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(12) United States Patent (10) Patent No.: US 8.492,557 B2 Chow Et Al

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(12) United States Patent (10) Patent No.: US 8.492,557 B2 Chow Et Al US008492.557B2 (12) United States Patent (10) Patent No.: US 8.492,557 B2 Chow et al. (45) Date of Patent: *Jul. 23, 2013 (54) ESTER PRO-DRUGS OF WO 2009089132 T 2009 3-(1-(IH-IMIDAZOL-4-YL)ETHYL)-2- W. WO 3. 1999 38 398 METHYLPHENYL METHANOL OTHER PUBLICATIONS (75) Inventors: Ken Chow, Newport Coast, CA (US); 1 f 1 f 1 Liming Wang, Irvine, CA (US); U.S. Appl. No. 233,844, U.S. Appl. No. 13/233,382, U.S. Appl. Michael E. Garst, Newport Beach, CA No. 13/233,665. s p is Larry Wheeler, From the Lab to the Clinic: Activation of an Alpha-2 (US); John E. Donello, Dana Point, CA Agonist Pathway is Neuroprotective in Models of Retinal and Optic (US); Daniel W. Gil, Corona Del Mar, Nerve Injury, Eur, J. Ophthalmology, 1999, 9 (1), S17-S22. CA (US); Mohammad I. Dibas, Laguna Caroline Strasinger, Prodrugs and Codrugs as Strategies for Improv Niguel, CA (US) ing Percutaneous Absorption, Expert Rev. Dermatol., 2008, 3 (2), 221-233. Bernard Testa, Design of Intramolecularly Activated Prodrugs, Drug (73) Assignee: Allergan, Inc., Irvine, CA (US) Metabolism Reviews, 1998, 30 (4), 787-807. Francesco Gentili, Agonists and Antagonists Targeting the Different (*) Notice: Subject to any disclaimer the term of this a2-Adrenoceptor Subtypes, Current Topics in Medicinal Chemistry, patent is extended or adjusted under 35 2007, 7 (2), 163-186. U.S.C. 154(b) by 0 days. Vincent Lee, Prodrugs for Improved Ocular Drug Delivery, Advanced Drug Delivery Reviews, 1989, 3 (1), 1-38. This patent is Subject to a terminal dis- Saul Merin, A Pilot Study of Topical Treatment with an a2-Agonist in claimer. Patients with Retinal Dystrophies, J. Ocular Pharmacology and Therapeutics, 2008, 24(1), 80-86. (21) Appl. No.: 13/233,891 Hui, Y-H et al.; "Analytical method development for the simulta neous quantitation of dexmedetomidine and three potential metabo (22) Filed: Sep.15, 2011 lites in plasma'; Journal of Chromatography, (1997), 762(1+2), 281 291. (65) Prior Publication Data Stoilov et al., Synthesis of detomidine and medetomidine metabo lites: 1,2,3-trisubstituted arenes with 4'(5)-imidazolylmethyl US 2012/O122945 A1 May 17, 2012 groups” in Journal of Heterocyclic Chemistry (1993), 30(6), (1645 1651). O O Salonen, et al. "Biotransformation of Medetomidine in the Rat' in Related U.S. Application Data Xenobiotica (1990), 2005), 471-80. (60) Eypal application No. 61/383,370, filed on Sep. MedetomidinePierce V. Kavanagh; {1-(2,3-Dimethylphenyl)-1-(imidazol-4(5)-yl) "Synthesis of Possible Metabolites of s ethane'; J. Chem. Research (S), 1993. (51) Int. Cl. * cited b CO7D 233/64 (2006.01) c1ted by examiner A6 IK3I/26 (2006.01) Primary Examiner —Yong Chu (52) U.S. Cl. Assistant Examiner — Sonya Wright USPC - - - - - - - - - - - r: 548/346.1: 514/532:548/335.1 (74) Attorney, Agent, or Firm — Doina G. Ene (58) Field of Classification Search USPC ............................. 548/335.1, 346.1, 514/532 (57) ABSTRACT See application file for complete search history. Theepresent p t 1 nVenuont relaleslatest to novel1 compounds,pounds, ester ppro (56) References Cited drugs of 3-(1-1H-imidazol-4-yl)ethyl)-2-methylphenyl methanol, processes for preparing them, pharmaceutical FOREIGN PATENT DOCUMENTS compositions containing them and their use as pharmaceuti WO 9514007 5, 1995 cals in the treatment of conditions mediated by adrenergic WO 2005034998 4/2005 receptors. WO 2005.115395 12/2005 WO 2006036480 4/2006 12 Claims, No Drawings US 8,492,557 B2 1. 2 ESTER PRO-DRUGS OF -continued 3-(1-(IH-IMIDAZOL-4-YL)ETHYL)-2- METHYLPHENYL METHANOL HO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 61/383,370 filed on Sep. 16, 2010, the entire (3-(1-(H-imidazol-4-yl)ethyl)- 10 2-methylphenyl)methanol disclosure of which is incorporated herein by this reference. CAS 128366-50-7 BACKGROUND OF THE INVENTION HO 1. Field of the Invention 15 The invention relates to the field of pharmaceutical com pounds in particular ester pro-drugs of 3-(1-(1H-imidazol 4-yl)ethyl)-2-methylphenylmethanol, and its enantiomers. (R)-(3-(1-(1H-imidazol-4-yl)ethyl)- The invention further concerns processes for preparing these 2-methylphenyl)methanol pharmaceutical compounds, compositions containing them CAS 1240244-32-9 and their use for the treatment and prevention of disease. 2. Summary of the Related Art Three alpha-1 and three alpha-2 adrenergic receptors have been characterized by molecular and pharmacological meth 25 ods. Activation of these alpha receptors evokes physiological responses with useful therapeutic applications. Compound, 4-1-(2,3-dimethylphenyl)ethyl-3H-imida (S)-(3-(1-(1H-imidazol-4-yl)ethyl)- Zole, generically known as, medetomidine is an alpha 2 adr 30 2-methylphenyl)methanol energic agonist, for use in the sedation of animals. The hydro CAS 1892.55-79-6 chloride salt of the (S) enantiomer of medetomidine, generically known as dexmedetomidine, (S) 4-1-(2,3-dim 3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)metha ethylphenyl)ethyl-3H-imidazole, is also indicated for use as nol is described in “Synthesis of detomidine and medetomi a sedative or analgesic in cats and dogs. 35 dine metabolites: 1,2,3-trisubstituted arenes with 4'(5')-imi The metabolite of dexmedetomidine is (S) 3-(1-(1H-imi dazolylmethyl groups” in Journal of Heterocyclic Chemistry dazol-4-yl)ethyl)-2-methylphenyl)methanol together with its (1993), 30(6), (1645-1651) by Stoilov et al. racemic mixture, compound 3-(1-(1H-imidazol-4-yl)ethyl)- Kavanagh, et al. describe 3-(1-(1H-imidazol-4-yl)ethyl)- 2-methylphenyl)methanol, are described in the literature in 40 2-methylphenyl)methanol in “Synthesis of Possible Metabo Journal of Chromatography, (1997), 762(1+2), 281-291 by lites of Medetomidine {1-(2,3-dimethylphenyl)-1-(imidazol Hui, Y-H et al. 4(5)-yl)ethane' in Journal of Chemical Research, Synopses (1993), (4), 152-3. 3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)metha 45 nol is described by Salonen, et al. in “Biotransformation of Medetomidine in the Rat' in Xenobiotica (1990), 20(5), 471 8O. PCT Int. Appl. WO 2010093.930 A1 discloses 3-(1-(1H imidazol-4-yl)ethyl)-2-methylphenyl)methanol and its (S) 50 and (R) enantiomers Medetomidine SUMMARY OF THE INVENTION 4-(1-(2,3-dimethylphenyl) ethyl)-1H-imidazole The present invention provides ester pro-drugs of 3-(1- CAS86347-14-0 55 (1H-imidazol-4-yl)ethyl)-2-methylphenylmethanol, pro cesses for preparing them, pharmaceutical compositions con taining them and their use as pharmaceuticals. Upon hydrolytic and/or enzymatic cleavage of the ester functional ity the parent compound, 3-(1-(1H-imidazol-4-yl)ethyl)-2- 60 methylphenylmethanol, is released to act as a selective modulator of the alpha 2 adrenergic receptors. In another aspect, the present invention provides ester pro Dexmedetomidine drugs of (S) 3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphe (S)-4-(1-(2,3-dimethylphenyl) nylmethanol, processes for preparing them, pharmaceutical ethyl)-1H-imidazole 65 compositions containing them and their use as pharmaceuti CAS 1892.55-79-6 cals. Upon hydrolytic and/or enzymatic cleavage of the ester functionality the parent compound, active metabolite, (S) US 8,492,557 B2 3 4 3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenylmethanol, In one aspect of the invention, relates to a pharmaceutical is released to act as a selective modulator of the alpha 2 composition comprising, consisting essentially of, or consist adrenergic receptors. ing of a therapeutically effective amount of ester pro-drugs of In another aspect the present invention provides ester pro 3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenylmethanol, drugs of (R) 3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphe or the enantiomers, diastereoisomers, hydrates, Solvates, nylmethanol, processes for preparing them, pharmaceutical crystal forms and individual isomers, tautomers or a pharma compositions containing them and their use as pharmaceuti ceutically acceptable salts thereof. cals. Upon hydrolytic and/or enzymatic cleavage of the ester In another aspect of the invention, relates to a pharmaceu functionality the parent compound (R) 3-(1-(1H-imidazol tical composition comprising, consisting essentially of, or 4-yl)ethyl)-2-methylphenylmethanol, is released to act as a 10 consisting of a therapeutically effective amount of ester pro selective modulator of the alpha 2 adrenergic receptors. drugs of (S) 3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphe These novel compounds are useful for the treatment or nylmethanol, or the enantiomers, diastereoisomers, prevention of mammals, including humans, in a range of hydrates, Solvates, crystal forms and individual isomers, tau conditions and diseases that are alleviated by alpha 2A, 2B, 15 tomers or a pharmaceutically acceptable salts thereof. 2C activation, including but not limited to treating or prevent In another aspect of the invention, relates to a pharmaceu ing glaucoma, elevated intraocular pressure, ischemic neuro tical composition comprising, consisting essentially of, or pathies, optic neuropathy, pain, visceral pain, corneal pain, consisting of a therapeutically effective amount of ester pro headache pain, migraine, cancer pain, back pain, irritable drugs of (R) 3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphe bowl syndrome pain, muscle pain and pain associated with nylmethanol, or the enantiomers, diastereoisomers, hydrates, Solvates, crystal forms and individual isomers, tau diabetic neuropathy, the treatment of diabetic retinopathy, tomers or a pharmaceutically acceptable salts thereof. other retinal degenerative conditions, stroke, cognitive defi “Prodrugs are frequently referred to by the term “meta cits, neropsychiatric conditions, drug dependence and addic bolically cleavable derivatives” which refers to compound tion, withdrawal of symptoms, obsessive-compulsive disor forms which are rapidly transformed in vivo to the parent ders, obesity, insulin resistance, stress-related conditions, 25 compound according to the invention, for example, by diarrhea, diuresis, nasal congestion, spasticity, attention defi hydrolysis in blood.
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