Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
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  • 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
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  • 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
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  • A61P25/00—Drugs for disorders of the nervous system
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  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

• the present invention relates to polymorphic forms of (S) -l-cyanobutan-2-yl (S)-I- (3- (3- (3-methoxy-4- (oxazol-5- yl) phenyl) ureido) phenyl) ethylcarbamate, processes therein, pharmaceutical compositions thereof, and methods therewith.
• the present invention relates to polymorphic forms of (S) -l-cyanobutan-2-yl (S) -1- (3- (3- (3 ⁇ methoxy-4- (oxazol-5- yl) phenyl ) ureido) phenyl) ethylcarbamate having the structure below (hereinafter "Compound 1”) :
• Compound 1 is a potent IMPDH inhibitor useful in treating IMPDH-mediated diseases.
• Compound 1, compositions thereof, and methods therewith are disclosed in United States Patent ' 6, 498,178 ((hereinafter "the '178 patent"), the entire disclosure whereof is incorporated herein by reference
• the present invention provides two polymorphic forms of Compound 1, namely, Form Al and Form B2.
• the present invention also relates to processes for making these polymorphic forms .
• the invention also relates to the use of these polymorphic forms in therapeutic methods and in the preparation of pharmaceutical compositions comprising such polymorphic forms .
• the present invention also relates to an amorphous form of Compound 1 and processes for producing such an amorphous form.
• FIGURE 1 is an x-ray powder diffraction pattern (XRPD) of Form Al of (S) -l-cyanobutan-2-yl (S) -1- (3- (3- (3-methoxy-4- (oxazol-5-yl ) phenyl) ureido) phenyl ) ethylcarbamate .
• FIGURE 2 is an XRPD of Form B2 of (S) -l-cyanobutan-2-yl (S)-I- (3- (3- (3-methoxy-4- (oxazol-5- yl ) phenyl ) ureido ) phenyl ) ethylcarbamate .
• FIGURE 3 is an XRPD of amorphous form of (S)-I- cyanobutan-2-yl (S) -1- (3- (3- (3-me ( thoxy-4- (oxazol-5- yl )phenyl ) ureido) phenyl) ethylcarbamate .
• FIGURE 4 is a Differential Scanning Calorimetry (DSC) thermogram of Form Al of (S) -l-cyanobutan-2-yl (S) -1- (3- (3- (3- methoxy-4- (oxazol-5-yl)phenyl) ureido) phenyl) ethylcarbamate .
• FIGURE 5 is a DSC thermogram of amorphous (S) -l-cyanobutan-2-yl (S)-I- (3- (3- (3-methoxy-4- (oxazol-5- yl ) phenyl ) ureido) phenyl ) ethylcarbamate .
• (S) -l-cyanobutan-2-yl (S) -1- (3- (3- (3-methoxy-4- (oxazol- 5-yl ) phenyl) ureido) phenyl) ethylcarbamate (Compound 1) is a potent IMPDH inhibitor useful in treating IMPDH-mediated diseases .
• Two polymorphic forms of the free base of Compound 1 (Form Al and Form B2) have been identified.
• the polymorphs of the present invention may occur as racemates , racemic mixtures, and diastereomeric mixtures with all possible isomers and mixtures thereof being included in the present invention.
• the present invention provides polymorphic Form Al and Form B2 of Compound 1 with the (S) stereochemistry as indicated in the structure of Compound 1 herein .
• the present invention provides a polymorphic Form Al of (S) -l-cyanobutan-2-yl (S)-I- (3- (3- (3-methoxy-4- (oxazol-5- yl ) phenyl ) ureido) phenyl ) ethylcarbamate .
• the present invention provides a substantially pure polymorphic Form Al of (S)-I- cyanobutan-2-yl (S) -1- (3- (3- (3-methoxy-4- (oxazol-5- yl ) phenyl) ureido) phenyl) ethylcarbamate, wherein said polymorph comprises less than about 5% by weight of amorphous form.
• the present invention provides a substantially pure polymorphic Form Al of (S)-I- cyanobutan-2-yl (S) -1- (3- (3- (3-methoxy-4- (oxazol-5- yl ) phenyl) ureido) phenyl ) ethylcarbamate, wherein said polymorph comprises less than about 4% by weight of amorphous form.
• the present invention provides a substantially pure polymorphic Form Al of (S)-I- cyanobutan-2-yl (S) -1- (3- (3- (3-methoxy-4- (oxazol-5- yl) phenyl) ureido) phenyl) ethylcarbamate, wherein said polymorph comprises less than about 3% by weight of amorphous form.
• the present invention provides a substantially pure polymorphic Form Al of (S)-I- cyanobutan-2-yl (S) -1- (3- (3- (3-methoxy-4- (oxazol-5- yl) phenyl) ureido) phenyl ) ethylcarbamate, wherein said polymorph comprises less than about 5% by weight of either amorphous form or Form B2.
• the present invention provides a polymorphic Form Al of Compound 1 wherein the polymorph has a peak position at about 20.7 degrees 2-theta in an x-ray powder diffraction pattern obtained using Cu K alpha radiation.
• the present invention provides a polymorphic Form Al of Compound 1 wherein the polymorph has at least one additional peak position at about 12.2, 15.2, 19.8, or 23.2 degrees 2-theta in an x-ray powder diffraction pattern obtained using Cu K alpha radiation.
• the present invention provides a polymorphic Form Al of Compound 1 wherein the polymorph exhibits an endothermic event between about 16O 0 C and about 17 ⁇ °C measured by a Differential Scanning Calorimeter (DSC) .
• DSC Differential Scanning Calorimeter
• the endotherms of the respective Forms Al, B2 , and amorphous form may vary by about 0.01 to 100 0 C above or below the endotherms depicted in the Figures.
• the observed endotherm may also differ from instrument to instrument; however, it will generally be within the ranges defined herein provided the instruments are calibrated similarly.
• the present invention provides a process for preparing Form Al, as exemplified herein below.
• the present invention provides a method of converting polymorph Form B2 to Form Al by spontaneous crystallization of Form B2 in methanol or acetone to give Form Al .
• the present invention provides a process for preparing substantially pure polymorphic Form Al of (S) -l-cyanobutan-2-yl (S) -1- (3- (3- (3- methoxy-4- (oxazol-5-yl) phenyl )ureido) phenyl) ethylcarbamate comprising slow evaporation, fast evaporation, slow cool, crash cool, vapor diffusion, or slurry, or combinations thereof in a suitable solvent or mixtures of suitable solvents .
• substantially pure polymorphic Form
• Al is prepared by slow evaporation in acetone.
• Form Al is prepared by fast evaporation in a mixture of about
• Form Al is prepared by slow cool in acetone.
• Form Al is prepared by a crash cool in acetone or methanol .
• Form Al is prepared by vapor diffusion in methanol and water.
• Form Al is prepared by a slurry in methanol, methyl t-butyl ether, or toluene or a mixture of acetone and water.
• Form Al is prepared by slow cool and fast evaporation in acetone.
• Form Al is prepared by
• the present invention provides a pharmaceutical composition comprising Form Al and a pharmaceutically acceptable carrier or adjuvant.
• the present invention provides a method of formulating a pharmaceutical composition comprising Form Al of Compound 1, comprising the step of combining said Form Al with one or more suitable pharmaceutical carrier or adjuvant.
• the present invention provides a method of treating an IMPDH-mediated disease in a patient comprising the step of administering to said patient a therapeutically effective amount of substantially pure Form Al or a pharmaceutical composition comprising substantially pure Form Al.
• the present invention provides a process for preparing a substantially pure polymorph of Form Al, said process comprising at least one of the following steps : a) dissolving (S) -l-cyanobutan-2-yl (S) -1- (3- (3- (3-methoxy- 4- (oxazol-5-yl) phenyl) ureido) phenyl ) ethylcarbamate in a suitable solvent with suitable agitation at a suitable temperature to give a suitable solution; b) cooling said solution to about room temperature to give a suspension; c) filtering or centrifuging said suspension to give polymorph Form Al ; d) rinsing said Form Al a suitable number of times with a suitable solvent; and e) drying said Form Al at a suitable temperature under a suitable reduced pressure for a suitable period of time to constant weight.
• suitable solvents for step a) include those listed in Table 1 herein below.
• the present invention provides a polymorphic Form B2 of (S) -l-cyanobutan-2-yl (S)-I- (3- (3- (3-methoxy-4- (oxazol-5- yl) phenyl ) ureido) phenyl ) ethylcarbamate .
• the present invention provides a polymorphic Form B2 wherein the polymorph has a peak position at about 4.1 degrees 2-theta in an x-ray powder diffraction pattern obtained using Cu K alpha radiation.
• the present invention provides a polymorphic Form B2 wherein the polymorph has at least one additional peak position at about 12.6, 14.4, 16.4, 22.1, or 27.1 degrees 2-theta in an x-ray powder diffraction pattern obtained using Cu K alpha radiation.
• the present invention provides a process for preparing Form B2 , as exemplified herein below.
• the present invention provides a pharmaceutical composition comprising Form B2 and a pharmaceutically acceptable carrier or adjuvant.
• the present invention provides a method of formulating a pharmaceutical composition comprising an amorphous form of Compound 1, comprising the steps of:
• the present invention provides a method of treating an IMPDH-mediated disease in a patient comprising the step of administering to said patient a therapeutically effective amount of Form B2 or a pharmaceutical composition comprising Form B2.
• the present invention provides a substantially pure amorphous form of (S)-I- cyanobutan-2-yl (S) -1- (3- (3- (3-methoxy-4- (oxazol-5- yl ) phenyl ) ureido) phenyl ) ethylcarbamate wherein said amorphous form comprises less than 5% by weight of Form Al .
• the present invention provides an amorphous form of (S) -l-cyanobutan-2-yl (S)-I- (3- (3- (3-methoxy-4- (oxazol-5- yl ) phenyl ) ureido) phenyl ) ethylcarbamate .
• the present invention provides an amorphous form wherein the amorphous form exhibits an endothermic event at about 168 0 C and a broad endothermic event at about 214 0 C as measured by a Differential Scanning Calorimeter.
• the present invention provides a process to prepare an amorphous form of (S)-I- cyanobutan-2-yl (S) -1- (3- (3- (3-methox ⁇ -4- (oxazol-5- yl ) phenyl )ureido) phenyl ) ethylcarbamate comprising slow cool, slow evaporation, crash cool, or fast evaporation or combinations thereof of a solution of polymorphic Form Al in a suitable solvent or mixtures of suitable solvents.
• the amorphous form is prepared by slow evaporation in 2-butanone.
• the amorphous form is prepared by fast evaporation in absolute ethanol or a mixture of acetonitrile and n-propanol.
• the amorphous form is prepared by slow cool and fast evaporation in methanol.
• the amorphous form is prepared by crash cool and fast evaporation in tetrahydrofuran.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising the amorphous form according to any of the embodiments herein, wherein said composition is produced by combining said amorphous form with one or more suitable pharmaceutical carriers or adjuvants.
• the present invention provides a pharmaceutical composition comprising an amorphous form of Compound 1 and a pharmaceutical acceptable adjuvant or carrier.
• the present invention provides a method of treating an IMPDH-mediated disease in a patient comprising the step of administering to said patient a therapeutically effective amount of amorphous form or a pharmaceutical composition comprising amorphous form.
• suitable describes solvent, temperature, filtrate, agitation, solution, medium, quantity, period of time, etc.
• suitable solvents, temperature, filtrate, agitation, solution, medium, quantity, period of time, etc. are readily known to one of skill in the art.
• pharmaceutically acceptable carrier or adjuvant refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
• compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates , waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.
• ion exchangers alumina, aluminum stearate, lecithin
• serum proteins such as human serum albumin
• buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate,
• Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
• suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate
• Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N + (Ci_ 4 alkyl) 4 salts.
• alkali metal e.g., sodium and potassium
• alkaline earth metal e.g., magnesium
• ammonium and N + (Ci_ 4 alkyl) 4 salts e.g., sodium and potassium
• alkali metal e.g., sodium and potassium
• alkaline earth metal e.g., magnesium
• ammonium and N + (Ci_ 4 alkyl) 4 salts e.g., sodium and potassium
• compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
• parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
• the compositions are administered orally, intraperitoneally or intravenously.
• Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol .
• a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1, 3-butanediol .
• acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or di ⁇ glycerides .
• Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
• oils such as olive oil or castor oil
• These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
• a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
• Other commonly used surfactants such as Tweens , Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
• compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
• carriers commonly used include lactose and corn starch.
• Lubricating agents such as magnesium stearate, are also typically added.
• useful diluents include lactose and dried cornstarch.
• aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
• compositions of this invention may be administered in the form of suppositories for rectal administration.
• suppositories for rectal administration.
• suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
• suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
• compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
• Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. TopicalIy-transdermal patches may also be used.
• the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers .
• Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, poIyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
• the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers .
• Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 ⁇ octyldodecanol, benzyl alcohol and water.
• the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
• the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
• compositions of this invention may also be administered by nasal aerosol or inhalation.
• Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons , and/or other conventional solubilizing or dispersing agents.
• the pharmaceutically acceptable compositions of this invention are formulated for oral administration.
• compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the compound can be administered to a patient receiving these compositions .
• a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
• the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
• additional therapeutic agents which are normally administered to treat or prevent that condition, may also be present in the compositions of this invention.
• additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition are known as "appropriate for the disease, or condition, being treated. "
• compositions of this invention comprise a combination of an IMPDH inhibitor of this invention and one or more additional therapeutic or prophylactic agents, such as those disclosed herein
• both the IMPDH inhibitor and the additional agent (s) should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 to 80% of the dosage normally administered in a monotherapy regimen.
• the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
• compositions of this invention comprise a combination of an IMPDH inhibitor of this invention and one or more additional therapeutic or prophylactic agents
• both the compound and the additional agent should be present at dosage levels of between about 10 to 100% and in another embodiment between about 10 to 80% of the dosage normally administered in a monotherapy regimen.
• the pharmaceutical compositions of this invention comprise an additional immunosuppression agent.
• additional immunosuppression agents include, but are not limited to, cyclosporin A, FK506, rapamycin, leflunomide, de ⁇ xyspergualin, prednisone, azathioprine, mycophenolate mofetil, OKT3 , ATAG, mizoribine, and interferon including alpha-interferon such as PEG-Intron® and Pegasys®.
• interferon means a member of a family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation, and modulate immune response, such as interferon alpha, interferon beta, or interferon gamma.
• the interferon is a-interferon.
• a therapeutic combination of the present invention utilizes natural alpha interferon 2a.
• the therapeutic combination of the present invention utilizes natural alpha interferon 2b.
• the therapeutic combination of the present invention utilizes recombinant alpha interferon 2a or 2b.
• the interferon is pegylated alpha interferon 2a or 2b.
• Interferons suitable for the present invention include:
• the pharmaceutical compositions of this invention may additionally comprise an anti-cancer agent.
• anti-cancer agents include, but are not limited to, cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol, colchicine, cyclosporin A, phenothiazines, interferon and thioxantheres .
• the compositions of this invention additionally comprise another anti-viral agent, including an anti-HCV agent.
• anti-viral agents include, but are not limited to, immunomodulatory agents, such as ⁇ -, ⁇ - , and ⁇ -interferons , pegylated derivatized interferon- ⁇ compounds, and thymosin; other anti-viral agents, such as ribavirin (and the combination therapy of ribavirin and pegylated interferon [Rebetrol®] ) , d4T, ddl, AZT, amprenavir, fos-amprenavir, acyclovir, NS3-NS4A protease inhibitors such as those disclosed in PCT publication No.
• immunomodulatory agents such as ⁇ -, ⁇ - , and ⁇ -interferons , pegylated derivatized interferon- ⁇ compounds, and thymosin
• other anti-viral agents such as ribavirin (and the combination therapy of ribavirin and pegylated interferon [Rebetrol®]
• WO 02/018369 amantadine, cytovene, ganciclovir, ritonivir, trisodium phosphonoformate, and telbivudine; other inhibitors of hepatitis C proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors); inhibitors of other targets in the HCV life cycle, including but not limited to, helicase and polymerase inhibitors; inhibitors of internal ribosome entry; and broad- spectrum viral inhibitors, such as IMPDH inhibitors (e.g., IMPDH inhibitors disclosed in United States Patents 5,807,876 and 6,498,178, mycophenolic acid and derivatives thereof) .
• IMPDH inhibitors e.g., IMPDH inhibitors disclosed in United States Patents 5,807,876 and 6,498,178, mycophenolic acid and derivatives thereof
• compositions of this invention additionally comprise another agent, including a cytochrome P- 450 inhibitor.
• cytochrome P-450 inhibitors include, but are not limited to, ritonavir.
• CYP inhibitors may be useful in increasing liver concentrations and/or increasing blood levels of compounds that are inhibited by CYP.
• any CYP inhibitor that improves the pharmacokinetics of the IMPDH inhibitor may be used in a method of this invention.
• CYP inhibitors include, but are not limited to, ritonavir (WO 94/14436) , ketoconazole, troleandomycin, 4-methyl pyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole, fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone, sertraline, indinavir, nelfinavir, amprenavir, fosamprenavir, saquinavir, lopinavir, delavirdine, erythromycin, VX-944, and VX-497.
• Preferred CYP inhibitors include ritonavir, ketoconazole, troleandomycin, 4- methyl pyrazole, cyclosporin, and clomethiazole.
• ritonavir see United States Patent 6,037,157, and the documents cited therein: United States Patent 5,484,801, United States Application 08/402,690, and International Applications WO 95/07696 and WO 95/09614) .
• Methods for measuring the ability of a compound to inhibit cytochrome P450 monooxygenase activity are known (see US 6,037,157 and Yun, et al . Drug Metabolism & Disposition, vol. 21, pp. 403-407 (1993).
• the pharmaceutical compositions of this invention may additionally comprise an anti-vascular hyperproliferative agent.
• anti-vascular hyperproliferative agents include, but are not limited to, HMG Co-A reductase inhibitors such as lovastatin, thromboxane A2 synthetase inhibitors, eicosapentanoic acid, ciprostene, trapidil, ACE inhibitors, low molecular weight heparin, mycophenolic acid, rapamycin and 5- (3 ' -pyridinylmethyl)benzofuran-2-carboxylate.
• HMG Co-A reductase inhibitors such as lovastatin, thromboxane A2 synthetase inhibitors, eicosapentanoic acid, ciprostene, trapidil, ACE inhibitors, low molecular weight heparin, mycophenolic acid, rapamycin and 5- (3 ' -pyridinylmethyl)benzofur
• a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms .
• the term "IMPDH-mediated disease” as used herein includes immune system related diseases such as transplant rejection (e.g., kidney, liver, heart, lung, pancreas (islet cells) , bone marrow, cornea, small bowel and skin allografts and heart valve xenografts) , graft versus host disease, and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel disease (Crohn's disease, ulcerative colitus) , lupus, diabetes, mellitus myasthenia gravis, psoriasis, dermatitis, eczema, seborrhea, pulmonary inflammation, eye uveitis, Grave's disease, Hashimoto's thyroiditis, Behcet's or Sjorgen's syndrome (dry eyes/mouth) , pernicious or immunohaemolytic anaemia, idiopathic adrenal in
• transplant rejection e.g
• the term "IMPDH- mediated disease” as used herein includes viral diseases such as DNA and RNA viral diseases caused by infection for example, by orthomyxoviruses (influenza viruses types A and B) , paramyxoviruses (respiratory syncytial virus (RSV) , subacute sclerosing panencephalitis (SSPE) virus) measles and parainfluenza type 3), herpesviruses (HSV-I, HSV-2 , HHV-6, HHV-7, HHV-8, Epstein Barr Virus (EBV), cytomegalovirus (HCMV) and varicella zoster virus (VZV)), retroviruses (HIV-I, HIV-2 , HTLV-I, HTLV-2), flavi- and pestiviruses (yellow fever virus (YFV), hepatitis C virus (HCV), dengue fever virus, bovine viral diarrhea virus (BVDV) ,
• viral diseases such as DNA and
• IMPDH- mediated disease includes vascular cellular hyperproliferative diseases such as restenosis, stenosis, artherosclerosis and other hyperproliferative vascular disease.
• IMPDH- mediated disease includes tumors and malignancies, such as lymphoma, leukemia and other forms of cancer such as breast cancer, prostate cancer, colon cancer, pancreatic cancer, etc.
• the term "IMPDH- mediated disease” as used herein includes inflammatory diseases such as osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma and adult respiratory distress syndrome.
• inflammatory diseases such as osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma and adult respiratory distress syndrome.
• Suitable methods for the conversion of a crystalline form, such as a polymorphic form of the present invention, into an amorphous form suitable for formulation are well known in the art. See, e.g., "Remington: The Science & Practice of Pharmacy”; Alfonso R. Gennaro, Editor, Mack Publishing, 1995, 19th Edition, Volume 2, the entire disclosure whereof is incorporated herein by reference.
• XRPD X-RAY Powder Diffraction
• thermogravimetric analyzer 2050 or 2950 thermogravimetric analyzer.
• the calibration standards were nickel and AlumelTM.
• T 3 glass transition temperature
• the sample was heated under nitrogen at a rate of 20 °C/min up to 100 0 C. The sample was held at this temperature for 1 minute and then allowed to cool and equilibrate at 0 0 C. After an isothermal hold for 5 minutes, the sample was again heated at a rate of 20 0 C/ min through the same cycle for a second time. The sample was then heated at 20 °C/min up to a final temperature of 200 or 250 0 C.
• TG/IR analyses were acquired on a TA Instruments thermogravimetric analyzer (TG) model 2050 interfaced to a Magna 560 ® Fourier transform infrared (FT-IR) spectrophotometer (Nicolet Instrument Corp.) equipped with an Ever-Glo mid/far IR source, a potassium bromide (KBr) beamsplitter, and a deuterated triglycine sulfate (DTGS) detector.
• FT-IR Fourier transform infrared
• DTGS deuterated triglycine sulfate
• the IR was calibrated (wavelength) with polystyrene at the time of use.
• the TGA was operated under a flow of helium at 90 and 10 cc/min for the purge and balance, respectively. Approximately 14 to 20 mg of sample was loaded into a platinum sample pan and heated from 25 0 C to 225 0 C at a rate of 20 °C/min.
• the TG instrument was started first, immediately followed by the IR instrument.
• the calibration standards were nickel and AlumelTM. Volatiles were identified from a search of the RH Nicolet TGA Vapor Phase spectral library.
• Infrared spectra were acquired on Magna 860 ® Fourier transform infrared (FT-IR) spectrophotometer (Nicolet Instrument Corp.) 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
• KBr extended range potassium bromide
• DTGS deuterated triglycine sulfate
• a Spectra-Tech, Inc. diffuse reflectance accessory (the CollectorTM) was used for sampling. Each spectrum represents 128 co-added scans at a spectral resolution of 4 cm "1 .
• Sample preparation for the drug substance consisted of placing the sample into a 13-mm diameter cup and leveling the material with a frosted glass slide.
• a background data set was acquired with an alignment mirror in place.
• the spectra represent a ratio of the sample single beam data
• Raman spectra were acquired on a Nicolet FT-Raman 960 spectrometer. This spectrometer uses an excitation wavelength of 1064 run. Approximately 0.5 W of Nd:YV ⁇ 4 laser power was used to irradiate the samples. The Raman spectra were measured with an indium gallium arsenide (InGaAs) detector. The samples were prepared for analysis by packing them in an NMR tube. The NMR tube was placed in a gold-coated NMR tube holder. Each spectrum is the result of 128 co-added scans acquired at 4 cm "1 solution and an autogain setting. The spectrometer was calibrated (wavelength) with sulfur and cyclohexane at the time of use.
• InGaAs indium gallium arsenide
• the sample (5.9 mg) was dissolved in 0.5 mL NMR- grade DMSO-cfc.
• the spectrum was acquired with a 1 H pulse width of 4 ⁇ s, a 5 second delay between scans, a spectral width of 5000 Hz with 8192 data points, and 128 co-added scans.
• Each free induction decay (FID) was processed with GRAMS/32 AI software v. 6.00 using a Fourier number equal to twice the number of acquired points with an exponential line broadening factor of 0.1 Hz to improve sensitivity.
• the spectrum was referenced to internal TMS at 0.0 ppm.
• Moisture sorption/desorption data were collected on a VTI SGA-100 moisture balance system. For sorption isotherms, a sorption range of 5 to 95% relative humidity (RH) and a desorption range of 95 to 5% RH in 10% RH increments were used for analysis. The samples were not dried prior to analysis. Equilibrium criteria used for analysis were less than 0.0100% weight change in 5 minutes with a maximum equilibration time of 3 hours if the weight criterion was not met. Data were not corrected for the initial moisture content of the samples .
• Solutions were prepared in various solvents and sonicated between aliquot additions to assist in dissolution. Once a mixture reached complete dissolution, as judged by visual observation, the solution was filtered through a 0.2 ⁇ m nylon filter. The filtered solution was allowed to evaporate at ambient temperature in a vial covered with aluminum foil perforated with pinholes . The solids that formed were isolated and analyzed.
• Vapor diffusion precipitation involved placing a vial with a saturated solution of the drug substance into a larger sealed vial containing an antisolvent at ambient temperature. The solids present were recovered by filtration.
• Enzyme activity is measured spectrophotometrically, by monitoring the increase in absorbance at 340 nm due to the formation of NADH (D340 is 6220 M "1 cm “1 ) .
• the reaction mixture contains 0.1 M potassium phosphate 8.0, 0.5 ⁇ i EDTA, 2 mM DTT, 200 ⁇ M IMP and enzyme (IMPDH human type II) at a concentration of 15 to 50 nM. This solution is incubated at
• the reaction is started by adding NAD to a final concentration of 200 ⁇ M and the initial rate is measured by following the linear increase in absorbance at 340 nm for 10 minutes.
• the final volume in the cuvette is 1.0 ml.
• the assay has also been adapted to a 96 well microtiter plate format; in this case the concentrations of all the reagents remain the same and the final volume is decreased to 200 ⁇ l .
• the compound in question is dissolved in DMSO to a final concentration of 20 mM and added to the initial assay mixture for preincubation with the enzyme at a final volume of 2- 5% (v/v) .
• the reaction is started by the addition of NAD, and the initial rates measured as above.
• K-j_ determinations are made by measuring the initial velocities in the presence of varying amounts of inhibitor and fitting the data using the tight-binding equations of Henderson (Henderson, P. J. F.
• PBMCs Human venous blood is drawn from normal healthy volunteers using heparin as an anti-coagulant. PBMCs are isolated from blood by centrifugation over Ficoll-paque gradient or CPT tubes (Becton-Dickinson) using standard conditions. PBMCs are harvested, washed and re-suspended in complete RPMI, counted and diluted to 1x1O 6 cells/mL. [000116] B. PBMC and splenocyte proliferation assays: 5x10 4 cells (for human PBMC T cells) or IxIO 5 cells (for human PBMC B cells) were added per well of a 96-well plate.
• PHA phyto-hemagglutinin
• S-cell assays For T-cell assays, phyto-hemagglutinin (PHA) is added to a final concentration of 10-20 ⁇ g/mL per well for cell.
• Staphylococcal protein A (SPAS) is added to a final concentration of 2 ⁇ g/mL per well.
• Serial 4-fold dilutions of inhibitor stocks is made in complete RPMI media and added to cells such that the final concentration of compounds ranged from 20 ⁇ M to 20 nM, while DMSO is maintained at a final concentration of 0.1%.
• the cells are then incubated for 3 days. All samples are tested in triplicate. Tritiated thymidine (0.4 ⁇ Ci/well) is added for the last 24 hours of the assay.
• the anti-viral efficacy of compounds may be evaluated in various in vitro and in vivo assays.
• compounds may be tested in in vitro viral replication assays.
• In vitro assays may employ whole cells or isolated cellular components .
• In vivo assays include animal models for viral diseases. Examples of such animal models include, but are not limited to, rodent models for HBV or HCV infection, the Woodchuck model for HBV infection, and chimpanzee model for HCV infection.
• PBMC peripheral blood mononuclear cells
• PHA phyto-hemagglutinin
• SPAS Staphylococcal protein A
• EDTA ethylenediaminetetraacetic acid
• NAD nicotinamide adenine dinucleotide
• HBV hepatitis B virus
• HCV hepatitis C virus
• Example 1 Preparation of Compound 1
• Compound 1 used to prepare the polymorphs of this invention may be synthesized using the methods described in the '178 patent.
• Compound 1 of this invention may be prepared by standard manipulations of methods known to those skilled in the art
• Example 2 Preparation of Form Al by Recrystallization
• Example 5 Methods to Prepare Form Al or Amorphous form
• Table 4 below provides a summary of experimental methods carried out on Compound 1 using various solvents, conditions, and experimental techniques .
• the resulting Form Al or amorphous form obtained was dried in vacuo then analyzed by XRPD. In each case, XRPD analysis was consistent with the indicated form obtained.
• CC crash cool
• CP crash precipitation
• FE fast evaporation
• SC slow cool
• SE slow evaporation
• VD vapor diffusion
• h hour
• RT room temperature
• Example 7 Preparation of Form Al From Form B2 Form B2 recrystallized spontaneously from methanol and acetone affording Form Al. The solid obtained was filtered, dried in vacuo, then analyzed by XRPD. The XRPD pattern was consistent with Form Al .

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