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WO2001021177A1 - Inhibiteurs d'expression de chemokine/cytokine - Google Patents

Inhibiteurs d'expression de chemokine/cytokine Download PDF

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Publication number
WO2001021177A1
WO2001021177A1 PCT/JP2000/006377 JP0006377W WO0121177A1 WO 2001021177 A1 WO2001021177 A1 WO 2001021177A1 JP 0006377 W JP0006377 W JP 0006377W WO 0121177 A1 WO0121177 A1 WO 0121177A1
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substituent
group
atom
hydrogen atom
alkoxy
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PCT/JP2000/006377
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English (en)
Japanese (ja)
Inventor
Yasuhiko Kawano
Tatsumi Matsumoto
Masami Isaka
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Takeda Chemical Industries, Ltd.
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Priority to AU73159/00A priority Critical patent/AU7315900A/en
Publication of WO2001021177A1 publication Critical patent/WO2001021177A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • 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.
  • R 1 represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom
  • 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 _
  • X is an oxygen atom or S (O) p (where p represents an integer from 0 to 2)
  • 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, or a substituent.
  • M represents an integer of 0 to 4 and n represents an integer of 0 to 4.
  • Japanese Unexamined Patent Publication Nos. 06-279447 and 08-198878 Japanese Unexamined Patent Publication Nos. 06-279447 and 08-198878.
  • Chemokines or cytokines such as interferon (IFN-a), eotaxin (EotaXin), MIP-1 ⁇ , inulin-leukin 13 (IL-13) or TNF- ⁇ 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.
  • R 1 represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom
  • 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)
  • 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 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 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;
  • 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-
  • 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;
  • X represents an oxygen atom or S ( ⁇ ) p (p represents an integer of 0 to 2)
  • 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
  • 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
  • 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, ⁇ ⁇ ⁇ ⁇ alkoxy, 8C alkylcarbonyloxy and 9halogen atom which may have a substituent selected from the group consisting of: 6 — 14 aryl group,
  • I 6 alkoxy, C bets 6 alkyl - is selected from the group consisting of forces Ruponiruo carboxymethyl and halogen atom-substituted ⁇ -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
  • 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
  • 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.
  • chemokine or cytokine is RANTE S, eotaxin (Eota Xin), MIP-1 ⁇ , interleukin 13 (IL-13), TNF- ⁇ or MCP-1.
  • eotaxin Eota Xin
  • MIP-1 ⁇ MIP-1 ⁇
  • IL-13 interleukin 13
  • TNF- ⁇ MCP-1.
  • the agent according to (1) which is a prophylactic / therapeutic agent for a disease based on the expression of a chemokine or cytokine.
  • 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 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 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:
  • R 1 represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom
  • R 2 and R 3 each represent a hydrogen atom or a lower alkyl which may have a substituent.
  • X represents an oxygen atom or S ( ⁇ ) p (p indicates an integer from 0 to 2)
  • Y is an expression
  • 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 ⁇ 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;
  • R 2 and R 3 represent a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom
  • X represents an oxygen atom or S ( ⁇ ) (Where p represents an integer from 0 to 2)
  • R 4 and R 5 each represent a hydrogen atom or a lower alkyl group which may have a substituent.
  • M represents an integer of 0 to 4
  • n represents an integer of 0 to 4.
  • R 1 represents a hydrogen atom, a lower alkyl group which may have a substituent or a halogen atom
  • R 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 substituent wherein R 2 and R 3 may form a 5- to 7-membered ring with adjacent —C CC—
  • X represents an oxygen atom or S ( ⁇ ) p (p is an integer from 0 to 2)
  • R 4 and R each represent a hydrogen atom or a lower alkyl group which may have a substituent
  • 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.
  • a salt thereof or a prodrug thereof Or a salt thereof or a prodrug thereof.
  • 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.
  • FIG. 1 shows the inhibitory effect of the compound of Reference Example 4 on EotaXin (eotaxin) mRNA expression.
  • EotaXin eotaxin
  • FIG. 2 shows the inhibitory effect of the compound of Reference Example 4 on MIP-1a mRN ⁇ 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- ⁇ production.
  • # # ⁇ ⁇ 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).
  • 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.
  • R or R 7 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.
  • C i-e alkylcarbonyloxy such as
  • substituents 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.
  • 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,
  • 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
  • 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
  • substituents 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.
  • ⁇ 6 alkyl eg, methyl, ethyl, propyl, etc.
  • 5- to 7-membered cyclic amino eg, pyrrolidino, morpholino, piperidino, piperazino, etc.
  • halogen atom represented by R 1
  • fluorine, chlorine, bromine, iodine and the like are used.
  • a 5- to 7-membered ring which may contain a hetero atom is used.
  • 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,
  • Etc. are used, and preferably
  • Etc. more preferably Are often used.
  • 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
  • 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,
  • 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,
  • 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.
  • 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.
  • lower alkoxy e.g., methoxy, ethoxy, Purobokishi, to such C Bok 6 alkoxy such as Kishiruokishi
  • lower alkyl Cal Poni Ruo carboxymethyl e.g., one to four members selected from a group consisting of Ci- 6 alkyl mono-alkenyloxy such as acetyloxy and ethyl carbonyloxy
  • a halogen atom fluorine, chlorine, bromine, iodine, etc.
  • 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.).
  • C i _ 6 alkyl e.g., methyl, Echiru, propyl, etc.
  • Ashiru e.g., Flip formyl, Asechiru, propionyl, such as butyryl Bok
  • 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.
  • 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.
  • C i _ 3 alkyl e.g., methyl, E Ji Le, n - propyl, etc.
  • 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.
  • X is preferably, for example, an oxygen atom or S, and particularly an oxygen atom is frequently used.
  • 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.
  • 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.
  • Y is a divalent group derived from a 3- to 7-membered homocyclic or heterocyclic ring which may have a substituent, for example,
  • Etc. more preferably Etc. are commonly used, especially Is the most frequently used.
  • 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.
  • E alkyl e.g., methylation, Echiru, eta - propyl, etc.
  • hydrogen atom is often used.
  • n is preferably an integer of 1 to 4, more preferably an integer of 1 to 3, especially 1 and the like.
  • 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.
  • 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.
  • inorganic acids eg, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid
  • 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
  • the triazolopyridazine derivative [I] 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.
  • 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, cyclohexyloxycarbonylethylestery
  • 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
  • antifungal agents eg, fluconazole, itraconazole, etc.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used.
  • excipient for example, lactose, saccharose, D-mannitol, starch, corn starch, crystalline cellulose, light caffeic anhydride and the like are used.
  • lubricant for example, magnesium stearate, calcium stearate, talc, colloidal silica and the like are used.
  • binder examples include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose. Are used.
  • disintegrant for example, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, L-hydroxypropylcellulose and the like are used.
  • solvent for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like are used.
  • solubilizer for example, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like are used.
  • suspending agent examples 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.
  • 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.
  • tonicity agent for example, glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like are used.
  • a buffer solution such as a phosphate, an acetate, a carbonate, and a citrate is used.
  • the soothing agent for example, benzyl alcohol and the like are used.
  • preservative for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like are used.
  • the antioxidant for example, sulfite, ascorbic acid and the like are used.
  • 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.
  • chemokines or cytokines examples include interleukin 8 (IL-18), eotaxin, MIP-1 (Macrophage Inflammatory Protein-1), MIP-1 i3 (Macrophage Inflammatory Protein-1 ⁇ ), 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 ⁇ / 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
  • the preparations of the present invention include, among others, Interferon (IFN-r), Eota It can suppress the expression of toxin (Eotaxin), MIP-1 ⁇ , RANTES, Inuichi Leukin 13 (IL-13), TNF-H, and MCP-1.
  • IFN-r Interferon
  • Eota It can suppress the expression of toxin (Eotaxin), MIP-1 ⁇ , RANTES, Inuichi Leukin 13 (IL-13), TNF-H, and MCP-1.
  • eotaxin, ⁇ ⁇ ⁇ _1 ⁇ , 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.
  • 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.
  • mammals eg, humans, mice, rats, cats, dogs, higgs, pomas, dogs, monkeys, etc.
  • 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.
  • 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.
  • the detection of the fraction containing the target substance in the reference example was performed under observation by TLC (Thin Layer Chromatography).
  • TLC Thin Layer Chromatography
  • 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.
  • 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.
  • 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.
  • 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.
  • an aerosol of physiological saline was inhaled instead of the 1% ⁇ A solution.
  • 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 TM 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.
  • 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.
  • the compound of Reference Example 4 shows that these etataxins (Fig. 1), MIP-1 ⁇ (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.
  • 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 TM and 0.2% protease “Inhibit Yuichi” cocktail
  • a microhomogenizer manufactured by Microtech Nichion
  • Lung homogenate MCP-1 and TNF- ⁇ levels were measured according to the use of a commercially available ELISA kit.
  • the amount of eotaxin (Eo taxi ⁇ ) 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.
  • 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- ⁇ .
  • chemokines and cytokines such as interferona (IFNr) and TNF- ⁇ .

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Abstract

L'invention concerne des inhibiteurs d'expression de chémokine/cytokine qui contiennent des composés représentés par la formule générale (I), leurs sels ou leurs promédicaments. R1 représente hydrogène, alkyle inférieur, etc.; R2 et R3 représentent chacun hydrogène, alkyle inférieur, etc., ou R2 et R3, réunis à-C=C- adjacent, peuvent former un cycle de 5 à 7 chaînons; X représente oxygène ou S (O)¿p? (p étant un nombre entier allant de 0 à 2); Y représente. (R?4 et R5¿ représentent chacun hydrogène, alkyle inférieur, etc.); R6 et R7 représentent chacun hydrogène, alkyle inférieur, etc., ou, réunis, ils peuvent former avec l'atome d'azote adjacent un hétérocycle contenant de l'azote; m est un nombre entier allant de 0 à 4; et n également un nombre entier allant de 0 à 4.
PCT/JP2000/006377 1999-09-20 2000-09-19 Inhibiteurs d'expression de chemokine/cytokine WO2001021177A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0648491A2 (fr) * 1993-09-21 1995-04-19 Takeda Chemical Industries, Ltd. Inhibiteur de la chimiotaxis des éosinophiles
WO1996008496A1 (fr) * 1994-09-16 1996-03-21 Takeda Chemical Industries, Ltd. Elaboration de triazolopyridazines et des intermediaires destines a leur preparation, et leur utilisation comme medicaments

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0648491A2 (fr) * 1993-09-21 1995-04-19 Takeda Chemical Industries, Ltd. Inhibiteur de la chimiotaxis des éosinophiles
WO1996008496A1 (fr) * 1994-09-16 1996-03-21 Takeda Chemical Industries, Ltd. Elaboration de triazolopyridazines et des intermediaires destines a leur preparation, et leur utilisation comme medicaments

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