Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/04—Antipruritics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• 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.
• 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.
• i-CD23 cell bound CD23
• s-CD23 well-defined soluble fragments
• s- CD23 has been implicated in the overproduction of IgE, the hallmark of allergic diseases such as extrinsic asthma, rhinitis, allergic conjunctivitis, eczema, atopic dermatitis and anaphylaxis (Sutton and Gould, Nature, 366, [1993] 421-428).
• S-CD23 Other biological activities attributed to S-CD23 include the stimulation of B cell growth and the induction of the release of mediators from monocytes.
• 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.
• 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, CD1 lb and CD1 lc 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.
• IL-4 or IFN induce the expression of CD23 and its release as sCD23 by human monocytes.
• 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.
• inhibition of CD23 cleavage should mitigate sCD23-induced monocyte activation and mediator formation, thereby reducing the inflammatory response.
• WO 99/06361 (Abbott) and WO 00/12478 (Zeneca Limited) describe a range of compounds which includes reverse hydroxamate sulfonyl and sulfonamide compounds, for use as metalloproteinase inhibitors.
• WO 99/38843 discloses a generic scope of compounds useful in the treatment of inter alia conditions mediated by enzymes involved in the shedding of CD23, which covers compounds of formula (A):
• PCT EPO1/05798 discloses compounds useful in the treatment and prophylaxis of conditions mediated by enzymes involved in the shedding of CD23 which covers compounds of formula (B):
• R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocyclyl; and R! is bicyclyl or heterobicyclyl.
• the present invention provides the use of a compound of formula (I) for the production of a medicament for the treatment or prophylaxis of disorders such allergy, allergic asthma, atopic dermatitis and other atopic diseases; inflammatory disorders; and autoimmune disease, in which the overproduction of S-CD23 is implicated.
• the invention provides a method for the treatment or prophylaxis of disorders such as allergy, allergic asthma, atopic dermatitis and other atopic diseases; inflammatory disorders; and autoimmune disease, in which the overproduction of S-CD23 is implicated, which method comprises the administration of a compound of formula (I), to a human or non-human mammal in need thereof.
• disorders such as allergy, allergic asthma, atopic dermatitis and other atopic diseases; inflammatory disorders; and autoimmune disease, in which the overproduction of S-CD23 is implicated, which method comprises the administration of a compound of formula (I), 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 allergy, allergic asthma, atopic dermatitis and other atopic diseases; inflammatory disorders; and autoimmune disease, in which the overproduction of S-CD23 is implicated which comprises a compound of formula (I) and optionally a pharmaceutically acceptable carrier therefor.
• Particular inflammatory disorders include CNS disorders such as Alzheimer's disease, multiple sclerosis, and multi-infarct dementia, as well as the inflammation mediated sequel of stroke and head trauma.
• the compound of the invention is a highly potent and selective inhibitor of CD23 processing, having little or no activity as an inhibitor of matrix metalloproteases.
• 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, tartrates 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.
• the compounds of the invention may be prepared by use of any appropriate conventional method.
• the present invention provides a process for preparing compounds of formula (I) as defined hereinabove, which process comprises :
• compositions of this invention may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebulizer, or as a micro fine powder for insufflation, alone or in combination with an inert carrier such as lactose.
• the particles of active compound suitably have diameters of less than 50 microns, preferably less than 10 microns for example diameters in the range of 1-50 microns, 1-10 microns or 1-5 microns.
• Step 6 (2S,3R)-2-Amino-3-methoxy-l-(3-quinolyImethanesulfonyl)butane dihydrochloride
• (2S,3R)-2-(N-t-butoxycarbonylamino)-3-methoxy- l-(3-quinolylmethanesulfonyl)butane (lg) in MDC (10ml) at rt was treated with 4M hydrogen chloride in dioxan (10ml). After lh the mixture was evaporated to give the subtitle compound (0.93g).
• Procedure 1 The ability of test compounds to inhibit the release of soluble CD23 was investigated by use of the following procedure.
• the membranes are further fractionated by partitioning between Dextran 500 (6.4% w/w) and polyethylene glycol (PEG) 5000 (6.4% w/w) (ref), at 0.25 M sucrose in a total of 16 g per 10-15 mg membrane proteins [Morre and Morre, BioTechniques 7, 946-957 (1989)].
• the phases are separated by brief centrifugation at lOOOXg and the PEG (upper) phase is collected, diluted 3-5 fold with 20 mM potassium phosphate buffer pH 7.4, and centrifuged at 100,000Xg to recover membranes in that phase.
• the pellet is resuspended in phosphate-buffered saline and consists of 3-4 fold enriched plasma membranes as well as some other cell membranes (e.g. lysosomes, Golgi).
• the membranes are aliquoted and stored at -80°C. Fractionation at 6.6 % Dextran/PEG yields plasma membranes enriched 10-fold.
• the fractionated membranes are incubated at 37°C for times up to 4 hrs to produce fragments of CD23 which are separated from the membrane by filtration in 0.2 micron Durapore filter plates (Millipore) after quenching the assay with a non-selecitve MMP inhibitor, e.g.
• Procedure 2 The ability of test compounds to inhibit matrix metalloproteases was investigated using the following procedures.
• the potency of compounds to act as inhibitors of collagenase was determined by the method of Cawston and Barrett (Anal. Biochem. 99, 340-345, 1979), hereby incorporated by reference, whereby a 1 mM solution of the inhibitor being tested or dilutions thereof, was incubated at 37 °C for 18 h with collagen and human recombinant collagenase, from synovial fibroblasts cloned, expressed and purified from E. Coli, (buffered with 150 mM Tris, pH 7.6, containing 15 mM calcium chloride, 0.05% Brij 35, 200 mM sodium chloride and 0.02% sodium azide).
• the collagen was acetylated ⁇ H type 1 bovine collagen prepared by the method of Cawston and Murphy (methods in Enzymology 80, 711,1981) The samples were centrifuged to sediment undigested collagen and an aliquot of the radioactive supernatant removed for assay on a scintillation counter as a measure of hydrolysis. The collagenase activity in the presence of lmM inhibitor, or dilution thereof, was compared to activity in a control devoid of inhibitor and the results reported as that concentration effecting 50% of the collagenase (IC50).
• MMP activity was determined using a fluorescence quench assay with appropriate substrate.
• MMP activity was determined using MMP activated using trypsin, according to Lark et al, Connective Tissue Res. 25, 52 (1990).
• the MMP is incubated at room temperature in a microtitre plate in a total volume of 100 ul, containing 0.15 M Tris Cl, 15 mM CaC12, 0.2 M NaCl, pH 7.6 (assay buffer); inhibitor at concentrations up to 100 uM, with no more than 2 % DMSO final concentration, 10 uM substrate (such as SDP-3815-PI for MMP-1, Peptides
• the MMP concentration is ⁇ 10 nM, and determined empirically with the appropriate substrate to give at least a 20-fold increase in fluorescence emission in 30 min. Fluorescent excitation wavelength was 355 ran, emission wavelength 400-460 nm, and data points are collected to generate slope (change in fluorescence with time). Percent inhibition for each concentration is calculated from the slope at time zero, and IC50 values from the concentration dependence. MMP-1, 2, 3, 7, 9, 13, 14 may all be assayed in the same manner, using commercially available substrates reported to be effective for each enzyme. Enzymes were obtained from Calbiochem and activated using the same trypsin method.

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• Health & Medical Sciences (AREA)
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• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Pharmacology & Pharmacy (AREA)
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• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Pulmonology (AREA)
• Immunology (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
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• Dermatology (AREA)
• Psychiatry (AREA)
• Pain & Pain Management (AREA)
• Rheumatology (AREA)
• Hospice & Palliative Care (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Quinoline Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 2001
  • 2001-11-27 GB GBGB0128376.1A patent/GB0128376D0/en not_active Ceased
• 2002
  • 2002-11-25 AU AU2002365510A patent/AU2002365510A1/en not_active Abandoned
  • 2002-11-25 AR ARP020104525A patent/AR037426A1/es not_active Application Discontinuation
  • 2002-11-25 DE DE60205035T patent/DE60205035T2/de not_active Expired - Fee Related
  • 2002-11-25 TW TW091134148A patent/TW200303746A/zh unknown
  • 2002-11-25 AT AT02790435T patent/ATE299497T1/de not_active IP Right Cessation
  • 2002-11-25 WO PCT/EP2002/013263 patent/WO2003045922A1/en not_active Ceased
  • 2002-11-25 JP JP2003547374A patent/JP2005513034A/ja active Pending
  • 2002-11-25 US US10/496,159 patent/US7038055B2/en not_active Expired - Fee Related
  • 2002-11-25 ES ES02790435T patent/ES2243783T3/es not_active Expired - Lifetime
  • 2002-11-25 EP EP02790435A patent/EP1448529B1/en not_active Expired - Lifetime

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