Thiazolopyrimidine compounds, its production and use

Details Thiazolopyrimidine compounds, its production and use Thiazolopyrimidine compounds, its production and use

2001-07-12

2003-06-24

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S228500, C514S225800, C514S233200, C514S232500, C514S252020, C514S252160, C514S255050, C514S259500, C514S261100, C544S278000, C544S264000, C544S235000, C544S237000, C544S238000, C544S117000, C544S102000, C544S080000, C544S061000, C544S058600, C544S035000

Reexamination Certificate

active

06583146

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel thiazolopyrimidine compounds having excellent adenosine A
3
receptor antagonistic activity, their production, pharmaceutical compositions comprising them, and the like.
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 A
3
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 concentration [Blood, 88, 3569-3574 (1996)].
Currently, as selective adenosine A
3
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).
WO 97/33879 discloses an adenosine A
3
receptor antagonist comprising a compound of the formula:
wherein R is hydrogen, chlorine, bromine, fluorine, iodine, hydroxy, C
1-4
alkyl, C
1-4
alkoxy or C
1-4
alkylcarboxy, or a salt thereof and, specifically discloses
On the other hand, as for thiazolopyrimidine compounds, the following compounds are reported.
1) As a compound having immunostimulating activity, a compound represented by the formula:
wherein X is nitrogen atom or R
2
—C group, R is hydrogen atom, a pharmaceutically acceptable cation or alkyl group (C
1-5
), R
1
and R
2
are the same and different and are hydrogen atom, alkyl group (C
1-5
) or, aralkyl, phenyl, thienyl or pyridyl group optionally substituted with halogen atom, alkyl or alkoxy (the number of carbon atom of alkyl being up to 4) or cycloalkyl group (C
1-5
), or a pharmaceutically acceptable salt, and specifically, the following compounds.
(JP 52-148096 A)
2) As a compound having anti-inflammatory activity, a compound represented by the formula:
wherein (a) R
a
together with R
b
forms —C(R
3
)═CH—CO—N═ or (b) R
a
is hydrogen atom and R
b
is ═N—CO—CH═CH—NR
7
R
8
, R
1
, R
2
and R
3
are the same or different, and are hydrogen atom, C
1-6
alkyl, C
1-6
alkoxy, C
2-7
carbonylalkoxy or phenyl, or R
3
is as defined above and R
1
together with R
2
forms phenyl optionally substituted with two C
1-6
alkyls, C
1-6
alkoxys, C
2-7
carbonylalkoxys, and R
7
and R
8
are independently hydrogen atom or C
1-6
alkyl, or they together with the adjacent nitrogen atom form pyrrolidino, piperidino or homopiperidino, and, the following specific compound:
(GB 1345148)
3) As agrochemicals,
(Journal of Agricultural and Food Chemistry, 39 (12), 2300-2303 (1991))
4)
(Journal für Praktische Chemie, 330 (4) 607-616 (1991))
5)
(Indian Journal of Chemistry, Section B, 23 B (2), 117-120 (1984))
6)
(Heterocyclics, 20 (6), 1089-1097 (1983))
7) As a compound having anti-microbial activity,
(Journal of Pharmaceutical Sciences, 62 (11), 1785-1789 (1973))
It is thought that adenosine causes asthma through its binding to an adenosine A
3
receptor, therefore A
3
adenosine receptor antagonists are expected to become a new type of anti-asthma drug and the like. Accordingly, an agent for antagonizing adenosine at adenosine A
3
receptors which has potent antagonistic activity, good oral absorption and good metabolical stability are expected to have potent therapeutic effects for asthma, inflammation, Addison's diseases, autoimmune hemolytic anemia, Crohn's diseases, psoriasis, rheumatism, central nerve diseases (e.g., cerebrovacular disorders such as haemorrhagia cerebri, cerebral infarction, etc., head injury, spinal injury, cerebral edema, etc.), diabetes and the like. However, as a prophylactic and therapeutic agent for adenosine A
3
receptor-related diseases, no good agent for antagonising adenosine at adenosine A
3
receptors are known in terms of potency, safety, bioavailability, metabolic stability, and the like. Therefore, a good agent for antagonising adenosine at adenosine A
3
receptors is expected to be developed.
DISCLOSURE OF THE INVENTION
As a result of the present inventors' intensive study, a compound represented by the formula (I):
wherein ring A is an optionally substituted benzene ring, ring B may further be substituted, and R
1
is an optionally substituted cyclic group, or a salt thereof [hereinafter sometimes abbreviated to compound (I)], whose chemical structure is characterized in that the 2-position of the thiazolopyrimidine ring is substituted with an optionally substituted cyclic group and the 3-position thereof is substituted with an optionally substituted benzene ring, has been synthesized for the first time, and it has been found that the resultant compound (I) has an unexpected, excellent selective affinity to adenosine A
3
receptor and antagonistic activity at an adenosine A
3
receptor and high stability suitable for a medicine, due to its specific chemical structure, and it is therefore satisfactory as a medicine. Further, the present inventors have also found that a compound represented by the formula (Ia):
wherein ring A is an optionally substituted benzene ring, ring B may further be substituted, and ring D may further be substituted, provided that the, when the 5-position of the thiazolopyrimidine ring (ring B) is substituted by amino, the 2 position thereof (ring D) is substituted, or a salt thereof [hereinafter sometimes abbreviated to compound (Ia)] including compound (I) has an unexpected, excellent selective affinity to adenosine A
3
receptor and antagonistic activity at an adenosine A
3
receptor. On the basis of these findings, the inventors have completed the present invention.
That is, the present invention relates to:
1. A compound represented by the formula:
wherein ring A is an optionally substituted benzene ring, ring B may be further substituted, and R
1
is an optionally substituted cyclic group, or a salt thereof;
2. The compound according to the above 1, wherein ring A is benzene ring which may have 1 to 5 substituents selected from the group consisting of (i) halogen atom, (ii) C
1-3
alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C
1-6
alkyl, (vi) optionally halogenated C
2-6
alkenyl, (vii) carboxy C
1-6
alkyl, (viii) carboxy C
2-6
alkenyl, (ix) optionally halogenated C
2-6
alkynyl, (x) optionally halogenated C
3-6
cycloalkyl, (xi) C
6-14
aryl, (xii) optionally halogenated C
1-6
alkoxy, (xiii) C
1-6
alkoxy-carbonyl-C
1-6
alkoxy, (xiv) hydroxy, (xv) C
6-14
aryloxy, (xvi) C
7-16
aralkyloxy, (xvii) mercapto, (xviii) optionally halogenated C
1-6
alkylthio, (xix) C
6-14
arylthio, (xx) C
7-16
aralkylthio, (xxi) amino, (xxii) mono-C
1-6
alkylamino, (xxiii) mono-C
6-14
arylamino, (xxiv) mono-C
7-16
aralkylamino, (xxv) di-C
7-16
aralkylamino, (xxvi) di-C
1-6
alkylamino, (xxvii) di-C
6-14
arylamino, (xxviii) formyl, (xxix) carboxy, (xxx) C
1-6
alkyl-carbonyl, (xxxi) C
3-6
cycloalkyl-carbonyl, (xxxii) C
1-6
alkoxy-carbonyl, (xxxiii) C
6-14
aryl-carbonyl, (xxxiv) C
7-16
aralkyl-carbonyl, (xxxv) C
6-14
aryloxy-carbonyl, (xxxvi) C
7-16
aralkyloxy-carbonyl, (xxxvii) 5- or 6-membered heterocyclic-carbonyl which contains, in addition to carbon atoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, (xxxviii) carbamoyl, (xxxix) thiocarbamoyl, (xxxx) mono-C
1-6
alkyl-carbamoyl, (xxxxi) di-C
1-6
alkyl-carbamoyl, (xxxxii) C
6-14
aryl-carbamoyl, (xxxxiii) 5- or 6-membered heterocyclic-carbamoyl which contains, in addition to carbon atoms, 1 to 3 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, (xxxxiv) C
1-6
alkylsulfonyl, (xxxxv) C
6-14
arylsulfonyl, (xxxxvi) formylamino, (xxxxvii) C
1-6
alkyl-carbonylamino, (xxxxviii) C
6-14
aryl-carbonylamino, (xxxxix) C
1-6
alkoxy-carbonylamino, (xxxxx) C
1-6
alkylsulfonylamino, (xxxxxi) C

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