US008.003636B2

(12) United States Patent (10) Patent No.: US 8,003,636 B2 Wollmann et al. (45) Date of Patent: Aug. 23, 2011

(54) CERTAIN CRYSTALLINE 7,407,938 B2 8, 2008 Jaehne et al. 7488,829 B2 2/2009 Glombik et al. DIPHENYLAZETIDINONE HYDRATES, 7,579,339 B2 8, 2009 Jaehne et al. PHARMACEUTICAL COMPOSITIONS 7,671,047 B2 3/2010 Jaehne et al. THEREOF AND METHODS FOR THEIR USE 2003/0212070 A1 11/2003 Schwink et al. 2004/OO77623 A1 4/2004 Jaehne et al. 2004/0082561 A1 4/2004 Jaehne et al. (75) Inventors: Theodor Andreas Wollmann, 2005/0239766 A1 10, 2005 Starke et al. Hattersheim (DE); Regina Duffy, 2005/0267038 A1 12/2005 Glombik et al. Hattersheim (DE); Frank Cullmann, 2007/O1495O1 A1 6/2007 Jendralla et al. Eschborn (DE) 2007/O197498 A1 8, 2007 Jaehne et al. 2008/0274947 A1* 11/2008 Jaehne et al...... 540,200 (73) Assignee: Sanofi-Aventis Deutschland GmbH 2008/0281092 A1 11/2008 Glombik et al. 2008/0319218 A1 12/2008 Haubrich et al. (DE) 2008/0319221 A1 12/2008 Junker et al. 2010, 0160282 A1 6, 2010 Glombik et al. *) Notice: Subject to anyy disclaimer, the term of this patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154(b) by 350 days. CA 2 136893 6, 2002 EP O 462.884 12/1991 (21) Appl. No.: 12/269,802 EP O 656 3.54 6, 1995 WO WO97, 16455 A1 5, 1997 WO WO 97.26265 A1 7/1997 (22) Filed: Nov. 12, 2008 WO WO 97/41097 A2 11/1997 WO WO 97.454.06 A1 12/1997 (65) Prior Publication Data WO WO 98.08871 A1 3, 1998 US 2009/O2O3578 A1 Aug. 13, 2009 WO WO99.03861 A1 1, 1999 (Continued) Related U.S. Application Data OTHER PUBLICATIONS (60) Provisional application No. 60/990,225, filed on Nov. Copending U.S. Appl. No. 1 1/155,109, filed Jun. 17, 2005, Glombik 26, 2007. et al. Copending U.S. Appl. No. 1 1/767.284, filed Jun. 22, 2007. Haubrich et al. (30) Foreign Application Priority Data Copending U.S. Appl. No. 12/219,196, filed Jul. 17, 2008, Glombik et al. Nov. 13, 2007 (DE) ...... 10 2007 O54 497 Copending U.S. Appl. No. 12/271.236, filed Nov. 13, 2008, Junker et al. (51) Int. Cl. Castaher, R. M., et al., “EZetimbe, Hypolipidemic Cholesterol CO7D 205/08 (2006.01) Absorption Inhibitor SCH-58235.” Drugs of the Future 2000, A 6LX3/397 (2006.01) 25(7):679-685. (52) U.S. Cl...... 514/210.02:540/200 (Continued) (58) Field of Classification Search ...... 540/200; 514/210.02 Primary Examiner — Mark Berch See application file for complete search history. (74) Attorney, Agent, or Firm — Finnegan, Henderson, Farabow, Garrett & Dunner, LLP (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS Provided are certain crystalline hydrates of the formula I 4,596,789 A 6, 1986 Dutta et al. 5, 190,923 A 3, 1993 Vincent et al. O 5,656,624 A 8, 1997 Vaccaro et al. 5,756,470 A 5, 1998 Yumibe et al. 5,846,966 A 12/1998 Rosenblum et al. OH 5,889,002 A 3, 1999 Nielsen et al. 6,221,633 B1 4/2001 Ertlet al. 6,221,897 B1 4/2001 Fricket al. 6,225,310 B1 5, 2001 Nielsen et al. 6,245,744 B1 6, 2001 Fricket al. 6,268,343 B1 7/2001 Knudsen et al. 6,342,512 B1 1/2002 Kirsch et al. 6,380.230 B1 4/2002 Brodin et al. 6,498,156 B2 12/2002 Glombik et al. O OH OH onH2O 6,525,083 B2 2/2003 Acton, III et al. 6,589,984 B1 7/2003 Naniwa et al. N 6,624,185 B2 9, 2003 Glombik et al. ~s H ~~" 6,861444 B2 3/2005 Ikuta et al. OH OH 6,884,812 B2 4/2005 Glombik et al. 6,992,067 B2 1/2006 Glombik et al. 7,067,689 B1 6, 2006 Renze et al. in which n has a value of from 0.5 to 1.8. The compound may 7,205.290 B2 4/2007 Jaehne et al. be suitable, for example, as a hypolipidemic. 7.388,004 B2 6, 2008 Jaehne et al. 7,390,790 B2 6, 2008 Jaehne et al. 16 Claims, 3 Drawing Sheets US 8,003,636 B2 Page 2

FOREIGN PATENT DOCUMENTS Office Action for U.S. Appl. No. 1 1/155,109 mailed on Dec. 3, 2008, WO WO 99/15525 4f1999 9 pages. WO WO99/46262 9, 1999 Notice of Allowance for U.S. Appl. No. 1 1/177,410 (issued patent WO WOOO,34331 6, 2000 7,067,689), mailed on Mar. 31, 2006, 4 pages. WO WOOOf 40569 T 2000 Office Action for U.S. Appl. No. 1 1/767,298, mailed Aug. 15, 2008, WO WOOOf 63703 A1 10, 2000 5 pages. WO WOOOf 64876 11, 2000 Office Action for U.S. Appl. No. 1 1/797.720 (issued patent WO WOOO64888 11, 2000 7488,829), mailed on Nov. 16, 2007, 6 pages. WO WOOOf71549 11, 2000 Final Office Action for U.S. Appl. No. 1 1/797,720 (issued patent WO WOOOf 78312 12/2000 7488,829), mailed on Apr. 21, 2008, 8 pages. WO WOO1/04156 1, 2001 Notice of Allowance for U.S. Appl. No. 1 1/797,720 (issued patent WO WOO1,09111 2, 2001 7488,829), mailed on Oct. 2, 2008, 6 pages. WO WOO1/62266 8, 2001 Asakawa, A. et al., Cocaine-Amphetamine-Regulated Transcript WO WOO1/83451 11, 2001 Influences Energy Metabolism, Anxiety and Gastric Emptying in WO WOO1.85695 11, 2001 Mice, Hormone and Metabolic Research, 2001, vol. 33, No. 9, pp. WO WOO1,90094 11, 2001 554-558. WO WO O2/44.150 6, 2002 Barf, T. et al., Arylsulfonamidothiazoles as a New Class of Potential WO WOO2,50027 6, 2002 Antidiabetic Drugs, Discovery of Potent and Selective Inhibitors of WO WOO3,O15769 2, 2003 the 11 B-Hydroxysteroid DehydrogenaseType 1, Journal of Medici WO WO 2009 112203 A1 * 9, 2009 nal Chemistry, 2002, vol. 45, No. 18, pp. 3813-3815. OTHER PUBLICATIONS Chaudhary, A. et al., CO. Offgas as a Mechanistic Probe and Scale Up Tool in N-Acylations. Using Mixed Anhydrides from Amino Goodman and Gilman's The Pharmacological Basis of Therapeutics, Acids and Isobutyl Chloroformate, Organic Process Research and 10th Ed., 2001, p. 54. Development, 2003, vol. 7, pp. 888-895. Kosoglou, T., et al., "Coadministration of Simvastatin and Ezetimibe Greene, T. et al., Protective Groups in Organic Synthesis, John Wiley Leads to Significant Reduction in LDL-Cholesterol.” Proceedings of and Sons, Inc., 1999, 3 Ed., pp. 1, 4-5, 372-374,383-387,415-419, the 3rd International Congress on Coronary Artery Disease. From 701-702, 705-707, and 728-731. Ishihara, K. et al., 3,4,5-Trifluorobenzeneboronic Acid as an Prevention to Intervention, 2000, p. 275. Extremely Active Amidation Catalyst, Journal of Organic Chemistry, Vaccaro, W. D., et al., “Sugar-Substituted 2-AZetidinone. As Choles 1996, vol. 61, pp. 4196-4197. terol Absorption Inhibitors.” Biorganic & Medicinal Chemistry Let Klausner, Y. et al., Coupling Reagents' in Peptide Synthesis, Synthe ters 8(1998):35-40. sis, 1972, No. 9, pp. 453-463. Vaccaro, W. D., et al., “Sugar-Substituted 2-AZetidinone Cholesterol Kunishima, M. et al., 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4- Absorption Inhibitors: Enhanced Potency by Modification of the methyl-morpholiniurn Chloride: An Efficient Condensing Agent Sugar,” Biorganic & Medicinal Chemistry Letters 8(1998):313-318. Leading to the Formation of Amides and Esters, Tetrahedron, 1999, van Heek, M., et al., “Comparison of the activity and disposition of vol. 55, pp. 13159-13170. the novel cholesterol absorption inhibitor, SCH58235, and its Larock, R., Interconversion of Nitriles, Carboxylic Acids and Deriva glucuronide, SCH60663.” British Journal of Pharmacology tives, Comprehensive Organic Transformations: A Guide to Func 129: 1748-1754 (2000). tional Group Preparations, VCHPublishers, NewYork, 1999, 2" Ed., Zaks, A., et al., “Enzymatic Glucuronidation of a Novel Cholesterol pp. 1929-1930. Absorption Inhibitor, SCH58235. Applied Biochemistry and Lee, D. et al., Leptin Agonists as a Potential Approach to the Treat Biotechnology, 73:205-214 (1998). ment of Obesity, Drugs of the Future, 2001, vol. 26, No. 9, pp. Non-Final Office Action for U.S. Appl. No. 10/021.502 (issued 873-881. patent 6,992,067), mailed on Sep. 10, 2003, 4 pages. Okada, H. et al., Synthesis and Antitumor Activities of Prodrugs of Final Office Action for U.S. Appl. No. 10/021.502 (issued patent Benzoylphenylureas, Chemical and Pharmaceutical Bulletin, 1994, 6,992,067), mailed on Apr. 16, 2004. 11 pages. vol. 42, No. 1, pp. 57-61. Non-Final Office Action for U.S. Appl. No. 10/021.502 (issued Prata, C. et al., Charge-Reversal Amphiphiles for Gene Delivery, patent 6,992,067), mailed on Aug. 25, 2004, 5 pages. Journal of the American Chemical Society, 2004, vol. 126, pp. 12196 Non-Final Office Action for U.S. Appl. No. 10/021.502 (issued 12197 patent 6,992,067), mailed on Feb. 8, 2005, 9 pages. Prata, C. et al., Supporting Information for Charge Reversal Notice of Allowance for U.S. Appl. No. 10/021.502 (issued patent Amphiphiles for Gene Delivery, Journal of the American Chemical 6,992,067), mailed on Jul. 12, 2005, 4 pages. Society, 2004, vol. 126, pp. S1-S8. Office Action for U.S. Appl. No. 10/813,954 (issued patent Saitoh, M. et al., Convenient Selective Monoesterification of O, 7.205.290), mailed on May 18, 2006, 8 pages. (D-Dicarboxylic Acids Catalyzed by Ion-Exchange Resins, Tetrahe Notice of Allowance for U.S. Appl. No. 10/813,954 (issued patent dron Letters, 1996, vol. 37, No. 37, pp. 6733-6736. 7.205.290), mailed on Nov. 27, 2006, 4 pages. Salvador, J. et al., Perspectives in the Therapeutic Use of Leptin, Office Action for U.S. Appl. No. 1 1/155,109 mailed on Aug. 17. Expert Opinion Pharmacotherapy, 2001, vol. 2, No. 10, pp. 1615 2006, 9 pages. 1622. Final Office Action for U.S. Appl. No. 1 1/155,109 mailed on Feb. 14, Speicher, A. et al., O-(1-Benzotriazolyl)-N,N,N',N'- 2007, 7 pages. tetramethyluroniumhexafluorophosphat (HBTU) and O-(7-Aza-1- Office Action for U.S. Appl. No. 1 1/155,109 mailed on Jul 16, 2007, benzotriazolyl)-N,N,N',N'-tetrarnethyluroniunnhexafluorophosphat 10 pages. (HATU)-Zwei moderne Kupplungsreagenzien Zur Peptidsynthese, Final Office Action for U.S. Appl. No. 1 1/155,109 mailed on Jan. 9. Journal flir Praktische Chemie, 1998, vol. 340, pp. 581-583. 2008, 7 pages. Zunft, H. et al., Carob Pulp Preparation for Treatment of Notice of Panel Decision from Pre-Appeal Brief Review U.S. Appl. Hypercholesterolemia, Advances in Therapy, 2001, vol. 18, No. 5, No. 1 1/155,109 mailed on May 2, 2008, 3 pages. pp. 230-236. Examiner's Answer to Appeal Brief for U.S. Appl. No. 1 1/155,109 mailed on Aug. 6, 2008, 9 pages. * cited by examiner U.S. Patent Aug. 23, 2011 Sheet 1 of 3 US 8,003,636 B2

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US 8,003,636 B2 1. 2 CERTAIN CRYSTALLINE provide a composition Suitable for administration. Also pro DIPHENYLAZETIDINONE HYDRATES, vided are uses of at least one crystalline hydrate described PHARMACEUTICAL COMPOSITIONS herein as a pharmaceutical. THEREOF AND METHODS FOR THEIR USE Also provided is a method of treating a mammal having a lipid metabolism disorder comprising administering at least This application claims the benefit of U.S. provisional one crystalline hydrate described herein to the mammal. Also application No. 60/990,255, filed Nov. 26, 2007, and German provided is a method of treating a mammal having a lipid patent application no. 102007054497.0, filed Nov. 13, 2007. metabolism disorder comprising formulating at least one The contents of both priority documents are incorporated by 10 crystalline hydrate described herein with one or more phar reference herein. maceutically acceptable diluents to form a composition and administering the composition to the mammal. Also provided is a use of at least one crystalline hydrate described hereinfor Provided are certain crystalline hydrates of a substituted preparation of a medicament for the treatment of lipid diphenylaZetidinone. 15 metabolism disorders. Also provided is a process for the preparation of a medicament comprising at least one crystal Certain amorphous diphenylaZetidinones are described in line hydrate described herein for the treatment of lipid U.S. Pat. No. 7,205,290. metabolism disorders. The crystalline polymorph or pseudopolymorph form of a 20 Also provided is a method of treating a mammal having particular drug may be a determinant, for example, of the hyperlipidemia comprising administering at least one crys drug's ease of preparation, stability, Solubility, storage stabil talline hydrate described herein to the mammal. Also pro ity, ease of formulation and in vivo pharmacology. In cases vided is a method of treating a mammal having hyperlipi where two or more polymorph Substances can be produced, it demia comprising formulating at least one crystalline hydrate may be desirable to have a method to make one or more of the 25 described herein with one or more pharmaceutically accept polymorphs in pure form. In deciding which polymorphis to able diluents to form a composition and administering the be used, the numerous properties of the polymorphs may be composition to the mammal. Also provided is a use of at least compared and a polymorph chosen based on the many physi one crystalline hydrate described herein for the preparation of a medicament for the treatment of hyperlipidemia. Also pro cal property variables. It is entirely possible that one poly 30 morph form can be more Suitable in some circumstances vided is a process for the preparation of a medicament com where certain aspects such as ease of preparation, stability, prising at least one crystalline hydrate described hereinforthe etc., are deemed to be important. In other situations, a differ treatment of hyperlipidemia. ent polymorph may be more suitable for greater solubility Also provided is a method of lowering the serum choles and/or Superior pharmacokinetics. Because improved drug 35 terol level of a mammal comprising administering at least one formulations, showing, for example, better bioavailability or crystalline hydrate described herein to the mammal. Also better stability are consistently sought, there is an ongoing provided is a method of lowering the serum cholesterol level need for new or purer polymorphic forms of existing drug of a mammal comprising formulating at least one crystalline molecules. hydrate described herein with one or more pharmaceutically 40 acceptable diluents to form a composition and administering Provided is at least one crystalline hydrate of the formula I, the composition to the mammal. Also provided is a use of at

OH 'a, N O OH onH2O F 9 O H N H O--O ~~"OH OH in which n has a value of from 0.5 to 1.8. least one crystalline hydrate described herein for the prepa Also provided is a pharmaceutical composition comprising 60 ration of a medicament for lowering serum cholesterol level. one or more pharmaceutically acceptable diluents and a Also provided is a process for the preparation of a medica therapeutically effective amount of at least one crystalline ment comprising at least one crystalline hydrate described hydrate described herein. Also provided is a process for the herein for lowering serum cholesterol level. preparation of a pharmaceutical composition described herein comprising formulating the therapeutically effective 65 Also provided is a process for the preparation of at least one amount of at least one crystalline hydrate described herein crystalline hydrate described herein which comprises dis with one or more pharmaceutically acceptable diluents to Solving an amorphous compound of the formula II US 8,003,636 B2 3 4

II O

OH 17, N F O OH OH O H E N --~~~~ H ~~ OH O OH OH in an organic solvent and adding the Solution to a suspension Solvates, are crystalline solid adducts containing either sto of seed crystals of at least one crystalline hydrate of formula ichiometric or nonstoichiometric amounts of Solvent mol I. Also provided is a process for the preparation of at least one 20 ecules incorporated within the crystal structure. If the incor crystalline hydrate as described herein comprising purifying porated solvent is water, the Solvates are also commonly a compound of the formula II by chromatography and con- known as hydrates. Amorphous Solids consist of disordered verting the purified compound of formula II to the at least one arrangements of molecules and do not possess a distinguish crystalline hydrate with water. Also provided is a process for able crystal lattice. the preparation of the at least one crystalline hydrate 25 described herein comprising maintaining a compound of the The term "solution' means a mixture of one or more sol formula II with a water content less than or equal to 1% under utes in one or more solvents. Solution is intended to encom defined conditions of humidity, temperature, and time suffi pass homogeneous mixtures as well as heterogeneous mix cient to produce at least one crystalline hydrate as described tures, such as slurries or other mixtures having a Suspension herein. 30 of insoluble (not dissolved) material. By a “detectable amount” is meant a sufficient amount to BRIEF DESCRIPTION OF THE DRAWINGS give positive identification but not necessarily quantitation of the compound by any suitable analytical technique, for FIG. 1 shows the X-ray powder diffraction (XRPD) pattern example HPLC, XRPD, or other means. of the crystalline hydrate of formula I prepared by Example 1. 35 The term “organic solvent' is broadly intended to mean FIG.2 shows the X-ray powder diffraction (XRPD) pattern any organic solvent. Examples include ethanol, acetone, of the crystalline hydrate of formula I prepared by Example 2. methylene chloride, hexane, heptane, ethyl acetate, tetrahy FIG.3 shows the X-ray powder diffraction (XRPD) pattern of the amorphous product prepared in Example 1. drofuran, toluene, chloroform, and diethyl ether. The following abbreviations and terms have the indicated " The term “therapeutically effective amount” of at least one meanings throughout: crystalline hydrate of the formula I means an amount effec “Polymorphism' is defined as in the International Confer- tive, when administered to a human or non-human patient, to ence on Harmonization (ICH) Guideline Q6A Guideline: provide be an amount sufficient to reduce lipid levels in the Specifications for New Drug Substances and Products: bloodstream or lower serum cholesterol. Chemical Substances, October 1999 and refers to the occur- Provided are crystalline hydrates of the formula I

I O

OH '.

N 0

F Clu N O OH OH OH nH2O N O --~~~~ H ~~ O OH OH rence of different solid forms of the same drug substance. in which n has a value of from 0.5 to 1.8 which correspond to Polymorphs can be unsolvated or solvated crystal forms. a percentage by mass of water of about 1.1% to 4.0%. Unsolvated crystal forms are crystals that do not have solvent 65 In some embodiments, n has a value of from 0.8 to 1.3 incorporated within the crystal structure and include anhy- which corresponds to a percentage by mass of water of about drous crystal forms or anhydrates. Solvated crystal forms, or 1.8% to 2.9%. In some embodiments, n has a value of from US 8,003,636 B2 5 6 0.9 to 1.1 which corresponds to a percentage by mass of water having at least peaks of the following 2 theta values: 7.33, of about 2.0% to 2.4%. In some embodiments, n has a value of 8.92, 12.19, 16.05, 17.31, 17.68, 18.83, 20.43, 20.83, 21.58, 1 which corresponds to a percentage by mass of water of 24.55, and 25.37, each of the diffraction angles being +0.2 about 2.2%. degrees 2 theta. In some embodiments, the at least one crystalline hydrate In some embodiments, the at least one crystalline hydrate of the formula I described herein contains no more than about of the formula I further comprises a detectable amount of at 50% of any other polymorphic forms. In some embodiments, least one organic solvent. In some embodiments, the at least the at least one crystalline hydrate of the formula I described one organic solvent corresponds to at least one of the solvents herein contain no more than about 10% of any other poly 10 initially incorporated within the crystal structure. In some morphic forms. In some embodiments, the at least one crys embodiments, the at least one organic Solvent corresponds to talline hydrate of the formula I described herein contain no a solvent used during preparation, e.g., a solvent used in the more than about 5% of any other polymorphic forms. In some crystallization, of the crystalline hydrate of the formula I. In embodiments, the at least one crystalline hydrate of the for some embodiments, the at least one crystalline hydrate of the mula I described herein contain no more than about 1% of any 15 formula I further comprises a detectable amount of ethanol. other polymorphic forms. In some embodiments, the at least one crystalline hydrate In some embodiments, the at least one crystalline hydrate of the formula I may be useful for the treatment of lipid of the formula I described herein have a chemical purity of metabolism disorders. In some embodiments, the at least one greater than about 95%. In some embodiments, the at least crystalline hydrate of the formula I may be useful for the one crystalline hydrate of the formula I described herein have treatment of hyperlipidemia. In some embodiments, the at a chemical purity of greater than about 98%. In some embodi least one crystalline hydrate of the formula I may be useful for ments, the at least one crystalline hydrate of the formula I lowering serum cholesterol level. described herein have a chemical purity of greater than about The amount of the at least one crystalline hydrate of for 99%. Chemical purity can be ascertained, for example, by 25 mula I necessary to achieve the desired biological effect high pressure liquid chromatography. depends on a number of factors, for example the specific In some embodiments, the crystalline hydrates of the for compound chosen, the intended use, the mode of administra mula I described herein may be identified by one or more tion and the clinical condition of the patient. The daily dose is Solid state analytical methods. For example, the crystalline 30 generally in the range from 0.01 mg to 100 mg (typically from hydrates of the formula I may be characterized according to 0.05 mg to 50 mg) per day and/or a range of the at least one one or more of, e.g., X-ray diffraction, unit cell constants, crystalline hydrate of the formula I per kilogram of body Fourier transform infrared spectroscopy, differential scan ning calorimetry curve data, Solid state nuclear magnetic weight, for example 0.05-10 mg/kg/day. Single-dose formu resonance spectroscopy, and Raman spectroscopy. A sample lations which can be administered orally, Such as, for is considered to be a crystalline hydrate of the formula I if it example, tablets or capsules may contain, for example, from is characterized as a crystalline hydrate of the formula I by at 1.0 to 1000 mg. typically from 5 to 600 mg. least one of the above methods, regardless of any inconsistent For the therapy of the abovementioned conditions, the at or contradictory results obtained by any of the other methods least one crystalline hydrate of formula I may be used as the described above. In addition, a sample is considered to be a 40 compound itself, but typically the at least one crystalline crystalline hydrate of the formula I if it is characterized as a hydrate of formula I is in the form of a pharmaceutical com crystalline hydrate of the formula I by at least one of the above position with an acceptable carrier. The carrier is acceptable methods under a particular set of experimental conditions, in the sense that it is compatible with the other ingredients of regardless of any inconsistent or contradictory results the composition and is not harmful for the patient’s health. obtained by the same method under a different set of experi 45 The carrier may be a solid or a liquid or both and may be mental conditions. formulated with at least one crystalline hydrate of formula I as In some embodiments, the crystalline hydrates of the for a single dose, for example as a tablet, which may be prepared mula I may be characterized according to melting point. from 0.05% to 95% by weight of the at least one crystalline In some embodiments, the crystalline hydrates of the for hydrate of formula I. Other active ingredients may likewise be mula I may be characterized according to crystal habit. 50 present, including further crystalline hydrates of the formula For example, also provided is an embodiment of a crystal I. The pharmaceutical compositions described herein can be line hydrate of the formula I with an XRPD, measured with produced by one of the known pharmaceutical methods, CuKO. radiation, having a main peak of 20.83 degrees 2 which essentially consist of mixing the ingredients with phar theta;+0.2 degrees 2 theta. macologically acceptable carriers and/or excipients. Also provided is an embodiment of a crystalline hydrate of 55 In Some embodiments, the composition may contain only a the formula I with an XRPD, measured with CuKO. radiation, single form of the crystalline hydrate of the formula I, such as having at least peaks of the following 2 theta values: 20.43, where n is 1, or a mixture of various forms of the crystalline 20.83, and 21.58, each of the diffraction angles being +0.2 hydrate, with or without amorphous form. In some embodi degrees 2 theta. 60 ments, the at least one crystalline hydrate of the formula I is Also provided is an embodiment of a crystalline hydrate of converted, in whole or in part, to one or more other forms, the formula I with an XRPD, measured with CuKO. radiation, including a non-Solid form, upon formulation with the one or having at least peaks of the following 2 theta values: 12.19. more pharmaceutically acceptable diluents. In some embodi 17.31, 20.43, 20.83, and 21.58, each of the diffraction angles ments, the at least one crystalline hydrate of formula I is being t0.2 degrees 2 theta. 65 dissolved when formulated. Accordingly, in Such cases, the Also provided is an embodiment of a crystalline hydrate of compound of formula I no longer exists in crystalline form in the formula I with an XRPD, measured with CuKO. radiation, the composition. US 8,003,636 B2 7 8 Pharmaceutical compositions described herein are those which are prepared from at least one crystalline hydrate of Suitable for oral and peroral (for example Sublingual) admin formula I with a flavoring, normally Sucrose and gum arabic istration, although the Suitable mode of administration may or tragacanth, and pastilles depend in each individual case on the nature and severity of The at least one crystalline hydrate of formula I described the condition to be treated and on the nature of the at least one 5 herein can also be administered in combination with further crystalline hydrate of formula I used in each case to prepare active ingredients. When administered as a combination, the the pharmaceutical composition. Coated formulations and active ingredients can beformulated as separate compositions coated slow-release formulations also are provided. Acid that are administered at the same time or sequentially at and gastric juice-resistant formulations are possible. Suitable different times, or the active ingredients can be administered 10 in a single composition, provided that the active ingredients coatings resistant to gastric juice comprise cellulose acetate are not incompatible with other active ingredients or the for phthalate, polyvinyl acetate phthalate, hydroxypropylmeth mulation, or otherwise undesirably combined in a single com ylcellulose phthalate and anionic polymers of methacrylic position. acid and methyl methacrylate. The phrase “co-therapy' (or “combination-therapy') or “in Suitable pharmaceutical compositions for oral administra 15 combination with', as used herein, defines the use of at least tion prepared from at least one crystalline hydrate of formula one crystalline hydrate of formula I as described herein and I may be in the form of separate units such as, for example, one or more further active ingredients, such as, for example: capsules, cachets, Suckable tablets or tablets, each of which is administration of each active ingredient in a sequential prepared with a defined amount of at least one crystalline manner in a regimen to provide beneficial effects of the drug hydrate of formula I; as powders or granules; as solution or combination; and/or Suspension in an aqueous or nonaqueous liquid; or as an co-administration of the aforementioned components in a oil-in-water or water-in-oil emulsion. These compositions Substantially simultaneous manner (e.g., as in a single capsule may, as already mentioned, be prepared by any suitable phar having a fixed ratio of the active ingredients or in multiple, maceutical method which includes a step in which at least one separate capsules for each active ingredient, etc.). crystalline hydrate of formula I and a carrier (which may 25 Thus, methods described herein are not limited in the consist of one or more additional ingredients) are brought into sequence of administration; the at least one crystalline contact. The compositions are generally produced by uniform hydrate of formula I may be administered either prior to, at the and homogeneous mixing of at least one crystalline hydrate same time with or after administration of the further active of formula I with a liquid and/or finely divided solid carrier, ingredient(s). after which the product is shaped if necessary. Thus, for 30 Further exemplary active ingredients suitable for combi example, a tablet can be produced by compressing or molding nation products include: all antidiabetics which are men a powder or granules of at least one crystalline hydrate of tioned in the Rote Liste 2007, chapter 12; all weight-reducing formula I, where appropriate with one or more additional agents/appetite Suppressants which are mentioned in the Rote ingredients. Compressed tablets can be produced by tableting Liste 2005, chapter 1; and all lipid-lowering agents which are at least one crystalline hydrate of formula I in free-flowing 35 mentioned in the Rote Liste 2007, chapter 58, the disclosures form Such as, for example, a powder or granules, where of which are incorporated by reference herein. They may be appropriate mixed with a binder, glidant, inert diluent and/or administered with at least one crystalline hydrate of formula one (or more) Surface-active/dispersing agent(s) in a suitable I described herein in particular for a synergistic improvement machine. Molded tablets can be produced by molding at least in the effect. Synergy can be in terms of lower incidence or one crystalline hydrate of formula I, which is in powder form 40 severity of side effects, increased therapeutic effect, or some and is moistened with an inert liquid diluent, in a Suitable other beneficial effect of the combination compared with the machine. Compositions can also be prepared by wet granu individual components. In some embodiments, when the at lation. Thus, for example, a composition can be prepared by least one crystalline hydrate of formula I is administered with wet granulation by mixing the at least one crystalline hydrate a statin drug, such as atorvastatin, a lower amount of the statin of formula I, one or more optional additional ingredients, a 45 can be used and achieve the same lipid lowering that would be Suitable solvent, and a binder to prepare a wet granulate, achieved with a higher amount of the statin and/or achieve drying the wet granulate, and milling the dried granulate. The reduced side effects. The active ingredient combination can method may further comprise adding at least one lubricant to be administered either by separate administration of the the dried milled granulate and compressing the dried milled active ingredients to the patient or in the form of combination granulate to form tablets. The optional additional ingredients 50 products in which a plurality of active ingredients is present in may include, for example, at least one diluent and/or at least a pharmaceutical preparation. Most of the active ingredients one disintegration agent. The Suitable solvent can be water. In mentioned hereinafter are disclosed in the USP Dictionary of Some embodiments, the diluent comprises calcium carbon USAN and International Drug Names, US Pharmacopeia, ate, calcium phosphate (dibasic and/or tribasic), calcium Sul Rockville 2001. fate, powdered cellulose, dextrates, dextrin, fructose, kaolin, 55 Antidiabetics include insulin and insulin derivatives such lactitol, anhydrous lactose, lactose monohydrate, maltose, as, for example, Lantus(R (see www.lantus.com) or HMR mannitol, microcrystalline cellulose, Sorbitol. Sucrose, or 1964 or Levemir R (insulin detemir) or those described in starch. In some embodiments, the diluent is present in an WO2005005477 (Novo Nordisk), fast-acting insulins such as amount of about 35% to about 90% by weight of the tablet. In Apidra.R. (see U.S. Pat. No. 6,221,633), inhalable insulins Some embodiments, the binder comprises acacia, alginic 60 Such as, for example, Exubera R or oral insulins such as, for acid, carbomer, Sodium carboxymethylcellulose, dextrin, example, IN-105 (Nobex) or Oral-lynTM (Generex Biotech ethylcellulose, gelatin, glucose, guar gum, hydroxypropyl nology), GLP-1 derivatives and GLP-1 agonists such as, for cellulose, maltose, methylcellulose, polyethylene oxide, or example, exenatide, liraglutide or those which have been poVidone. In some embodiments, the binder is present in an disclosed in WO98/08871 or WO2005027978, amount of about 0.5% to about 5% by weight of the tablet. 65 WO2006037811, WO2006037810 of Novo Nordisk NS, in Pharmaceutical compositions which are suitable for per WOO1/04156 of Zealand or in WOOO/34331 of Beaufour oral (Sublingual) administration comprise Suckable tablets Ipsen, pramlintide acetate (Symlin; Amylin Pharmaceuti US 8,003,636 B2 9 10 cals), BIM-51077, PC-DAC:exendin-4 (an exendin-4 analog WO2004000804, WO2004000803, WO2002050068, covalently bonded to recombinant human albumin), agonists WO2002050060, WO2005047248, WO2006086562, like those described for example in D. Chen et al., Proc. Natl. WO2006102674, WO2006116499, WO2006121861, Acad. Sci. USA 104 (2007) 943, those described in WO2006122186, WO200622216, WO2006127893, WO2006124529, and orally effective hypoglycemic active WO2006137794, WO2006137796, WO2006137782, ingredients. WO2006137793, WO2006137797, WO2006137795, Antidiabetics also include agonists of the glucose-depen WO2006137792, and WO2006138163. dent insulinotropic polypeptide (GIP) receptor as described In some embodiments, the at least one crystalline hydrate for example in WO2006121860. of formula I is administered in combination with VytorinTM, The orally effective hypoglycemic active ingredients 10 include, for example, Sulfonylureas, biguanidines, megli a fixed combination of eZetimibe with simvastatin. tinides, oxadiazolidinediones, thiazolidinediones, glucosi In some embodiments, the at least one crystalline hydrate dase inhibitors, inhibitors of glycogen phosphorylase, gluca of formula I is administered in combination with a fixed gon antagonists, glucokinase activators, inhibitors of combination of eZetimibe with atorvastatin. fructose-1,6-bisphosphatase, modulators of glucose trans 15 In some embodiments, the at least one crystalline hydrate porter 4 (GLUT4), inhibitors of glutamine-fructose-6-phos of formula I is administered in combination with a fixed phate amidotransferase (GFAT), GLP-1 agonists, potassium combination of eZetimibe with fenofibrate. channel openerS Such as, for example, pinacidil, cromakalim, In some embodiments, the at least one crystalline hydrate diazoxide or those described in R. D. Carret al., Diabetes 52, of formula I is administered in combination with a fixed 2003, 2513-2518, in J. B. Hansen et al., Current Medicinal combination offenofibrate with rosuvastatin. Chemistry 11, 2004, 1595-1615, in T. M. Tagmose et al., J. In some embodiments, the at least one crystalline hydrate Med. Chem. 47, 2004, 3202-3211 or in M. J. Coghlan et al., of formula I is administered in combination with synordia J. Med. Chem. 44, 2001, 1627-1653, or those which have (R), a fixed combination offenofibrate with metformin. been disclosed in WO 97.126265 and WO99/03861 of Novo In some embodiments, the at least one crystalline hydrate Nordisk AIS, inhibitors of dipeptidylpeptidase IV (DPP-IV), 25 of formula I is administered in combination with ISIS insulin sensitizers, inhibitors of liver enzymes involved in 301012, an antisense oligonucleotide able to regulate the stimulating gluconeogenesis and/or glycogenolysis, modula apolipoprotein B gene. tors of glucose uptake, of glucose transport and of glucose In some embodiments, the at least one crystalline hydrate reabsorption, inhibitors of 11 BHSD1, inhibitors of protein of formula I is administered in combination with a PPAR tyrosine phosphatase 1 B (PTPI B), modulators of the 30 sodium-dependent glucose transporter 1 or 2 (SGLT1, gamma agonist Such as, for example, rosiglitaZone, pioglita SGLT2), compounds which alter lipid metabolism such as Zone, JTT-501, GI 262570, R-483 or CS-01 (rivoglitazone). antihyperlipidemic active ingredients and antilipidemic In some embodiments, the at least one crystalline hydrate active ingredients, compounds which reduce feed intake, of formula I is administered in combination with Com compounds which increase thermogenesis, PPAR and RXR 35 petactTM, a fixed combination of pioglitazone hydrochloride modulators and active ingredients which act on the ATP with metformin hydrochloride. dependent potassium channel of the beta cells. In some embodiments, the at least one crystalline hydrate In some embodiments, the at least one crystalline hydrate of formula I is administered in combination with Tan of formula I is administered in combination with a HMGCoA demactTM, a fixed combination of pioglitazone with glime reductase inhibitor, commonly known as a statin, such as 40 pride. simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, In some embodiments, the at least one crystalline hydrate cerivastatin, rosuvastatin, or L-659699. In some embodi of formula I is administered in combination with a fixed ments, the at least one crystalline hydrate of formula I is combination of pioglitaZone hydrochloride with an angio administered in combination with atorvastatin. In some tensin II agonist Such as, for example, TAK-536. embodiments, the pharmaceutical composition comprises 45 In some embodiments, the at least one crystalline hydrate 1-50 mg of atorvastatin and 10-50 mg of at least one crystal of formula I is administered in combination with a PPAR line hydrate of formula I. In some embodiments, the pharma alpha agonist such as, for example, GW'9578, GW-590735, ceutical composition comprises 5-15 mg of atorvastatin and K-1 11, LY-674, KRP-101, DRF-10945, or LY-518674 or 15-50 mg of at least one crystalline hydrate of formula I. In those described in WO2001040207, WO20020.96894, and Some embodiments, the pharmaceutical composition com 50 WO2005097076. prises 10 mg of atorvastatin and 25 mg of at least one crys In some embodiments, the at least one crystalline hydrate talline hydrate of formula I. In some embodiments, the phar of formula I is administered in combination with a mixed maceutical composition comprises 10 mg of atorvastatin and PPAR alpha/gamma agonist Such as, for example, navegli 50 mg of at least one crystalline hydrate of formula I. tazar, LY-510929, ONO-5129, E-3030, AVE 8042, AVE In some embodiments, the at least one crystalline hydrate 55 8134, AVE 0847, or CKD-501 (lobeglitazone sulfate) or as of formula I is administered in combination with a cholesterol described in WOOO/64888, WOOO/64876, WO 03/020269 or absorption inhibitor Such as, for example, eZetimibe, tique in J. P. Berger et al., TRENDS in Pharmacological Sciences side, pamaqueside, FM-VP4 (sitostanol/campesterol ascor 28(5), 244-251, 2005. byl phosphate: Forbes Medi-Tech, WO2005042692, In some embodiments, the at least one crystalline hydrate WO2005005453), MD-O727 (Microbia Inc., 60 of formula I is administered in combination with a PPAR WO2005021497, WO2005021495) or with compounds as delta agonist such as, for example, GW-501516 or as described in WO2002066464, WO2005000353 (Kotobuki described in WO2006059744, WO2006084176, Pharmaceutical Co. Ltd.), or WO2005044256 or WO2006029699, WO2007039172, and WO200703.9178. WO2005062824 (Merck & Co.) or WO2005061451 and In some embodiments, the at least one crystalline hydrate WO2005061452 (AstraZeneca AB), and WO2006017257 65 of formula I is administered in combination with metagli (Phenomix) or WO2005033100 (Lipideon Biotechnology dasen or with MBX-2044 or other partial PPARgamma ago AG) or as described in WO2004097655, WO2004000805, nists/antagonists. US 8,003,636 B2 11 12 In some embodiments, the at least one crystalline hydrate GPRI O9A (HM74A receptor agonist: NAR (nicotinic acid of formula I is administered in combination with a fibrate receptor) agonist Such as, for example, nicotinic acid or such as, for example, fenofibrate, clofibrate or bezafibrate. extended release niacin in conjunction with MK-0524A or In some embodiments, the at least one crystalline hydrate the compounds described in WO2006045565, of formula I is administered in combination with an MTP WO2006045564, WO2006069242, WO2006124490, inhibitor such as, for example, implitapide, BMS-201038, WO2006113150, WO2007017261, WO2007017262, R-103757, AS-1552133 or those described in WO2007017265, WO200701 15744, and WO2007027532. WO2005085226, WO2005121091, and WO2006010423. In some embodiments, the at least one crystalline hydrate In some embodiments, the at least one crystalline hydrate of formula I is administered in combination with an agonist of of formula I is administered in combination with a CETP 10 GPR116 as described for example in WO2006067531 and inhibitor such as, for example, torcetrapib or JTT-705 or those WO2OO6067532. described in WO2006002342, WO2006010422, In some embodiments, the at least one crystalline hydrate WO2006012093, WO2006073973, WO2006072362, of formula I is administered in combination with a lipase WO2006097169, and WO2007041494. inhibitor such as, for example, orlistator cetilistat (ATL-962). In some embodiments, the at least one crystalline hydrate 15 In some embodiments, the at least one crystalline hydrate of formula I is administered in combination with a bile acid of formula I is administered in combination with insulin. absorption inhibitor (see, for example, U.S. Pat. No. 6.245, In some embodiments, the at least one crystalline hydrate 744, U.S. Pat. No. 6,221,897 or WO00/61568), such as, for of formula I is administered in combination with a sulfony example, HMR 1741 or those as described in DE 10 2005 lurea Such as, for example, tolbutamide, glibenclamide, glip O33.099.1 and DE 10 2005033100.9 and WO2OO7OO9655-56. izide or glimepiride. In some embodiments, the at least one crystalline hydrate In some embodiments, the at least one crystalline hydrate of formula I is administered in combination with a polymeric of formula I is administered in combination with a substance bile acid adsorbent such as, for example, cholestyramine or which enhances insulin secretion, Such as, for example, KCP colesevelam. 265 (WO2003097064) or those described in In some embodiments, the at least one crystalline hydrate 25 WO2007O26761. of formula I is administered in combination with an LDL In some embodiments, the at least one crystalline hydrate receptor inducer (see U.S. Pat. No. 6,342.512), such as, for of formula I is administered in combination with agonists of example, HMR1171, HMR1586 or those as described in the glucose-dependent insulinotropic receptor (GDIR), Such WO2005097738. as, for example, APD-668. In some embodiments, the at least one crystalline hydrate 30 In some embodiments, the at least one crystalline hydrate of formula I is administered in combination with an ABCA1 of formula I is administered in combination with a biguanide expression enhancer as described for example in such as, for example, metformin. WO2O06O72393. In some embodiments, the at least one crystalline hydrate In some embodiments, the at least one crystalline hydrate of formula I is administered in combination with a megli of formula I is administered in combination with an RNAi 35 tinide Such as, for example, repaglinide, nateglinide or therapeutic directed against PCSK9 (proprotein convertase mitiglinide. subtilisin/kexin type 9). In some embodiments, the at least one crystalline hydrate In some embodiments, the at least one crystalline hydrate of formula I is administered with a combination of mitiglinide of formula I is administered in combination with Omacor R with a glitaZone, e.g. pioglitaZone hydrochloride. (omega-3 fatty acids; highly concentrated ethyl esters of 40 In some embodiments, the at least one crystalline hydrate eicosapentaenoic acid and of docosahexaenoic acid). of formula I is administered with a combination of mitiglinide In some embodiments, the at least one crystalline hydrate with an alpha-glucosidase inhibitor. of formula I is administered in combination with an ACAT In some embodiments, the at least one crystalline hydrate inhibitor such as, for example, avasimibe or SMP-797. of formula I is administered in combination with a thiazo In some embodiments, the at least one crystalline hydrate 45 lidinedione Such as, for example, troglitaZone, ciglitaZone, of formula I is administered in combination with an antioxi pioglitaZone, rosiglitaZone or the compounds disclosed in dant such as, for example, OPC-14117, probucol, tocopherol, WO 97/41097 of Dr. Reddy's Research Foundation, in par ascorbic acid, B-carotene or selenium. ticular 5-4-(3,4-dihydro-3-methyl-4-oxo-2-quinazolinyl In some embodiments, the at least one crystalline hydrate methoxyphenylmethyl-2,4-thiazolidinedione. of formula I is administered in combination with a vitamin 50 In some embodiments, the at least one crystalline hydrate such as, for example, vitamin B6 or vitamin B12. of formula I is administered in combination with an O-glu In some embodiments, the at least one crystalline hydrate cosidase inhibitor Such as, for example, miglitol or acarbose. of formula I is administered in combination with a lipoprotein In some embodiments, the at least one crystalline hydrate lipase modulator such as, for example, ibrolipim (NO-1886). of formula I is administered in combination with an active In some embodiments, the at least one crystalline hydrate 55 ingredient which acts on the ATP-dependent potassium chan of formula I is administered in combination with an ATP nel of the beta cells, such as, for example, tolbutamide, glib citrate lyase inhibitor such as, for example, SB-204990. enclamide, glipizide, glimepiride or repaglinide. In some embodiments, the at least one crystalline hydrate In some embodiments, the at least one crystalline hydrate of formula I is administered in combination with a squalene of formula I is administered in combination with more than synthetase inhibitor such as, for example, BMS-188494, 60 one of the aforementioned compounds, e.g. in combination TAK-475 or as described in WO2005077907 and with a sulfonylurea and metformin, a Sulfonylurea and acar JP2007022943. bose, repaglinide and metformin, insulin and a sulfonylurea, In some embodiments, the at least one crystalline hydrate insulin and metformin, insulin and troglitaZone, insulin and of formula I is administered in combination with a lipoprotein lovastatin, etc. (a) antagonist Such as, for example, gemcabene (CI-1027). 65 In some embodiments, the at least one crystalline hydrate In some embodiments, the at least one crystalline hydrate of formula I is administered in combination with an inhibitor of formula I is administered in combination with an agonist of of glycogen phosphorylase, such as, for example, PSN-357 or US 8,003,636 B2 13 14 FR-258900 or those as described in WO2003084922, WO2004 103980, WO2004112784, WO2003065983, WO2004007455, WO2005073229-31 or WO2005067932. WO2003104207, WO2003104208, WO2004106294, In some embodiments, the at least one crystalline hydrate WO2004011410, WO2004033427, WO200404 1264, of formula I is administered in combination with glucagon WO2004037251, WO2004.056744, WO2004058730, receptor antagonists such as, for example, A-770077, NNC WO2004065351, WO2004089367, WO2004089380, 25-2504 or as described in WO2004100875 or WO2004089470-71, WO2004089896, WO2005016877, WO200506568O. WO2005097759, WO2006010546, WO2006012227, In some embodiments, the at least one crystalline hydrate WO2006012173, WO2006017542, WO2006034804, of formula I is administered in combination with activators of WO2006040329, WO2006051662, WO2006048750, glucokinase, such as, for example, LY-2121260 10 WO2006049952, WO2006048331, WO2006050908, (WO2004063179), PSN-105, PSN-110, GKA-50 or those as WO2006024627, WO2006040329, WO2006066109, are described for example in WO2004072031, WO2006074244, WO2006078006, WO2006106423, WO2004072066, WO2005080360, WO2005044801, WO2006132436, WO2006134481, WO2006134467, WO2006016194, WO2006058923, WO2006112549, WO2006135795, WO2006136502, WO2006138695, WO2006125972, WO2007017549, WO2007017649, 15 WO2006133926, WO2007003521, WO2007007688, WO2007007910, WO2007007040-42, WO2007006760-61, US2007066584, WO2007047625, WO2007051811, and WO2007006814, WO2007007886, WO2007028135, WO2007051810. WO2007031739, WO2007041365, WO2007041366, In some embodiments, the at least one crystalline hydrate WO2007037534, WO2007043638, WO2007053345, of formula I is administered in combination with inhibitors of WO2007051846, WO2007051845, WO2007053765, and protein tyrosine phosphatase 1B (PTP1 B), as are described WO20070518467. for example in WO2001 19830-31, WO200117516, In some embodiments, the at least one crystalline hydrate WO2004506446, WO2005012295, WO2005116003, of formula I is administered in combination with an inhibitor WO2005116003, WO2006007959, DE 10 2004 060542.4, of gluconeogenesis, such as, for example, FR-225654. WO2007009911, WO2007028145, and WO2007081755. In some embodiments, the at least one crystalline hydrate 25 In some embodiments, the at least one crystalline hydrate of formula I is administered in combination with inhibitors of of formula I is administered in combination with modulators fructose-1,6-bisphosphatase (FBPase), such as, for example, of the sodium-dependent glucose transporter 1 or 2 (SGLT1, CS-917 (MB-06322) or MB-07803 or those described in SGLT2), such as, for example, KGA-2727, T-1095, SGL WO2006023515, WO2006104030, and WO2007014619. 0010, AVE 2268, SAR 7226 and sergliflozin or as are In some embodiments, the at least one crystalline hydrate 30 described for example in WO2004.007517, WO200452903, of formula I is administered in combination with modulators WO200452902, PCT/EP2005/005959, WO2005085237, of glucose transporter 4 (GLUT4), such as, for example, JP2004359630, WO2005121161, WO2006018150, KST-48 (D.-O. Lee et al.: Arzneim.-Forsch. Drug Res. 54 WO2006035796, WO2006062224, WO2006058597, (12), 835 (2004)). WO2006073197, WO2006080577, WO2006087997, In some embodiments, the at least one crystalline hydrate 35 WO2006108842, WO2007000445, WO2007014895, and of formula I is administered in combination with inhibitors of WO2007080170 or by A. L. Handlon in Expert Opin. Ther. glutamine-fructose-6-phosphate amidotransferase (GFAT), Patents (2005) 15(11), 1531-1540. as are described for example in WO2004 101528. In some embodiments, the at least one crystalline hydrate In some embodiments, the at least one crystalline hydrate of formula I is administered in combination with modulators of formula I is administered in combination with inhibitors of 40 of GPR40 as described for example in WO2007013689 and dipeptidylpeptidase IV (DPP-IV), such as, for example, WO20070330O2. vildagliptin (LAF-237), sitagliptin (MK-0431), sitagliptin In some embodiments, the at least one crystalline hydrate phosphate, saxagliptin (BMS-477118), GSK-823093, PSN of formula I is administered in combination with modulators 9301, SYR-322, SYR-619, TA-6666, TS-021, GRC-8200, of GPR119b as described for example in WO2004041274. GW-825964X, KRP-104, DP-893, ABT-341, ABT-279 or 45 In some embodiments, the at least one crystalline hydrate another salt thereof, or the compounds described in of formula I is administered in combination with modulators WO2003074500, WO2003106456, WO2004037169, of GPR119 as described for example in WO2005061489 WO200450658, WO2005058901, WO2005012312, (PSN-632408), WO2004065380, WO2007003960-62 and WO2005/012308, WO2006039325, WO2006058064, WO2OO7003964. WO2006015691, WO2006015701, WO2006015699, 50 In some embodiments, the at least one crystalline hydrate WO2006015700, WO2006018117, WO2006099.943, of formula I is administered in combination with modulators WO20060.99941, JP2006160733, WO200607 1752, of GPR120. WO2006065826, WO2006078676, WO2006073167, In some embodiments, the at least one crystalline hydrate WO2006068163, WO2006090915, WO2006104356, of formula I is administered in combination with inhibitors of WO2006127530, WO2006111261, WO2007015767, 55 hormone-sensitive lipase (HSL) and/or phospholipases as WO2007024993, and WO2007029086. described for example in WO2005073199, WO2006074957, In some embodiments, the at least one crystalline hydrate WO20060873.09, WO2006111321, and WO2007042178. of formula I is administered in combination with JanumetTM, In some embodiments, the at least one crystalline hydrate a fixed combination of Sitagliptin phosphate with metformin of formula I is administered in combination with inhibitors of hydrochloride. 60 acetyl-CoA carboxylase (ACC). Such as, for example, those In some embodiments, the at least one crystalline hydrate as described in WO199946262, WO200372197, of formula I is administered in combination with inhibitors of WO2003072197, WO02005044814, WO2005108370, 11-beta-hydroxysteroid dehydrogenase 1 (113-HSD1), such JP2006131559, WO200701 1809, WO2007011811, and as, for example, BVT-2733, JNJ-25918646, INCB-13739 or WO2007O13691. those as are described for example in WO200190090-94, 65 In some embodiments, the at least one crystalline hydrate WO200343999, WO2004112782, WO200344000, of formula I is administered in combination with modulators WO200344009, WO2004112779, WO2004 113310, of xanthine oxidoreductase (XOR). US 8,003,636 B2 15 16 In some embodiments, the at least one crystalline hydrate 02/076949, WO2005080345, WO2005080328, of formula I is administered in combination with an inhibitor WO2005080343, WO2005075450, WO2005080357, of phosphoenolpyruvate carboxykinase (PEPCK), such as, WO200170700, WO2003026647-48, WO2003.02776, for example, those as described in WO2004074288. WO2003040 107, WO2003007887, WO2003027069, U.S. In some embodiments, the at least one crystalline hydrate Pat. No. 6,509,367, WO200132663, WO200308.6288, of formula I is administered in combination with an inhibitor WO2003087037, WO2004.048317, WO2004058145, of glycogen synthase kinase 3 beta (GSK-3 beta), as WO2003084930, WO2003084943, WO2004058744, described for example in US2005222220, WO2005085230, WO2004013 120, WO2004029204, WO2004035566, WO2005111018, WO2003078.403, WO2004022544, WO2004058249, WO2004058255, WO2004058727, WO20031064101, WO2005058908, US2005038023, 10 WO2004069838, US20040214837, US20040214855, WO2005.009997, US2005026984, WO2005000836, US20040214856, WO2004096209, WO2004096763, WO2004 106343, EP1460075, WO2004014910, WO2004096794, WO2005000809, WO2004.099157, WO2003076442, WO2005087727 and WO2004046117. US20040266845, WO2004110453, WO2004108728, In some embodiments, the at least one crystalline hydrate WO2004000817, WO2005000820, US20050009870, of formula I is administered in combination with an inhibitor 15 WO200500.974, WO2004111033-34, WO2004.11038-39, of the serum/glucocorticoid-regulated kinase (SGK) as WO2005016286, WO2005007111, WO2005.007628, described for example in WO2006072354. US2005.0054679, WO2005027837, WO2005028456, In some embodiments, the at least one crystalline hydrate WO2005063761-62, WO2005061509, WO2005077897, of formula I is administered in combination with an agonist of WO2006047516, WO2006060461, WO2006067428, the RUP3 receptor as described for example in WO2006067443, WO2006087480, WO2006087476, WO200703.5355. WO2006100208, WO2006106054, WO200611 1849, In some embodiments, the at least one crystalline hydrate WO2006113704, WO200700.9705, WO2007017124, of formula I is administered in combination with an inhibitor WO2007017126, WO2007018459, WO2007016460, of protein kinase C beta (PKC beta), such as, for example, WO2007020502, WO2007026215, WO2007028849, ruboxistaurin. 25 WO2007031720, WO2007031721, WO2007036945, In some embodiments, the at least one crystalline hydrate WO2007038.045, WO2007039740, US20070015810, of formula I is administered in combination with an activator WO2007046548, WO2007047737, WO20070843.19, and of the gene which codes for the ataxiatelangiectasia mutated WO2007084450); cannabinoid receptor 1/cannabinoid (ATM) protein kinase, such as, for example, chloroquine. receptor 2 (CB1/CB2) modulating compounds as described In some embodiments, the at least one crystalline hydrate 30 for example in WO2007001939, WO2007044215, of formula I is administered in combination with an endothe WO2007047737; MC4 agonists (e.g. 1-amino-1,2,3,4-tet lin A receptor antagonist such as, for example, avosentan rahydronaphthalene-2-carboxylic acid 2-(3a-benzyl-2-me (SPP-301). thyl-3-oxo-2.3.3a,4,6,7-hexahydropyrazolo 4.3-cpyridin In some embodiments, the at least one crystalline hydrate 5-yl)-1-(4-chlorophenyl)-2-oxoethylamide: WO 01/91752) of formula I is administered in combination with inhibitors of 35 or LB53280, LB53279, LB53278 or THIQ, MB243, RY764, “I-kappaB kinase” (IKK inhibitors), as are described for CHIR-785, PT-141 or those that are described in example in WO2001000610, WO2001030774, WO2005060985, WO2005.009950, WO2004087.159, WO2004O22553 and WO2005097 129. WO2004078717, WO2004078716, WO2004024720, In some embodiments, the at least one crystalline hydrate US20050124652, WO2005051391, WO2004112793, of formula I is administered in combination with modulators 40 US20050222014, US20050176728, US20050164914, of the glucocorticoid receptor (GR), like those described for US20050124636, US20050130988, US2004.01672.01, example in WO2005090336, WO2006071609, and WO2004.005324, WO2004.037797, WO2005042516, WO2O06135826. WO2005040109, WO2005030797, US20040224901, In some embodiments, the at least one crystalline hydrate WO200501921, WO200509184, WO2005000339, of formula I is administered in combination with CART 45 EP1460069, WO2005047253, WO2005047251, modulators (see "Cocaine-amphetamine-regulated transcript WO2005118573, EP1538159, WO2004072076, influences energy metabolism, anxiety and gastric emptying WO2004072077, WO2006021655-57, WO200700.9894, in mice’ Asakawa, A. et al.: Hormone and Metabolic WO2007015162, WO2007041061, WO2007041052; orexin Research (2001), 33(9), 554-558); NPY antagonists such as, receptor antagonists (e.g. 1-(2-methylbenzoxazol-6-yl)-3-1, for example, naphthalene-1-sulfonic acid {4-(4-amino 50 5 naphthyridin-4-ylurea hydrochloride (SB-334867-A) or quinazolin-2-ylamino)methylcyclohexylmethylamide those as are described for example in WO200196302, hydrochloride (CGP 71683A); NPY-5 receptor antagonists WO200185693, WO200408.5403, WO2005075458, and such as L-152804 or such as described, for example, in WO2006067224); histamine H3 receptoragonists (e.g. 3-cy WO2006001318; NPY-4 receptor antagonists such as clohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c. described, for example, in WO2007038942: NPY-2 receptor 55 pyridin-5-yl)propan-1-one oxalic acid salt (WO 00/63208) or antagonists such as described, for example, in those as are described in WO200064884, WO2005082893, WO2007038943; peptide YY 3-36 (PYY3-36) or analogous WO2006 107661, WO2007003.804, WO2007016496, and compounds, such as, for example, CJC-1682 (PYY3-36 con WO2007020213); histamine H1/histamine H3 modulators jugated with human serum albumin via Cys34), CJC-1643 such as, for example, betahistine or its dihydrochloride; CRF (derivative of PYY3-36 which conjugates in vivo to serum 60 antagonists (e.g. 2-methyl-9-(2,4,6-trimethylphenyl)-9H-1, albumin) or those as are described in WO2005080424 and 3,9-triazafluoren-4-yldipropylamine (WO 00/166585)); WO2006095166; derivatives of the peptide obestatin such as CRF BP antagonists (e.g. urocortin); urocortin agonists; ago those described in WO2006096847; CB1R (cannabinoid nists of the beta-3 adrenoceptor Such as, for example, 1-(4- receptor 1) antagonists (such as, for example, rimonabant, chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dim SR147778, SLV-319, AVE-1625, MK-0364 or salts thereofor 65 ethyl-1H-indol-6-yloxy)ethylaminoethanol hydrochloride compounds such as those described for example in EP (WO 01/83451) or solabegron (GW-427353) or N-5984 0656354, WO 00/115609, WO2001/64.632-64634, WO (KRP-204), or those as are described in JP2006111553, US 8,003,636 B2 17 18 WO2002038543, and WO2007048840-843; MSH (melano WO2005072740, JP2005206492, WO2005013907, cyte-stimulating hormone) agonists; MCH (melanin-concen WO2006004200, WO2006019020, WO2006064189, trating hormone) receptor antagonists (such as, for example, WO2006082952, WO2006120125, WO2006113919, NBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, WO2006134317, WO2007016538; inhibitors of fatty acid T-71, GW-803430 or compounds such as are described in 5 synthase (FAS) such as, for example, C75 or those as WO2005085200, WO2005019240, WO2004011438, described in WO2004005277: inhibitors of stearoyl-CoA WO2004012648, WO2003015769, WO2004072025, delta 9 desaturase (SCD1) as described for example in WO2005070898, WO2005070925, WO2004039780, WO2007009236, WO2007044085, WO2007046867, WO2004.092181, WO2003.033476, WO2002006245, WO2007046868, WO20070501124; oxyntomodulin; oleoyl WO2002089729, WO2002002744, WO2003004027, estrone or thyroid hormone receptor agonists or partial ago FR2868780, WO2006010446, WO2006038680, 10 nists such as, for example: KB-2115 or those as described in WO2006044293, WO2006044174, JP2006176443, WO20058279, WO200172692, WO200194293, WO2006018280, WO2006018279, WO2006118320, WO2003084915, WO2004018421, WO2005092316, WO2006130075, WO2007018248, WO2007012661, WO2007003419, WO2007009913, and WO2007039125. WO200702.9847, WO2007024004, WO20070394.62, In Some embodiments, the further active ingredient is WO2007042660, WO2007042668, WO2007042669, 15 Varenicline tartrate, a partial agonist of the alpha 4-beta 2 US2007093508, US2007093509, WO2007048802, and nicotinic acetylcholine receptor. JP2007091649); CCK-A agonists (such as, for example, 2 In some embodiments, the further active ingredient is tro 4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl) dusquemine. thiazol-2-ylcarbamoyl-5,7-dimethylindol-1-yl)acetic acid In some embodiments, the further active ingredient is a trifluoroacetic acid salt (WO99/15525) and SR-146131 (WO modulator of the SlRT1 enzyme. 0244150) and SSR-125180) or those as are described in WO2005116034; serotonin reuptake inhibitors (e.g. dexfen In some embodiments, the further active ingredient is lep fluramine); mixed serotonin/dopamine reuptake inhibitors tin; see, for example, “Perspectives in the therapeutic use of (e.g. bupropion) or fixed combinations of bupropion with leptin', Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, maltrexone; mixed serotoninergic and noradrenergic com Gema, Expert Opinion on Pharmacotherapy (2001), 2010), pounds (e.g. WO 00/71549): 5-HT receptor agonists, e.g. 25 1615-1622. 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO In some embodiments, the further active ingredient is dex 01/09111); mixed dopamine/norepinephrine/acetylcholine amphetamine or amphetamine. reuptake inhibitors (e.g. tesofensine); 5-HT2C receptor ago In some embodiments, the further active ingredient is fen nists (such as, for example, lorcaserin hydrochloride (APD fluramine or dexfenfluramine. 356) or BVT-933 or those as are described in WO200077010, 30 In Some embodiments, the further active ingredient is WO200077001-02, WO2005019180, WO2003064423, Sibutramine. WO200242304, WO2005035533, WO2005082859, In Some embodiments, the further active ingredient is WO2006077025, and WO2006103511); 5-HT6 receptor mazindole or phentermine. modulators such as, for example E-6837 or BVT-743 16 or In some embodiments, the at least one crystalline hydrate those as are described in WO2005058858 and 35 of formula I is administered in combination with bulking WO2007054257: bombesin receptor agonists (BRS-3 ago agents, such as insoluble bulking agents (see, for example, nists); galanin receptor antagonists; growth hormone (e.g. Carob/Caromax(R) (Zunft HJ; et al., Carob pulp preparation human growth hormone or AOD-9604); growth hormone for treatment of hypercholesterolemia, ADVANCES IN releasing compounds (tertiary butyl 6-benzyloxy-1-(2-diiso THERAPY (2001 September-October), 18(5), 230-6). Caro propylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline 40 2-carboxylate (WO 01/85695)); growth hormone max is a carob-containing product from Nutrinova, Nutrition secretagogue receptor antagonists (ghrelin antagonists) Such Specialties & Food Ingredients GmbH, Industriepark Höchst, as, for example, A-778193 or those as are described in 65926 Frankfurt/Main). Combination with Caromax(R) is pos WO2005030734; TRHagonists (see, for example, EP 0462 sible in one preparation or by separate administration of com 884); uncoupling protein 2 or 3 modulators; leptin agonists pounds of the formula I and Caromax(R). Caromax(R) can in (see, for example, Lee, Daniel W.; Leinung, Matthew C.; 45 this connection also be administered in the form of food Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin ago products Such as, for example, in bakery products or muesli nists as a potential approach to the treatment of obesity. Drugs bars. of the Future (2001), 26(9), 873-881); DA agonists (bro It will be understood that every suitable combination of the mocriptine or Doprexin); lipase/amylase inhibitors (for compounds of the invention with one or more of the afore example WO 00/40569); inhibitors of diacylglycerol O-acyl 50 mentioned compounds and optionally one or more further transferases (DGATs) such as for example BAY-74-41 13 or active ingredients will be regarded as falling within the pro as described for example in US2004/0224997, tection conferred by the present invention. WO2004094618, WO200058491, WO2005044250, Exemplary compounds are set forth below.

%

HO O O O

le HO o1 No E O O Na" Na" FM-VP4.

US 8,003,636 B2 25 26 -continued o1 1. r^^s r) N 2 o N 6 || Na2 T-1095 SPP-301

C F THIQ MB243

MeO O NH S O N N H F X w NH r N- NH RYT64 CHIR-785 colorsH ?o - COOor A-761 A-66.5798

US 8,003,636 B2 29 30 -continued

risO oleoyl-estrone

N N -Cl C N H N O O O

HO C OH KB-2115 KCP-265

On 1 N-OH

21 N x HCI O 2 HN O N N

O '', OH

SMP-797 JNJ-25918646 O N -O N NH2 A O N N N N O Na2 skO O PSN-6324.08 Š SYR-322

OH N HO N 1 N x HC 2 CONH HO, O O N OH N HO O DP-893 varenicline tartrate

US 8,003,636 B2 35 36 -continued O OH

N-4 N O /N \-\

O AS-15521.33 S

luJIXN-1No O N No CrorN Na N X H2SO4 CKD-501 (lobeglitaZone Sulphate) R = CHCH-CH

Also provided are processes for preparing the compound of seed crystals in water. The seed crystals required can be the formula I. prepared, for example, by process A. The water may also Process A: 35 comprise a proportion of an organic solvent. The compound of the formula II prepared according to The water content of the hydrate after drying under reduced U.S. Pat. No. 7,205,290 pressure at elevated temperatures may also be considerably

II

OH ,

O OH H F O 9 OH N --~~~~ H OH OH is purified by chromatography, for example on RP 18 silica less than the value of 2.2% calculated for a monohydrate gel using a solvent system of water, acetonitrile and trifluo (n=1). If the compound is exposed to ambient air (having, for roacetic acid, and then converted by treatment with water into 60 example, a relative humidity of 40-60%), the water content quickly returns to a value close to the theoretical value. the crystalline hydrate of the formula I. Also provided are crystalline hydrates of the formula I Process B: prepared by a process described herein. The compound of the formula II prepared according to The invention is further illustrated by the following non U.S. Pat. No. 7,205.290 is dissolved in an organic solvent or limiting examples. a mixture of organic solvents. In some embodiments, the 65 The preparation of Some examples is described in detail organic solvent used is ethanol. To increase the solubility, below, the other hydrates of the compound of the formula I water may be added. This solution is added to a suspension of were obtained analogously. US 8,003,636 B2 37 38 EXPERIMENTAL PART TABLE 1-continued Example 1 2 theta (+/-0.2 degrees 2 theta) 21.58 The amorphous compound of the formula II (purity 5 22.30 23.26 according to HPLC: 95.8%, water content: 0.3%) is purified 24.06 by chromatography: 24.SS Stationary phase: Kromasil C-18, 7 um 25.37 Column volume: 1.7L 26.65 10 27.79 Column length: 22 cm 28.41 Mobiles phases: 29.17 A: waterfacetonitrile=9/1 (vol/vol) with 0.1% by volume 30.04 of trifluoroacetic acid added 30.56 31.37 B: waterfacetonitrile=1/9 (vol/vol) with 0.1% by volume of 15 31.90 trifluoroacetic acid added 32.39 Flow rate: 200 ml/min 33.10 Gradient: t=0 min; 20% of mobile phase B Owing to natural deviations in the samples or in the mea t=90 min, 47% of mobile phase B Application of substance: 8g of compound II are dissolved Suring method, the 2 theta values of the peaks can be stated in 770 ml of mobile phase B and diluted with 3500 ml of with an accuracy of +/-0.2 degrees theta. However, it is mobile phase A. The solution is filtered and applied to the common to see Some measurement variations in reported data column using a flow rate of 200 ml/min. The substance is then due to, for example, instrumental variations and environmen eluted using the above gradient. Fractions having a purity of tal disturbances, such as preferred orientation, Sample Surface >99% are combined. The acetonitrile is distilled off on a 25 and inter-apparatus variability, and thus even the same forms rotary evaporator at a bath temperature of <40°C., and the of a compound may not exhibit the same exactXRPD data (in residue is freeze-dried. From 80 g, it was possible to obtain 60 terms of D-spacing and peak intensity) all the time. Thus, g of the compound of the formula II having a purity according even when the specific numerical values are not identical in to HPLC of >99%. The amorphous product contained 0.38% every measurement, if the overall pattern is reproduced and of water and 3.1% of trifluoroacetic acid. The XRPD of this " the peak locations and relative peak intensities are sufficiently amorphous product of formula II exhibits the XRPD shown in similar, one of skill in the art, using known and accepted FIG. 3. techniques for Such evaluation, can conclude that all of the 58 g of the compound of the formula II having a purity obtained data demonstrate a single crystalline form. according to HPLC of >99% in 1 L of 2% strength sodium bicarbonate solution were stirred at 20-25° C. for one hour 35 Example 2 and then in an ice bath for 30 minutes. The product is filtered off and triturated twice in total as described above with 1 L of 100 g of the amorphous compound II (purity according to water. The product is then dried under reduced pressure at 50° HPLC: 95.8%, water content: 0.3%) are dissolved in 400 ml C. This gives 55.5g of the crystalline compound of the for aqueous ethanol (denatured with methyl ethyl ketone, 80% mula I having a water content of 1.9%, which corresponds to 40 (vol/vol)) by heating to 40°C. The solution is allowed to cool n=0.8.6. Owing to natural deviations in the samples or in the to 20-25°C. At 20-25°C., 2 g of the crystalline compound I measuring method (according to Karl Fischer), the values for from Example 1 are suspended by stirring in 10 L of distilled the water content can be stated with an accuracy of +/-0.1%. water. Over a period of 70 minutes, the solution of compound The compound of the formula I obtained exhibits the II in 80% of ethanol is added to this suspension. The vessel XRPD shown in FIG. 1. Exemplary 2 theta values are sum 45 from which the solution was added is then rinsed with another marized in table 1. 40 ml of 80% ethanol. A white precipitate is formed. The mixture is then stirred at 20-25° C. for another 20 h. The TABLE 1. precipitate is filtered off with suction and washed a little at a time with a total of 5 L of distilled water. After drying at 40° 2 theta (+/-0.2 degrees 2 theta) 50 C. under reduced pressure, 88.3 g of the crystalline hydrate of 4.39 the formula I are obtained (water content: 2.9%, which cor 7.33 responds to n=1.3). 892 The compound of the formula I obtained exhibits the 1069 XRPD shown in FIG. 2. Exemplary 2 theta values are sum 12.19 55 12.59 marized in table 2. 13.38 1431 TABLE 2 15.83 16.OS 2 theta (+/-0.2 degrees 2 theta) 16.59 17.31 60 7.32 1768 8.89 18.39 9.15 1883 10.66 1952 12.18 2003 12.58 20.43 65 13.36 20.83 1428 US 8,003,636 B2 39 40 TABLE 2-continued sure, 7.879 of the crystalline hydrate of the formula I are obtained. The XRPD confirms that the crystalline hydrate of 2 theta (+/-0.2 degrees 2 theta) Formula I was obtained. 14.75 15.79 Example 5 16.OS 16.57 17.29 In 35.3 g of ethanol (denatured with methyl ethyl ketone) 1768 and 9.75 g of distilled water, 12 g of the amorphous com 1837 pound II (purity according to HPLC: 97.1%) are heated to the 1881 10 1950 boil. 2.3 g of liquid are distilled off. The solution is allowed to 2O.O2 cool to 20-25° C. At 20-25° C., 0.12 g of the crystalline 2O41 compound of the formula I is suspended by stirring in 414 ml 20.8 of distilled water. Over a period of 45 minutes, the solution of 21.10 compound II in ethanol/wateris added to this suspension. The 21.57 15 22.28 vessel from which the solution was added is rinsed with a 23.25 mixture of 9.75 g of ethanol and 2.25g of water. 23.70 24.52 The mixture is then stirred for another 18 h. The precipitate 24.69 is filtered off with suction and washed with 60 ml of distilled 25.36 water. After drying at 40°C. under reduced pressure, 11.7 g of 26.40 the crystalline hydrate of the formula I (water content: 2.3%, 26.87 27.78 which corresponds to n=1.05) are obtained. The XRPD con 28.38 firms that the crystalline hydrate of Formula I was obtained. 28.81 29.56 Example 6 30.02 25 30.56 31.40 The hydrate obtained in Example 2 was dried under 31.90 reduced pressure at 50° C. until a water content of 0.8% had 32.42 been reached. The crystalline product was stored at 23° 33.08 C./60% relative atmospheric humidity. 30

Example 3 Storage time (h) Water content (%) l O.S 1.1 O.S 25g of the amorphous compound II (purity according to 35 2 2.4 1.09 HPLC: 95.8%, water content: 0.3%) are dissolved in 100 ml 4 2.5 1.14 aqueous ethanol (denatured with methyl ethyl ketone, 80% 6 2.4 1.09 (vol/vol)) by heating to 40°C. The solution is allowed to cool 24 2.5 1.14 to 20-25° C. At 20-25° C., 500 mg of the crystalline com pound I from Example 1 are suspended by stirring in 500 ml 40 The XRPD after 24 hours confirms that the crystalline of distilled water. Over a period of 60 minutes, the solution of hydrate of Formula I was obtained. compound II in 80% of ethanol is added to this suspension. Test of Pharmacological Activity: The vessel from which the solution was added is then rinsed Using the method described below, the crystalline hydrate with another 10 ml of 80% ethanol. A white precipitate is of formula I was examined for its activity: formed. The mixture is then stirred at 20-25°C. for another 20 45 Effect on Cholesterol Absorption+H-Taurocholic Acid h. The precipitate is filtered off with suction and washed with Elimination via Fecal Elimination in Mice, Rats or Hamsters distilled water. After drying at 45° C. under reduced pressure, NMRI mice, Wistar rats or Golden Syrian hamsters (in 24.7 g of the crystalline hydrate are obtained. The XRPD groups of n 4-6) are kept with a standard diet (Altromin, confirms that the crystalline hydrate of Formula I was Lage (Lippe), Germany) in metabolic cages. The afternoon obtained. 50 prior to the administration of the radioactive tracers (C- cholesterol) the feed is withdrawn, and the animals are adapted to the cage wires. Example 4 In addition, 24 hours prior to the peroral administration of the test meal (''C-cholesterol in IntralipidR 20, Pharmacia 10 g of the amorphous compound II (purity according to 55 Upjohn), the animals are labelled s.c. with H-TCA (tauro HPLC: 95.8%, water content: 0.3%) are dissolved in 40 ml cholic acid) (for example 1 uCi/mouse to 5 uCi/rat). aqueous ethanol (denatured with methyl ethyl ketone, 80% Cholesterol absorption test: 0.25 ml/mouse Intralipid R. 20 (vol/vol)) by heating to 40°C. The solution is allowed to cool (Pharmacia-Upjohn) (spiked with 0.25uCi C-cholesterolin to 20-25°C. At 20-25°C., 0.2 g of the crystalline compound 0.1 mg of cholesterol) is administered perorally using a stom of the formula I from Example 1 is suspended by stirring in 60 ach tube. 1000 ml of distilled water. Over a period of 10 minutes, the Test substances are prepared separately in 0.5% methyl solution of compound II in 80% of ethanol is added to this cellulose (Sigma)/5% Solutol (BASF, Ludwigshafen, Ger suspension. A white precipitate is formed, which is filtered off many) or in a suitable vehicle. with suction and resuspended by stirring in 1 L of water. The The application volume of the test substance is 0.5 ml/mouse. mixture is then stirred at 20-25° C. for another 1 h. The 65 The test substance is administered immediately prior to the precipitate is filtered off with suction and washed with 20 ml test meal (Intralipid with ''C-cholesterol label) (cholesterol of distilled water. After drying at 50° C. under reduced pres absorption test). US 8,003,636 B2 41 42 The feces are collected over a period of 24 h: the fecal Compared to the amorphous compound of the formula II elimination of ''C-cholesterol and 3H-taurocholic acid from U.S. Pat. No. 7,205.290, the crystalline hydrates of the (TCA) is determined after 24 hours. formula I have a considerably increased dissolution rate. The livers are removed and homogenized, and aliquots are Accordingly, provided are crystalline hydrates of the for incinerated in an Oximate (Model 307, Packard) to determine mula I wherein, after 15 minutes at least 50% of the crystal the amount of ''C-cholesterol taken up/resorbed. line hydrate of the formula I is dissolved when the dissolution Evaluation: rate of 20 mg of the crystalline hydrate of the formula I in Feces Samples: 1000 ml of a 0.1% strength aqueous sodium dodecylsulfate The total weight is determined, the sample is made up with Solution is measured in a standard paddle apparatus according 10 to the USP27 at 37° C. and a stirrer speed of 75 rpm. water to a defined Volume and then homogenized, an aliquot In some embodiments, after 15 minutes at least 70% of the is evaporated to dryness and incinerated in an Oximate crystalline hydrate of the formula I are in solution. (Model 307, Packard, for the incineration of radioactively In some embodiments, after 15 minutes at least 85% of the labelled samples): the amount of radioactive H HO und crystalline hydrate of the formula I are in solution. "C CO is extrapolated to the amount of H-taurocholic 15 For active ingredients to be able to display their activity in acid or 'C-cholesterol eliminated (dual isotope technique). the body, they may be present, at least in part, in dissolved The EDoo values are interpolated as a dose from a dose form at the site of action. Here, solubility and dissolution rate activity curve as the doses which double the elimination of in aqueous environments are two important factors. There is TCA or cholesterol, based on a control group treated simul virtually no difference between the solubilities of amorphous taneously. and crystalline compounds as the Solubility is a thermody Liver Samples: namic quantity. This is different for the dissolution rate, since The amount of ''C-cholesterol taken up into the liver is it is a kinetic quantity. In general, crystalline compounds referenced to the dose administered. The EDs values are have, compared to amorphous compounds, a lower dissolu interpolated from a dose-activity curve as the dose which tion rate since the crystalline compounds are thermodynami halves the uptake of "C-cholesterol into the liver (50%), 25 cally more stable. based on a control group. It is therefore an advantage that the crystalline hydrate of Example No. 2 exhibits an EDoo value (fecal elimination the formula I has a considerably higher dissolution rate com mg/mouse) of 0.01 mg/mouse) pared to the amorphous compound II. After only 15 minutes, The measured EDoo value confirms the activity of the a large part of the active ingredient is already in Solution. This compounds of the formula I described herein and demon 30 is almost three times the amount of the amorphous active strates that the crystalline hydrates of the formula I have very ingredient. Thus, the onset of the action of the crystalline good cholesterol absorption-inhibiting activity. hydrate of the formula I will be faster than the onset of the Test of the Dissolution Rate: action of the amorphous compound of the formula II. The dissolution rate of the crystalline hydrates of the for As those skilled in the art will appreciate, numerous mula I was tested as follows: 35 changes and modifications may be made to the embodiments The dissolution rate is measured in a standard apparatus of the invention without departing from the spirit of the inven (paddle) according to the US Pharmacopeia (USP27) at 37° tion. It is intended that all such variations fall within the scope C. The stirrer speed is 75 rpm. of the invention. 20 mg of the substance to be examined are added to 1000 ml of a 0.1% strength aqueous sodium dodecylsulfate (SDS) 40 The invention claimed is: solution. After 15, 30, 45 and 60 minutes, samples of 20 ml 1. At least one crystalline hydrate of the formula I, are taken. The portion dissolved is determined photometrically at 256 nm using a comparison solution. The measurement is carried out in 10 mm cuvettes using, for example, a Perkin Elmer 45 Lambda 25 photometer. The samples are measured directly O after removal of the samples. In each case, a mean is calcu lated from three determinations. The comparison Solution is prepared as follows: 2-3 mg of OH the batch used are dissolved in 2 ml of dimethylformamide in 50 l, a measuring flask. The volume is then made up to 100.0 ml using 0.1% strength SDS solution. N The amorphous compound of the formula I used in Example 2 was compared to the crystalline compound of the formula I obtained in the same Example 2. The results are 55 compiled in the table below: NrnO O OH OH enH2O

~. N OH Amorphous compound Crystalline compound 60 H Time of the formula II of the formula I OH OH min (release %) (release %) 15 3O.O 88.0 wherein n has a value of from 0.8 to 1.3. 30 41.3 90.0 45 44.7 94.6 2. The at least one crystalline hydrate of claim 1 wherein n 60 46.2 98.7 65 has a value of 1. 3. The at least one crystalline hydrate of claim 1 wherein the XRPD, measured with CuKO. radiation, has at least peaks US 8,003,636 B2 43 44 of the following 2 theta values: 12.19, 17.31, 20.43, 20.83, 6. The pharmaceutical composition according to claim 5 and 21.58, each of the diffraction angles being +0.2 degrees 2 further comprising at least one HMGCoA reductase inhibitor. theta. 7. The pharmaceutical composition according to claim 6. wherein the HMGCoA reductase inhibitor is selected from 4. The at least one crystalline hydrate of claim 1 wherein simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, the XRPD, measured with CuKO. radiation, has at least peaks cerivastatin, and rosuvastatin. of the following 2 theta values: 7.33, 8.92, 12.19, 16.05, 8. The pharmaceutical composition according to claim 7. 17.31, 17.68, 18.83, 20.43, 20.83, 21.58, 24.55, and 25.37, wherein the HMGCoA reductase inhibitor is atorvastatin. each of the diffraction angles being t0.2 degrees 2 theta. 9. The pharmaceutical composition according to claim 8. 5. A pharmaceutical composition comprising a pharma 10 wherein the pharmaceutical composition comprises 1-50 mg ceutically acceptable carrier and a therapeutically effective of atorvastatin and 10-50 mg of the at least one crystalline amount of at least one crystalline hydrate of claim 1. hydrate of the formula I,

OH lo,

O O H H onH2O F g O YNYi Yi Yi --~~~~ rN O H

wherein n has a value of from 0.8 to 1.3. 10. The pharmaceutical composition according to claim 9. 30 wherein the pharmaceutical composition comprises 5-15 mg of atorvastatin and 15-50 mg of the at least one crystalline hydrate of the formula I. 11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition comprises 10 35 mg of atorvastatin and 25 mg of the at least one crystalline hydrate of the formula I. 12. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition comprises 10 mg of atorvastatin and 50 mg of the at least one crystalline 40 hydrate of the formula I. 13. A method of treating a mammal having hyperlipidemia comprising administering at least one crystalline hydrate of claim 1 to said mammal. 14. A method of treating a mammal having hyperlipidemia comprising 45 formulating at least one crystalline hydrate of claim 1 with one or more pharmaceutically acceptable diluents to form a composition and administering the composition to said mammal. 15. A method of lowering the serum cholesterol level of a 50 mammal comprising administering at least one crystalline hydrate of claim 1 to said mammal. 16. A method of lowering the serum cholesterol level of a mammal comprising formulating at least one crystalline hydrate of claim 1 with 55 one or more pharmaceutically acceptable diluents to form a composition and administering the composition to said mammal. k k k k k