USOO9617229B2

(12) United States Patent (10) Patent No.: US 9,617,229 B2 Blough et al. (45) Date of Patent: Apr. 11, 2017

(54) PHENYLMORPHOLINES AND ANALOGUES 4,360,519 A 11/1982 White et al. THEREOF 4,576,944 A 3, 1986 Lafon 4,766,212 A 8, 1988 Freedman et al. (75) Inventors: Bruce E. Blough, Raleigh, NC (US); 5,104,870 A 4/1992 Kelley et al. Richard Rothman, Ellicott City, MD 5,648,347 A 7/1997 Mehta et al. (US); Antonio Landavazo, Raleigh, 6,693, 192 B1 2/2004 Chrysselis et al. 8,906,908 B2 12/2014 Carroll et al. NC (US); Kevin M. Page, Willow 2005/0267,096 A1 12/2005 Alerton et al. Spring, NC (US); Ann Marie Decker, 2007/O155729 A1 7/2007 Morgan et al. Durham, NC (US) 2010, OO16312 A1 1/2010 Lee et al. (73) Assignees: Research Triangle Institute, Research 2012fOO71560 A1 3/2012 Carroll et al. Triangle Park, NC (US); The United FOREIGN PATENT DOCUMENTS States of America, As Represented by the Secretary Department of Health DE DD2O678 4f1958 DE 1135 464 8, 1962 and Human Services, Washington, DC DE 11 43 201 2, 1963 (US) DE 2152686 5, 1972 (*) Notice: Subject to any disclaimer, the term of this DE 2441350 3, 1976 patent is extended or adjusted under 35 EP O 116 373 8, 1984 EP O 170 430 2, 1986 U.S.C. 154(b) by 194 days. EP O 174 242 3, 1986 FI 852 657 1, 1986 (21) Appl. No.: 13/698,892 FR 1 397 563 4f1965 FR 2168139 8, 1973 (22) PCT Filed: May 20, 2011 FR 2285886 9, 1974 FR 2471378 * 6, 1981 (86). PCT No.: PCT/US2011/037361 (Continued) S 371 (c)(1), OTHER PUBLICATIONS (2), (4) Date: Mar. 4, 2013 RN 1097796-78-5, STN, file Registry, Jan. 30, 2009.* Carroll et al., “Synthesis and Biological Evaluation of Bupropion (87) PCT Pub. No.: WO2011/146850 analogues as Potential Pharmacotherapies for Cocaine Addiction.” J. Med Chem., 2009, pp. 6768-6781, vol. 52. PCT Pub. Date: Nov. 24, 2011 Carroll et al., “Synthesis of 2-(Substituted Phenyl)-3.5.5- trimethylmorpholine Analogues and Their Effects on Monoamine (65) Prior Publication Data Uptake, Nicotinic Acetylcholine Receptor Function, and Behavioral Effects of Nicotine,” Journal of Medicinal Chemistry, 2011, pp. 1441-1448, vol. 54, No. 5. US 2013/0203752 A1 Aug. 8, 2013 Hu et al., “Synthesis of 2-aryl-3,5,5-trimethyl-2-morpholinol Hydrochloride.” Yingyong Huaixue, 2005, pp. 343-345, vol. 22, No. 3 Related U.S. Application Data Lukas et al., “Synthesis and Characterization of InVitro and InVivo Profiles of Hydroxybupropion analogues: Aids to Smoking Cessa (60) Provisional application No. 61/347,259, filed on May tion.” Journal of Medicinal Chemistry, 2010, pp. 4731-4748, vol. 21, 2010. 53. Avramova et al., “Derivatives of 2-and 2,3-Disubstituted (51) Int. Cl. Tetrahydrooxazines.” Bulgarian Chemical Communications, 1992, CO7D 265/30 (2006.01) pp. 387-390, vol. 25, No. 3. Balsamo et al., “Synthesis and Pharmacological Properties of cis (52) U.S. Cl. 2-(2,5-dimethoxyphenyl)-3-Methylmorpholine and Its N-isopropyl CPC ...... C07D 265/30 (2013.01) Derivative.” Eur: J. Med. Chem.–Chimica. Therapeutica, 1978, pp. (58) Field of Classification Search 321-326, vol. 13, No. 4. CPC ...... CO7D 265/30 Bettoni et al., “Synthesis of Rigid Dopamine Congeners: CIS and USPC ...... 544/106; 514/231.2 TRANS 2-(p-Methoxyphenyl)-3- Methylmorpholine.” Tetrahe See application file for complete search history. dron, 1986, pp. 21.17-2120, vol. 42, No. 7. (Continued) (56) References Cited Primary Examiner — Rebecca Anderson U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm — Womble Carlyle Sandridge & Rice, LLP 1,867,982 A 7, 1932 Naunton et al. (57) ABSTRACT 2,364,347 A 12/1944 Dickey et al. 2,832,777 A 4, 1958 Kalm Provided herein are compounds and prodrugs and methods 2.996,504 A 8, 1961 Zimmermann et al. of preparation of compounds and prodrugs that are capable 2.997.469 A 8, 1961 Heel et al. of functioning as releasers and/or uptake inhibitors of one or 3,018,222 A 1/1962 Siemer et al. more monoamine neurotransmitters, including dopamine, 3,112,311 A 11, 1963 Zimmermann et al. serotonin, and norepinephrine. Also provided are pharma 3,117,967 A 1/1964 Anderson et al. ceutical compositions comprising one or more of these 3,125,572 A 3, 1964 Siemer et al. compounds or prodrugs, which may further comprise one or 3,225,042 A 12/1965 Dillard et al. more additional therapeutic agents. Also provided are meth 3,555,019 A 1/1971 Fouche et at 3,642,789 A 2f1972 Faith et al. ods of treatment of various conditions that may be respon 3,714,161 A 1/1973 Mallion et al. sive to modification of monoamine neurotransmitter levels, 3,959,273 A 5, 1976 Mallion et al. Such as pre-obesity, obesity, addiction, and depression. 4,044,131 A 8, 1977 Asselin et al. 21 Claims, No Drawings US 9,617.229 B2 Page 2

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CROSS-REFERENCE TO RELATED Phentermine is still available in many countries, including APPLICATIONS 5 the United States; however, it is classified as a controlled Substance due to its chemical and pharmacological similarity The present application is a national stage entry of PCT to amphetamines. One concern with Such compounds is the International Application No. PCT/US2011/037361, filed high potential for abuse. May 20, 2011, which claims the benefit of U.S. Provisional Another anorectic, which was prescribed for the short Application No. 61/347,259, filed May 21, 2010. 10 term treatment of obesity, is phenmetrazine Phenmetrazine is reportedly a potent Substrate for norepinephrine and FEDERALLY SPONSORED RESEARCH OR dopamine transporters and displays stimulant properties DEVELOPMENT similar to those of amphetamines. Some reports indicate that This invention was made with United States Government 15 phenmetrazine has been widely abused as a recreational support under DA 12970/0207690,000 awarded by the drug and has greater addiction potential than amphetamines. National Institutes of Health. The United States Government Because of phenmetrazine's high potential for abuse, it was pulled from the market. has certain rights in the invention. Subsequently, phendimetrazine, a close analogue of phen FIELD OF THE INVENTION 2O metrazine with a methyl substituent on the amine, was released onto the market as an anorectic. Recent research has The present application is directed to various compounds Suggested that phendimetrazine actually exerts its effect via and methods of preparation of compounds that are capable conversion to phenmetrazine. See Rothman et al., Eur: J. of functioning as releasers and/or reuptake inhibitors of one Pharmacology 447: 51-57 (2002), incorporated herein by or more monoamine neurotransmitters, including dopamine, 25 reference. Thus, as with phenmetrazine, phendimetrazine serotonin, and norepinephrine. The application is also also has a high potential for abuse. Although it is still directed to pharmaceutical compositions comprising one or available for the treatment of obesity, phendimetrazine is a more of these compounds, which may also comprise one or Class III controlled substance and there is a high likelihood more additional therapeutic agents. It is also directed to of abuse of this drug. methods of treatment of various conditions that may be 30 Accordingly, there is a need for an anorectic drug that acts responsive to modification of monoamine neurotransmitter similarly to the aforementioned drugs on the central nervous levels, such as pre-obesity, obesity, addiction, and depres system, but does not provide Such high potential for abuse S1O. and/or does not act as an agonist of the 5-HT2 receptor. Because of their effects on the central nervous system, such BACKGROUND OF THE INVENTION 35 compounds may be useful not only for treating obesity and Obesity is a serious public health concern, associated with pre-obesity, but also for other diseases related to the central a number of health conditions. The National Center for nervous system including addiction, depression, and anxiety. Health Statistics reports that 65% of adults are considered to be overweight (pre-obese), with greater than 34% of those 40 BRIEF SUMMARY OF THE INVENTION adults considered to be obese. The incidences of obesity have dramatically increased over the last twenty years, with The present invention relates generally to compounds and the percentage of obese adults having doubled from 1980 to prodrugs that may be useful as releasers and/or reuptake 2004. Children are at risk as well, with an estimated 17% of inhibitors of one or more monoamine neurotransmitters, children from age 2-19 classified as obese. Medical condi- 45 including dopamine, serotonin, and norepinephrine. It also tions commonly associated with obesity include diabetes relates to pharmaceutical formulations of Such compounds and high blood pressure, which may lead to cardiovascular and/or prodrugs and to methods of using Such compounds, disease, stroke, and premature mortality. prodrugs, or formulations thereof to treat various conditions As a result, there has been an increase in demand for that may be responsive to the modulation of neurotransmit medications to treat pre-obesity and obesity. One type of 50 ter levels. medication that is available to treat obesity is anorectics, In one aspect, the present invention provides a compound also known as appetite Suppressants. One well-known ano that may modulate the levels of one or more monoamine rectic is Fen-Phen, which was widely prescribed for weight neurotransmitters. In some embodiments, the invention pro loss in the early 1990s. Fen-Phen is a combination drug that vides a compound according to the following structure: comprises two compounds; namely, fenfluramine and phen- 55 termine. Fenfluramine acts via a serotonergic mechanism to increase a user's Satiety. Phentermine has a stimulant effect, Rs acting mainly through dopaminergic and noradrenergic R R6 mechanisms to decrease a user's appetite. Fen-Phen, although effective in the treatment of obesity, was linked to 60 possible valvular heart disease and pulmonary hypertension R 2 NR3 R4 in 1997. As a result, fenfluramine and the Fen-Phen com bination drug were pulled from the market in 1997. It is thought that the valvular heart disease and pulmonary wherein: hypertension associated with the use offenfluramine and its 65 R is optionally substituted aryl; active metabolite norfenfluramine may result from the R is H or optionally substituted C1-3 alkyl: stimulation of 5-hydroxytryptamine (5-HT) serotonin recep R is H, optionally substituted C1-3 alkyl, or benzyl: US 9,617,229 B2 3 4 R is H or optionally substituted C1-3 alkyl; and wherein: R is H or OH: each R, represents a Substituent independently selected R is H or optionally substituted C1-3 alkyl: from the group consisting of OH, optionally substituted with the proviso that when R is CH and R is phenyl, C1-4 alkyl, optionally substituted C1-3 alkoxy, option then (a) the phenyl ring of R is substituted with one or more 5 ally substituted C2-4 alkenyl, optionally substituted substituents; or (b) R is substituted C1 alkyl or optionally C2-4 alkynyl, halogen, amino, acylamido, CN, CF, substituted C2-C3 alkyl, or (c) one or more of R. Rs, and NO, N, CONH CO.R., CHOH, CHOR, R is not H, or a combination of two or more of (a) through NRR, NHCOR, NHCOR CONRR, C1-3 (c); or a pharmaceutically acceptable ester, amide, salt, alkylthio, RSO, RSO, CFS, and CFSO; and Solvate, prodrug, or isomer thereof. 10 In certain embodiments, a compound of the structure c is an integer from 0-7, above is provided, wherein R is phenyl, substituted phenyl, or a pharmaceutically acceptable ester, amide, salt, Sol naphthyl, or Substituted naphthyl. In some embodiments, R Vate, prodrug, or isomer thereof. is a substituted aryl group (e.g., a substituted phenyl) and R 15 In some embodiments of the present invention, a com is H. pound is provided, wherein R is H or CH. In some In some embodiments, a compound is provided having embodiments of the invention, a compound is provided the structure: wherein R is H or CH. In certain embodiments, R is optionally substituted C1-3 alkyl. In certain embodiments, one of R and R is Hand the other of R and R is optionally 21 substituted C1-3 alkyl. In some embodiments, such com (R- || R. pounds may comprise an enantiomeric excess of at least N R6 95% of one isomer (e.g., the (2S-5S) enantiomer). In one embodiment of the invention, certain compounds 25 are provided, selected from the group consisting of: 2-(2- R. N. R. naphthyl)morpholine: 2-methyl-6-phenyl-morpholine: 2-(3- chloro-phenyl)-3-methyl-morpholine: 2-(3-chloro-phenyl)- wherein the substituents are as noted above, except that: 3-methyl-morpholin-2-ol: 2-(3-chloro-phenyl)-5-methyl each R, represents a Substituent independently selected 30 morpholine; 2-(3-chloro-phenyl)-6-methyl-morpholine; from the group consisting of OH, optionally substituted 2-(3-fluoro-phenyl)-3-methyl-morpholine: 2-(3-fluoro-phe C1-4 alkyl, optionally substituted C1-4 alkoxy, option nyl)-3-methyl-morpholin-2-ol; 2-(3-fluoro-phenyl)-5- ally substituted C2-4 alkenyl, optionally substituted methyl-morpholine: 2-(3-methoxy-phenyl)-5-methyl-mor C2-4 alkynyl, halogen, amino, acylamido, CN, CF, pholine; 2-(4-fluorophenyl)morpholine; 2-(4-chloro NO, N, CONH CO.R., CHOH, CHOR, 35 phenyl)-5-methyl-morpholine; 2-(4-fluoro-phenyl)-5- NRR, NHCOR, NHCOR, CONRR, C1-3 methyl-morpholine; 3-methyl-2-phenylmorpholin-2-ol; alkylthio, RSO, RSO, CFS, and CFSO, wherein 3-methyl-2-(2-naphthyl)morpholine: 3-methyl-2-(3'-tolyl) R and R are each independently selected from Hor morpholine; 3-methyl-2-(3'-tolyl)morpholin-2-ol: 3-methyl optionally substituted C1-10 alkyl; and 2-(4-tolyl)morpholine: 3-methyl-(4-fluoro)-2-phenylmor b is an integer from 0-5: 40 pholine; 3-methyl-(4-chloro)-2-phenylmorpholine: with the proviso that when R is CH, then (a) b is an 3-methyl-(4-methoxy)-2-phenylmorpholine; 3-methyl integer from 1-5, or (b) R is substituted Clalkyl or option (4'-cyano)-2-phenylmorpholine: 3-methyl-(3'-hydroxy)- ally substituted C2-C3 alkyl, or (c) one or more of R. Rs 2-phenylmorpholine: 3-methyl-(3'-methoxy)-2-phenyl and R is not H, or a combination of two or more of (a) morpholine; 3-methyl-(3'-cyano)-2-Phenylmorpholine; through (c), 45 3-methyl-(3',4'-dichloro)-2-phenylmorpholine: 3-methyl or a pharmaceutically acceptable ester, amide, salt, Sol (3'-chloro-4'-fluoro)-2-Phenylmorpholine: 3-methyl-(3'- Vate, prodrug, or isomer thereof chloro-4'-methyl)-2-Phenylmorpholine; 5-methyl-2-(3-trif In certain embodiments, a compound of the above for luoromethyl-phenyl)-morpholine; 5-methyl-2-p-tolyl mula is provided, wherein b is an integer from 1-5, and each morpholine; 5-methyl-2-m-tolyl-morpholine; 5-methyl-2- R, is independently selected from the group consisting of 50 optionally substituted C1-4 alkyl, optionally substituted phenyl-morpholine; 5-methyl-2-(4-trifluoromethyl-phenyl)- C1-4 alkoxy, halo, OH, CN, and CF. In some embodiments, morpholine, or a pharmaceutically acceptable ester, amide, b is 1 and the R, substituent is located meta or para to the salt, Solvate, prodrug, or isomer thereof. morpholine Substituent on the phenyl ring. According to the invention, in some embodiments, the In some embodiments, a compound is provided having 55 compound is one or more of a dopamine releaser, norepi the structure: nephrine releaser, serotonin releaser, dopamine uptake inhibitor, norepinephrine uptake inhibitor, and serotonin uptake inhibitor. In certain embodiments, the compound is a 21 60 dopamine releaser or a dual serotonin and dopamine (R-, - releaser. In some embodiments, the compound is inactive at S the 5HT receptor. In another aspect of the invention is provided a prodrug of the compounds disclosed herein, comprising a compound 65 having R replaced with a labile protecting group. For example, certain prodrugs of the present invention have the following formula: US 9,617,229 B2 5 the singular forms “a”, “an”, “the’, include plural referents Rs unless the context clearly dictates otherwise. R R6 Many modifications and other embodiments of the inven tions set forth herein will come to mind to one skilled in the art to which these inventions pertain having the benefit of the R N R4 teachings presented in the foregoing description. Therefore, it is to be understood that the inventions are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within wherein: 10 X is a chemical moiety which, when the prodrug is the scope of the appended claims. Although specific terms administered in vivo, is cleaved in whole or in part to are employed herein, they are used in a generic and descrip provide a free amine on the morpholine ring; tive sense only and not for purposes of limitation. In some specific embodiments, a prodrug according to The present invention provides compounds that may this structure is provided, wherein X is an amino acid or 15 function to modify the release and/or reuptake of one or peptide. more monoamine neurotransmitters selected from dop amine, norepinephrine, and serotonin. The invention also In some embodiments, a prodrug is provided having the provides methods of preparation and pharmaceutical com formula: positions thereof. It also provides methods for using Such compounds to treat a variety of disorders that may be Rs responsive to the modulation of one or more of these R R6 neurotransmitters. In particular, the compositions and meth ods can be used in the treatment of obesity, various drug addictions, and depression. In some embodiments, treatment R N R4 25 can comprise the use of a compound of the present invention as a single active agent. In other embodiments, treatment can comprise the use of a compound of the present invention in Rs1s, combination with one or more further active agents. The specific pharmaceutical composition (or compositions) used wherein Rs is optionally substituted C1-10 alkyl, option 30 in the invention and the methods of treatment provided by ally substituted C1-10 alkoxy, optionally substituted the invention are further described below. phenyl, optionally substituted benzyl, or optionally substituted pyridyl. DEFINITIONS In a further aspect of the invention, a pharmaceutical composition is provided, wherein the composition com 35 The term “alkyl as used herein means saturated straight, prises a compound or prodrug as disclosed herein and one or branched, or cyclic hydrocarbon groups. In particular more pharmaceutically acceptable carriers. embodiments, alkyl refers to groups comprising 1 to 10 In a still further aspect of the invention, a method for carbonatoms (“C1-10 alkyl). In further embodiments, alkyl treating or delaying the progression of disorders that are refers to groups comprising 1 to 8 carbon atoms ("C1-8 40 alkyl), 1 to 6 carbon atoms (“C1-6 alkyl), 1 to 4 carbon alleviated by modulating monoamine release in a patient atoms (“C1-4 alkyl), or 1 to 3 carbon atoms (“C1-3 alkyl). comprising administering a therapeutically effective amount In other embodiments, alkyl refers to groups comprising of at least one compound or prodrug as disclosed herein is 3-10 carbon atoms (“C3-10 alkyl), 3-8 carbon atoms provided. For example, in certain embodiments, the disorder (“C3-8 alkyl”), or 3-6 carbon atoms (“C3-6 alkyl). In is selected from the group consisting of addiction, depres 45 specific embodiments, alkyl refers to methyl, ethyl, propyl. sion, obesity, bipolar disorder, attention deficit disorder isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, (ADD), attention deficit/hyperactivity disorder (ADHD), cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclo hypoactive sexual desire disorder, antidepressant-induced hexyl, cyclohexylmethyl 3-methylpenty1, 2,2-dimethylbu sexual dysfunction, orgasmic dysfunction, seasonal affective tyl, and 2,3-dimethylbutyl. Substituted alkyl refers to alkyl disorder/winter depression, mania, bulimia and other eating 50 substituted with one or more moieties selected from the disorders, panic disorders, obsessive compulsive disorder, group consisting of halo (e.g., Cl, F, Br, and I); halogenated schizophrenia, schizo-affective disorder, Parkinson's dis alkyl (e.g., CF, 2-Br-ethyl, CHF, CHC1, CHCF, or ease, narcolepsy, anxiety disorders, insomnia, chronic pain, CFCF); hydroxyl; amino; carboxylate; carboxamido; alky migraine headaches, and restless legs syndrome. lamino: arylamino; alkoxy: aryloxy; nitro; azido: cyano; 55 thio; Sulfonic acid; Sulfate; phosphonic acid; phosphate; and DETAILED DESCRIPTION OF THE phosphonate. INVENTION The term “alkenyl' as used herein means alkyl moieties wherein at least one saturated C-C bond is replaced by a The present invention now will be described more fully double bond. In particular embodiments, alkenyl refers to hereinafter with reference to the accompanying figures, in 60 groups comprising 2 to 10 carbon atoms (“C2-10 alkenyl). which some, but not all embodiments of the inventions are In further embodiments, alkenyl refers to groups comprising shown. Indeed, these inventions may be embodied in many 2 to 8 carbon atoms (“C2-8 alkenyl), 2 to 6 carbon atoms different focus and should not be construed as limited to the (“C2-6 alkenyl), or 2 to 4 carbon atoms (“C2-4 alkenyl). embodiments set forth herein; rather, these embodiments are In specific embodiments, alkenyl can be vinyl, allyl, 1-pro provided so that this disclosure will satisfy applicable legal 65 penyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pente requirements. Like numbers refer to like elements through nyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hex out. As used in the specification, and in the appended claims, enyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl. US 9,617,229 B2 7 8 The term “alkynyl as used herein means alkyl moieties The term "derivative' as used herein means a compound wherein at least one saturated C-C bond is replaced by a that is formed from a similar, beginning compound by triple bond. In particular embodiments, alkynyl refers to attaching another molecule or atom to the beginning com groups comprising 2 to 10 carbon atoms (“C2-10 alkynyl). pound. Further, derivatives, according to the invention, In further embodiments, alkynyl refers to groups comprising encompass one or more compounds formed from a precursor 2 to 8 carbon atoms ("C2-8 alkynyl), 2 to 6 carbon atoms compound through addition of one or more atoms or mol (“C2-6 alkynyl), or 2 to 4 carbon atoms (“C2-4 alkynyl). ecules or through combining two or more precursor com In specific embodiments, alkynyl can be ethynyl, 1-propy pounds. nyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-penty The term “prodrug as used herein means any compound nyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexy 10 which, when administered to a mammal, is converted in nyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl. whole or in part to a compound of the invention. The term “alkoxy” as used herein means straight or The term “active metabolite' as used herein means a branched chain alkyl groups linked by an oxygen atom (i.e., physiologically active compound which results from the —O-alkyl), wherein alkyl is as described above. In particu metabolism of a compound of the invention, or a prodrug lar embodiments, alkoxy refers to oxygen-linked groups 15 thereof, when Such compound or prodrug is administered to comprising 1 to 10 carbon atoms (“C1-10 alkoxy”). In a mammal further embodiments, alkoxy refers to oxygen-linked groups The terms “therapeutically effective amount’ or “thera comprising 1 to 8 carbon atoms (“C1-8 alkoxy”), 1 to 6 peutically effective dose” as used herein are interchangeable carbon atoms (“C1-6 alkoxy'), 1 to 4 carbon atoms (“C1-4 and mean a concentration of a compound according to the alkoxy”) or 1 to 3 carbon atoms (“C1-3 alkoxy”). invention, or a biologically active variant thereof, Sufficient The term “aryl as used herein means a stable monocy to elicit the desired therapeutic effect according to the clic, bicyclic, or tricyclic carbon ring of up to 8 members in methods of treatment described herein. each ring, wherein at least one ring is aromatic as defined by The term “pharmaceutically acceptable carrier as used the Hickel 4n+2 rule. Exemplary aryl groups according to herein means a carrier that is conventionally used in the art the invention include phenyl and naphthyl. 25 to facilitate the storage, administration, and/or the healing The term “halo' or “halogen' as used herein means effect of a biologically active agent. fluorine, chlorine, bromine, or iodine. The term “intermittent administration' as used herein The term “alkylthio’ as used herein means a thio group means administration of a therapeutically effective dose of a with one or more alkyl substituents, where alkyl is defined composition according to the invention, followed by a time as above. 30 period of discontinuance, which is then followed by another The term “acylamido” refers to an amide group with one administration of a therapeutically effective dose, and so or more acyl substituents, where acyl is as defined below. forth. The term “acyl as used herein means a group formed by The term “neurotransmitter” as used herein encompasses removing the hydroxyl group from a carboxylic acid, in monoamine neurotransmitters and neuromodulators. In par which the non-carbonyl moiety of the group is selected from 35 ticular, the term neurotransmitter as used herein includes, straight, branched, or cyclic alkyl or lower alkyl, alkoxy but is not limited to, dopamine, norepinephrine, and sero alkyl including methoxymethyl, aralkyl including benzyl; tonin. aryloxyalkyl such as phenoxymethyl: aryl including phenyl Active Agents optionally substituted with halogen, C1-6 alkyl or C1-6 The present invention provides compounds, methods of alkoxy; Sulfonate esters such as alkyl or aralkyl Sulfonyl 40 preparation of the compounds, pharmaceutical composi including methanesulfonyl: mono-, di-, or triphosphate tions, and methods of treatment of various conditions using ester; trity1 or monomethoxytrityl; substituted benzyl; tri Such compounds and pharmaceutical compositions. alkylsilyl such as dimethyl-t-butylsilyl or diphenylmethyl In some embodiments, morpholine compounds according silyl. to Formula I are provided, The terms “aralkyl and “arylalkyl as used herein mean 45 an aryl group as defined above linked to the molecule through an alkyl group as defined above. Formula I The term "amino” as used herein means a moiety repre Rs sented by the structure NR, and includes primary amines, R6 and secondary and tertiary amines Substituted by alkyl (i.e., 50 alkylamino). Thus, R may represent two hydrogen atoms, two alkyl moieties, or one hydrogen atom and one alkyl R2 NR3 R4 moiety. The term "cycloalkyl means a non-aromatic, monocyclic or polycyclic ring comprising carbon and hydrogen atoms. 55 wherein: Substituted cycloalkyl refers to alkyl substituted with one or R is optionally substituted aryl (e.g., naphthyl or phenyl); more moieties selected from the group consisting of halo R is H or optionally substituted C1-3 alkyl: (e.g., Cl, F, Br, and I); halogenated alkyl (e.g., CF, 2-Br R is H, optionally substituted C1-3 alkyl, or benzyl: ethyl, CHF, CHC1, CHCF, or CFCF); hydroxyl: Ra is H or optionally substituted C1-3 alkyl: amino; carboxylate; carboxamido; alkylamino: arylamino; 60 Rs is H or OH; and alkoxy: aryloxy; nitro; azido; cyano; thio; Sulfonic acid; R is H or optionally substituted C1-3 alkyl: Sulfate; phosphonic acid; phosphate; and phosphonate. with the proviso that when R is CH and R is phenyl, The term “analogue' as used herein means a compound in then (a) the phenyl ring of R is substituted with one or which one or more individual atoms or functional groups more substituents; or (b) R is substituted Clalkyl or have been replaced, either with a different atom or a different 65 optionally substituted C2-C3 alkyl, or (c) one or more functional, generally giving rise to a compound with similar of R. Rs, and R is not H, or a combination of two or properties. more of (a) through (c); US 9,617,229 B2 10 or a pharmaceutically acceptable ester, amide, salt, Sol In another particular embodiment, the compound of For Vate, prodrug, or isomer thereof. mula I may be represented by Formula III: In some preferred embodiments, a compound of Formula I is provided wherein R is aryl substituted at one or more available sites. Where multiple substitutions are present on Formula III R, multiple different types of substituents may be utilized. The one or more Substituents present on R may include, but 21 are not limited to, OH, optionally substituted C1-4 alkyl, (R)- - optionally substituted C1-4 alkoxy, optionally substituted S R6 C2-4 alkenyl, optionally substituted C2-4 alkynyl, halogen, 10 amino, acylamido, CN, CF, NO, N, CONH CO.R. CHOH, CHOR, NRR, NHCOR, NHCOR, DC CONRR, C1-3 alkylthio, RSO, RSO, CFS, and CFSO, wherein R and R are each independently selected from H or optionally substituted C1-10 alkyl. 15 wherein: In some preferred embodiments, a compound of Formula R is H or optionally substituted C1-3 alkyl: I is provided wherein R is H. In some preferred embodi R is H, optionally substituted C1-3 alkyl, or benzyl: ments, a compound of Formula I is provided wherein R is Ra is H or optionally substituted C1-3 alkyl: C1-3 alkyl (e.g., CH). In some preferred embodiments, a Rs is H or OH: compound of Formula I is provided wherein R is H. In R is H or optionally substituted C1-3 alkyl: Some preferred embodiments, a compound of Formula I is each R, represents a substituent independently selected provided wherein R is H. In some preferred embodiments, from the group consisting of OH, optionally substituted a compound of Formula I is provided wherein R is C1-3 C1-4 alkyl, optionally substituted C1-3 alkoxy, option alkyl (e.g., CH). In some preferred embodiments, a com ally substituted C2-4 alkenyl, optionally substituted pound of Formula I is provided wherein Rs is H. In some 25 C2-4 alkynyl, halogen, amino, acylamido, CN, CF, preferred embodiments, a compound of Formula I is pro NO, N, CONH CO.R., CHOH, CHOR, vided wherein Rs is OH. In one particular embodiment, the NRR, NHCOR, NHCOR CONRR, C1-3 compound of Formula I may be represented by Formula II. alkylthio, RSO, RSO, CFS, and CFSO; and c is an integer from 0-7, 30 or a pharmaceutically acceptable ester, amide, salt, Sol Formula II Vate, prodrug, or isomer thereof. 21 In some embodiments of the present invention, therapeu (R)- || R. tically inactive prodrugs are provided. Prodrugs are com S R6 pounds which, when administered to a mammal, are con 35 verted in whole or in part to a compound of the invention. In most embodiments, the prodrugs are pharmacologically R2 NR3 R4 inert chemical derivatives that can be converted in vivo to the active drug molecules to exert a therapeutic effect. Any of the compounds described herein can be administered as a wherein: 40 prodrug to increase the activity, bioavailability, or stability R is H or optionally substituted C1-3 alkyl: of the compound or to otherwise alter the properties of the R is H, optionally substituted C1-3 alkyl, or benzyl; compound. Typical examples of prodrugs include com R is H or optionally substituted C1-3 alkyl: pounds that have biologically labile protecting groups on a Rs is H or OH: functional moiety of the active compound. In preferred R is H or optionally substituted C1-3 alkyl: 45 embodiments, the nitrogen atom of the morpholine in For each R, represents a Substituent independently selected mulas I-III above is functionalized with such a chemical from the group consisting of OH, optionally substituted moiety. Prodrugs include, but are not limited to, compounds C1-4 alkyl, optionally substituted C1-4 alkoxy, option that can be oxidized, reduced, aminated, deaminated, ally substituted C2-4 alkenyl, optionally substituted hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, C2-4 alkynyl, halogen, amino, acylamido, CN, CF, 50 alkylated, dealkylated, acylated, deacylated, phosphory NO, N, CONH CO.R., CHOH, CHOR, lated, and/or dephosphorylated to produce the active com NRR, NHCOR, NHCOR CONRR, C1-3 pound. alkylthio, RSO, RSO, CFS, and CFSO, wherein A number of prodrug ligands are known. In general, R and R are each independently selected from Hor alkylation, acylation, or other lipophilic modification of one optionally substituted C1-10 alkyl; 55 or more heteroatoms of the compound, such as a free amine b is an integer from 0-5; and or carboxylic acid residue, may reduce polarity and allow for with the proviso that when R is CH, then (a) b is an integer the compounds passage into cells. The means by which the from 1-5, or (b) R is substituted C1 alkyl or optionally modification of one or more heteroatoms of the compound substituted C2-C3 alkyl, or (c) one or more of R. Rs, and is performed may vary, and typical methods for Such modi R is not H, or a combination of two or more of (a) through 60 fications are familiar to one of skill in the art of organic (c), or a pharmaceutically acceptable ester, amide, salt, synthesis. For example, general reaction conditions for the Solvate, prodrug, or isomer thereof. alkylation and acylation of heteroatoms are well known and In some preferred embodiments, b=0 or 1. In certain can be modified for application to the compounds provided embodiments, b=1 and R, is selected from the group con herein. sisting of CH, F, and Cl. In certain embodiments, the R, 65 In some prodrug embodiments, the amine of the morpho Substituent is located meta or para to the morpholine Sub line ring of any one of Formulas I-III is modified to provide stituent on the phenyl ring. a prodrug. Examples of Substituent groups that can replace US 9,617,229 B2 11 12 one or more hydrogen atoms on the free amine and/or pharmacological activity of the compound in comparison to carboxylic acid moiety include, but are not limited to, the the free compound. In some embodiments, X is any phar following: aryl; Steroids; carbohydrates (including Sugars); maceutically acceptable chemical moiety which, when the 1.2-diacylglycerol; alcohols; acyl (including lower acyl); prodrug is administered in Vivo, is cleaved in whole or in alkyl (including lower alkyl); Sulfonate ester (including part to provide a free amine on the morpholine ring. Exem alkyl or arylalkyl Sulfonyl. Such as methanesulfonyl and plary chemical moieties include, but are not limited to, benzyl, wherein the phenyl group is optionally substituted peptides, carbohydrates (including Sugars), lipids, nucleo with one or more substituents as provided in the definition sides, nucleic acids, and vitamins, aryl groups; steroids; of an aryl given herein); optionally substituted arylsulfonyl: 1.2-diacylglycerol; alcohols; optionally Substituted acyl lipids (including phospholipids); phosphotidylcholine; 10 groups (including lower acyl); optionally substituted alkyl phosphocholine; amino acid residues or derivatives; amino groups (including lower alkyl); Sulfonate esters (including acid acyl residues or derivatives; peptides; cholesterols; or alkyl or arylalkyl Sulfonyl. Such as methanesulfonyl and other pharmaceutically acceptable leaving groups which, benzyl, wherein the phenyl group is optionally substituted when administered in vivo, provide the free amine. Any of 15 with one or more substituents as provided in the definition these moieties can be used in combination with the disclosed of an aryl given herein); optionally Substituted arylsulfonyl active agents to achieve a desired effect. groups; lipids (including phospholipids); phosphotidylcho Prodrugs may be particularly useful according to the line; phosphocholine; amino acid residues or derivatives; present invention, as they may provide a safer alternative for amino acid acyl residues or derivatives; cholesterols; or treatment due to the noted high potential for abuse of other pharmaceutically acceptable leaving groups which, amphetamines and related compounds. Although the thera when administered in vivo, provide the free amine and/or peutic effect of the prodrugs may be similar to that provided carboxylic acid moiety. Peptides include dipeptides, tripep by the free compounds, the prodrugs of the present invention may be stable under conditions commonly used to provide tides, oligopeptides, and polypeptides. drugs in concentrated form for illicit use. Specifically, using In some preferred embodiments, X is an amino acid. a prodrug should reduce the risk that pills comprising the 25 Where X is an amino acid or peptide, the amino acid(s) may prodrug might be used to extract the drug and concentrate it be naturally occurring or unnatural, non-standard, or syn or use it via other methods (e.g., via intravenous adminis thetic, and may be either the L- or D enantiomer. Particularly tration, Snorting, or Smoking), because additional steps (i.e., preferable amino acids for use in the present invention for example, acid cleavage and extraction) are required to include alanine, lysine, serine, phenylalanine, arginine, gly provide the prodrug compound in the pure drug form. 30 cine, glutamic acid, or leucine. In some preferred embodi Additionally, a prodrug form may be advantageous in that it ments of the invention, a prodrug of Formula IV is provided, may deliver a constant low dose of the drug which reduces wherein m=0. In some preferred embodiments of the inven abuse liability by “slow onset, i.e., a pharmacokinetics tion, a prodrug of Formula IV is provided, wherein X is a approach. single amino acid. In other preferred embodiments, a pro 35 drug of Formula IV is provided, wherein X is a peptide. Prodrugs of the present invention may be represented by With regard to peptide conjugates, an iterative approach Formula IV: can be used to identify favorable conjugates by Synthesizing and testing single amino acid conjugates and Subsequently Formula IV extending the peptide by one amino acid at a time. The Rs 40 parent single amino acid prodrug candidate may exhibit R R6 more or less desirable characteristics than the Subsequent di or tri-, etc. peptide candidates. The iterative approach can be beneficial in determining whether peptide length influences R R4 bioavailability. 45 In some other embodiments, X may be represented by the X following: Zn

wherein: 50 R. R. R. Rs, and R are the same as indicated above for Formula I; X is a chemical moiety, wherein each X may be the same or different; n is an integer from 0 to 50, preferably 1 to 10; 55 Z is a chemical moiety that acts as an adjuvant, wherein - -. each Z may be the same or different, and wherein each O S. O S. Z is different from at least one X; and m is an integer from 0 to 50. In some embodiments, X may be alkyl. In some embodi 60 ments, when R is CH R is phenyl, R-R are H. n=1, and m=0, X is not CH. In some, but not all, embodiments of Formula IV, when R is phenyl, the phenyl ring is substituted with one or more Substituents and/or one or more of R. Rs. As noted, Z may be a chemical moiety that acts as an and R is not H. 65 adjuvant. Exemplary chemical moieties that may comprise Z The chemical moiety constituting X may be any chemical include those indicated for X, above (e.g., peptides, amino moiety that, while bound to the compound, decreases the acids, carbohydrates, vitamins) Further examples of Z may US 9,617,229 B2 13 14 be found, for example, in U.S. Patent Application Publica the (R) or (S) configuration, or which may comprise a tion 2009/0192093 to Mickle et al., incorporated by refer mixture thereof. Accordingly, the present invention also ence herein in its entirety. includes stereoisomers of the compounds and prodrugs In preferred embodiments, m=0, which is represented by described herein, where applicable, either individually or Formula V: admixed in any proportions. Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers can Formula V be prepared and separated using conventional techniques, Rs either by reacting enantiomeric starting materials, or by 10 separating isomers of compounds and prodrugs of the pres ent invention. Isomers may include geometric isomers. RC R6 Examples of geometric isomers include, but are not limited R R4 to, cis isomers or trans isomers across a double bond. Other X isomers are contemplated among the compounds of the 15 present invention. The isomers may be used either in pure form or in admixture with other isomers of the compounds wherein the substituents are the same as those indicated described herein. for Formula IV. The compounds of the present invention may be com In preferred embodiments, when R is CH, R is phenyl, pounds according to Formulas I-III with one or more chiral Ra-R are H, and n=1, X is not CH. centers, which may be either of the (R) or (S) configuration, In some preferred embodiments, prodrugs of the present or which may comprise a mixture thereof. The carbon to invention may be represented by the following formula: which R and Rs are connected may be either of the R or S configuration. When R is a substituent other than H, the carbon to which R is connected is a chiral center and may Formula VI 25 be either of the R or S configuration. When R is a substitu Rs ent other than H, the carbon to which R is connected to is R6 a chiral center and may be either of the R or S configuration. When R is a substituent other than H, the carbon to which R is connected is a chiral center and may be either of the R 30 or S configuration. The present invention includes both R 1. R4 racemic mixtures of a compound of Formula I and isolated isomers of Formulas I-III. Where more than one chiral Rs O center is present in a compound of the invention, Some, none, or all of the chiral centers may be enantiomerically wherein the substituents are the same as those indicated 35 enriched. Thus, mixtures of a compound of Formulas I-III for Formula IV, except that: may be racemic with respect to one or more chiral centers Rs is optionally substituted C1-10 alkyl, optionally sub and/or enantiomerically enriched with respect to one or stituted C1-10 alkoxy, optionally substituted phenyl, option more chiral centers. ally substituted benzyl, or optionally substituted pyridyl. For In some preferred embodiments, an enantiomerically example, in certain embodiments, Rs may be, but is not 40 enriched sample of a compound of Formulas I-III is pro limited to, CH, CHCH phenyl, benzyl, 4-CHNPh. vided wherein the carbon to which R and Rs are attached is 3-pyridyl, OCH, OCHCH (CH)N(CH), (CH)N" (R) or (S). In some preferred embodiments, an enantiomeri (CH), O(CH)NH2. O(CH)N(CH), and O(CH)-N-- cally enriched sample of a compound of Formulas I-III is (CH), or any of the following: provided wherein the carbon to which R is attached is (R) 45 or (S). In some preferred embodiments, an enantiomerically enriched sample of a compound of Formulas I-III is pro vided wherein the carbon to which R is attached is (R) or (S). In some preferred embodiments, an enantiomerically x-rr xxy enriched sample of a compound of Formulas I-III is pro 50 vided wherein the compound to which R is attached is (R) or (S). In some preferred embodiments, an enantiomerically enriched sample of a compound of Formulas I-III is pro vided wherein both the carbon to which R and Rs is attached and the carbon to which R is attached are inde 55 pendently (R) or (S) (e.g., (R, S), (S,R), (R,R), or (S,S)). In some preferred embodiments, an enantiomerically enriched sample of a compound of Formulas I-III is pro vided wherein both the carbon to which R and Rs is attached and the carbon to which R is attached are inde 60 pendently (R) or (S) (e.g., (R, S), (S,R), (R,R), or (S,S)). In some embodiments, compounds or prodrugs with one In some preferred embodiments, an enantiomerically or more chiral centers are provided. While racemic mixtures enriched sample of a compound of Formulas I-III is pro of compounds or prodrugs of the invention may be active, vided wherein both the carbon to which R and Rs is selective, and bioavailable, isolated isomers may be of attached and the carbon to which R is attached are inde interest as well. 65 pendently (R) or (S) (e.g., (R, S), (S,R), (R,R), or (S,S)). The compounds and prodrugs disclosed herein as active In some preferred embodiments, an enantiomerically agents may contain chiral centers, which may be either of enriched sample of a compound of Formulas I-III is pro US 9,617,229 B2 15 16 vided wherein both the carbon to which R is attached and ii) simultaneous crystallization whereby the individual the carbon to which R is attached are independently (R) or enantiomers are separately crystallized from a solution of (S) (e.g., (R, S), (S,R), (R, R), or (S, S)). Obviously, the racemate, possible only if the latter is a conglomerate in compounds are within the scope of the present invention the solid state; wherein one, two, three, or four chiral centers are provided iii) enzymatic resolutions whereby partial or complete on the morpholine ring. Accordingly, various enantiomeri separation of a racemate by virtue of differing rates of cally enriched compounds may be provided, wherein the reaction for the enantiomers with an enzyme; compounds may be racemic with respect to one or more iv) enzymatic asymmetric synthesis, a synthetic technique chiral centers and/or enantiomerically enriched with respect whereby at least one step of the synthesis uses an enzymatic 10 reaction to obtain an enantiomerically pure or enriched to one or more chiral centers. synthetic precursor of the desired enantiomer; The prodrugs of the present invention may be prodrugs V) chemical asymmetric synthesis whereby the desired according to Formula IV with one or more chiral centers, enantiomer is synthesized from an achiral precursor under which may be either of the (R) or (S) configuration, or which conditions that produce asymmetry (i.e., chirality) in the may comprise a mixture thereof. The carbon to which R and 15 product, which may be achieved using chiral catalysts or Rs are connected may be either of the R or S configuration. chiral auxiliaries; When R is a substituent other than H, the carbon to which vi) diastereomer separations whereby a racemic com R is connected is chiral and may be either of the R or S pound is reacted with an enantiomerically pure reagent (the configuration. When R is a substituent other than H, the chiral auxiliary) that converts the individual enantiomers to carbon to which R is connected to is chiral and may be diastereomers. The resulting diastereomers are then sepa either of the R or S configuration. When R is a substituent rated by chromatography or crystallization by virtue of their other than H, the carbon to which R is connected to is chiral now more distinct structural differences and the chiral and may be either of the R or S configuration. Accordingly, auxiliary later removed to obtain the desired enantiomer; the present invention includes both racemic mixtures of vii) first- and second-order asymmetric transformations prodrugs of Formula IV and isolated isomers of Formula IV. 25 whereby diastereomers from the racemate equilibrate to Where more than one chiral center is present in a compound yield a preponderance in Solution of the diastereomer from of the invention, Some, none, or all of the chiral centers may the desired enantiomer or where preferential crystallization be enantiomerically enriched. Thus, mixtures of a compound of the diastereomer from the desired enantiomer perturbs the of Formula IV may be racemic with respect to one or more equilibrium such that eventually in principle all the material chiral centers and/or enantiomerically enriched with respect 30 is converted to the crystalline diastereomer from the desired to one or more chiral centers. enantiomer. The desired enantiomer is then released from the diastereomers: In some preferred embodiments, an enantiomerically viii) kinetic resolutions comprising partial or complete enriched sample of a prodrug of Formula IV is provided resolution of a racemate (or of a further resolution of a wherein the carbon to which R and Rs are attached is (R) 35 partially resolved compound) by virtue of unequal reaction or (S). In some preferred embodiments, an enantiomerically rates of the enantiomers with a chiral, non-racemic reagent enriched sample of a prodrug of Formula IV is provided or catalyst under kinetic conditions; wherein the carbon to which R is attached is (R) or (S). In iX) enantiospecific synthesis from non-racemic precursors Some preferred embodiments, an enantiomerically enriched whereby the desired enantiomer is obtained from non-chiral sample of a prodrug of Formula IV is provided wherein the 40 starting materials and where the stereochemical integrity is carbon to which R is attached is (R) or (S). In some not or is only minimally compromised over the course of the preferred embodiments, an enantiomerically enriched synthesis; sample of a prodrug of Formula IV is provided wherein both X) chiral liquid chromatography whereby the enantiomers the carbon to which R and Rs are attached and the carbon of a racemate are separated in a liquid mobile phase by to which R is attached are independently (R) or (S) (e.g., (R, 45 virtue of their differing interactions with a stationary phase. S), (S,R), (R,R), or (S,S)). In some preferred embodiments, The stationary phase can be made of chiral material or the an enantiomerically enriched sample of a prodrug of For mobile phase can contain an additional chiral material to mula IV is provided wherein both the carbon to which R provoke the differing interactions; and Rs are attached and the carbon to which R is attached Xi) chiral gas chromatography whereby the racemate is are independently (R) or (S) (e.g., (R, S), (S,R), (R,R), or 50 volatilized and enantiomers are separated by virtue of their (S,S)). In some preferred embodiments, an enantiomerically differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent enriched sample of a prodrug of Formula IV is provided phase; wherein both the carbon to which R is attached and the xii) extraction with chiral solvents whereby the enantiom carbon to which R is attached are independently (R) or (S) 55 ers are separated by virtue of preferential dissolution of one (e.g., (R, S), (S,R), (R,R), or (S,S)). enantiomer into a particular chiral solvent; and Various methods are known in the art for preparing xiii) transport across chiral membranes whereby a race optically active forms and determining activity. Such meth mate is placed in contact with a thin membrane barrier. The ods include standard tests described herein and other similar barrier typically separates two miscible fluids, one contain tests which are well known in the art. Examples of methods 60 ing the racemate, and a driving force Such as concentration that can be used to obtain optical isomers of the compounds or pressure differential causes preferential transport across according to the present invention include the following: the membrane barrier. Separation occurs as a result of the i) physical separation of crystals whereby macroscopic non-racemic chiral nature of the membrane which allows crystals of the individual enantiomers are manually sepa only one enantiomer of the racemate to pass through. rated. This technique may particularly be used when crystals 65 The compound optionally may be provided in a compo of the separate enantiomers exist (i.e., the material is a sition that is enantiomerically enriched, Such as a mixture of conglomerate), and the crystals are visually distinct; enantiomers in which one enantiomer is present in excess, in US 9,617,229 B2 17 18 particular, to the extent of 95% or more, 96% or more, 97% In another embodiment, an alternative enantiomer is pro or more, 98% or more, or 99% or more, including 100%. vided, represented by Formula X: In some embodiments, a compound of Formula I or a prodrug of Formula V is provided, wherein the compound Formula X contains one or more chiral centers. Specifically, the carbon Rs to which R and Rs is attached is a chiral center, and may have either an R or S configuration. Depending on the Substituents on the compound, other chiral centers may be h R6 present in the compound as well. In some embodiments, the 10 R N R4 compound is provided in a composition that is enantiomeri 3 cally enriched. One preferred configuration is represented below in Figure VII. The chiral center(s) present in the or a pharmaceutically acceptable ester, amide, salt, Sol compounds may be designated as either R or S, depending Vate, prodrug, or isomer thereof. on the specific Substituents on the chiral center. For example, 15 These compounds or prodrugs, wherein two chiral centers in Formula VII below, when R is phenyl and Rs is H, the are present in the molecule, may be (R,R), (S,S), (R.S.), or carbon center is designated as R, whereas when R is phenyl (S,R) isomers. The “trans’ compounds, wherein one of R and Rs is OH, the carbon center is designated as S. and R is above the plane of the molecule and one of R and R is below the plane of the molecule are encompassed by Although various stereoisomers may be represented by the invention. The “cis' compounds, wherein R and R are the previous formulas, one particularly preferred configura both above the plane of the molecule, or wherein R and R. tion of Foilinula I is represented by Formula VII: are both below the plane of the molecule, are also within the purview of this invention. In these compounds, as noted above, the identity of the Substituents comprising R and Rs Formula VII 25 will determine whether the carbon center to which these 5 Substituents are attached is designated as R or S. As noted above, the carbon centers to which R, R and R r R are attached may be chiral, when these substituents are R N not H. Compounds wherein one or more of the four carbons 2 R3 R4 30 on the morpholine ring are chiral are encompassed within the present invention. Compounds that are enantiomerically enriched with regard to zero, one, two, three, or all four or a pharmaceutically acceptable ester, amide, salt, Sol carbon centers on the morpholine ring are encompassed. All Vate, prodrug, or isomer thereof. isomeric combinations are encompassed within the present In an alternative embodiment, a preferred configuration of 35 invention. The terms (R), (S), (R,R), (S,S), (R.S) and (S,R) as used Formula I is represented by Formula VIII, wherein R is not herein mean that the composition contains a greater propor H: tion of the named isomer of the compound or prodrug in relation to other isomers. In a preferred embodiment these 40 terms indicate that the composition contains at least 90% by Formula VIII weight of the named isomer and 10% by weight or less of the one or more other isomers; or more preferably about 95% by weight of the named isomer and 5% or less of the one or more other isomers. In some embodiments, the composition 45 may contain at least 99% by weight of the named isomer and 1% or less by weight of the one or more other isomers, or may contain 100% by weight of the named isomer and 0% by weight of the one of more other isomers. These percent or a pharmaceutically acceptable ester, amide, salt, Sol ages are based on the total amount of the compound of the Vate, prodrug, or isomer thereof. 50 present invention present in the composition. Additional chiral centers may be present in the com In one embodiment, R is not H and a chiral center exists pounds and prodrugs of the present invention. Compound both at the carbon to which R and Rs are attached, and at samples wherein the compounds contain any of the afore the carbon alpha to the amine of the morpholine ring (to mentioned chiral centers may be racemic or may be which R is attached), as shown below in Formula IX: 55 enantiomerically enriched. Where more than one chiral center is present in a compound or prodrug of the invention, Some, none, or all of the chiral centers may be enantiomeri Formula IX cally enriched. Thus, they may be racemic with respect to one or more chiral centers and/or enantiomerically enriched 60 with respect to one or more chiral centers. The compounds and prodrugs of the present invention may be utilized perse or in the form of a pharmaceutically acceptable ester, amide, salt, Solvate, prodrug, or isomer. For example, the compound or prodrug may be provided as a 65 pharmaceutically acceptable salt. If used, a salt of the drug or a pharmaceutically acceptable ester, amide, salt, Sol compound or prodrug should be both pharmacologically and Vate, prodrug, or isomer thereof. pharmaceutically acceptable, but non-pharmaceutically US 9,617,229 B2 19 20 acceptable salts may conveniently be used to prepare the but are not limited to, compounds according to the invention free active compound, prodrug, or pharmaceutically accept in combination with water, isopropanol, ethanol, methanol, able salts thereof and are not excluded from the scope of this DMSO, ethyl acetate, acetic acid, or ethanolamine. invention. Such pharmacologically and pharmaceutically In the case of Solid compositions, it is understood that the acceptable salts can be prepared by reaction of the drug with 5 compounds and prodrugs used in the methods of the inven an organic or inorganic acid, using standard methods tion may exist in different forms. For example, the com detailed in the literature. pounds or prodrugs may exist in stable and metastable Examples of pharmaceutically acceptable salts of the crystalline forms and isotropic and amorphous forms, all of compounds and prodrugs useful according to the invention which are intended to be within the scope of the present include acid addition salts. Salts of non-pharmaceutically 10 acceptable acids, however, may be useful, for example, in invention. the preparation and purification of the compounds. Suitable If a compound or prodrug useful as an active agent acid addition salts according to the present invention include according to the invention is a base, the desired salt may be organic and inorganic acids. Preferred salts include those prepared by any suitable method known to the art, including formed from hydrochloric, hydrobromic, sulfuric, phos 15 treatment of the free base with an inorganic acid, such as phoric, citric, tartaric, lactic, pyruvic, acetic, succinic, hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric fumaric, maleic, oxaloacetic, methanesulfonic, ethanesulfo acid, phosphoric acid and the like, or with an organic acid, nic, p-toluenesulfonic, benzenesulfonic, and isethionic Such as acetic acid, maleic acid, Succinic acid, mandelic acids. Other useful acid addition salts include propionic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, acid, glycolic acid, oxalic acid, malic acid, malonic acid, glycolic acid, Salicylic acid, pyranosidyl acids such as benzoic acid, cinnamic acid, mandelic acid, salicylic acid, glucuronic acid and galacturonic acid, alpha-hydroxy acids and the like. Particular example of pharmaceutically accept Such as citric acid and tartaric acid, amino acids such as able salts include, but are not limited to, Sulfates, pyrosul aspartic acid and glutamic acid, aromatic acids such as fates, bisulfates, Sulfites, bisulfites, phosphates, monohydro benzoic acid and cinnamic acid, Sulfonic acids such a genphosphates, dihydrogenphosphates, metaphosphates, 25 p-toluenesulfonic acid or ethanesulfonic acid, or the like. pyrophosphates, chlorides, bromides, iodides, acetates, pro If a compound or prodrug described herein as an active pionates, decanoates, caprylates, acrylates, formates, isobu agent is an acid, the desired salt may be prepared by any tyrates, caproates, heptanoates, propiolates, oxalates, suitable method known to the art, including treatment of the malonates. Succinates, Suberates, sebacates, fumarates, free acid with an inorganic or organic base, such as an amine maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzo 30 (primary, secondary or tertiary), an alkali metal or alkaline ates, chlorobenzoates, methylbenzoates, dinitrobenzoates, earth metal hydroxide or the like. Illustrative examples of hydroxybenzoates, methoxyenzoates, phthalates, sulfonates, suitable salts include organic salts derived from amino acids Xylenesulfonates, phenylacetates, phenylpropionates, phe Such as glycine and arginine, ammonia, primary, secondary nylbutyrates, citrates, lactates, Y-hydroxybutyrates, glyco and tertiary amines, and cyclic amines Such as piperidine, lates, tartrates, methanesulfonates, propanesulfonates, naph 35 morpholine and piperazine, and inorganic salts derived from thalene-1-sulfonates, naphthalene-2-sulfonates, and Sodium, calcium, potassium, magnesium, manganese, iron, mandelates. copper, Zinc, aluminum and lithium. An acid addition salt may be reconverted to the free base Some preferred compounds of the invention include the by treatment with a suitable base. Preparation of basic salts following, wherein Ra and Rs are H, the R substituent on the of acid moieties which may be present on a compound or 40 morpholine ring is phenyl and the Substituents on the phenyl prodrug useful according to the present invention may be are varied. prepared in a similar manner using a pharmaceutically acceptable base, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, tri R7B ethylamine, or the like. 45 R7C R7. Esters of the active agent compounds according to the present invention may be prepared through functionalization Rs of hydroxyl and/or carboxyl groups that may be present O within the molecular structure of the compound or prodrug. R7D Amides and prodrugs may also be prepared using techniques 50 RE known to those skilled in the art. For example, amides may R 2 NR3 R4 be prepared from esters, using Suitable amine reactants, or they may be prepared from anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine. Moreover, esters and amides of compounds and prodrugs of the inven 55 TABLE 1. tion can be made by reaction with a carbonylating agent (e.g., ethyl formate, acetic anhydride, methoxyacetyl chlo Representative Compounds of the Invention ride, benzoyl chloride, methyl isocyanate, ethyl chlorofor R2 R3 R. Rs R74 R7B R7C R7D R7. mate, methanesulfonyl chloride) and a suitable base (e.g., CH H H H CH H H H H 4-dimethylaminopyridine, pyridine, triethylamine, potas 60 CH, H H H H CH H H H sium carbonate) in a suitable organic solvent (e.g., tetrahy CH, H H H H H CH H H drofuran, acetone, methanol, pyridine, N,N-dimethylforma CH H H H CH, CH H H H mide) at a temperature of 0° C. to 60° C. Prodrugs are CH H H H CH H CH H H CH, H H H CH, H H CH H typically prepared by covalent attachment of a moiety, CH H H H CH H H H CH which results in a compound that is therapeutically inactive 65 CH, H H H H CH CH H H until modified by an individual's metabolic system. CH, H H H H CH H CH H Examples of pharmaceutically acceptable Solvates include, US 9,617,229 B2 21 22 TABLE 1-continued TABLE 1-continued Representative Compounds of the Invention Representative Compounds of the Invention US 9,617,229 B2 23 24 TABLE 1-continued TABLE 2

Representative Compounds of the Invention

R. R. Rs R7 R7e R7. R7e R3 R. Rs

US 9,617,229 B2 27 28 ments, there is little or no norepinephrine release. In some maceutical Excipients, 6" ed., Eds. Raymond C. Rowe et al., embodiments, the compounds show little or no activity at the Pharmaceutical Press (2009), which are incorporated herein 5HT receptor. In some embodiments, the compounds of by reference. the present invention function as uptake inhibitors of one or Binders are generally used to facilitate cohesiveness of more monoamine neurotransmitters. In particular embodi the tablet and ensure the tablet remains intact after com ments, the compounds show hybrid activity in that they pression. Suitable binders include, but are not limited to: cause release of one or more monoamines and also cause starch, polysaccharides, gelatin, polyethylene glycol, pro uptake inhibition of one or more monoamines. For example, pylene glycol, waxes, and natural and synthetic gums. in Some embodiments, compounds of the present invention Acceptable fillers include silicon dioxide, titanium dioxide, act as dopamine and/or norepinephrine releasers and as 10 alumina, talc, kaolin, powdered cellulose, and microcrystal line cellulose, as well as soluble materials, such as mannitol, serotonin uptake inhibitors. In certain embodiments, the urea, Sucrose, lactose, dextrose, Sodium chloride, and Sor compounds are serotonin releasers or serotonin uptake bitol. Lubricants are useful for facilitating tablet manufac inhibitors, but display little to no activity at the 5HT. ture and include vegetable oils, glycerin, magnesium Stear receptor. 15 ate, calcium Stearate, and Stearic acid. Disintegrants, which In some embodiments, phenyl ring Substitution increases are useful for facilitating disintegration of the tablet, gen serotonin release. In certain embodiments, increased sero erally include Starches, clays, celluloses, algins, gums, and tonin release is desirable in decreasing the addiction liability crosslinked polymers. Diluents, which are generally commonly demonstrated by dopamine releasers and some included to provide bulk to the tablet, may includedicalcium combination dopamine?serotonin releasers. phosphate, calcium sulfate, lactose, cellulose, kaolin, man Compositions nitol, Sodium chloride, dry starch, and powdered Sugar. While it is possible for the compounds and prodrugs of the Surfactants suitable for use in the formulation according to present invention to be administered in the raw chemical the present invention may be anionic, cationic, amphoteric, form, it is preferred for the compounds or prodrugs to be or nonionic Surface active agents. Stabilizers may be delivered as a pharmaceutical formulation. Accordingly, 25 included in the formulations to inhibit or lessen reactions there are provided by the present invention pharmaceutical leading to decomposition of the active agent, such as oxi compositions comprising at least one compound capable of dative reactions. inhibiting the reuptake of one or more monoamines. As Formulations of the present invention may include short Such, the formulations of the present invention comprise a term, rapid-onset, rapid-offset, controlled release, Sustained compound of any of the formulas noted herein, as described 30 release, delayed release, and pulsatile release formulations, above, or a pharmaceutically acceptable ester, amide, salt, or providing the formulations achieve administration of a com solvate thereof, together with one or more pharmaceutically pound as described herein. See Remington's Pharmaceutical acceptable carriers therefore, and optionally, other therapeu Sciences (18" ed.: Mack Publishing Company, Eaton, Pa., tic ingredients. 1990), herein incorporated by reference in its entirety. By “pharmaceutically acceptable carrier is intended a 35 Pharmaceutical formulations according to the present carrier that is conventionally used in the art to facilitate the invention are suitable for various modes of delivery, includ storage, administration, and/or the healing effect of the ing oral, parenteral (including intravenous, intramuscular, agent. The carrier(s) must be pharmaceutically acceptable in Subcutaneous, intradermal, and transdermal), topical (in the sense of being compatible with the other ingredients of cluding dermal, buccal, and Sublingual), and rectal admin the formulation and not unduly deleterious to the recipient 40 istration. The most useful and/or beneficial mode of admin thereof. A carrier may also reduce any undesirable side istration can vary, especially depending upon the condition effects of the agent. Such carriers are known in the art. See, of the recipient and the disorder being treated. However, in Wang et al. (1980) J. Parent. Drug Assn. 34 (6):452-462, preferred embodiments, the formulation is for oral delivery, herein incorporated by reference in its entirety. as oral administration may provide the drug while maintain Adjuvants or accessory ingredients for use in the formu 45 ing abuse resistance. lations of the present invention can include any pharmaceu The pharmaceutical formulations may be conveniently tical ingredient commonly deemed acceptable in the art, made available in a unit dosage form, whereby Such formu Such as binders, fillers, lubricants, disintegrants, diluents, lations may be prepared by any of the methods generally Surfactants, stabilizers, preservatives, flavoring and coloring known in the pharmaceutical arts. Generally speaking, Such agents, and the like. The compositions may further include 50 methods of preparation comprise combining (by various diluents, buffers, binders, disintegrants, thickeners, lubri methods) an active agent, such as the compounds of Formula cants, preservatives (including antioxidants), flavoring I according to the present invention (or a pharmaceutically agents, taste-masking agents, inorganic salts (e.g., sodium acceptable ester, amide, Salt, or Solvate thereof) or the chloride), antimicrobial agents (e.g., benzalkonium chlo prodrugs of Formula IV, with a suitable carrier or other ride), Sweeteners, antistatic agents, Surfactants (e.g., poly 55 adjuvant, which may consist of one or more ingredients. The sorbates such as “TWEEN 20 and “TWEEN 80, and combination of the active ingredient with the one or more pluronics such as F68 and F88, available from BASF), adjuvants is then physically treated to present the formula Sorbitan esters, lipids (e.g., phospholipids such as lecithin tion in a suitable form for delivery (e.g., shaping into a tablet and other phosphatidylcholines, phosphatidylethano or forming an aqueous Suspension). lamines, fatty acids and fatty esters, steroids (e.g., choles 60 Pharmaceutical formulations according to the present terol)), and chelating agents (e.g., EDTA, Zinc and other invention Suitable as oral dosage may take various forms, Such suitable cations). Other exemplary pharmaceutical Such as tablets, capsules, caplets, and wafers (including excipients and/or additives Suitable for use in the composi rapidly dissolving or effervescing), each containing a pre tions according to the invention are listed in Remington: The determined amount of the active agent. The formulations Science & Practice of Pharmacy, 21 ed., Lippincott Wil 65 may also be in the form of a powder or granules, a solution liams & Wilkins (2006); in the Physician’s Desk Reference, or Suspension in an aqueous or non-aqueous liquid, and as 64" ed., Thomson PDR (2010); and in Handbook of Phar a liquid emulsion (oil-in-water and water-in-oil). The active US 9,617,229 B2 29 30 agent may also be delivered as a bolus, electuary, or paste. deimal drug delivery may occur through passive diffusion or It is generally understood that methods of preparations of the may be facilitated using electrotransport or iontophoresis. above dosage forms are generally known in the art, and any Formulations for rectal delivery of the compounds of the such method would be suitable for the preparation of the present invention include rectal Suppositories, creams, oint respective dosage forms for use in delivery of the com ments, and liquids. Suppositories may be presented as the pounds according to the present invention. active agent in combination with a carrier generally known A tablet containing a compound or prodrug according to in the art, such as polyethylene glycol. Such dosage forms the present invention may be manufactured by any standard may be designed to disintegrate rapidly or over an extended process readily known to one of skill in the art, Such as, for period of time, and the time to complete disintegration can example, by compression or molding, optionally with one or 10 range from a short time, Such as about 10 minutes, to an extended period of time, such as about 6 hours. more adjuvant or accessory ingredient. The tablets may The compounds of the formulas above may be formulated optionally be coated or scored and may be formulated so as in compositions including those Suitable for oral, buccal, to provide slow or controlled release of the active agent. rectal, topical, nasal, ophthalmic, or parenteral (including Solid dosage forms may be formulated so as to provide a 15 intraperitoneal, intravenous, Subcutaneous, or intramuscular delayed release of the active agent, such as by application of injection) administration. The compositions may conve a coating. Delayed release coatings are known in the art, and niently be presented in unit dosage form and may be dosage from containing Such may be prepared by any known prepared by any of the methods well known in the art of suitable method. Such methods generally include that, after pharmacy. All methods include the step of bringing a com preparation of the Solid dosage form (e.g., a tablet or caplet), pound or prodrug of one of the formulas disclosed herein a delayed release coating composition is applied. Applica into association with a carrier that constitutes one or more tion can be by methods such as airless spraying, fluidized accessory ingredients. In general, the compositions are pre bed coating, use of a coating pan, or the like. Materials for pared by bringing a compound or prodrug of the invention use as a delayed release coating can be polymeric in nature, into association with a liquid carrier to form a solution or a Such as cellulosic material (e.g., cellulose butyrate phthalate, 25 Suspension, or alternatively, bringing a compound or prod hydroxypropyl methylcellulose phthalate, and carboxym rug of the invention into association with formulation com ethyl ethylcellulose), and polymers and copolymers of ponents Suitable for forming a solid, optionally a particulate acrylic acid, methacrylic acid, and esters thereof. product, and then, if warranted, shaping the product into a Solid dosage forms according to the present invention desired delivery form. Solid formulations of the invention, may also be Sustained release (i.e., releasing the active agent 30 when particulate, will typically comprise particles with sizes over a prolonged period of time), and may or may not also ranging from about 1 nanometer to about 500 microns. In be delayed release. Sustained release formulations are general, for solid formulations intended for intravenous known in the art and are generally prepared by dispersing a administration, particles will typically range from about 1 drug within a matrix of a gradually degradable or hydrolyZ nm to about 10 microns in diameter. able material. Such as an insoluble plastic, a hydrophilic 35 The amount of the compound or prodrug of any one of the polymer, or a fatty compound. Alternatively, a Solid dosage formulas disclosed herein contained in the formulation will form may be coated with Such a material. vary depending the specific compound or prodrug selected, Formulations for parenteral administration include aque dosage form, target patient population, and other consider ous and non-aqueous sterile injection Solutions, which may ations, and will be readily determined by one skilled in the further contain additional agents, such as anti-oxidants, 40 art. The amount of the compound or prodrug in the formu buffers, bacteriostats, and solutes, which render the formu lation will be that amount necessary to deliver a therapeu lations isotonic with the blood of the intended recipient. The tically effective amount of the compound to a patient in need formulations may include aqueous and non-aqueous sterile thereof to achieve at least one of the therapeutic effects Suspensions, which contain Suspending agents and thicken associated with the compounds or prodrugs of the invention. ing agents. Such formulations for patenteral administration 45 In practice, this will vary widely depending upon the par may be presented in unit-dose or multi-dose containers. Such ticular compound or prodrug, its activity, the severity of the as, for example, sealed ampoules and vials, and may be condition to be treated, the patient population, the stability stores in a freeze-dried (lyophilized) condition requiring of the formulation, and the like. Compositions will generally only the addition of the sterile liquid carrier, for example, contain anywhere from about 1% by weight to about 99% by water (for injection), immediately prior to use. Extempora 50 weight of a compound or prodrug of the invention, typically neous injection Solutions and Suspensions may be prepared from about 5% to about 70% by weight, and more typically from sterile powders, granules, and tablets of the kind from about 10% to about 50% by weight, and will also previously described. depend upon the relative amounts of excipients/additives The compounds according to the present invention may contained in the composition. also be administered transdermally, wherein the active agent 55 Combinations is incorporated into a laminated Structure (generally referred In specific embodiments, active agents used in combina to as a "patch') that is adapted to remain in intimate contact tion with compounds or prodrugs of the present invention with the epidermis of the recipient for a prolonged period of comprise one or more compounds generally recognized as time. Typically, Such patches are available as single layer useful for treating the conditions discussed herein. In one 'drug-in-adhesive' patches or as multi-layer patches where 60 embodiment, the use of two or more drugs, which may be of the active agent is contained in a layer separate from the different therapeutic classes, may enhance efficacy and/or adhesive layer. Both types of patches also generally contain reduce adverse effects associated with one or more of the a backing layer and a liner that is removed prior to attach drugs. ment to the skin of the recipient. Transdermal drug delivery For example, in certain embodiments, the present inven patches may also be comprised of a reservoir underlying the 65 tion provides a method for treating pre-obesity and obesity, backing layer that is separated from the skin of the recipient comprising a combination of a compound or prodrug of the by a semi-permeable membrane and adhesive layer. Trans present invention and one or more known antiobesity drugs. US 9,617,229 B2 31 32 Common therapeutic classes of obesity drugs include those melatonin, epinephrine, norepinephrine, and dopamine). that decrease food intake by either reducing appetite or Thus, MAOIs have been historically prescribed as antide increasing Satiety, those that decrease nutrient absorption, pressants and for treatment of other Social disorders. Such as and those that increase energy expenditure. In some embodi agoraphobia and social anxiety. The MAO-B isoform pref ments, the compounds disclosed herein, either in a form erentially deaminates phenylethylamine and trace amines according to any one of Formulas I, II, III, VI, VII, VIII, IX, Dopamine is equally deaminated by both isofouns. The or X or in prodrug form according to Formula IV or Formula activity of MAOIs may be reversible or non-reversible and V, may be used with one or more known antiobesity drugs. MAOIs may be selective for a specific isoform. For Examples of known antiobesity drugs include: phentermine, example, the MAOI moclobemide (also known as Manerix which is an appetite Suppressant; topiramate, which is an 10 depressant/epilepsy drug that has been shown to interfere or Aurorix) is known to be approximately three times more with binge eating and may result in decreased weight and selective for MAO-A than MAO-B. Any compound gener decreased blood pressure; Orlistat (Xenical, AlliR), which ally recognized as being an MAOI may be useful according reduces intestinal fat absorption by inhibiting pancreatic to the present invention. Non-limiting examples of MAOIs lipase: Sibutramine (Reductil or Meridia), which is an 15 useful in combination with compounds or prodrugs of the anorectic or appetite Suppressant; diethylpropion (diethyl present invention for preparing compositions according to cathinonefamfepramone, also sold as Anorex.R. Tenuate.(R) the invention include the following: isocarboxazid (MAR and TepanilR), which is a stimulant marketed as an appetite PLANR); moclobemide (Aurorix, Manerix, or Moclodura); Suppressant (which functions as a prodrug for ethcathinone); phenelzine (NARDIL(R); tranylcypromine (PARNATE(R): Mazindol (Mazanor, Sanorex), which is a tetracyclic stimu selegiline (ELDEPRYL(R), EMSAMR), or 1-deprenyl); lant drug used for short-term treatment of obesity; Rimona lazabemide, nialamide, iproniazid (marsilid, iprozid, ipro bant (Acomplia), which is a recently developed medication nid, rivivol, or propilniaZida); iproclozide, toloxatone; har that is a cannabinoid (CB1) receptor antagonist that acts mala; brofaromine (Consonar); benmoxin (Neuralex); and centrally on the brain to decrease appetite and may also certain tryptamines, such as 5-MeO-DMT (5-Methoxy-N, increase energy expenditure; metformin (glucophage) in 25 N-dimethyltryptamine) or 5-MeO-AMT (5-methoxy-C.- people with diabetes mellitus type 2; and Exenatide (Byetta) methyltryptamine). and Pramlintide (Symlin), which both delay gastric empty According to still another embodiment of the invention, ing and promote a feeling of Satiety. Other over-the-counter compounds or prodrugs of any one of the formulas disclosed weight loss products including herbal remedies, laxatives, herein may be combined with one or more compounds that diet pills, diuretic drugs, and/or pyruvate may also be 30 are norepinephrine reuptake inhibitors (NRIs). NRIs are also combined with the compounds and/or prodrugs disclosed known as noradrenaline reuptake inhibitors (NARIS) and herein. The compounds and prodrugs disclosed herein may generally function to elevate the level of norepinephrine in also be used in combination with non drug-based therapy, the central nervous system (CNS) by inhibiting reuptake of including caloric restriction, exercise, and behavioral norepinephrine from the synaptic cleft into the presynaptic therapy. 35 neuronal terminal. Norepinephrine is a catecholamine and In other embodiments, the present invention provides a phenylethylamine that functions as a neurotransmitter and is method for treating depression comprising administering a known to affect many conditions. Any compound typically combination of a compound or prodrug of the present recognized as inhibiting the reuptake of norepinephrine in invention and one or more known antidepressants. Antide the CNS can be used according to the present invention. pressants useful according to the invention comprise selec 40 Non-limiting examples of NRIs useful according to the tive serotonin reuptake inhibitors (SSRIs), tricyclics, sero invention comprise atomoxetine (STRATTERAR), rebox tonin norepinephrine reuptake inhibitors (5-HT-NE dual etine (EDRONAX(R), VESTRAR, or NOREBOX(R), vilox reuptake inhibitors), and norepinephrine and dopamine azine (EMOVITR, VIVALANR, VIVARINTR), or VIVI reuptake inhibitors (NDRIs). LANR), maprotiline (DEPRILEPTR), LUDIOMILR), or In one embodiment, compounds or prodrugs of the pres 45 PSYMIONR), bupropion (WELLBUTRINR) or ZYBANR), ent invention may be combined with one or more com and radafaxine. pounds that are serotonin reuptake inhibitors. Serotonin Further non-limiting examples of specific antidepressants reuptake inhibitors increase the extracellular level of the useful according to the invention include tricyclics such as serotonin by inhibiting its reuptake into the presynaptic cell, amitriptyline, nortriptyline, and desipramine; serotonin-nor which increases the level of serotonin available to bind to 50 epinephrine reuptake inhibitors such as venlafaxine (EF and stimulate the postsynaptic receptor. Examples of SSRIs FEXORR), duloxetine (CYMBALTAR), and milnacipran: include fluoxetine (PROZAC(R) paroxetine (PAXIL(R), ser tetracyclics such as maprotiline and mirtazapine; and other traline (ZOLOFTR), citalopram (CELEXAR), escitalopram classes of compounds, including triazolopyridines such as (LEXAPROR), nefazodone (SERZONE(R) and fluvoxam traZodone. ine (LUVOX(R). 55 The above compounds and classes of compounds are only In another embodiment, compounds or prodrugs of the examples of the types of active agents that can be used in present invention may be combined with one or more combination with a compound or prodrug of the present compounds that at least partially inhibit the function of invention for the treatment of mood disorders, sleep disor monoamine oxidase. Monoamine oxidase inhibitors ders, or attention deficit disorders and are not intended to be (MAOIs) comprise a class of compounds understood to act 60 limiting of the invention. Rather, various further active by inhibiting the activity of monoamine oxidase, an enzyme agents can be combined with one or more compounds of the generally found in the brain and liver of the human body, present invention according to the invention. For example, which functions to break down monoamine compounds, any drug generally recognized as being an antidepressant, typically through deamination. There are two isoforms of antinarcoleptic, or ADHD treatment can be used in combi monoamine oxidase inhibitors, MAO-A and MAO-B. The 65 nation with one or more compounds of the present invention. MAO-A isoform preferentially deaminates monoamines Moreover, it is possible according to the invention to com typically occurring as neurotransmitters (e.g., serotonin, bine two or more additional active agents with one or more US 9,617,229 B2 33 34 compounds or prodrugs of the present invention for treat therapeutically effective amount of at least one compound or ment of the noted conditions. prodrug of the formulas disclosed herein to the patient. Non-limiting examples of further active agents that can be In particular, the present invention relates to the field of combined with compounds of the present invention include: treating pre-obesity and obesity in animals, particularly mood stabilizers (such as lithium, olanzipine, Verapamil, humans and other mammals, and associated effects of these quetiapine, lamotrigine, carbamazepine, Valproate, oXcarba conditions. It may also relate to the treatment of other Zepine, risperidone, aripiprazole, and Ziprasidone); antipsy conditions that may benefit from modulation of neurotrans chotics (such as haloperidol and other butyrophenones, mitter levels. For example, it may relate to treatment of chlorpromazine, fluphenazine, perphenazine, prochlorpera depression and associated disorders, as well as cocaine Zine, and other phenothiazines, and clozapine); serotonin 10 and/or methamphetamine addictions. It may particularly receptor antagonist (5-HT2 and 5-HT3 antagonists) (Such as relate to the treatment of conditions that may benefit from ondansetron, tropisetron, katenserin, methysergide, cypro the release and/or reuptake inhibition of one or more of heptadine, and pizotifen); serotonin receptor agonists dopamine, norepinephrine, and serotonin. In some embodi (5-HT1A receptor agonists) (Such as buspirone); stimulants ments, the compounds and prodrugs of the present invention such as caffeine, ADDERALL(R), methylphenidate (META 15 are selective for one or more monoamine transporter. In DATER, RITALINR, or CONCERTAR), pemoline (CY Some embodiments, the compounds bind more strongly to LERTR), or modafinil (PROVIGIL(R); and gamma-hy the dopamine and/or serotonin transporters than to the droxybutyrate (GHB) (XYREMR). Although the above norepinephrine transporters. compounds are described in terms of classes of compounds In some embodiments, the present invention may relate to and specific compounds, it is understood that there is Sub the use of compounds or prodrugs of the present invention stantial overlap between certain classes of compounds (such to treat diseases that are responsive to the modulation of the as between mood Stabilizers, antipsychotics, antidepres level of one or more monoamine neurotransmitter. For sants, and serotonin receptor antagonists). Thus, specific example, in some embodiments, the invention provides for compounds exemplifying a specific class of compounds may the use of compounds or prodrugs of the present invention also properly be identified with one or more further classes 25 to treat diseases responsive to one or more of dopamine, of compounds. Accordingly, the above classifications should serotonin, and/or norepinephrine release. In some embodi not be viewed as limiting the scope of the types of com ments, the invention provides for the use of compounds or pounds useful in combination with compounds and prodrugs prodrugs of the present invention to treat diseases responsive of the present invention for treating the conditions described to dopamine release. In some embodiments, the invention herein. 30 provides for the use of compounds or prodrugs of the present Since the compounds and prodrugs of the present inven invention to treat diseases responsive to joint dopamine and tion may also be useful in the treatment of stimulant (e.g., serotonin release. In some embodiments, the invention pro cocaine and/or methamphetamine) addiction, they may be vides for the use of compounds or prodrugs of the present combined with other drugs for the treatment of addiction. invention to treat diseases responsive to one or more of For example, drugs that are commonly used for the treat 35 dopamine, serotonin, and/or norepinephrine uptake inhibi ment of methamphetamine addiction include, but are not tion. In certain embodiments, the invention provides for the limited to, bupropion, modafinil, Ibogaine, Mirtzapine, dex use of compounds or prodrugs of the present invention to troamphetamine, monoamine reuptake inhibitors (such as treat diseases responsive to a combination of monamine indatraline, fluoxetine, bupropion and imipramine), and neurotransmitter release and uptake inhibition. For example, amino acids. Although cocaine replacement therapies to 40 in some embodiments, the invention provides for the use of treat addiction are being researched, there is currently no compounds or prodrugs of the present invention to treat FDA-approved treatment for cocaine addiction. diseases responsive to dopamine and norepinephrine release Combinations of compounds or prodrugs of the present and/or serotonin uptake inhibition. invention with other therapeutic agents are also included in Obesity has its common meaning, e.g., the medical con the present invention, wherein the condition to be treated is 45 dition that exists when an individual has accumulated excess any condition that may be responsive to the inhibition of body fat, which may lead to a variety of related health dopamine, serotonin and/or norepinephrine reuptake. problems, and which is characterized by a body mass index The compound or prodrug of any of the formulas dis (BMI) of 30 kg/m or more. Pre-obesity, also known as closed herein and the one or more other therapeutic agents overweight, refers to the condition wherein an individuals may be contained within a single composition or alterna 50 BMI is between 25 kg/m and 30 kg/m. tively may be administered concurrently or sequentially Addiction has its common meaning, e.g., the condition (consecutively) in any order. For sequential administration, that exists when an individual persists in the use of a each of the compound or prodrug of the formulas disclosed Substance despite impairment or distress related to the use of herein and the one or more other therapeutic agents can be the Substance. In preferred embodiments, the compounds formulated in its own pharmaceutical composition, each of 55 and prodrugs of the present invention show a slow onset and which is to be administered sequentially, in any order. long duration of activity. These features make the com Alternatively, the compound or prodrug of the formulas pounds and prodrugs of the present invention particularly disclosed herein and the one or more other therapeutic suitable for the treatment of addiction to abused substances, agents can be formulated together. The compositions may be which commonly exhibit a fast onset and/or short duration formulated for oral, Systemic, topical, intravenous, intrapar 60 of activity. Administration of compounds or prodrugs of the enteral, intravaginal, intraocular, transbuccal, transmucosal, present invention to Subjects with addiction to one or more or transdermal administration. substances may be particularly suited for the treatment of Methods of Use cocaine, methamphetamine, and nicotine addiction. In a further embodiment, the present invention provides a The compounds and prodrugs of the present invention method for treating or delaying the progression of disorders 65 may also be applicable to treating depression and depressive that are alleviated by the modulation of neurotransmitter conditions in animals, particularly humans and other mam levels in a patient, the method comprising administering a mals, and associated effects of these conditions. Depression US 9,617,229 B2 35 36 has its common meaning, e.g., a common mental disorder In another embodiment, a method of treating depression that presents with depressed mood, loss of interest or plea is provided. A therapeutically effective amount of a com sure, feelings of guilt or low self-worth, disturbed sleep or pound or prodrug of the present invention to treat a patient appetite, low energy, and poor concentration or a mental with depression may be that amount capable of providing 5 Some relief from Symptoms such as changes in mood, state characterized by a pessimistic sense of inadequacy and feelings of intense sadness and despair, mental slowing, loss a despondent lack of activity. Physical changes, such as of concentration, pessimistic worry, agitation, and self insomnia, anorexia, weight loss, and decreased energy and deprecation and/or from physical changes such as insomnia, libido can also occur as a result of depression. Depression anorexia and weight loss, and decreased energy and libido. includes dysthymic disorder or dysthymia, defined as a The levels of one or more of dopamine, norepinephrine, and chronic low-grade depression and major depression as well 10 serotonin may be low in Subjects with depression and thus, as other stages or levels of depression. It also includes increase in the release of or inhibition of the uptake of any post-partum depression. of these monoamines by the appropriate transporter may be The compounds or prodrugs of the present invention may effective to adjust the monoamine levels and treat the symptoms of depression. also be used for other conditions that may be responsive to 15 The therapeutically effective dosage amount of any spe release or inhibition of reuptake of one or more type of cific formulation will vary somewhat from drug to drug, neurotransmitter. In some embodiments, the compounds or patient to patient, and will depend upon factors such as the prodrugs may be used to treat patients for conditions that are condition of the patient and the route of delivery. When responsive to the release or uptake inhibition of dopamine, administered conjointly with other pharmaceutically active norepinephrine, and/or serotonin. For example, in some agents, even less of the compound or prodrug of the inven embodiments, compounds or prodrugs of the present inven tion may be therapeutically effective. Furthermore, the tion may be used to treat patients with bipolar disorder, therapeutically effective amount may vary depending on the attention deficit disorder (ADD), attention-deficit/hyperac specific condition to be treated. tivity disorder (ADHD), hypoactive sexual desire disorder, The compound or prodrug of the invention can be admin antidepressant-induced sexual dysfunction, orgasmic dys 25 istered once or several times a day or according to any other function, seasonal affective disorder/winter depression, obe intermittent administration schedule. The daily dose can be sity and food addiction, mania, bulimia and other eating administered either by a single dose in the form of an disorders, panic disorders, obsessive compulsive disorder, individual dosage unit or several Smaller dosage units or by schizophrenia, schizo-affective disorder, Parkinson's dis multiple administration of Subdivided dosages at certain ease, narcolepsy, anxiety disorders, insomnia, chronic pain, 30 intervals. Possible routes of delivery include buccally, sub migraine headaches, and restless legs syndrome. cutaneously, transdermally, intramuscularly, intravenously, The method of treatment generally includes administering orally, or by inhalation. a therapeutically effective amount of a compound or prodrug The compounds and prodrugs of the invention may be of a formula disclosed herein, optionally in a pharmaceutical used with other types of therapy, including those which are composition including one or more pharmaceutically 35 non-drug based. For example, obesity is commonly treated acceptable carriers. The therapeutically effective amount is using one or more therapeutics in combination with behav preferably sufficient to cause the release of one or more ioral treatment (e.g., diet and exercise changes), which may neurotransmitter and/or inhibit the uptake of one or more lead to a better outcome than using a drug alone. Depression neurotransmitter. The therapeutically effective amount is is commonly treated with some combination of therapeutics further preferably sufficient to cause some relief to the 40 and some sort of psychotherapy. Thus, in some embodi patient in the symptoms of the disorder for which the patient ments, the methods of the present invention comprise is being treated. administering to a subject a compound or prodrug of the For example, in one embodiment, a method of treating invention that that is capable of modulating neurotransmitter pre-obesity or obesity is provided. In such methods, a levels in conjunction with one or more other types of therapeutically effective amount of a compound or prodrug 45 non-drug-based therapy. of the present invention to treat a patient with pre-obesity or obesity may be that amount capable of effecting the release EXAMPLES and/or reuptake of one or more monoamine neurotransmit ter. Such compound or prodrug may cause the patient to Certain compounds in the Examples Section are referred experience decreased appetite and/or may create a sensation 50 to with an alphanumerical designation. The compound struc of fullness. The method of treating pre-obesity or obesity ture for these compounds can be found, for example, in the may be used to attain or maintain a patients weight loss. specific synthesis examples, Schemes 1-3, or in the data In another embodiment, a method of treating cocaine tables provided herein. addiction is provided. In Such methods, a therapeutically Example 1 effective amount of a compound or prodrug of the present 55 invention to treat a patient with cocaine addiction may be that amount capable of exerting some dopaminergic effect. Representative Preparation of Compounds of the Cocaine functions by inhibiting the reuptake of dopamine by Present Invention Preparation of PAL-583 blocking the dopamine transporter that transports excess dopamine back into the presynaptic cell. It has a fast onset 60 of activity and short duration. Chronic cocaine use produces a withdrawal syndrome that is associated with depletion of dopamine and deficits in dopaminergic signaling By pro CH3 + viding a compound or prodrug of the present invention with slow onset and long duration of activity, the compound or 65 prodrug may be able to reverse dopaminergic deficits in Br chronic cocaine users. US 9,617,229 B2 37 38 -continued HC EN Her EN 40° C. is \ . OH CH + in V 40° C. OH Br

10 OH

HC N) 15 OH H O

A 0.4 M solution of 2-Bromopropiophenone (1.54 mL, 1 F D H3C N eq) in acetonitrile (26 mL) was mixed in a 50 mL round H bottom flask under N (g). Ethanolamine (1.25 mL. 2 eq) was added changing the color of Solution from olive green to amber and forming a precipitate. The reaction was A 0.4 M solution of 2-bromo-1-(3-fluorophenyl)propan refluxed at 40° C. for 3.5 hrs and then cooled to room 1-one (3.05 g, 1 eq) in acetonitrile (33 mL) was mixed in a 100 mL round bottom flask under N, (g). Ethanolamine (1.6 temperature to stir overnight. The next morning the orange 25 yellow mixture with precipitate was refluxed at 40°C. for 2 mL, 2 eq) was added and stirred/refluxed for 6 hrs at 40°C. hrs. After cooling to room temperature the reaction was After cooling to room temperature overnight the volatiles diluted with ethylacetate, washed with saturated sodium were removed under reduced pressure, the residue was then bicarbonate (2x50 mL), water (2x50 mL), brine (2x50 mL), taken up in ethyl acetate, washed with Saturated Sodium and then dried over anhydrous sodium sulfate. After filtra 30 bicarbonate (3x50 mL), brine (2x50 mL), and dried over tion the volatiles were removed under reduced pressure anhydrous sodium sulfate. After filtration the volatiles were affording 0.807 g (40%) of crude product. Purified on 12 g removed under reduced pressure affording 1.464 g (53%) of column (ISCO) using a system of chloroform (A)/9:1 metha crude product. Purified on 12 g column (ISCO) using a nol:ammonium hydroxide (B) with a 20-30% gradient (B). system of methylene chloride (A)/methanol (B) with a Fractions 8-10 were collected and concentrated under 35 20-30% gradient (B). Fractions 13-32 were collected and reduced pressure affording 0.351 g (18%) of purified prod concentrated under reduced pressure affording 0.638 g uct. The free base was salted with 0.2108 g of fumaric acid (23%) of purified product. The free base was salted with and recrystalized using methanol/ether yielding 0.2135 g of 0.3506 g of fumaric acid and recrystalized using methanol/ final product. ethyl acetate yielding 0.5672 g of final product. Preparation of PAL-587 40 Preparation of PAL-589

CH3Cl2 CH3Cl2 CH + Br-Br --> 45 CH + Br-Br -->

CH3 50

CH3 CH3

Br Br 55

CH3

1-(3-fluorophenyl)propan-1-one (4.53 g, 1 eq) and bro 60 1-(3-methylphenyl)propan-1-one (8.746g, 1 eq) and bro mine (1.53 mL, 1 eq) were combined and stirred in 50 mL mine (3.04 mL, 1 eq) were combined and stirred in 100 mL of methylene chloride overnight at room temperature. The of methylene chloride overnight at room temperature. The next day the mixture was washed with water (4x50 mL), next day the mixture was washed with water (4x50 mL), brine (2x50 mL), and dried over anhydrous sodium sulfate. brine (2x50 mL), and dried over anhydrous sodium sulfate. After filtration the volatiles were removed under reduced 65 After filtration the volatiles were removed under reduced pressure affording 6.435 g (94%) of crude 2-bromo-1-(3- pressure affording 12.923 g (96%) of crude 2-bromo-1-(3- fluorophenyl)propan-1-one. methylphenyl)propan-1-one. US 9,617,229 B2 40 0.4054 g of fumaric acid and recrystalized using methanol/ ethyl acetate, yielding 0.7213 g of final product. Preparation of PAL-592

OH CH3 O EtOH/H2O (1:1) 10 -e- OH D fumarate + NaBH4 H2SO4 O H3C N HC D H HC N H 15

A 0.4 M solution of 2-bromo-1-(3-methylphenyl)propan 1-one (6.57 g, 1 eq) in acetonitrile (72 mL) was mixed in a 250 mL round bottom flask under N (g). Ethanolamine (3.5 mL, 2 eq) was added and stirred/refluxed for 6 hrs at 40°C. After cooling to room temperature overnight the Volatiles A solution of 3-methyl-2-phenylmorpholin-2-ol fumarate were removed under reduced pressure, the residue was then salt (0.464.6 g. 1 eq) in 1:1 ethanol: water (3.6 mL) was taken up in ethyl acetate, washed with Saturated sodium chilled to 0° C. under N (g). With constant stirring, a bicarbonate (3x50 mL), brine (2x50 mL), and dried over 25 solution of sodium borohydride (0.2278 g. 4 eq) in water anhydrous sodium sulfate. After filtration the volatiles were removed under reduced pressure affording 3.777 g (63%) of (2.5 mL) was added drop wise. The reaction was allowed to crude product. Purified on 12 g column (ISCO) using a warm to room temperature and stir overnight. The next system of methylene chloride (A)/methanol (B) with a morning the reaction was chilled to 0° C. and 2.2 mL of 20-30% gradient (B). Product fractions were collected and 30 concentrated hydrochloric acid was added drop wise. The concentrated under reduced pressure affording 1.183 g ethanol was then removed under reduced pressure and the (20%) of purified product. The free base was salted with crude mixture was diluted with water, chilled to 0°C., made 0.6624 g of fumaric acid and recrystalized using methanol/ basic by adding 40% aqueous sodium hydroxide (tested with ethyl acetate, yielding 0.3459 g of final product. litmus), extracted with methylene chloride (3x25 mL), dried Preparation of PAL-590 35 over anhydrous sodium sulfate, filtered, and volatiles removed under reduced pressure to afford 0.200 g of solid residue. The intermediate residue dissolved in methylene HC-EN -e- chloride was then added drop wise to 4.8 mL of concentrated 40° C. CH + in V 40 OH sulfuric acid at 0°C. and stirred overnight. The next morning Br the reaction was poured into ice water, the layers were separated, and the aqueous layer was chilled to 0°C. The

C aqueous layer was then made basic with 40% aqueous 45 sodium hydroxide (tested with litmus), extracted with meth OH ylene chloride (3x25 mL), dried over anhydrous sodium O sulfate, filtered, and volatiles removed under reduced pres sure to afford 0.172 g of oil. The oil was then dissolved in C D methylene chloride and 0.0681 g of fumaric acid in metha H3C N 50 H nol was added to form the fumarate salt of the product. Anal. Calcd for 2CHCNOCHOI: C, 66.36; H, 7.28; N, A 0.4 M solution of 2-bromo-1-(3-chlorophenyl)propan 5.95. Found: C, 66.12; H, 7.29; N, 5.85. 1H NMR (300 1-one (4.22 g, 1 eq) in acetonitrile (43 mL) was mixed in a MHz, MeOH) 8 ppm 1.01 (d. J=6.78 Hz, 3H)3.20-3.41 (m, 100 mL round bottom flask under N (g). Ethanolamine 55 3H) 3.84-3.99 (m. 1H) 4.13 (d. J=14.32 Hz, 1H) 4.32 (d. (2.05 mL, 2 eq) was added and stirred/refluxed for 6 hrs at J=10.17 Hz, 1H) 6.70 (s, 1H) 7.39 (s, 5H). 40° C. After cooling to room temperature overnight the Preparation of PAL-593 volatiles were removed under reduced pressure, the residue was then taken up in ethyl acetate, washed with Saturated sodium bicarbonate (3x50 mL), brine (2x50 mL), and dried 60 over anhydrous sodium sulfate. After filtration the volatiles OH were removed under reduced pressure affording 3.319 g O (70%) of crude product. Purified on 12 g column (ISCO) F EtOH/H2O (1:1) using a system of methylene chloride (A)/methanol (B) with D fumarate + NaBH4 H2SO4 65 a 20-30% gradient (B). Product fractions were collected and H3C N concentrated under reduced pressure affording 0.970 g H (20%) of purified product. The free base was salted with US 9,617,229 B2 41 42 -continued drop wise. The reaction was allowed to warm to room temperature and stir overnight. The next morning the reac tion was chilled to 0° C. and 1.7 mL of concentrated O hydrochloric acid was added drop wise. The ethanol was 5 then removed under reduced pressure and the crude mixture r was diluted with water, chilled to 0° C., made basic by HC N adding 40% aqueous sodium hydroxide (tested with litmus), H extracted with methylene chloride (3x25 mL), dried over anhydrous sodium sulfate, filtered, and volatiles removed A solution of 2-(3-fluorophenyl)-3-methylmorpholin-2-ol 10 under reduced pressure to afford 0.247 g of white solid. The fumarate salt (0.4326g, 1 eq) in 1:1 ethanol: water (3.3 mL) solid intermediate dissolved in methylene chloride was then was chilled to 0°C. under N (g). With constant stirring, a added drop wise to 5.1 mL of concentrated sulfuric acid at solution of sodium borohydride (0.2000 g, 4 eq) in water 0° C. and stirred overnight. The next morning the reaction (2.2 mL) was added drop wise. The reaction was allowed to was poured into ice water, the layers were separated, and the warm to room temperature and stir overnight. The next 15 aqueous layer was chilled to 0°C. The aqueous layer was morning the reaction was chilled to 0° C. and 1.9 mL of then made basic with 40% aqueous sodium hydroxide concentrated hydrochloric acid was added drop wise. The (tested with litmus), extracted with methylene chloride ethanol was then removed under reduced pressure and the (3x25 mL), dried over anhydrous sodium sulfate, filtered, crude mixture was diluted with water, chilled to 0°C., made and volatiles removed under reduced pressure to afford basic by adding 40% aqueous sodium hydroxide (tested with 0.245 g of oil. The oil was then dissolved in methylene litmus), extracted with methylene chloride (3x25 mL), dried chloride and 0.0868 g of fumaric acid in methanol was over anhydrous sodium sulfate, filtered, and volatiles added to form the fumarate salt of the product. Anal. Calcd removed under reduced pressure to afford 0.176 g of clear for 2CHCINOCHOI: C, 57.89; H, 5.98: N, 5.19. oil. The inteimediate oil dissolved in methylene chloride was 25 Found: C, 57.75; H, 5.88: N, 5.10. then added drop wise to 1.9 mL of concentrated sulfuric acid H NMR (300 MHz, MeOH)8 ppm 1.06 (d. J=6.78 Hz, at 0°C. and stirred overnight. The next morning the reaction 3H)3.17-3.28 (m, 1H)3.27-3.35 (m, 1H)3.34-3.39 (m, 1H) was poured into ice water, the layers were separated, and the 3.93 (t, J=11.87 Hz, 1H) 4.19 (d. J=12.43 Hz, 1H)4.32 (d. aqueous layer was chilled to 0°C. The aqueous layer was J=9.80 Hz, 1H) 6.79 (s, 1H) 737-7.44 (m. 1H) 7.47 (d. then made basic with 40% aqueous sodium hydroxide 30 J=5.27 Hz, 1H) 7.53 (s, 1H). (tested with litmus), extracted with methylene chloride (3x25 mL), dried over anhydrous sodium sulfate, filtered, Example 2 and volatiles removed under reduced pressure to afford Preparation of Additional Compounds 0.168 g of oil. The oil was then dissolved in methylene Representative Preparation chloride and 0.0626 g of fumaric acid in methanol was 35 added to form the fumarate salt of the product. Anal. Calcd for 2CHCFNOCHOI: C, 61.65; H, 6.37; N, 5.53. Step 1: Preparation of N-Benzyl-N-(2-hydroxy Found: C, 61.67; H, 6.36: N, 5.53. H NMR (300 MHz, ethyl)-1-methyl-2-oxo-2-tolylethylamine METHANOL-d) & ppm 0.96 (d. J=6.78 Hz, 3H)3.04-3.17 (m. 1H)3.17-3.24 (m. 1H)3.26 (m, 1H)3.83 (t, J=11.11 Hz, 40 1H)4.09 (d. J=11.68 Hz, 1H)4.23 (d. J=9.42 Hz, 1H) 6.68 (s, 1H) 7.03-7.24 (m, 3H) 7.39 (dd, J=7.91, 7.16 Hz, 1H). O Preparation of PAL-594 Br -- 45

OH OH O C fumarate + ? THF, 50 HN 18 h, 50 C. -e- HC N H EtOH/H2O (1:1) NaBH4 H2SO4

55 OH

O C D O H3C N 60 H

A solution of 2-(3-chlorophenyl)-3-methylmorpholin-2-ol fumarate salt (0.3884g, 1 eq) in 1:1 ethanol: water (2.8 mL, la plus methanol drop wise till dissolved) was chilled to 0°C. 65 under N (g). With constant stirring, a solution of sodium A Solution of 2-bromo-2'-acetonaphthone (3 g, 12 mmol) borohydride (0.1710 g, 4 eq) in water (1.8 mL) was added and 2-benzylaminoethanol (3.64 g. 24.1 mmol) in THF (50 US 9,617,229 B2 43 44 mL) was stirred 18 h at 50 C. The mixture was concentrated (d. 1H, J=9 Hz), 4.21-4.10 (m, 2H), 3.85-3.74 (m, 2H), 3.18 and taken up into ethyl acetate and washed with Saturated (d. 1H, J=15 Hz), 2.68-2.64 (m, 1H), 2.51-2.38 (m, 2H), 2.34 aqueous NaHCO, water and brine. The organics were dried (s, 3H), 0.97 (d. 3H, J=6 Hz); ESI-MS, calculated for (MgSO), concentrated and purified by automated flash CHNO (M+H)"282.4; observed 282.4. chromatography (silica gel, 4/1 hexane/ethyl acetate) to 5 yield 4.93 g (84%) of 1a as a white solid. "H NMR (CDC1 Step 4: Preparation of 300 MHz) & 7.52-7.11 (m, 9H), 4.17-4.13 (m, 2H), 3.66-3.59 3-Methyl-2-(4'-Tolyl)morpholine fumarate (PAL (m, 3H), 2.84-2.65 (m, 2H), 2.43-2.33 (m, 4H), 0.96-0.79 747) (m, 3H): APCI-MS, calculated for CHNO (M+H)" 298.4; observed 298.4. 10 Step 2: Preparation of N-Benzyl-N-(2-hydroxy ethyl)-2-hydroxy-1-methyl-2-tolylethylamine DCE, reflux, 1.5 h O NH 2. MeOH, reflux, 1 h 15 3a -- 3. Fumaric acid, ether, MeOH, rt, 18 h OH Fumarate

OH NaBH4, MeOH N 4a la rt, 1 h A solution of 3a (1.86 g. 6.61 mmol) and 1-chloroethyl 25 chloroformate (0.95 mL, 8.72 mmol) in DCE (30 mL) was refluxed for 1.5 h and then concentrated. The residue was dissolved in MeOH (30 mL) and refluxed for 1 h. The A solution of 1a (4.9 g, 16.5 mmol) in MeCH (150 mL) mixture was concentrated again and this residue was taken was treated with NaBH (0.69 g, 18.1 mmol) and the up into ethyl acetate and washed with Saturated aqueous reaction stirred for 1 hat room temperature. The mixture was 30 NaHCO, water and brine, dried (MgSO) and concentrated. concentrated and the residue was taken up into ethyl acetate The crude product was purified by automated flash chroma and washed with saturated aqueous NaHCO, water and tography (silica gel, 10% MeOH/DCM) to yield 572 mg brine. The organic phase was dried (MgSO4) and concen (45%) of pale yellow solid. An initial attempt was made to trated to generate a quantitative amount of colorless oil (2a). isolate the hydrochloride salt, but if it wouldn’t crystallize, which required no further purification. "H NMR (CDC1300 35 the mixture was neutralized and the fumarate salt was MHz) & 7.38-7.09 (m, 9H), 4.33 (d. 1H, J=9 Hz), 3.94 (d. 1H, J=15 Hz), 3.70-3.62 (m, 2H), 3.49 (d. 1H, J=12 Hz), formed. After several recrystallization attempts, 66 mg (9%) 2.87-2.83 (m, 2H), 2.67-2.58 (m, 1H), 2.32 (s, 3H), 0.83 of pure 4a was obtained. "H NMR (D.O.300 MHz) & 7.20 0.80 (m, 3H): APCI-MS, calculated for CHNO (M+H)" (d. 2H, J=9 Hz), 7.15 (d. 2H, J=9 Hz), 3.97 (d. 1H, J=9 Hz), 300.4; observed 300.5. 40 3.89-3.85 (m, 2H), 2.98-2.81 (m, 3H), 2.29 (s.3H), 0.73 (d. 3H, J-6 Hz); ESI-MS, calculated for CHNO (M+H)" Step 3: Preparation of 192.3; observed 192.1; Anal. Calculated for CHNO N-Benzyl-3-methyl-2-tolylmorpholine (with 0.2 mol of water): C, 66.49; H, 7.73: N, 5.54. Found: C, 66.14; H, 7.46; N, 5.31. 45 The following compounds were prepared based on the above procedure (Steps 1-4) with the indicated modifica tions. Characterization data for representative compounds of O 60% aq. HCl, the present invention is presented below. reflux 2a -> 50 3-Methyl-2-(4'-Tolyl)morpholine H NMR (CDC1300 MHz) & 723-7.16 (m, 4H), 4.41 (d. 1H, J–12 Hz), 4.14-4.09 (m, 2H), 3.30-3.19 (m, 3H), 2.35 (s, 3H), 1.19 (d. 3H, J=9 Hz). 55 3a 2-(2-Naphthyl)morpholine hydrochloride (4b, PAL 703) A suspension of 2a (4.9 g, 16.5 mmol) in 60% (v/v) of aqueous HCl Solution (150 mL) was introduced to a glass The product of the de-benzylation step was recrystallized reactor and sealed with a Teflon cap and was heated to 105 60 from methanol/ether to yield a white solid in 86% yield C for 18 h. The mixture was made alkaline with solid KOH (1.34g); H NMR (d-DMSO, 300 MHz) & 9.38 (brs, 2H), and extracted with ethyl acetate. The organic phase was 7.97-7.93 (m, 4H), 7.58-7.51 (m, 3H), 4.93 (d. 1H, J=9 Hz), washed with brine, dried (MgSO) and concentrated to yield 4.19-4.15 (m. 1H), 3.98-3.97 (m, 1H), 3.54-3.50 (m, 1H), 5.13 g of brown oil. This crude material was purified by 3.41-3.28 (m. 1H), 3.20-3.06 (m, 2H); ESI-MS, calculated automated flash chromatography (silica gel, 1/1 hexanes/ 65 for CHNO (M--H)"214.3; observed 214.1; Anal. Calcu ethyl acetate) to obtain 1.86 g (40%) of pale orange solid lated (with 0.1 mol water) for CHCINO; C, 66.84; H, (3a). "H NMR (CDC1300 MHz) & 7.34-7.23 (m, 8H), 7.15 6.49; N, 5.57. Found: C, 66.75; H, 6.50: N, 5.47.

US 9,617,229 B2 47 48 18.4: ESI-MS, calculated for CHCINO (M+H)"247.2: 3H, J=6 Hz); C NMR (CDC1, 75 MHz) & 1600, 1418, observed 246.2: Anal. Calculated for CHCINO; C, 129.6, 120.4, 114.0, 113.3, 86.7, 68.6, 56.5, 55.6, 46.9, 18.7. 46.75; H, 4.99; N, 4.96; C1, 37.63. Found: C, 46.92; H, 4.89: N, 5.02; C1, 37.78. Example 3 3-Methyl-(3'-Chloro-4'-Fluoro)-2-Phenylmorpho Preparation of Additional Compounds line hydrochloride (41, PAL 821) Additional compounds were prepared according to the The product was isolated as a white solid in 25% yield following procedures. The procedure used to prepare vari (169 mg); H NMR (CDOD, 300 MHz) & 7.60 (dd. 1H, J=3 10 ous compounds is noted and the reagents and intermediates HZ, 6 Hz), 7.40-7.36 (m. 1H), 7.29 (t, 1H, J=9 Hz), 4.40 (d. are represented in Schemes 1, 2, and 3, below. 1H, J–9 Hz), 4.24-4.18 (m, 1H), 4.01-3.91 (m, 1H), 3.43 General Procedure A. 3.37 (m, 3H), 1.07 (d. 3H, J=6 Hz); 'C NMR (free amine) To a stirring solution under N of the commercially (CDC1, 75 MHz) & 143.0, 140.0, 130.0, 127.0, 123.0, 81.4, available amine (1.0 equiv.) in MeOH (dried over 4 A 56.0, 49.8, 46.0, 34.8, 15.4; ESI-MS, calculated for 15 molecular sieves, 0.20 M) was added an aryl epoxide (0.83 CHCIFNO (M+H)"230.7: observed 230.3: Anal. Calcu equiv.). The reaction mixture was heated to reflux for 4 hand lated for CHCIFNO; C, 49.64; H, 5.30; N, 5.26; C1, then cooled to room temperature. The solution was allowed 26.64: F, 7.14. Found: C, 49.41; H, 5.30; N, 5.22; C1, 26.84; to stir at room temperature for 3 days and then concentrated under reduced pressure to yield an oily residue which was F, 7.07. purified by flash chromatography on silica gel (10% to 20% 3-Methyl-(3'-Chloro-4-Methyl)-2-Phenylmorpho MeOH/CHCl gradient) to remove the unreacted starting line hydrochloride (4m, PAL 822) amine. General Procedure B. The product was isolated as a white solid in 25% yield The secondary amine (1.0 equiv.) was dissolved in a 50%, (248 mg); H NMR (CDOD, 300 MHz) & 7.44 (d. 1H, J=3 25 60%, or 90% aqueous HCl solution (0.37 M) and heated to Hz), 7.33 (d. 1H, J=6 Hz), 7.24 (d. 1H, J-6 Hz), 4.36 (d. 1H, 90° C. overnight under N. The reaction mixture was J=12 Hz), 4.24-4.17 (m, 1H), 4.02-3.90 (m. 1H), 3.42-3.36 allowed to cool to room temperature and poured onto ice (m, 3H), 2.37 (s, 3H), 1.07 (d. 3H, J=6 Hz); 'C NMR (free water. After chilling to 0° C., the solution was carefully amine) (CDC1, 75 MHz) & 131.0, 128.4, 127.9, 126.2, 85.9, basified to pH 12 with a 3 Maqueous NaOH solution. After 68.6, 56.5, 46.8, 20.1, 18.7: APCI-MS, calculated for 30 warming to room temperature, ether was added and the CHCINO (M+H)226.7: observed 226.2: Anal. Calcu biphasic mixture was partitioned in a separatory funnel. The lated for CHC1NO; C, 54.98: H, 6.54: N, 5.34; C1, aqueous portion was extracted twice with EtO and the 27.04. Found: C, 55.16; H, 6.52: N, 5.41; C1, 27.18. combined organic extracts were washed with water and brine and dried over NaSO Filtration and concentration 3-Methyl-(3'-Methoxy)-2-Phenylmorpholine (0.5 35 under reduced pressure, followed by flash chromatography fumarate) (4n, PAL 823) on silica gel (5% to 20% MeOH/CHC1 gradient) afforded the cyclized product. The product was isolated as a white solid in 53% yield General Procedure C. (218 mg); H NMR (CDOD, 300 MHz) & 7.29 (t, 1H, J=6 The secondary amine (1.0 equiv.) was dissolved in con Hz, 9 Hz), 6.95-6.90 (m, 3H), 6.68 (s, 1H), 4.23 (d. 1H, J=9 40 centrated HSO (0.4 M) and allowed to stand at room Hz), 4.13-4.05 (m, 1H), 3.92-3.82 (m. 1H), 3.80 (s, 3H), temperature overnight. The reaction mixture was then 3.26-3.19 (m, 3H), 0.97 (d. 3H, J=6 Hz); ESI-MS, calculated poured onto ice water. After chilling to 0°C., the solution for CHNO (M+H)"208.3: observed 208.0: Anal. Cal was carefully basified to pH 12 with a 10 Naqueous NaOH culated for CHNO: C, 63.38: H, 7.22; N, 5.28. Found: Solution. After warming to room temperature, ether was C, 63.35; H, 7.28: N, 5.25. 45 added and the biphasic mixture was partitioned in a sepa ratory funnel. The aqueous portion was extracted twice with 3-Methyl-(3'-Methoxy)-2-Phenylmorpholine EtO and the combined organic extracts were washed with water and brine and dried over NaSO Filtration and "H NMR (CDC1, 300 MHz) & 727-7.22 (m, 2H), 6.93- concentration under reduced pressure, followed by flash 6.82 (m, 2H), 4.01-3.91 (m, 2H), 3.81 (s, 3H), 3.70 (t, 1H, chromatography on silica gel (5% to 20% MeOH/CH.Cl J=12 Hz), 3.15 (t, 1H, J=12 Hz), 2.96-2.83 (m, 2H), 0.83 (d. gradient) afforded the cyclized product.

Scheme 1 S mCPBA,CHC. He

X 1a:X = H 1b: X = OMe 1c:X = Me 1: X = Cl 1e: X = F

US 9,617,229 B2 53 54 -continued aqueous HCl (5.4 mL) under N to afford a mixture of separable isomers in a 1.9:1 (anti:syn) ratio. Anti isomer 9c: 143 mg (38% yield) isolated as a clear oil. C.?',-11.7 (c 0.0095, MeOH); H NMR (CDC1, 300 MHz) & 7.22-7.10 (m, 4H), 4.38 (dd, J=12.0, 3.0 Hz, 1H), 3.96 (dd, J=12.0, 3.0 HZ, 1H), 3.31 (t, J=21.0, 12.0 Hz, 1H), 3.07 (dd, J=12.0, 3.0 HZ, 1H), 3.03-2.96 (m, 1H), 2.86 (br. t, J=21.0, 9.0 Hz, 1H), N 2.34 (s, 3H), 1.88 (br. s. 1H), 1.02 (d. J=6.0 Hz, 3H); 'C NMR (CDC1, 75 MHz) ppm 140.2, 138.0, 128.4, 128.2, 10 126.7, 123.2, 78.8, 7.4.3, 53.3, 49.9, 21.4, 17.5: MS (ESI) (2S.5R)-5-Methyl-2-m-tolyl-morpholine (6c) and calcd for (M+1)"192.3, found 192.2. The hydrochloride salt (2R,5R)-5-Methyl-2-m-tolyl-morpholine (7c) had mp 194-195° C.; Anal. (C.H.CINO) C, H, N. Syn isomer 10c: 76 mg (20% yield) isolated as a clear oil General procedure A was followed using amine 3 (0.56 contaminated with unreacted Starting material. The fumarate mL, 7.17 mmol) and epoxide 2c (875 mg, 6.52 mmol) in dry 15 had mp 168-170° C.: C-14.5 (c 0.0020, MeOH); H MeOH (22 mL) under N to afford 625 mg (46% yield) of NMR (CDOD, 300 MHz) & 7.30-7.15 (m, 4H), 6.70 (s. 2H), amine 5c as a thick yellow oil. General procedure B was then 4.72 (dd, J=9.0, 6.0 Hz, 1H), 4.10 (dd, J=12.0, 3.0 Hz, 1H), followed using amine 5c (575 mg, 2.75 mmol) in 90% 3.94 (d. J=12.0 Hz, 1H), 3.66-3.58 (m. 1H), 3.27-3.24 (m, aqueous HCl (7.4 mL) under N to afford a mixture of 2H), 2.35 (s, 3H), 1.55 (d. J=6.0 Hz, 3H); 'C NMR separable isomers in a 1.4:1 (anti:Syn) ratio. Anti isomer 6c: (CDOD, 75 MHz) ppm 171.5, 139.7, 139.0, 136.2, 130.4, 166 mg (32% yield) isolated as a clear oil. C.",-33.3 (c 129.7, 127.7, 124.2, 77.1, 69.5, 48.2, 44.0, 21.4, 13.6; MS 0.00135, MeOH); H NMR (CDC1, 300 MHz) & 7.22-7.07 (ESI) calcd for (M+1)*192.3, found 192.1 (free base); Anal. (m, 4H), 4.39 (dd, J=9.0, 3.0 Hz, 1H), 3.96 (dd, J=9.0, 3.0 (CHNOs) C. H. N. HZ, 1H), 3.31 (t, J=21.0, 9.0 Hz, 1H), 3.06 (dd, J=12.0, 3.0 HZ, 1H), 3.02-2.94 (m. 1H), 2.85 (t, J=24.0, 12.0 Hz, 1H), 25 2.34 (s, 3H), 1.96 (br. s. 1H), 1.02 (d. J=6.0 Hz, 3H); 'C NMR (CDC1, 75 MHz) ppm 140.2, 138.0, 128.4, 128.2, 126.7, 123.2, 78.8, 7.4.3, 53.3, 49.9, 21.4, 17.5: MS (ESI) O calcd for (M+1)*192.3, found 192.5. The hydrochloride salt had mp 194-195° C.; Anal. (C.H.CINO) C, H, N. Syn 30 C C isomer 7c. 117 mg (22% yield) isolated as a clear oil N and contaminated with unreacted Starting material. The fumarate H had mp 175-176° C.: C-19.2 (c 0.0012, MeOH); H NMR (CDOD,300 MHz) & 7.30-7.15 (m, 4H), 6.70 (s. 2H), 4.72 (br. t, J=15.0, 6.0 Hz, 1H), 4.08 (dd, J=12.0, 3.0 Hz, 35 1H), 3.96 (br. d, J=15.0 Hz, 1H), 3.65-3.58 (m. 1H), 3.27 3.24 (m, 2H), 2.35 (s.3H), 1.55 (d. J=6.0 Hz, 3H); 'C NMR (CDOD, 75 MHz) ppm 171.5, 139.7, 138.9, 136.2, 130.4, 129.7, 127.7, 124.2, 77.1, 69.5, 48.2, 44.1, 21.4, 13.6; MS 40 Co. (ESI) calcd for (M+1)"192.3, found 192.3 (free base); Anal. (CHNO.0.25HO) C, H, N. (2S.5R)-2-(3-Chloro-phenyl)-5-methyl-morpholine (6d) and (2R,5R)-2-(3-Chloro-phenyl)-5-methyl morpholine (7d) 45 O General procedure A was followed using amine 3 (0.50 mL, 6.42 mmol) and epoxide 2d (824 mg, 5.33 mmol) in dry Me D MeOH (21 mL) under N to afford 649 mg (53% yield) of N °, and amine 5d as a thick clear oil. General procedure C was then H 50 followed using amine 5d (649 mg, 2.83 mmol) in concen trated HSO (7 mL) to afford a mixture of separable isomers in a 10.3:1 (anti:syn) ratio. Anti isomer 6d: 261 mg (44% O yield) as a clear sticky oil. O'', 42.1 (c 0.0024, MeOH): Me "H NMR (CDC1, 300 MHz) & 7.37 (s, 1H), 7.29-7.20 (m, 55 '', 3H), 4.39 (dd, J=9.0, 3.0 Hz, 1H), 3.96 (dd, J=12.0, 3.0 Hz, N 1H), 3.30 (t, J-210, 9.0 Hz, 1H), 3.06 (dd, J=12.0, 3.0 Hz, H 1H), 3.01-2.92 (m, 1H), 2.79 (t, J-210, 9.0 Hz, 1H), 2.01 (br. s. 1H), 1.01 (d. J=6.0 Hz, 3H); 'C NMR (CDC1, 75 MHz) ppm 142.7, 134.6, 130.0, 128.1, 126.6, 124.6, 78.3, (2R,5S)-5-Methyl-2-m-tolyl-morpholine (9c) and 60 74.5, 53.6, 50.1, 17.8; MS (ESI) calcd for (M+1)"212.7, (2S,5S)-5-Methyl-2-m-tolyl-morpholine (10c) found 212.1. The hydrochloride salt had mp 170-171° C.: Anal. (CHCINO) C. H. N. Syn isomer 7d: 36 mg (6% General procedure A was followed using amine 4 (0.56 yield) as a clear sticky oil. C.,-6.7 (c 0.0015, MeOH); H mL, 7.17 mmol) and epoxide 2c (875 mg, 6.52 mmol) in dry NMR (CDC1, 300 MHz) & 7.42 (s, 1H), 7.32-7.23 (m, 3H), MeOH (22 mL) under N to afford 416 mg (31% yield) of 65 4.52 (dd, J=6.0, 3.0 Hz, 1H), 3.86 (dd, J=12.0, 3.0 Hz, 1H), amine 8c as a yellow oil. General procedure B was then 3.70 (dd, J=9.0, 3.0 Hz, 1H), 3.18-3.10 (m, 2H), 2.97 (dd, followed using amine 8c (416 mg, 1.99 mmol) in 90% J=12.0, 3.0 Hz, 1H), 2.35 (br. s. 1H), 1.31 (d. J=6.0 Hz, 3H):

US 9,617,229 B2 69 70 Example 4

DA, NE, 5-HT Release Assays C '', A. 10 -- A series of compounds were assayed for release of N dopamine, serotonin, and norepinephrine as well as for H activity at the 5-HT, receptor. This data is shown below in Table 3. 10 DA, NE and 5-HT Release Assays HMPP" was used as the radioligand for both the DA and NE release assays, because this method led to an improved signal-to-noise ratio. Rat caudate (for DA release) Cyr. 15 or whole brain minus cerebellum and caudate (for NE and 5-HT release), was homogenized in ice-cold 10% sucrose containing 1 uM reserpine. Nomifensine (100 nM) and GBR12935 (100 nM) were added to the sucrose solution for (2S,6S)-2-(3-Chloro-phenyl)-6-methyl-morpholine H5-HT release experiments to block any potential H (20d) and (2R,6S)-2-(3-Chloro-phenyl)-6-methyl 5-HT reuptake into NE and DA nerve terminals. For the DA morpholine (21 d) release assay, 100 nM desipramine and 100 nM citalopram were added to block HIMPP" uptake into NE and 5-HT General procedure A was followed using amine 17 (0.50 nerves. For the NE release assay, 50 nM GBR12935 and 100 mL, 6.35 mmol) and epoxide 2d (814 mg, 5.27 mmol) in dry 25 nM. citalopram were added to block HMPP" uptake into MeOH (21 mL) under N to afford 787 mg (65% yield) of DA and 5-HT nerves. After 12 strokes with a Potter amine 19d as a thick clear oil. General procedure C was then Elvehjem homogenizer, homogenates were centrifuged at followed using amine 19d (787 mg, 3.43 mmol) in concen 1000xg for 10 min at 0-4° C. and the supernatants were trated HSO (8.6 mL) to afford 354 mg (49% yield) of retained on ice (synaptosomal preparation). inseparable morpholines 20d and 21d as a clear sticky oil in 30 Synaptosomal preparations were incubated to steady state a 3:1 (syn:anti) ratio. C.?',-37.7 (c 0.0022, MeOH); MS with 5 nM. HMPP (60 min) or 5 nM H5-HT (60 min) (ESI) calcd for (M+1)"212.7, found 212.1. The fumarate had in Krebs-phosphate buffer (without BSA) (pH 7.4), which mp 136-137° C. Anal (C.H.CINOs) C, H, N. contained 154.4 mM NaCl, 2.9 mM KCl, 1.1 mM CaCl, 0.83 mM MgCl, 5 mM glucose, 1 mg/mL ascorbic acid, 50 35 uM pargyline plus 1 LM reserpine in a polypropylene beaker with stirring at 25°C. with the appropriate blockers. After incubation to steady state, 850 ul of synaptosomes preloaded C with HIligand were added to 12x75 mm polystyrene test 40 tubes that contained 150 ul test drug in uptake buffer plus 1 mg/ml BSA. After 5 min (H5-HT) or 30 min (NE and DA assays) the release reaction was terminated by dilution with 4 ml wash buffer (10 mM Tris-HCl pH 7.4 containing 0.9% NaCl at 25°C.) followed by rapid vacuum filtration over 45 Whatman GF/B filters using a Brandel Harvester. The filters C were rinsed twice with 4 ml wash buffer using the Brandel Harvester, and the retained tritium was counted by a Taurus liquid scintillation counter at 40% efficiency after an over 50 night extraction in 3 ml Cytoscint (ICN). Substrate Reversal Experiments For substrate reversal experiments, test drugs were tested (2R,6R)-2-(3-Chloro-phenyl)-6-methyl-morpholine at approximately EDso doses in the absence and presence of (23d) and (2S,6R)-2-(3-Chloro-phenyl)-6-methyl blockers (250 nM GBR1209 for DAT, 166 nM desipramine morpholine (24d) 55 for NET, 100 nM fluoxetine for SERT). Substrate activity was detected by a significant reversal of the releasing effect General procedure A was followed using amine 18 (0.50 of the test drug. mL, 6.35 mmol) and epoxide 2d (815 mg, 5.27 mmol) in dry Data Analysis and Statistics MeOH (21 mL) under N to afford 663 mg (55% yield) of 60 As previously described (Rothman R B, Baumann M. H. amine 22d as a thick pale yellow oil. General procedure C Dersch CM, Romero DV, Rice KC, Carroll FI and Partilla was then followed using amine 22d (663 mg, 2.89 mmol) in J S Synapse 39: 32-41 (2001), incorporated herein by concentrated HSO (7.2 mL) to afford 406 mg (66% yield) reference), ECso values were determined using the nonlinear of inseparable morpholines 23d and 24d as a clear sticky oil least squares curve fitting program MLAB-PC (Civilized in a 3:1 (syn:anti) ratio. C.?', 22.2 (c 0.0037, MeOH); MS 65 Software, Bethesda, Md.). In substrate reversal experiments, (ESI) calcd for (M+1)"212.7, found 212.1. The fumarate had statistical significance was determined using the Students mp 136-137° C.; Anal. (C.H.CINOs) C, H, N. t-teSt. US 9,617,229 B2 71 72 TABLE 3

Monoamine Release and 5HT Activity of a Series of Phenmetrazine Analogs

Release 5-HT2 Activity

EC50 nm or % 10 l M Agonist Antagonist

Compound DA 5-HT NE (% (a) 10 M) (% at 1 IM)

131 7765 50

N

87 3246 37 42

N

415 inactive 63

N

1457 Inactive 349

N

29% 69% 6%

PALS83

34% 6% 67%

PALS87 US 9,617,229 B2 73 TABLE 3-continued

Monoamine Release and 5HT Activity of a Series of Phenmetrazine Analogs Release 5-HT2B Activity EC50 nm or % (a) 10 M Agonist Antagonist Compound DA 5-HT NE (% (a) 10 M) (% at 1 IM)

28% S6% 47% O 12 OH

N) H

PALS89

39% 41% 62% O 16 OH O C D N H

PALS90

100% 95% 93% O 1

-O F D w N H

PALS93

100% 95% 82% 2 28

O C D w N H

PALS94

98% 31% 96% 2 12

N H

PAL632

F 95% 88% 100% O%

N O H

PAL635 * denotes relative configuration US 9,617,229 B2 75 76 An additional series of compounds of the present inven TABLE 5 tion, having the Stereochemistry indicated in the figure Comparison of the DA, 5-HT, and NE Releasing above Table 4 below, was synthesized and tested for dop Activity of a Series of (2S,5S)-5-methyl-2-phenylmorpolines amine, serotonin, and norepinephrine release, as well as for serotonin uptake inhibition. The initial set of compounds was based on PAL-56, which is (+)-phenmetrazine, and which was found to be an effective DA/5HT releaser. The ~" (-)-isomer is also active as a releaser, but is not as potent. N -N- The two cis compounds were weaker uptake inhibitors. YX-H Adding Substituents to the phenyl ring resulted in improve 10 2 ments in 5HT release, such as the 3-chloro compounds (PAL-594), shown in Table 4. The data in Table 4 is shown PALii X,Y DA Rel DAUp SHT Rel NE Rel either as % EC50 of release or the EC50 value has been 730 H 212 107 79 calculated in nM. Two of the compounds, PAL-704 and 738 3C 58 23 65 15 880 3OMe. 56% 100% 76% PAL-788, show unique and interesting hybrid activity in that 886 3Me 86% 98% 88% they are DA/NE releasers, but are 5HT uptake inhibitors. 890 3F 96% 89% 96% 895 3CF 45% 100% 770, TABLE 4 899 4C 90% 76% 65% 903 4F 65% 100% 100% 910 4CF 15% 80% 15% Comparison of the DA, 5-HT, and NE Releasing 914 4Me 88% 88% 81% Activity of a Series of Phenmetrazine Analogs

25 That which is claimed: r 1. A compound according to the formula: N ' N YX Rs 2 R 30

PALi R X,Y DA Rel 5HT Rel 5HT Up NE Rel r R R. R4

56 Me H 87nM 3246 nM 38 nM 35 593 Me 3F 43 nM 2558 M 30 nM wherein: 594 Me 3C 27 M 301 nM 75 nM R is optionally substituted aryl, wherein the substituents 632 H H 86 nM 20260 nM 79 nM are selected from the group consisting of OH, option 63S H 4F 529 nM 2403 nM 285 nM 40 ally substituted C1-4 alkyl, optionally substituted C1-4 678 H Naphthyl 79% 92% 88% alkoxy, optionally substituted C2-4 alkenyl, optionally 704 Me Naphthyl 111 nM 105 nM 203 nM substituted C2-4 alkynyl, Cl, F, I, acylamido, CN, CF, 747 Me 4Me 91% 79% 95% N. CONH CO.R., CHOH, CHOR, NHCOR, 748 Me 4F 98% 94% 93% NHCOR, CONRR, C1-3 alkylthio, RSO, 45 RSO, CFS, and CFSO, wherein R and R are 749 Me 4C 88% 76% 93% each independently selected from H or optionally sub 751 Me 4OMe. SO% 64% 84% stituted C1-10 alkyl: 772 Me 4CN O% 53% 100% R is H or optionally substituted C1-3 alkyl: 773 Me 3Me 98% 82% 80% 780 Me 3OH 97% 70% 100% 50 R is H; 786 Me 3CN 99% 99% 100% Ra is optionally substituted C1-3 alkyl; and 788 Me 3,4-diCl 60% 95% 98% Rs is H or OH: 821 Me 4F,3CI 94% 71.9% 80% R is H or optionally substituted C1-3 alkyl: 823 Me 3OMe 96% 78% 86% 55 with the proviso that when R is CH and R is phenyl, 1001 H 2CF3 64% 25% SO% then the phenyl ring of R is substituted with one or more Substituents and R is trans to R; wherein the compound comprises an enantiomeric excess An additional set of compounds, wherein all compounds 60 of at least 95% of the (2S-5S) enantiomer, have a CH group at the R position, was generated, and or a pharmaceutically acceptable ester, amide, Salt, or tested for dopamine release, dopamine reuptake, serotonin solvate thereof. release, and norepinephrine release. In all cases, the (2S, 2. The compound of claim 1, wherein R is phenyl, 5S)-analog was more active as a releaser, as shown in Table 65 substituted phenyl, naphthyl, or substituted naphthyl. 5. The other isomers were either inactive or uptake inhibi 3. The compound of claim 1, wherein R is H and R is tors, the potency depending on the Substituent (not shown). substituted aryl. US 9,617,229 B2 77 78 4. The compound according to claim 1, having the for NRR, NHCOR, NHCOR CONRR, C1-3 mula: alkylthio, RSO, RSO, CFS, and CFSO; and c is an integer from 0-7, or a pharmaceutically acceptable ester, amide, Salt, or solvate thereof. 21 8. The compound according to claim 1, wherein R is H (R, , Rs or CH. 9. The compound according to claim 1, wherein R is CH. S. r 10. The compound of claim 1, wherein the compound is R R. R4 10 selected from the group consisting of: 2-(3-chloro-phenyl)-5-methyl-morpholine; 2-(3-fluoro-phenyl)-5-methyl-morpholine; wherein: 2-(3-methoxy-phenyl)-5-methyl-morpholine; each R, represents a Substituent independently selected 2-(4-chloro-phenyl)-5-methyl-morpholine; and from the group consisting of OH, optionally substituted 15 2-(4-fluoro-phenyl)-5-methyl-morpholine; or a pharmaceutically acceptable ester, amide, Salt, or C1-4 alkyl, optionally substituted C1-4 alkoxy, option solvate thereof. ally substituted C2-4 alkenyl, optionally substituted 11. The compound according to claim 1, wherein the C2-4 alkynyl, Cl, F, I, acylamido, CN, CF, N. compound is one or more of a dopamine releaser, norepi CONH CO.R., CHOH, CHOR, NHCOR, nephrine releaser, serotonin releaser, dopamine uptake NHCOR, CONRR, C1-3 alkylthio, RSO, inhibitor, norepinephrine uptake inhibitor, and serotonin RSO, CFS, and CFSO, wherein R and Rs are uptake inhibitor. each independently selected from H or optionally sub 12. The compound according to claim 1, wherein the stituted C1-10 alkyl; and compound is a dopamine releaser or a dual serotonin and b is an integer from 0-5: 25 dopamine releaser. 13. The compound according to claim 1, wherein the with the proviso that when R is CH, then b is an integer compound is inactive at the 5HT receptor. from 1-5 and the phenyl is trans to R, 14. A pharmaceutical composition comprising a com wherein the compound comprises an enantiomeric excess pound according to claim 1 and one or more pharmaceuti of at least 95% of the (2S-5S) enantiomer, cally acceptable carriers. or a pharmaceutically acceptable ester, amide, Salt, or 30 15. A method for treating or delaying the progression of solvate thereof. disorders that are alleviated by modulating monoamine 5. The compound according to claim 4, wherein b is an release in a patient comprising administering a therapeuti integer from 1-5, and each R, is independently selected from cally effective amount of at least one compound according the group consisting of optionally Substituted C1-4 alkyl, 35 to claim 1. optionally substituted C1-4 alkoxy, OH, CN, and CF. 16. The method of claim 15, wherein the disorder is 6. The compound according to claim 5, wherein b is 1 and selected from the group consisting of addiction, depression, the R-7 Substituent is located meta or para to the morpholine obesity, bipolar disorder, attention deficit disorder (ADD), Substituent on the phenyl ring. attention deficit/hyperactivity disorder (ADHD), hypoactive 7. The compound according to claim 1, having the for 40 sexual desire disorder, antidepressant-induced sexual dys mula: function, orgasmic dysfunction, seasonal affective disorder/ winter depression, mania, bulimia and other eating disor ders, panic disorders, obsessive compulsive disorder, 21 schizophrenia, schizo-affective disorder, Parkinson's dis (R-, - Rs 45 ease, narcolepsy, anxiety disorders, insomnia, chronic pain, N R6 migraine headaches, and restless legs syndrome. 17. The compound according to claim 4, wherein R is H or CH. R R. R4 18. The compound according to claim 7, wherein R is H or CH. 50 19. The compound according to claim 4, wherein R is wherein: CH. each R, represents a Substituent independently selected 20. The compound according to claim 7, wherein R is from the group consisting of OH, optionally substituted CH. C1-4 alkyl, optionally substituted C1-3 alkoxy, option 55 21. The compound according to claim 5, wherein b is 1 ally substituted C2-4 alkenyl, optionally substituted and the R, substituent is located meta to the morpholine C2-4 alkynyl, halogen, amino, acylamido, CN, CF, Substituent on the phenyl ring. NO, N, CONH CO.R., CHOH, CHOR, k k k k k