WO2001021177A1 - Chemokine/cytokine expression inhibitors - Google Patents

Abstract

Chemokine/cytokine expression inhibitors which contain compounds represented by general formula [I], salts thereof or prodrugs of the same, wherein R1 represents hydrogen, lower alkyl, etc.; R?2 and R3¿ represent each hydrogen, lower alkyl, etc., or R?2 and R3¿ may form together with -C=C- adjacent thereto a 5- to 7-membered ring; X represents oxygen or S(O)¿p? (wherein p is an integer of from 0 to 2); Y represents (A) (wherein R?4 and R5¿ represent each hydrogen, lower alkyl, etc.); R?6 and R7¿ represent each hydrogen, lower alkyl, etc., or R?6 and R7¿ may form together with the nitrogen atom adjacent thereto a nitrogen-containing heterocycle; m is an integer of from 0 to 4; and n is an integer of from 0 to 4.

Description

 Description Chemokine ・ Cytokine expression inhibitor Technical field

 The present invention includes a triazolopyridazine derivative such as 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,4] triazolo [l, 5_b] pyridazine. The present invention relates to a chemokine or cytokine expression inhibitor. Background art

 Expression

[I]

[In the formula, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and R ³ represent a hydrogen atom and a lower alkyl group which may have a substituent, respectively. Represents a cycloalkyl group which may have a group or a substituent, wherein R ² and R ³ may be adjacent to each other and form a 5- to 7-membered ring with C = C _, and X is an oxygen atom or S (O) p (where p represents an integer from 0 to 2),

Y is the expression

R ⁴

 — C—

R ⁵

Wherein R ⁴ and R ° each represent a hydrogen atom or a lower alkyl group which may have a substituent, or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent And R ⁶ and R ′ each represent a hydrogen atom, a lower alkyl group which may have a substituent, or a substituent. An optionally substituted cycloalkyl group or an optionally substituted aryl group, wherein R ⁶ and R ⁷ together with an adjacent nitrogen atom form an optionally substituted nitrogen-containing heterocyclic group. M represents an integer of 0 to 4 and n represents an integer of 0 to 4. Is a compound useful as an anti-asthmatic, anti-PAF, anti-allergic, eosinophil chemotaxis inhibitor, allergic rhinitis prophylactic or therapeutic agent, and atopic dermatitis prophylactic or therapeutic agent. (Japanese Unexamined Patent Publication Nos. 06-279447 and 08-198878).

 However, it has not been reported that these compounds suppress the expression of chemokines and cytokines.

 Chemokines or cytokines such as interferon (IFN-a), eotaxin (EotaXin), MIP-1α, inulin-leukin 13 (IL-13) or TNF-α are monocytes, Accumulates and activates inflammatory cells, such as macrophages, eosinophils, and basophils, at the local pathology. Therefore, compounds that suppress the expression of these chemokines and cytokins will be excellent preventive and therapeutic agents for diseases caused by accumulation and activation of inflammatory cells, and their development is desired. Disclosure of the invention

 The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, found that 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,4] triazolo [1 , 5-b] pyrazodines or their salts and other triazolopyridazine derivatives [I] unexpectedly suppress the expression of chemokines or cytokins, resulting in allergic diseases, inflammation, circulatory disorders, nephritis, etc. Have been found to be able to exert excellent preventive and therapeutic effects on diseases caused by abnormal accumulation or activation of inflammatory cells. The present inventors have further studied based on this finding, and have completed the present invention.

 That is, the present invention

(1 set Z ^R6 ,

.X-(CH-Y- (CH ₂ ) _N -S0 ₂ [I]

N Coo

R '

[In the formula, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and ^RG each represent a hydrogen atom or a lower alkyl which may have a substituent. A cycloalkyl group which may have a group or a substituent, wherein R ² and R ³ may form a 5- to 7-membered ring together with an adjacent —C = C—, and X is an oxygen atom or S (O) p (p is an integer from 0 to 2)

Y is the expression

R ⁴

 — C—

R ⁵

(R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group which may have a substituent) or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent And R ^D and R ⁷ are a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or Represents an aryl group which may have a substituent; R ⁶ and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom; And n is an integer of 0 to 4. A chemokine or cytokine expression inhibitor comprising a compound represented by the formula or a salt thereof or a prodrug thereof;

 (2) the agent according to (1), which is a chemokine or cytokinin mRNA expression inhibitor;

(3) The agent according to (1), which is a chemokine or cytokine production inhibitor, (4) R ¹ is (i) a hydrogen atom, (ii) hydroxy, amino, carboxyl, nitro, mono- or di- A C alkyl group which may have a substituent selected from the group consisting of C i—e alkylamino, ₆ alkoxy, ₁₆ alkyl carbonyloxy and a halogen atom, or (iii) a halogen atom, R ² and R ³ are each (i) a hydrogen atom, (ii) a hydroxy, Amino, Cal Pokishiru, nitro, mono- - or di - C Arukiruamino, CI_ ₆ an alkoxy, a group consisting of C E alkylcarbonyl O alkoxy and a halogen atom An alkyl group which may have a substituent selected from the group consisting of: (iii) hydroxy, amino, carboxyl, nitro, mono- or di-(^- ₆ alkylamino,

A C ₃ _ ₆ cycloalkyl group which may have a substituent selected from the group consisting of C alkoxy, C alkyl carbonyloxy and a halogen atom;

R ² and R ³ with one C = C one adjacent, ① hydroxy, Amino, Mono one or di- _ C doctor ₆ Arukiruamino, (^ 6 alkoxy, C WINCH ₆ alkyl - carbonylation Ruokishi the group consisting of halogen atoms May have a substituent selected from — _6- alkyl, (2) _6- alkyl, C ぃ₆ acyl or amino optionally substituted with 5- to 7-membered cyclic amino, (3) hydroxy, ④ carboxyl, ⑤ nitro, It may have a substituent selected from the group consisting of ⑥C ₆ alkoxy and ⑦halogen, and contains 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur in addition to carbon. May form a 5- to 7-membered ring,

 X represents an oxygen atom or S (〇) p (p represents an integer of 0 to 2),

 Y is the equation (a)

R ⁴

 — C— n

(R ⁴ and R ⁵ are each (i) hydrogen atom or (ii) hydroxy, Amino, carboxyl, nitro, mono- or di - C ^ 6 Arukiruamino, alkoxy, a group consisting of C Bok ₆ alkylcarbonyl O alkoxy and a halogen atom Represents an alkyl group which may have a substituent selected from) or a group represented by

(b) ①Hydroxy, amino, mono or di (: ₆ alkylamino,

C ₆ alkoxy, alkyl-carbonyloxy and halogen atom Alkyl which may have a substituent selected from the group consisting of: ② amino, optionally substituted by C alkyl, C ^ 6 acyl or 5- to 7-membered cyclic amino, ③ hydroxy, ④ carboxyl, ⑤ nitro , ⑥ ^ e alkoxy and ⑦halogen atom, which may have a substituent selected from the group consisting of 3-, 7- or 7-membered cyclic hydrocarbon or nitrogen atom, oxygen atom and sulfur atom other than carbon atom A divalent group derived from a 3- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from the group consisting of

R ⁶ and R ⁷ are each (i) a hydrogen atom, (ii) a hydroxy, Amino, Cal Pokishiru, nitro, mono- - or di - CI_ ₆ Arukiruamino, CI_ ₆ an alkoxy, a ci- 6 alkylcarbonyl O alkoxy and a halogen atom A C ₆ alkyl group which may have a substituent selected from the group consisting of: (iii) hydroxy, amino, carboxyl, nitro, mono- or di-alkylamino, _6- alkoxy, (^ _ _6- alkylcarbonyl A C ₃ _ ₆ cycloalkyl group which may have a substituent selected from the group consisting of xy and halogen atoms, or () ① hydroxy, amino, mono or di-C ₆ alkylamino, (^ alkoxy and halogen atoms May have a substituent selected from the group consisting of

₆ alkyl, ② alkyl or amino which may be substituted with a 5- to 7-membered cyclic amino, ③ acetoamide, ④hydroxy, ⑤carboxyl, ⑥nitro, ア ル コ キ シ alkoxy, ⑧C alkylcarbonyloxy and ⑨halogen atom Which may have a substituent selected from the group consisting of: ₆ — ₁₄ aryl group,

① hydroxy together with the nitrogen atom R ⁶ and R ⁷ adjacent, Amino, mono- - or di - C I ₆ Arukiruamino, (: I ₆ alkoxy, C bets ₆ alkyl - is selected from the group consisting of forces Ruponiruo carboxymethyl and halogen atom-substituted Δ-alkyl, which may have a group, ②dialkyl, _6- alkyl, amino which may be substituted by C- or 5- to 7-membered cyclic amino, ③hydroxy, ④carpoxyl, ⑤nitto, ⑥alkoxy and ⑦halogen Containing one nitrogen atom, which may have a substituent selected from the group consisting of atoms, and further containing one to four heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom May be 3 It may form a group in which one hydrogen atom has been removed from the ring of the 13-membered nitrogen-containing heterocyclic ring, wherein m is an integer of 0 to 4 and n is an integer of 0 to 4 (1) Agent described in item,

(5) R ¹ is a hydrogen atom or an alkyl group, R ² is a hydrogen atom or an alkyl group, R ³ is a hydrogen atom or a Ci- ₆ alkyl group, X is an oxygen atom,

Y is an expression

R ⁴ '

 — C—

 ,Five'

 R

 Four

Wherein, R and R ⁵ 'are each (i) hydrogen atom or (ii) hydroxy shea, Amino, carboxyl, nitro, mono- or di-one C ^ - e alkylamino 6 alkoxy, c i_ ₆ alkyl - carbonyl O carboxymethyl or to 1 selected halogen atoms or al shows the four optionally substituted C Bok ₃ alkyl group. A group represented by the formula (1), wherein R ⁶ and R ⁷ each represent a hydrogen atom or a ₃ alkyl group, and m and n each represent 1;

 (6) The compound according to (1), wherein the compound is 6- (2,2-dimethyl-3-sulfamoyl-11-propoxy) —7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine. Agent,

 (7) The agent according to (1), wherein the chemokine or cytokine is RANTE S, eotaxin (Eota Xin), MIP-1α, interleukin 13 (IL-13), TNF-α or MCP-1. ,

 (8) The agent according to (1), which is a prophylactic / therapeutic agent for a disease based on the expression of a chemokine or cytokine.

 (9) Formula for mammals

[I]

Wherein R ¹ is a hydrogen atom, a lower alkyl group which may have a substituent or R ² and R ³ each represent a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted cycloalkyl group, and R ² and R ³ are adjacent to each other May form a 5- to 7-membered ring together with C = C—, X represents an oxygen atom or S (O) p (p represents an integer of 0 to 2),

Y is the expression

R ⁴

 — C—

R ⁵

Wherein R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group which may have a substituent, or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent And R ^D and R ⁷ are a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or Represents an aryl group which may have a substituent; R ⁶ and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom; And n is an integer of 0 to 4. A method for inhibiting the expression of chemokines or cytokines, which comprises administering an effective amount of a compound represented by the formula (I) or a salt thereof or a prodrug thereof:

 (10) Formula for mammals

X- (CH ₂ ) _m -Y- (CH ₂ ) _n -S0 ₂ N ', (门

[In the formula, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and R ³ each represent a hydrogen atom or a lower alkyl which may have a substituent. A cycloalkyl group which may have a group or a substituent, wherein R ² and R ³ may form a 5- to 7-membered ring together with an adjacent —C == C—, and X represents an oxygen atom or S (〇) p (p indicates an integer from 0 to 2), and Y is an expression R ⁴

 — C—

Wherein R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group which may have a substituent, or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent R ⁶ and R ⁷ each represent a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or substituted indicates which may Ariru ^group, R ϋ and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom, m is 0 And n is an integer of 0 to 4. A method for preventing or treating diseases based on the expression of chemokines or cytokines, which comprises administering an effective amount of the compound represented by the formula (I) or a salt thereof or a prodrug thereof;

(11) Formula for producing an inhibitor of chemokine or cytosine expression [|]

[In the formula, represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and R ³ represent a hydrogen atom, a lower alkyl group which may have a substituent or Represents a cycloalkyl group which may have a substituent, wherein R ² and R ³ may form a 5- to 7-membered ring together with an adjacent C = C—, and X represents an oxygen atom or S (〇 ) (Where p represents an integer from 0 to 2)

Y is the expression

R ⁴

 — C—

(Wherein R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group which may have a substituent). Represents a divalent group derived from a 7-membered homocyclic or heterocyclic ring, wherein R ⁶ and R ⁷ each have a hydrogen atom, a lower alkyl group which may have a substituent, and a substituent Represents an optionally substituted cycloalkyl group or an optionally substituted aryl group, and R ⁶ and R ⁷ together with an adjacent nitrogen atom form a nitrogen-containing heterocyclic group which may have a substituent. M represents an integer of 0 to 4, and n represents an integer of 0 to 4. Use of a compound represented by the formula (I) or a salt thereof or a prodrug thereof; and

 (12) Formula for producing a prophylactic / therapeutic agent for a disease based on the expression of a chemokine or cytokine, [I]

 No

[In the formula, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R and R ³ represent a hydrogen atom and a lower alkyl group which may have a substituent, respectively. Or a cycloalkyl group which may have a substituent, wherein R ² and R ³ may form a 5- to 7-membered ring with adjacent —C CC—, and X represents an oxygen atom or S ( 〇) p (p is an integer from 0 to 2)

Y is the expression

R ⁴

 — C—

R ⁵

(Wherein R ⁴ and R "each represent a hydrogen atom or a lower alkyl group which may have a substituent) or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent And R ^D and R ⁷ are a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or Represents an aryl group which may have a substituent; R ⁶ and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom; N is an integer from 0 to 4 Indicates an integer. ] Or a salt thereof or a prodrug thereof.

 Further, the present invention provides

 (13) Based on the whole preparation, compound [I] or a salt thereof or a prodrug thereof is contained in about 0.01 to 9.9% by weight and a carrier is contained in about 0.1 to 99% by weight. Agent according to paragraph (1),

 (14) The agent according to (8), wherein the disease based on the expression of a chemokine or cytokine is inflammation, cardiovascular disease or nephritis.

 (15) The treatment method according to (10), wherein the disease based on the expression of a chemokine or a cytokin is inflammation, circulatory disorder or nephritis, and

 (16) The use according to (12), wherein the disease based on the expression of a chemokine or cytokine is inflammation, circulatory disorder or nephritis. When the triazolopyridazine derivative [I] or a salt thereof used in the preparation of the present invention contains an asymmetric carbon in the structure, an optically active compound and a racemic mixture are also included in the scope of the triazolopyridazine derivative [I]. BRIEF DESCRIPTION OF THE FIGURES

 FIG. 1 shows the inhibitory effect of the compound of Reference Example 4 on EotaXin (eotaxin) mRNA expression. ## P <0.01 indicates the comparison (Student test) with the negative control group (saline inhalation group). ** P <0.01 indicates comparison with the control group (Dunnett test).

 FIG. 2 shows the inhibitory effect of the compound of Reference Example 4 on MIP-1a mRNΑ expression. ## p <0.01 indicates comparison (Student test) with the negative control group (saline inhalation group). * P <0.05 indicates a comparison with the control group (Dunnett test).

FIG. 3 shows the inhibitory effect of the compound of Reference Example 4 on RANTE S mRNA expression. ## p <0.01 indicates comparison (Student test) with the negative control group (saline inhalation group). ** P <0.01 is comparison with control group (Dunnett test) Is shown.

 FIG. 4 shows the inhibitory effect of the compound of Reference Example 4 on IL-13 mRNA expression. ## p 0,001 indicates a comparison (Student test) with a negative control group (saline inhalation group). * P <0.05 indicates comparison with the control group (Dunnett test).

 FIG. 5 shows the inhibitory effect of the compound of Reference Example 4 on TNF-specific mRNA expression. ## P <0.01 indicates comparison (Student test) with the negative control group (saline inhalation group). ** P <0.01 indicates comparison with the control group (Dunnett test).

 FIG. 6 shows the inhibitory effect of the compound of Reference Example 4 on EotaXin (eotaxin) production. ## P <0.01 indicates comparison (Student test) with the negative control group (saline inhalation group). * P <0.05 indicates comparison with the control group (Dunnett test).

 FIG. 7 shows the inhibitory effect of the compound of Reference Example 4 on MCP-1 production. # # P <0.01 indicates comparison (Student test) with the negative control group (saline inhalation group). ** P <0.01 indicates comparison with the control group (Dunnett test).

 FIG. 8 shows the inhibitory effect of the compound of Reference Example 4 on TNF-α production. # # Ρ <0.01 indicates comparison (Student test) with a negative control group (saline inhalation group). ** P <0.01 indicates comparison with the control group (Dunnett test). BEST MODE FOR CARRYING OUT THE INVENTION

In the above formulas, R ^1, R, as ^{R 3, R 4, R 0} , "lower alkyl" represented by R ^u or R ^7, for example, methyl, Echiru, n- propyl, i- propyl Le, n - butyl, i-butyl, Tert_ butyl, .eta. pentyl, what a hexyl .eta. linear or branched and C, are used like _ ₆ alkyl group.

Examples of the “cycloalkyl group” represented by R ² , R ³ , R ⁰ or R ⁷ include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Such as C _{3 6} cycloalkyl group is used.

 6

Represented by R or R ⁷ as "Ariru group", for example, phenyl, C _6, such as naphthyl - _{1 4} 7 aryl group used.

Examples of the substituent which the “lower alkyl” and “cycloalkyl group” may have include, for example, hydroxy, amino, carboxyl, nitro, mono, or di-lower alkylamino (eg, methylamino, ethylamino, propylamino) , Jimechiruamino, such as mono- one or di- one Al Kiruamino such Jechiruamino), lower alkoxy (e.g., methoxy, ethoxy, C WINCH ₆ alkoxy such as Provo carboxymethyl to, Kishiruokishi), lower alkyl carbonylation Ruokishi (e.g., Asetokishi, E One to four members selected from C i-e alkylcarbonyloxy such as tylcarbonyloxy) and halogen atoms (fluorine, chlorine, bromine, iodine, etc.) are used.

Examples of the substituent which the “aryl group” may have include, for example, lower alkyl which may have a substituent, amino which may have a substituent, acetoamide, hydroxy, carboxyl, nitro Lower alkoxy (for example, alkoxy such as methoxy, ethoxy, propoxy, etc.), lower alkyl-carbonyloxy (for example, C ₆ alkylcarbonyloxy such as acetyloxy, ethylcarbonyloxy, etc.) and halogen atoms (fluorine, One to five selected from chlorine, bromine, iodine, etc.) are used. Here, (For example, methyl, Echiru, C j _ ₆ alkyl groups such as n-propyl) lower alkyl as is optionally has substituents such as hydroxy, Amino, mono- or di-lower alkylamino (e.g. Mono- or di-C _6- alkylamino such as methylamino, ethylamino, propylamino, dimethylamino, and acetylamino; lower alkoxy (eg, Ciealkoxy such as methoxy, ethoxy, propoxy, hexyloxy) and halogen atom One to four selected from (fluorine, chlorine, bromine, iodine, etc.) are used. Examples of the substituent which the amino group may have include, for example, ^ ₆ alkyl (eg, methyl, ethyl, propyl, etc.) and 5- to 7-membered cyclic amino (eg, pyrrolidino, morpholino, piperidino, piperazino, etc.) 1 or selected from Two are used.

As the “halogen atom” represented by R ¹ , for example, fluorine, chlorine, bromine, iodine and the like are used.

Examples of the 5- to 7-membered ring formed by R and R ³ together with an adjacent C = C— include, for example, in addition to a carbon atom, 1 to 4 members selected from a nitrogen atom, an oxygen atom, a sulfur atom, and the like. A 5- to 7-membered ring which may contain a hetero atom is used. Specifically, cyclopentene, cyclohexene, C _5, such as heptene cyclohexane - ₇ cycloalkene, 5 to 7-membered cyclic hydrocarbons, nitrogen-containing heterocyclic 5- or 6-membered consisting of carbon and nitrogen atoms, such as benzene Rings (eg, pyrrole, pyridine, piperidine, etc.) are frequently used.

Examples of the “3- to 7-membered homocyclic ring” of the “divalent group derived from a 3- to 7-membered homocyclic ring” represented by Y include, for example, a 3- to 7-membered cyclic hydrocarbon consisting only of carbon atoms. Used. Specifically, for example cyclopropane, cyclobutane, cyclopentane, cyclohexane, C _3, such as cycloheptane - ₇ Shikuroaruka emissions, e.g. cyclopropene, cyclobutene, cyclopentene, xenon emission, C _3, such as Sik port heptene cyclohexane - ₇ Cycloargen is commonly used.

 The divalent group derived from the “3- to 7-membered homocyclic ring” refers to two hydrogen atoms from one carbon atom in the aforementioned three- to seven-membered cyclic hydrocarbon, or two different hydrogen atoms. It means a divalent group in which one hydrogen atom has been removed from each carbon atom. Specifically, for example,

などが用いられ、 好ましくは

Etc. are used, and preferably

などが繁用される。 Etc., more preferably

Are often used.

 The term “3- to 7-membered heterocyclic ring” of the “divalent group derived from a 3- to 7-membered heterocyclic ring” represented by Y includes, for example, other than a carbon atom, for example, a nitrogen atom, an oxygen atom, a sulfur atom For example, a 3- to 7-membered heterocyclic ring containing 1 to 4 hetero atoms selected from the group consisting of: Specifically, for example, oxetane, tetrahydrofuran, tetrahydropyran, pyrrole, azetidine, pyrrolidine, piberidine, piperazine, tetrahydrothiophene, homopiperidine, morpholine and the like are used.

 The divalent group derived from the “3- to 7-membered heterocyclic ring” refers to two hydrogen atoms from the same carbon atom in the above-mentioned 3- to 7-membered heterocyclic ring, or two different atoms from two different atoms. It means a divalent group with one hydrogen atom removed. Specifically, for example,

などが用いられる。

Are used.

The “nitrogen-containing heterocyclic group” formed by R ⁶ and R ⁷ together with an adjacent nitrogen atom includes, for example, one nitrogen atom and a carbon atom, and further includes, for example, a nitrogen atom, an oxygen atom, a sulfur atom, and the like. A group obtained by removing one hydrogen atom from a nitrogen atom in a ring such as a 3- to 13-membered nitrogen-containing heterocyclic ring which may contain 1 to 3 selected hetero atoms is used. Specifically, for example,

などの 3ないし 9員含窒素複素環基などが繁用される。

And 3 to 9-membered nitrogen-containing heterocyclic groups are frequently used.

The substituents that the “3- to 7-membered homocyclic ring”, “3- to 7-membered heterocyclic group” and “nitrogen-containing heterocyclic group” may have, for example, may have a substituent Lower alkyl, optionally substituted amino, hydroxy, carboxyl, nitro, lower alkoxy (eg, methoxy, ethoxy, propoxy, etc.) and halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) One to five selected from among others are used. Here, the substituent which the lower alkyl (for example, ₆ alkyl groups such as methyl, ethyl, n-propyl and the like) may have is, for example, hydroxy, amino, mono or di-lower alkylamino (for example, methylamino, or di one C ^ - - Echiruamino, Puropiruamino, dimethyl Amino, mono- such Jechiruamino etc. e Arukiruamino), lower alkoxy (e.g., methoxy, ethoxy, Purobokishi, to such C Bok ₆ alkoxy such as Kishiruokishi), lower alkyl Cal Poni Ruo carboxymethyl (For example, one to four members selected from a group consisting of Ci- ₆ alkyl mono-alkenyloxy such as acetyloxy and ethyl carbonyloxy) and a halogen atom (fluorine, chlorine, bromine, iodine, etc.) are used. Is a substituent which may be possessed Amino groups, e.g., C i _ ₆ alkyl (e.g., methyl, Echiru, propyl, etc.), Ashiru (e.g., Flip formyl, Asechiru, propionyl, such as butyryl Bok And one or two members selected from 5- to 7-membered cyclic amino (for example, pyrrolidino, morpholino, piperidino, piperazino, etc.).

R ¹ is preferably, for example, a hydrogen atom or ^ _-3 alkyl (eg, methyl, ethyl, n-propyl, etc.), and particularly a hydrogen atom is frequently used.

The R ", for example, hydrogen atom, C i _ ₃ alkyl (e.g., methyl, E Ji Le, n - propyl, etc.) is preferable, and, especially hydrogen atom is often used.

The R, for example, a hydrogen atom, a C physician ₆ alkyl group is preferable, particularly, branched C ₃ _ ₆ alkyl group (e.g., i one propyl) and the like are frequently used.

R ^O and R ³ are adjacent - is also preferred when forming a C = C 5 not with one to 7-membered cyclic hydrocarbon, in particular, it is a case of forming hexene, benzene and the like cyclohexane.

 X is preferably, for example, an oxygen atom or S, and particularly an oxygen atom is frequently used.

 As Y, for example, the formula

R ⁴ '

 — C—

R ⁵ '

Wherein R ⁴ 'and R ⁵ ' are each (i) a hydrogen atom or (ii) hydroxy, amino, carboxyl, nitro, monono or di-C ^ -ealkylamino, C i- ₆ alkoxy, C i- ₆ alkyl-C ₃ alkyl group which may have 1 to 4 substituents selected from carbonyloxy or halogen atom. And the like.

As "Ji Bok ₃ alkyl group" represented by and R ^"1 ', for example, methyl, Echiru, n - propyl, i - propyl, etc. is found using particularly suitable methyl, E chill.

It is also preferable that Y is a divalent group derived from a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent, for example,

などが繁用され、 特に

などが最も繁用される。 Etc., more preferably

Etc. are commonly used, especially

Is the most frequently used.

The R ^Y and R ^7, for example, hydrogen atom, (: E alkyl (e.g., methylation, Echiru, eta - propyl, etc.) is preferable, and, especially hydrogen atom is often used.

 m is preferably an integer of 1 to 4, more preferably an integer of 1 to 3, especially 1 and the like.

 As n, an integer of 1 to 4 is preferable, and especially 1 and the like are frequently used. It is most preferable that both m and n are 1.

Specific examples of the triazolopyridazine derivative [I] used in the preparation of the present invention include JP-A-Heisei 06-279494 and JP-A-Heisei 08-1981. All the compounds prepared in the examples of the invention are preferred, but in particular 6- (2,2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [1,2,4) triazolo [l, 5_ b] Pyridazine or a salt thereof is preferred. As the salt of the triazolopyridazine derivative [I], a physiologically acceptable acid addition salt is particularly preferable. Such salts include, for example, salts with inorganic acids (eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) or organic acids (eg, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, Succinic acid, tartaric acid, citric acid, Malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) and the like are used.

Further, when the triazolopyridazine derivative [I] has an acidic group such as COOH as a substituent, the triazolopyridazine derivative [I] may be an inorganic base (for example, an alkali such as sodium, potassium, calcium, or magnesium). metals or alkaline earth metals, ammonia, etc.) or organic bases (e.g. tree (^ _ ₃ Arukiruamin etc. and tri Echiruamin) and may form a salt. the tri § Zorro pyridazine derivative [I] or a salt thereof, especially It can be produced based on the description in Japanese Unexamined Patent Publication No. Hei 6-279447 or Japanese Unexamined Patent Publication No. Hei 08-199687, in particular, the description in the examples of the publication.

 The prodrug of the triazolopyridazine derivative [I] or a salt thereof is a compound which is converted into the triazolopyridazine derivative [I] or a salt thereof by a reaction with an enzyme or stomach acid under physiological conditions in vivo, that is, enzymatic oxidation, A compound that undergoes reduction, hydrolysis, etc., and changes to a triazolopyridazine derivative [I] or a salt thereof, and a compound, which undergoes hydrolysis, etc., by gastric acid or the like, to change to a triazolopyridazine derivative [I], or a salt thereof.

As a prodrug of the triazolopyridazine derivative [I] or a salt thereof, a compound in which the amino group of the triazolopyridazine derivative [I] or a salt thereof is acylated, alkylated, or phosphorylated (eg, a triazolopyridazine derivative [ I] or the amino group of a salt thereof is eicosanoylated, alanylated, pentylamino-hydroxylated, (5-methyl-2-oxo-1,3-dioxolen-14-yl) methoxycarponylated, tetrahydrofuranylated , Pyrrolidylmethylated, bivaloyoxymethylated, tert-butylated compounds, etc.); compounds in which the hydroxyl group of the triazolopyridazine derivative [I] or a salt thereof has been acylated, alkylated, phosphorylated, or borated (eg, tria). The hydroxyl group of the zolopyridazine derivative [I] or a salt thereof is acetylated, , Propanylation, bivaloylation, succinylation, fumarylation, alanylation, dimethylaminomethylcarbonylation, etc.); triazolopyridazine derivative [I] or a carboxyl group of its salt is esterified, Amidated compounds (eg, triazolopyridazine-derived Compound (I) or its salt The propyloxyl group is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, vivaloyloxymethyl-esterified, ethoxycarbonyloxy-esterified, phthalidyl Esterification, (5-methyl-2-oxo-1,3-dioxolen-14-yl) methyl esterification, cyclohexyloxycarbonylethylesterylation, methylamidated compound, etc.) and the like. . These compounds can be produced from the triazolopyridazine derivative [I] or a salt thereof by a method known per se.

 Also, prodrugs of the triazolopyridazine derivative [I] or a salt thereof are described in Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, Molecular Design, pp. 163 to 198. It may be a triazolopyridazine derivative [I] or a salt thereof under physiological conditions.

 The preparation of the present invention may contain other pharmaceutical ingredients other than the triazolopyridazine derivative [I] or a salt thereof or a prodrug thereof as an active ingredient. Such pharmaceutically active ingredients include, for example, other chemokine / site force-in expression inhibitors or inhibitors, anti-asthmatics (eg, theophylline, pro-power terol, ketotifen, azelastine, seratrodast (pro-ni-force), etc. ), Antiallergic agents (eg, ketotifen, terfenadine, azelastine, epinastine, etc.), anti-inflammatory agents (eg, diclofenac sodium, ibuprofen, indomethacin, etc.), antibacterial agents (eg, cefixime, cefdinir, ofloxacin, tosfloxacin) And antifungal agents (eg, fluconazole, itraconazole, etc.). These components are not particularly limited as long as the object of the present invention is achieved, and can be used in an appropriate mixing ratio.

 Specific examples of the dosage form of the preparation of the present invention include, for example, tablets (including sugar-coated tablets and film-coated tablets), pills, capsules (including microcapsules), granules, fine granules, powders, and syrups. Preparations, emulsions, suspensions, injections, inhalants, ointments, eye drops, aerosols, creams, nasal drops, patches, etc. are used. These preparations are prepared according to a conventional method (for example, a method described in the Japanese Pharmacopoeia).

Specifically, the tablet manufacturing method is based on excipients, binders, Alternatively, add the appropriate additives and mix evenly, granulate by an appropriate method, then add lubricants, etc., and compression-mold or Add a binder, disintegrant or other suitable additives and mix evenly, then directly press-mold or make the granules pre-made as they are, or mix evenly by adding appropriate additives After that, it can also be manufactured by compression molding. The agent can be added with a coloring agent, a flavoring agent, and the like as needed. In addition, the agent can be coated with an appropriate coating agent.

 Injectables are prepared by dissolving, suspending or emulsifying a certain amount of the drug in water for injection, physiological saline, Ringer's solution, etc. for aqueous solvents, and usually in vegetable oil for non-aqueous solvents. Alternatively, a predetermined amount of the drug can be taken and sealed in a container for injection.

 As the pharmacologically acceptable carrier that may be used in the production of the preparation of the present invention, various organic or inorganic carrier substances commonly used as preparation materials are used. For example, vehicles, lubricants, binders, disintegrants in solid preparations, solvents, dissolution aids, suspending agents, isotonic agents, buffers, soothing agents and the like in liquid preparations are used. If necessary, additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used.

 As the excipient, for example, lactose, saccharose, D-mannitol, starch, corn starch, crystalline cellulose, light caffeic anhydride and the like are used.

 As the lubricant, for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like are used.

 Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose. Are used.

As the disintegrant, for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropylcellulose and the like are used. Can be

 As the solvent, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like are used.

 As the solubilizer, for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like are used.

 Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; Hydrophilic polymers such as alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose are used.

 As the tonicity agent, for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like are used.

 As the buffer, for example, a buffer solution such as a phosphate, an acetate, a carbonate, and a citrate is used.

 As the soothing agent, for example, benzyl alcohol and the like are used.

 As the preservative, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like are used.

 As the antioxidant, for example, sulfite, ascorbic acid and the like are used. In the preparation of the present invention, the content of the triazolopyridazine derivative [I] or a salt thereof varies depending on the target disease, the age and sex of the target patient, the state of the disease, and the like. It is about 0.1 to 99.9% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight.

The content of the carrier and various additives varies depending on the target disease, the age and gender of the target patient, the condition of the disease, and the like, but is usually about 0.1 to 99% by weight based on the whole preparation. It is preferably about 10 to 99% by weight, more preferably about 50 to 99% by weight, and particularly preferably about 70 to 99% by weight.

 The content of other pharmaceutical ingredients other than the triazolopyridazine derivative (I) or a salt thereof varies depending on the target disease, the age and sex of the target patient, the state of the disease, and the like. The amount is from 0.1 to 99.9% by weight, preferably from about 0.1 to 50% by weight, and more preferably from about 0.5 to 20% by weight. The formulation of the present invention, for example, can efficiently suppress the expression of chemokines and cytokines and has low toxicity (acute toxicity: LD50> 2 gZkg).

 Inhibition of chemokine and cytokine expression includes suppression of chemokine and cytokine mRNA expression, suppression of chemokine and cytokine production, suppression of chemokine and cytokine DNA expression, suppression of chemokine and cytokine expression promoters, suppression of chemokine and cytokine expression. Includes secretion suppression, translational inhibition of chemokine and cytokine mRNA.

 Examples of chemokines or cytokines include interleukin 8 (IL-18), eotaxin, MIP-1 (Macrophage Inflammatory Protein-1), MIP-1 i3 (Macrophage Inflammatory Protein-1 β), RANT ES (Regulated on Activation, Normal T cell Expressed and Secreted; Rantes), roa / MGSA (growth-related gene / melanoma growth stimulating activity), gro / 3 / MGSA (growth-related gene β / melanoma growth stimulating activity), EN A-7 8 (Epithelia cell-derived Neutrophi 1-Act activating protein-78), PF-4 (Platelet .Factor-4), IP-10 (Interferon inducible Protein-10), MC P-1, --2 Or — 3 (Monocyte Chemoattractant Protein-1, -2 or-3), I — 309, In Yuichi Leukin 1, 2, 3, 6, 10 or 13 (IL-1, 2, 3, 4, 10 or 13), interferon-, 13 or: r (IFN-α, β or r), cause of cell necrosis Shed (TNF-Fei), lymphotoxin, colony stimulating factor (C S F), erythropoietin, epidermal growth factor (EGF), fibroblast growth factor (FGF) and the like.

The preparations of the present invention include, among others, Interferon (IFN-r), Eota It can suppress the expression of toxin (Eotaxin), MIP-1α, RANTES, Inuichi Leukin 13 (IL-13), TNF-H, and MCP-1. In particular, eotaxin, Μ Ι Ρ_1α, RANTE S, In-Yuichi Leukin 13 (IL-13), TNF-Q! And other chemokines and cytokins efficiently suppress mRNA expression, eotaxin, Production of chemokines and cytokines such as TNF_Q! And MCP-1 can be suppressed efficiently.

Therefore, the preparation of the present invention can be applied to mammals (eg, humans, mice, rats, cats, dogs, higgs, pomas, dogs, monkeys, etc.) for allergic diseases, inflammation, circulatory disorders, etc. Specifically, allergic rhinitis, atopic dermatitis, nephritis, acute bacterial meningitis, acute viral encephalitis, adult respiratory distress syndrome (ARDS), bacterial pneumonia, cancer (eg, bladder cancer, breast cancer, uterus Part, colon cancer, non-small cell lung cancer, small cell lung cancer, ovarian cancer, prostate cancer, gastric cancer, etc.), chronic lymphocytic leukemia, chronic myeloid leukemia, helicobacter pylori infection, hepatitis (eg, A Hepatitis B, hepatitis B, hepatitis C, alcoholic hepatitis), simple herpes virus infection, varicella-zoster virus infection, Hodgkin's disease, AIDS infection, human papillosis Mavirus infection, Influenza infection, Severe systemic fungal infection, Insulin-dependent diabetes mellitus type I, Insulin-dependent diabetes mellitus type II, Invasive bud and streptococcal infection, Malignant melanoma, Metastasis, Organ transplantation, Multiple bone marrow Tumor, spinal cord injury, non-Hodgkin's lymphoma, peptic ulcer, sepsis, septic shock, severe systemic fungal infection, tuberculosis, osteoarthritis, osteomalacia, osteopenia, osteoporosis, bone Petit's disease, pain, renal failure, Rheumatoid arthritis, systemic lupus erythematosus, valvular heart disease, acute ischemic stroke, acute myocardial infarction, sequelae of myocardial infarction, acute inflammation, chronic knee inflammation, acute cerebral thrombosis, Alzheimer's disease, angina, unstable angina , Ankylosing spondylitis, asthma, arteriosclerosis, fracture, cerebral vasospasm after subarachnoid hemorrhage, cirrhosis, Crohn's disease, bedsore, dementia, mixed Dementia, vascular multiple infarction dementia, diabetic complications, diabetic nephritis, diabetic nephropathy, diabetic retinopathy, epilepsy, gastric atony, hemorrhoids, liver failure, hypercalcemia, hypercholesterolemia, Hyperglyceridemia, hyperlipidemia, peripheral vascular disease, fever, reflux esophagitis, reocclusion after atherectomy, re-occlusion after stenting It can be used as an excellent preventive / therapeutic agent for diseases such as stenosis, restenosis after percutaneous intracoronary angioplasty, thrombocytopenia due to dialysis, and transient ischemic attack.

 The dosage of the formulation of the present invention varies depending on the target disease, age, body weight, symptoms, administration route, number of administrations, and the like. For example, for the purpose of treating nephritis, the dose of the active ingredient (tria Usually, about 0.1 to 10 OmgZkg, preferably about l to 50 mgZkg, more preferably about 1 to 10 mgOmgZkg per day in terms of zolopyridazine derivative [I] or a salt or a prodrug thereof. It is recommended to administer the drug in 1 or 2 divided doses. The administration route may be oral or parenteral. Hereinafter, the present invention will be more specifically described with reference examples, examples, and test examples, but the present invention is not limited thereto.

 The detection of the fraction containing the target substance in the reference example was performed under observation by TLC (Thin Layer Chromatography). In the TLC observation, 60 F254 manufactured by Merck was used as a TLC plate, and a UV detector was used as a detection method. Silica gel 60 (70-230 mesh) manufactured by Merck was used as a silica gel for column chromatography.

 Abbreviations used in the text have the following meanings.

 J Coupling constant

s singlelet

 t triplet

m multiplet

H z hertz

d doublet

Q quartet

 NMR proton nuclear magnetic resonance

CDC 13 Clotholm

v Z v capacity Z capacity %: Village%

Example

 Reference example 1

 Production of 3-Amino-6_Cross_5—Isopropylpyridazine

 2,1.7 g of 3,6-dichloro-4-isopropylpyridazine, 1.7 ml of 25% aqueous ammonia, and 10 ml of ethanol were placed in a sealed stainless steel reaction tube, and the mixture was placed at 130-140 ° C. Stir for 2 hours. After cooling, the mixture was concentrated, water was added to the residue, and the precipitated crystals were collected by filtration, washed with water and ethyl ether, and dried to obtain 11.1 g of the title compound.

Melting point 1 6 4— 1 6 5 ° C

 NMR (C D C 13) δ: 1.26 (6Η, d, J = 7 Hz), 3.16 (1H, m), 4.89 (2H, br.s), 6.65 (1H, s)

 Reference example 2

 Production of N- (6-cloth-5-isopropylpyridazine-3-yl) formamidoxime

 8.6 g of 3-amino-6-chloro-5-isopropylpyridazine was suspended in 58 ml of toluene, 6.2 ml of dimethylformamide dimethyl acetal was added, and the mixture was heated and perfused for 2 hours. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: methanol = 10: 1. The desired fraction was collected and concentrated, the residue was dissolved in methanol (40 ml), hydroxylamine hydrochloride (1.8 g) was added, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration to obtain 10.6 g of the title compound.

Melting point 1 7 0— 1 7 1:

Elemental analysis: as CsHnN OCl

 Calculated value (%): C, 44.76; H, 5.17; N, 26.10

 Obtained value (%): C, 46.62; H, 5.02; N, 26.01

 Reference example 3

6-Black 7-isopropyl [1,2,4] triazolo [1,5-b] 20—04 g of N— (6-—mouth—5-isopropylpyridazine—3-yl) formamidoxime and 97 g of polyphosphoric acid were kneaded, and reacted in an oil bath at 110—115: for 1 hour. After cooling, ice water was added, and the mixture was extracted with dichloromethane. The extract was washed with water and dried over magnesium sulfate. After concentrating under reduced pressure, hexane was added to the residue and the precipitated crystals were collected by filtration to obtain 12.7 g of the title compound.

Melting point 53- 54 ° C

Elementary analysis: as C ₈ H ₉ C1N ₄

 Calculated value (%): C, 48.87; H, 4.61; N, 28.49

 Obtained value (%): C, 48.85; H, 4.55; N, 28.48

 Reference example 4

 6- (2,2-Dimethyl_3-sulfamoyl_1_propoxy) — 7-Isopropyl [1,2,4] triazolo [l, 5_b] Preparation of pyridazine

 0.336 g of 60% oily sodium hydride was suspended in 3 Oml of tetrahydrofuran, 0.669 g of 3-hydroxy-2,2-dimethylpropane-1-sulfonamide was added, and the mixture was heated and perfused for 1 hour. After cooling, 0.748 g of 6-chloro- 7-isopropyl [1,2,4] triazolo [1,5-b] pyridazine was added, and the mixture was heated and perfused for 4 hours. After cooling, ice water was added, the pH was adjusted to 6.0 with 1N hydrochloric acid, and the mixture was extracted with tetrahydrofuran ethylfuran acetate (1: 1). The extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with dichloromethane: ethyl acetate: methanol = 10: 10: 1. The desired fraction was collected and the resulting crystals were recrystallized from acetone-water to give 1.10 g of the title compound.

Melting point 197— 1 98 ° C

Elementary analysis: as _{C 13 H 21 N 5 0 3} S

 Calculated value (%): C, 47.69 H, 6.46 N, 21.39

 Observed value (%): C, 47.84 H, 6.60 N, 21.33

 Example 1

 (1) Compound of Reference Example 4 1 Omg

(2) Lactose 6 Omg (3) Corn starch 3 5mg

 (4) Gelatin 3mg

 (5) Magnesium stearate 2mg

 A mixture of 1 Omg of the compound obtained in Reference Example 4, 6 Omg of lactose, and 35 mg of corn starch was granulated through a limn mesh sieve using 0.03 ml of a 10% aqueous gelatin solution (3 mg as gelatin), and then granulated. Dried at ° C and sieved again. The granules thus obtained were mixed with 2 mg of magnesium stearate and compressed. The obtained central tablets were coated with a sugar coating using a water suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were glossed out with beeswax to obtain coated tablets.

 Example 2

 (1) Compound of Reference Example 4 1 Omg

 (2) Lactose 7 Omg

 (3) Corn starch 5 Omg

(4) Soluble starch 7mg

 (5) Magnesium stearate 3mg

 1 Omg of the compound obtained in Reference Example 4 and 3 mg of magnesium stearate were granulated with 0.07 ml of an aqueous solution of a soluble starch (7 mg as a soluble starch), dried, and mixed with 7 Omg of lactose and 5 Omg of corn starch. The mixture was compressed to give tablets.

 Example 3

 (1) 5 mg of the compound of Reference Example 4

 (2) Salt 2 Omg

 (3) Total volume of distilled water is 2ml

 5 mg of the compound obtained in Reference Example 4 and 20 mg of common salt were dissolved in distilled water, and water was added to make a total volume of 2 ml. The solution was filtered and filled into 2 ml ampoules under aseptic conditions. The ampoule was sterilized and sealed to obtain a solution for injection.

Test Example 1 Effect on antigen-induced chemokine 'cytokine mRNA expression in lungs of sensitized rats A mixture of ovalbumin (OA) and aluminum hydroxide gel was intramuscularly administered to male Brown Norway rats (8-week old, Nippon Thiers River), and a pertussis suspension (1 × 101 ^Q ) was simultaneously administered. It was administered intraperitoneally and sensitized. Three weeks after the sensitization, the rats were placed in an inhalation box, and a 1% OA solution dissolved in physiological saline was aerosolized with an ultrasonic nebulizer under spontaneous spontaneous respiration and inhaled for 5 minutes. The compound of Reference Example 4 was suspended in a 0.5% methylcellulose solution and orally administered 1 hour before inhalation of the antigen. In addition, as a negative control group, an aerosol of physiological saline was inhaled instead of the 1% 〇A solution. Three hours after inhalation of the antigen, the lungs were removed, perfused with a physiological saline solution, rapidly frozen in liquid nitrogen, and stored at 180 ° C until extraction was performed.

 The preparation of the total RNA preparation was performed by the following method. Frozen lung (approximately 1.0 g) is crushed with a polytron homogenizer in a 15 ml RNA extraction reagent (Isogen: Nitsubon Gene Co., Ltd.). : 15 minutes) to isolate the upper RNA layer and further concentrated with isopropanol. The concentrated and precipitated RNA sample was dissolved in a TE solution (10 mM Tris-HCl / lmM EDTA, pH 8.0). After performing 50 units DNase I treatment (Nitsubon Gene Co., Ltd.) (37 ^ :, 15 minutes), extraction was performed with phenol Z-cloth form, and the upper RNA layer obtained by centrifugation was concentrated with ethanol. . The concentrated precipitate was dissolved in a TE solution, and used as a total RNA sample used for a quantitative RT_PCR method type III for measuring the expression level of each chemokine / cytokine mRNA.

RT—As a method for quantitatively measuring PCR products, an automated PCR product detection and quantification system (TaqMan ™ System ABI 7700) from PE Biosystems was used. After synthesizing single-stranded DNA from the above total RNA preparation, PCR reaction of 20 ng / reaction—each target gene and GAPDH gene as internal standard from single-stranded DNA was performed (2 min, 50 times, once; Amplification was performed for 10 minutes at 95 ° C once; at 15 seconds and 95 times for 1 minute at 60 ° C for 40 times), and the amplified product was measured with an ABI 7700. The content of the reaction solution was in accordance with the attached document of the reagent (TaqMan PCR Core Reagent; PE Biosystems, N808-0289). The results were obtained by calculating the ratio of the amplified copy number of each chemokine / cytocytoin to the amplified copy number of GAPDH. The mean value of the inhalation group was 1 and the relative ratio was expressed.

 Three hours after antigen challenge, mRNA expression of Eota Xin, MIP-I, RANTES, IL-I3, and TNF-I in rat lung was significantly increased compared to the negative control group. . On the other hand, the compound of Reference Example 4 shows that these etataxins (Fig. 1), MIP-1α (Fig. 2), RANTES (Fig. 3), IL-13 (Fig. 4) and TNF_H (Fig. 5) Increased mRNA expression was suppressed in a dose-dependent manner.

 Test Example 2 Effects on antigen-induced chemokine and cytokine production in lungs of sensitized rats

A mixture of ovalbumin (OA) and aluminum hydroxide gel was intramuscularly administered to male Brown Norway rats (8-week-old, Nippon Thiales River), and a pertussis suspension (1 X 101 ^Q ) was simultaneously administered. It was administered intraperitoneally and sensitized. Three weeks after the sensitization, the rats were placed in an inhalation box, and a 1% OA solution dissolved in physiological saline was aerosolized with an ultrasonic nebulizer under spontaneous spontaneous respiration and inhaled for 5 minutes. The compound of Reference Example 4 was suspended in a 0.5% methylcellulose solution and orally administered 1 hour before inhalation of the antigen. As a negative control group, an aerosol of physiological saline was inhaled instead of the 1% OA solution. Three hours after inhalation of the antigen, the lungs were excised, perfused with physiological saline, rapidly frozen in liquid nitrogen, and stored at 180 ° C until extraction.

Preparation of lung tissue was performed 6 hours after antigen induction. The rat was opened, and 25 ml of physiological saline was injected through a sonde inserted from the right ventricle into the pulmonary artery to perfuse the pulmonary circulation. The right anterior lobe of the lung is collected and Hiscotron in PBS (1 ml / 0.1 g wet weight) containing 0.1% Triton X—100 ^™ and 0.2% protease “Inhibit Yuichi” cocktail After homogenizing with a microhomogenizer (manufactured by Microtech Nichion), the mixture was centrifuged at 10,000 X g for 5 minutes at 4 ° C. Lung homogenate MCP-1 and TNF-α levels were measured according to the use of a commercially available ELISA kit. The amount of eotaxin (Eo taxi η) was calculated as an amount equivalent to eotaxin by the sandwich ELISA method using an anti-mouse eotaxin antibody. Samples below the detection limit are calculated as 0 pg / m1. Calculated.

 Six hours after antigen challenge, eotaxin (EotaXin), MCP-1 and TNF- production in rat lungs was significantly increased as compared to the negative control group. On the other hand, the compound of Reference Example 4 dose-dependently suppressed the increase in the production of eotaxin (FIG. 6), MCP-1 (FIG. 7) and TNF-α (FIG. 8). Industrial applicability

 The preparation of the present invention containing the triazolopyridazine derivative [I] can efficiently suppress the expression of chemokines and cytokines such as interferona (IFNr) and TNF-α.

Claims

The scope of the claims 1 set X- (CH ₂ ) _m -Y- (CH ₂ ) _n -S0 ₂ N [I]

[In the formula, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and R ³ represent a hydrogen atom and a lower alkyl group which may have a substituent, respectively. Represents a cycloalkyl group which may have a group or a substituent, wherein R and R ³ may be adjacent to each other to form a 5- to 7-membered ring together with C = C, and X is an oxygen atom or S ( 〇) p (p is an integer from 0 to 2), and Y is an expression R ⁴  — C— R ⁵ Wherein R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group which may have a substituent, or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent And R ^D and R ⁷ are a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or Represents an aryl group which may have a substituent; R ⁶ and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom; And n is an integer of 0 to 4. Or a salt thereof or a prodrug thereof.  2. The agent according to claim 1, which is an agent for suppressing the expression of chemokine or cytokine mRNA.  3. The agent according to claim 1, which is a chemokine or cytokine production inhibitor. 4. R ¹ is (i) a hydrogen atom, (ii) hydroxy, amino, carboxyl, nitro Mouth, mono - or di - c Arukiruamino, ^ - ₆ alkoxy, Ci-e Al Kill carbonyl O carboxymethyl and may have a substituent group selected from the group consisting of halogen atoms C ^ 6 alkyl group or (iii) Halogen atom, R ² and R ³ are each (i) a hydrogen atom, (ii) a hydroxy, Amino, Cal Pokishiru, nitro, mono- - or di - C Arukiruamino, (^ _ ₆ an alkoxy, the group consisting of alkylcarbonyl O alkoxy and a halogen atom may have a substituent group selected from C i_ ₆ alkyl group or (iii) hydroxy, Amino, carboxyl, nitro, mono- - or di one C i-e Arukiruamino, C DOO ₆ alkoxy, C I ₆ alkyl carbonyl the Okishi and substituents may c ₃ _ ₆ cycloalkyl group optionally having a selected from the group consisting of halogen atoms indicates, R ² and R ³ with one C = C one adjacent, ① hydroxy, Amino, Mono one or di- _ C E - consists of ₆ alkylamino, (^ _ ₆ alkoxy, C alkyl one carbonylation Ruokishi and halogen atoms It may have a substituent group selected from the group (: Bok ₆ alkyl, ② C ^ - ₆ alkyl, C Ashiru or 5 to 7 membered ring shape may be substituted with Amino Amino, ③ hydroxy, ④ Karupokishiru , ニ ト ロ nitro, ア ル コ キ シ alkoxy and ⑦halogen atoms, which may have a substituent, and 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur other than carbon May form a 5- to 7-membered ring,  X represents an oxygen atom or S (〇) (p represents an integer of 0 to 2)  Y is the equation (a) R ⁴  — C— (R and R ⁵ are each (i) hydrogen atom or (ii) hydroxy, Amino, carboxyl, nitro, mono- - consisting of C DOO ₆ Arukiruamino, alkoxy, C i-6 alkyl Cal Poni Ruo carboxymethyl and halogen atoms - or di C represents an alkyl group which may have a substituent selected from the group), Or (B) ① hydroxy, Amino, mono one or di- - 6 Arukiruamino, _ ₆ alkoxy which may have a substituent selected from the ing group from C Bok ₆ alkyl Ichiriki Ruponiruokishi and halogen alkyl, ② C ^ — A substituent selected from the group consisting of amino, which may be substituted with ₆ alkyl, C acyl, or 5 to 7 membered cyclic amino, ③ hydroxy, ④ carboxyl, ⑤ nitro, ⑥ ₆ alkoxy and ⑦ halogen atom. A 3- to 7-membered cyclic hydrocarbon or a 3- to 7-membered member containing 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom A divalent group derived from a heterocyclic ring of R ⁶ and R 'are each (i) a hydrogen atom, (ii) a hydroxy, Amino, Cal Pokishiru, nitro, mono - consists 6 Arukiruamino, ₆ an alkoxy, C WINCH ₆ alkylcarbonyl O alkoxy and halogen atom - or di - which may have a substituent Ru selected in the group C I ₆ alkyl group, (iii) hydroxy, Amino, carboxyl, nitro, mono- - or di - Arukiruamino, alkoxy, C WINCH ₆ alkylcarbonyl O alkoxy and halogen A C ₃ _ ₆ cycloalkyl group which may have a substituent selected from the group consisting of atoms or (iv) (1) consisting of hydroxy, amino, mono or di-C _6- alkylamino, alkoxy and halogen atoms Optionally substituted with 6-alkyl, ② (^ alkyl or 5- to 7-membered cyclic amino selected from the group consisting of May be had Amino, ③ Asetoamido, ④ hydroxy, ⑤ carboxyl, ⑥ two Toro, ⑦ alkoxy, ⑧ C ₆ alkylcarbonyl O alkoxy and ⑨ may have a substituent group selected from the group consisting of halo gen atom C ₆ _ ₁₄ shows a reel group, R ⁶ and R ⁷ have a substituent selected from the group consisting of ①hydroxy, amino, mono- or di-c ^ 6alkylamino, alkoxy, C ₆ alkyl-carbonyloxy and halogen together with the adjacent nitrogen atom. May _6- alkyl, ② (^ alkyl, (^ _ _6- amino or amino optionally substituted with 6- or 7-membered cyclic amino, ③ hydroxy, ④ carboxyl, ⑤ nitro Mouth, ⑥ C WINCH ₆ alkoxy and ⑦ may have a substituent group selected from the group consisting of halogen atom, contains one nitrogen atom, further nitrogen atom, selected from oxygen atom and a sulfur atom It may contain 1 to 4 heteroatoms and may form a group in which one hydrogen atom has been removed from the ring of 3 or 1 3 membered nitrogen-containing heterocyclic ring, and m is 0 to 4 The agent according to claim 1, wherein n is an integer of 0 to 4. 5. R ¹ is a hydrogen atom or — 3 alkyl group; R ² is a hydrogen atom or ^ —sT alkyl group; R ³ is a hydrogen atom or an alkyl group; X is an oxygen atom; R ⁴ '  — C—  s' [Wherein R ⁴ ′ and R ⁵ ′ are each (i) a hydrogen atom or (ii) a hydroxy, amino, carboxyl, nitro, mono- or di-C ^ -ealkylamino, C ₆ alkoxy, C i- ₆ alkyl - shows the ₃ alkyl groups - carbonyl O alkoxy or halogen atom or al chosen one to four may have a substituent group C _1. The agent according to claim 1, wherein R ⁶ and R ⁷ each represent a hydrogen atom or an alkyl group, and m and n represent 1.  6. The agent according to claim 1, wherein the compound is 6- (2,2-dimethyl-3-sulfamoyl-11-propoxy) -17-isopropyl [1,2,4] triazolo [1,5-b] pyridazine.  7. The agent according to claim 1, wherein the chemokine or cytokine is RANTES, eotaxin, MIP-1 or inuichi leukin 13 (IL-13), TNF-α or MC-1. .  8. The agent according to claim 1, which is an agent for preventing or treating a disease based on expression of a chemokine or cytokine. 9. Formula for mammals R ⁶ X- (CH ₂ ) _m -Y- (CH ₂ ) _n -S0 ₂ N ([I]  R  N ku Y [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and R ³ each represent a hydrogen atom or a lower alkyl which may have a substituent. A cycloalkyl group which may have a group or a substituent, R ² and R ³ may form a 5- to 7-membered ring with adjacent _C = C—, and X represents an oxygen atom or S ( O) p (p is an integer from 0 to 2), Y is the expression R ⁴  — C— (R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group which may have a substituent) or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent And R ⁶ and R ⁷ are a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or Represents an aryl group which may have a substituent, and R ⁶ and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom; m represents an integer of 0 to 4, and n represents an integer of 0 to 4. Or a salt thereof, or a prodrug thereof, in an effective amount.  1 0. Formula for mammals X- (CH ₂ ) _m -Y- (CH ₂ ) _n -S0 ₂ N [I] R [In the formula, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or an octogen atom, and R ² and R represent a hydrogen atom and a lower alkyl group which may have a substituent, respectively. Or a cycloalkyl group which may have a substituent, and R ² and R may be adjacent to each other to form a 5- to 7-membered ring together with —C CC, and X represents an oxygen atom or S (〇 ) P (where p is an integer from 0 to 2) Y is the expression R ⁴  — C— R ⁵ (Wherein R ⁴ and R "each represent a hydrogen atom or a lower alkyl group which may have a substituent) or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent R ⁶ and R ′ each represent a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or substituted indicates which may § Li Ichiru group, R ^O and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom, m represents an integer of 0 to 4, and n represents an integer of 0 to 4.], wherein the compound or a salt thereof or a prodrug thereof is administered in an effective amount, and the disease is based on the expression of a chemokine or cytokine. Prevention and treatment methods.  1 1. The formula for producing a chemokine or cytokinin expression inhibitor is as follows: X- (CH ₂ ) _m -Y- (CH ₂ ) _n -S0 ₂ N; [|] , ^R

[In the formula, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and R ³ represent a hydrogen atom and a lower alkyl group which may have a substituent, respectively. A cycloalkyl group which may have a group or a substituent, R and R ³ may form a 5- to 7-membered ring together with an adjacent C = C 1, and X represents an oxygen atom or S ( O) p (p represents an integer of 0 or 2) Y is the expression R ⁴  — C— R ⁵ Wherein R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group which may have a substituent, or a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent And R ⁶ and R ⁷ are a hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or Represents an aryl group which may have a substituent; R ⁶ and R ⁷ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom; And n is an integer of 0 to 4. Or a salt thereof or a prodrug thereof.  1 2. Formulas for producing preventive and therapeutic agents for diseases based on the expression of chemokines or cytokines X- (CH ₂ ) _m -Y- (CH ₂ ) _n -S0 ₂ N [I]

[In the formula, R ¹ represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom, and R ² and R ³ represent a hydrogen atom and a lower alkyl group which may have a substituent, respectively. A cycloalkyl group which may have a group or a substituent, wherein R ² and R ³ may form a 5- to 7-membered ring together with an adjacent —C = C—, and X is an oxygen atom or S (〇) p (p is an integer from 0 to 2) Y is the expression R ⁴  — C— (R ⁴ and R "are each a hydrogen atom or a lower group which may have a substituent. Represents an alkyl group) or a divalent group derived from a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent, wherein R ¹³ and R ⁷ are respectively A hydrogen atom, a lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent or an aryl group which may have a substituent, wherein R ⁶ and R ′ are adjacent May form a nitrogen-containing heterocyclic group which may have a substituent together with the nitrogen atom to be formed, m represents an integer of 0 to 4, and n represents an integer of 0 to 4. ] Use of the compound represented by the formula, its salt, or its prodrug.