|HAO WAKAT I AKITOLEAUS009943514B2 MAIMARE UNAUTO (12 ) United States Patent ( 10 ) Patent No. : US 9 , 943 ,514 B2 Deaver et al. ( 45 ) Date of Patent: * Apr. 17, 2018 ( 54 ) METHODS FOR TREATING (52 ) U . S . CI. ANTIPSYCHOTIC - INDUCED WEIGHT GAIN CPC . .. .. A61K 31/ 485 (2013 .01 ) ; A61K 9 / 20 ( 2013 .01 ) ; A61K 31 /551 ( 2013 .01 ) (71 ) Applicant : Alkermes Pharma Ireland Limited , ( 58 ) Field of Classification Search Dublin ( IE ) CPC .. .. A61K 31/ 485 ; A61K 31 / 551; A61K 9 / 20 ( 72 ) Inventors : Daniel Deaver , Franklin , MA (US ) ; See application file for complete search history . Mark Todtenkopf, Franklin , MA (US ) ( 73) Assignee : Alkermes Pharma Ireland Limited , (56 ) References Cited Dublin (IE ) U . S . PATENT DOCUMENTS ( * ) Notice : Subject to any disclaimer, the term of this 8 , 778 , 960 B2 * 7 /2014 Deaver .. .. A61K 31 /439 514 /289 patent is extended or adjusted under 35 9 , 126 , 977 B2 * 9 / 2015 Deaver . .. .. .. A61K 31/ 439 U . S . C . 154 ( b ) by 0 days . 9 ,211 , 293 B2 * 12 / 2015 Deaver A61K 31 /485 This patent is subject to a terminal dis 9 ,517 , 235 B2 * 12 /2016 Deaver . .. .. A61K 31/ 439 claimer . OTHER PUBLICATIONS (21 ) Appl. No. : 15 /342 , 263 Science Daily plataforma Sinc ( 2012 ). * ( 22 ) Filed : Nov . 3 , 2016 * cited by examiner (65 ) Prior Publication Data US 2017 /0119757 A1 May 4 , 2017 Primary Examiner — Shirley V Gembeh ( 74 ) Attorney, Agent, or Firm — Elmore Patent Law Related U . S . Application Data Group , P . C .; Joseph Zucchero ; Carolyn Elmore (63 ) Continuation of application No . 14 /813 , 260 , filed on Jul. 30 , 2015 , now Pat. No . 9 ,517 ,235 , which is a continuation of application No. 14 / 297 , 171 , filed on (57 ) ABSTRACT Jun . 5 , 2014 , now Pat. No . 9 ,126 , 977 , which is a The present invention relates to the discovery of a novel continuation of application No . 13 /215 ,718 , filed on opioid modulator effective in reducing pharmacologically Aug . 23 , 2011 , now Pat. No . 8 ,778 , 960 . induced weight gain associated with atypical antipsychotic ( 60 ) Provisional application No . 61/ 376 , 120 , filed on Aug . use . The present invention provides methods of reducing 23 , 2010 . antipsychotic induced weight gain , methods for suppressing food intake and reducing ghrelin levels induced by atypical (51 ) Int. CI. antipsychotic medications in a patient . A61K 31 /485 ( 2006 . 01 ) A61K 9 / 20 ( 2006 . 01 ) A61K 31/ 551 ( 2006 . 01 ) 29 Claims, 6 Drawing Sheets atent Apr . 17 , 2018 Sheet 1 of 6 US 9 ,943 , 514 B2 * + Olanzapine * Olanzapine + Compound- 1 CumulativeWeightGain(9) Olanzapine Naltrexone * . wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww planning pampumpen 1 2 3 4 5 6 1 8 9 10 Treatment Day FIG . 1 atent Apr . 17 , 2018 Sheet 2 of 6 US 9 ,943 , 514 B2 pa WWWWWW ????? MT Naltrexone * Compound 1 0 .0 0. 5 1. 0 1. 5 2 . 0 Time (Hours ) FIG . 2 . atent Apr . 17 , 2018 Sheet 3 of 6 US 9 , 943 , 514 B2 259 - Vehicle - - - - - Olanzapine - + + Olanzapine + Compound 1 - - - - - - - %WeightChangea? RRRRRRRRR 1 4 7 10 13 16 19 22 25 28 Day FIG . 3 atent Apr . 17 , 2018 Sheet 4 of 6 US 9 ,943 , 514 B2 Olanzapine+Compound1 Vehicle Olanzapine FatSubcutaneous CTScanData:MeanFatContent FIG.4 FatAbdominal š š š š ne z Scan Baseline % atent Apr . 17 , 2018 Sheet 5 of 6 US 9 , 943, 514 B2 ( a ) Olanzapine Day 28 Baseline wwwwww * wwwwwwwwwwwwwwtoShare W ww mundummánmhmmmmmmmmmmmmmmmmmm 7cm * * (b ) Olanzapine + Compound 1 Day 28 Baseline wwwwwwwwwwwwwwwwwwww A.N bo m Li ·m wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww HE* * .N" Wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww FIG . 5 atent Apr . 17 , 2018 Sheet 6 of 6 US 9 ,943 , 514 B2 Olanzapine+Compound1 Vehicle Olanzapine ..TrigTrig SerumChemistry FIG.6 LDLLDL 1257 ? ? p /bu US 9 , 943 ,514 B2 METHODS FOR TREATING disorders . A recent study reported that young children who ANTIPSYCHOTIC - INDUCED WEIGHT GAIN take antipsychotics risk long term health risks associated with rapid weight gain , for example , metabolic changes that RELATED APPLICATIONS could lead to diabetes, hypertension and other illnesses . 5 (Varley et al. , JAMA . 2009 ; 302 ( 16 ) :1811 - 1812 ). This application is a continuation of U . S . application Ser. Excessive weight gain associated with atypical antipsy No. 14 / 813 , 260 , filed Jul. 30 , 2015 , which is a continuation chotic use is a significant issue given its impact on general of U . S . application Ser. No . 14 /297 , 171 , filed Jun . 5 , 2014 , health and psychological issues . Unwanted weight gain is now U . S . Pat. No. 9 , 126 , 977 , issued Sep . 8 , 2015 , which is 10 also one of the most common reasons for a patient' s non a continuation of U . S . application Ser. No. 13 /215 ,718 , filed compliance of an atypical antipsychotic administration Aug . 23 , 2011 , now U . S . Pat . No . 8 , 778, 960 , issued Jul. 15 , schedule , ultimately leading to the failure of the treatment . 2014 , which claims the benefit of U . S . Provisional Appli Therefore, there is a continuing need to identify and develop cation No . 61/ 376 , 120 , filed on Aug. 23 , 2010 . The entire more effective drug treatments for preventing or reducing teachings of the above applications are incorporated herein 15 this side effect of atypical treatment. by reference . SUMMARY OF INVENTION FIELD OF INVENTION Applicants have surprisingly discovered that compounds The present invention relates to medications used for 20 of Formula I are effective in reducing pharmacologically weight control . More particularly , the present invention induced weight gain associated with atypical antipsychotic relates to the use of a novel opioid receptor modulator to use . minimize weight gain associated with antipsychotic drugs. Formula I BACKGROUND OF INVENTION 25 23 Antipsychotic medications are among the most important RPR N therapeutic tools for treating various psychotic disorders . P There are two categories of antipsychotics, typical and atypical. Typical antipsychotics e . g . , haloperidol and chlo - 30 rpromazine, were first developed in the 1950 ' s and were used to treat psychosis , particularly schizophrenia . Common side effects of typical antipsychotics include: dry mouth , tremors , weight gain , muscle tremors , and stiffness . In 35 addition , typical antipsychotics yield extrapyramidal side wherein , effects . These side effects include : motor disturbances, par A is chosen from — CEO) NH , and CES)NH2 ; kinsonian effects, akathesia , dystonia , akinesia , tardive dys Rl and R are both hydrogen or taken together R and R ’ are kinesia , and neuroleptic malignant syndrome. Some of these 40 R3CO is ; chosen from hydrogen , alkyl, alkenyl, aryl, heterocy side effects have been described to be worse than the actual clyl and hydroxyalkyl; symptoms of schizophrenia . Atypical antipsychotics are R4 is chosen from hydrogen , hydroxy, amino , alkoxy , considered to be the first line of treatment for schizophrenia C , -C20 alkyl and C . - C20 alkyl substituted with hydroxy or because of the improved extrapyramidal side effect profile in carbonyl ; vchot- 45 R is selected from hydrogen , hydroxyl, alkoxy and alkyl; comparison to typical antipsychotics . Atypical antipsychot- 4 RÓ is chosen from hydrogen , hydroxy, alkoxy and ics are also associated with superior tolerability , adherence — NR10R11. and relapse prevention and have led to improved treatment or together , R and R form a carbonyl or a vinyl substituent ; for patients with serious mental illness . However , they are R10 and R11 are chosen independently from hydrogen , alkyl also associated with significant weight gain . Numerous 50 and aliphatic ; and , reports based on extensive clinical studies have reported that - -- - - - represents a single or double bond . 40 - 80 % of patients under chronic atypical antipsychotic As such , the present invention provides methods of reduc ing antipsychotic induced weight gain induced by atypical treatment experience substantial weight gain , ultimately antipsychotic medications in a patient. The method com exceeding their ideal body weight by 20 % (Umbricht et al. , 55 prises administration of a therapeutically effective amount of J Clin . Psychiatry 55 ( Suppl. B ) : 157 - 160 ; Baptista , Acta a compound of Formula I to the patient in need thereof , Psychiatr . Scand . 100 : 3 - 16 , 1999 ) . Weight gain was found to preferably , Compound 1 . be greatest with clozapine , olanzapine , risperidone , and In one aspect, the invention relates to the lowering of quetiapine , and less with aripiprazole and ziprasidone . ( Tay - circulating ghrelin levels and /or the levels of ghrelin in lor et al. , Acta Psychiatr Scand . 2001 February ; 103 ( 2 ) : 158 ). 60 gastrointestinal tracts . As such , the present invention is further directed to methods of suppressing food intake Weight gain associated with atypical antipsychotics comprising administering to the patient in need of treatment increases the risk of obesity in patients undergoing treat an effective amount of the compounds of Formula I , wherein ment. Obesity is a leading cause ofmortality as it frequently the increased appetite is induced by administration of an leads to conditions such as diabetes and cardiovascular 65 atypical antipsychotic . disorders . In addition , atypical antipsychotics are increas - In one embodiment, the induced weight gain is associated ingly prescribed to children and adolescents with psychiatric with administration of olanzapine , clozapine, risperidone , US 9 ,943 ,514 B2 quetiapine, aripiprazole , ziprasidone, and pharmaceutically