JP2002234850A - Combined medicament - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a combined anti-septicemic medicament. SOLUTION: This combined medicament is obtained by combining the anti- septicemic medicament (for example, a cycloalkene compound) with one or more kinds of medicaments selected from a group comprising antibacterial, antifungal, nonsteroidal anti-inflammatory, steroidal, and anticoagulant medicaments.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a cycloalkene compound concomitant useful as an anti-sepsitic agent and the like, and a method for treating sepsis and the like.

[0002]

2. Description of the Related Art WO99 / 46242 has the following formula (i):

[0003]

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[Wherein R is an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, and a heterocyclic ring which may have a substituent Group, formula: -O
A group represented by R ¹ (wherein, R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent) or a formula represented by the following formula:

[0005]

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(Wherein, R ^1b is a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent, and R ^1c is the same or different from R ^1b and has a hydrogen atom or a substituent. Represents a good aliphatic hydrocarbon group.)
R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R ¹ and R ⁰ together form a bond, and ring A is (1) an aliphatic hydrocarbon group which may have a substituent. Hydrogen group,
(2) an aromatic hydrocarbon group which may have a substituent,
(3) a group represented by the formula: -OR ¹¹ (wherein, R ¹¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent) and (4) a halogen atom. 1-4
Represents an optionally substituted cycloalkene, Ar represents an aromatic hydrocarbon group which may have a substituent, and has the formula:

[0007]

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The group represented by the formula:

[0009]

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Wherein n is an integer of 1 to 4. And a compound represented by the formula (ii):

[0011]

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[Wherein, R ^a represents an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent. Ring group, formula:-
OR ^1a (wherein, R ^1a represents a hydrogen atom or an optionally substituted aliphatic hydrocarbon group) or a group represented by the formula:

[0013]

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[0014] (wherein, R ^4a and R ^5a are the same or different. Represents a hydrogen atom or an optionally substituted aliphatic hydrocarbon group) a group represented by, R ^0a is Represents a hydrogen atom or an aliphatic hydrocarbon group, or R ^a and R ^0a together form a bond, and Ar ^a represents an aromatic hydrocarbon group which may have ^a substituent; :

[0015]

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The group represented by the formula:

[0017]

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Wherein n is an integer of 1 to 4. And salts of these compounds and their prodrugs have an inhibitory effect on the production of nitric oxide (NO) and an inhibitory effect on the production of inflammatory cytokines such as TNF-α, IL-1, and IL-6. It is described as being useful as a prophylactic / therapeutic agent for diseases such as heart disease, autoimmune disease, inflammatory disease, central nervous system disease, infectious disease, sepsis and septic shock.

[0019]

SUMMARY OF THE INVENTION An object of the present invention is to provide a concomitant agent of a cycloalkene compound useful as an antisepsitic agent and the like, and a method of treating sepsis and the like.

[0020]

Means for Solving the Problems In view of the above problems, the present inventors have conducted intensive studies, and as a result, have found that the above cycloalkene compounds, antibacterial drugs, antifungal drugs, nonsteroidal antiinflammatory drugs, steroids It has been found that diseases such as sepsis can be effectively treated by using a drug, an anticoagulant or the like in combination. The present inventors have further studied based on this finding, and as a result, have completed the present invention.

That is, the present invention relates to [1] an anti-sepsis drug, and at least one drug selected from the group consisting of antibacterial drugs, antifungal drugs, non-steroidal anti-inflammatory drugs, steroid drugs and anticoagulants. A medicine comprising a combination of [2]
The medicament of the above-mentioned [1], wherein the anti-sepsis drug is a non-peptidic compound, [3] the medicament of the above-mentioned [1], wherein the anti-sepsis drug is a cycloalkene compound, [4]
(I):

[0022]

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[Wherein, R is an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, and a heterocyclic ring which may have a substituent Group, formula: -O
A group represented by R ¹ (wherein, R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent) or a formula represented by the following formula:

[0024]

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[0025] (wherein, R ^1b and R ^1c are the same or different and represent a hydrogen atom or an optionally substituted aliphatic hydrocarbon group.) A group represented by, R ⁰ is Represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R
And a bond is formed by bonding with ^0, and ring A ¹ is (1) an aliphatic hydrocarbon group which may have a substituent, and (2) an aromatic hydrocarbon which may have a substituent. Group, formula (3): -OR ¹¹
(Wherein, R ¹¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent.) And 1 to 4 groups selected from the group consisting of (4) halogen atoms A cycloalkene which may be substituted with a substituent,
Ar represents an aromatic hydrocarbon group which may have a substituent, and has the formula:

[0026]

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The group represented by the formula:

[0028]

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Wherein n is an integer of 1 to 4. Is a compound or a salt thereof or a prodrug represented by the pharmaceutical above [1], [in 5] Formula (I), R is formula: -OR ¹ (wherein, R ¹ represents the [4] R ⁰ is a hydrogen atom or an aliphatic hydrocarbon group, ring A ¹ is unsubstituted cyclohexene, and Ar is an aromatic group which may have a substituent. The pharmaceutical of the above-mentioned [4], which is a group hydrocarbon group and n is 2;
[6] The anti-sepsis drug has the formula (II):

[0030]

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[Wherein R ^{1 ′} is an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, or a substituent which may have a substituent. Heterocyclic group, formula:-
OR ^{1a ′} (wherein, R ^{1a ′} represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent) or a group represented by the formula:

[0032]

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Wherein R ^{1b ′} and R ^{1c ′} are the same or different and each represent a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent. Represents a methylene group, NH, a sulfur atom or an oxygen atom, Y represents an optionally substituted methylene group or an optionally substituted NH, and ring A ′ represents (1) a substituent An aliphatic hydrocarbon group which may have (2) an aromatic hydrocarbon group which may have a substituent, (3) a formula: —OR ^{2 ′} (where R ^{2 ′} is a hydrogen atom Or an aliphatic hydrocarbon group which may have a substituent (s).) And (4) 1 to 4 substituents selected from the group consisting of halogen atoms. A 5- to 8-membered ring, and Ar 'represents an aromatic hydrocarbon group which may have a substituent;

[0034]

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The group represented by the formula:

[0036]

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Wherein s is an integer of 0 to 2, t is an integer of 1 to 3, and the sum of s and t is 4 or less; provided that when X is a methylene group, And Y represent a methylene group which may have a substituent. Is a compound or a salt thereof or a prodrug represented by the pharmaceutical above [1], [in 7] formula (II), R 1 ^'has the formula: -OR
^{1a ′} (wherein R ^{1a ′} is C _1-6 alkyl), X is a methylene group or an oxygen atom, Y is a methylene group or —NH—, and Ar ′ is 1 selected from the group consisting of a halogen atom and a C _1-6 alkoxy group
Or a phenyl group optionally having two substituents, having the formula:

[0038]

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The group represented by the formula:

[0040]

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A group represented by the formula (1), wherein s is 1 and t is 1, and one or more drugs selected from the pharmaceutical agent of the above [6], [8] an antibacterial agent and an antifungal agent [9] the medicament of the above-mentioned [1], which is combined with an anti-sepsis drug;
The medicine of the above-mentioned [1], which is a combination of one or more drugs selected from non-steroidal anti-inflammatory drugs and steroids, and an anti-sepsis drug; [10] A combination of an anti-coagulant and an anti-sepsis drug [1].
1] The medicament of the above-mentioned [1] or [4], which is an agent for preventing or treating sepsis, [12] The medicament of the above-mentioned [1] or [4], which is an agent for preventing or treating septic shock, [13] Inflammatory The pharmaceutical agent of the above-mentioned [1] or [4], which is an agent for preventing or treating a disease or an infectious disease;
4] combining a mammal with an effective amount of an anti-sepsitic agent and an effective amount of at least one drug selected from an antibacterial agent, an antifungal agent, a non-steroidal anti-inflammatory agent, a steroid agent and an anticoagulant [15] a method of preventing or treating sepsis, comprising administering to a mammal an effective amount of an anti-sepsitic drug, an antibacterial drug, an antifungal drug, a nonsteroidal anti-inflammatory drug, a steroid drug, A method for preventing or treating an inflammatory disease or an infectious disease, which is administered in combination with an effective amount of at least one drug selected from the group consisting of a blood clot, [16] an agent for preventing or treating sepsis Use of an anti-sepsis drug and at least one drug selected from the group consisting of antibacterial drugs, antifungal drugs, non-steroidal anti-inflammatory drugs, steroid drugs and anticoagulants for the production of And [17] comprising an anti-sepsitic drug, an antibacterial drug, an antifungal drug, a nonsteroidal anti-inflammatory drug, a steroid drug, and an anticoagulant for producing a prophylactic or therapeutic agent for an inflammatory disease or an infectious disease. A use with at least one drug selected from the group.

[0042]

DETAILED DESCRIPTION OF THE INVENTION Further, the present invention provides a method of formula (1)
(I):

[0043]

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[Wherein, R represents an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, and a heterocyclic ring which may have a substituent. Group, formula: -O
A group represented by R ¹ (wherein, R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent) or a formula represented by the following formula:

[0045]

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[0046] (wherein, R ^1b and R ^1c are the same or different and represent a hydrogen atom or an aliphatic substituted hydrocarbon group.) A group represented by, R ⁰ is Represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R
And a bond is formed by bonding with ^0, and ring A ¹ is (1) an aliphatic hydrocarbon group which may have a substituent, and (2) an aromatic hydrocarbon which may have a substituent. Group, formula (3): -OR ¹¹
(Wherein, R ¹¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent.) And 1 to 4 groups selected from the group consisting of (4) halogen atoms A cycloalkene which may be substituted with a substituent,
Ar represents an aromatic hydrocarbon group which may have a substituent, and has the formula:

[0047]

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The group represented by the formula:

[0049]

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Wherein n is an integer of 1 to 4. Or a salt thereof or a prodrug thereof and an antibacterial agent, an antifungal agent, a nonsteroidal anti-inflammatory agent, a steroidal agent and an anticoagulant.
Or a medicine comprising a combination of two or more drugs,
[2] a drug obtained by combining the above compound (I) or a salt thereof or a prodrug thereof with one or more drugs selected from antibacterial and antifungal agents; [3] a compound of the above compound (I) or a salt thereof Alternatively, a medicament obtained by combining the prodrug with one or more drugs selected from nonsteroidal anti-inflammatory drugs and steroid drugs,
[4] the medicament according to [1], which is a prophylactic / therapeutic agent for sepsis or septic shock; [5] the medicament according to [1], which is a prophylactic / therapeutic agent for an inflammatory disease or an infectious disease [6] an effective amount of the compound (I) or a salt thereof or a prodrug thereof and an antibacterial agent for a mammal;
Prevention of sepsis or septic shock, characterized by administering in combination with an effective amount of one or more drugs selected from antifungal drugs, non-steroidal anti-inflammatory drugs, steroid drugs and anticoagulants. Treatment method, [7]
For mammals, an effective amount of the compound (I) or a salt thereof or a prodrug thereof, and one or two selected from antibacterial agents, antifungal agents, nonsteroidal antiinflammatory agents, steroidal agents and anticoagulants A method for preventing or treating an inflammatory disease or an infectious disease, which is characterized by administering an effective amount of the above-mentioned drug in combination with the compound represented by the formula (I):

[0051]

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[Wherein R is an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, and a heterocyclic ring which may have a substituent Group, formula: -O
A group represented by R ¹ (wherein, R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent) or a formula represented by the following formula:

[0053]

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(In the formula, R ^1b is a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent, and R ^1c is the same or different from R ^1b and has a hydrogen atom or a substituent. Represents a good aliphatic hydrocarbon group.)
R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ⁰ together form a bond, and ring A ² is (1) an aliphatic hydrocarbon group which may have a substituent. Hydrogen group,
(2) an aromatic hydrocarbon group which may have a substituent,
(3) a group represented by the formula: -OR ¹¹ (wherein, R ¹¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent) and (4) a halogen atom. 1-4
Represents an optionally substituted cycloalkene, Ar represents an aromatic hydrocarbon group which may have a substituent, and has the formula:

[0055]

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The group represented by the formula:

[0057]

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Wherein n is an integer of 1 to 4. A compound represented by the formula (ii):

[0059]

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[Wherein, R ^a is an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent. Ring group, formula:-
OR ^1a (wherein, R ^1a represents a hydrogen atom or an optionally substituted aliphatic hydrocarbon group) or a group represented by the formula:

[0061]

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[0062] (wherein, R ^4a and R ^5a are the same or different. Represents a hydrogen atom or an optionally substituted aliphatic hydrocarbon group) a group represented by, R ^0a is Represents a hydrogen atom or an aliphatic hydrocarbon group, or R ^a and R ^0a together form a bond, and Ar ^a represents an aromatic hydrocarbon group which may have ^a substituent; :

[0063]

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The group represented by the formula:

[0065]

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Wherein n is an integer of 1 to 4. ] The pharmaceutical according to [1], which is a compound represented by the formula:

[9] A compound represented by the formula (Iaa):

[0067]

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[0068] [wherein each symbol is the [8] This shows the section according as defined above] The [8] a compound represented by the above, wherein the pharmaceutical, [10] the ring A ² is a lower alkyl, phenyl or A medicament according to [8], wherein the medicament is a cycloalkene substituted with halogen, R ¹ is a lower alkyl group, Ar is a phenyl group which may have a substituent, and n is 2;

[11] The compound represented by the formula (Ie) is
formula:

[0070]

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[Wherein R is an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, and a heterocyclic ring which may have a substituent Group, formula: -O
A group represented by R ¹ (wherein, R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent) or a formula represented by the following formula:

[0072]

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(Wherein, R ^1b is a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent, and R ^1c is the same or different from R ^1b and has a hydrogen atom or a substituent. Represents a good aliphatic hydrocarbon group.)
R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ⁰ together form a bond, Ar represents an aromatic hydrocarbon group which may have a substituent, formula:

[0074]

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The group represented by the formula:

[0076]

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Wherein n is an integer of 1 to 4], the compound according to item [8],

[12] The compound represented by the formula (Ia)
formula:

[0079]

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[Wherein, R ² represents a hydrogen atom or an aliphatic hydrocarbon group, and R ¹ , Ar, n and the formula:

[0081]

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[0082] group represented by have the [11], wherein the medicament is a compound represented by the [11] This shows the section according as defined above], a [13] R ¹ is a substituted group [14] The drug according to [12], wherein R ¹ is an ethyl group; [15] R ²
Is a hydrogen atom or a lower alkyl group, the drug according to item [12], [16] the drug according to item [12], wherein R ² is a hydrogen atom, and [17] even if Ar has a substituent. The pharmaceutical according to [12], which is a good phenyl group, [18] A
The pharmaceutical according to [12], wherein r is a phenyl group substituted with halogen and / or lower alkyl,

[19] Ar is a compound represented by the formula:

[0084]

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Wherein R ⁴ and R ⁵ are the same or different and each represents a halogen atom or a lower alkyl group, and n represents an integer of 0 to 2. [20] The pharmaceutical according to [12], wherein the halogen atom is a fluorine atom or a chlorine atom, the pharmaceutical according to [18] or [19],
1] Formula:

[0086]

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A group represented by the formula:

[0088]

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[Wherein, n has the same meaning as described in the item [12]. ] The medicament according to [12], which is a group represented by the formula:
[22] the medicament according to [12], wherein n is 1 to 3,
[23] R ¹ is a lower alkyl group which may have a substituent, R ² is a hydrogen atom or a lower alkyl group, Ar is a phenyl group which may have a substituent, and n [12] wherein R is 1, 2 or 3, [24] R ¹ is a lower alkyl group which may have a substituent, R ² is a hydrogen atom, and Ar is a halogen atom The pharmaceutical according to [12], wherein the phenyl group is substituted with

[25] The compound represented by the formula (Ia)
formula:

[0091]

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[Wherein, Ar and n have the same meanings as in item [11]], the drug according to item [11], and [26] Ar has a substituent. A phenyl group, wherein n is 2;

[27] A compound represented by the formula (Ia)
formula:

[0094]

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[Wherein R ¹ , R ² and Ar are the same as [12]
The meaning is as described in the formula:

[0096]

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The group represented by the formula:

[0098]

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And a group represented by However, when Ar is a phenyl group, R ¹ is a hydrogen atom or an ethyl group, and R ² is a methyl group, the formula:

[0100]

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The group represented by the formula:

[0102]

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Is a group represented by ] The pharmaceutical according to [11], which is a compound represented by the formula:

[28] A compound represented by the formula (Ie):
formula:

[0105]

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[Wherein R ^2a represents a hydrogen atom or an aliphatic hydrocarbon group, and R ^1a , Ar ^a , n and the formula:

[0107]

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The group represented by has the same meaning as described in the item [8]. ] The pharmaceutical according to [8], which is a compound represented by the formula:

[29] A compound represented by the formula (Ie)
formula:

[0110]

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[Wherein R ^1a , R ^2a and Ar ^a are the same as [2]
8] is as defined in the formula:

[0112]

[Of 60]

The group represented by the formula:

[0114]

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The group represented by [8] the compound of [8], wherein the compound [30] is ethyl (6R) -6-[(2-chloro-4-fluoroanilino) sulfonyl] -1-cyclohexene-1- Carboxylate, d-ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-
Cyclohexene-1-carboxylate, ethyl 6- [N-
(2-Chlorophenyl) sulfamoyl] -1-cyclohexene
1-carboxylate, or ethyl 6- [N- (2-chloro
-4-Methylphenyl) sulfamoyl] -1-cyclohexene
1-carboxylate or a salt thereof [1]
[31] The medicament according to [1], which is an inhibitor of nitric oxide and / or cytokine production; and [32] A pharmaceutical agent according to [1], which is a prophylactic or therapeutic agent for heart disease or autoimmune disease. 3. The medicament according to the above item is provided.

[0116] The anti-sepsitic drug used in the medicament of the present invention includes rBPI-21 (bactericidal permeability).
Increasing protein), BI-51017 (antithrombin III), SC-59735 (rTFPI), r-PAF acetylhydrolase, LY-203638 (r-activated protein C),
Peptidic compounds such as anti-TNF-α antibody, JTE-607, E-5
531, E-5564, S-5920, FR-167653, ONO-1714, ONO-5046
(sivelestat), non-peptidic compounds such as GW-273629, RWJ-67657, and cycloalkene compounds are used. Of these, non-peptidic compounds such as cycloalkene compounds are preferred, and cycloalkene compounds are particularly preferred. As the cycloalkene compound, compounds represented by the above formulas (I) and (II), salts thereof, and prodrugs thereof are preferable.

The above compounds will be described in detail. In the present specification, R is an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, Formula: -OR ¹
(Wherein, R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent), or a group represented by the formula:

[0118]

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(Wherein, R ^1b and R ^1c are the same or different and each represent a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent); Together with ⁰ forms a bond, in particular, the formula:
OR ¹ [R ¹ is as defined above. ] Is preferable.

R ^a is an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent. , Formula: -O
A group represented by R ^1a (wherein R ^1a represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent) or a formula represented by the formula:

[0121]

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(Wherein R ^4a and R ^5a are the same or different and each represent a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent), or together with R ^0a To form a bond,
Formula: -OR ^1a [R ^1a is as defined above. ] Are preferable.

When R and R ⁰ together represent a bond, the compound represented by the formula (Iaa) has the formula:

[0124]

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Wherein each symbol is as defined above. ]
Which can be represented by the formula:

[0126]

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Wherein each symbol is as defined above. ]
Or

[0128]

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[Wherein the symbols are as defined above. ]
Can be represented by

When R and R ⁰ together represent a bond, the compound represented by the formula (Ia) has the formula:

[0131]

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[Wherein the symbols are as defined above. ]
Which can be represented by the formula:

[0133]

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Wherein each symbol is as defined above. ]
Or

[0135]

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Wherein each symbol is as defined above. ]
Can be represented by

When R ^a and R ^0a together represent a bond, the compound represented by the formula (Ie) has the formula:

[0138]

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Wherein each symbol is as defined above. ]
Which can be represented by the formula:

[0140]

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[Wherein the symbols are as defined above. ]
Or

[0142]

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[Wherein the symbols are as defined above. ]
Can be represented by

R is a group represented by the formula: -OR ¹ wherein R ¹ is as defined above. Is a group represented by the formula (Iaa):

[0145]

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[Wherein the symbols are as defined above. ]
Which can be represented by the formula:

[0147]

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[Wherein the symbols are as defined above. ]
Or

[0149]

[Of 75]

[Wherein the symbols are as defined above. ]
Can be represented by

R is a group represented by the formula: -OR ¹ wherein R ¹ is as defined above. Is a group represented by the formula (Ia):

[0152]

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[Wherein the symbols are as defined above. ]
Which can be represented by the formula:

[0154]

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[Wherein the symbols are as defined above. ]
Or

[0156]

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[Wherein the symbols are as defined above. ]
Can be represented by

R ^a is ^{a group} represented by the formula: —OR ^1a wherein R ^1a is as defined above. And a group represented by the formula (Ie)
The compound represented by the formula:

[0159]

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[Wherein the symbols are as defined above. ]
Which can be represented by the formula:

[0161]

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Wherein each symbol is as defined above. ]
Or

[0163]

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[Wherein the symbols are as defined above. ]
Can be represented by

As the compound represented by the formula (Iaa), a compound represented by the formula (Iaa)
cc) or a compound represented by the formula (Inn) is preferable. As the compound represented by the formula (Ia), the compound represented by the formula (Ic) or the formula (I
The compound represented by n) is preferable, and the compound represented by formula (Ie) is preferably a compound represented by formula (Ik) or formula (Ip).

Similarly, the compound represented by the formula (Id) has the formula:

[0167]

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[Wherein the symbols have the same meanings as described above. ] Or the formula:

[0169]

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[Wherein the symbols have the same meanings as described above. The compound represented by the formula (Ig) is represented by the formula:

[0171]

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[Wherein the symbols have the same meanings as described above. ] Or the formula:

[0173]

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[Wherein the symbols have the same meanings as described above. ]. As the compound represented by the formula (Id), a compound represented by the formula (Ir) is preferable.
As the compound represented by g), a compound represented by the formula (It) is preferable.

In the compound represented by the formula (Ia), n is 1 to 4, (i) R ¹ is a hydrogen atom or a lower alkyl group which may have a substituent, and R ⁰ is a substituent. When a lower alkyl group which may be possessed and Ar is a phenyl group which may be substituted, or (ii) R ¹
And R ⁰ together represent a bond, and when Ar is a phenyl group which may have a substituent, the formula:

[0176]

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The group represented by the formula:

[0178]

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A group represented by the following formula is preferred.

In the compound represented by formula (Ib), n is 1 to 4, R ¹ is a hydrogen atom or a lower alkyl group which may have a substituent, and R ⁰ is a substituent. When Ar is a phenyl group which may have a substituent, and

[0181]

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The group represented by the formula:

[0183]

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The group represented by the following is preferred.

R, R ¹ , R ¹¹ , R ^1a , R ^1b , R ^1c ,
R ^4a , “aliphatic hydrocarbon group” of “ ^optionally substituted aliphatic hydrocarbon group” represented by R ^5a , R ⁰ , R ^0a ,
As the “aliphatic hydrocarbon group” represented by R ² and R ^2a ,
For example, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkenyl group, an alkynyl group and the like are preferable.

The alkyl group includes, for example, a linear or branched alkyl group having 1 to 20 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-
Butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, dodecyl group, etc.) and the like. 6 lower alkyl groups (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, etc.) and the like are preferable.

As the cycloalkyl group, for example, a cycloalkyl group having 3 to 10 carbon atoms (eg, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, etc.) and the like are preferable. Particularly, for example, a cycloalkyl group having 3 to 6 carbon atoms (eg, a cyclopropyl group, a cyclobutyl group,
And a cyclopentyl group and a cyclohexyl group. As the cycloalkylalkyl group, for example,
A cycloalkylalkyl group having 4 to 12 carbon atoms (e.g., cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, etc.) and the like are preferable, and particularly, for example, having 4 to 8 carbon atoms (4 to 8 carbon atoms among others). 7) The cycloalkylalkyl group (eg, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, etc.) and the like are preferable.

The alkenyl group is preferably, for example, a lower alkenyl group having 3 to 6 carbon atoms (eg, propenyl group, butenyl group, pentenyl group and the like).
For example, a lower alkenyl group having 3 or 4 carbon atoms (eg, a propenyl group, a butenyl group, etc.) is preferable.

The alkynyl group is preferably, for example, a lower alkynyl group having 3 to 6 carbon atoms (eg, a propynyl group, a butynyl group, a pentynyl group and the like).
For example, a lower alkynyl group having 3 or 4 carbon atoms (eg, a propynyl group, a butynyl group, etc.) is preferable.

The “substituent” of the “aliphatic hydrocarbon group optionally having substituent (s)” includes, for example, a heterocyclic group,
Oxo group, hydroxyl group, C _1-6 alkoxy group, C _3-10 (among which is C _3-6 ) cycloalkyloxy group, C _6-10 aryloxy group, C _7-19 (among which is C _7-12 ) aralkyl Oxy group, heterocyclic oxy group, C _1-6 alkylthio group (the sulfur atom may be oxidized), C _3-10 (among which is C _3-6 ) cycloalkylthio group (the sulfur atom is oxidized) A C _6-10 arylthio group (the sulfur atom may be oxidized), a C _7-19 (among which is a C _7-12 ) aralkylthio group (the sulfur atom is oxidized). A heterocyclic thio group, a heterocyclic sulfinyl group, a heterocyclic sulfonyl group, a nitro group, a halogen atom,
Cyano group, carboxyl group, C _1-10 (among others, C _1-6 )
An alkoxy-carbonyl group, a C _3-6 cycloalkyloxy-carbonyl group, a C _6-10 aryloxy-carbonyl group, a C _7-19 (among which is C _7-12 ) aralkyloxy-carbonyl group, a heterocyclic oxycarbonyl group, C _6-10 aryl-carbonyl group, C _1-6 alkanoyl group, C _3-5 alkenoyl group, C _6-10 aryl-carbonyloxy group, C _2-6
Alkanoyloxy group, C _3-5 alkenoyloxy group,
A carbamoyl group which may have a substituent, a thiocarbamoyl group which may have a substituent, a carbamoyloxy group which may have a substituent, a C _1-6 alkanoylamino group, a C _6-10 Aryl-carbonylamino group, C _1-10
(Among others C _1-6 ) alkoxy-carboxamide group, C
_6-10 aryloxy-carboxamide group, C _7-19 (among others, C _7-12 ) aralkyloxy-carboxamide group, C
_1-10 (among others, C _1-6 ) alkoxy-carbonyloxy group, C _6-10 aryloxy-carbonyloxy group, C
_7-19 (among which is C _7-12 ) aralkyloxy-carbonyloxy group, C _3-10 (among which is C _3-6 ) cycloalkyloxy-carbonyloxy group, ureido group which may have a substituent, A C _6-10 aryl group which may have a substituent is used. These substituents are substituted at substitutable sites of the above “aliphatic hydrocarbon group”, and the number of the substituents is not limited to one, but may be the same or different and plural (preferably 2 to 4). You may.

Examples of the "C _1-6 alkoxy group" include, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, tert-butoxy group,
-Pentyloxy group, n-hexyloxy group and the like,
As the “C _3-10 cycloalkyloxy group”, for example,
Examples of a cyclopropyloxy group, a cyclohexyloxy group, and the like, as “C _6-10 aryloxy group”, for example, a phenoxy group, a naphthyloxy group, and the like, as a “C _7-19 aralkyloxy group”, such as benzyloxy Group,
A 1-phenylethyloxy group, a 2-phenylethyloxy group, a benzhydryloxy group, a 1-naphthylmethyloxy group or the like is a “C _1-6 alkylthio group (the sulfur atom may be oxidized)”. As, for example, methylthio, ethylthio, n-propylthio, n-
Examples of the butylthio group, methylsulfinyl group, methylsulfonyl group and the like as “C _3-10 cycloalkylthio group (the sulfur atom may be oxidized)” include, for example, cyclopropylthio group, cyclohexylthio group, cyclopentyl Examples of the “C _6-10 arylthio group (the sulfur atom may be oxidized)” such as a sulfinyl group and a cyclohexylsulfonyl group include, for example, a phenylthio group, a naphthylthio group, a phenylsulfinyl group, and a phenylsulfonyl group. , "C _7-19 aralkylthio group (the sulfur atom may be oxidized)"
Examples thereof include a benzylthio group, a phenylethylthio group, a benzhydrylthio group, a benzylsulfinyl group, and a benzylsulfonyl group. Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom represented by “C. <sub>As the `` 1-10</sub> alkoxy-carbonyl group '', for example, a methoxycarbonyl group, an ethoxycarbonyl group,
n- propoxycarbonyl group, isopropoxycarbonyl group, n- butoxycarbonyl group, isobutoxycarbonyl group, tert- butoxycarbonyl group, "C <sub>3-6</sub>
Examples of the "cycloalkyloxy-carbonyl group" include, for example, a cyclopropyloxycarbonyl group, a cyclopentyloxycarbonyl group, a cyclohexyloxycarbonyl group, and the like, and a "C <sub>6-10</sub> aryloxy-carbonyl group".
As a <sub>C7-19</sub> aralkyloxy-carbonyl group, for example, a benzyloxycarbonyl group, a benzhydryloxycarbonyl group,
Examples of the phenethyloxycarbonyl group and the like as a “C <sub>6-10</sub> aryl-carbonyl group” include a benzoyl group,
Examples of the naphthoyl group and the “C <sub>1-6</sub> alkanoyl group” include a formyl group, an acetyl group, a propionyl group, a butyryl group, a valeryl group, and a pivaloyl group.
Examples of the “C <sub>3-5</sub> alkenoyl group” include an acryloyl group and a crotonoyl group, and examples of the “C <sub>6-10</sub> aryl-carbonyloxy group” include a benzoyloxy group and a naphthoyloxy group. <sub>As</sub> the `` _2-6 alkanoyloxy group '', for example, an acetoxy group, a propionyloxy group, a butyryloxy group, a valeryloxy group, a pivaloyloxy group, and the like, as the `` C _3-5 alkenoyloxy group '', for example, an acryloyloxy group,
A crotonoyloxy group or the like is used.

The “carbamoyl group optionally having substituent (s)” includes, for example, C _1-4 alkyl (eg, methyl,
Substituted with one or two substituents selected from ethyl, etc.), phenyl, C _1-7 acyl (eg, acetyl, propionyl, benzoyl, etc.), C _1-4 alkoxy-phenyl (eg, methoxyphenyl, etc.) May be
A carbamoyl group or a cyclic amino (for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, etc.) carbonyl group and the like are used. Specifically, for example, carbamoyl group, N-methylcarbamoyl group, N-
Ethylcarbamoyl group, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N-phenylcarbamoyl group, N-acetylcarbamoyl group, N-benzoylcarbamoyl group, N- (p-methoxyphenyl)
Carbamoyl group, 1-pyrrolidinylcarbonyl group, piperidinocarbonyl group, 1-piperazinylcarbonyl group,
A morpholinocarbonyl group is used. The “optionally substituted thiocarbamoyl group” is, for example, substituted with one or two substituents selected from C _1-4 alkyl (eg, methyl, ethyl and the like), phenyl and the like. And a thiocarbamoyl group, for example, a thiocarbamoyl group, an N-methylthiocarbamoyl group, and an N-phenylthiocarbamoyl group. The “carbamoyloxy group optionally having substituent (s)” is, for example, substituted with one or two substituent (s) selected from C _1-4 alkyl (eg, methyl, ethyl and the like), phenyl and the like. A carbamoyloxy group which may be used, for example, a carbamoyloxy group, an N-methylcarbamoyloxy group, an N, N-dimethylcarbamoyloxy group, an N-ethylcarbamoyloxy group, an N-phenylcarbamoyloxy group Are used.

[C]_1-6Alkanoylamino group "
Is, for example, an acetamido group, a propionamido group,
Tyroamide group, valeroamide group, pivaloamide group, etc.
But "C _6-10Aryl-carbonylamino group "
Is, for example, a benzamide group, a naphthamide group, a phthalate
An imide group is represented by “C_1-10Alkoxy-carboxamide
Examples of the “group” include methoxycarboxamide (CH
_ThreeOCONH-) group, ethoxycarboxamide group, tert
A butoxycarboxamide group, etc._6-10Aryl
Examples of the "oxy-carboxamide group" include, for example, pheno
Xycarboxamide (C₆H_FiveAn OCONH-) group,
"C_7-19Aralkyloxy-carboxamide group "
Is, for example, benzyloxycarboxamide (C₆H_FiveC
H_TwoOCONH-) group, benzhydryloxycarboxy
When a samide group or the like is represented by “C_1-10Alkoxy-carbonyloxy
As the `` group '', for example, methoxycarbonyloxy
Group, ethoxycarbonyloxy group, n-propoxycal
Bonyloxy group, isopropoxycarbonyloxy group,
n-butoxycarbonyloxy group, tert-butoxycal
Bonyloxy group, n-pentyloxycarbonyloxy
Group, n-hexyloxycarbonyloxy group and the like,
"C<sub>6-10</sub>An aryloxy-carbonyloxy group "
Is, for example, a phenoxycarbonyloxy group, a naphthyl
An oxycarbonyloxy group or the like is represented by “C<sub>7-19</sub>Aralkyl
Examples of the "oxy-carbonyloxy group" include, for example, benzene
Ziroxycarbonyloxy group, 1-phenylethylo
Xycarbonyloxy group, 2-phenylethyloxyca
Rubonyloxy group, benzhydryloxycarbonyloxy
When a xy group or the like is represented by “C<sub>3-10</sub>Cycloalkyloxy-carbo
As the `` nyloxy group '', for example, cyclopropyloxy
Cicarbonyloxy group, cyclohexyloxy carbonyl
A ruoxy group or the like is used.

"Ureido group optionally having substituent (s)"
As a C _1-4 alkyl group (eg, a methyl group,
An ureide group which may be substituted with 1 to 3 (among 1 or 2) substituents selected from an ethyl group), a phenyl group and the like, for example, a ureide group, a 1-methylureide group, A 3-methylureide group, a 3,3-dimethylureide group, a 1,3-dimethylureide group, a 3-phenylureide group, and the like are used.

As the “substituent” of the “optionally substituted aliphatic hydrocarbon group”, a heterocyclic group, a heterocyclic oxy group, a heterocyclic thio group, a heterocyclic sulfinyl group, a heterocyclic sulfonyl group or When a heterocyclic oxycarbonyl group is used, the heterocyclic group has one hydrogen atom bonded to the heterocyclic ring.
Represents a group that can be formed individually, and includes, for example, 5 to 8 containing 1 to several, preferably 1 to 4 heteroatoms such as a nitrogen atom (which may be oxidized), an oxygen atom, and a sulfur atom.
A membered ring (in particular, a 5- to 6-membered ring) group or a condensed ring group thereof. Such heterocyclic groups include, for example, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl Group, 1,2,3-oxadiazolyl group, 1,2,4-
An oxadiazolyl group, a 1,2,5-oxadiazolyl group,
1,3,4-oxadiazolyl group, thiazolyl group, isothiazolyl group, 1,2,3-thiadiazolyl group, 1,2,4-
Thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,
3,4-thiadiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, pyranyl group, thiopyranyl group, dioxinyl group, dioxolyl group, quinolyl group, pyrido [2,3-d] pyrimidyl group, 5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridyl, thieno [2,3-d] pyridyl, benzopyranyl, tetrahydrofuryl, tetrahydropyrani And a dioxolanyl group, a dioxanyl group and the like. These heterocyclic groups include C _1-4 alkyl (eg, methyl, ethyl, etc.), hydroxy, oxo, C _1-4 alkoxy (eg, methoxy, ethoxy, etc.)
It may be substituted at a substitutable site by 1 to 3 substituents selected from the above.

As the “C _6-10 aryl group” of the “C _6-10 aryl group _optionally having substituent (s)”, for example, a phenyl group, a naphthyl group and the like are used. The C _6-10 aryl group is a “substituent” of the “aliphatic hydrocarbon group _optionally having substituent (s)” (C _{6-10 optionally} having substituent (s)).
Excluding the aryl group), the substitutable site may be substituted with a substituent selected from the above. The number of the substituents is not limited to one, and a plurality (preferably 2 to 4) of the same or different substituents may be present. Further, the `` aliphatic hydrocarbon group which may have a substituent '' may form a condensed ring group in which the substituent may be substituted together with the aliphatic hydrocarbon group, As such a condensed ring group, an indanyl group, a 1,2,3,4-tetrahydronaphthyl group or the like is used. In this condensed ring group, a substitutable site may be substituted with a substituent selected from “substituents” of the “aliphatic hydrocarbon group optionally having substituent (s)”. These substituents are substituted at substitutable sites of the condensed ring group, and the number of the substituents is not limited to one and may be the same or different, and may be plural (preferably 2 to 4). .

In the above “optionally substituted aliphatic hydrocarbon group”, R, R ¹ , R ¹¹ R ^1a , R ^1b , R ^1c ,
Preferred examples of R ^4a and R ^5a include a lower alkyl group having 1 to 6 carbon atoms which may have a substituent (eg, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-
Butyl group, isobutyl group, tert-butoxycarbonylmethyl group, hydroxyethyl group and the like), and among them, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, etc. Are preferred, for example, a methyl group, an ethyl group, an n-propyl group and the like are more preferred, and an ethyl group and the like are particularly preferred.

As R ² and R ^2a , for example, a hydrogen atom,
A lower alkyl group having 1 to 6 carbon atoms (eg, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group,
An isobutyl group, a tert-butoxycarbonylmethyl group, a hydroxyethyl group and the like are preferably used, and particularly, a hydrogen atom, a methyl group, and the like are preferably used, and among them, a hydrogen atom and the like are preferably used.

The “aromatic hydrocarbon group” in the “aromatic hydrocarbon group optionally having substituent (s)” represented by R is an aromatic hydrocarbon group having 6 to 14 carbon atoms (eg, phenyl Group, naphthyl group, anthryl group, indenyl group, etc.), and particularly, for example, an aryl group having 6 to 10 carbon atoms (eg, phenyl group, naphthyl group, etc.)
And the like, and among them, a phenyl group and the like are particularly preferable. Examples of the “substituent” in the “aromatic hydrocarbon group which may have a substituent” represented by R include, for example, a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom) and a lower (C _1-4 ) alkyl group (eg, methyl group, ethyl group, propyl group, butyl group, etc.), lower (C _1-4 ) alkoxy group (eg, methoxy group, ethoxy group, propoxy group, butoxy group, etc.), lower group (C _1-4 ) alkoxy-carbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, etc.), carboxyl group, nitro group, cyano group, hydroxyl group, acylamino group (eg, acetylamino group Alkanoylamino group having 1 to 4 carbon atoms such as a propionylamino group and a butyrylamino group; cycloalkyl group having 3 to 6 carbon atoms (eg, Ropuropiru group, cyclopentyl group), an aryl group (e.g. having 6 to 10 carbon atoms, a phenyl group, a naphthyl group, an indenyl group and the like), halogeno lower (C _1-4) alkyl group (e.g., trifluoromethyl group,
Trifluoroethyl group, etc.), halogeno lower (C _1-4 )
Alkoxy group (eg, trifluoromethoxy group, 1,1,
2,2-tetrafluoroethoxy group, 2,2,3,3,3-
Pentafluoropropoxy group, etc.), lower (C _1-4 ) alkylthio group (eg, methylthio group, ethylthio group, propylthio group, etc.), lower (C _1-4 ) alkanesulfonyl group (eg, methanesulfonyl group, ethanesulfonyl group) , A propanesulfonyl group, etc.), a lower (C _1-4 ) alkanoyl group (eg, formyl group, acetyl group, propionyl group, etc.), a 5-membered aromatic heterocyclic group (eg, 1,2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group,
Thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, thiadiazolyl group, thienyl group, furyl group, etc.), carbamoyl group, lower (C _1-4 ) alkyl-carbamoyl group (eg, methylcarbamoyl group, dimethylcarbamoyl group, propylcarbamoyl) Group),
Lower (C _{1- 4)} alkoxy - carbonyl - lower (C _1-4)
Alkyl-carbamoyl group (eg, butoxycarbonylmethylcarbamoyl group, ethoxycarbonylmethylcarbamoyl group, etc.), 1,3-diacylguanidino-lower (C _1-4 ) alkyl group (eg, 1,3-diacetylguanidinomethyl, 3-bis- (tert-butoxycarbonyl) guanidinomethyl and the like, preferably a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), a lower (C _1-4 ) alkyl group (eg, a methyl group, Ethyl group, propyl group, butyl group, etc.), and more preferably a fluorine atom, a chlorine atom, and a methyl group. These substituents are substituted on substitutable sites of the aromatic hydrocarbon group, and the number of substituents is preferably 1 to 5,
One to three are more preferable, and one or two are particularly preferable. When two or more substituents are present, the substituents may be the same or different.

The "heterocyclic group" in the "heterocyclic group optionally having substituent (s)" for R is, for example, a nitrogen atom (which may be oxidized), an oxygen atom, a sulfur atom or the like. A 5- to 8-membered ring (among which is a 5- to 6-membered ring) group containing one to several, preferably one to four heteroatoms, and a condensed ring group thereof. Such heterocyclic groups include, for example, pyrrolyl, pyrazolyl, imidazolyl, 1,2,
3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group, furyl group, thienyl group, oxazolyl group,
Isoxazolyl group, 1,2,3-oxadiazolyl group,
1,2,4-oxadiazolyl group, 1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, thiazolyl group, isothiazolyl group, 1,2,3-thiadiazolyl group,
1,2,4-thiadiazolyl group, 1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, pyranyl group, thiopyranyl group, dioxinyl group ,
Dioxolyl group, quinolyl group, pyrido [2,3-d] pyrimidyl group, 1,5-, 1,6-, 1,7-, 1,8-,
2,6- or 2,7-naphthyridyl group, thieno [2,3
-D] pyridyl group, benzopyranyl group, tetrahydrofuryl group, tetrahydropyranyl group, dioxolanyl group,
A dioxanyl group or the like is used. These heterocyclic groups are
Substitution at a site substitutable by one to three substituents selected from C _1-4 alkyl (eg, methyl, ethyl, etc.), hydroxy, oxo, C _1-4 alkoxy (eg, methoxy, ethoxy, etc.) It may be.

As the “aromatic hydrocarbon group” in the “aromatic hydrocarbon group optionally having substituent (s)” represented by Ar and Ar ^a , an aromatic hydrocarbon group having 6 to 14 carbon atoms ( For example, a phenyl group, a naphthyl group, an anthryl group, an indenyl group and the like are preferable, and particularly, for example, an aryl group having 6 to 10 carbon atoms (eg, a phenyl group, a naphthyl group and the like) and the like are preferable. Is particularly preferred. Examples of the “substituent” in the “aromatic hydrocarbon group optionally having substituent (s)” represented by Ar and Ar ^a include a halogen atom (a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom). A lower (C _1-4 ) alkyl group (eg, methyl group, ethyl group, propyl group, isopropyl group, butyl group, etc.), a lower (C _1-4 ) alkoxy group (eg, methoxy group, ethoxy group, propoxy group, A lower (C _1-4 ) alkoxy-carbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group,
Propoxycarbonyl, butoxycarbonyl, etc.), carboxyl, nitro, cyano, hydroxyl,
An acylamino group (eg, an acetylamino group, a propionylamino group, an alkanoylamino group having 1 to 4 carbon atoms such as a butyrylamino group), a cycloalkyl group having 3 to 6 carbon atoms (eg, a cyclopropyl group, a cyclopentyl group, etc.), An aryl group having 6 to 10 carbon atoms (eg, a phenyl group,
Naphthyl group, indenyl group, etc.), halogeno lower (C
_1-4 ) alkyl group (eg, trifluoromethyl group, trifluoroethyl group, etc.), halogeno lower (C _1-4 ) alkoxy group (eg, trifluoromethoxy group, 1,1,2,2-
Tetrafluoroethoxy group, 2,2,3,3,3-pentafluoropropoxy group, etc., lower (C _1-4 ) alkylthio group (eg, methylthio group, ethylthio group, propylthio group, etc.), lower (C _{1- 4} ) Alkanesulfonyl group (eg,
Methanesulfonyl group, ethanesulfonyl group, propanesulfonyl group, etc., lower (C _1-4 ) alkanoyl group (eg, formyl group, acetyl group, propionyl group, etc.), 5-membered aromatic heterocyclic group (eg, 1, 2,3-triazolyl group, 1,2,4-triazolyl group, tetrazolyl group,
Thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, thiadiazolyl group, thienyl group, furyl group, etc.), carbamoyl group, lower (C _1-4 ) alkyl-carbamoyl group (eg, methylcarbamoyl group, dimethylcarbamoyl group, propionylcarbamoyl) Group), lower (C _1-4 ) alkoxy-carbonyl-lower (C _1-4 ) alkyl-carbamoyl group (eg, butoxycarbonylmethylcarbamoyl group, tert-butoxycarbonylmethylcarbamoyl group, ethoxycarbonylmethylcarbamoyl group, etc.) 1,3-diacylguanidino-lower (C _1-4 ) alkyl groups (eg, 1,3-diacetylguanidinomethyl, 1,3-bis- (tert-butoxycarbonyl) guanidinomethyl and the like), and preferably halogen Atom (fluorine atom, Atom, a bromine atom, an iodine atom), a lower (C _1-4) alkyl group (e.g., methyl group,
Ethyl group, propyl group, butyl group, etc.), and more preferably a fluorine atom, a chlorine atom, and a methyl group. These substituents are substituted on a substitutable site of the aromatic hydrocarbon group, and the number of the substituents is preferably 1 to 5, more preferably 1 to 3, and particularly preferably 1 or 2. When two or more substituents are present, the substituents may be the same or different.

Specific examples of Ar and Ar ^a include, for example, a phenyl group, a halogenophenyl group, a lower (C _1-4 )
Alkylphenyl group, lower ( _C1-4 ) alkoxyphenyl group, lower ( _C1-4 ) alkoxy-carbonylphenyl group, carboxyphenyl group, nitrophenyl group, cyanophenyl group, halogeno lower ( _C1-4 ) alkylphenyl Group, halogeno lower (C _1-4 ) alkoxyphenyl group, lower (C _1-4 ) alkanoylphenyl group, phenyl group substituted by a 5-membered aromatic heterocyclic group, lower (C _1-4 ) alkoxy-carbonyl A lower ( _C1-4 ) alkyl-carbamoylphenyl group, a 1,3-diacylguanidino-lower ( _C1-4 ) alkylphenyl group, a phenyl group substituted with a halogen atom and a lower ( _C1-4 ) alkyl group. , halogen atom and lower (C _1-4) alkoxy - carbonyl-substituted phenyl, phenyl group substituted with a halogen atom and a cyano group, Androgenic atoms and 5-membered aromatic heterocycle-substituted phenyl group, a halogen atom and lower (C _1-4) alkoxy - carbonyl - lower (C
_1-4 ) A phenyl group substituted with an alkyl-carbamoyl group or the like is used. Ar and Ar ^a are preferably a phenyl group which may have a substituent, among which a halogenophenyl group, a lower (C _1-4 ) alkylphenyl group, a halogen atom and a lower (C _1-4 ) alkoxycarbonyl group are preferable. And a phenyl group substituted with a halogen atom and a lower (C _1-4 ) alkyl group. Ar and Ar ^a have the formula:

[0203]

Embedded image

Wherein R ⁴ and R ⁵ are the same or different and each represents a halogen atom or a lower alkyl group, and n represents an integer of 0 to 2. Are more preferable, and those in which at least one of R ⁴ and R ⁵ is a halogen atom are more preferable. The halogen atom represented by R ⁴ and R ⁵ is preferably a fluorine atom or a chlorine atom.

As the halogenophenyl group, for example,
2,3-difluorophenyl group, 2,3-dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2,5-difluorophenyl group, 2,5-dichlorophenyl group, 2,6-difluoro Phenyl group, 2,
6-dichlorophenyl group, 3,4-difluorophenyl group, 3,4-dichlorophenyl group, 3,5-difluorophenyl group, 3,5-dichlorophenyl group, 2-fluorophenyl group, 2-chlorophenyl group, 3-fluorophenyl Group, 3-chlorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-chloro-2-fluorophenyl group, 2-chloro-4-fluorophenyl group, 4
-Bromo-2-fluorophenyl group, 2,3,4-trifluorophenyl group, 2,4,5-trifluorophenyl group, 2,4,6-trifluorophenyl and the like are used. As the lower (C _1-4 ) alkylphenyl group, for example, a 2-ethylphenyl group, a 2,6-diisopropylphenyl group and the like are preferably used, and the lower (C _1-4 ) alkylphenyl group is preferably used.
As the alkoxyphenyl group, for example, 4-methoxyphenyl and the like are preferably used. The lower (C _1-4 ) alkoxy-carbonylphenyl group includes, for example, 2
-Ethoxycarbonylphenyl, 2-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, and the like are preferably used. Examples of the halogeno lower (C _1-4 ) alkylphenyl include 2-trifluoromethylphenyl. Are preferably used. Examples of the halogeno lower (C _1-4 ) alkoxyphenyl group include, for example,
2-trifluoromethoxyphenyl group, 4- (2,2,
A (3,3,3-pentafluoropropoxy) phenyl group is preferably used. As the lower (C _1-4 ) alkanoylphenyl group, for example, a 2-acetylphenyl group is preferably used, and as the phenyl group substituted with the 5-membered aromatic heterocyclic group, for example, 4- ( 2H-
1,2,3-triazol-2-yl) phenyl group, 4-
(2H-tetrazol-2-yl) phenyl group, 4-
(1H-tetrazol-1-yl) phenyl group, 4-
Etc. (IH-1,2,3-triazol-1-yl) phenyl group are preferably used, said lower (C _1-4) alkoxy - carbonyl - The carbamoyl phenyl group, - a lower (C _1-4) alkyl For example, a 4- (N-ethoxycarbonylmethylcarbamoyl) phenyl group is preferably used, and the 1,3-diacylguanidino-lower (C
_1-4 ) Examples of the alkylphenyl group include, for example, 4- (1,
A 3-bis-tert-butoxycarbonylguanidinomethyl) phenyl group and the like are preferably used. Examples of the phenyl group substituted with the halogen atom and a lower (C _1-4 ) alkyl group include a 2-fluoro-4-methylphenyl group, a 2-chloro-4-methylphenyl group, and a 4-fluoro-2- A methylphenyl group or the like is preferably used, and the halogen atom and lower (C _1-4 ) alkoxy-
As the phenyl group substituted with a carbonyl group, for example, a 2-chloro-4-methoxycarbonylphenyl group or the like is preferably used. As the phenyl group substituted with the halogen atom and a cyano group, 2-chloro-4- A cyanophenyl group or the like is preferably used. Examples of the phenyl group substituted with the halogen atom and a 5-membered aromatic heterocyclic group include 2-fluoro-4- (1H-1,2,4-triazole-1 -Yl) phenyl and the like are preferably used, and the halogen atom and lower (C _1-4 ) alkoxy-
Examples of the phenyl group substituted with a carbonyl-lower (C _1-4 ) alkyl-carbamoyl group include a 2-chloro-4- (N-tert-butoxycarbonylmethylcarbamoyl) phenyl group and a 2-chloro-4- ( An (N-ethoxycarbonylmethylcarbamoyl) phenyl group or the like is preferably used.

More specifically, as Ar and Ar ^a ,
In particular, a phenyl group, a phenyl group substituted by 1 to 3 (among them, 1 to 2) halogen atoms (eg, a 2,3-difluorophenyl group, a 2,3-dichlorophenyl group,
4-difluorophenyl group, 2,4-dichlorophenyl group, 2,5-difluorophenyl group, 2,5-dichlorophenyl group, 2,6-difluorophenyl group, 2,6-dichlorophenyl group, 3,4-difluorophenyl group 3,4
-Dichlorophenyl group, 3,5-difluorophenyl group, 3,5-dichlorophenyl group, 4-bromo-2-fluorophenyl group, 2-fluorophenyl group, 2-chlorophenyl group, 3-fluorophenyl group, 3-chlorophenyl group , 4-fluorophenyl group, 4-chlorophenyl group, 2-fluoro-4-chlorophenyl group, 2-chloro-4-fluorophenyl group, 2,3,4-trifluorophenyl group, 2,4,5-trifluoro Phenyl group), a phenyl group substituted with a halogen atom and a lower (C _1-4 ) alkyl group (eg, 2-chloro-4-methylphenyl group, 4-fluoro-2-methylphenyl group, etc.)
Are preferred. Among them, 1 to 3 (1 to 2
Phenyl groups substituted with halogen atoms (eg, 2,
3-dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2,6-dichlorophenyl group, 2-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 2-chloro-4-fluoro Phenyl group, 2,4,5-trifluorophenyl group, etc.), phenyl group substituted with a halogen atom and a lower (C _1-4 ) alkyl group (eg, 2-chloro-4-methylphenyl group, 4-fluoro -2-methylphenyl group, etc.)
Are preferred. In particular, a 2,4-difluorophenyl group, a 2-chlorophenyl group, a 2-chloro-4-fluorophenyl group, a 2-chloro-4-methylphenyl group and the like are preferable, and a 2,4-difluorophenyl group, a 2-chloro- group and the like are preferable. A 4-fluorophenyl group and the like are preferred.

In the present specification, ring A ¹ is (i) an aliphatic hydrocarbon group optionally having a substituent, (ii) an aromatic hydrocarbon group optionally having a substituent, (iii) Formula: -OR ¹¹
(In the formula, R ¹¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent.) And (iv) 1 to 4 substituents selected from halogen atoms. Represents an optionally substituted cycloalkene, (i) an aliphatic hydrocarbon group optionally having a substituent, (ii) an aromatic hydrocarbon group optionally having a substituent, and (iv) a halogen atom. Preferred are cycloalkenes optionally substituted with 1 to 4 selected from In the present specification, ring A ² is (i) an aliphatic hydrocarbon group optionally having a substituent, (ii) an aromatic hydrocarbon group optionally having a substituent, (iii) a formula:
—OR ¹¹ (wherein R ¹¹ is as defined above) and (iv) a cycloalkene substituted with 1 to 4 halogen atoms selected from the group consisting of (i) A cycloalkene substituted with 1 to 4 selected from an aliphatic hydrocarbon group which may have a group, (ii) an aromatic hydrocarbon group which may have a substituent, and (iv) a halogen atom Is preferred. These substituents (i) ~ (iv) is substituted on substitutable carbon atoms in the ring A ¹ and ring A ^2, ring A ¹
And when ring A ² is substituted with a plurality of substituents,
The types of those substituents may be the same or different. Further, two substituents may be substituted on the same carbon atom, or plural substituents may be substituted on different carbon atoms.

Examples of the “optionally substituted aliphatic hydrocarbon group” which is a substituent on ring A ¹ and ring A ² include, for example, R, R ¹ , R ¹¹ , R ^1a , R ^{1 1b} , ^R1c , ^R4a ,
The same as the “aliphatic hydrocarbon group which may have a substituent” represented by R ^5a can be used. Examples of the “aromatic hydrocarbon group optionally having substituent (s)” which is a substituent of ring A ¹ and ring A ² include, for example, the aforementioned Ar, A
It can be the same as the "optionally substituted aromatic hydrocarbon group" represented by r ^a. Examples of the “heterocyclic group optionally having substituent (s)” which is a substituent of ring A ¹ and ring A ² include, for example, the aforementioned R, R ¹ , R ¹¹ ,
The same as the “heterocyclic group” that is the “substituent” of the “optionally substituted aliphatic hydrocarbon group” represented by R ^1a , R ^1b , R ^1c , R ^4a , and R ^5a Can be used.

Examples of the substituent for the ring A ¹ and the ring A ² include one or two C _1-6 alkyl groups (eg, C _1-4 alkyl groups such as methyl group and tert-butyl group), phenyl group, Halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom)
And the like are preferably used.

Formula:

[0211]

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Wherein n is as defined above. A group represented by the formula:

[0213]

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Wherein n is as defined above. And a group represented by the formula:

[0215]

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Wherein n is as defined above. ] Is preferable.

Formula:

[0218]

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Wherein n is as defined above. A group represented by the formula:

[0220]

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Wherein n is as defined above. And a group represented by the formula:

[0222]

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Wherein n is as defined above. ] Is preferable.

Also, the formula:

[0225]

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A group represented by the formula:

[0227]

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And a group represented by the following formula:

[0229]

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Preferably, the group is represented by the formula: As an integer of 1 to 4 represented by n, 1 to 3 is preferable, and 2 is particularly preferable.

The compound represented by the formula (Iaa) includes a compound represented by the formula
The compound represented by the formula (Ibb ') is preferable, and the compound represented by the formula (Ia) is preferably the compound represented by the formula (Ib).
The compound represented by the formula (Ibb ') is preferably a compound represented by the formula (Inn), and the compound represented by the formula (Ib) is preferably a compound represented by the formula (In). Formula (Ibb '),
In the compound represented by (Ib), R ¹ is a lower alkyl group which may have a substituent, R ² is a hydrogen atom or a lower alkyl group, and Ar has a substituent. And n is preferably 1, 2 or 3, R ¹ is a lower alkyl group which may have a substituent, R ² is a hydrogen atom, and Ar is a halogen atom. And n is 2 is more preferable. As the compounds represented by the formulas (Icc) and (Ic), those in which Ar is a phenyl group which may have a substituent and n is 2 are preferable.

As the compound represented by the formula (I) or (Ia), specifically, the compound obtained in Reference Example B described later is used, and among them, d-ethyl 6- [N- (2 , 4-Difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate, ethyl 6- [N- (2-chlorophenyl) sulfamoyl] -1
-Cyclohexene-1-carboxylate, ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate, and ethyl (6R) -6-[(2-chloro- 4-Fluoranilino) sulfonyl] -1-cyclohexene-1-carboxylate and salts thereof are preferred.

The compound of the formula (II) will be described in detail. [1] Formula:

[0234]

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[Wherein R ^{1 ′} is an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, or a substituent. Heterocyclic group, formula:-
A group represented by OR ^{1a ′} (wherein R ^{1a ′} represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent), or a formula:

[0236]

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(Wherein, R ^{1b ′} and R ^{1c ′} are the same or different and each represent a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent). Is a methylene group, NH, a sulfur atom or an oxygen atom, Y is a methylene group which may have a substituent or NH which may have a substituent, and ring A ′ has (1) a substituent. An aliphatic hydrocarbon group which may be substituted, (2) an aromatic hydrocarbon group which may have a substituent, (3) a formula: —OR ^{2 ′} (where R ^{2 ′} is a hydrogen atom, or And (4) an aliphatic hydrocarbon group which may have a substituent.
A 5- to 8-membered ring which may be further substituted with 1 to 4 selected from halogen atoms, and Ar 'represents an aromatic hydrocarbon group which may have a substituent, having the formula:

[0238]

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The group represented by the formula:

[0240]

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Wherein s is an integer of 0 to 2;
t represents an integer of 1 to 3, and the sum of s and t is 4 or less. However, when X is a methylene group, Y represents a methylene group which may have a substituent. Or a salt thereof,

[2] R^{1 '}Is (i) C_1-20Alkyl group, C
_3-10Cycloalkyl group, C_4-12Cycloalkylalkyl
Group, C_3-6Alkenyl group and C_3-6Select from alkynyl groups
Aliphatic hydrocarbon groups (these aliphatic hydrocarbon groups are heterocyclic groups, oxo groups,
Group, C_1-6Alkoxy group, C_3-10Cycloalkyloxy
Group, C_6-10Aryloxy group, C_7-19Aralkyloxy
Group, heterocyclic oxy group, C_1-6Alkylthio group (the sulfur source
May be oxidized), C_3-10Cycloal
A quinthio group (the sulfur atom may be oxidized
I), C_6-10Arylthio group (the sulfur atom is oxidized
), C_7-19Aralkylthio group (the sulfur
An atom may be oxidized), a heterocyclic thio group,
Heterocyclic sulfinyl group, heterocyclic sulfonyl group, nitro
Group, halogen atom, cyano group, carboxyl group, C_1-10
Alkoxy-carbonyl group, C_{3- 6}Cycloalkyloxy
C-carbonyl group, C_6-10Aryloxy-carbonyl
Group, C_7-19Aralkyloxy-carbonyl group, heterocyclic
Xycarbonyl group, C_6-10Aryl-carbonyl group, C
_1-6Alkanoyl group, C_3-5Alkenoyl group, C_6-10Ants
Carbonyloxy group, C_2-6Alkanoyloxy
Group, C_3-5Alkenoyloxy group, carbamoyl group (C
_1-4Alkyl, phenyl, C_1-7Acyl and C _1-4Al
With one or two substituents selected from coxy-phenyl
Optionally substituted), a thiocarbamoyl group (C_1-4
One or two positions selected from alkyl and phenyl
Carbamoyloxy group)
(C_1-4One selected from alkyl and phenyl or
Optionally substituted with two substituents), C_1-6Arca
Noylamino group, C_6-10Aryl-carbonylamino
Group, C_1-10Alkoxy-carboxamide group, C_6-10Ants
Oxy-carboxamide group, C_7-19Aralkyl
C-carboxamide group, C_1-10Alkoxy-carbonyl
Oxy group, C_6-10Aryloxy-carbonyloxy
Group, C_7-19Aralkyloxy-carbonyloxy group, C
_3-10A cycloalkyloxy-carbonyloxy group and
Ureido group (C_1-4Select from alkyl and phenyl groups
May be substituted with one to three substituents)
Selected from the group consisting of
C which may have 1 to 4 substituents_6-10Ally
Selected from the group consisting of
It may have 1 to 4 groups. The heterocycle is a carbon atom
Nitrogen atom (which may be oxidized), acid
1 to 1 heteroatoms selected from elementary atoms and sulfur atoms
A 5- to 8-membered heterocyclic group containing 4 or a fused ring group thereof
Then C_1-4Alkyl, hydroxy, oxo and C_1-4A
Having one to three substituents selected from lucoxy,
Is also good. The above substituents are combined with the aliphatic hydrocarbon group.
And has 1 to 4 substituents selected from substituent group B
May form a condensed ring group which may be

(Ii) C _6-14 aryl group (this C _6-14 aryl group is a halogen atom, C _1-4 alkyl group, C _1-4 alkoxy group, C _1-4 alkoxy-carbonyl group, carboxyl group, Nitro group, cyano group, hydroxyl group,
C _1-4 alkanoylamino group, C _3-6 cycloalkyl group,
C _6-10 aryl group, halogeno C _1-4 alkyl group, halogeno C _1-4 alkoxy group, C _1-4 alkylthio group, C _1-4 alkylsulfonyl group, C _1-4 alkanoyl group, 5-membered aromatic heterocyclic group, a carbamoyl group, C _1-4 alkyl - carbamoyl group, C _1-4 alkoxy - carbonyl -C _1-4 alkyl - carbamoyl group and 1,3-diacylguanidino -C _1-4 group consisting of alkyl groups ( Hereinafter, substituent group C)
And may have 1 to 5 substituents selected from

(Iii) A 5- to 8-membered heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom (which may be oxidized), an oxygen atom and a sulfur atom other than a carbon atom, or a condensed ring group thereof (This heterocyclic group may have 1 to 3 substituents selected from C _1-4 alkyl, hydroxy, oxo and C _1-4 alkoxy), (iv) Formula: —OR ^{1a ′} (Wherein, R ^{1a ′} is a hydrogen atom or a C which may have a substituent selected from substituent group B)
_1-20 alkyl group, C _3-10 cycloalkyl group, C _4-12 cycloalkyl alkyl group, C _3-6 alkenyl group and C _3-6
Shows an aliphatic hydrocarbon group selected from alkynyl groups. )
Or a group represented by the formula (v):

[0245]

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[0246] (wherein, R ^{1b 'and} R ^1c' are the same or different and each represents a hydrogen atom respectively or may have a substituent group selected from substituent group B group C _1-20 alkyl group,, C _{3- Ten}
Cycloalkyl group, C _4-12 cycloalkylalkyl group,
It represents an aliphatic hydrocarbon group selected from a C _3-6 alkenyl group and a C _3-6 alkynyl group. )

X represents a methylene group, NH, a sulfur atom or an oxygen atom; Y represents (i) a C _1-6 alkyl group, a hydroxy-substituted C _1-6 alkyl group and a C _1-4 alkoxy-carbonyl-C _{1- A} methylene group which may have a substituent selected from ₄ alkyl groups, or (ii) a C _1-6 alkyl group, a hydroxy-substituted C _1-6 alkyl group and a C _1-4 alkoxy-
NH which may have a substituent selected from a carbonyl-C _1-4 alkyl group is substituted with C _1-20 wherein ring A ′ may have a substituent selected from (1) Substituent B group. Alkyl group,
C _3-10 cycloalkyl group, C _4-12 cycloalkylalkyl group, an aliphatic hydrocarbon group selected from C _3-6 alkenyl and C _3-6 alkynyl group, a substituted selected from (2) substituent group C A C _6-14 aryl group _optionally having a group,
(3) Formula: —OR ^{2 ′} (wherein, R ^{2 ′} is a hydrogen atom or C _1-20 which may have a substituent selected from substituent group B)
Alkyl group, a C _3-10 cycloalkyl group, C _4-12 cycloalkylalkyl group, an aliphatic hydrocarbon group selected from C _3-6 alkenyl and C _3-6 alkynyl group. And (4) a 5- to 8-membered ring which may be further substituted with 1 to 4 members selected from halogen atoms,

Ar ′ is a C _6-14 aryl group which may have a substituent selected from substituent group C,

[0249]

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The group represented by the formula:

[0251]

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S is an integer of 0 to 2,
the compound according to [1], wherein t represents an integer of 1 to 3, and the sum of s and t is 4 or less;

[3] a 5- to 8-membered ring in which ring A ′ may be substituted with lower alkyl, phenyl or halogen,
R1 ^′ is a group represented by the formula: —OR1a ^′ and ^{R1a ′} is a lower alkyl group which may have a substituent, and Ar ′ is a phenyl group which may have a substituent. [4] R
The compound of [3], wherein ^{1a '} is an ethyl group, [5]
Ar 'is a halogenophenyl group, a lower alkylphenyl group, or a phenyl group substituted with halogen and lower alkyl, the compound according to item [3], wherein [6] Ar' is
formula:

[0254]

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(Wherein R ^{3 ′} represents a halogen atom or a lower alkyl group, and ring B ′ may be further substituted with a halogen atom). Compound,

[7] Formula:

[0257]

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A group represented by the formula:

[0259]

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The compound according to item [1], wherein [8] Ar ′ is a group represented by the formula:

[0261]

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(Wherein R ^{3a ′} and R ^{3b ′} are the same or different and each represent a halogen atom).

[9] R ^{1 ′} is a formula: —OR
A group represented by ^{1a ′} (R ^{1a ′} represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent);
t Compounds of the is the [1], wherein 1, [10] R ^1: a ^'has the formula -OR ^1a' (R ^{1a ''} represents a C _1-6 alkyl group), a group represented by the formula :

[0263]

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A group represented by the formula:

[0265]

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X is a methylene or oxygen atom, Y is a methylene or -NH-, and Ar 'is one or two substituents selected from the group consisting of a halogen atom and C _1-6 alkoxy. A compound according to item [1], which represents a phenyl group which may have a group,

[11] R ^{1 ′} is a group represented by the formula: —OR ^{1a ′} (R ^{1a ′} is C
_1-6 alkyl group) is represented by the formula:

[0268]

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A group represented by the formula:

[0270]

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X is methylene and Y is methylene, or X is an oxygen atom and Y is -NH-,
A phenyl group in which Ar ′ may have two halogen atoms (eg, 2-chloro-4-fluorophenyl group, etc.)
The compound according to item (1), wherein [12] ethyl 6-
[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate, ethyl (+)-6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1- Carboxylate or ethyl 3-[(2-chloro-4-
Fluorophenyl) sulfamoyl] -3,6-dihydro-2H-
Pyran-4-carboxylate,

In the present specification, R ^{1 ′} represents an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, or a group which may have a substituent. A good heterocyclic group, a group represented by the formula: -OR ^{1a '} or a group represented by the formula (a) is shown, and a group represented by the formula: -OR ^1a' is particularly preferable. R ^{1 ′} “optionally substituted aliphatic hydrocarbon group”, “optionally substituted aromatic hydrocarbon group”, “optionally substituted substituent” As the “heterocyclic group” and the “group represented by the formula: —OR ^{1a ′} ”, those similar to those in R can be used.

The “optionally substituted aliphatic hydrocarbon group” for R ^{1a ′} includes, for example, the aforementioned “optionally substituted aliphatic hydrocarbon group” for R. The same thing as "hydrogen group" can be used. R ^{1a ′} is, for example, C ^{1 to} C 6 which may have a substituent.
Lower alkyl groups (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butoxycarbonylmethyl group, hydroxyethyl group, etc.) are preferably used. For example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group and the like are preferably used. Inter alia, for example, methyl, ethyl, n-
A propyl group and the like are preferable, and among them, an ethyl group and the like are preferable.

Examples of the “optionally substituted aliphatic hydrocarbon group” represented by R ^{1b ′} and R ^{1c ′} include, for example,
The same ones as the “aliphatic hydrocarbon group which may have a substituent” represented by R described above can be used. R
^{As 1b '} and ^R1c' , for example, a lower alkyl group having 1 to 6 carbon atoms which may have a substituent (eg, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-
Butyl group, isobutyl group, tert-butoxycarbonylmethyl group, hydroxyethyl group and the like are preferably used, and among them, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group And the like are preferably used. Particularly, for example, a methyl group, an ethyl group, an n-propyl group and the like are preferable, and among them, an ethyl group and the like are preferable.

As R ^{1 ′} , for example, a lower alkyl group having 1 to 6 carbon atoms which may have a substituent (eg, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-
Butyl group, isobutyl group, tert-butoxycarbonylmethyl group, hydroxyethyl group and the like are preferably used, and among them, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group And the like are preferably used. Particularly, for example, a methyl group, an ethyl group, an n-propyl group and the like are preferable, and among them, an ethyl group and the like are preferable.

Examples of the “substituent” in the “methylene group which may have a substituent” represented by Y include, for example,
C _1-6 alkyl group (for example, methyl group, ethyl group, n-
Propyl group, isopropyl group, n-butyl group, isobutyl group, etc.), hydroxy-substituted C _1-6 alkyl group (eg, hydroxymethyl group, hydroxyethyl group, etc.),
C _1-4 alkoxy-carbonyl-C _1-4 alkyl group (for example, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, tert-butoxycarbonylmethyl group, methoxycarbonylethyl group, ethoxycarbonylethyl group,
tert-butoxycarbonylethyl group and the like), among which a methyl group is preferable, and an unsubstituted methylene is particularly preferable.

As the “substituent” in the “NH which may have a substituent” represented by Y, a C _1-6 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl group, isobutyl group, etc.), hydroxy-substituted C _1-6 alkyl group (eg, hydroxymethyl group, hydroxyethyl group, etc.), C _1-4 alkoxy-carbonyl-C _1-4 alkyl group (eg, methoxy group) Carbonylmethyl group, ethoxycarbonylmethyl group, tert
-Butoxycarbonylmethyl group, methoxycarbonylethyl group, ethoxycarbonylethyl group, tert-butoxycarbonylethyl group, etc.), among which a methyl group is preferable, and unsubstituted NH is particularly preferable.

The “aromatic hydrocarbon group optionally having substituent (s)” represented by Ar ′ is the same as the “aromatic hydrocarbon group optionally having substituent (s)” in Ar. Can be used. In particular, Ar ′ is preferably the same as Ar, but is particularly preferably a group represented by the formula (c), and more preferably a group represented by the formula (c1).

In the formula (c), the halogen atom represented by R ^{3 ′} and the halogen atom which is a substituent of the ring B ′ and the formula (c)
In 1), the halogen atom represented by R ^{3a ′} and R ^{3b ′} is preferably a fluorine atom or a chlorine atom. Equation (c)
In the formula, examples of the lower alkyl group represented by R ^{3 ′} include C _1-4 alkyl groups such as methyl, ethyl and propyl. Among the groups represented by the formula (c), a 2,4-difluorophenyl group, a 2-chloro-4-fluorophenyl group, a 2-methyl-4-chlorophenyl group and the like are preferable, and a group represented by the formula (c1) Among these groups, a 2,4-difluorophenyl group, a 2-chloro-4-fluorophenyl group and the like are preferable.

X represents a methylene group, NH, a sulfur atom or an oxygen atom, and among them, NH, a sulfur atom or an oxygen atom is preferable. Ring A ′ has the formula: —CO—R ^{1 ′} (wherein, R ^{1 ′}
Is as defined above. And a group represented by the formula: -SO
_2- Y-Ar '(wherein, Y and Ar' have the same meanings as described above), and (i) an aliphatic carbon which may have a substituent. Hydrogen group, (i
i) an aromatic hydrocarbon group which may have a substituent,
i) a group represented by the formula: -OR ^{2 '} (wherein R ^2' has the same meaning as described above) and (iv) 1 to 4 substituents selected from the group consisting of halogen atoms. Shows a 5- to 8-membered ring which may be substituted, (i) an aliphatic hydrocarbon group which may have a substituent, (ii) an aromatic hydrocarbon group which may have a substituent, and (Iv) 5 to 8 optionally substituted with 1 to 4 substituents selected from halogen atoms
Member rings are preferred.

These substituents may be substituted at substitutable positions on ring A ′. When X constituting the ring is NH or a methylene group, the NH or the methylene group can be substituted. When ring A ′ is substituted with a plurality of substituents, the types of those substituents may be the same or different. Further, two substituents may be substituted on the same carbon atom.

Examples of the “optionally substituted aliphatic hydrocarbon group” and the “optionally substituted aromatic hydrocarbon group” which are the substituents on ring A ′ include, for example, those described above. And the same as those for R in the above.

As the “aliphatic hydrocarbon group optionally having substituent (s)” for R ^{2 ′} , for example, those similar to the aforementioned groups for R can be mentioned.

Examples of the substituent for ring A ′ include one or two C _1-6 alkyl groups (eg, C _1-4 alkyl groups such as methyl group and tert-butyl group), a phenyl group, a halogen atom (eg, ,
Fluorine, chlorine, bromine, iodine, etc.) are preferably used. s represents an integer of 0 to 2, t represents an integer of 1 to 3, and the sum of s and t is 4 or less, and it is preferable that s is 1 and t is 1.

As the compound represented by the formula (II), for example, the following compounds are preferred. (1) R ^{1 ′} has the formula: —O
A group represented by R ^{1a ′} (R ^{1a ′} represents a C _1-6 alkyl group);

[0286]

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A group represented by the formula:

[0288]

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Wherein X is a methylene or oxygen atom, Y is methylene or -NH-,
And compound (II), wherein Ar ′ is a phenyl group optionally having one or two substituents selected from the group consisting of a halogen atom and C _1-6 alkoxy.

(2) R ^{1 ′} is a formula: —OR ^{1a ′} (R ^{1a ′} is C
_1-6 alkyl group), which is represented by the formula:

[0291]

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A group represented by the formula:

[0293]

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Wherein X and Y are both methylene, or X is an oxygen atom, Y is -NH-, and Ar 'has two halogen atoms. Compound (II) which is a good phenyl group (eg, 2-chloro-4-fluorophenyl group and the like).

(3) Ethyl 6- (benzylsulfonyl) -1
-Cyclohexene-1-carboxylate (compound 1), ethyl 6-[(4-methoxybenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 2), ethyl 6-
[(2,4-difluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 3), ethyl 6-[(2-
Chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 4), ethyl (-)-6-
[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 5), ethyl (+)
-6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 6), ethyl
3-[(2,4-difluorophenyl) sulfamoyl] -3,6-
Dihydro-2H-pyran-4-carboxylate (compound 7),
And ethyl 3-[(2-chloro-4-fluorophenyl) sulfamoyl] -3,6-dihydro-2H-pyran-4-carboxylate (compound 8).

(4) Ethyl 6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 4), ethyl (+)-6-[(2-chloro-4 -Fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 6) and ethyl 3-[(2-chloro
-4-fluorophenyl) sulfamoyl] -3,6-dihydro-2
H-pyran-4-carboxylate (compound 8).

Formulas (I), (Iaa), (Ibb), (Icc),
(Ia), (Ib), (Ic), (Id), (Ie), (If),
When stereoisomers are present in the compounds represented by (Ig) and (II), each of the stereoisomers and a mixture of these stereoisomers is included in the present invention. Further, when the compound represented by the formula (Iaa) is a compound represented by the formula (Icc) or (Inn), the compound represented by the formula (Ia) is represented by the formula (Ic) or (In). When the compound represented by the formula (Ie) is a compound represented by the formula (Ik) or (Ip), the compound represented by the formula (Id) is represented by the formula (Ir) If the compound is
When the compound represented by the formula (Ig) is the compound represented by the formula (It), and when the compound represented by the formula (II) has the formula (b) represented by the formula (b1), and s and t are In the case of 1, there are optical isomers each based on the asymmetric carbon in the cycloalkene or cyclohexene ring, and each optical isomer and a mixture of these optical isomers are included in the present invention. Things.

Compound (I) used in the medicament of the present invention,
(Iaa), (Ia), (Ib), (Ic), (Id), (Ie),
(If), (Ig), (Ibb), (Icc), and (II) (hereinafter collectively abbreviated as compound A) include, for example, a salt with an inorganic base, a salt with an organic base, and an inorganic acid. , Salts with organic acids, salts with basic or acidic amino acids, and the like. Examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt and ammonium salt. For example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like are used. As salts with inorganic acids, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like are used.As salts with organic acids, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, Salts with oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like are used. As a salt with a basic amino acid, for example, a salt with arginine, lysine, ornithine and the like, and as a salt with an acidic amino acid, for example,
Salts with aspartic acid, glutamic acid and the like are used.

The prodrug of compound A or a salt thereof is
A compound that is converted into compound A by a reaction with an enzyme or stomach acid under physiological conditions in a living body, that is, a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. to change into compound A, or hydrolyzed by stomach acid, etc. Means a compound that changes to compound A. As a prodrug of compound A, the amino group of compound A is acylated, alkylated,
Phosphorylated compounds (e.g., when the amino group of compound A is eicosanoylated, alanylated, pentylaminocarbonylated, 2-hydroxypropionylated, 2-acetoxypropionylated, (5-methyl-2-oxo-1,3- Dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound, etc.); the hydroxyl group of compound A is acylated, alkylated, phosphorylated, Borated compounds (eg, compounds in which the hydroxyl group of compound A is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumalylated, alanylated, dimethylaminomethylcarbonylated, etc.); the carboxyl group of compound A Is an esterified or amidated compound (eg, compound A Carboxyl group with ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2
-Oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compound, and the like). These compounds are prepared by a method known per se.
It can be prepared from compound A. Further, the prodrug of Compound A may be a compound that changes to Compound A under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, pp. 163 to 198, Molecular Design. Good.

Compound (I) or a salt thereof or a prodrug thereof can be produced by a method known per se, for example, WO99 / 4
Compound (II) or a salt thereof or a prodrug thereof can be produced according to the production method described in 6242 or a method analogous thereto, and according to the production method described in WO 01/10826 or a method analogous thereto.

Incidentally, among the compounds A, d-ethyl 6- [N- (2
-Chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (ethyl (6R) -6-[(2-
Chloro-4-fluoroanilino) sulfonyl] -1-cyclohexene-1-carboxylate) (hereinafter referred to as “Compound B
Crystal) is d-ethyl 6- [N- (2
-Chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (ethyl (6R) -6-[(2-
Chloro-4-fluoroanilino) sulfonyl] -1-cyclohexene-1-carboxylate) can be produced by crystallization by a method known per se.

[0302] Examples of such a crystallization method include crystallization from a solution, crystallization from steam, and crystallization from a melt. Examples of the method of “crystallization from a solution” include a concentration method, a cooling method, a reaction method (diffusion method, electrolysis method), a hydrothermal growth method, and a flux method. Examples of the solvent used include aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), and saturated hydrocarbons (eg, hexane, heptane, cyclohexane, etc.) ), Ethers (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.),
Nitriles (eg, acetonitrile, etc.), ketones (eg,
Acetone, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), acid amides (eg, N, N-dimethylformamide, etc.), esters (eg, ethyl acetate, etc.), alcohols (eg, methanol, ethanol, isopropyl alcohol) Etc.), water and the like. These solvents may be used alone or in an appropriate ratio of two or more (eg, 1: 1 to 1:
100). Preferably, ethanol, methanol, isopropyl alcohol, hexane,
Heptane, diisopropyl ether, ethyl acetate, water and the like are used, and these solvents are used alone or as a mixture of two or more kinds at an appropriate ratio (eg, 1: 1 to 1: 100).

The method of “crystallization from steam” is as follows.
For example, a vaporization method (sealed tube method, air flow method), a gas phase reaction method, a chemical transport method, and the like can be mentioned. Examples of the method of “crystallization from the melt” include a normal freezing method (pulling method, temperature gradient method, Bridgman method), a zone melting method (zone leveling method, a float zone method), and a special growth method (VL).
S method, liquid phase epitaxy method) and the like.

As a method of analyzing the obtained crystal, a method of crystal analysis by X-ray diffraction is generally used. Further, as a method of determining the crystal orientation, a mechanical method or an optical method may be used. d-ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (ethyl (6R) -6-[(2-chloro
-4-fluoroanilino) sulfonyl] -1-cyclohexene-1
-Carboxylate) or a salt thereof is a known substance;
For example, it can be produced by the method described in WO 99/46242 or a method analogous thereto. By applying this to the above-mentioned crystallization method, a crystal of compound B is obtained.

The crystals of Compound B have a melting point of, for example, about 60 ° C. or more, preferably about 65 ° C. to about 75 ° C., more preferably about 67 ° C. to about 70 ° C. Surface spacing (d value) about 10.3, about 9.28, about 6.7
2, about 5.89, about 5.16, about 4.54, about 4.3
8, about 3.59, about 3.52, about 3.45, about 3.39
The diffraction pattern having a characteristic peak at Angstrom is shown. The crystals of compound B are high-purity (99% or more in purity), high-quality, have low hygroscopicity, do not deteriorate even under long-term storage under ordinary conditions, and are extremely excellent in stability. Also, a compound of formula (I) or a salt thereof,

[0306]

Embedded image

[Wherein, X represents a halogen atom, and other symbols have the same meanings as described above. ] Or a salt thereof is represented by the formula

[0308]

Embedded image

Wherein each symbol is as defined above. ]
And a salt thereof with a halogenating agent.

Examples of the halogenating agent include halogen atoms (eg, chlorine atom, bromine atom, iodine atom, etc.), hydrohalic acids (eg, hydrogen chloride, hydrogen bromide, etc.), organic acid chlorides (eg, oxalyl chloride) And the like, N-haloamides (eg, N-chlorosuccinamide, N-bromosuccinamide, etc.), halogenated Meldrum's acid (eg, dibromomerdrum's acid, etc.), thionyl chloride and the like.

The amount of the halogenating agent to be used is generally 1.0 to 15 equivalents, relative to compound (IIIa) or a salt thereof.

Examples of the reaction solvent include sulfoxides (eg, dimethyl sulfoxide), ethers (eg, diethyl ether, dioxane, etc.), nitriles (eg, acetonitrile, etc.), and aromatic hydrocarbons (eg, benzene, etc.). , Toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,
2-dichloroethane, etc.), esters (eg, ethyl acetate, etc.), amides (eg, dimethylformamide, acetamide, dimethylacetamide, 1,3-dimethyl-2-imidazoline, 1-methyl-2-pyrrolidone, etc.), organic Acids (eg, acetic acid, etc.), water and the like are used. These solvents may be used alone or as a mixture. The reaction temperature is generally -50 to 100C, preferably -30 to 4
0 ° C. The reaction time is generally 0.1 to 6 hours, preferably 0.3 to 3 hours.

When the optically active compound or a salt thereof contains an enantiomer, it is separated by an ordinary separation method, for example, an optically active acid (eg, camphorsulfonic acid or the like) or an optically active base (eg, Diastereomer salt method to form a salt with 1-methylbenzylamine or optically active host molecule (eg, 1,6-bis (2-chlorophenyl)
Inclusion compound method using -1,6-diphenylhexa-2,4-diyne-1,6-diol), various types of chromatography (eg, liquid chromatography using an optically active column), separation by fractional recrystallization, etc. By means, optically pure compounds can be obtained. Compound A or a salt thereof or a prodrug thereof may be a hydrate or an anhydrate. Compound A or a salt thereof or a prodrug thereof is an isotope (eg, ³ H, ¹⁴ C,
³⁵ S, ¹²⁵ I etc.).

Compound A has high safety to the human body,
Pharmaceuticals (eg, prophylactic / therapeutic agents for various diseases), veterinary drugs, etc., mammals (eg, rats, mice, guinea pigs,
Monkey, cow, dog, pig, human, etc.). Compound A has a low toxicity and has an inhibitory action on nitric oxide (NO) production and an inhibitory action on the production of inflammatory cytokines such as TNF-α, IL-1, and IL-6. For example, cats, cows, dogs, horses, goats, monkeys, humans, etc.) heart disease, autoimmune disease, inflammatory disease,
Diseases such as central nervous system diseases, infectious diseases, sepsis, septic shock, hypoimmune function, such as sepsis,
Endotoxin shock, exotoxic shock, systemic inflammatory response syndrome (SIRS), compensatory anti-inflammatory response syndrome (CARS), burn, trauma, postoperative complications, heart failure, shock, hypotension, rheumatoid arthritis, osteoarthritis, gastritis, Ulcerative colitis, peptic ulcer, stress gastric ulcer, Crohn's disease,
Autoimmune disease, tissue damage and rejection after organ transplantation,
Ischemic reperfusion injury, acute coronary microvascular embolism, shock vascular embolism (such as disseminated intravascular blood coagulation (DIC)), ischemic encephalopathy, arteriosclerosis, pernicious anemia, Fanconi anemia, sickle cell anemia , Pancreatitis, nephrotic syndrome, nephritis, renal failure, insulin-dependent diabetes, non-insulin-dependent diabetes, hepatic porphyria, alcoholism, Parkinson's disease, chronic leukemia, acute leukemia, tumor, myeloma,
Infant and adult respiratory distress syndrome, emphysema, dementia, Alzheimer's disease, multiple sclerosis, vitamin E deficiency, aging, sunburn, muscular dystrophy, myocarditis, cardiomyopathy,
Myocardial infarction, sequelae of myocardial infarction, osteoporosis, pneumonia, hepatitis, psoriasis, pain, cataract, influenza infection, malaria,
Human immunodeficiency virus (HIV) infection, radiation damage,
Burns, in vitro fertilization efficiency, hypercalcemia, ankylosing spondylitis, osteopenia, bone Pechet disease, osteomalacia, fractures, acute bacterial meningitis, Helicobacter pylori infection,
Invasive staphylococcal infections, tuberculosis, systemic fungal infections,
Herpes simplex virus infection, varicella-zoster virus infection, human papillomavirus infection, acute viral encephalitis, encephalitis, meningitis, reduced immune function associated with infection, asthma, atopic dermatitis, allergic rhinitis, reflux Esophagitis, fever, hypercholesterolemia, hyperglyceridemia,
Hyperlipidemia, diabetic complications, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, gout, gastric atony, hemorrhoids, systemic lupus erythematosus, spinal cord injury, insomnia, schizophrenia, epilepsy, cirrhosis, Liver failure, unstable angina, valvular heart disease,
Dialysis thrombocytopenia or hypotension, acute ischemic stroke, acute cerebral thrombosis, cancer metastasis, bladder cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, ovarian cancer, prostate cancer, small cell lung cancer,
It can be used as a prophylactic / therapeutic agent for non-small cell lung cancer, malignant melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, side effects due to administration of anticancer drugs or immunosuppressive drugs, especially prophylactic / therapeutic agents such as sepsis and septic shock Useful as

Therefore, the concomitant drug of the present invention containing an anti-sepsitic drug such as Compound A or a salt thereof or a prodrug thereof can be used in mammals (eg, cats, cows, dogs, horses, goats, monkeys, humans, etc.). Heart disease, autoimmune disease,
Inflammatory disease, central nervous system disease, infectious disease, sepsis,
Disorders such as septic shock, hypoimmune disorders, such as sepsis, endotoxin shock, exotoxin shock, systemic inflammatory response syndrome (SIRS), compensatory anti-inflammatory response syndrome (CARS), burns, trauma, post-operative complications, Heart failure, shock, hypotension, rheumatoid arthritis, osteoarthritis,
Gastritis, ulcerative colitis, peptic ulcer, stress gastric ulcer,
Crohn's disease, autoimmune disease, tissue damage and rejection after organ transplantation, ischemia-reperfusion injury, acute coronary microvascular embolism, shock vascular embolism (such as disseminated intravascular blood coagulation (DIC)), ischemic brain injury , Arteriosclerosis, pernicious anemia, Fanconi anemia, sickle cell anemia, pancreatitis, nephrotic syndrome, nephritis, renal failure, insulin-dependent diabetes, non-insulin-dependent diabetes, hepatic porphyria, alcoholism, Parkinson's disease, Chronic leukemia, acute leukemia, tumor, myeloma, reduced side effects of anticancer drugs, infant and adult respiratory distress syndrome, emphysema, dementia, Alzheimer's disease, multiple sclerosis, vitamin E deficiency, aging, sunburn, muscular dystrophy, myocarditis, myocardium Disease, myocardial infarction, sequelae of myocardial infarction, osteoporosis, pneumonia, hepatitis, psoriasis, pain, cataract, influenza infection Malaria, human immunodeficiency virus (HIV) infection, radiation injury, burns, in vitro fertilization efficiency, hypercalcemia, ankylosing spondylitis, osteopenia, bone Petchet disease, osteomalacia, fractures, acute bacterial meninges Inflammation, Helicobacter pylori infection, invasive staphylococcal infection, tuberculosis, systemic fungal infection, herpes simplex virus infection, varicella-zoster virus infection, human papillomavirus infection, acute viral encephalitis, encephalitis, marrow Meningitis, reduced immune function associated with infectious diseases, asthma, atopic dermatitis, allergic rhinitis, reflux esophagitis, fever, hypercholesterolemia, hyperglyceridemia, hyperlipidemia, diabetic complications, diabetes Sexual nephropathy, diabetic neuropathy, diabetic retinopathy, gout, gastric atony, hemorrhoids, systemic lupus erythematosus, spinal cord injury, insomnia, schizophrenia, epilepsy Cirrhosis, liver failure, unstable angina, valvular heart disease, thrombocytopenia or hypotension due to dialysis, acute ischemic stroke, acute cerebral thrombosis, cancer metastasis, bladder cancer, breast cancer, cervical cancer, colorectal cancer , Gastric cancer, ovarian cancer, prostate cancer, small cell lung cancer, non-small cell lung cancer, malignant melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, can be used as a prophylactic / therapeutic agent such as side effects due to administration of immunosuppressants. It is useful as a prophylactic / therapeutic agent for sepsis and septic shock.

Examples of drugs that can be used in combination with Compound A (hereinafter sometimes abbreviated as concomitant drugs) include, for example, antibacterial drugs,
Antifungals, non-steroidal anti-inflammatory drugs, steroids, anticoagulants, platelet aggregation inhibitors, thrombolytics, immunomodulators,
Antiprotozoal drugs, antibiotics, antivirals, antitussives / antiseptic,
Sedatives, anesthetics, anti-ulcer drugs, arrhythmic drugs, antihypertensive diuretics, tranquilizers, antipsychotics, antitumor drugs, antihyperlipidemic drugs, muscle relaxants, antiepileptics, antidepressants, antidepressants Allergic, inotropic, arrhythmic, vasodilator, vasoconstrictor,
Antihypertensive diuretics, antidiabetic drugs, narcotic antagonists, vitamins,
Vitamin derivatives, arthritis drugs, antirheumatic drugs, antiasthmatic drugs, pollakiuria / urinary incontinence drugs, atopic dermatitis drugs, allergic rhinitis drugs, vasopressors, proteolytic drugs, proteolytic enzyme inhibitors, SIDS drugs, anti-sepsis drugs, anti-septic shock drugs, endotoxin antagonists or antibodies, signal transduction inhibitors, inflammatory mediator action inhibitors, inflammatory mediator action inhibitory antibodies,
Inflammatory mediator production inhibitors, anti-inflammatory mediator action inhibitors, anti-inflammatory mediator action inhibitory antibodies, anti-inflammatory mediator production inhibitors, α1 adrenergic agonists, etc. Steroidal anti-inflammatory drugs, steroid drugs, anticoagulants and the like are preferred. Specifically, the following are mentioned.

(1) Antibacterial agents Sulfa drugs Sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole, salazosulfapyridine, silver sulfadiazine and the like. Quinoline antibacterials nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosfloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin and the like. Antituberculous drugs isoniazid, ethambutol (ethambutol hydrochloride), paraaminosalicylic acid (calcium paraaminosalicylate), pyrazinamide, ethionamide, prothionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and the like. Mycobacterials, such as diphenylsulfone and rifampicillin. Antivirals idoxuridine, acyclovir, vitarabine, ganciclovir and the like. Anti-HIV drugs Zidovudine, didanosine, zalcitabine, indinavir sulfate ethanol adduct, ritonavir and the like. Anti-spirochetes Antibiotics Tetracycline hydrochloride, Ampicillin, Piperacillin,
Gentamicin, dibekacin, canendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomycin, tetracycline, oxytetracycline, lolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalotin, cephapirin, cephaloridine, cephachlorexil, cephachlorexil, cephachlorexil, cephachlorexil , Cefamandor, cephtoam, cefuroxime,
Cefotiam, cefotiam hexetil, cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime, cefpyramide, cefsulodin, cefmenoxime, cefpodoxime proxetil, cefpirom, cefazoplan, cefepime, cefxemozine, cefumezine, cefximezine
Cefbuperazone, latamokinasef, flomoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, azthreonam or a salt thereof, griseofulvin, lancasidines [J. Antibiotics (J.
5 (1985)]. (2) Antifungals Polyethylene antibiotics (eg, amphotericin B, nystatin, tricomycin) Griseofulvin, pyrrolnitrin, etc. Cytosine antimetabolites (eg, flucytosine) Imidazole derivatives (eg, econazole, clotrimazole, miconazole nitrate, bifonazole) , Croconazole) Triazole derivatives (eg, fluconazole, itraconazole, azole compounds [2-[(1R, 2R)-
2- (2,4-difluorophenyl) -2-hydroxy-1-methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3 , 3
-Tetrafluoropropoxy) phenyl] -3 (2H,
4H) -1,2,4-triazolone) Thiocarbamic acid derivatives (eg, trinaphthol) Echinocandin-based derivatives (eg, caspofungin, micafungin, anidurafungin) and the like. (3) Non-steroidal anti-inflammatory drugs acetaminophen, phenacetin, etenzamid, sulpyrine, antipyrine, migrenine, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin , Flurbiprofen, fenbufen, pranoprofen, flotafenin, epilizol, tiaramid hydrochloride, zaltoprofen, gabexate mesilate, camostat mesylate, ulinastatin, colchicine, probenedide, sulfinpyrazone, benzbromarone, allopurinol, sodium gold thiomalate, Sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, Atropine, scopolamine, morphine, pethidine, levorfinol, ketoprofen, naproxen, oxymorphone or salts thereof. (4) steroid drugs dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide,
Prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, beclomethasone propionate, estriol. (5) anticoagulant sodium heparin, sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III,
Dalteparin sodium, warfarin potassium, argatroban, gabexate, sodium citrate and the like.

(6) Platelet aggregation inhibitors Ozacrel sodium, ethyl icosapentanate, beraprost sodium, alprostadil, ticlopidine hydrochloride, pentoxifylline, dipyridamole and the like. (7) thrombolytic drugs tisokinase, urokinase, streptokinase and the like. (8) Immunomodulators Cyclosporin, tacrolimus, gusperimus, azathioprine, antilymphatic serum, dried sulfonated immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon and the like. (9) Antiprotozoal drugs metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate and the like. (10) Antitussive and antiseptic ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate,
Dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, allochloride, chlorphedianol, picoperidamine, cloperastine, protochlorol, isoproterenol, salbutamol, tereptalin, oxypetebanol, morphine hydrochloride, morphine hydrochloride, bromide Dextropetorphan hydrochloride, Oxycodone hydrochloride, Dimorphan phosphate, Tipepidine hibenzate, Pentoxiverine citrate, Clofedanol hydrochloride, Benzonate, Guaifenesin, Bromhexine hydrochloride, Ambroxol hydrochloride, Acetylcysteine, Ethylcysteine hydrochloride, Carbocysteine, etc. . (11) Sedatives Chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital, amobarbital, pentobarbital, sodium thiopental, thiamylal sodium, nitrazepam, estazolam, flurazapam, haloxazolam, triazolam, flunitrazepam, bromvaleryl urea, chlorphosral Sodium and the like. (12) Anesthetics (12-1) Local anesthetics Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxesazein) and the like. (12-2) General anesthetic Inhalation anesthetic (eg, ether, halothane, nitrous oxide,
Influrane, enflurane), intravenous anesthetics (eg, ketamine hydrochloride, droperidol, sodium thiopental, thiamylal sodium, pentobarbital), etc. (13) Antiulcer drug metaclopromide, histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrin, oxesazein, proglumide, omeprazole, sucralfate, sulpiride, settraxate, gefarnate, aldioxagranone, aldioxaprenone . (14) antiarrhythmic agent sodium channel blocker (eg, quinidine, procainamide, disopyramide, adimarin, lidocaine,
Mexiletine, phenytoin), beta-blockers (eg, propranolol, alprenolol, pfetrol, oxprenolol, athenol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, allotyrol), potassium channel blockers (eg, amiodarone), Calcium channel blockers (eg, verapamil, diltiazem) and the like. (15) Antihypertensive diuretic hexamethonium bromide, clonidine hydrochloride, hydrochlorothiazide, trichlormethiazide, furosemide, ethacrynic acid, bumetanide, mefluside, azosemide, spironolactone, potassium canrenoate, triamterene, amiloride, acetazolamide, D-mannitol,
Isosolubide, aminophylline and the like.

(16) Tranquilizers Diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam, cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxyzine and the like. (17) Antipsychotics Chlorpromazine hydrochloride, prochlorperazine, trifloperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride, haloperidol, bromperidol , Spiperone, reserpine, clocapramine hydrochloride, sulpiride, zotepine and the like. (18) Antitumor drug 6-O- (N-chloroacetylcarbamoyl) fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5 -Fluorouracil, picibanil, lentinan, levamisole, bestatin, azimexone, glycyrrhizin, doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycin hydrochloride, hepromycin sulfate, vincristine sulfate, vinblastine sulfate, irinotecan hydrochloride, cyclophosphamide, melphalan, dusulfan, thiotepaine hydrochloride , Cisplatin, azathioprine, mercaptopurine, tegafur, carmofur, cytarabine , Methyltestosterone, testosterone propionate, testosterone enanthate, mepithiostane, phosphestrol, chlormadinone acetate, euprine acetate, buserelin acetate and the like. (19) Antihyperlipidemic agent Clofibrate, ethyl 2-chloro-3- [4- (2-methyl-2-phenylpropoxy) phenyl] propionate [Chemical and Pharmaceutical Co., Ltd.
Bulletin (Chem. Pharm. Bull), 38, 2792
-2796 (1990)], pravastatin, simvastatin, probucol, bezafibrate, clinofibrate, nicomol, cholestyramine, dextran sodium sulfate and the like. (20) Muscle relaxants Pridinol, tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesin carbamate, baclofen, chlormezanone, mephenesin, clozoxazone, eperisone, tizanidine and the like. (21) antiepileptic drugs phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, tripetadione, carbamazepine,
Phenobarbital, primidone, sultiam, sodium palproate, clonazepam, diazepam, nitrazepam and the like. (22) Antidepressants Imipramine, clomipramine, noxiptiline, phenelzine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, sulpiride, fluvoxamine maleate, trazodone hydrochloride and the like. (23) antiallergic drugs diphenhydramine, chlorpheniramine, tripelenamine, methdilamine, clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglycate,
Tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, acelastin, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast and the like. (24) Cardiotonic agents transbioxocamphor, terephyllol, aminophylline, ethylrefrin, dopamine, dobutamine, denopamine, aminophylline, besinarine, amrinone,
Pimobendan, ubidecarenone, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophantin and the like. (25) Vasodilators Oxyfedrine, diltiazem, tolazoline, hexobendine, bamethane, clonidine, methyldopa, guanabenz and the like. (26) vasoconstrictor dopamine, dobutamine denopamine and the like. (27) Antihypertensive diuretics hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine, diltiazem, nifedipine and the like. (28) antidiabetic agent tolbutamide, chlorpropamide, acetohexamide,
Glibenclamide, tolazamide, acarbose, epalrestat, troglitazone, glucagon, glymidine, glipzide, phenformin, pformin, metformin and the like. (29) Narcotic antagonists Levallorphan, nalorphine, naloxone or a salt thereof and the like. (30) Vitamin Drugs Vitamin A: Vitamin A ₁ , Vitamin A ₂ and Retinol Palmitate Vitamin D: Vitamin D ₁ , D ₂ , D ₃ , D ₄ and D
₅ Vitamin Es: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, dl-α-tocopherol nicotinate Vitamin Ks: vitamins K ₁ , K ₂ , K ₃ and K ₄ folic acid (vitamin M) Vitamin class B: vitamin B _1, vitamin B _2, vitamin B _3, vitamin B _5, vitamin B ₆ and vitamin B ₁₂ biotin (vitamin H). (31) Various derivatives of vitamin derivatives vitamins, for example, 5,6-trans - cholecalciferol, 2,5-hydroxycholecalciferol, vitamin D ₃ derivatives such as 1-alpha-hydroxycholecalciferol, 5,6 Vitamin D ₂ derivatives such as trans-ergocalciferol and the like. (32) antiasthmatic drug isoprenaline hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimethoquinol hydrochloride,
Tulobuterol hydrochloride, orciprenaline sulfate, fenoterol hydrobromide, ephedrine hydrochloride, iprotropium bromide, oxitropium bromide, flutropium bromide,
Theophylline, aminophylline, sodium cromoglycate, tranilast, repirinast, amlexanone,
Ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride,
Pranlukast hydrate, seratrodast, dexamethasone, prednisolone, hydrocorthiaone, beclopetazone propionate and the like. (33) Treatment for pollakiuria / urinary incontinence Flavoxate hydrochloride and the like. (34) Atopic dermatitis therapeutic agent Sodium cromoglycate and the like. (35) Drugs for treating allergic rhinitis Sodium cromoglycate, chlorpheniramine maleate, alimemazine tartrate, clemastine fumarate, homochlorcyclidine hydrochloride, terfenadine, mequitazine and the like. (36) Vasopressors dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophantin and the like. (37) Others hydroxycam, diaserine, megestrol acetate,
Niselogolin, prostaglandins and the like.

[0320] The concomitant drug of the present invention has the following effects. (1) than when the cyclohexene compound or a salt thereof, or a prodrug thereof or a concomitant drug is administered alone,
These dosages can be reduced. (2) A synergistic therapeutic effect is obtained for the above-mentioned diseases such as sepsis, septic shock, inflammatory disease, and infectious disease. (3) It has a wide therapeutic effect on various diseases caused by diseases such as bacterial infection. When using the concomitant drug of the present invention, the administration time of the compound A and the concomitant drug is not limited, and the compound A or the pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof are simultaneously administered to a subject to be administered. The administration may be carried out at an interval. The dose of the concomitant drug may be in accordance with the dose clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination, and the like. The administration form of the concomitant drug of the present invention is not particularly limited as long as compound A and the concomitant drug are combined at the time of administration. Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously preparing compound A or a pharmaceutical composition thereof and a concomitant drug, and (2) combination use of compound A or a pharmaceutical composition thereof. Simultaneous administration of the two preparations obtained by separately formulating a drug or a pharmaceutical composition thereof by the same administration route,
(3) administration of two preparations obtained by separately preparing compound A or a pharmaceutical composition thereof and a concomitant drug or a pharmaceutical composition thereof at the same administration route with a time lag, (4) compound A or Simultaneous administration of two types of preparations obtained by separately formulating the pharmaceutical composition and the concomitant drug or the pharmaceutical composition by different administration routes, (5) Compound A or the pharmaceutical composition and the concomitant drug or the pharmaceutical thereof Administration of two preparations obtained by separately formulating the composition and the two preparations at different times by different administration routes (for example, Compound A or a pharmaceutical composition thereof; administration of a concomitant drug or a pharmaceutical composition thereof in the order of: ,
Or administration in the reverse order).

The combination drug of the present invention has low toxicity.
According to a method known per se, compound A or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier to prepare a pharmaceutical composition such as a tablet (including sugar-coated tablets and film-coated tablets), powders, granules, and capsules. It can be safely administered orally or parenterally (eg, topically, rectally, intravenously, etc.) as agents, (including soft capsules), liquids, injections, suppositories, sustained release agents and the like. The injection can be administered intravenously, intramuscularly, subcutaneously or into an organ or directly to a lesion. Pharmacologically acceptable carriers that may be used in the production of the concomitant drug of the present invention include various organic or inorganic carrier substances commonly used as pharmaceutical materials, for example, excipients in solid formulations, lubricants Binders and disintegrants, or solvents in liquid preparations, solubilizers, suspending agents, isotonic agents, buffers, soothing agents and the like.
Further, if necessary, usual additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents and wetting agents can be used in appropriate amounts.

Examples of the excipient include lactose, sucrose, D-
Examples include mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. Disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. Examples of the dissolution aid include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate;
For example, polyvinyl alcohol, polyvinyl pyrrolidone,
Examples include hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like. As preservatives, for example, paraoxybenzoates, chlorobutanol,
Examples include benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. As antioxidants,
For example, sulfite, ascorbic acid, α-tocopherol and the like can be mentioned.

The compounding ratio of compound A to the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like. For example, the content of Compound A in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and Preferably, it is about 0.5 to 20% by weight. The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about 0.1 to 50% by weight, based on the whole preparation. It is about 0.5 to 20% by weight. The content of additives such as carriers in the concomitant preparation of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. . The same content may be used when the compound A and the concomitant drug are separately formulated.

These preparations can be produced by a method known per se which is generally used in the preparation process. For example, Compound A or the concomitant drug is a dispersant (eg, Tween 80 (manufactured by Atlas Powder Co., USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose,
Dextrin, etc.), stabilizers (eg, ascorbic acid,
Sodium pyrosulfite, etc.), surfactant (eg, polysorbate 80, macrogol, etc.), solvent (eg, glycerin, ethanol, etc.), buffer (eg, phosphoric acid and its alkali metal salt, citric acid and its alkali metal) Salts), tonicity agents (eg, sodium chloride, potassium chloride, mannitol, sorbitol, glucose, etc.), pH regulators (eg,
Hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, ethyl paraoxybenzoate, benzoic acid, methylparaben, propylparaben, benzyl alcohol, etc.), solubilizers (eg, concentrated glycerin, meglumine, etc.), solubilizing agents (eg, propylene) Glycol, sucrose, etc.) and soothing agents (eg, glucose, benzyl alcohol, etc.) in aqueous injections or in solubilizers such as olive oil, sesame oil, cottonseed oil, vegetable oils such as corn oil, and propylene glycol. Alternatively, it can be emulsified and formed into an oily injection to give an injection.

In order to prepare a preparation for oral administration, Compound A or a concomitant drug is used in accordance with a method known per se, for example, excipients (eg, lactose, sucrose, starch, etc.), disintegrants (eg, starch, calcium carbonate, etc.) ), Binders (eg, starch,
Gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) are added and compression-molded, and if necessary, taste masking, intestine Oral preparations can be prepared by coating with a method known per se for the purpose of solubility or sustainability.
Examples of the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (ROHM) Co., Ltd., Germany, methacrylic acid / acrylic acid copolymer) and pigments (eg, bengalara, titanium dioxide, etc.). The preparation for oral administration may be any of a quick release preparation and a sustained release preparation.

For example, in order to prepare a suppository, Compound A or a concomitant drug can be converted into an oily or aqueous solid, semi-solid or liquid suppository according to a method known per se. Examples of the oily base used in the composition include glycerides of higher fatty acids (eg, cocoa butter, witepsol (manufactured by Dynamite Nobel, Germany), etc.), and intermediate fatty acids [eg, miglyols (manufactured by Dynamite Nobel, Germany, Germany) ) Etc.) or vegetable oils (eg, sesame oil, soybean oil,
Cottonseed oil). Examples of the aqueous base include polyethylene glycols and propylene glycol, and examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers. Examples of the sustained release preparation include sustained release microcapsules. A method known per se can be used to obtain sustained release microcapsules. For example, it is preferable to administer a sustained release formulation shown in the following [2] by shaping. Compound A is preferably formed into a preparation for oral administration such as a solid preparation (eg, powder, granules, tablets, capsules) or a preparation for rectal administration such as a suppository. In particular, preparations for oral administration are preferred. The concomitant drug can be in the above-described dosage form depending on the type of the drug.

The followings are [1] Injection of Compound A or a concomitant drug and its preparation, [2] Sustained release preparation or immediate release preparation of Compound A or a concomitant drug and its preparation, [3] Compound A or a concomitant drug The sublingual tablet, buccal or oral fast disintegrating agent of the drug and its preparation are specifically described. [1] Injection and its preparation An injection prepared by dissolving Compound A or a concomitant drug in water is preferred. The injection may contain a benzoate and / or a salicylate. This injection is obtained by dissolving both Compound A or the concomitant drug and, if desired, a benzoate and / or a salicylate in water. If necessary, the following additives can be further added.
These dissolutions may be performed in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injection.

Examples of the salts of benzoic acid and salicylic acid include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, meglumine salts, and organic acid salts such as trometamol. Can be Each concentration of the compound A or the concomitant drug in the injection is 0.5 to 50 w / v%,
Preferably, it is about 3 to 20 w / v%. The concentration of each of the benzoate and / or salicylate in the injectable preparation is 0.1.
5 to 50 w / v%, preferably 3 to 20 w / v% is preferred.

In addition, the present agent may contain additives generally used in injections, such as stabilizers (ascorbic acid, sodium pyrosulfite, etc.), surfactants (polysorbate 80, macrogol, etc.), solvents (glycerin, Ethanol, etc.), buffers (phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), tonicity agents (sodium chloride, potassium chloride, etc.), dispersants (hydroxypropyl methylcellulose, dextrin), pH adjustment Agents (hydrochloric acid, sodium hydroxide, etc.), preservatives (ethyl parahydroxybenzoate, benzoic acid, etc.), solubilizers (concentrated glycerin, meglumine, etc.), solubilizers (propylene glycol, sucrose, etc.), soothing agents (glucose, Benzyl alcohol, etc.) can be appropriately compounded. These additives are generally blended in a ratio usually used for an injection. Injectables are prepared by adding a pH adjuster to adjust the pH to 2 to 12, preferably to pH 2.
It is better to adjust to 2.5 to 8.0. The aqueous solution for injection is preferably heated, and can be used as an injection by performing, for example, sterilization by filtration or high-pressure heat sterilization in the same manner as a usual injection. The aqueous solution for injection is, for example, 100 ° C.
It is preferable to perform high-pressure heat sterilization for 5 to 30 minutes at ~ 121 ° C. Further, a formulation having antibacterial properties of the solution may be used so that it can be used as a multiple-dose formulation.

[2] Sustained-release preparation or immediate-release preparation and preparation thereof A sustained-release preparation comprising a core containing Compound A or a concomitant drug optionally coated with a film-forming agent such as a water-insoluble substance or a swellable polymer. Formulations are preferred. For example, a once-daily sustained release preparation for oral administration is preferred. Examples of the water-insoluble substance used in the coating agent include cellulose ethers such as ethyl cellulose and butyl cellulose; cellulose esters such as cellulose acetate and cellulose propionate; polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate; Methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymer, poly (methyl methacrylate) , Polymethacrylate, polymethacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), glycidyl methacrylate copolymer, Eudragit RS-100, RL-100, RS-30
D, RL-30D, RL-PO, RS-PO (ethyl acrylate / methyl methacrylate / trimethyl methacrylate / ammonium ethyl copolymer), Eudragit NE-30D (methyl methacrylate / ethyl acrylate) Eudragits such as polymers)
Pharmaceuticals), hardened oils such as hardened castor oil (eg, Lovely Wax (Freund Corporation)), carnauba wax, fatty acids glycerin esters, waxes such as paraffin, polyglycerin fatty acid esters, and the like. .

As the swellable polymer, a polymer having an acidic dissociating group and exhibiting pH-dependent swelling is preferable. The swelling polymer swells little in an acidic region such as the stomach and swells in a neutral region such as the small intestine and large intestine. Is preferred. Having such an acidic dissociating group, pH
Examples of polymers exhibiting a dependent swelling include, for example, Carbomer 934P, 940, 941, 974P,
980, 1342, etc., polycarbophi
l), calcium polycarbophil (carcium polycarbo)
phil) (all manufactured by BF Goodrich), and Hibiswako 103, 104, 105, 304 (all manufactured by Wako Pure Chemical Industries, Ltd.).

The coating agent used in the sustained-release preparation may further contain a hydrophilic substance. As the hydrophilic substance,
For example, pullulan, dextrin, polysaccharides that may have a sulfate group such as an alkali metal salt of alginic acid, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polysaccharides having a hydroxyalkyl group or a carboxyalkyl group such as sodium carboxymethyl cellulose, methyl cellulose, Polyvinylpyrrolidone,
Examples include polyvinyl alcohol and polyethylene glycol. The content of the water-insoluble substance in the film of the sustained release preparation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w), and more preferably about 4 to about 80% (w / w).
0 to 75% (w / w), content of swellable polymer is about 3 to about 30% (w / w), preferably about 3 to about 1
5% (w / w). The coating agent may further include a hydrophilic substance, in which case the content of the hydrophilic substance in the coating agent is about 50% (w / w) or less, preferably about 5 to about 40% (w / w).
/ w), more preferably about 5 to about 35% (w / w).
Here, the above-mentioned% (w / w) indicates the weight% based on the coating agent composition obtained by removing the solvent (eg, water, lower alcohol such as methanol, ethanol, etc.) from the coating agent liquid.

A sustained-release preparation is prepared by preparing a nucleus containing a drug as shown below, and then dissolving the obtained nucleus by heating or dissolving or dispersing a water-insoluble substance or a swellable polymer in a solvent. It is manufactured by coating with a chemical solution. I. Preparation of Drug-Containing Core A drug-containing core (hereinafter, sometimes simply referred to as a core) to be coated with a coating agent is not particularly limited, but is preferably formed into particles such as granules or fine granules. When the core is granules or fine granules, the average particle size is preferably about 1
50 to 2,000 μm, more preferably about 500
Or about 1,400 μm. The nucleus can be prepared by a usual production method. For example, suitable excipients for the drug, binders, disintegrants, lubricants, stabilizers and the like,
It is prepared by a wet extrusion granulation method, a fluidized bed granulation method or the like. The drug content of the nucleus is about 0.5 to about 95% (w / w);
Preferably it is about 5.0 to about 80% (w / w), more preferably about 30 to about 70% (w / w).

Examples of excipients contained in the core include sucrose, lactose, saccharides such as mannitol and glucose, starch, crystalline cellulose, calcium phosphate, corn starch and the like. Among them, crystalline cellulose and corn starch are preferred. As the binder, for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, Pluronic F68, gum arabic, gelatin, starch and the like are used. As the disintegrant, for example, carboxymethylcellulose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), crosslinked polyvinylpyrrolidone (crospovidone), low-substituted hydroxypropylcellulose (L-HPC) and the like are used. Among them, hydroxypropylcellulose, polyvinylpyrrolidone and low-substituted hydroxypropylcellulose are preferred. For example, talc, magnesium stearate and inorganic salts thereof are used as a lubricant and an anti-agglomeration agent, and polyethylene glycol and the like are used as a lubricant. Acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used as stabilizers.

The nucleus may be formed by spraying a binder dissolved in a suitable solvent such as water or a lower alcohol (eg, methanol, ethanol, etc.) on the inert carrier particles serving as the center of the nucleus, in addition to the above-mentioned production method. It can also be prepared by a tumbling granulation method, a pan coating method, a fluidized bed coating method or a melt granulation method in which a small amount of a drug or a mixture thereof with an excipient, a lubricant and the like are added. As the inert carrier particles, for example, those made of sucrose, lactose, starch, crystalline cellulose, and waxes can be used, and those having an average particle diameter of about 100 μm to about 1,500 μm are preferable. In order to separate the drug contained in the nucleus from the coating agent, the surface of the nucleus may be coated with a protective agent. As the protective agent, for example, the above-mentioned hydrophilic substance, water-insoluble substance and the like are used. As the protective agent, polyethylene glycol or a polysaccharide having a hydroxyalkyl group or a carboxyalkyl group is preferably used, and hydroxypropylmethylcellulose and hydroxypropylcellulose are more preferably used. The protective agent may contain, as a stabilizer, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, and maleic acid, and a lubricant such as talc. When a protective agent is used, its coverage is about 1 to about 15% (w /
w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% (w / w). The protective agent can be coated by a usual coating method. Specifically, the protective agent can be coated by spray-coating the nucleus by, for example, a fluidized-bed coating method or a pan coating method.

II. Coating of nucleus with coating agent The nucleus obtained in I is coated with a coating agent solution in which the water-insoluble substance, the pH-dependent swellable polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent. Produces a sustained-release preparation. Examples of the method of coating the nucleus with a coating agent solution include a spray coating method. The composition ratio of the water-insoluble substance, the swellable polymer or the hydrophilic substance in the coating agent solution is appropriately selected such that the content of each component in the coating becomes the above-mentioned content.
The coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w), more preferably, about the core (not including the protective agent). About 5 to 3
5% (w / w).

As the solvent for the coating solution, water or an organic solvent can be used alone or in a mixture of both. Mixing ratio of water and organic solvent (water / organic solvent:
Weight ratio) can vary from 1 to 100%, preferably from 1 to about 30%. The organic solvent is not particularly limited as long as it dissolves a water-insoluble substance.
Acetonitrile, chloroform, methylene chloride and the like are used. Of these, lower alcohols are preferred,
Ethyl alcohol and isopropyl alcohol are particularly preferred. Water and a mixture of water and an organic solvent are preferably used as a solvent for the coating agent. At this time, if necessary, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, and maleic acid may be added to the coating agent solution for stabilizing the coating agent solution. The operation in the case of coating by spray coating can be carried out by a usual coating method. Specifically, it is carried out by spray-coating a coating solution onto a nucleus by, for example, a fluidized bed coating method or a pan coating method. Can be. At this time, if necessary, use talc, titanium oxide, magnesium stearate, calcium stearate, light silicic anhydride, etc. as lubricants, and plasticize glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc. It may be added as an agent. After coating with the coating agent, an antistatic agent such as talc may be mixed as necessary.

Immediate release preparations can be liquid (solutions, suspensions, emulsions, etc.) or solid (particles, pills, tablets, etc.).
It may be. Parenteral preparations such as oral preparations and injections are used, but oral preparations are preferred. The immediate-release preparation may contain, in addition to the drug as the active ingredient, usually a carrier, an additive or an excipient (hereinafter may be abbreviated as an excipient) commonly used in the field of formulation. . The formulation excipient used is not particularly limited as long as it is a commonly used excipient. For example, excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (Asahi Kasei Co., Ltd., Avicel PH101, etc.), powdered sugar,
Granular sugar, mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate, L-cysteine, and the like, preferably corn starch, mannitol, and the like. These excipients can be used alone or in combination of two or more. The content of the excipient is, for example, about 4.5 to about 99.4 w / w based on the whole amount of the immediate release preparation.
%, Preferably from about 20 to about 98.5 w / w%, more preferably from about 30 to about 97 w / w%. The content of the drug in the immediate-release preparation is about 0.5 to the total amount of the immediate-release preparation.
It can be appropriately selected from the range of 5 to about 95%, preferably about 1 to about 60%.

When the immediate-release preparation is an oral solid preparation, it usually contains a disintegrant in addition to the above components. Examples of such disintegrants include carboxymethylcellulose calcium (ECG-505, manufactured by Gotoku Pharmaceutical Co., Ltd.), croscarmellose sodium (e.g., Aczisol, manufactured by Asahi Kasei Corporation), and crospovidone (e.g., BASF Corp., Kollidon CL). Low-substituted hydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (Matsuya Chemical Co., Ltd.), carboxymethyl starch sodium (Kimura Sangyo, Explotab), partially pregelatinized starch (Asahi Kasei Co., Ltd.) PCS) and the like, for example, those that disintegrate the granules by contacting with water to absorb or swell, or to form a channel between the excipient and the excipient constituting the core can be used. These disintegrants can be used alone or in combination of two or more. It is appropriately selected depending on the type and blending amount of the product, the design of the release preparation, etc.
For example, about 0.05 to about 30% w / w, preferably about 0.
5 to about 15% w / w.

When the immediate-release preparation is an oral solid preparation, in the case of an oral solid preparation, in addition to the above-mentioned composition, if necessary, conventional additives in the solid preparation may be further contained. Examples of such additives include binders (eg, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose,
Polyvinylpyrrolidone, pullulan, dextrin, etc.), lubricants (eg, polyethylene glycol, magnesium stearate, talc, light anhydrous silicic acid (eg, Aerosil (Nippon Aerosil)), surfactants (eg, anions such as sodium alkyl sulfate) Surfactants, non-ionic surfactants such as polyoxyethylene fatty acid esters and polyoxyethylene sorbitan fatty acid esters, and polyoxyethylene castor oil derivatives, etc.), coloring agents (for example, tar dyes, caramel, red iron oxide, titanium oxide) Riboflavins), if necessary, bridging agents (eg, sweeteners, flavors, etc.), adsorbents, preservatives,
Wetting agents, antistatic agents and the like are used. Further, an organic acid such as tartaric acid, citric acid, succinic acid and fumaric acid may be added as a stabilizer.

As the binder, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone and the like are preferably used. Immediate release formulations
Based on the usual formulation manufacturing technology, mix each of the above components,
If necessary, it can be prepared by kneading and molding. The mixing is generally used,
For example, the mixing and kneading are performed. In particular,
For example, when the rapid release preparation is formed into particles, a vertical granulator, a universal kneading machine (manufactured by Hata Iron Works), a fluidized bed granulator FD may be used in the same manner as the method for preparing the core of the sustained release preparation. It can be prepared by mixing using -5S (manufactured by Powrex Co., Ltd.) and then granulating by wet extrusion granulation, fluidized bed granulation, or the like. The thus obtained immediate-release preparation and sustained-release preparation can be administered as they are or separately, separately and appropriately formulated together with excipients and the like by a conventional method, and then administered simultaneously or in combination at an arbitrary administration interval. It is also possible to prepare a preparation for oral administration, either as it is or as appropriate, together with a formulation excipient, etc. in one oral administration preparation (eg,
Granules, fine granules, tablets, capsules, etc.). Both preparations may be made into granules or fine granules and filled into the same capsule or the like to prepare a preparation for oral administration.

[3] Sublingual Tablet, Buccal or Oral Rapid Disintegrating Agent and Preparation Thereof The sublingual tablet, buccal preparation, or oral rapid disintegrating agent may be a solid preparation such as a tablet, or an oral mucosa patch ( the film)
It may be. As the sublingual tablet, buccal or intraoral quick disintegrant, a preparation containing compound A or a concomitant drug and an excipient is preferable. Further, auxiliary agents such as a lubricant, a tonicity agent, a hydrophilic carrier, a water-dispersible polymer, and a stabilizer may be contained. Further, β-cyclodextrin or a β-cyclodextrin derivative (eg, hydroxypropyl-β-cyclodextrin or the like) may be contained to facilitate absorption and increase the bioavailability. Examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica, and the like. Particularly, magnesium stearate and colloidal silica are preferable. Sodium chloride, glucose, fructose, mannitol, sorbitol,
Lactose, saccharose, glycerin, urea and the like are mentioned, and mannitol is particularly preferred. Examples of the hydrophilic carrier include swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, crosslinkable polyvinylpyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, and calcium carbonate. In particular, crystalline cellulose (eg, microcrystalline cellulose, etc.)
Is preferred. Water-dispersible polymers include gums (eg, tragacanth gum, acacia gum, guar gum), alginate (eg, sodium alginate), cellulose derivatives (eg, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose),
Gelatin, water-soluble starch, polyacrylic acid (eg, carbomer), polymethacrylic acid, polyvinyl alcohol,
Examples thereof include polyethylene glycol, polyvinylpyrrolidone, polycarbophil, ascorbic acid, and palmitate, and preferred are hydroxypropylmethylcellulose, polyacrylic acid, alginate, gelatin, carboxymethylcellulose, polyvinylpyrrolidone, and polyethyleneglycol. Particularly, hydroxypropyl methylcellulose is preferable. Examples of the stabilizer include cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite, and the like, with citric acid and ascorbic acid being particularly preferred.

A sublingual tablet, buccal or buccal disintegrant may be
It can be produced by mixing Compound A or a concomitant drug and an excipient by a method known per se. Further, if necessary, the above-mentioned auxiliary agents such as a lubricant, a tonicity agent, a hydrophilic carrier, a water-dispersible polymer, a stabilizer, a coloring agent, a sweetening agent and a preservative may be mixed. The above components are mixed at the same time or with a time lag, and then press-molded to give sublingual tablets, buccal tablets or rapidly disintegrating tablets in the oral cavity. In order to obtain an appropriate hardness, it may be produced by humidifying / wetting a solvent such as water or alcohol as needed before and after the process of tableting, followed by molding and drying.

When molded into a mucosa-adhered tablet (film), compound A or a concomitant drug and the above-mentioned water-dispersible polymer (preferably hydroxypropylcellulose,
(Hydroxypropyl methylcellulose), excipients and the like are dissolved in a solvent such as water, and the resulting solution is cast (c
ast) film. Further, additives such as a plasticizer, a stabilizer, an antioxidant, a preservative, a coloring agent, a buffer, and a sweetener may be added. Contains glycols such as polyethylene glycol and propylene glycol to give the film an appropriate elasticity, and contains bioadhesive polymers (eg, Polycarbophil, Carbopol) to enhance the adhesion of the film to the mucosal lining of the oral cavity You may.
The casting is carried out by pouring the solution onto the non-adhesive surface and applying a uniform thickness (preferably 10 to 100) with an application tool such as a doctor blade.
It is achieved by spreading it to about 0 microns) and then drying the solution to form a film. The film thus formed may be dried at room temperature or under heating, and cut into a desired surface area.

A preferred rapid intraoral disintegrating agent is a solid rapid diffusion administration agent comprising a network of Compound A or a concomitant drug and a water-soluble or water-diffusible carrier inactive with Compound A or the concomitant drug. Is mentioned. The network can be obtained by sublimating a solvent from the solid composition comprising Compound A or a solution in which a concomitant drug is dissolved in an appropriate solvent. It is preferable that the composition of the intraoral quick disintegrating agent contains a matrix forming agent and a secondary component in addition to the compound A or the concomitant drug.
Examples of the matrix-forming agent include gelatins, dextrins, and animal or vegetable proteins such as soybean, wheat, and psyllium seed proteins; gums such as gum arabic, guar gum, agar and xanthan; polysaccharides Alginic acids; carboxymethyl celluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and substances derived from gelatin-gum arabic complex. In addition, mannitol,
Sugars such as dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate; glycine, L-alanine, L-aspartic acid, L-glutamic acid, L- Hydroxyproline, L-isoleucine, L-leucine, L-phenylalanine and the like having 2 to 1 carbon atoms
Up to two amino acids and the like are included. One or more of the matrix-forming agents can be introduced into a solution or suspension before solidification. Such a matrix-forming agent may be present in addition to the surfactant, or may be present without the surfactant.
In addition to forming the matrix, the matrix-forming agent can help maintain the diffusion state of Compound A or the concomitant drug in the solution or suspension.

The composition may contain secondary components such as preservatives, antioxidants, surfactants, thickeners, coloring agents, pH adjusters, flavors, sweeteners, and taste masking agents. Suitable colorants include red, black and yellow iron oxides and Ellis &Everard's FD &
FDs such as C Blue 2 and FD & C Red 40
& C dyes. Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavor and combinations thereof. Suitable pH adjusters include citric, tartaric, phosphoric, hydrochloric and maleic acids. Suitable sweeteners include aspartame, acesulfame K and thaumatin. Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbate materials, and microencapsulated apomorphine. The formulations usually contain from about 0.1 to about 50% by weight, preferably from about 0.1 to about 30% by weight of Compound A or the concomitant drug, between about 1 minute and about 60 minutes, preferably between about 1 minute and about 1 minute. A formulation capable of dissolving 90% or more of Compound A or a concomitant drug (in water) for about 15 minutes, more preferably for about 2 minutes to about 5 minutes (eg, sublingual tablets, buccal, etc.) Or within 1 to 60 seconds after being placed in the mouth,
Preferably within 1 to 30 seconds, more preferably 1
Oral fast disintegrating agents that disintegrate within 10 seconds are preferred.

The content of the above excipient with respect to the whole preparation is as follows:
It is about 10 to about 99% by weight, preferably about 30 to about 90% by weight. The content of β-cyclodextrin or β-cyclodextrin derivative in the whole preparation is from 0 to about 30.
% By weight. The content of the lubricant in the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight.
It is. The content of the tonicity agent in the whole preparation is about 0.1.
1 to about 90% by weight, preferably about 10 to about 70% by weight
It is. The content of the hydrophilic carrier in the whole preparation is about 0.5.
It is 1 to about 50% by weight, preferably about 10 to about 30% by weight. The content of the water-dispersible polymer with respect to the whole preparation is
It is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight. The content of the stabilizer in the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight. The above-mentioned preparation may further contain additives such as a coloring agent, a sweetening agent and a preservative, if necessary.

The dose of the concomitant drug of the present invention varies depending on the type, age, body weight, symptom, dosage form, administration method, administration period and the like of the compound. Usually, about 0.01 to about 1000 mg / k each day as Compound A and the concomitant drug.
g, preferably from about 0.01 to about 100 mg / kg, more preferably from about 0.1 to about 100 mg / kg, especially about 0.1 to about 100 mg / kg.
1 to about 50 mg / kg, especially about 1.5 to about 30 mg
/ Kg once a day or several times a day. Of course, as described above, since the dose varies under various conditions, a dose smaller than the above-mentioned dose may be sufficient, or it may be necessary to administer beyond the range. The concomitant drug can be used in any amount as long as side effects do not matter. The daily dose as a concomitant drug depends on the degree of symptoms, age, gender, weight, sensitivity difference, time of administration, interval, nature of pharmaceutical preparation, preparation, type,
The amount of the drug varies depending on the type of the active ingredient and the like, and is not particularly limited. .
The dose is about 1 to 100 mg, which is usually administered once to four times a day.

In administering the medicament of the present invention, the medicament of the present invention may be administered at the same time. However, the concomitant drug may be administered first, and then the compound A may be administered. Thereafter, the concomitant drug may be administered. When the administration is carried out with a time lag, the time lag varies depending on the active ingredient to be administered, the dosage form, and the administration method. Methods of administering Compound A within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compound A is administered first, the compound A is administered within 1 minute to 1 day, preferably 10 minutes to 6 hours, and more preferably 1 minute to 1 day.
A method of administering the concomitant drug within 5 minutes to 1 hour is mentioned.

[0350]

EXAMPLES Hereinafter, the present invention will be described in detail with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited thereto. ^{The 1} H-NMR spectrum was measured using a Varian Gemini 200 using tetramethylsilane as an internal standard.
(200MHz) type spectrum meter
The values are given in ppm. The numerical values shown in parentheses in the mixed solvents are volume mixing ratios of the respective solvents. % Means percent by weight unless otherwise specified. The ratio of the solvent in the silica gel chromatography indicates the volume ratio of the mixed solvents.

The highly polar diastereomer is defined as an R under normal phase thin layer chromatography under the same conditions (for example, ethyl acetate / hexane can be used as a solvent).
When the f values are compared, the diastereomer having the smaller Rf value means the diastereomer having the larger Rf value. The melting point was measured using a melting point measuring device manufactured by Yanagi Head Office. Data of powder X-ray crystal diffraction using Cu-K [alpha ₁ line as a radiation source, RINT
It measured using 2500 type (Rigaku Denki Co., Ltd.).

The symbols in the examples have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, t
t: triple triplet, m: multiplet, b
r: Wide, J: Coupling constant

The following Reference Example A is a reference example of WO99 / 46242, Reference Example B is a reference example of WO99 / 46242, Reference Example C is a reference example of WO01 / 10826, and Reference Example D is a reference example of WO01 / 10826. It can be manufactured according to the example.

Reference Example A Reference Example A1 Ethyl 2-sulfo-1-cyclohexene-1-carboxylate Reference Example A2 Ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate Reference Example A3 Ethyl 2-chlorosulfonyl- 1-cyclopentene-1-carboxylate Reference Example A4 Ethyl 2-chlorosulfonyl-1-cycloheptene-1-carboxylate Reference Example A5 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene- 1-carboxylic acid sodium salt Reference Example A6 1- (3-fluoro-4-nitrophenyl) -1H-1,
2,4-Triazole Reference Example A7 1- (4-amino-3-fluorophenyl) -1H-1,
2,4-triazole Reference Example A8 4- (benzyloxycarbonylamino) -3-
Chlorobenzoic acid methyl ester Reference Example A9 4- (benzyloxycarbonylamino) -3-
Chlorobenzoic acid Reference Example A10 tert-butyl N- (4-benzyloxycarbonylamino-3-chlorobenzoyl) glycinate

Reference Example A11 tert-butyl N- (4-amino-
3-chlorobenzoyl) glycinate Reference Example A12 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylic acid Reference Example A13 Ethyl 2-mercapto-5-phenyl-1-cyclohexene-1 -Carboxylate Reference Example A14 Ethyl 2-chlorosulfonyl-5-phenyl-1-cyclohexene-1-carboxylate Reference Example A15 Ethyl 5-tert-butyl-2-mercapto-1
-Cyclohexene-1-carboxylate Reference Example A16 Ethyl 5-tert-butyl-2-chlorosulfonyl-1-cyclohexene-1-carboxylate Reference Example A17 Ethyl 5,5-dimethyl-2-mercapto-1-
Cyclohexene-1-carboxylate Reference Example A18 Ethyl 2-chlorosulfonyl-5,5-dimethyl-1-cyclohexene-1-carboxylate

Reference Example B Reference Example B1 Ethyl 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 1) Reference Example B2 Ethyl 6- [N -(4-Chloro-2-fluorophenyl) -N-methylsulfamoyl] -1-cyclohexene-1-carboxylate (Compound 2) Reference Example B3 Ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl ] -1-Cyclohexene-1-carboxylate (Compound 3) Reference Example B4 Ethyl 6- [N- (2,6-diisopropylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 4) Reference Example B5 Ethyl 6- [N- (4-nitrophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 5) Reference Example B6 Ethyl 6- (N-phenylsulfamoyl) -1-
Cyclohexene-1-carboxylate (Compound 6) Ethyl 2- (N-phenylsulfamoyl) -1-cyclohexene-1-carboxylate (Compound 7) Reference Example B7 Ethyl 2- [N- (4-chloro-2- Fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 9) Reference Example B8 2- (4-methoxyphenyl) -4,5,6,7-tetrahydro-1,2-benzoisothiazole-3 ( 2H) -one 1,1-dioxide (compound 67) ethyl 2- [N- (4-methoxyphenyl) sulfamoyl] -1-
Cyclohexene-1-carboxylate (Compound 8) Reference Example B9 Ethyl 6- [N- (2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 10) Reference Example B10 Ethyl 6- [N- ( 3-Fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 11)

Reference Example B11 2- (4-fluorophenyl)
-4,5,6,7-Tetrahydro-1,2-benzisothiazol-3 (2H) -one 1,1-dioxide (compound 68) ethyl 6- [N- (4-fluorophenyl) sulfamoyl] -1 -
Cyclohexene-1-carboxylate (compound 12) ethyl 2- [N- (4-fluorophenyl) sulfamoyl] -1-
Cyclohexene-1-carboxylate (Compound 18) Reference Example B12 Ethyl 6- [N- (2,6-difluorophenyl)
Sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 13) Reference Example B13 Ethyl 6- [N- (2,3-difluorophenyl)
Sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 14) Reference Example B14 Ethyl 6- [N- (2,5-difluorophenyl)
Sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 15) Reference Example B15 Ethyl 6- [N- (3,4-difluorophenyl)
Sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 16) Reference Example B16 Ethyl 6- [N- (3,5-difluorophenyl)
Sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 17) Reference Example B17 l-ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 19) d -Ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 20) Reference Example B18 Ethyl 6- [N- (2-ethoxycarbonylphenyl) sulfamoyl] -1 -Cyclohexene-1-carboxylate (Compound 21) Reference Example B19 Methyl 6- [N- (2,4-difluorophenyl)
Sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 22) Reference Example B20 Propyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 23)

Reference Example B21 Methyl 6- [N- (4-chloro-2-
Fluorophenyl) sulfamoyl] -1-cyclohexene-
1-carboxylate (compound 24) Reference Example B22 Isopropyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 25) Reference Example B23 Ethyl 6- [N- ( 2-methoxycarbonylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 26) Reference Example B24 Ethyl 6- [N- (2-fluoro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxy (Compound 27) Reference Example B25 Ethyl 6- [N- (2-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 28) Reference Example B26 Ethyl 6- [N- (2-chloro-4- Fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 29) Reference Example B27 Ethyl 6- [N- (4-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 30) Reference Example B2 8 Ethyl 6- [N- (2,3,4-trifluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 31) Reference Example B29 Isobutyl 6- [N- (2,4-difluorophenyl) Sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 32) Reference Example B30 Butyl 6- [N- (2,4-difluorophenyl)
Sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 33)

Reference Example B31 Ethyl 6- [N- (4-bromo-2-
Fluorophenyl) sulfamoyl] -1-cyclohexene-
1-carboxylate (Compound 34) Reference Example B32 Ethyl 6- [N- (2,4-dichlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate
(Compound 35) Reference Example B33 Ethyl 6- [N- (2-acetoxyphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate
(Compound 36) Reference Example B34 Ethyl 6- [N- (3-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 37) Reference Example B35 Ethyl 6- [N- (2,3-dichlorophenyl) sulfamoyl ] -1-cyclohexene-1-carboxylate
(Compound 38) Reference Example B36 Ethyl 6- [N- (2-ethylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 39) Reference Example B37 Ethyl 6- [N- [4- (2H-1 , 2,3-Triazol-2-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 40) Reference Example B38 Ethyl 6- [N- (2,5-dichlorophenyl) sulfamoyl] -1-cyclohexene -1-carboxylate
(Compound 41) Reference Example B39 Ethyl 6- [N- (2-trifluoromethoxyphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 42) Reference Example B40 Ethyl 6- [N- (2,4, 5-trifluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 43)

Reference Example B41 Ethyl 6- [N- [4- (2H-tetrazol-2-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 44) Reference Example B42 Ethyl 6- [N- (2-Chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 45) Reference Example B43 Ethyl 6- [N- (4-fluoro-2-methylphenyl) sulfamoyl] -1-cyclohexene -1-carboxylate (compound 46) Reference Example B44 Ethyl 6- [N- (2,6-dichlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate
(Compound 47) Reference Example B45 Ethyl 6- [N- [4- (1H-tetrazol-1-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 48) Reference Example B46 Ethyl 6- [N -(4- (1H-1,2,3-triazol-1-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 49) Reference Example B47 Ethyl 6- [N- (2-trifluoro Methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 50) Reference Example B48 Ethyl 6- [N- (4-methoxycarbonylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 51) Reference Example B49 Benzyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 52) Reference Example B50 Ethyl 6- [N- [4- [2,3-bis ( tert-butoxycarbonyl) guanidinomethyl] phenyl] sulfamoyl] -1-cycl Hexen-1-carboxylate (Compound 5
3)

Reference Example B51 Ethyl 6- [N- (2-chloro-4-
Methoxycarbonylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 54) Reference Example B52 Ethyl 6- [N- (2-chloro-4-cyanophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate ( Compound 55) Reference Example B53 2-hydroxyethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 56) Reference Example B54 Ethyl 6- [N- [2- Fluoro-4- (1H-1,2,4-
Triazol-1-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 57) Reference Example B55 Ethyl 2- [N- (2,4-difluorophenyl)
Sulfamoyl] -1-cyclopentene-1-carboxylate (compound 66) Ethyl 5- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclopentene-1-carboxylate (compound 58) Reference Example B56 tert-butyl [6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexen-1-yl] carbonyloxyacetate (Compound 59) Reference Example B57 [6- [N- (2,4-difluorophenyl) Sulfamoyl] -1-cyclohexen-1-yl] carbonyloxyacetic acid (Compound 60) Reference Example B58 Ethyl 7- [N- (2,4-difluorophenyl)
Sulfamoyl] -1-cycloheptene-1-carboxylate (Compound 61) Reference Example B59 Ethyl 6- [N- [2-chloro-4- (N-tert-butoxycarbonylmethylcarbamoyl) phenyl] sulfamoyl] -1-cyclohexene- 1-carboxylate (compound
62) Reference Example B60 Ethyl 6- [N- [2-chloro-4- (N-ethoxycarbonylmethylcarbamoyl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 63)

Reference Example B61 Ethyl 5- [N- (2-chloro-4-
Fluorophenyl) sulfamoyl] -1-cyclopentene-
1-carboxylate (compound 64) Reference Example B62 2- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] -4,5,6,7-tetrahydro-1,2-benziso Thiazol-3 (2H) -one 1,1-dioxide (Compound 69) Reference Example B63 Ethyl 7- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cycloheptene-1-carboxylate (Compound 65 Reference Example B64 2- (2,4-difluorophenyl) -5,6,7,7a-
Tetrahydro-1,2-benzisothiazol-3 (2H) -one
1,1-dioxide (Compound 70) Reference Example B65 Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 29) Reference Example B66 Ethyl (6S) -6-[(2-chloro-4-fluoroanilino) sulfonyl] -1-cyclohexene-1-carboxylate (1-ethyl 6- [N- (2-chloro-4-fluorophenyl)
Sulfamoyl] -1-cyclohexene-1-carboxylate) (Compound 71) Ethyl (6R) -6-[(2-chloro-4-fluoroanilino) sulfonyl] -1-cyclohexene-1-carboxylate (d-ethyl
6- [N- (2-chloro-4-fluorophenyl) sulfamoyl]
1-cyclohexene-1-carboxylate) (Compound 72) Reference Example B67 Ethyl 6- [N- (2-bromo-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 73) Reference Example B68 Ethyl 6- [N- (4-bromo-2-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 74) Reference Example B69 Ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -3-phenyl-1-cyclohexene-1-
Highly polar diastereomers of carboxylate (compound 75)
And low-polar diastereomer (Compound 76) Reference Example B70 Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-phenyl-1-cyclohexene
Highly polar diastereomers of 1-carboxylate (compound
77) and the less polar diastereomer (compound 78)

Reference Example B71 Highly polar diastereomer of ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -3-tert-butyl-1-cyclohexene-1-carboxylate (Compound 79) and a less polar compound Diastereomer (Compound 80) Reference Example B72 Highly polar diastereomer of ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-tert-butyl-1-cyclohexene-1-carboxylate
(Compound 81) and Low Polar Diastereomer (Compound 82) Reference Example B73 Ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -3,3-dimethyl-1-cyclohexene-1
-Carboxylate (Compound 83) Reference Example B74 Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3,3-dimethyl-1-cyclohexene-1-carboxylate (Compound 84) Reference Example B75 Ethyl 3-bromo-6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 85) Further, specific examples are shown in Tables 1 to 5.

[0364]

[Table 1]

[0365]

[Table 2]

[0366]

[Table 3]

[0367]

[Table 4]

[0368]

[Table 5]

Reference Example C1 Ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (1 g, WO
99/46242) and phenylmethanethiol (719 mg) in N, N-dimethylformamide (20 m
l) Under ice cooling, 1,8-diazabicyclo [5,4,0] -7-undecene (441 mg) was added dropwise to the solution, and the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate (100 ml), washed with water (70 ml × 2) and saturated saline (70 ml), and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by flash silica gel column chromatography (eluent: toluene) to give ethyl 6- (benzylsulfanyl) -1.
-Cyclohexene-1-carboxylate (673 mg) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.0 Hz), 1.55-2.3
6 (6H, m), 3.76 (1H, m), 3.86 (2H, s), 4.19 (2H,
q, J = 7.0Hz), 6.95 (1H, t, J = 4.0Hz), 7.22-7.39
(5H, m).

Reference Example C2 By the same operating method as in Reference Example C1, ethyl 6- [N- (2,4
-Difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (1 g) was reacted with (4-methoxyphenyl) methanethiol (893 mg) to give ethyl 6-[(4-
Methoxybenzyl) sulfanyl] -1-cyclohexene-1-
The carboxylate (848 mg) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.0 Hz), 1.57-2.3
2 (6H, m), 3.74 (1H, m), 3.80 (3H, s), 3.82 (2H,
s), 4.20 (2H, q, J = 7.0Hz), 6.84 (2H, d, J = 8.4H
z), 6.94 (1H, t, J = 4.0Hz), 7.29 (2H, d, J = 8.4H
z).

Reference Example C3 By the same procedure as in Reference Example C1, ethyl 6- [N- (2,4
-Difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (455 mg) and (2,4-difluorophenyl) methanethiol (421 mg) gave ethyl
6-[(2,4-Difluorobenzyl) sulfanyl] -1-cyclohexene-1-carboxylate (185 mg) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.60-2.4
0 (6H, m), 3.78 (1H, m), 3.84 (2H, s), 4.18 (2H,
q, J = 7.0Hz), 6.76-6.88 (2H, m), 6.97 (1H, t, J =
4.4Hz), 7.34-7.46 (1H, m).

Reference Example C4 By the same operating method as in Reference Example C1, ethyl 6- [N- (2,4
-Difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (835 mg) and (2-chloro-4-fluorophenyl) methanethiol (853 mg)
Ethyl 6-[(2-chloro-4-fluorobenzyl) sulfanyl] -1-cyclohexene-1-carboxylate (625 mg) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.0Hz), 1.56-2.
36 (6H, m), 3.82 (1H, m), 3.94 (2H, s), 4.19 (2H,
q, J = 7.0Hz), 6.96 (1H, td, J = 8.6Hz, 2.6Hz), 6.
98 (1H, m), 7.12 (1H, dd, J = 8.6Hz, 2.6Hz), 7.46
(1H, dd, J = 8.6Hz, 6.0Hz).

Reference Example C5 3-Pyranone (20.0 g) was added to Tetrahedron., 1963, 19, 16
When the reaction is carried out in the same manner as described on page 25, ethyl 5-hydroxy-3,6-dihydro-2H-pyran-4-
The carboxylate (7.52 g) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.2 Hz), 2.31-
2.38 (2H, m), 3.79 (2H, t, J = 5.6 Hz), 4.14 (2H,
t, J = 1.8 Hz), 4.24 (2H, q, J = 7.2 Hz), 11.85 (1
H, s). SIMS: 172 (M ⁺ ).

Reference Example C6 Ethyl 5-hydroxy-3,6-dihydro-2H-pyran-4-carboxylate (12.9 g) was added to Tetrahedron, 1974, Volume 30, 3
When the reaction is carried out in the same manner as described on page 753, ethyl 5-sulfanyl-3,6-dihydro-2H-pyran-
4-Carboxylate (12.0 g) was obtained as a pale blue oil. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.2 Hz), 2.42-
2.50 (2H, m), 3.70 (1H, s), 3.84 (2H, t, J = 5.6 H
z), 4.22 (2H, t, J = 2.2 Hz), 4.25 (2H, q, J = 7.2
Elemental analysis: C ₈ H ₁₂ O ₃ S Calculated (%): C, 51.04; H, 6.43; S, 17.03. Observed (%): C, 50.99; H, 6.54; S, 16.91 .

Reference Example C7 Sodium peroxoborate tetrahydrate (24.5 g) was treated with acetic acid.
(130 ml) and heated to 50-55 ° C.
A solution of sulfanyl-3,6-dihydro-2H-pyran-4-carboxylate (10.0 g) in acetic acid (30 ml) was added dropwise over 2 hours. After stirring at 50 to 55 ° C for 3 hours, the reaction solution was concentrated under reduced pressure. Acetonitrile (230 ml) was added to the residue, the mixture was stirred at room temperature for 2 days, and the resulting insolubles were separated by filtration. The insolubles were washed with acetonitrile (70 ml), and the filtrate and the washing were combined and concentrated under reduced pressure. The residue was dissolved in acetonitrile (160 ml) and stirred at room temperature for 6 hours. The resulting insolubles were filtered off, and the filtrate was concentrated under reduced pressure. Diisopropyl ether (100 ml) was added to the residue, and the precipitated insoluble material was filtered. (27.6 g). ¹ H-NMR (DMSO-d ₆ ) δ: 1.19 (3H, t, J = 7.2 Hz), 2.17-
2.21 (2H, m), 3.65 (2H, t, J = 5.5 Hz), 4.04 (2H,
q, J = 7.2 Hz), 4.16 (2H, t, J = 2.4 Hz).

Reference Example C8 4- (Ethoxycarbonyl) -5,6-dihydro-2H-pyran-3-sulfonic acid (27.5 g) was dissolved in thionyl chloride (82.6 ml).
The mixture was stirred at room temperature → 85 ° C. for 3 hours. The reaction solution was dried under reduced pressure, and the residue was dissolved in ethyl acetate (100 ml). The resulting solution was separated by adding diluted saline (120 ml), and the ethyl acetate layer was washed twice with saturated saline (50 ml) and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (eluent: ethyl acetate / hexane).
= 1/7 → 1/5), purify and concentrate the desired product under reduced pressure, and wash the crystal formed under freezing with hexane to give ethyl 5- (chlorosulfonyl) -3,6-dihydro-2H- Pyran-4-carboxylate (7.81 g) was obtained as pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 7.2 Hz), 2.62-
2.70 (2H, m), 3.87 (2H, t, J = 5.5 Hz), 4.34 (2H,
q, J = 7.2 Hz), 4.53 (2H, t, J = 2.6 Hz). Elemental analysis: C ₈ H ₁₁ ClO ₅ S Calculated (%): C, 37.73; H, 4.35. ): C, 37.64; H, 4.27.

Reference Example D1 m-chlorobenzoate was added to a solution of ethyl 6- (benzylsulfanyl) -1-cyclohexene-1-carboxylate (100 mg) obtained in Reference Example C1 in methylene chloride (3 ml) under ice-cooling. Acid (1
96 mg) and stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution (20 ml) was added to the reaction solution, and ethyl acetate was added.
(20 ml × 2). The ethyl acetate layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (20 ml), water (20 ml), and a saturated saline solution (20 ml).
ml) and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was subjected to flash silica gel chromatography (eluent: hexane → ethyl acetate / hexane).
= 1/30) and crystallized from hexane to give ethyl 6- (benzylsulfonyl) -1-cyclohexene-1-carboxylate (Compound 1 ', 106 mg) as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.2 Hz), 1.41-2.
50 (6H, m), 4.28 (2H, q, J = 7.2Hz), 4.29 (1H, d, J
= 13.8Hz), 4.35 (1H, m), 4.55 (1H, d, J = 13.8Hz),
7.37-7.45 (4H, m), 7.50-7.55 (2H, m). Elemental analysis: C ₁₆ H ₂₀ O ₄ S ・ 0.5H ₂ O Calculated (%): C, 60.55; H, 6.67 (%): C, 60.98; H, 6.32.

Reference Example D2 By the same procedure as in Reference Example D1, the ethyl 6-[(4-methoxybenzyl) sulfanyl] -1-cyclohexene-1-carboxylate (98 mg) obtained in Reference Example C2 was reacted. And ethyl 6-[(4-methoxybenzyl) sulfonyl] -1-
Cyclohexene-1-carboxylate (Compound 2 ', 88 m
g) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.34 (3H, t, J = 7.0 Hz), 1.42-2.
50 (6H, m), 3.82 (3H, s), 4.21 (1H, d, J = 13.6Hz),
4.28 (2H, q, J = 7.0Hz), 4.31 (1H, m), 4.50 (1H,
d, J = 13.6Hz), 6.92 (2H, d, J = 8.8Hz), 7.41 (1H,
t, J = 3.6Hz), 7.47 (2H, d, J = 8.8Hz). Elemental analysis: C ₁₇ H ₂₂ O ₅ S Calculated (%): C, 60.33; H, 6.55 Actual (%) : C, 60.42; H, 6.58.

Reference Example D3 Ethyl 6-[(2,4-difluorobenzyl) sulfanyl] -1-obtained in Reference Example C3 by the same procedure as Reference Example D1.
When cyclohexene-1-carboxylate (161 mg) was reacted, ethyl 6-[(2,4-difluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (Compound 3 ′, 134 mg) was obtained as white crystals. Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.0 Hz), 1.59-2.
50 (6H, m), 4.27 (2H, q, J = 7.0Hz), 4.35 (1H, d, J
= 14.0Hz), 4.39 (1H, m), 4.51 (1H, d, J = 14.0Hz),
6.83-6.96 (2H, m), 7.42 (1H, t, J = 4.0Hz), 7.49-
7.61 (1H, m). Elemental analysis: C ₁₆ H ₁₈ F ₂ O ₄ S Calculated (%): C, 55.80; H, 5.27 Found (%): C, 55.95; H, 5.40.

Reference Example D4 By the same procedure as in Reference Example D1, ethyl 6-[(2-chloro-4-fluorobenzyl) sulfanyl] -1-cyclohexene-1-carboxylate (509 mg) obtained in Reference Example C4 To give ethyl 6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate
(Compound 4 ', 422 mg) was obtained as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.0 Hz), 1.55-2.
52 (6H, m), 4.25 (2H, q, J = 7.0Hz), 4.41 (1H, d, J
= 5.6Hz), 4.59 (2H, s), 7.03 (1H, td, J = 8.4Hz,
2.6Hz), 7.21 (1H, dd, J = 8.4Hz, 2.6Hz), 7.42 (1H,
t, J = 4.0Hz), 7.62 (1H, dd, J = 8.4Hz, 6.2Hz). Elemental analysis: C ₁₆ H ₁₈ ClFO ₄ S Calculated (%): C, 53.26; H, 5.03 (%): C, 53.08; H, 4.95.

Reference Example D5 Ethyl 6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (Compound 4 ', 100 mg) obtained in Reference Example D4 was subjected to high performance liquid chromatography.
(CHIRALPAK AD; eluent: hexane / ethanol 8/2), separated into two optical isomers, filtered through a 0.45 μm filter, concentrated, and crystallized from hexane to give ethyl
(-)-6-[(2-Chloro-4-fluorobenzyl) sulfonyl] -1-
Cyclohexene-1-carboxylate (compound 5 ', 50 m
g) and ethyl (+)-6-[(2-chloro-4-fluorobenzyl) sulfonyl] -1-cyclohexene-1-carboxylate (compound 6 ′, 49 mg) were each obtained as white crystals.

Compound 5 ′ ¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.0 Hz), 1.56-2.
55 (6H, m), 4.26 (2H, q, J = 7.0Hz), 4.42 (1H, d, J
= 5.6Hz), 4.59 (2H, s), 7.03 (1H, td, J = 8.6Hz,
2.4Hz), 7.21 (1H, dd, J = 8.6Hz, 2.4Hz), 7.42 (1H,
. t, J = 4.2Hz), 7.61 (1H, dd, J = 8.6Hz, 6.0Hz) Elemental analysis: C ₁₆ H ₁₈ ClFO ₄ Calculated S (%): C, 53.26 ; H, 5.03 Found (%):. C, 53.24 ; H, 4.85 [α] D 20 -97.0 ° (c = 0.5, in methanol).

Compound 6 ′ ¹ H-NMR (CDCl ₃ ) δ: 1.32 (3H, t, J = 7.0 Hz), 1.56-2.
55 (6H, m), 4.26 (2H, q, J = 7.0Hz), 4.42 (1H, d, J
= 6.2Hz), 4.59 (2H, s), 7.03 (1H, td, J = 8.6Hz,
2.4Hz), 7.21 (1H, dd, J = 8.6Hz, 2.4Hz), 7.42 (1H,
. t, J = 4.4Hz), 7.60 (1H, dd, J = 8.6Hz, 6.0Hz) Elemental analysis: C ₁₆ H ₁₈ ClFO ₄ Calculated S (%): C, 53.26 ; H, 5.03 Found (%): C, 53.29; H, 4.82. [Α] _D ²⁰ + 95.0 ° (c = 0.5, in methanol).

Reference Example D6 2,4-Difluoroaniline (0.45 g) was dissolved in ethyl acetate (10 ml), and triethylamine (0.55 g) was added to the resulting solution under ice-cooling.
mg), and a solution of ethyl 5- (chlorosulfonyl) -3,6-dihydro-2H-pyran-4-carboxylate (0.69 g) obtained in Reference Example C8 in ethyl acetate (4 ml) was further added dropwise. The reaction solution was stirred at 0 ° C. for 30 minutes and further at room temperature for 5.8 hours under a nitrogen stream. Dilute the reaction with ethyl acetate, add water (50 ml), 0.5
The mixture was washed sequentially with N hydrochloric acid (50 ml), water (50 ml × 2), and saturated saline (50 ml). The ethyl acetate layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate / hexane = 1 /
Purified by 2). After the target fraction was concentrated under reduced pressure, the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to give ethyl 3-[(2,4-difluorophenyl) sulfamoyl] -3,6-dihydro-2H-pyran-4- The carboxylate (compound 7 '; 0.57 g) was obtained as white crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 1.14 (3H, t, J = 7.0 Hz), 3.69
(1H, dd, J = 12.8 Hz, 3.0 Hz), 4.08 (2H, q, J = 7.0
Hz), 4.25 (2H, s), 4.33 (1H, d, J = 1.8 Hz), 4.41
-4.48 (1H, m), 7.00-7.05 (1H, m), 7.12 (1H, br),
7.22-7.33 (1H, m), 7.43-7.55 (1H, m), 9.82 (1H, s). Elemental analysis: C ₁₄ H ₁₅ F ₂ NO ₅ S Calculated (%): C, 48.41; H , 4.35; N, 4.03. Found (%): C, 48.47; H, 4.35; N, 3.96.

Reference Example D7 By the same procedure as in Reference Example D6, the ethyl 5- (chlorosulfonyl) -3,6-dihydro-2H-pyran- obtained in Reference Example C8 was obtained.
Reaction of 4-carboxylate (0.70 g) with 2-chloro-4-fluoroaniline (0.52 g) gave ethyl 3-[(2-chloro-4
-Fluorophenyl) sulfamoyl] -3,6-dihydro-2H-
Pyran-4-carboxylate (compound 8 '; 0.54 g) was obtained as white crystals. ¹ H-NMR (DMSO-d ₆ ) δ: 1.11 (3H, t, J = 7.0 Hz), 3.72
(1H, dd, J = 12.8 Hz, 3.0 Hz), 4.07 (2H, q, J = 7.0
Hz), 4.15-4.25 (2H, m), 4.37 (1H, d, J = 2.2 Hz),
4.46-4.55 (1H, m), 7.15 (1H, br), 7.22-7.26 (1H,
m), 7.46-7.59 (2H, m), 9.68 (1H, s). Elemental analysis: C ₁₄ H ₁₅ ClFNO ₅ S Calculated (%): C, 46.22; H, 4.16; N, 3.85. Value (%): C, 46.35; H, 4.11; N, 3.73.

Tables 6 and 7 show specific examples of the compound (II) which can be synthesized in the same manner as in Reference Example D, but the compound (II) is limited to the compounds shown in Tables 6 and 7. Not something.

[0387]

[Table 6]

[0388]

[Table 7]

Reference Example E1 (1) 10 mg of compound 72 of Reference Example B66 (2) 60 mg of lactose (3) 35 mg of corn starch (4) 3 mg of gelatin (5) 2 mg of magnesium stearate 10 mg of Compound 72 of Reference Example B66, 60 mg of lactose and corn starch 35 mg of the mixture is granulated through a 1 mm mesh sieve using 0.03 ml of a 10% aqueous gelatin solution (3 mg as gelatin), dried at 40 ° C. and sieved again. The granules thus obtained are mixed with 2 mg of magnesium stearate and compressed. The resulting central tablet is sucrose,
Coat with sugar coating with aqueous suspension of titanium dioxide, talc and gum arabic. The coated tablets are polished with beeswax to obtain coated tablets.

Reference Example E2 (1) 10 mg of Compound 72 of Reference Example B66 (2) 70 mg of lactose (3) 50 mg of corn starch (4) 7 mg of soluble starch (5) 3 mg of magnesium stearate 10 mg of Compound 72 of Reference Example B66 and magnesium stearate 3 mg are granulated with 0.07 ml of an aqueous solution of soluble starch (7 mg as soluble starch), dried and mixed with 70 mg of lactose and 50 mg of corn starch. The mixture is compressed to give tablets.

Reference Example E3 (1) 10 mg of Compound 29 of Reference Example B65 (2) 60 mg of lactose (3) 35 mg of corn starch (4) Gelatin 3 mg (5) 2 mg of magnesium stearate 10 mg of Compound 29 of Reference Example B65, 60 mg of lactose and corn starch 35 mg of the mixture is granulated through a 1 mm mesh sieve using 0.03 ml of a 10% aqueous gelatin solution (3 mg as gelatin), dried at 40 ° C. and sieved again. The granules thus obtained are mixed with 2 mg of magnesium stearate and compressed. The resulting central tablet is sucrose,
Coat with sugar coating with aqueous suspension of titanium dioxide, talc and gum arabic. The coated tablets are polished with beeswax to obtain coated tablets.

Reference Example E4 (1) 10 mg of Compound 29 of Reference Example B65 (2) 70 mg of lactose (3) 50 mg of corn starch (4) 7 mg of soluble starch (5) 3 mg of magnesium stearate 10 mg of Compound 29 of Reference Example B65 and magnesium stearate 3 mg are granulated with 0.07 ml of an aqueous solution of soluble starch (7 mg as soluble starch), dried and mixed with 70 mg of lactose and 50 mg of corn starch. The mixture is compressed to give tablets.

Reference Example E5 (1) 5.0 mg of ceftazidime (2) 20.0 mg of sodium chloride (3) Distilled water Make up to 2 ml in total 5.0 mg of ceftazidime and 20.0 mg of sodium chloride were dissolved in distilled water, and water was added to the whole. Make up to 2.0 ml. The solution is filtered and filled under aseptic conditions into 2 ml ampules. After sterilizing the ampoule, seal it to obtain a solution for injection.

Reference Example F1

[0395]

Embedded image

To 109.4 g (0.59 mol) of MCH, 555 ml of acetonitrile and water
555 ml was added, and the mixture was cooled to 0 ° C or lower. While stirring this mixture well, 255 g (3.25 times mol) of N-chlorosuccinic acid imito (NCS)
Is added so that the internal temperature does not exceed 25 ° C.
Stirred at 5 ° C for 1 hour. 770 ml of isopropyl ether (IPE) was added to the reaction solution, and the mixture was separated. The organic layer was washed three times with 440 ml of water, and the solvent was distilled off under reduced pressure to remove ECSC as an oil.
9 g was obtained.

Reference Example F2 d-Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (ethyl (6R) -6-[(2-chloro-4 -Fluoroanilino) sulfonyl] -1-cyclohexene-1-carboxylate) d-ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] obtained according to Example 66 described in WO 99/46242. -1-cyclohexene-1-carboxylate (ethyl (6R) -6-[(2-chloro-4-fluoroanilino) sulfonyl] -1-cyclohexene-1-carboxylate) (3.6
g) was dissolved in ethanol (3 ml) and concentrated under reduced pressure. Crystals precipitated by adding a mixture of ethanol (1 ml) and hexane (3 ml) to the residue were collected by filtration and washed with hexane.
After drying under reduced pressure, 2.8 g of the title compound was obtained as colorless crystals having a melting point of 68-69 ° C. FIG. 2 shows the powder X-ray crystal diffraction pattern. ¹ H-NMR (d ₆ -DMSO) δ 1.05 (3H, t, J = 7.0Hz), 1.56-1.8
3 (2H, m), 1.97-2.43 (4H, m), 4.00 (2H, q, J = 7.0 H
z), 4.29 (1H, d, J = 5.0Hz), 7.10 (1H, br), 7.20-7.30
(1H, m), 7.50-7.58 (2H, m), 9.75 (1H, s). Elemental analysis: C ₁₅ H ₁₇ ClFNO ₄ S Calculated: C, 49.79; H, 4.74; N, 3.87. Experimental : C, 49.73; H, 4.69; N, 3.81. [Α] _D ²⁰ + 111.0 ° C (c = 1.0, in methanol).

[0398]

[Table 8]

Example 1 (Concomitant drug) Any of the preparations of Reference Examples E1 to E4 and Reference Example E
Combine with 5 formulations.

Test Example 1 The E. coli O111 strain was suspended in 5% mucin, and 0.5 ml of a mouse (BALB / c, male, 5 weeks old) was intraperitoneally inoculated (9 × 10 ⁴ CFU per mouse). One hour after inoculation, the antibacterial agent ceftazidime (CAZ)
12.5 μg / kg was administered subcutaneously, and simultaneously, compound 29 (30 mg / kg) of Reference Example B65 suspended in a 0.5% methylcellulose (MC) solution was orally administered, and the survival of each mouse was observed for one week. did. The results are shown in FIG.
From FIG. 1, it was found that a significant increase in the survival rate was observed when the ineffective or low-effective amount of the compound of Reference Example B1 was used in combination with ceftazidime.

[0401]

The combination drug of the present invention is useful as a preventive / therapeutic agent for diseases such as sepsis, septic shock, inflammatory disease, infectious disease and other diseases.

[Brief description of the drawings]

BRIEF DESCRIPTION OF THE DRAWINGS FIG. The vertical axis indicates the survival rate (Survival (%)) of the mouse after infection with E. coli O111.
CAZ indicates ceftazidime, and the test compound indicates Compound 29 of Reference Example B65. ● is E. When nothing was administered to mice infected with E. coli O111, □ indicates E. coli. coli
Compound 29 of Reference Example B65 was injected into mice infected with O111.
Is given when △ is administered. When CAZ was administered to a mouse infected with E. coli O111, .largecircle. coli
Compound 29 of Reference Example B65 was injected into mice infected with O111.
And the results when CAZ was administered.

FIG. 2 shows a powder X-ray crystal diffraction pattern of the crystal obtained in Reference Example F2.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (reference) A61P 43/00 121 A61P 43/00 121 F term (reference) 4C084 AA20 AA24 MA02 NA05 ZA542 ZB111 ZB112 ZB351 ZB352 ZC751 ZC752 4C086 AA01 AA02 CC12 CC16 MA02 MA03 MA04 NA05 NA14 ZB11 ZB35 ZC75 4C206 AA01 AA02 JA11 KA01 MA02 MA03 MA04 NA05 NA14 ZB11 ZB35 ZC75

Claims (17)

[Claims] 1. A medicament comprising a combination of an antiseptic drug and at least one drug selected from the group consisting of antibacterial drugs, antifungal drugs, nonsteroidal antiinflammatory drugs, steroid drugs and anticoagulants. 2. The medicament according to claim 1, wherein the anti-sepsis drug is a non-peptidic compound. 3. The medicament according to claim 1, wherein the anti-sepsis drug is a cycloalkene compound. 4. The method of claim 1, wherein the antisepsitic agent is of the formula (I): [Wherein, R is an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, : -OR ¹ (wherein,
R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent. Or a group represented by the formula: (Wherein, R ^1b and R ^1c are the same or different and each represent a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent.), And R ⁰ represents a hydrogen atom or R ¹ represents an aliphatic hydrocarbon group, or R and R ⁰ combine to form a bond, and ring A ¹ is (1) an aliphatic hydrocarbon group which may have a substituent, (2) An aromatic hydrocarbon group which may have a substituent, (3) a formula: -OR ¹¹ (wherein R
¹¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent. And cycloalkene which may be substituted with 1 to 4 substituents selected from the group consisting of (4) halogen atoms, and Ar is an aromatic group which may have a substituent. Represents a hydrocarbon group and has the formula: Is a group represented by the formula: And n represents an integer of 1 to 4. Or a salt thereof or a prodrug thereof. 5. In the formula (I), R represents the formula: —OR ¹ (where R is
¹ has the same meaning as in claim 4. ) Is a group represented by R ⁰
Is a hydrogen atom or an aliphatic hydrocarbon group, ring A ¹ is unsubstituted cyclohexene, Ar is an aromatic hydrocarbon group which may have a substituent, and n is 2. The medicament according to claim. 6. The method of claim 1, wherein the anti-sepsis drug has the formula (II): [Wherein, R ^{1 ′} is an aliphatic hydrocarbon group which may have a substituent, an aromatic hydrocarbon group which may have a substituent, and a heterocyclic group which may have a substituent. A group represented by the formula: —OR ^{1a ′} (wherein, R ^{1a ′} represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent) or a formula represented by the following formula: (Wherein, R ^{1b ′} and R ^{1c ′} are the same or different and each represent a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent), and X represents a methylene group. , N
H represents a sulfur atom or an oxygen atom, Y represents a methylene group which may have a substituent or NH which may have a substituent, and ring A ′ has (1) a substituent. An aliphatic hydrocarbon group which may be substituted, (2) an aromatic hydrocarbon group which may have a substituent, (3) a formula: —OR ^{2 ′} (where R ^{2 ′} represents a hydrogen atom or a substituent, 5 to 8 members optionally having 1 to 4 substituents selected from the group consisting of: A ring, Ar ′ represents an aromatic hydrocarbon group which may have a substituent, and has the formula: The group represented by is represented by the formula: Wherein s is an integer of 0 to 2, t is an integer of 1 to 3, and the sum of s and t is 4 or less; provided that when X is a methylene group, Y is It represents a methylene group which may have a substituent. Or a salt thereof or a prodrug thereof. 7. In the formula (II), R ^{1 ′} is a group represented by the formula: —OR ^{1a ′} (where R ^{1a ′} is C _1-6 alkyl), and X is a methylene group. Or phenyl which is an oxygen atom, Y is a methylene group or —NH—, and Ar ′ optionally has one or two substituents selected from the group consisting of a halogen atom and a C _1-6 alkoxy group. Group,
Formula: The group represented by is represented by the formula: The pharmaceutical according to claim 6, wherein s is 1 and t is 1. 8. The medicament according to claim 1, wherein one or two or more drugs selected from an antibacterial drug and an antifungal drug are combined with an antiseptic drug. 9. The medicament according to claim 1, wherein one or more drugs selected from nonsteroidal anti-inflammatory drugs and steroid drugs are combined with an anti-sepsitic drug. 10. The medicament according to claim 1, which comprises a combination of an anticoagulant and an antisepsitic agent. 11. The medicament according to claim 1, which is a prophylactic or therapeutic agent for sepsis. 12. The medicament according to claim 1, which is a prophylactic or therapeutic agent for septic shock. 13. The medicament according to claim 1, which is an agent for preventing or treating an inflammatory disease or an infectious disease. 14. An effective amount of an anti-Sepsis drug and an effective amount of at least one drug selected from an antibacterial drug, an antifungal drug, a nonsteroidal anti-inflammatory drug, a steroid drug and an anticoagulant for a mammal. A method for preventing or treating sepsis, which is administered in combination with the above. 15. A mammal, comprising administering to a mammal an effective amount of an anti- sepsis agent, an antibacterial agent, an antifungal agent, a non-steroidal anti-inflammatory agent,
A method for preventing or treating an inflammatory disease or an infectious disease, which comprises administering an effective amount of at least one drug selected from the group consisting of a steroid drug and an anticoagulant in combination. 16. An anti-Sepsis drug and at least one selected from the group consisting of antibacterial drugs, antifungal drugs, non-steroidal anti-inflammatory drugs, steroid drugs and anticoagulants for producing a prophylactic or therapeutic agent for sepsis. Use with one drug. 17. A method for producing a prophylactic or therapeutic agent for an inflammatory disease or an infectious disease, comprising an antiseptic drug, an antibacterial drug, an antifungal drug, a nonsteroidal antiinflammatory drug, a steroid drug and an anticoagulant drug. Use with at least one drug selected from the group consisting of: