Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Reexamination Certificate
2001-06-29
2003-04-22
Spivack, Phyllis G. (Department: 1614)
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
C544S295000, C544S360000, C544S386000, C544S391000, C514S218000, C514S253010
Reexamination Certificate
active
06552188
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel cyclic diamine compounds which have inhibitory effects on both cell adhesion and cell infiltration and are useful as anti-asthmatic agents, anti-allergic agents, anti-rheumatic agents, anti-arteriosclerotic agents, anti-inflammatory agents or the like, and medicines containing such compounds.
2. Description of the Background Art
In various inflammatory diseases, infiltration of leukocytes into inflammatory sites is observed. For example, infiltration of eosinophils into the bronchus in asthma (Ohkawara, Y. et al., Am. J. Respir. Cell Mol. Biol., 12, 4-12 (1995)), infiltration of macrophages and T lymphocytes into the aorta in arteriosclerosis (Sakai, A. et al., Arterioscler Thromb. Vasc. Biol., 17, 310-316 (1997)), infiltration of T lymphocytes and eosinophils into the skin in atopic dermatitis (Wakita H. et al, J. Cutan. Pathol., 21, 33-39 (1994)) or contact dermatitis (Satoh, T. et al., Eur. J. Immunol., 27, 85-91 (1997)), and infiltration of various leukocytes into rheumatoid synovial tissue (Tak, P P. et al., Clin. Immunol. Immunopathol., 77, 236-242 (1995)), have been reported.
Infiltration of these leukocyteds is elicited by cytokines, chemokines, lipids, and complements produced in inflammatory sites (Albelda, S M. et al., FASEB J., 8, 504-512 (1994)). Activated leukocytes adhere to vascular endothelial cells through an interaction called rolling or tethering with endothelial cells activated likewise. Thereafter, the leukocytes transmigrate through endothelium to infiltrate into the inflammatory sites (Springer, T A., Annu. Rev. Physiol., 57, 827-872 (1995)). In adhesion of leukocytes to the vascular endothelial cells in this process, various cell adhesion molecules such as an immunoglobulin superfamily (ICAM-1, VCAM-1 and the like), a selectin family (E-selectin and the like), an integrin family (LFA-1, VLA-4 and the like) and CD44, which are induced on the surfaces of the cells by stimulation by cytokines or the like, play important roles (“Rinsho Meneki (Clinical Immune)”, 30, Supple. 18 (1998)), and relationship between the disorder state and aberrant expression of the cell adhesion molecules is noted.
Accordingly, an agent capable of inhibiting cell adhesion can be useful as an agent for preventing and treating allergic diseases such as bronchial asthma, dermatitis, rhinitis and conjunctivitis; autoimmune diseases such as rheumatoid arthritis, nephritis, inflammatory bowel diseases, diabetes and arteriosclerosis; and chronic inflammatory diseases. In fact, it has been reported that antibodies against adhesion molecules on leukocytes such as LFA-1, Mac-1 and VLA-4 or antibodies against ICAM-1, VCAM-1, P-selectin, E-selectin and the like on vascular endothelial cells, which become ligands thereof, inhibit infiltration of leukocytes into inflammatory sites in animal models. For example, neutralizing antibodies against VCAM-1 and VLA-4, which is a counter receptor thereof, can delay development of diabetes in an NOD mouse model which spontaneously causes the diabetes (Michie, S A. et al., Curr. Top. Microbiol. Immunol., 231, 65-83 (1998)). It has also been reported that an antibody against VLA-4 or ICAM-1 and its counter receptor, LFA-1, inhibits infiltration of eosinophils in a guinea pig and mouse allergic conjunctivitis model (Ebihara et al., Current Eye Res., 19, 20-25 (1999); Whitcup, S M et al., Clin. Immunol., 93, 107-113 (1999)), and a monoclonal antibody against VCAM-1 inhibits infiltration of leukocytes in a mouse DSS-induced colitis model to attenuate colitis (Soriano, A. et al., Lab. Invest., 80, 1541-1551 (2000)). Further, an anti-VLA-4 antibody and an anti-CD44 antibody reduce the incidence of disease symptoms in a mouse collagen arthritis model (Zeidler, A. et al., Autoimmunity, 21, 245-252 (1995)). Even in cell adhesion molecule deficient-mice, inhibition of infiltration of leukocytes into inflammatory tissues is observed, likewise in inflammatory models (Bendjelloul, F. et al., Clin. Exp. Immunol., 119, 57-63 (2000); Wolyniec, W W. et al., Am. J. Respir. Cell Mol. Biol., 18, 777-785 (1998); Bullard, DC. et al., J. Immunol., 157, 3153-3158 (1996)).
However, it is difficult to develop antibody-based drugs because they are polypeptides and so oral administration is a problem. Moreover, possible side effects due to antigenicity and allergic reactions are problems.
On the other hand, there have been various investigations of low-molecular weight compounds having an inhibitory effect on cell adhesion with a view toward permitting oral administration. These compounds include benzothiophene derivatives (Boschelli, D H. et al., J. Med. Chem., 38, 4597-4614 (1995)), naphthalene derivatives (Japanese Patent Application Laid-Open No. 10-147568), hydroxybenzoic acid derivatives (Japanese Patent Application Laid-Open No. 10-182550), lignans (Japanese Patent Application Laid-Open No. 10-67656), 2-substituted benzothiazole derivatives (Japanese Patent Application Laid-Open No. 2000-086641 through PCT route), condensed pyrazine compounds (Japanese Patent Application Laid-Open No. 2000-319277 through PCT route), 2,6-dialkyl-4-silylphenol (Japanese Patent Application Laid-Open Re-Publication No. 2000-509070 through PCT route) and the like. However, the goal has not often been sufficiently achieved under the circumstances. Cyclic diamine compounds described in Japanese Patent Application Laid-Open Nos. 9-143075 and 11-92382 do not exhibit a sufficient inhibitory effect on cell adhesion, and so there is a demand for further improvement in activity.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a substance having inhibitory effects on both cell adhesion and cell infiltration, plus excellent anti-asthmatic effects, anti-allergic effects, anti-rheumatic effects, anti-arteriosclerotic effects and anti-inflammatory effects.
With the foregoing circumstances in mind, the present inventors carried out an extensive investigation to find a substance which inhibits cell adhesion and cell infiltration. As a result, we found that compounds represented by the general formula (1), have excellent cell adhesion-inhibiting effects and cell infiltration-inhibiting effects and are useful as anti-allergic agents, anti-asthmatic agents, anti-rheumatic agents, anti-arteriosclerotic agents or anti-inflammatory agents.
The present invention provides a cyclic diamine compound represented by the following general formula (1):
wherein
A is (CH
2
)
n
, (CH
2
)
n
—CH═CH, CO—(CH
2
)
n
or CO—(CH
2
)
n
—CH═CH, in which n is a number of 0 to 3; Z represents a formula (2) or (3):
in which R
1
, R
2
, R
4
, R
5
and R
6
are the same or different from one another and individually a hydrogen atom, alkyl group, alkoxy group, halogen atom or nitro group; R
3
is a hydrogen atom, alkyl group, alkoxy group, halogen atom, nitro group, naphthyl group, or phenyl group which may be substituted by 1 to 3 substituents selected from alkyl groups, alkoxy groups, halogen atoms, a nitro group and a phenyl group; and X and Y are the same or different from each other and individually CH or a nitrogen atom; and m is a number of 1 or 2;
an acid-addition salt thereof, or a hydrate thereof.
According to the present invention, there is also provided a medicine comprising the above cyclic diamine compound, an acid-addition salt thereof, or a hydrate thereof as an active ingredient.
According to the present invention, there is further provided a medicinal composition comprising the above cyclic diamine compound, the acid-addition salt thereof, or the hydrate thereof and a pharmaceutically acceptable carrier.
According to the present invention, there is still further provided a method for treating a disease caused by cell adhesion and/or cell infiltration, which comprises administering an effective amount of the above cyclic diamine compound, an acid-addition salt thereof, or a hydrate thereof to a patient who requires such treatment.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The alkyl group
Doi Takeshi
Kodama Tatsuhiko
Kyotani Yoshinori
Nishikawa Masahiro
Oda Toshiaki
Kowa Co. Ltd.
Spivack Phyllis G.
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