JP2001261557A - Injection composition having improved dissolution or stability - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition for injection that has improved dissolving properties or stability. SOLUTION: The objective medicinal composition includes a compound represented by formula (I) [wherein R is an aliphatic hydrocarbon group, an aromatic hydrocarbon group, a heterocyclic group, a group of the formula: -OR1 (R1 is H or an aliphatic hydrocarbon group) or a group represented by formula (II) (wherein R1b is H or an aliphatic hydrocarbon group; R1c is H or an aliphatic hydrocarbon group); R0 is H or an aliphatic hydrocarbon group; or R and R0 are incorporated to give a bond; ring A1 is a cycloalkene which may be mono-, di-, tri- or tetra-substituted with (1) aliphatic hydrocarbon group, (2) aromatic hydrocarbon group, (3) a group represented by the formula: -OR1 (R1 is identical with the above-stated R1) and (4) halogen atoms; Ar is an aromatic hydrocarbon group which may be substituted; the group represented by the formula (III) is a group represented by formula (IV) or by formula (V); (n) is an integer of 1-4], the salts thereof or its prodrug are adjusted in their pH from >=13 down to <=12 characteristically, when needed, freeze-dried to give the objective stabilized medicinal composition. This invention further provides a method of producing the medicinal composition and a method of improving the dissolving properties and the stability of the above compound, salts thereof or prodrugs thereof.

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 hardly soluble cycloalkene compound, a method for producing the same, and improved solubility or stability of the cycloalkene compound. On how to do it.

[0002]

2. Description of the Related Art In WO99 / 46242, the formula (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 (Wherein, R ^1a has the same meaning as described above, and R ^1b is the same or different from R ^1a and represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent.) and the R ^0a represents a hydrogen atom or an aliphatic hydrocarbon group, or R ^a and R ^0a
Is a bond together, Ar is 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. 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]

DISCLOSURE OF THE INVENTION The present invention provides a pharmaceutical composition having improved solubility or stability of the above compound, a method for producing the same, and a method for improving the solubility or stability of the above compound. Aim.

[0004]

Means for Solving the Problems In view of the above problems, the present inventors have conducted intensive studies. As a result, once an aqueous solution containing the above compound having a pH of about 13 or more was prepared, the pH was adjusted.
Was adjusted to about 12 or less, and freeze-drying was performed, if necessary, to unexpectedly find a lyophilized product in which the solubility or stability of the compound was significantly improved. The present inventors have further studied based on this finding, and as a result, have completed the present invention.

[0005] That is, the present invention provides the following [1]

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 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 represents an aromatic hydrocarbon group which may have a substituent. ,formula

Embedded image The group represented by the formula

Embedded image Or

Embedded image And n represents an integer of 1 to 4. PH of the compound represented by the formula or a salt thereof or a prodrug thereof
Pharmaceutical composition having improved solubility or stability of the compound or a salt thereof or a prodrug thereof, wherein the pH of an aqueous solution of about 13 or more can be adjusted to about 12 or less and freeze-dried if necessary. [2] The composition according to [1], which is an injectable composition, and [3] 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] the composition according to [1], which is 1-carboxylate or a salt thereof, [4] the composition according to [1], which is a nitric oxide and / or cytokine production inhibitor, [5]
The composition according to item [1], which is a prophylactic / therapeutic agent for heart disease, autoimmune disease or septic shock, formula [6]

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 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 represents an aromatic hydrocarbon group which may have a substituent. ,formula

Embedded image The group represented by the formula

Embedded image Or

Embedded image And n represents an integer of 1 to 4. PH of the compound represented by the formula or a salt thereof or a prodrug thereof
A method for producing a pharmaceutical composition having improved solubility or stability of the compound or a salt thereof or a prodrug thereof, wherein the aqueous solution of about 13 or more is adjusted to a pH of about 12 or less and freeze-dried as necessary. And [7]

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 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 represents an aromatic hydrocarbon group which may have a substituent. ,formula

Embedded image The group represented by the formula

Embedded image Or

Embedded image And n represents an integer of 1 to 4. PH of the compound represented by the formula or a salt thereof or a prodrug thereof
It is intended to provide a method for improving the solubility or stability of the compound or a salt thereof or a prodrug thereof, which comprises adjusting the pH of an aqueous solution of about 13 or more to about 12 or less and freeze-drying as necessary.

Further, the present invention provides a compound represented by the formula (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 ² 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 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 (Wherein, R ^1a has the same meaning as described above, and R ^1b is the same or different from R ^1a and represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent.) and the R ^0a represents a hydrogen atom or an aliphatic hydrocarbon group, or R ^a and R ^0a
Is a bond together, Ar is 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. ] The composition according to [1], which is a compound represented by the formula:

[9] Formula (Ia
a) a compound represented by the formula:

Embedded image [Wherein each symbol has the same meaning as described in the item [1]], the composition according to the item [8], which is a compound represented by the formula [10]:
Ring A ² is a cycloalkene substituted with lower alkyl, phenyl or halogen, R ¹ is a lower alkyl group, Ar is a phenyl group which may have a substituent, and n is 2 [8] The composition according to the above,

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

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 Ar has a substituent. An aromatic hydrocarbon group which may be represented by the formula

Embedded image The group represented by the formula

Embedded image Or

Embedded image And n represents 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 Ar represents a phenyl group, a 2-methylphenyl group, or 4
-A bromophenyl group, a 4-methoxyphenyl group or a 2,6-dimethylphenyl group,

Embedded image The group represented by the formula

Embedded image Is a group represented by ] The composition according to [8], which is a compound represented by the formula:

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

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

Embedded image The group represented by has the same significance as described in the item [11]. However, when 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,

Embedded image The group represented by the formula

Embedded image Is a group represented by [1] which is a compound represented by the formula:
[1] The composition according to [12], wherein [ ¹ ] R ¹ is a lower alkyl group which may have a substituent; [14] The composition according to [12], wherein R ¹ is an ethyl group. 12] the composition according to claim, [15] a [12] the composition according to claim wherein R ² is a hydrogen atom or a lower alkyl group, [16] the composition of the [12], wherein R ² is a hydrogen atom [17] Ar is a phenyl group which may have a substituent [12].
[18] The composition according to [1], wherein [18] Ar is a phenyl group substituted with halogen or / and lower alkyl.
2] The composition according to the above,

[19] Ar is a formula

Embedded image [In the formula, 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. ] The composition according to [12], which is a group represented by the formula:
[20] the composition of [12], wherein the halogen atom is a fluorine atom or a chlorine atom,

Embedded image Is a group represented by the formula

Embedded image [In the formula, n has the same meaning as described in the item [11]. The composition according to [12], which is a group represented by the formula [22] n:
[12] The composition according to [12], wherein
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;
Or the composition according to item [12], which is 3, or [24] R
¹ is a lower alkyl group which may have a substituent,
The composition according to [12], wherein R ² is a hydrogen atom, Ar is a phenyl group substituted with a halogen atom, and n is 2.

[25] A compound represented by the formula (Ia) is

Embedded image [Wherein Ar and n have the same meanings as in item [11]], the composition according to item [11], wherein [26] Ar has a substituent A composition according to [25], which is a good phenyl group and n is 2.

[27] The compound represented by the formula (Ia) is

Embedded image [Wherein, R ¹ , R ² and Ar have the same meanings as described in [11].

Embedded image The group represented by the formula

Embedded image Or

Embedded image Represents a 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,

Embedded image The group represented by the formula

Embedded image Is a group represented by [1] which is a compound represented by the formula:
1) The composition according to the above,

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

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

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

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

Embedded image [Wherein R ^1a , R ^2a and Ar ^a have the same meaning as described in the item [28],

Embedded image The group represented by the formula

Embedded image Or

Embedded image Represents a group represented by ] The composition according to [8], which is a compound represented by the formula:

In the present specification, R represents 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:

Embedded image (Wherein, R ^1b is a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent, and R ^1c is the same as or different from R ^1b and has a hydrogen atom or a substituent. a group represented by.) showing an aliphatic hydrocarbon group, or show to form a bond together with R ^0, especially, the formula -OR ¹ [R ¹ is as defined above . ] 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 aliphatic hydrocarbon group which may have a substituent), or a group represented by the formula:

Embedded image (Wherein, R ^1a has the same meaning as described above, and R ^1b is the same or different from R ^1a and represents a hydrogen atom or an aliphatic hydrocarbon group which may have a substituent.) And R ^0a together with a group to form a bond, and particularly, a group represented by the formula —OR ^1a wherein R ^1a is as defined above. ] Are preferable.

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

Embedded image [Wherein the symbols have the same meanings as described above. ], And specifically, the formula

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

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

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

Embedded image [Wherein the symbols have the same meanings as described above. ], And specifically, the formula

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

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

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

Embedded image [Wherein the symbols have the same meanings as described above. ], And specifically, the formula

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

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

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):

Embedded image [Wherein the symbols have the same meanings as described above. ], And specifically, the formula

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

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

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):

Embedded image [Wherein the symbols have the same meanings as described above. ], And specifically, the formula

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

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

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):

Embedded image [Wherein the symbols have the same meanings as described above. ], And specifically, the formula

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

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

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

Similarly, the compound represented by the formula (Id)

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

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

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

Embedded image [Wherein the symbols have the same meanings as described above. ]. The compound represented by the formula (Id) is represented by the formula (Ir)
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,

Embedded image The group represented by the formula

Embedded image Is a group represented by Further, n is 1 to 4,
(I) 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, or (ii) when R and R ⁰ together represent a bond, and Ar is a phenyl group which may have a substituent,

Embedded image The group represented by the formula

Embedded image And may be a group represented by

In the compound represented by the 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,

Embedded image The group represented by the formula

Embedded image Is a group represented by Further, n is 1 to 4, and R ¹
Is a hydrogen atom or a lower alkyl group optionally having substituent (s), R ⁰ is a lower alkyl group optionally having substituent (s), and Ar is a phenyl group optionally having substituent (s) ,formula

Embedded image The group represented by the formula

Embedded image And may be a group represented by

The "aliphatic hydrocarbon group" of the "aliphatic hydrocarbon group ^optionally having substituent (s)" represented by R, R ¹ , R ^1a , R ^1b and R ^1c , R ⁰ , R ^0a As the “aliphatic hydrocarbon group” represented by R ² and R ^2a , for example, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an alkenyl group, an alkynyl group and the like are preferable. As the alkyl group, for example, a linear or branched alkyl group having 1 to 20 carbon atoms (eg, a methyl group, an ethyl group, an n-propyl group,
Isopropyl group, n-butyl group, isobutyl group, sec-
Butyl group, tert-butyl group, pentyl group, hexyl group,
A heptyl group, an octyl group, a nonyl group, a decyl group, a dodecyl group and the like are preferable, and particularly, for example, a lower alkyl group having 1 to 6 carbon atoms (eg, a methyl group, an ethyl group, n
-Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like). As the cycloalkyl group, for example, a cycloalkyl group having 3 to 10 carbon atoms (eg, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, etc.) and the like are preferable. A cycloalkyl group having 3 to 6 carbon atoms (eg, cyclopropyl group, cyclobutyl group,
And a cyclopentyl group and a cyclohexyl group. As the cycloalkylalkyl group, for example,
A cycloalkylalkyl group having 4 to 12 carbon atoms (e.g., cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, etc.) and the like are preferable, and particularly, for example, having 4 to 8 carbon atoms (4 to 8 carbon atoms among others). 7) The cycloalkylalkyl group (eg, cyclopropylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, etc.) and the like are preferable. Examples of the alkenyl group include a lower alkenyl group having 3 to 6 carbon atoms (eg, a propenyl group, a butenyl group, a pentenyl group, etc.).
And the like, particularly, for example, having 3 or 4 carbon atoms.
(E.g., propenyl group, butenyl group, etc.) are preferred. As the alkynyl group, for example,
A lower alkynyl group having 3 to 6 carbon atoms (eg, a propynyl group,
Butynyl group, pentynyl group, etc.), and more preferably, for example, a lower alkynyl group having 3 or 4 carbon atoms (eg, propynyl group, butynyl group, etc.).

As the “substituent” of the “aliphatic hydrocarbon group which may have a substituent”, 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 above “aliphatic hydrocarbon group”, and the number of the substituents is not limited to one, and may be the same or different and plural (2
~ 4).

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, n
-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 and the like, and as the `` halogen atom '', for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like , “C <sub>1-10</sub> 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 <sub>3-6</sub> 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,
A butyryloxy group, a valeryloxy group, a pivaloyloxy group and the like, and as the “C _3-5 alkenoyloxy group”, for example, an acryloyloxy group and a crotonoyloxy group are used.

As the “carbamoyl group optionally having substituent (s)”, 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 which may be 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.

Examples of the "C _1-6 alkanoylamino group" include, for example, an acetamido group, a propionamide group, a butyroamide group, a valeroamide group and a pivaloamide group, and examples of the "C _6-10 aryl-carbonylamino group" , A benzamide group, a naphthamide group, a phthalimide group and the like as the “C _1-10 alkoxy-carboxamide group” include, for example, methoxycarboxamide (CH
₃ OCONH-) group, ethoxycarboxamide group, tert
- such as butoxy carboxamide group, - As the "C _6-10 aryloxy-carboxamide group", for example, phenoxy carboxamide (C ₆ H ₅ OCONH-) group,
As the “C _7-10 aralkyloxy-carboxamide group”, for example, benzyloxycarboxamide (C ₆ H ₅ C
H ₂ OCONH-) group, etc. benzhydryloxy carboxamide group, - a "C _1-10 alkoxy-carbonyloxy group", for example, a methoxycarbonyloxy group, an ethoxycarbonyloxy group, n- propoxycarbonyl group, iso A propoxycarbonyloxy group,
n-butoxycarbonyloxy group, tert-butoxycarbonyloxy group, n-pentyloxycarbonyloxy group, n-hexyloxycarbonyloxy group and the like,
Examples of the “C _6-10 aryloxy-carbonyloxy group” include a phenoxycarbonyloxy group and a naphthyloxycarbonyloxy group, and examples of the “C _7-19 aralkyloxy-carbonyloxy group” include a benzyloxycarbonyl group. An oxy group, a 1-phenylethyloxycarbonyloxy group, a 2-phenylethyloxycarbonyloxy group, a benzhydryloxycarbonyloxy group and the like are examples of the “C _3-10 cycloalkyloxy-carbonyloxy group”. A propyloxycarbonyloxy group, a cyclohexyloxycarbonyloxy group and the like are used.

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

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

As the "C _6-10 aryl group" of the "C _6-10 aryl group _optionally having substituent (s)", for example, a phenyl group, a naphthyl group and the like are used. The C _6-10 aryl group is a “substituent” of the “aliphatic hydrocarbon group _optionally having substituent (s)” (C _{6-10 optionally} having substituent (s)).
Excluding the aryl group), the substitutable site may be substituted. 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). Further, the `` aliphatic hydrocarbon group which may have a substituent '' may form a condensed ring group in which the substituent may be substituted together with the aliphatic hydrocarbon group, As such a condensed ring group, an indanyl group, a 1,2,3,4-tetrahydronaphthyl group or the like is used. In this condensed ring group, a substitutable site may be substituted with a substituent selected from the “substituent” of the “aliphatic hydrocarbon group which may have a substituent”. These substituents are substituted on the 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 (two to four).

R, R ¹ , R ^1a , R ^1b , R ^1c are as follows:
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, n
-Propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butoxycarbonylmethyl group, hydroxyethyl group, etc.) are preferably used,
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, etc.) are preferable, and particularly, for example, an aryl group having 6 to 10 carbon atoms (eg, a phenyl group, a naphthyl group, etc.) is preferable. A phenyl group and the like are particularly preferred. Examples of the “substituent” in the “aromatic hydrocarbon group optionally having substituent (s)” represented by Ar and Ar ^a include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (C _1-4 ) alkyl group (eg, methyl group, ethyl group, propyl group, butyl group, etc.), lower (C _1-4 ) alkoxy group (eg, methoxy group, ethoxy group, propoxy group, butoxy group, etc.) A lower (C _1-4 ) alkoxycarbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, etc.), a carboxyl group, a nitro group, a cyano group, a hydroxyl group, an acylamino group (eg, acetylamino Group, a propionylamino group, a butyrylamino group, etc., an alkanoylamino group having 1 to 4 carbon atoms), a cycloalkyl group having 3 to 6 carbon atoms (eg, cyclopropyl Propyl group, cyclopentyl group), 6-1 carbon atoms
0 aryl group (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-tetrafluoroethoxy group, 2,2,3,3,3-pentafluoropropoxy group, etc.), lower (C _1-4 ) alkylthio group (Eg, methylthio, ethylthio, propionylthio, etc.), lower (C _1-4 ) alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl, propanesulfonyl, etc.), lower (C _1-4 ) alkanoyl Group (eg, formyl group, acetyl group, propionyl group, etc.), 5-membered aromatic heterocyclic group (eg, 1,2,3-triazolyl group, 1,2,4-
Triazolyl group, tetrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group,
Thiadiazolyl group, thienyl group, furyl group, etc.), carbamoyl group, lower (C _1-4 ) alkyl-carbamoyl group (eg, methylcarbamoyl group, dimethylcarbamoyl group, propionylcarbamoyl group, etc.), lower (C _1-4 ) alkoxy -Carbonyl-lower (C _1-4 ) alkyl-carbamoyl group (eg, butoxycarbonylmethylcarbamoyl group, ethoxycarbonylmethylcarbamoyl group, etc.), 1,3-diacylguanidino-lower (C _1-4 ) alkyl group (eg, 1,3-diacetylguanidinomethyl, 1,3-bis-tert-butoxycarbonylguanidinomethyl 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) alkyl group (e.g., methyl group, an ethyl group, a propyl group and a butyl group), etc. , More preferably a fluorine atom, a chlorine atom, a methyl group is used. These substituents are substituted at substitutable sites of the aromatic hydrocarbon group, and the number of the substituents is preferably 1 to 5, preferably 1 to 5.
~ 3 are more preferred, and 1-2 are especially 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. Ar, Ar
^{As a} , a halogenophenyl group, a lower (C _1-4 ) alkylphenyl group, a phenyl group substituted with a halogen and a lower (C _1-4 ) alkoxycarbonyl are preferably used. Ar and Ar ^a are represented by the formula

Embedded image [In the formula, 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. As the lower (C _1-4 ) alkylphenyl group, for example, a 2-ethylphenyl group, a 2,6-diisopropylphenyl group and the like are preferably used, and the lower (C _1-4 ) alkylphenyl group is preferably used.
As the alkoxyphenyl group, for example, 4-methoxyphenyl and the like are preferably used. The lower (C _1-4 ) alkoxy-carbonylphenyl group includes, for example, 2
-Ethoxycarbonylphenyl, 2-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, and the like are preferably used. Examples of the halogeno lower (C _1-4 ) alkylphenyl include 2-trifluoromethylphenyl. Are preferably used. Examples of the halogeno lower (C _1-4 ) alkoxyphenyl group include, for example,
2-trifluoromethoxyphenyl group, 4- (2,2,
A (3,3,3-pentafluoropropoxy) phenyl group is preferably used. As the lower (C _1-4 ) alkanoylphenyl group, for example, a 2-acetylphenyl group is preferably used, and as the phenyl group substituted with the 5-membered aromatic heterocycle, for example, 4- (2H -1,
2,3-triazol-2-yl) phenyl group, 4-
(2H-tetrazol-2-yl) phenyl group, 4-
(1H-tetrazol-1-yl) phenyl group, 4-
Etc. (IH-1,2,3-triazol-1-yl) phenyl group are preferably used, said lower (C _1-4) alkoxy - carbonyl - The carbamoyl phenyl group, - a lower (C _1-4) alkyl For example, a 4- (N-ethoxycarbonylmethylcarbamoyl) phenyl group is preferably used, and the 1,3-diacylguanidino-lower (C
_1-4 ) Examples of the alkylphenyl group include, for example, 4- (1,
A 3-bis-tert-butoxycarbonylguanidinomethyl) phenyl group and the like are preferably used. Examples of the phenyl group substituted with the halogen and lower (C _1-4 ) alkyl include a 2-fluoro-4-methylphenyl group, a 2-chloro-4-methylphenyl group, and a 4-fluoro-2-methylphenyl And the like, and examples of the phenyl group substituted by halogen and lower (C _1-4 ) alkoxy-carbonyl include 2-chloro-4
-Methoxycarbonylphenyl group and the like are preferably used, and as the phenyl group substituted with halogen and cyano, 2-chloro-4-cyanophenyl group and the like are preferably used. Examples of the substituted phenyl group include 2-fluoro-4-
(1H-1,2,4-triazol-1-yl) phenyl and the like are preferably used, and the halogen and lower (C
_1-4 ) Examples of the phenyl group substituted with an alkoxy-carbonyl-lower (C _1-4 ) -alkyl-carbamoyl include a 2-chloro-4- (N-tert-butoxycarbonylmethylcarbamoyl) phenyl group and 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 1 to 3 (especially 1 to 2) 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 optionally having a substituent, (ii) an aromatic hydrocarbon group optionally having 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 which may have a substituent, (ii) an aromatic hydrocarbon group which may have a substituent, (iii) a formula -OR ¹ wherein R ¹ is as defined above. And (iv) a cycloalkene substituted with 1 to 4 halogen atoms selected from halogen atoms, and (i) an aliphatic hydrocarbon group which may have a substituent. And (ii) a cycloalkene substituted with 1 to 4 substituents selected from an aromatic hydrocarbon group which may have a substituent and (iv) a halogen atom. These substituents are substituted on substitutable carbon atoms in the ring A ¹ and ring A ^2, ring A ¹ and ring A ²
Is substituted with a plurality of substituents, the types of those substituents may be the same or different. Also,
Two substituents may be substituted on the same carbon atom, or a plurality of substituents may be substituted on different carbon atoms.

Examples of the “optionally substituted aliphatic hydrocarbon group” which is a substituent of the ring A ¹ and the ring A ² include, for example, the aforementioned 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. Examples of the “aromatic hydrocarbon group optionally having substituent (s)” that is a substituent of ring A ¹ and ring A ² include, for example, “having a substituent represented by Ar, Ar ^a described above. And the like. " Examples of the “heterocyclic group which may have a substituent” which is a substituent of the ring A ¹ and the ring A ² include, for example, those represented by R, R ¹ , R ^1a , R ^1b and R ^1c described above. The same “heterocyclic group” as the “substituent” of the “optionally substituted aliphatic hydrocarbon group” can be used.

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

Equation

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

Embedded image Or

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

Embedded image [Wherein, n has the same meaning as described above. ] Is preferable.

Equation

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

Embedded image Or

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

Embedded image [Wherein, n has the same meaning as described above. ] Is preferable.

Also, the equation

Embedded image The group represented by the formula

Embedded image Or

Embedded image Is a group represented by the formula,

Embedded image It is preferably a group represented by 1 to n
As an integer of 4, 1-3 are preferable, and 2 is particularly preferable.

The compound represented by the formula (Iaa) is preferably a compound represented by the formula (Ibb), and the compound represented by the formula (Ia) is preferably a compound represented by the formula (Ib) . The compound represented by the formula (Ibb) is preferably a compound represented by the formula (Inn), and the compound represented by the formula (Ib) is preferably a compound represented by the formula (In). The formula (Ib
In the compounds represented by b) and (Ib), R ¹ is a lower alkyl group which may have a substituent, R ² is a hydrogen atom or a lower alkyl group, and Ar has a substituent. And n is preferably 1, 2 or 3, R ¹ is a lower alkyl group which may have a substituent, R ² is a hydrogen atom, Ar Is a phenyl group substituted with a halogen atom, and n is preferably 2. As the compounds represented by the formulas (Icc) and (Ic), those in which Ar is a phenyl group which may have a substituent and n is 2 are preferable. Examples of the leaving group represented by X ¹ include a halogen atom (eg,
Chlorine, bromine, iodine, etc.) are preferable, and a chlorine atom is particularly 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 later is used, and among them, d-ethyl 6- [N- (2 , 4-Difluorophenyl) sulfamoyl] -1-cyclohexene-
1-carboxylate, ethyl 6- [N- (2-chlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate, ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene Preferred is 1-carboxylate or d-ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate or a salt thereof.

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, etc. 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 a 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 causing 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 eicosanoylated, 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. Also,
Prodrugs of the compound of the present invention are described in “Development of Pharmaceuticals”, Hirokawa Shoten, 1990, Vol. 7, Molecular Design, p.
It may be one that changes to a compound of the present invention under physiological conditions, as described on page. 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. Further, the compound of the present invention, a salt thereof, or a prodrug thereof may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.).

The pharmaceutical composition of the present invention can be produced by adjusting the pH of an aqueous solution of the compound of the present invention or a salt thereof or a prodrug thereof to a pH of about 13 or more to about 12 or less and, if necessary, freeze-drying. And the solubility or stability of the compound or a salt thereof or a prodrug thereof is improved. The aqueous solution of the compound of the present invention or a salt thereof or a prodrug thereof having a pH of about 13 or more contains the compound of the present invention or a salt thereof or a prodrug thereof, and contains p
It is an aqueous solution in which H is adjusted to about 13 or more, specifically, to about pH 13 to 14, preferably to pH 14. The concentration of the compound of the present invention or a salt thereof or a prodrug thereof in this aqueous solution is usually about 5 mg / ml or more, preferably about 10 mg / ml or more, specifically about 1 mg / ml at room temperature.
0-20 mg / ml, more specifically about 18 mg / ml
It is. The aqueous solution may contain an organic solvent as needed.Examples of the organic solvent include polyethylene glycol, propylene glycol, ethanol, methanol, acetonitrile, acetone, tetrahydrofuran,
Dimethylformamide, dimethylsulfoxide and the like are used. The term “pH of about 12 or less” indicates preferably about pH 11 or less, specifically about pH 7 to 11, and particularly preferably pH 11. The aqueous solution of the present invention can be adjusted to an appropriate pH using a pH adjuster widely used in the present technical field. As the pH adjuster, for example, phosphoric acid, carbonic acid, citric acid, hydrochloric acid, sodium hydroxide and the like are used. Specifically, when adjusting the pH to about 13 or more, sodium hydroxide or the like is used, and the pH is adjusted to about 12 or more.
When adjusting below, hydrochloric acid or the like is used.

The aqueous solution having a pH of 13 or more may contain, for example, a stabilizer, an isotonic agent, a pH buffer and the like used in the composition for injection. As the stabilizer, for example, an antioxidant (eg, ascorbic acid, tocopherol, sorbic acid, retinol, etc.), a chelating agent (eg, citric acid, tartaric acid, etc.) and the like are used. The amount of the stabilizer used is usually about 0.
00001-10% (W / V), preferably about 0.00
It is about 01 to 5% (W / V). As the tonicity agent,
For example, glycerin, sugar alcohol, monosaccharide (eg, mannitol), disaccharide, amino acid, dextran, albumin and the like are used. These tonicity agents can be used alone or in combination of two or more. The amount of the tonicity agent used is usually about 0.00001 to 10% based on the whole solution of the present invention.
(W / V), preferably about 0.0001 to 5% (W / V).
V). Examples of the pH buffer include meglumine, phosphoric acid, citric acid, carbonic acid, hydrochloric acid, acetic acid, sodium hydroxide, L-arginine, sodium sulfite, monoethanolamine, diethanolamine, triethanolamine, tromethamol, and the like. The amount of the pH buffer used is usually about 0.0
0001-10% (W / V), preferably about 0.000
It is about 1 to 5% (W / V). The pharmaceutical composition prepared by adjusting the aqueous solution having a pH of about 13 or more to a pH of about 12 or less has improved solubility of the water-insoluble or poorly soluble compound of the present invention, a salt thereof, or a prodrug thereof.

"Improvement of solubility" means that the concentration of the compound of the present invention or a salt thereof or a prodrug thereof in an aqueous solution is improved to a level higher than the solubility. Here, the solubility refers to the concentration of a drug dissolved and present in an aqueous solution under a constant pH condition at room temperature, and is expressed, for example, in mg / ml. The solubility of the compound of the present invention or a salt thereof or a prodrug thereof is about 2.5 at room temperature and a pH of about 11.
mg / ml, about 1.4 mg / ml at about pH 10, about 0.4 mg / ml at about pH 9, and 0.1 mg / ml or less at about pH 3 to about 7. "The concentration of the compound of the present invention or a salt thereof or a prodrug thereof in an aqueous solution is improved over the solubility" means that the concentration of the compound of the present invention or a salt thereof or a prodrug thereof in the aqueous solution is at least the solubility. For example, room temperature and pH of about 11
About 3 mg / ml or more, preferably about 5 mg
/ Ml or more, more preferably about 10 mg / ml or more, and still more preferably about 8 to 12 mg / ml. That is, as shown in Comparative Example 1 below,
The compound of the present invention or a salt thereof or a prodrug thereof is generally used in an amount of about 2 mg at room temperature and pH range of 3 to 11.
/ Ml, but the pH of the aqueous solution is once adjusted to about 13 or more according to the method of the present invention.
At room temperature and pH of about 11 to about 5
Concentrations of at least mg / ml can be maintained.

The aqueous solution obtained above may be used, if necessary,
Lyophilization can be performed by a method known per se. Before the freeze-drying, the aqueous solution is desirably sterilized and pyrogen-removed by a method known per se. The freeze-dried product thus obtained has improved stability of the compound of the present invention, a salt thereof, or a prodrug thereof, and can be stored for a long time. Further, the freeze-dried product is
A sample obtained by freeze-drying an aqueous solution containing the compound of the present invention or a salt thereof or a prodrug thereof at a concentration equal to or higher than the solubility, and when the compound of the present invention or a salt thereof or a prodrug thereof is redissolved again. Can be obtained. Specifically, the concentration of the compound of the present invention or a salt thereof or a prodrug thereof is about 5 mg / ml at room temperature and pH of about 11.
As described above, an aqueous solution having a concentration of preferably about 10 mg / ml or more, more specifically about 8 to 12 mg / ml, is obtained.

The pharmaceutical composition of the present invention has a pH of about 1
It may be an aqueous solution in which three or more aqueous solutions are adjusted to a pH of about 12 or less, or may contain a freeze-dried product obtained by freeze-drying this aqueous solution. The pharmaceutical composition of the present invention is preferably an injectable composition. The amount of the lyophilized product in the pharmaceutical composition of the present invention containing the lyophilized product varies depending on the pharmacological activity or pharmacokinetics of the compound.
It is 1 to 100% by weight, preferably about 20 to 100% by weight. The pharmaceutical composition of the present invention containing the freeze-dried product can be used after dissolving it before use. When dissolved at the time of use, the concentration of the compound of the present invention or a salt or a prodrug thereof is usually about 5 mg / ml or more at room temperature and pH of about 11, although it differs depending on the pharmacological activity or pharmacokinetics of the compound. Preferably about 10 mg / ml or more (for example, about 10 mg / ml)
-20 mg / ml), more specifically about 8-12 mg / ml.
ml. As described above, the pH of an aqueous solution having a pH of about 13 or more of the compound of the present invention or a salt thereof or a prodrug thereof is adjusted to about 12 or less and, if necessary, lyophilized to give the compound or a salt thereof or a prodrug thereof. Solubility or stability can be improved. Further, the pharmaceutical composition of the present invention is obtained by freeze-drying the above-mentioned aqueous solution having a pH of about 13 or more and then dissolving the solution at a pH of about 12 when dissolving it before use.
It can also be manufactured by adjusting as follows.
Each operation can be performed in the same manner as described above. The pharmaceutical composition of the present invention is sterilized and sealed after replacing with nitrogen gas, if necessary.

The compound of the present invention or a salt thereof or a prodrug thereof has a low toxicity and an inhibitory effect on the production of nitric oxide (NO) and an inhibitory effect on the production of inflammatory cytokines such as TNF-α, IL-1, and IL-6. Therefore, the composition of the present invention containing the compound of the present invention or a salt thereof or a prodrug thereof can be used for heart disease in mammals (eg, cats, cattle, dogs, horses, goats, monkeys, humans, etc.), Diseases such as autoimmune diseases, inflammatory diseases, central nervous system diseases, infectious diseases, sepsis, septic shock, such as sepsis, endotoxin shock, exotoxic 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, Blood 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 Disease, pancreatitis,
Nephrotic syndrome, nephritis, renal failure, insulin-dependent diabetes, non-insulin-dependent diabetes, hepatic porphyria, alcoholism, Parkinson's disease, chronic leukemia,
Acute leukemia, tumor, myeloma, reduction of anticancer drug side effects, infant and adult respiratory distress syndrome, emphysema, dementia, Alzheimer's disease, multiple sclerosis, vitamin E deficiency, aging, sunburn, muscular dystrophy, myocarditis, cardiomyopathy, myocardium Infarction, sequelae of myocardial infarction, osteoporosis, pneumonia, hepatitis, psoriasis, pain, cataract, influenza infection, malaria, human immunodeficiency virus (HIV) infection, radiation injury, burn,
In vitro fertilization efficiency, hypercalcemia, ankylosing spondylitis, osteopenia, bone Pechet disease, osteomalacia, fracture, 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, acute ischemic stroke, acute cerebral thrombosis, cancer Transfer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, stomach cancer, ovarian cancer, prostate cancer, small cell lung cancer,
It can be used as a prophylactic / therapeutic agent for non-small cell lung cancer, malignant melanoma, Hodgkin's disease, non-Hodgkin's lymphoma and the like.

The dose of the pharmaceutical composition of the present invention (particularly, the composition for injection) depends on the type, age, body weight,
Depends on symptoms, dosage form, administration method, administration period, etc.
For example, a subject (an adult, a body weight of about 60 kg) of Sepsis is usually used as the compound (I) of the present invention in an amount of about 0.2 mg / day.
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 dose may be sufficient, or may need to be administered out of the range.

[0057]

BEST MODE FOR CARRYING OUT THE INVENTION 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 to these. ^{The 1} H NMR spectrum was measured with a Varian Gemini 200 (200 MHz) type spectrometer using tetramethylsilane as an internal standard, and all δ values were shown in ppm. The numerical values shown in parentheses in the mixed solvents are volume mixing ratios of the respective solvents.
% Means percent by weight unless otherwise specified. The ratio of the solvent in the silica gel chromatography indicates the volume ratio of the mixed solvents. 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. Each symbol in the examples has the following meaning. s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, t
t: triple triplet, m: multiplet, b
r: Wide, J: Coupling constant

[0058]

[Reference Example A]

Reference Example A1 Ethyl 2-sulfo-1-cyclohexene-1-carboxylate Reference Example A2 Ethyl 2-chlorosulfonyl-1-cyclohexene-1-carboxylate Reference Example A3 Ethyl 2-chlorosulfonyl-1-cyclopentene-1-carboxylate Reference Example A4 Ethyl 2-chlorosulfonyl-1-cycloheptene-1-carboxylate Reference Example A5 6- [N- (4-chloro-2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylic acid sodium salt Reference Example A6 1- (3-Fluoro-4-nitrophenyl) -1H-1,
2,4-Triazole Reference Example A7 1- (4-amino-3-fluorophenyl) -1H-1,
2,4-triazole Reference Example A8 4-benzyloxycarbonylamino-3-chlorobenzoic acid methyl ester Reference Example A9 4-benzyloxycarbonylamino-3-chlorobenzoic acid Reference Example A10 tert-butyl N- (4-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 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) -4,5,6,7tetrahydro-1,2-benzoisothiazole-3 (2H ) -One 1,1-dioxide (compound 67) ethyl 2- [N- (4-methoxyphenyl) sulfamoyl] -1-
Cyclohexene-1-carboxylate (Compound 8) Reference Example B9 Ethyl 6- [N- (2-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 10) Reference Example B10 Ethyl 6- [N- ( 3-Fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (compound 11)

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

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

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

Reference Example B41 Ethyl 6- [N- [4- (2H-tetrazol-2-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 44) Reference Example B42 Ethyl 6- [N- (2-Chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 45) Reference Example B43 Ethyl 6- [N- (4-fluoro-2-methylphenyl) sulfamoyl] -1-cyclohexene -1-carboxylate (compound 46) Reference Example B44 Ethyl 6- [N- (2,6-dichlorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate
(Compound 47) Reference Example B45 Ethyl 6- [N- [4- (1H-tetrazol-1-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 48) Reference Example B46 Ethyl 6- [N -(4- (1H-1,2,3-triazol-1-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 49) Reference Example B47 Ethyl 6- [N- (2-trifluoro Methylphenyl) sulfamoyl] -1-cyclohexene-1-
Carboxylate (Compound 50) Reference Example B48 Ethyl 6- [N- (4-methoxycarbonylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 51) Reference Example B49 Benzyl 6- [N- (2,4 -Difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 52) Reference Example B50 Ethyl 6- [N- [4- [2,3-bis (tert-butoxycarbonyl) guanidinomethyl] phenyl] sulfamoyl] -1-cyclohexene-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 and ethyl 6- [N- (2-chloro-4-cyanophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 55) Reference Example B53 2-hydroxyethyl 6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 56) Reference Example B54 Ethyl 6- [N- [2 -Fluoro-4- (1H-1,2,4-
Triazol-1-yl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 57) Reference Example B55 Ethyl 2- [N- (2,4-difluorophenyl)
Sulfamoyl] -1-cyclopentene-1-carboxylate (compound 66) Ethyl 5- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclopentene-1-carboxylate (compound 58) Reference Example B56 tert-butyl [6- [N- (2,4-difluorophenyl) sulfamoyl] -1-cyclohexen-1-yl] carbonyloxyacetate (Compound 59) Reference Example B57 [6- [N- (2,4-difluorophenyl) Sulfamoyl] -1-cyclohexen-1-yl] carbonyloxyacetic acid (compound 60) Reference Example B58 Ethyl 7- [N- (2,4-difluorophenyl)
Sulfamoyl] -1-cycloheptene-1-carboxylate (Compound 61) Reference Example B59 Ethyl 6- [N- [2-chloro-4- (N-tert-butoxycarbonylmethylcarbamoyl) phenyl] sulfamoyl] -1-cyclohexene- 1-carboxylate (compound
62) Reference Example B60 Ethyl 6- [N- [2-chloro-4- (N-ethoxycarbonylmethylcarbamoyl) phenyl] sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 63)

Reference Example B61 Ethyl 5- [N- (2-chloro-4-
Fluorophenyl) sulfamoyl] -1-cyclopentene-
1-carboxylate (compound 64) Reference Example B62 2- [4- (2,2,3,3,3-pentafluoropropoxy) phenyl] -4,5,6,7-tetrahydro-1,2-benziso Thiazol-3 (2H) -one 1,1-dioxide (Compound 69) Reference Example B63 Ethyl 7- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cycloheptene-1-carboxylate (Compound 65 Reference Example B64 2- (2,4-difluorophenyl) -5,6,7,7a-
Tetrahydro-1,2-benzisothiazol-3 (2H) -one
1,1-dioxide (Compound 70) Reference Example B65 Ethyl 6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -1-cyclohexene-1-carboxylate (Compound 29) Reference Example B66 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 the less polar diastereomer (compound 78)

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

[0068]

[Table 1]

[0069]

[Table 2]

[0070]

[Table 3]

[0071]

[Table 4]

[0072]

[Table 5]

Comparative Example 1 Solubility of Compound 72 Compound 0.5 of Reference Example B66 was added to 0.5 ml of Britton-Robinson buffer at pH 3, 5, 7, 9, 10, and 11, respectively.
0, 1.09, 1.01, 0.98, 4.97, and 5.08 mg were added, and the mixture was stirred and dissolved at room temperature for 24 hours. After 24 hours, the insoluble material was centrifuged (15000 rpm, 5 min), the supernatant was filtered through a membrane filter with a pore size of 0.45 μm, and the filtrate was directly diluted with a high-performance liquid chromatography (HPLC) mobile phase and analyzed by HPLC. The solubility of compound 72 was determined (FIG. 1).
The solubility of compound 72 at pH 3, 5, 7, 9, 10, 11 was 0.043, 0.039, 0.043, 0.353, 1.448, 2.5, respectively.
34. At pH 3 to pH 7, the solubility of Compound 72 was 0.1 mg / ml or less, and at pH 9 or more, the solubility increased, but at pH 11, it was only dissolved up to 2.534.

Example 1 1) Compound 72 of Reference Example B66 100 mg 2) D-mannitol 180 mg 3) meglumine 30 mg 4) 1 mol / L sodium hydroxide 0.5 ml 5) 1 mol / L hydrochloric acid 0.25 ml 6) distilled water for injection 4.25 ml To 89.95 mg of the compound 72 of Reference Example B66, 0.5 ml of 1 mol / L sodium hydroxide was added and dissolved. Add 1 ml of distilled water for injection, 180.02 mg of D-mannitol, 30.11 mg of meglumine
Was added and dissolved. Furthermore, add 2 ml of distilled water for injection,
The pH was adjusted to 11.17 with 0.25 ml of 1 mol / L hydrochloric acid. 1.25 ml of distilled water for injection was added to make the total volume 5 ml. Final pH is pH
It was 11.07. This was rapidly frozen with dry ice-acetone and freeze-dried overnight to obtain 323.4 mg of a white powder having the above composition.

Test Example 1 Solubility and Stability of Compound 72 in Preparation Example 1 36.06 mg of the white powder obtained in Example 1 was added to 1 ml of physiological saline.
And the redissolvability was good. pH is p
H was 10.57. After filtration through a membrane filter with a pore size of 0.22 μm, high performance liquid chromatography (HP
LC) The mixture was diluted with a mobile phase, and the content of compound 72 was measured by HPLC. The result was 10.35 mg / ml, and no formation of an aniline derivative which was a decomposition product of compound 72 was observed.

Test Example 2 Inhibitory Effect on NO Production Using a mouse macrophage cell line RAW264.7 as iNOS-induced cells, the inhibitory rate of a test compound on NO production was measured. The test compound was dissolved in N, N-dimethylformamide to a concentration of 10 mM and 0.1 mM
Was diluted with the RPMI-1640 medium so that
Further, a final concentration was adjusted from 10 μM to 10 nM by 10-fold dilution and added to the culture solution. The day before the experiment,
Cells were prepared in 5x10 ⁵ cells / ml so as inactivated fetal bovine serum 10% added RPMI-1640 fold areas, cells 1x10 ⁵ cells per well into 96 well plates /0.2ml
Sowed. 37 ° C, 5% CO ₂ /95% air
After overnight culture under test, the prepared test compound was added, and LP was added.
S and interferon gamma are each 5n in final concentration
g / ml and 1 U / ml. After further culturing overnight, the concentration of nitrite ion (stable metabolite of NO) in the culture supernatant was measured and used as an index of NO production. The nitrite ion concentration was 20 μg / ml2,3-
After adding 25 μl of diaminonaphthalene (DAN) and incubating at room temperature for 10 minutes, 0.5N Na
OH (25 μl) was added, and 450 nm (excitation wavelength 365 n
It was quantified by measuring the fluorescence of m). Table 6 shows the results. IC ₅₀ indicates the concentration of a test compound that shows 50% inhibition of NO production.

[0077]

[Table 6] In Table 6, 7 times for Compound 1 performs measurement 9 times for compound 3 showed the lowest and highest values of the IC _50. The test compound strongly inhibited NO production from RAW 264.7 cells, indicating that the oxazole derivative of the present invention has an excellent NO production inhibiting action.

Test Example 3 Inhibitory Effect on Cytokine Production Using a mouse macrophage cell line RAW264.7, the inhibitory rate of a test compound on cytokine production was measured. The test compound was dissolved in N, N-dimethylformamide at 10 mM and diluted with RPMI-1640 medium to 0.1 mM. Further, a final concentration was adjusted from 10 μM to 10 nM by 10-fold dilution and added to the culture solution. The day before the experiment, the cells were 5x
Prepared in RPMI-1640 medium supplemented with 10% inactivated fetal bovine serum to a concentration of 10 ⁵ cells / ml.
Cells were seeded at 1 × 10 ⁵ cells / 0.2 ml per well. After culturing overnight at 37 ° C. and 5% CO ² /95% air, the prepared test compound was added, and LPS and interferon gamma were each dissolved at a final concentration of 5 ng / m 2.
1 and 1 U / ml. After further culturing overnight, the concentrations of TNF-α and IL-6 in the culture supernatant were measured. In addition, in the case of IL-1α measurement, 1.0 μg of LPS was used.
/ Ml, and the same test was performed without the addition of interferon gamma. The quantification of each cytokine was performed using a quantification kit manufactured by Amersham. Table 7 shows the results. IC ₅₀
Indicates the concentration of the test compound showing 50% inhibition of cytokine production.

[0079]

[Table 7] In Table 7, TNF-α and IL-6 were measured twice, and the respective IC ₅₀ values were shown.

Test Example 4 Effect on Elevated Blood Nitrogen Oxide Concentration When NO is produced in a living body due to biological defense reactions against infection and immune abnormalities, it is immediately metabolized to nitrite and nitric acid, and Nitrogen oxide concentration (NOx) increases. Therefore, the effect of the test compound on the increase in blood NOx concentration was examined using experimental animals. Female BALB / c mice (6 weeks old) were purchased and, after 1 week of preliminary breeding, 6
-8 animals were grouped. 0.5% test compound in test group
It was suspended in an aqueous methylcellulose solution and orally administered at 30 mg / kg. The control group was similarly administered with the solvent. Part 1
After an hour, LPS (10 mg / kg) was intraperitoneally administered to the test group and the control group, blood was collected 6 hours after the LPS administration, and the concentration of nitrate ion + nitrite ion in the serum was measured. Nitrate ions are converted into nitrite ions by nitrate reducetase, and the above-mentioned DA
It was quantified by a fluorescence method using N. Table 8 shows the inhibition rate of the test group relative to the control group.

[0081]

[Table 8]

Test Example 5 Effect on Elevated Blood Cytokine Concentration Various cytokines are produced in vivo in response to biological defense reactions against infection and immune abnormalities. Therefore, the effect of the test compound on the increase in the blood cytokine concentration was examined using experimental animals. Female BALB / c mice (6 weeks old) were purchased, and after pre-breeding for one week, they were divided into groups of 6 to 8 mice. In the test group, the test compound was suspended in a 0.5% aqueous solution of methylcellulose and orally administered at 30 mg / kg. The control group was similarly administered with the solvent. One hour later,
LPS (10 mg / kg) was intraperitoneally administered to the test group and the control group, blood was collected one hour after LPS administration, and T
The NF-α concentration was measured. In addition, IL-1α, IL-1
β and IL-6 concentrations were measured in serum collected 6 hours after LPS administration. Table 9 shows the inhibition rate of the test group with respect to the control group.
It was shown to. The quantification of each cytokine was performed using a quantification kit manufactured by Amersham.

[0083]

[Table 9]

From Tables 6 to 9 above, it can be seen that the compound (I
e) has an excellent NO production suppressing effect, cytokine production suppressing effect, blood nitrogen oxide concentration increase suppressing effect, and blood cytokine concentration increase suppressing effect. The compound numbers in Tables 6 to 9 indicate the compound numbers shown in Tables 1 to 5.

[0085]

According to the present invention, a pharmaceutical composition having improved solubility or stability of water-insoluble or poorly water-soluble compound (I) or a salt thereof or a prodrug thereof can be obtained. In particular, the composition for injection is useful for treating a target disease by intravenous administration.

[0086]

[Brief description of the drawings]

FIG. 1 shows the results of analyzing the solubility of Compound 72 at each pH. The horizontal axis indicates pH, and the vertical axis indicates solubility.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4196 A61K 31/4196 A61P 9/02 A61P 9/02 37/02 37/02 43/00 105 43 / 00 105 F term (reference) 4C076 AA12 AA29 BB11 CC07 CC11 DD23Z DD30Z DD38D DD49Z FF15 FF63 GG47 4C086 AA01 AA02 BC60 BC62 MA01 MA17 MA44 MA66 NA02 NA03 ZA36 ZB07 ZB21 4C206 AA01 AA02 MA11 MA01 Z

Claims (7)

[Claims] (1) Formula (1) [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 represents an aromatic hydrocarbon group which may have a substituent. , The formula The group represented by the formula is Or And n represents an integer of 1 to 4. PH of the compound represented by the formula or a salt thereof or a prodrug thereof
Pharmaceutical composition having improved solubility or stability of the compound or a salt thereof or a prodrug thereof, wherein the pH of an aqueous solution of about 13 or more can be adjusted to about 12 or less and freeze-dried if necessary. object. 2. The composition according to claim 1, which is an injectable composition. (3) 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,
The composition according to claim 1, which is ethyl 6- [N- (2-chloro-4-methylphenyl) sulfamoyl] -1-cyclohexene-1-carboxylate or a salt thereof. 4. The composition according to claim 1, which is an inhibitor of nitric oxide and / or cytokine production. 5. The composition according to claim 1, which is an agent for preventing or treating heart disease, autoimmune disease or septic shock. 6. A compound of the formula [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 represents an aromatic hydrocarbon group which may have a substituent. , The formula Is a group represented by the formula: Or And n represents an integer of 1 to 4. PH of the compound represented by the formula or a salt thereof or a prodrug thereof
A method for producing a pharmaceutical composition having improved solubility or stability of the compound, a salt thereof, or a prodrug thereof, wherein an aqueous solution of about 13 or more is adjusted to pH of about 12 or less and freeze-dried as necessary. 7. A compound of the formula [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 represents an aromatic hydrocarbon group which may have a substituent. , The formula The group represented by the formula is Or And n represents an integer of 1 to 4. PH of the compound represented by the formula or a salt thereof or a prodrug thereof
A method for improving the solubility or stability of the compound, a salt thereof, or a prodrug thereof, comprising adjusting the pH of an aqueous solution of about 13 or more to about 12 or less and freeze-drying as necessary.