Organic compounds -- part of the class 532-570 series – Organic compounds – Hydroxamic acids – chalcogen analogs or salts thereof
Reexamination Certificate
2002-07-16
2004-01-06
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Hydroxamic acids, chalcogen analogs or salts thereof
C514S417000, C514S459000, C514S221000
Reexamination Certificate
active
06673965
ABSTRACT:
This invention relates to a novel inhibitor of the formation of soluble human CD23 and its use in the treatment of conditions associated with excess production of soluble CD23 (s-CD23) such as autoimmune disease, inflammation and allergy. 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 welldefined 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 activities include: a) antigen presentation, b) IgE mediated eosinophil 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
, 71 [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, CD11b and CD11c on monocyte/macrophage (S. Lecoanet-Henchoz et al, Immnunity, vol 3; 119-125 (1995)) which trigger NO2
−
, hydrogen peroxide and cytokine (IL-1, IL-6, and TNF) release. Finally, IL-4 or IFN induce the expression of CD23 and its release as sCD23 by human monocytes. Ligation of the membrane bound CD23 receptor with IgE/anti-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.
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.
International Patent Application No. WO 97/02239 (British Biotech Pharmaceuticals Limited) discloses that certain compounds of formula (A) have matrix metalloprotease activity:
International Patent Application No. WO 99/67201 (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:
It has now been surprisingly found that certain compounds of formula (I) have unexpectedly good bioavailability.
Accordingly, the present invention provides a compound of formula (I) above, wherein:
n is 0;
R is isopropyl;
R
1
is naphthylmethyl;
R
2
is t-butyl; and
R
3
is methyl.
According to a further aspect, the present invention provides the use of the compound of the invention for the production of a medicament for the treatment or prophylaxis of disorders such as allergy, inflammatory disorders and autoimmune disease in which the overproduction of s-CD23 is implicated.
In a further aspect the invention provides a method for the treatment or prophylaxis of disorders such as allergy, inflammatory disorders and autoimmune disease in which the overproduction of s-CD23 is implicated, which method comprises the administration of the compound of the invention, to a human or non-human mammal in need thereof.
The invention also provides a pharmaceutical composition for the treatment or prophylaxis of disorders such as allergy, inflammatory disorders and autoiimmune disease in which the overproduction of s-CD23 is implicated which comprises the compound of the invention and optionally a pharmaceutically acceptable carrier therefor.
Particular inflammatory disorders include CNS disorders such as Alzheimers disease, multiple sclerosis, and multi-infarct dementia, as well as the inflammation mediated sequelae of stroke and head trauma.
It is to be understood that the pharmaceutically acceptable salts, solvates and other pharmaceutically acceptable derivatives of the compound of the invention are also included in the present invention.
Salts of compounds of formula (I) include for example acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, hydroiodides, p-toluenesulphonates, phosphates, sulphates, acetates, trifluoroacetates, propionates, citrates, maleates, fumarates, malonates, succinates, lactates, oxalates, tartarates and benzoates.
Salts may also be formed with bases. Such salts include salts derived from inorganic or organic bases, for example alkali metal salts such as sodium or potassium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
It has surprisingly been found that the compound of the present invention exhibits advantageous in-vivo absorption properties via the oral route as well as being a potent and selective inhibitor of CD23 processing.
The compound of the invention may be prepared by use of any appropriate conventional meth
Faller Andrew
Ward John Gerard
Kinzig Charles M.
McCarthy Mary E.
Reyes Hector M
Rotman Alan L.
Simon Soma G.
LandOfFree
Hydroxamic acid derivative as inhibitor of the formation of... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Hydroxamic acid derivative as inhibitor of the formation of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Hydroxamic acid derivative as inhibitor of the formation of... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3191875