DERIVES DE TRIAZOLOPYRIDAZINE POUR TRAITER LES MALADIES RESPIRATOIRES OBSTRUCTIVES CHRONIQUES

TRIAZOLO-PYRIDAZINE DERIVATIVES FOR THE TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASES

Abrégé français

La présente invention concerne un agent pouvant avoir une action antiasthmatique, etc., cet agent renfermant des dérivés de triazolopyridazine [I] tels que 6-(2,2-diméthyl-3-sulfamoyl-1-propoxy)-7-isopropyl[1,2,4]triazolo[1,5-b]pyridazine, etc., ou des sels de celle-ci. Cet agent agissant spécifiquement sur les bronches ou sur les tissus entourant les bronches, on peut donc éviter d'administrer une quantité des dérivés de triazolopyridazine [I] dans le corps tout entier, pour procéder à une administration locale d'une quantité efficace minimale de ces dérivés de triazolopyridazine [I].

Abrégé anglais

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.

Revendications

38
CLAIMS
1. A agent for acting on bronchi which comprises a compound
of the formula:
<IMG>
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(O)p
(p is a whole number of 0 to 2); Y is a group of the formula:
<IMG>
(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 C1-6 alkyl group optionally
having substituents selected from the group consisting of
hydroxy, amino, carboxyl, nitro, mono- or di-C1-6 alkylamino,

39
C1-6 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-C1-6 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-C1-6 alkylamino,
C1-6 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-C1-6
alkylamino, C1-6 alkoxy, C1-6 alkylcarbonyloxy and a halogen
atom, (ii) an amino which may be substituted by C1-6 alkyl,
C1-6 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(O)p (p is a whole number of 0 to
2),
Y is (a) a group of the formula:
<IMG>
(R4 and R5 respectively is (i) a hydrogen atom or (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, C1-6 alkylcarbonyloxy
and a halogen atom), or
(b) a divalent group derived from a 3- to 7-membered cyclic

40
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) C1-6 alkyl optionally having
substituents selected from the group consisting of hydroxy,
amino, mono- or di-C1-6 alkylamino, C1-6 alkoxy, C1-6
alkylcarbonyloxy and a halogen atom, (ii) an amino which
may be substituted by C1-6 alkyl, C1-6 acyl or 5- to 7-membered
cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi)
C1-6 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, 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 di-C1-6 alkylamino,
C1-6 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) C1-6 alkyl optionally having
substituents selected from the group consisting of hydroxy,
amino, mono- or di-C1-6 alkylamino, C1-6 alkoxy, C1-6
alkylcarbonyloxy and a halogen atom, (b) an amino which may
be substituted by C1-6 alkyl, C1-6 acyl or 5- to 7-membered
cyclic amino , (c) acetamido, (d) hydroxy, (e) carboxyl, (f)
nitro, (g) C1-6 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

41
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-C1-6 alkylamino, C1-6 alkoxy, C1-6
alkylcarbonyloxy and a halogen atom, (ii) an amino which
may be substituted by C1-6 alkyl, C1-6 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 C1-3 alkyl group, R2 is a hydrogen atom or a C1-3
alkyl group, R3 is a hydrogen atom or a C2-6 alkyl group, X
is an oxygen atom, Y is a group of the formula:
<IMG>
wherein R4' and R5' each is (i) a hydrogen atom or (ii) a C1-3
alkyl group optionally substituted by 1 to 4 substituents
selected from hydroxy, amino, carboxyl, nitro, mono- or
di-C1-6 alkylamino, C1-4 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 claimed in claim 1, wherein the compound
is 6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-isopropyl
(1,2,4) triazolo (1,5-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:

42
<IMG>
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(O)p
(p is a whole number of 0 to 2 ) ; Y is a group of the formula:
<IMG>
(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 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, 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

43
alkyl group optionally having substitutes selected from the
group consisting of hydroxy, amino, carboxyl, nitro, mono-
or di-C1-6 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-C1-6 alkylamino,
C1-6 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-C1-6
alkylamino, C1-6 alkoxy, C1-6 alkylcarbonyloxy and a halogen
atom, (ii) an amino which may be substituted by C1-6 alkyl,
C1-6 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(O)p (p is a whole number of 0 to
2),
Y is (a) a group of the formula:
<IMG>
(R4 and R5 respectively is (i) a hydrogen atom or (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, 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

44
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-C1-6 alkylamino, C1-6 alkoxy, C1-6
alkylcarbonyloxy and a halogen atom, (ii) an amino which
may be substituted by C1-6 alkyl, C1-6 acyl or 5- to 7-membered
cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi)
C1-6 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, 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 di-C1-6 alkylamino,
C1-6 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) C1-6 alkyl optionally having
substituents selected from the group consisting of hydroxy,
amino, mono- or di-C1-6 alkylamino, C1-6 alkoxy, C1-6
alkylcarbonyloxy and a halogen atom, (b) an amino which may
be substituted by C1-6 alkyl, C1-6 acyl or 5- to 7-membered
cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f)
nitro, (g) C1-6 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,

45
amino, mono- or di-C1-6 alkylamino, C1-6 alkoxy, C1-6
alkylcarbonyloxy and a halogen atom, (ii) an amino which
may be substituted by C1-6 alkyl, C1-6 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.
9. The use as claimed in claim 7, wherein R1 is hydrogen
atom or a C1-3, 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:
<IMG>
wherein R4' and R5' each is (i) a hydrogen atom or (ii) a C1-3
alkyl group optionally substituted by 1 to 4 substituents
selected from hydroxy, amino, carboxyl, nitro, mono- or
di-C1-6 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.
10 . The use as claimed in claim 7, wherein the compound is
6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-isopropyl
(1,2,4) triazolo (1,5-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

46
formula:
<IMG>
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(O)p
(p is a whole number of 0 to 2); Y is a group of the formula:
<IMG>
(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 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, C1-6 alkylcarbonyloxy and a halogen atom or (iii)
a halogen atom,

47
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-C1-6 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-C1-6 alkylamino,
C1-6 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-C1-6
alkylamino, C1-6 alkoxy, C1-6 alkylcarbonyloxy and a halogen
atom, (ii) an amino which may be substituted by C1-6 alkyl,
C1-6 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(O)p (p is a whole number of 0 to
2),
Y is (a) a group of the formula:
<IMG>
(R4 and R5 respectively is (i) a hydrogen atom or (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, 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

48
consisting of nitrogen, oxygen and sulfur atoms in adidtion
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-C1-6 alkylamino, C1-6 alkoxy, C1-6
alkylcarbonyloxy and a halogen atom, (ii) an amino which
may be substituted by C1-6 alkyl, C1-6 acyl or 5- to 7-membered
cyclic amino, (iii) hydroxy, (iv) carboxyl, (v) nitro, (vi)
C1-6 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, 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 di-C1-6 alkylamino,
C1-6 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) C1-6 alkyl optionally having
substituents selected from the group consisting of hydroxy,
amino, mono- or di-C1-6 alkylamino, C1-6 alkoxy, C1-6
alkylcarbonyloxy and a halogen atom, (b) an amino which may
be substituted by C1-6 alkyl, C1-6 acyl or 5- to 7-membered
cyclic amino, (c) acetamido, (d) hydroxy, (e) carboxyl, (f)
nitro, (g) C1-6 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

49
substituents selected from the group consisting of hydroxy,
amino, mono- or di-C1-6 alkylamino, C1-6 alkoxy, C1-6
alkylcarbonyloxy and a halogen atom, (ii) an amino which
may be substituted by C1-6 alkyl, C1-6 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.
15. The method as claimed in claim 13, wherein R1 is hydrogen
atom or a C1-3 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:
<IMG>
wherein R4' and R5' each is (i) a hydrogen atom or (ii) a C1-3
alkyl group optionally substituted by 1 to 4 substituents
selected from hydroxy, amino, carboxyl, nitro, mono- or
di-C1-6 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.
16. The method as claimed in claim 13, wherein the compound
is 6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-isopropyl
(1,2,4) triazolo (1,5-b) pyridazine.

Description

CA 02319426 2000-08-03
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1
TRIAZOLO-PYRIDAZINE DERIYATIYES 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-dimeth~3-~3-sulfamoyl-1-propoxy)-7-
isopropyl X1,2,4) triazolo ~I,5-b) pyridazine, etc..
Background
Triazolopyridazine derivatives represented by the
formula:
z R3 Re .
,. R , X- (CH2) "-Y- (CHZ) ~-S02N ~
II R ,
R'
wherein R1 is a hydrogen atom, an optionally substituted
lower alkyl group or a halogen atom; RZ and R' respectively
is a hydrogen atom or an optionally substituted lower alkyl
group, or RZ and R' 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:
R'
I
-C-
( R' and RS 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 R' each is a hydrogen atom, an
optionally substituted lower alkyl group, an optionally
substituted cycloalkyl group or an optionally substituted

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aryl group, or R6 and R' 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 W096/08496).
And, it is desired to develop agents which show actions
of the triazolopyridazine derivatives (I] locally.
Disclosure of Invention
The present inventors diligently made extensivestudies
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-propvxy)-7-isopropyl (1,2,4)
triazolo X1,5-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:
I z ..R3 R6 .
' R , X- (CN2) ~-Y- (CH2) ~-S02N ~ T ~ L I
R .
R~
wherein R1 is a hydrogen atom, an optionally substituted
lower alkyl group or a halogen atom; RZ and R' respectively
is a hydrogen atom or an optionally substituted lower alkyl
group, or RZ and R' may, taken together with the adjacent

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3
-C=C- group, form a 5- to 7-membered ring; X is an oxygen
atom or S(O)p (p is a whole number of 0 to 2); Y is a group
of the formula:
Ra
-C
R5
( R' 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 R' 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 R' 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, ( 11 ) a Cl_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, C1_6 alkylcarbonyloxy and a halogen atom or ( iii )
a halogen atom,
Rz and R' respectively is ( i ) a hydrogen atom or ( ii ) a C1_s
alkyl group optionally having substitutes selected from the
group consisting of hydroxy, amino, carboxyl, nitro, mono-
or di-Cl_6 alkylamino , C,_6 alkoxy, C1_6 alkylcarbonyloxy and
a halogen atom or (iii) a C,_6 cycloalkyl group optionally
having substitutes selected from the group consisting of
hydroxy, amino, carboxyl, nitro, mono- or di-C1_6 alkylamino,
C,_6 alkoxy, C,_6 alkylcarbonyloxy and a halogen atom, or
R~ and R' 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

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4
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-C1_6
alkylamino , C1_6 alkoxy, Ci_6 alkylcarbonyloxy and a halogen
atom, ( ii ) an amino which may be substituted by C1_6 alkyl ,
C1_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(O)p (p is a whole number of 0 to
2),
Y is (a) a group of the formula:
R4
-C
Rs
( R' and RS respectively is ( i ) a hydrogen atom or ( 11 ) a Cl_s
alkyl group optionally having substituents selected from
the group consisting of hydroxy, amino, carboxyl, vitro,
mono- or di-C1_6 alkylamino, C1_6 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 ) C1_6 alkyl optionally having
substituents selected from the group consisting of hydroxy,
amino, mono- or di-C1_6 alkylamino, C1_6 alkoxy, C1_s
alkylcarbonyloxy and a halogen atom, (ii) an amino which
may be substituted by C1_6 alkyl, C1_6 acyl or 5- to 7-membered
cyclic amino , ( iii ) hydroxy , ( iv ) carboxyl , ( v ) vitro , ( vi )
C1_6 alkoxy and (vii) a halogen atom,
R6 and R' respectively is ( i ) a hydrogen atom, ( ii ) a C,_6
alkyl group optionally having substituents selected from
the group consisting of hydroxy, amino, carboxyl, vitro,

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mono- or di-C1_6 alkylamino, C1_6 alkoxy, C1_6 alkylcarbonyloxy
and a halogen atom, ( iii ) a C,_6 cycloalkyl group optionally
having substituents selected from the group consisting of
hydroxy, amino, carboxyl, vitro, mono- or di-Cl_6 alkylamino,
C1_6 alkoxy. C1_6 alkylcarbonyloxy and a halogen atom, or ( iv)
a C6_1, aryl group optionally having substituents selected
from the group consisting of ( a ) C,_6 alkyl optionally having
substituents selected from the group consisting of hydroxy,
amino, mono- or di-C1_6 alkylamino, C1_6 alkoxy, CI_6
alkylcarbonyloxy and a halogen atom, ( b ) an amino which may
be substituted by C1_6 alkyl, C1_6 acyl or 5- to 7-membered
cyclic amino , ( c ) acetamido , ( d ) hydroxy , ( a ) carboxyl , ( f )
vitro , ( g ) C1_6 alkoxy , ( h ) C1_6 alkylcarbonyloxy and ( i ) a
halogen atom, or
R' and R' may, taken together with the ad jacent 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-C1_6 alkylamino, C1_6 alkoxy, C1_6
alkylcarbonyloxy and a halogen atom. (ii) an amino which
may be substituted by C1_6 alkyl, C1_6 acyl or 5- to 7-membered
cyclic amino , ( iii ) hydroxy , ( iv ) carboxyl , ( v ) vitro , ( 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 defined in ( 1 ) , wherein R1 is hydrogen atom
or a C1_3 alkyl group, RZ is a hydrogen atom or a C1_, alkyl
group, R' is a hydrogen atom or a C,_6 alkyl group. X is an
oxygen atom, Y is a group of the formula:

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6
R4.
-C
R5,
wherein R' ~ and RS ~ each is ( i ) a hydrogen atom or ( ii ) a Cl_,
alkyl group optionally substituted by 1 to 4 substituents
selected from hydroxy, amino, carboxyl, nitro, mono- or
di-C1_6 alkylamino , C1_6 alkoxy, C1_6 alkyl-carbonyloxy and
halogen atom, R6 and R' 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-1-propoxy)-7-isopropyl
X1,2,4) triazolo (1,5-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:
~..RZ R' /Re..
/ X- (CHZ) ~-Y- (CH2) n-SOzN ~ 7 [ ~ ~
R .
R'
wherein R1 is a hydrogen atom, an optionally substituted
lower alkyl group or a halogen atom: R~ and R' respectively
is a hydrogen atom, an optionally substituted lower alkyl
group or an optionally substituted cycloalkyl group, or RZ
and R' may, taken together with the adjacent -C=C- group,
form a 5- to 7-membered ring; X is an oxygen atom or S(O)p
f p is a whole number of 0 to 2 ) ; Y is a group of the formula:

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7
R4
-C
Rs
( R' and RS 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' and R' 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 R' 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 thPrPnf
preparing an agent for acting on bronchi,
(8) The use as defined in (7), wherein
R1 is ( i ) a hydrogen atom, ( if ) 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, C,_6 alkylcarbonyloxy and a halogen atom or ( iii )
a halogen atom,
RZ and R' respectively is ( i ) a hydrogen atom or ( ii ) a C1_s
alkyl group optionally having substitutes selected from the
group consisting of hydroxy, amino, carboxyl, nitro, mono-
or di-C1_6 alkylamino, Cl_6 alkoxy, C,_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-Ci_6 alkylamino,
C1_6 alkoxy, C1_6 alkylcarbonyloxy and a halogen atom, or
R2 and R' 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 optionallyhaving substituents selected from

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8
the group consisting of hydroxy, amino, mono- or di-C1_s
alkylamino, C1_6 alkoxy, C1_6 alkylcarbonyloxy and a halogen
atom, (ii) an amino which may be substituted by C1_6 alkyl,
C1_6 acyl or 5- to 7-membered cyclic amino, (iii) hydroxy,
( iv ) carboxyl , ( v ) vitro , ( vi ) Cl_6 alkoxy and ( vii ) a halogen
atom;
X is an oxygen atom or S(O)p (p is a whole number of 0 to
2),
Y is (a) a group of the formula:
R4
-C-
I
R5
( R' and RS respectively is ( i ) a hydrogen atom or ( ii ) a C1_s
alkyl group optionally having substituents selected from
the group consisting of hydroxy, amino, carboxyl, vitro,
mono- or di-C1_6 alkylamino, C1_6 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 ) Cl_6 alkyl optionally having
substituents selected from the group consisting of hydroxy,
amino, mono- or di-C1_6 alkylamino, CI_6 alkoxy, C1_s
alkylcarbonyloxy and a halogen atom, (ii) an amino which
may be substituted by C1_6 alkyl, C1_6 acyl or 5- to 7-membered
cyclic amino , ( iii ) hydroxy , ( iv ) carboxyl , ( v ) vitro , ( vi )
C1_6 alkoxy and (vii) a halogen atom,
R6 and R' respectively is ( i ) a hydrogen atom, ( ii ) a C1_6
alkyl group optionally having substituents selected from
the group consisting of hydroxy, amino, carboxyl, vitro,
mono- or di-Cl_6 alkylamino, C1_6 alkoxy, C,_6 alkylcarbonyloxy
and a halogen atom, ( iii ) a C,_6 cycloalkyl group optionally

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9
having substituents selected from the group consisting of
hydroxy, amino, carboxyl, nitro, mono- or di-C1_6 alkylamino,
Cl_6 alkoxy, C1_6 alkylcarbonyloxy and a halogen atom, or ( iv)
a C6_1, aryl group optionally having substituents selected
from the group consisting of ( a ) C1_6 alkyl optionally having
substituents selected from the group consisting of hydroxy,
amino, mono- or di-C,_6 alkylamino, C1_6 alkoxy, Cl_6
alkylcarbonyioxy and a halogen atom , ( b ) an amino which may
be substituted by C1_6 alkyl, C1_6 acyl or 5- to 7-membered
cyclic amino , ( c ) acetamido , ( d ) hydroxy , ( a ) carboxyl , ( f )
nitro , ( g ) C1_6 alkoxy, ( h ) C1_6 alkylcarbonyloxy and ( i ) a
halogen atom, or
R6 and R' 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-C1_6 alkylamino, C1_6 alkoxy, C1_s
alkylcarbonylaxy and a halogen atom, (ii) an amino which
may be substituted by Cl_6 alkyl, C~_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,
( 9 ) The use as defined in ( 7 ) , wherein R1 is hydrogen atom
or a C1_, alkyl group, R~ is a hydrogen atom or a Cl_3 alkyl
group, R' is a hydrogen atom or a C1_6 alkyl group, X is an
oxygen atom, Y is a group of the formula:

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10
R4,
I
-C
R5.
wherein R'' and RS' each is ( i ) a hydrogen atom or ( ii ) a C1_3
alkyl group optionally substituted by 1 to 4 substituents
selected from hydroxy, amino, carboxyl, vitro, mono- or
di-C1_6 alkylamino, C1_6 alkoxy, C1_6 alkyl-carbonyloxy and
halogen atom, R6 and R' respectively is a hydrogen atom or
a C1_3 alkyl group, m and n is l,
(10) The use as defined in (7), wherein the compound is
6-(2,2-dimethyl-3-sulfamoyl-1-propoxy)-7-isopropyl
~1, 2 , 4) triazolo ~1, 5-b) pyridazine,
(il) 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:
2 . ~R' Rs .
R , X- (CHZ) ~-Y- (CH2) ~-S02N ~
R .
R~
wherein R1 is a hydrogen atom, an optionally substituted
lower alkyl group or a halogen atom; R~ and R' respectively
is a hydrogen atom, an optionally substituted lower alkyl
group or an optionally substituted cycloalkyl group, or RZ

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11
and R' may, taken together with the adjacent -C=C- group,
form a 5 - to 7 -membered ring; X is an oxygen atom or S ( O ) p
(p is a whole number of 0 to 2 ) ; Y is a group of the formula:
R4
R5
( R' and RS 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 R' 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 R' 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
Ri 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-C,_6 alkylamino ,
Cl_6 alkoxy, C,_6 alkylcarbonyloxy and a halogen atom or ( iii )
a halogen atom,
RZ and R' respectively is ( i ), a hydrogen atom or ( ii ) a C1_s
alkyl group optionally having substitutes selected from the
group consisting of hydroxy, amino, carboxyl, nitro, mono-
or di-C1_6 alkylamino, C1_6 alkoxy, C1_6 alkylcarbonyloxy and
a halogen atom or (iii) a C,_6 cycloalkyl group optionally
having substitutes selected from the group consisting of
hydroxy, amino, carboxyl, nitro, mono- or di-C,_6 alkylamino,
C1_6 alkoxy, C1_6 alkylcarbonyloxy and a halogen atom, or
RZ and R' 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

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12
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-C1_6
alkylamino, C,_6 alkoxy. C1_6 alkylcarbonyloxy and a halogen
atom, ( ii ) an amino which may be substituted by C1_6 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(O)p (p is a whole number of 0 to
2),
Y is (a) a group of the formula:
R4
I
-C
R5
( R' and RS respectively is ( i ) a hydrogen atom or ( 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, C,_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 ) C1_6 alkyl optionally having
substituents selected from the group consisting of hydroxy,
amino, mono- or di-C1_6 alkylamino, C1_6 alkoxy, C1_6
alkylcarbonyloxy and a halogen atom, (ii) an amino which
may be substituted by C,_6 alkyl, C1_6 acyl or 5- to 7-membered
cyclic amino , ( iii ) hydroxy , ( iv ) carboxyl , ( v ) nitro , ( vi )
C1_6 alkoxy and (vii) a halogen atom,
R6 and R' respectively is ( i ) a hydrogen atom, ( ii ) a C,_6
alkyl group optionally having substituents selected from

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13
the group consisting of hydroxy, amino, carboxyl, vitro,
mono- or di-C1_6 alkylamino, C1_6 alkoxy, C1_6 alkylcarbonyloxy
and a halogen atom, ( iii ) a C,_6 cycloalkyl group optionally
having substituents selected from the group consisting of
hydroxy, amino, carboxyl, vitro, mono- or di-C1_6 alkylamino,
C1_6 alkoxy, C1_6 alkylcarbonyloxy and a halogen atom, or (iv)
a C6_1, aryl group optionally having substituents selected
from the group consisting of ( a ) C1_6 alkyl optionally having
substituents selected from the group consisting of hydroxy,
amino, mono- yr di-CI_6 alkylamino, Cl_6 alkoxy, C1_s
alkylcarbonyloxy and a halogen atom, ( b ) an amino which may
be substituted by C1_6 alkyl, C1_6 acyl or 5- to 7-membered
cyclic amino , ( c ) acetamido , ( d ) hydroxy , ( a ) carboxyl , ( f )
vitro , ( g ) Cl_6 alkoxy, ( h ) C1_6 alkylcarbonyloxy and ( i ) a
halogen atom, or
R6 and R' 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-CI_6 alkylamino, C1_6 alkoxy, C1_6
alkylcarbonyloxy and a halogen atom, (ii) an amino which
may be substituted by C1_6 alkyl, C1_6 acyl or 5- to 7-membered
cyclic amino , ( iii ) hydroxy, ( iv ) carboxyl , ( v ) vitro , ( vi )
CI_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 Cl_3 alkyl group, R2 is a hydrogen atom or a Cl_3
alkyl group, R3 is a hydrogen atom or a C1_6 alkyl group, X

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14
is an oxygen atom, Y is a group of the formula:
R4,
-C
R5,
wherein R'~ and RS' each is ( i ) a hydrogen atom or ( ii ) a C1_3
alkyl group optionally substituted by 1 to 4 substituents
selected from hydroxy, amino, carboxyl, vitro, mono- or
di-C1_6 alkylamino, C1_6 alkoxy, C1_6 alkyl-carbonyloxy and
halogen atom, R6 and R' respectively is a hydrogen atom or
a C1_, 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
X1,2,4) triazolo X1,5-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)-?-isopropyl X1,2,4) triazolo (1,5-b)
pyridazine or a salt thereof and sprays ( a . g . , an inhalation
for acting on bronchi),
(20) An aerosol which comprises 6-(2,2-dimethyl-3-
sulfamoyl-1-propoxy)-7-isopropyl X1,2,4) triazolo (1,5-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:
3
~..R2 R / R6 ..
X- (CH2) m-Y- (CHz) ~-SOzN ~ 7 .
IN R
R'

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15
wherein R1 is a hydrogen atom, an optionally substituted
lower alkyl group or a halogen atom; RZ and R3 respectively
is a hydrogen atom or an optionally substituted lower alkyl
group, or RZ and R' may, taken together with the adjacent
-C=C- group, form a 5- to 7-membered ring; X is an oxygen
atom or S ( O ) p ( p is a whole number of 0 to 2 ) ; Y is a group
of the formula:
R4
I
R5
{ R' and RS 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 R' each is a hydrogen atom, an
optionally substituted lower alkyl group, an optionally
substituted cycloalkyl group or an optionally substituted
aryl group, or R' and R' 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
11,2,4) triazolo X1,5-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

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16
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:
R3 Rs .
.. R , X- (CH2) ~,-Y- tCH2) ~-S02N ~ ~
R .
R'
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:
s
R.
... R , X- (CHZ) m Y- (CHZ) ~-S02N ~ ~ . L I
IN R
R'
wherein R' is a hydrogen atom, an optionally substituted
lower alkyl group or a halogen atom; R2 and R' respectively
is a hydrogen atom or an optionally substituted lower alkyl
group, or Rz and R' may, taken together with the adjacent
-C=C- group, form a 5- to 7-membered ring; X is an oxygen
atom or S ( O ) p ( p is a whole number of 0 to 2 ) ; Y is a group
of the formula:
Ra
I
-C-
R5
( R' and RS respectively is a hydrogen atom or an optionally
substituted lower alkyl group ) or a divalent group derived

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17
from an optionally substituted 3- to 7-membered homocyclic
or heterocyclic ring; R6 and R' 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 R' 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
(11) 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-1-propoxy)-7-isopropyl X1,2,4)
triazolo (1,5-b) pyridazine, are known compounds described
in EP-A-0562439, EP-A-0648491 or WC?96/08496.
In the formula mentioned above, examples of the "lower

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18
alkyl group" represented by R1, RZ , R' , R' , RS , R6 or R' include
a straight or branched C1_6 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 Rz,
R', R6 or R' include a C,_6 cycloalkyl group such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and so on.
Examples of the "aryl group" represented by R6 or R'
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 ( a . g . mono- or di-Cl_6 alkylamino groups
such as methylamino, ethylamino, propylamino,
dimethylamino , diethylamino , etc . ) , lower alkoxy ( a . g . C1_6
alkoxy groups such as methoxy, ethoxy, propoxy, hexyloxy,
etc.), lower alkylcarbonyloxy (e. g. C1_6 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 ( a . g . C, _6
alkoxy groups such as methoxy, ethoxy, propoxy, etc. ) , lower
alkylcarbonyloxy ( a . g . C1_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 ( a . g . C1_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 ( a . g . mono- or di-C1_6 alkylamino groups
such as methylamino, ethylamino, propylamino,

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dimethylamino , diethylamino , etc . ) , lower alkoxy ( a . 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 C1_6 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 CS_, cycloalkenes ( a . 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, C,_, cycloalkanes such as
cyclopropane, cyclobutane, cyclopentane, cyclohexane,
cycloheptane , etc . , C,_, 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

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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:
~ ~ Q. ~.Q.--~, Q.
-~- Q Q
Particularly, the following groups may be used as the
common species
~.~..Q. ~~Q,-~-, Q,
, y . v / . W .
More preferable examples in above groups include the
following groups:
~ ~ Q ~ Q
Q
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

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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
H
~N~ 0\
N , ,
H ~ H H
H
N 0
0 > r
N
H
Examples of the "nitrogen-containing heterocyclic
group" formed by R6 and R' 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:

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-N~ . - N~~ , -N~ , -N
--\ .- N~0 ~ N ~ \
-N~NH , V , N ~ ,
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. C1_6 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 ( a . g . C1_6 alkyl group such as methyl , ethyl , n-propyl ,
etc.) mentioned dust above may have, include 1 to 4
substituents selected from among hydroxy, amino, mono- or
di-lower alkylamino ( a . g . mono- or di-C1_6 alkylamino groups
such as methylamino, ethylamino, propylamino,
dimethylamino , diethylamino , etc . ) , lower alkoxy ( a . g . C1_6
alkoxy groups such as methoxy, ethoxy, propoxy, hexyloxy,
etc.), lower alkylcarbonyloxy (e. g. C1_6 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 C1_6 alkyl ( a . g . methyl , ethyl , propyl ,
etc.), acyl (e. g. C1_6 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 Cl_3
alkyl group (e. g. methyl, ethyl, n-propyl, etc.) and more

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preferable examples are a hydrogen atom and so on.
Preferable examples of RZ are a hydrogen atom or a C1_,
alkyl group (e. g. methyl, ethyl, n-propyl, etc.) and more
preferable examples are a hydrogen atom and so on.
Preferable examples of R' are a hydrogen atom or a CI_s
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 Rz and R' 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.
-C
R5,
wherein R' ~ and RS ~ each is ( i ) a hydrogen atom or ( ii ) a C1_3
alkyl group optionally substituted by 1 to 4 substituents
selected from hydroxy, amino, carboxyl, nitro, mono- or
di-C1_6 alkylamino, C,_6 alkoxy, Cl_6 alkyl-carbonyloxy and
halogen atom, and so on.
Examples of the "C1_3 alkyl group" represented by R~~ 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:

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~Q n Q a Q a
Thus, for example, the followinggroups can
be
frequently used the common species
as of Y:
0
More preferably
examples
of Y
include
the
follow:
-~-- .
Preferable examples of R6 and R' are a hydrogen atom,
a C1_, alkyl group ( a . 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
W096/08496, and most preferable example is 6-(2,2-
dimethyl-3-sulfamoyl-1-propoxy)-7-isopropyl X1.2,4)
triazolo X1,5-b) pyridazine or a salt thereof.
The salt of triazolopyridazine derivatives (I] is
preferably a physiologically acceptable acid addition salt.

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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, fumaric acid, maleic acid,
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 ( a . g . , a tri-C1_, alkylamine
such as triethylamine).
The triazolopyridazine derivatives [ I ] or salts thereof
can be prepared according to the descriptions of EP-A-
0562439 or W096/08496, 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 a . g . inert liquid such

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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 adjustor 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 ( a . 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,
tosf loxacin etc . ) and anti-fungus agents ( a . g . f luconazole ,

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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
O.OI 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 . O1 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

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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 ( a . 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

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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 ad juvant and a solvent to form
a uniform suspension, (2) a method of kneading the
triazolopyridazine derivative [I] or a salt thereof with

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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 (Astray, 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

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reactions , and is with a low toxic potential ( acute toxicity:
LDso>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

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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 60FZ5, was used as the TLC plate and a
W 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
CDC1, . deuteriochloroform
v/v . volume/volume
. weight
m.p. . melting point
i.v. . intravenous injection

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b (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 (CDC1,) ~S : 1.26(6H,d,J=7Hz), 3.16(lH,m), 4.89(2H,br.s),
6.65(IH,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 CeHIIN,OCl

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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 CeH9CIN,
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[1,2,4]triazolo[1,5-b]pyridazine
To a solution of 0.669 g of 3-hydroxy-2,2-
dimethyl-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[1,2,4]triazolo[1,5-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 1N-hydrochloric acid, and extracted with ethyl
acetate-tetrahydrofuran (1:1). The extract was washed with

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saturated aqueous solution of sodium chloride and dried
(MgSO,) 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 C1,HZ1NSO,S
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 pg/kg i.v.,
in.guinea pigs was measured using to the method of
Konzett-Roessler. 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 HZO, 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 P.g/kg, dissolved in
physiological saline was administered through a jugular
vein cannula and the induced bronchoconstriction was

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36
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
% Inhibition of PAF-induced
Reference bronchoconstriction
Example
No.
1 mg/kg, p.o. 3 mg/kg, p.o.
4 72 _
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
ul.
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).

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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 X1,2,4) triazolo X1,5-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.