USOO7763612B2

(12) United States Patent (10) Patent No.: US 7,763,612 B2 Morgan et al. (45) Date of Patent: Jul. 27, 2010

(54) THERAPEUTIC Bundgaard, Hans, “Novel chemical approaches in design'. AMINEARYLSULFONAMIDE CONUGATE Drugs of the Future, 1991, p. 443-458, vol. 16(5). COMPOUNDS Cooper, Barrett, R., et al., “Animal Models Used in Prediction of Effects in Man”. J. Clin. Psychiatry, 1983, p. 63-66, vol. 44:5(Sec. 2). (75) Inventors: Philip F. Morgan, Cary, NC (US); Crooks, P. et al., “Synthetic Strategies for the Preparation of James L. Kelley, Raleigh, NC (US) "Gemini” Codrugs of , and Heterocodrugs of &beta Naltrexol with Hydroxybupropion for Transdermal Delivery', 2005 (73) Assignee: Algebra, Inc., Cary, NC (US) AAPS Annual Meeting and Exposition Nov. 5, 2005-Nov. 10, 2005, Abstract. (*) Notice: Subject to any disclaimer, the term of this Folkmann, Michael, et al., “Acyloxymethyl Carbonochloridates. patent is extended or adjusted under 35 New Intermediates in Prodrug Synthesis”. Synthesis, Dec. 1990, p. U.S.C. 154(b) by 852 days. 1159-1166. Greene, Theodora, et al., Protective Groups in Organic Synthesis, (21) Appl. No.: 11/619,291 1991, p. 240. Greene, Theodora, et al., Protective Groups in Organic Synthesis, (22) Filed: Jan. 3, 2007 1991, p. 232. Greene, Theodora, et al., Protective Groups in Organic Synthesis, (65) Prior Publication Data 1991, p. 228. Kelley, James L., et al., “(2S,3S,5R)-2-(3,5-Difluoropenyl)-3,5- US 2007/O155729 A1 Jul. 5, 2007 dimethyl-2-morpholinol: A Novel Antidepressant Agent and Selec tive Inhibitor of Uptake”. J. Med Chem., 1996, p. Related U.S. Application Data 347-349, vol. 39. (60) Provisional application No. 60/755,923, filed on Jan. (Continued) 3, 2006. Primary Examiner Bernard Dentz (51) Int. Cl. (74) Attorney, Agent, or Firm—Christopher J. Knors; Moore A 6LX 3/5.377 (2006.01) & Van Allen PLLC CO7D 413/12 (2006.01) (52) U.S. Cl...... 514/231.5: 514/217: 514/444; (57) ABSTRACT 514/471; 540/522:544/152:546/197; 549/60; Therapeutic amine-arylsulfonamide conjugate compounds, 549/467; 549/494 of the general formula: (58) Field of Classification Search ...... 540/522; 544/152; 546/197; 549/60,467,494; 514/217, 514/231.5, 444, 471 (I) See application file for complete search history. (56) References Cited Cy HN U.S. PATENT DOCUMENTS R 3,819,706 A 6, 1974 Mehta 3,885,046 A 5, 1975 Mehta C 4,356,165 A 10/1982 Findlay et al. O 4.495,180 A 1, 1985 Alexander SO 5,104,870 A 4/1992 Kelley et al. / 6,051,576 A 4/2000 Ashton et al. R"R"N 6,274,579 B1 8/2001 Morgan et al. 6,391,875 B2 5/2002 Morgan et al. 2002fO142955 A1 10, 2002 DuBois et al. wherein 2004/0214804 A1 10, 2004 Gulve et al. R" is D-W-), hydroxyl, or alkoxyl; 2005/OOO8695 A1 1/2005 Ashton et al. R" is independently D-W-, hydrogen, alkoxy, alkyl, 2005, OO14786 A1 1/2005 Sun et al. cycloalkyl, alkenyl, alkynyl or aryl, or R" and R" 2005, 0043332 A1 2/2005 Castelhano et al. together with the nitrogen atom to which they are 2005/O187280 A1 8, 2005 Minnich et al. attached form a 4-, 5-, 6-, 7- or 8-membered ring option ally containing one or two further heteroatoms indepen OTHER PUBLICATIONS dently selected from nitrogen, oxygen and Sulfur, Ahmad, et al., “Controlled trial of frusemide as an antiepileptic drug D is independently a therapeutic amine radical comprising in focal epilepsy”. Br. J. Clin. Pharmac. 1976, p. 621-25 vol. 3. at least one nitrogen atom and optionally at least one Alexander, J. et al., “(Acyloxy)alkyl Carbamates as Novel Biorevers oxygenatom coupled to WorW" by a nitrogen or oxygen ible for Amines: Increased Permeation through Biological atom; Membranes”. J. Med. Chem., 1988, p. 318-322, vol. 31. W and Ware a chemical bond or linker; Bodor, Nicholas, “Soft Drugs. 1. Labile Quaternary Ammonium Salts as Soft Antimicrobials”. J. Med. Chem., 1980, p. 469-474, vol. wherein either R' is D-W- or at least one R" is D-W-, 23. and pharmaceutically acceptable esters, amides, salts or Sol Boswell. G. Evan, et al., “Synthesis and Anti- Activity Vates thereof, pharmaceutical compositions containing same, of C-3 analogues of Dimethyl-2-phenylmorpholines”. J. Heterocy methods for their preparation, and their use in treating psy clic Chem., 1996, p. 33-39, vol. 33. chiatric, neurologic and metabolic disorders are disclosed. US 7,763,612 B2 Page 2

16 Claims, No Drawings OTHER PUBLICATIONS Liddens, Hartmut, et al., “Structure—activity relationship of furosemide-derived compounds as antagonists of cerebellum-spe cific GABA receptors”, Eur, J. Pharmacol., 1998, p. 269-277, vol. 344. Mendes, Eduarda, et al., “Synthesis, Stability and In Vitro Dermal Evaluation of Aminocarbonyloxymethyl Esters as Prodrugs of Carboxylic Acid Agents'. Bioorganic & Medicinal Chemistry, 2002, p. 809-816, vol. 10. Musso, David L., et al., “Design and Synthesis of a Chiral Hapten for a Radioimmunoassay of the Antidepressant (2S, 3S, 5R)-2-(3.5- Difluorophenyl)-3,5-dimethyl-2-morpholinol Hydrochloride'. Tet rahedron: Assymetry, 1995, p. 1841-1844, vol. 6. Musso, David L., et al., “Indanylidenes. 2. Design and Synthesis of (E)-2-(4-Chloro-6-fluoro-1-indanylidene)-N-methylacetamide, a Potent Antiinflammatory and Analgesic Agent without Centrally Act ing Muscle Relaxant Activity”. J. Med. Chem, 2003, p.409-416, vol. 46. Patonay, Tamás, et al., "O-Haloalkyl Haloformates and Related Com pounds 1. A Convenient Synthesis of Carbamates Via Chloromethyl Carbonates'. Synthetic Communications, 1990, p. 2865-2885, vol. 20(18). Pitman, Ian H., “Pro-Drugs of Amides, Imides, and Amines”. Medicinal Research Reviews, 1981, p. 189-214, vol. 1. Rasmusson, Gary H., et al., “2-Cyclopentene-1,4-Dione'. Organic Syntheses, 1973, p. 324-325, vol. 5. Sandler, Stanley R., et al., “Preparation of 4-Methylcyclohexanone 14'. Organic Functional Group Preparations, 1968, p. 171. Sandler, Stanley R. et al., “Preparation of N-tert-Butylbenzylamine 8', Organic Functional Group Preparations, 1968, p. 324. Sandler, Stanley R., et al., “Preparation of Methyl Acetate 1”. Organic Functional Group Preparations, 1968, p. 249. Schlatter, E. et al., “Effect of “High Ceiling” Diuretics on Active Salt Transport in the Cortical Thick Ascending Limb of Henle’s Loop of Rabbit Kidney, Pflügers Arch., 1983, p. 210-217, vol. 396. Shani, J., et al., “Structure Activity Correlation for Diuretic Furosemide Congeners'. Pharmacology, 1983, p. 172-180, vol. 26. Yamaoka, Yumiko et al., “Low-Melting Phenytoin Prodrugs as Alter native Oral Delivery Modes for Phenytoin: A Model for Other High Melting Sparingly Water-Soluble Drugs'. Journal of Pharmaceutical Sciences, Apr. 1983, p. 400-405, vol. 72, No. 4. US 7,763,612 B2 1. 2 THERAPEUTC maceutical formulations containing them, and their prepara AMINEARYLSULFONAMIDE CONUGATE tion and use in medicine. The various embodiments encom COMPOUNDS pass therapeutic amine-arylsulfonamide conjugate compounds, particularly those that contain therapeutic amine CROSS-REFERENCE TO RELATED moieties with potentially intrinsic convulsant, pro-convul APPLICATION sant, or abuse liability properties. By conjugating therapeutic amines with arylsulfonamides via an in vivo cleavable chemi This application claims benefit of U.S. Provisional Patent cal linker, otherwise seizure-prone or abuse liable compounds Application No. 60/755,923, filed Jan. 3, 2006, which is may be rendered effective as viable treatments to psychiatric, incorporated herein by reference in its entirety. 10 neurologic and metabolic disorders. In embodiments, therapeutic-arylsulfonamide conjugate FIELD compounds are provided, including pharmaceutically accept able esters, amides, salts or Solvates thereof, comprising the Therapeutic amines conjugated to arylsulfonamides, their Structures: pharmaceutical compositions, methods of making, and meth ods of using same are provided. 15 BACKGROUND Cy (I) A number of therapeutic amine compounds have been developed for the treatment of psychiatric, neurologic and HN O metabolic disorders including, but not limited to, depression, R obesity, fibromyalgia, neuropathic pain, restless leg Syn drome, attention deficit hyperactivity disorder (ADHD). C migraine, pain, sexual dysfunction, Parkinson's disease, O 25 Alzheimer's disease, anxiety, narcolepsy-cataplexy Syn SO drome, seizures or drug/substance addiction/cessation. These M include hydrochloride salt, 1-(3-chlorophenyl)-2- (1,1-dimethylethyl)amino-1-propanone.HCl which is the active ingredient of WELLBUTRINR). It is marketed in the where R' is D-W-), hydroxyl, or alkoxyl: United States for the treatment of depression. Bupropion 30 R" is independently D-W-, hydrogen, alkoxy, alkyl, hydrochloride is also the active ingredient of ZYBANR), cycloalkyl, alkenyl, alkynyl or aryl, or R" and R" together which is marketed in the United States as an aid to Smoking with the nitrogen atom to which they are attached form a 4-, cessation. 5-, 6-, 7- or 8-membered ring optionally containing one or The compound (+)-(2S,3S)-2-(3-chlorophenyl)-3.5.5-tri two further heteroatoms independently selected from nitro methyl-2-morpholinol hydrochloride salt, which is an active 35 gen, oxygen and Sulfur, metabolite of bupropion hydrochloride, is the active ingredi D is independently a therapeutic amine radical comprising ent of , and is proposed for the treatment of depres at least one nitrogen atom and optionally at least one oxygen sion, obesity and other conditions. (U.S. Pat. No. 6,274.579 atom coupled to W or W by a nitrogen or oxygen atom; and and U.S. Pat. No. 6,391.875). Another therapeutic amine W and Ware a chemical bond or linker; compound, for example, (2S,3S.5R)-2-(3,5-difluorophenyl)- 40 wherein either R' is D-W- or at least one R" is D-W-. 3,5-dimethyl-2-morpholinol, the active ingredient of mani In embodiments, the therapeutic amine radical is derived faxine, has been proposed for the treatment of depression, from an amine selected from: (2S,3S.5R)-2-(3,5-difluo among other ailments (U.S. Pat. No. 5,104,870). rophenyl)-3,5-dimethyl-2-morpholinol (manifaxine), 2-(1- Bupropion, however, is known to cause seizures in high (3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-methyletha therapeutic doses (Harris, et al., Fatal bupropion overdose, J. 45 nol, (2S,3S)-2-(3-chlorophenyl)-3.5.5-trimethyl-2- Toxicol. Clin Toxicol. (1997) 35: 321-4; Kuate, et al., A. morpholinol, (+)-(2S,3S)-2-(3-chlorophenyl)-3.5.5- Bupropion-induced epileptic seizures, Rev. Neurol. (2004), trimethyl-2-morpholinol (radafaxine), 2-(1-(3- 160: 701-3.) Several therapeutic amines, including bupropion chlorobenzoyl)-(R.S)-ethylamino)-2,2-dimethylethanol, and radafaxine, are known to elicit seizures in animals (U.S. 1-(3-chlorophenyl)-2-(1,1-dimethylethyl)amino-1-pro Pat. No. 6,274,579; and U.S. Pat. No. 6,391,875; see also 50 panone (bupropion), , , , Shepard, Pharmacotherapy (2005) 10: 1378-82). Other , , , , tranyl undesirable side effects may also occur in the administration cypromine, , , , of therapeutic amine compounds and Such compounds may , doxepine, , nortryptyline, protrip be considered in trials conducted for potential abuse liability. tyline, , , , dulloxetine, Thus, such compounds may be under-utilized at administra 55 , , and . tion dose maximums, even if favorable treatment outcomes In embodiments, the linker W comprises: are possible. CHRO : To the extent these and other therapeutic amine compounds C(O)OCHRO : exhibit undesirable side effects, compounds and/methods of treatment which avoid such side effects would be advanta 60 C(O)OCHROC(O)RO : geous. The conjugate compounds and methods disclosed herein provide Such advantages. CHROC(O)RO : SUMMARY 65 wherein R' is independently: Disclosed herein are therapeutic amine-arylsulfonamide —(CH2) ; conjugate compounds, processes for preparing them, phar —(CH2)CHY (CH), ; US 7,763,612 B2 3 —(CH2)CH=CH(CH), ; —(CH2)O(CH2)—, —(CH2)NR(CH2) ; —(CH2)C=C(CH2), ;

—(CH2), S(O)(CH2)—; R —(CH),C(O)O(CH), ; —(CH),C(O)O(CH2)CHY (CH) ; —(CH),C(O)O(CH2)CH=CH(CH), ; 10 —(CH),C(O)O(CH)O(CH.) : SO —(CH),C(O)O(CH), NR(CH.) : —(CH),C(O)O(CH), S(O)(CH.) : 15 where R' is D-W-), hydroxyl, or alkoxyl: —(CH),C(O)O(CH),C=C(CH), ; or R" is independently D-W-, hydrogen, alkoxy, alkyl, a 5- or 6-membered aromatic ring diradical optionally con cycloalkyl, alkenyl, alkynyl or aryl, or R" and R" together taining 1 or more heteroatoms independently selected with the nitrogen atom to which they are attached form a 4-, from oxygen, nitrogen and Sulfur, 5-, 6-, 7- or 8-membered ring optionally containing one or R is independently hydrogen, alkyl, cycloalkyl or aryl; two further heteroatoms independently selected from nitro gen, oxygen and Sulfur, Y is a halogen; D is independently a therapeutic amine radical comprising n is independently 1-8; at least one nitrogen atom and optionally at least one m is 0, 1, or 2; and oxygenatom coupled to WorW" by a nitrogen or oxygen o is 0-8. 25 atom; and W and Ware a chemical bond or linker; wherein either R' is D-W- or at least one R" is D-W-: In embodiments, the linker W comprises: or a pharmaceutically acceptable ester, amide, salt or Sol CHROC(O)RC(O)OCHR ; vate thereof. C(O)RC(O)CCHR ; C(O)OCHROC(O)RC(O)OCHR : 30 DETAILED DESCRIPTION CHROC(O)RC(O)OCHROC(O) ; A number of therapeutic amine compounds have been pro C(O)RC(O)CCHROC(O) ; or posed and/or approved for a variety of psychiatric and/or C(O)OCHROC(O)RC(O)OCHROC(O) ; neurologic and/or metabolic disorders. The mechanisms of 35 action and side effects caused by Such therapeutic amines are wherein R. R.Y. n,m and o are as described above. not all known. Therapeutic amine compounds such as bupro In embodiments, the linker may provide for conjugation of pion and radafaxine are relatively weak inhibitors of the neu more than one therapeutic amine radical and more than one ronal uptake of norepinephrine (NE), (DA), and to arylsulfonamide radical to enable independently varying the a lesser extent, (5-hydroxytryptamine, 5-HT). (U.S. dosage of each component of the conjugate. 40 Pat. No. 6,274.579; and U.S. Pat. No. 6,391,875, incorporated In embodiments, the linker W or W is enzymatically cleav herein by reference in their entireties). The therapeutic amine able, enzymatically degradable, or physiologically hydrolyZ compound manifaxine, like bupropion, exhibits significant able in vivo. The linker may provide for cleavage of either the activity in the mouse antitetrabenazine Screen for antidepres therapeutic amine or arylsulfonamide from the conjugate sant activity (U.S. Pat. No. 5,104,870 incorporated herein by 45 reference in its entirety), a test that has been validated with a compound with the remaining linker moiety, if any, being wide range of known to act through norepi enzymatically degradable or physiologically hydrolyzable. nephrine mechanisms (Cooper, et al., Animal models used in In embodiments, a method of making a pharmaceutical the prediction of antidepressant effects in man, Journal of composition Suitable for treating psychiatric, neurologic and Clinical Psychiatry, (1983)44: 63-66). While the mechanism metabolic disorders such as depression, obesity, fibromyal 50 of action of bupropion is unknown, it may be that this action gia, neuropathic pain, restless leg syndrome, attention deficit is mediated by norepinephrine and/or dopaminergic mecha hyperactivity disorder (ADHD), migraine, pain, sexual dys nisms. Available evidence Suggests that bupropion is a selec function, Parkinson's disease, Alzheimer's disease, anxiety, tive inhibitor of norepinephrine (NA) reuptake at doses that narcolepsy-cataplexy syndrome, seizures or drug/substance are predictive of antidepressant activity in animal models. addiction/cessation, is disclosed, comprising reacting athera 55 (Ascher, et al., Bupropion: A Review of its Mechanism of peutic amine, an arylsulfonamide, and optionally a linker, and Antidepressant Activity, Journal of Clinical Psychiatry, isolating a therapeutic amine-arylsulfonamide conjugate (1995) 56: 395-401.) Similarly, the therapeutic efficacy of compound, or a pharmaceutically acceptable salt or Solvate of manifaxine and radafaxine are also considered to be mediated the therapeutic amine-arylsulfonamide conjugate compound. by actions upon norepinephrine and/or dopaminergic 60 reuptake mechanisms. (U.S. Pat. No. 5,104,870; U.S. Pat. No. In embodiments, a method is provided for ameliorating or 6,274,579; and U.S. Pat. No. 6,391,875). attenuating a convulsant, pro-convulsant, or abuse liability However, bupropion and radafaxine are known to elicit condition resulting from the administration of therapeutic seizures (U.S. Pat. No. 6,274.579; and U.S. Pat. No. 6,391, amines used in treating psychiatric, neurologic and metabolic 875). Another concern with drugs that block dopamine uptake disorders, comprising administering to a patient in need 65 sites is their potential reinforcing effects and abuse liability thereofatherapeutically effective amount of an amine-aryl (Volkow, et al., The slow and long-lasting blockade of dopam Sulfonamide conjugate compound: ine transporters in human brain induced by the new antide US 7,763,612 B2 5 6 pressant drug radafaxine predict poor reinforcing effects, Biol The therapeutic amine radical of the therapeutic amine Psychiatry, (2005) 15: 640-46.). Furthermore, the rate of arylsulfonamide may be derived from at least one therapeutic entry of drugs into brain is thought to be a factor in their abuse amine selected from: manifaxine: 2-(1-(3,5-difluoroben liability (Stathis et al., Rate of binding of various inhibitors at Zoyl)-(R.S)-ethylamino)-(R)-2-methylethanol; (2S,3S)-2- the in Vivo, Psychopharmacology, (3-chlorophenyl)-3.5.5-trimethyl-2-morpholinol; radafax (1995) 119(4): 376-84). ine; 2-(1-(3-chlorobenzoyl)-(R.S)-ethylamino)-2.2- Arylsulfonamide compounds Such as furosemide (or dimethylethanol; bupropion; citalopram; escitalopram; frusemide), which is the active ingredient in the antidiuretic paroxetine; fluoxetine; fluvoxamine; Sertraline; phenelzine; LASIX(R), may exhibit anticonvulsant properties. (Ahmad, et ; amitriptyline; amoxapine; clomipramine; al., Controlled trial of frusemide as an antiepileptic drug in 10 desipramine: doxepine; imipramine; nortryptyline; protrip focal epilepsy, Br. J. Clin. Pharmac., (1976) 3: 621-25; tyline; trimipramine; maprotiline, mirtazapine; dulloxetine; Ahmad, et al., The effect of frusemide, mexiletine, (+)-pro nefazodone; traZodone; and Venlafaxine. pranolol and three benzodizaepine drugs on the interictal Therapeutic amine radicals may be conjugated with aryl spike discharges in the electroencephalograms of epileptic Sulfonamide radicals by employing a chemical bond or a patients. Br. J. Clin. Pharmac., (1977) 4:683-88: Espinosa, L. 15 linker. For example, a linker group may contain one or more J., The anticonvulsant activity of Lasix (Spanish), Medicina chemical groups which are susceptible to catabolic hydroly Espanola, (1969) 61:280-82; Kielczewska-Mrozikiewicz, sis, physiological hydrolysis, or enzymatic cleavage, includ D., Experimental studies on the effect of Lasix on the occur ing combinations thereof. Such hydrolysis may be, for rence of Cardiazol convulsions, Przeglad Lekarski, (1968) example, by esterase enzymes within biocompartments such 24:716-18.) as blood plasma, brain, or GI tract. Such cleavage of the Compounds and their compositions comprising conjugate chemical linker may liberate at least one of the conjugated compounds of at least one therapeutic amine radical with at bioactive compounds, either simultaneously, or sequentially. least one arylsulfonamide radical are provided for treatment Each component of the conjugate may have an independent or of psychiatric, neurologic and metabolic disorders. Such con identical rate of cleavage from the linker, an independent or jugate compounds may be suitable for use as therapeutics 25 identical rate of uptake, an independent or identical rate of with the benefit of attenuation oramelioration of undesirable clearance, or combinations thereof. side effects of the therapeutic amine component of the con Furthermore, by designing the linker chemistries between jugate. By virtue of potential intrinsic anticonvulsant proper the therapeutic amine and aryl Sulfonamide radicals to be ties of arylsulfonamides, amine-arylsulfonamide conjugate enzymatically cleaved, the rate of appearance and rate of compounds may attenuate or ameliorate the adverse side 30 clearance of the active therapeutic amine drug Substance in effects such as convulsions associated with therapeutic biocompartments, such as blood plasma, brain, or GI tract amines, for example, bupropion, manifaxine and radafaxine. may be controlled. By controlling the rate of appearance or By way of example, such therapeutic amine radicals are clearance of the therapeutic amine, seizure liability and derived from, but are not limited to, therapeutic amines potential drug abuse liability may be attenuated or amelio including bupropion, manifaxine and radafaxine, and Such 35 rated. This is particularly desirable following illicit intrave arylsulfonamides radicals are derived from, without limita nous bolus injection where rate of delivery of active drug tion, furosemide or furosemide congeners or derivatives. Substance and peak drug concentration are critical determi In embodiments, an amine-arylsulfonamide conjugate nants of abuse liability. compound: An example of a linker group W is, but not limited to, a 40 linker comprising a chemical bond, one or more ester groups or one or more carbamate groups selected from: CHRO : / Cy C(O)OCHRO : O HN C(O)OCHROC(O)RO : 45 R CHROC(O)RO :

SO 50 wherein R' is independently: —(CH2) ; —(CH2)CHY (CH), ; —(CH2)CH=CH(CH.) : where R is D-W-, hydroxyl, or alkoxyl: —(CH)O(CH.) : R" is independently D-W-), hydrogen, alkoxy, alkyl, 55 cycloalkyl, alkenyl, alkynyl or aryl, or R" and R" together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7- or 8-membered ring optionally containing one or two further heteroatoms independently selected from nitro —(CH),C(O)O(CH),CHY(CH.) : gen, oxygen and Sulfur, 60 D is independently a therapeutic amine radical comprising —(CH),C(O)O(CH), O(CH.) : at least one nitrogen atom and optionally at least one —(CH),C(O)O(CH), NR(CH.) : oxygenatom coupled to WorW" by a nitrogen or oxygen —(CH),C(O)O(CH), S(O)(CH.) : atom; and W and Ware a chemical bond or linker; wherein either R' is D-W- or at least one R" is D-W-: 65 a 5- or 6-membered aromatic ring diradical optionally con or a pharmaceutically acceptable ester, amide, salt or Sol taining 1 or more heteroatoms independently selected vate thereof is provided. from oxygen, nitrogen and Sulfur, the 5- or 6-membered US 7,763,612 B2 7 8 aromatic ring diradical optionally Substituted by with a hydroxy functionality, for example, —CHCH-OH, or hydroxy, hydroxyalkyl, halogen, amino, alkyl, or an alkoxy functionality, for example, —CHCHOCH, alkoxyalkyl, respectively. R is independently hydrogen, alkyl, cycloalkyl or aryl, As used herein, the term "cycloalkyl refers to a non wherein any of cycloalkyl or aryl are optionally substi 5 aromatic carbocyclic ring having from 3 to 8 carbon atoms tuted with alkyl, hydroxy, alkoxy, halogen or amino; absent any carbon-carbon double bonds. By way of example, Y is a halogen; “cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, n is independently 1-8; cyclohexyl, cycloheptyl and cyclooctyl. "Cycloalkyl also m is 0, 1, or 2; and includes Substituted cycloalkyl. The cycloalkyl may option o is 0-8. 10 ally be substituted on an available carbon with one or more An example of a linker group W is, but not limited to, a Substituents selected from hydroxy, alkoxy, amino, mercapto, linker comprising one or more ester groups, one or more nitro, cyano, halogen, and alkyl. carbamate groups, or one or more chemical bonds selected As used herein, the term “alkenyl refers to straight or from: branched hydrocarbon chains containing from 2 to 8 carbon 15 atoms and at least one and up to three carbon-carbon double CHROC(O)RC(O)OCHR ; bonds. By way of example, “alkenyl includes ethenyl and C(O)RC(O)CCHR ; propenyl. Alkenyl also includes substituted alkenyl. The C(O)OCHROC(O)RC(O)OCHR : alkenyl groups may optionally be substituted on an available CHROC(O)RC(O)OCHROC(O) ; carbon with one or more Substituents selected from the group C(O)RC(O)CCHROC(O)NH ; or consisting of hydroxy, alkoxy, amino, mercapto, nitro, cyano, C(O)OCHROC(O)RC(O)OCHROC(O) ; halogen, and alkyl. wherein R. R.Y. n,m and o are as described above. As used herein, the term “cycloalkenyl refers to refers to For example, such ester groups include groups which are a non-aromatic carbocyclic ring having from 3 to 8 carbon Susceptible to catabolic hydrolysis by esterase enzymes atoms and up to 3 carbon-carbon double bonds. By way of within various biocompartments such as blood plasma, brain, 25 example, "cycloalkenyl' includes cyclobutenyl, cyclopente or GI tract. nyl and cyclohexenyl. "Cycloalkenyl also includes substi In embodiments, one or more therapeutic amine radicals tuted cycloalkenyl. The cycloalkenyl may optionally be sub may be conjugated with one or more arylsulfonamide radicals stituted on an available carbon with one or more substituents employing a linker group comprising at least one carbamate selected from hydroxy, alkoxy, amino, mercapto, nitro, group. In embodiments, only one of R' and R" is D-WI or 30 cyano, halogen, and alkyl. D-W". The above disclosed conjugate compound embodi As used herein, the term “alkynyl refers to straight or ments include pharmaceutically acceptable esters, amides, branched hydrocarbon chains containing from 2 to 8 carbon salts or solvates thereof. atoms and at least one and up to three carbon-carbon triple It is further understood that the embodiments disclosed 35 bonds. By way of example, “alkynyl includes ethynyl and herein include enantiomeric and diastereomeric forms of 2-propynyl. “Alkynyl also includes substituted alkynyl. The compound (I) either individually or admixed in any propor alkynyl may optionally be substituted on an available carbon tion. with one or more substituents selected from hydroxy, alkoxy, One or more therapeutic amines radicals may be conju amino, mercapto, nitro, cyano, halogen, and alkyl. gated with one or more arylsulfonamide radicals by employ 40 As used herein, the term “aryl' refers to monocyclic car ing a poly-functional chemical linker. In this embodiment, the bocyclic groups and fused bicyclic carbocyclic groups having ratio of therapeutic amine to arylsulfonamide may be adjusted from 6 to 10 carbon atoms and having at least one aromatic to a desired pharmacokinetic or pharmacodynamic profile ring. By way of example, aryl includes phenyl, and naphthyl. range as needed to ameliorate or treat a particular disorder. Aryl also includes substituted aryl. The aryl may be option In addition, the conjugate compound embodiments further 45 ally substituted on an available carbon with one or more include prodrugs and active metabolites of compound (I). A Substituents selected from alkyl, hydroxyalkyl, alkoxyalkyl, prodrug includes any compound which, for example, when cycloalkyl, alkenyl, alkynyl, aryloxy, aryl, haloalkyl, administered to a mammal, is converted in whole or in part to haloalkoxy, cyano, nitro, Sulfonamido, alkylsulfonyl, alkyl any of the embodiments represented by (I). An active metabo Sulfinyl, alkylthio, hydroxy, carboxyl, alkoxycarbonyl, car lite is a physiologically active compound which results from 50 boxamido, Sulfoxy, alkoxy, amino, alkylamino, carbamoyl or the metabolism of (I), or a prodrug thereof, when Such com halogen. By way of example, Substituted aryl includes benzyl pound (I), or a prodrug thereof is administered to a mammal. and phenethyl. As used herein, the terms “alkyl and “alkylene' refer to As used herein, the term "R" and R" together with the straight or branched hydrocarbon chains containing from 1 to nitrogen atom to which they are attached form a 4-, 5-, 6-, 7 8 carbonatoms. By way of example, “alkyl includes methyl, 55 or 8-membered ring refers to a monocyclic saturated or ethyl, n-propyl. n-butyl, n-pentyl, isobutyl, isopropyl, and unsaturated non-aromatic ring or a fused bicyclic aromatic tert-butyl. Examples of “alkylene' as used herein include, but and non-aromatic ring, the ring having the specified number are not limited to, methylene, ethylene, propylene, butylene, of members (total carbon atoms and the nitrogen of the aryl and isobutylene. “Alkyl also includes substituted alkyl or Sulfonamide group). The ring may optionally contain 1, 2, 3 alkylene. The alkyl groups may be optionally substituted one 60 or 4 heteroatoms independently selected from N, O and S. or more times on an available carbon with a substituent The ring may be optionally Substituted on any available car selected from hydroxy, alkoxy, amino, mercapto, nitro, bon or heteroatom, with one or more Substituents optionally cyano, cycloalkyl or halogen. By way of example, Substituted selected from alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, alkyl includes trifluoromethyl, 2.2.2-trifluoroethyl, 2,2-dif alkenyl, alkynyl, aryloxy, aryl, haloalkyl, haloalkoxy, cyano, luoroethyl 2-fluoroethyl, and cyclopropylmethyl. 65 nitro, Sulfonamido, alkylsulfonyl, alkylsulfinyl, alkylthio. As used herein, the terms “hydroxyalkyl and “alkoxy hydroxy, carboxyl, alkoxycarbonyl, carboxamido, Sulfoxy, alkyl refer to alkyl groups of 1 to 6 carbon atoms substituted alkoxy, amino, alkylamino, carbamoyl or halogen. By way of US 7,763,612 B2 10 example, Substituted ring Substituents include hydroxy, hydroxyalkyl, Oxo, alkyl, haloalkyl, and/or haloalkoxy. "Halogen' means F, Cl, Br, or I. "Radical refers to one or more residues derived from: 1) Cy the corresponding amine by eliminating a —H portion of a HN O primary amine group or —H, -alkyl, or -alkoxyl portion of a secondary amine group, or an alkyl group of a quaternary C ammonium salt; 2) the corresponding carbonyl by eliminat O ing a -OH group, a -NH group, a —OR ester group, or a 10 —R portion of the carbonyl group; and 3) the corresponding SON thiol by eliminating a —H portion of a -SH group. “5- or 6-membered aromatic ring diradical refers to a chemical moiety represented by the following: 15 Exemplary embodiments of arylsulfonamide radicals include, but are not limited to radicals derived from furo semide (or frosemide) or furosemide congeners. In embodi ments, the arylsulfonamide radical is covalently bonded to a linker moiety by the carbonyl portion of the corresponding carbonyl group. In embodiments, the arylsulfonamide radical is covalently bonded to at least one linker moiety by one or more of the Sulfamidyl portions of the corresponding Sulfa midyl group. In embodiments, the arylsulfonamide radical is where Z is S. O. NR or C=C; and where R is hydrogen, alkyl, covalently bonded to a therapeutic amine moiety by a single or cycloalkyl or aryl. The 5- or 6-membered aromatic ring 25 bond. diradical may be substituted on an available carbon with one The term “linker” and “chemical linker are used herein or more substituents selected from alkyl, hydroxyalkyl, interchangeably. The term “linker” refers to an atom, or a alkoxyalkyl, cycloalkyl, alkenyl, alkynyl, aryloxy, aryl, collection of atoms used to link interconnecting moieties Such haloalkyl, haloalkoxy, cyano, nitro, Sulfonamido, alkylsulfo as a therapeutic amine radical and an arylsulfonamide radical. nyl, alkylsulfinyl, alkylthio, hydroxy, carboxyl, alkoxycarbo 30 A linker may be hydrolytically stable or undergo spontaneous nyl, carboxamido, Sulfoxy, alkoxy, amino, alkylamino, car cleavage in the presence of water, or may include a physi bamoylorhalogen. By way of example, diradical Substituents ologically hydrolyzable, enzymatically cleavable, or enzy include hydroxy, hydroxyalkyl, halogen, amino, alkyl, or matically degradable linkage. "Linker comprises functional alkoxyalkyl. groups selected from carboxylate, carbonyl, carboxyl, car 35 bamate, carbonate, ester, thioamidyl, thiocarbamyl, or thiol “Therapeutic amine radical means a radical derived from ester groups. an amine-containing chemical moiety that when adminis “Enzymatically degradable” refers to a chemical bond or a tered to a subject provides for a therapeutic effect. Typically, linker, wherein all or part of the bond or linker may be the therapeutic amine radical from an amine-containing degraded by one or more enzymes. chemical moiety administered to a Subject for treating psy 40 “Enzymatically cleavable' refers to a chemical bond or a chiatric and/or neurologic and/or metabolic disorders, linker, wherein either the therapeutic amine or the arylsul wherein the amine-containing chemical moiety may induce fonamide constitutents may be cleaved from the chemical adverse side effects Such as convulsant, pro-convulsant, or bond or linker, by one or more enzymes. A linker may provide abuse liability. By way of example, therapeutic amine radi 45 an enzymatic cleavage site with the remaining portion of the cals may be derived from the therapeutic amines selected linker being enzymatically degradable or physiologically from manifaxine: 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethy hydrolyzable. The linker may be enzymatically degraded or lamino)-(R)-2-methylethanol; (2S,3S)-2-(3-chlorophenyl)- physiologically hydrolyzable prior to cleavage of either the therapeutic amine or the arylsulfonamide constitutents from 3.5.5-trimethyl-2-morpholinol; radafaxine: 2-(1-(3-chlo the chemical bond or linker. 50 robenzoyl)-(R.S)-ethylamino)-2,2-dimethylethanol: “Physiological hydrolysis” or “physiologically hydrolyz bupropion; citalopram; escitalopram, paroxetine; fluoxetine; able.” or “physiologically hydrolyzing” means replacement fluvoxamine; Sertraline; phenelzine; tranylcypromine; ami of the linker that is connected to either the therapeutic amine triptyline; amoxapine; clomipramine; desipramine; doX radical or the arylsulfonamide radical of the conjugate com epine; imipramine; nortryptyline; ; trimi 55 pound with a hydroxyl group on the carbonyl radical of the pramine; maprotiline; mirtazapine; dulloxetine; nefazodone; arylsulfonamide, or a hydrogen on the Sulfonamide radical of traZodone; or Venlafaxine. the arylsulfonamide or the nitrogen or oxygen atom of the Arylsulfonamide radical means a chemical moiety hav therapeutic amine connected to the linker, in the presence of ing the following general structure: water or aqueous media of biological origin. 60 “Psychiatric, neurologic and metabolic disorders' is meant to include, but not be limited to, depression, obesity, fibro myalgia, neuropathic pain, restless leg syndrome, attention deficit hyperactivity disorder (ADHD), migraine, pain, sexual dysfunction, Parkinson's disease, Alzheimer's dis 65 ease, anxiety, narcolepsy-cataplexy syndrome, seizures, drug/substance addiction/cessation and combinations thereof. US 7,763,612 B2 11 12 “Conjugate compound” refers to at least one first com medical applications, due to their greater Solubility in water pound or part of a first compound that has pharmacological compared with the starting or base compounds are also envis activity linked to at least one second compound or part of a aged as additional embodiments. Said salts have a pharma second compound that has independent pharmacological ceutically acceptable anion or cation. Suitable pharmaceuti activity, whereas the linked first and second compound form cally acceptable acid addition salts of compound (I) include a conjugate that optionally has pharmacological activity. salts of inorganic acids such as hydrochloric acid, hydrobro Typically, both the first or second compounds have indepen mic acid, phosphoric acid, metaphosphoric acid, nitric acid, dent pharmacologic activity without being linked as in the Sulfonic acid, and Sulfuric acid, and also of organic acids Such conjugate. The conjugate may facilitate therapeutic use of as, for example, acetic acid, benzenesulfonic acid, benzoic both the first and second compounds by providing indepen 10 dent pharmacologic activity, independent clearance, and acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic independent uptake of each first and second compound. A acid, glycolic acid, isethionic acid, lactic acid, lactobionic conjugate formed from a first compound and a second com acid, maleic acid, malic acid, methanesulfonic acid. Succinic pound can have higher or lower pharmacologic activity, clear acid, p-toluenesulfonic acid, tartaric acid and trifluoroacetic ance activity, or uptake activity than either compound alone. 15 acid and, additionally L-ascorbic acid, Salicylic acid, 1.2- The individual compounds (or constituents) of a conjugate benzisothiazol-3(2H)-one and 6-methyl-1,2,3-oxathiazin-4 compound may be linked by covalent bonds. Additional com (3H)-one 2,2-dioxide. Suitable pharmaceutically acceptable pounds, for example a third, fourth, etc., compound are also basic salts include ammonium salts, alkali metal salts (such as within the scope of the various conjugate compound embodi Sodium salts and potassium salts) and alkaline earth metal ments herein described. Preferably, the conjugate compound salts (such as magnesium salts and calcium salts). Salts hav has at least one of a first compound derived from a therapeutic ing a pharmaceutically unacceptable anion or cation are like amine and at least one of a second compound derived from an wise included within the scope of the present invention as arylsulfonamide. useful intermediates for preparing or purifying pharmaceuti “Therapeutically effective amount’ means the quantity of cally acceptable salts and/or for use in nontherapeutic appli conjugate compound, that when administered to an individual 25 cations, for example in vitro applications. Suitable pharma or animal results in a sufficiently high level of therapeutic ceutically acceptable carriers and their formulations are amine and/orarylsulfonamide constituent in the individual or described in standard formulation treaties, e.g., Remington's animal to cause a discernible attenuation or amelioration of Pharmaceutical Science by E. W. Martin. See also Wang et al., symptoms of an underlying psychiatric, neurologic or meta Parental Formulations of Proteins and Peptides: Stability and bolic disorder with a concomitant reduced likelihood of 30 Stabilizer, Journals of Parental Sciences and Technology, adverse effects. Technical Report No. 10, Supp. 42: 2S (1988). In addition, the As used herein, the term “treatment” and its grammatical pharmaceutically acceptable salt of compound (I) may be a equivalents refer to the alleviation, amelioration, attenuation quaternary ammonium compound formed by reacting a ter or elimination of etiological or pathological symptoms and tiary amine of the therapeutic amine with an alkyl derivative include, for example, the elimination of Such symptom cau 35 of the arylsulfonamide. sation either on a temporary or permanent basis, or to alter or Exemplary therapeutic amine-ary Sulfonamide conjugate slow the appearance of such symptoms or symptom worsen compounds, where the arylsulfonamide radical is covalently ing. For example, the term “treatment includes alleviation or bonded to a linker moiety by the carbonyl portion of the elimination of causation of symptoms associated with, but not corresponding carbonyl group are presented in Table I. A limited to, any of the adverse effects caused by the therapeutic 40 chemical bond between the therapeutic amine radical and amine or the psychiatric, neurologic and metabolic disorders linker radical is represented by the wavy line. A chemical described herein. bond between the linker radical and arylsulfonamide is rep “Pharmaceutically acceptable salts' refers to relatively resented by the dashed line. The wavy and dashed lines taken non-toxic, inorganic and organic acid addition salts of com together would represent a chemical bond between the thera pound (I). Pharmaceutically acceptable salts suitable for peutic amine radical and arylsulfonamide radical.

US 7,763,612 B2 25 26 2-(4-(2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) 1-(3-chlorophenyl)-1-propanone; and pharmaceutically aminobenzoyloxy)ethoxy)(4-oxo)butanoyloxymethoxy acceptable esters, amides, salts or Solvates thereof. carbonyl)(1,1-dimethylethyl)amino-1-(3-chlorophenyl)- The conjugate compound (I) and their salts and Solvates 1-propanone; may be prepared in accordance with the methods hereinafter 2-(4-(4-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) described, or in any manner known in the art for the prepara aminobenzoyloxy)butoxy)(4-oxo)butanoyloxymethoxy tion of compounds of analogous structure. carbonyl)(1,1-dimethylethyl)amino-1-(3-chlorophenyl)- By way of illustration, therapeutic amine-arylsulfonamide 1-propanone; conjugate compounds may be prepared by processes that are 2-(4-(5-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) known to those skilled in the art of organic synthesis. The aminobenzoyloxy)pentyloxy)(4-oxo)butanoy 10 following Examples illustrate the present invention but loxymethoxycarbonyl)(1,1-dimethylethyl)amino-1-(3- should not be construed as a limitation to the scope thereof. chlorophenyl)-1-propanone; 2-(4-(6-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) Prophetic Example 1 aminobenzoyloxy)hexyloxy)(4-oxo)butanoy loxymethoxycarbonyl)(1,1-dimethylethyl)amino-1-(3- 15 Preparation of 2-(1-(3,5-difluorobenzoyl)-(R.S)- chlorophenyl)-1-propanone; ethylamino)-(R)-2-methylethyl 5-(aminosulfonyl)-4- 2-(4-(2-(2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm chloro-2-(2-furanylmethyl)aminobenzoate (220) ethyl)aminobenzoyloxy)ethoxy)ethoxy)(4-oxo)butanoy loxymethoxycarbonyl)(1,1-dimethylethyl)amino-1-(3- Scheme A depicts a synthesis of a therapeutic amine chlorophenyl)-1-propanone; ary Sulfonamide conjugate compound wherein the linking 2-(5-(3-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) group (W) represents a chemical bond. The free base of aminobenzoyloxy)propoxy)(5-oxo)pentanoy (2S,3S.5R)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-mor loxymethoxycarbonyl)(1,1-dimethylethyl)amino-1-(3- pholinol (20a) and/or (20b) (0.023 mole) (U.S. Pat. No. chlorophenyl)-1-propanone; 5,104,870) and benzene (30 mL) (or toluene) is added to a 2-(5-(2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) 25 round-bottomed flask. Furosemide (5-(aminosulfonyl)-4- aminobenzoyloxy)ethoxy)(5-oxo)pentanoy chloro-2-(2-furanylmethyl)aminobenzoic acid, (10) (Ald loxymethoxycarbonyl)(1,1-dimethylethyl)amino-1-(3- rich) (0.025 mole), benzene (30 mL), and p-toluenesulfonic chlorophenyl)-1-propanone; acid (0.026 mole) catalyst is added to the flask. A Dean-Stark 2-(5-(4-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) trap is filled with benzene, and the contents of the flask is aminobenzoyloxy)butoxy)(5-oxo)pentanoy 30 refluxed with stirring for several hours or until no additional loxymethoxycarbonyl)(1,1-dimethylethyl)amino-1-(3- water is collected in the trap. The reaction is cooled, extracted chlorophenyl)-1-propanone; with sodium bicarbonate solution, washed with water, and 2-(5-(5-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) then with a saturated Sodium chloride solution. The organic aminobenzoyloxy)pentyloxy)(5-oxo)pentanoy layer is dried over sodium sulfate, filtered and concentrated in loxymethoxycarbonyl)(1,1-dimethylethyl)amino-1-(3- 35 vacuo to give crude product, which may be purified by col chlorophenyl)-1-propanone; umn chromatography on silica gel with hexanes/ethyl acetate 2-(5-(6-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) as eluent. The fractions that contain pure product may be aminobenzoyloxy)hexyloxy)(5-oxo)pentanoy combined and spin evaporated in vacuo to give a solid that loxymethoxycarbonyl)(1,1-dimethylethyl)amino-1-(3- may be recrystallized to give 2-(1-(3,5-difluorobenzoyl)-(R, chlorophenyl)-1-propanone; 40 S)-ethylamino)-(R)-2-methylethyl 5-(aminosulfonyl)-4- 2-(5-(2-(2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm chloro-2-(2-furanylmethyl)aminobenzoate (220). See eg. ethyl)aminobenzoyloxy)ethoxy)ethoxy)(5-oxo)pen Sandler et al., Organic Functional Group Preparations, p. 249 tanoyloxymethoxycarbonyl)(1,1-dimethylethyl)amino (1968). US 7,763,612 B2 27 28

SCHEMEA --> O

HOC C

SONH2 10 20a

F F O O Cy CCHCH cich NHCH O lucci, Nich F biot F cio- C 2Ob O SONH2 220

The following conjugate compound may be prepared by solids. This solution is cooled with an ice bath, made basic by the same general method: treatment with 40% aqueous sodium hydroxide and extracted 2-(1-(3-chlorobenzoyl)-(R.S)-ethylamino)-2,2-dimethyl three times with diethyl ether. The combined ether extracts is ethyl 5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) 35 washed with a saturated sodium chloride solution, dried over aminobenzoate. Sodium Sulfate and spin evaporated in vacuo to give the free base of (rac)-(R*.S*)-2-((2-hydroxy-(R)-1-methylethyl) Prophetic Example 2 amino)-1-(3,5-difluorophenyl)propanol (21). A sample of the free base is treated with ethereal hydrogen chloride to give a Alternate preparation of 2-(1-(3,5-difluorobenzoyl)- 40 solid that may be recrystallized from ethanol/ether to give the (RS)-ethylamino)-(R)-2-methylethyl 5-(aminosulfo hydrochloride salt of (rac)-(R*.S*)-2-((2-hydroxy-(R)-1- nyl)-4-chloro-2-(2-furanylmethyl)aminobenzoate methylethyl)amino)-1-(3,5-difluorophenyl)propanol. See (220) eg. Boswell et al., J. Heterocyclic Chem. (1996) 33:33. Scheme B depicts an alternate synthesis of a therapeutic 45 b Preparation of (rac)-(R*.S*)-2-((2-(3,5-difluo amine-arylsulfonamide conjugate compound (220) as previ rophenyl)-2-hydroxy-1-methylethyl)amino)-(R)-2- ously described in Example 1 by a three step process (a-c). methylethyl 5-(aminosulfonyl)-4-chloro-2-(2-fura wherein the linker (W) is a chemical bond, by way of reduc nylmethyl)aminobenzoate tion of the morpholinol group of the therapeutic amine, esteri fication with the arylsulfonamide, followed by oxidation of 50 The free base of (rac)-(R*.S*)-2-((2-hydroxy-(R)-1-meth the difluorophenyl hydroxyl group to prepare the conjugate ylethyl)amino)-1-(3,5-difluorophenyl)propanol (21) (0.023 compound. mole) and benzene (30 mL) (or toluene) is added to a round bottomed flask. Furosemide (5-(aminosulfonyl)-4-chloro-2- a Preparation of (rac)-(R*.S*)-2-((2-hydroxy-(R)-1- (2-furanylmethyl)aminobenzoic acid (10), (Aldrich) (0.025 methylethyl)amino)-1-(3,5-difluorophenyl)propanol 55 mole), benzene (30 mL), and p-toluenesulfonic acid (0.026 mole) catalyst is added to the flask. A Dean-Stark trap is filled The hydrobromide salt of (2S,3S.5R)-2-(3,5-difluorophe with benzene, and the contents of the flask is refluxed with nyl)-3,5-dimethyl-2-morpholinol (0.023 mole) (U.S. Pat. No. stirring for several hours or until no additional water is col 5,104,870) is dissolved in a 50:50 mixture of ethanol/water lected in the trap. The reaction is cooled, extracted with (150 mL) and chilled to 0°C. while being stirred under a 60 sodium bicarbonate solution, washed with water, and then nitrogen atmosphere. A Solution of sodium borohydride with a saturated Sodium chloride solution. The organic layer (0.093 mole) in water (25 mL) is added dropwise, and the is dried over sodium sulfate, filtered and concentrated in Solution is allowed to warm to room temperature while being vacuo to give crude product, which may be purified by col stirred overnight. The solution is cooled to 0°C., and concen umn chromatography on silica gel with hexanes/ethyl acetate trated hydrochloric acid (25 mL) is carefully added dropwise. 65 as eluent. The fractions that contain pure product may be The mixture is concentrated under reduced pressure to combined and spin evaporated in vacuo to give a solid that remove ethanol and then diluted with water to dissolve the may be recrystallized to give (rac)-(R*.S*)-2-((2-(3,5-difluo US 7,763,612 B2 29 30 rophenyl)-2-hydroxy-1-methylethyl)amino)-(R)-2-methyl 5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl)amino ethyl 5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) benzoate (220). See eg., Sandler et al., Organic Functional aminobenzoate (210). See eg., Sandier et al., Organic Group Preparations, p. 171 (1968). Functional Group Preparations, p. 249 (1968) The following conjugate compound may be prepared by c Preparation of 2-(1-(3,5-difluorobenzoyl)-(R.S)- the same general method: ethylamino)-(R)-2-methylethyl 5-(aminosulfonyl)-4- 2-(1-(3-chlorobenzoyl)-(R.S)-ethylamino)-2,2-dimethyl chloro-2-(2-furanylmethyl)aminobenzoate ethyl 5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) aminobenzoate.

SCHEME B. -> O

HOC C

SONH2 20a 10

a NaBH4 F F pi pi Cy b citch NHCH O citch NHCHCH NHCHCH F F CH2OH CHO - C O 21 SONH2 210 )- cichl 220

A solution of chromic oxide (9.2 mmole) in 80% acetic 50 Prophetic Example 3 acid (10 mL) is added to a stirred solution of (rac)-(R*.S*)- 2-((2-(3,5-difluorophenyl)-2-hydroxy-1-methylethyl) Scheme C, synthetic route (i) depicts a synthesis ofathera amino)-(R)-2-methylethyl 5-(aminosulfonyl)-4-chloro-2- peutic amine-arylsulfonamide conjugate compound wherein (2-furanylmethyl)aminobenzoate (210) (18 mmole) in the linker (W) is C(O)R'O ; where R' is —(CH), and glacial acetic acid (10 mL) at a rate as to maintain a tempera 55 n is 3. ture of 50°C. The mixture is allowed to stand for 24 hours and Preparation of 2-(1-(3,5-difluorobenzoyl)-(R.S)- then extracted with benzene (three 20 mL portions). The ethylamino)-(R)-2-methylethyl 4-(5-(aminosulfo combined extracts is washed with sodium bicarbonate solu nyl)-4-chloro-2-(2-furanylmethyl)aminobenzoy tion, with water, and then with a saturated sodium chloride 60 loxy)butanoate (320) Solution. The organic layer is dried over Sodium sulfate, fil tered and concentrated in vacuo to give crude product, which A mixture of furosemide (5-(aminosulfonyl)-4-chloro-2- may be purified by column chromatography on silica gel with (2-furanylmethyl)aminobenzoic acid (10), (Aldrich) (0.060 hexanes/ethyl acetate as eluent. The fractions that contain mole), ethyl 4-bromobutyrate (Aldrich) (0.055 mole), DBN pure product may be combined and spin evaporated in vacuo 65 (1,5-diazabicyclo[4.3. Onon-5-ene, Aldrich) (0.060 mole) to give a white solid that may be recrystallized to give 2-(1- and dry acetonitrile (100 mL) is stirred at ambient tempera (3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-methylethyl ture for 10 hours. The reaction mixture is diluted with dichlo US 7,763,612 B2 31 32 romethane (200 mL) and extracted with sodium bicarbonate with a saturated Sodium chloride solution. The organic layer Solution, washed with water, and then with a saturated sodium is dried over sodium sulfate, filtered and concentrated in chloride solution. The organic layer is dried over sodium vacuo to give crude product, which may be purified by col Sulfate, filtered and concentrated in vacuo to give crude prod umn chromatography on silica gel with hexanes/ethyl acetate uct, which may be purified by column chromatography on as eluent. The fractions that contain pure product may be silica gel with hexanes/ethyl acetate as eluent. The fractions combined and spin evaporated in vacuo to give a solid that that contain pure product may be combined and spin evapo may be recrystallized to give 2-(1-(3,5-difluorobenzoyl)-(R, rated in vacuo to give ethyl 4-(5-(aminosulfonyl)-4-chloro-2- S)-ethylamino)-(R)-2-methylethyl 4-(5-(aminosulfonyl)-4- (2-furanylmethyl)aminobenzoyloxy)butanoate (300). See chloro-2-(2-furanylmethyl)aminobenzoyloxy)butanoate eg., T. W. Greene and P. G. M. Wuts, Protective Groups in 10 (320). See eg., Sandler et al., Organic Functional Group Organic Synthesis, p. 228 (1991). Preparations, p. 249 (1968).

SCHEMEC -> ROCCH2CH2CH2OC C --- EtOCCH2CH2CH2Br R = H SONH 300

F O| W \ cich NHCH O Nich F chochschich C O O SONH2 320

A mixture of ethyl 4-(5-(aminosulfonyl)-4-chloro-2-(2- The following conjugate compounds may be prepared, for furanylmethyl)aminobenzoyloxy)butanoate (300) (0.060 example, by the same general method as described above in mole) in ethanol (100 mL) is cooled in an ice water bath. A 45 Example 3 and depicted in Scheme C: solution of 1.0 N sodium hydroxide (60 mL) is added drop 2-(1-(3-chlorobenzoyl)-(R.S)-ethylamino)-2,2-dimethyl wise with stirring, and the reaction is stirred for 12 hours at ethyl 4-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) ambient temperature. The volatiles is removed by spin evapo aminobenzoyloxy)butanoate; ration in vacuo. The residue is dissolved in coldwater, and the 50 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-meth solution is washed with diethyl ether. The aqueous solution is ylethyl 2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm cooled in an ice bath and acidified by dropwise addition of 1.0 ethyl)aminobenzoyloxy)ethanoate; N hydrochloric acid solution (60 mL). The resulting solid 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-meth may be collected and recrystallized to give 4-(5-(aminosul ylethyl 3-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm fonyl)-4-chloro-2-(2-furanylmethyl)aminobenzoyloxy)bu 55 ethyl)aminobenzoyloxy)propanoate; tanoic acid. 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-meth The free base of (2S,3S.5R)-2-(3,5-difluorophenyl)-3,5- ylethyl 2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm dimethyl-2-morpholinol (0.023 mole) (U.S. Pat. No. 5,104, ethyl)aminobenzoyloxy)propanoate; 870) and benzene (30 mL) (or toluene) is added to a round 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-meth bottomed flask. 4-(5-(Aminosulfonyl)-4-chloro-2-(2- 60 ylethyl 4-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm furanylmethyl)aminobenzoyloxy)butanoic acid (0.025 ethyl)aminobenzoyloxy)crotonate; mole), benzene (30 mL), and p-toluenesulfonic acid (0.026 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-meth mole) catalyst is added to the flask. A Dean-Stark trap is filled ylethyl 5-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm with benzene, and the contents of the flask is refluxed with ethyl)aminobenzoyloxy)pentanoate; stirring for several hours or until no additional water is col 65 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-meth lected in the trap. The reaction is cooled, extracted with ylethyl 6-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm sodium bicarbonate solution, washed with water, and then ethyl)aminobenzoyloxy)hexanoate; US 7,763,612 B2 33 34 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-meth loxy)butanoate (320) ylethyl 8-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm ethyl)aminobenzoyloxy)octanoate; A solution of chromium trioxide (10 mmole) and 1.6 mL of 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-meth concentrated sulfuric acid in water (5 mL) is added dropwise ylethyl 2-(2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm to an ice water bath cooled, stirred solution of (rac)-(R*.S*)- ethyl)aminobenzoyloxy)ethoxy)ethanoate: 2-((2-(3,5-difluorophenyl)-2-hydroxy-1-methylethyl) 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-meth amino)-(R)-2-methylethyl 4-(5-(aminosulfonyl)-4-chloro-2- ylethyl 2-(2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm (2-furanylmethyl)aminobenzoyloxy)butanoate (19 mmole) ethyl)aminobenzoyloxy)ethylthio)ethanoate: in water (5 mL) and dichloromethane (10 mL). The reaction 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-meth 10 is stirred at ambient temperature for 1 hour and then dichlo ylethyl 2-(2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm romethane (20 mL) is added. The mixture is stirred for 15 ethyl)aminobenzoyloxy)ethylsulfinyl)ethanoate: minutes, and the organic layer is separated. The aqueous layer 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-meth is extracted with dichloromethane (two 10 mL portions). The ylethyl 2-(2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm combined organic extracts is washed with sodium bicarbon ethyl)aminobenzoyloxy)ethylsulfonyl)ethanoate: 15 ate solution, with water, and then with a saturated sodium 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-meth chloride solution. The organic layer is dried over sodium ylethyl 2-((2-(5-(aminosulfonyl)-4-chloro-2-(2-furanyl Sulfate, filtered and concentrated in vacuo to give crude prod methyl)aminobenzoyloxy)ethyl)(methyl)amino)etha uct, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions noate; and that contain pure product may be combined and spin evapo 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-meth rated in vacuo to give a solid that may be recrystallized to give ylethyl 4-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-meth ethyl)aminobenzoyloxy)(2-fluoro)butanoate. ylethyl 4-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) Prophetic Example 4 aminobenzoyloxy)butanoate (320). See eg., Org. Syn. Coll. 25 (1973) 5:324. The following conjugate compound may be prepared by Scheme C. Synthetic route (ii) depicts an alternate synthe the same general method: sis of a therapeutic amine-arylsulfonamide conjugate com 2-(1-(3-chlorobenzoyl)-(R.S)-ethylamino)-2,2-dimethyl pound (320) having a linker (W) that is—C(O)R'O ; where ethyl 4-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) R" is -(CH2), ; and n is 3. 30 aminobenzoyloxy)butanoate. Preparation of 2-(1-(3,5-difluorobenzoyl)-(R.S)- Prophetic Example 5 ethylamino)-(R)-2-methylethyl 4-(5-(aminosulfo nyl)-4-chloro-2-(2-furanylmethyl)aminobenzoy Scheme D depicts a synthesis of a therapeutic amine-aryl loxy)butanoate (320) 35 Sulfonamide conjugate compound wherein the linker (W) is Preparation of (rac)-(R*.S*)-2-((2-(3,5-difluorophe —CHO—. nyl)-2-hydroxy-1-methylethyl)amino)-(R)-2-methyl Preparation of (2S,3S.5R)-4-(5-(aminosulfonyl)-4- ethyl 4-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm chloro-2-(2-furanylmethyl)aminobenzoyloxym ethyl)aminobenzoyloxy)butanoate 40 ethyl)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-mor pholinol (520) The free base of (rac)-(R*.S*)-2-((2-hydroxy-(R)-1-meth ylethyl)amino)-1-(3,5-difluorophenyl)propanol (21) (0.023 a Preparation of 5-(aminosulfonyl)-4-chloro-2-(2- mole) and benzene (30 mL) (or toluene) is added to a round furanylmethyl)aminobenzoyl chloride (13) bottomed flask. 4-(5-(Aminosulfonyl)-4-chloro-2-(2-fura 45 nylmethyl)aminobenzoyloxy)butanoic acid (0.025 mole), A solution of oxalyl chloride (0.040 mole) in dichlo benzene (30 mL), and p-toluenesulfonic acid (0.026) catalyst romethane (20 mL) is added dropwise to an ice bath cooled is added to the flask. A Dean-Stark trap is filled with benzene, solution of furosemide (5-(aminosulfonyl)-4-chloro-2-(2- and the contents of the flask is refluxed with stirring for furanylmethyl)aminobenzoic acid), (10) (Aldrich) (0.040 several hours or until no additional water is collected in the 50 mole) in dichloromethane (50 mL). The reaction is stirred at trap. The reaction is cooled, extracted with sodium bicarbon ambient temperature for 5 hours. The reaction solution is ate Solution, washed with water, and then with a saturated washed with 5% aqueous sodium bicarbonate, with water, sodium chloride solution. The organic layer is dried over and then with a saturated sodium chloride solution. The Sodium sulfate, filtered and concentrated in vacuo to give organic layer is dried over Sodium sulfate, filtered and may be crude product, which may be purified by column chromatog 55 concentrated in vacuo to give 5-(aminosulfonyl)-4-chloro-2- raphy on silica gel with hexanes/ethyl acetate as eluent. The (2-furanylmethyl)aminobenzoyl chloride (13). See eg. fractions that contain pure product may be combined and spin Musso, et. al., J. Med. Chem. (2003) 46:409. evaporated in vacuo to give a solid that may be recrystallized to give (rac)-(R*.S*)-2-((2-(3,5-difluorophenyl)-2-hydroxy b Preparation of chloromethyl 5-(aminosulfonyl)-4- 1-methylethyl)amino)-(R)-2-methylethyl 4-(5-(aminosulfo 60 chloro-2-(2-furanylmethyl)aminobenzoate (15) nyl)-4-chloro-2-(2-furanylmethyl)aminobenzoyloxy)bu tanoate. See eg., Sandler et al., Organic Functional Group A mixture of 5-(aminosulfonyl)-4-chloro-2-(2-furanylm Preparations, p. 249 (1968). ethyl)aminobenzoyl chloride (13) (0.040 mole) and paraformaldehyde (0.040 mole) is heated in a sealed vessel at Preparation of 2-(1-(3,5-difluorobenzoyl)-(R.S)- 65 90° C. for 3 hours. The reaction is cooled, and the solids is ethylamino)-(R)-2-methylethyl 4-(5-(aminosulfo dissolved in dichloromethane. The solution is washed with nyl)-4-chloro-2-(2-furanylmethyl)aminobenzoy 5% aqueous sodium bicarbonate, with water, and then with a US 7,763,612 B2 35 36 saturated sodium chloride Solution. The organic layer is dried fied by column chromatography on silica gel with hexanes/ over sodium sulfate, filtered and concentrated in vacuo to give ethyl acetate as eluent. The fractions that contain pure product crude product, which may be purified by column chromatog may be combined and spin evaporated in vacuo to give a solid raphy on silica gel with hexanes/ethyl acetate as eluent. The that may be recrystallized to give (2S,3S.5R)-4-(5-(amino fractions that contain pure product may be combined and spin 5 sulfonyl)-4-chloro-2-(2-furanylmethyl)aminobenzoy evaporated in vacuo to give chloromethyl 5-(aminosulfonyl)- loxymethyl)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-mor 4-chloro-2-(2-furanylmethyl)aminobenzoate (15). See eg. pholinol (520). See eg., U.S. Pat. No. 5,104,870) and Sandler, Bodor, et al., J. Med. Chem., (1980) 23: 469, and Ulich et al., et al., Organic Functional Group Preparations, p. 324 (1968). J. Am. Chem. Soc., (1921) 43: 660. Cy O O

HOC C 10

8. SONH2

O

CC 13 b ( O CICH2OC C c 15

O f / \ NHCH O N1 °CH, CHO C O SONH2 520

c Preparation of (2S,3S.5R)-4-(5-(aminosulfonyl)-4- The following conjugate compounds may be prepared, for chloro-2-(2-furanylmethyl)aminobenzoyloxym example, by the same general method: ethyl)-2-(3,5-difluorophenyl)-3,5-dimethyl-2-mor 50 (2S,3S)-4-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm pholinol (520) ethyl)aminobenzoyloxymethyl)-2-(3 chlorophenyl)-3.5, 5-trimethyl-2-morpholinol: A solution of free base of (2S,3S.5R)-2-(3,5-difluorophe (2S,3S.5R)-4-(1-(5-(aminosulfonyl)-4-chloro-2-(2-furanyl nyl)-3,5-dimethyl-2-morpholinol (20a) (0.023 mole) (U.S. 55 methyl)aminobenzoyloxy)-(R.S)-ethyl)-2-(3,5-difluo Pat. No. 5,104,870), triethylamine (0.055 mole) and acetoni rophenyl)-3,5-dimethyl-2-morpholinol; and trile (30 mL) is stirred with cooling on an ice bath. A solution (2S,3S)-4-(1-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm of chloromethyl 5-(aminosulfonyl)-4-chloro-2-(2-furanyl ethyl)aminobenzoyloxy)-(R.S)-ethyl)-2-(3-chlorophe methyl)aminobenzoate (15) (0.025 mole) in acetonitrile (30 nyl)-3, 5,5-trimethyl-2-morpholinol. mL) is added dropwise. After the addition is complete, the 60 Prophetic Example 6 reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin evaporation, and the residue Scheme E depicts a synthesis of a therapeutic amine-aryl partitioned between dichloromethane and 5% aqueous Sulfonamide conjugate compound wherein the linker (W) is Sodium bicarbonate. The organic layer is washed with water, —CHROC(O)R'O—; where R is H; R is —(CH), ; and and then with a saturated sodium chloride solution. The 65 where n is 3. organic layer is dried over Sodium Sulfate, filtered and con centrated in vacuo to give crude product, which may be puri Preparation of (2S,3S.5R)-4-4-(5-(aminosulfonyl)- US 7,763,612 B2 37 38 4-chloro-2-(2-furanylmethyl)aminobenzoyloxy) ethyl acetate as eluent. The fractions that contain pure product butanoyloxymethyl-2-(3,5-difluorophenyl)-3,5-dim may be combined and spin evaporated in vacuo to give chlo ethyl-2-morpholinol (620) romethyl 4-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm ethyl)aminobenzoyloxy)butanoate (315). See eg. Bodor, et a Preparation of 4-(5-(aminosulfonyl)-4-chloro-2- 5 al., J. Med. Chem., 23, 469 (1980), and Ulich, et al., J. Am. (2-furanylmethyl)aminobenzoyloxy)butanoyl chlo Chem. Soc., (1921) 43: 660. ride (313) c Preparation of (2S,3S.5R)-4-4-(5-(aminosulfo A solution of oxalyl chloride (0.040 mole) in dichlo nyl)-4-chloro-2-(2-furanylmethyl)aminobenzoy romethane (20 mL) is added dropwise to an ice bath cooled 10 loxy)butanoyloxymethyl-2-(3,5-difluorophenyl)-3, solution of 4-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm 5-dimethyl-2-morpholinol (620) ethyl)aminobenzoyloxy)butanoic acid (300) (0.040 mole) in dichloromethane (50 mL). The reaction is stirred at ambient A solution of the free base of (2S,3S.5R)-2-(3,5-difluo temperature for 5 hours. The reaction solution is washed with rophenyl)-3,5-dimethyl-2-morpholinol (20a (0.023 mole) 5% aqueous sodium bicarbonate, with water, and then with a 15 (U.S. Pat. No. 5,104,870), triethylamine (0.025 mole) and saturated sodium chloride Solution. The organic layer is dried acetonitrile (30 mL) is stirred with cooling on an ice bath. A over sodium sulfate, filtered and concentrated in vacuo to give solution of chloromethyl 4-(5-(aminosulfonyl)-4-chloro-2- 4-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl)amino (2-furanylmethyl)aminobenzoyloxy)butanoate (315) benzoyloxy)butanoyl chloride (313). See eg., D. L. Musso, et. (0.025 mole) in acetonitrile (30 mL) is added dropwise. After al., J. Med. Chem. (2003) 46: 409. the addition is complete, the reaction is heated to reflux for 2 hours. The reaction is cooled, the volatiles removed by spin b Preparation of chloromethyl 4-(5-(aminosulfonyl)- evaporation, and the residue partitioned between dichlo 4-chloro-2-(2-furanylmethyl)aminobenzoyloxy) romethane and 5% aqueous sodium bicarbonate. The organic butanoate (315) layer is washed with water, and then with a saturated sodium 25 chloride solution. The organic layer is dried over sodium A mixture of 4-(5-(aminosulfonyl)-4-chloro-2-(2-fura Sulfate, filtered and concentrated in vacuo to give crude prod nylmethyl)aminobenzoyloxy)butanoyl chloride (313) uct, which may be purified by column chromatography on (0.040 mole) and paraformaldehyde (0.040 mole) is heated in silica gel with hexanes/ethyl acetate as eluent. The fractions a sealed vessel at 90° C. for 3 hours. The reaction is cooled, that contain pure product may be combined and spin evapo and the solids dissolved in dichloromethane. The solution is 30 rated in vacuo to give a solid that may be recrystallized to give washed with 5% aqueous sodium bicarbonate, with water, (2S,3S.5R)-4-4-(5-(aminosulfonyl)-4-chloro-2-(2-furanyl and then with a saturated sodium chloride solution. The methyl)aminobenzoyloxy)butanoyloxymethyl-2-(3,5-dif organic layer is dried over Sodium Sulfate, filtered and con luorophenyl)-3,5-dimethyl-2-morpholinol (620). See eg. centrated in vacuo to give crude product, which may be puri U.S. Pat. No. 5,104,870 and Sandler, et al., Organic Func fied by column chromatography on silica gel with hexanes/ tional Group Preparations, p. 324 (1968).

O O O

HOCCH2CH2CH2OC C

8. ( 300 O SONH2 I CICCH?VVVV b ( 313 O II CICHOCCHVVVVVV 315 US 7,763,612 B2 39 40

-continued

'''OH

''',CH CHOCCH2CH2CH2OC C O O SONH2 620

The following conjugate compounds may be prepared, for paraformaldehyde (0.040 mole) is heated in a sealed vessel at example, by the same general method: 90° C. for 3 hours. The reaction is cooled, and the solids (2S,3S.5R)-4-1-(4-(5-(aminosulfonyl)-4-chloro-2-(2-fura dissolved in dichloromethane. The solution is washed with nylmethyl)aminobenzoyloxy)butanoyloxy)-(R.S)-ethyl 5% aqueous sodium bicarbonate, with water, and then with a 2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol: saturated Sodium chloride solution. The organic layer is dried (2S,3S)-4-1-(4-(5-(aminosulfonyl)-4-chloro-2-(2-furanyl over sodium sulfate, filtered and concentrated in vacuo to give methyl)aminobenzoyloxy)butanoyloxy)-(R.S)-ethyl-2- 25 crude product, which may be purified by column chromatog (3-chlorophenyl)-3.5.5-trimethyl-2-morpholinol; and 2-(1-(4-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) raphy on silica gel with hexanes/ethyl acetate as eluent. The aminobenzoyloxy)butanoyloxy)-(R.S)-ethyl)(1,1-dim fractions that contain pure product may be combined and spin ethylethyl)amino-1-(3-chlorophenyl)-1-propanone. evaporated in vacuo to give chloromethyl 5-(aminosulfonyl)- 30 4-chloro-2-(2-furanylmethyl)aminobenzoate (15). See eg. Prophetic Example 7 Bodor, et al., J. Med. Chem., 23, 469 (1980), and Ulich, et al., J. Am. Chem. Soc., (1921) 43: 660. Scheme F depicts a synthesis of a therapeutic amine-aryl Sulfonamide conjugate compound wherein the linker (W) is c Preparation of 2-(5-(aminosulfonyl)-4-chloro-2- —CHO—. 35 (2-furanylmethyl)aminobenzoyloxymethyl)(1,1- dimethylethyl)amino-1-(3-chlorophenyl)-1-pro Preparation of 2-(5-(aminosulfonyl)-4-chloro-2-(2- panone (720) furanylmethyl)aminobenzoyloxymethyl)(1,1-dim ethylethyl)amino-1-(3-chlorophenyl)-1-propanone A solution of bupropion1-(3-chlorophenyl)-2-(1,1-dim (720) 40 ethylethyl)amino-1-propanone hydrochloride (700), (U.S. a Preparation of 5-(aminosulfonyl)-4-chloro-2-(2- Pat. No. 3,819,706 and U.S. Pat. No. 3,885,046) (0.025 furanylmethyl)aminobenzoyl chloride (13) mole), triethylamine (0.055 mole) and acetonitrile (30 mL) is stirred with cooling on an ice bath. A solution of chloromethyl A solution of oxalyl chloride (0.040 mole) in dichlo 45 5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl)amino romethane (20 mL) is added dropwise to an ice bath cooled benzoate (15) (0.025 mole) in acetonitrile (30 mL) is added solution of furosemide (5-(aminosulfonyl)-4-chloro-2-(2- dropwise. After the addition is complete, the reaction is furanylmethyl)aminobenzoic acid), (10) (Aldrich) (0.040 heated to reflux for 2 hours. The reaction is cooled, the vola mole) in dichloromethane (50 mL). The reaction is stirred at tiles removed by spin evaporation, and the residue partitioned ambient temperature for 5 hours. The reaction solution is 50 between dichloromethane and 5% aqueous sodium bicarbon washed with 5% aqueous sodium bicarbonate, with water, ate. The organic layer is washed with water, and then with a and then with a saturated sodium chloride solution. The saturated Sodium chloride solution. The organic layer is dried organic layer is dried over Sodium Sulfate, filtered and con over sodium sulfate, filtered and concentrated in vacuo to give centrated in vacuo to give 5-(aminosulfonyl)-4-chloro-2-(2- crude product, which may be purified by column chromatog furanylmethyl)aminobenzoyl chloride (13). See eg., D. L. 55 raphy on silica gel with hexanes/ethyl acetate as eluent. The Musso, et. al., J. Med. Chem., (2003) 46: 409. fractions that contain pure product may be combined and spin evaporated in vacuo to give a solid that may be recrystallized b Preparation of chloromethyl 5-(aminosulfonyl)-4- to give 2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) chloro-2-(2-furanylmethyl)aminobenzoate (15) aminobenzoyloxymethyl)(1,1-dimethylethyl)amino-1-(3- 60 chlorophenyl)-1-propanone (720). See eg., U.S. Pat. No. A mixture of 5-(aminosulfonyl)-4-chloro-2-(2-furanylm 5,104.870 and Sandler, et al., Organic Functional Group ethyl)aminobenzoyl chloride (13) (0.040 mole) and Preparations, p. 324 (1968). US 7,763,612 B2 41 42 Cy NHCH O

HOC C 10

C 8. SONH2 citch, O NH oHCI (CH3)3C CC -(, 13 700 t( O CICH2OC C c 15 C ( y NHCH CCHCH 2 O

-Choc C (CH3)3C SONH2 720

The following conjugate compounds may be prepared, for 35 sodium chloride solution. The organic layer is dried over example, by the same general method: Sodium sulfate, filtered and concentrated in vacuo to give (2S,3S)-4-5-(aminosulfonyl)-4-chloro-2-(2-furanylm crude product, which may be purified by column chromatog ethyl)aminobenzoyloxymethyl-2-(3-chlorophenyl)-3.5, raphy on silica gel with hexanes/ethyl acetate as eluent. The 5-trimethyl-2-morpholinol; and fractions that contain pure product may be combined and spin (2S,3S.5R)-4-5-(aminosulfonyl)-4-chloro-2-(2-furanylm 40 evaporated in vacuo to give 3-(5-(aminosulfonyl)-4-chloro ethyl)aminobenzoyloxymethyl-2-(3,5-difluorophenyl)- 2-(2-furanylmethyl)aminobenzoyloxy)propanol (805). See 3,5-dimethyl-2-morpholinol. eg., T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, p. 228 (1991). Prophetic Example 8 45 b Preparation of 4-(3-(5-(aminosulfonyl)-4-chloro-2- (2-furanylmethyl)aminobenzoyloxy)propoxy)(4- Scheme G depicts a synthesis of a therapeutic amine-aryl Sulfonamide conjugate compound where the linker (W) is oxo)butanoic acid (810) —C(O)R'O , where R' is —(CH),C(O)O(CH), ; and A mixture of 3-(5-(aminosulfonyl)-4-chloro-2-(2-fura where n is 2 and 3, respectively. 50 nylmethyl)aminobenzoyloxy)propanol (805) (0.060 mole), succinic anhydride (Aldrich) (0.060 mole), DBN (1.5-diaz Preparation of 2-(1-(3,5-difluorobenzoyl)-(R.S)- abicyclo4.3.0non-5-ene.(Aldrich) (0.060 mole) and dry ethylamino)-(R)-2-methylethyl 4-(3-(5-(aminosulfo acetonitrile (50 mL) is stirred at ambient temperature for 10 nyl)-4-chloro-2-(2-furanylmethyl)aminobenzoy hours. The reaction mixture is diluted with dichloromethane loxy)propoxy)(4-oxo)butanoate (820) 55 (200 mL) and extracted with 0.1 Nhydrochloric acid solution, washed with water, and then with a saturated sodium chloride a Preparation of 3-(5-(aminosulfonyl)-4-chloro-2- Solution. The organic layer is dried over Sodium sulfate, fil (2-furanylmethyl)aminobenzoyloxy)propanol (805) tered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with A mixture of furosemide (5-(aminosulfonyl)-4-chloro-2- 60 hexanes/ethyl acetate as eluent. The fractions that contain (2-furanylmethyl)aminobenzoic acid), (10) (Aldrich) pure product may be combined and spin evaporated in vacuo (0.060 mole), 3-bromo-1-propanol (Aldrich) (0.055 mole), to give to give 4-(3-(5-(aminosulfonyl)-4-chloro-2-(2-fura DBN (1,5-diazabicyclo[4.3.0non-5-ene, (Aldrich) (0.060 nylmethyl)aminobenzoyloxy)propoxy)(4-oxo)butanoic mole) and dry acetonitrile (100 mL) is stirred at ambient acid (810). temperature for 10 hours. The reaction mixture is diluted with 65 dichloromethane (200 mL) and extracted with sodium bicar c Preparation 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethy bonate solution, washed with water, and then with a saturated lamino)-(R)-2-methylethyl 4-(3-(5-(aminosulfonyl)- US 7,763,612 B2 43 44 4-chloro-2-(2-furanylmethyl)aminobenzoyloxy) The following conjugate compound may be prepared by propoxy)(4-oxo)butanoate (820) the same general method: 2-(1-(3-chlorobenzoyl)-(R.S)-ethylamino)-2,2-dimethyl ethyl 4-(3-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm ethyl)aminobenzoyloxy)propoxy)(4-oxo)butanoate.

NHCH O O

HOC C 10

/ SONH2 tongue (, 805

O b/ O O policiencin'-(, 810

CCHCH / \ NHCH YO Nich CHOCCH2CH2CH2COCH2CH2CH2OC C O O O SONH2 820

The free base of (2S,3S.5R)-2-(3,5-difluorophenyl)-3,5- Prophetic Example 9 dimethyl-2-morpholinol (20a) (0.023 mole) (U.S. Pat. No. 45 5,104,870) and benzene (30 mL) (or toluene) is added to a Scheme H depicts a synthesis of another therapeutic round-bottomed flask. 4-(3-(5-(aminosulfonyl)-4-chloro-2- amine-arylsulfonamide conjugate compound as in Example (2-furanylmethyl)aminobenzoyloxy)propoxy)(4-oxo)bu 8, where the linker (W) is CHOC(O)RO , R is tanoic acid (810) (0.025 mole), benzene (30 mL), and p-tolu —(CH),C(O)C(CH), ; where n is 2 and 3, respectively. 50 enesulfonic acid (0.026 mole) catalyst is added to the flask. A Preparation of 2-(4-(3-(5-(aminosulfonyl)-4-chloro Dean-Stark trap is filled with benzene, and the contents of the 2-(2-furanylmethyl)aminobenzoyloxy)propoxy)(4- flask is refluxed with stirring for several hours or until no oxo)butanoyloxymethyl)(1,1-dimethylethyl)amino additional water is collected in the trap. The reaction is 1-(3-chlorophenyl)-1-propanone (920) cooled, extracted with sodium bicarbonate solution, washed 55 with water, and then with a saturated sodium chloride solu a Preparation of 4-(3-(5-(aminosulfonyl)-4-chloro-2- tion. The organic layer is dried over sodium sulfate, filtered (2-furanylmethyl)aminobenzoyloxy)propoxy)(4- and concentrated in vacuo to give crude product, which may oxo)butanoyl chloride (813) be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain 60 A solution of oxalyl chloride (0.040 mole) in dichlo pure product may be combined and spin evaporated in vacuo romethane (20 mL) is added dropwise to an ice bath cooled to give a solid that may be recrystallized to give 2-(1-(3.5- solution of 4-(3-(5-(aminosulfonyl)-4-chloro-2-(2-furanyl difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-methylethyl methyl)aminobenzoyloxy)propoxy)(4-oxo)butanoic acid 4-(3-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) (810) (0.040 mole) in dichloromethane (50 mL). The reaction aminobenzoyloxy)propoxy)(4-oxo)butanoate (820). See eg. 65 is stirred at ambient temperature for 5 hours. The reaction Sandler, et al., Organic Functional Group Preparations, p. 249 solution is washed with 5% aqueous sodium bicarbonate, (1968). with water, and then with a saturated sodium chloride solu US 7,763,612 B2 45 46 tion. The organic layer is dried over sodium sulfate, filtered amino-1-(3-chlorophenyl)-1-propanone (920) and concentrated in vacuo to provide 4-(3-(5-(aminosulfo nyl)-4-chloro-2-(2-furanylmethyl)aminobenzoyloxy)pro A solution of bupropion1-(3-chlorophenyl)-2-(1,1-dim poxy)(4-oxo)butanoyl chloride (813). See eg., D. L. Musso, ethylethyl)amino-1-propanone hydrochloride (700), (U.S. et. al., J. Med. Chem., (2003) 46: 409. Pat. No. 3,819,706 and U.S. Pat. No. 3,885,046) (0.025 mole), triethylamine (0.055 mole) and acetonitrile (30 mL) is b Preparation of chloromethyl 4-(3-(5-(aminosulfo stirred with cooling on an ice bath. A solution of chloromethyl nyl)-4-chloro-2-(2-furanylmethyl)aminobenzoy 4-(3-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) loxy)propoxy)(4-oxo)butanoate (815) 10 aminobenzoyloxy)propoxy)(4-oxo)butanoate (0.025 mole) in acetonitrile (30 mL) is added dropwise. After the addition A mixture of 4-(3-(5-(aminosulfonyl)-4-chloro-2-(2- is complete, the reaction is heated to reflux for 2 hours. The furanylmethyl)aminobenzoyloxy)propoxy)(4-oxo)butanoyl reaction is cooled, the Volatiles removed by spin evaporation, chloride (813) (0.040 mole) and paraformaldehyde (0.040 and the residue partitioned between dichloromethane and 5% mole) is heated in a sealed vessel at 90° C. for 3 hours. The 15 aqueous sodium bicarbonate. The organic layer is washed reaction is cooled, and the solids are dissolved in dichlo romethane. The solution is washed with 5% aqueous sodium with water, and then with a saturated sodium chloride solu bicarbonate, with water, and then with a saturated sodium tion. The organic layer is dried over sodium sulfate, filtered chloride solution. The organic layer is dried over sodium and concentrated in vacuo to give crude product, which may Sulfate, filtered and concentrated in vacuo to give crude prod be purified by column chromatography on silica gel with uct, which may be purified by column chromatography on hexanes/ethyl acetate as eluent. The fractions that contain silica gel with hexanes/ethyl acetate as eluent. The fractions pure product may be combined and spin evaporated in vacuo that contain pure product may be combined and spin evapo to give a solid that may be recrystallized to give 2-(4-(3-(5- rated in vacuo to give chloromethyl 4-(3-(5-(aminosulfonyl)- (aminosulfonyl)-4-chloro-2-(2-furanylmethyl)aminoben 4-chloro-2-(2-furanylmethyl)aminobenzoyloxy)propoxy) Zoyloxy)propoxy)(4-oxo)butanoyloxymethyl)(1,1-dimeth (4-oxo)butanoate (815). See eg. Bodor, et al., J. Med. Chem., 25 ylethyl)amino-1-(3-chlorophenyl)-1-propanone (920). See 23, 469 (1980), and Ulich, et al., J. Am. Chem. Soc., (1921) eg., U.S. Pat. No. 5,104,870 and Sandler, et al., Organic 43: 660. Functional Group Preparations, p. 324 (1968).

NHCH O C O HOCCH2CH2COCH2CH2CH2OC C CCHCH O O O NH 810 SONH (CH3)3C 1 * , HCI 8. ( 21y 12 700 O| Cl-CCHCHM 813 b (

CICH2OCCH2CH2 VVV C 815

C O W \ st| NHCH YO - NCHOCH2CH2COCH2CH2CH2O C (CH3)3C O O O SONH2 920

c Preparation of 2-(4-(3-(5-(aminosulfonyl)-4- 65 chloro-2-(2-furanylmethyl)aminobenzoyloxy)pro poxy)(4-oxo)butanoyloxymethyl)(1,1-dimethylethyl) US 7,763,612 B2 47 48 Prophetic Example 10 chloro-2-(2-furanylmethyl)aminobenzoyloxymethyl) S-ethyl carbonothioate (1005) (0.050 mole) in dichlo Scheme I depicts a synthesis of a therapeutic amine-aryl romethane (25 mL) at 0-5°C. with stirring during 15 minutes Sulfonamide conjugate compound having carbamate func followed by stirring at ambient temperature for 45 minutes. tionality, wherein the linker (W) is C(O)OCHRO , where 5 The volatiles are removed by evaporation at ambient tempera R is H; and the therapeutic amine radical is coupled to the ture and then at 20 millibar for 16 hours. The crude product is linker by a nitrogen atom. dissolved in ethyl acetate and applied to a column of silica gel. The column may be eluted with hexanes/ethyl acetate, and the Preparation of 2-(5-(aminosulfonyl)-4-chloro-2-(2- fractions that contain pure product may be combined and spin furanylmethyl)aminobenzoyloxymethoxycarbonyl) 10 evaporated in vacuo to give 5-(aminosulfonyl)-4-chloro-2- (1,1-dimethylethyl)amino-1-(3-chlorophenyl)-1- (2-furanylmethyl)aminobenzoyloxymethyl carbonochlori propanone (1020) date (1010). See eg. Folkmann, et al., Synthesis, 1159 (1990), Method G. a Preparation of O-(5-(aminosulfonyl)-4-chloro-2- (2-furanylmethyl)aminobenzoyloxymethyl) S-ethyl 15 c Preparation of 2-(5-(aminosulfonyl)-4-chloro-2- carbonothioate (1005) (2-furanylmethyl)aminobenzoyloxymethoxycarbo nyl)(1,1-dimethylethyl)amino-1-(3-chlorophenyl)-1- Furosemide (5-(aminosulfonyl)-4-chloro-2-(2-furanylm propanone (1020) ethyl)aminobenzoic acid), (10) (Aldrich) (0.050 mole) is added to a stirred solution of sodium bicarbonate (0.100 A solution of bupropion1-(3-chlorophenyl)-2-(1,1-dim mole) and tetrabutylammonium hydrogen sulfate (0.050 ethylethyl)amino-1-propanone hydrochloride (700), (U.S. mole) in water (100 mL) at ambient temperature. After 10 Pat. Nos. 3,819,706 and 3,885,046) (0.025 mole), triethy minutes 1,2-dichloroethane (100 mL) is added and then after lamine (0.055 mole) and acetonitrile (30 mL) is stirred with 30 minutes O-iodomethyl S-ethyl carbonothioate (0.050 cooling on an ice bath. A solution of 5-(aminosulfonyl)-4- mole) in 1,2-dichloroethane (25 mL) is added over 15 min 25 chloro-2-(2-furanylmethyl)aminobenzoyloxymethyl car utes. The mixture is stirred for 1 hour at ambient temperature. bonochloridate (1010) (0.025 mole) in acetonitrile (30 mL) is The organic layer is separated, washed with water (50 mL), added dropwise. After the addition is complete, the reaction is dried (magnesium sulfate), and the solvent is evaporated. The heated to reflux for 2 hours. The reaction is cooled, the vola residue is stirred with diethyl ether (100 mL), insoluble mate tiles removed by spin evaporation, and the residue partitioned rial is filtered off and washed with diethyl ether. The com 30 between dichloromethane and 5% aqueous sodium bicarbon bined ether phases is evaporated, and the residue may be ate. The organic layer is washed with water, and then with a crystallized to give O-(5-(aminosulfonyl)-4-chloro-2-(2- saturated Sodium chloride solution. The organic layer is dried furanylmethyl)aminobenzoyloxymethyl) S-ethyl carbono over sodium sulfate, filtered and concentrated in vacuo to give thioate (1005). See eg. Folkmann, et al., Synthesis, 1159 crude product, which may be purified by column chromatog (1990), Method D. 35 raphy on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin b Preparation of 5-(aminosulfonyl)-4-chloro-2-(2- evaporated in vacuo to give a solid that may be recrystallized furanylmethyl)aminobenzoyloxymethyl carbon to give 2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) ochloridate (1010) aminobenzoyloxymethoxycarbonyl)(1,1-dimethylethyl) 40 amino-1-(3-chlorophenyl)-1-propanone (1020). See eg. Freshly distilled sulfuryl chloride (0.050 mole) in dichlo U.S. Pat. No. 5,104,870 and Sandler, et al., Organic Func romethane (25 mL) is added to O-(5-(aminosulfonyl)-4- tional Group Preparations, p. 324 (1968). US 7,763,612 B2 49 50

NHCH O O

HOC C O C 10 O CHCHSCOCHI / SONH citch, O O 0 | NH HC CHCHSCOCHOC (CH3)3C 1005 700 b O O CICOCH2OC | c 1010

C C ( y NHCH CCHCH 2 O

(CH3)3C N-ochocl C SONH2 102O

The following conjugate compounds may be prepared, for and then with a saturated sodium chloride solution. The example, by the same general method: organic layer is dried over Sodium Sulfate, filtered and con (2S,3S)-4-5-(aminosulfonyl)-4-chloro-2-(2-furanylm centrated in vacuo to give 5-(aminosulfonyl)-4-chloro-2-(2- ethyl)aminobenzoyloxymethoxycarbonyl-2-(3-chlo 40 furanylmethyl)aminobenzoyl chloride (13). See D. L. rophenyl)-3.5.5-trimethyl-2-morpholinol; and Musso, et. al., J. Med. Chem. (2003) 46: 409. (2S,3S.5R)-4-5-(aminosulfonyl)-4-chloro-2-(2-furanylm ethyl)aminobenzoyloxymethoxycarbonyl-2-(3,5-difluo b Preparation of chloromethyl 5-(aminosulfonyl)-4- rophenyl)-3,5-dimethyl-2-morpholinol. chloro-2-(2-furanylmethyl)aminobenzoate (15) 45 Prophetic Example 11 A mixture of 5-(aminosulfonyl)-4-chloro-2-(2-furanylm ethyl)aminobenzoyl chloride (13) (0.040 mole) and Preparation of (5-(aminosulfonyl)-4-chloro-2-(2- paraformaldehyde (0.040 mole) is heated in a sealed vessel at furanylmethyl)aminobenzoyloxymethyl)(10.11 90° C. for 3 hours. The reaction is cooled, and the solids is dissolved in dichloromethane. The solution is washed with dihydro-5H-dibenzb.fazepine-5-propyl)dimethy 50 5% aqueous sodium bicarbonate, with water, and then with a lammonium chloride (1120) saturated Sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give Scheme J depicts a synthesis of a therapeutic amine-aryl crude product, which may be purified by column chromatog Sulfonamide conjugate compound wherein the linker (W) is raphy on silica gel with hexanes/ethyl acetate as eluent. The —CH2O—, and where the conjugate compound formed 55 fractions that contain pure product may be combined and spin would be a quaternary ammonium salt. evaporated in vacuo to give chloromethyl 5-(aminosulfonyl)- a Preparation of 5-(aminosulfonyl)-4-chloro-2-(2- 4-chloro-2-(2-furanylmethyl)aminobenzoate (15). See furanylmethyl)aminobenzoyl chloride (13) Bodor, et al., J. Med. Chem., 23, 469 (1980), and Ulich, et al., 60 J. Am. Chem. Soc., (1921) 43: 660. A solution of oxalyl chloride (0.040 mole) in dichlo c Preparation of (5-(aminosulfonyl)-4-chloro-2-(2- romethane (20 mL) is added dropwise to an ice bath cooled furanylmethyl)aminobenzoyloxymethyl)(10,11 solution of furosemide (5-(aminosulfonyl)-4-chloro-2-(2- dihydro-5H-dibenzb.fazepine-5-propyl)dimethy furanylmethyl)aminobenzoic acid), (10) (Aldrich) (0.040 lammonium chloride (1120) mole) in dichloromethane (50 mL). The reaction is stirred at 65 ambient temperature for 5 hours. The reaction solution is A mixture of imipramine(10,11-dihydro-N,N-dimethyl washed with 5% aqueous sodium bicarbonate, with water, 5H-dibenzb.fazepine-5-propanamine), (1100)(Aldrich) US 7,763,612 B2 51 52 (0.023 mole) and acetonitrile (30 mL) is stirred with cooling semide (10) (5-(aminosulfonyl)-4-chloro-2-(2-furanylm on an ice bath. A solution of chloromethyl 5-(aminosulfonyl)- ethyl)aminobenzoic acid, Aldrich) (0.025 mole), benzene 4-chloro-2-(2-furanylmethyl)aminobenzoate (15) (0.023 (30 mL), and p-toluenesulfonic acid (0.001 mole) catalyst are mole) in acetonitrile (30 mL) is added dropwise. After the added to the flask. A Dean-Stark trap is filled with benzene, addition is complete, the reaction is heated to reflux for 2 and the contents of the flask are refluxed with stirring for hours. The reaction is cooled, anhydrous ether (120 mL) is several hours or until no additional water is collected in the added, and the mixture is stirred for 10 hours. The solid is trap. The reaction is cooled, extracted with sodium bicarbon collected by suction filtration and washed with anhydrous ate Solution, washed with water, and then with a saturated ether. The solid is dried in vacuo to give (5-(aminosulfonyl)- Sodium chloride Solution. The organic layer may be dried 4-chloro-2-(2-furanylmethyl)aminobenzoyloxymethyl) over sodium sulfate, filtered and concentrated in vacuo to give (10,11-dihydro-5H-dibenzb.fazepine-5-propyl)dimethy 2.2.2-trichloroethyl 5-(aminosulfonyl)-4-chloro-2-(2-fura lammonium chloride (1120). U.S. Pat. No. 5,104,870 and nylmethyl)aminobenzoate. See Sandler et al., Organic Bodor, et al., J. Med. Chem., (1980) 23: 469. Functional Group Preparations, (1968) p. 249. Cy NHCH

O C 10

8. OJO ( SONH2 (CH2)N(CH3)2CH)N(CH CC 1100 13

t( O CICHOC C | ( 15

N O O NHCH . City' choc C Cr 7 CH3 CH3 SONH2 1120

Prophetic Example 12 b Preparation of 6-methoxy-6-oxohexanoyl chloride 50 Scheme K depicts a synthesis of a therapeutic amine-aryl A solution of oxalyl chloride (0.040 mole) in dichlo Sulfonamide conjugate compound where the therapeutic romethane (20 mL) is added dropwise to an ice bath cooled amine is linked to the Sulfonamide group of furosemide via a solution of adipic acid monomethyl ester (Aldrich) (0.040 linker (W) that is CHROC(O)RC(O)OCHR ; where R' mole) in dichloromethane (50 mL). The reaction is stirred at is —(CH), , where n is 4; and R is H. 55 ambient temperature for 5 hours. The reaction solution is washed with 5% aqueous sodium bicarbonate, with water, Preparation of 2-(6-(5-carboxy-2-chloro-4-(2-fura and then with a saturated sodium chloride solution. The nylmethyl)aminophenylsulfonamidomethoxy) organic layer may be dried over Sodium sulfate, filtered and (6-oxo)hexanoyloxymethyl)(1,1-dimethylethyl) concentrated in vacuo to give 6-methoxy-6-oxohexanoyl amino-1-(3-chlorophenyl)-1-propanone (1220) 60 chloride. See Musso, et. al., J. Med. Chem. (2003) 46:409. a Preparation of 2.2.2-trichloroethyl 5-(aminosulfo c Preparation of chloromethyl nyl)-4-chloro-2-(2-furanylmethyl)aminobenzoate 6-methoxy-6-oxohexanoate (11) 65 A mixture of 6-methoxy-6-oxohexanoyl chloride (0.040 Benzene (30 mL) (or toluene) and 2.2.2-trichloroethanol mole) and paraformaldehyde (0.040 mole) are heated in a (0.024 mole) are added to a round-bottomed flask. Furo sealed vessel at 90 degrees for 3 hours. The reaction is cooled, US 7,763,612 B2 53 54 and the solids are dissolved in dichloromethane. The solution romethane (Aldrich) (0.060 mole) is slowly added to the is washed with 5% aqueous sodium bicarbonate, with water, solution. The reaction is stirred at ambient temperature in the and then with a saturated sodium chloride solution. The dark for 12 hours. The mixture is filtered to remove cesium organic layer is dried over Sodium Sulfate, filtered and con bromide, and the Volatiles are removed by spin evaporation in centrated in vacuo to give crude product, which is purified by vacuo. The reaction mixture is diluted with dichloromethane column chromatography on silica gel with hexanes/ethyl (200 mL) and extracted with sodium bicarbonate solution, acetate as eluent. The fractions that contain pure product may washed with water, and then with a saturated sodium chloride be combined and spin evaporated in vacuo to give chlorom Solution. The organic layer may be dried over Sodium sulfate, ethyl 6-methoxy-6-oxohexanoate. See Bodor et al., J. Med. filtered and concentrated in vacuo to give crude product, Chem., (1980) 23:469; Ulichet al., J. Am. Chem. Soc., (1921) 10 which may be purified by column chromatography on silica 43: 660. gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in d Preparation of methyl 6-(2-chloro-4-(2-furanylm vacuo to give chloromethyl 6-(2-chloro-4-(2-furanylmethyl) ethyl)amino-5-(2.2.2-trichloroethoxycarbonyl)phe amino-5-(2.2.2-trichloroethoxycarbonyl)phenylsulfonami nylsulfonamidomethoxy)(6-oxo)hexanoate 15 domethoxy)(6-oxo)hexanoate. A mixture of 2.2.2-trichloroethyl 5-(aminosulfonyl)-4- g Preparation of 2-(6-(2-chloro-4-(2-furanylm chloro-2-(2-furanylmethyl)aminobenzoate (0.060 mole), ethyl)amino-5-(2.2.2-trichloroethoxycarbonyl)phe chloromethyl 6-methoxy-6-oxohexanoate (0.060 mole), nylsulfonamidomethoxy)(6-oxo)hexanoyloxym DBN (1,5-diazabicyclo[4.3.0non-5-ene, Aldrich) (0.060 ethyl)(1,1-dimethylethyl)amino-1-(3-chlorophenyl)- mole) and dry acetonitrile (100 mL) is stirred at ambient 1-propanone temperature for 10 hours. The reaction mixture is diluted with dichloromethane (200 mL) and extracted with sodium bicar A solution of bupropion1-(3-chlorophenyl)-2-(1,1-dim bonate solution, washed with water, and then with a saturated ethylethyl)amino-1-propanone hydrochloride, (700) (U.S. sodium chloride solution. The organic layer is dried over 25 Pat. No. 3,819,706; U.S. Pat. No. 3,885,046) (0.025 mole), Sodium sulfate, filtered and concentrated in vacuo to give triethylamine (0.055 mole) and acetonitrile (30 mL) are crude product, which is purified by column chromatography stirred with cooling on an ice bath. A solution of chloromethyl on silica gel with hexanes/ethyl acetate as eluent. The frac 6-(2-chloro-4-(2-furanylmethyl)amino-5-(2.2.2-trichloro tions that contain pure product may be combined and spin ethoxycarbonyl)phenylsulfonamidomethoxy)(6-oxo)hex evaporated in vacuo to give methyl 6-(2-chloro-4-(2-fura 30 anoate (0.025 mole) in acetonitrile (30 mL) is added drop nylmethyl)amino-5-(2.2.2-trichloroethoxycarbonyl)phe wise. After the addition is complete, the reaction is heated to nylsulfonamidomethoxy)(6-oxo)hexanoate. reflux for 2 hours. The reaction is cooled, the volatiles are removed by spin evaporation, and the residue is partitioned e Preparation of 6-(2-chloro-4-(2-furanylmethyl) between dichloromethane and 5% aqueous sodium bicarbon amino-5-(2.2.2-trichloroethoxycarbonyl)phenylsul 35 ate. The organic layer is washed with water, and then with a fonamidomethoxy)(6-oxo)hexanoic acid saturated sodium chloride solution. The organic layer may be dried over sodium sulfate, filtered and concentrated in vacuo A mixture of methyl 6-(2-chloro-4-(2-furanylmethyl) to give crude product, which may be purified by column amino-5-(2.2.2-trichloroethoxycarbonyl)phenylsulfonami chromatography on silica gel with hexanes/ethyl acetate as domethoxy)(6-oxo)hexanoate (0.060 mole), sodium cyanide 40 eluent. The fractions that contain pure product may be com (0.060 mole) and hexamethylphosphoramide (Aldrich) (100 bined and spin evaporated in vacuo to give a solid that is mL) is stirred at 75° C. for 24 hours. The volatiles are recrystallized to give 2-(6-(2-chloro-4-(2-furanylmethyl) removed by spin evaporation in vacuo. The residue is dis amino-5-(2.2.2-trichloroethoxycarbonyl)phenylsulfonami solved in cold water, and the solution is washed with diethyl domethoxy)(6-oxo)hexanoyloxymethyl)(1,1-dimethylethyl) ether. The aqueous Solution is cooled in an ice bath and 45 amino-1-(3-chlorophenyl)-1-propanone. See U.S. Pat. No. acidified by dropwise addition of 1.0 N hydrochloric acid 5,104.870; Sandler et al., Organic Functional Group Prepa solution (60 mL). The resulting solid may be collected and rations, (1968) p. 324. recrystallized to give 6-(2-chloro-4-(2-furanylmethyl) amino-5-(2.2.2-trichloroethoxycarbonyl)phenylsulfonami h Preparation of 2-(6-(5-carboxy-2-chloro-4-(2- domethoxy)(6-oxo)hexanoic acid. See Greene et al., Protec 50 furanylmethyl)aminophenylsulfonamidomethoxy) tive Groups in Organic Synthesis, Second Edition, (1991) p. (6-oxo)hexanoyloxymethyl)(1,1-dimethylethyl) 232. amino-1-(3-chlorophenyl)-1-propanone (1220) f Preparation of chloromethyl 6-(2-chloro-4-(2-fura A solution of 2-(6-(2-chloro-4-(2-furanylmethyl) nylmethyl)amino-5-(2.2.2-trichloroethoxycarbonyl) 55 amino-5-(2.2.2-trichloroethoxycarbonyl)phenylsulfonami phenylsulfonamidomethoxy)(6-oxo)hexanoate domethoxy)(6-oxo)hexanoyloxymethyl)(1,1-dimethylethyl) amino-1-(3-chlorophenyl)-1-propanone (0.060 mole) in The 6-(2-chloro-4-(2-furanylmethyl)amino-5-(2.2.2- acetic acid (100 mL) is cooled in an ice water bath. Zinc dust trichloroethoxycarbonyl)phenylsulfonamidomethoxy)(6- (0.12 mole) is added in several portions with stirring, and the oxo)hexanoic acid (0.060 mole) is dispersed with stirring in a 60 reaction is stirred for 2.5 hours at 0°C. The mixture is filtered methanol-water mixture (100 mL), and an aqueous Solution to remove Zinc salts, and the Volatiles are removed by spin of cesium carbonate (2 molar) is added dropwise until the evaporation in vacuo. The residue is dissolved in cold water, solution pH is 6.6. The volatiles are removed by spin evapo and the solution is washed with diethyl ether. The aqueous ration in vacuo. The resulting cesium salt is dried by addition solution is cooled in an ice bath and acidified by dropwise of toluene and removal of the volatiles under reduced pres 65 addition of 1.0 N hydrochloric acid solution (60 mL). The sure. This is repeated several times. The dry cesium salt is resulting Solid may be collected and recrystallized to give dissolved in dimethylformamide (100 mL), and bromochlo 2-(6-(5-carboxy-2-chloro-4-(2-furanylmethyl)aminophe

US 7,763,612 B2 57 58

-continued C COH CCH Coccipicoch.Ni NHCH (CH3)3C O 7 O C le 1220

Scheme L represents a therapeutic amine radical coupled 15 followed by subsequent reaction with 2.2.2-trichloroethanol to a linker by a nitrogen atom of the arylsulfonamide via a ester of furosemide (11). The resulting product (1300) is linker (W) that is C(O)RC(O)OCHROC(O)–: where R' hydrolyzed, condensed with (21), and oxidized to provide is —(CH), , where n is 4, and R is H. Thus, (ethylthio) 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-meth carbonyloxymethyl methyl adipate (1313), prepared from 20 ylethyl 6-(5-carboxy-2-chloro-4-(2-furanylmethyl)amino 6-methoxyl-6-oxohexanoic acid (1307) and O-iodomethyl phenylsulfonamidocarbonyloxymethoxy)(6-oxo)hexanoate S-ethyl carbonothioate (see Example 10a), is converted to (1320). (chlorocarbonyl)oxymethyl methyl adipate (1317), in a manner analogus to that for compound (1010) in Scheme I.

SCHEMEL

O O M CHOCCH2CH2CH2CH2COH furosemide 1307 10

O O O O M CHOC(CH2)COCH2OCSCHCH HNS NHCH 1313 O / O | C le

11 O O O || || CH3OC(CH2)4COCH2OCC 1317 Yr US 7,763,612 B2 59 60

-continued O O O CH3OC(CH2)4COCHOCNHSO2 /

C 1300

O O O HOC(CH2)4COCHOCNHSO /

F pi C citch,

F NichCHOH N 21 N F pi CHCHCH C(O)OCHCCl3 NHCHCH, O O F \ CHOC(CH2)COCHOCNHSO NHCH 7 O C le sain in F O O Cecil, COH NetCit F CHOC(CH2)4COCHOCNHSO NHCH 7 O C le 1320

Experimental Example 13 55 Preparation of (2S,3S.5R)-4-5-(aminosulfonyl)-4- chloro-2-(2-furanylmethyl)aminobenzoy General: Solvents and reagents were purchased from loxymethoxycarbonyl-2-(3,5-difluorophenyl)-3,5- Sigma-Aldrich (St. Louis, Mo.) and were used as received. dimethyl-2-morpholinol (1420) Nuclear Magnetic Resonance (NMR) data was acquired on a 60 Varian 400 and/or Varian 500 mHz spectrometer. LC/MS data Preparation of (2S,3S.5R)-2-(3,5-difluorophenyl)-2- was acquired using a Thermo-Finnegin Surveyor HPLC hydroxy-3,5-dimethylmorpholine-4-carboxylic acid equipped with a Phenomenex C18 column connected to an chloromethyl ester (1410) AQA mass spectrometer. Scheme M is a synthesis of a therapeutic amine-arylsul- 65 To a stirring solution of (2S,3S.5R)-2-(3,5-difluorophe fonamide conjugate compound wherein the linker (W) is nyl)-2-hydroxy-3,5-dimethylmorpholine (2.5 g. 10.28 —C(O)OCHRO-; where R is hydrogen. mmol) in dichloromethane (50 mL) at room temperature US 7,763,612 B2 61 under nitrogen, was added potassium carbonate (1.42 gm,

10.28 mmol). The mixture was cooled to 5°C. with a wet ice -continued bath, and chloromethyl chloroformate (0.915 mL, 10.28 mmol) in dichloromethane (10 mL) was added dropwise. The mixture was allowed to warn to room temperature slowly and O O HN O stirred over night. TLC analysis (1:1 heptane:ethyl acetate) indicated that the starting material was consumed and a new ---, less polar spot had formed. Water was added to the mixture O ~ '' '. C and then it was extracted with dichloromethane (3x). The 10 organic layers were combined and dried over magnesium H2NetS2so sulfate, filtered and the solvent was removed to afford a crude weight of 2.8 grams of (2S,3S.5R)-2-(3,5-difluorophenyl)-2- 1420 hydroxy-3,5-dimethylmorpholine-4-carboxylic acid chlo romethyl ester (1410) as an opaque tar. 15 Preparation of (2S,3S.5R)-4-5-(aminosulfonyl)-4- 'HNMR (400 MHz, CDC1,) & 1.27-129 (d,3H), 1.47-1.49 chloro-2-(2-furanylmethyl)aminobenzoy (d. 3H), 3.79-3.90 (m, 2H), 4.10-4.16 (m. 1H), 4.55-4.60 (m, loxymethoxycarbonyl-2-(3,5-difluorophenyl)-3,5- 1H), 5.64-5.65 (d. 1H), 5.77-5.78 (d. 1H), 6.73-6.77 (m, 1H), dimethyl-2-morpholinol (1420) 7.02-7.04 (d. 2H). Compound (1410) was used without puri fication. To a stirring solution of (2S,3S.5R)-2-(3,5-difluorophe nyl)-2-hydroxy-3,5-dimethylmorpholine-4-carboxylic acid Preparation of the cesium salt of furosemide (cesium chloromethyl ester (1410) (2.24 g. 6.67 mmol) in 150 mL of 5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) anhydrous tetrahydrofuran was added the furosemide cesium aminobenzoate) (10c) 25 salt (10c) (3.09 gm, 6.67 mmol) and sodium iodide (1.10 gm, 7.34 mmol). The mixture was heated to ~60° C. and moni Furosemide (10) (5-(aminosulfonyl)-4-chloro-2-(2-fura tored by TLC (1:1 heptane:ethyl acetate). After heating for 6 hours, TLC analysis indicated a slowing down of product nylmethyl)aminobenzoic acid, Aldrich) (4.0 g, 12.1 mmol) formation with starting materials remaining. The reaction was added to dioxane (100 mL), and water (50 mL) was added 30 was halted so as not to allow by-product formation. The with stirring to give a solution. Cesium carbonate (1.97 g. 6.0 solvent was removed from the crude yellow mixture, and it mmol) was added, and the clear solution was stirred for 1 was dried onto silica gel. This crude material was purified on hour. The solvent was removed by spin evaporation, and the an Optix Companion Automated Chromatography system Solid was dried overnight on a vacuum pump to afford 5.31 g using an 80gm silica cartridge and eluting with ethyl acetate/ of cesium 5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) 35 heptane (0 to 70% over 50 minutes). This material was dried on a vacuum pump for 24 hours and afforded 0.560 g of aminobenzoate as a white solid. (2S,3S.5R)-4-5-(aminosulfonyl)-4-chloro-2-(2-furanylm ethyl)aminobenzoyloxymethoxycarbonyl-2-(3,5-difluo rophenyl)-3,5-dimethyl-2-morpholinol (1420) as a light yel 40 low foamy solid. Melting point range was 105°C. to 110°C. Elemental analysis calculated for ICHN 0.3 EtOAc): C, 49.76; H, 4.36: N, 6.4. found C, 50.08; H, 4.65; N, 6.23. H NMR (400 MHz, CDC1) & 0.86-0.89 (t, 3H), 1.34 (m, 3H), 3.60-3.67 (m. 1H), 4.23 (m. 1H), 4.33 (m. 1H), 4.45-4.46 (d. 45 2H), 4.47 (s, 1H), 5.07-5.11 (d. 2H), 6.00-6.05 (dd, 2H), 6.28 (s, 1H), 6.35 (s, 1H), 6.75-6.79 (t, 1H), 6.89 (m. 1H), 7.12 7.14 (br. d, 2H), 737-7.39 (d. 1H), 8.53 (br. d. 1H), 8.63 (s, 1H). The following conjugate compounds may be prepared, for 50 example, by the same general method as described above in Example 13 and depicted in Scheme M: (2S,3S.5R)-4-2-(5-(aminosulfonyl)-4-chloro-2-(2-furanyl methyl)aminobenzoyloxy)ethanoyloxymethoxycarbo nyl-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol: 55 (2S,3S.5R)-4-2-(5-(aminosulfonyl)-4-chloro-2-(2-furanyl CSO methyl)aminobenzoyloxy)propanoyloxymethoxycarbo nyl-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol: C (2S,3S.5R)-4-3-(5-(aminosulfonyl)-4-chloro-2-(2-furanyl methyl)aminobenzoyloxy)propanoyloxymethoxycarbo 60 nyl-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol: (2S,3S.5R)-4-2-(5-(aminosulfonyl)-4-chloro-2-(2-furanyl methyl)aminobenzoyloxy)butanoyloxymethoxycarbo nyl-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol: 65 (2S,3S.5R)-4-3-(5-(aminosulfonyl)-4-chloro-2-(2-furanyl methyl)aminobenzoyloxy)butanoyloxymethoxycarbo nyl-2-(3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol:

US 7,763,612 B2 69 70 2-(4-(5-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) aminobenzoyloxy)pentyloxy)(4-oxo)butanoy TABLE 3 loxymethoxycarbonyl)(1,1-dimethylethyl)amino-1-(3- chlorophenyl)-1-propanone; Antitetrabenazine Activity in the Mouse 2-(4-(6-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) 5 aminobenzoyloxy)hexyloxy)(4-oxo)butanoy Compound EDso (mg/kg i.p.) loxymethoxycarbonyl)(1,1-dimethylethyl)amino-1-(3- (2S,3S,5R)-4-5-(aminosulfonyl)-4-chloro-2-(2- 3.6 furanylmethyl)aminobenzoyloxymethoxycarbonyl-2- chlorophenyl)-1-propanone; (3,5-difluorophenyl)-3,5-dimethyl-2-morpholinol 2-(4-(2-(2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm (1420) ethyl)aminobenzoyloxy)ethoxy)ethoxy)(4-oxo)butanoy- 10 (2S,3S,5R)-2-(3,5-difluorophenyl)-2-hydroxy-3,5- O.2 loxymethoxycarbonyl)(1,1-dimethylethyl)amino-1-(3- dimethylmorpholine (20a) chlorophenyl)-1-propanone; furosemide (10) >30 2-(5-(3-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) aminobenzoyloxy)propoxy)(5-oxo)pentanoy Thus, conjugate compound (1420) inhibited tetrabenazine loxymethoxycarbonyl)(1,1-dimethylethyl)amino-1-(3- 15 induced behavioral effects as did the therapeutic amine com chlorophenyl)-1-propanone; pound (20a). 2-(5-(2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) Safety and Toxicity: Dose-ranging studies were performed aminobenzoyloxy)ethoxy)(5-oxo)pentanoy to determine the range of safe doses for compound (1420). loxymethoxycarbonyl)(1,1-dimethylethyl)amino-1-(3- Animals were observed for the presence of serious adverse chlorophenyl)-1-propanone; 2O events (e.g. seizures and deaths) following administration of 2-(5-(4-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) compound (1420) by the oral route. Mice, groups of 6 CD1 aminobenzoyloxy)butoxy)(5-oxo)pentanoy males each, were administered compound Suspended in a loxymethoxycarbonyl)(1,1-dimethylethyl)amino-1-(3- 0.5% 4000-centipoise methyl cellulose vehicle at a volume of chlorophenyl)-1-propanone; 10 mL/kg p.o. using a 22-gauge stainless steel mouse feeding 2-(5-(5-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) 25 tube and 1-mL Syringe at doses up to 300 mg/kg. Animals aminobenzoyloxy)pentyloxy)(5-oxo)pentanoy were observed for a period of one hour. No seizures or deaths loxymethoxycarbonyl)(1,1-dimethylethyl)amino-1-(3- were observed in any animals at any dose (data not shown). chlorophenyl)-1-propanone; The following examples illustrated above are also repre 2-(5-(6-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) sentative of pharmaceutical compositions where the “Active aminobenzoyloxy)hexyloxy)(5-oxo)pentanoy 30 Ingredient may be any conjugate compound of (I) or a phar loxymethoxycarbonyl)(1,1-dimethylethyl)amino-1-(3- maceutical acceptable salt thereof. chlorophenyl)-1-propanone; and The conjugate compounds herein disclosed may be pro 2-(5-(2-(2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylm duced by a method of reacting at least one therapeutic amine ethyl)aminobenzoyloxy)ethoxy)ethoxy)(5-oxo)pen radical, at least one arylsulfonamide radical, and optionally a tanoyloxymethoxycarbonyl)(1,1-dimethylethyl)amino 35 linker as described above. 1-(3-chlorophenyl)-1-propanone. Methods of using therapeutic amine-arylsulfonamide con jugate compounds include, for example, the treatment of Animal Studies of Therapeutic Amine-Arylsulfonamide psychiatric, neurologic and metabolic disorders such as Conjugate Compound depression, obesity, fibromyalgia, neuropathic pain, restless Substances having an antidepressant action antagonize a 40 leg syndrome, attention deficit hyperactivity disorder number of the behavioral effects induced by tetrabenazine (ADHD), migraine, pain, sexual dysfunction, Parkinson's including locomotor activity, ptosis and hypothermia. Tetra disease, Alzheimer's disease, anxiety, narcolepsy-cataplexy benazine-induced behavioral effects can be quantified using a syndrome, seizures or drug/substance addiction/cessation. In composite index, X, where X=(1-ptosis score)/(activity embodiments, the use of a therapeutic amine-arylsulfona score*Temp., treated/Temp., control) as described by Coo- 45 mide conjugate compound as described herein is provided for per, B. R. J. L. Howard, and F. E. Soroko, Animal models the manufacture of a composition intended to treat a known or used in prediction of antidepressant effects in man, Journal of potential convulsant condition, a known or potential pro Clinical Psychiatry 44:63-6, 1983). 50% effective dose convulsant condition, a known or potential abuse liability, one (EDs) values indicate a dose of compound with antitetra or more psychiatric disorders and/or one or more neurologic benazine activity at which the composite index, X, induced 50 disorders and/or one or more metabolic disorders in an indi by 20 mg/kg of tetrabenazine intraperitoneally is reduced vidual in need thereof by administering a therapeutically 50%. effective amount of the therapeutic amine-arylsulfonamide Prevention of tetrabenazine-induced behavioral effects conjugate. were measured using a modification of the method of Vernier Conjugate compounds described herein may be adminis et al., First Hahnemann Symposium on Psychosomatic Medi- 55 tered to a patient in a variety of routes, for example, orally, cine, ed. Nodim and Moyer, pub Lea and Febiger, Philadel parenterally, intravenously, intradermally, intranasally, Sub phia 1962 as described previously (Cooper, B. R. J. L. cutaneously, or topically, in liquid, cream, gel or Solid form. Howard, and F. E. Soroko, Animal models used in prediction The conjugate compounds may be formulated into, for of antidepressant effects in man, Journal of Clinical Psychia example, a reconstitutable powder, a paste, ointment, cream, try 44:63-6, 1983). Mice, groups of 12 CD1 males each, were 60 gel, or transdermal patch. For example, an oral administration injected intraperitoneally (i.p.) with the compounds (1420), of the conjugate compounds for therapeutic amine com (20a) and furosemide (10) suspended in a 0.5% 4000-centi pounds with potential seizure or abuse liability would be the poise methyl cellulose solution at 3 mg/mL or vehicle. All preferred method of administration. injections were administered at a vehicle volume of 10 ml/kg. In most embodiments, the conjugate compound will con The 50% effective dose (EDs) of each compound was deter- 65 tain the substances to be delivered in an amount sufficient to mined by linear regression analysis of log probit plots of dose deliver to a patient a therapeutically effective amount of at effect curves and is reported in Table 3: least one of the individual components of the conjugated US 7,763,612 B2 71 72 compound and independently or simultaneously alleviate or ine: 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)- ameliorate the severity of, or reduce the likelihood of, adverse 2-methylethanol; (2S,3S)-2-(3-chlorophenyl)-3.5.5-tri effects of one or more of the individual components of the methyl-2-morpholinol: radafaxine; 2-(1-(3- conjugate compound. The desired concentration of either chlorobenzoyl)-(R.S)-ethylamino)-2,2- compound in the conjugate compound will depend on absorp dimethylethanol; bupropion; citalopram; escitalopram; tion, inactivation, and excretion rates. Dosage values may paroxetine; fluoxetine; fluvoxamine; Sertraline; also vary with the severity of the condition to be alleviated. phenelZine; tranylcypromine; amitriptyline; amoxap Effective amounts of each constituent of the conjugate com ine; clomipramine; desipramine: doxepine; imipramine; pound are known or may be determined by routine experi nortryptyline; protriptyline; trimipramine; maprotiline; mentation. Thus, appropriate combinations of each constitu 10 mirtazapine; dulloxetine; nefazodone; traZodone; and ent of the conjugate compound are determinable by one Venlafaxine. skilled in the art, for example, by selection of the appropriate 2. The therapeutic amine-arylsulfonamide conjugate com chemical linker to provide the desired molar ratio of thera pound of claim 1, wherein the therapeutic amine radical is peutic amine radical to arylsulfonamide radical. derived from amines selected from the group consisting of Such factors to be considered in selecting the appropriate 15 manifaxine: 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)- ratio of therapeutic amine to arylsulfonamide include, but are (R)-2-methylethanol; (2S,3S)-2-(3-chlorophenyl)-3.5.5-tri not limited to: the enzymatic degradability and enzymatic methyl-2-morpholinol; radafaxine: 2-(1-(3-chlorobenzoyl)- cleavability of the chemical linker; the bioavailability of each (RS)-ethylamino)-2,2-dimethylethanol: bupropion; constituent therapeutic amine and arylsulfonamide and com citalopram; escitalopram; paroxetine; fluoxetine; fluvoxam binations thereof interactions between the constituents; ine; Sertraline; phenelzine; tranylcypromine; amitriptyline; pharmacokinetic and pharmacodynamic properties of the amoxapine; clomipramine; desipramine; doxepine; imi therapeutic amine and arylsulfonamide and combinations pramine; nortryptyline; protriptyline; trimipramine; mapro thereof; and the degree and severity of the patient’s condition. tiline; mirtazapine; dulloxetine; nefazodone; traZodone; and Further, for any particular patient, specific dosage regimens Venlafaxine. may be adjusted over time according to the individual need 25 3. The therapeutic amine-arylsulfonamide conjugate of and the professional judgment of the person administering or claim 1, wherein at least one of the R" is cycloalkyl, alkenyl, Supervising the administration of the conjugate compound alkynyl, or aryl optionally substituted with alkyl, hydroxy, compositions. hydroxyalkyl, alkoxy, amino, mercapto, nitro, or cyano. The conjugate compounds may be administered once, or 4. The therapeutic amine-arylsulfonamide conjugate of may be divided into a number of smaller doses to be admin 30 claim 1, wherein the R" and R" together with the nitrogen istered at varying intervals of time, depending in part on the in atom to which they are attached form a 4-, 5-, 6-, 7- or vivo degradation rate of the linker and the desired dosage. 8-membered ring optionally containing one or two further Those skilled in the art will recognize, or be able to ascer heteroatoms independently selected from nitrogen, oxygen tain using no more than routine experimentation, many and Sulfur, the ring being optionally Substituted by hydroxy, equivalents to the specific embodiments of the invention 35 hydroxyalkyl, oxo, alkyl, haloalkyl, and/or haloalkoxy. described herein. 5. The therapeutic amine-arylsulfonamide conjugate of The invention claimed is: claim 1, wherein the linker W is selected from the group 1. A therapeutic amine-arylsulfonamide conjugate com consisting of: pound, comprising structure (I): CHRO : 40 C(O)OCHRO : C(O)OCHROC(O)RO : (I) C(O)RO : CHROC(O)RO : C(O)R'OC(O)RO ; and 45 CHROC(O)ROC(O)RO : NHCH wherein R R" is, independently, C —(CH), ; O —(CH) CHY(CH.) : 50 —(CH2)CH=CH(CH.) : SO —(CH), O(CH), ; M R"R"N —(CH2)NR(CH2) ; —(CH)OC=C(CH.) : —(CH),C(O)C(CH), ; wherein 55 —(CH),C(O)C(CH2)CHY (CH), ; R" is D-W-), hydroxyl, or alkoxyl: —(CH),C(O)C(CH2)CH=CH(CH), ; R" is independently D-W-, hydrogen, alkyl, or alkoxyl: —(CH),C(O)C(CH), O(CH), ; D is independently a therapeutic amine radical comprising —(CH),C(O)C(CH2)NR(CH), ; at least one nitrogen atom and optionally at least one —(CH),C(O)C(CH2), S(O)(CH.) : oxygenatom coupled to WorW" by a nitrogen or oxygen 60 —(CH),C(O)C(CH2)C=C(CH), ; or atom; a 5- or 6-membered aromatic ring diradical optionally W and Ware a chemical bond or linker; containing 1 or more heteroatoms independently wherein either R' is D-W- or at least one R" is D-W-: selected from oxygen, nitrogen and Sulfur, the 5- or and pharmaceutically acceptable esters, amides, salts or 6-membered aromatic ring diradical optionally Sub solvates thereof; 65 stituted by hydroxy, hydroxyalkyl, halogen, amino, wherein the therapeutic amine radical is derived from alkyl, or alkoxyalkyl; amines selected from the group consisting of manifax R is independently hydrogen, alkyl, cycloalkyl or aryl; US 7,763,612 B2 73 74 Y is a halogen; (2 S.3S)-4-2-(5-(aminosulfonyl)-4-chloro-2-(2-furanyl n is independently 1-8; methyl)aminobenzoyloxy)ethanoyloxymethoxycarbo m is 0, 1, or 2; and nyl-2-(3-chlorophenyl)-3, 5,5-trimethyl-2-morpholi o is 0-8. nol; 6. The therapeutic amine-arylsulfonamide conjugate of 5 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-me claim 1, wherein the linker W is selected from the group thylethyl 4-(3-(5 (aminosulfonyl)-4-chloro-2-(2-fura consisting of: nylmethyl)aminobenzoyloxy)propoxy)(4-oxo)bu CHROC(O)RC(O)OCHR ; tanoate: C(O)RC(O)CCHR ; 2-(1-(3-chlorobenzoyl)-(R.S)-ethylamino)-2,2-dimethyl C(O)OCHROC(O)RC(O)OCHR : 10 ethyl 4-(3-(5-(aminosulfonyl)-4-chloro-2-(2-furanyl CHROC(O)RC(O)OCHROC(O) ; methyl)aminobenzoyloxy)propoxy)(4-oxo)butanoate; C(O)RC(O)CCHROC(O) ; and 2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) C(O)OCHROC(O)RC(O)OCHROC(O) ; aminobenzoyloxymethoxycarbonyl)(1,1-dimethylet wherein 15 hypamino-1-(3-chlorophenyl)-1-propanone; R" is independently 2-(2-(5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) —(CH), ; aminobenzoyloxy)ethanoyloxymethoxycarbonyl)(1.1- —(CH2)CHY (CH), ; dimethylethyl)amino-1-(3-chlorophenyl)-1-propanone; —(CH2)CH=CH(CH.) : 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-me —(CH), O(CH), : 2O thylethyl 5-(aminosulfonyl)-4-chloro-2-(2-furanylm —(CH2)NR(CH2) ; ethyl)aminobenzoate: —(CH2)C=C(CH2) ; 2-(1-(3-chlorobenzoyl)-(R.S)-ethylamino)-2,2-dimethyl —(CH),C(O)C(CH), ; ethyl 5-(aminosulfonyl)-4-chloro-2-(2-furanylmethyl) —(CH),C(O)C(CH2)CHY (CH), ; aminobenzoate; or —(CH),C(O)C(CH2)CH=CH(CH.) : 25 2-(1-(3,5-difluorobenzoyl)-(R.S)-ethylamino)-(R)-2-me —(CH),C(O)C(CH), O(CH), ; thylethyl 6-(5-carboxy-2-chloro-4-(2-furanylmethyl) —(CH),C(O)C(CH2)NR(CH), ; aminophenylsulfonamidocarbonyloxymethoxy)(6- —(CH),C(O)C(CH2), S(O)(CH.) : OXo)hexanoate. —(CH),C(O)C(CH2)C=C(CH), or: 11. A method of making a therapeutic amine-Sulfonamide a 5- or 6-membered aromatic ring diradical optionally con 30 conjugate compound as defined in claim 1, comprising: taining 1 or more heteroatoms independently selected reacting a therapeutic amine radical, an arylsulfonamide from oxygen, nitrogen and Sulfur, the 5- or 6-membered radical, and optionally a linker; and aromatic ring diradical optionally Substituted by isolating a therapeutic amine-arylsulfonamide conjugate hydroxy, hydroxyalkyl, halogen, amino, alkyl, or compound connected by a chemical bond or the linker, alkoxyalkyl, 35 or a pharmaceutically acceptable salt or Solvate of said R is independently hydrogen, alkyl, cycloalkyl or aryl; therapeutic amine-arylsulfonamide conjugate com Y is a halogen; pound. n is independently 1-8; 12. A method of ameliorating or attenuating a known or m is 0, 1, or 2; and 40 potential convulsant, pro-convulsant, or abuse liability con o is 0-8. dition, said condition resulting from administration ofathera 7. The therapeutic amine-arylsulfonamide conjugate of peutic amine, comprising: administering to a patient in need claim 1, wherein WorW' is enzymatically degradable in vivo. thereof a therapeutically effective amount of an therapeutic 8. The therapeutic amine-arylsulfonamide conjugate of amine-arylsulfonamide conjugate compound (I): claim 1, wherein said D or said arylsulfonamide is enzymati 45 cally cleaved in vivo from said chemical bond or linker. 9. The therapeutic amine-arylsulfonamide conjugate of (I) claim 1, wherein said D or said arylsulfonamide is physi ologically hydrolyzed in vivo from said chemical bond or linker. 10. The therapeutic amine-arylsulfonamide conjugate of 50 NHCH claim 1, wherein said therapeutic amine-arylsulfonamide R conjugate is: C (2S,3S.5R)-4-5-(aminosulfonyl)-4-chloro-2-(2-furanyl O methyl)aminobenzoyloxymethoxycarbonyl-2-(3.5- 55 difluorophenyl)-3,5-dimethyl-2-morpholinol: SO M (2 S.3S.5R)-4-2-(5-(aminosulfonyl)-4-chloro-2-(2-fura R"R"N nylmethyl)aminobenzoyloxy)ethanoyloxymethoxy carbonyl-2-(3,5-difluorophenyl)-3,5-dimethyl-2-mor wherein pholinol: 60 (2S,3S.5R)-4-2-(2-(5-(aminosulfonyl)-4-chloro-2-(2- R" is D-W-), hydroxyl, or alkoxyl; furanylmethyl)aminobenzoyloxy)ethoxy)ethanoy R" is independently D-W-, hydrogen, alkoxy, alkyl, loxymethoxycarbonyl-2-(3,5-difluorophenyl)-3,5- cycloalkyl, alkenyl, alkynyl or aryl, or R" and R" dimethyl-2-morpholinol: together with the nitrogen atom to which they are (2S,3S)-4-5-(aminosulfonyl)-4-chloro-2-(2-furanylm 65 attached form a 4-, 5-, 6-, 7- or 8-membered ring option ethyl)aminobenzoyloxymethoxycarbonyl-2-(3-chlo ally containing one or two further heteroatoms indepen rophenyl)-3.5.5-trimethyl-2-morpholinol: dently selected from nitrogen, oxygen and Sulfur, US 7,763,612 B2 75 76 D is independently a therapeutic amine radical comprising R" is independently D-W-, hydrogen, alkoxy, alkyl, at least one nitrogen atom and optionally at least one cycloalkyl, alkenyl, alkynyl or aryl, or R" and R" oxygenatom coupled to WorW" by a nitrogen or oxygen together with the nitrogen atom to which they are atom; attached form a 4-, 5-, 6-, 7- or 8-membered ring option W and Ware a chemical bond or linker; ally containing one or two further heteroatoms indepen wherein either R' is D-W- or at least one R" is D-W-, dently selected from nitrogen, oxygen and Sulfur, and pharmaceutically acceptable esters, amides, salts or D is independently a therapeutic amine radical comprising solvates thereof. at least one nitrogen atom and optionally at least one 13. The method of claim 12, wherein the therapeutic amine oxygenatom coupled to WorW" by a nitrogen or oxygen radical is derived from amines selected from the group con 10 atom; sisting of manifaxine: 2-(1-(3,5-difluorobenzoyl)-(R.S)- W and Ware a chemical bond or linker; ethylamino)-(R)-2-methylethanol; (2S,3S)-2-(3-chlorophe wherein either R' is D-W- or at least one R" is D-W-, nyl)-3.5.5-trimethyl-2-morpholinol; radafaxine: 2-(1-(3- and pharmaceutically acceptable esters, amides, salts or chlorobenzoyl)-(R.S)-ethylamino)-2,2-dimethylethanol: solvates thereof. bupropion; citalopram; escitalopram, paroxetine; fluoxetine; 15 15. The method of claim 14, wherein the psychiatric, neu fluvoxamine; Sertraline; phenelzine; tranylcypromine; ami rologic and/or metabolic disorder is depression, obesity, triptyline; amoxapine; clomipramine; desipramine; doX fibromyalgia, neuropathic pain, restless leg syndrome, atten epine; imipramine; nortryptyline; protriptyline; trimi tion deficit hyperactivity disorder (ADHD), migraine, pain, pramine; maprotiline; mirtazapine; dulloxetine; nefazodone; sexual dysfunction, Parkinson's disease, Alzheimer's dis traZodone; and Venlafaxine. ease, anxiety, narcolepsy-cataplexy syndrome, seizures, 14. A method of treating one or more or a combination of drug/substance addiction/cessation or combinations thereof. one or more of a psychiatric, a neurologic and/or a metabolic 16. A therapeutic amine-arylsulfonamide conjugate com disorder, the method comprising: pound: (2 S.3S.5R)-4-5-(aminosulfonyl)-4-chloro-2-(2- administering to a patient in need thereofatherapeutically furanylmethyl)aminobenzoyloxymethoxycarbonyl-2-(3,5- effective amount of a therapeutic amine-arylsulfona- 25 difluorophenyl)-3,5-dimethyl-2-morpholinol, represented by mide conjugate compound (I): the structure:

(I) 30 O HN O NHCH A R C 35 C O HN-ji=o SO O M R"R"N 40 and pharmaceutically acceptable esters, amides, salts or solvates thereof. wherein R" is D-W-), hydroxyl, or alkoxyl: UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. : 7,763,612 B2 Page 1 of 2 APPLICATIONNO. : 1 1/619291 DATED : July 27, 2010 INVENTOR(S) : Philip F. Morgan et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Columns 15 and 16: Lines 25-30: In the middle of column, just above the row beginning with “if the words “wherein R1 may be are missing. Columns 35 and 36, Lines 10-45: Scheme designation “Scheme D'' is missing. Columns 37 and 38, Lines 35-65: Scheme designation “Scheme E is missing. Columns 41 and 42, Lines 5-30: Scheme designation “Scheme F is missing. Columns 43 and 44, Lines 5-40: Scheme designation “Scheme G” is missing. Columns 45 and 46, Lines 30-60: Scheme designation “Scheme H” is missing. Columns 49 and 50, Lines 1-35: Scheme designation “Scheme I is missing. Columns 51 and 52, Lines 15-45: Scheme designation “Scheme J is missing. Column 76, Line 23, Claim 16: “pound: (2.S.3S.5R)-4-5-aminosulfonyl)-4-chloro-2-(2-, should be - -pound: (2S,3S.5R)-4-5-(aminosulfonyl)-4-chloro-2-(2---

Signed and Sealed this Thirteenth Day of March, 2012

()

David J. Kappos Director of the United States Patent and Trademark Office CERTIFICATE OF CORRECTION (continued) Page 2 of 2 U.S. Pat. No. 7,763,612 B2

Columns 61 and 62: structure should be

SCHEMEM