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WO2006064286A1 - Inhibiteurs de cathepsine s - Google Patents

Inhibiteurs de cathepsine s Download PDF

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Publication number
WO2006064286A1
WO2006064286A1 PCT/GB2005/050243 GB2005050243W WO2006064286A1 WO 2006064286 A1 WO2006064286 A1 WO 2006064286A1 GB 2005050243 W GB2005050243 W GB 2005050243W WO 2006064286 A1 WO2006064286 A1 WO 2006064286A1
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WIPO (PCT)
Prior art keywords
alkyl
methyl
ethyl
compound according
hydroxy
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PCT/GB2005/050243
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English (en)
Inventor
David Hardick
Matt Tozer
Julie Canfield
Michelle Wilson
Alastair Rae
Philip Fallon
Bjorn Classon
Charlotta Lindquist
Susana Ayesa
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Medivir Uk Ltd
Peptimmune, Inc
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Priority claimed from GB0427169A external-priority patent/GB0427169D0/en
Priority claimed from GB0507628A external-priority patent/GB0507628D0/en
Priority claimed from GB0510304A external-priority patent/GB0510304D0/en
Application filed by Medivir Uk Ltd, Peptimmune, Inc filed Critical Medivir Uk Ltd
Publication of WO2006064286A1 publication Critical patent/WO2006064286A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D307/32—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to inhibitors of cathepsin S, and their use in methods of treatment for disorders involving cathepsin S such as autoimmune, allergy and chronic pain conditions.
  • the papain superfamily of cysteine proteases are widely distributed in diverse species including mammals, invertebrates, protozoa, plants and bacteria.
  • Pathogenic cathepsin like enzymes include the bacterial gingipains, the malarial falcipains I, II, III et seq and cysteine proteases from Pneumocystis carinii, Trypanosoma cruzei and brucei, Crithidia fusiculata, Schistosoma spp.
  • Cathepsin S is a highly active cysteine protease belonging to the papain superfamily. Its primary structure is 57%, 41% and 45% homologous with that of the human cathepsin L and H and plant cysteine proteases papain respectively, although only 31% homologous with cathepsin B. It is found mainly in B cells, dendritic cells and macrophages and this limited occurrence suggests the potential involvement of this enzyme in the pathogenesis of degenerative disease.
  • cathepsin S is implicated are asthma, chronic obstructive pulmonary disease, endometriosis and chronic pain.
  • R 1 R', R 1 C(O) , R' C(S), R' SO2 , R' OC(O), R' NHC(O) wherein R' is a monocyclic ring;
  • R 2 , R 4 H, Ci- 7 -alkyl, C 3 - 7 -cycloalkyl;
  • R 3 Ci- 7 -alkyl, C 3 - 7 -cycloalkyl, Ar-Ci - 7 -alkyl;
  • R 5 Ci- 7 -alkyl, Halogen, Ar-Ci - 7 -alkyl, Ci- 3 -alkyl-CONR'",
  • R 6 H, Ci-7-alkyl, Ar-Ci -7-alkyl, Cr 3 -BIkYl-SO 2 -R 1 ", Ci- 3 -alkyl-C(0)-NHR ix or CH 2 XAr,
  • R 3 groups specifically disclosed in WO00/69855 are branched chain alkyl moieties such as n-butyl, t-butyl, 3-(2,2-dimethylpropyl), 4-(2-methylbutyl), 4-(3,3-dimethylbutyl), 4-(3,3-dimethyl- 2-methylbutyl), 4-(3-methyl-2-methylbutyl), or 5-(2-methyl-3-methylpentyl).
  • Page 27, line 13 of WO00/69855 discloses the compound morpholine-4-carboxylic acid [3,3-dimethyl-1S-(2-ethyl-4- oxo-tetrahydrofuran-3-ylcarbamoyl)butyl]amide.
  • R 1 is CrC 4 straight or branched alkyl, optionally substituted with up to three substituents selected from halo and hydroxy;
  • R 2 is halo, hydroxy, methyloxy, or C r C 2 alkyl, which alkyl is optionally substituted with up to three halogens or an hydroxy or a methyloxy;
  • D is -C 3 -C7 alkylene-, thereby defining a cycloalkyl ring;
  • R 3 is a carbocyclic ring selected from C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl or phenyl, or a heterocyclic ring I selected from azepanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, pyrazolyl, indolyl, which ring is optionally substituted with up
  • R 4 is independently selected from halo, oxo, nitrile, nitro, d-C 4 alkyl, -NRaRb, NH 2 CO-, X-R 5 ,
  • R 5 is H, CrC 4 alkyl, C 3 -C 6 cycloalkyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, phenyl, benzyl, any of which is optionally substituted with R 6 ;
  • R 5a is R 5 or -NRaRb
  • R 6 is independently selected from hydroxy, -NH 2 , NHC r C 3 alkyl, N(C r C 3 alkyl) 2 , nitro, cyano, carboxy, oxo, d-C 4 alkyl, Ci-C 4 -alkoxy, d-C 4 alkanoyl, carbamoyl;
  • Ra and Rb are independently selected from H, C r C 4 alkyl and acetyl, or Ra, Rb and the N atom to which they both are joined form a ring selected from morpholine, piperazine, piperidine, pyrrolidine;
  • Ra and Rb are independently selected from H, C r C 4 alkyl and acetyl, or Ra, Rb and the N atom to which they both are joined form a ring selected from morpholine, piperazine, piperidine, pyrrolidine
  • Rc is H, CrC 4 alkyl, C 0 -C 3 alkylcarbocyclyl
  • X is independently a bond or C r C 4 alkylenyl; m is independently 0,1 or 2; and pharmaceutically acceptable salts thereof.
  • R 1 examples include ethyl, 2-fluoroethyl or 2-hydroxyethyl, and methyl, fluoromethyl and hydroxyethyl, especially ethyl and methyl.
  • the stereochemistry at the C-4 and C- 5 positions of the furanone ring is enantiomerically pure, or at least 85%, for example at least 90% or more preferably at least 95% enantiomerically pure 4S, 5S configuration.
  • Preferred P1 groups (as defined below) therefore include:
  • R 10 is conveniently H or a CrC 4 alkyl ether or d-C 4 alkylthioether such as methyloxy, ethyloxy, methylthio- or ethylthio or the corresponding ketals.
  • P1 groups thus include:
  • R 1 ' is H or -CH 3 .
  • R 10 is other than H, it is currently preferred that the stereochemistry at the ring carbon atom which bears R 10 comprises at least 85%, for example at least 90% preferably at least 95% and more preferably 100% enantiomerically pure alpha configuration:
  • D is conveniently pentylene, thereby defining a cyclohexyl ring, or propylene, thereby defining a cyclobutyl ring, but more preferably D is butylene, thereby defining a cyclopentyl ring.
  • R 2 include a halogen such as fluoro, fluoro methyl, difluoromethyl or trifluoromethyl, and most preferably methyl.
  • the side chain comprising D and R 2 ie the P2 group (as defined below) may be in the R or S configuration, or a racemate thereof.
  • the P2 group is substantially, for example greater than 90% and most preferably greater than 95% in the S stereoconfiguration, that is reflecting that of an L-amino acid.
  • Preferred side chains thus include:
  • typical values for R 3 include: unsubstituted or substituted furanyl, especially furan-2-yl or furan-3- yl, or alkyl substituted furanyl such as 2-methylfuran-3-yl, 2,4-dimethylfuran-3-yl, or aryl substituted furanyl, even more especially 5-phenylfuran-2-yl, 5-(2-chlorophenyl)furan-2-yl, 5-(3chlorophenyl)furan-2-yl, 5-(4- chlorophenyl)furan-2- yl, 5-(4-fluorophenyl)furan-2-yl, 5-(4hydroxyphenyl)furan-2-yl, 5-(3- trifluoromethylphenyl)furan-2-yl, 5-(4-trifluoromethylphenyl)furan-2-yl, 5-(3- trifluoromethylphenyl)furan-2-yl, 5-(4-methylphenyl)furan-2-yl,
  • 2H-pyrazolyl unsubstituted or ar ⁇ l-substituted triazolyl, particularly phenyl-substituted triazoles including 3- phenyl-3H-[1 ,2,3]triazol-3-yl; unsubstituted or substituted pyrazinyl, particularly pyrazin-2-yl and 5-methylpyrazin-2-yl; unsubstituted or substituted imidazolyl, particularly 1 -H-imidazol-2-yl, 1 -methyl-1 H-imidazol-4-yl or 1-methyl-IH-imidazol-2-yl; thiophenyl, especially thiophene-3-yl and thiophen-2-yl, more especially heterocycle or aryl substituted C 0 -C 6 alkylthiophenyl, particularly 5-pyridin-2-ylthiophen-2-yl, more especially C r
  • C 6 alkylthiophenyl particularly 5-methylthiophenyl or 3-methylthiophen-2-yl; more especially d- C 6 alkoxythiophenyl, particularly 3-ethoxythiophen-2-yl; phenyl, especially alkyl-substituted phenyl, halogen-substituted phenyl, trihaloalkylsubstituted phenyl, alkoxy-substituted phenyl, or acetoxy-substituted phenyl, especially 4-methylphenyl, 3- chlorophenyl, 4-chlorophenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl,
  • R 3 include optionally substituted thienyl, pyrazinyl, pyridyl, pyrrolyl, and especially furyl or morpholinyl.
  • R 3 Favoured values for R 3 include fur-3-yl, thien-3-yl, pyrazin-2-yl, pyrid-4-yl, pyrrol-2-yl and especially N-morpholino.
  • R 3 is phenyl particularly phenyl substituted as follows:
  • Ry is halomethyl such as CF 3 or CF 2 or an hydroxylated methyl group, such as HOCH 2 or HO(CH 2 J 2 )C-, any of these preferences being optionally further substituted with an R 4 group such as Rx.
  • R3 comprises phenyl which is substituted with a urea, such as a cyclic urea:
  • a favoured aspect of the invention thus comprises compounds of the formula:
  • R 12 typically comprises a pharmaceutically acceptable ether or ester prodrug which is hydrolysed in vivo to release the parent phenol.
  • R 4 is at the 3, or the 3 and 5 positions of the phenyl ring.
  • Representative values include R 4 as halo, such as 3-fluoro, 3,5-difluoro, 3-chloro or 3,5-dichloro.
  • R 4 values include one or more d-C 4 alkyl, such as methyl, ethyl, i-propyl or t-butyl.
  • Representative values for this aspect of the invention thus include 5-methyl, 5-ethyl, 5-i-propyl, 5-t-butyl, 6-methyl, 5-methyl-3-fluoro.
  • a favoured aspect of the invention comprises compounds of the formula I, wherein R 3 has the partial structure:
  • R 5a is R 5 as defined above, preferably CrC 4 alkyl, such as methyl, ethyl or i-propyl or t-butyl; halogenated CrC 4 alkyl such as trifluoromethyl; C 3 -C 6 cycloalkyl, such as cyclopropyl or cyclohexyl; or phenyl or benzyl, any of which is optionally substituted with R 6 .
  • R 5a may be NRaRb as defined above including cyclic amines, such as -NHMe or -N(Me) 2 , or piperazine, N-methyl piperazine, pyrrolidine, piperidine or morpholine.
  • cyclic amines such as -NHMe or -N(Me) 2
  • piperazine N-methyl piperazine, pyrrolidine, piperidine or morpholine.
  • R 5 include heteroaryl rings such as pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl or indolyl, especially thiazolyl, any of which is substituted with R 6 groups such as d-C 4 alkyl.
  • a currently favoured sulphonamide has the partial structure:
  • Rd' is Me or preferably H
  • R 6 is H or methyl, especially at the ring position, adjacent the N for example:
  • R 5 as defined above, preferably C r C 4 alkyl, such as methyl, ethyl or i-propyl or t-butyl; halogenated CrC 4 alkyl such as trifluoromethyl; C 3 -C 6 cycloalkyl, such as cyclopropyl or cyclohexyl; or phenyl or benzyl, any of which is optionally substituted with R 6 .
  • R 5 together with Rd defines a 3-6 membered N-containing ring such as azidine, pyrrolidine, pyridine, piperidine, morpholine, piperazine or N-methylpiperizine.
  • a sulphonamide substituted phenyl is optionally substituted with an additional substituent R 4 , typically, but not invariably, in the 4 position if the sulphonamide is in the 3 position and vice versa.
  • R 4 groups thus include halo such as chloro or fluoro, CrC 4 alkyl such as methyl (including 2-methyl) and d-C 4 alkoxy such as methoxy.
  • Rd is conveniently d-C 4 alkyl or together with R 5 defines a 3-6 membered N-containing ring such as azidine, pyrrolidine, pyridine, piperidine, morpholine, piperazine or N-methylpiperizine.
  • m is typically 1 (sulphenamide) or preferably 2 (sulphonamide).
  • An alternative phenyl-based R 3 value is phenyl substituted with a pair of R 4 groups which together constitute a nitrogen containing chain of 3 or 4 atoms thereby defining a ring fused to the phenyl such as:
  • R 4 is methyl or especially H.
  • the linkage to E is para to a nitrogen in the fused ring:
  • fused rings for constituting a nitrogen containing ring fused to a phenyl R 3 include
  • Rz is CH; NH or O, especially O and preferably NH
  • R 4 is methyl or especially H.
  • the linkage to E is para to a nitrogen in the fused ring.
  • Still further fused rings for R 3 include variants wherein the fused nitrogen-containing ring defines a saturated or unsaturated 6 membered heterocycle, such as:
  • Rz is NH, O or CH, especially O and preferably NH
  • R 4 and R 4 ' are optional substituents as defined above, preferably H, and O' is absent (ie 2 hydrogen atoms) or keto.
  • the linkage to E is para to a nitrogen in the fused ring.
  • Still further fused rings for R 3 include variants wherein the fused nitrogen containing ring defines an optionally substituted quinoline, isoquinoline, tetrohydroquinoline or tetrahydroisoquinoline moiety, such as
  • R 4 and R 4 ' are H and the linkage to E is para to the nitrogen in the fused ring.
  • R 3 groups include pyrimidyl, such as 2-pyrimidyl, for example 5-OH-pyrimid-2-yl; or pyridyl, such as pyrid-4-yl, for example O ⁇ pyrid-4yl; or pyrid-3-yl, for example 6-hydroxy- pyrid-3-yl.
  • pyrimidyl such as 2-pyrimidyl, for example 5-OH-pyrimid-2-yl
  • pyridyl such as pyrid-4-yl, for example O ⁇ pyrid-4yl
  • pyrid-3-yl for example 6-hydroxy- pyrid-3-yl.
  • a further aspect of the invention comprises a method employing the compounds of the invention for the treatment of diseases caused by aberrant expression or activation of cathepsin, ie diseases or conditions alleviated or modified by inhibition of cathepsin S, preferably without substantial concomitant inhibition of other members of the papain superfamily.
  • diseases or conditions include those enumerated in WO 97/40066, such as autoimmune diseases, allergies, such as asthma and hayfever, multiple sclerosis, rheumatoid arthritis and the like.
  • a further example is the treatment of endometriasis, and especially chronic pain, as disclosed in WO0320287.
  • the invention further provides the use of the compounds of formula IV in therapy and in the manufacture of a medicament for the treatment of diseases or conditions alleviated or moderated by inhibition of cathepsin S.
  • the methods are employed to treat mammals, particularly humans at risk of, or afflicted with, autoimmune disease.
  • autoimmunity is meant the phenomenon in which the host's immune response is turned against its own constituent parts, resulting in pathology.
  • Many human autoimmune diseases are associated with certain class Il MHC-complexes. This association occurs because the structures recognized by T cells, the cells that cause autoimmunity, are complexes comprised of class Il MHC molecules and antigenic peptides.
  • Autoimmune disease can result when T cells react with the host's class Il MHC molecules when complexed with peptides derived from the host's own gene products.
  • any autoimmune disease in which class Il MHC/antigenic complexes play a role may be treated according to the methods of the present invention.
  • autoimmune diseases include, e.g., juvenile onset diabetes (insulin dependent), multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis and Hashimoto's thyroiditis.
  • the methods are employed to treat mammals, particularly humans, at risk of, or afflicted with, allergic responses.
  • allergic response is meant the phenomenon in which the host's immune response to a particular antigen is unnecessary or disproportionate, resulting in pathology. Allergies are well known in the art, and the term “allergic response” is used herein in accordance with standard usage in the medical field.
  • allergies include, but are not limited to, allergies to pollen, "ragweed,” shellfish, domestic animals (e.g., cats and dogs), bee venom, house dust mite allergens and the like.
  • Another particularly contemplated allergic response is that which causes asthma. Allergic responses may occur, in man, because T cells recognize particular class Il MHC/antigenic peptide complexes. If these class Il MHC/antigenic peptide complexes are inhibited from being formed, the allergic response is reduced or suppressed.
  • Immunosuppression by the methods of the present invention will typically be a prophylactic or therapeutic treatment for severe or life-threatening allergic responses, as may arise during asthmatic attacks or anaphylactic shock.
  • the methods are employed to treat mammals, particularly humans, which have undergone, or are about to undergo, an organ transplant or tissue graft.
  • tissue transplantation e.g., kidney, lung, liver, heart
  • skin grafting when there is a mismatch between the class Il MHC genotypes (HLA types) of the donor and recipient, there may be a severe "allogeneic" immune response against the donor tissues which results from the presence of non-self or allogeneic class Il MHC molecules presenting antigenic peptides on the surface of donor cells. To the extent that this response is dependent upon the formation of class Il
  • cathepsin S inhibition of cathepsin S may suppress this response and mitigate the tissue rejection.
  • An inhibitor of cathepsin S can be used alone or in conjunction with other therapeutic agents, e.g., as an adjunct to cyclosporin A and/or antilymphocyte gamma globulin, to achieve immunosuppression and promote graft survival.
  • administration is accomplished by systemic application to the host before and/or after surgery.
  • perfusion of the donor organ or tissue either prior or subsequent to transplantation or grafting, may be effective.
  • the above embodiments have been illustrated with an MHC class Il mechanism but the invention is not limited to this mechanism of action. Suppression of cathepsin S as a treatment of COPD or chronic pain may not, for example, involve MHC class Il at all.
  • Non-automimmune indications include allergic rhinitis, asthma, artherosclerosis, chronic obstructive pulmonary disease (COPD) and chronic pain.
  • COPD chronic obstructive pulmonary disease
  • the compounds of the invention can form salts which form an additional aspect of the invention.
  • Appropriate pharmaceutically acceptable salts of the compounds of the invention include salts of organic acids, especially car boxy lie acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, isethionate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate,
  • the compounds of the invention include a number of handles such as OH, NH or COOH groups to which conventional prodrug moieties can be applied.
  • Prodrugs are typically hydrolysed in vivo to release the parent compound in the plasma, liver or intestinal wall.
  • Favoured prodrugs are esters of hydroxyl groups such as a phenolic hydroxyl group at R 3 , or amine functions such as an R 4 sulphonamide amine function.
  • Preferred pharmaceutically acceptable esters include those derived from CrC 6 carboxylic acids such as acetyl or pivaloyl or optionally substituted benzoic acid esters, preferably unsubstituted or substituted with R 6 .
  • Favoured sulphonamide prodrugs include aminoacyls derived from d-C 6 carboxylic acids such as acetyl or pivaloyl or optionally substituted benzoic acid esters, preferably unsubsbstituted or substituted with R 6 .
  • Co-C 3 alkylcarbocyclyl comprises C 0 -C 3 alkylaryl and Co-C 3 alkylC 3 C 7 cycloalkyl.
  • 'Co-C 3 alkylaryr as applied herein is meant to include an ar ⁇ l moiety such as a phenyl, naphthyl or phenyl fused to a C 3 -C 7 CyClOaI kyl (for example indanyl), which aryl is directly bonded (i.e. C 0 ) or through an intermediate methylene, ethylene, or propylene group.
  • 'C 0 -C 3 alkylC 3 C 7 cycloalkyr as applied herein is meant to include a C 3 -C 7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, which cycloalkyl is directly bonded (i.e. C o alkyl) or through an intermediate methylene, ethylene, propylene or isopropylene group.
  • the cycloalkyl group may contain an unsaturated bond.
  • the ar ⁇ l or cycloalkyl group is optionally substituted with 1-3 substituents selected from halo, hydroxy, nitro, cyano, carboxy, CrC 6 alkyl, CrC 6 alkoxy, C r C 6 alkoxyCi-C 6 alkyl, CrC 6 alkanoyl, amino, azido, oxo, mercapto, nitro, or C 0 -C 3 alkylR 3 .
  • the active agent While it is possible for the active agent to be administered alone, it is preferable to present it as part of a pharmaceutical formulation.
  • a pharmaceutical formulation will comprise the above defined active agent together with one or more acceptable carriers/excipients and optionally other therapeutic ingredients.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.
  • the formulations include those suitable for rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration, but preferably the formulation is an orally administered formulation.
  • the formulations may conveniently be presented in unit dosage form, e.g. tablets and sustained release capsules, and may be prepared by any methods well known in the art of pharmacy.
  • Such methods include the step of bringing into association the above defined active agent with the carrier.
  • the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • the invention extends to methods for preparing a pharmaceutical composition comprising bringing a compound of Formula IV or its pharmaceutically acceptable salt in conjunction or association with a pharmaceutically acceptable carrier or vehicle. If the manufacture of pharmaceutical formulations involves intimate mixing of pharmaceutical excipients and the active ingredient in salt form, then it is often preferred to use excipients which are non-basic in nature, i.e. either acidic or neutral.
  • Formulations for oral administration in the present invention may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion and as a bolus etc.
  • suitable carrier includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate, sodium stearate and other metallic stearates, glycerol stearate stearic acid, silicone fluid, talc waxes, oils and colloidal silica.
  • Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring or the like can also be used. It may be desirable to add
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may be optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
  • compositions suitable for oral administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
  • the appropriate dosage for the compounds or formulations of the invention will depend upon the indication, the severity of the disease, the size and metabolic vigour and the patient, the mode of administration and is readily determined by conventional animal trials. Dosages providing intracellular (for inhibition of physiological proteases of the papain superamily) concentrations of the order 0.01-100 uM, more preferably 0.01-10 uM, such as 0.1-5 uM are typically desirable and achievable. Synthesis of the compounds of the present invention can be performed by different chemical strategies in solution or solid phase or a combination of both. The compounds are typically prepared as building blocks reflecting the P1 , P2 and P3 moieties of the end product inhibitor.
  • the P1 building block will be an N-protected C-5-substituted furan-3-onamine
  • P2 will be an N-protected amino acid in which the side chain comprises the D-containing saturated ring and branched alkyl linker
  • P3 typically comprises a capping group such as a substituted, heteroaroyl or aroyl moiety.
  • the suitably protected individual building blocks can first be prepared and subsequently coupled together i.e. P2+P1 ⁇ P2-P1.
  • precursors of the building blocks can be coupled together and modified at a later stage of the synthesis of the inhibitor sequence.
  • Further building blocks, precursors of building blocks or prefabricated bigger fragments of the desired structure can then be coupled to the growing chain, e.g. R 3 -E-P2*+ P1 ⁇ R 3 -E-P2-P1 or R 3 -E*+P2-P1 ⁇ R 3 -E-P2-P1 , where * denotes an activated form.
  • Coupling between two amino acids, an amino acid and a peptide, or two peptide fragments can be carried out using standard coupling procedures such as the azide method, mixed carbonic- car boxy lie acid anhydride (isobutyl chloroformate) method, carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimide) method, active ester (pnitrophenyl ester, N-hydroxysuccinic imido ester) method, Woodward reagent K- method, carbonyldiimidazole method, phosphorus reagents or oxidation-reduction methods. Some of these methods (especially the carbodiimide method) can be enhanced by adding 1- hydroxybenzotriazole or 4-DMAP. These coupling reactions can be performed in either solution (liquid phase) or solid phase.
  • the coupling step involves the dehydrative coupling of a free carboxyl of one reactant with the free amino group of the other reactant in the present of a coupling agent to form a linking amide bond.
  • coupling agents are found in general textbooks on peptide chemistry, for example, M. Bodanszky, "Peptide Chemistry", 2nd rev ed., Springer- Verlag, Berlin, Germany, (1993) hereafter simply referred to as Bodanszky, the contents of which are hereby incorporated by reference.
  • suitable coupling agents are N 1 NT- dicyclohexylcarbodiimide, 1-hydroxybenzotriazole in the presence of N 1 N 1 - dicyclohexylcarbodiimide or N-ethyl-N 1 - [ (3dimethylamino) propyl] carbodiimide.
  • a practical and useful coupling agent is the commercially available (benzotriazol-1-yloxy) tris- (dimethylamino) phosphonium hexafluorophosphate, either by itself or in the present of 1-hydroxybenzotriazole or 4-DMAP.
  • Another practical and useful coupling agent is commercially available 2-(IH- benzotriazol-1-yl)-N, N, N 1 , N 1 - tetramethyluronium tetrafluoroborate. Still another practical and useful coupling agent is commercially available 0-(7-azabenzotrizol-1-yl)-N, N 1 N 1 , N 1 - tetramethyluronium hexafluorophosphate.
  • the coupling reaction is conducted in an inert solvent, e. g. dichloromethane, acetonitrile or dimethylformamide.
  • An excess of a tertiary amine e. g. diisopropylethylamine, N- methylmorpholine, N-methylpyrrolidine or 4-DMAP is added to maintain the reaction mixture at a pH of about 8.
  • the reaction temperature usually ranges between 0 °C and 50 °C and the reaction time usually ranges between 15 min and 24 h.
  • the functional groups of the constituent non-natural amino acids generally must be protected during the coupling reactions to avoid formation of undesired bonds.
  • the protecting groups that can be used are listed in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York (1981) and "The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1981), hereafter referred to simply as Greene, the disclosures of which are hereby incorporated by reference.
  • the alpha-carboxyl group of the C-terminal residue is usually protected as an ester that can be cleaved to give the carboxylic acid.
  • Protecting groups that can be used include 1) alkyl esters such as methyl, trimethylsilyl and t.butyl, 2) aralkyl esters such as benzyl and substituted benzyl, or 3) esters that can be cleaved by mild base or mild reductive means such as trichloroethyl and phenacyl esters.
  • the alpha-amino group of each amino acid to be coupled is typically be protected. Any protecting group known in the art can be used. Examples of such groups include: 1) acyl groups such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate groups such as benzyloxycarbonyl (Cbz or Z) and substituted bensyloxycarbonyls, and 9- fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate groups such as tertbutyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate groups such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl groups such as triphenylmethyl and benzyl; 6) trialkylsilyl
  • the alpha-amino protecting group is typically cleaved prior to the next coupling step.
  • Boc group the methods of choice are trifluoroacetic acid, neat or in dichloromethane, or HCI in dioxane or in ethyl acetate.
  • the resulting ammonium salt is then neutralized either prior to the coupling or in situ with basic solutions such as aqueous buffers, or tertiary amines in dichloromethane or acetonitrile or dimethylformamide.
  • the Fmoc group the reagents of choice are piperidine or substituted piperidine in dimethylformamide, but any secondary amine can be used.
  • the deprotection is carried out at a temperature between 0 0 C and room temperature usually 20-22 0 C.
  • any of the natural or non-natural amino acids having side chain functionalities will typically be protected during the preparation of the peptide using any of the above described groups.
  • Those skilled in the art will appreciate that the selection and use of appropriate protecting groups for these side chain functionalities depend upon the amino acid and presence of other protecting groups in the peptide. In the selection of such protecting groups it is desirable that the group is not removed during the deprotection and coupling of the alpha-amino group.
  • Boc when used as the alpha-amino protecting group, the following side chain protecting groups are suitable: p-toluenesulfonyl (tosyl) moieties can be used to protect the amino side chain of amino acids such as Lys and Arg; acetamidomethyl, benzyl (Bn), or tert- butylsulfonyl moities can be used to protect the sulfide containing side chain of cysteine; benzyl (Bn) ethers can be used to protect the hydroxy containing side chains of serine, threonine or hydroxyproline; and benzyl esters can be used to protect the carboxy containing side chains of aspartic acid and glutamic acid.
  • p-toluenesulfonyl (tosyl) moieties can be used to protect the amino side chain of amino acids such as Lys and Arg
  • Fmoc is chosen for the alpha-amine protection
  • usually tert. butyl based protecting groups are acceptable.
  • Boc can be used for lysine and arginine, tert.butyl ether for serine, threonine and hydroxyproline, and tert-butyl ester for aspartic acid and glutamic acid.
  • Triphenylmethyl (Trityl) moiety can be used to protect the sulfide containing side chain of cysteine.
  • the P1 building block may be elongated with the P2 amino acid (or the ready formed P3-P2 intermediate) while the P1 is in the furanone form.
  • elongation with P2/P3 may take place on a furanol which is subsequently oxidised by Dess Martin chemistry in an organic solvent such as DCM.
  • Scheme 1 depicts that a suitable aldehyde 1 , such as cyclopentylaldehyde, can be derivatised into the silyl enol ether 2 using, for example, N-Methyl-N-trimethylsilylacetamide in DMF at room temperature. 2 can then act as a suitable precursor for a number of variations of X.
  • a suitable alkyl halide in the presence of fluoride anion, X can represent suitable alkyl groups.
  • suitable electrophilic fluorinating agents such as SelectfluorTM in a solvent such as DMF or acetonitrile, X can represent fluorine.
  • the conversion of 4 into the chiral amino acid 5 can be achieved with a chiral catalyst, such as [EtDuPHOS-Rh (COD)]+ in a solvent such as methanol under hydrogen pressure of between 1 and 5 bar.
  • a chiral catalyst such as [EtDuPHOS-Rh (COD)]+ in a solvent such as methanol under hydrogen pressure of between 1 and 5 bar.
  • 4 can be converted into the achiral amino acid 6 using a non-chiral catalyst such as that based on a palladium or rhodium-containing species e.g. Wilkinson's catalyst. Resolution of the amino acid will then follow one of many well documented methods, such as enzymatic hydrolysis of the ester, or separation of the racemates by chiral-HPLC.
  • Scheme 2 depicts that the preparation of 3 can also be achieved from direct reaction of a suitable lithium enolate with a suitable electrophilic reagent, such as an alkyl halide. Therefore, treatment of 7 with LDA in THF at -78 0 C followed by quenching of the resultant anion affords 8.
  • the ester group of 8 can be reduced, for example with lithium aluminium hydride to the corresponding alcohol 9.
  • Compound 3 is then prepared by oxidation of the alcohol with a suitable oxidant, such as pyridinium chlorochromate in DCM at room temperature.
  • Scheme 3 shows an alternative synthesis to prepare the C5 alkylene amino acid 16 in homochiral form.
  • Geraniol 10 is converted to the phosphate 11 with diethyl chlorophosphonate and then reacted with a homochiral zinc/copper couple of alanine 12.
  • Compound 13 is obtained from Sn2 reaction of the zinc/copper couple, whilst compound 14 is obtained from the alternative Sn2' mechanism.
  • Ring-closing metathesis reaction of 14 using for example Grubb's catalyst gives the methylcyclopentene derivative 15. Atmospheric pressure hydrogenation of the methylcyclopentene double bond can be achieved with a palladium catalyst in a solvent like methanol to afford the amino acid 16.
  • Enantioselectivity is in excess of 95%.
  • An alternative for substitution at R 2 involves the method shown in Scheme 5.
  • An appropriate cycloalkanone is treated with a zinc/copper couple of alpha-bromomethylacetate in a solvent such as THF at reflux.
  • the hydroxyl group in 24 can be left underivatised and the ester can be reduced to the primary alcohol with a reducing agent such as lithium aluminium hydride.
  • a compound such as 25 can be treated in the same way as compound 20 to afford the desired substituted cycloalkyl alanine.
  • the hydroxyl group in 24 can be derivatised to form the alkyloxy at R 2 , using a reagent such as sodium hydride and an alkyl halide in THF at room temperature or reflux. The same procedure for the synthesis of the achiral amino acid would then apply.
  • a suitable dibromoalkane can be reacted with diethylmalonate with, for example, sodium ethoxide in ethanol to afford the diester 26.
  • This can be converted into the ester/aldehyde 27 in a number of ways, for example with diisobutylaluminium hydride in dichloromethane at -78 deg C.
  • This aldehyde serves as a useful precursor for a number of derivatives.
  • the methylene alcohol 28 can be prepared by reduction of the aldehyde with sodium borohydride in a solvent such as ethanol; the alkyloxy methylene 29 is produced by alkylation of the methylene alcohol 28 with an alkyl halide and a suitable base such as sodium hydride; the methylene fluoride 30 is produced by fluorination of 28 with a suitable fluorinating agent such as DAST or Deoxyfluor.
  • a suitable fluorinating agent such as DAST or Deoxyfluor.
  • cyclohexylalanines can be prepared as in Scheme 7. Diels-Alder reaction of 1,3-butadiene with appropriately substituted dieneophiles can afford the cyclohexene derivative 32. Reduction of the cyclohexene double bond and manipulation of the ester moiety to the aldehyde 33, as shown in the scheme, provides the precursor to the substituted cyclohexyl alanine amino acids. These final steps can be achieved using the chemistry outlined in Scheme 8.
  • Scheme 8 depicts the synthesis of a methylcyclopentylalanine building block.
  • Commercially available methyl cyclopentane carboxylate 34 is methylated with LDA and iodomethane (i, BuLi, diisopropylamine, MeI) to give 35.
  • Hydrolysis of the ester with LiOH followed by treatment with oxalyl chloride (ii, LiOH, oxalylchloride) gives acid chloride 36.
  • Wolff rearrangement with diazomethane (iii, CH 2 N 2 , Et 3 N) and silver benzoate (iv, silver benzoate, Et 3 N, MeOH) gives the ester 38.
  • a suitable base such as triethylamine or dimethylaminopyridine.
  • the N- protected P1-P2 intermediate is treated with 4M HCI in dioxan.
  • An optionally substituted R 3 - SO 2 CI is added with Et 3 N and a catalytic amount of DMAP.
  • the isocyanate, or equivalent reactive intermediate can be formed by reaction of the amino group of the P2-amino acid with phosgene, or with dinitrophenylcarbonate in the presence of a suitable base, e.g. triethylamine.
  • a suitable base e.g. triethylamine.
  • they can be formed by reaction of the amino group of the P2 amino acid with a suitable chloroformate, e.g. benzylchloroformate.
  • the R3 amine is reacted with the isocyanate of the P2-P1 intermediate under similar conditions.
  • the time, temperature and sequence of addition used depends on the reactivity of the individual reagents.
  • a special case of a urea derivative are compounds wherein R 3 represents an unsaturated ring such as morpholine, piperazine or piperidine which is N-bonded to E as carbonyl.
  • R 3 represents an unsaturated ring such as morpholine, piperazine or piperidine which is N-bonded to E as carbonyl.
  • Such compounds are readily prepared, for example by treating the N-protected P2-P1 intermediate with 4M HCI/dioxane, adding the R3-chloride, for example morpholinyl carbonyl chloride, together with TEA in DCM.
  • R 10 is an hydroxyl, ether, ester or ketone
  • Oxalyl chloride (89 mmol) was added to a solution of 1 -methyl-cyclopentanecarboxylic acid (74 mmol) in DCM at O 0 C. This was followed by a few drops of DMF. The mixture was stirred overnight then the solvents were removed in vacuo to give a pale brown semi-solid which was dissolved 1 :1 THF:MeCN. Triethylamine (96 mmol) was added followed by diazomethane (222 mmol) in diethyl ether. The mixture was stirred overnight then the solvents were removed in vacuo. The residue was dissolved in TBME. The organics were washed (water then NaHCO 3 (sat. aq.)), dried (MgSO 4 ) then concentrated in vacuo to give a yellow oil which was used with no further purification (66.2 mmol, 90%).
  • LiAIH 4 (99.3 mmol) was added portionwise to a solution of (i-methylcyclopentyl)acetic acid methyl ester (66.2 mmol) in THF at O 0 C. The mixture was allowed to warm to room temperature and stirring was continued for 1.5 hours. Ether was added and the mixture cooled to O 0 C. 3.8 ml of water was added followed by 3.8 ml of 15% aqueous NaOH solution then 11.4 ml of water. The mixture was warmed to room temperature and stirred for 15 minutes. Anhydrous MgSO 4 was added and stirring was continued for a further 15 minutes. The mixture was filtered and the filtrate was concentrated in vacuo. Distillation (76 0 C @ 17 mmHg) gave the product as a clear oil (40.7 mmol, 62%).
  • Furan-3-carboxylic acid [(1 S)-((2S)-ethyl-4-oxo-tetrahydrofuran-(3S)-ylcarbamoyl)-2-(1- methyl-cyclopentyl)-ethyl]-amide
  • Electrospray ionisation eluting with acetonitrile / ammonium formate buffer.
  • Electrospray ionisation eluting with acetonitrile / ammonium formate buffer.
  • Triethylamine (26.5 mmol, 3.69 ml, 5.3 eq) was then added (keeping the temperature less than -7O 0 C) and the mixture was then stirred for 1 hour during which time it was allowed to warm to O 0 C. The mixture was quenched with NH 4 CI solution : water (1 :1). The organics were isolated, dried (MgSO 4 ) then concentrated to give the crude aldehyde.
  • Cyclohexane-1,1-dicarboxylic acid diethyl ester,1 was prepared in accordance with JACS 43, 1921, 1368 from diethyl malonate and 1 ,5-dibromopentane.
  • Cyclohexane-1,1-dicarboxylic acid diethyl ester, 1 was taken up in anhydrous THF under nitrogen at room temperature. This was treated with LiAI(O 1 Bu) 3 H (2.5eq) portionwise before refluxing overnight. The reaction mixture was cooled in an ice-bath and treated carefully with 10% KHSO 4 (aq) and allowed to stir for 10 minutes. The resulting precipitate was removed by vacuum filtration and the mother liquors were partitioned between EtOAc and brine. The organic phases were combined, dried over MgS04, filtered and concentrated in vacuo to give a mobile oil.
  • reaction mixture was poured onto ice and the organics were washed with 1M HCI (aq), saturated NaHCO 3 (aq) and brine, then dried over MgSO4, filtered and concentrated in vacuo, to give trifluoro-methanesulfonic acid-1-fluoromethyl-cyclohexylmethyl ester, 5, as an amber oil which was used immediately without further purification in the next step.
  • N-(Diphenylmethylene)glycine ethyl ester was dissolved in DMF and under a nitrogen atmosphere was cooled to O 0 C. This was treated with KO'Bu (1.1eq) and stirred for 20 minutes. To this solution was added trifluoro-methanesulfonic acid-1-fluoromethyl-cyclohexylmethyl ester, 5 dropwise. The reaction mixture was stirred at room temperature under nitrogen overnight then poured into a 1 :1 mixture of diethyl ether : NH 4 CI (aq). The phases were separated and the aqueous phase was washed twice with diethyl ether.
  • Electrospray ionisation eluting with acetonitrile / ammonium formate buffer.
  • Boc protecting group Although the example has been illustrated with a Boc protecting group it will be apparent that other conventional N protecting groups such as those described above in Greene will be amenable to this route and/or the Boc group can be removed and replaced by another conventional N-protecting group such as Fmoc or CBz using conventional protecting group manipulation.
  • Furan-3-carboxylic acid [(1 ft,S)-((2S)-ethyl-4-oxo-tetrahydro-furan-(3S)-ylcarbamoyl)-2-(1 ⁇ methyl-cycloheptyl)-ethyl]-amide Data is given for a mixture of diastereoisomers (1 :1 ratio).
  • Morpholine-4-carboxylic acid [(1 f?,S)-((2S)-ethyl-4-oxo-tetrahydro-furan-(3S)-ylcarbamoyl)- 2-(1-methyl-cycloheptyl)-ethyl]-amide
  • Furan-3-carboxylic acid [1 -(R,S)-(2-(S)-ethyl-4-oxo-tetrahydro-furan-3-(S)-ylcarbamoyl)-2- (1-fluoro-cyclopentyl)-ethyl]-amide
  • step e) The title compound is prepared from the material of step c) above using the same procedure as Example 10, step e).
  • Immobilisation of a P1 buliding block, such as those prepared in WO05/82876, onto a resin via Murphy's linker proceeds as described in Scheme 7 of WO00/69855 and its accompanying text.
  • the Fmoc-protected 5-substituted furan-4-amine is de-protected, extended with the P2 building block of the invention, such as those described at examples 1 and 5, using conventional peptide activation and coupling reagents such as HOBt/HBTU/DMF, as described in WO00/69855.
  • the resin was suspended in a 5% solution of hydrazine in DMF for 1 h. The mixture was filtered, and the resin washed with DMF. The hydrazine treatment and DMF wash was then repeated.
  • the resin was suspended in a 20% solution of piperidine in DMF for 0.5h. The mixture was filtered, and the resin washed with DMF. The piperidine treatment and DMF wash was then repeated.
  • the resin was suspended in a 20% solution of piperidine in DMF for 0.5h. The mixture was filtered, and the resin washed with DMF. The piperidine treatment and DMF wash was then repeated.
  • the resin was suspended in a solution of benzyl chloroformate and ⁇ /-methyl morpholine in DMF, filtered and the residue washed with 1 :1 water: DMF, DMF, THF, DCM and MTBE.
  • the resin was suspended in a 20% solution of piperidine in DMF for 0.5h. The mixture was filtered, and the resin washed with DMF. The piperidine treatment and DMF wash was then repeated.
  • the resin was suspended in a solution of benzylaldehyde in DMF, and a solution of dibutyltin dichloride in THF was added. After 10 minutes, phenyl silane was added and the mixture was shaken overnight. The mixture was filtered and the residue washed with DMF, THF, DCM and MTBE.
  • methods A-F have been illustrated with methyl or ethyl as R 1 , and 1-methyl- cyclopentyl-L-Ala as P2, it will be apparent that corresponding methodology, in conjunction with conventional protection of hydroxyl groups, will be applicable to other P1 and P2 building blocks. Similarly, methods A-F are not limited to the specified classes of P3, but are widely applicable to other species of R 3 , optionally in conjunction with conventional protection of amine, hydroxyl and carboxyl groups.
  • BBr 3 (20 mmol, 5g, 10 eq.) was added to a solution of 4-methoxy-2-methyl benzoic acid (2 mmol, 0.332g) in DCM (20 ml) and the mixture was stirred under argon until HPLC indicated no starting material remained. HCI (0.1 M, 20 ml) was added and the mixture was filtered. The aqueous layer was evaporated then dissolved in methanol. The solvent was evaporated. The dissolution/evaporation protocol was repeated a further 3 times and gave the pure product as a yellow solid (0.24g, 80%).
  • 3-Fluorosalicylaldehyde (117 mg, 0.83 mmol) was dissolved in dry ethyl acetate (15 ml) and Pd/C (12mg, 10 % w/w) was added. The solution was vigorously stirred at room temperature under a hydrogen atmosphere for 6 hrs. Filtration through celite and removal of the ethyl acetate under vacuo afforded the product (70 mg, 67 %) without need for further purification.
  • a buffer solution at pH 5.5 was prepared by the addition of acetic acid to a 1M aqueous sodium acetate solution.
  • Methyl 3-amino-4-hydroxybenzoate (254mg, 1.5 mmol) was dissolved in a mixture of buffer (1ml) and methanol (2ml).
  • Formaldehyde solution (37% by weight in water; 0.75ml, lOmmol) was added, the mixture stirred for 15 minutes, and then sodium cyanoborohydride (283mg, 4.5mmol) was added portionwise. The reaction mixture was stirred for an additional 0.5h and then concentrated. The residual oil was partitioned between water and ethyl acetate.
  • Methanesulfonyl chloride (615 uL) was added to a solution of 4-Amino-3-methoxy-benzoic acid methyl ester (1 g) in dichloromethane (20 ml.) and pyridine (1.5 ml.) and a catalytic amount of DMAP. After 1-16 hrs the mixture was concentrated to near dryness and the product crystallized from added ethanol. This product was hydrolyzed in 2.5 M LiOH (5 ml_), THF (14 ml_), MeOH (7 ml.) in a microwave oven at 110 deg C for 30 min. After cooling, the solution was acidified with aq. HCI and extracted with ethyl acetate, dried with Na 2 SO 4 and concentrated to dryness.
  • the remaining powder was used for coupling to the resin bound P1-P2 building block (described above).
  • the title compound was obtained when cleaved from the resin with 95% TFA in water. After concentration the product was purified on HPLC and freeze dried. The product was characterized by HPLC-MS and NMR.
  • Example 1533, 15.4, 15.6, 15.7, 15.8, 15.9, 15.15, 15.16, 15.17, 15.18, 15.19, 15.22, 15.24, 15.27, 15.28, 15.32, 15.33, 15.36, 15.40, 15.51 , 15.54, 15.64, 15.70 and 15.71 the same procedure as in Example 15.1 was followed.
  • 5-Amino-furan-2-carboxylic acid methyl ester (0.42 g, 3.0 mmol) were mixed together with methyl vinyl ketone (10 ml.) in benzene and heated at reflux for 1 h. Evaporation of solvents were followed by flash chromatography using DCM / MeOH (95:5) as eluent to yield 44% (278 mg. 1.31 mmol) of 5-Acetyl-4-amino-1-hydroxy-cyclohexa-2,4-dienecarboxylic acid methyl ester. This compound were mixed with BF 3 OEt 2 ((284 mg, 2.0 mmol) in benzene (15 ml.) and refluxed for 0.5 h.
  • Trifluoromethane sulfonic anhydride 38OuL was added to polymer supported tiriphenylphosphine oxide (1g) in dichloromethane (15mL). After 1 hrs the mixture was cooled to 0 deg C and a solution of pyridine 3-sulfonic acid (360 mg) as pyridine salt in DCM (4mL) was added. After 30 min. 4-Methanesulfonylamino-benzoic acid methyl ester (318 mg) in dichloromethane (4mL) was added. The mixture was shaken at 25 deg C for 16 hrs. The resin was filtered off and the filtrate concentrated to dryness. The crude was purified by silica column chromatography. Subsequent synthesis was done according to the procedure in Example 1.
  • Example 15.23, 15.35, and 15.52 For the synthesis of Examples 15.23, 15.35, and 15.52 the same procedure as in Example 15.20 was followed.
  • Example 15.29 was synthesized via solid phase synthesis methodology. First coupling of the 4- Amino-benzoic acid to the P1-P2 building block was done followed by washing as described in WO00/69055. Secondly 4-Cyano-benzenesulfonyl chloride (53.2 mg, 0.26 mmol) and a catalytic amount DMAP dissolved in pyridine (2 ml.) and DCM (4 ml.) was added to the P1-P2 building block (220 mg, 0.053 mmol). The reaction was left on agitation at room temperature over weekend. Cleavage from resin was done by addition of 95% TFA (aq, 6 ml.) and agitation for 0.5 h. Toluene (3 ml.) was added after filtration from resin, followed by evaporation.
  • TFA 95% TFA
  • Example 15.38 was synthesized as described in Example 15.1 by successive coupling of the P3 substituent to the P3 building block, hydrolysis of the ester and coupling to the P1-P2 building block. After cleavage from P1 -P2 resin, reduction of nitro group was done by dissolving 4-(4- Nitro-benzenesulfonylamino)-N-[1-(2-ethyl-4-oxo-tetrahydro-furan-3-ylcarbamoyl)-2-(1-methyl- cyclopentyl)-ethyl]-benzamide (13.9 mg, 23.4 ⁇ mol) in MeOH (3ml_) and degassing the solution with N 2 gas. A catalytic amount of palladium on carbon was then added to the reaction solution and a H 2 atmosphere was connected. After 2 hrs, filtration through celite was done, with MeOH as eluent, to yield 11.8 mg (91%) of product after concentration.
  • ⁇ -Fornnyl-thiophene ⁇ -carboxylic acid was coupled to the resin as described in example 1.
  • the resin was swollen in DCM-trimethylortoformate 1 :1 and 4 equiv. of methoxyethylamine was added. After 4 hrs of agitation the resin was washed with DCM and MeOH (2X) and the resin was dried. To this resin in DCM-MeOH-HOAc 2:2:1 borane-pyridine complex was added. After 16 hrs of agitation the resin was washed and cleaved and purified as described in Example 15.1.
  • the assay uses baculovirus-expressed human cathepsin S and the boc-Val-Leu-Lys-AMC fluorescent substrate available from Bachem in a 384 well plate format, in which 7 test compounds can be tested in parallel with a positive control comprising a known cathepsin S inhibitor comparator.
  • 280 ⁇ l/well of 12.5% DMSO are added to rows B - H of two columns of a 96 deep well polypropylene plate. 70 ⁇ l/well of substrate is added to row A. 2 x 250 ⁇ l/well of assay buffer (10OmM Na phosphate, 10OmM NaCI, pH 6.5) is added to row A, mixed, and double diluted down the plate to row H.
  • the first test compound prepared in DMSO is added to column 1 of the top row, typically at a volume to provide between 10 and 30 times the initially determined rough Kj.
  • the rough Ki is calculated from a preliminary run in which 10 ⁇ l/well of 1 mM boc-VLK-AMC (1/10 dilution of 10 rtiM stock in DMSO diluted into assay buffer) is dispensed to rows B to H and 20 ⁇ l/well to row A of a 96 well Microfluor TM plate. 2 ⁇ l of each 1OmM test compound is added to a separate well on row A, columns 1-10.
  • the second test compound is added to column 6 of the top row, the third to column 1 of the second row etc. Add 1 ⁇ l of comparator to column 6 of the bottom row. Mix column 1 and double dilute to column 5. Mix column 6 and double dilute to column 10.
  • ⁇ -channel multistepping pipette set to 5 x 10 ⁇ l, distribute 10 ⁇ l/well of substrate to the 384 well assay plate. Distribute the first column of the substrate dilution plate to all columns of the assay plate starting at row A. The tip spacing of the multichannel pipette will correctly skip alternate rows. Distribute the second column to all columns starting at row B.
  • a distributor such as a Multidrop 384, add 30 ⁇ l/well to all wells of the assay plate and read in fluorescent spectrophotomoter such as an Ascent.
  • Fluorescent readings (excitation and emission wavelengths 390nm and 460nm respectively, set using bandpass filters) reflecting the extent of enzyme cleavage of the fluorescent substrate, notwithstanding the inhibitor, are linear rate fitted for each well.
  • Cathepsin K Ki The procedure of Biological Example 1 with the following amendments is used for the determination of Ki for cathepsin K.
  • the enzyme is E coli expressed human cathepsin K.
  • the substrate is H-D-Ala-Leu-Lys-AMC from Bachem.
  • the assay buffer is 100 rtiM Na phosphate, 1 mM EDTA, 0.1% PEG 4000, pH 6.5.
  • the DMSO stock (see substrate dilutions) is diluted to 10% in assay buffer .
  • 56 ul of substrate is added to row A and 2 x 256 ul of buffer is added to row A.
  • the final cathepsin K concentration is 0.5 nM.
  • the majority of compounds illustrated above provide selectivities over cathepsin K of at least 10-100 fold.
  • the enzyme is commercially available human cathepsin L (for example Calbiochem).
  • the substrate is H-D-Val-Leu-Lys-AMC available from Bahcem.
  • the assay buffer is 10OmM sodium acetate 1mM EDTA, pH5.5)
  • the DMSO stock (1OmM in 100%DMSO) is diluted to 10% in assay buffer.
  • the majority of the compounds illustrated above provide selectivity over cathepsin L of at least 10-100 fold.
  • This example measures transport of inhibitors through the cells of the human gastroenteric canal.
  • the assay uses the well known Caco-2 cells with a passage number between 40 and 60.
  • the basolateral and the apical wells will contain 1.5 ml. and 0.4 ml. transport buffer (TB), respectively, and the standard concentration of the tested substances is 10 ⁇ M. Furthermore all test solutions and buffers will contain 1% DMSO. Prior to the experiment the transport plates are pre-coated with culture medium containing 10% serum for 30 minutes to avoid nonspecific binding to plastic material. After 21 to 28 days in culture on filter supports the cells are ready for permeability experiments.
  • TB transport buffer
  • Transport plate no 1 comprises 3 rows of 4 wells each. Row 1 is denoted Wash, row 2 "30 minutes” and row 3 "60 minutes”. Transport plate no 2 comprises 3 rows of 4 wells, one denoted row 4 "90 minutes”, row 5 "120 minutes and the remaining row unassigned.
  • the culture medium from the apical wells is removed and the inserts are transferred to a wash row (No. 1) in a transport plate (plate no.1) out of 2 plates without inserts, which have already been prepared with 1.5 ml. transport buffer (HBSS, 25 mM HEPES, pH 7.4) in rows 1 to 5.
  • transport buffer HBSS, 25 mM HEPES, pH 7.4
  • the TB in basolateral well also contains 1% Bovine Serum Albumin.
  • TEER Transepithelial electrical resistance value
  • the transport buffer (TB, pH 6.5) is removed from the apical side and the insert is transferred to the 30 minutes row (No. 2) and fresh 425 ⁇ l_ TB (pH 6.5), including the test substance is added to the apical (donor) well.
  • the plates are incubated in a polymix shaker at 37 0 C with a low shaking velocity of approximately 150 to 300 rpm.
  • 25 ⁇ L samples will be taken from the apical solution after -2 minutes and at the end of the experiment. These samples represent donor samples from the start and the end of the experiment.
  • 300 ⁇ L will be taken from the basolateral (receiver) wells at each scheduled time point and the post value of TEER is measured at the end the experiment.
  • acetonitrile will be added to a final concentration of 50% in the samples.
  • the collected samples will be stored at -2O 0 C until analysis by HPLC or LC-MS.
  • Basolateral to apical transport Generally every compound will be tested in 2-4 wells. The basolateral and the apical wells will contain 1.55 mL and 0.4 mL TB, respectively, and the standard concentration of the tested substances is 10 ⁇ M. Furthermore all test solutions and buffers will contain 1% DMSO. Prior to the experiment the transport plates are precoated with culture medium containing 10% serum for 30 minutes to avoid nonspecific binding to plastic material.
  • the transport plate comprises 3 rows of 4 wells. Row 1 is denoted “wash” and row 3 is the “experimental row”.
  • the transport plate has previously been prepared with 1.5 mL TB (pH 7.4) in wash row No. 1 and with 1.55 mL TB (pH 7.4), including the test substance, in experimental row No. 3 (donor side).
  • transport buffer HBSS, 25 rtiM MES, pH 6.5
  • HBSS HBSS
  • 25 rtiM MES pH 6.5
  • TEER value is measured in each well by an EVOM chop stick instrument.
  • the transport buffer (TB, pH 6.5) is removed from the apical side and the insert is transferred to row 3 and 400 ⁇ L fresh TB, pH 6.5 is added to the inserts. After 30 minutes 250 ⁇ L is withdrawn from the apical (receiver) well and replaced by fresh transport buffer. Thereafter 250 ⁇ L samples will be withdrawn and replaced by fresh transport buffer every 30 minutes until the end of the experiment at 120 minutes, and finally a post value of TEER is measured at the end of the experiment. A 25 ⁇ L samples will be taken from the basolateral (donor) compartment after ⁇ 2 minutes and at the end of the experiment. These samples represent donor samples from the start and the end of the experiment.
  • acetonitrile will be added to a final concentration of 50% in the samples.
  • the collected samples will be stored at -2O 0 C until analysis by HPLC or LC-MS.
  • FA cum Determination of the cumulative fraction absorbed, FA cum , versus time.
  • FA cum is calculated from: FA - Y ⁇ M. rM cum ⁇ L-I r
  • k is the transport rate (mirr ' ' ) defined as the slope obtained by linear regression of cumulative fraction absorbed (FA cum ) as a function of time (min)
  • VR is the volume in the receiver chamber (ml_)
  • A is the area of the filter (cm 2 ).
  • This example describes procedures for assessing potency of cathepsin S inhibitors on inhibition of in vitro T cell activation by determining concentration of the compound required for reducing 50% of the IL-2 secretion in T cells stimulated with compound-treated antigen presenting cells in an antigen presentation assay using the 19.3 cells and the 9001 cells as the effector cells and the antigen presenting cells, respectively.
  • 19.3 cells are murine T cell hybridomas recognizing type Il collagen (260-272) in the context of HLA-DR1
  • 9001 is an EBV-transformed human B cell line expressing homozygous DR1 molecule.
  • the 9001 cells will be pre-treated with varying concentration of the compounds for 1 hour and then incubated with the T cells in the presence of collagen at a final concentration of 0.1 mg/ml.
  • the cultures will be incubated overnight at 37°C with 5% CO 2 and amount of IL-2 in the supernatant determined with ELISA.
  • the IC 50 -IL-2 values representing the concentration of compounds at which secretion of IL-2 from the T cells is reduced by 50% will be determined by regression analysis
  • MHC class Il molecules bind peptides generated by degradation of endocytosed antigens and display them as MHC class ll-peptide complexes at the cell surface for recognition by CD4+ T cells.
  • MHC class Il molecules are assembled with the assistance of invariant chain (Ii) in the endoplasmic reticulum (ER) and transported to an endocytic compartment where Ii undergoes rapid degradation by endosomal and lysosomal proteases.
  • Ii invariant chain
  • ER endoplasmic reticulum
  • a peptide fragment of Ii, CLIP class ll-associated Invariant chain Peptides
  • cathepsin S In dendritic cells and B cells, cathepsin S is required for complete invariant chain processing and CLIP generation. Inactivating cathepsin S with inhibitors will impair MHC class Il peptide loading and formation of stable MHC/peptide complexes leading to reduced antigen presentation and T cell activation.
  • an antigen presentation assay uses a collagen specific,HLA-DR1 restricted mouse T cell hybridoma (19.3) as effector cells, human EBV-transformed B cells (9001) as antigen presenting cells (APC), and mlL-2 ELISA as the read-out system.
  • Inhibition of Cathepsin S with specific inhibitors will impair the processing and presentation of collagen in APCs which in turn reduces the activation of the T cells.
  • the extent of inhibition on T cells is measured by the degree of reduction in IL-2 secretion.
  • IC 50 -IL-2 represents the concentration of compounds at which secretion of IL-2 from the T cells is reduced by 50% in the antigen presentation assay.
  • Cathepsin S inhibitors Compounds will be dissolved in DMSO to a final concentration of 10 nriM, aliquotted, and stored at -80 C until used.
  • DMEM medium Invitrogen, cat #11995-065
  • fetal bovine serum Hyclone, cat #SH30070.03
  • penicillin 100 ug/ml streptomycin
  • 2 mM L-glutamine Invitrogen, cat #10378-016
  • T cell 19.3, murine DR1 transgenic T cell hybridomas, DR1 restricted, Type Il collagen 260-272 specific
  • Antigen presentation cells (APCs): 9001 , EBV-transformed human B cells expressing homozygous DR1
  • Type Il collagen from chicken sternal cartilage (Sigma, cat. # C-9301) will be dissolved in PBS at 1 mg/ml and stored in aliquots at -80 C.
  • Tissue culture incubator (Forma Scientific, model. #3120) Sorvall centrifuge (Sorvall RC-3B) Plate washer Plate-reader (Tecan, Spectra shell, cat. #20-074)
  • Two-fold serial dilutions of the compounds, starting at 40OuM in AIMV medium, will be transferred to a 96-well round-bottom microtiter plate at a volume of 50ul/well.
  • Antigen-presenting cells will be washed and resuspended in AIMV medium to a density of 0.8x10 6 /ml, and then added to the plates at a volume of 50ul/well, giving the number of cells per well as 40,000.
  • the APCs will be pretreated with compounds for 1 hour at 37C with 5% CO 2 . 4.
  • the T cells will be washed and resuspended in AIMV to a density of 0.8x10 6 /ml.
  • the antigen will be diluted to a 4X concentration in AIMV and mixed 1 to 1 with
  • T cells/antigen mixture will then be added to the assay plates at a volume
  • the plates will be incubated overnight at 37C with 5% CO 2 .
  • Mouse IL-2 ELISA kits will be purchased from Pharmingen (Mouse IL-2 OptEIA set, #2614KI). The ELISA will be performed per manufacturer's instruction.
  • Anti-mlL-2 antibodies will be diluted in carbonate buffer to a final concentration of 2 ug/ml, transferred to an ELISA plate (Costar) at 100 u I/well and then incubated overnight at 4 degreesC.
  • the ELISA plates will be washed 4 times with PBS/0.5% FBS containing 0.05% Tween 20 (wash buffer).
  • the plates will be blocked with the blocking buffer, 10% FBS (fetal bovine serum, Hyclone) for 2 hrs at room temperature (RT) and then washed 4 times with wash buffer.
  • FBS fetal bovine serum, Hyclone
  • the plate will be incubated for 1 hr at RT with a mixture of a biotinylated anti-mlL2 antibody and avidin-HRP prepared in blocking buffer.
  • the plates will be measured at 450 nm with an ELISA plate reader (Spectra, Tecan).
  • a set of purified recombinant mlL-2 with known concentration will be prepared from the stock solution (provided in the kit) with the blocking buffer and assayed in each plate to provide a standard curve for quantification of IL-2.
  • IC 50 represents the concentration of compound at which secretion of IL-2 from the T cells is reduced by 50%.
  • the absorbance at 450 nm from each well will be converted into amount of IL-2 (pg/ml) using the Winselect software (Tecan) based on the standard curve generated from in-plate standards of purified recombinant mlL-2. Means and standard deviations will be calculated from triplicates with Excel.
  • Percent Inhibition average of control wells - average of test wells x 100 average of control wells
  • a dose response curve will be generated by plotting the percent inhibition versus concentration of the compound and the IC 50 -IL-2 value will be calculated with regression analysis.
  • DR-1 transgenic T cell hybridoma has been prepared by E. Rosloniec, University of Tennessee.
  • T + APCs without antigen, without compound treatment, for background signal. We usually get negligible amounts of IL-2 form these wells, and usually don't perform background subtraction. T + APCs, with anti-CD3/CD28, with compounds, for toxicity associated with compounds.
  • T + APCs with antigen, with DMSO (comparable to those received compounds), for toxicity associated with DMSO and for calculation of percent of inhibition.
  • Metabolic stability is determined by commercially available human liver microsome assays, such as XEN 042, assayed in accordace with manufacturer's recommendations.

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Abstract

La présente invention décrit des composés de formule (I) où R1 est un groupement alkyle linéaire ou ramifié en C1-C4, éventuellement substitué par jusqu'à trois substituants sélectionnés parmi les halogènes et le groupement hydroxy ; R2 représente un atome d'halogène, un groupement hydroxy, un groupement méthyloxy, ou un groupement alkyle en C1-C2, ledit alkyle étant éventuellement substitué par jusqu'à trois atomes d'halogène, un groupement hydroxy ou un groupement méthyloxy ; D représente un groupement alkylène en C3-C7, délimitant un cycle cycloalkyle ; E représente un groupement -C(=O)-, -S(=O)m-, -NRdS(=O)m-, -NRaC(=O)- ou -OC(=O)-, R3 représente un groupement carbocyclique ou hétérocyclique éventuellement substitué, R10 représente H, ORc, SRc ou représente =O or (ORc)2 avec le gem H ; Ra est sélectionné de façon indépendante parmi H et et les groupements alkyle en d-C4. Lesdits composés peuvent être employés en tant qu'inhibiteurs de la cathepsine S et présentent donc une utilité pharmaceutique contre les troubles tels que les troubles auto-immuns et les douleurs chroniques.
PCT/GB2005/050243 2004-12-13 2005-12-13 Inhibiteurs de cathepsine s WO2006064286A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB0427169.8 2004-12-13
GB0427169A GB0427169D0 (en) 2004-12-13 2004-12-13 Cathepsin S inhibitors
GB0507628A GB0507628D0 (en) 2005-04-15 2005-04-15 Protease inhibitors
GB0507628.6 2005-04-15
GB0510304A GB0510304D0 (en) 2005-05-20 2005-05-20 Cathepsin S Inhibitors
GB0510304.9 2005-05-20

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007071358A1 (fr) * 2005-12-20 2007-06-28 Novartis Ag Dérivés d'acide nicotinique en tant que modulateurs des récepteurs métabotropiques du glutamate
WO2007144379A1 (fr) * 2006-06-13 2007-12-21 Medivir Ab Composés bicycliques utiles en tant qu'inhibiteurs de cathepsine s
WO2009127546A1 (fr) 2008-04-16 2009-10-22 F. Hoffmann-La Roche Ag Activateurs de pyrrolidinone glucokinase
WO2010070615A1 (fr) 2008-12-19 2010-06-24 Medivir Uk Ltd Inhibiteurs de cystéine protéase
WO2011009845A1 (fr) 2009-07-23 2011-01-27 F. Hoffmann-La Roche Ag Activateurs de la glucokinase à base de pyridine
WO2011157682A1 (fr) 2010-06-17 2011-12-22 F. Hoffmann-La Roche Ag 3 -oxo-3, 9 -dihydro- 1h-chroméno [2, 3 -c] pyrroles convenant comme activateurs de glucokinase
EP2719700A1 (fr) 2008-01-09 2014-04-16 Amura Therapeutics Limited Derives de tetrhydrofur(3,2-b)pyrrol-3-one comme inhibiteurs des proteases de cysteine
EP2752404A1 (fr) 2010-06-16 2014-07-09 Medivir UK Ltd Inhibiteurs de la cystéine protéase
WO2014142255A1 (fr) * 2013-03-14 2014-09-18 武田薬品工業株式会社 Composé hétérocyclique
CN104387265A (zh) * 2014-10-30 2015-03-04 盐城师范学院 一种4,5-二羟基-2-甲基苯甲酸的制备方法
US10053468B2 (en) 2013-07-03 2018-08-21 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10472376B2 (en) 2013-07-03 2019-11-12 Takeda Pharmaceutical Company Limited Amide compound
WO2020201572A1 (fr) 2019-04-05 2020-10-08 Université De Bretagne Occidentale Inhibiteurs du récepteur 2 activé par une protéase pour le traitement d'une neuropathie sensorielle induite par une intoxication neurotoxique marine

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WO2000069855A2 (fr) * 1999-05-18 2000-11-23 Medivir Uk Limited Derives furanones inhibiteurs de cathepsine s
WO2002057249A1 (fr) * 2001-01-17 2002-07-25 Amura Therapeutics Limited 2-carbonylaminocetones cycliques, inhibiteurs de la cruzipain et autres cysteine proteases
WO2003024924A1 (fr) * 2001-09-14 2003-03-27 Aventis Pharmaceuticals Inc. Nouveaux composes et nouvelles compositions utiles comme inhibiteurs de la cathepsine
WO2005082876A1 (fr) * 2004-03-01 2005-09-09 Medivir Uk Ltd Inhibiteurs de la cathepsine du furanone dipeptide substitue en c-5

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000069855A2 (fr) * 1999-05-18 2000-11-23 Medivir Uk Limited Derives furanones inhibiteurs de cathepsine s
WO2002057249A1 (fr) * 2001-01-17 2002-07-25 Amura Therapeutics Limited 2-carbonylaminocetones cycliques, inhibiteurs de la cruzipain et autres cysteine proteases
WO2003024924A1 (fr) * 2001-09-14 2003-03-27 Aventis Pharmaceuticals Inc. Nouveaux composes et nouvelles compositions utiles comme inhibiteurs de la cathepsine
WO2005082876A1 (fr) * 2004-03-01 2005-09-09 Medivir Uk Ltd Inhibiteurs de la cathepsine du furanone dipeptide substitue en c-5

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007071358A1 (fr) * 2005-12-20 2007-06-28 Novartis Ag Dérivés d'acide nicotinique en tant que modulateurs des récepteurs métabotropiques du glutamate
WO2007144379A1 (fr) * 2006-06-13 2007-12-21 Medivir Ab Composés bicycliques utiles en tant qu'inhibiteurs de cathepsine s
EP2719700A1 (fr) 2008-01-09 2014-04-16 Amura Therapeutics Limited Derives de tetrhydrofur(3,2-b)pyrrol-3-one comme inhibiteurs des proteases de cysteine
WO2009127546A1 (fr) 2008-04-16 2009-10-22 F. Hoffmann-La Roche Ag Activateurs de pyrrolidinone glucokinase
US8853281B2 (en) 2008-12-19 2014-10-07 Medivir Uk Ltd Cysteine protease inhibitors
WO2010070615A1 (fr) 2008-12-19 2010-06-24 Medivir Uk Ltd Inhibiteurs de cystéine protéase
WO2011009845A1 (fr) 2009-07-23 2011-01-27 F. Hoffmann-La Roche Ag Activateurs de la glucokinase à base de pyridine
EP2752404A1 (fr) 2010-06-16 2014-07-09 Medivir UK Ltd Inhibiteurs de la cystéine protéase
WO2011157682A1 (fr) 2010-06-17 2011-12-22 F. Hoffmann-La Roche Ag 3 -oxo-3, 9 -dihydro- 1h-chroméno [2, 3 -c] pyrroles convenant comme activateurs de glucokinase
WO2014142255A1 (fr) * 2013-03-14 2014-09-18 武田薬品工業株式会社 Composé hétérocyclique
JPWO2014142255A1 (ja) * 2013-03-14 2017-02-16 武田薬品工業株式会社 複素環化合物
US9834520B2 (en) 2013-03-14 2017-12-05 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10053468B2 (en) 2013-07-03 2018-08-21 Takeda Pharmaceutical Company Limited Heterocyclic compound
US10472376B2 (en) 2013-07-03 2019-11-12 Takeda Pharmaceutical Company Limited Amide compound
US11053262B2 (en) 2013-07-03 2021-07-06 Takeda Pharmaceutical Company Limited Heterocyclic amide compounds having RORyT inhibitory action
US11851449B2 (en) 2013-07-03 2023-12-26 Takeda Pharmaceutical Company Limited Heterocyclic amide compounds having an RORvt inhibitory action
CN104387265A (zh) * 2014-10-30 2015-03-04 盐城师范学院 一种4,5-二羟基-2-甲基苯甲酸的制备方法
WO2020201572A1 (fr) 2019-04-05 2020-10-08 Université De Bretagne Occidentale Inhibiteurs du récepteur 2 activé par une protéase pour le traitement d'une neuropathie sensorielle induite par une intoxication neurotoxique marine

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