Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-01-23
2004-06-15
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S344000, C514S352000, C546S257000, C546S289000, C546S309000, C546S310000
Reexamination Certificate
active
06750232
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel 2-aminopyridine compound, a process for producing it, and use thereof as a medicament.
PRIOR ART
Adenosine is an important regulatory factor involved in various intracellular metabolisms such as regulation of energy levels and cAMP levels in the living body, opening and closing calcium channels, and inflow of calcium ions into cells, and can exhibit its physiological activity by interaction with G protein-conjugated receptors on the surface of a cell. Adenosine receptors were at first classified into 2 classes, that is, A
1
receptor and A
2
receptor on the basis of their participation in adenylate cyclase (J. Neurochem., 33, 999-1003 (1979)), and thereafter, the A
2
receptor was classified into 2 subtypes, that is, A
2A
and A
2B
on the basis of their affinity for NECA and CGS-21680 (Mol. Pharmacol., 29, 331-346 (1986); J. Neurochem., 55, 1763-1771 (1990)) which are adenosine A
2
receptor agonists. Thus, 4 receptor subtypes, A
1
, A
2
(A
2A
, A
2B
) and A
3
, have been identified until now. The A
1
receptor is a protein conjugated with G
i/o
family protein. By binding of ligands, it inhibits adenylate cyclase to suppress cAMP levels and activates phospholipase C (PLC) to promote production of inositol-1,4,5-triphosphate (IP
3
) and release of intracellular calcium ions. It is known that similar to the A
1
receptor, the A
3
receptor is a receptor suppressing cAMP levels and activating PLC to promote production of IP
3
and release of intracellular calcium ions. On the other hand, the A
2A
and A
2B
receptors are those activating adenylate cyclase and promoting production of cAMP levels. It is also reported that A
2B
is conjugated with PLC via G
q
/G
11
protein, and promotes production of IP
3
levels and inflow of calcium ions into cells (din. Invest., 96, 1979-1986 (1995)). These subtypes are different from one another in their distribution in tissues; that is, the A
1
receptor occurs relatively abundantly in the heart, aorta, bladder, etc., the A
2A
receptor in the eyeballs, skeletal muscles, etc., and the A
3
receptor in the spleen, uterus, prostate, etc., while the A
2B
receptor occurs relatively abundantly in proximity to the large intestine and in the eyeballs, lung, uterus and bladder (Br. J. Pharmacol., 118, 1461-1468 (1996)). The reason that adenosine receptor subtypes can exhibit their inherent functions is attributable to a difference in their distribution in tissues, a difference in topical adenosine levels and a difference in affinity of each subtype for ligands. Adenosine is involved in various physiological functions such as platelet agglutination, heartbeats, contraction of smooth muscles, inflammations, release of neurotransmitters, neurotransmission, release of hormones, cellular differentiation, growth of cells, death of cells, biosynthesis of DNA, etc., thus suggesting the relationship of adenosine with diseases in the neutral nerves, cardiovascular diseases, inflammatory diseases, diseases in the respiratory organs, immune diseases, etc., so usefulness of adenosine receptor agonists/antagonists against these diseases is expected. On one hand, important reports have been made in recent years on the relationship between the adenosine A
2
receptor and the intestinal tracts. For example, it is reported that a relaxing action on colon longitudinal muscles is mediated by A
2
receptor (Naunyn-Schmiedeberg's Arch. Pharmacol., 359, 140-146 (1999)), and that the relaxing action of adenosine on contraction of guinea pig distant colon longitudinal muscles is mediated by A
1
receptor and A
2b
receptor in longitudinal muscles (Br. J. Pharmacol., 129, 871-876 (2000)). Heretofore, antagonists for adenosine receptors, particularly for adenosine A
2
receptor, have been noted to be useful as an agent for treating or preventing diabetes, diabetic complications, diabetic retinopathy, obesity or asthma, and expected to be useful as a hypoglycemic agent, an improving agent for impaired glucose tolerance, a potentiating agent for insulin sensitivity, a hypotensive agent, a diuretic, a therapeutic agent for osteoporosis, an anti-Parkinson's disease agent, an anti-Alzheimer's disease agent, a therapeutic agent for inflammatory intestinal diseases or a therapeutic agent for Crohn's disease, etc.
For example, there are following reports on compounds having an antagonistic action particularly on A
2B
receptor.
(1) Compounds represented by the formulae:
2,4-Dioxobenzo [g]pteridine
(2) Purine derivatives represented by the formula:
(wherein R
1
means (1) the formula
(wherein X means hydrogen atom, hydroxyl group, an optionally substituted lower alkyl group, an optionally substituted lower alkoxy group etc.; and R
5
and R
6
are the same as or different from each other and each means hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted saturated or unsaturated C
3-8
cycloalkyl group etc.) or (2) a 5- to 6-membered aromatic ring which may have a substituent group and a hetero atom; W means the formula —CH
2
CH
2
—, —CH═CH— or —C≡C—; R
2
means an amino group which may be substituted with an optionally substituted lower alkyl group etc., etc.; R
3
means an optionally substituted C
3-8
cycloalkyl group, an optionally substituted aryl group, etc.; and R
4
means an optionally substituted lower alkyl group etc.), or a pharmacologically acceptable salt thereof or a hydrate of them (JP-A 11-263789).
(3) Purine derivatives represented by the formula:
(wherein R
1
represents hydrogen atom, hydroxyl group, a halogen atom, an optionally substituted C
1-8
alkyl group, etc.; R
2
represents an amino group which may be substituted with a C
1-8
alkyl group, etc.; R
3
represents a C
3-8
alkynyl group which may be substituted with a halogen atom, hydroxyl group or a C
1-4
alkyl group, etc.; Ar represents an optionally substituted aryl group, an optionally substituted heteroaryl group, etc.; and Q and W are the same as or different from each other and each represents N or CH), a pharmacologically acceptable salt thereof or a hydrate of them.
(4) A
2B
receptor antagonists described in Drug Development Research, 48: 95-103 (1999) and J. Med. Chem., 43: 1165-1172 (2000).
On one hand, as pyridine compounds, for example, there are reports relating to 5,6-aromatic substituted pyridine compound in WO 96/24584, U.S. Pat. No. 5,686,470 and U.S. Pat. No. 5,916,905. Further, in DE-A1 4117802, there are reports relating to 2-amino-3-pyridinecarbonitrile, and relating to the compound in which the 4-, 5- and 6-positions of the pyridine ring are substituted with phenyl groups. However, the relationship of these compounds with an adenosine receptor is not described or suggested, and is not known at all.
As described above, those compounds having an antagonism to an adenosine receptor, particularly an antagonism to an adenosine A
2
receptor (especially A
2b
receptor), are expected to exhibit an excellent action as pharmaceutical preparations and desired to be provided. However, those compounds having an excellent antagonism to an adenosine receptor and also acting effectively as a medicament have never been found. Accordingly, the object of the present invention is to search for, and find, the receptor inhibiting compound which is useful as an agent for treating or preventing a disease to which an adenosine receptor (particularly A
2
receptor, A
2b
receptor) relates.
DISCLOSURE OF THE INVENTION
Considering the above-described circumstances, the present inventors made intensive study. As a result, they have succeeded for the first time in synthesizing a compound represented by the formula:
(wherein R
1
represents cyano group, carboxyl group or an optionally substituted carbamoyl group; R
2
represents hydrogen atom, hydroxyl group, an optionally substituted C
1-6
alkoxy group, an optionally substituted C
6-14
aromatic hydrocarbon cyclic group or an optionally substituted 5- to 14-membered aromatic heterocyclic group; and R
3
and R
4
are the same
Asano Osamu
Harada Hitoshi
Miyazawa Shuhei
Ueda Masato
Yasuda Masahiro
Davis Zinna Northington
Eisai Co. Ltd.
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