Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• • 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
• • 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
  • A61P3/04—Anorexiants; Antiobesity agents
• • 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
  • 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
• • 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
  • A61P9/12—Antihypertensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to novel crystalline forms of a dipeptidyl peptidase-IV inhibitor. More particularly, the invention relates to novel crystalline forms of (2i?,3S,5i?)-2- (2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)- yl]tetrahydro-2H-pyran-3 -amine, which is a potent, long acting inhibitor of dipeptidyl peptidase- IV.
• novel crystalline forms are useful for the treatment and prevention of diseases and conditions for which an inhibitor of dipeptidyl peptidase-IV is indicated, in particular Type 2 diabetes, obesity, and high blood pressure.
• the invention further concerns pharmaceutical compositions comprising the novel crystalline forms of the present invention useful to treat Type 2 diabetes, obesity, and high blood pressure as well as processes for the preparation of such forms and their pharmaceutical compositions.
• DP-IV dipeptidyl peptidase-IV
• GIP glucose-dependent insulinotropic peptide
• GLP-1 glucagon-like peptide 1
• NIDDM non-insulin dependent diabetes mellitus
• WO 2010/056708 (published 20 May 2010), assigned to Merck & Co., describes a class of aminotetrahydropyrans, which are potent inhibitors of DP-IV and therefore useful for the treatment of Type 2 diabetes. Specifically disclosed in WO 2010/056708 is (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2- (methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine.
• the present invention is concerned with novel crystalline forms of the dipeptidyl peptidase-IV (DP-IV) inhibitor (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine (Compound I).
• DP-IV dipeptidyl peptidase-IV
• Certain crystalline forms have advantages in the preparation of pharmaceutical compositions of (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2- (methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine, such as ease of processing and crystallisation, handling, stability to stress and dosing. In particular, they exhibit improved physicochemical properties, such as stability to stress, rendering them particularly suitable for the manufacture of various pharmaceutical dosage forms.
• the invention also concerns pharmaceutical compositions containing the novel forms thereof, as well as methods for using them as DP-IV inhibitors, in particular for the prevention or treatment of Type 2 diabetes, obesity, and high blood pressure.
• compositions comprising crystalline (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)- yl]tetrahydro-2H-pyran-3 -amine and a pharmaceutically acceptable carrier.
• FIG. 1 is a X-ray diffraction pattern of crystalline Form I of Compound I.
• FIG. 2 is a thermogravimetric analysis (TGA) curve of crystalline Form I of Compound I.
• FIG. 3 is a differential scanning calorimetry (DSC) curve of crystalline Form I of Compound I.
• FIG. 4 is a solid state NMR spectra of crystalline Form I of Compound I.
• FIG. 5 is an IR spectra of crystalline Form ⁇ of Compound I.
• FIG. 6 is a X-ray diffraction pattern of crystalline Form ⁇ of Compound I.
• FIG. 7 is a thermogravimetric analysis (TGA) curve of crystalline Form ⁇ of Compound I.
• FIG. 8 is a differential scanning calorimetry (DSC) curve of crystalline Form II of Compound I.
• FIG. 9 is a solid state NMR spectra of crystalline Form II of Compound I.
• FIG. 10 is an IR spectra of crystalline Form II of Compound I.
• FIG. 11 is a X-ray diffraction pattern of crystalline Form ⁇ of Compound I.
• FIG. 12 is a thermogravimetric analysis (TGA) curve of crystalline Form HI of Compound I.
• FIG. 13 is a differential scanning calorimetry (DSC) curve of crystalline Form III of Compound
• FIG. 14 is a X-ray diffraction pattern of crystalline Form IV of Compound I.
• FIG. 15 is a thermogravimetric analysis (TGA) curve of crystalline Form IV of Compound I.
• FIG. 16 is a differential scanning calorimetry (DSC) curve of crystalline Form IV of Compound DETAILED DESCRIPTION OF THE INVENTION
• This invention relates to crystalline (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methyIsulfonyl)- 2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine of Compound I:
• crystalline (2R,35',5R)-2-(2,5-Difluorophenyl)-5-[2- (methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine refers to all crystalline forms of (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine described herein.
• Still another embodiment of the crystalline forms described herein is (2R,3S,5R)-2-(2,5- Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran- 3-amine (Form ⁇ ).
• Form III is further described below.
• a further embodiment of the present invention provides a particular drug substance that comprises at least one of the crystalline forms described herein.
• drug substance is meant the active pharmaceutical ingredient.
• the amount of crystalline form in the drug substance can be quantified by the use of physical methods such as X-ray powder diffraction, solid-state fluorine- 19 magic-angle spinning (MAS) nuclear magnetic resonance spectroscopy, solid-state carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance spectroscopy, solid state Fourier-transform infrared spectroscopy, and Raman spectroscopy.
• MAS solid-state fluorine- 19 magic-angle spinning
• CPMAS cross-polarization magic-angle spinning
• the crystalline form of the present invention is present in about 5% to about 100% by weight of the drug substance.
• the crystalline form of the present invention is present in about 10% to about 100% by weight of the drug substance.
• the crystalline form of the present invention is present in about 25% to about 100% by weight of the drug substance.
• the crystalline form of the present invention is present in about 50% to about 100% by weight of the drug substance.
• the crystalline form of the present invention is present in about 75% to about 100% by weight of the drug substance.
• substantially all of the drug substance is the crystalline form of the present invention, i.e., the drug substance is substantially phase pure crystalline.
• At least 5% by weight of the drug substance is the crystalline form of the present invention.
• at least 10% by weight of the drug substance is the crystalline form of the present invention.
• at least 5% by weight of the drug substance is the crystalline form of the present invention.
• At least 15% by weight of the drug substance is the crystalline form of the present invention.
• at least 20% by weight of the drug substance is the crystalline form of the present invention.
• at least 25% by weight of the drug substance is the crystalline form of the present invention.
• at least 30% by weight of the drug substance is the crystalline form of the present invention.
• at least 35% by weight of the drug substance is the crystalline form of the present invention.
• at least 40% by weight of the drug substance is the crystalline form of the present invention.
• at least 45% by weight of the drug substance is the crystalline form of the present invention.
• At least 50% by weight of the drug substance is the crystalline form of the present invention. In yet another class of this embodiment, at least 55% by weight of the drug substance is the crystalline form of the present invention. In still another class of this embodiment, at least 60% by weight of the drug substance is the crystalline form of the present invention. In another class of this embodiment, at least 65% by weight of the drug substance is the crystalline form of the present invention. In a yet another class of this embodiment, at least 70% by weight of the drug substance is the crystalline form of the present invention. In a still another class of this embodiment, at least 75% by weight of the drug substance is the crystalline form of the present invention.
• At least 80% by weight of the drug substance is the crystalline form of the present invention.
• at least 85% by weight of the drug substance is the crystalline form of the present invention.
• at least 90% by weight of the drug substance is the crystalline form of the present invention.
• at least 95% by weight of the drug substance is the crystalline form of the present invention.
• at least 100% by weight of the drug substance is the crystalline form of the present invention.
• the crystalline forms of the present invention exhibit pharmaceutical advantages over the amorphous free base of Compound I as described in WO 2010/056708 in the preparation of a pharmaceutical drug product containing the pharmacologically active ingredient.
• the enhanced chemical and physical stability of the crystalline forms constitute advantageous properties in the preparation of solid pharmaceutical dosage forms containing the pharmacologically active ingredient.
• the crystalline forms of the present invention which exhibit long acting, potent DP-IV inhibitory properties, are particularly useful for the prevention or treatment of Type 2 diabetes, obesity, and high blood pressure.
• Another aspect of the present invention provides a method for the prevention or treatment of clinical conditions for which an inhibitor of DP-IV is indicated, which method comprises administering to a patient in need of such prevention or treatment a prophylactically or therapeutically effective amount of a crystalline form of the present invention, or a hydrate thereof.
• Such clinical conditions include diabetes, in particular Type 2 diabetes, hyperglycemia, insulin resistance, and obesity.
• the present invention also provides for the use of a crystalline form of Compound I of the present invention for the prevention or treatment in a mammal of clinical conditions for which an inhibitor of DP-IV is indicated, in particular Type 2 diabetes, hyperglycemia, insulin resistance, and obesity.
• the present invention also provides for the use of a crystalline form of Compound I of the present invention for the manufacture of a medicament for the prevention or treatment in a mammal of clinical conditions for which an inhibitor of DP-IV is indicated, in particular Type 2 diabetes, hyperglycemia, insulin resistance, and obesity.
• the present invention also provides pharmaceutical compositions comprising a crystalline form described herein, in association with one or more pharmaceutically acceptable carriers or excipients.
• the pharmaceutical composition comprises a therapeutically effective amount of the active pharmaceutical ingredient in admixture with pharmaceutically acceptable excipients wherein the active pharmaceutical ingredient comprises a detectable amount of a crystalline (2R,3S,5R)-2-(2,5- Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyiTolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran- 3 -amine.
• the pharmaceutical composition comprises a therapeutically effective amount of the active pharmaceutical ingredient in an admixture with pharmaceutically acceptable excipients wherein the active pharmaceutical ingredient comprises about 1% to about 100% by weight of crystalline (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol- 5(4H)-yl]tetrahydro-2H-pyran-3-amine.
• the active pharmaceutical ingredient in such compositions comprises about 5% to about 100% by weight of crystalline (2R,3S,5R)- 2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyiTolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H- pyran-3-amine.
• the active pharmaceutical ingredient in such compositions comprises about 10% to about 100% by weight of crystalline (2R,3S,5R)-2-(2,5- Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran- 3-amine.
• the active pharmaceutical ingredient in such compositions comprises about 25% to about 100% by weight of crystalline (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2- (methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine.
• the active pharmaceutical ingredient in such compositions comprises about 50% to about 100% by weight of crystalline (2R,3S,5R)-2-(2,5-DifluorophenyI)-5-[2-(methylsulfonyl)- 2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine.
• the pharmaceutical composition comprises a therapeutically effective amount of the active pharmaceutical ingredient in an admixture with pharmaceutically acceptable excipients wherein the active pharmaceutical ingredient comprises at least 1% by weight of crystalline (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)- yl]tetrahydro-2H-pyran-3-amine.
• the active pharmaceutical ingredient in such compositions comprises about 5% by weight of crystalline (2i?,3S,5R)-2-(2,5- Difluorophenyl)-5-[2-(methylsulfonyI)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran- 3-amine.
• the active pharmaceutical ingredient in such compositions comprises about 5% by weight of crystalline (2i?,3S,5R)-2-(2,5- Difluorophenyl)-5-[2-(methylsulfonyI)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran- 3-amine.
• the active pharmaceutical ingredient in such compositions comprises about 5% by weight of crystalline (2i?,3S,5R)-2-(2,5- Difluorophenyl)-5-[2-(methylsulfonyI)-2,
• compositions comprises at least 10% by weight of crystalline (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2- (methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine.
• the active pharmaceutical ingredient in such compositions comprises at least 25% by weight of crystalline (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6- dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine.
• the active pharmaceutical ingredient in such compositions comprises at least 50% by weight of crystalline (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine.
• compositions in accordance with the invention are suitably in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories.
• the compositions are intended for oral, parenteral, intranasal, sublingual, or rectal administration, or for administration by inhalation or insufflation.
• Formulation of the compositions according to the invention can conveniently be effected by methods known from the art, for example, as described in Remington's Pharmaceutical Sciences. 17 th ed., 1995.
• the dosage regimen is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; and the renal and hepatic function of the patient.
• An ordinarily skilled physician, veterinarian, or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
• Oral dosages of the present invention when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg kg/day.
• the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
• a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 200 mg of active ingredient.
• the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion.
• the crystalline forms of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
• (2R,3S,5R)-2- (2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H- pyran-3-amine is a long acting DPP-IV inhibitor.
• the crystalline forms of the present invention may be administered in a single weekly dose.
• the crystalline forms of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
• the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
• the crystalline forms described herein can form the active pharmaceutical ingredient, and are typically administered in admixture with suitable
• 'carrier' materials suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
• the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug component can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
• suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
• Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
• Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
• Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
• the present invention provides a method for the treatment and/or prevention of clinical conditions for which a DP-IV inhibitor is indicated, which method comprises administering to a patient in need of such prevention or treatment a prophylactically or therapeutically effective amount of a crystalline form of Compound I as defined above in combination with another agent useful for the treatment of Type 2 diabetes, obesity, and high blood pressure.
• % enantiomeric excess (abbreviated “ee) shall mean the % major enantiomer less the % minor enantiomer. Thus, a 70% enantiomeric excess corresponds to formation of 85% of one enantiomer and 15% of the other.
• enantiomeric excess is synonymous with the term “optical purity.”
• Compound I can be made by the following methods:
• Step A te -Butyl (l-[methoxy(methynamino]-l-oxopent-4-yn-2-yl)carbamate
• N.N-diphenyl glycine ethyl ester 105.45 kg, 394.5 mol
• tetrabutyl ammonium bromide 14 kg, 43.4 mol
• propargyl benzenesulfonate 94.45 kg, 481 mol
• MTBE 750 kg
• cesium carbonate fine mesh grade, 390 kg, 1 197 mol
• the batch was then cooled to 0-5 °C and water (422 kg) was slowly added.
• tert-butyl methyl ether (170 kg) was added and the batch concentrated to 473-578 L.
• 462 kg HC1 solution 43 kg cone. HC1 in 420 kg water
• was added to reach a pH l-2 below room temperature. After 7h of stirring, the pH was 1.5 and the organic layer was separated and discarded.
• Step B tert-Butyl [ 1 -(2,5-diffuorophenylV 1 -oxopent-4-vn-2-yll carbamate
• Step C tert-Butyl [( 1 S ,2SV 1 -f 2.5-difluorophenylV 1 -hvdroxypent-4-vn-2-yll carbamate
• DMF 133 kg was added and the batch was further concentrated to 70-105 L.
• the resulting DMF solution was 165.6 kg containing 19.4% tert-butyl [(lS,2S)-l-(2,5-difluorophenyl)-l-hydroxypent-4-yn-2-yl]carbamate (8.1/1 diastereomeric ratio and 97.9% ee).
• Step D tert-Butyl ⁇ (l S,2RV l-(2,5-difluorophenvD-l -hvdroxypent-4-yn-2-yl]carbamate This compound was made by following the same method described in Intermediate 1 ,
• Step E tert-Butyl r(lR,2R)-l-(2,5-difluorophenylVl-hvdroxypent-4-yn-2-yl1carbamate
• Step F tert-Butyl IT 1 R,2SV 1 -(Z5-difluorophenylV 1 -hvdroxypent-4-vn-2-yl1carbamate
• Step G fert-Butyl
• triphenylphosphine (892 g, 3.40 mol) was added and the reaction was vacuum purged with nitrogen back-filling three times. The reaction was then heated to 75-85 °C overnight. To complete the reaction, additional chloro(cyclopentadienyl)bis(triphenylphosphine) ruthenium (II) (826 g, 1.14 mol) and triphenylphosphine (892 g, 3.40 mol) was added and the reaction heated at 75-85 °C an additional 12-16h. After cooling to room temperature, water (250 kg) and tert-butyl methyl ether (210 kg) was added.
• Step H terr-Butyl r(2i?.3j?V2-(2.5-difluorophenylV3.4-dihvdro-2H-pyran-3-yl " )carbamate This compound was made by following the same method described in Intermediate 1 ,
• Step I tert-Butyl r(25 , .3S' -2-(2.5-difluorophenylV3.4-dihvdro-2H-pyran-3-yllcarbamate
• Step H tert-Butyl rf2 l S,3i?V2-(2.5-difluorophenylV3,4-dihvdro-2H-pyran-3-yllcarbamate
• Step K tert-Butyl r(2i?.3 ⁇ -2-(2.5-difluorophenylV5-hvdroxytetrahvdro-2H-pyran-3- yl] carbamate
• the reaction was then extracted with ethyl acetate (230 kg) and the resulting organics washed with 3% aqueous NaHC0 3 (500 kg), followed by brine (376 kg). The combined aqueous layers were further extracted with ethyl acetate (2 x 325 kg). The organics were then treated with activated carbon (14.4 kg) for 2h at 50-60 °C. After filtration, the organics were then concentrated and solvent switched to n-heptane to form a crystalline slurry. This slurry was then filtered and the cake was washed with n-heptane. This wet cake was then dissolved in ethyl acetate (99 kg) at 50-60 °C.
• n-Heptane (251 kg) was then added and the batch cooled to 0 °C. The resulting slurry was then filtered and the cake washed with n-heptane. The solids were then dried at 40-50 °C under vacuum to give te t-butyl [(2#,3S)-2-(2,5-difluorophenyl)-5- hydroxytetrahydro-2H-pyran-3-yl]carbamate.
• Step L fe -Butyl r(2/?,3i?)-2-r2.5-difluorophenylV5-hvdroxytetrahvdro-2H-pyran-3- yl] carbamate
• Step M fert-Butyl rr2 l y.3i? -2-r2.5-difluorophenvn-5-hvdroxytetrahvdro-2H-pyran-3- yl]carbamate
• Step N fert-Butyl [f2,S.3 -2-r2.5-difluorophenyl -5-hvdroxytetrahvdro-2H-pyran-3- yl] carbamate
• Step O te -Butyl [(2/?.3S)-2-r2.5-difluorophenylV5-oxotetrahvdro-2H-pyran-3- yl] carbamate
• Step A tert-Butyl (3Z)-3-[(dimethylarnino)niethylene]-4-oxopyrrolidine-l-carboxylate.
• tert-butyl 3-oxopyrroIidine-l-carboxylate 53.4 kg, 288 mol
• THF 133 kg
• DMF-DMA 103 kg, 864 mol
• THF 472 kg
• the solution was cooled, evaporated under reduced pressure and solvent switched under distillation to cyclohexane.
• the resulting slurry was then filtered, cake washed with cyclohexane, and then water.
• the solids were then dried under vacuum at 35-40°C to give tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-l-carboxylate.
• Step B tert-Butyl 6a-hvdroxy-3a,4,6,6a-tetrahydropyiTol[3.4-c1pyrazole-5(lH)- carboxylate
• Step C tert-Butyl 4,6-dihvdropyrrolo[3,4-c]pyrazole-5(lH -carboxylate
• Step E tert-Butyl l-( ' methylsulfonyl ' )-4,6-dihydropyrrolo 3,4-c1pyrazole-5(lH - carboxylate
• Step F 2-(methylsulfonyl -2,4,5,6-tetrahvdropyrrolo[ " 3,4-clpyrazol-5-ium
• Step A tert-Butyl (r2i?.3 .5i?V2- .5-difluorophenvn-5- 2-( ' methylsulfonylV2.6- dihydropyrrolo [3 A-c] pyrazol-5 (4H)-yl] tetrahydro-2H-pyran-3 -yl I carbamate
• Step B ? .5j?)-2-(2,5-Difluorophenyl)-5-r2-rmethylsulfonvn-2.6-dihvdropyrrolor3,4- clpyrazol-5(4H)-ylltetrahvdro-2H-pyran-3-amine
• Benzenesulfonic acid (32.95 kg, 271 mol) was dissolved in dichloromethane (1020 kg) under nitrogen. Then, 880g of water was added such that the solution KF was 0.2%.
• tert- butyl ⁇ (2i?,35,5i?)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-yl ⁇ carbamate (38.4 kg, 100 mol) was added in three equal portions over 30 min. The reaction was then aged overnight at room temperature.
• Form I was produced by direct crystallization of the amorphous free base of Compound I in ethyl acetate.
• the characterization results for XRPD, ssNMR, DSC, TGA and IR are shown below.
• Crystalline Form II was produced by re-crystallization of Form I in isopropyl acetate and heptane 1 : 1 at room temperature.
• Form II was characterized using XRPD, ssNMR, DSC, TGA and IR. Conversion of Form ⁇ into Form I is slow but observed in all turnover experiments with 50-50 seed including DCM-Heptane 25°C over two days, IP Ac 25°C 17 hr, IP Ac 60°C for one day, H 2 0 60°C over two weeks, three days, NMP-water 1-1 35°C over three days.
• the relationship between Form I and Form II is enantiotropic having Form I as the most stable phase above 13°C.
• Form III was produced by dissolving Form I in MeOH and evaporating the solvent, followed by heating to 140°C and isothermal for 10 min. This phase is metastable to Form I and II and its characterization was limited to the amount of sample available. Form III was analyzed by XRPD and DSC. Form IV
• Form IV was produced by dissolving Form I in 1 :1 THF -water and evaporating the solvent. Anhydrous Form IV is metastable to Form I and II and therefore the characterization was limited to the amount of sample available. Form ⁇ was analyzed using XRPD, DSC and TGA.
• X-ray powder diffraction studies are widely used to characterize molecular structures, crystalinity, and polymorphism.
• the X-ray powder diffraction patterns for the solid phases for crystalline forms of Compound I were generated on a Philips Analytical X'Pert PRO X-ray Diffraction System with PW3040/60 console.
• a PW3373/00 ceramic Cu LEF X-ray tube It- Alpha radiation was used as the source.
• the diffraction peak positions were referenced by silicon (internal standard) which has a 2 theta value of 28.443 degree.
• the experiments were analyzed at ambient condition.
• phase purity of at least about 5% of the form with the above X-ray powder diffraction and DSC physical characteristics.
• the phase purity is at least about 10% of the form with the above solid-state physical characteristics.
• the phase purity is at least about 25% of the form with the above solid-state physical characteristics.
• the phase purity is at least about 50% of the form with the above solid-state physical characteristics.
• the phase purity is at least about 75% of the form with the above solid-state physical characteristics.
• the phase purity is at least about 90% of the form with the above solid-state physical characteristics.
• the crystalline forms of the present invention are the substantially phase pure forms with the above solid- state physical characteristics.
• phase purity is meant the solid state purity of the particular form with regard to a particular crystalline form as determined by the solid-state physical methods described in the present application.
• FIG. 1 is the X-ray powder diffraction (XRPD) pattern for Form I of Compound I with selected d-spacings listed in Table 1.
• the crystalline Form 1 can be characterized by the following four peaks in its powder X-ray diffraction pattern 17.8 ⁇ 0.1 2 ⁇ , 19.2 ⁇ 0.1 20, 22.2 ⁇ 0.1 20 and 24.1 ⁇ 0.1 20.
• the crystalline Form 1 can be characterized by the following four peaks in its powder X-ray diffraction pattern of FIG. 3.
• FIG. 6 is the X-ray powder diffraction (XRPD) pattern for Form II of Compound I with selected d-spacings listed in Table 2.
• the crystalline Form II can be characterized by the following four peaks in its powder X-ray diffraction pattern 20.9 ⁇ 0.1 20, 22.0 ⁇ 0.1 20, 27.0 ⁇ 0.1 20 and 27.6 ⁇ 0.1 20.
• Crystalline Form II of can be characterized by the X-ray powder diffraction pattern of FIG 6.
• FIG. 1 1 is the X-ray powder diffraction (XRPD) pattern for Form III of Compound I with selected d-spacings listed in Table 3.
• Crystalline Form III can be characterized by the following four peaks in its powder X-ray diffraction pattern 19.5 ⁇ 0.1 20, 21.2 ⁇ 0.1 20, 22.0 ⁇ 0.1 20 and 23.2 ⁇ 0.1 20. Crystalline Form III can be characterized by the X-ray powder diffraction pattern of FIG 11.
• FIG. 14 is the X-ray powder diffraction (XRPD) pattern for Form rv of Compound I with selected d-spacings listed in Table 4.
• Crystalline (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4- c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine (Form rV) can be characterized by having at least four peaks in its powder X-ray diffraction pattern selected from the group consisting of 8.1 ⁇ 0.1 20, 10.6 ⁇ 0.1 20, 16.0 ⁇ 0.1 20, 16.9 ⁇ 0.1 20, 19.5 ⁇ 0.1 20, 21.3 ⁇ 0.1 20, 23.3 ⁇ 0.1 20 and 25.4 ⁇ 0.1 20.
• Crystalline Form IV can be characterized by the following four peaks in its powder X-ray diffraction pattern 16.9 ⁇ 0.1 20, 19.5 ⁇ 0.1 20, 21.3 ⁇ 0.1 20 and 23.3 ⁇ 0.1 20. Crystalline Form IV can be characterized by the X-ray powder diffraction pattern of FIG. 14. W ssNMR Spectra
• Solid-state carbon- 13 nuclear magnetic resonance spectrum was recorded on a Bruker AV400 NMR spectrometer using a Bruker 4 mm H/F/X BB double resonance CPMAS probe.
• the spectrum were collected utilizing proton/carbon- 13 variable-amplitude cross-polarization (VACP) at 10 kHz, with a contact time of 3 ms.
• VACP variable-amplitude cross-polarization
• Other experimental parameters used for data acquisition were a proton 90-degree pulse of 100 kHz, SPINAL64 decoupling at 100 kHz, a pulse delay of 5 s, and signal averaging for 1024 scans.
• the magic-angle spinning (MAS) rate was set to 10 kHz.
• a Lorentzian line broadening of 10 Hz was applied to the spectrum before Fourier Transformation. Chemical shifts are reported on the TMS scale using the carbonyl carbon of glycine (176.70 ppm.) as a secondary reference.
• Crystalline Form I can further characterized by the nuclear magnetic resonance (NMR) spectra of FIG. 4.
• FIG. 4 is the ssNMR spectra for Form I of Compound I with selected peaks listed in Table 5. Table 5. Selected ssNMR peaks for Form I of Compound I
• Crystalline Form II can be further characterized by the nuclear magnetic resonance (NMR) spectra of FIG. 9.
• FIG. 9 is the ssNMR spectra for Form ⁇ of Compound I with selected peaks listed in Table 6.
• the Infrared spectrum was obtained using Attenuated Total Reflectance (ATR).
• ATR Attenuated Total Reflectance
• the sample was placed directly onto the ATR-FTIR sampling device and the infrared spectrum was recorded using a Nicolet Nexus 670 FTIR spectrometer.
• FIG. 5 is an IR spectra of Form I of Compound I. Crystalline Form I can be further characterized by the IR spectra of FIG. 5.
• FIG. 10 is an IR spectra of Form II of Compound I. Crystalline Form II can be further characterized by the IR spectra of FIG. 10.
• the crystalline forms of Compound I of the present invention were further characterized by means of their differential scanning calorimetry (DSC) curves and their thermogravimetric analysis (TGA) curves.
• DSC differential scanning calorimetry
• TGA thermogravimetric analysis
• Differential Scanning Calorimetry data were acquired using TA Instruments DSC 2910 or DSC2000. Between 2 and 6 mg sample was weighed into a pan and covered. This pan was then covered and placed at the sample position in the calorimeter cell. An empty pan is placed at the reference position. The calorimeter cell is closed and a flow of nitrogen is passed through the cell. The heating program is set to heat the sample at a heating rate of 10 °C/min to a temperature of approximately 250 °C. The data was analyzed using Universal Analysis 2000 Version 3.9A. The thermal events were integrated between baseline temperature points that are above and below the temperature range over which the thermal event is observed. The data reported are the onset temperature, peak temperature and enthalpy.
• Crystalline Form I can be further characterized by the differential scanning calorimetric (DSC) curve of FIG. 3.
• Crystalline Form II can be further characterized by the differential scanning calorimetric (DSC) curve of FIG. 8.
• Crystalline Form ⁇ can be further characterized by the differential scanning calorimetric (DSC) curve of FIG. 13.
• Crystalline Form IV can be further characterized by the differential scanning calorimetric (DSC) curve of FIG. 16.
• Thermogravinietric data was acquired using a Perkin Elmer model TGA 7. Experiments were performed under a flow of nitrogen and using a heating rate of 10 °C/min to a maximum temperature of approximately 250 °C. After automatically taring the balance, 5 to 20 mg of sample was added to the platinum pan, the furnace was raised, and the heating program started. Weight/temperature data are collected automatically by the instrument. Analyses of the results were carried out by selecting the Delta Y function within the instrument software and choosing the temperatures between which the weight loss is to be calculated. Weight losses are reported up to the onset of decomposition/evaporation. Crystalline Form I can be further characterized by the thermogravimetric analysis (TGA) curve of FIG. 2.
• TGA thermogravimetric analysis
• Crystalline Form II can be further characterized by the thermogravimetric analysis (TGA) curve of FIG. 7.
• Crystalline Form III can be further characterized by the thermogravimetric analysis (TGA) curve of FIG. 12.
• Crystalline Form IV can be further characterized by the thermogravimetric analysis (TGA) curve of FIG. 15.
• Thermogravimetric analysis exhibits insignificant weight loss between room temperature and melting point of Form I (FIG. 2).
• a representative sample of Form II was analyzed by DSC (FIG. 8) and TGA (FIG. 7) according to the methods described above.
• TG analysis exhibits minimum weight loss (trapped solvent) between room temperature and melting of Form I.
• Thermogravimetric analysis (FIG. 12) shows -1% w/w residual solvent in the initial material which was removed by heating at 140C and holding for 10 min.

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