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Obesity Small Molecules (19) TZZ ¥¥_T (11) EP 2 633 884 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 04.09.2013 Bulletin 2013/36 A61P 3/04 (2006.01) A61K 31/427 (2006.01) (21) Application number: 13156136.7 (22) Date of filing: 07.01.2011 (84) Designated Contracting States: • Pospisilik, Andrew AL AT BE BG CH CY CZ DE DK EE ES FI FR GB 79108 Freiburg (DE) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • Mcmanus, Shane PL PT RO RS SE SI SK SM TR 1030 Vienna (AT) Designated Extension States: BA ME (74) Representative: Sonn & Partner Patentanwälte Riemergasse 14 (30) Priority: 07.01.2010 EP 10150270 1010 Wien (AT) (62) Document number(s) of the earlier application(s) in Remarks: accordance with Art. 76 EPC: •This application was filed on 21-02-2013 as a 11700051.3 / 2 521 594 divisional application to the application mentioned under INID code 62. (71) Applicant: Akron Molecules GmbH •Claims filed after the date of receipt of the divisional 1030 Vienna (AT) application (Rule 68(4) EPC). (72) Inventors: • Penninger, Josef 1130 Vienna (AT) (54) Obesity small molecules (57) The present invention relates to new therapies to treat obesity and related diseases, as well as for reducing triglyceride levels and body weight. EP 2 633 884 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 633 884 A1 Description [0001] The present invention relates to the field of pharmaceutical compounds and methods for the treatment of overweight and obesity. 5 [0002] The world health organization currently estimates that as of 2009 over 1 billion individuals worldwide are overweight. Almost one third of these individuals are clinically obese, markedly raising their chances of cardiovascular disease, type-2 diabetes, cancer, and stroke. The regulation of body fat content in animals results from the integration of multiple nutrient, sensory, and hormonal inputs primarily at the level of the brain and adipose tissues. This integrative network is influenced not only by genetics, but also by circadian rhythm and physical and social environments. Obesity 10 is thus, a complex, systems level disease. [0003] Spurned by the discovery of leptin, tremendous progress has been made in identifying the molecular players and pathways regulating adiposity. The impressive bounds made through the study of gene-targeted mice and the tracking of monogenic obesity disorders in humans, have been complemented by studies in lower organisms. Virtually all key metabolic regulators examined to date display conserved functions across phyla, including for instance, insulin 15 signaling, mTOR, and key lipases such as ATGL. Similar to mammals, model organisms such asDrosophila mela- nogaster, Danio rerio, and Caenorhabditis elegans employ multiple molecular and tissue-based regulatory networks to balance energy needs, nutritional state, and aging and thus represent potent genomics tools for the study of metabolism. For instance, an RNAi feeding model was used to identify potential regulators of fat storage in the C. elegans genome. [0004] It is a goal of the present invention to identify further genes, enzymatic pathways and active compounds for 20 their modulation suitable for the treatment of triglyceride dysfunction, overweight and obesity. [0005] The present invention therefore provides a method of reducing weight and/or body fat in a subject comprising the administration of a therapeutic compound selected from the compounds of table 1. E.g. a therapeutic dose disclosed or approved for other therapeutic uses for each of these compounds can be used. [0006] In a further aspect the present invention provides a method of reducing triglyceride levels, in particular LDL 25 levels, in a subject comprising the administration of a therapeutic compound selected from the compounds of table 1. [0007] In a related aspect the present invention provides the use of a compound of table 1 for the manufacture of a medicament for the therapeutic administration to reduce body weight and/or body fat or to treat obesity in a subject. Also provided are these compounds for use in the therapies discloed herein. The invention is further defined by the subject matter of the claims. 30 [0008] In particular the present invention relates to use of the following compounds for the above tratments, in particular for reducing weight and/or body fat in a subject: • Vandetanib, • Dasatinib, 35 • Tanespimycin (17- allylamino- demethoxygeldamycin, "17- AAG") , • S-17092, • Sorafenib, • Lintopride, • Fenoprofen, 40 • Sulfaphenazole, • Fluticasone (including Fluticasone propionate, "Ubizol"), • Rolipram, • Febuxostat, • Verapamil (including Norverapamil), 45 • a therapeutic compound selected from a modulator of gene CG9438, or an ortholog thereof, in particular the human orthologue CYP3A4, the compounds being selected from erlotinib, gefitinib and lapatinib, • a therapeutic compound selected from a modulator of gene CG8222, or an ortholog thereof, in particular the human orthologue KDR, the compounds being selected from axitinib, pazopanib and semaxanib (also known as Semaxinib or SU 5416), 50 • a therapeutic compound selected from a modulator of gene CG6919, or an ortholog thereof, in particular the human orthologue HTR4, the compounds being selected from cisapride, mosapride, piboserod, prucalopride, renzapride, tegaserod, tropisetron and zacopride, or any combination of the above compounds with any one or more compounds selected from the compounds of table 55 1, preferably with the compounds given above. However, in other embodiments the compounds may be used alone in the inventive treatment described herein. According to this embodiment the invention provides for the inventive therapy wherein the compound is administered as the only therapeutic compound active (or indicated) in a treatment of reducing weight and/or body fat or of obesity in a subject. In particular, the inventive compound, especially Lintopride, is used for 2 EP 2 633 884 A1 administration without a DPP IV inhibitor as disclosed in the WP 2006/005613 [0009] The inventive use of the compounds given herein includes the use of any pharmaceutically acceptable salt or hydrate form thereof. [0010] In preferred embodiments the inventive compounds are used in the treatment of obesity, in particular severe 5 obesity. Obesity is defined as an excess of body fat. Body mass index (BMI - the ratio of body weight in kg to the square of the height of an individual in m), is a useful measure of fat distribution. Importantly it allows the stratification of pati ent categories to identify increased risk of morbidity and mortality and the identification of suitable interventions. Furthermore it provides a firm basis for the assessment of intervention strategies. The stratification of obesity using BMI is as follows. BMI ≥25 = Overweight, BMI 25-29.99 = Preobese, BMI 30-34.99 = Obese class I, BMI 35-39.99 = Obese class II, BMI 10 ≥ 40 = Obese class III (WHO 2000). Class II obesity is severe obesity and class III obesity is referred to as extreme obesity, associated with an extremely high risk of comorbidities including Type 2 diabetes mellitus; Hypertension; Dys- lipidemia; Cardiovascular disease including Coronary artery disease, Stroke and Congestive heart failure; Nonalcoholic fatty liver disease (steatosis, steatohepatitis, cirrhosis); Respiratory disease including Obstructive sleep apnea, Obesity- hypoventilation syndrome, Asthma, Restrictive lung disease; Cancer; Osteoarthritis; Cholelithiasis; Gastroesophageal 15 reflux disease; Gynecologic abnormalities including Infertility, Abnormal menses; Venous stasis; Skin problems such as Intertrigo and Cellulitis; Increased risk of complications during surgery or pregnancy; Urinary incontinence; Idiopathic intracranial hypertension (Hensrud et al., 2006). As the degree of obesity increases so does the risk of all cause mortality. Extreme obesity has been estimated to lead to a shortening of life of between 5 and 20 years depending on other factors including sex, age and racial group (Fontaine et al., 2003). Bariatric surgery is a common treatment for severely obese 20 patients and the numbers of surgery performed per year is increasing along with the increased prevalence of obesity and in particular severe obesity. The number of bariatric surgeries performed in the US increased from 13,386 in 1998 to an estimated 170,000 in 2005 (Ecinosa et al., 2005). However only 0.6% of over 11 million extremely obese patients in 2002 are eligible for surgery actually underwent a bariatric procedure (Ecinosa et al., 2005). Furthermore extreme obesity is also associated with an increased prevalence of psychiatric illnesses. Between a half and two-thirds of all 25 bariatric surgery candidates possess an Axis I psychiatric disorder such as depression, somatization, social phobia, hypochondriasis, or obsessive-compulsive disorder (Rosick et al., 2005; Sarwer et al., 2004). [0011] The subject to be treated according to the present invention can be any nun-human animal or a human. Preferably the subject is a mammal, in particular preferred embodiments a human. [0012] According to the present invention obesity, diseases associated with obesity, e.g. diabetes, can be treated or 30 prevented, in particular in the meaning of a prophylactic administration. "Preventing" or "prevention" herein does not require absolute success in the sense of an absolute prevention of a heart disease but indicates a reduced risk of developing a disease, or developing a disease with reduced severity. Likewise, "treatment" shall not be construed as an absolute cure,
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