Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-04-14
2001-06-19
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S236000
Reexamination Certificate
active
06248740
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel condensed pyridazine derivatives exhibiting an excellent anti-allergic, anti-histaminic, anti-inflammatory or eosinophil chemotaxis-inhibiting activity, or other activities, and useful as an agent for treating or preventing atopic dermatitis, allergic rhinitis, bronchial asthma, allergic conjunctivitis, chronic urticaria, etc., a method for producing them, and a pharmaceutical composition containing them.
BACKGROUND ART
Many condensed pyridazine derivatives are currently synthesized as drugs for a variety of diseases. For example, U.S. Pat. No. 3,915,968 discloses a compound represented by the formula:
wherein R and R
3
independently represent a hydrogen atom or a lower alkyl group (at least one of R and R
3
is a lower alkyl group); R
1
and R
2
represent a heterocyclic group selected from the group consisting of pyrrolidine, piperidine, piperazine and morpholine taken together with the adjacent nitrogen atom; or a salt thereof. U.S. Pat. No. 4,136,182 discloses that a compound represented by the formula:
wherein R represents a hydrogen atom, a phenyl group or a lower alkylcarbonylamino group; R
1
represents morpholino or piperidino; R
2
represents a hydrogen atom or a lower alkyl group (at least one of R and R
2
is a group other than a hydrogen atom; when R is a phenyl group, R
1
is morpholino and R
2
is a lower alkyl group); or a salt thereof, is useful as a bronchodilator for mitigating bronchial spasms. Also, Japanese Patent Unexamined Publication No. 279447/1995 discloses that a compound represented by the formula:
wherein R
1
represents a hydrogen atom, a lower alkyl group that may be substituted, or a halogen atom; R
2
and R
3
independently represent a hydrogen atom or a lower alkyl group which may be substituted, or may form a 5- to 7-membered ring with the adjacent —C═C—; X represents an oxygen atom or S(O)
p
(p represents an integer from 0 to 2);
Y represents a group represented by the formula:
(R
4
and R
5
independently represent a hydrogen atom or a lower alkyl group which may be substituted) or a divalent group derived from a 3- to 7-membered homocycle or heterocycle which may be substituted; R
6
and R
7
independently represent a hydrogen atom, a lower alkyl group which may be substituted, a cycloalkyl group which may be substituted, or an aryl group that may be substituted, or may form a nitrogen-containing heterocyclic group which may be substituted, with the adjacent nitrogen atom; m represents an integer from 0 to 4, and n represents an integer from 0 to 4; or a salt thereof; and, as an example synthetic product, a compound of the formula:
exhibits anti-asthmatic, anti-PAF, anti-inflammatory and anti-allergic activities. Furthermore, Japanese Patent Unexamined Publication No. 279446/1995 describes a compound represented by the formula:
wherein R
1
represents a hydrogen atom, a lower alkyl group which may be substituted, or a halogen atom; R
2
and R
3
independently represent a hydrogen atom or a lower alkyl group which may be substituted (provided that either of R
2
and R
3
is a hydrogen atom, the other represents a lower alkyl group which may be substituted), or may form a 5- to 7-membered ring taken together with the adjacent —C═C—; X represents an oxygen atom or S(O)
p
(p represents an integer from 0 to 2); Y represents a group represented by the formula:
(R
4
and R
5
independently represent a hydrogen atom or a lower alkyl group which may be substituted) or a divalent group derived from a 3- to 7-membered homocycle or heterocycle which may be substituted; R
6
and R
7
independently represent a hydrogen atom, a lower alkyl group which may be substituted, a cycloalkyl group which may be substituted, or an aryl group which may be substituted, or may form a nitrogen-containing heterocyclic group which may be substituted, taken together with the adjacent nitrogen atom; m represents an integer from 0 to 4, and n represents an integer from 0 to 4; or a salt thereof; and discloses that these compounds possess anti-allergic, anti-inflammatory and anti-PAF (platelet activating factor) activities to suppress bronchial spasms and bronchial contraction, therefore could be utilized as effective anti-asthmatic agents.
On the other hand, as compounds exhibiting anti-allergic or anti-histaminic activities, there may be mentioned, for example, terfenadine (The Merck Index, 12th edition, 9307) and ebastine (The Merck Index, 12th edition, 3534), which are already in clinical use.
There is demand for the development of novel compounds more satisfactory than conventional anti-allergic agents, anti-histaminic, anti-inflammatory agents etc., in terms of action efficacy, sustained action, safety etc.
Through various extensive investigations, the present inventors produced for the first time novel condensed pyridazine compounds represented by the formula:
wherein Ar
1
and Ar
2
are independently an aromatic group which may be substituted, and Ar
1
and Ar
2
may form a condensed cyclic group with an adjacent carbon atom; ring B is a nitrogen-containing heterocycle may be substituted; X and Y are the same or different and are independently a bond, an oxygen atom, S(O)
p
(p is an integer from 0 to 2), NR
4
wherein R
4
is a hydrogen atom or a lower alkyl group, or a divalent linear lower hydrocarbon group which may contain 1 to 3 hetero atoms and the bivalent linear lower hydrocarbon group may be substituted; A is a nitrogen atom or CR
7
(R
7
is a hydrogen atom, a halogen atom, a hydrocarbon group which may be substituted, an acyl group or a hydroxy group which may be substituted; R
1
, R
2
and R
3
are the same or different and are independently a hydrogen atom, a halogen atom, a hydrocarbon group which may be substituted, an acyl group or a hydroxy group which may be substituted; R
8
is a hydrogen atom, a hydroxy group which may be substituted by lower alkyl, or a carboxyl group; or a salt thereof, and found that these compounds, owing to their unique chemical structure characterized by the presence of substitutional piperidine or piperazine via a spacer from the 6-position of the [1,2,4]triazolo[1,5-b]pyridazine or imidazo[1,2-b]pyridazine skeleton, exhibits unexpectedly excellent anti-allergic, anti-histaminic, anti-inflammatory, and eosinophil chemotaxis-inhibiting activities, with excellent sustained activity and safety, and that it serves as an agent for treating or preventing atopic dermatitis, allergic rhinitis, bronchial asthma, allergic conjunctivitis, chronic urticaria, etc., on the basis of these pharmacological activities. The inventors conducted further investigations based on these findings, and developed the present invention.
DISCLOSURE OF INVENTION
The present invention provides:
(1) A compound represented by the formula:
wherein Ar
1
and Ar
2
are independently an aromatic group which may be substituted, and Ar
1
and Ar
2
may form a condensed cyclic group with an adjacent carbon atom; ring B is a nitrogen-containing heterocycle which may be substituted; X and Y are the same or different and are independently a bond, an oxygen atom, S(O)p (p is an integer of 0 ot 2), NR
4
wherein R
4
is a hydrogen atom or a lower alkyl group, or a bivalent linear lower hydrocarbon group which may contain 1 to 3 hetero atoms and the bivalent linear lower hydrocarbon group may be substituted; A is a nitrogen atom or CR
7
wherein R
7
is a hydrogen atom, a halogen atom, a hydrocarbon which may be substituted, an acyl group or a hydroxy group which may be substituted; R
1
, R
2
and R
3
are the same or different and are independently a hydrogen atom, a halogen atom, a hydrocarbon group which may be substituted, an acyl group or a hydroxy group which may be substituted; R
8
is a hydrogen atom, a hydroxy group which may be substituted by lower alkyl or a carboxyl group, or a salt thereof,
(2) The compound as defined in (1) wherein Ar
1
and Ar
2
are independently (i) a C
6-14
aromatic hydrocarbon group, (ii) a 5 to 8 membered aromatic heterocycl
Gyoten Michiyo
Kawano Yasuhiko
Nagaya Hideaki
Berch Mark L.
Chao Mark
McKenzie Thomas C
Riesen Philippe Y.
Takeda Chemical Industries Ltd.
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