WO2012168852A1 - Inhibiteurs de cystéine protéase - Google Patents

Inhibiteurs de cystéine protéase Download PDF

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Publication number
WO2012168852A1
WO2012168852A1 PCT/IB2012/052810 IB2012052810W WO2012168852A1 WO 2012168852 A1 WO2012168852 A1 WO 2012168852A1 IB 2012052810 W IB2012052810 W IB 2012052810W WO 2012168852 A1 WO2012168852 A1 WO 2012168852A1
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Prior art keywords
compound
compound according
added
cathepsin
methyl
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PCT/IB2012/052810
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English (en)
Inventor
Susana Ayesa
Daniel Jönsson
Pia Kahnberg
Urszula Grabowska
Ellen Hewitt
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Medivir Uk Ltd
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Publication of WO2012168852A1 publication Critical patent/WO2012168852A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings 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
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N

Definitions

  • This invention relates to inhibitors of cathepsin S, and their use in the treatment of disorders involving cathepsin S such as autoimmune disorders, 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,
  • Cathepsin S is a highly active cysteine protease belonging to the papain superfamily. Its primary structure is 57%, 41 % and 45% homologous with human cathepsin L and H and the plant cysteine protease 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 also produced by inflammatory cells, such as dendritic cells, B cells and macrophages. It is involved in the pathology of several conditions including atherosclerosis and a condition known as abdominal aortic aneurysm (AAA).
  • AAA abdominal aortic aneurysm
  • the extracellular modelling of the cells is a continuously ongoing process to repair damaged arterial wall, wherein cathepsin S plays a role of degrading the extracellular matrix proteins such as elastin and collagen that make up the arterial wall.
  • cathepsin S plays a role of degrading the extracellular matrix proteins such as elastin and collagen that make up the arterial wall.
  • the endothelial cells may malfunction, e.g. due to factors such as high levels of cholesterol, stress, overall health and genetics. This malfunction leads to the production and recruitment of inflammatory cells from the blood that penetrate the arterial wall to protect from damage and the inflammatory cells ultimately produce cathepsin S.
  • the imbalance in the remodelling may lead to more proteolytic degradation which in turn may lead to instability of plaque formed within the arterial wall. Too much plaque instability could result in plaque rupture and potentially thrombotic-related events.
  • the extracellular matrix of the abdominal aorta may be weekend due to excess degradation leading AAA.
  • inhibition of cathepsin S provides a means for treating atherosclerosis and AAA.
  • cathepsin S is implicated are asthma, chronic obstructive pulmonary disease, endometriosis and chronic pain.
  • R 1 is CrC 6 alkyl, CrC 6 haloalkyl or C 3 -C 6 cycloalkyl, wherein C 3 -C 6 cycloalkyl is optionally substituted with CF 3 , methyl, ethyl or one or two F;
  • R 2a and R 2b are independently selected from H, F and CH 3 0;
  • R 3 is F or CH 3 ;
  • R 2a and R 2b are both hydrogen.
  • one of R 2a and R 2b is H and the other is F or CH 3 0.
  • R and R are both F.
  • R 3 is F.
  • R 3 is CH 3 .
  • R 1 is CrC 6 alkyl.
  • R 1 is ethyl, isopropyl or tert. butyl.
  • R 1 is CrC 6 haloalkyl, such as chloroalkyi or fluoroalkyl.
  • R 1 is mono, di or tri fluoroCrC 6 alkyl, such as monofluoropropyl, difluoropropyl, trifluoropropyl or trifluorobutyl.
  • a preferred compound of the invention is the compound of formula lb:
  • the compounds of formula I or any subgroup of formula I are characterised by various advantageous pharmaceutical properties and exhibit at least one improved property in view of the compounds of the prior art.
  • the inhibitors of the present invention are superior in one or more of the following pharmacological related properties, i.e. potency, decreased cytotoxicity, improved pharmacokinetics, acceptable dosage and pill burden.
  • a further aspect of the invention comprises a method employing the compounds of formula I or any subgroup of formula I for the prophylaxis or treatment of diseases caused by aberrant expression or activation of cathepsin, i.e. diseases or conditions alleviated or modified by inhibition of cathepsin S, preferably without substantial concomitant inhibition of other members of the papain superfamily.
  • the invention concerns a method employing the compounds of formula I or any subgroup of formula I as specified herein, for the treatment of diseases caused by aberrant expression or activation of cathepsin, i.e. diseases or conditions alleviated or modified by inhibition of cathepsin S, preferably without substantial concomitant inhibition of other members of the papain superfamily.
  • a further aspect of the invention provides the use of the compounds of formula I or any subgroup of formula I for the prophylaxis or treatment of diseases caused by aberrant expression or activation of cathepsin, i.e. diseases or conditions alleviated or modified by inhibition of cathepsin S, preferably without substantial concomitant inhibition of other members of the papain superfamily.
  • the invention concerns the use of compounds of formula I or any subgroup of formula I as specified herein, for the treatmentdiseases caused by aberrant expression or activation of cathepsin, i.e. diseases or conditions alleviated or modified by inhibition of cathepsin S, preferably without substantial concomitant inhibition of other members of the papain superfamily
  • a further aspect of the invention provides the use of the compounds of formula I or any subgroup of formula I for the manufacture of a medicament for the prophylaxis or treatment of diseases caused by aberrant expression or activation of cathepsin S, i.e. diseases or conditions alleviated or modified by inhibition of cathepsin S, preferably without substantial concomitant inhibition of other members of the papain superfamily.
  • the invention concerns the use of compounds of formula I or any subgroup of formula I as specified herein, for the treatment manufacture of a medicament for the prophylaxis or treatment of diseases caused by aberrant expression or activation of cathepsin S, i.e. 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 for which the compounds of the invention may be useful include those enumerated in WO 97/40066, such as autoimmune diseases, allergies, such as asthma and hay fever, multiple sclerosis, rheumatoid arthritis and the like.
  • a further example is endometriasis, and especially chronic pain, as disclosed in WO03/20287.
  • Further examples are atherosclerosis, plaque instability and abdominal aortic aneurysm (AAA).
  • the invention further provides the use of the compounds of formula I or any subgroup of formula I in therapy and in the manufacture of a medicament for the treatment of diseases or conditions alleviated or moderated by inhibition of cathepsin S.
  • a further aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients, and optionally one or more other therapeutic agents.
  • 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 II MHC-complexes. This association occurs because the structures recognized by T cells, the cells that cause autoimmunity, are complexes comprised of class II MHC molecules and antigenic peptides.
  • Autoimmune disease can result when T cells react with the host's class II MHC molecules when complexed with peptides derived from the host's own gene products.
  • class II MHC/antigenic peptide complexes are inhibited from being formed, the autoimmune response is reduced or suppressed. Any autoimmune disease in which class II MHC/antigenic complexes play a role may be treated according to the methods of the present invention.
  • Such autoimmune diseases include, e.g. juvenile onset diabetes (insulin dependent), multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus
  • 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 II MHC/antigenic peptide complexes. If these class II MHC/antigenic peptide complexes are inhibited from being formed, the allergic response is reduced or suppressed. Any allergic response in which class II MHC/antigenic peptide complexes play a role may be treated according to the methods of the present invention.
  • 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 treatment is a therapeutic treatment.
  • 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 II 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 II MHC molecules presenting antigenic peptides on the surface of donor cells. To the extent that this response is dependent upon the formation of class II
  • 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.
  • a related aspect of the invention is directed to a method of treating a patient undergoing a therapy wherein the therapy causes an immune response, preferably a deleterious immune response, in the patient comprising administering to the patient a compound of Formula I or a pharmaceutically acceptable salt, n-oxide or hydrate thereof.
  • the immune response is mediated by MHC class II molecules.
  • the compound of this invention can be administered prior to, simultaneously, or after the therapy.
  • the therapy involves treatment with a biologic, such as a protein, preferably an antibody, more preferably a monoclonal antibody. More preferrably, the biologic is Remicade®, Refacto®, ReferonA®, Factor VIII, Factor VII,
  • the treatment involves use of heparin, low molecular weight heparin, procainamide or hydralazine.
  • Non-automimmune indications include allergic rhinitis, asthma, artherosclerosis, chronic obstructive pulmonary disease (COPD) and chronic pain.
  • 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 carboxylic 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
  • benzenesulphonate p-chlorobenzenesulphonate and p-toluenesulphonate
  • inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoric and sulphonic acids.
  • the compounds of the invention may in some cases be isolated as the hydrate. Hydrates are typically prepared by recrystallisation from an aqueous/organic solvent mixture using organic solvents such as dioxin, tetrahydrofuran or methanol. Hydrates can also be generated in situ by administration of the corresponding keton to a patient.
  • the N-oxides of compounds of the invention can be prepared by methods known to those of ordinary skill in the art.
  • N-oxides can be prepared by treating an unoxidized form of the compound of the invention with an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at a suitable inert organic solvent (e.g., a halogenated hydrocarbon such as dichloromethane) at
  • the N-oxides of the compounds of the invention can be prepared from the N-oxide of an appropriate starting material.
  • Compounds of the invention in unoxidized form can be prepared from N-oxides of the corresponding compounds of the invention by treating with a reducing agent (e.g., sulphur, sulphur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus dichloride, tribromide, or the like) in an suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or the like) at 0 to 80 °C.
  • a reducing agent e.g., sulphur, sulphur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus dichloride, tribromide, or the like
  • an inert organic solvent e.g., acetonitrile, ethanol, aqueous dioxane, or the like
  • isotopes that may be incorporated into the compounds of formula I or any subgroup of formula I, include but are not limited to isotopes of hydrogen, such as 2 H and 3 H (also denoted D for deuterium and T for tritium respectively), carbon, such as 11 C, 13 C and 14 C, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 31 P and 32 P, sulphur, such as 35 S, fluorine, such as 18 F, chlorine, such as 36 CI, bromine such as 75 Br, 76 Br, 77 Br and 82 Br, and iodine, such as 123 l, 124 l, 125 l and 131 l.
  • isotopes include but are not limited to isotopes of hydrogen, such as 2 H and 3 H (also denoted D for deuterium and T for tritium respectively), carbon, such as 11 C, 13 C and 14 C, nitrogen, such as 13 N and 15 N,
  • isotope included in an isotope-labelled compound will depend on the specific application of that compound. For example, for drug or substrate tissue distribution assays, compounds wherein a radioactive isotope such as 3 H or 14 C is incorporated will generally be most useful. For radio-imaging applications, for example positron emission tomography (PET) a positron emitting isotope such as 11 C, 18 F, 13 N or 15 0 will be useful.
  • PET positron emission tomography
  • a heavier isotope such as deuterium, i.e. 2 H, may provide greater metabolic stability to a compound of formula I or any subgroup of formula I, which may result in, for example, an increased in vivo half life of the compound or reduced dosage requirements.
  • 2 H isotope(s) are typically incorporated at position(s) disposed to metabolic liability.
  • suitable positions for incorporation of 2 H isotopes are e.g. as substituents to the 1 ,1 -cycloalkylene group, i.e. one or both of R 2a and R 2b is 2 H.
  • Isotopically labelled compounds of formula I or any subgroup of formula I can be prepared by processes analogous to those described in the Schemes and/or Examples herein below by using the appropriate isotopically labelled reagent or starting material instead of the corresponding non-isotopically labelled reagent or starting material, or by conventional techniques known to those skilled in the art.
  • radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable.
  • C m -C n alkyl used herein represents a straight or branched alkyl radical having the number of carbon atoms designated, e.g. CrC 4 alkyl means an alkyl radical having from 1 to 4 carbon atoms.
  • Preferred alkyl radicals for use in the present invention are CrC 4 alkyl and includes methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl and isobutyl. Methyl and t-butyl are typically preferred.
  • CrC 6 alkyl has a corresponding meaning, including also all straight and branched chain isomers of pentyl and hexyl.
  • C m -C n alkyl may be used on its own or in composite expressions such as C m -C n haloalkyl, C m -C n alkylcarbonyl, C m -C n alkylamine etc.
  • Me means methyl
  • MeO means methoxy
  • Et means ethyl
  • Ac means acetyl
  • C m -C n haloalkyl as used herein represents C m -C n alkyl as defined above, wherein at least one C atom is substituted with a halogen, preferably chloro or fluoro. Trifluoromethyl is typically preferred
  • C m -C n alkoxy represents a radical C m -C n alkyl-0 wherein C m -C n alkyl is as defined above.
  • Typical C m -C n alkoxy includes Ci-C 4 alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-butoxy and isobutoxy. Methoxy and isopropoxy are typically preferred.
  • CrC 6 alkoxy has a corresponding meaning, expanded to include all straight and branched chain isomers of pentoxy and hexoxy.
  • C m -C n haloalkoxy represents C m -C n alkoxy wherein at least one C-atom is substituted with one or more halogen atom(s), typically chloro or fluoro. In many cases trifluoromethyl is preferred. Among the C m -C n haloalkoxy Ci-C 4 haloalkoxy are preferred.
  • C 3 -C n Cycloalkyl as used herein represents to a cyclic monovalent alkyl radikal having the number of carbon atoms indicated, e.g. C 3 -C 6 cycloalkyl means a cyclic monovalent alkyl radical having from 3 to 6 carbon atoms. Preferred cycloalkyl radicals for use in the present invention are C 3 -C 4 alkyl i.e. cyclopropyl and cyclobutyl.
  • C 3 -CnCycloalkylenyl as used herein represents to a divalent cycloalkyl radikal having the number of carbon atoms indicated.
  • cycloalkylenyl radicals for use in the present invention are C 3 -C 4 alkylenyl i.e. cyclopropylenyl and cyclobutylenyl.
  • 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 1 , or amine functions such as a sulphonamide amine function.
  • Preferred pharmaceutically acceptable esters include those derived from Ci-C 6 carboxylic acids such as acetyl or pivaloyl or optionally substituted benzoic acid esters, preferably unsubstituted or substituted with substituents broadly as described for R 1a , typically 1 -3 halo (e.g.
  • F C C 4 alkyl (e.g. Me), C C 4 haloalkyl (e.g. CF 3 ) or C C 4 alkyloxy (e.g. MeO) groups.
  • Favoured sulphonamide prodrugs include aminoacyls derived from Ci-C 6 carboxylic acids such as acetyl or pivaloyl or optionally substituted benzoic acid esters, preferably unsubstituted or substituted with substituents broadly as described for variable R 1a , typically 1 -3 halo (e.g. F), Ci-C 4 alkyl (e.g. Me), Ci-C 4 haloalkyl (e.g. CF 3 ) or Ci-C 4 alkyloxy (e.g. MeO) groups.
  • stereoisomerically pure concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%.
  • enantiomerically pure and “diastereomerically pure” should be understood in a similar way, but then having regard to the enantiomeric excess, and the diastereomeric excess, respectively, of the mixture in question.
  • Compounds of the invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. While resolution of enantiomers can be carried out using covalent diasteromeric derivatives of compounds of Formula I, dissociable complexes are preferred (e.g., crystalline; diastereoisomeric salts). Diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by taking advantage of these dissimilarities.
  • the diastereomers can be separated by chromatography, for example HPLC or, preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • a more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and
  • 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
  • composition comprising bringing a compound of Formula I 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 colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art.
  • 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 gelatine and glycerine, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
  • 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 gelatine and glycerine, or sucrose and acacia
  • 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 superfamily) concentrations of the order 0.01 -100 ⁇ , more preferably 0.01 -10 ⁇ , such as 0.1 -5 ⁇ are typically desirable and achievable.
  • Compounds of the invention are prepared by a variety of solution and solid phase chemistries.
  • a typical first step is the preparation of a P1 building block of the formula II.
  • Pg is a conventional N protecting group such as Boc, CBz or Fmoc.
  • a suitable starting material is an N-protected cycloalkyl amino acid, of which several are available commercially or can be prepared as shown in the following Examples or as described by Allan et al. in J. Med. Chem., 1990 33(10) 2905-2915.
  • the carboxylic acid (1 a) is transformed via a Weinreb synthesis to a ⁇ , ⁇ -dimethylhydroxamic acid (1 b) which provides the corresponding aldehyde (1 c).
  • the aldehyde may also be accessed by reduction of the carboxylic function of a cycloalkyl amino acid followed by oxidation under Dess Martin conditions.
  • the aldehyde (1 c) can be subsequently reacted with t. butyl isocyanide or equivalent in a Passerini reaction to afford the ohydroxy amide (1 d). Subsequent hydrolysis of the amide then provides the required ohydroxycarboxylic acid P1 building block (1 e).
  • the strongly acidic conditions required to hydrolyse the amide also lead to loss of the NBoc protection, if used.
  • the amine can be used directly to couple to a P2 building block or else if it needs to be stored, the amine can be reprotected.
  • the P1 building block thus afforded is then modified/extended at the C and N termini to provide co
  • the C terminus of the building block of formula II is extended at the C-termini by reaction with with N-methyl pyrazole amine. using any suitable conventional peptide coupling stategy.
  • the thus prepared P1 -prime side unit (2a) is thereafter deprotected at the N terminus and elongated with the P2 and subsequently P3 building blocks using conventional peptide chemistries.
  • a P2 residue can be introduced via BocP2-OH using standard coupling conditions such as HATU, DIPEA in DMF.
  • the terminal Boc protection is again removed with acetyl chloride in methanol or equivalent and the P3 residue introduced via coupling of P3-OH using standard coupling conditions such as HATU, DIPEA in DMF.
  • a P3-P2-building block may be prepared separately and added directly to the P1 - prime side-building block (2a) in one step, thus affording the dipeptide derivative (2c).
  • Oxidation of the ohydroxy amide to the corresponding a-keto amide is then effected using any convenient oxidation method known in the art, such as Dess Martin oxidation or Moffat oxidation or the like.
  • An extensive range of appropriately protected L-amino acids suitable for P2 building blocks and carboxylic acids, carboxylic acid halides and carbamoyl halides suitable for P3 building blocks are commercially available or accessed by simple chemistries or as shown in WO06/064286.
  • the P3 and P2 building blocks may alternatively be coupled first and then reacted with the P1 - prime side unit.
  • Elongation is typically carried out in the presence of a suitable coupling agent e.g.,
  • reaction is typically carried out at 20 to 30 °C, preferably at about 25 °C, and requires 2 to 24 h to complete.
  • Suitable reaction solvents are inert organic solvents such as halogenated organic solvents (e.g., methylene chloride, chloroform, and the like), acetonitrile, N,N- dimethylformamide, ethereal solvents such as tetrahydrofuran, dioxane, and the like.
  • halogenated organic solvents e.g., methylene chloride, chloroform, and the like
  • acetonitrile e.g., N,N- dimethylformamide
  • ethereal solvents such as tetrahydrofuran, dioxane, and the like.
  • the above elongation coupling step can be carried out by first converting the
  • P3/P2 building block into an active acid derivative such as succinimide ester and then reacting it with the P1 amine.
  • the reaction typically requires 2 to 3 h to complete.
  • the conditions utilized in this reaction depend on the nature of the active acid derivative. For example, if it is an acid chloride derivative, the reaction is carried out in the presence of a suitable base (e.g.
  • reaction solvents are polar organic solvents such as acetonitrile, ⁇ , ⁇ -dimethylformamide, dichloromethane, or any suitable mixtures thereof.
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups in Organic Synthesis” (John Wiley & Sons, New York, 1981 ), which is hereby incorporated by reference.
  • N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoracetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p- toluenesulfonyl, and the like, carbamate forming groups such as benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
  • diisopropylmethoxycarbonyl isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl,
  • N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl (Bz), t-butoxycarbonyl (BOC) and benzyloxycarbonyl (CBz).
  • Hydroxy and/or carboxy protecting groups are also extensively reviewed in Greene ibid and include ethers such as methyl, substituted methyl ethers such as methoxymethyl,
  • silyl ethers such as trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS) tribenzylsilyl, triphenylsilyl, t- butyldiphenylsilyl triisopropyl silyl and the like, substituted ethyl ethers such as 1 -ethoxymethyl, 1 -methyl-1 -methoxyethyl, t-butyl, allyl, benzyl, p-methoxybenzyl, dipehenylmethyl,
  • Ester hydroxy protecting groups include esters such as formate, benzylformate, chloroacetate, methoxyacetate, phenoxyacetate, pivaloate,
  • Carbonate hydroxy protecting groups include methyl vinyl, allyl, cinnamyl, benzyl and the like.
  • NMR Nuclear Magnetic Resonance
  • multiplicities are denoted s, d, t, m, br and app for singlet, doublet, triplet, multiplet, broad and apparent, respectively.
  • MS Mass Spectrometry
  • LC-MS was obtained with a Waters 2790 LC-system equipped with a Waters XterraTM MS C 8 2.5 ⁇ 2.1 x 30 mm column, a Waters 996 Photodiode Array Detector and a Micromass ZMD.
  • HPLC High pressure liquid chromatography
  • LiAIH 4 (202 mg, 5.33 mmol) was added to a solution of the Weinreb amide BB1 -a (1 .10 g, 4.27 mmol) dissolved in dry diethyl ether (35 mL) at 0 °C. The solution was stirred at 15 minutes before the reaction was quenched with slow addition of potassium hydrogen tartaric acid (sat, aq) and stirred for 10 minutes. The solution was poured into a separatory funnel and the water phase was extracted with ethyl acetate twice. The combined organic phases were washed with 0.5 M HCI (3 times), NaHC0 3 (aq) (2 times) and brine (1 time).
  • BB1 -b (1.75 g, 8.78 mmol) was dissolved in CH 2 CI 2 (18 mL) and cooled in an ice bath, under inert gas. Pyridine (2.85 mL) was added, followed by t-butyl isocyanide (1 .50 mL, 13.3 mmol). Trifluoroacetic acid (1.35 mL, 17.5 mmol) was then added dropwise over 30 min. The yellow solution was stirred at RT overnight. The mixture was concentrated, diluted with EtOAc (100 mL) and washed successively with 1 N HCI (50 mL), saturated NaHC0 3 (50 mL) and saturated NaCI (2 x 50 mL).
  • BB1 -c (1 .30 g, 4.33 mmol) was refluxed with 6N HCI (40 mL) until amide hydrolysis was complete as monitored by LCMS. The mixture was evaporated, co-evaporating several times with water. 1 M NaOH (15 mL) was added to the residue and the basic solution was stirred under vacuum for 15 min. Boc 2 0 (1 .92 g, 8.80 mmol) in dioxane (10 mL) was added, keeping pH at 10 - 1 1 , and the mixture was stirred at RT overnight.
  • Step a) ((1 -Bromo-3-chloropropan-2-yloxy)methyl)benzene (BB2-a)
  • benzyl bromide 185 g, 1 .08 mol
  • (1 .5 g) of mercurous chloride was added epichlorohydrin (100 g, 1.08 mol).
  • the reaction mixture was heated for 12 hr at 100 °C.
  • TLC analysis confirmed formation of product.
  • Compound BB2-j (1 g) was dissolved in 6N HCI (40 mL), and heated to reflux for 24 h after which TLC showed that the reaction had reached completion.
  • the reaction mixture was concentrated in vacuo and residue was dissolved in THF; H 2 0 (7; 3, 50 mL), and TEA (1 .8 mL, 0.012 mol) and Boc anhydride (2.6 g, 0.012 mol) were both added.
  • the mixture was stirred at RT for 8 h when TLC confirmed the reaction had reached completion.
  • Step g) tert-Butyl 3-fluoro-1 -(hvdroxymethyl)cvclobutylcarbamate (BB3-g) To a ice cooled solution of compound BB3-f (0.27 g, 0.001 mol) in dry THF (10 mL) was slowly added a solution of 2M lithium borohydride (2 mL, 0.004 mol) and the mixture was allowed to warm up to room temperature. The mixture was stirred for 3 h at room temperature. The reaction mixture was quenched with ice water (2 mL) and 5 % citric acid (5 mL) and the crude product was extracted with DCM (2 x 50mL).
  • Alcohol BB4-a was dissolved in DCM (20 mL) and Dess-Martin reagent was added in one portion. The reaction was stirred for 2.5 hours. Once the reaction was deemed to have reached completion, it was diluted with 50 mL of DCM and 20 mL of 10% Na 2 S 2 0 3 was added. The mixture was stirred, washed with sodium bicarbonate, brine, and the organic phase was dried over sodium sulphate. Purification on silica (EtOAc-hexane 1 :1 to neat EtOAc) gave the title compound (500 mg, 59%).
  • Step b) Tert-butyl (3-(1 -fluorocvclopentyl)-1 -((1 -(1 -hvdroxy-2-((1 -methyl-1 H-pyrazol-3-yl)amino)- 2-oxoethyl)cvclobutyl)amino)-1 -oxopropan-2-yl)carbamate (1 -b)
  • the Boc-protected amine 1 -b (0.1 1 mmol) was kept in a solution of 4M HCI in dioxane (3 ml.) for 4h and then the solution was concentrated to dryness, which gave the amine as the hydrochloride salt.
  • step c The residue afforded in step c was re-dissolved in DCM (1.5 ml.) and Dess-Martin periodinane (1 .4 eq) was added in one portion at room temperature. The reaction was stirred at room temperature for 2h after which time LC/MS analysis indicated complete oxidation. The reaction mixture was diluted with DCM and the solution washed with a 1 :1 mixture of 10% Na 2 S 2 03 (aq) and 10% NaHC0 3 (aq). The organic layer was concentrated in vacuo.and the afforded residue purified by preparative LC/MS which gave the title compound in 47 % yield. MS: 517.9 [M+H] + .
  • Step c) Tert-butyl (1 -((3.3-difluoro-1 -(2-((1 -methyl-1 H-pyrazol-3-vnamino>2- oxoacetyl)cvclobutyl)amino)-3-(1 -methylcvclopentyl)-1 -oxopropan-2-yl)carbamate (2-c)
  • the Boc protected amine 2-c (0.339 mmol) was dissolved in a dioxane (4.2 ml) and 4M HCI in dioxane (4.2 ml) was added. The mixture was stirred over night whereafter the solvent was removed under high vacuum.
  • the crude product was dissolved in DMF (1 .5 mL) at 0 °C and cyclopropanecarbonyl chloride (15 mL) was added followed by DIEA (75 ⁇ ). After 3.5 h at RT the solvent was removed by rotary evaporation. The crude product was purified on silica, which gave the title compound (20.2 mg, 50%) yield. [M+H] + 480.3. Purity > 98% assessed by LCMS.
  • step c Introduction of the P3 moiety in step c was performed using the P3-acid chloride instead of the P3-acid and HATU.
  • Convenient assays for cathepsin K are carried out using human recombinant enzyme, such as that described in PDB.
  • the recombinant cathepsin K can be expressed in a variety of commercially available expression systems including E coli, Pichia and Baculovirus systems.
  • the purified enzyme is activated by removal of the prosequence by conventional methods.
  • Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically H-D-Ala-Leu-Lys-AMC, and were determined in either 100 mM Mes/Tris, pH 7.0 containing 1 mM EDTA and 10 mM 2-mercaptoethanol orl OOmMNa phosphate, imM EDTA, 0.1 % PEG4000 pH 6.5 or 100 mM Na acetate, pH 5.5 containing 5 mM EDTA and 20 mM cysteine, in each case optionally with 1 M DTT as stabiliser.
  • the enzyme concentration used was 5 nM.
  • the stock substrate solution was prepared at 10 mM in DMSO.
  • 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.
  • 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 K,.
  • the rough K is calculated from a preliminary run in which 10 ⁇ -Jwell of 1 mM boc-VLK-AMC (1/10 dilution of 10 mM stock in DMSO diluted into assay buffer) is dispensed to rows B to H and 20 ⁇ /well to row A of a 96 well MicrofluorTM plate. 2 ⁇ of each 10 mM 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 ⁇ _ 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.
  • a distributor such as a Multidrop 384, add 30 ⁇ -Jwell to all wells of the assay plate and read in fluorescent spectrophotometer such as an Ascent.
  • Fluorescent readings (excitation and emission wavelengths 390 nm and 460 nm 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.
  • 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 100mM sodium acetate 1 mM EDTA, pH5.5)
  • the DMSO stock (10 mM in 100%DMSO) is diluted to 10% in assay buffer.
  • Enzyme is prepared at 5 nM concentration in assay buffer plus 1 mM dithiothreitol just before use. 2 ⁇ _ of 10mM inhibitor made up in 100% DMSO is dispensed into row A.
  • v 0 is the velocity of the reaction
  • V is the maximal velocity
  • S is the concentration of substrate with Michaelis constant of K M
  • / is the concentration of inhibitor.
  • the compounds of formula I are thus potent inhibitors of cathepsin S and yet selective over the closely related cathepsin K and L.
  • This experiment 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.
  • 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 ⁇ _ 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 °C with a low shaking velocity of approximately 150 to 300 rpm.
  • 25 ⁇ _ samples are 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 ⁇ _ 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 -20 °C until analysis by HPLC or LC-MS.
  • 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 ⁇ . Furthermore all test solutions and buffers will contain 1 % DMSO.
  • the transport plates 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. After 21 to 28 days in culture on filter supports the cells are ready for permeability experiments. The culture medium from the apical wells are removed and the inserts are transferred to a wash row (No.1 ) in a new plate without inserts (Transport plate).
  • 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 0.5 ml. transport buffer (HBSS, 25 mM MES, pH 6.5) is added to the inserts in row No. 1 and the cell monolayers are equilibrated in the transport buffer system for 30 minutes, 37 °C in a polymix shaker. After being equilibrated to the buffer system the 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 ⁇ _ fresh TB, pH 6.5 is added to the inserts.
  • 250 ⁇ _ is withdrawn from the apical (receiver) well and replaced by fresh transport buffer.
  • 250 ⁇ _ 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 ⁇ _ 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 -20 °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:
  • C jj is the receiver concentration at the end of the interval i and Cpj is the donor concentration at the beginning of interval i.
  • Cpj is the donor concentration at the beginning of interval i.
  • k is the transport rate (min "1 ) defined as the slope obtained by linear regression of cumulative fraction absorbed (FA CU M ) as a function of time (min)
  • VR is the volume in the receiver chamber (ml_)
  • A is the area of the filter (cm 2 ).
  • Greater permeability through the gastrointestinal tissue is advantageous in that it allows for the use of a smaller dose to achieve similar levels of exposure to a less permeable compound administered in a higher dose.
  • a low dose is advantageous in that it minimizes the cost of goods for a daily dose, which is a crucial parameter in a drug which is taken for protracted time periods.

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Abstract

L'invention concerne des composés de formule I, dans laquelle R1 représente CrC6alkyle, CrC6haloalkyle, C3-C6cycloalkyle, C3-C6cycloalkyle étant facultativement substitué par CF3, méthyle, éthyle ou un ou deux F ; R2a et R2b représentent indépendamment H, F et CH30 ; R3 représente F ou CH3 ; ou un sel, un hydrate ou un N-oxyde pharmaceutiquement acceptable de ceux-ci, destinés à être utilisés dans la prévention ou le traitement d'un trouble se caractérisant par l'expression ou l'activation inappropriée de cathepsine S.
PCT/IB2012/052810 2011-06-08 2012-06-05 Inhibiteurs de cystéine protéase WO2012168852A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2582660A1 (fr) * 2010-06-16 2013-04-24 Medivir UK Ltd Nouveaux inhibiteurs de cathepsine s protéase, utiles dans le traitement, par ex., de maladies auto-immunes, d'allergies et de douleurs chroniques

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010070615A1 (fr) * 2008-12-19 2010-06-24 Medivir Uk Ltd Inhibiteurs de cystéine protéase
WO2011070541A1 (fr) * 2009-12-10 2011-06-16 Medivir Uk Limited Inhibiteurs des cystéine protéases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010070615A1 (fr) * 2008-12-19 2010-06-24 Medivir Uk Ltd Inhibiteurs de cystéine protéase
WO2011070541A1 (fr) * 2009-12-10 2011-06-16 Medivir Uk Limited Inhibiteurs des cystéine protéases

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2582660A1 (fr) * 2010-06-16 2013-04-24 Medivir UK Ltd Nouveaux inhibiteurs de cathepsine s protéase, utiles dans le traitement, par ex., de maladies auto-immunes, d'allergies et de douleurs chroniques
EP2582660A4 (fr) * 2010-06-16 2013-11-27 Medivir Uk Ltd Nouveaux inhibiteurs de cathepsine s protéase, utiles dans le traitement, par ex., de maladies auto-immunes, d'allergies et de douleurs chroniques
EP2752404A1 (fr) * 2010-06-16 2014-07-09 Medivir UK Ltd Inhibiteurs de la cystéine protéase

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