Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-27
2002-08-20
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S341000, C514S342000, C546S270400, C546S271400, C546S274400
Reexamination Certificate
active
06436966
ABSTRACT:
This Application is the National Stage of International Application Serial No. PCT/JP98/04837, filed Oct. 26, 1998.
TECHNICAL FIELD
The present invention relates to an agent for antagonizing adenosine at adenosine A
3
receptors and a novel thiazole compound having a superior antagonistic activity at adenosine A
3
receptor.
BACKGROUND ART
As subtypes of adenosine receptors, A
1
, A
2a
, A
2b
and A
3
are known. Adenosine induces bronchial constriction in asthma patients, while theophylline, which is known as an antiasthmatic, antagonizes adenosine. Recently several reports showed that activation of adenosine A3 receptors in rats promotes degranulation of mast cells [Journal of Biological Chemistry, 268, 16887-16890 (1993)], that adenosine A
3
receptors exist on peripheral blood eosinophils and that the stimulation of adenosine A
3
receptors activates phospholipase C and elevates intracellular calcium [Blood, 88, 3569-3574 (1996)].
Currently, as selective A
3
adenosine receptor antagonists, xanthine derivatives are reported in GB-A-2288733 and WO 95/11681, and the following compounds are reported in Journal of Medicinal Chemistry, 40, 2596-2608(1997).
The following thiazole compounds are known.
1) A thiazole derivative of the formula:
wherein R
1
represents i) cycloalkyl, ii) cyclic amino, iii) amino which may be substituted by 1 or 2 substituents selected from the group consisting of lower alkyl, phenyl, acetyl and lower alkoxycarbonylacetyl, iv) alkyl which may be substituted by a substituent selected from the group consisting of hydroxy, carboxy and lower alkoxycarbonyl or v) phenyl which may be substituted by a substituent selected from the group consisting of carboxy, 2-carboxyethenyl and 2-carboxy-1-propenyl; R
2
represents pyridyl which may be substituted by a lower alkyl; and R
3
represents phenyl which may be substituted by a substituent selected from the group consisting of lower alkoxy, lower alkyl, hydroxy, halogen and methylenedioxy, or a salt thereof, which has analgesic, anti-pyretic, anti-inflammatory, anti-ulcer, thromboxane A
2
(TXA
2
) synthetase inhibitory and platelet aggregation inhibiting actions (JP-A-60-58981).
2) A 1,3-thiazole derivative of the formula:
wherein R
1
represents an optionally substituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heterocyclic group having carbon as the attachment point or amino; R
2
represents pyridyl which may be substituted by an alkyl; and R
3
represents phenyl which may be substituted, or a salt thereof, which has analgesic, anti-pyretic, anti-inflammatory, anti-ulcer, thromboxane A
2
(TXA
2
) synthetase inhibitory and platelet aggregation inhibiting actions (JP-A-61-10580).
3) A 1,3-thiazole derivative of the formula:
wherein R
1
represents an optionally substituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, heterocyclic group having carbon as the attachment point or amino; R
2
represents pyridyl which may be substituted by an alkyl; and R
3
represents aryl which may be substituted, or a salt thereof, which has analgesic, anti-pyretic, anti-inflammatory, anti-ulcer, thromboxane A
2
(TXA
2
) synthetase inhibitory and platelet aggregation inhibiting actions (U.S. Pat. No. 4,612,321).
4) A compound of the formula:
wherein R
1
is an optionally substituted phenyl, R
2
is C
1-6
alkyl or (CH
2
)
n
Ar, n is 0-2, Ar is an optionally substituted phenyl, R
3
is hydrogen or C
1-4
alkyl, R
4
is hydrogen, C
1-4
alkyl, etc, R
5
is hydrogen or C
1-4
alkyl, R
6
is hydrogen, C
1-4
alkyl, etc, or salt thereof, which has an activity of inhibiting gastric acid secretion (JP-A-07-503023, WO 93/15071).
5) A compound of the formula:
wherein R
1
is pyridyl, etc, R
2
is phenyl, etc, R
3
and R
4
are hydrogen or methyl, R
5
is methyl, etc, R
6
is hydrogen or methyl, etc, or a salt thereof, which is useful as anti-inflammatory and anti-allergic agents (DE-A-3601411).
6) A compound of the formula:
wherein R
1
is lower alkyl substituted by halogen, R
2
is pyridyl, etc, R
3
is phenyl, etc, or a salt thereof, which has anti-inflammatory, antipyretic, analgesic and anti-allergic activities (JP-A-5-70446).
From the prior art described above, it is thought that adenosine causes asthma through its binding to adenosine A
3
receptor, therefore A
3
adenosine receptor antagonists are expected to become a new type of antiasthma drug. Accordingly, an agent for antagonizing adenosine at adenosine A
3
receptors which has potent antagonistic activity, good bioavailability upon administration and good metabolical stability are expected to have potent therapeutic effects for asthma, inflammation, Addison's diseases, autoallergic hemolytic anemia, Crohn's diseases, psoriasis, rheumatism and diabetes. However, as a prophylactic and therapeutic agent for adenosine A
3
receptor-related diseases, no good agents for antagonising adenosine at gadenosine A
3
receptors are known in terms of potency, safety, bioavailability, and metabolic'stability. Therefore a good agent for antagonising adenosine at adenosine A
3
receptor is expected to be developed.
DISCLOSURE OF INVENTION
We, the present inventors, have studied various compounds having an antagonistic activity at adenosine A
3
receptors, and as a result, have found for the first time that a 1,3-azole compound substituted on the 4- or 5-position, or both, by a pyridyl which may be substituted (hereinafter sometimes referred to briefly as compound (I)], has an unexpected, excellent selective affinity to adenosine A
3
receptor, antagonistic activity at adenosine A
3
receptor and high stability, and is therefore satisfactory as a medicine.
Compound (I) comprises, for example, a compound of the formula:
wherein R
1
represents a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, an amino which may be substituted or an acyl;
at least one of R
2
and R
3
represents a hydrogen atom, a pyridyl which may be substituted or an aromatic hydrocarbon group which may be substituted, and the other represents a pyridyl which may be substituted; and
X represents a sulfur atom which may be oxidized, an oxygen atom or a group of the formula: NR
4
wherein R
4
represents a hydrogen atom, a hydrocarbon group which may be substituted or an acyl;
or a salt thereof, which may be N-oxidized [hereinafter sometimes referred to briefly as compound (Ia)], and a novel compound of the formula:
wherein R
1a
represents (i) an aromatic heterocyclic group which may be substituted, (ii) an amino which may be substituted by substituent(s) selected from the group consisting of a substituted carbonyl and a hydrocarbon group which may be substituted, (iii) a cyclic amino which may be substituted or (iv) an acyl;
R
2a
represents an aromatic hydrocarbon group which may be substituted; and
R
3a
represents a pyridyl which may be substituted, or a salt thereof [hereinafter sometimes referred to briefly as compound (Ib)] being within the scope of compound (Ia).
On the basis of these findings, the inventors have completed the present invention.
Specifically, the present invention relates to:
(1) A pharmaceutical composition for antagonizing adenosine at adenosine A
3
receptors which comprises compound (I);
(2) a composition of the above (1), wherein the 1,3-azole compound is compound (Ia);
(3) a composition of the above (2), wherein R
1
is
(i) a hydrogen atom,
(ii) a C
1-8
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl, C
6-14
aryl or C
7-16
aralkyl group which may be substituted by 1 to 5 substituents,
(iii) a 5- to 14-membered heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of nitrogen, sulfur and oxygen atoms in addition to carbon atoms, which group may be substituted by 1 to 5 substituents,
(iv) an amino which may be substituted by 1 or 2 substituents selected from the group consisting of
(a) a C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-6
cycloalkyl, C
6-14
aryl or C
7-16
aralkyl group which may be substituted by 1 to 5 substit
Kanzaki Naoyuki
Kimura Hiroyuki
Ohkawa Shigenori
Chao Mark
Ramesh Elaine M.
Seaman D. Margaret
Takeda Chemical Ind. Ltd.
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