Inhibitors of the production of S-CD23 and the secretion of TNF

Details Inhibitors of the production of S-CD23 and the secretion of TNF Inhibitors of the production of S-CD23 and the secretion of TNF

1999-01-21

2001-05-22

Richter, Johann (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S367000, C514S443000, C514S467000, C514S469000, C514S575000, C546S174000, C548S180000, C549S058000, C549S452000, C549S467000, C562S623000

Reexamination Certificate

active

06235753

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel inhibitors of the formation of soluble human CD23 and their use in the treatment of conditions associated with excess production of soluble CD23 (s-CD23) such as autoimmune disease and allergy. The compounds of the invention are also inhibitors of the release of tumour necrosis factor (TNF).
CD23 (the low affinity IgE receptor FceRII, Blast 2), is a 45 kDa type II integral protein expressed on the surface of a variety of mature cells, including B and T lymphocytes, macrophages, natural killer cells, Langerhans cells, monocytes and platelets (Delespesse et al,
Adv Immunol
, 49[1991]149-191). There is also a CD23-like molecule on eosinophils (Grangette et al,
J Immunol
, 143[1989]3580-3588). CD23 has been implicated in the regulation of the immune response (Delespesse et al,
Immunol Rev
, 125[1992]77-97). Human CD23 exists as two differentially regulated isoforms, a and b, which differ only in the amino acids at the intracellular N-terminus (Yokota et al,
Cell
, 55[1988]611-618). In man the constitutive a isoform is found only on B-lymphocytes, whereas type b, inducible by IL4, is found on all cells capable of expressing CD23.
Intact, cell bound CD23 (i-CD23) is known to undergo cleavage from the cell surface leading to the formation of a number of well-defined soluble fragments (s-CD23), which are produced as a result of a complex sequence of proteolytic events, the mechanism of which is still poorly understood (Bourget et al
J Biol Chem
, 269[1994]6927-6930). Although not yet proven, it is postulated that the major soluble fragments (Mr 37, 33, 29 and 25 kDa) of these proteolytic events, all of which retain the C-terminal lectin domain common to i-CD23, occur sequentially via initial formation of the 37 kDa fragment (Letellier et al,
J Exp Med
, 172[1990]693-700). An alternative intracellular cleavage pathway leads to a stable 16 kDa fragment differing in the C-terminal domain from i-CD23 (Grenier-Brosette et al,
Eur J Immunol
, 22[1992]1573-1577).
Several activities have been ascribed to membrane bound i-CD23 in humans, all of which have been shown to play a role in IgE regulation. Particular cytotoxicity, c) B cell homing to germinal centres of lymph nodes and spleen, and d) downregulation of IgE synthesis (Delespesse et al,
Adv Immunol
, 49,[1991]149-191). The three higher molecular weight soluble CD23 fragments (Mr 37, 33 and 29 kDa) have multifunctional cytokine properties which appear to play a major role in IgE production. Thus, the excessive formation of s-CD23 has been implicated in the overproduction of IgE, the hallmark of allergic diseases such as extrinsic asthma, rhinitis, allergic conjuctivitis, eczema, atopic dermatitis and anaphylaxis (Sutton and Gould,
Nature
, 366,[1993]421-428). Other biological activities attributed to s-CD23 include the stimulation of B cell growth and the induction of the release of mediators from monocytes. Thus, elevated levels of s-CD23 have been observed in the serum of patients having B-chronic lymphocytic leukaemia (Sarfati et al,
Blood
, 7[1988]94-98) and in the synovial fluids of patients with rheumatoid arthritis (Chomarat et al,
Arthritis and Rheumatism
, 36[1993]234-242). That there is a role for CD23 in inflammation is suggested by a number of sources. First, sCD23 has been reported to bind to extracellular receptors which when activated are involved in cell-mediated events of inflammation. Thus, sCD23 is reported to directly activate monocyte TNF, IL-1, and IL-6 release (Armant et al, vol 180
, J.Exp. Med
., 1005-1011 (1994)). CD23 has been reported to interact with the B2-integrin adhesion molecules, CD 11b and CD11c on monocyte/macrophage (S. Lecoanet-Henchoz et al, Immunity, vol 3; 119-125 (1995)) which trigger NO2
−
, hydrogen peroxide and cytokine (IL-1, IL-6, and TNF) release. Finally, IL4 or IFN induce the expression of CD23 and its release as sCD23 by human monocytes. Ligation of the membrane bound CD23 receptor with IgEtanti-IgE immune complexes or anti CD23 mAb activates cAMP and IL-6 production and thromboxane B2 formation, demonstrating a receptor-mediated role of CD23 in inflammation.
Because of these various properties of CD23, compounds which inhibit the formation of s-CD23 should have twofold actions of a) enhancing negative feedback inhibition of IgE synthesis by maintaining levels of i-CD23 on the surface of B cells, and b) inhibiting the immunostimulatory cytokine activities of higher molecular weight soluble fragments (Mr 37, 33 and 29 kDa) of s-CD23. In addition, inhibition of CD23 cleavage should mitigate sCD23-induced monocyte activation and mediator formation, thereby reducing the inflammatory response.
TNF&agr; is a pro-inflammatory cytokine which is released from stimulated cells by specific cleavage of a 76-amino acid signal sequence in the inactive precursor to generate the mature form. The cleavage of TNF&agr; has been reported to be carried out by a metalloprotease (Gearing, A. J. H. et al, (1994) Nature 370, 555-557; McGeehan, G. M. et al, (1994) Nature 370, 558-561; Mohler, K. M. et al, (1994) Nature 370, 218-220). Compounds reported to inhibit the cleavage of TNF&agr; by the TNF processing enzyme can be broadly described as matrix metalloprotease inhibitors, particularly of the hydroxamic acid class.
TNF&agr; is induced in a variety of cell types in response to bacteria, endotoxin, various viruses and parasites, so that one physiological function ascribed to TNF&agr; is a contribution to the inflammatory response to acute infection by bacteria, parasites, etc (Dinarello, C. A. (1992) Immunol. 4, 133-145). Overproduction of TNF&agr; has been implicated in disease states such as rheumatoid arthritis, septic shock, Crohn's disease and cachexia (Dinarello, 1992). Inhibition of processing of TNF&agr; to the mature, active form would therefore be beneficial in the treatment of these inflammatory disorders. TNF&agr; may also contribute to the destruction of tissue in autoimmune disease although it is not a initiating factor in these diseases. Confirming the importance of TNF&agr; in rheumatoid arthritis, TNF&agr; antibodies have been shown to reduce the severity of disease in short term studies in rheumatoid arthritis models (Elliott, M. J., et al (1993) Arthrit. Rheum. 12, 1681-1690; Elliott et al (1994) Lancet 344, 1125-1127).
International Patent Application No. WO 96/02240 (Smithkline Beecham plc) discloses that compounds which inhibit the action of matrix metalloproteases (eg collagenase, stromelysin and gelatinase) are effective inhibitors of the release of human soluble CD23 transfected into mammalian cell culture systems.
UK Patent Application No. 9601041.8 (Smithkline Beecham plc) discloses that certain compounds of formula (I) are effective inhibitors of the release of human soluble CD23 transfected into mammalian cell culture systems:
SUMMARY OF THE INVENTION
According to the present invention, there is provided a compound of formula (I) above, wherein:
R is hydroxy, hydrogen, alkyl, alkenyl, alkynyl or aryl;
R
1
is arylmethyl or heterocyclylmethyl;
R
2
is alkyl, alkenyl, aryl, cycloalkyl or cycloalkenyl; and
R
3
is hydrogen, alkyl, alkenyl, alkynyl or aryl;
with the proviso that;
if R
1
is phenylmethyl or naphthylmethyl, wherein the phenyl or naphthyl group is unsubstituted or substituted by up to five substituents selected from the group consistingofhalogen,(C
1-6
)alkyl,aryl(C
1-6
)alkyl,(C
1-6
)alkoxy, (C
1-6
)alkoxy(C
1-6
)alkyl, halo(C
1-6
)alkyl, hydroxy, nitro, amino, mono- and di-N-(C
1-6
)alkylamino, acylamino, acyloxy, carboxy, carboxy salts, carboxy esters, carbamoyl, mono- and di-N-(C
1-6
)alkylcarbamoyl, (C
1-6
)alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino, sulphonylamino, aminosulphonyl, (C
1-6
)alkylthio, (C
1-6
)alkyl sulphinyl (C
1-6
)alkylsulphonyl, heterocyclyl, heterocyclyl (C
1-6
)alkyl, and a (C
3-5
)alkylene chain linking two adjacent ring carbon atoms to form a carbocy

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