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Us 2008/0280991 A1 8, 2007. Pdco US 20080280991A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0280991 A1 Gant et al. (43) Pub. Date: Nov. 13, 2008 (54) SUBSTITUTED NAPHTHALENES (52) U.S. Cl. ......................................... 514/630; 564/219 (75) Inventors: Thomas G. Gant, Carlsbad, CA (US); Sepehr Sarshar, Cardiff by the Sea, CA (US) (57) ABSTRACT Correspondence Address: Disclosed herein are substituted naphthalene-based melato GLOBAL PATENT GROUP - APX nin (MT) receptor modulators and/or 5-HT receptor modula Ms. LaVern Hall tors of Formula I, process of preparation thereof, pharmaceu 10411 Clayton Road, Suite 304 tical compositions thereof, and methods of use thereof. ST. LOUIS, MO 63131 (US) (73) Assignee: AUSPEX O Formula I PHARMACEUTICALS, INC., Vista, CA (US) Ran R15 (21) Appl. No.: 12/116,636 R R16 R11 R13 7 (22) Filed: May 7, 2008 R12 R16 Related U.S. Application Data Ro (60) Provisional application No. 60/928,343, filed on May R O Rs 2 R3 8, 2007. Publication Classification PDCOR R (51) Int. Cl. Rs R6 A6 IK3I/I65 (2006.01) C07C 23.3/05 (2006.01) US 2008/0280991 A1 Nov. 13, 2008 SUBSTITUTED NAPHTHALENES nant metabolite is a naphthol. “S 21517. that has 100-fold less potency for the melatonin receptor than the parent com pound. Long term toxicology studies of these metabolites are 0001. This application claims the benefit of priority of lacking. All of these transformations, among other potential U.S. provisional application No. 60/928,343, filed May 8, transformations, can and do occur through polymorphically 2007, the disclosure of which is hereby incorporated by ref expressed enzymes thus exacerbating interpatient variability. erence as if written herein in its entirety. Further, the terminal elimination half-life is only 2.3 hours. A medicine with a longer half-life will therefore attenuate inter FIELD patient variatibility and improve efficacy. 0002 The present invention is directed to naphthalene based 5-HT receptor modulators and/or melatonin receptor SUMMARY OF THE INVENTION modulators, pharmaceutically acceptable salts and prodrugs 0005 Disclosed herein is a compound having structural thereof, the chemical synthesis thereof, and medical use of Such compounds for the treatment and/or management of Formula I: 5-HT receptor-mediated disorders and/or melatonin receptor mediated disorders. Formula I O BACKGROUND R14 R15 0003) Agomelatine (Valdoxan R,S 20098), N-(2-(7-meth NN R16 oxy-naphthalen-1-yl)-ethyl-acetamide, is an orally adminis R17 tered putative agonist of the melatonin MT and MT recep R11 R13 tors. Agomelatine also antagonizes the 5-HT, receptor. R12 Another drug of agomelatine's class is Ramelteon (Roza R16 remR). Ramelton, however, does not elicit the same effect on R9 5-HT, receptors as agomelatine, and therefore is not as R O Rs effective as agomelatine in treating certain disorders. Ago melatine can be used to treat sleep disorders and depressive DrR3 disorders. As compared with other sleep disorder and depres R4 R7 sive disorder medications, agomelatine does not cause sexual side-effects, daytime drowsiness, and withdrawal effects Rs R6 upon discontinuation. Agomelatine has been shownto attenu ate sexual disorders that are induced by 5-HT, receptor agonism in rats (Loo et al. International Clinical Psychop or a pharmaceutically acceptable salt, Solvate, or prodrug harmacology 2002, 17, 239-247; Chagraoui et al., Psychop thereof, wherein: harmacology 2003, 170, 17-22; Bertaina-Anglade et al. 0006 R. R. R. R. Rs. R. R-7, Rs. Ro Ro, R. R. R. Behavioural Pharmacology 2006, 17, 703-713; Kupfer, R. R. R. and R7 are independently selected from the European Neuropsychopharmacology 2006, 16, S639-S643; group consisting hydrogen and deuterium; and Norman, Australian and New Zealand Journal of Psychiatry 0007 at least one of R. R. R. R. R. R. R. R. R. R. 2006, 40, 394-401; Montgomery, European Neuropsychop R. R. R. R. Rs. Rio, and R7 is deuterium. harmacology 2006, 16, S633-S638; Zupancic et al. CNS 0008 Further disclosed herein is a method for treating, Drugs 2006, 20(12),981-992: Preketal, Psychopharmacol preventing, or ameliorating one or more symptoms of a mela tonin (MT) receptor-mediated disorder and/or serotonin ogy 2007, 190, 575-579). (5-HT) receptor-mediated disorder which comprises admin istering to a subject a therapeutically effective amount of at O least one compound as disclosed herein or a pharmaceutically acceptable salt, Solvate, or prodrug thereof. 0009. Additionally disclosed herein is a method for treat - ing, preventing, or ameliorating one or more symptoms of a disorder involving, but not limited to, depressive disorders, seasonal affective disorders, anxiety, sleep disorders, dys thymia, sexual side effects associated with the use of 5-HT, MeO agonists, any disorder which can lessened, alleviated, or ben efited by modulating MT receptors, and/or any disorder which can lessened, alleviated, or benefited by modulating Agomelatine 5-HT receptors. 0010. Also disclosed herein are articles of manufacture and kits containing compounds as disclosed herein. By way 0004. The agomelatine chemical structure contains a num of example only a kit or article of manufacture can include a ber of moieties that we posit will produce clinically-inactive container (Such as a bottle) with a desired amount of at least (at best) and toxic (at worst) metabolites, the formation of one compound (or pharmaceutical composition of a com which can be prevented or diminished by the approach pound) as disclosed herein. Further, such a kit or article of described herein. For example, agomelatine's methoxy group manufacture can further include instructions for using said is subject to enzymatic oxidation at the C–H bonds. Three compound (or pharmaceutical composition of a compound) agomelatine metabolites have been detected. The predomi disclosed herein. The instructions can be attached to the con US 2008/0280991 A1 Nov. 13, 2008 tainer, or can be included in a package (such as a box or a 0022. In other embodiments said therapeutic agent is an plastic or foil bag) holding the container. antipsychotic medication. 0011. In another aspect is the use of a compound as dis 0023. In further embodiments said antipsychotic medica closed herein in the manufacture of a medicament for treating tion is selected from the group consisting of chlorpromazine, a disorder in a subject, by modulating MT receptors and/or by fluphenazine, perphenazine, prochlorperazine, thioridazine, modulating 5-HT receptors. In a further or alternative trifluoperazine, haloperidol, haloperidol decanoate, droperi embodiment, said disorder is depressive disorders, seasonal dol, pimozide, amisulpride, aripiprazole, bifeprunoX, cloza affective disorders, anxiety, sleep disorders, dysthymia, pine, melperone, norclozapine, olanzapine, risperidone, pali sexual side effects associated with the use of 5-HT, agonists, peridone, quetapine, Symbyax, tetrabenazine, and any disorder which can lessened, alleviated, or benefited by Ziprazidone. modulating MT receptors, and/or any disorder which can 0024. In other embodiments said therapeutic agent is an lessened, alleviated, or benefited by modulating 5-HT recep antidepressant. tOrS. 0025. In further embodiments said antidepressant is 0012. In another aspectare processes for preparing a com selected from the group consisting of amitriptyline, bupro pound as disclosed herein as a MT receptor modulator and/or pion, citalopram, clomipramine, dapoxetine, desipramine, a 5-HT receptor modulator, or other pharmaceutically accept dothiepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, able derivatives such as prodrug derivatives, or individual imipramine, iofepramine, nortriptyline, paroxetine, protrip isomers and mixture of isomers or enantiomers thereof. tyline, Sertraline, traZodone, trimipramine, and Venlafaxine. 0013 Also disclosed herein are processes for formulating 0026. In other embodiments said therapeutic agent is a pharmaceutical compositions with a compound disclosed 5-HT, receptor modulator. herein. 0027. In yet other embodiments said 5-HT, receptor 0014. In further embodiments, said pharmaceutical com modulator is selected from the group consisting of alpha position comprises a compound disclosed herein and one or methyl-5-HT, DOI, lysergic acid diethylamide (LSD), and more pharmaceutically acceptable carriers. meSulergine. 0015. In certain embodiments said pharmaceutical com 0028. In further embodiments, a method for the treatment, position comprises one or more release-controlling excipi prevention, or amelioration of one or more symptoms of a MT entS. receptor-mediated disorder, a 5-HT receptor mediated disor 0016. In other embodiments said pharmaceutical compo der, or a MT receptor-mediated disorder and 5-HT receptor sition further comprises one or more non-release controlling mediated disorder in a subject comprises administering a excipients. therapeutically effective amount of a compound as disclosed 0017. In certain embodiments said pharmaceutical com herein. position is Suitable for oral, parenteral, or intravenous infu 0029. In other embodiments said MT receptor-mediated sion administration. disorder, said 5-HT receptor mediated disorder, or said MT 0018. In yet other embodiments said pharmaceutical com receptor-mediated disorder and 5-HT receptor mediated dis position comprises a tablet, or capsule. order is selected from the group consisting of depressive 0019. In certain embodiments the compounds as disclosed disorders, seasonal affective disorders, anxiety, sleep disor herein are
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