the medium containing the compound (final concentration 10 μM). Released from bone into medium
⁴⁵ Ca ratio of (%) was determined according to the following equation by measuring the radioactivity of ⁴⁵ Ca ⁴⁵ radioactivity and in bone Ca in medium.

[Equation 1] Bone from a litter of fetuses was similarly tested without compound 2
Those that were cultured for a day were used as a symmetric group. The average value ± standard deviation of the values obtained from 5 bones in each group was calculated, and the ratio (%) of this value to the value of the symmetric group was calculated and shown in [Table 2].

[Table 2]

[0052]

The present invention will be described in detail below with reference to reference examples and examples, but the present invention is not limited thereto. The optical rotation was measured at 20 to 25 ° C. Room temperature means 15-25 ° C. In the following Reference Examples and Examples, the constituent amino acids used are L-forms unless otherwise specified, and in the case of abbreviations, Gly: glycine; Leu: leucine; Il.
e: IUPAC (International U
nion of Pure and Applied Chemistry) -IUB (Inter
It is described according to the naming convention of the National Union of Biochemistry. Example 1 N-benzyloxycarbonyl-L-isoleucyl- (2R, 3S)-
3-Amino-2-hydroxy-4-phenylbutanoic acid benzylamide (5.0 g) was dissolved in a mixed solvent of dimethyl sulfoxide (DMSO) (20 ml) and toluene (60 ml). 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD.HCl) (5.4 g) and trifluoroacetic acid pyridine salt (1.6 g) were added to this solution at room temperature. After stirring for 1 hour, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with aqueous citric acid solution, water, aqueous NaHCO ₃ , and brine, and dried (MgS
O ₄ ). The solvent was evaporated under reduced pressure, the resulting pale yellow solid was washed with ethyl acetate-hexane, N-benzyloxycarbonyl-L-isoleucyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid benzylamide (4.15 g, 83%) of a white solid was obtained. Melting point 201-202 ° C. [α] _D = -33.5 ° (c 0.35, MeOH)
(20 ° C). Elemental analysis Calculated value as C ₃₁ H ₃₅ N ₃ O ₅ : C, 70.30; H, 6.66; N, 7.93 Analytical value: C, 70.12; H, 6.48; N, 8.12 Example 2 In the same manner as Example 1, N-[(3S) -3-dibenzylacetylamino-2-oxo-4-phenylbutyryl] -L-leucine methyl ester was obtained. Melting point 120-121 ° C. [α] _D = -7.5 ° (c
0.48, MeOH) (20 ° C).

Example 3 In the same manner as in Example 1, N-[(3S) -3-dibenzylacetylamino-2-oxo-4-phenylbutyryl] -L-leucine benzylamide was obtained. Melting point 172-174 ° C. [α] _Hg = + 37.5 °
(c 0.31, DMSO) (20 ° C). Example 4 In the same manner as in Example 1, (3S) -3-dibenzylacetylamino-2-oxo-4-phenylbutanoic acid benzylamide was obtained. Melting point 157-158 ° C. [α] _D = -24.6 ° (c 0.50, MeOH). Example 5 In the same manner as in Example 1, N-[(3S) -3-dibenzylacetylamino-2-oxo-4-phenylbutyryl] -β-methyl-L-aspartic acid benzylamide was obtained. Melting point 178-179 ° C.
[α] _Hg = + 54.4 ° (c 0.60, DMSO) (20 ° C). Example 6 N-[(3S) -3-dibenzylacetylamino-2-oxo-4-phenylbutyryl] -β-methyl-L-aspartic acid benzylamide (0.30 g) was dissolved in tetrahydrofuran (THF) (6 ml) and methanol (4 ml). ) Was dissolved in a mixed solvent. An aqueous solution of potassium hydroxide (65 mg) was added to this solution under ice cooling. 5 under ice cooling
After stirring for an hour, the reaction solution was acidified with 1N-hydrochloric acid and extracted with ethyl acetate. The organic layer was dried (MgSO ₄ ) and the solvent was evaporated under reduced pressure. The obtained pale yellow oily substance was crystallized from ethyl acetate-hexane to give N-[(3S) -3-dibenzylacetylamino-2-oxo-4-phenylbutyryl] -L-aspartic acid benzylamide (0.18 g, 61 %) White crystals were obtained. Melting point 178 ー
179 ° C. [α] _Hg = + 54.4 ° (c 0.60, DMSO) (20 ° C).

Example 7 In the same manner as in Example 1, N- (1-naphthalenesulfonyl) -L
-Isoleucyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid benzylamide colorless crystals were obtained. Melting point 183-185
° C. [α] _D = + 28.5 ° (c 0.35, DMSO) (20 ° C). Example 8 In the same manner as in Example 1, N-benzyloxycarbonyl-L
A white solid of -isoleucyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid 2-pyridylmethylamide was obtained. Melting point 164-165 ° C. [α] _Hg = + 31.5 ° (c 0.60, DMSO) (20 ° C). Example 9 In the same manner as in Example 1, N-benzyloxycarbonyl-L
A white solid of -isoleucyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid 4-pyridylmethylamide was obtained. Melting point 204-205 ° C. [α] _D = −1.4 ° (c 0.74, DMSO) (20 ° C.). Example 10 In the same manner as in Example 1, N-benzyloxycarbonyl-L
A light yellow solid of isoleucyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid p-diethylphosphonomethylphenylamide was obtained. Melting point 139-140 ° C. [α] _D = -6.4 ° (c 0.8
8, DMSO) (20 ° C). Example 11 In the same manner as in Example 1, N-benzyloxycarbonyl-L
A white solid of -isoleucyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid isobutyramide was obtained. Melting point 215 ー
216 ° C. [α] _D = + 9.9 ° (c 1.00, DMSO) (20 ° C).

Example 12 In the same manner as in Example 1, N-benzyloxycarbonyl-L
A white solid of -isoleucyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid 3- (2-oxopyrrolidin-1-yl) propylamide was obtained. Melting point 268-269 ° C. [α] _D = + 2.5 ° (c
0.93, DMSO) (20 ° C). Example 13 In the same manner as in Example 1, N- (quinoline-2-carbonyl) -L-
White crystals of isoleucyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid benzylamide were obtained. Melting point 181-182
° C. [α] _D = + 34.5 ° (c 0.79, DMSO) (20 ° C). Example 14 In the same manner as in Example 1, a white solid of N- (p-diethylphosphonomethylcinnamoyl) -L-isoleucyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid benzylamide was obtained. Melting point 207-209 ° C. [α] _D = + 22.7 ° (c 0.893, DMSO) (20
° C). Example 15 In the same manner as in Example 1, N- (1-naphthalenesulfonyl) -L
A colorless crystal of -phenylalanyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid benzylamide was obtained. Melting point 18
9-191 ° C. [α] _D = + 11.9 ° (c 0.87, DMSO) (20 ° C). Example 16 In the same manner as in Example 1, N- (1-naphthalenesulfonyl) -L
-Isoleucyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid 4-pyridylmethylamide colorless crystals were obtained. Melting point 162-163 ° C. [α] _D = + 16.9 ° (c 0.38, DMSO) (20 ° C).

Examples 17 to 27 In the same manner as in Example 1, the compounds shown in Table 3 were obtained.

[Table 3] 1) 1/4 hydrate, 2) 1/2 hydrate, 3) [α] Hg value Val = valine, Phe = phenylalanine, Leu = leucine, Il
e = isoleucine, Ph = phenyl, Cbz = benzyloxycarbonyl, 1-Nap = 1-naphthalenesulfonyl, 2-Qnl = quinoline-2-carbonyl, DMF = N, N-dimethylformamide, D
MSO = dimethyl sulfoxide

Reference Example 1 N-benzyloxycarbonyl-L-isoleucyl- (2R, 3S)-
3-Amino-2-hydroxy-4-phenylbutanoic acid benzylamide (4.7g) and 5% Pd-C (2.5g) were added to tetrahydrofuran (TH
F) (20 ml) and a mixed solvent of methanol (20 ml) were added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hr. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (DMF) (30 ml). Α-naphthalenesulfonyl chloride (2.1 g) and N, N-dimethylaminopyridine (1.2 g) were added to this solution under ice cooling. After stirring for 15 hours under ice cooling, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with an aqueous citric acid solution, water, an aqueous NaHCO ₃ solution, and a saline solution, and dried (MgSO ₄ ). The solvent was evaporated under reduced pressure, the obtained residue was washed with ethyl acetate, N- (1-naphthalenesulfonyl) -L-isoleucyl- (2R, 3S) -3-amino-2-hydroxy-4-phenylbutanoic acid benzylamide (4.75 g) colorless crystals were obtained. Melting point 178-179 ° C. [α] _D = + 5.7 ° (c 0.5
2, DMSO) (20 ° C). Elemental analysis Calculated as C ₃₃ H ₃₇ N ₃ O ₅ S: C, 67.44; H, 6.35; N, 7.15 Analytical value: C, 67.22; H, 6.45; N, 7.15 Reference example 2 Same as reference example 1 , N- (1-naphthalenesulfonyl) -L-
Colorless crystals of phenylalanyl- (2R, 3S) -3-amino-2-hydroxy-4-phenylbutanoic acid benzylamide were obtained.
Melting point 210-211 ° C. [α] _D = -40.1 ° (c 0.76, DMSO) (20 ° C).

Reference Example 3 In the same manner as in Reference Example 1, N- (1-naphthalenesulfonyl) -L-
Colorless crystals of isoleucyl- (2R, 3S) -3-amino-2-hydroxy-4-phenylbutanoic acid 4-pyridylmethylamide were obtained. Melting point 210-211 ° C. [α] _D = -3.2 ° (c 0.21, DMSO) (20
° C). Reference Example 4 N-benzyloxycarbonyl-L-isoleucyl- (2R, 3S)-
3-Amino-2-hydroxy-4-phenylbutanoic acid benzylamide (4.5 g) and 5% Pd-C (2.2 g) were added to tetrahydrofuran (TH
F) (30 ml) and a mixed solvent of methanol (30 ml) were added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue and quinoline-2-carboxylic acid (1.54 g) were dissolved in N, N-dimethylformamide (DMF) (40 ml). 1-Hydroxybenzotriazole (HOBt) (1.43 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCDHCl) (1.79 g) were added to this solution under ice cooling.
g) was added. After stirring at room temperature for 16 hours, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer is an aqueous citric acid solution,
Wash sequentially with water, NaHCO ₃ aqueous solution, and brine, then dry (MgSO ₄ ).
did. The solvent was evaporated under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (4: 1) from a portion eluted with N- (quinoline-2-carbonyl) -L-isoleucyl- (2R, 3S) -3-Amino-2-hydroxy-4
-Phenylbutanoic acid benzylamide (4.2 g) was obtained as colorless crystals. Melting point 157-158 [deg.] C. [α] _D = + 2.6 ° (c0.87, MeOH) (20
° C). Elemental analysis Calculated as C ₃₃ H ₃₆ N ₄ O ₄ : C, 71.72; H, 6.57; N, 10.14 Analytical value: C, 71.68; H, 6.58; N, 10.05

Reference Example 5 In the same manner as in Reference Example 4, a pale yellow color of N- (4-diethylphosphonomethylcinnamoyl) -L-isoleucyl- (2R, 3S) -3-amino-2-hydroxy-4-phenylbutanoic acid benzylamide was obtained. Crystals were obtained. Melting point 153-154 ° C. [α] _D = -14.8 ° (c 0.76, Me
OH) (20 ° C). Reference Example 6 N-benzyloxycarbonyl- (2R, 3S) -3-amino-2-hydroxy-4-phenylbutanoic acid (3.0 g) and L-isoleucine methyl ester hydrochloride (1.74 g) N, N-dimethyl Formamide (DMF) solution under ice cooling, triethylamine (1.4 ml), 1
-Hydroxybenzotriazole (HOBt) (1.54g) and 1-
Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD.HCl) (1.92g) was added. After stirring at room temperature for 16 hours, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed successively with an aqueous citric acid solution, water, an aqueous NaHCO ₃ solution, and a saline solution, and dried (MgSO ₄ ). The solvent was evaporated under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (2: 1) from the portion eluted with N-
Colorless crystals of [(2R, 3S) -2-benzyloxycarbonylamino-3-hydroxy-4-phenylbutyryl] -L-isoleucine methyl ester (2.3 g) were obtained. Melting point 120-121 ° C. [α] _D =
-58.5 ° (c 0.78, MeOH) (20 ° C). Elemental analysis C ₂₅ H ₃₂ N ₂ O ₆ Calculated: C, 65.77; H, 7.06 ; N, 6.14 Analytical values: C, 65.78; H, 6.95 ; N, 6.08

Reference Example 7 In the same manner as in Reference Example 4, colorless crystals of N-[(2R, 3S) -2-dibenzylacetylamino-3-hydroxy-4-phenylbutyryl] -L-isoleucine methyl ester were obtained. Obtained. Melting point 130-
131 ° C. [α] _D = -47.8 ° (c 0.63, MeOH) (20 ° C). Reference Example 8 In the same manner as in Reference Example 4, colorless needle-like crystals of (2R, 3S) -2-dibenzylacetylamino-3-hydroxy-4-phenylbutanoic acid methyl ester were obtained. Melting point 107-108 ° C. [α] _D = -8
4.8 ° (c 0.53, MeOH) (20 ° C). Reference Example 9 (2R, 3S) -2-dibenzylacetylamino-3-hydroxy-4-
An aqueous solution of potassium hydroxide (1.2 g) was added dropwise to a mixed solvent of tetrahydrofuran (THF) (20 ml) and methanol (10 ml) of phenylbutanoic acid methyl ester (4.3 g) under ice cooling.
After stirring under ice cooling for 6 hours, the reaction solution was acidified with 1N-hydrochloric acid. After extraction with ethyl acetate, the organic layer was washed with brine and dried (MgSO _4). The solvent was evaporated under reduced pressure, the obtained white solid was recrystallized from ethyl acetate-hexane to give (2R, 3S) -2-dibenzylacetylamino-3-hydroxy-4-phenylbutanoic acid (3.0 g). Colorless crystals were obtained. Melting point 128-130 ° C. [α] _D =
-60.3 ° (c 0.38, CHCl ₃ ) (20 ° C). Elemental analysis _{C 26 H 27 NO 4 · 1} / 4H 2 O Calculated: C, 74.00; H, 6.57 ; N, 3.32 Analytical values: C, 74.09; H, 6.50 ; N, 3.17

Reference Example 10 In the same manner as in Reference Example 6, colorless crystals of (2R, 3S) -2-dibenzylacetylamino-3-hydroxy-4-phenylbutanoic acid benzylamide were obtained. Melting point 148-149 ° C. [α] _D = -15.7 °
(c 0.99, MeOH) (20 ° C). Reference Example 11 In the same manner as in Reference Example 9, colorless crystals of N-[(2R, 3S) -2-dibenzylacetylamino-3-hydroxy-4-phenylbutyryl] -L-isoleucine were obtained. Melting point 93-94 ° C. [α] _D = -35.9 °
(c 0.65, DMSO) (20 ° C). Reference Example 12 In the same manner as in Reference Example 6, colorless crystals of N-[(2R, 3S) -2-dibenzylacetylamino-3-hydroxy-4-phenylbutyryl] -L-isoleucine benzylamide were obtained. Melting point 156-15
8 ° C. [α] _D = -49.5 ° (c 0.61, MeOH) (20 ° C). Reference Example 13 In the same manner as in Reference Example 4, N-benzyloxycarbonyl-L
Colorless crystals of -isoleucyl- (2R, 3S) -3-amino-2-hydroxy-4-phenylbutanoic acid methyl ester were obtained. Melting point
128-130 ℃. [α] _D = -77.1 ° (c 0.36, DMSO) (20 ° C). Reference Example 14 In the same manner as in Reference Example 9, N-benzyloxycarbonyl-L
A white solid of -isoleucyl- (2R, 3S) -3-amino-2-hydroxy-4-phenylbutanoic acid was obtained. Melting point 180-181 ° C. [α] _D = -64.3 ° (c 0.43, DMSO) (20 ° C). Reference Example 15 In the same manner as in Reference Example 6, N-benzyloxycarbonyl-L
A white solid of -isoleucyl- (2R, 3S) -3-amino-2-hydroxy-4-phenylbutanoic acid benzylamide was obtained. Melting point 178-179 ° C. [α] _D = -21.8 ° (c 0.52, MeOH) (20 ° C). Reference Example 16 In the same manner as in Reference Example 6, N-benzyloxycarbonyl-L
A white solid of 2-isoleucyl- (2R, 3S) -3-amino-2-hydroxy-4-phenylbutanoic acid 2-pyridylmethylamide was obtained. Melting point 156-157 ° C. [α] _D = -22.2 ° (c 0.47, DMSO) (20
° C). Reference Example 17 In the same manner as in Reference Example 6, N-benzyloxycarbonyl-L-
A white solid of isoleucyl- (2R, 3S) -3-amino-2-hydroxy-4-phenylbutanoic acid 4-pyridylmethylamide was obtained. Melting point 223-225 ° C. [α] _D = -21.5 ° (c 0.60, DMSO) (20
° C). Reference Example 18 In the same manner as in Reference Example 6, N-benzyloxycarbonyl-L
A white solid of -isoleucyl- (2R, 3S) -3-amino-2-hydroxy-4-phenylbutanoic acid 4-diethylphosphonomethylphenylamide was obtained. Melting point 145-146 ° C. [α] _D = -31.1 ° (c
0.89, DMSO) (20 ° C). Reference Example 19 In the same manner as in Reference Example 6, N-benzyloxycarbonyl-L
-Isoleucil- (2R, 3S) -3-amino-2-hydroxy-4-phenylbutanoic acid Isobutyramide white solid was obtained. Melting point 185-186 ° C. [α] _D = -40.7 ° (c 0.57, DMSO) (20 ° C).

Reference Example 20 In the same manner as in Reference Example 6, N-benzyloxycarbonyl-L-
A white solid of isoleucyl- (2R, 3S) -3-amino-2-hydroxy-4-phenylbutanoic acid 3- (2-oxopyrrolidin-1-yl) propylamide was obtained. Melting point 153-154 ° C. [α] _D = -35.
2 ° (c 0.59, MeOH) (20 ° C). Reference Example 21 L-phenylalaninol (15.1 g) and triethylamine (1
4.7 ml) to dichloromethane (50 ml) and tetrahydrofuran (T
HF) (50 ml). To this suspension under ice cooling,
Ethyl chloroformate (9.5 ml) was added dropwise. After stirring at room temperature for 1 hour, the reaction solution was concentrated. Ethyl acetate was added to the residue,
After washing with water and brine, dried (MgSO _4). The solvent was distilled off under reduced pressure, and the obtained residue was dimethyl sulfoxide (DMSO).
It was dissolved in a mixed solvent of (100 ml) and dichloromethane (50 ml). Next, triethylamine (35 ml) was added to this solution,
Chilled with ice. After a solution of sulfur trioxide / pyridine complex (40 g) in dimethyl sulfoxide (DMSO) (160 ml) was added dropwise, the reaction solution was stirred at the same temperature for 2 hours. The solution was poured into ice water and extracted with ethyl acetate. The organic layer is an aqueous citric acid solution, water, NaHCO ₃
Washed successively with an aqueous solution, and dried (MgSO _4). The solvent was distilled off under reduced pressure, and the obtained yellow oily substance was diluted with dichloromethane (300 ml).
And a mixture of water (300 ml). Then, sodium cyanide (5.3 g), acetic anhydride (10.3 ml) and benzyltributylammonium chloride (7.5 g) were added, and the mixture was vigorously stirred at room temperature for 5 hours. Separate the organic layer, wash with brine, and dry.
(MgSO ₄₎ was. The solvent was evaporated under reduced pressure, the resulting yellow oil was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 2) from (2S) -1-cyano-2-ethoxycarbonylamino. -3-phenylpropyl
Diastereomeric mixture of acetate (R: S = 5: 2) (19.9 g)
A pale yellow oily substance was obtained. 1H-NMR (δ ppm in CDCl ₃ ): 1.21 & 1.26 (3H, each t, J =
7.0Hz), 2.13 & 2.17 (3H, each s), 2.8-3.2 (2H, m), 4.0-
4.2 (2H, m), 4.2-4.5 (1H, m), 4.7-5.0 (1H, m), 5.38 & 5.4
0 (1H, each d, J = 5.8Hz), 7.1-7.4 (5H, m).

Reference Example 22 (2S) -1-Cyano-2-ethoxycarbonylamino-3-phenylpropyl acetate (30 g) was added to 6N-hydrochloric acid (140 ml),
The mixture was heated under reflux for 3 days. The reaction solution was concentrated, the residue was added to a 2% -hydrochloric acid-methanol solution (200 ml), and the mixture was heated under reflux for 2 days. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in water. The aqueous solution was washed with ethyl acetate and then made basic with NaHCO ₃ . The aqueous layer was extracted twice with chloroform and the combined organic layers were dried (MgSO _4). The solvent was evaporated under reduced pressure, the obtained brown solid was recrystallized from ethyl acetate-hexane, and (3S, 2
Colorless needle crystals of (R) -3-amino-2-hydroxy-4-phenylbutanoic acid methyl ester (9.0 g) were obtained. Melting point: 108-109
° C. [α] _D = -34.2 ° (c 0.60, MeOH) (20 ° C). Reference Examples 23 to 31 In the same manner as in Reference Example 4, the compounds in Table 4 were obtained.

[0064]

[Table 4] 1) hemihydrate, 2) 1/4 hydrate Val = valine, Leu = leucine, Ile = isoleucine, DMSO =
Dimethyl sulfoxide, Ph = phenyl, Cbz = benzyloxycarbonyl, 2-Qnl = quinoline-2-carbonyl,

Reference Example 32 (3S, 2R) -3-Amino-2-hydroxy-4-phenylbutanoic acid
A solution of methyl ester (3.3 g) and N-benzyloxycarbonyl-L-valine (4.2 g) in N, N-dimethylformamide (DMF) (40 ml) under ice-cooling 1-hydroxybenzotriazole (HOBt) ( 2.7 g) and 1-ethyl
-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
(WSCD.HCl) (3.4 g) was added. Mix the mixture at room temperature 18
After stirring for a time, the mixture was poured into ice water and extracted with ethyl acetate.
The ethyl acetate layer was washed with water, a citric acid aqueous solution, water, a NaHCO ₃ aqueous solution, and brine in this order, and dried (MgSO ₄ ). The solvent was distilled off under reduced pressure, and the remaining solid was collected by filtration with ethyl acetate-hexane, (2R, 3S) -3- [N- [N-benzyloxycarbonyl-L-valyl] amino] -2-hydroxy-4. -Phenylbutanoic acid methyl ester was obtained. Melting point 131-132 [deg.] C. [Α] _D −
98.3 ° (c = 0.33, CH ₃ OH). Reference Examples 33 to 37 In the same manner as in Reference Example 32, the compounds shown in Table 5 were obtained.

[0066]

[Table 5] Val = valine, Leu = leucine, Ph = phenyl, Cbz = benzyloxycarbonyl, DMSO = dimethylsulfoxide

Reference Examples 38 and 39 In the same manner as in Reference Example 9, compounds shown in Table 6 were obtained.

[Table 6] Val = valine, Leu = leucine, Cbz = benzyloxycarbonyl,

Reference Examples 40 and 41 In the same manner as in Reference Example 1, the compounds shown in Table 7 were obtained.

[Table 7] 1) Hemihydrate

Reference Example 42 N-benzyloxycarbonyl-L-phenylalaninol (2.0 g), triphenylphosphine (Ph ₃ P) (1.9
g), hydantoin (0.71 g) and tetrahydrofuran (THF) (50 ml) were added dropwise with diethyl azodicarboxylate (DEAD) (1.24 g) under ice cooling. After stirring for 16 hours at room temperature, the reaction mixture was poured into ethyl acetate, washed with water, NaHCO ₃ aqueous solution, and saturated saline in this order, and dried (MgS
O ₄ ). The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. From the portion eluted with ethyl acetate-hexane (3: 1, v / v), 1-[(2
S) -2- (N-benzyloxycarbonylamino) -3-phenylpropyl] hydantoin (1.15 g, 44%) was obtained. Melting point 159-160 [deg.] C. [Α] _D + 1.5 ° (c
= 0.79, CH ₃ OH).

[0070]

[Formulation example]

Formulation Example Compounds (I), (Ia), (I ') and (I ") referred to in the present invention
Alternatively, a cathepsin L inhibitor containing a salt thereof as an active ingredient can be produced, for example, by the following formulation. 1. Capsule (1) N- (p-diethylphosphonomethylcinnamoyl) -L-isoleucyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid benzylamide 10 mg (2) Lactose 90 mg (3 ) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2) and 1/2 of (3) and (4) are mixed and then granulated. The rest (4) is added to this and the whole is enclosed in a gelatin capsule. 2. Tablets (1) N-benzyloxycarbonyl-L-isoleucyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid benzylamide 10 mg (2) lactose 35 mg (3) corn starch 150 mg (4) microcrystals Cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1) 2/3 of (2), (3), (4) and 1 of (5)
After mixing / 2, granulate. Remaining (4) and (5)
Is added to the granules and pressed into tablets.

3. Injectable (1) N- (quinoline-2-carbonyl) -L-isoleucyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid benzylamide 10 mg (2) inosit 100 mg (3) benzyl alcohol 20 mg 1 ampoule 130 mg (1), (2) and (3) are dissolved in distilled water for injection so that the total amount becomes 2 ml, and the ampoule is sealed. All steps are performed aseptically. 4. Capsule (1) N- (1-naphthalenesulfonyl) -L-isoleucyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid 4-pyridylmethyl amide 10 mg (2) Lactose 90 mg (3) Fine Crystalline cellulose 70 mg (4) Magnesium stearate 10 mg 1 capsule 180 mg (1), (2) and 1/2 of (3) and (4) are mixed and then granulated. The rest (4) is added to this and the whole is enclosed in a gelatin capsule.

5. Tablets (1) N- (1-naphthalenesulfonyl) -L-phenylalanyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid benzylamide 10 mg (2) lactose 35 mg (3) corn starch 150 mg ( 4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg 1 tablet 230 mg (1) (2), (3), 2/3 of (4) and 1 of (5)
After mixing / 2, granulate. Remaining (4) and (5)
Is added to the granules and pressed into tablets. 6. Injectable (1) N-benzyloxycarbonyl-L-isoleucyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid isobutylamide 10 mg (2) Inosit 100 mg (3) Benzyl alcohol 20 mg 1 ampoule 130 mg ( Dissolve 1), (2), and (3) in distilled water for injection so that the total amount becomes 2 ml, and seal in an ampoule. All steps are performed aseptically.

[0073]

Industrial Applicability The compounds represented by the general formulas (I), (Ia), (I ') and (I ") or salts thereof have a strong cathepsin L inhibitory action, and therefore exhibit an excellent bone resorption inhibitory action. Therefore, it can be advantageously used for the prevention or treatment of osteoporosis in mammals.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 31/47 31/50 38/55 ADD C07C 237/06 9547-4H 237/22 9547-4H 333 / 02 7106-4H C07D 213/40 233/72 237/04 307/33 C07K 5/062 8517-4H 5/083 8517-4H

Claims (16)

[Claims] 1. A compound represented by the general formula (Ia): [Wherein, Q is a bond or an optionally substituted 1 or 2 amino acid residue, R ¹ is hydrogen or an optionally substituted hydrocarbon or heterocyclic group, and R ⁴ is an acyl group or In the optionally esterified carboxyl group, R ⁵ and R ⁶ are the same or different and each represents hydrogen or an optionally substituted hydrocarbon or heterocyclic group. R ⁵ and R ⁶ may combine with each other to form a ring], and a cathepsin L inhibitor comprising a compound represented by the formula: or a salt thereof. 2. The compound is represented by the general formula (I): [Wherein R ¹ , R ² and R ³ are the same or different,
Hydrogen or an optionally substituted hydrocarbon or heterocyclic group, R ⁴ is an acyl group or an optionally esterified carboxyl group, and R ⁵ and R ⁶ are the same or different and are hydrogen or substituted. Represents a hydrocarbon or a heterocyclic group which may be present. R ⁵ and R ⁶ may combine with each other to form a ring. m and n are the same or different and represent 0 or 1.] The cathepsin L inhibitor according to claim 1. 3. A compound represented by the general formula (I ′): [Wherein R ¹ , R ² and R ³ are the same or different,
Hydrogen or an optionally substituted hydrocarbon or heterocyclic group, R ^4a has the formula —COR ^a or —SO ₂ R ^b (wherein
R ^a and R ^b are the same or different and each represents an optionally substituted aryl or aromatic heterocyclic group), and R ^5a and R ^6a are the same or different and are substituted. An optionally substituted aryl or aromatic heterocyclic group or a linear or branched lower alkyl group optionally substituted with an optionally esterified carboxyl group, m and n are the same or different, and Or 1 is shown. However, when R ^a is an optionally substituted aromatic heterocyclic group, R ^5a and R ^6a are the same or different,
A linear or branched lower alkyl group substituted with an optionally substituted aryl or aromatic heterocyclic group or an optionally esterified carboxyl group]
Or a salt thereof. 4. R ¹ , R ² and R ³ 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
A hydrocarbon group selected from _3-7 cycloalkyl-C _1-8 alkyl, C _5-7 cycloalkenyl-C _1-8 alkyl and C _6-14 aryl or (B) containing 2 or less nitrogen atoms 6 (A) one sulfur atom, which may be condensed with a five-membered ring containing a member ring, a benzene ring or one sulfur atom,
5- to 7-membered aromatic heterocyclic group containing nitrogen atom or oxygen atom, 5- or 6-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms, or 1 to 2 nitrogen atoms and 1 sulfur atom or 5- or 6-membered aromatic heterocyclic group containing an oxygen atom or (b) one sulfur atom, nitrogen atom or a 5- to 7-membered non-aromatic heterocyclic group containing an oxygen atom or one nitrogen atom and 3 or less A heterocyclic group selected from a 4- to 7-membered non-aromatic heterocyclic group containing a hetero atom selected from nitrogen, oxygen and sulfur atoms, wherein said hydrocarbon and heterocyclic group are (i) hydroxyl group, C C _6-14 aryl which may be substituted with _1-3 alkoxy, halogen or C _1-3 alkyl, (ii) hydroxyl group, C _1-3 alkoxy, which may be substituted with halogen or C _1-3 alkyl C _3-7 cycloalkyl or C _3-6 Sik Alkenyl, a (iii) C _1-3 optionally substituted by alkyl, 1 sulfur atom, a nitrogen atom or a 5- to 7-membered aromatic heterocyclic group containing an oxygen atom, 2-4 nitrogen atoms A 5- or 6-membered aromatic heterocyclic group or a 5- or 6-membered aromatic heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur atom or oxygen atom, or 1 sulfur atom, nitrogen atom or oxygen atom A 5- to 7-membered non-aromatic heterocyclic group containing or a 4- to 7-membered non-aromatic heterocyclic group containing one nitrogen atom and a hetero atom selected from 3 or less nitrogen, oxygen and sulfur atoms A cyclic 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
^a and R ^b are the same or different and (A) a C _6-10 aryl group or (B) a 6-membered ring containing 2 or less nitrogen atoms,
5- to 7-membered aromatic heterocyclic group containing 1 sulfur atom, nitrogen atom or oxygen atom, which may be condensed with benzene ring or 5-membered ring containing 1 sulfur atom, 2 to 4 nitrogens 5- or 6-membered aromatic heterocyclic group containing atoms or 1-2
A 5- or 6-membered aromatic heterocyclic group containing 1 nitrogen atom and 1 sulfur atom or oxygen atom, wherein the aryl and aromatic heterocyclic group are C _1-6 alkyl, C _1-6 alkoxy, Optionally substituted with hydroxyl groups or halogens;
R ^5a and R ^6a are the same or different and each is a linear or branched C _1-6 alkyl group, wherein the alkyl group is
(A) C _6-10 aryl group, (B) 1-membered sulfur optionally condensed with a 6-membered ring containing 2 or less nitrogen atoms, a benzene ring or a 5-membered ring containing 1 sulfur atom A 5- to 7-membered aromatic heterocyclic group containing an atom, a nitrogen atom or an oxygen atom,
A 5- or 6-membered aromatic heterocyclic group containing 2 to 4 nitrogen atoms or a 5- or 6-membered aromatic heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur atom or oxygen atom,
The aryl and aromatic heterocyclic groups are C _1-6 alkyl,
It may be substituted with C _1-6 alkoxy, hydroxyl group or halogen, or (C) carboxyl, (lower (C
_1-6 ) Alkoxy) carbonyl, (C _6-10 aryloxy)
The compound according to claim 3, which is _optionally substituted with carbonyl or (C _7-13 aralkyloxy) carbonyl. 5. The compound according to claim 3, wherein the aryl group of R ^a and R ^b is naphthyl. 6. The compound according to claim 3, wherein the aromatic heterocyclic group for R ^a and R ^b is quinolyl. 7. The compound according to claim 3, wherein one of R ^5a and R ^6a is hydrogen and the other is benzyl. 8. The compound according to claim 3, wherein R ¹ is a phenyl-substituted linear or branched C _1-6 alkyl group. 9. The compound according to claim 3, wherein R ² and R ³ are the same or different and each is a linear or branched C _1-6 alkyl group. 10. N- (quinoline-2-carbonyl) -L-
Isoleucine- (3S) -3-amino-2-oxo-4-
Phenylbutanoic acid benzylamide or a salt thereof. 11. N- [N- (6-oxo-1,4,5,5
6-Tetrahydropyridazine-3-carbonyl) -L-
Leucyl]-(3S) -3-amino-2-oxo-4-
Phenylbutanoic acid benzylamide or a salt thereof. 12. N-benzyloxycarbonyl-L-leucyl-L-leucyl- (3S) -3-amino-2-oxo-4-phenylbutanoic acid benzylamide or a salt thereof. 13. N- (quinoline-2-carbonyl) -L
-Leucyl-L-leucyl- (3S) -3-amino-2
-Oxo-4-phenylbutanoic acid benzylamide or a salt thereof. 14. A compound represented by the general formula (I "): [Wherein R ¹ , R ² and R ³ are the same or different,
Hydrogen or an optionally substituted hydrocarbon or heterocyclic group, R ^4b is represented by the formula —COR ^c (wherein R ^c is a straight chain substituted by an optionally substituted aryl or aromatic heterocyclic group or A group represented by a branched lower alkyl group), R ^5b and R ^6b are the same or different, and are substituted with an optionally substituted aryl group or an optionally esterified carboxyl group. A linear or branched lower alkyl group, and m and n are the same or different and represent 0 or 1, or a salt thereof. 15. A composition containing the compound according to claim 3. 16. A composition containing the compound according to claim 14.