(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`( 43) International Publication Date
`10 March 2005 (10.03.2005)
`
`PCT
`
`(10) International Publication Number
`WO 2005/020920 A2
`
`(51) International Patent Classification7:
`
`A61K
`
`(21) International Application Number:
`PCT/US2004/027983
`
`(22) International Filing Date: 27 August 2004 (27.08.2004)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/499,629
`
`2 September 2003 (02.09.2003) US
`
`(71) Applicant (for all designated States except US): MERCK
`& CO., INC. [US/US]; 126 East Lincoln Avenue, Rahway,
`NJ 07065-0907 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): WENSLOW,
`Robert, M. [US/US]; 126 East Lincoln Avenue, Rah(cid:173)
`way, NJ 07065-0907 (US). ARMSTRONG, Joseph,
`D., III [US/US]; 126 East Lincoln Avenue, Rahway, NJ
`07065-0907 (US). CHEN, Alex, M. [CN/US]; 126 East
`Lincoln Avenue, Rahway, NJ 07065-0907 (US). CYPES,
`
`Stephen [US/US]; 126 East Lincoln Avenue, Rahway,
`NJ 07065-0907 (US). FERLITA, Russell, R. [US/US];
`126 East Lincoln Avenue, Rahway, NJ 07065-0907 (US).
`HANSEN, Karl [US/US]; 126 East Lincoln Avenue,
`Rahway, NJ 07065-0907 (US). LINDEMANN, Christo(cid:173)
`pher, M. [US/US]; 126 East Lincoln Avenue, Rahway, NJ
`07065-0907 (US). SPARTALIS, Evangelia [US/US]; 126
`East Lincoln Avenue, Rahway, NJ 07065-0907 (US).
`
`(74) Common Representative: MERCK & CO., INC.; 126
`East Lincoln Avenue, Rahway, NJ 07065-0907 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, Fl,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
`MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG,
`PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
`TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
`zw.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`
`[Continued on next page}
`
`(54) Title: NOVEL CRYSTALLINE FORMS OF A PHOSPHORIC ACID SALT OF A DIPEPTIDYL PEPTIDASE-N INHIBITOR
`
`- ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
`!!!!!!!! -
`
`-iiiiiiiiiiii
`
`iiiiiiiiiiii ---
`
`iiiiiiiiiiii ----iiiiiiiiiiii
`iiiiiiiiiiii ----
`
`Counts
`
`6400
`
`3600
`
`1600
`
`400
`
`10
`
`20
`Position L2Theta]
`
`30
`
`0
`
`M °" 0
`
`M
`0
`l{) (57) Abstract: The present invention relates to crystalline anhydrate polymorphs of the dihydrogenphosphate salt of
`Q
`(2R)-4-oxo-4-[3-( trifluoromethyl)-5,6-dihydro[l ,2,4 ]triazolo[ 4,3-a ]pyrazin-7 (SH)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine
`as
`0 well as a process for their preparation, pharmaceutical compositions containing these novel forms, and methods of use of the
`M novel forms and pharmaceutical compositions for the treatment of diabetes, obesity, and high blood pressure. The invention also
`0 concerns novel crystalline solvates of the dihydrogenphosphate salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]tria(cid:173)
`> zolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine as well as a crystalline desolvated polymorph and their use
`
`~ for the preparation of the anhydrate polymorphs of the present invention.
`
`Merck Exhibit 2117, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2005/020920 A2
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI,
`SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`-
`without international search report and to be republished
`upon receipt of that report
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`Merck Exhibit 2117, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2005/020920
`
`PCT/US2004/027983
`
`TITLE OF THE INVENTION
`
`NOVEL CRYSTALLINE FORMS OF A PHOSPHORIC ACID SALT OF A DIPEPTIDYL
`
`PEPTIDASE-IV INHIBITOR
`
`5
`
`FIELD OF THE INVENTION
`
`The present invention relates to novel crystalline forms of a dihydrogenphosphate salt of
`
`a dipeptidyl peptidase-IV inhibitor. More particularly, the invention relates to novel crystalline solvates
`
`and anhydrates of the dihydrogenphosphate salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-
`
`dihydro[ 1,2,4]triazolo[ 4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine, which is a potent
`
`10
`
`inhibitor of dipeptidyl peptidase-IV (DPP-IV). These novel crystalline forms of the DPP-IV inhibitor are
`
`useful for the preparation of pharmaceutical compositions containing the inhibitor which 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, hyperglycemia, insulin resistance, obesity, and high blood
`
`pressure. The invention further concerns pharmaceutical compositions comprising the novel crystalline
`
`15
`
`dihydrogenphosphate salt anhydrate polymorphic forms of the present invention; processes for preparing
`
`the dihydrogenphosphate salt solvates and anhydrates and their pharmaceutical compositions; and
`
`methods of treating conditions for which a DPP-IV inhibitor is indicated comprising administering a
`
`composition of the present invention.
`
`20
`
`BACKGROUND OF THE INVENTION
`
`Inhibition of dipeptidyl peptidase-IV (DPP-IV), an enzyme that inactivates both glucose(cid:173)
`
`dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1), represents a novel approach
`
`to the treatment and prevention of Type 2 diabetes, also known as non-insulin dependent diabetes
`
`mellitus (NIDDM). The therapeutic potential of DPP-IV inhibitors for the treatment of Type 2 diabetes
`
`25
`
`has been reviewed: C. F. Deacon and J.J. Holst, "Dipeptidyl peptidase IV inhibition as an approach to the
`
`treatment and prevention of Type 2 diabetes: a historical perspective," Biochem. Biophys. Res.
`
`Commun., 294: 1-4 (2000); K. Augustyns, et al., "Dipeptidyl peptidase IV inhibitors as new therapeutic
`
`agents for the treatment of Type 2 diabetes," Exp. Opin. Ther. Patents, 13: 499-510 (2003); and D.J.
`
`Drucker, "Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of Type 2
`
`30
`
`diabetes," Exp. Opin. Investig. Drugs, 12: 87-100 (2003).
`
`WO 03/004498 (published 16 January 2003) and U.S. Patent No. 6,699,871 (issued
`
`March 2, 2004), both assigned to Merck & Co., describe a class of beta-amino tetrahydrotriazolo[4,3-
`
`a]pyrazines, which are potent inhibitors ofDPP-IV and therefore useful for the treatment of Type 2
`
`diabetes. Specifically disclosed in WO 03/004498 is (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-
`
`35
`
`dihydro[l ,2,4]triazolo[ 4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine.
`
`- 1 -
`
`Merck Exhibit 2117, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2005/020920
`
`PCT/US2004/027983
`
`However, there is no disclosure in the above references of the newly discovered
`
`crystalline solvates and anhydrates of the dihydrogenphosphate salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-
`
`5,6-dihydro[1,2,4 ]triazolo[ 4,3-a]pyrazin-7 (8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine of structural
`
`formula I below (hereinafter referred to as Compound I).
`
`5
`
`SUMMARY OF THE INVENTION
`
`The present invention is concerned with novel crystalline solvates and anhydrates of the
`
`dihydrogenphosphate salt of the dipeptidyl peptidase-N (DPP-N) inhibitor (2R)-4-oxo-4-[3-
`
`(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-
`
`10
`
`amine of structural formula I (Compound I). The crystalline solvates and anhydrates of the present
`
`invention have advantages in the preparation of pharmaceutical compositions of the
`dihydrogenphosphate salt of (2R)-4-oxo-4-[3-( trifluoromethy 1)-5 ,6-dihydro[ l ,2,4]triazolo[ 4,3-a ]pyrazin-
`7 (8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine, such as ease of processing, handling, and dosing. In
`particular, they exhibit improved physicochemical properties, such as solubility, stability to stress, and
`
`15
`
`rate of dissolution, rendering them particularly suitable for the manufacture of various pharmaceutical
`
`dosage forms. The invention also concerns pharmaceutical compositions containing the novel anhydrate
`
`polymorphs; processes for the preparation of these solvates and anhydrates and their pharmaceutical
`
`compositions; and methods for using them for the prevention or treatment of Type 2 diabetes,
`
`hyperglycemia, insulin resistance, obesity, and high blood pressure.
`
`20
`
`BRIEF DESCRIPTION OF THE FIGURES
`
`FIG. 1 is a characteristic X-ray diffraction pattern of the crystalline anhydrate Form I of
`
`Compound I.
`
`FIG. 2 is a carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear
`25 magnetic resonance (NMR) spectrum of the crystalline anhydrate Form I of Compound I.
`FIG. 3 is a fluorine-19 magic-angle spinning (MAS) nuclear magnetic resonance (NMR)
`spectrum of the crystalline anhydrate Form I of Compound I.
`FIG. 4 is a typical DSC curve of the crystalline anhydrate Form I of Compound I.
`FIG. 5 is a typical thermogravimetric (TG) curve of the crystalline anhydrate Form I of
`
`30
`
`Compound I.
`
`FIG. 6 is a characteristic X-ray diffraction pattern of the crystalline desolvated
`anhydrate Form II of Compound I.
`FIG. 7 is a carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear
`magnetic resonance (NMR) spectrum of the crystalline desolvated anhydrate Form II of Compound I.
`
`-2-
`
`Merck Exhibit 2117, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
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`

`WO 2005/020920
`
`PCT/US2004/027983
`
`FIG. 8 is a fluorine-19 magic-angle spinning (MAS) nuclear magnetic resonance (NMR)
`spectrum of the crystalline desolvated anhydrate Form II of Compound I.
`
`FIG. 9 is a typical DSC curve of the crystalline desolvated anhydrate Form II of
`
`Compound I.
`
`5
`
`FIG. 10 is a typical TG curve of the crystalline desolvated anhydrate Form II of
`
`Compound I.
`
`FIG. 11 is a characteristic X-ray diffraction pattern of the crystalline anhydrate Form ill
`of Compound I.
`
`FIG. 12 is a carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear
`10 magnetic resonance (NMR) spectrum of the crystalline anhydrate Form ill of Compound I.
`FIG. 13 is a fluorine-19 magic-angle spinning (MAS) nuclear magnetic resonance
`(NMR) spectrum of the crystalline anhydrate Form ill of Compound I.
`FIG. 14 is a typical DSC curve of the crystalline anhydrate Form ill of Compound I.
`FIG. 15 is a typical TG curve of the crystalline anhydrate Form ill of Compound I.
`FIG. 16 is a characteristic X-ray diffraction pattern of the crystalline ethanol solvate of
`
`15
`
`Compound I.
`
`FIG. 17 is a carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear
`magnetic resonance (NMR) spectrum of the crystalline ethanol solvate of Compound I.
`FIG. 18 is a fluorine-19 magic-angle spinning (MAS) nuclear magnetic resonance
`(NMR) spectrum of the crystalline ethanol solvate of Compound I.
`FIG. 19 is a typical DSC curve of the crystalline ethanol solvate of Compound I.
`FIG. 20 is a typical TG curve of the crystalline ethanol solvate of Compound I.
`
`20
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`25
`
`This invention provides novel crystalline solvates and anhydrates of the
`
`dihydrogenphosphate salt of (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-
`
`7(8H)-yl]-l-(2,4,5-trifluorophenyl)butan-2-amine of structural formula I (Compound I):
`
`F
`
`F
`
`F
`
`-3-
`
`Merck Exhibit 2117, Page 5
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2005/020920
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`PCT/US2004/027983
`
`fu one embodiment the solvate is a Ct-4 alkanolate of Compound I. fu a class of this
`embodiment the Cl-4 alkanolate is a methanolate, ethanolate, 1-propanolate, or 2-propanolate. fu
`
`another embodiment the solvate comprises an organic solvent such as acetone or acetonitrile. The
`
`crystalline solvates are useful for the preparation of the crystalline desolvated anhydrate Form II which
`
`5
`
`converts spontaneously into crystalline anhydrate Form I or Form ID or a mixture thereof, the
`
`composition of the mixture being dependent upon the conditions of treatment or storage. Anhydrate
`Forms I and ID represent stable desolvated anhydrates of Compound I.
`
`10
`
`The present invention also provides a novel crystalline desolvated anhydrate Form II of
`Compound I which is obtained from the crystalline solvates of Compound I of the present invention.
`The present invention also provides novel crystalline anhydrate Forms I and ID of
`Compound I and mixtures thereof.
`A further embodiment of the present invention provides the Compound I drug substance
`that comprises the crystalline anhydrate Form I or ID or a mixture thereof in a detectable amount. By
`
`"drug substance" is meant the active pharmaceutical ingredient (API). The amount of crystalline
`anhydrate Form I or ID or mixture thereof in the drug substance can be quantified by the use of physical
`
`15
`
`20
`
`25
`
`methods such as X-ray powder diffraction (XRPD), 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. fu a class of this embodiment, about 5 % to about 100% by weight of the
`crystalline anhydrate Form I or ID or mixture thereof is present in the drug substance. fu a second class
`of this embodiment, about 10% to about 100% by weight of the crystalline anhydrate Form I or ID or
`
`mixture thereof is present in the drug substance. fu a third class of this embodiment, about 25% to about
`100% by weight of the crystalline anhydrate Form I or ID or mixture thereof is present in the drug
`substance. In a fourth class of this embodiment, about 50% to about 100% by weight of the crystalline
`anhydrate Form I or ID or mixture thereof is present in the drug substance. fu a fifth class of this
`embodiment, about 75% to about 100% by weight of the crystalline anhydrate Form I or ID or mixture
`thereof is present in the drug substance. In a sixth class of this embodiment, substantially all of the
`Compound I drug substance is the crystalline anhydrate Form I or ID or mixture thereof, i.e., the
`Compound I drug substance is substantially phase pure anhydrate Form I or ID or a mixture thereof.
`
`30
`
`The crystalline solvates of the present invention are useful for the preparation of the
`
`crystalline anhydrate Forms I and ID and mixtures thereof. The crystalline solvates are desolvated to
`
`afford the intermediate desolvated anhydrate Form II which converts into anhydrate Form I or Form III or
`
`a mixture thereof upon heating at 45°C for about 2 h.
`
`Another aspect of the present invention provides a method for the prevention or
`
`35
`
`treatment of clinical conditions for which an inhibitor of DPP-N is indicated, which method comprises
`
`-4-
`
`Merck Exhibit 2117, Page 6
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2005/020920
`
`PCT/US2004/027983
`
`administering to a patient in need of such prevention or treatment a prophylactically or therapeutically
`effective amount of the crystalline anhydrate Form I or ill or a mixture thereof of Compound I. Such
`clinical conditions include diabetes, in particular Type 2 diabetes, hyperglycemia, insulin resistance,
`
`5
`
`obesity, and high blood pressure.
`The present invention also provides for the use of the crystalline anhydrate Form I or ill
`or a mixture thereof of the present invention in the manufacture of a medicament for the prevention or
`
`treatment, of clinical conditions for which an inhibitor of DPP-N is indicated, in particular, Type 2
`diabetes, hyperglycemia, insulin resistance, obesity, and high blood pressure. In one embodiment the
`clinical condition is Type 2 diabetes.
`
`Another aspect of the present invention provides the crystalline anhydrate Form I or
`Form ill or a mixture thereof for use in the treatment of clinical conditions for which an inhibitor of
`DPP-N is indicated, in particular, Type 2 diabetes, hyperglycemia, insulin resistance, obesity, and high
`blood pressure. In one embodiment of this aspect the clinical condition is Type 2 diabetes.
`
`The present invention also provides pharmaceutical compositions comprising the
`crystalline anhydrate Form I or ill or a mixture thereof, in association with one or more pharmaceutically
`acceptable carriers or excipients. In one embodiment the pharmaceutical composition comprises a
`prophylactically or therapeutically effective amount of the active pharmaceutical ingredient (API) in
`
`admixture with pharmaceutically acceptable excipients wherein the API comprises a detectable amount
`of the crystalline anhydrate Form I or ill or a mixture thereof of the present invention. In a second
`embodiment the pharmaceutical composition comprises a prophylactically or therapeutically effective
`
`amount of the API in admixture with pharmaceutically acceptable excipients wherein the API comprises
`
`about 5% to about 100% by weight of the crystalline anhydrate Form I or III or a mixture thereof of the
`present invention. In a class of this second embodiment, the API in such compositions comprises about
`10% to about 100% by weight of the crystalline anhydrate Form I or ID or a mixture thereof. In a second
`class of this embodiment, the API in such compositions comprises about 25 % to about 100% by weight
`of the crystalline anhydrate Form I or ill or a mixture thereof. In a third class of this embodiment, the
`API in such compositions comprises about 50% to about 100% by weight of the crystalline anhydrate
`Form I or ill or a mixture thereof. In a fourth class of this embodiment, the API in such compositions
`comprises about 75% to about 100% by weight of the crystalline anhydrate Form I or III or a mixture
`thereof. In a fifth class of this embodiment, substantially all of the API is the crystalline anhydrate Form
`I or ID or a mixture thereof of Compound I, i.e., the API is substantially phase pure Compound I
`
`anhydrate Form I or III or a mixture thereof.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`The 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
`
`35
`
`liquid sprays, drops, ampoules, auto-injector devices or suppositories. The compositions are intended for
`
`-5-
`
`Merck Exhibit 2117, Page 7
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2005/020920
`
`PCT/US2004/027983
`
`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, 17th ed.,
`1995.
`
`5
`
`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.
`
`10
`
`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 0.1to5.0 mg/kg/day. For oral administration, 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 API for the symptomatic adjustment of the dosage
`
`15
`
`to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the
`
`API, preferably, from about 1 mg to about 200 mg of APL Intravenously, the most preferred doses will
`
`range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, the
`
`crystalline anhydrate 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. Furthermore,
`
`20
`
`the crystalline anhydrate 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. To be administered in the form of a transdermal
`
`delivery system, the dosage administration will, of course, be continuous rather than intermittent
`
`throughout the dosage regimen.
`In the methods of the present invention, the Compound I anhydrate Forms I and ill or a
`
`25
`
`mixture thereof herein described in detail can form the API, and are typically administered in admixture
`
`with suitable pharmaceutical diluents, excipients or can·iers (collectively referred to herein as 'carrier'
`
`materials) suitably selected with respect to the intended fom1 of administration, that is, oral tablets,
`
`capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
`
`30
`
`For instance, for oral administration in the form of a tablet or capsule, the active
`
`pharmaceutical ingredient 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
`
`API can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol,
`
`35
`
`glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants,
`
`-6-
`
`Merck Exhibit 2117, Page 8
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

`WO 2005/020920
`
`PCT/US2004/027983
`
`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, com 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
`
`5
`
`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 crystalline anhydrate Forms I and III or mixtures thereof of Compound I have been
`
`found to possess a high solubility in water, rendering them especially amenable to the preparation of
`
`10
`
`formulations, in particular intranasal and intravenous formulations, which require relatively concentrated
`
`aqueous solutions of the API. The solubility of the crystalline Compound I anhydrate Form I or Form III
`
`or mixture thereof in water is greater than 120 mg/mL.
`
`In a still further aspect, the present invention provides a method for the treatment and/or
`
`prevention of clinical conditions for which a DPP-N inhibitor is indicated, which method comprises
`
`15
`
`administering to a patient in need of such prevention or treatment a prophylactically or therapeutically
`
`effective amount of anhydrate Form I or III or a mixture thereof of the present invention or a
`
`pharmaceutical composition containing a prophylactically or therapeutically effective amount of
`
`anhydrate Form I or III or a mixture thereof.
`
`The following non-limiting Examples are intended to illustrate the present invention and
`
`20
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`should not be construed as being limitations on the scope or spirit of the instant invention.
`
`Compounds described herein may exist as tautomers such as keto-enol tautomers. The
`
`individual tautomers as well as mixtures thereof are encompassed with compounds of structural formula
`
`I.
`
`The term"% enantiomeric excess" (abbreviated "ee") shall mean the% major
`
`25
`
`enantiomer less the% minor enantiomer. Thus, a 70% enantiomeric excess corresponds to formation of
`
`85% of one enantiomer and 15% of the other. The term "enantiomeric excess" is synonymous with the
`
`term "optical purity."
`
`GENERAL METHODS FOR PREP ARING SOLV ATES OF COMPOUND I AND THE
`
`30 DESOLVATED ANHYDRATE FORM II AND FOR PREPARING AND INTERCONVERTING
`
`BETWEEN ANHYDRATE FORMS I AND III:
`
`Compound I forms non-stoichiometric, isomorphous solvates with several organic
`
`solvents, such as methanol, ethanol, 1-propanol, 2-propanol, acetone, and acetonitrile. The various
`
`solvates of the present invention are isomorphic and exhibit similar X-ray powder diffraction patterns, F-
`
`35
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`19 solid-state NMR spectra, and DSC curves.
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`-7-
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`Merck Exhibit 2117, Page 9
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`IPR2020-00040
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`Solvates are prepared by contacting anhydrate Form I, II, or ill, or mixtures thereof, with
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`the solvating agent for about 5 min at about room temperature. Solvates will also result from the process
`
`of preparing the dihydrogenphosphate salt from free base in the presence of a solvating agent where the
`
`water activity is such that the solvate has a lower solubility than any of the other anhydrates or
`
`5 monohydrate. For example, the ethanol solvate can be formed by treating the free base with aqueous
`
`phosphoric acid in ethanol.
`
`The ethanol solvate can be converted to desolvated anhydrate Form II by (a) drying with
`
`nitrogen flow over the sample for about 5 h at about 25 °C or (b) drying in vacuum for about 5 h at about
`
`25 °C.
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`10
`
`Desolvated anhydrate Form II is metastable and converts to anhydrate Form I or Form ill
`
`or mixtures thereof in about 2 h at about 45 °C.
`Anhydrate Form I can be converted into anhydrate Form ill by (a) drying with physical
`agitation, (b) compaction, or ( c) grinding. Anhydrate Form ill can be converted into anhydrate Form I by
`
`heating at about 110 °C for about 30 min.
`Mixtures of varying composition of anhydrate Forms I and ill form upon grinding or
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`15
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`compaction of Form I or mixtures thereof at room temperature, which results in the increased proportion
`of Form ill in the mixture.
`The anhydrate polymorphic Form I and Form ill have an enantiotropic relationship, that
`
`is, one form is more stable at a lower temperature range, while the other is more stable at a higher
`temperature with a transition temperature of about 34 °C. Anhydrate Form ill is the low temperature
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`20
`
`stable form and is stable below about 34 °C. Anhydrate Form I is the high temperature stable form and is
`
`stable above about 34 °C.
`The anhydrate Forms I and ill can be directly crystallized from a solvent that Compound
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`I does not solvate with, such as isoamyl alcohol, at a water activity where the hydrate is not stable. Form
`ill can be preferentially crystallized below about 34 °C, and Form I can be preferentially crystallized
`
`25
`
`above about 34 °C.
`
`GENERAL CONDITIONS FOR PREFERENTIALLY CRYSTALLIZING ANHYDRATE FORM I:
`In isoamyl alcohol (IAA)/water system at 40 °C:
`
`30
`
`(1) crystallization from a mixture of compound I in IAA and water, such that the water concentration is
`
`below 3.4 weight percent;
`
`(2) recovering the resultant solid phase; and
`
`(3) removing the solvent therefrom.
`
`In IAA/water system at 60°C:
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`-8-
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`Merck Exhibit 2117, Page 10
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`WO 2005/020920
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`PCT/US2004/027983
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`(l).crystallization from a mixture of compound I in IAA and water, such that the water concentration is
`
`below 4.5 weight percent;
`
`(2) recovering the resultant solid phase; and
`
`(3) removing the solvent therefrom.
`
`5
`
`GENERAL CONDITIONS FOR PREFERENTIALLY CRYSTALLIZING ANHYDRATE FORM ill:
`In isoamyl alcohol (IAA)/water system at 25°C:
`
`(1) crystallization from a mixture of compound I in IAA and water, such that the water concentration is
`
`below 2.7 weight percent;
`
`10
`
`(2) recovering the resultant solid phase; and
`
`(3) removing the solvent therefrom.
`
`EXAMPLE 1
`
`F
`
`F
`
`15
`
`C2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4Jtriazolo[ 4,3-alpyrazin-7(8ffi-yll-1-(2,4,5-
`
`trifluorophenyl)butan-2-amine dihydrogenphosphate anhydrate Form I and Form ill mixture
`
`Preparation of 3-(trifluoromethyl)-5,6, 7,8-tetrahydro[l,2,4 Jtriazolof 4,3-alpvrazine hydrochloride Cl-4)
`
`Scheme 1
`
`1. CF3COOEt, CH3CN
`
`2. CICOCH2CI, NaOH
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`-9-
`
`Merck Exhibit 2117, Page 11
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`

`

`WO 2005/020920
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`PCT/US2004/027983
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`POCl3 ...
`
`N-N
`F3C_/(0 )L_CH2CI
`1-2
`
`MeOH
`
`MeOH, HCI, 55 °C
`
`Step A:
`
`Preparation of bishydrazide Cl-1)
`
`Hydrazine (20.1 g, 35 wt% in water, 0.22 mol) was mixed with 310 mL of acetonitrile.
`31.5 g of ethyl trifluoroacetate (0.22 mol) was added over 60 min. The internal temperature was
`
`5
`
`increased to 25 °C from 14 °C. The resulting solution was aged at 22 - 25 °C for 60 min. The solution
`
`was cooled to 7 °C. 17.9 g of 50 wt% aqueous NaOH (0.22 mol) and 25.3 g of chloroacetyl chloride
`
`(0.22 mol) were added simultaneously over 130 min at a temperature below 16 °C. When the reaction
`
`was complete, the mixture was vacuum distilled to remove water and ethanol at 27 - 30 °C and under 26
`
`- 27 in Hg vacuum. During the distillation, 720 mL of acetonitrile was added slowly to maintain
`
`10
`
`constant volume (approximately 500 mL). The slurry was filtered to remove sodium chloride. The cake
`
`was rinsed with about 100 mL of acetonitrile. Removal of the solvent afforded bis-hydrazide 1-1 (43.2 g,
`
`96.5% yield, 94.4 area% pure by HPLC assay).
`lH-NMR (400 MHz, DMSO-d6): o 4.2 (s, 2H), 10.7 (s, lH), and 11.6 (s, lH) ppm.
`Bc-NMR (100 MHz, DMSO-d6): o 41.0, 116.1(q,J=362 Hz), 155.8 (q, J = 50 Hz), and 165.4 ppm.
`
`15
`
`20
`
`25
`
`Step B:
`
`Preparation of 5-(trifluoromethyl)-2-( chloromethyl)-1,3,4-oxadiazole (1-2)
`
`Bishydrazide 1-1 from Step A (43.2 g, 0.21 mol) in ACN (82 mL) was cooled to 5 °C.
`
`Phosphorus oxychloride (32.2 g, 0.21 mol) was added, maintaining the temperature below 10 °C. The
`
`mixture was heated to 80 °C and aged at this temperature for 24 h until HPLC showed less than 2 area%
`of 1:1. In a separate vessel, 260 mL of IP Ac and 250 mL of water were mixed and cooled to 0 °C. The
`reaction slurry was charged to the quench keeping the internal temperature below 10 °C. After the
`addition, the mixture was agitated vigorously for 30 min, the temperature was increased to room
`temperature and the aqueous layer was cut. The organic layer was then washed with 215 mL of water,
`215 mL of 5 wt% aqueous sodium bicarbonate and finally 215 mL of 20 wt% aqueous brine solution.
`HPLC assay yield after work up was 86-92%. Volatiles were removed by distillation at 75-80 mm Hg,
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`- 10-
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`Merck Exhibit 2117, Page 12
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`WO 2005/020920
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`PCT/US2004/027983
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`55 °C to afford an oil which could be used directly in Step C without further purification. Otherwise the
`
`product can be purified by distillation to afford 1-2 in 70-80% yield.
`
`lH-NMR (400 MHz, CDCh): 8 4.8 (s, 2H) ppm.
`13C-NMR (100 MHz, CDCh): 8 32.1, 115.8 (q, J = 337 Hz), 156.2 (q, J = 50 Hz), and 164.4 ppm.
`
`5
`
`Step C:
`
`Preparation of N-[(22)-piperazin-2-ylideneltrifluoroacetohydrazide Cl-3)
`
`To a solution of ethylenediamine (33.1g,0.55 mol) in methanol (150 mL) cooled at-20
`
`°C was added distilled oxadiazole 1-2 from Step B (29.8 g, 0.16 mol) while keeping the internal
`
`temperature at