WO1997042168A1 - Derives thio d'acides hydroxamiques - Google Patents

Derives thio d'acides hydroxamiques Download PDF

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Publication number
WO1997042168A1
WO1997042168A1 PCT/GB1997/001164 GB9701164W WO9742168A1 WO 1997042168 A1 WO1997042168 A1 WO 1997042168A1 GB 9701164 W GB9701164 W GB 9701164W WO 9742168 A1 WO9742168 A1 WO 9742168A1
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Prior art keywords
tert
isobutyl
leucine
methylamide
alkyl
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PCT/GB1997/001164
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English (en)
Inventor
Thomas Geoffrey Colerick Bird
Bernard Christophe Barlaam
Christine Marie Paul Lambert
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Zeneca Limited
Zeneca Pharma
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Priority to AU26454/97A priority Critical patent/AU2645497A/en
Publication of WO1997042168A1 publication Critical patent/WO1997042168A1/fr

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    • 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
    • C07D215/16—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 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
    • C07C323/65—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfone or sulfoxide groups bound to the carbon skeleton
    • 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
    • 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
    • C07D215/16—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 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
    • C07D215/36—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/70—Sulfur atoms
    • C07D277/74—Sulfur atoms substituted by carbon atoms

Definitions

  • This invention relates to thio compounds and in particular to thio compounds wherein a thio substituent is located adjacent to a hydroxycarbamate group. This invention further relates to processes for preparing such thio compounds, to pharmaceutical compositions containing them and to their use in methods of therapeutic treatment.
  • the compounds of this invention are inhibitors ofthe production of TNF (Tumour Necrosis Factor) which is believed to be formed by the cleavage of a pro-form, or larger precursor, by the enzyme pro-TNF Convertase. Applicants believe that the compounds ofthe present invention inhibit TNF production by mechanisms which include inhibition of pro- TNF Convertase.
  • TNF Tumour Necrosis Factor
  • 'TNF' is used herein to refer to Tumour Necrosis Factor in general but, in particular, to TNF ⁇ .
  • the compounds of this invention will be useful in the treatment of disease or medical conditions in which excessive TNF production is known to give rise via a cascade of processes to a variety of physiological sequelae including the production of physiologically- active eicosanoids such as the prostaglandins and leukotrienes, the stimulation ofthe release of proteolytic enzymes such as collagenase, the activation of osteoclast activity leading to the resorption of calcium, the stimulation ofthe release of proteoglycans from, for example, cartilage, the stimulation of cell proliferations and to angiogenesis.
  • physiologically- active eicosanoids such as the prostaglandins and leukotrienes
  • proteolytic enzymes such as collagenase
  • osteoclast activity leading to the resorption of calcium the stimulation ofthe release of proteoglycans from, for example, cartilage
  • the stimulation of cell proliferations and to angiogenesis to angiogenesis.
  • Excessive TNF production has also been implicated in mediating or exacerbating the development of various inflammatory and allergic diseases such as inflammation ofthe joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis and allergic rhinitis), and in the production and development of various cardiovascular disorders such as myocardial infarction, angina and peripheral vascular disease.
  • various inflammatory and allergic diseases such as inflammation ofthe joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis and gastritis), skin disease (especially psoriasis, eczema and dermatitis) and respiratory disease (especially asthma, bronchitis and allergic rhinit
  • the compounds ofthe invention may also be inhibitors of one or more matrix metal loproteinases such as coUagenases, stromelysins and gelatinases. Thus they may also be of use in the therapeutic treatment of disease conditions mediated by such enzymes for example arthritis (rheumatoid and osteoarthritis), osteoporosis and tumour metastasis.
  • matrix metal loproteinases such as coUagenases, stromelysins and gelatinases.
  • the present invention provides novel thio compounds which have activity as inhibitors of TNF production and/or are inhibitors of one or more matrix metalloproteinase enzymes.
  • R 1 is is aryl, arylC, .6 alkyl, heteroaryl or heteroarylC, ⁇ alkyl
  • R 2 is is hydrogen, C, .8 alkyl, C M alkenyl, C alkynyl, C 3 . g cycloalkyl, aryl, heteroaryl, heterocyclyl, arylC,. 6 alkyl, heteroarylC ⁇ alkyl, heterocyclylC,. 6 alkyl or C j . 8 cycloalkylC,. 6 alkyl
  • R 3 is C ⁇ alkyl, C 2.6 alkenyl, arylC, .6 alkyl, heteroarylC,.
  • Aryl in the terms “aryl” and “arylC ⁇ alkyl” typically means phenyl or naphthyl, preferably phenyl.
  • Heteroaryl in the terms “heteroaryl” and “heteroarylC ⁇ alkyl” means an aromatic mono- or bicyclic 5-10 membered ring with up to five ring heteroatoms selected from nitrogen, oxygen and sulphur.
  • heteroaryl' examples include thienyl, pyrrolyl, furanyl, imidazolyl, thiazolyl, pyrimidinyl, pyridinyl, indolyl, benzimidazolyl, benzthiazolyl, quinolinyi and isoquinolinyl.
  • Heterocyclyl in the terms “heterocyclyl” and heterocyclyl- C, ⁇ alkyl means a non-aromatic mono- or bicyclic 5-10 membered ring with up to five ring hetero atoms selected from nitrogen, oxygen and sulphur.
  • Examples of 'heterocyclyl' include pyrrolidinyl, morpholinyl, piperidinyl, dihydropyridinyl and dihydropyrimidinyl.
  • 6 alkylsulphonyl for example methylsulphonyl, arylsulphonyl for example phenylsulphonyl, C,. 6 alkylaminosulphonyl for example methylaminosulphonyl, di-(C,_ 6 alkyl)aminosulphonyl for example dimethylamino- sulphonyl, nitro, cyano, cyanoC ⁇ alkyl for example cyanomethyl, hydroxyC,. 6 alkyl for example hydroxymethyl, amino C,. 6 alkyl for example aminoethyl, C,. 6 alkanoylamino for example acetamido, C,.
  • side chain of a naturally occurring amino acid means the side chain X of an amino acid NH 2 -CHX-COOH.
  • Suitable amino acids include alanine, arginine, aspartic acid, cysteine, asparagine, glutamine, histidine, homoserine, isoleucine, leucine, lysine, methionine, norleucine, norvaline, ornithine, serine, threonine, tryptophan, tyrosine and valine.
  • R 1 is an optionally substituted aryl group.
  • R' is an optionally substituted phenyl group.
  • R 1 is optionally substituted arylC ⁇ alkyl.
  • R 1 is optionally substituted heteroaryl or heteroaryl- C w alkyl.
  • R 1 is phenyl, phenylC ⁇ alkyl, naphthylC, ⁇ alkyl, heteroaryl or heteroarylC ⁇ alkyl wherein any of such rings is unsubstituted or substituted by one or two groups selected from halogen for example chloro or fluoro, C,. 6 alkylcarbonyl for example acetyl, C ⁇ alkylsulphonyl for example methylsulphonyl, trifluoromethyl, cyano, C ⁇ alkyl for example methyl, isopropyl or tert-butyl, C,.
  • R 1 is phenyl, phenylC ⁇ alkyl, naphthylC ⁇ alkyl, heteroaryl or wherein any of such rings is unsubstituted or substituted by one or two groups selected from halogen for example chloro or fluoro, C, ⁇ alkylcarbonyl for example acetyl, C, ⁇ alkylsulphonyl for example methylsulphonyl, trifluoromethyl, C ⁇ alkyl for example methyl, isopropyl or tert-butyl, C,.
  • R 1 is phenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 3,5-difluoro- phenyl, 4-acetylphenyl, 4-cyanophenyl, 4-methylsulphonylphenyl, 4-( 1 -cyano- 1- methylethyl)phenyl, 3,4-dimethoxyphenyl, 3,5-dichlorophenyl or 3,5-di-trifluoromethyl- phenyl.
  • R' is 3-(l -cyano- 1-methy lethyl)phenyl, naphth-1-yl, 3-hydroxynaphth-7-yl or 2-chloro-4-fluorophenyl.
  • R 1 may be benzyl, phenethyl, phenylprop- 1 -yl, 1 -methyl- phenylmethyl (PhCHMe-), 1,1-dimethylphenylmethyl (PhCMe 2 -), thiazolyl, benzthiazolyl, 4- methoxybenzyl, indolyl, benzimidazolyl or indolylmethyl.
  • R 1 may be l-methyl-2-oxo-quinolin-6-yl, 1 -methyl -2-oxodihydro- quinolinyl, l-methyl-2-oxotetrahydroquinolinyl, 2-methyl-l-oxodihydroisoquinolinyl or 2- methyl- 1 -oxotetrahydroisoquinolinyl ; of these 1 -methy l-2-oxotetrahydroquinolin-7-y 1 is preferred.
  • cycloalkyl for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or C 3 .
  • g cycloalkylC M alkyl for example cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyL
  • alkyl interrupted by an oxygen or sulphur atom for example methoxypropyl, ethoxyethyl, propoxymethyl, ethylthioethyl, methylthiopropyl; phenylC ⁇ alkyl for example benzyl, phenethyl, phenylpropyl or phenylbutyl; C 3 .
  • R 5 are hydrogen and C ⁇ alkyl for example methyl or ethyl.
  • R 5 is hydrogen.
  • R 4 and R5 together with the nitrogen atom to which they are joined form a heterocyclic ring, for example a 5 or 6 membered heterocyclic ring such as morpholino, piperidino, piperazino orN-methylpiperazino. Of these morpholino is preferred.
  • a preferred class of compounds ofthe formula (II) is that wherein R 1 is phenyl unsubstituted or substituted by one or two groups selected from halogen for example chloro or fluoro; C, ⁇ alkylsulphonyl for example methylsulphonyl; trifluoromethyl; C, .6 alkyl for example methyl, isopropyl or tert-butyl; C, ⁇ alkoxy for example methoxy; cyano; C
  • alkanoyl for example acetyl; cyanoC ⁇ alkyl for example 1 -cyano- 1-methylethyl; or two adjacent carbon atoms on the phenyl ring are linked to form a methylenedioxy (-OCH 2 O-) group;
  • R 2 is isobutyl;
  • R 3 is isobutyl, tert-butyl, 1,1-dimethylmethylthiomethyl or benzyl;
  • R 4 is methyl, ethyl, n-propyl, isobutyl, tert-butyl, dimethylaminoethyl, 2-morpholinoethyl or benzyl; and
  • R 5 is hydrogen or methyl, or R 4 and R5 together with the nitrogen atom to which they are joined form a morpholine ring.
  • a further preferred class of compounds ofthe formula (II) is that wherein R 1 is phenylC ⁇ alkyl, heteroaryl or heteroarylC ⁇ alkyl wherein any of such rings is unsubstituted or substituted by one or two groups selected from halogen for example chloro or fluoro, C, ⁇ alkylsulphonyl for example methylsulphonyl, trifluoromethyl, C alkyl for example methyl, isopropyl or tert-butyl, C l-6 alkoxy for example methoxy, cyano, Ci ⁇ alkanoyl for example acetyl, cyanoC ⁇ alkyl for example 1 -cyano- 1-methylethyl, or two adjacent carbon atoms on the phenyl ring are linked to form a methylenedioxy (-OCH 2 O-) group; R 2 is isobutyl; R 3 is isobutyl, tert-butyl, 1,1-dimethylmethylthio
  • R 6 alkyl for example 1 -cyano- 1-methylethyl, or two adjacent carbon atoms on the phenyl ring are linked to form a methylenedioxy (-OCH 2 O-) group
  • R 2 is isobutyl
  • R 3 is isobutyl, tert-butyl or benzyl
  • R 4 is methyl, ethyl, n-propyl, isobutyl, tert-butyl or benzyl
  • R 5 is hydrogen.
  • Suitable pharmaceutically acceptable salts include acid addition salts such as hydrochloride, hydrobromide, citrate and maleate salts and salts formed with phosphoric and sulphuric acid.
  • suitable salts are base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, or organic amine salt for example triethylamine.
  • In vivo hydrolysable esters are those pharmaceutically acceptable esters that hydrolyse in the human body to produce the parent compound. Such esters can be identified by administering, for example intravenously to a test animal, the compound under test and subsequently examining the test animal's body fluids. Suitable in vivo hydrolysable esters for carboxy include methoxymethyl and for hydroxy include acetyl.
  • a compound ofthe formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound ofthe formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester and pharmaceutically acceptable carrier.
  • R l -R 5 are as hereinbefore defined, or an activated derivative thereof with hydroxylamine, O-protected hydroxylamine or a salt thereof; or b) coupling a compound ofthe formula (IV) with a compound ofthe formula (V):
  • R'-R 5 are as hereinbefore defined; wherein any functional group is protected, if necessary, and: i. removing any protecting groups; ii. optionally forming a pharmaceutically acceptable salt or jn vivo hydrolysable ester.
  • Protecting groups may in general be chosen from any ofthe groups described in the literature or known to the skilled chemist as appropriate for the protection of the group in question, and may be introduced by conventional methods. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal ofthe protecting group in question, such methods being chosen so as to effect removal ofthe protecting group with minimum disturbance of groups elsewhere in the molecule.
  • a carboxyl protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms).
  • carboxy protecting groups include straight or branched chain
  • (l-12C)alkyl groups eg isopropyl, t-butyl
  • lower alkoxy lower alkyl groups eg methoxy methyl, ethoxymethyl, isobutoxymethyl
  • lower aliphatic acyloxy lower alkyl groups eg isopropyl, t-butyl
  • alkoxy lower alkyl groups eg methoxy methyl, ethoxymethyl, isobutoxymethyl
  • lower aliphatic acyloxy lower alkyl groups eg isopropyl, t-butyl
  • aryl lower alkyl groups eg benzyl, p-methoxybenzyl,
  • lower alkenyl groups eg allyl
  • lower alkanoyl groups eg acetyl
  • lower alkoxycarbonyl groups eg t-butoxycarbonyl
  • lower alkenyloxycarbonyl groups eg ally loxy carbonyl
  • aryl lower alkoxycarbonyl groups eg benzoyloxycarbonyl, g-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl
  • tri lower alkylsilyl eg trimethylsilyl, t-butyldimethylsilyl
  • aryl lower alkyl eg benzyl
  • an activated ester of a compound ofthe formula (III) and hydroxylamine or O-protected hydroxylamine is performed in the presence of a base, for example 2,6-lutidine, (optionally in the presence of dimethylaminopyridine) or N-methylmorpholine in an anhydrous aprotic solvent, for example dimethylformamide, at a non-extreme temperature, for example in the region -30° to +25°, preferably about 0°C.
  • a base for example 2,6-lutidine
  • dimethylaminopyridine dimethylaminopyridine
  • N-methylmorpholine in an anhydrous aprotic solvent, for example dimethylformamide
  • the compound ofthe formula (III) may be prepared by reacting a compound ofthe formula (VIII) with a compound ofthe formula (V):
  • enzyme After loading and washing with Buffer C, enzyme is eluted using a 0-500mM NaCl gradient in Buffer C. Active enzyme fractions are pooled and used as partially purified proTNF ⁇ convertase. In all cases the active fractions are assayed using the fluorogenic synthetic peptide substrate assay described below. This enzyme preparation cleaves 21kD soluble proTNF ⁇ at the correct cleavage site (Ala- Val) and enzyme activity is inhibited by matrix metalloprotease inhibitors (Gearing, A.J.H. etal., 1995, J Leukocyte Biol., 57,774-777).
  • the amino- peptidyl-resin so obtained was acylated by treatment for 1.5-2hr at 70°C with 1.5-2 equivalents of 4',5'-dimethoxy-fluorescein-4(5)-carboxylic acid (Khanna & Ullman, Anal Biochem, 108, 156-161, 1980) which had been preactivated with diisopropylcarbodiimide and 1-hydroxybenzotriazole in DMF.
  • the dimethoxyfluoresceinyl-peptide was then simultaneously deprotected and cleaved from the resin by treatment with trifluoroacetic acid containing 5% each of water and triethylsilane.
  • the starting material was prepared as follows:
  • L-tert-leucine 2-(dimethylamino)ethylamide was prepared by the reaction of L-tert-leucine with triphosgene to give 3-(S)-tert-butyloxazolidine-l,4-dione which was then treated with N,N-dimethyl ethylenediamine.
  • N-(L-tert-leucine)-(4-mo ⁇ holine)amide was prepared by the reaction of L-tert-leucine with triphosgene to give 3-(S)-tert-butyloxazolidine-l,4-dione which was then treated with 30 mo ⁇ holine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de la formule (I), dans laquelle R1 représente un groupe aryle, aryle C¿1-6?alkyle, hétéroaryle ou hétéroaryle C1-6alkyle; R?2¿ représente hydrogène, C¿1-8?alkyle, C2-6alkényle, C2-6alkynyle, C3-8cycloalkyle, hétéroaryle, hétérocyclyle, aryle C1-6alkyle, hétéroaryle C1-6alkyle, hétérocyclyle C1-6alkyle ou C3-8cycloalkyle C1-6alkyle; R?3¿ représente C¿1-6?alkyle, C2-6alkényle, aryle, C1-6alkyle, hétéroaryle C1-6alkyle ou la chaîne latérale d'un aminoacide d'origine naturelle; R?4¿ représente hydrogène, C¿1-6?alkyle, C3-8cycloalkyle, C4-8cycloalkényle, aryle C1-6alkyle, hétéroaryle C1-6alkyle ou hétérocyclyle C1-6alkyle; R?5¿ représente hydrogène ou C¿1-6?alkyle; ou R?4 et R5¿ constituent, avec l'atome d'azote auquel ils sont joints, un anneau hétérocyclique; dans laquelle tout groupe ou tout anneau, compris entre R1 et R5, peut être éventuellement substitué; ou bien leurs sels acceptables sur le plan pharmacologique ou leurs esters hydrolysables in vivo, ces composés étant des inhibiteurs de la production du facteur de nécrose des tumeurs et/ou d'une ou de plusieurs métalloprotéinases matricielles. La présente invention concerne également des compositions contenant ces composés ainsi que leur préparation.
PCT/GB1997/001164 1996-05-06 1997-04-29 Derives thio d'acides hydroxamiques WO1997042168A1 (fr)

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Application Number Priority Date Filing Date Title
AU26454/97A AU2645497A (en) 1996-05-06 1997-04-29 Thio derivatives of hydroxamic acids

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP96400958 1996-05-06
EP96400958.3 1996-05-06
EP96402032 1996-09-25
EP96402032.5 1996-09-25

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055449A1 (fr) * 1997-06-06 1998-12-10 The University Of Queensland Composes d'acide hydroxamique ayant des proprietes anticancereuses et antiparasitaires
US7892825B2 (en) 2003-08-08 2011-02-22 Arriva Pharmaceuticals, Inc. Method of protein production in yeast
US7914771B2 (en) 2004-03-09 2011-03-29 Arriva Pharmaceuticals, Inc. Treatment of chronic obstructive pulmonary disease by low dose inhalation of protease inhibitor
US20110230479A1 (en) * 2005-04-15 2011-09-22 Longo Frank M Neurotrophin mimetics and uses thereof
US8916556B2 (en) 2005-04-15 2014-12-23 The University Of North Carolina At Chapel Hill Pharmaceutical formulations comprising neurotrophin mimetics
US10273219B2 (en) 2009-11-12 2019-04-30 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US10532988B2 (en) 2009-11-12 2020-01-14 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
WO2020070239A1 (fr) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de l'egfr pour traiter les kératodermies

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0236872A2 (fr) * 1986-03-11 1987-09-16 F. Hoffmann-La Roche Ag Dérivés hydroxylamine, leur préparation et emploi comme médicaments
WO1990005719A1 (fr) * 1988-11-23 1990-05-31 British Bio-Technology Limited Inhibiteurs de collagenase a base d'acide hydroxamique
WO1994010990A1 (fr) * 1992-11-13 1994-05-26 British Biotech Pharmaceuticals Limited Inhibition de la production du facteur de necrose tumorale
EP0613883A1 (fr) * 1991-11-06 1994-09-07 Yamanouchi Pharmaceutical Co. Ltd. Derive d'acide hydroxamique
WO1995009841A1 (fr) * 1993-10-07 1995-04-13 British Biotech Pharmaceuticals Limited Derives d'acide hyroxamique utilises comme inhibiteurs de production de cytokine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0236872A2 (fr) * 1986-03-11 1987-09-16 F. Hoffmann-La Roche Ag Dérivés hydroxylamine, leur préparation et emploi comme médicaments
WO1990005719A1 (fr) * 1988-11-23 1990-05-31 British Bio-Technology Limited Inhibiteurs de collagenase a base d'acide hydroxamique
EP0613883A1 (fr) * 1991-11-06 1994-09-07 Yamanouchi Pharmaceutical Co. Ltd. Derive d'acide hydroxamique
WO1994010990A1 (fr) * 1992-11-13 1994-05-26 British Biotech Pharmaceuticals Limited Inhibition de la production du facteur de necrose tumorale
WO1995009841A1 (fr) * 1993-10-07 1995-04-13 British Biotech Pharmaceuticals Limited Derives d'acide hyroxamique utilises comme inhibiteurs de production de cytokine

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998055449A1 (fr) * 1997-06-06 1998-12-10 The University Of Queensland Composes d'acide hydroxamique ayant des proprietes anticancereuses et antiparasitaires
US7892825B2 (en) 2003-08-08 2011-02-22 Arriva Pharmaceuticals, Inc. Method of protein production in yeast
US7914771B2 (en) 2004-03-09 2011-03-29 Arriva Pharmaceuticals, Inc. Treatment of chronic obstructive pulmonary disease by low dose inhalation of protease inhibitor
US20110230479A1 (en) * 2005-04-15 2011-09-22 Longo Frank M Neurotrophin mimetics and uses thereof
US8916556B2 (en) 2005-04-15 2014-12-23 The University Of North Carolina At Chapel Hill Pharmaceutical formulations comprising neurotrophin mimetics
US10273219B2 (en) 2009-11-12 2019-04-30 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US10532988B2 (en) 2009-11-12 2020-01-14 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
US11225467B2 (en) 2009-11-12 2022-01-18 Pharmatrophix, Inc. Crystalline forms of neurotrophin mimetic compounds and their salts
WO2020070239A1 (fr) 2018-10-04 2020-04-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Inhibiteurs de l'egfr pour traiter les kératodermies

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