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(12) Patent Application Publication (10) Pub. No.: US 2008/0214559 A1 Lange Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2008/0214559 A1 Lange Et Al US 20080214559A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0214559 A1 Lange et al. (43) Pub. Date: Sep. 4, 2008 (54) COMPOUNDS WITH A COMBINATION OF A6IP3/04 (2006.01) CANNABINOID CB1 ANTAGONSMAND A63L/45 (2006.01) SEROTONN REUPTAKE INHIBITION A63L/464 (2006.01) (52) U.S. Cl. .............. 514/252.19; 548/371.7: 548/341.5; (75) Inventors: Josephus H.M. Lange, Weesp 514/.407: 514/400: 544/370, 544/371; 514/254.05 (NL); Cornelis G. Kruse, Weesp (NL) (57) ABSTRACT Correspondence Address: Compounds with a combination of cannabinoid CB antago FINNEGAN, HENDERSON, FARABOW, GAR- nism and serotonin re-uptake inhibition, pharmaceutical RETT & DUNNER compositions containing these compounds, methods for pre LLP paring these compounds, methods for preparing novel inter 901 NEW YORKAVENUE, NW mediates useful for their synthesis, and methods for preparing WASHINGTON, DC 20001-4413 (US) these compositions are disclosed. Uses of Such compounds and compositions, particularly their use in administering (73) Assignee: Solvay Pharmaceuticals B.V. them to patients to achieve a therapeutic effect in psychosis, anxiety, depression, attention deficits, cognitive disorders, (21) Appl. No.: 11/970,229 obesity, drug dependence, Parkinson's disease, Alzheimer's disease, pain disorders, neuropathic pain disorders and sexual (22) Filed: Jan. 7, 2008 disorders are disclosed. Related U.S. Application Data In at least one embodiment, the invention relates to com pounds of the general formula (1); (60) Provisional application No. 60/879,533, filed on Jan. 10, 2007. (1) Publication Classification R (51) Int. Cl. -N- A 6LX 3L/2197 (2006.01) CO7D 23L/38 (2006.01) CO7D 233/54 (2006.01) wherein the substitutents have the definitions given in the CO7D 403/02 (2006.01) specification. US 2008/0214559 A1 Sep. 4, 2008 COMPOUNDS WITH A COMBINATION OF reviews (Landsman, 1997; Lichtman, 2002: De Petrocellis, CANNABINOID CB1 ANTAGONSMAND 2004: Di Marzo, 2004; Hertzog, 2004; Lange, 2004, 2005; SEROTONN REUPTAKE INHIBITION Smith, 2005: Thakur, 2005; Padgett, 2005; Muccioli, 2005; Lambert, 2005; Vandevoorde, 2005). Potential therapeutic applications of CB receptor modulators disclosed in the 0001. This application claims the benefit of priority of quoted reviews include medicaments for treating psychosis, U.S. Provisional Application No. 60/879,533, filed on Jan. anxiety, depression, attention deficits, memory disorders, 10, 2007, the disclosure of which is incorporated herein by cognitive disorders, appetite disorders, obesity, addiction, reference. appetence, drug dependence, neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, mul tiple Sclerosis, traumatic brain injury, stroke, Parkinson's dis ease, Alzheimer's disease, epilepsy, Huntington's disease, NDEX page Tourette's syndrome, cerebral ischaemia, cerebral apoplexy, Title of the invention 1 craniocerebral trauma, spinal cord injury, neuroinflammatory index 2 Disclosure 10 disorders, plaque Sclerosis, viral encephalitis, demyelinisa Definitions 22 tion related disorders, pain disorders, including neuropathic Abbreviations 30 pain disorders, septic shock, glaucoma, diabetes, cancer, Example 1: Analytical methods 31 emesis, nausea, gastrointestinal disorders, gastric ulcers, Example 2: General aspects of syntheses 32 Example 3: Syntheses of intermediates 37 diarrhea, sexual disorders, impulse control disorders, and Example 4: Syntheses of specific compounds 42 cardiovascular disorders. Example 5: Formulations used in animal studies 48 0005 Mood disorders and anxiety disorders cause enor Example 6: Pharmacological methods 49 Example 7: Pharmacological test results 49 mous suffering. The introduction of selective serotonin Example 8: Pharmaceutical preparations 51 reuptake inhibitors more than two decades ago has been a Bibliography S4 major step in the evolution of safer antidepressants. Repre Claims 57 sentative examples of selective serotonin reuptake inhibitors Abstract 68 are fluvoxamine, fluoxetine, paroxetine, Sertraline, citalo pram, Zimeldine, clomipramine, indalpine, and indatraline. In 0002 This invention relates to the fields of pharmaceutical spite of the remarkable structural diversity, most selective and organic chemistry, and provides compounds with a com serotonin reuptake inhibitors are mono-amine-based: they bination of cannabinoid CB antagonism and serotonin re contain a basic nitrogen atom (Pacher, 2004). Scientific uptake inhibition, intermediates, formulations, methods for articles, patents and patent applications indicate the following preparing these compounds, methods for preparing compo therapeutic applications for serotonin reuptake inhibitors: sitions comprising these compounds, and methods of treat alcoholism, Alzheimer's disease, anorexia nervosa, anxiety ment using these compounds. disorder, attention deficit hyperactivity disorder, bipolar dis 0003. A reductionist one target—one disease approach order, bulimia nervosa, bentral nervous system disease, che has dominated the pharmaceutical industry for some decades. motherapy induced emesis, cocaine addiction, cognitive dis Using this strategy, many successful drugs were discovered. order, diabetic neuropathy, drug dependence, eating disorder, Despite these successes, many diseases remain inadequately female sexual dysfunction, functional bowel disorder, gener treated. These findings rationalize an alternative approach, alized anxiety disorder, headache, inflammation, irritable wherein chemical entities are developed that simultaneously bowel syndrome, male sexual dysfunction, major depressive modulate multiple targets. Such drugs may show advanta disorder, menopause, migraine, myalgia, neuralgia, neuro geous properties such as increased clinical efficacy, lack of pathic pain, obesity, obsessive compulsive disorder, osteoar undesired pharmacokinetic drug-drug interactions, or lack of thritis, pain, panic disorder, Parkinson's disease, premature unfavorable pharmacokinetic and pharmacodynamic proper ejaculation, premenstrual syndrome, psychosexual disorder, ties. Unfavorable pharmacokinetic and pharmacodynamic psychosis, rheumatoid arthritis, Schizophrenia, Sleep disor properties may lead to unpredictable variability between indi der, and urinary incontinence. vidual patients. In order to combine different therapeutic 0006 Because of the frequently observed co-morbidity of mechanisms, cocktails of two or more drugs are still used in symptoms of different diseases, compounds combining can clinical practice. Alternatively, multicomponent drugs are nabinoid CB antagonism with serotonin reuptake inhibition being used wherein two or more pharmaceutically active can be useful to treat the conditions wherein either a cannab compounds are co-formulated in a single tablet or capsule in inoid CB antagonist or a serotonin reuptake inhibitor is order to improve patient compliance. Another approach ulti potentially effective. Thus the compounds of the invention lizes a pharmaceutical treatment with a chemical entity that is can be used for treating: addiction, alcoholism, Alzheimer's able to modulate more than one biological target simulta disease, anorexia nervosa, anxiety disorder, appetite disor neously. It is clear that such a single entity—multiple target ders, attention deficit hyperactivity disorder, bipolar disorder, approach offers the advantage of a lower risk of undesired bulimia nervosa, cancer, cardiovascular disorders, central drug-drug interactions compared to drug cocktails or multi nervous system disease, cerebral ischaemia, cerebral apo component drugs. Several multiple target ligands are known. plexy, chemotherapy induced emesis, cocaine addiction, cog The majority were found retrospectively or by accident; only nitive disorder, dementia, demyelinisation related disorders, a few were rationally designed. diabetes, diabetic neuropathy, diarrhea, drug dependence, 0004 Cannabinoid receptors are part of the endo-cannab dystonia, eating disorder, emesis, epilepsy, female sexual inoid system, involved in many diseases. Detailed informa dysfunction, functional bowel disorder, gastrointestinal dis tion on cannabinoid receptors, CB receptor modulators, and orders, gastric ulcers, generalized anxiety disorder, glau their pharmacological activities are the Subject of recent coma, headache, Huntington's disease, impulse control dis US 2008/0214559 A1 Sep. 4, 2008 orders inflammation, irritable bowel syndrome, male sexual interact with the Lys-192 amino acid residue side chain in the dysfunction, major depressive disorder, memory disorders CB receptor, thereby stabilizing its inactive state. menopause, migraine, muscle spasticity, multiple Sclerosis, I0011) To illustrate the CB receptor antagonist pharma myalgia, nausea, neuralgia, neurodegenerative disorders, cophore model, a number of concrete examples of CB recep neuroinflammatory disorders, neuropathic pain, obesity, tor antagonists are depicted below. The putative hydrogen obsessive compulsive disorder, osteoarthritis, pain, panic dis bond acceptor atom (oxygen atom from a carbonyl group, order, Parkinson's disease, plaque Sclerosis, premature ejacu lation, premenstrual syndrome, psychosexual disorder, psy oxygen atom from a Sulfonyl group, or nitrogen atom in a chosis, rheumatoid arthritis, septic shock, Schizophrenia, heteroaromatic ring) is indicated bold. sexual disorders, sleep disorder, spinal cord injury, stroke, Tourette's syndrome, traumatic brain injury, tremor, urinary incontinence, and viral encephalitis. C
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