JP2002265362A - Medicinal composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicinal composition which has improved solubility or stability. SOLUTION: This medicinal composition comprises a compound represented by the general formula (I) [R is an aliphatic hydrocarbon group, an aromatic hydrocarbon group, a heterocyclic group, OR<1> or N(R<1b> )(R<1c> ); R<0> is H or an aliphatic hydrocarbon group; or R and R<0> together exhibit a direct bound; a ring A<1> is a cycloalkene which may be substituted; Ar is a aromatic hydrocarbon group which may have one or more substituents; a group of formula (a) is a group of formula (b) or (c); and (n) is an integer of 1 to 4] or its salt or its prodrug, and a nonionic surfactant and/or an easily water-dissolvable cyclodextrin derivative. A method for improving the solubility, stability or colorability or the compound of formula (I) is also provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition having improved solubility or stability of a water-insoluble or poorly water-soluble cycloalkene compound, and a method for improving the solubility or stability of the cycloalkene compound. .

[0002]

2. Description of the Related Art WO99 / 46242 includes the following equation (i).

Embedded image [Wherein, R represents an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, a formula -OR ¹ (wherein, R ¹
Represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent. ) Group or formula

Embedded image (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 as R ^1b and is an aliphatic hydrocarbon group which may have a hydrogen atom or a substituent. R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ⁰ together form a bond, 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 ¹ wherein R ¹ is as defined above. And (4) a cycloalkene substituted with 1 to 4 halogen atoms selected from halogen atoms; and Ar represents an aromatic hydrocarbon group which may have a substituent;

Embedded image The group represented by the formula

Embedded image Or

Embedded image And n represents an integer of 1 to 4. A compound represented by the formula (ii):

Embedded image [Wherein, R ^a 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 ^1a (where
R ^1a represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent. ) Group or formula

Embedded image(Where R^1aIs as defined above,^1bIs R^1aSame as
Is different and may have a hydrogen atom or a substituent
Shows an aliphatic hydrocarbon group. ) Represents a group represented by R ^0aIs water
A hydrogen atom or an aliphatic hydrocarbon group, or R^aAnd R^0a
Are joined together, Ar^aMay have a substituent
A good aromatic hydrocarbon group has the formula

Embedded image The group represented by the formula

Embedded image Or

Embedded image And n represents an integer of 1 to 4. Or a salt thereof or a prodrug thereof has an inhibitory effect on nitric oxide (NO) production and TNF-α, IL
-1, has an inhibitory effect on the production of inflammatory cytokines such as IL-6, and prevents diseases such as heart disease, autoimmune disease, inflammatory disease, central nervous system disease, infectious disease, sepsis and septic shock -It is described that it is useful as a therapeutic agent.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a pharmaceutical composition having improved solubility and stability of the above compound and a method for improving the solubility and stability of the above compound. I do.

[0004]

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 compounds and non-ionic surfactants such as polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil. By mixing an agent and / or a water-soluble cyclodextrin derivative, unexpectedly, a pharmaceutical composition having significantly improved solubility, stability, coloring property and the like of the compound has been successfully obtained. 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] (a) Formula (I)

[0006]

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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 -OR
¹ (wherein, R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent.)

[0008]

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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. A group represented by R ⁰ ).
Represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R
⁰ is a bond together, 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 group represented by the formula -OR ¹ (wherein R ¹ has the same meaning as described above) and (4) a cycloalkene optionally substituted with 1 to 4 halogen atoms selected from a halogen atom. And Ar represents an aromatic hydrocarbon group which may have a substituent,

[0010]

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The group represented by the formula is

[0012]

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Or

[0014]

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Wherein n is an integer of 1 to 4. A pharmaceutical composition comprising a compound represented by the formula: or a salt thereof or a prodrug thereof, and (b) a nonionic surfactant and / or a water-soluble cyclodextrin derivative.

[2] Formula (I)

[0017]

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[Wherein each symbol has the same meaning as in item [1]], a pharmaceutical composition containing a compound or a salt thereof or a prodrug thereof and a nonionic surfactant; ] The composition according to item [2], wherein the nonionic surfactant is polyoxyethylene castor oil or polyoxyethylene hydrogenated castor oil; [4] the composition according to item [2], which further contains ethanol; [5] the compound is
d-ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -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, ethyl 6- [N- (2-chloro
-4-Methylphenyl) sulfamoyl] -1-cyclohexene
The composition according to item [2], which is -1-carboxylate or a salt thereof,

[6] The composition according to [2], wherein the content of the nonionic surfactant is about 10% by weight to about 70% by weight based on the whole composition, [7] The content of ethanol Is about 30% by weight to about 90% by weight with respect to the whole composition; [8] The compounding ratio of the nonionic surfactant and ethanol is nonionic surfactant About 1 agent
The composition according to [4], wherein the amount of ethanol is about 90 parts by weight to about 10 parts by weight with respect to 0 parts by weight to about 90 parts by weight,

[9] The composition according to [2], which is an injectable composition,
[10] The first non-emulsifying composition

[9] The composition according to the above,
[11] The composition according to [2], which is clear, [12]
The composition according to [2], which is an inhibitor of nitric oxide and / or cytokine production; [13] The composition according to [2], which is an agent for preventing or treating heart disease, autoimmune disease or septic shock. object,

[14] Formula (I)

[0021]

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[Wherein the symbols have the same meanings as in item [1]], the compound comprising mixing a compound or a salt thereof or a prodrug thereof with a nonionic surfactant; Or a method for improving the solubility, stability or coloring of a salt or a prodrug thereof, [1.
5) a method for preventing or treating a heart disease, an autoimmune disease or a septic shock, comprising administering an effective amount of the composition according to the above item [2] to a mammal; [16] a heart disease, an autoimmune disease Or prevention of septic shock
Use of the composition according to item [2] for producing a therapeutic agent,

[17] Formula (I)

[0024]

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[Wherein the symbols have the same meanings as in item [1]], a pharmaceutical composition comprising a compound represented by the formula (1) or a salt thereof or a prodrug thereof and a water-soluble cyclodextrin derivative:

[18] A water-soluble cyclodextrin derivative represented by the formula

[0027]

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[In the formula, q represents an integer from 6 to 12, and R ⁶ , R ⁷ and R ⁸ are the same or different in each repeating unit, and represent a hydrogen atom, a dihydroxyalkyl group, a sugar residue or A hydroxyalkyl group;
^At least one of ⁶ , R ⁷ and R ⁸ is a dihydroxyalkyl group, a sugar residue or a hydroxyalkyl group. ] The composition according to item [17], wherein [19]
The composition according to [18], wherein at least one of R ⁶ , R ⁷ and R ⁸ is a sugar residue, and the remaining groups are hydrogen atoms.

[20] the composition of [18] or [19], wherein the sugar residue is selected from the group consisting of a glucosyl group, a maltosyl group, a maltotriosyl group and a dimaltosyl group; The composition according to [17], wherein the water-soluble cyclodextrin derivative is maltosyl-β-cyclodextrin, [22] the compound represented by the formula (I) or a salt thereof or 1 mol of a prodrug thereof, Water-soluble cyclodextrin derivative about 0.1 to
The composition of claim 17 containing about 100 moles,
[23] A compound [17] containing about 1 to about 5 mol of a water-soluble cyclodextrin derivative per 1 mol of the compound represented by the formula (I) or a salt thereof or a prodrug thereof.
Item 24, wherein the compound is d-ethyl 6-
[N- (2-chloro-4-fluorophenyl) sulfamoyl] -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, ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate or a salt thereof, wherein the composition according to item [17],

[25] The composition according to [17], which is an injectable composition, [26] the composition according to [17], which is a nitric oxide and / or cytokine production inhibitor,
[27] the composition of [17], which is a prophylactic / therapeutic agent for heart disease, autoimmune disease or septic shock;

[28] Formula (I)

[0032]

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[Wherein the symbols have the same meanings as in item [1]], including mixing a compound or a salt thereof or a prodrug thereof with a water-soluble cyclodextrin derivative. Or a method for improving the solubility, stability or colorability of water or a salt thereof or a prodrug thereof in water, [29] comprising administering an effective amount of the composition according to [17] to a mammal. A method for preventing or treating a disease, an autoimmune disease or septic shock, and [30] use of the composition according to [17] for producing an agent for preventing or treating a heart disease, an autoimmune disease or septic shock. I will provide a.

The present invention further relates to a compound represented by the formula (I):

[0035]

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[In the formula, 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 -OR
¹ (wherein, R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent.)

[0037]

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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. A group represented by R ⁰ ).
Represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R
⁰ is a bond together, ring A ² is (1) an aliphatic hydrocarbon group which may have a substituent, (2) an aromatic hydrocarbon group which may have a substituent, (3) a group represented by the formula -OR ¹ (wherein R ¹ has the same meaning as described above) and (4) a cycloalkene substituted with 1 to 4 halogen atoms selected from halogen atoms, and Ar is An aromatic hydrocarbon group which may have a substituent is represented by the formula

[0039]

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The group represented by the formula is

[0041]

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Or

[0043]

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

[0045]

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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 -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:

[0047]

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Where R^1aIs as defined above,^1bIs R
^1aHaving the same or different, a hydrogen atom or a substituent
Represents an aliphatic hydrocarbon group which may be substituted. Group represented by)
And R ^0aRepresents a hydrogen atom or an aliphatic hydrocarbon group, or
Is R^aAnd R^0aAre joined together, Ar^aIs a substituent
An aromatic hydrocarbon group which may have

[0049]

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The group represented by the formula is

[0051]

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Or

[0053]

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And n is an integer of 1 to 4. The composition according to the above [1], [2] or [17], which is a compound represented by the formula [Iaa]:

[0055]

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[0056] [wherein each symbol is the [1] This shows the section according as defined above] The composition of the [31], wherein a compound represented by, [33] the ring A ² is a lower alkyl, phenyl Or 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; , [34] a compound represented by the formula (Ie)

[0057]

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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 -OR
¹ (wherein, R ¹ represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent.)

[0059]

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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. A group represented by R ⁰ ).
Represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R
⁰ is a bond together, Ar is an aromatic hydrocarbon group which may have a substituent,

[0061]

[Of 60]

The group represented by the formula is

[0063]

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Or

[0065]

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Wherein n is an integer of 1 to 4. However, when n is 1 or 2, (i) when R ¹ is a hydrogen atom or an ethyl group, R ⁰ is a methyl group, and Ar is a phenyl group, or (ii) R and R ⁰ together When Ar is a phenyl group, a 2-methylphenyl group, a 4-bromophenyl group, a 4-methoxyphenyl group or a 2,6-dimethylphenyl group,

[0067]

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The group represented by the formula is

[0069]

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Is a group represented by The composition according to item [31], which is a compound represented by the formula (Ia):

[0071]

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

[0073]

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The group represented by has the same significance as described in the item [33]. Here, n is 1 or 2, Ar is a phenyl group, R ¹
Is a hydrogen atom or an ethyl group, and R ² is a methyl group,

[0075]

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The group represented by the formula is

[0077]

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Is a group represented by Is a compound represented by the composition of the first [34], wherein, [36] the R ¹ is an optionally substituted lower alkyl group [35]
The composition of claim wherein, [37] the R ¹ is an ethyl group [3
[5] The composition according to [35], wherein [ ² ] R ² is a hydrogen atom or a lower alkyl group;
9] The composition according to [35], wherein R ² is a hydrogen atom,
[40] the composition of [35], wherein Ar is a phenyl group which may have a substituent, [41] the composition of [35], wherein Ar is a phenyl group substituted with halogen or / and lower alkyl; ] The composition according to the above, [42] Ar is a compound of the formula

[0079]

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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. [35] the composition according to [35], wherein the halogen atom is a fluorine atom or a chlorine atom;

[0081]

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The group represented by the formula is

[0083]

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[Wherein, n has the same meaning as described in the item [34]. [45] The composition according to [35], wherein n is 1 to 3, and [46] R ¹ has a substituent. [35] wherein R ² is a hydrogen atom or a lower alkyl group, Ar is a phenyl group which may have a substituent, and n is 1, 2 or 3; Wherein R ¹ is a lower alkyl group which may have a substituent, R ² is a hydrogen atom, Ar is a phenyl group substituted with a halogen atom, and n is The composition according to item [35], wherein the compound represented by the formula (Ia) is a compound represented by the formula:

[0085]

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[Wherein Ar and n have the same meanings as in item [34]], the composition according to item [34], wherein [49] Ar has a substituent. A composition according to [48], wherein n is 2; [50] a compound represented by the formula (Ia),

[0087]

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Wherein R ¹ , R ² and Ar are [35]
Is equivalent to

[0089]

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The group represented by the formula is

[0091]

[Of 75]

Or

[0093]

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The group represented by Provided that when Ar is a phenyl group, R ¹ is a hydrogen atom or an ethyl group, and R ² is a methyl group,

[0095]

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The group represented by the formula is

[0097]

Embedded image

Is a group represented by The composition according to item [34], which is a compound represented by the formula (Ie):

[0099]

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

[0101]

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The group represented by has the same significance as described in the item [31]. The composition according to item [31], which is a compound represented by the formula (Ie), and a compound represented by the formula (Ie):
formula

[0103]

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[Wherein R ^1a , R ^2a and Ar ^a are the same as [5]
1] has the same meaning as described in the formula

[0105]

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The group represented by the formula is

[0107]

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Or

[0109]

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And the group represented by ] The composition according to [31], which is a compound represented by the formula:

In the present specification, R 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 ring group, a group represented by the 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:

[0112]

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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. even though showing an aliphatic hydrocarbon group.) or a group represented by or show to form a bond together with R ^0, especially, the formula -OR ¹ [R ¹ is the same as the Show meaning. ] Are 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. , Expression -OR
^1a (wherein, R ^1a represents a hydrogen atom or an optionally substituted aliphatic hydrocarbon group), or a group represented by the formula:

[0115]

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(Wherein R^1aIs as defined above,^1bIs R
^1aSame or different from the above, has a hydrogen atom or a substituent
Represents an aliphatic hydrocarbon group which may be substituted. )
Group or R^0aTo form a bond with
And, inter alia, the formula -OR ^1a[R^1aIs as defined above
Is shown. ] Are preferable.

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

[0118]

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

[0120]

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[Wherein the symbols are as defined above. ]
Or

[0122]

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Wherein each symbol is 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

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

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):

[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 (Ia):

[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]

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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. Is a group represented by the formula (Ie):

[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 The compound represented by the formula (Iaa) is preferably a compound represented by the formula (Icc) or the formula (Inn), and the compound represented by the formula (Ia) is represented by the formula (Ic) or the formula (In). The compound represented by the formula (Ie) is preferably a compound represented by the formula (Ik) or the formula (Ip).

Similarly, the compound represented by the formula (Id) is

[0159]

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

[0161]

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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

[0163]

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

[0165]

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

The compound represented by the formula (Id) includes a compound represented by the formula (I
As the compound represented by the formula (Ig), the compound represented by the formula (Ig) is preferably a compound represented by the formula (It).

In the compound represented by the formula (Ia), n is 1 or 2, and (i) when R ¹ is a hydrogen atom or an ethyl group, R ⁰ is a methyl group, and Ar is a phenyl group, or (Ii) R and R ⁰ together represent a bond, and Ar is a phenyl group, a 2-methylphenyl group,
-A bromophenyl group, a 4-methoxyphenyl group or a 2,6-dimethylphenyl group,

[0169]

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The group represented by the formula is

[0171]

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A group represented by the following formula: Further, n is 1 to 4
(I) R ¹ is a hydrogen atom or a lower alkyl group which may have a substituent, R ⁰ is a lower alkyl group which may have a substituent, and Ar 1 has a substituent Or (ii) when R and R ⁰ together represent a bond, and Ar is a phenyl group which may have a substituent,

[0173]

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A group represented by the formula:

[0175]

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A group represented by the formula:

[0177] In the compound represented by formula (Ib), n is 1 or 2, R ¹ is a hydrogen atom or an ethyl group, R ⁰
Is a methyl group and Ar is a phenyl group,

[0178]

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The group represented by the formula is

[0180]

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A group represented by the following formula: Further, n is 1 to 4
R ¹ may be a hydrogen atom or a lower alkyl group which may have a substituent, R ⁰ may be a lower alkyl group which may have a substituent, and Ar may have a substituent. When it is a phenyl group, the formula

[0182]

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The group represented by the formula is

[0184]

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A group represented by the formula:

[0186]

BEST MODE FOR CARRYING OUT THE INVENTION An "optionally substituted aliphatic hydrocarbon group" represented by R, R ¹ , R ^1a , R ^1b and R ^1c
Examples of the “aliphatic hydrocarbon group” represented by R ⁰ , R ^0a , R ² , and R ^2a include, for example, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, and an alkenyl group. And an alkynyl group are preferred.

Examples of the alkyl group include linear or branched alkyl groups 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.) is 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 (eg, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group) and the like are preferable. , For example, having 4 to 4 carbon atoms
8 (among others, 4 to 7) cycloalkylalkyl groups (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 includes, for example, those having 3 carbon atoms.
And lower alkynyl groups having 6 to 6 carbon atoms (eg, propynyl group, butynyl group, pentynyl group, etc.), and more preferably, for example, lower alkynyl groups having 3 or 4 carbon atoms (eg, propynyl group, butynyl group, etc.).

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 on a substitutable site of the aforementioned “aliphatic hydrocarbon group”, and the substituent is 1
The number is not limited to the same,
).

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)"
As, for example, a benzylthio group, a phenylethylthio group, a benzhydrylthio group, a benzylsulfinyl group, a benzylsulfonyl group, etc. , “C _1-10 alkoxy-carbonyl group”
As, for example, a methoxycarbonyl group, an ethoxycarbonyl group, n- propoxycarbonyl group, isopropoxycarbonyl group, n- butoxycarbonyl group, isobutoxycarbonyl group, tert- butoxycarbonyl group, "C _3-6 cycloalkyl As the `` oxycarbonyl group '', for example, a cyclopropyloxycarbonyl group, a cyclopentyloxycarbonyl group, a cyclohexyloxycarbonyl group, a norbornyloxycarbonyl group, and the like, as the `` C _6-10 aryloxy-carbonyl group '', for example, phenoxycarbonyl group, etc. naphthyloxycarbonyl group, - as the "C _7-19 aralkyloxy group", for example, benzyloxycarbonyl group, benzhydryloxy group, 2-phenethyl oxycarbonyl group Etc. is - as the "C _6-10 aryl-carbonyl group", for example, benzoyl group, naphthoyl group, a phenyl acetyl group, the "C _1-6 alkanoyl group", for example, a formyl group, an acetyl group,
Propionyl group, butyryl group, valeryl group, pivaloyl group, and examples of the "C _3-5 alkenoyl group", for example, an acryloyl group, a crotonoyl group, "C _6-10
As the "aryl-carbonyloxy group", for example, a benzoyloxy group, a naphthoyloxy group, a phenylacetoxy group, and the like, and as the " _C2-6 alkanoyloxy group", for example, an acetoxy group, a propionyloxy group,
Butyryloxy group, valeryloxy group, such as pivaloyloxy group, and examples of the "C _3-5 alkenoyloxy group", for example, acryloyloxy group, etc. crotonoyloxy group 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 aminocarbonyl group is 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-
A piperazinylcarbonyl group, a morpholinocarbonyl group and the like are used. The “optionally substituted thiocarbamoyl group” includes, for example, C _1-4 alkyl (eg,
A thiocarbamoyl group optionally substituted with one or two substituents selected from methyl, ethyl and the like), phenyl and the like. Specifically, for example, a thiocarbamoyl group, an N-methylthiocarbamoyl group, An N-phenylthiocarbamoyl group or the like is used. 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_7-10Aralkyloxy-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 may be C _1-4 alkyl (eg,
A substitutable site may be substituted by 1 to 3 substituents selected from methyl, ethyl, etc.), hydroxy, oxo, C _1-4 alkoxy (eg, methoxy, ethoxy, etc.).

As the “C _6-10 aryl group” of the “ _optionally substituted C _6-10 aryl group”, 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. Those substituents are the C
The substituent is substituted on a substitutable site of the _6-10 aryl group, and the number of the substituents is not limited to one, and may be the same or different (two to four).

The “aliphatic hydrocarbon group optionally having substituent (s)” is a group in which the substituent forms a condensed ring group which may be substituted together with the aliphatic hydrocarbon group. And such a condensed ring group may be an indanyl group, 1,2,
For example, a 3,4-tetrahydronaphthyl group 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)”. Those substituents are
The substituent is substituted at a substitutable site of the condensed ring group, and the number of the substituents is not limited to one, and may be the same or different and plural (2
~ 4).

As R, R ¹ , R ^1a , R ^1b , R ^1c ,
For example, a lower alkyl group having 1 to 6 carbon atoms which may have a substituent (eg, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, te
rt-butoxycarbonylmethyl group, hydroxyethyl group, etc.) are preferably used, and among them, for example, methyl group, ethyl group, n-propyl group, isopropyl group,
An n-butyl group, an 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 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 Ar and Ar ^a is an aromatic hydrocarbon group having 6 to 14 carbon atoms ( For example, a phenyl group, a naphthyl group, a biphenyl 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. A phenyl group and the like are particularly preferred.

The “substituent” in the “aromatic hydrocarbon group optionally having substituent (s)” represented by Ar and Ar ^a is, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.). ), Lower (C _1-4 ) alkyl groups (eg, methyl, ethyl, propyl, butyl, etc.), lower (C _1-4 ) alkoxy groups (eg, methoxy, ethoxy, propoxy, butoxy) Group), lower (C _1-4 )
Alkoxycarbonyl group (eg, methoxycarbonyl group,
Ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), carboxyl, nitro,
A cyano group, a hydroxyl group, an acylamino group (eg, an alkanoylamino group having 1 to 4 carbon atoms such as an acetylamino group, a propionylamino group, and a butyrylamino group);
To 6 cycloalkyl groups (eg, cyclopropyl group, cyclopentyl group, etc.), aryl groups having 6 to 10 carbon atoms (eg, 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) A tetrafluoroethoxy group, 2,2,
3,3,3-pentafluoropropoxy group, etc., lower (C _1-4 ) alkylthio group (eg, methylthio group, ethylthio group, propionylthio group, etc.), lower (C _1-4 ) alkylsulfonyl group (eg, Methanesulfonyl, ethanesulfonyl, propanesulfonyl, etc.), lower (C
_1-4 ) alkanoyl group (eg, formyl group, acetyl group,
A 5-membered aromatic heterocyclic group (eg, propionyl group)
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 (e.g., methylcarbamoyl group, dimethylcarbamoyl group, propionyloxy, etc. carbamoyl group), a lower (C _1-4) alkoxy - carbonyl - lower (C _1-4) alkyl - carbamoyl group (e.g., Butoxycarbonylmethylcarbamoyl group,
An ethoxycarbonylmethylcarbamoyl group), 1,
3-diacylguanidino-lower (C _1-4 ) alkyl group (eg, 1,3-diacetylguanidinomethyl, 1,3-bis-tert-butoxycarbonylguanidinomethyl, etc.)
And the like, preferably a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.), a lower (C _1-4 )
An alkyl group (eg, a methyl group, an ethyl group, a propyl group, a butyl group, etc.) and the like are more preferable, and a fluorine atom, a chlorine atom and a methyl group are more preferably used.

These substituents are substituted on substitutable sites of the aromatic hydrocarbon group, and the number of substituents is preferably 1 to 5, more preferably 1 to 3, and 1 to 2 is preferable. Particularly preferred. When two or more substituents are present, the substituents may be the same or different.

As Ar and Ar ^a , specifically, for example,
A phenyl group, a halogenophenyl group, a lower (C _1-4 ) alkylphenyl group, a lower (C _1-4 ) alkoxyphenyl group, a lower (C _1-4 ) alkoxycarbonylphenyl group,
Carboxylphenyl group, nitrophenyl group, cyanophenyl group, halogeno lower (C _1-4 ) alkylphenyl group, halogeno lower (C _1-4 ) alkoxyphenyl group, lower (C _1-4 ) alkanoylphenyl group, 5-membered A phenyl group substituted with an aromatic heterocycle, a lower (C _1-4 ) alkoxy-carbonyl-lower (C _1-4 ) alkyl-carbamoylphenyl group, a 1,3-diacylguanidino-lower (C
_1-4 ) alkylphenyl group, phenyl group substituted with halogen and lower (C _1-4 ) alkyl, phenyl group substituted with halogen and lower (C _1-4 ) alkoxycarbonyl, substituted with halogen and cyano A phenyl group, a phenyl group substituted with a halogen and a 5-membered aromatic heterocyclic ring, a phenyl group substituted with a halogen and a lower (C _1-4 ) alkoxy-carbonyl-lower (C _1-4 ) alkyl-carbamoyl, and the like. Used.

[0208] Ar, as Ar ^a is a halogenophenyl group, a lower (C _1-4) alkylphenyl group, a halogen and a lower (C _1-4) alkoxyphenyl group substituted with a carbonyl is preferably used.

Ar and Ar ^a are represented by the formula

[0210]

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, 2-fluoro-4-chlorophenyl 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.

[0214] As the lower (C _1-4) alkylphenyl group, for example, 2-ethylphenyl group, 2,6-diisopropylphenyl group are preferably used, as said lower (C _1-4) alkoxyphenyl group Is, for example, 4-
Methoxyphenyl and the like are preferably used.

Examples of the lower (C _1-4 ) alkoxy-carbonylphenyl group include a 2-ethoxycarbonylphenyl group, a 2-methoxycarbonylphenyl group and a 4-methoxycarbonylphenyl group.
A methoxycarbonylphenyl group or the like is preferably used. As the halogeno lower (C _1-4 ) alkylphenyl group, for example, a 2-trifluoromethylphenyl group is preferably used, and the halogeno lower (C _1-4 ) alkoxy group is preferably used. As the phenyl group, for example, a 2-trifluoromethoxyphenyl group, a 4- (2,2,3,3,3-pentafluoropropoxy) phenyl group and the like are preferably used.

As the lower (C _1-4 ) alkanoylphenyl group, for example, 2-acetylphenyl group and the like are preferably used, and as the phenyl group substituted with the 5-membered aromatic heterocyclic ring, 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- ( 1H-1,2,3-
Triazol-1-yl) phenyl group are preferably used, said lower (C _1-4) alkoxy - carbonyl - lower (C _1-4) alkyl - as a carbamoylphenyl group, for example, 4-(N-ethoxycarbonyl A methylcarbamoyl) phenyl group and the like are preferably used.
Examples of the 3-diacylguanidino-lower (C _1-4 ) alkylphenyl group include 4- (1,3-bis-tert-)
A butoxycarbonylguanidinomethyl) phenyl group is preferably used.

Examples of the phenyl group substituted by halogen and lower (C _1-4 ) alkyl include, for example, 2-fluoro-4-methylphenyl group, 2-chloro-4-methylphenyl group, 4-fluoro-2 -Methylphenyl group and the like are preferably used, and as the phenyl group substituted with the halogen and lower (C _1-4 ) alkoxy-carbonyl, for example, a 2-chloro-4-methoxycarbonylphenyl group is preferably used, As the phenyl group substituted with halogen and cyano, 2-chloro-4-cyanophenyl group and the like are preferably used.
As the phenyl group substituted with a membered aromatic heterocyclic ring, for example, 2-fluoro-4- (1H-1,2,4-triazol-1-yl) phenyl and the like are preferably used, and the halogen and lower ( Examples of the phenyl group substituted with C _1-4 ) alkoxy-carbonyl-lower (C _1-4 ) -alkyl-carbamoyl include, for example, 2-chloro-4- (N
A -tert-butoxycarbonylmethylcarbamoyl) phenyl group, a 2-chloro-4- (N-ethoxycarbonylmethylcarbamoyl) phenyl group and the like are preferably used.

More specifically, as Ar and Ar ^a phenyl groups, phenyl groups substituted with one to three (among one or two) halogens (eg, 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-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-trifluorophenyl group, etc.), halogen and lower (C _1-4 ) A phenyl group substituted with alkyl (eg, 2-chloro-4-methylphenyl group, 4-fluoro-2-methylphenyl group, etc.) is preferred. Among them, a phenyl group substituted with 1 to 3 (especially 1 to 2) halogens (eg, 2,3-dichlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 2,2 6-dichlorophenyl group, 2-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 2-chloro-4-fluorophenyl group, 2,4,5
-Trifluorophenyl group), a phenyl group substituted with halogen and lower (C _1-4 ) alkyl (eg, 2-
Chloro-4-methylphenyl group, 4-fluoro-2-methylphenyl group) and the like. In particular, 2,4-
A 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-4-fluorophenyl group and the like are preferable. Is preferred.

In the present specification, ring A ¹ is (i) an aliphatic hydrocarbon group which may have a substituent, (ii) an aromatic hydrocarbon group which may have a substituent, (iii) A group represented by formula -OR ¹ (wherein R ¹ has the same meaning as described above) and (iv) a cycloalkene which may be substituted with 1 to 4 halogen atoms selected from And (i) an aliphatic hydrocarbon group which may have a substituent, (ii) an aromatic hydrocarbon group which may have a substituent and (iv) 1 to 4 halogen atoms selected from halogen atoms. An optionally substituted cycloalkene is preferred.

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 group represented by the formula -OR ¹ (wherein R ¹ has the same meaning as described above) and (iv) a cycloalkene substituted with 1 to 4 halogen atoms selected from the group consisting of (i) An aliphatic hydrocarbon group optionally having a substituent, (ii) an aromatic hydrocarbon group optionally having a substituent, and (iv) a cyclo group substituted with 1 to 4 cycloalkyl atoms selected from halogen atoms. Alkenes are preferred.

[0221] These substituents are substituted on substitutable carbon atoms in the ring A ¹ and ring A ^2, wherein ring A ¹ and ring A ² is substituted by 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 ^1a , R ^1b , R 1 ^{The same} as the “aliphatic hydrocarbon group which may have a substituent” represented by ^1c can be used.

[0223] As a substituent of the ring A ¹ and ring A ² "optionally substituted aromatic hydrocarbon group", for example, the aforementioned Ar, the "substituent represented by Ar ^a The same as the "aromatic hydrocarbon group which may be possessed" can be used.

Examples of the “heterocyclic group optionally having substituent (s)” which is a substituent of ring A ¹ and ring A ² include, for example, R, R ¹ , R ^1a , R ^1b and R ^1c described above. The same “heterocyclic group” as the “substituent” of the “aliphatic hydrocarbon group optionally having substituent (s)” 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, a C _1-4 alkyl group such as a methyl group and a tert-butyl group), a phenyl group, Halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) are preferably used.

Expression

[0227]

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[Wherein, n has the same meaning as described above. The group represented by the formula

[0229]

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Or

[0231]

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[Wherein, n has the same meaning as described above. Is a group represented by the formula:

[0233]

Embedded image

Wherein n is as defined above. ] Is preferable.

Formula

[0236]

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

[0238]

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Or

[0240]

Embedded image

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

[0242]

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Wherein n is as defined above. ] Is preferable.

Further, the formula

[0245]

Embedded image

The group represented by the formula is

[0247]

Embedded image

Or

[0249]

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The group is represented by the formula:

[0251]

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A group represented by the following formula is preferable.

As integers of 1 to 4 represented by n, 1 to 4
3 is preferred, and 2 is particularly preferred. As the compound represented by the formula (Iaa), a compound represented by the formula (Ibb) is preferable, and as the compound represented by the formula (Ia), the compound represented by the formula (Ib)
Is preferably represented by 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).

[0254] Formula (Ibb), as 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,
Ar is a phenyl group which may have 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 phenyl group substituted with a halogen atom. , N is more preferably 2. Formula (Ic
As the compounds represented by c) and (Ic), those in which Ar is a phenyl group which may have a substituent and n is 2 are preferable.

Formulas (I), (Iaa), (Ibb), (Icc),
(Ia), (Ib), (Ic), (Id), (Ie), (If),
When stereoisomers are present in the compound represented by (Ig), each of the stereoisomers and a mixture of those 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) When the compound represented by the formula (Ig) is a compound represented by the formula (It), the optical isomer exists based on the asymmetric carbon in the cycloalkene or cyclohexene ring. However, each of the optical isomers and a mixture of the optical isomers are included in the present invention.

As the compound represented by the formula (I) or (Ia), specifically, the compound obtained in Reference Example B described below 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 Preferred is 1-carboxylate or d-ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate or a salt thereof.

The compounds (I), (Iaa), (Ia), (Ib), (Ic), (Id), and (I) used in the composition of the present invention.
(Ie), (If), (Ig), (Ibb), (Icc) (hereinafter abbreviated as the compound of the present invention) include, for example, a salt with an inorganic base, a salt with an organic base, and a salt with an inorganic acid. Salts, salts with organic acids, salts with basic or acidic amino acids, and the like can be used. As salts with inorganic bases, for example, sodium salts,
Alkali metal salts such as potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts, ammonium salts and the like are used. As salts with organic bases, for example, trimethylamine, triethylamine, pyridine, picoline, ethanol Salts with amines, 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 salts with basic amino acids,
For example, salts with arginine, lysine, ornithine and the like are used, and as salts with acidic amino acids, for example, salts with aspartic acid and glutamic acid are used.

The prodrug of the compound of the present invention or a salt thereof is a compound which is converted into the compound of the present invention by a reaction with an enzyme or stomach acid under physiological conditions in a living body, that is, a compound which is enzymatically oxidized, reduced or hydrolyzed. A compound which is converted to the compound of the present invention and a compound which is converted to the compound of the present invention by hydrolysis or the like by stomach acid.
Examples of the prodrug of the compound of the present invention include compounds in which the amino group of the compound of the present invention is acylated, alkylated, and phosphorylated (eg, the amino group of the compound of the present invention is eicanosylated, alanylated, pentylaminocarbonylated). , (5
-Methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation,
Pyrrolidyl methylation, pivaloyloxymethylation, te
tert-butylated compounds, etc.); compounds in which the hydroxyl group of the compound of the present invention is acylated, alkylated, phosphorylated, and borated (eg, the hydroxyl group of the compound of the present invention is acetylated, palmitoylated, propanoylated, Pivaloylation,
Succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.); compounds in which the carboxyl group of the compound of the present invention is esterified or amidated (eg, the carboxyl group of the compound of the present invention is ethyl esterified) Phenylesterification, carboxymethylesterification, dimethylaminomethylesterification, pivaloyloxymethylesterification, ethoxycarbonyloxyethylesterification, phthalidylesterification, (5-methyl-2-oxo-1,3-dioxolene) -4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methyl amidated compound, etc.); These compounds can be produced from the compound of the present invention by a method known per se.

The prodrug of the compound of the present invention is
Compounds of the present invention may be converted under physiological conditions as described in Hirokawa Shoten, 1990, "Development of Pharmaceuticals", Vol. 7, Molecular Design, pp. 163 to 198.
The compound of the present invention, a salt thereof, or a prodrug thereof can be produced according to a method known per se, for example, the production method described in WO 99/46242 or a method analogous thereto. The compound of the present invention or a salt thereof or a prodrug thereof may be a hydrate or an anhydrate. The compound or a salt thereof, or a prodrug thereof isotopes present invention ^{(Example, 3 H, 14 C, 35} S, 125
I etc.).

The nonionic surfactants used in the pharmaceutical composition of the present invention include higher alcohol ethylene oxide adducts, alkylphenol ethylene oxide adducts, fatty acid ethylene oxide adducts, polyhydric alcohol fatty acid ester ethylene oxide adducts, higher alcohol Alkylamine ethylene oxide adducts, fatty acid amide ethylene oxide adducts, ethylenoxide adducts of fats and oils, polypropylene glycol ethylene oxide adducts, fatty acid esters of glycerol, fatty acid esters of pentaerythritol, fatty acid esters of sorbitol and sorbitan, and sucrose Fatty acid esters, alkyl ethers of polyhydric alcohols, fatty acid amides of alkanolamines, polyoxyethylene castor oil derivatives and the like are used.

Among the nonionic surfactants, for example,
Polyoxyethylene castor oil (polyethoxylated castor)
oil), polyoxyethylene hydrogenated castor oil (polyethoxy)
Polyoxyethylene castor oil derivatives such as lated hydrogenated castor oil) are preferably used.

Polyoxyethylene castor oil (polyethoxy)
As a related castor oil, in particular, polyoxyethylene glycerol triricinoleate 35 (Polyoxy 35 Cas
Preferred are torOil, trade name Cremophor EL or EL-P, and BSF Japan Ltd.

Polyoxyethylene hydrogenated castor oil (polyet
As hoxylated hydrogenated castor oil, in particular, polyoxyethylene hydrogenated castor oil 50 (Polyoxyeth)
ylene Hydrogenated Castor Oil 50), Polyoxyethylene hydrogenated castor oil 60 (Polyoxyethylene Hydrogenated)
Castor Oil 60) is preferred.

The pharmaceutical composition of the present invention may contain a surfactant other than the nonionic surfactant, and specifically contains an anionic surfactant, a cationic surfactant, and an amphoteric surfactant. You may go out.

Examples of the anionic surfactant include sulfates (eg, higher alcohol sulfates, higher alkyl ether sulfates, sulfated oils, sulfated fatty acid esters, sulfated fatty acids, and sulfated olefins).
Sulfonates (eg, sodium alkylbenzene sulfonate, oil-soluble alkylbenzene sulfonate, α-olefin sulfonate, Igepon T type, aerosol OT
Type), phosphates (eg, a phosphate ester salt of a higher alcohol ethylene oxide adduct), dithiophosphate ester salts, and the like.

Examples of the cationic surfactant include amine salt type cationic surfactants (eg, amine salt type cationic surfactants made from higher alkylamines, amine salt type cationic surfactants made from lower alkylamines) ), Quaternary ammonium salt type cationic surfactants (eg, quaternary ammonium salt type cationic surfactants made from higher alkylamines, quaternary ammonium salt type surfactants made from lower alkylamines), etc. Is used.

As the amphoteric surfactant, for example, an amino acid type amphoteric surfactant, a betaine type amphoteric surfactant and the like are used.

Further, the pharmaceutical composition of the present invention may contain ethanol, benzyl alcohol or dimethylacetamide. Of these, ethanol is preferred.

When the pharmaceutical composition of the present invention is an injection, the pH
Should be adjusted to about 3 to 10, preferably about 4 to 9, and more preferably about 4 to 7.

The pharmaceutical composition of the present invention can be prepared by a known method using compound (I) or a salt thereof or a prodrug thereof (hereinafter simply referred to as compound (I)) and a nonionic surfactant, if necessary. It can be produced by mixing with additives such as ethanol and other surfactants.

The pharmaceutical composition of the present invention may be the solution obtained as described above, or may be a solution obtained by dissolving the obtained powder in a suitable solvent. May be added as appropriate.

The pharmaceutical composition of the present invention has low toxicity, and the compound (I) is mixed with a pharmacologically acceptable carrier according to a method known per se, for example, a pharmaceutical composition such as a tablet (sugar-coated tablet,
Orally or parenterally (eg, topically, including film-coated tablets), powders, granules, capsules (including soft capsules), solutions, injections, suppositories, sustained-release preparations, etc.
Rectally, intravenously, etc.). The pharmaceutical composition of the present invention is preferably an injection, and more preferably a non-emulsified composition or a clear injection.

In the present invention, the term "non-emulsified composition" refers to a composition that is not an emulsion, that is, an O / W emulsion or a composition that is not a W / O emulsion. That is, it refers to a composition in which two liquids are mixed uniformly in one phase without causing phase separation or emulsification in which one phase is dispersed in the form of fine particles in the other phase.

In the present invention, “clear” means a state that is not clouded by visible oil droplets or particles.

The pharmacologically acceptable carriers that may be used in the production of the preparation of the present invention include various organic or inorganic carrier substances commonly used as preparation materials, such as excipients and lubricants in solid preparations. Sachets, binders and disintegrants, or solvents in liquid formulations, solubilizers, suspending agents
And tonicity agents, buffers and soothing agents. Further, if necessary, normal preservatives, antioxidants, coloring agents, sweeteners,
Additives such as adsorbents and wetting agents can be used in appropriate amounts.

As the excipient, for example, 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 solubilizer 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 glyceryl monostearate; for example, polyvinyl alcohol, Examples include hydrophilic polymers such as polyvinylpyrrolidone, 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, paraoxybenzoic acid esters,
Examples thereof include chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.
Antioxidants include, for example, sulfites, ascorbic acid,
α-tocopherol and the like.

In particular, when the pharmaceutical composition of the present invention is used as an injection, carriers for the injection include, for example, solvents, dissolution aids, suspending agents, isotonic agents, buffers, soothing agents and the like. Is used. Examples of the solvent include water for injection, physiological saline, Ringer's solution and the like. Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. 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. Hydrochloric acid, phosphoric acid,
Citric acid, sodium hydroxide and the like.

The thus-obtained injectable composition of the present invention can be freeze-dried with a sterilized freeze dryer and stored in the form of a powder, or can be directly used as an injectable container (eg,
Ampules) can be sealed and stored. In addition, the pharmaceutical composition of the present invention can be diluted with the above-mentioned carrier for injections before use.

Compound (I) in the pharmaceutical composition of the present invention
Is usually about 0.01 to about 99% by weight, preferably about 0.1 to about 50% by weight, and more preferably about 0.5 to about 100% by weight, based on the whole preparation. It is about 20% by weight.

The content of the nonionic surfactant in the pharmaceutical composition of the present invention varies depending on the form of the preparation.
Usually from about 1 to about 99.99% by weight of the total formulation,
It is preferably about 10 to about 90% by weight, more preferably about 10 to about 70% by weight.

Ethanol in the pharmaceutical composition of the present invention,
The content of benzyl alcohol or dimethylacetamide varies depending on the form of the preparation, but is usually about 1 to about 99.99% by weight, preferably about 1 to about 99.99% by weight, based on the whole preparation.
It is about 0 to about 90% by weight, and more preferably about 30 to about 90% by weight.

The compounding ratio (weight ratio) of the nonionic surfactant and ethanol in the pharmaceutical composition of the present invention is as follows:
Although not particularly limited, for example, a nonionic surfactant:
Ethanol = about 0.01-99.99: 99.99-
0.01, preferably about 1-99: 99-1, more preferably about 10-90: 90-10. More preferably, a nonionic surfactant: ethanol = about 10 to 80:90 to 20, about 50 to 80:50 to 20, and the like, among which about 20:80 and about 65:35 are suitable. is there.

Although the content of the water-soluble cyclodextrin derivative in the pharmaceutical composition of the present invention varies depending on the form of the preparation, it is usually about 1 to about 99.% based on the whole preparation.
It is about 99% by weight, preferably about 10 to about 99.99% by weight, more preferably about 20 to about 97% by weight, particularly preferably about 50 to about 97% by weight.

The content of other additives in the pharmaceutical composition of the present invention varies depending on the form of the preparation, but is usually about 1 to about 99.99% by weight, preferably about 10 to about 90% by weight, based on the whole preparation. %, More preferably about 10 to about 70% by weight.

The pharmaceutical composition of the present invention may be a pharmaceutical composition containing compound (I), a nonionic surfactant and a water-soluble cyclodextrin derivative. In this case, the content of each component of the compound (I), the nonionic surfactant or the easily water-soluble cyclodextrin derivative in the whole composition is in the same range as in the above case.

When the pharmaceutical composition of the present invention containing a complex of the compound (I) and a water-soluble cyclodextrin derivative is used as an injection, a composition obtained by mixing the above-mentioned various components is used to obtain a compound having a molecular weight cut off of about 1 2,000-8,000, preferably about 2,000-7,000, more preferably 30,000
By filtering through a hollow fiber ultrafiltration membrane having a molecular weight of 00 to 7,000, particularly preferably about 6,000, pyrogens (eg, endotoxin) can be efficiently removed. As such a hollow fiber membrane ultrafiltration membrane, a commercially available one can be appropriately used. For example, a hollow fiber membrane ultrafiltration membrane SIP- manufactured by Asahi Kasei Corporation having a molecular weight cut off of 6,000 can be used.
0013; Pencil type module (20φ × 130m
m) etc. are used. The pore size of the hollow fiber ultrafiltration membrane is usually about 10 to 100 angstroms, preferably about 20 to 60 angstroms. Although only one hollow fiber ultrafiltration membrane may be used, if necessary, two or more (for example, two to three, preferably two) may be directly used. In particular, a combination of a hollow fiber ultrafiltration membrane having a molecular weight cut off of 6,000 and a hollow fiber ultrafiltration membrane having a molecular weight cut off of 3,000 is preferred. Hollow fiber membrane ultrafiltration membrane
Before use, it is immersed in, for example, a sodium hypochlorite solution for about 1 to 30 hours, and then washed with a pyrogen-free aqueous solution for injection until the pH of the passing solution becomes about 7.0. The pressure during ultrafiltration is usually about 0.05 to
1.0 kg / cm ³ , preferably about 0.1 to 0.5 kg
/ Cm ³ . Filtration can be performed at room temperature,
It is preferably performed under aseptic conditions.

The content of pyrogen in the composition for injection is generally about 100 EU / g or less, preferably about 50 EU / g or less.
It is at most EU / g, particularly preferably at most about 30 EU / g. The content of the pyrogen in the composition for injection is
It can be quantified according to a method known per se. More specifically, the endotoxin concentration (EU) is set to 405 nm using an endotoxin measuring reagent such as Toxicolor System Et-2 set (standard endotoxin) and Toxicolor System LS-20 set manufactured by Seikagaku Corporation.
Can be determined from the absorbance of The composition for injection thus obtained can be freeze-dried with a sterilized freeze-dryer and stored in the form of a powder, or can be stored as it is in an injection container (eg, ampoule) sealed. it can.

As the water-soluble cyclodextrin derivative used in the pharmaceutical composition of the present invention, a commercially available product may be used, or it may be produced according to a method known per se.
As the water-soluble cyclodextrin derivative, preferably, hydrogen of a part or all of hydroxyl groups at positions 2, 3, and 6 of glucose of a cyclic oligosaccharide composed of 6 to 12 glucose units is replaced with another functional group (for example, dihydroxy group). Compounds substituted with an alkyl group, a sugar residue, a hydroxyalkyl group, and the like are used.

The easily water-soluble cyclodextrin derivative is
The solubility in water is about 50 mg / ml or more, preferably about 1 mg / ml.
It is more than 00 mg / ml.

Preferred specific examples of the water-soluble cyclodextrin derivative include a compound represented by the following general formula:

[0292]

Embedded image

[Wherein q is an integer satisfying 6 to 12,
R ^6, R ⁷ and R ⁸ are the same or different in each repeating unit, each a hydrogen atom, dihydroxyalkyl group, a saccharide residue or a hydroxyalkyl group, R ^6,
At least one of R ⁷ and R ⁸ is a dihydroxyalkyl group, a sugar residue or a hydroxyalkyl group. ]
The compound represented by these is mentioned. As a specific example,
For example, α-CyD (q = 6), β-CyD (q = 7), γ
And ether derivatives of hydroxyl groups such as -CyD (q = 8) and δ-CyD (q = 9). Among them, β-CyD
(In the present specification, CyD means cyclodextrin).

As the dihydroxyalkyl group represented by R ^{6 to} R ⁸ , for example, a dihydroxy-C _1-6 alkyl group (eg, dihydroxymethyl, 2,2-dihydroxyethyl, 2,2-dihydroxypropyl, 2,2- Dihydroxypentyl, 2,2-dihydroxyhexyl, etc.), preferably a dihydroxy-C _1-4 alkyl group (eg, dihydroxymethyl, 2,2-dihydroxyethyl, 2,2-
Dihydroxypropyl).

Examples of the sugar residues represented by R ^{6 to} R ⁸ include C _3-24 sugar residues (erythrosyl, threosyl, arabinosyl, ribosyl, glucosyl, galactosyl, glycero-gluco-heptosyl, maltosyl, lactosyl, maltotrio) Syl, dimaltosyl, etc.), preferably a C _6-24 sugar residue (eg, glucosyl, galactosyl, glycero-gluco-heptosyl, maltosyl, lactosyl, maltotriosyl, dimaltosyl, etc.), particularly preferably a C _6-12 sugar residue (Eg, glucosyl, galactosyl, glycero-gluco-heptosyl, maltosyl, lactosyl, etc.).

[0296] The hydroxyalkyl group represented by R ⁶ to R ^8, such as hydroxy -C _1-6 alkyl group (e.g.,
Hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxypentyl, 2-hydroxyhexyl, etc.), preferably a hydroxy-C _1-4 alkyl group (eg, hydroxymethyl, 2-hydroxyethyl,
2-hydroxypropyl, etc.), and particularly a 2-hydroxypropyl group is preferably used.

As a more preferable specific example of the water-soluble cyclodextrin derivative, in the compound represented by the general formula (II), at least one of R ^{6 to} R ⁸ is a sugar residue or a hydroxyalkyl group, and Wherein the group is a hydrogen atom.

The compound (II) in which at least one of R ^{6 to} R ⁸ is a sugar residue and the remaining group is a hydrogen atom includes, for example, glucosyl-α, β, γ, δ-CyD, maltosyl-α , Β, γ, δ-CyD, maltotriosyl-
α, β, γ, δ-CyD, dimaltosyl-α, β, γ,
δ-CyD and the like. Among these, maltosyl-α, β, γ, δ-CyD, glucosyl-α, β, γ,
δ-CyD is preferred (in the present specification, α, β,
γ, δ-CyD is α-CyD, β-CyD, γ-Cy
D or δ-CyD). Further maltosyl-
β-CyD (hereinafter abbreviated as G2-β-CyD) and glucosyl-β-CyD are particularly preferred.

As the compound (II) in which at least one of R ^{6 to} R ⁸ is a hydroxyalkyl group and the remaining groups are hydrogen atoms, for example, hydroxypropyl-α, β,
γ, δ-CyD (particularly, 2-hydroxypropyl-α,
β, γ, δ-CyD) and the like. Among these, hydroxypropyl-β-CyD (particularly, 2-hydroxypropyl-β-CyD) is more preferable.

As the water-soluble cyclodextrin derivative used in the pharmaceutical composition of the present invention, a branched cyclodextrin-carboxylic acid can be used. The branched cyclodextrin-carboxylic acid includes not only the free carboxylic acid but also salts thereof with alkali metals (eg, lithium, sodium, potassium, etc.), alkaline earth metals (eg, calcium, magnesium, etc.). It is. These branched cyclodextrin-carboxylic acids may be used alone or in combination of two or more, or may be used in a state where a free carboxylic acid and a salt thereof are mixed.

The branched cyclodextrin-carboxylic acid is a cyclodextrin having an organic group containing at least one carboxyl group at the 6-O position of at least one glucose unit of the cyclodextrin ring.
The cyclodextrin ring of the branched cyclodextrin-carboxylic acid has, for example, 6, 7, or 8 glucose units. Preferably, the cyclodextrin ring has 7 glucose units. Examples of the cyclodextrin ring include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and the like.

[0302] The organic group containing at least one carboxyl group has 1 to 3 glucose units, and at least one hydroxymethyl group of the glucose unit in the organic group is oxidized to a carboxyl group. The case is preferred.

Specific examples of the above-mentioned branched cyclodextrin-carboxylic acid include 6-O-cyclomaltohexaosyl- (6 → 1) -α-D-glucosyl- (4 → 1) -O-α-
D-glucuronic acid (cyclomaltohexaosyl- (6 →
1) -α-D-glucopyranosyl- (4 → 1) -O-α-
D-glucopyranoside uronic acid) (hereinafter α-CyDG-G ₂
-COOH; the following compounds are also abbreviated in parentheses), 6-O-cyclomaltoheptaosyl- (6 → 1) -α-D-glucosyl- (4
→ 1) -O-α-D-glucuronic acid (cyclomaltoheptaosyl- (6 → 1) -O-α-D-glucopyranosyl-
(4 → 1) -O-α-D-glucopyranoside uronic acid) (β
_{-CyD-G 2 -COOH), 6} -O- cycloalkyl maltooctaose O Sil - (6 → 1) -α- D- glucosyl - (4 → 1) -
O-α-D-glucuronic acid (cyclomaltooctaosyl- (6 → 1) -O-α-D-glucopyranosyl- (4 → 1)
-O-α-D-glucopyranoside uronic acid (γ-CyD-
G ₂ -COOH), 6-O-cyclomaltohexaosyl-
(6 → 1) -α-D-glucuronic acid (cyclomaltohexaosyl- (6 → 1) -O-α-D-glucopyranoside uronic acid) (α-CyD-G ₁ -COOH), 6-O- Cyclomaltoheptaosyl- (6 → 1) -α-D-glucuronic acid
(Cyclomaltoheptaosyl- (6 → 1) -O-α-D-
Glucopyranosiduronic acid) (β-CyD-G ₁ -COO
H), 6-O-cyclomaltooctaosyl- (6 → 1)-
α-D-glucuronic acid (cyclomaltooctaosyl- (6
→ 1) -O-α-D-glucopyranoside uronic acid) (γ-
CyD-G ₁ -COOH), 2-O- (6-cyclomaltohexaosyl) -acetic acid (α-CyD-CH ₂ COOH), 2-
O- (6-cyclomaltoheptaosyl) -acetic acid (β-CyD
_{-CH 2 COOH), 2-O-} (6- cyclo maltooctaose O Sil) - acetic acid _{(γ-CyD-CH 2 COOH} ), 3-O-
(6-cyclomaltoheptaosyl) -propionic acid (β-
_{CyD-CH 2 CH 2 COOH)} , 2- hydroxy -3-O
-(6-cyclomaltoheptaosyl) -propionic acid (3
-O- (6- cyclo maltoheptaose O Sil) -2-hydroxy - propionic _{acid) (β-CyD-CH 2} CH (OH) -C
OOH), 7 ^A , 7 ^C -di-O- [α-D-glucuronyl-
(1 → 4) -O-α-D-glucosyl]-(1 → 6) -maltoheptaose (β-CyD- (G ₂ COOH) ₂ ), 6-O
-Cyclomaltoheptaosyl-O-α-D-maltosyl- (4 → 1) -O-α-D-glucuronic acid (cyclomaltoheptaosyl- (6 → 1) -O-α-D-glucopyranosyl- (4 → 1) -O-α-D-glucopyranosyl- (4 →
1) -O-α-D-glucopyranoside uronic acid) (β-Cy
DG ₃ -COOH) and the above salts [eg, β-
CyD-G ₂ -COOH sodium salt (cyclo maltoheptaose O sill of - (6 → 1) -O- α-D- glucopyranosyl - (4 → 1) -O- α-D- glucopyranoside guidance sodium Ron acid (Similarly β -CyD-G ₂ -COONa)))]. Above all, β-CyD-G ₂ -C
OONa is preferred.

More specifically, 6-O-cyclomaltohexaosyl- (6 → 1) -α-D-glucosyl- (4 →
1) -O-α-D-glucuronic acid (α-CyD-G ₂ -C
OOH), 6-O-cyclomaltoheptaosyl- (6 →
1) -α-D-glucosyl- (4 → 1) -O-α-D-
Glucuronic acid (β-CyD-G ₂ -COOH) and 6-O-cyclomaltooctaosyl-α-D-glucosyl- (4 → 1) -O-α-D-glucuronic acid (γ-Cy
DG ₂ -COOH) is a branched cyclodextrin-carboxy containing α-cyclodextrin (6 glucose units), β-cyclodextrin (7 glucose units) and γ-cyclodextrin (8 glucose units), respectively. Maltose is α- (1 → 6) -linked to one glucose unit of the cyclodextrin ring, and the 6-hydroxymethyl group at the terminal glucose of the maltose is oxidized to a carboxyl group to form glucuronic acid. ing.

Also, 6-O-cyclomaltohexaosyl- (6 → 1) -α-D-glucuronic acid (α-CyD-G _1-
COOH), 6-O-cyclomaltoheptaosyl- (6 →
1) -α-D-glucuronic acid (β-CyD-G ₁ -COO
H), and 6-O-cyclomaltooctaosyl- (6 →
1) -α-D-glucuronic acid (γ-CyD-G ₁ -COO
H) is such that glucose is α- (1 → 6) -linked to one glucose unit of the cyclodextrin ring, and the 6-hydroxymethyl group of the branched glucose is oxidized to a carboxyl group to form glucuronic acid. It is a branched cyclodextrin-carboxylic acid.

Then, 2-O- (6-cyclomaltohexaosyl) -acetic acid (α-CyD-CH ₂ COOH),
-(6-cyclomaltoheptaosyl) -acetic acid (β-CyD-
CH ₂ COOH) and 2-O- (6-cyclomaltooctaosyl) -acetic acid (γ-CyD-CH ₂ COOH) have a carboxymethyl group bonded to one glucose unit of the cyclodextrin ring. Branched cyclodextrin-
It is a carboxylic acid.

These branched cyclodextrin-carboxylic acids or salts thereof are described in JP-A-7-76594 and JP-A-7-215895. For example, JP-A-10-210996 and JP-A-10-210996 disclose such branched cyclodextrin-carboxylic acids and salts thereof. It can be produced by the method described in JP-A-10-210996 or a method analogous thereto. One of these water-soluble cyclodextrin derivatives may be used alone, or two or more thereof may be used in combination.

The amount of the water-soluble cyclodextrin derivative used is not particularly limited and can be selected from a wide range.
Considering the water solubility of these substances, the readily water-soluble cyclodextrin derivative is used in an amount of about 0.1 to 1 mol of the compound (I).
1 to about 100 moles, preferably about 0.2 to about 20 moles, more preferably about 0.5 to about 10 moles, and more preferably about 1 to about 5 moles.

Compound (I) and a cyclodextrin derivative represented by the general formula (II) (hereinafter abbreviated as compound (II))
May form a complex, and as a form of the complex, the drug is generally more stable in the solid state, and it is preferable to form a powder by removing coexisting water. Examples of the method for distilling off include freeze-drying, drying under reduced pressure, and vaporization at normal pressure. Freeze-drying is performed after freezing for drug stabilization,
Alternatively, freeze-drying under reduced pressure is appropriate.

The method for producing this composite is carried out, for example, as follows. That is, the compound (II) and the compound (I) are usually converted into an aqueous solution with water or a buffer at about -5 ° C to 35 ° C. The aqueous solution is prepared, for example, by mixing the compound (I) with water or a buffer solution of the compound (II) and a water or buffer solution of the compound (I). It can be obtained by mixing, mixing the compound (II) and the compound (I) with water or a buffer, or mixing the compound (II) with a suspension of the compound (I) in water or a buffer. At this time, the solution may be cooled or heated as needed to form an aqueous solution. The concentration of compound (II) is usually preferably about 50 mg / ml or more, more preferably about 100 mg / ml or more. Compound (II) is compound (I)
About 0.1 to about 100 moles, preferably about 0.2 to about 20 moles, more preferably about 0.5 to about 1 mole.
It is preferably added so as to be 0 moles, more preferably about 1 to about 5 moles.

After mixing the compound (II) with the compound (I),
When the suspension is stirred, the compound (I) gradually dissolves. Usually, stirring is continued for 1 minute or more, and the stirring is stopped when the progress of dissolution is completed. If there is any undissolved residue in the solution, the solution is filtered to obtain a compound (I) having improved solubility. To powder this complex, the obtained solution is freeze-dried, dried under reduced pressure, or dried under normal pressure.

After mixing Compound (II) and Compound (I),
A base may optionally be added to the resulting suspension or solution for stabilization. Examples of the base include alkali metal hydroxides (eg, potassium hydroxide, sodium hydroxide, etc.), alkali metal hydrogencarbonates (eg, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal carbonates (eg, sodium carbonate, Potassium carbonate), alkali metal phosphates (eg, sodium phosphate, sodium monohydrogen phosphate,
Inorganic bases such as potassium phosphate and potassium monohydrogen phosphate, for example, alkali metal salts of organic monocarboxylic acids (eg,
Organic bases such as sodium acetate and potassium acetate). The amount of the base to be added is preferably about 0.0002 to about 0.2 mol per 1 mol of compound (I).
Further from about 0.001 to about 0.035 mol is particularly preferred. The base may be added as it is or as an aqueous solution having an appropriate concentration.

The powder obtained according to these procedures forms an inclusion or a complex by electrostatic, hydrophobic interaction or hydrogen bonding. Further, the powder may contain the compound (I) or (and) the compound (II) in addition to the clathrate or the complex, and such a powder is also a complex.

The inclusion compound of the compound (I) and the water-soluble cyclodextrin derivative can be prepared, for example, generally by the following four methods. (1) Coprecipitation method [Crassons et al., 5th Conference of Pharmaceutical Technology (5th lnt. Conf. Pharmaceutical Technol.)
ogy), Paris, 30 May-1 June 1989
Days], (2) freeze-drying or spray-drying method [Kurozumi
Et al., Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), 23, 3062 (1975);
Kata et al., Pharmazie 39,8.
56 (1984)], (3) Phase-melt diagram crystallization method [Uekama et al., International Journal of Pharmaceuticals (Int. J. Pharmac.) 10, 1 (1982)], ( 4) Kneading method [J. Szejtli
Et al., "Cyclodextrin and its inclusion complex (Cycl
odextrins and their inclusion complexes), Akadeimial Kiado, Budapest (B
udapest) (1982), p. 109-114; Kyowa Ja
p. Prov. Pat. Pubin. No. 106 698 (198
2)].

More specifically, (1) a target inclusion compound is added to an aqueous solution of a water-soluble cyclodextrin derivative, and if necessary, the mixture is heated and stirred.
(Shake). When the remaining unreacted clathrate is removed by filtration, centrifugation, or the like, an clathrate is obtained. (2) A water-soluble cyclodextrin derivative is dissolved in water, and the target inclusion compound is added thereto and mixed. The mixing time is not particularly limited, but is, for example, about 10 minutes to several hours. After mixing, freeze-drying (M. Kurozumi et al., Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull)
l.), 23, 142 (1975)) to obtain a powder. This is dissolved in water, and an unreacted clathrate is removed to obtain an aqueous solution of the clathrate. (3) The inclusion compound is previously dissolved in an appropriate organic solvent compatible with water, and this is brought into contact with a water-soluble cyclodextrin derivative in an aqueous solution, and then the organic solvent and water are distilled off in vacuo. Or lyophilization (EP-A-519)
428, JP-A-5-178765), water is added to the residue to dissolve it, and the unreacted clathrate is removed to obtain an aqueous solution of the clathrate. (4) The acidic inclusion compound is dissolved in aqueous ammonia, to which a water-soluble cyclodextrin derivative is added and freeze-dried. During the freeze-drying process, excess ammonia is removed, and an inclusion compound of the ammonium salt of the inclusion compound is obtained. (5) The inclusion compound is dissolved in a lipophilic organic solvent (eg, ethyl ether, etc.), mixed with a saturated aqueous solution of a water-soluble cyclodextrin derivative, and shaken vigorously. The shaking time is not particularly limited, but is, for example, 10 minutes to several hours. After shaking, the mixture is allowed to stand overnight in a cool place to precipitate an inclusion reaction product, and then separated by centrifugation and filtration. The obtained powder is dissolved in water to obtain an aqueous solution of the clathrate compound. (6) Both powders of the inclusion compound and the water-soluble cyclodextrin derivative are mixed, and a small amount of water is added thereto and kneaded [Y. Nakai et al., Chemical and Pharmaceutical Co., Ltd.] Bretin (Chem. Pharm. Bul
l.), 26, 2419 (1978), or thereafter freeze-dried. (7) For the inclusion compound, an aqueous solution of the inclusion compound is obtained by mixing the aqueous solution of the easily water-soluble cyclodextrin derivative and the aqueous solution of the inclusion compound.

The aqueous solution or powder thus obtained according to the known clathration method is often an inclusion complex or forms a complex by electrostatic, hydrophobic interaction or hydrogen bonding. are doing. Therefore, in the present specification, the clathrate compound includes not only the clathrate, the complex itself,
It also means inclusion complexes, complexes, free inclusion compounds and / or mixtures of free water-soluble cyclodextrin derivatives. That is, the obtained powder and aqueous solution may contain, in addition to the clathrate and the complex, an unclathrate or an uncomplexed water-insoluble or sparingly soluble compound and / or a free-branched cyclodextrin. Including the body itself,
Such powders and aqueous solutions have extremely high water solubility and also have the property of being instantaneously dissolved in water.

The pharmaceutical composition of the present invention may be the aqueous solution obtained as described above, or may be a solution obtained by dissolving the obtained powder in a suitable solvent. May be added as appropriate.

As described above, the pharmaceutical composition of the present invention, particularly the injectable composition, has improved water solubility, solubility or (and) stability of compound (I) and is free from pyrogen. , It is highly safe for the human body, and is used as a drug (for example, an agent for preventing or treating various diseases), an animal drug, etc.
Used for mammals (eg, rat, mouse, guinea pig, monkey, cow, dog, pig, human, etc.). The composition for injection according to the present invention can be administered intravenously, intramuscularly, subcutaneously or intraorganically, or directly to a lesion.

Compound (I) has low toxicity and nitric oxide (N
O) Production inhibitory action and TNF-α, IL-1, IL-
6, the composition of the present invention containing the compound of the present invention or a salt thereof or a prodrug thereof may be used in mammals (for example, cats, cows, dogs, horses, Goat, monkey, human, etc.)
Heart disease, autoimmune disease, inflammatory disease, central nervous system disease, infectious disease, sepsis, septic shock and other diseases such as sepsis, endotoxin shock, exotoxin shock, 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 generalized intravascular coagulation syndrome (DIC)), ischemic encephalopathy, arteriosclerosis, pernicious anemia, Fanconi anemia, sickle cell anemia, pancreatitis, nephrosis Syndrome, nephritis, renal failure, insulin-dependent diabetes, non-insulin-dependent diabetes,
Hepatic porphyria, alcoholism, Parkinson's disease, chronic leukemia, acute leukemia, tumor, myeloma, anticancer drug side effects reduction, 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 injury, burns, in vitro fertilization efficiency, hypercalcemia, ankylosing spondylitis, osteopenia, bone page Jet disease, osteomalacia,
Fractures, acute bacterial meningitis, 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, 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, thrombocytopenia due to dialysis Disease, 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, non-small cell lung cancer It can be used malignant melanoma, Hodgkin's disease, as a prophylactic or therapeutic agent such as non-Hodgkin's lymphoma.

The dose of the pharmaceutical composition of the present invention (particularly, the composition for injection) varies depending on the type, age, body weight, symptoms, dosage form, administration method, administration period and the like of compound (I). Usually, about 0.2 mg / day of the compound (I) of the present invention per adult patient (adult, body weight: about 60 kg).
01 to about 1000 mg / kg, preferably about 0.01 to about 1
00 mg / kg, more preferably from about 0.1 to about 100 mg / kg
kg, especially about 0.1 to about 50 mg / kg, especially about 1.5 to about 30 mg / kg, is administered intravenously once to 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.

In the present invention, “effective amount” means an effective amount of compound (I), and “administering an effective amount” means
It means administering a pharmaceutical composition of the invention containing an effective amount of compound (I).

[0322]

EXAMPLES Hereinafter, the present invention will be described in detail with reference to Reference Examples, Examples, Comparative Examples, and Test Examples, but the present invention is not limited thereto. The ratio of the mixed solvent is a weight mixing ratio of each solvent. % Means percent by weight unless otherwise specified. A highly polar diastereomer is a diastereomer having a smaller Rf value under the same conditions (for example, ethyl acetate / hexane or the like can be used as a solvent) when the Rf values of normal phase thin layer chromatography are compared. It means a stereoisomer, and the less polar diastereomer means a diastereomer having a larger Rf value.

The following Reference Example A can be manufactured according to the reference example of WO99 / 46242, and Reference Example B can be manufactured according to the example of WO99 / 46242. 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 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-benzyloxy Carbonylamino-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) -On 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-benzoisothiazole- 3 (2H) -ON 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-benzoiso 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 l-ethyl 6 -[N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 71) 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 a less polar diastereomer (Compound 78) Reference Example B71 Ethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -3-tert-butyl-1-cyclohexene-
Highly polar diastereomers of 1-carboxylate (compound
79) and a less polar diastereomer (Compound 80) Reference Example B72 Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -3-tert-butyl-1-cyclohexene-1-carboxylate Polar diastereomer
(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.

[0329]

[Table 1]

[0330]

[Table 2]

[0331]

[Table 3]

[0332]

[Table 4]

[0333]

[Table 5]

Example 1 1) 100 mg of Compound 72 of Reference Example B66 2) 1 mL of polyoxyethylene glycerol triricinolate 35 3) 4 mL of ethanol Polyoxyethylene glycerol triricinolate 35 was added to 100 mg of Compound 72 of Reference Example B66. 1 mL and 4 mL of ethanol were added and dissolved.

Example 2 1) 100 mg of compound 72 of Reference Example B66 2) Polyoxyethylene glycerol triricinolate 35 3.25 mL 3) 1.75 mL of ethanol Polyoxyethylene glycerol triricinolate 35 was added to 100 mg of Compound 72 of Reference Example B66. 3.25 mL and 1.75 mL of ethanol were added and dissolved.

Example 3 1) Compound 72 8 mg of Reference Example B66 2) G2-β-CyD 145.2 mg G1-β-CyD 145.2 mg was dissolved in 1 ml of distilled water for injection. Thereto, 728 mg of the compound of Reference Example B66 was added and dissolved.

Example 4 1) Compound 72 8 mg of Reference Example B66 2) G2-β-CyD 145.2 mg G2-β-CyD14 was added to a phosphate / citrate buffer solution at pH 7.
5.2 mg was added and dissolved. Thereto, 728 mg of the compound of Reference Example B66 was added and dissolved.

Example 5 1) Compound 72 5 mg of Reference Example B66 2) 40% aqueous solution of 2-hydroxypropyl-β-cyclodextrin 3 mL 40% 2-hydroxypropyl-β-compound was added to Compound 725 mg of Reference Example B66. 3 mL of an aqueous cyclodextrin solution was added and dissolved.

Example 6 1) Compound 72 5 mg of Reference Example B66 2) 40% 2-hydroxypropyl-β-cyclodextrin aqueous solution 3 mL 40% 2-hydroxypropyl-β-compound was added to Compound 725 mg of Reference Example B66. Add 3 mL of cyclodextrin aqueous solution to dissolve. Adjust to pH 7 with phosphate / citrate buffer.

Comparative Example 1 Solubilizing Auxiliary Effect of Solubilizing Agent for Compound 72 To 5 mg of Compound 72, 1 mL of the dissolving solution shown in Table 6 was added, and sonication and vortexing were performed to confirm the solubility. If not dissolved, 1 mL of the lysis solution was further added, and sonication and vortexing were performed in the same manner to confirm the solubility. The concentration at the time of dissolution was defined as the solubility. As compared with the solubility in water, a 10% aqueous solution of sodium desoxycholate showed a solubilizing effect, but the solubility of 1 mg / mL expected for developing as an injection was not obtained.

[0341]

[Table 6]

Test Example 1 To 5 mg of Compound 72, 50 μL of a polyoxyethylene glycerol triricinoleate 35 / ethanol solution in the ratio (weight ratio) shown in Table 7 was added, and the mixture was stirred to confirm the solubility. At any mixing ratio, compound 72 dissolved, resulting in a clear solution. Therefore, the solubility of Compound 72 in the solvent used was 100 mg / mL or more. From Table 7, it was found that the solubility of Compound 72 was significantly improved in the pharmaceutical composition of the present invention.

[0343]

[Table 7]

Test Example 2 The concentration of Compound 72 in Formula 1 and Formula 2 of Test Example 1 was 20 mg.
/ ML, and a stability test was carried out to obtain a result shown in Table 8. Table 8 shows that the pharmaceutical composition of the present invention is extremely stable.

[0345]

[Table 8]

Test Example 3 Compound 72 was dissolved in a solution of polyoxyethylene glycerol triricinoleate 35 / ethanol solution at a weight ratio of 20/80, and maleic acid or citric anhydride was added thereto as a pH adjuster in the amounts shown in Table 9. The added drug solution was prepared. The prepared drug solution was filtered with a 0.22 μm filter. The filtrate was filled into ampoules (1P) in 1 mL portions, and the space was replaced with nitrogen and sealed. Table 1 shows the stability test.
0 was obtained. From Table 10, it was found that the pharmaceutical composition of the present invention was extremely stable.

[0347]

[Table 9]

[0348]

[Table 10]

Test Example 4 50 parts of a polyoxyethylene hydrogenated castor oil 50 / ethanol solution having a ratio (weight ratio) shown in Table 11 was added to 50 mg of Compound 72.
μL was added and the mixture was stirred to confirm the solubility. At any mix ratio,
Compound 72 dissolved to give a clear solution. Therefore, the solubility of compound 72 in the solvent used is 100 mg
/ ML or more. From Table 11, it was found that the solubility of Compound 72 was significantly improved in the pharmaceutical composition of the present invention.

[0350]

[Table 11]

Test Example 5 Compound 72 was dissolved in a solution of polyoxyethylene hydrogenated castor oil 50 / ethanol in a weight ratio of 20/80, and a chemical solution was prepared by adding citric anhydride as a pH adjuster in the amount shown in Table 12. did. The prepared drug solution was filtered with a 0.22 μm filter. The filtrate was filled into ampoules (1P) in 1 mL portions, and the space was replaced with nitrogen and sealed. When the stability test was performed, the results shown in Table 13 were obtained. Table 13 shows that the pharmaceutical composition of the present invention is extremely stable.

[0352]

[Table 12]

[0353]

[Table 13]

Test Example 6 To a compound (725 mg), a polyoxyethylene hydrogenated castor oil 60 / ethanol solution in a ratio (weight ratio) shown in Table 14 was added to 50 mg.
μL was added and the mixture was stirred to confirm the solubility. Compound 72 dissolved to give a clear solution. Therefore, the solubility of Compound 72 in the solvent used was 100 mg / mL or more. From Table 14, it was found that the solubility of Compound 72 was remarkably improved in the pharmaceutical composition of the present invention.

[0355]

[Table 14]

Test Example 7 Compound 72 was dissolved in a solution of polyoxyethylene hydrogenated castor oil 60 / ethanol at a weight ratio of 20/80, and a chemical solution was prepared by adding citric anhydride as a pH adjuster in the amount shown in Table 15. did. The prepared drug solution was filtered with a 0.22 μm filter. The filtrate was filled into ampoules (1P) in 1 mL portions, and the space was replaced with nitrogen and sealed. When a stability test was performed, the results in Table 16 were obtained. Table 16 shows that the pharmaceutical composition of the present invention was extremely stable.

[0357]

[Table 15]

[0358]

[Table 16]

Test Example 8 To 5 mg of Compound 72, 1 mL of a 40% aqueous solution of 2-hydroxypropyl-β-cyclodextrin (hereinafter abbreviated as HP-β-CyD) was added, and sonication and vortexing were performed to confirm the solubility. If it does not dissolve,
1 mL of a 40% HP-β-CyD solution was further added, and sonication and vortexing were performed in the same manner to confirm solubility. The concentration at the time of dissolution was defined as the solubility. Table 17 shows the results. From Table 17, it was found that the solubility of Compound 72 was significantly increased in the pharmaceutical composition of the present invention.

[0360]

[Table 17]

Test Example 9 Maltosyl- at a concentration shown in Table 18 was added to 100 mg of Compound 72.
An aqueous solution of β-cyclodextrin (hereinafter abbreviated as G2-β-CyD) was added and shaken at 25 ° C. for 3 hours. The solution was filtered through a 0.45 μm filter, and the solubility of Compound 72 was quantified by HPLC. The results are shown in Table 18. From Table 18, it was found that the solubility of Compound 72 was significantly increased in the pharmaceutical composition of the present invention.

[0362]

[Table 18]

Test Example 10 Compound 72 and G2-β-CyD were prepared by the method described below.
Was prepared at a ratio shown in Table 19 to prepare a lyophilized preparation. After adding and dissolving 145.2 mg of G2-β-CyD to 1 mL of water, 288 mg of the compound was added and dissolved. After dissolving Compound 72, the drug solution was filtered with a 0.22 μm filter. 1 mL of the filtered drug solution was filled in a 9P vial, and lyophilized under the following conditions. After freezing at -50 ° C or lower for 2 hours, the temperature was raised to 0 ° C at a rate of temperature increase of 10 ° C / hr, and primary drying was performed for 10 hours. Thereafter, the temperature was increased to 25 ° C. at a rate of 10 ° C./hr and secondary drying was performed for 6 hours. Vacuum degree is 8.0P for primary drying
a, In the secondary drying, it was set to 13.3 Pa. Low moisture nitrogen was used for the decompression. The content of compound 72 in the obtained preparation was 98.3% based on the charged amount. When dissolved in 1 mL physiological saline, a colorless and clear solution was obtained, and the solution was colorless and clear 24 hours after dissolution at room temperature (about 23 ° C.).

[0364]

[Table 19]

Test Example 11 The stability test of the freeze-dried preparation obtained in Test Example 10 was carried out, and the results shown in Table 20 were obtained. From Table 20, it was found that the pharmaceutical composition of the present invention was extremely stable. When the lyophilized preparation was dissolved in 1 mL of physiological saline, a colorless and clear solution was obtained. The solution was colorless and clear for 24 hours after dissolution at room temperature (about 23 ° C.).

[0366]

[Table 20]

[0367]

Industrial Applicability The pharmaceutical composition of the present invention has improved solubility, stability, colorability, etc. of the water-insoluble or poorly water-soluble compound (I). The pharmaceutical composition of the present invention can be used as an inhibitor of nitric oxide and / or cytokine production for diseases such as heart disease, autoimmune disease, inflammatory disease, central nervous system disease, infectious disease, sepsis, and septic shock. Useful for prevention and treatment.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/44 A61K 47/44 A61P 9/00 A61P 9/00 37/00 37/00 // C07D 275 / 06 C07D 275/06 F term (reference) 4C033 AA12 4C076 AA29 AA31 AA36 AA44 AA53 BB01 BB13 BB29 CC03 CC11 DD07 DD37 DD42 DD43 EE39 EE53 4C086 AA01 AA02 BC81 MA01 MA05 MA16 MA31 MA35 MA37 MA41 MA01 MA32 MA32 MA01 MA05 MA36 MA51 MA55 MA57 MA61 MA63 MA72 MA75 MA80 MA86 NA14 ZA36 ZB01 ZC54

Claims (30)

[Claims] (A) Formula (I) [Wherein, R represents an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, a 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: (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 as R ^1b and is an aliphatic hydrocarbon group which may have a hydrogen atom or a substituent. R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ⁰ together form a bond, and ring A ¹ represents (1) substituted An aliphatic hydrocarbon group which may have a group, (2) an aromatic hydrocarbon group which may have a substituent, (3) a formula -OR ¹ wherein R ¹ is as defined above. And (4) a cycloalkene which may be substituted with 1 to 4 halogen atoms selected from halogen atoms, and Ar is an aromatic hydrocarbon group which may have a substituent. With the formula The group represented by the formula is Or And n represents an integer of 1 to 4. And a salt thereof or a prodrug thereof,
(B) A pharmaceutical composition containing a nonionic surfactant and / or a water-soluble cyclodextrin derivative. 2. A compound of the formula (I) [Wherein, R represents an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, a 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: (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 as R ^1b and is an aliphatic hydrocarbon group which may have a hydrogen atom or a substituent. R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ⁰ together form a bond, and ring A ¹ represents (1) substituted An aliphatic hydrocarbon group which may have a group, (2) an aromatic hydrocarbon group which may have a substituent, (3) a formula -OR ¹ wherein R ¹ is as defined above. And (4) a cycloalkene which may be substituted with 1 to 4 halogen atoms selected from halogen atoms, and Ar is an aromatic hydrocarbon group which may have a substituent. With the formula Is a group represented by the formula: Or And n represents an integer of 1 to 4. Or a salt thereof, or a prodrug thereof, and a nonionic surfactant. 3. The composition according to claim 2, wherein the nonionic surfactant is polyoxyethylene castor oil or polyoxyethylene hydrogenated castor oil. 4. The composition according to claim 2, further comprising ethanol. 5. The compound according to claim 1, wherein the compound is d-ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate, d-ethyl 6- [N- (2,4 -Difluorophenyl) sulfamoyl] -1-cyclohexene-1-
Carboxylate, ethyl 6- [N- (2-chlorophenyl)
The composition according to claim 2, which is sulfamoyl] -1-cyclohexene-1-carboxylate, ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate or a salt thereof. object. 6. The composition according to claim 2, wherein the content of the nonionic surfactant is about 10% to about 70% by weight based on the whole composition. 7. The composition according to claim 4, wherein the content of ethanol is about 30% to about 90% by weight based on the whole composition. 8. The compounding ratio of the nonionic surfactant and ethanol is from about 10 parts by weight to about 9 parts by weight of the nonionic surfactant.
5. The composition according to claim 4, wherein the amount of ethanol is about 90 parts by weight to about 10 parts by weight based on 0 parts by weight. 9. The composition according to claim 2, which is an injectable composition. 10. The composition according to claim 9, which is a non-emulsified composition. 11. The composition according to claim 9, which is clear. 12. The composition according to claim 2, which is an inhibitor of nitric oxide and / or cytokine production. 13. The composition according to claim 2, which is a prophylactic / therapeutic agent for heart disease, autoimmune disease or septic shock. 14. A compound of the formula (I) [Wherein, R represents an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, a 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: (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 as R ^1b and is an aliphatic hydrocarbon group which may have a hydrogen atom or a substituent. R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ⁰ together form a bond, and ring A ¹ represents (1) substituted An aliphatic hydrocarbon group which may have a group, (2) an aromatic hydrocarbon group which may have a substituent, (3) a formula -OR ¹ wherein R ¹ is as defined above. And (4) a cycloalkene which may be substituted with 1 to 4 halogen atoms selected from halogen atoms, and Ar is an aromatic hydrocarbon group which may have a substituent. With the formula: The group represented by the formula is Or And n represents an integer of 1 to 4. A method for improving the solubility, stability or colorability of a compound or a salt thereof or a prodrug thereof, comprising mixing a compound or a salt thereof or a prodrug thereof with a nonionic surfactant. . 15. A method for preventing or treating a heart disease, an autoimmune disease or a septic shock, comprising administering an effective amount of the composition according to claim 2 to a mammal. 16. A method for producing a prophylactic / therapeutic agent for heart disease, autoimmune disease or septic shock.
Use of the described composition. 17. A compound of the formula (I) [Wherein, R represents an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, a 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: (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 as R ^1b and is an aliphatic hydrocarbon group which may have a hydrogen atom or a substituent. R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ⁰ together form a bond, and ring A ¹ represents (1) substituted An aliphatic hydrocarbon group which may have a group, (2) an aromatic hydrocarbon group which may have a substituent, (3) a formula -OR ¹ wherein R ¹ is as defined above. And (4) a cycloalkene which may be substituted with 1 to 4 halogen atoms selected from halogen atoms, and Ar is an aromatic hydrocarbon group which may have a substituent. With the formula: The group represented by the formula is Or And n represents an integer of 1 to 4. Or a salt thereof or a prodrug thereof, and a water-soluble cyclodextrin derivative. 18. A water-soluble cyclodextrin derivative represented by the formula: [In the formula, q represents an integer of 6 to 12, and R ⁶ , R ⁷ and R ⁸ are the same or different in each repeating unit, and represent a hydrogen atom, a dihydroxyalkyl group, a sugar residue or a hydroxyalkyl group, respectively. Wherein at least one of R ⁶ , R ⁷ and R ⁸ is a dihydroxyalkyl group,
It is a sugar residue or a hydroxyalkyl group. The composition according to claim 17, which is represented by the formula: 19. The composition according to claim 18, wherein at least one of R ⁶ , R ⁷ and R ⁸ is a sugar residue, and the remaining groups are hydrogen atoms. 20. The composition according to claim 18, wherein the sugar residue is selected from the group consisting of a glucosyl group, a maltosyl group, a maltotriosyl group and a dimaltosyl group. 21. The composition according to claim 17, wherein the water-soluble cyclodextrin derivative is maltosyl-β-cyclodextrin. 22. The composition according to claim 17, which contains about 0.1 to about 100 mol of a water-soluble cyclodextrin derivative per 1 mol of the compound represented by the formula (I), a salt thereof or a prodrug thereof. object. 23. The composition according to claim 17, which comprises about 1 to about 5 mol of a water-soluble cyclodextrin derivative per 1 mol of the compound represented by the formula (I), a salt thereof or a prodrug thereof. 24. The compound according to claim 1, wherein the compound is d-ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -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, ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene The composition according to claim 17, which is 1-carboxylate or a salt thereof. 25. The composition according to claim 17, which is an injectable composition. 26. The composition according to claim 17, which is an inhibitor of nitric oxide and / or cytokine production. 27. The composition according to claim 17, which is a prophylactic / therapeutic agent for heart disease, autoimmune disease or septic shock. 28. A compound of the formula (I) [Wherein, R represents an aliphatic hydrocarbon group optionally having a substituent, an aromatic hydrocarbon group optionally having a substituent, a heterocyclic group optionally having a substituent, a 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: (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 as R ^1b and is an aliphatic group which may have a hydrogen atom or a substituent. R ⁰ represents a hydrogen atom or an aliphatic hydrocarbon group, or R and R ⁰ together form a bond, and ring A ¹ represents (1) substituted An aliphatic hydrocarbon group which may have a group, (2) an aromatic hydrocarbon group which may have a substituent, (3) a formula -OR ¹ wherein R ¹ is as defined above. And (4) a cycloalkene optionally substituted with 1 to 4 halogen atoms selected from halogen atoms, and Ar is an aromatic hydrocarbon group optionally having a substituent. With the formula: The group represented by the formula is Or And n represents an integer of 1 to 4. Improving the solubility, stability, or colorability of the compound or a salt thereof or a prodrug thereof in water, which comprises mixing the compound or a salt thereof or a prodrug thereof with a water-soluble cyclodextrin derivative. how to. 29. A method for preventing or treating a heart disease, an autoimmune disease or a septic shock, comprising administering an effective amount of the composition according to claim 17 to a mammal. 30. The method for producing a prophylactic / therapeutic agent for heart disease, autoimmune disease or septic shock.
Use of the composition of claim 7.