WO1999044611A1 - Triazolo-pyridazine derivatives for the treatment of chronic obstructive pulmonary diseases - Google Patents

Triazolo-pyridazine derivatives for the treatment of chronic obstructive pulmonary diseases Download PDF

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Publication number
WO1999044611A1
WO1999044611A1 PCT/JP1999/001010 JP9901010W WO9944611A1 WO 1999044611 A1 WO1999044611 A1 WO 1999044611A1 JP 9901010 W JP9901010 W JP 9901010W WO 9944611 A1 WO9944611 A1 WO 9944611A1
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Prior art keywords
group
amino
hydroxy
alkoxy
optionally
Prior art date
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PCT/JP1999/001010
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French (fr)
Inventor
Yasuko Ashida
Yasuhiko Kawano
Kenichirou Kiyoshima
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Takeda Chemical Industries, Ltd.
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Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to AU32741/99A priority Critical patent/AU3274199A/en
Priority to CA002319426A priority patent/CA2319426A1/en
Priority to EP99937873A priority patent/EP1059924A1/en
Publication of WO1999044611A1 publication Critical patent/WO1999044611A1/en

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    • 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

Definitions

  • the present invention relates to an agent for acting on bronchi which comprises triazolopyridazine derivatives such as 6- ( 2 , 2-dimethyl-3 -sulfamoyl-l-propoxy) -7- isopropyl (l , 2 , 4) triazolo (l , 5-b] pyridazine , etc . .
  • triazolopyridazine derivatives such as 6- ( 2 , 2-dimethyl-3 -sulfamoyl-l-propoxy) -7- isopropyl (l , 2 , 4) triazolo (l , 5-b] pyridazine , etc . .
  • Triazolopyridazine derivatives represented by the formula:
  • R 1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom
  • X is an oxygen atom or S(0) p (p is a whole number of 0 to 2)
  • Y is a group of the formula:
  • R 4 and R 5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring
  • R 6 and R 7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R 6 and R 7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group
  • m is a whole number of 0 to 4
  • n is a whole number of 0 to 4
  • the present inventors diligently made extensive studies in order to solve the problems and, as a result, they found that it could make actions of the derivatives act at bronchi locally by preparing an inhalation, etc. comprising 6- (2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [l , 2 , 4) triazolo Cl,5-b] pyridazine or a salt thereof. And, they further studied based on the finding, the present invention has been accompliched.
  • a agent for acting on bronchi which comprises a compound of the formula:
  • R 1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom
  • X is an oxygen atom or S(0) p (p is a whole number of 0 to 2)
  • Y is a group of the formula:
  • R 4 and R 5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring
  • R 6 and R 7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R 6 and R 7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group
  • m is a whole number of 0 to 4
  • n is a whole number of 0 to 4 , or a salt thereof
  • R 1 is (i) a hydrogen atom, (ii) a C 1 _ 6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- ordi-Cj.j alkylamino, Ci.
  • R 2 and R 3 respectively is (i) a hydrogen atom or (ii) a C 1 . 6 alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or i-C ⁇ alkylamino, C 1-6 alkoxy, C ⁇ alkylcarbonyloxy and a halogen atom or (iii) a C 3 .
  • X is an oxygen atom or S(0) p (p is a whole number of 0 to 2).
  • Y is (a) a group of the formula: R 4 —C—
  • R 4 and R 5 respectively is (i) a hydrogen atom or (ii) a C ⁇ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C ⁇ alkylamino, C ⁇ alkoxy, C x _ 6 alkylcarbonyloxy and a halogen atom) , or
  • R 6 and R 7 respectively is (i) a hydrogen atom, (ii) a C 1-6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro. mono- or di-C 1 . 6 alkylamino, C 1 , 6 alkoxy, C ⁇ , 6 alkylcarbonyloxy and a halogen atom, (iii) a C 3 . 6 cycloalkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C 1 .
  • R 6 and R 7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms, optionally having substituents selected from the group consisting of (i) C 1 _ 6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C ⁇ alkylamino, ⁇ _ 6 alkoxy, C ⁇ alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C 1 _ 6 alkyl, C ⁇ acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Ci. s alkoxy and (vii) a halogen atom
  • R 1 is hydrogen atom or a C ⁇ alkyl group
  • R 2 is a hydrogen atom or a C 1 _ 3 alkyl group
  • R 3 is a hydrogen atom or a C 1 _ 6 alkyl group
  • X is an oxygen atom
  • Y is a group of the formula: wherein R 4' and R 5' each is (i) a hydrogen atom or (ii) a C ⁇ alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-C ⁇ alkylamino, C 1 _ 6 alkoxy, C 1 _ 6 alkyl-carbonyloxy and halogen atom, R 6 and R 7 respectively is a hydrogen atom or a C 1 . 3 alkyl group, m and n is 1.
  • the agent as defined in (1) which is an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD) , an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia,
  • COPD chronic obstructive pulmonary disease
  • R 1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom
  • X is an oxygen atom or S(0) p (p is a whole number of 0 to 2)
  • Y is a group of the formula: R 4
  • R 4 and R 5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring
  • R 6 and R 7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R 6 and R 7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group
  • m is a whole number of 0 to 4
  • n is a whole number of 0 to 4 , or a salt thereof for preparing an agent for acting on bronchi, (8)
  • R 1 is (i) a hydrogen atom, (ii) a C ⁇ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C ⁇ alkylamino, Ci. 6 alkoxy, C 1 . 6 alkylcarbonyloxy and a halogen atom or (iii) a halogen atom,
  • R 2 and R 3 respectively is (i) a hydrogen atom or (ii) a C 1-6 alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C ⁇ alkylamino, C 1 _ 6 alkoxy, C 1-6 alkylcarbonyloxy and a halogen atom or (iii) a C 3 .
  • X is an oxygen atom or S(0) p (p is a whole number of 0 to
  • Y is (a) a group of the formula:
  • R 4 and R 5 respectively is (i) a hydrogen atom or (ii) a C ⁇ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C x _ 6 alkylamino, C ⁇ alkoxy, C 1 _ 6 alkylcarbonyloxy and a halogen atom) , or
  • a divalent group derived from a 3- to 7-membered cyclic hydrocarbon or 3- to 7-membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in adidtion to carbon atoms, optionally having substituents selected from the group consisting of (i) 1 , alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C x , 6 alkylamino, C 1 _ alkoxy, C ⁇ alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C 1 . 6 alkyl, C ⁇ acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) alkoxy and (vii) a halogen atom,
  • R 6 and R 7 respectively is (i) a hydrogen atom, (ii) a C ⁇ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C ⁇ alkylamino, C 1 . 6 alkoxy, C 1 . 6 alkylcarbonyloxy and a halogen atom, (iii) a C 3 . 6 cycloalkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or i-C ⁇ alkylamino, alkoxy, C 1 . 6 alkylcarbonyloxy and a halogen atom, or (iv) a C 6 .
  • aryl group optionally having substituents selected from the group consisting of (a) Cj.g alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C ⁇ alkylamino, C x _ 6 alkoxy, C ⁇ alkylcarbonyloxy and a halogen atom, (b) an amino which may be substituted by C 1 . 6 alkyl, C ⁇ acyl or 5- to 7-membered cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f) nitro, (g) C 1 _ 6 alkoxy, (h) C ⁇ alkylcarbonyloxy and (i) a halogen atom, or
  • R ⁇ and R 7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms, optionally having substituents selected from the group consisting of (i) C 1 mentally alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or alkylamino, C 1-6 alkoxy, C x _ 6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C ⁇ alkyl, Cj.
  • R 4' and R 5' each is (i) a hydrogen atom or (ii) a C ⁇ alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-Cj.g alkylamino, Cj_. 6 alkoxy, C 1 _ 6 alkyl-carbonyloxy and halogen atom, R 6 and R 7 respectively is a hydrogen atom or a C x _ 3 alkyl group, m and n is 1,
  • the agent is an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD) , an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia,
  • COPD chronic obstructive pulmonary disease
  • a method for preventing or treating asthma, chronic obstructive pulmonary disease (COPD), hypersensitive pneumonia or simple pulmonary eosinophilia which comprises administering an effective amount of a compound of the formula:
  • R 1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom
  • X is an oxygen atom or S(0) p (p is a whole number of 0 to 2)
  • Y is a group of the formula:
  • R 4 and R 5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring
  • R 6 and R 7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R 6 and R 7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group
  • m is a whole number of 0 to 4
  • n is a whole number of 0 to 4 , or a salt thereof to bronchi of mammals ,
  • R 1 is (i) a hydrogen atom, (ii) a C x _ 6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C 1 . 6 alkylamino, Cj_ 6 alkoxy, C ⁇ alkylcarbonyloxy and a halogen atom or (iii) a halogen atom,
  • R 2 and R 3 respectively is (i) a hydrogen atom or (ii) a C x _ 6 alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or alkylamino, C x _ 6 alkoxy, C x _ 6 alkylcarbonyloxy and a halogen atom or (iii) a C 3 .
  • alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or alkylamino, C ⁇ alkoxy, C 1-6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C ⁇ alkyl, acyl or 5- to 7-membered cyclic amino, (iii) hydroxy,
  • X is an oxygen atom or S(0) p (p is a whole number of 0 to
  • Y is (a) a group of the formula:
  • R 4 and R 5 respectively is (i) a hydrogen atom or (ii) a C ⁇ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or i-C ⁇ alkylamino, C ⁇ _ 6 alkoxy, C ⁇ alkylcarbonyloxy and a halogen atom) , or
  • a divalent group derived from a 3- to 7-membered cyclic hydrocarbon or 3- to 7-membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in adidtion to carbon atoms, optionally having substituents selected from the group consisting of (i) alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C x .
  • R 6 and R 7 respectively is (i) a hydrogen atom, (ii) a C ⁇ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C j .g alkylamino, C 1 _ 6 alkoxy, C x . 6 alkylcarbonyloxy and a halogen atom, (iii) a C 3 .
  • alkylcarbonyloxy and a halogen atom (b) an amino which may be substituted by C ⁇ alkyl, C ⁇ acyl or 5- to 7-membered cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f) nitro, (g) C ⁇ alkoxy, (h) C ⁇ alkylcarbonyloxy and (i) a halogen atom, or
  • R 6 and R 7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms , optionally having substituents selected from the group consisting of (i) C ⁇ alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C x _ 6 alkyl, C ⁇ acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) C x . 6 alkoxy and (vii) a halogen atom, m is a whole number of 0 to 4; n is a whole
  • R 4' and R 5 each is (i) a hydrogen atom or (ii) a C 1 alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-Cj.g alkylamino, C x _ 6 alkoxy, C 1 . 6 alkyl-carbonyloxy and halogen atom, R 6 and R 7 respectively is a hydrogen atom or a C x _ 3 alkyl group, m and n is 1 , and
  • An aerosol which comprises 6- ( 2 , 2-dimethyl-3- sulfamoyl-1-propoxy) -7-isopropyl [l,2,4] triazolo [l,5-b] pyridazine or a salt thereof and sprays (e.g., an aerosol for acting on bronchi),
  • R 1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom
  • R 2 and R 3 respectively is a hydrogen atom or an optionally substituted lower alkyl group, or R 2 and R 3 may, taken together with the adjacent
  • X is an oxygen atom or S(0) p (p is a whole number of 0 to 2);
  • Y is a group of the formula:
  • R 4 and R 5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring
  • R 6 and R 7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R 6 and R 7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group
  • m is a whole number of 0 to 4
  • n is a whole number of 0 to 4 , or a salt thereof and about 0.1 to 99wt% of additives for inhalation to the total composition
  • the inhalation as defined in (21) which is an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD) , an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia,
  • R 1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom
  • X is an oxygen atom or S(0) p (p is a whole number of 0 to 2)
  • Y is a group of the formula:
  • R 5 (R 4 and R 5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring;
  • R 6 and R 7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R 6 and R 7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group;
  • m is a whole number of 0 to 4 ;
  • n is a whole number of 0 to 4 , or a salt thereof and sprays which comprises
  • triazolopyridazine derivatives [I] used for the agent of the present invention contains asymmetric carbon within its structure, it may occur as optically active isomers as well as racemic mixtures and that these isomers and mixtures also fall within the scope of the triazolopyridazine derivatives [I].
  • triazolopyridazine derivatives [I] used for the agent of the present invention which contain 6- (2, 2- dimethyl-3-sulfamoyl-l-propoxy) -7-isopropyl [l ,2, 4] triazolo Cl,5-b] pyridazine, are known compounds described in EP-A-0562439, EP-A-0648491 or O96/08496.
  • examples of the "lower alkyl group" represented by R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 include a straight or branched C ⁇ alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl and so on.
  • Examples of the "cycloalkyl group" represented by R 2 , R 3 , R 6 or R 7 include a C 3 . 6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
  • substituents of the "lower alkyl group” and “cycloalkyl group” include 1 to 4 substituents selected from among hydroxy, amino, carboxyl, nitro, mono- or di-lower alkylamino (e.g. mono- or alkylamino groups such as methylamino, ethylamino, propylamino, dimethylamino , diethylamino , etc.), lower alkoxy (e.g. C ⁇ alkoxy groups such as methoxy, ethoxy, propoxy, hexyloxy, etc.), lower alkylcarbonyloxy (e.g. C ⁇ alkylcarbonyloxy groups such as acetoxy, ethylcarbonyloxy, etc.), halogen (e.g. fluorine, chlorine, bromine and iodine) and so on.
  • mono- or alkylamino e.g. mono- or alkylamino groups such as methylamino, eth
  • substituents of the "aryl group” include 1 to 5 substituents selected from among optionally substituted lower alkyl, optionally substituted amino, acetamido, hydroxy, carboxyl, nitro, lower alkoxy (e.g. x _ 6 alkoxy groups such as methoxy, ethoxy, propoxy, etc. ) , lower alkylcarbonyloxy (e.g. C x . 6 alkylcarbonyloxy groups such as acetoxy, ethylcarbonyloxy, etc.), halogen atoms (e.g. fluorine, chlorine, bromine and iodine) and so on.
  • substituents by which the lower alkyl e.g.
  • C x . 6 alkyl group such as methyl, ethyl, n-propyl, etc.
  • C x . 6 alkyl group such as methyl, ethyl, n-propyl, etc.
  • substituents selected from among hydroxy, amino, mono- or di-lower alkylamino (e.g. mono- or di-C ⁇ alkylamino groups such as methylamino, ethylamino, propylamino. dimethylamino , diethylamino , etc.), lower alkoxy (e.g. C 1 . 6 alkoxy groups such as methoxy, ethoxy, propoxy, hexyloxy, etc.), halogen (e.g. fluorine, chlorine, bromine and iodine) and so on.
  • hydroxy, amino, mono- or di-lower alkylamino e.g. mono- or di-C ⁇ alkylamino groups such as
  • substituents by which the amino group mentioned above may have include 1 or 2 substituents selected from among C ⁇ alkyl (e.g. methyl, ethyl, propyl, etc.), 5- to 7-membered cyclic amino (e.g. pyrrolidino, morpholino, piperidino, piperazino, etc.) and so on.
  • C ⁇ alkyl e.g. methyl, ethyl, propyl, etc.
  • 5- to 7-membered cyclic amino e.g. pyrrolidino, morpholino, piperidino, piperazino, etc.
  • halogen represented by R 1
  • examples of the "halogen” represented by R 1 include fluorine, chlorine, bromine, iodine and so on.
  • a 5- to 7-membered cyclic hydrocarbon such as C 5 . 7 cycloalkenes (e.g.
  • cyclopentene cyclohexene, cycloheptene, etc.
  • benzene and so on and a 5- or 6- membered nitrogen-containing heterocyclic group consisting of carbon and nitrogen atoms e.g., pyrrole, pyridine, piperidine , etc.
  • nitrogen-containing heterocyclic group consisting of carbon and nitrogen atoms
  • Examples of the "3- to 7-membered homocyclic ring" of the "divalent group derived from the 3- to 7-membered homocyclic ring" represented by Y include a 3- to 7-membered homocyclic ring consisting exclusively of carbon atoms, for instance.
  • C 3 . 7 cycloalkanes such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc.
  • C 3 . 7 cycloalkenes such as cyclopropene , cyclobutene, cyclopentene, cyclohexene, cycloheptene, etc. and benzene can be mentioned as the common species.
  • Examples of the "divalent group derived from the 3- to 7-membered homocyclic ring” include a group resulting from either elimination of two hydrogen atoms from a single carbon atom in the 3- to 7-membered homocyclic ring or elimination of one hydrogen atom from each of two different carbon atoms .
  • the following groups can be included by way of example:
  • Examples of the "3- to 7-membered heterocyclic ring" of the "divalent group derived from the 3- to 7-membered heterocyclic ring" represented by Y include a 3- to 7- membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from among nitrogen, oxygen, sulfur and other atoms in adidtion to carbon atoms, for instance.
  • oxetane, tetrahydrofuran , tetrahydropyran, pyrrole, azetidine, pyrrolidine, piperidine, piperazine, tetraydrothiophene , homopiperidine, morpholine, etc. can be employed.
  • divalent group derived from the "3- to 7-membered heterocyclic ring” is a group resulting from either elimination of two hydrogen atoms from a single carbon atom in the 3- to 7-membered heterocyclic ring or elimination of one hydrogen atom from each of two different atoms .
  • the following groups can be included
  • nitrogen-containing heterocyclic group formed by R 6 and R 7 with the adjacent nitrogen atom
  • examples of the "nitrogen-containing heterocyclic group" formed by R 6 and R 7 with the adjacent nitrogen atom include a group resulting from elimination of one hydrogen atom from a nitrogen atom in a ring such as a 3- to 13- membered nitrogen-containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain one to four hetero atoms , for example , selected from nitrogen, oxygen, sulfur and other atoms.
  • the following 3- to 9-membered nitrogen- containing heterocyclic groups can be generally used:
  • substituents by which the "3- to 7- membered homocyclic ring", “3- to 7-membered heterocyclic ring” and “nitrogen-containing heterocyclic group” may have include 1 to 5 substituents selected from among an optionally substituted lower alkyl, an optionally substituted amino, hydroxy, carboxyl, nitro, lower alkoxy (e.g. C ⁇ alkoxy groups such as methoxy, ethoxy, propoxy, etc. ) , halogen (e.g. fluorine, chlorine, bromine and iodine) and so on.
  • substituents by which the lower alkyl e.g.
  • C ⁇ alkyl group such as methyl, ethyl, n-propyl, etc.) mentioned just above may have, include 1 to 4 substituents selected from among hydroxy, amino, mono- or di-lower alkylamino (e.g. mono- or alkylamino groups such as methylamino , ethylamino , propylamino , dimethylamino , diethylamino, etc.), lower alkoxy (e.g. C ⁇ alkoxy groups such as methoxy, ethoxy, propoxy, hexyloxy, etc.), lower alkylcarbonyloxy (e.g.
  • mono- or alkylamino groups such as methylamino , ethylamino , propylamino , dimethylamino , diethylamino, etc.
  • lower alkoxy e.g. C ⁇ alkoxy groups such as methoxy, ethoxy, propoxy, hex
  • C ⁇ alkylcarbonyloxy groups such as acetoxy, ethylcarbonyloxy, etc.), halogen (e.g. fluorine, chlorine, bromine and iodine) and so on.
  • substituents by which the amino group mentioned above may have include 1 to 2 substituents selected from among C ⁇ alkyl (e.g. methyl, ethyl, propyl, etc.), acyl (e.g. Q. x . b acyl groups such as formyl, acetyl, propionyl, butyryl, etc.), 5- to 7-membered cyclic amino (e.g. pyrrolidino, morpholino, piperidino, piperazino, etc. ) and so on.
  • R 1 are a hydrogen atom or a C ⁇ alkyl group (e.g. methyl, ethyl, n-propyl, etc.) and more preferable examples are a hydrogen atom and so on.
  • R 2 are a hydrogen atom or a C ⁇ alkyl group (e.g. methyl, ethyl, n-propyl, etc.) and more preferable examples are a hydrogen atom and so on.
  • R 3 are a hydrogen atom or a C ⁇ alkyl group (e.g. methyl, ethyl, n-propyl, i-propyl, etc.) and more preferable examples are a branched C 3 . 6 alkyl group (e.g. i-propyl, etc.).
  • Particularly preferred is the case of cyclohexene, benzene or the like.
  • X is preferably an oxygen atom or S and more preferably an oxygen atom.
  • Y are a group of the formula:
  • R 4' and R 5' each is (i) a hydrogen atom or (ii) a C ⁇ alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or alkyl-carbonyloxy and halogen atom, and so on.
  • Examples of the "C ⁇ alkyl group" represented by R 4' and R 5' are methyl, ethyl, n-propyl, i-propyl and so on, and more preferable examples are methyl, ethyl and so on.
  • Y is a divalent group derived from a 3- to 7-membered homocyclic ring or heterocyclic ring which may be substituted.
  • Y is preferably a group of the formula:
  • Y More preferably examples of Y include the follow:
  • R 6 and R 7 are a hydrogen atom, a C j . 3 alkyl group (e.g. methyl, ethyl, n-propyl, etc.) and so on, and particularly a hydrogen atom is preferred.
  • Preferable example of m is a whole number of 1 to 4 , more preferable example is a whole number of 1 to 3 and most preferable example is 1.
  • n is a whole number of 1 to 4 and more preferable example is 1.
  • triazolopyridazine derivatives [ I ] used for the agent of the present invention are all compounds prepared in Examples of EP-A-0562439 and WO96/08496, and most preferable example is 6- (2, 2- dimethyl-3-sulfamoyl-l-propoxy) -7-isopropyl [l , 2 , 4] triazolo [l,5-b] pyridazine or a salt thereof.
  • the salt of triazolopyridazine derivatives [I] is preferably a physiologically acceptable acid addition salt.
  • Such salts include salt with inorganic acids (e.g., hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) and salts with organic acids (e.g., acetic acid, formic acid, propionic acid, fumaricacid, maleicacid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) .
  • inorganic acids e.g., hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid
  • organic acids e.g., acetic acid, formic acid, propionic acid, fumaricacid, maleicacid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulf
  • the triazolopyridazine derivatives [I] have an acidic group, such as -COOH, they may form a salt with an inorganic base (e.g., an alkali metal or alkaline earth metal such as sodium, potassium, calcium or magnesium; or ammonia) or an organic base (e.g., a tri-C ⁇ alkylamine such as triethylamine) .
  • an inorganic base e.g., an alkali metal or alkaline earth metal such as sodium, potassium, calcium or magnesium; or ammonia
  • an organic base e.g., a tri-C ⁇ alkylamine such as triethylamine
  • triazolopyridazine derivatives [ I ] or salts thereof can be prepared according to the descriptions of EP-A- 0562439 or O96/08496, particularly the descriptions of Examples of the references .
  • the agent for acting on bronchi of the present invention makes the triazolopyridazine derivatives [I] or salts thereof act on bronchi specifically, on the other hand do not make them act on a whole body. And, the agent of the present invention may act on tissues around bronchi such as trachea, lung, etc..
  • agent of the present invention can show the local actions of triazolopyridazine derivatives [ I ] or salts thereof, types of the agent are not limited.
  • the agent of the present invention can be preferably used as an inhalation.
  • additives for the inhalation may be any additives generally used in an inhalation, and examples are solid fillers such as pressurizing agents, white sugar, lactose, glucose, mannitol and sorbitol, liquid fillers e.g.
  • inert liquid such as propylene glycol
  • binders such as methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone , polyethylene glycol and white sugar
  • lubricants such as magnesium stearate, light silicate anhydride, talk and sodium lauryl sulfate
  • taste correctives such as citric acid, menthol, glythylithin ammonium salt, glycine and orange powder
  • preservatives such as sodium benzoate, sodium bisulfite, methyl parabene and propyl parabene, stabilizers such as citric acid and sodium citrate
  • suspending agents such as methyl cellulose, polyvinylpyrrolidone, lecithin and sorbitan trioleate
  • dispersing agents such as surface active agents, solvents such as water, isotonicity agents such as sodium chloride, pH a justor such as sulfuric acid and hydrochloric acid, and solubilizers such as ethanol.
  • the pressurizing agents include liquefied gas pressurizing agents, compressed gas etc.
  • the liquefied gas pressurizing agents include e.g. hydrocarbon fluoride (e.g. substitute Freon such as HCFC22, HCFC-123, HCFC-134a, and HCFC142), liquefied petroleum, and dimethyl ether.
  • the compressed gas includes e.g. soluble gas (e.g. carbon dioxide gas, nitrous oxide gas etc. ) and insoluble gas (e.g. nitrogen gas ) .
  • the pharmaceutical preparation of the invention may contain as active ingredients any pharmaceutical ingredients other than triazolopyridazine derivative [I] or salts thereof.
  • pharmaceutical active ingredients include anti-asthma agents (e.g. theophylline , procaterol, ketotifen, azelastine, seratrodast (bronica) etc.), anti-allergy agents (e.g. ketotifen, terfenadine, azelastine, epinastine etc.), anti-inflammatory agents (e.g. diclophenac sodium, ibuprofen, indomethacin etc.), antimicrobial agents (e.g.
  • cefixme, cefdinir, ofloxacin, tosfloxacin etc. ) and anti-fungus agents e.g. fluconazole. itraconazole etc.
  • these ingredients are not particularly limited insofar and can be used in a suitable ratio.
  • the content of the triazolopyridazine derivative [I] or salts thereof in the pharmaceutical preparation of the invention vary depending on the disease treated, the age or sex of the patient and the conditions of the disease, the content is in the range of usually about 0.01 to 99.9 % by weight, preferably about 0.1 to 50 % by weight , more preferably about 0.5 to 20 % by weight , relative to the whole of the pharmaceutical preparation.
  • the content of various additives such as additives for an inhalation varies depending on the disease treated, the age or sex of the patient and the conditions of the disease, the content is in the range of usually about 0.1 to 99 % by weight, preferably about 10 to 99 % by weight, more preferably about 50 to 99 % by weight, most preferably about 70 to 99 % by weight, relative to the whole of the pharmaceutical preparation.
  • the content of other pharmaceutical ingredients than the triazolopyridazine derivative [I] or salts thereof varies depending on the disease treated, the age or sex of the patient and the conditions of the disease, the content is in the range of usually about 0.01 to 99.9 % by weight, preferably about 0.1 to 50 % by weight , more preferably about 0.5 to 20 % by weight, relative to the whole of the pharmaceutical preparation.
  • the agent of the invention can be formed into a powder for inharation, a suspension for inharation, a liquid preparation for inharation or a capsule for inharation by a method known in the art and administered by means of a suitable inhaler.
  • the agent of the invention can be used as an aerosol.
  • the aerosol is made completely contamination-free during use, and because the inside of the aerosol is maintained always under pressure, the content introduced in the can is completely prevented from being contaminated from the outside.
  • the aerosol is composed usually of 5 elements i.e. a vessel, a valve, a button, a content and a pressurizing agent, and is classified into a 2-phase system, a 3-phase system and a membrane system (double vessel).
  • the vessel used is a vessel stipulated under a high-pressure gas regulation , and its material is metal (e.g. tin, aluminum), glass or plastics.
  • metal vessel e.g. tin, aluminum
  • the glass vessel is excellent in solvent resistance and corrosion resistance and is easily processed, so it can be easily formed into a deformed vessel.
  • the valve is a part most influential over the jet characteristics and sealing properties of the aerosol.
  • the valve is constituted usually of a mountain cup, a stem, a housing, a spring, a dip tube and gasket rubber, and use is made of a valve equipped with a gas-phase hole or a quantification valve.
  • the stem is pressed whereby the stem hole closed with sealing gasket rubber is allowed to communicate with the inside of the vessel so that the content is released through the stem hole.
  • the button used includes a straight button, a brake cap button, a button for foam, and a button with a long nozzle.
  • the content is the topical working agent (inhalation) of the invention described above.
  • the pressurizing agent is the same as described above .
  • a 2-phase system aerosol using a liquefied gas pressurizing agent as the pressurizing agent forms an uniform liquid phase in which a suspension (stock solution) containing the triazolopyridazine derivative [ I ] or salts thereof are made compatible with the pressurizing agent, and the inside of the vessel is composed of 2 phases i.e. a liquid phase and a gaseous phase of a gas of the pressurizing agent in an upper space in the vessel.
  • fine droplets can be obtained due to the propellant force of the pressurizing agent when the liquefied pressurizing agent under pressure in the vessel is jetted out through a valve under normal pressure.
  • compressed gas the compressed gas present under compression in an upper space merely presses the stock solution.
  • the former consists of a 2-phase emulsification state of the liquid phase and a gaseous phase in an upper space
  • the latter consists of a powder solid phase, a liquefied gaseous phase, and a gaseous phase in an upper space.
  • the membrane system is a system in which only the stock solution itself is jetted out from a double vessel in which the pressurizing agent is filled in an outer vessel and the stock solution is filled in an inner vessel communicating with a valve.
  • the agent of the invention is used as an aerosol, it is formed preferably into a powder aerosol.
  • Production of the aerosol consists usually of the 2 steps of preparing the content and filling the content and the pressurizing agent .
  • Preparation of the content can be conducted in any method known in the art, and the following methods are used: (1) a method of mixing the triazolopyridazine derivative [I] or a salt thereof with an adjuvant and a solvent to form a uniform suspension, (2) a method of kneading the triazolopyridazine derivative [I] or a salt thereof with a surface active agent to form powder, and (3) a method of mixing the triazolopyridazine derivative [I] or a salt thereof with water-soluble additives for inhalation and then stirring, heating and cooling the mixture into an emulsion.
  • Filling of the content and the pressurizing agent consists usually of the steps of washing the vessel, filling the content, degassing the inside of the vessel, filling the pressurizing agent, and attaching the valve thereto.
  • Filling of the pressurizing agent involves filling under cooling, filling under pressure, or undercup filling.
  • crimp conditions are confirmed in order to examine whether the valve is correctly fitted. Further, in order to examine linkage from the product, a hot water test is conducted and water droplets are removed.
  • a flame-length test and tests for changes with time are conducted in order to confirm the storage and safety of the aerosol for use.
  • the devices used for administration may be commercial inhalers, and examples include Ventolin Rotacaps, Glaxo), Spin Heller * (Fujisawa Pharmaceutical Co., Ltd.), Intal Spincaps (Fisonz), Atrovent and Berotec Inhaletten (Boehringer Ingelheim) , Foradil (Chiba), Bentodisks (Glaxo), Pabrizer * (Teijin Ltd. ) , Bricanyl Turbuhaler (Astra) , Miat Insufflator) .
  • the triazolopyridazine derivatives [I] or salts thereof used for the agent of the present invention possess excellent an anti-allergic action, an anti-asthmatic action, an anti-PAF (platelet activating factor) action, an inhibitory action of eosinophil chemotaxis, an inhibitory action of local eosinophilic infiltration in allergic and asthmatic reactions , and is with a low toxic potential (acute toxicity: LD 50 >2g/kg).
  • the agent of the present invention can act specifically on the bronchus or its surrounding tissues by administering it topically into the mouth, throat etc.
  • Topical administration of the triazolopyridazine derivative [I] or its salts achieve a minimum effective amount, thus eliminating general and high-dosage administration. Accordingly, it can be administered into even children easily and safely. In particular, outstanding local acting effects can be demonstrated in the case of an inhalation or an aerosol.
  • the agent of the present invention can be used safety as an anti-asthmatic agent, an anti- PAF agent, an anti-allergic agent, an agent for inhibiting eosinophil chemotaxis , an agent for preventing or treating diseases related to eosinophilic infiltration (for example, allergic diseases such as urticaria, atopic dermatitis, allergic rhinitis, hypersensitive pneumonia, etc,; diseases of the skin such as eczema, dermatitis herpetiformis , psoriasis, etc., and respiratory diseases such as simple pulmonary eosinophilia (PIE syndrome), chronic obstructive pulmonary disease (COPD), etc.), particularly as an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD), an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia, in mammals (e.g., humans, mice,
  • the dose of the agents of the present invention varies depending on age, body weight, symptoms, route and frequency of administration and other factors , they may be administered at about 0.001 to 10 mg/kg, preferably about 0.01 to 10 mg/kg, more preferably about 0.1 to 10 mg/kg, particularly preferably about 0.1 to 5 mg/kg in one to two portions daily for an adult .
  • Preferable route of administration may be direct inhalation into mouth, etc. by using tools for inhalation.
  • Detection of the fractions containing each object compound in the Reference Examples was carried out under TLC (Thin Layer Chromatography) monitoring.
  • TLC monitoring Merck's 60F 254 was used as the TLC plate and a UV detector for detection .
  • Merck' s silica gel 60 (70 to 230 mesh) was used as a silica gel for column chromatography.
  • mice Male Hartley guinea pigs (body weights about 500 g) were used. Bronchoconstriction induced by PAF, 1 ⁇ g/kg i.v. , in guinea pigs was measured using to the method of Konzett-Roessle . With the guinea pig immobilized in the dorsal position, tracheotomy was performed under urethane (1.5 g/kg i.v.) anesthesia and the trachea was connected through a cannula to a respirator. The side branch of the tracheal cannula was connected to a transducer (Model 7020, Ugobasile).
  • Solubitantriolate 20.0 mg Suspensions for inhalation can be prepared by mixing the above components.
  • Quantitative valve can be used for 50 11 1 .
  • Liquid preparations for inhalation can be prepared by mixing the above components .
  • the liquid preparation for inhalation can be used by using Nebulizer (Trade Mark) .
  • the powders for inhalation can be prepared by mixing the above components .
  • the capsules for inhalation can be used by using Spinhalor
  • the agent of the present invention can make an anti-asthmatic action, etc., of the triazoropyridazine derivatives [I] such as 6- (2 , 2-dimethyl-3-sulfamoyl-1- propoxy) -7-isopropyl [l,2,4] triazolo Cl,5-b] pyridazine, etc., or salts thereof act on bronchi or tissues around bronchi specifically, and therefore, since local administering could be performed by a minimum effective amount of by the triazolopyridazine derivatives [I], it could avoid to administer an amount of the triazolopyridazine derivatives [I] into a whole body.
  • the triazoropyridazine derivatives [I] such as 6- (2 , 2-dimethyl-3-sulfamoyl-1- propoxy) -7-isopropyl [l,2,4] triazolo Cl,5-b] pyridazine, etc., or salts thereof act on bron

Abstract

The agent of the present invention can make an anti-asthmatic action, etc., of the triazolopyridazine derivatives [I] such as 6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-isopropyl[1,2,4]triazolo[1,5-b]pyridazine, etc., or salts thereof act on bronchi or tissues around bronchi specifically, and therefore, since local administering could be performed by a minimum effective amount of by the triazolopyridazine derivatives [I], it could avoid to administer an amount of the triazolopyridazine derivatives [I] into a whole body.

Description

TRIAZOLO-PYRIDAZINE DERIVATIVES FOR THE TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASES
Technical Field
The present invention relates to an agent for acting on bronchi which comprises triazolopyridazine derivatives such as 6- ( 2 , 2-dimethyl-3 -sulfamoyl-l-propoxy) -7- isopropyl (l , 2 , 4) triazolo (l , 5-b] pyridazine , etc . .
Background
Triazolopyridazine derivatives represented by the formula:
Figure imgf000003_0001
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom or an optionally substituted lower alkyl group, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p (p is a whole number of 0 to 2); Y is a group of the formula:
R4 —C—
(R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4 ; n is a whole number of 0 to 4 , are compounds which are useful for an anti-asthmatic agent, an anti-PAF (platelet activating factor) agent, an anti-allergic agent, an agent for inhibiting eosinophil chemotaxis , an agent for preventing or treating allergic rhinitis or an agent for preventing or treating atopic dermatitis (EP-A-0562439 , EP-A-0648491 and WO96/08496).
And, it is desired to develop agents which show actions of the triazolopyridazine derivatives [I] locally.
Disclosure of Invention
The present inventors diligently made extensive studies in order to solve the problems and, as a result, they found that it could make actions of the derivatives act at bronchi locally by preparing an inhalation, etc. comprising 6- (2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [l , 2 , 4) triazolo Cl,5-b] pyridazine or a salt thereof. And, they further studied based on the finding, the present invention has been accompliched.
More specifically, the present invention provides ( 1 ) A agent for acting on bronchi which comprises a compound of the formula:
Figure imgf000004_0001
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom or an optionally substituted lower alkyl group, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p (p is a whole number of 0 to 2); Y is a group of the formula:
R4 I
— c—
I R5
(R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4; n is a whole number of 0 to 4 , or a salt thereof, ( 2 ) The agent as defined in ( 1 ) , wherein R1 is (i) a hydrogen atom, (ii) a C1_6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- ordi-Cj.j alkylamino, Ci.j alkoxy, C1.6 alkylcarbonyloxy and a halogen atom or (iii) a halogen atom,
R2 and R3 respectively is (i) a hydrogen atom or (ii) a C1.6 alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or i-C^ alkylamino, C1-6 alkoxy, C^ alkylcarbonyloxy and a halogen atom or (iii) a C3.6 cycloalkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono-
Figure imgf000005_0001
alkylamino, C1_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms , optionally having substituents selected from the group consisting of (i) C1_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C^ alkylamino, C1-6 alkoxy, C^ alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C^ alkyl, C1-6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Cj.6 alkoxy and (vii) a halogen atom;
X is an oxygen atom or S(0)p (p is a whole number of 0 to 2).
Y is (a) a group of the formula: R4 —C—
(R4 and R5 respectively is (i) a hydrogen atom or (ii) a C^ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C^ alkylamino, C^ alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom) , or
(b) a divalent group derived from a 3- to 7-membered cyclic hydrocarbon or 3- to 7-membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in adidtion to carbon atoms, optionally having substituents selected from the group consisting of (i) Cx_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cj__6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by Cx_6 alkyl, Cx_6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Cj.j alkoxy and (vii) a halogen atom,
R6 and R7 respectively is (i) a hydrogen atom, (ii) a C1-6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro. mono- or di-C1.6 alkylamino, C1,6 alkoxy, Cλ,6 alkylcarbonyloxy and a halogen atom, (iii) a C3.6 cycloalkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C1.6 alkylamino, C1_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, or (iv) a C6.14 aryl group optionally having substituents selected from the group consisting of (a) C^ alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C^ alkylamino, Cx_6 alkoxy, Cx.6 alkylcarbonyloxy and a halogen atom, (b) an amino which may be substituted by C^ alkyl, C^ acyl or 5- to 7-membered cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f) nitro, (g) Cx.6 alkoxy, (h) C1_6 alkylcarbonyloxy and (i) a halogen atom, or
R6 and R7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms, optionally having substituents selected from the group consisting of (i) C1_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C^ alkylamino, λ_6 alkoxy, C^ alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C1_6 alkyl, C^ acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Ci.s alkoxy and (vii) a halogen atom, m is a whole number of 0 to 4; n is a whole number of 0 to 4,
( 3 ) The agent as defined in ( 1 ) , wherein R1 is hydrogen atom or a C^ alkyl group, R2 is a hydrogen atom or a C1_3 alkyl group, R3 is a hydrogen atom or a C1_6 alkyl group, X is an oxygen atom, Y is a group of the formula:
Figure imgf000008_0001
wherein R4' and R5' each is (i) a hydrogen atom or (ii) a C^ alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-C^ alkylamino, C1_6 alkoxy, C1_6 alkyl-carbonyloxy and halogen atom, R6 and R7 respectively is a hydrogen atom or a C1.3 alkyl group, m and n is 1.
( 4 ) The agent as defined in ( 1 ) , wherein the compound is 6- ( 2 , 2-dimethyl-3-sulfamoyl-l-propoxy) -7-isopropyl
[l,2,4] triazolo [l,5-b] pyridazine,
(5) The agent as defined in (1) , which is an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD) , an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia,
(6) The agent as defined in (1) , which is an inhalation for acting on bronchi,
(7) Use of a compound of the formula:
Figure imgf000008_0002
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted cycloalkyl group, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p (p is a whole number of 0 to 2) ; Y is a group of the formula: R4
I
— c—
(R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4 ; n is a whole number of 0 to 4 , or a salt thereof for preparing an agent for acting on bronchi, (8) The use as defined in (7), wherein
R1 is (i) a hydrogen atom, (ii) a C^ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C^ alkylamino, Ci.6 alkoxy, C1.6 alkylcarbonyloxy and a halogen atom or (iii) a halogen atom,
R2 and R3 respectively is (i) a hydrogen atom or (ii) a C1-6 alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C^ alkylamino, C1_6 alkoxy, C1-6 alkylcarbonyloxy and a halogen atom or (iii) a C3.6 cycloalkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C^ alkylamino, Cj_6 alkoxy, C1-6 alkylcarbonyloxy and a halogen atom, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms , optionally having substituents selected from the group consisting of (i) C1_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C^ alkylamino, C1-6 alkoxy, C^6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C1,6 alkyl, acyl or 5- to 7-membered cyclic amino, (iii) hydroxy,
(iv) carboxyl, (v) nitro, (vi) C1_6 alkoxy and (vii) a halogen atom;
X is an oxygen atom or S(0)p (p is a whole number of 0 to
2),
Y is (a) a group of the formula:
R4
I
—C—
(R4 and R5 respectively is (i) a hydrogen atom or (ii) a C^ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino, C^ alkoxy, C1_6 alkylcarbonyloxy and a halogen atom) , or
(b) a divalent group derived from a 3- to 7-membered cyclic hydrocarbon or 3- to 7-membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in adidtion to carbon atoms, optionally having substituents selected from the group consisting of (i) 1, alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cx,6 alkylamino, C1_ alkoxy, C^ alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C1.6 alkyl, C^ acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) alkoxy and (vii) a halogen atom,
R6 and R7 respectively is (i) a hydrogen atom, (ii) a C^ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C^ alkylamino, C1.6 alkoxy, C1.6 alkylcarbonyloxy and a halogen atom, (iii) a C3.6 cycloalkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or i-C^ alkylamino, alkoxy, C1.6 alkylcarbonyloxy and a halogen atom, or (iv) a C6.14 aryl group optionally having substituents selected from the group consisting of (a) Cj.g alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C^ alkylamino, Cx_6 alkoxy, C^ alkylcarbonyloxy and a halogen atom, (b) an amino which may be substituted by C1.6 alkyl, C^ acyl or 5- to 7-membered cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f) nitro, (g) C1_6 alkoxy, (h) C^ alkylcarbonyloxy and (i) a halogen atom, or
Rδ and R7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms, optionally having substituents selected from the group consisting of (i) C1„6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or
Figure imgf000011_0001
alkylamino, C1-6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C^ alkyl, Cj.6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) alkoxy and (vii) a halogen atom, m is a whole number of 0 to 4; n is a whole number of 0 to 4,
( 9 ) The use as defined in ( 7 ) , wherein R1 is hydrogen atom or a C1_3 alkyl group, R2 is a hydrogen atom or a C^-j alkyl group, R3 is a hydrogen atom or a C1-6 alkyl group, X is an oxygen atom, Y is a group of the formula: •c-
,5'
R wherein R4' and R5' each is (i) a hydrogen atom or (ii) a C^ alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-Cj.g alkylamino, Cj_.6 alkoxy, C1_6 alkyl-carbonyloxy and halogen atom, R6 and R7 respectively is a hydrogen atom or a Cx_3 alkyl group, m and n is 1,
(10) The use as defined in (7), wherein the compound is 6- ( 2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl
[l,2,4] triazolo [l,5-b] pyridazine,
(11) The use as defined in (7), wherein the agent is an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD) , an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia,
(12) The use as defined in (7), wherein the agent is an inhalation for acting on bronchi,
(13) A method for preventing or treating asthma, chronic obstructive pulmonary disease (COPD), hypersensitive pneumonia or simple pulmonary eosinophilia which comprises administering an effective amount of a compound of the formula:
Figure imgf000012_0001
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted cycloalkyl group, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p (p is a whole number of 0 to 2) ; Y is a group of the formula:
R4
I
—c—
I R5
(R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4 ; n is a whole number of 0 to 4 , or a salt thereof to bronchi of mammals ,
(14) The method as defined in (13), wherein R1 is (i) a hydrogen atom, (ii) a Cx_6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C1.6 alkylamino, Cj_6 alkoxy, C^ alkylcarbonyloxy and a halogen atom or (iii) a halogen atom,
R2 and R3 respectively is (i) a hydrogen atom or (ii) a Cx_6 alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or
Figure imgf000013_0001
alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom or (iii) a C3.6 cycloalkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C^ alkylamino, C1-6 alkoxy, Cj__6 alkylcarbonyloxy and a halogen atom, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms , optionally having substituents selected from the group consisting of
(i) alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or
Figure imgf000014_0001
alkylamino, C^ alkoxy, C1-6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C^ alkyl, acyl or 5- to 7-membered cyclic amino, (iii) hydroxy,
(iv) carboxyl, (v) nitro, (vi) C1.6 alkoxy and (vii) a halogen atom;
X is an oxygen atom or S(0)p (p is a whole number of 0 to
2).
Y is (a) a group of the formula:
R4
I
—c—
(R4 and R5 respectively is (i) a hydrogen atom or (ii) a C^ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or i-C^ alkylamino, Cλ_6 alkoxy, C^ alkylcarbonyloxy and a halogen atom) , or
(b) a divalent group derived from a 3- to 7-membered cyclic hydrocarbon or 3- to 7-membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in adidtion to carbon atoms, optionally having substituents selected from the group consisting of (i)
Figure imgf000014_0002
alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cx.6 alkylamino, C1-6 alkoxy, C^ alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by C^ alkyl, C1_6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Cx.6 alkoxy and (vii) a halogen atom,
R6 and R7 respectively is (i) a hydrogen atom, (ii) a C^ alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cj.g alkylamino, C1_6 alkoxy, Cx.6 alkylcarbonyloxy and a halogen atom, (iii) a C3.6 cycloalkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-C^ alkylamino, Cj.g alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, or (iv) a C6.14 aryl group optionally having substituents selected from the group consisting of (a) Cx.6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or
Figure imgf000015_0001
alkylamino, Cx_6 alkoxy, Cj_.β alkylcarbonyloxy and a halogen atom, (b) an amino which may be substituted by C^ alkyl, C^ acyl or 5- to 7-membered cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f) nitro, (g) C^ alkoxy, (h) C^ alkylcarbonyloxy and (i) a halogen atom, or
R6 and R7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms , optionally having substituents selected from the group consisting of (i) C^ alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or
Figure imgf000015_0002
alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by Cx_6 alkyl, C^ acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Cx.6 alkoxy and (vii) a halogen atom, m is a whole number of 0 to 4; n is a whole number of 0 to 4,
(15) The method as defined in (13), wherein R1 is hydrogen atom or a Cx_3 alkyl group, R2 is a hydrogen atom or a C^ alkyl group, R3 is a hydrogen atom or a C^ alkyl group, X is an oxygen atom, Y is a group of the formula:
R4'
I
— c—
wherein R4' and R5 each is (i) a hydrogen atom or (ii) a C1 alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-Cj.g alkylamino, Cx_6 alkoxy, C1.6 alkyl-carbonyloxy and halogen atom, R6 and R7 respectively is a hydrogen atom or a Cx_3 alkyl group, m and n is 1 , and
(16) The method as defined in (13), wherein the compound is 6- ( 2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl
[l,2,4J triazolo [l,5-b] pyridazine. Furthermore, the present invention provides:
(17) The agent as defined in (1), which is an aerosol for acting on bronchi,
(18) The use as defined in (8), wherein the agent is an aerosol for acting on bronchi,
(19) An inhalation which comprises 6- ( 2 , 2-dimethyl-3- sulfamoyl-1-propoxy) -7-isopropyl Cl,2,4] triazolo [l,5-b) pyridazine or a salt thereof and sprays (e.g. , an inhalation for acting on bronchi) ,
(20) An aerosol which comprises 6- ( 2 , 2-dimethyl-3- sulfamoyl-1-propoxy) -7-isopropyl [l,2,4] triazolo [l,5-b] pyridazine or a salt thereof and sprays (e.g., an aerosol for acting on bronchi),
(21) An inhalation which comprises about 0.01 to 99.9 wt% of a compound of the formula:
Figure imgf000016_0001
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom or an optionally substituted lower alkyl group, or R2 and R3 may, taken together with the adjacent
-C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p (p is a whole number of 0 to 2); Y is a group of the formula:
R4
I
—C—
I R5
(R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4 ; n is a whole number of 0 to 4 , or a salt thereof and about 0.1 to 99wt% of additives for inhalation to the total composition,
(22) The inhalation as defined in (21) , wherein the compound is 6- ( 2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl
[l,2,4] triazolo [l,5-b] pyridazine,
(23) The inhalation as defined in (21) which is a powder for inharation, a capsule for inharation, a suspension for fot inharation or a liquid preparation for inharation,
(24) The inhalation as defined in (21) which is an aerosol,
(25) The inhalation as defined in (21) , wherein the additive for inhalation is spray,
(26) The inhalation as defined in (21) which is an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD) , an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia, (27) A method for producing the inhalation as defined in (21), which comprises mixing about 0.01 to 99.9 wt% of a compound of the formula:
R
Figure imgf000018_0001
wherein each symbol is the same as defined in claim 13, or a salt thereof and about 0.1 to 99wt% of additives for inhalation to the total composition, and
(28) A method for preparing an aerosol comprising a compound of the formula:
[|]
Figure imgf000018_0002
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom or an optionally substituted lower alkyl group, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p (p is a whole number of 0 to 2); Y is a group of the formula:
R4
I
R5 (R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4 ; n is a whole number of 0 to 4 , or a salt thereof and sprays which comprises
(i) (a) mixing the compound [I] or a salt thereof with an adjuvant and a solvent to form a uniform suspension, (b) kneading the compound [ I ] or a salt thereof with a surface active agent to form powder, and (c) mixing the compound [I] or a salt thereof with water-soluble additives for inhalation and then stirring, heating and cooling the mixture into an emulsion, and
(ii) filing the suspension, powder or emulsion into the vessel and degassing the inside of the vessel, and (iii) filing the pressurizing agent into the vessel and attaching the valve to vessel.
It should be understood that where the triazolopyridazine derivatives [I] used for the agent of the present invention contains asymmetric carbon within its structure, it may occur as optically active isomers as well as racemic mixtures and that these isomers and mixtures also fall within the scope of the triazolopyridazine derivatives [I].
The triazolopyridazine derivatives [I] used for the agent of the present invention, which contain 6- (2, 2- dimethyl-3-sulfamoyl-l-propoxy) -7-isopropyl [l ,2, 4] triazolo Cl,5-b] pyridazine, are known compounds described in EP-A-0562439, EP-A-0648491 or O96/08496.
In the formula mentioned above, examples of the "lower alkyl group" represented by R1, R2, R3, R4, R5, R6 or R7 include a straight or branched C^ alkyl group such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, n-pentyl, n-hexyl and so on.
Examples of the "cycloalkyl group" represented by R2, R3 , R6 or R7 include a C3.6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.
Examples of the "aryl group" represented by R6 or R7 include a C6_14 aryl group such as phenyl , naphthyl and so on.
Examples of the substituents of the "lower alkyl group" and "cycloalkyl group" include 1 to 4 substituents selected from among hydroxy, amino, carboxyl, nitro, mono- or di-lower alkylamino (e.g. mono- or
Figure imgf000020_0001
alkylamino groups such as methylamino, ethylamino, propylamino, dimethylamino , diethylamino , etc.), lower alkoxy (e.g. C^ alkoxy groups such as methoxy, ethoxy, propoxy, hexyloxy, etc.), lower alkylcarbonyloxy (e.g. C^ alkylcarbonyloxy groups such as acetoxy, ethylcarbonyloxy, etc.), halogen (e.g. fluorine, chlorine, bromine and iodine) and so on.
Examples of the substituents of the "aryl group" include 1 to 5 substituents selected from among optionally substituted lower alkyl, optionally substituted amino, acetamido, hydroxy, carboxyl, nitro, lower alkoxy (e.g. x_6 alkoxy groups such as methoxy, ethoxy, propoxy, etc. ) , lower alkylcarbonyloxy (e.g. Cx.6 alkylcarbonyloxy groups such as acetoxy, ethylcarbonyloxy, etc.), halogen atoms (e.g. fluorine, chlorine, bromine and iodine) and so on. In this connection, examples of the substituents by which the lower alkyl (e.g. Cx.6 alkyl group such as methyl, ethyl, n-propyl, etc.) mentioned just above may have, include 1 to 4 substituents selected from among hydroxy, amino, mono- or di-lower alkylamino (e.g. mono- or di-C^ alkylamino groups such as methylamino, ethylamino, propylamino. dimethylamino , diethylamino , etc.), lower alkoxy (e.g. C1.6 alkoxy groups such as methoxy, ethoxy, propoxy, hexyloxy, etc.), halogen (e.g. fluorine, chlorine, bromine and iodine) and so on. Examples of the substituents by which the amino group mentioned above may have include 1 or 2 substituents selected from among C^ alkyl (e.g. methyl, ethyl, propyl, etc.), 5- to 7-membered cyclic amino (e.g. pyrrolidino, morpholino, piperidino, piperazino, etc.) and so on.
Examples of the "halogen" represented by R1 include fluorine, chlorine, bromine, iodine and so on.
Examples of the "5- to 7-membered ring formed in combination with the adjacent -C=C- group" include a 5- to 7-membered ring which may contain 1 to 4 hetero atoms selected from among nitrogen, oxygen, sulfur, etc. in addition to carbon atoms. Thus, in particular, a 5- to 7-membered cyclic hydrocarbon such as C5.7 cycloalkenes (e.g. , cyclopentene, cyclohexene, cycloheptene, etc.), benzene and so on and a 5- or 6- membered nitrogen-containing heterocyclic group consisting of carbon and nitrogen atoms (e.g., pyrrole, pyridine, piperidine , etc.), can be mentioned as the common species .
Examples of the "3- to 7-membered homocyclic ring" of the "divalent group derived from the 3- to 7-membered homocyclic ring" represented by Y include a 3- to 7-membered homocyclic ring consisting exclusively of carbon atoms, for instance. Thus, for example, C3.7 cycloalkanes such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc., C3.7 cycloalkenes such as cyclopropene , cyclobutene, cyclopentene, cyclohexene, cycloheptene, etc. and benzene can be mentioned as the common species.
Examples of the "divalent group derived from the 3- to 7-membered homocyclic ring" include a group resulting from either elimination of two hydrogen atoms from a single carbon atom in the 3- to 7-membered homocyclic ring or elimination of one hydrogen atom from each of two different carbon atoms . To be specific, the following groups can be included by way of example:
Figure imgf000022_0001
Particularly, the following groups may be used as the common species :
Figure imgf000022_0002
More preferable examples in above groups include the following groups :
Figure imgf000022_0003
Examples of the "3- to 7-membered heterocyclic ring" of the "divalent group derived from the 3- to 7-membered heterocyclic ring" represented by Y include a 3- to 7- membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from among nitrogen, oxygen, sulfur and other atoms in adidtion to carbon atoms, for instance. Thus, oxetane, tetrahydrofuran , tetrahydropyran, pyrrole, azetidine, pyrrolidine, piperidine, piperazine, tetraydrothiophene , homopiperidine, morpholine, etc. can be employed.
Examples of the divalent group derived from the "3- to 7-membered heterocyclic ring" is a group resulting from either elimination of two hydrogen atoms from a single carbon atom in the 3- to 7-membered heterocyclic ring or elimination of one hydrogen atom from each of two different atoms . Thus , for example, the following groups can be included
Figure imgf000023_0001
Examples of the "nitrogen-containing heterocyclic group" formed by R6 and R7 with the adjacent nitrogen atom include a group resulting from elimination of one hydrogen atom from a nitrogen atom in a ring such as a 3- to 13- membered nitrogen-containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain one to four hetero atoms , for example , selected from nitrogen, oxygen, sulfur and other atoms. Specifically, the following 3- to 9-membered nitrogen- containing heterocyclic groups can be generally used:
Figure imgf000024_0001
Examples of the substituents by which the "3- to 7- membered homocyclic ring", "3- to 7-membered heterocyclic ring" and "nitrogen-containing heterocyclic group" may have, include 1 to 5 substituents selected from among an optionally substituted lower alkyl, an optionally substituted amino, hydroxy, carboxyl, nitro, lower alkoxy (e.g. C^ alkoxy groups such as methoxy, ethoxy, propoxy, etc. ) , halogen (e.g. fluorine, chlorine, bromine and iodine) and so on. In this connection, examples of the substituents by which the lower alkyl (e.g. C^ alkyl group such as methyl, ethyl, n-propyl, etc.) mentioned just above may have, include 1 to 4 substituents selected from among hydroxy, amino, mono- or di-lower alkylamino (e.g. mono- or
Figure imgf000024_0002
alkylamino groups such as methylamino , ethylamino , propylamino , dimethylamino , diethylamino, etc.), lower alkoxy (e.g. C^ alkoxy groups such as methoxy, ethoxy, propoxy, hexyloxy, etc.), lower alkylcarbonyloxy (e.g. C^ alkylcarbonyloxy groups such as acetoxy, ethylcarbonyloxy, etc.), halogen (e.g. fluorine, chlorine, bromine and iodine) and so on. Examples of the substituents by which the amino group mentioned above may have, include 1 to 2 substituents selected from among C^ alkyl (e.g. methyl, ethyl, propyl, etc.), acyl (e.g. Q.x.b acyl groups such as formyl, acetyl, propionyl, butyryl, etc.), 5- to 7-membered cyclic amino (e.g. pyrrolidino, morpholino, piperidino, piperazino, etc. ) and so on.
Preferable examples of R1 are a hydrogen atom or a C^ alkyl group (e.g. methyl, ethyl, n-propyl, etc.) and more preferable examples are a hydrogen atom and so on.
Preferable examples of R2 are a hydrogen atom or a C^ alkyl group (e.g. methyl, ethyl, n-propyl, etc.) and more preferable examples are a hydrogen atom and so on.
Preferable examples of R3 are a hydrogen atom or a C^ alkyl group (e.g. methyl, ethyl, n-propyl, i-propyl, etc.) and more preferable examples are a branched C3.6 alkyl group (e.g. i-propyl, etc.).
Also preferred is the case in which R2 and R3 form a 5- to 7-membered homocyclic ring in combination with the adjacent -C=C- group. Particularly preferred is the case of cyclohexene, benzene or the like.
X is preferably an oxygen atom or S and more preferably an oxygen atom.
Preferable examples of Y are a group of the formula:
R4' I
— c—
wherein R4' and R5' each is (i) a hydrogen atom or (ii) a C^ alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or
Figure imgf000025_0001
alkyl-carbonyloxy and halogen atom, and so on.
Examples of the "C^ alkyl group" represented by R4' and R5' are methyl, ethyl, n-propyl, i-propyl and so on, and more preferable examples are methyl, ethyl and so on.
Also preferred are cases in which Y is a divalent group derived from a 3- to 7-membered homocyclic ring or heterocyclic ring which may be substituted.
Y is preferably a group of the formula:
Figure imgf000026_0001
Thus , for example , the following groups can be frequently used as the common species of Y:
Figure imgf000026_0002
More preferably examples of Y include the follow:
Figure imgf000026_0003
Preferable examples of R6 and R7 are a hydrogen atom, a Cj.3 alkyl group (e.g. methyl, ethyl, n-propyl, etc.) and so on, and particularly a hydrogen atom is preferred.
Preferable example of m is a whole number of 1 to 4 , more preferable example is a whole number of 1 to 3 and most preferable example is 1.
Preferable example of n is a whole number of 1 to 4 and more preferable example is 1.
The most useful is the case in which both m and n represent 1.
Preferable specific examples of the triazolopyridazine derivatives [ I ] used for the agent of the present invention are all compounds prepared in Examples of EP-A-0562439 and WO96/08496, and most preferable example is 6- (2, 2- dimethyl-3-sulfamoyl-l-propoxy) -7-isopropyl [l , 2 , 4] triazolo [l,5-b] pyridazine or a salt thereof.
The salt of triazolopyridazine derivatives [I] is preferably a physiologically acceptable acid addition salt. Such salts include salt with inorganic acids (e.g., hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid) and salts with organic acids (e.g., acetic acid, formic acid, propionic acid, fumaricacid, maleicacid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid) .
Provided that the triazolopyridazine derivatives [I] have an acidic group, such as -COOH, they may form a salt with an inorganic base (e.g., an alkali metal or alkaline earth metal such as sodium, potassium, calcium or magnesium; or ammonia) or an organic base (e.g., a tri-C^ alkylamine such as triethylamine) .
The triazolopyridazine derivatives [ I ] or salts thereof can be prepared according to the descriptions of EP-A- 0562439 or O96/08496, particularly the descriptions of Examples of the references .
The agent for acting on bronchi of the present invention makes the triazolopyridazine derivatives [I] or salts thereof act on bronchi specifically, on the other hand do not make them act on a whole body. And, the agent of the present invention may act on tissues around bronchi such as trachea, lung, etc..
So long as the agent of the present invention can show the local actions of triazolopyridazine derivatives [ I ] or salts thereof, types of the agent are not limited. For example, the agent of the present invention can be preferably used as an inhalation.
For example, if the pharmaceutical preparation of the invention is used as an inhalation, additives for the inhalation may be any additives generally used in an inhalation, and examples are solid fillers such as pressurizing agents, white sugar, lactose, glucose, mannitol and sorbitol, liquid fillers e.g. inert liquid such as propylene glycol, binders such as methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone , polyethylene glycol and white sugar, lubricants such as magnesium stearate, light silicate anhydride, talk and sodium lauryl sulfate, taste correctives such as citric acid, menthol, glythylithin ammonium salt, glycine and orange powder, preservatives such as sodium benzoate, sodium bisulfite, methyl parabene and propyl parabene, stabilizers such as citric acid and sodium citrate, suspending agents such as methyl cellulose, polyvinylpyrrolidone, lecithin and sorbitan trioleate, dispersing agents such as surface active agents, solvents such as water, isotonicity agents such as sodium chloride, pH a justor such as sulfuric acid and hydrochloric acid, and solubilizers such as ethanol.
The pressurizing agents include liquefied gas pressurizing agents, compressed gas etc. The liquefied gas pressurizing agents include e.g. hydrocarbon fluoride (e.g. substitute Freon such as HCFC22, HCFC-123, HCFC-134a, and HCFC142), liquefied petroleum, and dimethyl ether. The compressed gas includes e.g. soluble gas (e.g. carbon dioxide gas, nitrous oxide gas etc. ) and insoluble gas (e.g. nitrogen gas ) .
Further, the pharmaceutical preparation of the invention may contain as active ingredients any pharmaceutical ingredients other than triazolopyridazine derivative [I] or salts thereof. Examples of such pharmaceutical active ingredients include anti-asthma agents (e.g. theophylline , procaterol, ketotifen, azelastine, seratrodast (bronica) etc.), anti-allergy agents (e.g. ketotifen, terfenadine, azelastine, epinastine etc.), anti-inflammatory agents (e.g. diclophenac sodium, ibuprofen, indomethacin etc.), antimicrobial agents (e.g. cefixme, cefdinir, ofloxacin, tosfloxacin etc. ) and anti-fungus agents (e.g. fluconazole. itraconazole etc. ) . Insofar as the object of the invention can be achieved, these ingredients are not particularly limited insofar and can be used in a suitable ratio.
Although the content of the triazolopyridazine derivative [I] or salts thereof in the pharmaceutical preparation of the invention vary depending on the disease treated, the age or sex of the patient and the conditions of the disease, the content is in the range of usually about 0.01 to 99.9 % by weight, preferably about 0.1 to 50 % by weight , more preferably about 0.5 to 20 % by weight , relative to the whole of the pharmaceutical preparation.
Although the content of various additives such as additives for an inhalation varies depending on the disease treated, the age or sex of the patient and the conditions of the disease, the content is in the range of usually about 0.1 to 99 % by weight, preferably about 10 to 99 % by weight, more preferably about 50 to 99 % by weight, most preferably about 70 to 99 % by weight, relative to the whole of the pharmaceutical preparation.
The content of other pharmaceutical ingredients than the triazolopyridazine derivative [I] or salts thereof varies depending on the disease treated, the age or sex of the patient and the conditions of the disease, the content is in the range of usually about 0.01 to 99.9 % by weight, preferably about 0.1 to 50 % by weight , more preferably about 0.5 to 20 % by weight, relative to the whole of the pharmaceutical preparation.
If the agent of the invention is used as an inhalation, it can be formed into a powder for inharation, a suspension for inharation, a liquid preparation for inharation or a capsule for inharation by a method known in the art and administered by means of a suitable inhaler.
Furthermore, the agent of the invention can be used as an aerosol. The aerosol is made completely contamination-free during use, and because the inside of the aerosol is maintained always under pressure, the content introduced in the can is completely prevented from being contaminated from the outside.
The aerosol is composed usually of 5 elements i.e. a vessel, a valve, a button, a content and a pressurizing agent, and is classified into a 2-phase system, a 3-phase system and a membrane system (double vessel).
The vessel used is a vessel stipulated under a high-pressure gas regulation , and its material is metal (e.g. tin, aluminum), glass or plastics. There are 3 types of metal vessel, that is, a 3-piece side seam can, a 2-piece seamless can and a 1-piece mono-block can. The glass vessel is excellent in solvent resistance and corrosion resistance and is easily processed, so it can be easily formed into a deformed vessel.
The valve is a part most influential over the jet characteristics and sealing properties of the aerosol. The valve is constituted usually of a mountain cup, a stem, a housing, a spring, a dip tube and gasket rubber, and use is made of a valve equipped with a gas-phase hole or a quantification valve. In the mechanism of the valve, the stem is pressed whereby the stem hole closed with sealing gasket rubber is allowed to communicate with the inside of the vessel so that the content is released through the stem hole.
The button used includes a straight button, a brake cap button, a button for foam, and a button with a long nozzle.
The content is the topical working agent (inhalation) of the invention described above.
The pressurizing agent is the same as described above .
A 2-phase system aerosol using a liquefied gas pressurizing agent as the pressurizing agent forms an uniform liquid phase in which a suspension (stock solution) containing the triazolopyridazine derivative [ I ] or salts thereof are made compatible with the pressurizing agent, and the inside of the vessel is composed of 2 phases i.e. a liquid phase and a gaseous phase of a gas of the pressurizing agent in an upper space in the vessel. In this system, fine droplets can be obtained due to the propellant force of the pressurizing agent when the liquefied pressurizing agent under pressure in the vessel is jetted out through a valve under normal pressure. In the case of compressed gas, the compressed gas present under compression in an upper space merely presses the stock solution. In the 3-phase system, there are an emulsification system and a suspension system; the former consists of a 2-phase emulsification state of the liquid phase and a gaseous phase in an upper space , and the latter consists of a powder solid phase, a liquefied gaseous phase, and a gaseous phase in an upper space. The membrane system is a system in which only the stock solution itself is jetted out from a double vessel in which the pressurizing agent is filled in an outer vessel and the stock solution is filled in an inner vessel communicating with a valve.
If the agent of the invention is used as an aerosol, it is formed preferably into a powder aerosol.
Production of the aerosol consists usually of the 2 steps of preparing the content and filling the content and the pressurizing agent .
Preparation of the content can be conducted in any method known in the art, and the following methods are used: (1) a method of mixing the triazolopyridazine derivative [I] or a salt thereof with an adjuvant and a solvent to form a uniform suspension, (2) a method of kneading the triazolopyridazine derivative [I] or a salt thereof with a surface active agent to form powder, and (3) a method of mixing the triazolopyridazine derivative [I] or a salt thereof with water-soluble additives for inhalation and then stirring, heating and cooling the mixture into an emulsion.
Filling of the content and the pressurizing agent consists usually of the steps of washing the vessel, filling the content, degassing the inside of the vessel, filling the pressurizing agent, and attaching the valve thereto. Filling of the pressurizing agent involves filling under cooling, filling under pressure, or undercup filling.
After filling, crimp conditions are confirmed in order to examine whether the valve is correctly fitted. Further, in order to examine linkage from the product, a hot water test is conducted and water droplets are removed.
Further, a flame-length test and tests for changes with time (e.g. tests for reduction in weight, jet characteristics, corrosion of the vessel, valve functions and internal pressure) are conducted in order to confirm the storage and safety of the aerosol for use.
When the agent of the invention is used, the devices used for administration may be commercial inhalers, and examples include Ventolin Rotacaps, Glaxo), Spin Heller* (Fujisawa Pharmaceutical Co., Ltd.), Intal Spincaps (Fisonz), Atrovent and Berotec Inhaletten (Boehringer Ingelheim) , Foradil (Chiba), Bentodisks (Glaxo), Pabrizer* (Teijin Ltd. ) , Bricanyl Turbuhaler (Astra) , Miat Insufflator) .
The triazolopyridazine derivatives [I] or salts thereof used for the agent of the present invention possess excellent an anti-allergic action, an anti-asthmatic action, an anti-PAF (platelet activating factor) action, an inhibitory action of eosinophil chemotaxis, an inhibitory action of local eosinophilic infiltration in allergic and asthmatic reactions , and is with a low toxic potential (acute toxicity: LD50>2g/kg).
The agent of the present invention can act specifically on the bronchus or its surrounding tissues by administering it topically into the mouth, throat etc. Topical administration of the triazolopyridazine derivative [I] or its salts achieve a minimum effective amount, thus eliminating general and high-dosage administration. Accordingly, it can be administered into even children easily and safely. In particular, outstanding local acting effects can be demonstrated in the case of an inhalation or an aerosol.
As mentioned above, the agent of the present invention can be used safety as an anti-asthmatic agent, an anti- PAF agent, an anti-allergic agent, an agent for inhibiting eosinophil chemotaxis , an agent for preventing or treating diseases related to eosinophilic infiltration (for example, allergic diseases such as urticaria, atopic dermatitis, allergic rhinitis, hypersensitive pneumonia, etc,; diseases of the skin such as eczema, dermatitis herpetiformis , psoriasis, etc., and respiratory diseases such as simple pulmonary eosinophilia (PIE syndrome), chronic obstructive pulmonary disease (COPD), etc.), particularly as an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD), an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia, in mammals (e.g., humans, mice, rats, cats, dogs, sheeps , horses, bovines , monkeys, etc. ) .
Although the dose of the agents of the present invention varies depending on age, body weight, symptoms, route and frequency of administration and other factors , they may be administered at about 0.001 to 10 mg/kg, preferably about 0.01 to 10 mg/kg, more preferably about 0.1 to 10 mg/kg, particularly preferably about 0.1 to 5 mg/kg in one to two portions daily for an adult . Preferable route of administration may be direct inhalation into mouth, etc. by using tools for inhalation.
Best Mode for Carrying out the Invention
In the following, the Examples and Reference Examples are merely intended to describe the present invention in further detail and should by no means be construed as defining the metes and bounds of the invention.
Detection of the fractions containing each object compound in the Reference Examples was carried out under TLC (Thin Layer Chromatography) monitoring. In TLC monitoring, Merck's 60F254 was used as the TLC plate and a UV detector for detection . Merck' s silica gel 60 (70 to 230 mesh) was used as a silica gel for column chromatography.
Abbreviations used in the following have the following meanings .
J : coupling constant s : singlet bs : broad singlet t : triplet m : multiplet
Hz : hertz d : doublet q : quartet
NMR : Nuclear Magnetic Resonance
DMSO : Dimethyl sulfoxide
CDC13 : deuteriochlorofor v/v : volume/volume
% : weight % m. p . : melting point i.v. : intravenous injection δ (ppm) : chemical shift (part per million)
Working Example
Reference Example 1
Production of 3-amino-6-chloro-5-isopropylpyridazine
A mixture of 21.7 g of 3 , 6-dichloro-4- isopropylpyridazine, 170 ml of 25% ammonium hydroxide solution, and 10 ml of ethanol , was heated at 130 to 140 "C in sealed tube for 22 hours. After cooling, the solvent was distilled off. Water was added to the residue and resulting crystals were collected by filtration and washed water and ethyl ether to pronide 11.1 g of the title compound, m.p. 164-165 ° C
NMR (CDC13) δ : 1.26(6H,d, J=7Hz) , 3.16(lH,m) , 4.89(2H,br. s ) , 6.65(lH,s) .
Reference Example 2
Production of N- ( 6-chloro-5-isopropylpyridazine-3-yl) formamide oxime
To a suspension of 8.6 g of 3-amino-6-chloro-5- isopropylpyridazine in 58 ml of toluene was added 6.2 ml of dimethylformamide dimethyl acetal and the reaction mixture was refluxed for 2 hours . The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and elution was carried out with ethyl acetate-methanol (10:1). The fractions containing the objective compound were pooled and concentrated. The residue was dissolved in methanol ( 40 ml) and 1.8 g of hydroxylamine hydrochloride was added to the solution and stirred at room temperature for 2 hours. The resulting crystals were collected by filteration to provide 12.7g of the title compound, m.p. 170-171 ° C Elemental analysis for C8HnN4OCl /44611
34
Calcd.(%): C, 44.76; H, 5.17; N, 26.10 Found (%): C, 44.62; H, 5.02; N, 26.01
Reference Example 3
Production of 6-chloro-7-isopropyl[ 1 , 2 , 4 ] triazolo! 1 , 5- b]pyridazine
A mixture of 20.04 g of N- ( 6-chloro-5- isopropylpyridazine-3-yl)formamide oxime and 97 g of polypyhosphoric acid was heated at 110 to 115 °C for 1 hour in oil bath. After cooling, the reaction mixture was poured into ice water and extracted with dichloromethane. The extract was washed with water and dried (MgS04) and the solvent was distilled off under reduced pressure. Hexane was added to the residue and the resulting crystals were collected by filtration, to provide 12.7 g of the title compound, m.p. 53-54 °C Elemental analysis for C8H9C1N4
Calcd.(%): C, 48.87; H, 4.61; N, 28.49 Found (%): C, 48.85; H, 4.55; N, 28.48
Reference Example 4
Production of 6- ( 2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7- isopropyl[l,2 , 4] triazolo [ 1, 5-b]pyridazine
To a solution of 0.669 g of 3-hydroxy-2 , 2- di ethyl-1-propanesulfonamide in 30 ml of tetrahydrofuran was added 0.336 g of 60% sodium hydride in oil and the mixture was refluxed for 1 hour. After cooling, to the reaction mixture was added 0.748 g of 6-chloro-7- isopropyl[l ,2 , 4] triazolotl, 5-b]pyridazine and the mixture was refluxed with stirring for 4 hours. After cooling, the reaction mixture was poured into ice water, adjusted to pH6 with lN-hydrochloric acid, and extracted with ethyl acetate-tetrahydrofuran (1:1). The extract was washed with saturated aqueous solution of sodium chloride and dried (MgS04) and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and elution was carried out with dichloromethane-ethyl acetate-methanol (10:10:1). The fractions containing the objective compound were pooled and concentrated. The resulting crystals were recrystallized from acetone-water to provide 1.10 g of the title compound, m.p. 197-198 " C Elemental analysis for C13H21N503S
Calcd.(%): C, 47.69; H, 6.46; N, 21.39 Found (%): C, 47.84; H, 6.60; N, 21.33
Reference Example 5
The result of a pharmacological test of the compound of Reference Example 4 is shown below.
[Effect on platelet activating factor (PAF) -induced guinea pig bronchoconstriction]
Male Hartley guinea pigs (body weights about 500 g) were used. Bronchoconstriction induced by PAF, 1 μg/kg i.v. , in guinea pigs was measured using to the method of Konzett-Roessle . With the guinea pig immobilized in the dorsal position, tracheotomy was performed under urethane (1.5 g/kg i.v.) anesthesia and the trachea was connected through a cannula to a respirator. The side branch of the tracheal cannula was connected to a transducer (Model 7020, Ugobasile). With the volume of air per feed being controlled at 3-7 ml, the ventilation frequency at 70/min. and the pulmonary loading pressure at 10 cm H20, the volume of overflow air was recorded on a rectigraph (Recte-Hori-8s , San-ei Sokki) through the transducer. After administration of gallamine (1 mg/kg i.v.), PAF, 1 μg/kg, dissolved in physiological saline was administered through a jugular vein cannula and the induced bronchoconstriction was recorded for 15 minutes . The drug suspended in a 5% solution of gum arabic was administered orally in a dose of 3 mg/kg or 1 mg/kg one hour before PAF treatment. The result is presented in Table 1. [Table 1] Effect on PAF-induced bronchoconstriction in guinea pigs
Figure imgf000038_0001
It will be apparent from Table 1 that the compound of Reference Example 4 has excellent inhibitory activity against PAF (platelet activating factor) induced bronchoconstriction .
Example 1 Suspension for inhalation
(1) Compound of Reference Example 4 20.0 mg
(2) HCFC-123 1560.0 mg
(3) HCFC-134a 2400.0 mg
(4) Solubitantriolate 20.0 mg Suspensions for inhalation can be prepared by mixing the above components. Quantitative valve can be used for 50 11 1 .
Example 2 Liquid preparation for inhalation
(1) Compound of Reference Example 4 20.0 mg
(2) Distilled Water 1000.0 g Liquid preparations for inhalation can be prepared by mixing the above components . The liquid preparation for inhalation can be used by using Nebulizer (Trade Mark) . Example 3 Powder for inhalation
(1) Compound of Reference Example 4 25 g
(2) Lactose 250 g
The powders for inhalation can be prepared by mixing the above components .
Example 4 Capsule for inhalation
(1) Compound of Reference Example 4 25 g
(2) Lactose 250 g
Mixing the above components , and fill them into capsule
No.2 as 2.5mg of the compound of Reference Example 4 per a capsule to obtain ten thousands of capsules for inhalation.
The capsules for inhalation can be used by using Spinhalor
(Fujisawa Pharm. Ltd. , Japan) as small sized atmizer.
INDUSTRIAL APPLICABILITY The agent of the present invention can make an anti-asthmatic action, etc., of the triazoropyridazine derivatives [I] such as 6- (2 , 2-dimethyl-3-sulfamoyl-1- propoxy) -7-isopropyl [l,2,4] triazolo Cl,5-b] pyridazine, etc., or salts thereof act on bronchi or tissues around bronchi specifically, and therefore, since local administering could be performed by a minimum effective amount of by the triazolopyridazine derivatives [I], it could avoid to administer an amount of the triazolopyridazine derivatives [I] into a whole body.

Claims

1. A agent for acting on bronchi which comprises a compound of the formula:
[|]
Figure imgf000040_0001
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted cycloalkyl group, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p (p is a whole number of 0 to 2) ; Y is a group of the formula:
Figure imgf000040_0002
(R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4 ; n is a whole number of 0 to 4 , or a salt thereof .
2. The agent as claimed in claim 1 , wherein
R1 is (i) a hydrogen atom, (ii) a
Figure imgf000040_0003
alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or
Figure imgf000040_0004
alkylamino. alkoxy, C1_6 alkylcarbonyloxy and a halogen atom or (iii) a halogen atom,
R2 and R3 respectively is (i) a hydrogen atom or (ii) a C^g alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or
Figure imgf000041_0001
alkoxy,
Figure imgf000041_0002
alkylcarbonyloxy and a halogen atom or (iii) a C3.6 cycloalkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or
Figure imgf000041_0003
alkylamino, Cj.g alkoxy,
Figure imgf000041_0004
alkylcarbonyloxy and a halogen atom, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, optionally having substituents selected from the group consisting of (i) Cj.g alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or
Figure imgf000041_0005
alkylamino, Cj_6 alkoxy, C1_6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by
Figure imgf000041_0006
alkyl, ci-6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) C1.6 alkoxy and (vii) a halogen atom;
X is an oxygen atom or S(0)p (p is a whole number of 0 to 2),
Y is (a) a group of the formula: R4 —C—
_•
(R4 and R5 respectively is (i) a hydrogen atom or (ii) a
Figure imgf000041_0007
alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- ordi-Cj., alkylamino, alkoxy,
Figure imgf000041_0008
alkylcarbonyloxy and a halogen atom) , or (b) a divalent group derived from a 3- to 7-membered cyclic hydrocarbon or 3- to 7-membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in adidtion to carbon atoms, optionally having substituents selected from the group consisting of (i)
Figure imgf000042_0001
alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or
Figure imgf000042_0002
alkylamino, C1.6 alkoxy,
Figure imgf000042_0003
alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by
Figure imgf000042_0005
alkyl,
Figure imgf000042_0004
acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Cj.g alkoxy and (vii) a halogen atom,
R6 and R7 respectively is (i) a hydrogen atom, (ii) a
Figure imgf000042_0006
alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or
Figure imgf000042_0007
alkylamino,
Figure imgf000042_0008
alkoxy,
Figure imgf000042_0009
alkylcarbonyloxy and a halogen atom, (iii) a C3.6 cycloalkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cj.g alkylamino, Cx_6 alkoxy,
Figure imgf000042_0010
alkylcarbonyloxy and a halogen atom, or (iv) a C6.14 aryl group optionally having substituents selected from the group consisting of (a)
Figure imgf000042_0011
alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or
Figure imgf000042_0012
alkylamino,
Figure imgf000042_0013
alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (b) an amino which may be substituted by
Figure imgf000042_0014
alkyl,
Figure imgf000042_0015
acyl or 5- to 7-membered cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f) nitro, (g)
Figure imgf000042_0016
alkoxy, (h)
Figure imgf000042_0017
alkylcarbonyloxy and (i) a halogen atom, or
R6 and R7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms, optionally having substituents selected from the group consisting of (i) Cx_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or
Figure imgf000043_0001
alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by
Figure imgf000043_0002
alkyl, Cx.6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) C1_6 alkoxy and (vii) a halogen atom, m is a whole number of 0 to 4; n is a whole number of 0 to 4.
3. The agent as claimed in claim 1 , wherein R1 is hydrogen atom or a
Figure imgf000043_0003
alkyl group, R2 is a hydrogen atom or a Cx_3 alkyl group, R3 is a hydrogen atom or a
Figure imgf000043_0004
alkyl group, X is an oxygen atom, Y is a group of the formula:
R4' I —C— " wherein R4' and R5' each is (i) a hydrogen atom or (ii) a Cx.3 alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-Cj.g alkylamino,
Figure imgf000043_0005
alkyl-carbonyloxy and halogen atom, R6 and R7 respectively is a hydrogen atom or a Cx„3 alkyl group, m and n is 1.
4. The agent as claimed in claim 1 , wherein the compound is 6- ( 2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl
[l,2,4] triazolo Cl,5-b] pyridazine.
5. The agent as claimed in claim 1, which is an anti- asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD), an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia.
6. The agent as claimed in claim 1 , which is an inhalation for acting on bronchi.
7. Use of a compound of the formula: /44611
42
Figure imgf000044_0001
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted cycloalkyl group, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p
(p is a whole number of 0 to 2); Y is a group of the formula:
—
Figure imgf000044_0002
(R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4 ; n is a whole number of 0 to 4 , or a salt thereof for preparing an agent for acting on bronchi.
8. The use as claimed in claim 7 , wherein R1 is (i) a hydrogen atom, (ii) a
Figure imgf000044_0003
alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or
Figure imgf000044_0004
alkylamino, alkoxy, C1.6 alkylcarbonyloxy and a halogen atom or (iii) a halogen atom, R2 and R3 respectively is (i) a hydrogen atom or (ii) a alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or alkylamino,
Figure imgf000045_0001
alkoxy,
Figure imgf000045_0002
alkylcarbonyloxy and a halogen atom or (iii) a C3.6 cycloalkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, optionally having substituents selected from the group consisting of (i)
Figure imgf000045_0003
alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-C^g alkylamino,
Figure imgf000045_0005
alkoxy,
Figure imgf000045_0004
alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by Cx_6 alkyl, C1-6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Cx_6 alkoxy and (vii) a halogen atom;
X is an oxygen atom or S(0)p (p is a whole number of 0 to 2).
Y is (a) a group of the formula: R<
(R4 and R5 respectively is (i) a hydrogen atom or (ii) a
Figure imgf000045_0006
alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or
Figure imgf000045_0007
alkylamino, C1-6 alkoxy, Cl_6 alkylcarbonyloxy and a halogen atom) , or
(b) a divalent group derived from a 3- to 7-membered cyclic hydrocarbon or 3- to 7-membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in adidtion to carbon atoms , optionally having substituents selected from the group consisting of (i) Cx_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cx.6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by Cx_6 alkyl, Cx_6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Cj.g alkoxy and (vii) a halogen atom,
R6 and R7 respectively is (i) a hydrogen atom, (ii) a Cx_6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (iii) a C3.6 cycloalkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, or (iv) a C6.14 aryl group optionally having substituents selected from the group consisting of (a) Cx_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cx.6 alkylamino, Cx,6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (b) an amino which may be substituted by Cx_6 alkyl, Cx_6 acyl or 5- to 7-membered cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f ) nitro, (g) Cx.6 alkoxy, (h)
Figure imgf000046_0001
alkylcarbonyloxy and (i) a halogen atom, or
R6 and R7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms, optionally having substituents selected from the group consisting of (i) Cx_6 alkyl optionally having substituents selected from the group consisting of hydroxy. amino, mono- or di-Cx.6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by Cx_6 alkyl, Cx_6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi)
Cx.g alkoxy and (vii) a halogen atom, m is a whole number of 0 to 4; n is a whole number of 0 to
4.
9. The use as claimed in claim 7 , wherein R1 is hydrogen atom or a Cx_3 alkyl group, R2 is a hydrogen atom or a Cx_3 alkyl group, R3 is a hydrogen atom or a Cx_6 alkyl group, X is an oxygen atom, Y is a group of the formula:
R4' I
I , R5 wherein R4' and R5' each is (i) a hydrogen atom or (ii) a Cx_3 alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-Cx.6 alkylamino, Cx„6 alkoxy, Cx_6 alkyl-carbonyloxy and halogen atom, R6 and R7 respectively is a hydrogen atom or a Cx_3 alkyl group, m and n is 1.
10. The use as claimed in claim 7, wherein the compound is 6- ( 2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl
[l,2,4] triazolo [l,5-b] pyridazine.
11. The use as claimed in claim 7, wherein the agent is an anti-asthmatic agent, an agent for preventing or treating chronic obstructive pulmonary disease (COPD) , an agent for preventing or treating hypersensitive pneumonia or an agent for preventing or treating simple pulmonary eosinophilia.
12. The use as claimed in claim 7, wherein the agent is an inhalation for acting on bronchi.
13. A method for preventing or treating asthma, chronic obstructive pulmonary disease (COPD), hypersensitive pneumonia or simple pulmonary eosinophilia which comprises administering an effective amount of a compound of the formula:
: ; [I]
Figure imgf000048_0001
wherein R1 is a hydrogen atom, an optionally substituted lower alkyl group or a halogen atom; R2 and R3 respectively is a hydrogen atom, an optionally substituted lower alkyl group or an optionally substituted cycloalkyl group, or R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring; X is an oxygen atom or S(0)p (p is a whole number of 0 to 2); Y is a group of the formula:
Figure imgf000048_0002
(R4 and R5 respectively is a hydrogen atom or an optionally substituted lower alkyl group) or a divalent group derived from an optionally substituted 3- to 7-membered homocyclic or heterocyclic ring; R6 and R7 each is a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group, or R6 and R7 may, taken together with the adjacent nitrogen atom, form an optionally substituted nitrogen- containing heterocyclic group; m is a whole number of 0 to 4 ; n is a whole number of 0 to 4 , or a salt thereof to bronchi of mammals .
14. The method as claimed in claim 13, wherein R1 is (i) a hydrogen atom, (ii) a Cx_6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx.6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom or (iii) a halogen atom, R2 and R3 respectively is (i) a hydrogen atom or (ii) a Cx.6 alkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx.6 alkylamino, Cx.6 alkoxy, Cx.6 alkylcarbonyloxy and a halogen atom or (iii) a C3.6 cycloalkyl group optionally having substitutes selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino,
Cx.6 alkoxy, Cx„5 alkylcarbonyloxy and a halogen atom, or
R2 and R3 may, taken together with the adjacent -C=C- group, form a 5- to 7-membered ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in addition to carbon atoms, optionally having substituents selected from the group consisting of
(i) Cx.6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cx_6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by Cx_6 alkyl,
Cx.6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy,
(iv) carboxyl, (v) nitro, (vi) Cx_6 alkoxy and (vii) a halogen atom;
X is an oxygen atom or S(0)p (p is a whole number of 0 to
2),
Y is (a) a group of the formula:
—
Figure imgf000049_0001
(R4 and R5 respectively is (i) a hydrogen atom or (ii) a Cx_6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino, Cx.6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom) , or
(b) a divalent group derived from a 3- to 7-membered cyclic hydrocarbon or 3- to 7-membered heterocyclic ring which may contain 1 to 4 hetero atoms selected from the group consisting of nitrogen, oxygen and sulfur atoms in adidtion to carbon atoms, optionally having substituents selected from the group consisting of (i) Cx_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cx.6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by Cx_6 alkyl, Cx_6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi) Cx_6 alkoxy and (vii) a halogen atom,
R6 and R7 respectively is (i) a hydrogen atom, (ii) a Cx_6 alkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino, Cx.6 alkoxy, Cx.6 alkylcarbonyloxy and a halogen atom, (iii) a C3.6 cycloalkyl group optionally having substituents selected from the group consisting of hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino, Cx„6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, or (iv) a C6.X4 aryl group optionally having substituents selected from the group consisting of (a) Cx_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cx_6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (b) an amino which may be substituted by Cx_6 alkyl, Cx.6 acyl or 5- to 7-membered cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f) nitro, (g) Cx„6 alkoxy, (h) Cx_6 alkylcarbonyloxy and (i) a halogen atom, or
R6 and R7 may, taken together with the adjacent nitrogen atom, form a group resulting from elimination of one hydrogen atom from a nitrogen atom in a 3- to 13-membered nitrogen- containing heterocyclic ring which contains one nitrogen atom in addition to carbon atoms and which may also contain 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur atoms, optionally having substituents selected from the group consisting of (i) Cx_6 alkyl optionally having substituents selected from the group consisting of hydroxy, amino, mono- or di-Cx.6 alkylamino, Cx_6 alkoxy, Cx_6 alkylcarbonyloxy and a halogen atom, (ii) an amino which may be substituted by Cx.6 alkyl, Cx„6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi)
Cx_6 alkoxy and (vii) a halogen atom, m is a whole number of 0 to 4; n is a whole number of 0 to
4.
15. The method as claimed in claim 13 , wherein R1 is hydrogen atom or a Cx_3 alkyl group, R2 is a hydrogen atom or a Cx_3 alkyl group, R3 is a hydrogen atom or a Cx_6 alkyl group, X is an oxygen atom, Y is a group of the formula:
R4' I
— c—
wherein R4' and R5' each is (i) a hydrogen atom or (ii) a Cx_3 alkyl group optionally substituted by 1 to 4 substituents selected from hydroxy, amino, carboxyl, nitro, mono- or di-Cx_6 alkylamino, Cx_6 alkoxy, Cx_6 alkyl-carbonyloxy and halogen atom, R6 and R7 respectively is a hydrogen atom or a Cx.3 alkyl group, m and n is 1.
16. The method as claimed in claim 13, wherein the compound is 6- ( 2 , 2-dimethyl-3-sulfamoyl-1-propoxy) -7-isopropyl [l,2,4] triazolo [l,5-b] pyridazine.
PCT/JP1999/001010 1998-03-04 1999-03-03 Triazolo-pyridazine derivatives for the treatment of chronic obstructive pulmonary diseases WO1999044611A1 (en)

Priority Applications (3)

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AU32741/99A AU3274199A (en) 1998-03-04 1999-03-03 Triazolo-pyridazine derivatives for the treatment of chronic obstructive pulmonary diseases
CA002319426A CA2319426A1 (en) 1998-03-04 1999-03-03 Triazolo-pyridazine derivatives for the treatment of chronic obstructive pulmonary diseases
EP99937873A EP1059924A1 (en) 1998-03-04 1999-03-03 Triazolo-pyridazine derivatives for the treatment of chronic obstructive pulmonary diseases

Applications Claiming Priority (2)

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JP10/51583 1998-03-04
JP5158398 1998-03-04

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0562439A1 (en) * 1992-03-18 1993-09-29 Takeda Chemical Industries, Ltd. Triazolopyridazines as antioasthmatics
EP0648491A2 (en) * 1993-09-21 1995-04-19 Takeda Chemical Industries, Ltd. Eosinophil chemotaxis inhibitor
WO1996008496A1 (en) * 1994-09-16 1996-03-21 Takeda Chemical Industries, Ltd. Triazolopyridazines process and intermediates for their preparation and their use as medicaments

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0562439A1 (en) * 1992-03-18 1993-09-29 Takeda Chemical Industries, Ltd. Triazolopyridazines as antioasthmatics
EP0648491A2 (en) * 1993-09-21 1995-04-19 Takeda Chemical Industries, Ltd. Eosinophil chemotaxis inhibitor
WO1996008496A1 (en) * 1994-09-16 1996-03-21 Takeda Chemical Industries, Ltd. Triazolopyridazines process and intermediates for their preparation and their use as medicaments

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AU3274199A (en) 1999-09-20
CA2319426A1 (en) 1999-09-10

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