Heterocyclecarboxamide derivative

Details Heterocyclecarboxamide derivative Heterocyclecarboxamide derivative

2001-12-10

2004-09-28

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252100, C514S255060, C544S224000, C544S336000, C544S406000, C544S407000

Reexamination Certificate

active

06797706

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a heterocyclecarboxamide derivative useful as a medicament, particularly a Syk inhibitor.
BACKGROUND OF THE INVENTION
It is known that type I (immediate type) allergic reaction which plays a main role at allergic diseases as typified by bronchial asthma, allergic rhinitis or atopic dermatitis is initiated by the interaction between an extrinsic antigen such as pollen or house dust and immunoglobulin E (IgE) specific thereto. IgE is captured on the cell surface of mast cell and basophile manifesting IgE receptor (Fc &egr; RI) having a high affinity. When the antigen binds thereto and cross-links the receptor, the cell is activated and inflammatory mediators such as histamine, serotonin and the like inducing anaphylaxis reaction are released from cytoplasmic secretory granules. Also, it is known that the production of cytokine which takes part in the progress of inflammatory reactions is accelerated.
It is known that at least two types of cytoplasmic tyrosine kinase, i.e., Lyn (Eiseman, E. and Bolen, J. B., Nature, 355: 78-80 (1992)) and Spleen tyrosine kinase (Syk) (Taniguchi, T. et al., J. Biol. Chem., 266: 15790-15796 (1991)), are concerned in the intracellular signal transduction which accompanies this Fc &egr; RI activation. It is known that Syk undergoes tyrosine phosphorylation by the action of Lyn after crosslinking of Fc &egr; RI by an antigen, whereby the activity of the tyrosine kinase increases (Hutchcroft, J. E. et al., Proc. Natl. Acad. Sci. USA, 89: 9107-9111 (1992)). It has been also shown that the activation 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)).
Moreover, it is known that Syk is essential for a life-extending signal of eosinophiles mediated by GM-CSF receptor, because antisense oligonucleotide of Syk inhibits the eosinophile's life-extending action of GM-CSF (Yousefi, S. et al., J. Exp. Med., 183: 1407-1414 (1996)).
As described above, it is expected that Syk takes part in allergic or inflammatory reaction through controlling the functions of mast cell, basophile, and eosinophile.
In addition, Syk is suggested to be concerned in various diseases as described below.
It has been reported that Syk is deeply concerned in the phosphatidylinositol metabolism and increase in the intracellular calcium concentration caused by the stimulation of B cell antigen receptor and thus plays an important role at the activation of B cells (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, a Syk inhibitor may control the function of B cell and therefore is expected as an therapeutic agent for the diseases in which the antibody produced by B cell are concerned.
Also, it has been reported that Syk associates with a T cell antigen receptor and quickly undergoes tyrosine phosphorylation and is activated through crosslinking of the receptor. Accordingly, there is shown a possibility that Syk synergistically acts in combination with a tyrosine kinase such as Lck, ZAP-70, or the like to take part in the T cell activation signal (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)).
Moreover, it has been reported that the tyrosine phosphorylation of intracellular protein and the phagocytosis induced by stimulation of immunoglobulin G (IgG) receptor (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)). Therefore, Syk plays an extremely important role in the Fc &ggr; R-mediated phagocytosis of macrophage, and it is shown that Syk is concerned in tissue damage induced by antibody-dependent cellular cytotoxicity (ADCC).
Furthermore, it has been reported that the release of arachidonic acid and serotonin and the aggregation of platelets 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 participation in anticoagulation is also shown.
And, as compounds having a Syk inhibitory action, there have been reported a 2-anilinopyrimidine derivative (WO98/18782) represented by the following formula:
(wherein Ar represents an aromatic cyclic group which may be substituted, and R
2
represents H, a halogen, or a group represented by —X
1
—R
2a
. Refer to the publication for other symbols), and a natural product derived from a plant, Piceatannol (Oliver, J. M. et al., J. Biol. Chem., 269: 29697-29703 (1994)).
Moreover, as heterocyclecarboxamide derivatives having a substituted amino group, the following compound is disclosed in Indian J. Chem., Sect. B, 16B(10), 932-933 (1978),
the following compound in EP475206 and U.S. Pat. No. 5,104,877,
and the following compound in Japanese Patent Laid-Open No. 94677/1974,
but the action on Syk of these compounds is neither disclosed nor suggested.
DISCLOSURE OF THE INVENTION
As a result of the extensive studies on the compounds inhibiting Syk, the present inventors have found that a heterocyclecarboxamide derivative has a satisfactory Syk inhibitory activity and is useful as an agent for preventing, treating, or diagnosing diseases in which Syk takes part, and thereby have accomplished the invention.
Namely, the invention relates to a novel heterocyclecarboxamide derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, and a medicament comprising the same as the active ingredient.
(wherein the symbols in the formula have the following meanings.
A: a lower alkylene which may have substituent(s), an arylene which may have substituent(s), a heteroarylene which may have substituent(s), a cycloalkylene which may have substituent(s), or H;
X: NR
4
, CONR
4
, NR
4
CO, O, or S;
a dotted line between Y and Z: presence (Y═Z) or absence (Y—Z) of a bond;
Y—Z: N(R
5
)—C(O), C(O)—N(R
5
), N(R
5
)—N(R
5
), or C(O)—C(O);
Y═Z: N═C(R
6
), C(R
7
)═N, N═N, or C(R
7
)═C(R
7
);
R
1
, R
4
: H, a lower alkyl, —CO-lower alkyl, or —SO
2
-lower alkyl;
R
2
: H, a lower alkyl, a halogen, a lower alkyl substituted by halogen(s), —O-lower alkyl, —S-lower alkyl, —O-aryl, —O-lower alkylene-aryl, —S-lower alkylene-aryl, nitro, cyano, —OCH
2
O—, or —(CH═CH-CH═CH)—;
R
3
: —CO
2
H, —CO
2
-lower alkyl, -lower alkylene-CO
2
H, -lower alkylene-CO
2
-lower alkyl, —CONHOH, —CONHO-lower alkyl, -lower alkylene-CONHOH, -lower alkylene-CONHO-lower alkyl, —NH
2
, —(NH
2
in a prodrug form), -lower alkylene-NH
2
, or -lower alkylene-(NH
2
in a prodrug form);
R
5
: H or a lower alkyl group;
R
6
: a lower alkyl, —OH, —O-lower alkyl, —O-aryl which may have substituent(s), —O-lower alkylene-aryl which may have substituent(s), —NR
1
-aryl which may have substituent(s), —CO-lower alkyl, or -aryl group which may have substituent(s);
R
7
: the same or different, H or the same group as R
6
. The same shall apply to the following).
By the way, when Y═Z represents N═C(R
6
), C(R
7
)═N, N═N, or C(R
7
)═C(R
7
) in the formula, the central heterocycle part:
represents any of the following formulae:
and when Y—Z represents N(R
5
)—C(O), C(O)—N(R
5
), N(R
5
)—N(R
5
), or C(O)—C(O) in the formula, the central heterocycle part represents any of the following formulae.
In the above formulae, there is a case that tautomers are present as the case of the compound wherein R
6
of N═C(R
6
) is OH and the compound wherein R
5
of C(R
5
)—C(O) is H or the case of the compound wherein R
7
of C(R
7
)═N is OH and the compound wherein R
5
of C(O)—N(R
5
) is H. The invention also includes these isomers.
According to the invention, also provided is a pharmaceutical composition, particularly a Syk tyrosine kinase inhibitor comprising the above heterocyclecarboxamide derivative or a salt thereof.
The following will explain the invention in detail.
In thi

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