(19) TZZ _¥¥¥Z_T (11) EP 2 134 330 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/00 (2006.01) 08.05.2013 Bulletin 2013/19 (86) International application number: (21) Application number: 08744091.3 PCT/US2008/057557 (22) Date of filing: 19.03.2008 (87) International publication number: WO 2008/116024 (25.09.2008 Gazette 2008/39) (54) COMBINATIONS OF 5-HT2A INVERSE AGONISTS AND ANTAGONISTS WITH ANTIPSYCHOTICS KOMBINATIONEN AUS 5-HT2A-INVERSAGONISTEN UND -ANTAGONISTEN MIT ANTIPSYCHOTIKA COMBINAISONS D’AGONISTES INVERSES OU ANTAGONISTES DE 5-HT2A AVEC ANTIPSYCHOTIQUES (84) Designated Contracting States: (74) Representative: Weber, Martin AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Jones Day HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT Prinzregentenstraße 11 RO SE SI SK TR 80538 München (DE) Designated Extension States: AL BA MK RS (56) References cited: WO-A-2004/064738 WO-A-2007/133802 (30) Priority: 19.03.2007 US 895735 P US-A1- 2006 204 486 29.03.2007 US 908921 P 10.12.2007 US 12771 • "ACP-103" DRUGS OF THE FUTURE, PROUS 04.02.2008 US 26092 SCIENCE, ES, vol. 31, no. 11, 1 January 2006 (2006-01-01), pages 939-943, XP002446571 ISSN: (43) Date of publication of application: 0377-8282 23.12.2009 Bulletin 2009/52 • GRAHNEN A E ET AL: "Reduction of haloperidol- induced side effects by ACP-103 in healthy (73) Proprietor: Acadia Pharmaceuticals Inc. volunteers" CLINICAL PHARMACOLOGY & San Diego, CA 92121-1402 (US) THERAPEUTICS, MOSBY-YEAR BOOK, ST LOUIS, MO, US, vol. 77, no. 2, 1 February 2005 (72) Inventors: (2005-02-01), page P98, XP004802689 ISSN: • PETERS, Perry 0009-9236 San Diego, CA 92122 (US) • LI ZHU ET AL: "ACP-103, a 5-HT2A/2C inverse • FURLANO, David agonist, potentiates haloperidol-induced San Diego, CA 92107 (US) dopamine release in rat medial prefrontal cortex • BAHR, Daun and nucleus accumbens" San Diego, CA 92130 (US) PSYCHOPHARMACOLOGY, vol. 183, no. 2, • VAN KAMMEN, Daniel December 2005 (2005-12), pages 144-153, San Diego, CA 92131 (US) XP002497507 ISSN: 0033-3158 • BRANN, Mark • MELTZER ET AL: "Co- therapy with pimavanserin Rye, NH 03870 (US) and risperidone 2 mg provides an improved clinical profile" SCHIZOPHRENIA RESEARCH, ELSEVIER, vol. 98, 16 January 2008 (2008-01-16), page 16, XP022423672 ISSN: 0920-9964 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 134 330 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 134 330 B1 Description [0001] The present invention relates to the fields of chemistry and medicine. More particularly, the invention relates to co-administration of 5-HT2A receptor inverse agonists or antagonists with antipsychotics. 5 [0002] Serotonin or 5-hydroxytryptamine (5-HT) plays a significant role in the functioning of the mammalian body. In the central nervous system, 5-HT is an important neurotransmitter and neuromodulator that is implicated in such diverse behaviors and responses as sleeping, eating, locomotion, perceiving pain, learning and memory, sexual behavior, controlling body temperature and blood pressure. In the spinal column, serotonin plays an important role in the control systems of the afferent peripheral nociceptors (Moulignier, Rev. Neurol. 150:3-15, (1994)). Peripheral functions in the 10 cardiovascular, hematological and gastrointestinal systems have also been ascribed to 5-HT. 5-HT has been found to mediate a variety of contractile, secretory, and electrophysiologic effects including vascular and nonvascular smooth muscle contraction, and platelet aggregation. (Fuller, Biology of Serotonergic Transmission, 1982; Bou llin, Serotonin In Mental Abnormalities 1: 316 (1978); Barchas, et al., Serotonin and Behavior, (1973)). The 5- HT2A receptor subtype (also referered to as subclass) is widely yet discretely expressed in the human brain, including many cortical, limbic, and 15 forebrain regions postulated to be involved in the modulation of higher cognitive and affective functions. This receptor subtype is also expressed on mature platelets where it mediates, in part, platelet aggregation, one of the initial steps in the process of vascular thrombosis. [0003] Given the broad distribution of serotonin within the body, it is understandable that tremendous interest in drugs that affect serotonergic systems exists (Gershon, et al., The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); 20 Saxena, et al., J. Cardiovascular Pharmacol. 15: Supp. 7 (1990)). Serotonin receptors are members of a large human gene family of membrane-spanning proteins that function as transducers of intercellular communication. They exist on the surface of various cell types, including neurons and platelets, where, upon their activation by either their endogenous ligandserotonin orexogenously administered drugs,they change their conformational structure and subsequently interact with downstream mediators of cellular signaling. Many of these receptors, including the 5- HT2A subclass, are G-protein 25 coupled receptors (GPCRs) that signal by activating guanine nucleotide binding proteins (G-proteins), resulting in the generation, or inhibition of, second messenger molecules such as cyclic AMP, inositol phosphates, and diacylglycerol. These second messengers then modulate the function of a variety of intracellular enzymes, including kinases and ion channels, which ultimately affect cellular excitability and function. [0004] At least 15 genetically distinct 5-HT receptor subtypes have been identified and assigned to one of seven 30 families (5-HT1-7). Each subtype displays a unique distribution, preference for various ligands, and functional correlate (s). [0005] Serotonin may be an important component in various types of pathological conditions such as certain psychiatric disorders (depression, aggressiveness, panic attacks, obsessive compulsive disorders, psychosis, schizophrenia, sui- cidal tendency), certain neurodegenerative disorders (Alzheimer-type dementia, Parkinsonism, Huntington’s chorea), anorexia, bulimia, disorders associated with alcoholism, cerebral vascular accidents, and migraine (Meltzer, Neuropsy- 35 chopharmacology, 21:106S-115S (1999); Barnes & Sharp, Neuropharmacology, 38:1083-1152 (1999); Glennon, Neu- rosci. Biobehavioral Rev., 14:35 (1990)). [0006] Given the broad distribution of serotonin within the body and its role in a wide range of physiological and pathological processes, it is understandable that there is tremendous interest in drugs that affect serotonergic sys- tems(Gershon, et al., The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); Saxena, et al., J. Cardiovascular 40 Pharmacol. 15: Supp. 7 (1990)). [0007] The effects of serotonin are mediated by at least 15 genetically distinct 5-HT receptor subtypes have been identified and assigned to one of seven families (5-HT1-7). Each subtype displays a unique distribution, preference for various ligands, and functional correlate(s). Serotonin receptors are members of a large human gene family of membrane- spanning proteins that function as transducers of intercellular communication. They exist on the surface of various cell 45 types, including neurons and platelets, where, upon their activation by either their endogenous ligand serotonin or exogenously administered drugs, they change their conformational structure and subsequently interact with downstream mediators of cellular signaling. Many of these receptors, including the 5- HT2A subclass, are G- protein coupled receptors (GPCRs)that signal by activating guaninenucleotide binding proteins (G- proteins),resulting in the generation, orinhibition of, second messenger molecules such as cyclic AMP, inositol phosphates, and diacylglycerol. These second messengers 50 then modulate the function of a variety of intracellular enzymes, including kinases and ion channels, which ultimately affect cellular excitability and function. [0008] The 5-HT2A receptor subtype (also referred to as subclass) is widely yet discretely expressed in the human brain, including many cortical, limbic, and forebrain regions postulated to be involved in the modulation of higher cognitive and affective functions. This receptor subtype is also expressed on mature platelets where it mediates, in part, platelet 55 aggregation, one of the initial steps in the process of vascular thrombosis. Recent evidence strongly implicates the 5-HT2 receptor subtype in the etiology of such medical conditions as hypertension, thrombosis, migraine, vasospasm, ischemia, depression, anxiety, psychosis, schizophrenia, sleep disorders and appetite disorders. [0009] Schizophrenia is a particularly devastating neuropsychiatric disorder that affects approximately 1% of the human 2 EP 2 134 330 B1 population. It has been estimated that the total financial cost for the diagnosis, treatment, and lost societal productivity of individuals affected by this disease exceeds 2% of the gross national product (GNP) of the United States. Current treatment primarily involves pharmacotherapy with a class of drugs known as antipsychotics. Antipsychotics are effective in ameliorating positive symptoms (e.g., hallucinations and delusions), yet they frequently do not improve negative 5 symptoms (e.g., social and emotional