(12) Patent Application Publication (10) Pub. No.: US 2013/0203752 A1 Blough Et Al

US 201302O3752A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0203752 A1 Blough et al. (43) Pub. Date: Aug. 8, 2013 (54) PHENYLMORPHOLINES AND ANALOGUES Publication Classification THEREOF (51) Int. Cl. (76) Inventors: Bruce E. Blough, Raleigh, NC (US); C07D 265/30 (2006.01) Richard Rothman, Ellicott City, MD (52) U.S. Cl. (US); Antonio Landavazo, Raleigh, NC CPC .................................... C07D 265/30 (2013.01) (US); Kevin M. Page, Willow Spring, USPC ......... 514/231.2: 544/106; 544/174: 544/163 NC (US); Ann Marie Decker, Durham, NC (US) (57) ABSTRACT (21) Appl. No.: 13/698,892 Provided herein are compounds and prodrugs and methods of (22) PCT Filed: May 20, 2011 preparation of compounds and prodrugs that are capable of functioning as releasers and/or uptake inhibitors of one or (86). PCT No.: PCT/US2011/037361 more monoamine neurotransmitters, including dopamine, serotonin, and norepinephrine. Also provided are pharmaceu S371 (c)(1), tical compositipos1u1ons compris1ng one or more OIf uneseth com (2), (4) Date: Mar. 4, 2013 pounds or prodrugs, which may further comprise one or more Related U.S. Application Data additional therapeutic agents. Also provided are methods of treatment of various conditions that may be responsive to (60) Provisional application No. 61/347,259, filed on May modification of monoamine neutrotransmitter levels, such as 21, 2010. pre-obesity, obesity, addiction, and depression. US 2013/0203752 A1 Aug. 8, 2013 PHENYLMORPHOLINES AND ANALOGUES 0006 Another anorectic, which was prescribed for the THEREOF short-term treatment of obesity, is phenmetrazine Phenmetra Zine is reportedly a potent Substrate for norephinephrine and FEDERALLY SPONSORED RESEARCHOR dopamine transporters and displays stimulant properties DEVELOPMENT similar to those of amphetamines. Some reports indicate that phenmetrazine has been widely abused as a recreational drug 0001. This invention was made with United States Gov and has greater addiction potential than amphetamines. ernment support under DA 12970/0207690,000 awarded by Because of phenmetrazine's high potential for abuse, it was the National Institutes of Health. The United States Govern pulled from the market. ment has certain rights in the invention. 0007 Subsequently, phendimetrazine, a close analogue of FIELD OF THE INVENTION phenmetrazine with a methyl Substituent on the amine, was released onto the market as an anorectic. Recent research has 0002 The present application is directed to various com Suggested that phendimetrazine actually exerts its effect via pounds and methods of preparation of compounds that are conversion to phenmetrazine. See Rothman et al., Eur: J. capable of functioning as releasers and/or reuptake inhibitors Pharmacology 447: 51-57 (2002), incorporated herein by of one or more monoamine neurotransmitters, including reference. Thus, as with phenmetrazine, phendimetrazine dopamine, serotonin, and norepinephrine. The application is also has a high potential for abuse. Although it is still available also directed to pharmaceutical compositions comprising one for the treatment of obesity, phendimetrazine is a Class III or more of these compounds, which may also comprise one or controlled substance and there is a high likelihood of abuse of more additional therapeutic agents. It is also directed to meth this drug. ods of treatment of various conditions that may be responsive 0008 Accordingly, there is a need for an anorectic drug to modification of monoamine neurotransmitter levels, such that acts similarly to the aforementioned drugs on the central as pre-obesity, obesity, addiction, and depression. nervous system, but does not provide Such high potential for abuse and/or does not act as an agonist of the 5-HT2 receptor. BACKGROUND OF THE INVENTION Because of their effects on the central nervous system, such 0003) Obesity is a serious public health concern, associ compounds may be useful not only for treating obesity and ated with a number of health conditions. The National Center pre-obesity, but also for other diseases related to the central for Health Statistics reports that 65% of adults are considered nervous system including addiction, depression, and anxiety. to be overweight (pre-obese), with greater than 34% of those BRIEF SUMMARY OF THE INVENTION adults considered to be obese. The incidences of obesity have dramatically increased over the last twenty years, with the 0009. The present invention relates generally to com percentage of obese adults having doubled from 1980 to pounds and prodrugs that may be useful as releasers and/or 2004. Children are at risk as well, with an estimated 17% of reuptake inhibitors of one or more monoamine neurotrans children from age 2-19 classified as obese. Medical condi mitters, including dopamine, serotonin, and norepinephrine. tions commonly associated with obesity include diabetes and It also relates to pharmaceutical formulations of Such com high blood pressure, which may lead to cardiovascular dis pounds and/or prodrugs and to methods of using such com ease, stroke, and premature mortality. pounds, prodrugs, or formulations thereof to treat various 0004. As a result, there has been an increase in demand for conditions that may be responsive to the modulation of neu medications to treat pre-obesity and obesity. One type of rotransmitter levels. medication that is available to treat obesity is anorectics, also 0010. In one aspect, the present invention provides a com known as appetite Suppressants. One well-known anorectic is pound that may modulate the levels of one or more monoam Fen-Phen, which was widely prescribed for weight loss in the ine neurotransmitters. In some embodiments, the invention early 1990s. Fen-Phen is a combination drug that comprises provides a compound according to the following structure: two compounds; namely, fenfluramine and phentermine. Fenfluramine acts via a serotonergic mechanism to increase a user's satiety. Phentermine has a stimulant effect, acting Rs mainly through dopaminergic and noradrenergic mecha nisms to decrease a user's appetite. Fen-Phen, although effec tive in the treatment of obesity, was linked to possible valvular R N r heart disease and pulmonary hypertension in 1997. As a 2 R3 R4 result, fenfluramine and the Fen-Phen combination drug were pulled from the market in 1997. 0005. It is thought that the valvular heart disease and pull 0011 wherein: monary hypertension associated with the use offenfluramine 0012 R is optionally substituted aryl; and its active metabolite norfenfluramine may result from the 0013 R is H or optionally substituted C1-3 alkyl: stimulation of 5-hydroxytryptamine (5-HT) serotonin recep 0.014 R is H, optionally substituted C1-3 alkyl, or ben tors. Studies have shown that, in particular, fenfluramine is a Zyl; potent agonist of a particular type of 5-HT receptor, the 0.015 R is H or optionally substituted C1-3 alkyl; and 5-HT2 receptor, which is present in human cardiac valves. 0016 Rs is H or OH: Phentermine is still available in many countries, including the 0017 R is H or optionally substituted C1-3 alkyl; United States; however, it is classified as a controlled sub 0018 with the proviso that when R is CH and R is stance due to its chemical and pharmacological similarity to phenyl, then (a) the phenyl ring of R is substituted with one amphetamines. One concern with Such compounds is the high or more substituents; or (b) R is substituted C1 alkyl or potential for abuse. optionally substituted C2-C3 alkyl, or (c) one or more of R, US 2013/0203752 A1 Aug. 8, 2013 Rs, and R is not H, or a combination of two or more of (a) 0028 wherein: through (c); or a pharmaceutically acceptable ester, amide, 0029 each R, represents a substituent independently salt, Solvate, prodrug, or isomer thereof. Selected from the group consisting of OH, optionally 0019. In certain embodiments, a compound of the struc substituted C1-4 alkyl, optionally substituted C1-3 ture above is provided, wherein R is phenyl, substituted alkoxy, optionally substituted C2-4 alkenyl, optionally phenyl, naphthyl, or Substituted naphthyl. In some embodi Substituted C2-4 alkynyl, halogen, amino, acylamido, ments, R is a Substituted aryl group (e.g., a Substituted phe CN, CF, NO, N, CONH CO.R. CH-OH, nyl) and R is H. CHOR, NRR, NHCOR, NHCOR, 0020. In some embodiments, a compound is provided hav CONRR, C1-3 alkylthio. RSO, RSO, CFS, ing the structure: and CFSO; and 0.030 c is an integer from 0-7. 0031 or a pharmaceutically acceptable ester, amide, salt, Solvate, prodrug, or isomer thereof. 0032. In some embodiments of the present invention, a 21 compound is provided, wherein R is H or CH. In some (R-, - || Rs embodiments of the invention, a compound is provided wherein R is Hor CH. In certain embodiments, R is option ally substituted C1-3 alkyl. In certain embodiments, one of R N r and R is Hand the other of RandR is optionally substituted R R. R4 C1-3 alkyl. In some embodiments, such compounds may comprise an enantiomeric excess of at least 95% of one iso mer (e.g., the (25-5S) enantiomer). 0021 wherein the substituents areas noted above, except 0033. In one embodiment of the invention, certain com that: pounds are provided, selected from the group consisting of 0022 each R, represents a substituent independently 2-(2-naphthyl)morpholine: 2-methyl-6-phenyl-morpholine: selected from the group consisting of OH, optionally Substi 2-(3-chloro-phenyl)-3-methyl-morpholine: 2-(3-chloro-phe tuted C1-4 alkyl, optionally substituted C1-4 alkoxy, option nyl)-3-methyl-morpholin-2-ol: 2-(3-chloro-phenyl)-5-me ally substituted C2-4 alkenyl, optionally substituted C2-4 thyl-morpholine: 2-(3-chloro-phenyl)-6-methyl-morpho alkynyl, halogen, amino, acylamido, CN, CF, NO, N, line: 2-(3-fluoro-phenyl)-3-methyl-morpholine: 2-(3-fluoro CONH CO.R., CHOH, CHOR, NRR, NHCOR, phenyl)-3-methyl-morpholin-2-ol: 2-(3-fluoro-phenyl)-5- NHCOR, CONRR, C1-3 alkylthio.

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