Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
  • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
  • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D333/30—Hetero atoms other than halogen
  • C07D333/34—Sulfur atoms
• • 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
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
  • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
  • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms

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 cd, Adv Immunol, 42 [1991] 149-191). There is also a CD23-like molecule on eosinophils (Grangette et al, J Immunol, 142 [1989] 3580-3588). CD23 has been implicated in the regulation of the immune response (Delespesse et al, Immunol Rev, 125. [1 92] 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, 5 ⁇ [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 ove ⁇ roduction of IgE, the hallmark of allergic diseases such as extrinsic asthma, rhinitis, allergic conjuctivitis, eczema, atopic dermatitis and anaphylaxis (Sutton and Gould, Nature, 3 & [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, 21 [1988] 94-98) and in the synovial fluids of patients with rheumatoid arthritis (Chomarat et al, Arthritis and Rheumatism, 3 ⁇ [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, LL-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, CDl lb and CDl 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.
• EP-A-0 262 053 Compounds of formula 1 to 15.
• EP-A-0 276436 optionally as further 1 to 44.
• EP-A-0 274453 subde fined in the 1 to 8.
• EP-A-0 497 192 1 to 80.
• EP-A-0 621 270 1 to 40 EP-A-0 621 270 1 to 40.
• WO 94/07481 optionally as further 1 to 15.
• R and R3 are each independently hydrogen, alkyl, alkenyl, alkynyl or aryl; Rl is arylmethyl; and R2 is alkyl, alkenyl, aryl, cycloalkyl or cycloalkenyl.
• Alkyl, alkenyl and alkynyl groups referred to herein include straight and branched groups containing up to six carbon atoms and are optionally substituted by one or more groups selected from the group consisting of aryl, heterocyclyl, (C ⁇ _ ⁇ )alkylthio, (C ⁇ _6)alkenylthio, (C ⁇ _6)alkynylthio, arylthio, heterocyclylthio, (C ⁇ _6)alkoxy, aryl(C ⁇ _6)aIkoxy, aryl(C ⁇ _6)alkylthio, amino, mono- or di-(C ⁇ .6)alkylamino, cycloalkyl, cycloalkenyl, carboxy and esters thereof, hydroxy, and halogen.
• Cycloalkyl and cycloalkenyl groups referred to herein include groups having between three and eight ring carbon atoms and are optionally substituted as described hereinabove for alkyl, alkenyl and alkynyl groups.
• aryl includes phenyl and naphthyl such as 2-naphthyl.
• any aryl group, including phenyl and naphthyl may be optionally substituted by up to five, preferably up to three substituents.
• Suitable substituents include halogen, (C ⁇ _ 6 )alkyl, aryl(C 1 . 6 )alkyl, (C ⁇ _ 6 )alkoxy, (C 1 . 6 )alkoxy(C 1 . 6 )alkyl, halo(C 1 .
• heterocyclyl and “heterocyclic” suitably include, unless otherwise defined, aromatic and non-aromatic, single and fused, rings suitably containing up to four heteroatoms in each ring, each of which is selected from oxygen, nitrogen and sulphur, which rings, may be unsubstituted or substituted by, for example, up to three " substituents.
• Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms.
• a fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring.
• a substituent for a heterocyclyl group is selected from halogen, (C . ⁇ )alky ⁇ , aryl(C ⁇ _6)alkyl, (C ⁇ _ 6 )alkoxy, (C ⁇ _ 6 )alkoxy(C ⁇ _6)alkyl, halo C ⁇ alkyl, hydroxy, amino, mono- and di-N-(C ⁇ _6)alkyl-amino, acylamino, carboxy salts, carboxy esters, carbamoyi, mono- and di-N-(C ⁇ _6)alkylcarbonyl, aryloxycarbonyl, (Ci.
• R is hydrogen or methyl, optionally substituted by arylthio or heterocyclylthio; and/or Rl is a benzyl group; and/or R2 is a benzyl group; and or R3 is hydrogen, methyl or benzyl.
• 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 as allergy, inflammatory disorders, and autoimmune disease, in which the ove ⁇ roduction of S-CD23 is implicated.
• the invention provides a method for the treatment or prophylaxis of disorders such as allergy, inflammatory disorders, and autoimmune disease, in which the ove ⁇ roduction 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 as allergy, inflammatory disorders, and autoimmune disease, in which the ove ⁇ roduction of S-CD23 is implicated which comprises a compound of formula (I) and optionally a pharmaceutically acceptable carrier therefor.
• Particular inflammatory disorders include C ⁇ S disorders such as Alzheimers disease, multiple sclerosis, and multi-infarct dementia, as well as the inflammation mediated sequelae of stroke and head trauma.
• 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 mo ⁇ holine, piperidine, dimethylamine or diethylamine salts.
• the compounds of the present invention are potent and selective inhibitors of CD23 processing, whilst exhibiting reduced collagenase inhibitory activity in comparison with the above-mentioned compounds of the prior art.
• the compounds of the invention may be prepared by use of any appropriate conventional method, for example by analogy with the methods disclosed in patent publications WO 90/05716, WO 93/24475, WO 94/21625, WO 95/19956, WO 90/05719, WO 91/02716, WO 92 13831, WO 93/20047, EP-A-0214639, EP-A-0236872, EP-A- 0274453, EP-A-0489577, EP-A-0489579, EP-A-0497192, EP-A-0574758 and USP 4599361.
• a further aspect of the invention provides a process for preparing a compound of formula (I) as defined hereinabove, which process comprises:
• Compounds of formula (LI) can be prepared from compounds of formula (III) by reaction with a protected hydroxylamine.
• Compounds of formula (III) can be prepared by hydrolysis of a compound of formula (V):
• R to R3 are as defined hereinabove
• Y is a protecting group such as t-butyl.
• Suitable protecting groups for a hydroxamic acid are well known in the art and include benzyl, trimethylsilyl, t-butyl and t-butyldimethylsilyl.
• Suitable protecting groups for a carboxylic acid are well known in the art and include t-butyl , benzyl and methyl.
• the starting materials and other reagents are available commercially or can be synthesised by well-known and conventional methods.
• the isomers, including stereoisomers, of the compounds of the present invention may be prepared as mixtures of such isomers or as individual isomers.
• the individual isomers may be prepared by any appropriate method, for example individual stereoisomers may be prepared by stereospecific chemical synthesis starting from chiral substrates or by separating mixtures of diastereoisomers using known methods.
• the invention provides compounds of formula (IA):
• the compounds are isolated in substantially pure form. As stated herein an inhibitor of the formation of soluble human CD23 has useful medical properties. Preferably the active compounds are administered as pharmaceutically acceptable compositions.
• compositions are preferably adapted for oral administration. However, they may be adapted for other modes of administration, for example in the form of a spray, aerosol or other conventional method for inhalation, for treating respiratory tract disorders; or parenteral administration for patients suffering from heart failure. Other altemative modes of administration include sublingual or transdermal administration.
• compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
• a composition of the invention is in the form of a unit dose.
• Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
• binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
• fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
• tabletting lubricants for example magnesium stearate
• disintegrants for example star
• T e solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art.
• the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
• Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
• Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
• suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats
• emulsifying agents for example lecithin, sorbitan monooleate, or
• fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
• the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
• adjuvants such as a local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle.
• the composition can be frozen after filling into the vial and the water removed under vacuum.
• Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
• the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
• 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 microfine 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.
• small amounts of other anti-asthmatics and bronchodilators for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; xanthine derivatives such as theophylline and aminophylline and corticosteroids such as prednisolone and adrenal stimulants such as ACT ⁇ may be included.
• sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine
• xanthine derivatives such as theophylline and aminophylline and corticosteroids
• prednisolone and adrenal stimulants such as ACT ⁇
• compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending upon the method of administration.
• a preferred range for inhaled administration is 10-99%, especially 60-99%, for example 90, 95 or 99%.
• Microfine powder formulations may suitably be administered in an aerosol as a metered dose or by means of a suitable breath-activated device.
• Suitable metered dose aerosol formulations comprise conventional propellants, cosolvents, such as ethanol, surfactants such as oleyl alcohol, lubricants such as oleyl alcohol, desiccants such as calcium sulphate and density modifiers such as sodium chloride.
• Suitable solutions for a nebulizer are isotonic sterilised solutions, optionally buffered, at for example between pH 4-7, containing up to 20mg/ml of compound but more generally 0.1 to lOmg ml, for use with standard nebulisation equipment.
• An effective amount will depend on the relative efficacy of the compounds of the present invention, the severity of the disorder being treated and the weight of the sufferer.
• a unit dose form of a composition of the invention may contain from 0.1 to lOOOmg of a compound of the invention (0.001 to lOmg via inhalation) and more usually from 1 to 500mg, for example 1 to 25 or 5 to 500mg.
• compositions may be administered from 1 to 6 times a day, more usually from 2 to 4 times a day, in a manner such that the daily dose is from lmg to lg for a 70 kg human adult and more particularly from 5 to 500mg. That is in the range of about 1.4 x W 2 mg/kg/day to 14 mg/kg/day and more particularly in the range of about 7 x 10" 2 mg/kg/day to 7 mg/kg/day.
• Procedure 1 The ability of test compounds to inhibit the release of soluble CD23 was investigated by use of the following procedure.
• Plasma membranes from RPMI 8866 cells, a human Epstein-Barr virus transformed B-cell line (Sarfati et al., Immunology 60 [1987] 539-547) expressing high levels of CD23 are purified using an aqueous extraction method.
• Cells resuspended in homogenization buffer (20mM HEPES pH 7.4, 150 mM NaCl, 1.5 mM MgC12, 1 mM DTT) are broken by N2 cavitation in a Parr bomb and the plasma membrane fraction mixed with other membranes is recovered by centrifugation at lO.OOOXg.
• the light pellet is resuspended in 0.2 M potassium phosphate, pH 7.2 using 2 ml per 1-3 g wet cells and the nuclear pellet is discarded.
• 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 lOO.OOOXg 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 5 uM Preparation 1 from P 30994.
• sCD23 released from the membrane is determined using the EIA kit from The Binding Site (Birmingham, UK) or a similar one utilizing MHM6 anti-CD23 mAb [Rowe et al., Int. J. Cancer, 29, 373-382 (1982)] or another anti-CD23 mAb as the capture antibody in a sandwich EIA..
• the amount of soluble CD23 made by 0.5 ug membrane protein in a total volume of 50 ul phosphate-buffered saline is measured by EIA and compared to the amount made in the presence of various concentrations of inhibitors.
• Inhibitors are prepared in solutions of water or dimethylsulfoxide (DMSO) and the final DMSO concentration is not more than 2 %.
• IC50's are determined by curve fitting as the concentration where 50 % inhibition of production of sCD23 is observed relative to the difference in sCD23 between controls incubated without inhibitor.
• Procedure 2 The ability of test compounds to inhibit collagenase was investigated using the following procedure.
• 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 inco ⁇ orated 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 Mu ⁇ hy (methods in Enzymology ⁇ , 711,1981) The samples were centrifuged to sediment undigested collagen and an aliquot of the radioactive supematant removed for assay on a scintillation counter as a measure of hydrolysis. The collagenase activity in the presence of ImM 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).
• the second eluting diastereoisomer (12.5min) was shown to be N-(2-(S)-benzyl-4- hydroxyaminosuccinyl)-(S)-phenylalanine-N'-benzylamide (30mg,12%) mp 203-5°C.
• the solution was buffered to pH 9 with sodium hydrogen carbonate and the THF evaporated.
• the residue was partitioned between water (300ml) and dichloromethane (300ml) and the aqueous layer washed with dichloromethane (2x200ml).
• the aqueous layer was acidified with IM HCl and extracted with ethyl acetate (3x200ml). Drying of the organic layer (MgSO 4 ), filtration and evaporation gave the required acid as a clear oil (3.4g, 100%).
• Triflic anhydride (21.85ml, 36.6g, 130.2 mmol) was added in one portion to a solution of benzyl 3-(R)-phenyllactate(24g, 93.75mmol) and pyridine (7.09ml, 86.8mmol) in dichloromethane (220ml) at 0°C. The solution was stirred for lh under argon. The mixture was washed with ice cold water, brine, dried (MgSO4), and filtered.
• R is CH2S -(2- thienyl) and R is methyl

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• 1996
  • 1996-01-17 GB GBGB9601041.8A patent/GB9601041D0/en active Pending
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