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EP1797032A1 - Formes polymorphes du n-(1-cyanocyclopropyl)-3-cyclopropylméthanesulfonyl-2(r)-(2,2,2-trifluoro-1(s)-(4-fluorophényl)éthylamino)propionamide, un inhibiteur de la cystéine protéase - Google Patents

Formes polymorphes du n-(1-cyanocyclopropyl)-3-cyclopropylméthanesulfonyl-2(r)-(2,2,2-trifluoro-1(s)-(4-fluorophényl)éthylamino)propionamide, un inhibiteur de la cystéine protéase

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Publication number
EP1797032A1
EP1797032A1 EP05798153A EP05798153A EP1797032A1 EP 1797032 A1 EP1797032 A1 EP 1797032A1 EP 05798153 A EP05798153 A EP 05798153A EP 05798153 A EP05798153 A EP 05798153A EP 1797032 A1 EP1797032 A1 EP 1797032A1
Authority
EP
European Patent Office
Prior art keywords
compound
theta
exhibits
formula
diffraction pattern
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05798153A
Other languages
German (de)
English (en)
Inventor
Sheila M. Zipfel
Soon H. Woo
Donglai Yang
Simon Bates
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Bayer Schering Pharma AG
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Filing date
Publication date
Priority claimed from PCT/US2004/030442 external-priority patent/WO2005028429A2/fr
Application filed by Bayer Schering Pharma AG filed Critical Bayer Schering Pharma AG
Publication of EP1797032A1 publication Critical patent/EP1797032A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • 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
    • 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
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention is directed to polymorphs of N-(l-cyanocyclopropyl)-3- cyclopropylmethanesulfonyl-2(i?)-[2,2,2-trifluoro-l(>S)-(4-fluorophenyl)ethy-lamino]- propionamide, methods of using them to treat a disease mediated by catheps ⁇ n S, pharmaceutical compositions comprising such polymorphs, and processes for preparing them.
  • Polymorphs are crystals of the same molecule having different physical properties as a result of the order of the molecules in the crystal lattice.
  • the differences in the physical properties exhibited by polymorphs can affect the pharmaceutical properties of a drug such as storage stability, compressibility and density which is important in formulation and manufacturing, and solubility/dissolution rates that can in turn affect the bioavailability of a drug.
  • solubility/dissolution differences in some cases, polymorphoic transitions can result in lack of potency and/or toxicity. Therefore, the Food and Drug Administration requires tight controls on the polymorphoic content of the active component in solid dosage forms.
  • thermodynamically stable polymorphs may also be useful as intermediates that may be converted to the more stable polymorph.
  • the compound of Formula (I) can exist in three different crystalline polymorphic forms referred to herein as Forms A, B, and C, and an amorphous form referred to herein as Form D, Form A being the most thermodynamically stable.
  • the present invention is directed to a compound of Formula (I) having a polymorphic form which exhibits an X-ray powder diffraction pattern having characteristic peaks at about 6.19, 19.47, and 21.67° (2-theta) and is referred to herein as Form A.
  • the present invention is directed to a compound of Formula (I) having a polymorphic form which exhibits an X-ray powder diffraction pattern having a characteristic peak at about 5.65° (2 theta) and is referred to herein as Form B.
  • the present invention is directed to a compound of Formula (I) having a polymorphic form which exhibits an X-ray powder diffraction pattern having characteristic peaks at about 6.24 and 7.50° (2-theta) and is referred to herein as Form C.
  • the present invention is directed to a compound of Formula (I) having an amorphous form which exhibits an X-ray powder diffraction pattern having broad peaks, between about 5 and 12 and about 14 and 25° (2-theta) and is referred to herein as Form D.
  • this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) having a polymorphic form which exhibits an X-ray powder diffraction pattern having characteristic peaks at about 6.19, 19.47, and 21.67° (2-theta) (Form A) and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (I) that is in substantially pure polymorphic form which exhibits an X-ray powder diffraction pattern having characteristic peaks at about 6.19, 19.47, and 21.67° (2-theta) (Form A) and a pharmaceutically acceptable excipient. More preferably, Form A is present in greater than 80% purity. Even more preferably, in greater than 90% purity. Even more preferably, Form A is present in greater than 95% purity.
  • this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) having a polymorphic form which exhibits an X-ray powder diffraction pattern having characteristic peak at about 5.65° (2 theta) (Form B) and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (I) having a polymorphic form which exhibits an X-ray powder diffraction pattern having characteristic peaks at about 5.65, 6.68, 10.12, 18.63, 19.40, 20.66, 21.47, 21.93, 22.47, 23.78, 25.52, 25.76, and 26.79° (2-theta) and FT-IR spectrum peaks at about 704, 731, 791, 808, 823, 837, 856, 893, 936, 1028, 1053, 1080, 11 15, 1128, 1161, 1180, 1230, 1287, 1361, 1418, 1465, 1514, 1548, 1607, 1663, and 3349 cm "1 (Form B) and a pharmaceutically acceptable excipient.
  • Formula (I) having a polymorphic form which exhibits an X-ray powder diffraction pattern having characteristic peaks at about 5.65, 6.68, 10.12, 18.63, 19.40, 20.66, 21.47,
  • a pharmaceutical composition comprising a compound of Formula (I) that is in substantially pure polymorphic form which exhibits an X-ray powder diffraction pattern having characteristic peak at about 5.65° (2 theta) (Form B) and a pharmaceutically acceptable excipient.
  • Form B is present in greater than 80% purity. Even more preferably, in greater than 90% purity. Even more preferably, Form B is present in greater than 95% purity.
  • this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) having a polymorphic form which exhibits an X-ray powder diffraction pattern having characteristic peaks at about 6.24 and 7.50° (2-theta) (Form C) and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (I) having a polymorphic fo ⁇ n which exhibits an X-ray powder diffraction having peaks at having peaks at about 6.24, 7.50, 17.68, 18.76, 19.80, 21.86, 23.93, and 25.28° (2-theta).
  • a pharmaceutical composition comprising a compound of Formula (I) that is in substantially pure polymorphic form which exhibits an X-ray powder diffraction pattern having characteristic peaks at about 6.24 and
  • Form C 7.50° (2-theta) (Form C) and a pharmaceutically acceptable excipient. More preferably, Form C is present in greater than 80% purity. Even more preferably, in greater than 90% purity. Even more preferably, Form C is present in greater than 95% purity.
  • this invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I) having a polymorphic form which exhibits an X-ray powder diffraction pattern having broad peaks between about 5 and 12 and about 14 and 25° (2-theta) (Form D) and a pharmaceutically acceptable excipient.
  • a pharmaceutical composition comprising a compound of Formula (I) that is in substantially pure polymorphic form which exhibits an X-ray powder diffraction pattern having broad peaks between about 5 and about 12 and 14 and 25° (2-theta) (Form D) and a pharmaceutically acceptable excipient.
  • Form D is present in greater than 80% purity. Even more preferably, in greater than 90% purity. Even more preferably, Form D is present in greater than 95% purity.
  • this invention is directed to a method of treating a disease in an animal which is mediated by Cathepsin S which method comprises administering to the animal any of the pharmaceutical compositions described above.
  • the animal is human and the disease is juvenile onset diabetes, psoriasis, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis, Hashimoto's thyroiditis, allergic disorders including, but not limited to, asthma, allogeneic immune responses including, but not limited to, organ transplants or tissue grafts and endometriosis, chronic obstructive pulmonary disease (e.g., emphysema), bronchiolitis, excessive airway elastolysis in asthma and bronchitis, chronic pain, cancer, pneumonities and cardiovascular disease such as plaque rupture and atheroma, systemic amyloidosis, Alzheimer'
  • FIG. 1 is an X-ray powder diffraction (XRPD) of the compound of Formula (I) Form A.
  • FIG. 2 is a Fourier infrared spectroscopy (FT-IR) of the compound of Formula (I) Form A.
  • FIG. 3 is an X-ray powder diffraction (XRPD) of the compound of Formula (I) Form B.
  • FIG. 4 is a Fourier infrared spectroscopy (FT-IR) of the compound of Formula (I) Form B.
  • FIG. 5 is an X-ray powder diffraction (XRPD) of the compound of Formula (I) Form C.
  • FIG. 6 is an X-ray powder diffraction (XRPD) of the compound of Formula (I) Form
  • a “pharmaceutically acceptable carrier or excipient” means a carrier or an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier or an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • “A pharmaceutically acceptable carrier/excipient” as used in the specification and claims includes both one and more than one such excipient.
  • Treating” or “treatment” of a disease includes:
  • a “therapeutically effective amount” means the amount of a compound of Formula (I) that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • compound of Formula (I) refers to a polymorphic form ofN-(l -cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(i?)-[2,2,2-trifluoro-l(5)-(4- fluorophenyl)ethylamino]propionamide which is about 80% pure, preferably from about 85 to about 95 pure, even more preferably from about 98 to about 99.9% pure.
  • the amount of other polymorphic form(s) of N-( 1 -cyanocyclopropyl)-3 -cyclopropylmethane- sulfonyl-2(i?)-[2,2,2-trifluoro-l( ⁇ S)-(4-fluorophenyl)ethylamino]propionamide present is(are) not more that about 20%, preferably not more than about 15 to about 5%, even more preferably not more than about 2 to about 0.1%.
  • Animal includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).
  • non-human mammals e.g., dogs, cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like
  • non-mammals e.g., birds, and the like.
  • “Sufficient chemical affinity” when used in reference to a solvent or solvent mixture refers to a solvent or solvent mixture having the capability of dissolving the compound of Formula (I) in an amount to enable crystallization of the compound. This capability may be a function of the temperature or may vary with different polymorphs of the compound.
  • “Mechanical stress” when used herein in reference to a processing step means that the compound of Formula (I) is subjected to a mechanical force or a change (reduction or increase) of mechanical force such as a shear force and includes filtration, capillary action, ultrasound, particle size changes, such as grinding, milling, micronizing, stirring, drying, sublimation or removal of solvent, and other mechanical force exposures described herein in more detail.
  • an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed.
  • intensities in an X-ray diffraction pattern may fluctuate depending upon measurement conditions employed.
  • relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account.
  • a measurement error of diffraction angle for a conventional X-ray diffraction pattern is typically about 5% or less, and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles.
  • the term "about" when used herein in reference to X-ray powder diffraction patterns means that the crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figures disclosed herein. Any crystal form that provides X-ray diffraction patterns that is substantially identical as to those disclosed in the accompanying Figures fall within the scope of the present invention.
  • the ability to ascertain whether the polymorphic forms of a compound are the same albeit the X-ray diffraction patterns are not completely identical is within the purview of one of ordinary skill in the art. The same is true when determining the polymorphic form using the FT-IR spectra disclosed herein i.e., any crystal form that provides FT-IR spectrum that is substantially identical as to those disclosed in the accompanying Figures fall within the scope of the present invention.
  • without substantially affecting the integrity of the compound when used herein in reference to a processing step means that the chemical identity of the compound of Formula (I) is not significantly altered after completion of the processing step; in other words chemical bonds remain substantially intact.
  • the term "without substantially affecting the two asymmetric centers of the compound” means that after the completion of the process of preparing a polymorph the optical configuration of the two asymmetric centers is retained at least to about 90%, preferably to about 95% or above.
  • Bioavailability the ability to process, and stability of the product are influenced by the existence of varied physical and chemical properties of the solid-state forms associated with the various polymorphs.
  • polymorphs of the invention have the same elemental composition, they exhibit different physico-chemical and physico-technical properties such as free energy, entropy, heat capacity, melting point, sublimation temperature, solubility, stability, dissolution rate, bioavailability, hardness, compatibility, flowability, tensile strength and compressibility, all of those being factors to determine the suitability of a polymorph for its pharmaceutical use.
  • the thermodynamically most stable polymorph is generally the preferred choice for marketing, other polymorphs of an active ingredient may also play an important role, not only in drug quality assurance monitoring. For example, the less stable polymorphs can be used as important intermediates to prepare the more stable polymorph. Characterization of the polymorphic forms of compound (T):
  • the polymorphic forms of compound (I) were characterized by melting point, X-ray powder diffractometry (XRPD) and Fourier Transform Infrared Spectroscopy (FT-IR).
  • XRPD X-ray powder diffractometry
  • FT-IR Fourier Transform Infrared Spectroscopy
  • the X- ray diffraction (XRPD) analyses were performed using an Inel XRG-3000 diffractometer equipped with a CPS (Curved Position Sensitive) detector with a 2 ⁇ range of 120°. Real time data were collected using Cu-Ka radiation starting at approximately 4° 2 ⁇ at a resolution of 0.03° 2 ⁇ . The tube voltage and amperage were set to 40 kV and 30 mA, respectively. The pattern was displayed from 2.5-40° 2 ⁇ . Samples were prepared for analysis by packing them into thin-walled glass capillaries.
  • Each capillary was mounted onto a goniometer head that is motorized to permit spinning of the capillary during data acquisition.
  • the samples were analyzed for 5 or 10 min.
  • Instrument calibration was performed using a silicon reference standard.
  • Infrared spectra were acquired on a Magna-IR 860 ® Fourier transform infrared (FT-IR) spectrophotometer (Thermo Nicolet) equipped with an Ever-Glo mid/far IR source, an extended range potassium bromide (KBr) beamsplitter, and a deuterated triglycine sulfate (DTGS) detector.
  • FT-IR Fourier transform infrared
  • DTGS deuterated triglycine sulfate
  • ATR attenuated total reflectance
  • ThunderdomeTM ThunderdomeTM, ThermoSpectra-Tech
  • Ge germanium
  • a background data set was acquired with a clean Ge crystal.
  • a background data set was acquired on a sample of KBr.
  • Form A is an anhydrous, non-hygroscopic, crystalline material with a melting point at about 175 °C.
  • the XRPD of Form A is shown in FIG. 1 having peaks at about 6.19, 8.52, 9.15, 14.42, 17.67, 18.79, 19.47, 19.74, 21.67, 23.16, 23.89, 25.31, and 27.06° (2-theta).
  • the unique peaks for Form A in XRPD are at about 6.19, 19.47, and 21.67° (2-theta).
  • Form A The FT-IR spectrum of Form A showed peaks at about 704, 731, 777, 791, 808, 822, 837, 856, 892, 921, 935, 987, 1008, 1028, 1053, 1080, 1115, 1128, 1161, 1180, 1230, 1261, 1288, 1361, 1418, 1465, 1513, 1548, 1607, 1663, and 3349 cm "1 .
  • Form B
  • Form B is a solvate and maybe a hydrate.
  • the XRPD of form B is shown in FIG. 3 having peaks at about 5.65, 6.68, 10.12, 18.63, 19.40, 20.66, 21.47, 21.93, 22.47, 23.78, 25.52, 25.76, and 26.79° (2-theta).
  • the unique peak for Form B in XRPD is at about 5.65° (2-theta).
  • Form B The FT-IR spectrum of Form B showed peaks at about 704, 731, 791, 808, 823, 837, 856, 893, 936, 1028, 1053, 1080, 1115, 1128, 1161, 1180, 1230, 1287, 1361, 1418, 1465, 1514, 1548, 1607, 1663, and 3349 cm "1 .
  • Form C Form C:
  • Form C is anhydrous.
  • the XRPD of form C is shown in FIG. 5 having peaks at about 6.24, 7.50, 17.68, 18.76, 19.80, 21.86, 23.93, and 25.28° (2-theta).
  • the unique peaks for Form C in XRPD are at about 6.24 and 7.50° (2-theta).
  • Form D is amorphous and has XRPD shown in FIG 6 with broad peaks, between about 5 and 12 and about 14 and 25° (2-theta).
  • the different polymorphs of the invention may be produced by solvent crystallization or non-solvent crystallization.
  • the different methods of crystallization generate different crystal forms by providing varied reaction conditions. Crystallization from solution (single solvent or solvent mixtures) and non-solvent methods such as sublimation, thermal treatment, desolvation, processing (grinding) and crystallization from melting are the commonly used methods. Capillary crystallization, laser-induced crystallization and sonocrystallization target the nucleation stage to enhance the crystallization rate.
  • Suitable solvents are solvents that have sufficient chemical affinity for the compound of the invention and do not substantially affect the two asymmetric centers of the molecule during the crystallization process.
  • lower alkanols with 1 to 6 carbon atoms such as ethanol or 2-propanol etc.
  • ketones with 3-6 carbon atoms such as acetone, methyl ethyl ketone, etc.
  • halogenated hydrocarbons with 1 to 4 carbon atoms such as methylene chloride, 1,1-dichloroethane, etc.
  • aqueous solvents such as mixtures of water with lower alkyl nitriles, such as acetonitrile, propionitrile, and the like and aromatic solvents with 6 to 8 carbon atoms such as benzene, toluene, or xylenes, etc. and suitable mixtures of these solvents.
  • a mixture of the solvent with the compound of Formula (I) will be heated to an elevated temperature between 40 0 C to 100 0 C, preferably 50 to 90 0 C. After the selected higher temperature is reached and the compound is in solution commonly at about saturation concentration, the solution will be cooled down slowly. Often it is useful to control the cooling with a cooling rate between 0.5 to 10 0 C/ h, preferably 1 to 8 °C/h, most preferably 1 to 5 °C/h. For certain solvents it may be preferred to allow slow evaporation of the solvent, for example with acetone. In that case it may not be necessary to start the crystallization step with a saturated solution of the compound of Formula (I).
  • a preheated filtering device may be useful to remove impurities.
  • the isolated compound will be allowed to dry and its polymorphic form be determined by one of the methods herein described. Solvent crystallization is preferred for the preparation of the more stable polymorphs, in particular the most stable polymorph (for example, Form A).
  • certain selected solvents may be used, for example, halogenated lower alkanols, preferably perhalogenated alkanols with 2 to 6 carbon atoms, most preferably trifluoroethanol.
  • halogenated lower alkanols preferably perhalogenated alkanols with 2 to 6 carbon atoms, most preferably trifluoroethanol.
  • non-solvent crystallizations such as sublimation, thermal treatment, desolvation, processing (grinding), sonication such as electrosonication or laser-induced crystallization may be suitable.
  • Newer crystallization strategies such as laser-induced crystallization, capillary crystallization and sonocrystallization, target the nucleation stage.
  • These techniques by use of unusual reaction conditions or mechanical stress (e.g. ultrasound and laser as a source of energy), are often helpful in the screening process and for preparing different polymorphs of the compound of Formula (I), in particular thermodynamically less stable polymorphs.
  • These techniques are comprehensive and are accompanied by enhanced crystallization rates. Ascertaining the metastable forms through, a capillary environment can prove to be of assistance.
  • the scalability advantage of sono-crystallization and laser-induced crystallization certainly has good prospects.
  • sonocrystallization can be effectively utilized to reduce the particle size.
  • This technique uses capillary tubes as crystallization vessels and captures metastable forms of the active ingredient by manipulating the metastable zone width.
  • metastable forms having greater solubility tend to dissolve and the stable form crystallizes out at the expense of it.
  • a capillary environment possessing a small volume of solution with reduced convection and low turbulence is ideal for the isolation of alternative less stable forms.
  • the capillary system technique allows a slow evaporation rate, thereby prolonging the metastable zone and generating high concentration enough for the solution to be supersaturated relative to the metastable phases. The careful selection of evaporation conditions is often important to obtain the metastable form.
  • Lasers are a form of electromagnetic radiation, characterized by an oscillating electric field. They produce light at different wavelengths in visible, infrared and ultraviolet regions of the spectrum in both continuous and pulsed format.
  • Laser-induced crystallization makes use of solid-state lasers, particularly the Q-switched neodymium yttrium aluminium garnet (Nd:YAG) laser, which generates intense pulses in the near infrared region. It is characterized by continuous output of a few tens of watts to 1,80OW.
  • An apt way for crystallization to take place is to employ a pulsed source, which acts for few nanoseconds.
  • Laser pulses predominantly act on the pre-existing clusters, thereby assisting in the organization of the pre- nucleating clusters and embryos into nuclei.
  • the basic principle of laser-induced crystallization involves the induction of a dipole moment in molecules by the oscillating electric field. The same field then interacts with the induced dipole, applying a torque to the molecules and aligning them along the most polarizable axis parallel to the field.
  • the general methodology applicable for laser-induced crystallization starts with the preparation of a saturated solution at a specific temperature in pyrex screw-capped test tubes. Supersaturation is achieved either by temperature cycling for several days or by sonication. The solution is then cooled slowly to room temperature and held at the same temperature for a few days.
  • the aging allows enrichment of the cluster size and number, thus improving the probability of nucleation.
  • the solution is then illuminated with high-energy laser pulses (Nd: YAG laser oscillator amplifier system) showing the appearance of macroscopic crystals within seconds. Sonocrystallization
  • Sonocrystallization utilizes ultrasound power characterized by a frequency range of 20- 100 kHz for inducing crystallization. It not only enhances the nucleation rate, but is also an effective means of size reduction and controlling size distribution of the active ingredient.
  • the technique proves to be a good alternative to mechanical size reduction, which may be accompanied by polymorphic transformations. It can be promising in the crystallization of an active ingredient to be formulated for inhalation purposes, which requires an active ingredient in size-reduced form.
  • Sonic waves exert alternate cycles of compression and rarefaction within a liquid, creating bubbles during the rarefaction stage. These bubbles survive repeated cycles of compression and rarefaction until a critical size is reached, and then collapse to form cavities. This process is known as cavitation.
  • Grinding will often be carried out with mixing-milling equipment either at room temperature or temperatures below room temperature, sometime at temperatures down to about - 200 0 C, approximately the boiling point of liquid nitrogen for 10 to 60 minutes, more preferably 15 to 45 minutes. After the grinding step is completed the sample will be allowed to warm up to room temperature.
  • Amorphous polymorphs may be prepared by liquefaction of the compound of Formula (I), for example by heating the compound to a temperature above its melting point, followed by rapid cooling. The rapid cooling of the melt prevents crystallization.
  • amorphous polymorphs may be prepared by particle size reduction at temperature significantly below room temperature, for example at about -200 0 C.
  • Polymorphs of the compound of Formula (I) are selective inhibitors of catihepsin S, and accordingly are useful for treating diseases in which cysteine protease activity contributes to the pathology and/or symptomatology of the disease.
  • the polymorphs of the invention are useful in treating autoimmune disorders, including, but not limited to, juvenile onset diabetes, psoriasis, multiple sclerosis, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto's thyroiditis, allergic disorders, including, but not limited to, asthma, allogeneic immune responses, including, but not limited to, organ transplants or tissue grafts and endometriosis.
  • Cathepsin S is also implicated in disorders involving excessive elastolysis, such as chronic obstructive pulmonary disease (e.g., emphysema), bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonities and cardiovascular disease such as plaque rupture and atheroma.
  • Cathepsin S is implicated in fibril formation and, therefore, inhibitors of cathepsins S are of use in treatment of systemic amyloidosis.
  • the Cathepsin S inhibitory activity of the polymorphs of compound of Formula (I) can be determined by methods known to those of ordinary skill in the art. Suitable in vitro assays for measuring protease activity and the inhibition thereof by test compounds are known. Details of assays for measuring Cathepsin S inhibitory activity are set forth in Biological Examples 1 and 2, infra.
  • the polymorphs of the compound of Formula (I) will be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents.
  • a therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used and other factors.
  • therapeutically effective amounts of a compound of Formula (I) may range from about 10 micrograms per kilogram body weight ( ⁇ g/kg) per day to about 100 milligram per kilogram body weight (mg/kg) per day, typically from about 100 ⁇ g/kg/day to about 10 mg/kg/day.
  • a therapeutically effective amount for an 80 kg human patient may range from about 1 mg/day to about 8 g/day, typically from about 1 mg/day to about 800 mg/day.
  • a therapeutically effective amount for an 80 kg human patient may range from about 1 mg/day to about 8 g/day, typically from about 1 mg/day to about 800 mg/day.
  • compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate composition and are comprised of, in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient.
  • Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the active ingredient.
  • excipient may be any solid, liquid, semisolid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
  • Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, and the like.
  • Liquid and semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like).
  • Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose and glycols.
  • a composition of a polymorph of compound of Formula (I) for treating a given disease will comprise from 0.0 l%w to 90%w, 5%w to 50%w, of active ingredient with the remainder being the excipient or excipients.
  • the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required.
  • Representative pharmaceutical formulations containing a polymorph of compound of Formula (I) are described in Example 1 below.
  • Catecholborane (249 g as a 2M solution in toluene; purchased from BASF) was added dropwise at a rate to maintain an internal temperature below -75 0 C. After the addition was complete, the reaction mixture was stirred overnight at -75 0 C for -15 h and then quenched by slow addition of 4N HCl in 1,4- dioxane (31 mL; 0.124 mol), maintaining the internal temperature below -75 0 C. The ice bath was removed and the reaction mixture allowed to warm up to room temperature over a 3 h period. The reaction mixture was concentrated to a final volume of -200 mL to afford a white suspension. Hexane (800 mL) was added and the suspension filtered.
  • trifluoromethanesulfonic anhydride (60 g, 334 mL, 1.98 mol, 105 mole%) was added via an addition funnel over 0.75 h, maintaining the solution at -50 ⁇ 5 0 C and the solution was stirred at that temperature for 4-6 h, by which time formation of the triflate was determined to be complete by 19 F-NMR analysis.
  • Solid S-trityl-L-cysteine (686 g, 1.89 mol, 100 mole%) was added in one portion, causing the internal temperature of the solution to rise to -40 0 C. The reaction mixture was allowed to warm to 10 0 C overnight to give a homogenous solution.
  • reaction mixture was stirred for an additional 10 hours at 10 0 C, by which time no further reaction had taken place as determined by HPLC analysis.
  • Toluene (5 L) was added, followed by removal of the dichloromethane in vacuo.
  • the precipitated trifluoromethanesulfonic acid salt of DIPEA was removed by filtration.
  • the filtrate was washed with 2N aqueous HCl (4 L), followed by saturated aqueous NaCl (4 L).
  • Triethylsilane (247 mL; 180 g; 1.55 mol; 194 mole%) was added dropwise. After the addition was complete, the ice-bath was removed and the reaction mixture was allowed to warm up to room temperature. After stirring for an additional 1 hour, HPLC-MS analysis showed the reaction was complete. The dichloromethane was removed in vacuo. The concentrated material was diluted with toluene (300 mL) and the mixture was concentrated in vacuo to remove volatile residues (triethylsilane and TFA). The azeotropic distillation process was repeated by the addition of another portion of toluene to the crude product.
  • the resulting dark residue was diluted with hexane (800 mL) and the mixture was extracted with a 3N NaOH solution (500 mL) and then a 2N NaOH solution.
  • the combined, basic (pH > 13) aqueous extracts were washed with hexane and then treated with tris(2- carboxyethyl)phosphine*HCl (22.1 g; 77.1 mmol; 9.7 mole%) and cyclopropylmethyl bromide (104.6 g; 775 mmol).
  • the reaction mixture was stirred, keeping the mixture basic (pH > 13) with the addition of 3N aqueous NaOH solution. After 2 h, HPLC analysis showed the reaction to be complete.
  • NMP iV-methylpyrrolidinone
  • DIPEA
  • the internal temperature was below 24 0 C.
  • the reaction was stirred at room temperature and the progress of the reaction was monitored by HPLC and LC- MS. After 3 h, HPLC analysis showed an excess of starting material. Additional DIPEA (30 mL; 22.3 g; 172 mmol) was added to increase the pH from 3 to 10. No appreciable conversion was observed after an additional 1 hour reaction time. An additional 10% (5.6 g; 14.7 mmol) of HATU was added and the reaction was complete after 1 h, as determined by LC-MS analysis.
  • the reaction mixture was diluted with NMP (100 mL) and the mixture was treated with a solution of OXONE ® (157 g; 255 mmol; 180 mole%) in water (360 mL) which was prepared by heating at 70 0 C, then, cooled to 45 0 C for the addition. Addition of the aqueous solution of OXONE ® afforded a suspension that was difficult to stir. The slurry was stirred overnight at which time, LC-MS showed the reaction to be complete. The reaction mixture was diluted with water (500 mL) and the resulting suspension stirred for an additional 30 minutes. The solids were filtered and washed with water (500 mL) and then isopropanol (250 mL).
  • the filter cake was dissolved in ethyl acetate (1.5 L) and the solution washed with water (1.5 L), water (500 mL), and saturated aqueous NaCl (500 mL).
  • the organic phase was concentrated in vacuo to give 50 g of an off-white solid.
  • the solid was dissolved in a mixture of isopropanol (500 mL) and water (50 mL) in an oil bath at 90 0 C then the solution was allowed to cool overnight with stirring.
  • a thick white crystalline solid was produced which was diluted with isopropanol (200 mL) to aid in transfer for filtration.
  • the solid was filtered, washed with isopropanol (200 mL), air-dried then dried in vacuo to give the title compound (42.0 g) as a crystalline solid.
  • Lithium aluminum hydride (200 mL, 1.5M solution in tetrahydrofuran) was cooled in an ice bath and solid 2-(i?)-amino-3-cyclopropylmethanesulfanylpropionic acid (20 g) was added by tapping into the flask through a powder funnel to control gas evolution. Once the addition was complete, the bath was removed and the reaction mixture was heated at reflux overnight. The reaction mixture was cooled in an ice bath and diethyl ether (110 mL) was added followed by dropwise addition of 5 rnL water, 5mL 15% aq. NaOH, and then 15mL more water. Stirring in the ice bath was continued for 2 h, and then the reaction mixture was vacuum filtered.
  • Step 3 A solution of 2(i?)-amino-3 -cyclopropylmethanesulfanylpropan- 1 -ol ( 15.03 g) and trifluoroacetaldehyde methyl hemiacetal (12.2 g) in toluene (100 mL) was heated at reflux with Dean Stark trapping of water for 24 h. The reaction mixture was concentrated to give 4- cyclopropylmethanesulfanylmethyl-2-trifluoromethyloxazolidine (17.61 g) as a pale yellow oil.
  • Part A A solution of 4-cyclopropylmethanesulfanylmethyl-2- trifluoromethyloxazolidine (17.6 g) in anhydrous tetrahydrofuran (145 mL) was cooled in an ice water bath and treated with chlorotrimethylsilane (11 mL) and lithium bis(trimethylsilyl)amide (87.5 mL of 1.0M solution in tetrahydrofuran). The reaction mixture was allowed to stir under ice bath cooling for 30 min and then at room temperature for 1 h. Part B.
  • reaction was monitored by TLC (l%acetic acid in 1:1 hexanes:ethyl acetate) and portions of the chromium trioxide solution were added (95 mL at 1.5 h reaction time, 40 rnL at 4.5 h reaction time). After 1 more hour reaction time, the reaction was complete by HPLC analysis. Isopropanol (200 mL) was added and the reaction mixture was allowed to warm to room temperature and then was concentrated. The resulting solids were partitioned between ethyl acetate and saturated aqueous KH 2 PO 4 . The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate.
  • TLC l%acetic acid in 1:1 hexanes:ethyl acetate
  • reaction mixture was cooled to 0° C and a solution of trifluoromethanesulfonyl chloride (44.24 g, 0.263 mol) in ethyl ether (50 mL) was added.
  • the reaction mixture was allowed to warm up to room temperature and stirred for 1 h. After removing the solvent, the residue was diluted with hexane (500 mL) and ⁇ vashed with a saturated NaHCO 3 solution and brine.
  • reaction mixture was diluted with IL ethyl ether and washed with saturated NaHC ⁇ 3 solution and brine. After drying with MgSO 4 , the solvent was removed to give N-(l-cyanocyclopropyl)-3-cyclopropylmethanesulfanyl-2(i?)-[2,2,2-trifluoro-l(5)-4- (fluorophenyl)ethylamino]-propionamide (41.4 g) as a brown oil.
  • a 2: 1 by volume acetonitrile:water solution was prepared and N-(l-cyanocyclopropyl)- 3-cyclopropylmethanesulfonyl-2(i?)-[2,2,2-trifluoro-l(5)-4-(fluorophenyl)ethylamino]- propionamide (Form A with some Form B or C) was added.
  • the vial was capped and placed onto a 60 0 C hot plate to give a clear solution. Additional amount of N-(l-cyanocyclopropyl)- 3-cyclopropylmethanesulfonyl-2(i?)-[2,2,2-trifluoro-l( 1 S)-4-(fluorophenyl)ethylamino]- propionamide was added to the above solution. The solution was then filtered with a 0.2 ⁇ m nylon filter into a warm receiving vial and capped. The hot plate was shut off and the solution was allowed to slowly cool to room temperature.
  • N-(l-cyanocyclopropyl)-3-cyclopr ⁇ pylmethanesulfonyl-2(i?)-[2,2,2-trifluoro- l(5)-4-(fluorophenyl)ethylamino]-propionamide as pure Form A.
  • N-(l-Cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(i?)-[2,2,2-trifluoro-l(5)-4- (fluorophenyl)ethylamino]-propionamide (Form A with some Form B or C) was dissolved in acetone to give a clear, light yellow solution.
  • N-(I -Cyanocyclopropyl)-3-cyclopropylmethanesulfonyl-2(i?)-[2,2,2-trifluoro- 1 ⁇ S)-4- (fluorophenyl)ethylamino] -propionamide (24.4 mg) (Form A with some Form B or C) was added to toluene (500 ⁇ L ). The solution was heated to approximately 100 0 C on a hot plate. A clear solution was obtained. The solution was filtered through a pre-warmed syringe and 0.2 ⁇ m nylon syringe filter. The filtrate was collected in a pre-warmed vial.
  • the capillary tube was then removed from the melting point apparatus and placed immediately in a liquid nitrogen bath to give N-(l-cyanocyclopropyl)-3- cyclopropylmethanesulfonyl-2(i?)-[2,2,2-trifluoro-l(5)-4-(fluorophenyl)ethylamino]- propionamide as Form D.
  • XPRD analysis showed the amount of Form D in the product was about 90% pure.
  • the polymorphic purity of the compound of Formula (I) was determined using XRPD analysis which has a detection error of about 3%. It should be understood that other more sensitive spectroscopic methods such as Raman Spectroscopy and solid state ⁇ MR could be used to determine the polymorphic purity of the compounds of the invention more precisely.
  • test compounds in varying concentrations were prepared in 10 ⁇ L of dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 ⁇ L, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and ⁇ aCl, 100 mM); ⁇ -mercaptoethanol, 2.5 mM; and BSA, 0.00%.
  • Assay buffer 40 ⁇ L, comprising: MES, 50 mM (pH 6.5); EDTA, 2.5 mM; and ⁇ aCl, 100 mM); ⁇ -mercaptoethanol, 2.5 mM; and BSA, 0.00%.
  • Human cathepsin S (0.05 pMoles in 25 ⁇ L of assay buffer) was added to the dilutions.
  • the assay solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 min at room temperature.
  • lip 10 is proteolytically degraded to enable loading of a peptide fragment and subsequent MHC-II presentation on the surface of antigen presenting cells.
  • the cleavage process is mediated by Cathepsin S.
  • the lip 10 assay is an in vitro measure of a compound's ability to block cathepsin S and by extension antigen presentation. A compound that causes the accumulation of lip 10 at low concentration would be expected to block presentation of antigens.
  • Raji cells (4 x 10 6 ) were cultured with 0.02% DMSO or different concentrations of Cathepsin S inhibitors in RPMI medium 1640 containing 10 % (v/v) FBS, 10 mM HEPES, 2 mM L-glutamine, and 1 mM sodium pyruvate for four h at 37°C in 5% CO 2 humidified atmosphere. After the culture period, cells were washed with cold PBS and cells were then lysed in NP-40 lysis buffer (5 mM EDTA, 1% NP-40, 150 mM NaCl, and 50 mM Tris, pH 7.6) with protease inhibitors. Protein determinations were performed and Iy sate samples were boiled in reducing SDS sample buffer.
  • NP-40 lysis buffer 5 mM EDTA, 1% NP-40, 150 mM NaCl, and 50 mM Tris, pH 7.6
  • Proteins were separated by electrophoresis on 12% NuP AGE® Bis-Tris gels. Proteins were then transferred to nitrocellulose membranes, and after incubation with blocking buffer (5% non-fat dry milk in PBS-Tween), the blots were incubated with the primary antibody against human CD74 invariant chain synthetic peptide

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Abstract

La présente invention a pour objet des formes polymorphes du N-(1-cyanocyclopropyl)-3-cyclopropylméthanesulfonyl-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophényléthylamino)propionamide, ainsi que des méthodes d’utilisation desdites formes pour traiter une maladie induite par la cathepsine S, des préparations pharmaceutiques contenant lesdites formes, et des procédés de synthèse desdites formes.
EP05798153A 2004-09-17 2005-09-16 Formes polymorphes du n-(1-cyanocyclopropyl)-3-cyclopropylméthanesulfonyl-2(r)-(2,2,2-trifluoro-1(s)-(4-fluorophényl)éthylamino)propionamide, un inhibiteur de la cystéine protéase Withdrawn EP1797032A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
PCT/US2004/030442 WO2005028429A2 (fr) 2003-09-18 2004-09-17 Composes contenant un haloalkyle utilise comme inhibiteurs de cysteine protease
US10/943,768 US7547701B2 (en) 2003-09-18 2004-09-17 Haloalkyl containing compounds as cysteine protease inhibitors
US66424405P 2005-03-21 2005-03-21
PCT/US2005/033074 WO2006034006A1 (fr) 2004-09-17 2005-09-16 Formes polymorphes du n-(1-cyanocyclopropyl)-3-cyclopropylméthanesulfonyl-2(r)-(2,2,2-trifluoro-1(s)-(4-fluorophényl)éthylamino)propionamide, un inhibiteur de la cystéine protéase

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US7893093B2 (en) * 2005-03-22 2011-02-22 Virobay, Inc. Sulfonyl containing compounds as cysteine protease inhibitors
EP3946332A1 (fr) 2019-04-05 2022-02-09 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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