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 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. Thus, prodrugs are compounds bearing cit disorder, psychoses, anxiety, depression, autoimmune dis groups which are removed by biotransformation prior to ease, Crohn's disease, gastritis, Alzheimer's, and Parkinson's exhibiting their pharmacological action. Such groups include ALS other neurodegenerative diseases, dermatological con moieties which are readily cleaved in vivo from the com ditions, skin erythema (redness) and inflammation, acne, age 30 pound bearing it, which compound after cleavage remains or related macular degeneration, wet macular degeneration, dry becomes pharmacologically active. Such metabolically macular degeneration, geographic atrophy, diabetic macular cleavable groups form a class well known to practitioners of edema, tumors, wound healing, inflammation and retinal vein the art. They include, but are not limited to Such groups as occlusion, enhancing vision in patients with vision loss from alkanoyl (i.e. acetyl, propionyl, butyryl, and the like), unsub conditions including glaucoma, retinitis pigmentosa and neu 35 stituted and Substituted carbocyclic aroyl (such as benzoyl, ritis secondary to multiple Sclerosis, rosacea (dilation of the Substituted benzoyland 1- and 2-maphthoyl), alkoxycarbonyl blood vessels just under the skin), Sunburn, chronic Sundam (such as ethoxycarbonyl), trial klysilyl (such as trimethyl age, discreet erythemas, psoriasis, acne rosacea, menopause and triethylsilyl), monoesters formed with dicarboxylic acids associated hot flashes, hot flashes resulting from orchiecto (such as Succinyl), phosphate, Sulfate, Sulfonate, Sulfonyl, myatopic dermatitis, photoaging, seborrheic dermatitis, 40 sulfinyl and the like. The compounds bearing the metaboli allergic dermatitis, redness of the skin, telangiectasia (dila cally cleavable groups have the advantage that they may tions of previously existing small blood vessels) of the face, exhibit improved bioavailability as a result of enhanced solu rhinophymia (hypertrophy of the nose with follicular dila bility and/or rate of absorption conferred upon the parent tion), red bulbous nose, acne-like skin eruptions (may ooze or compound by virtue of the presence of the metabolically crust), burning or stinging sensation of the face, irritated and 45 cleavable group. (T. Higuchi and V. Stella, “Pro-drugs as bloodshot and watery eyes, erythema of the skin, cutenous Novel Delivery System’. Vol. 14 of the A.C.S. Symposium hyperactivity with dilation of blood vessels of the skin, Series: “Bioreversible Carriers in Drug Design, ed. Edward Lyell’s syndrome, Stevens-Johnson syndrome, erythema B. Roche, American Pharmaceutical Association and Perga multiforme minor, erythema multiforme major and other mon Press, 1987). inflammatory skin diseases. 50 In one aspect, the invention therefore provides a compound having Formula I, its individual enantiomers, its individual DETAILED DESCRIPTION OF THE INVENTION diastereoisomers, its individual hydrates, its individual Sol Vates, its individual crystal forms, its individual isomers, its The present invention relates to novel compounds which individual tautomers or a pharmaceutically acceptable salt are ester pro-drugs of 3-(1-(1H-imidazol-4-yl)ethyl)-2-me 55 thylphenyl)methanol of (S) 3-(1-(1H-imidazol-4-yl)ethyl)- thereof, 2-methylphenyl)methanol and of (R) 3-(1-(1H-imidazol-4- yl)ethyl)-2-methylphenylmethanol as alpha-2 agonists with Formula I therapeutic utility. O R2 R1 In a preferred embodiment the present invention relates to 60 ester pro-drugs of (S)-3-(1-(1H-imidazol-4-yl)ethyl)-2-me thylphenylmethanol as alpha-2 agonists with therapeutic -- N utility. Upon hydrolytic or enzymatic cleavage of the ester y N functionality the parent compound, active metabolite, (S)-3- V (1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol, is 65 R3 released to act as a selective modulator of the alpha 2 adren ergic receptors. US 8,492,557 B2 6 wherein The term "heterocycle” as used herein is defined as an R" is Hor C alkyl: aromatic or non aromatic 5 to 10 membered monocyclic or R’ is H or C. alkyl: bicyclic ring containing at least one heteroatom selected from R is H. Clo alkyl, heterocycle or aryl; and O or NorS or combinations thereof, interrupting the carbocy R is Co alkyl, heterocycle or aryl. clic ring structure. Heterocycles can optionally be substituted In a preferred aspect, the invention therefore provides a by, but not limited to, Ce alkyl, amino, halogen, —O(C- compound having Formula II, its individual enantiomers, its alkyl). —OC(O)(C. alkyl), —C(O)O(C- alkyl), NHC individual diastereoisomers, its individual hydrates, its indi (O)(C. alkyl), —C(O)NH(C. alkyl). —S(O. alkyl) vidual solvates, its individual crystal forms, its individual groups. Examples include, but are not limited to, furyl, pyrryl. isomers, its individual tautomers or a pharmaceutically 10 pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl pyrazi acceptable salt thereof, nyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl. iSoindolyl, benzimida Zolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, Formula II 1.2.5-thiadiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, quinazoli 15 nyl, pyridazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, Xan thinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauraci lyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, pyrrolidinyl, pip eridinyl and piperazinyl. The term “aryl' as used herein, is defined as including an organic moiety derived from an aromatic hydrocarbon con wherein sisting of a monocyclic or bicyclic ring containing 6-10 car R" is H or Cs alkyl: bonatoms by removal of one atom, Such as phenyl R’ is Hor C alkyl: 25 R is H. Clio alkyl, heterocycle or aryl; and or naphtyl. Aryl groups can optionally be substituted by, but R is Co alkyl, heterocycle or aryl. not limited to, Ce alkyl, amino, halogen, —O(C- alkyl). In another aspect, the invention therefore provides a com —OC(O)(Calkyl), —C(O)O(C-alkyl), —NHC(O)(C- pound having Formula III, its individual enantiomers, its alkyl). —C(O)NH(C. alkyl). —S(C. alkyl) groups. individual diastereoisomers, its individual hydrates, its indi 30 Examples include, but are not limited to, phenyl, naphtyl. vidual solvates, its individual crystal forms, its individual The term “H” as used herein refers to a hydrogenatom. isomers, its individual tautomers or a pharmaceutically acceptable salt thereof, The term “O'” as used herein refers to an oxygen atom. The term “S” as used herein refers to a sulfur atom. 35 The term “N” as used herein refers to a nitrogenatom. Formula III O R2 RI The term “amino” as used herein refers to a group of formula - NH. -- N The term "amide' as used herein refers to a group of formula –C(O)NH or -NHC(O)-. y 40 N The term “halogen', as used herein refers to an atom of V chlorine, bromine, iodine or fluorine. R3 The term “carbonyl as used herein refers to a group of formula—C—O. wherein 45 R" is H or Cs alkyl: The term “carboxyl', as used herein refers to a group of R’ is Hor C alkyl: formula—C(O)O— or —OC(O)—. R is H. Clio alkyl, heterocycle or aryl; and Generally R' is H or Cs alkyl. Preferred R' is C, alkyl. R is Coalkyl, heterocycle or aryl. Most preferred R' is methyl. The following paragraphs provide definitions of the vari 50 Generally R is H or C alkyl. Preferred R is C alkyl. ous chemical moieties that make up the compounds of the Most preferred R is methyl. invention and are intended to apply uniformly throughout the Generally R is H, Co alkyl, heterocycle or aryl. Pre specification and claims unless expressly stated otherwise. The term “alkyl as used herein, is defined as including a ferred R is H. phenyl or Co alkyl. Most preferred R is H. saturated monovalent alkane moiety having straight or 55 Generally R is Coalkyl, heterocycle or aryl. Preferred R branched alkane moieties or combinations thereof and con is methyl, iso-butyl, tert-butyl, iso-propyl, ethylphenyl, phe taining 1-10 carbon atoms, preferably 1-8 carbon atoms and nyl, 2-amino-1-phenylethyl, 2-(2-amino-3-methyl-butyry more preferably 1-4 carbonatoms. Alkyl moieties can option lamino)-2-methyl-prop-1-yl, 1-amino-2-methyl-prop-1-yl, ally be substituted by, but not limited to, amino groups, aryl 2-(2-amino-acetylamino)-2-methyl-prop-1-yl. Most pre groups, halogens. One methylene (—CH2—) can be replaced 60 ferred R groups are tert-butyl, iso-propyl. by carbonyl, -NH-, carboxyl, amide, Sulfur or by oxygen. As used herein, “tautomer refers to the migration of pro Examples include, but are not limited to, methyl, ethyl, pro tons between adjacent single and double bonds. The tau pyl, butyl, sec-butyl, pentyl, iso-pentyl, neo-pentyl, hexyl, tomerization process is reversible. Compounds described iso-hexyl, 3-methyl-butyl, 2-amino-N-isobutyl acetamide, herein can undergo any possible tautomerization that is iso-butyl, tert-butyl, iso-propyl, ethylphenyl, methylphenyl, 65 within the physical characteristics of the compound. The 2-amino-3-methyl-butanamide-N-2-methyl-1-propyl, following is a tautomerization example that can occur in 1-amino-2-methyl-prop-1-yl. compounds described herein: US 8,492,557 B2 8 Compounds according to the present invention may existin different polymorphic forms. Although not explicitly indi cated in the above formula, such forms are intended to be included within the scope of the present invention. Compounds of Formula I, Formula II or Formula III and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like. Compounds of the invention are: The term “pharmaceutically acceptable salts' refers to iso-Butyric acid 3-(S)-1-(1H-imidazol-4-yl)ethyl-2-me 10 salts or complexes that retain the desired biological activity of thyl-benzyl ester; the above identified compounds and exhibit minimal or no 2,2-Dimethyl-propionic acid 3-(S)-1-(1H-imidazol-4-yl) undesired toxicological effects. The “pharmaceutically ethyl-2-methyl-benzyl ester; acceptable salts' according to the invention include therapeu Acetic acid 3-(S)-1-(1H-imidazol-4-yl)-ethyl-2-methyl tically active, non-toxic base or acid salt forms, which the benzyl ester; 15 compounds of Formula I, Formula II or Formula III are able Benzoic acid 3-(S)-1-(1H-imidazol-4-yl)-ethyl-2-methyl to form. benzyl ester; The acid addition salt form of a compound of Formula I, 3-Methyl-butyric acid 3-(S)-1-(1H-imidazol-4-yl)-ethyl-2- Formula II or Formula III that occurs in its free form as a base methyl-benzyl ester; can be obtained by treating the free base with an appropriate 3-Phenyl-propionic acid 3-(S)-1-(1H-imidazol-4-yl)-ethyl acid such as an inorganic acid, for example but not limited to, 2-methyl-benzyl ester; hydrochloric acid, hydrobromic acid, Sulfuric acid, phospho 2-Amino-3-methyl-butyric acid 3-(S)-1-(1H-imidazol-4- ric acid, nitric acid and the like; or an organic acid such as for yl)-ethyl-2-methyl-benzyl ester; example but not limited to, as citric acid, acetic acid, oxalic 2-(2-Amino-3-methyl-butyrylamino)-3-methyl-butyric acid acid, tartaric acid, Succinic acid, malic acid, fumaric acid, 3-(S)-1-(1H-imidazol-4-yl)-ethyl-2-methyl-benzyl 25 ascorbic acid, benzoic acid, tannic acid, palmoic acid, alginic ester, acid, polyglutamic acid, naphthalene-Sulfonic acid, naptha 2-(2-Amino-acetylamino)-3-methyl-butyric acid 3-(S)-1- lenedisulfonic, and polygalacturonic acid as well as base (1H-imidazol-4-yl)-ethyl-2-methyl-benzyl ester; addition salts such as those formed with alkali- and alkaline 2-Amino-3-phenyl-propionic acid 3-(S)-1-(1H-imidazol-4- earth metals such as Sodium, potassium and calcium and the yl)-ethyl-2-methyl-benzyl ester. 30 like (Handbook of Pharmaceutical Salts, P. Heinrich Stahal & Intermediates of the invention are: Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta iso-Butyric acid 3-(S)-1-(1-iso-butyryl-1H-imidazol-4-yl)- Zürich, 2002, 329-345). ethyl-2-methyl-benzyl ester; The compounds can also be administered as pharmaceuti 2,2-Dimethyl-propionic acid 3-(S)-1-1-(2,2-dimethyl-pro cally acceptable quaternary salts known by those skilled in pionyl)-1H-imidazol-4-yl-ethyl)-2-methyl-benzyl ester; 35 the art, which specifically include, but not limiting to the Acetic acid 3-(S)-1-(1-acetyl-1H-imidazol-4-yl)-ethyl-2- quaternary ammonium salt of the formula—NYZ, wherein methyl-benzyl ester; Y is hydrogen, alkyl, or benzyl, and Z is a counterion, includ Benzoic acid 3-(S)-1-(1-benzoyl-1H-imidazol-4-yl)-ethyl ing but not limited to, chloride, bromide, iodide, —O-alkyl, 2-methyl-benzyl ester; toluenesulfonate, methylsulfonate, Sulfonate, phosphate, or 3-Methyl-butyric acid 2-methyl-3-(S)-1-1-(3-methyl-bu 40 carboxylate (such as fumarate, benzoate, Succinate, acetate, tyryl)-1H-imidazol-4-yl-ethyl-benzyl ester; glycolate, maleate, malate, fumarate, citrate, tartrate, ascor Phenyl-propionic acid 2-methyl-3-(S)-1-1-(3-phenyl-pro bate, benzoate, cinnamoate, mandeloate, benzyloate, and pionyl)-1H-imidazol-4-yl-ethyl-benzyl ester; diphenylacetate). 2-tert-Butoxycarbonylamino-3-methyl-butyric acid 3-(S)- In another embodiment of the invention, there are provided 1-1-(2-tert-butoxy carbonylamino-3-methyl-butyryl)- 45 pharmaceutical compositions including at least one com 1H-imidazol-4-yl-ethyl-2-methyl-benzyl ester; pound of the invention in a pharmaceutically acceptable car 2-tert-Butoxycarbonylamino-3-methyl-butyric acid 3-(S)- rier thereof. The phrase “pharmaceutically acceptable' 1-(1H-imidazol-4-yl)-ethyl-2-methyl-benzyl ester; means the carrier, diluent or excipient must be compatible 2-(2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3- with the other ingredients of the formulation and not delete methyl-butyric acid 3-(S)-1-1-(2-tert-butoxycarbony 50 rious to the recipient thereof. lamino-3-methyl-butyryl)-1H-imidazol-4-yl-ethyl-2- Pharmaceutical compositions of the present invention can methyl-benzyl ester; be used in the form of a solid, a solution, an emulsion, a 2-(2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3- dispersion, a patch, a micelle, a liposome, and the like, methyl-butyric acid 3-(S)-1-(1H-imidazol-4-yl)-ethyl-2- wherein the resulting composition contains one or more com methyl-benzyl ester; 55 pounds of the present invention, as an active ingredient, in 2-(2-tert-Butoxycarbonylamino-acetylamino)-3-methyl-bu admixture with an organic or inorganic carrier or excipient tyric acid 3-(S)-1-(1H-imidazol-4-yl)-ethyl-2-methyl Suitable for enteral or parenteral applications. Invention com benzyl ester; pounds may be combined, for example, with the usual non 2-tert-Butoxycarbonylamino-3-phenyl-propionic acid toxic, pharmaceutically acceptable carriers for tablets, pel 3-(S)-1-(1H-imidazol-4-yl)-ethyl-2-methyl-benzyl 60 lets, capsules, Suppositories, solutions, emulsions, ester. Suspensions, and any other form Suitable for use. The carriers Some compounds of Formula I, Formula II and Formula III which can be used include but are not limited to, glucose, and some of their intermediates have at least one stereogenic lactose, gum acacia, gelatin, mannitol, starch paste, magne center in their structure. This stereogenic center may be sium trisilicate, talc, corn starch, keratin, colloidal silica, present in an (R) or (S) configuration, said (R) and (S) nota 65 potato starch, urea, medium chain length triglycerides, dex tion is used in correspondence with the rules described in Pure trans, and other carriers suitable for use in manufacturing Appli. Chem. (1976), 45, 11-13. preparations, in Solid, semisolid, or liquid form. In addition US 8,492,557 B2 10 auxiliary, stabilizing, thickening and coloring agents and per necessary, particularly if the patient Suffers from nausea. fumes may be used. Invention compounds are included in the Such other routes may include, without exception, transder pharmaceutical composition in an amount Sufficient to pro mal, parenteral, Subcutaneous, intranasal, via an implant duce the desired effect upon the process or disease condition. stent, intrathecal, intravitreal, topical to the eye, back to the Pharmaceutical compositions containing invention com eye, intramuscular, intravenous, and intrarectal modes of pounds may be in a form Suitable for oral use, for example, as delivery. The actual amount of the compound to be adminis tablets, troches, lozenges, aqueous or oily suspensions, dis tered in any given case will be determined by a physician persible powders or granules, emulsions, hard or soft cap taking into account the relevant circumstances, such as the Sules, or syrups or elixirs. Compositions intended for oral use severity of the condition, the age and weight of the patient, the may be prepared according to any method known in the art for 10 the manufacture of pharmaceutical compositions and Such patient’s general physical condition, the cause of the condi compositions may contain one or more agents selected from tion, and the route of administration. Additionally, the formu the group consisting of a Sweetening agent Such as Sucrose, lations may be designed to delay release of the active com lactose, or saccharin, flavoring agents such as peppermint, oil pound over a given period of time, or to carefully control the of wintergreen or cherry, coloring agents and preserving 15 amount of drug released at a given time during the course of agents in order to provide pharmaceutically elegant and pal therapy. atable preparations. Tablets containing invention compounds Ester pro-drugs of 3-(1-(1H-imidazol-4-yl)ethyl)-2-me in admixture with non-toxic pharmaceutically acceptable thylphenyl)methanol, of (S) 3-(1-(1H-imidazol-4-yl)ethyl)- excipients may also be manufactured by known methods. The 2-methylphenyl)methanol or of (R)3-(1-(1H-imidazol-4-yl) excipients used may be, for example, (1) inert diluents such as ethyl)-2-methylphenylmethanol and their pharmaceutically calcium carbonate, lactose, calcium phosphate or sodium acceptable salts may be administered through different phosphate; (2) granulating and disintegrating agents such as routes, including but not limited to topical eye drops, direct corn starch, potato starch or alginic acid; (3) binding agents injection, application at the back of the eye or formulations Such as gum tragacanth, corn Starch, gelatin or acacia, and (4) that may further enhance the long duration of actions such as lubricating agents such as magnesium Stearate, Stearic acid or 25 a slow releasing pellet, Suspension, gel, or Sustained delivery talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in devices such as any suitable drug delivery system (DDS) the gastrointestinal tract and thereby provide a Sustained known in the art. While topical administration is preferred, action over a longer period. For example, a time delay mate this compound may also be used in an intraocular implant as rial Such as glyceryl monostearate or glyceryl distearate may 30 described in U.S. Pat. No. 7.931,909 which is hereby incor be employed. In some cases, formulations for oral use may be porated by reference. Such biocompatible intraocular in the form of hard gelatin capsules wherein the invention implants include ester pro-drugs of 3-(1-(1H-imidazol-4-yl) compounds are mixed with an inert Solid diluent, for example, ethyl)-2-methylphenylmethanol, of (S) 3-(1-(1H-imidazol calcium carbonate, calcium phosphate or kaolin. They may 4-yl)ethyl)-2-methylphenyl)methanol or of (R) 3-(1-(1H also be in the form of soft gelatin capsules wherein the inven 35 imidazol-4-yl)ethyl)-2-methylphenylmethanol and a tion compounds are mixed with water or an oil medium, for polymer associated with ester pro-drugs of 3-(1-(1H-imida example, peanut oil, liquid paraffin or olive oil. Zol-4-yl)ethyl)-2-methylphenylmethanol, of (S) 3-(1-(1H The pharmaceutical compositions may be in the form of a imidazol-4-yl)ethyl)-2-methylphenyl)methanol or of (R) 3 sterile injectable Suspension. This suspension may be formu (1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol to lated according to known methods using Suitable dispersing 40 facilitate release thereof into an eye for an extended period of or wetting agents and Suspending agents. The sterile inject time. able preparation may also be a sterile injectable solution or Suspension in a non-toxic parenterally-acceptable diluent or Ophthalmic formulations of drug products are well known , for example, as a solution in 1,3-butanediol. Sterile, in the art and described in, for example, U.S. Patent Applica fixed oils are conventionally employed as a solvent or Sus 45 tion Publication No. 20050059583; No. 20050277584; U.S. pending medium. For this purpose any bland fixed oil may be Pat. No. 7,297,679; and No. 20070015691; and U.S. Pat. Nos. employed including synthetic mono- or diglycerides, fatty 5,474,979 and 6,582,718, the disclosures of all which are acids (including oleic acid), naturally occurring vegetable incorporated herein by reference. The ester pro-drugs of 3 oils like sesame oil, coconut oil, peanut oil, cottonseed oil, (1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol, of etc., or synthetic fatty vehicles like ethyl oleate or the like. 50 (S) 3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)metha Buffers, preservatives, antioxidants, and the like can be incor nol or of (R) 3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphe porated as required. nylmethanol may be formulated with efficacy enhancing The present invention concerns also the use of a compound components as disclosed in U.S. Pat. No. 7,491.383 B2, of Formula I, Formula II or Formula III, or a pharmaceutically which is hereby incorporated by reference in its entirety. acceptable salt thereof, for the manufacture of a medicament 55 for the therapeutic application. The present invention con With respect to the present invention reference to a com cerns also the a method for manufacturing a medicament pound or compounds, is intended to encompass that com intended for therapeutic application wherein a compound pound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to spe having general Formula I, Formula II or Formula III, or a cifically. pharmaceutically active derivative or salt thereof is used. 60 Since individual Subjects may present a wide variation in The present invention also concerns a process for preparing severity of symptoms and each drug has its unique therapeutic the compounds having general Formula I. Formula II or For characteristics, the precise mode of administration and dos mula III. age employed for each subject is left to the discretion of the The synthetic scheme set forth below, illustrates how com practitioner. The patient will be administered the compound 65 orally in any acceptable form, Such as a tablet, liquid, capsule, pounds according to the invention can be made. Those skilled powder and the like, or other routes may be desirable or in the art will be able to routinely modify and/or adapt the US 8,492,557 B2 11 12 following scheme to synthesize any compounds of the inven invention. These compounds can be prepared in accord with tion covered by Formula I, Formula II or Formula III. the preparations described by use of isotopically enriched reagents. General Scheme for Synthesizing Ester Prodrugs of The following examples are for illustrative purposes only (S)-3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl and are not intended, nor should they be construed as limiting methanol the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention. O 10 The IUPAC names of the compounds mentioned in the examples were generated with ACD version 8. R us CIFTEADMAP Unless specified otherwise in the examples, characteriza DMFTHF tion of the compounds is performed according to the follow N ing methods: y 15 NMR spectra are recorded on 300 MHz Varian and acquired at room temperature. Chemical shifts are given in (S)-(3-(1H-imidazol-4-yl)ethyl)- ppm referenced either to internal TMS or to the residual 2-methylphenyl)methanol Solvent signal. All the reagents, , catalysts for which the synthesis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Lancaster, however Some known reac tion intermediates, for which the CAS registry number is MeOH mentioned, were prepared in-house following known proce -3- dures. 25 Usually the compounds of the invention were purified by flash column chromatography.

The following abbreviations are used in the examples:

DCM dichloromethane MeOH methanol CDOD deuterated methanol NH, ammonia Na2SO sodium sulfate R is H DMF N,N-dimethylformamide 35 MgSO magnesium Sulfate EtOAC ethylacetate -Pr(OH iso-propanol CDCl MPLC medium pressure liquid In a first step (S)-3-(1-(1H-imidazol-4-yl)ethyl)-2-meth chromatography ylphenyl)methanol (CAS 189255-79-6) can react with the 40 DMF dimethylformamide desired acyl chloride, in the presence of N,N-dimethyl for TEA triethylamine mamide (DMF), tertahydrofuran (THF), triethylamine THF tertahydrofuran DMAP 4-dimethylaminopyridine (TEA) and 4-dimethylaminopyridine (DMAP). After a typi RT room temperature cal work-up by extraction, the residue can be purified by Boc-L-Valine N-(tert-Butoxycarbonyl)-L-valine medium pressure liquid chromatography (MPLC) (0% to 45 Boc-Glycine N-(tert-Butoxycarbonyl)glycine Boc-L- N-(tert-Butoxycarbonyl)-L- 40% ethyl acetate in hexanes) to yield the intermediate com Phenylalanine phenylalanine pound as a solid. HCI hydrochloric acid In a second step, the intermediate obtained in the first HO Water reaction, can react with methanol (MeOH). The residue can EDCI 1-ethyl-3-(3-dimethylamino be purified by MPLC (50% ethyl acetate in hexanes then 5% 50 propyl)carbodiimide 7Nammonia/methanol/dichloromethane) to yield the desired NaHCO sodium bicarbonate compound as a Solid. It is to be understood that both the foregoing general description and the following detailed description are exem EXAMPLE 1. plary and explanatory only and are not restrictive of the inven 55 tion claimed. As used herein, the use of the singular includes Intermediate 1 the plural unless specifically stated otherwise. The present invention includes all pharmaceutically iso-Butyric acid 3-(S)-1-(1-isobutyryl-1H-imidazol acceptable isotopically enriched compounds. Any compound 4-yl)-ethyl-2-methyl-benzyl ester of the invention may contain one or more isotopic atoms 60 enriched or different than the natural ratio such as To a solution of (S)-3-(1-(1H-imidazol-4-yl)ethyl)-2-me *H (or D) in place of protium H (or H) or use of C enriched thylphenyl)methanol (1.34g, 6.2 mmol) in DMF (8 ml) and material in place of Cand the like. Similar substitutions can THF (50 ml), were added TEA (3.5 ml, 24.8 mmol), DMAP be employed for N, O and S. The use of isotopes may assist in (780 mg, 6.2 mmol) and iso-butyryl chloride (2.18 g. 20.5 analytical as well as therapeutic aspects of the invention. For 65 mmol). The resulting mixture was stirred at RT for 16 h, example, use of deuterium may increase the in vivo half-life quenched with HO and extracted with ethyl acetate. The by altering the metabolism (rate) of the compounds of the combined organic layers were washed with brine, and dried

US 8,492,557 B2 19 20 The title compound was prepared from Intermediate 11 mM HEPES, pH 7.4) prior to the addition of Fluo-4-AM (4 (320 mg, 0.68 mmol) with 10 ml of 4N HC1/Dioxane accord uM Fluo-4-AM, 0.04% pluronic acid in HBSS/HEPES ing the procedure described in Example 5. Buffer), a calcium-sensitive dye. Cells are loaded with dye for 'H-NMR (CDOD; 8 ppm): 0.89 (d. J=6.74 Hz, 3H), 0.91 40 minutes at 37°C., thenwashed 4 times with HBSS/HEPES (d. J=6.74 Hz, 3H), 2.14 (hept, J=6.74 Hz, 1H), 2.33 (s.3H), Buffer. For both the agonist and antagonist assay, the test 4.37 (d. J=5.90 Hz, 1H), 4.42(q, J=7.03 Hz, 1H), 5.20-5.25 compounds are tested between 0.64 nM-10,000 nM. (m. 2H), 6.67 (s, 1H), 7.10-7.12 (m, 2H), 7.13-7.20 (m. 1H), For an agonist assay, the reaction is initiated by the addition 7.55 (s, 1H). of the appropriate dilutions of compounds and the transient 10 calcium signal captured. The peak height of the calcium curve EXAMPLE 11 is determined and utilized for calculation of ECs and efficacy using ActivityBase. Norepinephrine is the standard full ago Intermediate 12 nist used for evaluating alpha-1 and alpha-2 receptor activity. 2-tert-Butoxycarbonylamino-3-phenyl-propionic For an antagonist assay, the addition of the drug does not acid 3-(S)-1-(1H-imidazol-4-yl)-ethyl-2-methyl 15 elicit a transient calcium signal. However, the antagonist benzyl ester blocks the transient calcium signal of the standard agonist norepinephrine in a dose-dependent manner. The residual The title compound was prepared from (S)-3-(1-(1H-imi norepinephrine peak height is compared to the non-antago dazol-4-yl)ethyl)-2-methylphenyl)methanol (216 mg, 1.0 nized norepinephrine peak height for the determination of% mmol), Boc-L-Phenylalanine (795 mg, 3.0 mmol), EDCI antagonism. (671 mg, 3.5 mmol) and DMAP (427 mg, 3.5 mmol) accord ing to the procedure described in Example 3. Intermediate 12 was purified by a column chromatography using 35-100% TABLE 3 ethyl acetate in hexane. 'H-NMR (CDOD; 8 ppm): 1.36 (s, 9H), 1.55 (d. J=7.03 25 In Vitro Pharmacology of (S)-3-(1- Hz, 3H), 2.28 (s.3H), 2.85-2.95 (m, 1H), 3.05-3.11 (m, 1H), (1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol 4.38 (m, 1H), 4.40 (q, J=7.03 Hz, 1H), 5.17 (s. 2H), 6.69 (s. and its prodrugs at adrenergic receptor Subtypes 1H), 7.08-7.24 (m, 8H), 7.55 (s, 1H). EXAMPLE 12 30 FLIPR Assay

Compound 10 Entry Compound Number a1A a2A

2-Amino-3-phenyl-propionic acid 3-(S)-1-(1H-imi 1 Brimonidine 600-2400 (0.3) 5 (0.95) dazol-4-yl)-ethyl-2-methyl-benzyl ester 35 2 (S)-3-(1-(1H-imidazol-4- 340-2400 (0.7) 25 (0.9) yl)ethyl)-2-methylphenyl methanol

3 Compound 1 na na 40 4 Compound 2 na na

NH2 EC50 (eff) nM. na: Not active

45 What is claimed is: The title compound was prepared from Intermediate 12 1. A compound of Formula I, its individual enantiomers, its (240 mg 0.52 mmol) with 8ml of 4N HCl/Dioxane according individual diastereoisomers, its individual tautomers or a to the procedure described in Example 5. pharmaceutically acceptable salt thereof, H-NMR (CDOD; 8 ppm): 1.54 (d. J=7.03 Hz, 3H), 2.26 50 (s, 3H), 2.90-3.00 (m, 2H), 3.73 (t, J=6.40 Hz, 1H), 4.40 (q, J=7.03 Hz, 1H), 5.13-5.18 (m, 2H), 6.68 (s, 1H), 7.08-7.12 Formula I (m, 5H), 7.13-7.22 (m, 3H), 7.55 (s, 1H). O R2 R1 The following assay was used to demonstrate the potency and selectivity of the compounds according to the invention. 55 -- N EXAMPLE 13 y N V FLIPR Cat Influx Assay R3 60 HEK 293 cells stably expressing the bovine C. receptor, human alpha 2A receptor and the chimeric G protein Gs, are wherein plated in poly-D-lysine coated 384-well plates at 20,000-40, R" is Hor C alkyl: 000 cells per well and grown overnight in DMEM supple R’ is Hor C alkyl: mented with 10% fetal bovine serum. For FLIPR (fluoromet 65 ric image plate reader) evaluation, cells are washed twice with R is H. Clio alkyl, heterocycle or aryl; and HBSS/HEPES Buffer (1x Hanks Buffered Salt Solution, 20 R is Co alkyl, heterocycle or aryl.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 8.492,557 B2 Page 1 of 2 APPLICATIONNO. : 13/233891 DATED : July 23, 2013 INVENTOR(S) : Ken Chow et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

On the Title page, in item (57), under “ABSTRACT, in column 2, line 2, delete “1H' and insert -- (1H --, therefor.

In the Specification In column 2, line 9, delete “(H' and insert -- (1H --, therefor. In column 2, line 50, delete “enantiomers and insert -- enantiomers. --, therefor. In column 3, line 23, delete “neropsychiatric and insert -- neuropsychiatric --, therefor. In column 3, line 43, delete “rhinophymia and insert -- rhinophyma --, therefor. In column 3, line 46, delete “cutenous and insert -- cutaneous --, therefor. In column 4, line 38, delete “trial klysilyl and insert -- trialkylsilyl --, therefor. In column 6, line 8, delete “-S(O1-6 alkyl)' and insert ---S(C1-6 alkyl)--, therefor. In column 6, line 14, delete “isooxazolyl, and insert -- isoxazolyl, --, therefor. In column 7, line 10, delete “yl)ethyl and insert --yl)-ethyl-, therefor. In column 7, line 13, delete “ethyl and insert ---ethyl-, therefor. In column 8, line 25, delete “palmoic and insert -- pamoic --, therefor. In column 8, lines 26-27, delete “napthalenedisulfonic, and insert -- naphthalenedisulfonic, --, therefor. In column 8, line 30, delete “Stahal and insert -- Stahl --, therefor. In column 8, line 31, delete “Chemica and insert -- Chimica -, therefor. In column 9, line 57, before “method delete “a. In column 11, line 42, delete “tertahydrofuran and insert -- tetrahydrofuran --, therefor. In column 12, line 42, delete “tertahydrofuran and insert -- tetrahydrofuran --, therefor.

Signed and Sealed this Twenty-second Day of October, 2013 2 2a-2s? a.Sé Teresa Stanek Rea Deputy Director of the United States Patent and Trademark Office CERTIFICATE OF CORRECTION (continued) Page 2 of 2 U.S. Pat. No. 8,492,557 B2

In the Claims In column 21, line 42, in claim 4, delete “alkyl R” and insert -- alkyl, R --, therefor. In column 21, line 46, in claim 6, delete “yl)ethyl and insert --yl)-ethyl-, therefor. In column 21, line 49, in claim 6, delete “ethyl and insert ---ethyl-, therefor. In column 21, line 50, in claim 6, delete “yl)ethyl and insert --yl)-ethyl-, therefor. In column 23, line 30, in claim 11, delete “yl)ethyl and insert --yl)-ethyl-, therefor. In column 23, line 33, in claim 11, delete “ethyl and insert ---ethyl-, therefor. In column 23, line 34, in claim 11, delete “yl)ethyl and insert --yl)-ethyl-, therefor. In column 24, line 11, in claim 12, delete “ethyl and insert ---ethyl-, therefor.