Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-15
2002-08-13
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S269000, C514S272000, C514S273000, C514S275000, C544S310000, C544S311000, C544S316000, C544S317000, C544S320000, C544S321000, C544S323000, C544S324000, C544S328000, C544S329000, C544S331000, C544S332000, C544S333000, C544S335000
Reexamination Certificate
active
06432963
ABSTRACT:
TECHNICAL FIELD
This invention relates to medicaments, particularly pyrimidine-5-carboxamide derivatives having Syk tyrosine kinase inhibition activity.
BACKGROUND ART
It is known that type I (immediate type) allergic reaction such as bronchial asthma, allergic rhinitis or atopic dermatitis is mediated mainly by the interaction between immunoglobulin E (IgE) and mast cells or basophiles. Mast cells and basophiles have an Fc receptor (Fc&egr;RI) having high affinity for IgE. Firstly, IgE binds to Fc&egr;RI and then antigens such as pollen, house dust or the like cross-link the receptor by binding to its specific IgE, thereby making progress of an allergic reaction. As a result of such a response, cytoplasmic secretory granules containing inflammatory mediators such as histamine, leukotriene and the like are released, which cause acute inflammatory reactions, and production of cytokine which takes part in various allergic and inflammatory reactions is accelerated.
It is known that at least two types of protein tyrosine kinase, Lyn (Eiseman, E. and Bolen, J. B.,
Nature
, 355: 78-80 (1992)) and Syk (Taniguchi, T. et al.,
J. Biol. Chem
., 266: 15790-15796 (1991)), are concerned in the intracellular signal transduction accompanied by this Fc&egr;RI activation. These tyrosine kinases are activated (tyrosine phosphorylated) after crosslinking of Fc&egr;RI by antigens (Hutchcroft, J. E. et al.,
Proc. Natl. Acad. Sci. USA
, 89: 9107-9111 (1992)). It has been shown also that the SH2 domain and tyrosine kinase activity of Syk are necessary for the degranulation and cytokine production acceleration induced by the activation of Fc&egr;RI (Rivera, V. M. and Brugge, J. S.,
Mol. Cell. Biol
., 15: 1582-1590 (1995)).
In consequence, it is expected that the release of mediators and the production of cytokines concerned in IgE stimulation-dependent allergic and inflammatory reactions from mast cells and basophiles can be controlled by inhibiting the tyrosine kinase activity of Syk.
It has been reported that the tyrosine phosphorylation of intracellular protein (activation) induced by stimulation of a receptor for IgG antibody, Fc&ggr;R, and the phagocytosis mediated by Fc&ggr;R are considerably inhibited in macrophages derived from Syk deficient mouse (Crowley, M. T. et al.,
J. Exp. Med
., 186: 1027-1039 (1997)), suggesting that Syk has a markedly important role in the Fc&ggr;R-mediated phagocytosis of macrophage. In consequence, there is a possibility that Syk inhibitors can inhibit cell or tissue damage induced by antibody-dependent cellular cytotoxicity (ADCC).
It has been reported that an antisense oligonucleotide of Syk suppresses the apoptosis inhibition of eosinophils induced by GM-CSF (Yousefi, S. et al.,
J. E. Med
., 183: 1407-1414 (1996)), showing that Syk is essential for the life extending signal of eosinophils caused by GM-CSF and the like. Since life extension of eosinophils is closely related to the transition of diseases into a chronic state in allergic disorders such as asthma, Syk inhibitors can also become therapeutic agents for chronic eosinophilic inflammation.
Syk is important for the activation of B cells via a B cell antigen receptor and deeply concerned in the phosphatidylinositol metabolism and increase in the intracellular calcium concentration caused by the antigen receptor stimulation (Hutchcroft, J. E. et al.,
J. Biol. Chem
., 267: 8613-8619 (1992) and Takata, M. et al.,
EMBO J
., 13: 1341-1349 (1994)). In consequence, Syk inhibitors have a possibility of controlling the function of B cells and therefore are expected as therapeutic agents for antibody-related diseases.
Syk binds to a T cell antigen receptor, quickly undergoes tyrosine phosphorylation through crosslinking of the receptor and synergistically acts upon intracellular signals in which tyrosine kinases essential for the T cell activation such as Lck takes part (Couture, C. et al.,
Proc. Natl. Acad. Sci. USA
, 91: 5301-5305 (1994) and Couture, C. et al.,
Mol. Cell. Biol
., 14: 5249-5258 (1994)). In consequence, it is suggested that Syk inhibitors have a potential to be agents for inhibiting cellular immunity mediated by T cell antigen receptor.
Release of arachidonic acid and serotonin and platelet aggregation induced by collagen are markedly-inhibited in platelets derived from Syk deficient mouse (Poole, A. et al.,
EMBO J
., 16: 2333-2341 (1997)), so that an anticoagulation action is also expected in Syk inhibitors.
On the other hand, WO 97/19065 discloses that a 2-anilinopyrimidine derivative represented by the following formula selectively inhibits p56
lck
, p59
fyn
, ZAP-70 and protein kinase C. However, it does not disclose or suggest about its action upon Syk.
(In the formula, R
6
represents H, —NH
2
, substituted amino, nitro, —COOH, ester or the like. See said document for other symbols.)
As pyrimidine compounds having substituted amino group at the 4-position and carboxamido group at the 5-position, the following compound
is disclosed in Indian
J. Chem., Sect. B
, 16 (B) (10), 932-933 (1978), and the following compound
is disclosed in EP 475206 and U.S. Pat. No. 5,104,877. However, there is no disclosure or suggestion about the action of these compounds upon Syk.
Also, antilipidemic activity of pyrimidine compounds having a phenylamino group at the 4-position is disclosed in EP 73328, U.S. Pat. No. 3,901,887, U.S. Pat. No. 3,910,910 and U.S. Pat. No. 3,940,394. However, these compounds do not have a carboxamido group at the 5-position, and there is no disclosure about the action upon Syk.
A plant natural product, Piceatannol, has so far been reported as a Syk tyrosine kinase inhibitor (Oliver, J. M. et al. ,
J. Biol. Chem
., 269: 29697-29703 (1994)). However, since its in vitro Syk kinase inhibition activity is weak, great concern has been directed toward the creation of more excellent Syk tyrosine kinase inhibitor.
DISCLOSURE OF THE INVENTION
The present inventors have made extensive studies on compounds capable of inhibiting tyrosine kinase activity of Syk and, as a result, found that a pyrimidine derivative having a carboxamido group at the 5-position has excellent Syk tyrosine kinase inhibitory activity and a:Th is useful as an agent for preventing, treating or diagnosing diseases in which Syk takes part, and thereby have accomplished the invention.
Accordingly, the present invention relates to a pyrimidine-5-carboxamide derivative represented by the following general formula (I) or a salt thereof.
[In the formula, each symbol has the following meaning;
X: O, S, NR
1
, CO, NR
1
CO, CONR
1
, C═N—OR
1
or a bond,
Y: a lower alkylene group which may be substituted by OR
1
or —NHR
1
, or a bond,
Z: O, NR
2
or a bond,
A: H, or a lower alkyl which may have a substituent, a —CO-lower alkyl which may have a substituent, an aryl which may have a substituent, a heteroaryl which may have a substituent, a cycloalkyl which may have a substituent or a nitrogen-containing saturated heterocyclic group which may have a substituent,
B: an aryl which may have a substituent (provided that 2′-(1H-tetrazol-5-yl)biphenyl-4-yl group is excluded) or a heteroaryl group which may have a substituent, and
R
1
, R
2
: H, a lower alkyl or a —CO-lower alkyl group. The same shall apply hereinafter.]
Also, according to the present invention, there is provided a pharmaceutical composition, particularly a Syk tyrosine kinase inhibitor, which comprises the aforementioned pyrimidine-5-carboxamide derivative or a salt thereof.
The following further describes the compound of general formula (I).
In this specification, the term “lower” means a straight or branched hydrocarbon chain having from 1 to 6 carbon atoms. The “lower alkyl group” is preferably a lower alkyl group having from 1 to 4 carbon atoms, more preferably a methyl group, an ethyl group or an isopropyl group. The “lower alkylene group” is preferably a methylene group.
The “aryl group” is preferably a monocyclic to tricyclic aryl group having from 6 to 14 carbon atoms, more preferably, a phenyl group or a naphthyl group. Also, the p
Hisamichi Hiroyuki
Ichikawa Atsushi
Kawazoe Souichirou
Naito Ryo
Nakai Ei-ichi
McKenzie Thomas C
Raymond Richard L.
Yamanouchi Pharmaceutical Co. Ltd.
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