WO2008034781A1 - Sel d'inhibiteur de cystéine protéase - Google Patents

Sel d'inhibiteur de cystéine protéase Download PDF

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Publication number
WO2008034781A1
WO2008034781A1 PCT/EP2007/059752 EP2007059752W WO2008034781A1 WO 2008034781 A1 WO2008034781 A1 WO 2008034781A1 EP 2007059752 W EP2007059752 W EP 2007059752W WO 2008034781 A1 WO2008034781 A1 WO 2008034781A1
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Prior art keywords
compound
methyl
compound according
benzenesulphonate
butyl
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PCT/EP2007/059752
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English (en)
Inventor
Craig Grant
Stephen Watt
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Medivir Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • 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

Definitions

  • the present invention relates to a novel salt of a known cysteine protease inhibitor.
  • it relates to the benzenesulphonate salt of N-[(S)-1-((3aS,6S,6aS)-6-fluoro-3-oxo-hexahydro- furo[3,2-b]pyrrole-4-carbonyl)-3-methyl-butyl]-4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]- benzamide.
  • the present invention also relates to pharmaceutical formulations containing the compound and to therapeutic uses thereof, particularly for the treatment of inflammatory and allergic conditions.
  • Pathogenic cathepsin like enzymes include the bacterial gingipains, the malarial falcipains I, II, III et seq and cysteine proteases from Pneumocystis carinii, Trypanosoma cruzei and brucei, Crithidia fusiculata, Schistosoma spp.
  • Metastatic neoplastic cells typically express high levels of proteolytic enzymes that degrade the surrounding matrix and inhibition of cathepsin K may thus assist in treating neoplasias.
  • Compound I benzenesulphonate has an improved physico-chemical profile, especially in terms of crystallinity, moisture stability and adequate water solubility than Compound I free base and other salt forms of Compound I.
  • Figure 1 shows an X-ray powder diffraction pattern of Compound I benzenesulphonate.
  • Figure 2 shows a comparison of the X-ray powder diffraction patterns of Compound I benzenesulphonate, methanesulphonate and free base.
  • Figure 5 shows a gravimetric vapour sorption isotherm for Compound I benzenesulphonate.
  • Figure 6 shows X-ray powder diffraction patterns of Compound I benzenesulphonate before and after gravimetric vapour sorption testing.
  • Figure 7 shows X-ray powder diffraction patterns of Compound I benzenesulphonate prepared at different scales.
  • Figure 8 XRPD of Compound I benzenesulphonate precipitate from different solvents.
  • Figure 9 XRPD of Compound I benzenesulphonate recovered from water.
  • Benzenesulphonate (also known as 'besylate') is the anion formed by the reaction of benzene sulphonic acid with a base:
  • Water solubility i.e. hydrophilicity
  • hydrophilicity is an important physical property of pharmaceutical agents which impacts their pharmacokinetics. In many circumstances an increased water solubility is desirable.
  • Crystallinity is another important physical property. Highly crystalline solids are generally easier to handle (for example, having more consistent physical properties) compared to amorphous or partially-crystalline solids. Furthermore, the exact crystalline form can affect, for example, dissolution rates and stability (such as moisture stability).
  • Compound I benzenesulphonate in solid crystalline form.
  • the crystalline form in which Compound I benzenesulphonate is obtained when a solution of benzenesulphonic acid in tetrahydrofuran is added to a solution of Compound I free base in dichloromethane is provided.
  • the same crystalline form of Compound I benzenesulphonate may be prepared from other solvents or solvent mixtures.
  • Consistency and reliability in pharmaceutical applications are of the utmost importance, both in the context of the initial manufacture of a pharmaceutical product and during the subsequent period prior to administration. Stability of a pharmaceutical agent, for example stability of the physical form to moisture, is therefore also a desirable property.
  • the Compound I benzenesulphonate is unsolvated.
  • the Compound I benzenesulphonate is in the form of a physiologically acceptable solvate (for example a hydrate).
  • Compound I may be prepared by solution or solid phase synthetic procedures which are known to those skilled in the art, for example, according to the procedure described in WO2005/066180 (summarised in Scheme 1 below).
  • Compound I benzenesulphonate may be prepared by the reaction of Compound I free base with benzenesulphonic acid.
  • Compound I free base is dissolved in a suitable solvent (for example dichloromethane) before mixing with benzenesulphonic acid in a suitable solvent (for example tetrahydrofuran).
  • a suitable solvent for example dichloromethane
  • benzenesulphonic acid for example tetrahydrofuran
  • Additional solvents in which Compound I free-base may be dissolved include acetone, and also mixtures of acetone and with methyl-tert-butyl ether (MTBE), methyl-ethyl-ketone (MEK) or methyl-isobutyl-ketone (MIBK).
  • MTBE methyl-tert-butyl ether
  • MEK methyl-ethyl-ketone
  • MIBK methyl-isobutyl-ketone
  • Compound I benzenesulphonate may be expected to be of use in the treatment of disorders mediated by cathepsin K.
  • Compound I benzenesulphonate as a medicament. Also provided is the use of Compound I benzenesulphonate in the manufacture of a medicament for the treatment of disorders mediated by cathepsin K. Additionally provided is a method for the treatment of a disorder mediated by cathepsin K comprising administering a safe and effective amount of Compound I benzenesulphonate.
  • Compound I benzenesulphonate While it is possible for Compound I benzenesulphonate to be administered in isolation, it will typically be presented as part of a pharmaceutical composition. Such a composition will comprise Compound I benzenesulphonate together with one or more pharmaceutically acceptable excipients. Said pharmaceutically acceptable excipients will be suitable for administration and will be compatible with the other ingredients of the composition.
  • An additional aspect of the present invention is therefore a pharmaceutical composition comprising Compound I benzenesulphonate and one or more pharmaceutically acceptable diluents or carriers.
  • compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the pharmaceutical composition is an orally administered formulation.
  • the compositions may conveniently be presented in unit dosage form (e.g. tablets and sustained release capsules) and may be prepared by any method known in the art of pharmacy.
  • Such methods include the step of bringing into association Compound I benzenesulphonate with the one or more pharmaceutically acceptable diluents or carriers.
  • the compositions are prepared by uniformly and intimately bringing into association the Compound I benzenesulphonate with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • 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.
  • Compound I benzenesulphonate is also useful in combination with known agents useful for treating or preventing osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally increased bone turnover, periodontal disease, tooth loss, bone fractures, atherosclerosis, obesity, parasitic infection, rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignancy, and multiple myeloma. Combinations Compound I benzenesulphonate with other agents useful in treating or preventing osteoporosis or other bone disorders are therefore considered to fall within the scope of the invention.
  • agents include the following: an organic bisphosphonate; an estrogen receptor modulator; an androgen receptor modulator; an inhibitor of osteoclast proton ATPase; an inhibitor of HMG- CoA reductase; an integrin receptor antagonist; Vitamin D or an analogue thereof, an osteoblast anabolic agent, such as PTH; a selective cyclooxygenase-2 inhibitor (COX-2 inhibitor); an inhibitor of interleukin-1- beta; a LOX/COX inhibitor, a RANKL inhibitor; and pharmaceutically acceptable salts and mixtures thereof.
  • HMG-CoA reductase inhibitors where an open-acid form can exist
  • salt and ester forms may preferably be formed from the open-acid, and all such forms are included within the meaning of the term "HMG-CoA reductase inhibitor" as used herein.
  • the HMG-CoA reductase inhibitor is selected from lovastatin and simvastatin, and most preferably simvastatin.
  • the term "pharmaceutically acceptable salts" with respect to the HMG-CoA reductase inhibitor shall mean non toxic salts of the compounds employed in this invention which are generally prepared by reacting the free acid with a suitable organic or inorganic base, particularly those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc and tetramethylammonium, as well as those salts formed from amines such as ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N, N'- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, 1-p-chlorobenzyl-2-pyrrolidine-1 '-yl-methylbenz-imidazole, diethylamine, piperazine, and tris(hydroxymethyl) aminomethane.
  • a suitable organic or inorganic base particularly those formed from cations such as sodium
  • salt forms of HMG-CoA reductase inhibitors may include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexyl resorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pama
  • Ester derivatives of the described HMG-CoA reductase inhibitor compounds may act as prodrugs which, when absorbed into the bloodstream of a warm-blooded animal, may cleave in such a manner as to release the drug form and permit the drug to afford improved therapeutic efficacy.
  • integrin receptor antagonists refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the alpha-v-beta-3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the alpha-v-beta-5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the alpha-v-beta-3 integrin and the alpha-v-beta-5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
  • the term also refers to antagonists of the alpha-v-beta-6, alpha-v-beta-8, alpha-1-beta-1 , alpha-2-beta-1 , alpha-6-beta-1 and alpha-6- beta-4 integrins.
  • the term also refers to antagonists of any combination of alpha-v-beta-3, alpha-v-beta-5, alpha-v-beta-6, alpha-v-beta-8, alpha-1-beta-1 , alpha-2-beta-1 , alpha-5-beta-1 , alpha-6-beta-1 and alpha-6-beta-4 integrins.
  • An osteoblast anabolic agent refers to agents that build bone, such as PTH.
  • PTH parathyroid hormone
  • the intermittent administration of parathyroid hormone (PTH) or its amino-terminal fragments and analogues have been shown to prevent, arrest, partially reverse bone loss and stimulate bone formation in animals and humans.
  • PTH parathyroid hormone
  • Studies have demonstrated the clinical benefits of parathyroid hormone in stimulating bone formation and thereby increasing bone mass and strength. Results were reported by RM Neer et al., in New Eng J Med 344 1434-1441 (2001 ).
  • a selective cyclooxygenase-2 inhibitor refers to a type of nonsteroidal anti- inflammatory drug (NSAID), that inhibit the with the COX-2 coenzyme, which contributes to pain and inflammation in the body.
  • NSAID nonsteroidal anti- inflammatory drug
  • Nonlimiting examples of COX-2 inhibitors include: celecoxib, etoricoxib, parecoxib, rofecoxib, lumaricoxib and valdecoxib.
  • parathyroid hormone-related protein fragments or analogues such as PTHrP (1-36) have demonstrated potent anticalciuric effects; see M.A. Syed et al., "Parathyroid hormone- related protein-(1-36) stimulates renal tubular calcium reabsorption in normal human volunteers: implications for the pathogenesis of humoral hypercalcemia of malignancy, " JCEM 86: 1525- 1531 (2001 ) and may also have potential as anabolic agents for treating osteoporosis.
  • a preferred combination in accordance with the invention comprises codosing the salt of the invention simultaneously or sequentially with parathyroid hormone (PTH) or a fragment thereof, such as PTHrP (1-36).
  • PTH parathyroid hormone
  • PTHrP a fragment thereof
  • treatment may also be extended to cover prophylaxis.
  • XRPD patterns were collected either on a Bruker AXS C2 GADDS or a Siemens D5000 diffractometer.
  • X-ray powder diffraction patterns on the Bruker C2 were acquired using Cu Ka radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for auto-sample positioning and a HiStar 2-dimensional area detector.
  • X-ray optics consist of a single Gobel multilayer mirror coupled with a pinhole collimator of 0.3 mm.
  • the beam divergence i.e. the effective size of the X-ray beam on the sample, was approximately 4 mm.
  • a ⁇ - ⁇ continuous scan mode was employed with a sample-detector distance of 20 cm which gives an effective 2 ⁇ range of 3.2-29.8°.
  • the sample would be exposed to the X-ray beam for 120 seconds.
  • Samples run under ambient conditions were prepared as flat plate specimens using powder as received without grinding. Approximately 1-2 mg of the sample was lightly pressed on a glass slide to obtain a flat surface.
  • X-ray powder diffraction patterns on samples acquired on a Siemens D5000 diffracto meter using Cu Ka radiation (40 kV, 40 mA), ⁇ - ⁇ goniometer, automatic divergence and receiving slits, a graphite secondary monochromator and a scintillation counter. The data were collected over an angular range of 2° to 42° 2 ⁇ in continuous scan mode using a step size of 0.05° 2 ⁇ and a step time of 5 second.
  • Example 1 Synthesis of N-[(S)-1 -((3aS,6S,6aS)-6-Fluoro-3-oxo-hexahydro-furo[3,2- b]pyrrole-4-carbonyl)-3-methyl-butyl]-4-[2-(4-methyl-piperazin-1 -yl)-thiazol-4-yl]- benzamide free base.
  • Trifluoroacetic acid 21 Benzene sulphonic acid, acetone, 2% water.
  • a 160 L glass-lined steel reactor set-up for cooling to -10 0 C and heating to 70 0 C is charged with N,N-dimethylformamide (7.9 kg) and (3R,3aR,6S,6aS)-6-fluoro-hexahydro-furo[3,2-b]pyrrol- 3-ol hydrochloride (1.9 kg, 10.3 mol).
  • To the suspension is added 1-hydroxybenzotriazole (12 % H 2 O) (1.6 kg, 10.6 mol), Z-L-Leucine (94 % pure, 2.9 kg, 10.3 mol) followed by N-(3- dimethylaminopropyl)-N'-ethyl-carbodiimide hydrochloride (3.6 kg, 1 8.8 mol).
  • the reaction mixture is kept under nitrogen, and the temperature is adjusted to 20-25 0 C. Over a period of 1 - 2 hours, 4-methylmorpholine (1.6 kg, 15.8 mol) is added. The resulting solution is allowed to react for 4 to 24 hours. The course of the reaction is followed by TLC until the reaction is deemed complete (typically 10 to 24 hours). The completed reaction mixture is quenched using tap water (79 kg). The product is extracted into dichloromethane (4 x 13 kg). The organic phases are washed with 1 M hydrochloric acid (2 x 10 kg) and 6 % sodium hydrogencarbonate (10.6 kg). The organic extracts are combined, and the solvent is removed by distillation at reduced pressure, finally at 50 - 60 0 C and at a pressure ⁇ 150 mbar.
  • the residue is dissolved in tert-butyl methyl ether (10 kg), and washed with tap water (2 x 13 kg) and saturated with 25 % sodium chloride (5.2 kg).
  • the aqueous phases are extracted with tert-butyl methyl ether (10 kg).
  • the organic phases are combined, and the solvent is removed by distillation to dryness at reduced pressure, finally at 50 - 60 0 C and at a pressure ⁇ 150 mbar.
  • Toluene (5 kg) is added, and distillation is continued as above.
  • the distillation residue is re-dissolved in toluene (8 kg), and purified by column chromatography on a column prepared from silica gel 60, 40-63 ⁇ (24 kg) and toluene (53-74 kg).
  • a 63 L glass-lined steel reactor set up for cooling to -10 0 C and heating to 70 0 C is charged with the dichloromethane solution of [1S-1-((3R,3aR,6S,6aS)-6-fluoro-3-hydroxy-hexahydro- furo[3,2b]pyrrole-4-carbonyl)-3-methyl-butyl]-carbamic acid benzyl ester (neat 3.8 kg, 9.6 mol). Dess-Martin periodinane (4.6 kg, 10.8 mol) is added. The suspension is kept under nitrogen and the temperature is adjusted to 20 - 25 0 C. The reaction is stirred for 10 to 24 hours. The course of the reaction is followed by LC-MS.
  • the reaction is stirred for another 4 - 24 hours.
  • the reaction mixture is quenched with a suspension of sodium hydrogen carbonate (2.4 kg, 28.6 mol) and tap water (26 kg).
  • the reaction mixture is stirred for 2 to 4 hours, and celite 545 (2.1 kg) is added.
  • the suspension is filtered on a pad of celite 545 back into the reactor.
  • the lower, organic phase is separated and secured.
  • the filter cake is washed with dichloromethane (26 - 40 kg).
  • the filtrate is used to wash the upper, aqueous phase.
  • the lower, organic phase is separated and secured.
  • the organic phases are washed with 6 % sodium hydrogen carbonate (26 kg), and then washed with 25 % sodium chloride (5.2 kg).
  • the organic phases are combined and dried with magnesium sulfate (3 - 5 kg).
  • the suspension is filtered.
  • the filter cake is washed with dichloromethane (10 - 15 kg).
  • the filtrate and wash are combined and evaporated by distillation at reduced pressure until a final volume of 10 - 15 L, using a jacket temperature of 50 - 60 0 C.
  • Methanol (15 - 20 kg) is added to the residue and concentrated to a final volume of 15 - 20 L by distillation at reduced pressure, using a jacket temperature of 50 - 60 0 C.
  • a sample of this solution is used for estimating the yield 4.3 kg (113 %).
  • a 63 L glass-lined steel reactor set up for cooling to - 10 0 C and heating to 70 0 C is charged with the methanol solution of [1S-1-((3aS,6S,6aS)-6-fluoro-3-oxo-hexahydro-furo[3,2-b]pyrrole- 4-(carbonyl)-3-methyl-butyl]-carbamic acid benzyl ester (neat 4.3 kg, 11.0 mol). Trimethyl orthoformate (6 kg, 56.5 mol) is added. Benzenesulfonic acid (0.2 kg, 1.3 mol) is added. The mixture is kept under nitrogen, and the temperature is adjusted to 40 - 60 0 C. The reaction is continued for 4 to 8 hours (acceptance criteria; absent or barely visible, based on TLC), allowing the formed methyl formate to distill off.
  • the solvent is removed by distillation at reduced pressure, finally at pressure ⁇ 50 mBar and at a jacket temperature of 50 - 60 0 C.
  • the residue is dissolved in toluene (8 kg).
  • the resulting solution is quenched on 6 % sodium hydrogencarbonate (11 kg).
  • the phases are separated, and the aqueous phase is extracted with additional toluene (4 kg).
  • the organic phases are washed with 25e/e sodium chloride solution (5.2 kg).
  • the organic phases are combined, and the solvent is removed by distillation at reduced pressure, finally at p ⁇ 50 mBar and at a jacket temperature of 50 - 60 0 C.
  • the evaporation residue is re-dissolved in toluene (4.5 kg).
  • the crude product solution is purified on a column prepared from silica gel 60 (21 kg) and toluene (45 kg).
  • the toluene solution of the crude product is applied to the column.
  • the column is eluted with toluene (95 kg), 2.5 % (v/v) acetone in toluene (230 kg) and then with 5 % (v/v) acetone in toluene (138 kg).
  • Fractions of approximately 10 L are taken.
  • Fractions which look pure by TLC purity > 90 % by TLC
  • the solvent is removed by distillation at reduced pressure, finally at p ⁇ 50 mBar, and at a jacket temperature of 50 - 60 0 C.
  • the residue is re- dissolved in methanol (10 kg).
  • a sample of this solution is used for estimating the yield - 4.3 kg (90 %).
  • a 63 L glass-lined steel reactor set up for cooling to - 10 0 C and heating to 70 0 C is filled with nitrogen and charged with 10 % palladium on charcoal (0.17 - 0.18 kg).
  • the methanolic solution of [1 S-1 -((3aS,6S,6aS)-6-fluoro-3,3-dimethoxy-hexahydro-furo-[3,2-b]pyrrole-4-carbonyl)-3- methyl-butyl]-carbamic acid benzyl ester (neat 3.5 kg, 8.0 mol) is added.
  • the solution is kept under hydrogen, and the temperature is adjusted to 20 - 3OeC.
  • the hydrogenation is continued in a stream of hydrogen for 4 to 8 hours.
  • a 160 L glass-lined steel reactor set up for cooling to - 10 0 C and heating to 70 0 C is filled with nitrogen and charged with the N,N-dimethylformamide solution of 2-amino-[1S-1-((3aS,6S,6aS)- fluoro-3,3-dimethoxy-hexahydro-furo-[3,2-b]pyrrole-4-yl)-4-methyl]-pentan-1-one ( ⁇ 50 kg, neat - 3.5 kg, 11 .5 mol).
  • the reaction mixture is quenched on a mixture of tap water (120 kg) , sodium hydrogencarbonate (7.4 kg) and tert-butyl methyl ether (43 kg).
  • the organic phase is separated.
  • the aqueous phase is further extracted with tert-butyl methyl ether (3 x 21 kg).
  • the organic phases are initially washed with tap water (81 kg), then with a mixture of tap water (41 kg) and sodium hydrogencarbonate (0.4 kg) and finally with 25 % sodium chloride (20 kg).
  • the organic phases are combined, and the solvent is removed by distillation at reduced pressure, finally at 50 - 60 0 C and p ⁇ 100 mbar.
  • the suspension is filtered, and the filter cake is washed with dichloromethane (20 kg).
  • Toluene (15 kg) is added to the filtrate and the wash.
  • the solvent is removed by distillation at reduced pressure, finally at 50 - 60 0 C and p ⁇ 100 mbar.
  • the residue is dissolved in a mixture of toluene (5.55 kg) and acetone (1.30 kg), and purified on a column prepared from silica gel 60 (63 kg) and a mixture of toluene (104 kg) and acetone (24 kg).
  • the column is eluted with a mixture of toluene (945 kg) and acetone (216 kg), followed by toluene (627 kg) and acetone (380 kg), and finally acetone (400 kg).
  • the pure fractions (purity ⁇ 90 %) are selected by HPLC, and the solvent is then removed by distillation at reduced pressure, finally at 50 - 60 0 C and p ⁇ 100 mbar.
  • the residue is dissolved in dichloromethane (7 kg) Yield: 5.2 kg (76 %) (based on an evaporation residue).
  • a 63 L glass-lined steel reactor set up for cooling to - 10 0 C and heating to 30 0 C is filled with nitrogen, and charged with trifluoroacetic acid (37.5 kg), and cooled to 9 - 10 0 C. Keeping the reaction temperature below 15 0 C, the solution of N-[1 S-1-((3aS,6S,6aS)-6-fluoro-3,3- dimethoxy-hexahydro-furo[3,2-b]pyrrole-4-carbonyl)-3-methyl-butyl]-4-[2-(4-methyl-piperazin-1- yl)-thiazol-4-yl]benzamide (2.6 kg, 4.4 mol) in dichloromethane is added.
  • the temperature of the reaction mixture is adjusted to 20 - 22 0 C, and the reaction is continued until deemed to have reached completion by HPLC (typically 5 - 6 hours).
  • Heptanes 35 kg are added.
  • the solvent is evaporated by distillation at reduced pressure, using a jacket temperature of 20 - 22 0 C until a residue of approximately 8 L remains.
  • Heptanes 25 kg are added.
  • the solvent is again evaporated by distillation at reduced pressure, using a jacket temperature of 20 - 22 0 C until a residue of approximately 3 L remains.
  • the residue is dissolved in dichloromethane (66 kg).
  • the dichloromethane solution is quenched on a suspension of sodium hydrogencarbonate (3.6 kg) and tap water (60 kg).
  • the organic phase is separated.
  • the aqueous phase is extracted with dichloromethane, and the organic phase is secured.
  • the organic phases are washed with 6 % aqueous sodium hydrogencarbonate (2 x 43.5 kg).
  • the organic phases are washed with 25 % sodium chloride (62 kg).
  • the combined organic phase is applied onto a column prepared from silica gel 60 (11 kg) and dichloromethane.
  • the column is then washed with dichloromethane (20 kg).
  • the product is then washed out with 5 % aqueous acetone (w/w) (123 kg).
  • the fractions containing the desired compound are pooled and evaporated, finally using a rotary evaporator, to dryness at reduced pressure and at a jacket temperature of 15 - 25 0 C.
  • Oils were triturated using diethylether as a means for obtaining solids for further characterisation.
  • Aqueous solubility was determined by suspending sufficient test compound in 0.25 ml of water to give a maximum final concentration equivalent to ⁇ 10 mg/ml of the parent free base form of the compound. The suspension was equilibrated at 25 0 C for 24 hours then the pH was measured. The suspension was then filtered through a glass fibre C filter into a 96 well plate. The filtrate was then diluted by a factor of 101.
  • Example 2 Salts prepared in Example 2 were stored for 1 week at 4O 0 C and 75% relative humidity before being analysed again by XRPD.
  • Figure 5 shows the GVS results and Figure 6 shows XRPD patterns obtained prior and subsequent to GVS analysis.
  • FIG. 8 illustrates the XRPD patterns obtained following preceiptation from aceteone, acetone/Ml BK and acetone/MEK. This provides evidence that the crystalline form of Compound I benzenesulphonate having the XRPD pattern shown in Figure 1 can be reliably produced under a range of conditions.
  • Example 6a An optimised procedure for the preparation of N-[(S)-1 -((3aS,6S,6aS)-6- Fluoro-3-oxo-hexahydro-furo[3,2-b]pyrrole-4-carbonyl)-3-methyl-butyl]-4-[2-(4-methyl- piperazin-1 -yl)-thiazol-4-yl]-benzamide benzenesulphonate.
  • a 63 L glass-lined steel reactor set up for cooling to -10 0 C and heating to 30 0 C is filled with nitrogen, and charged with N-[(S)-1-((3aS,6S,6aS)-6-fluoro-3-oxo-hexahydro-furo[3,2-b]pyrrole- 4-carbonyl)-3-methyl-butyl]-4-[2-(4-methyl-piperazin-1 -yl)-thiazol-4-yl]-benzamide (where the ketone existed as a mixture of ketone and hydrate) (5.0 kg, 8.9 mol) and acetone (16 kg). Purified water (0.5 kg) is added. A pH electrode is installed for measuring pH in the range of 1 to 7.
  • the temperature of the suspension is adjusted to 15-20 0 C. Keeping the reaction temperature below 20 0 C, benzenesulphonic acid (approximately 1.5 kg, 9.5 mol) is added in order to obtain a final pH of 3.5 to 4.5. The resulting solution is seeded.
  • the crystallizing suspension is cooled to 5 - 8 0 C. Stirring at this temperature is continued for 20-72 hours.
  • the suspension is filtered, and the filter cake is washed with acetone (6-10 kg).
  • the wet filter cake is dried in a vacuum dryer, finally at 20 - 25 0 C and pressure ⁇ 5 mBar for 3-5 days, or until the level of acetone is below an acceptable level. Yield 5.5 kg (86 %).
  • Example 7 Recovery of undissolved N-[(S)-1 -((3aS,6S,6aS)-6-Fluoro-3-oxo-hexahydro- furo[3, 2-b]pyrrole-4-carbonyl)-3 -methyl -butyl]-4-[2-(4-methyl-piperazin-1 -yl)-thiazol-4-yl]- benzamide benzenesulphonate from water.
  • Figure 9 illustrates the XRPD patterns for crystalline Compound I benzenesulphonate and for the residue recovered from aqueous solution. Although the diffraction pattern for the recovered material is weak due to the quantity of material obtained, the pattern is essentially the same as that for crystalline Compound I benzenesulphonate which had not been contacted with water, thereby further demonstrating the stability of crystalline Compound I benzenesulphonate.

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Abstract

Composé N-[(S)-1-((3aS,6S,6aS)-6-fluoro-3-oxo-hexahydro-furo[3,2-b]pyrrole-4-carbonyl)-3-méthyl-butyl]-4-[2-(4-méthyl-pipérazin-1-yl)-thiazol-4-yl]-benzamide benzènesulphonate, son utilisation en tant que médicament et ses procédés de préparation.
PCT/EP2007/059752 2006-09-18 2007-09-17 Sel d'inhibiteur de cystéine protéase WO2008034781A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0618263.8 2006-09-18
GBGB0618263.8A GB0618263D0 (en) 2006-09-18 2006-09-18 Compound

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WO2008034781A1 true WO2008034781A1 (fr) 2008-03-27

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GB (1) GB0618263D0 (fr)
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005066180A1 (fr) * 2004-01-08 2005-07-21 Medivir Ab Inhibiteurs de cysteine protease

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005066180A1 (fr) * 2004-01-08 2005-07-21 Medivir Ab Inhibiteurs de cysteine protease

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GB0618263D0 (en) 2006-10-25

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