Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-16
2003-08-12
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S419000, C548S466000, C548S469000
Reexamination Certificate
active
06605633
ABSTRACT:
This application is a 371 of PCT/FR00/03278 filed Nov. 24, 2000.
The present invention relates to novel compounds which inhibit the action of CXC chemokines, such as IL-8, Gro, NAP-2, ENA-78 etc., on their receptors, to the process for their preparation and to their use for obtaining drugs.
PRIOR ART
IL-8 (interleukin-8) is a protein of 72 amino acids belonging to the superfamily of proteins capable of attracting leukocytes, said proteins also being referred to as C—X—C cytokines or C—C intercrine cytokines or, more recently, chemokines (Oppenheim et al.,
Annu. Rev. Immunol
., 1991, 9, 617-648). Different names have been attributed to interleukin-8, such as NAP-1 (neutrophil attractant/activation protein 1), NAF (neutrophil activating factor) and T-cell lymphocyte chemotactic factor. Numerous members of the chemokine family have been described as being involved in inflammatory processes and leukocyte migration. The chemokine family is made up of two distinct subfamilies: alpha- and beta-chemokines. Alpha-chemokines, such as IL-8, NAP-2 (neutrophil activating peptide-2), MGSA/Gro or Gro-alpha (melanoma growth stimulatory activity) and ENA-78, all have effects on the attraction and activation of leukocytes and more particularly neutrophils. This subfamily also includes PF-4 (platelet factor-4), beta-thromboglobulin and CTAPIII, which have no effect on neutrophils.
IL-8 was originally identified by its capacity to attract and activate polymorphonuclear leukocytes (neutrophils). More recently, it was shown that the expression of IL-8 was rapidly induced in different tissues or cells, such as macrophages, fibroblasts, endothelial and epithelial cells and even neutrophils, in response to pro-inflammatory cytokines like IL-1 alpha or beta or TNF alpha, or other pro-inflammatory agents like LPS (Van Damme J.,
Interleukin-
8
and related chemotactic cytokines
; 1994
; The Cytokines Handbook
, 2nd ed., edited by A. W. Thomson, Academic Press, London, pp. 185-208). Furthermore, some literature data have demonstrated high systemic levels of IL-8 in certain inflammatory pathological conditions involving neutrophils, suggesting that IL-8 and other chemokines of the same family may be fundamental mediators of neutrophil activation (Van Damme,
Interleukin
-8
and related chemotactic cytokines
; 1994
; The Cytokines Handbook
, 3rd ed., edited by A. W. Thomson, Academic Press, London, pp. 271-311).
Gro-alpha, Gro-beta, Gro-gamma and NAP-2 belong to the chemokine family and, like IL-8, these proteins have also been given different names. Thus Gro-alpha, beta and gamma have been called MGSA (Melanoma Growth Stimulatory Activity) a, b and g respectively (Richmond and Thomas,
J. Cell Physiol
., 1986, 129, 375-384; Cheng et al.,
J. Immunol
., 1992, 148, 451-456). All these chemokines belong to the group of alpha-chemokines which possess an ELR unit (Aspartate-Leucine-Arginate) upstream of the CXC unit characteristic of this subgroup. These chemokines all bind to the type 2 receptor or CXCR2.
Two IL-8 receptors belonging to the family of receptors with seven transmembrane domains coupled to G proteins have been characterized and cloned: the type A IL-8 receptor (IL-8RA) or CXCR1, which binds IL-8 and GCP-2 with a strong affinity, and the type B IL-8 receptor (IL-8RB) or CXCR2, which has IL-8, GCP-2, Gro-alpha, Gro-beta, Gro-gamma and NAP-2 as specific ligands (Ponath,
Exp. Opin. Invest. Drugs
, 1998, 7, 1-18). These two receptors have an amino acid sequence homology of 77%. Numerous publications have demonstrated abnormally high levels of IL-8 in rheumatoid polyarthritis, septic shock, asthma, mucoviscidosis, myocardial infarction and psoriasis (Baggiolini et al.,
FEBS Lett
., 1992, 307, 97-101; Mille and Krangel,
Crit. Rev. Immunol
., 1992, 12, 17-46; Oppenheim et al.,
Annu. Rev. Immunol
., 1991, 9, 617-648; Seitz et al,
J. Clin. Invest
., 1991, 87, 463-469; Miller et al.,
Am. Rev. Resp. Dis
., 1992, 146, 427-432; Donnelly et al.,
Lancet
, 1993, 341, 643-647). IL-8 seems to be involved in pulmonary ischemia/reperfusion phenomena (Sekido et al.,
Nature
, 1993, 365, 654-657). An antibody directed against IL-8, with the capacity to block the in vitro migration of rabbit neutrophils induced by IL-8, prevents the tissue damages resulting from a pulmonary ischemia/reperfusion process in the rabbit. IL-8 seems to play a major role in the changes due to myocardial hypoxia/reperfusion (Kukielka et al.,
J. Clin. Invest
., 1995, 95, 89-103).
More recently, another study has demonstrated the beneficial effects of an IL-8-neutralizing antibody in a model of pleurisy induced by endotoxins in the rabbit (Broadus et al.,
J. Immunol
., 1994, 152, 2960-2967). The involvement of IL-8 in pulmonary inflammations, and its deleterious role, have been demonstrated using IL-8-neutralizing antibodies in a model of pulmonary attack induced by instilling acid into rabbit's lungs (Folkesson et al.,
J. Clin. Invest
., 1995, 96, 107-116) and in a model of acute respiratory distress syndrome induced by endotoxins (Yokoi et al.,
Lab. Invest
., 1997, 76, 375-384). Other reports have shown similar beneficial effects with IL-8-neutralizing antibodies in animal models of dermatosis, arthritis and glomerulonephritis (Akahoshi et al.,
Lymphokine and Cytokine Res
., 1994, 13, 113-116; Nishimura et al.,
J. Leukoc. Biol
., 1997, 62, 444-449; Wada et al.,
J. Exp. Med
., 1994, 180, 1135-1140). Furthermore, mice deficient in interleukin-8 receptors have been produced by removing the gene coding for the murine IL-8 receptor homologous to the human type 2 receptor (CXCR2) (Cacalano et al.,
Science
, 1994, 265, 682-684). Although these mice are healthy, the characteristics of their neutrophils are modified. In fact, their capacity to migrate into the peritoneum is reduced in response to an intraperitoneal injection of thioglycolate.
All these results suggest that chemokines of the IL-8 family are important mediators of the migration and activation of neutrophils and other types of cells, such as endothelial cells, in certain inflammatory conditions. Furthermore, chemokines of the IL-8 family have been described as playing an important role in tumoral growth, metastasis formation and tumoral angiogenesis in numerous types of cancer (Hebert and Baker,
Cancer Invest
., 1993, 11, 743-750; Richards et al.,
Am. J. Surg
., 1997, 174, 507-512).
Study of the properties of chemokines of the IL-8 family suggests that compounds capable of antagonizing these chemokines at their receptors might have the potential to attenuate the consequences of their action in certain pathological conditions. Thus WO 96-18393 has disclosed compounds derived from 1-benzylindole-2-carboxylic acid which are capable of binding to IL-8 receptors with an inhibitory effect. More recently, according to WO 99-06354, compounds derived from urea or thiourea have also been put forward as IL-8 receptor antagonists.
OBJECT OF THE INVENTION
The invention proposes novel non-peptide compounds which have the property of binding to the CXCR2 receptor of IL-8 and other chemokines of the same family, behaving as antagonists of these receptors.
This property of the compounds according to the invention makes it possible to envisage their use as active principles of drugs for the preventive or curative treatment of diseases involving the receptors of IL-8 and chemokines of the same family, for example rheumatoid polyarthritis, psoriasis or atypical dermatitis, diseases associated with pathological angiogenesis (such as cancer), tumoral cell proliferation and metastasis formation (for example in the case of melanoma), asthma, chronic obstruction of the lungs, acute respiratory distress syndrome, inflammation of the colon, Crohn's disease, ulcerative colitis, gastric ulcer, septic shock, endotoxin shock, Gram-negative septicemia, toxic shock syndrome, cerebral ischemia, cardiac or renal ischemia/reperfusion phenomena, glomerulonephritis, thrombosis, Alzheimer's disease, graft versus host reactions or allograft rejections.
DESCRIPTION
According to the invention, n
Barth Martine
Dodey Pierre
Paquet Jean-Luc
Pruneau Didier
Fournier Industrie et Sante
McKane Joseph K.
Sackey Ebenezer
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