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US 2008O1086O2A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0108602 A1 Nagy et al. (43) Pub. Date: May 8, 2008

(54) PREVENTION OF OBESITY IN (21) Appl. No.: 11/687,954 , AND ANTIEPLEPTIC MEDCATION (22) Filed: Mar. 19, 2007 (75) Inventors: Peter Literati Nagy, Budapest Related U.S. Application Data (HU); Jesse Roth, Whitestone, NY (US); Zoltan Szilvassy, (60) Provisional application No. 60/856,177, filed on Nov. Debrecen-Jozsa (HU); Kalman 2, 2006. Tory, Budapest (HU); Mike Brownstein, Rockville, MD (US); Publication Classification Kalman Takacs, Budapest (HU); Laszlo Vigh, Szeged (HU); Jozsef (51) Int. Cl. Mandi, Budapest (HU); Balazs A6II 3/445 (2006.01) Sumegi. Pecs (HU); Sandor A 6LX 3/59 (2006.01) Bernath, Telki (HU); Attila A6II 3/55 (2006.01) Kolonics, Budapest (HU); Gabor A6IP3/04 (2006.01) Balogh, Szeged (HU); Janos Egri. Budapest (HU) (52) U.S. Cl...... 514/220; 514/259.41: 514/318 Correspondence Address: (57) ABSTRACT FSH & RICHARDSON PC P.O. BOX 1022 O-(3-piperidino-2-hydroxypropyl)-nicotinic amidoxime or a MINNEAPOLIS, MN 55440-1022 pharmaceutically suitable acid addition salt thereof (BGP 15) can be used for the prevention or reduction of weight (73) Assignee: N-Gene Research Laboratories, gain or obesity in a patient treated with an antipsychotic Inc. or an antidepressant drug or an antiepileptic drug. US 2008/0108602 A1 May 8, 2008

PREVENTION OF OBESITY IN amidoximic acid derivative including BGP-15. A preferred ANTIPSYCHOTIC, ANTIDEPRESSANT AND myopathy is cardiomyopathy. Neurodegenerative diseases ANTIEPLEPTIC MEDCATION include Parkinson's disease, Huntington's disease and amyotrophic lateral Sclerosis. RELATED APPLICATION INFORMATION 0006 U.S. Pat. No. 6,458,371 refers to a composition 0001. This application claims priority to U.S. provisional comprising 0.1-30% of a hydroximic acid derivative includ application Ser. No. 60/856,177, filed Nov. 2, 2006. ing BGP-15 as the active ingredient and a carrier that is in the form of a cream, lotion, foam or spray. The composition BACKGROUND is suitable for reducing the incidence of photodamage by 0002 Anti-psychotic are used for the treatment of radiation with UV-B. psychiatric disorders, particularly , while anti 0007 U.S. Pat. No. 6,884,424 refers to a method for depressants are administered to alleviate the symptoms of preventing actinic keratosis by applying a hydroximic acid depression. Many patients treated with anti-psychotics, e.g., derivative including BGP-15 to the affected skin surface. or feel acoria due to a failure in the 0008 U.S. Pat. No. 6,451,851 refers to a method of regulation of food uptake, thus, the treatment frequently treating a patient Suffering from a viral infection comprising leads to weight gain. Overweight and even obesity may administering to the patient a pharmaceutically effective occur within 3-6 months after the beginning of the treatment amount of a known antivirally active agent together with a as evidenced by reports on treated patients Blin, Can. J hydroximic acid derivative including BGP-15. Psychiatry 44:235-44 (1999). In a similar manner, medi cation with many e.g. , imi 0009 U.S. Pat. No. 6,440,998 refers to a pharmaceutical pramine etc. or antiepileptics () e.g. Valproic composition having antitumor activity with reduced side acid, sodium etc. results in weight gain that may effect comprising cisplatin or carboplatin and a hydroximic lead to obesity Ruetsch et al., L. Encéphale 31:507-16 acid derivative including BGP-15. (2005). Overweight and obesity themselves are associated (0010 U.S. Pat. No. 6,656,955 refers to a pharmaceutical with hypertension and abnormal metabolic changes Such as composition having antitumor activity with reduced side insulin resistance and dyslipidemia which are risk factors for effect comprising paclitaxel or docetaxel and a hydroximic diabetes. Obesity (particularly abdominal obesity), insulin acid derivative including BGP-15. resistance and dyslipidemia are major features of “pre (0011 U.S. Pat. No. 6,720,337 refers to a pharmaceutical diabetes’ (metabolic syndrome) that leads to type 2 diabetes composition having antitumor activity with reduced side mellitus. Diabetes is associated with serious complications Such as retinopathy, nephropathy, and neuropathy. In addi effect comprising oxaliplatin and a hydroximic acid deriva tion, diabetes is accompanied by increased mortality due to tive including BGP-15. a greater risk of cardiovascular disease. (0012 U.S. Pat. No. 6,838,469 refers to a pharmaceutical 0003. Due to the extensive and growing administration of composition having antitumor activity with reduced side antipsychotic and antiepileptic drugs and antidepressants to effect comprising pyrimidine derivatives and BGP-15. patients in the United States and throughout the developed 0013 PCT Patent Application WO 00/07580 disclosed countries, the above undesirable side effects are considered experimental data for the antidiabetic effect of BGP-15 in as an increasing problem which is related to increased rates the treatment of type 1 diabetes mellitus. It is to be noted that of mortality and morbidity. In addition, patients requiring a type 1 diabetes mellitus is an autoimmune disease occurring treatment with an antipsychotic or an antidepressant or an at young age, while type 2 diabetes mellitus is a metabolic antiepileptic may decide to stop treatment because of the disease occurring at higher age. induced weight gain. (0014 PCT Application WO 03/007951 refers to a phar 0004 O-(3-piperidino-2-hydroxy-1-propyl)-nicotinic maceutical combination of hydroximic acid derivatives amidoxime) (abbreviated as BGP-15) was patented in 1976 including BGP-15 and an antidiabetic or anti-hyperlipi as a new compound useful in the treatment of diabetic demic active agent for the prevention or treatment of a angiopathy, a complication of diabetes resulting in the prediabetic state, metabolic X-syndrome or diabetes mellitus damage of blood vessels (see, e.g., U.S. Pat. No. 4,187.220). as well as disorders which are associated with the states BGP-15 has the structure depicted below. listed above, namely endogenic metabolic disorders, insulin resistance, dislipidemia, alopecia, diffuse effluvium and/or female endocrine disorders based on androgenic preponder ance. In the description, laboratory data indicate that BGP NH2 OH 15 enhances, synergistically, the effect of the known antidia betic agent metformin and troglitaZone, respectively. The N N N1 N-- laboratory data also show that BGP-15 in itself enhances the insulin sensitivity (thus, reduces the insulin resistance) in 2 both normal and hyper-cholesterolemic animals relative to N the control. (0.015 PCT Application WO 2005/122678 refers to the 0005 U.S. Pat. No. 6,306,878 refers to a method for the use of BGP-15 in a pharmaceutical composition having protection of the mitochondrial genome and/or mitochon prokinetic effect (i.e. induces activity in the stomach and drion from damage leading to myopathies and neurodegen intestines. Prokinetic effect includes possible treatment of erative diseases which comprises administering an effective reflux esophagitis, gastroparesis, influencing bile flow from non-toxic dose to a patient Susceptible to such damage of an the gall bladder etc. US 2008/0108602 A1 May 8, 2008

0016 PCT Application WO 2005/123049 refers to the treated with an antipsychotic , the antipsychotic use of BGP-15 for mitochondrial genesis i.e. to increase the medication is an medication; the number of mitochondria in the cells resulting in a roborating antipsychotic medicine causes weight gain in at least some effect. patient; the antipsychotic medication is selected from the 0017 PCT Application WO 2006/079910 refers to the group consisting of olanzapine, clozapine, , que use of BGP-15 for the treatment of lesions in the oral cavity, tiapine, , , , , especially periodontal disease. , and N-; the phar maceutically acceptable salt of O-(3-piperidino-2-hydroxy SUMMARY 1-propyl)-nicotinic amidoxime is O-(3-piperidino-2-hy 0018. It has been found that O-(3-piperidino-2-hydrox droxy-1-propyl)-nicotinic amidoxime dihydrochloride; the ypropyl)-nicotinic amidoxime or a pharmaceutically Suit medication is an antidepressant; the patient has suffered able acid addition salt thereof (BGP-15) can be used for the weight gain after being administered the antipsychotic or prevention or reduction of weight gain or obesity in a patient antidepressant medication; the patient has a body mass index treated with an antipsychotic drug or an antidepressant drug greater than 25 kg/m; the patient has a body mass index or an antiepileptic drug. greater than 30 kg/m; and the antipsychotic medication is 0019 Described herein are methods for preventing or olanzapine, risperidone or clozapine. reducing the side effect leading to weight gain or obesity in 0023. Also described herein are pharmaceutical compo a patient requiring a treatment with an antipsychotic or sitions comprising an antipsychotic or antidepressant or antidepressant or antiepileptic drug comprising administer antiepileptic medication and O-(3-piperidino-2-hydroxy-1- ing an effective amount of a known antipsychotic or anti propyl)-nicotinic amidoxime or a pharmaceutically accept depressant or antiepileptic and an effective non-toxic able acid addition salt thereof. In various embodiments: the amount of O-(3-piperidino-2-hydroxy-1-propyl)-nicotinic antipsychotic medication is selected from the group consist amidoxime or a pharmaceutically acceptable acid addition ing of olanzapine, clozapine, risperidone, and salt thereof to the patient, wherein the administration of the Sulpiride, Ziprasidone, and aripiprazole; the antipsychotic O-(3-piperidino-2-hydroxy-1-propyl)-nicotinic amidoxime medication is selected from the group consisting of olan or a pharmaceutically acceptable acid addition salt thereof Zapine, riperidone and clozapine. prevents or reduces the metabolic side-effect experienced by 0024. Also described is packaging containing a first phar the patient requiring treatment with an antipsychotic or maceutical composition comprising an antipsychotic medi antidepressant or antiepileptic drug. Also described is a cation or an antidepressant medication or an antiepileptic pharmaceutical composition having antipsychotic or antide medication and a second pharmaceutical composition com pressant or antiepileptic activity with reduced side effect prising O-(3-piperidino-2-hydroxy-1-propyl)-nicotinic ami comprising a known antipsychotic or antidepressant or anti doXime or a pharmaceutically acceptable acid addition salt epileptic and O-(3-piperidino-2-hydroxy-1-propyl)-nico thereof. In various embodiments: the antipsychotic medica tinic amidoxime or a pharmaceutically acceptable acid addi tion is selected from the group consisting of olanzapine, tion salt thereof in admixture with one or more conventional clozapine, risperidone, quetiapine and Sulpiride. Also carrier(s). described as packaging containing a unit dosage formulation 0020. In various embodiments: the antipsychotic agent is comprising O-(3-piperidino-2-hydroxy-1-propyl)-nicotinic selected from the group consisting of olanzapine, clozapine, amidoxime or a pharmaceutically acceptable acid addition risperidone, quetiapine and Sulpiride; and O-(3-piperidino salt thereof and a unit dosage formulation of antipsychotic 2-hydroxy-1-propyl)-nicotinic amidoxime dihydrochloride medication or an antidepressant medication or an antiepi is administered. leptic medication. 0021. Also described is a pharmaceutical composition 0025. Also described is a pharmaceutical composition having antipsychotic or antidepressant or antiepileptic activ having antipsychotic or antidepressant or antiepileptic activ ity with reduced side effect comprising a known antipsy ity with reduced side effect comprising a known antipsy chotic or antidepressant and O-(3-piperidino-2-hydroxy-1- chotic or antidepressant or antiepileptic and O-(3-piperi propyl)-nicotinic amidoxime or a pharmaceutically dino-2-hydroxy-1-propyl)-nicotinic amidoxime or a acceptable acid addition salt thereof in admixture with one pharmaceutically acceptable acid addition salt thereof in or more conventional carrier(s). In various embodiments: admixture with one or more conventional carrier(s). the known antipsychotic agent is selected from the group consisting of olanzapine, clozapine, risperidone, quetiapine 0026. The details of one or more embodiments of the and Sulpiride; the composition comprises olanzapine and invention are set forth in the accompanying drawings and O-(3-piperidino-2-hydroxy-1-propyl)-nicotinic amidoxime the description below. Other features, objects, and advan or a pharmaceutically acceptable acid addition salt thereof; tages of the invention will be apparent from the description and the composition comprises clozapine and O-(3-piperi and drawings, and from the claims. dino-2-hydroxy-1-propyl)-nicotinic amidoxime or a phar maceutically acceptable acid addition salt thereof. DETAILED DESCRIPTION 0022. Also described is a method for treating a patient being treated with an antidepressant medication or antipsy 0027. An antipsychotic drug is a drug used to treat severe chotic medication, the method comprising administering to mental disorders (psychoses) including schizophrenia and the patient being treated with an antidepressant or antipsy mania as well as certain other conditions. Some antipsy chotic or antiepileptic medication, a composition comprising chotic agents are administered in Small doses to relieve O-(3-piperidino-2-hydroxy-1-propyl)-nicotinic amidoxime anxiety. or a pharmaceutically acceptable acid addition salt thereof to 0028. One useful group of antipsychotic drugs include the patient. In various embodiments: the patient is being derivatives of formula IA US 2008/0108602 A1 May 8, 2008

0035 In various embodiments of the compound of for mula IB IA R represent a dimethylamino, 4-methyl-1-piperazinyl, 4-(2- R-in-ch hydroxyethyl)-1-piperazinyl, 4-(2-acetoxyethyl)-1-piperazi nyl or 4-(2-decanoyloxyethyl)-1-piperazinyl group, R-tN R4 R stands for a chloro atom, trifluoromethyl or N,N-dimeth ylsulfonylamido group. S 0036 Among the useful compounds having formula IB a. (3-(2-chloro-9H-thioxanthen-9- ylidene)-N,N-dimethyl-1-propanamine), (4-3- 0029 and pharmaceutically suitable acid addition salts (2-chloro-9H-thioxanthen-9-ylidene)propyl)-1- thereof, wherein ethanol), thiothixene (N,N-dimethyl-9-3-(4-methyl-1- R represents a di(C. alkyl)amino. 1-(C. alkyl)piperidyl, piperazinyl)propylidene--2-), and 4-(C. alkyl)piperazinyl or 4-2-hydroxy(C. alkyl)-1- (4-3-(2-(trifluoromethyl)-9H-thioxanthen-9- piperazinyl group, ylidene)propyl-1-piperazine-ethanol), as well as pharma R and R stand, independently, for a hydrogen atom or Ca ceutically suitable acid addition salts thereof. alkyl group, 0037 Additional useful include com R means a hydrogen or halo atom, carboxy, C alkoxy, pounds of formula IC: C. alkanoyl, trifluoromethyl, methylmercapto or methyl SulfinylI-4 group, and 0030 n has a value of 0 or 1. IC 0031. In certain embodiments: R represents a dimethy lamino. 1-methylpiperidyl, 4-methylpiperazinyl or 4-(2-hy droxyethyl)-1-piperazinyl group, R and R Stand, independently, for a hydrogen atom or methyl group, R means a hydrogen or chloro atom, carboxy, methoxy, acetyl, trifluoromethyl, methylmercapto or methylsulfinyl group, and 0032 n has a value of 0 or 1. 0038 wherein 0033 Among the compound having formula IA are: (2-chloro-N,N-dimethyl-10H-phenothiaz X stands for a nitrogen atom or a group of formula —C= ine-10-propanamine), (N,N-dimethyl-10H-phe or —CH . nothiazine-10-propanamine), (10-2-(1-me thyl-2-piperidinyl)ethyl-2-(methylsulfinyl)-10H Y represents a group of formula —NH-, oxygen or nitro phenothiazine), gen atom, (4-3-2-(trifluoromethyl)-10H-phenothiazin R means a 4-(2-hydroxyethoxyethyl)-1-piperazinyl, 4-(Ca 10-yl)propyl)-1-piperazineethanol), and (10 alkyl)-1-piperazinyl or 4-(3-hydroxypropyl)-1-piperazinyl 3-(4-methyl-1-piperazinyl)propyl)-2-(trifluoromethyl)- grOup, 1OH-phenothiazine), as well as pharmaceutically suitable acid addition salts thereof. R is a hydrogen or halo atom, 0034. Another useful group of antipsychotics include 0039 ring C represents a benzene ring optionally substi thioxanthene derivatives of formula IB tuted by a halo atom or N,N-dimethylsulfonamido group or ring C stands for a heterocyclic group that forms with the portion a thieno2.3-b1.5benzodiazepine IB CH-CH-CH- R structure, wherein the 5-membered thieno ring is optionally substituted in position 2 by a methyl group, the dotted line between X and the adjacent carbon atom has no meaning in R2 case of the saturated ring, otherwise the dotted line repre sents a valence bond, and, if chemically possible, pharmaceutically suitable acid addition salts thereof. and pharmaceutically suitable acid addition salts thereof, 0040. In certain embodiments of the compounds of for wherein mula IC: R represent a di(C. alkyl)amino, 4-(C. alkyl)-1-piper R means a 4-(2-hydroxyethoxyethyl)-1-piperazinyl, 4-(me azinyl, 4-2-hydroxy(C. alkyl)-1-piperazinyl, 4-2-(Ca thyl)-1-piperazinyl or 4-(3-hydroxypropyl)-1-piperazinyl alkanoyloxy)-(C. alkyl)-1-piperazinyl or 4-(2-decanoy grOup, loxyethyl)-1-piperazinyl group, R stands for a halo atom, trifluoromethyl or N,N-dimeth R is a hydrogen or chloro atom, and ylsulfonylamido group. X, Y, ring C and the dotted line are as defined above. US 2008/0108602 A1 May 8, 2008

0041 Among the useful compounds having formula IC are: clozapine (8-chloro-11-(4-methyl-1-piperazinyl)-5H dibenzob.e. 1.4diazepine), olanzapine (2-methyl-4-(4-me thyl-1-piperazinyl)-10H-thieno2,3-b1,5-benzodiaz epine), quetiapine (2-2-(4-dibenzob.f. 14thiazepin-11 yl-1-piperazinyl)ethoxy-ethanol), Zotepine (2-(8- chlorodibenzob.f thiepin-10-yl)oxy-N,N- dimethylethanamine), isoclozapine (chloro-11-(4-methyl-1- piperazinyl)-5H-dibenzob.e. 1,4-diazepine), clothiapine (2-chloro-11-(4-methyl-1-piperazinyl)dibenzob.f. 14thi azepine), OXithepine (10-4-(3-hydroxypropyl)piperazino 10,11-dihydrodibenzob.f-thiepine), and, if chemically pos sible, pharmaceutically suitable acid addition salts thereof. wherein 0042 Additional useful antipsychotics include benza mide derivatives of formula ID R represents a hydrogen atom or hydroxy group. 0046 Among the useful derivatives of ID formula IF are: risperidone (3-2-4-(6-fluoro-1,2-benzisox azol-3-yl)-1-piperidinylethyl-6,7,8,9-tetrahydro-2-methyl 4H-pyrido 1,2-alpyrimidin-4-one) and (3-2- 4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinylethyl-6.7, 8.9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido 1,2-cy pyrimidin-4-one) and Suitable salts thereof. 0047. Additional useful antipsychotics include diphenyl butyl-piperidine derivatives of formula IG

IG and pharmaceutically suitable acid addition salts thereof, wherein R represents an N-1-(C. alkyl)-2-pyrrolidinyl-(Ca alkyl), 2-di(C. alkyl)-amino-(C. alkyl) or 1-benzyl-3- pyrrolidinyl group, in-ch-en-en-O- R stands for a hydrogen or halo atom, aminosulfonyl or (C. alkyl)sulfonyl group, R means a hydrogen or halo atom, amino or (C. alkyl) amino group, wherein R is hydrogen or halo atom or methoxy group, R represents a 2-benzimidazolon-1-yl group. Rs represents a C alkoxy or allyloxy group. 0048. Among the useful compounds having formula IG 0043. In some embodiments: R represents an N-(1- is: (1-1-4.4-bis(4-fluorophenyl)butyl-4-pip ethyl-2-pyrrolidinyl)methyl, 2-(diethylamino)ethyl or eridinyl-1,3-dihydro-2H-benzimidazol-2-one). 1-benzyl-3-pyrrolidinyl group, 0049 Additional useful antipsychotics include buty rophenone derivatives and pharmaceutically suitable acid R stands for a hydrogen or chloro atom, aminosulfonyl or addition salts thereof Such as the following compounds: ethylsulfonyl group, i.e. 4-4-(4-chlorophenyl)-4-hydroxy-1-pip eridinyl-1-(4-fluorophenyl)-1-butanone, i.e. R means a hydrogen or chloro atom, amino or methylamino 4-4-(4-bromophenyl)-4-hydroxy-1-piperidinyl-1-(4-fluo grOup, rophenyl)-1-butanone or i.e. 1-(4-fluorophe R is hydrogen or bromo atom or methoxy group. nyl)-4-4-hydroxy-4-3-(trifluoromethyl)phenyl-1-pip eridinyl-1-butanone. 0044 Among the useful antipsychotics having formula 0050 Additional antipsychotics include indole deriva ID are: Sulpiride (5-(aminosulfonyl)-N-(1-ethyl-2-pyrro tives and pharmaceutically suitable acid addition salts lidinyl)methyl-2-methoxy-), thereof Such as the following compounds: amisulpride (4-amino-N-(1-ethyl-2-pyrrolidinyl)methyl (3-ethyl-1,5,6,7-tetrahydro-2-methyl-5-(4-morpholinylm 5-(ethylsulfonyl)-2-methoxybenzamide) and ethyl)-4H-indol-4-one), ziprasidone (5-2-4-(1,2-ben ((S)-3-bromo-N-(1-ethyl-2-pyrrolidinyl)-methyl-2,6- Zisothiazol-3-yl)-1-piperazinylethyl-6-chloro-1,3-dihy dimethoxybenzamide), as well as pharmaceutically suitable dro-2H-indol-2-one), sertindole (1-2-4-5-chloro-1-(4- acid addition salts thereof. fluorophenyl)-1H-indol-3-yl)-1-piperidinyl-ethyl-2- 0045. Additional useful antipsychotics consists of the imidazolidinone) and (5,6-dimethoxy-2-methyl benzisoxazole derivatives of formula IF 3-2-(4-phenyl-1-piperazinyl)ethyl)-1H-indole). US 2008/0108602 A1 May 8, 2008

0051. The term antidepressant refers to a drug that alle 0056. An additional useful group of antiepileptics viates the symptoms of depression. A preferred group of includes gamma-aminobutyric acid (GABA) derivatives antidepressants includes bicyclic compounds such as paroX Such as (1-(aminomethyl)cyclohexaneacetic etine ((3S-trans)-3-(1,3-benzodioxol-5-yloxy)methyl-4- acid), (4-(4-chlorophenyl)(5-fluoro-2-hydrox (4-fluorophenyl)-piperidine) and pharmaceutically suitable yphenyl)methylene-aminobutanamide), acid addition salts thereof. (4-amino-5-hexenoic acid), piracetam (2-oxo-1-pyrro 0052 Another useful group of antidepressants include lidineacetamide), oxiracetam (4-hydroxy-2-oxo-1-pyrro compounds such as amitriptyline (3-(10,11-dihy lidineacetamide), nefiracetam (N-(2,6-dimethylphenyl)-2- dro-5H-dibenzoa,dcyclohepten-5-ylidene)-N,N-dimethyl oXo-1-pyrrolidineacetamide) etc. and pharmaceutically 1-propanamine), (3-dibenz beloxepin-11 (6H) suitable metal salts of the acids, carbamate derivatives such ylidene-N,N-dimethyl-propanamine), (10.11 as meprobamate (2-methyl-2-propyl-1,3-propanediol dicar dihydro-N,N-dimethyl-5H-dibenzb.fazepine-5-propan bamate) having also anxiolytic effect, (2-phenyl amine), (3-chloro-10,11-dihydro-N,N- 1,3-propanediol dicarbamate) etc., Some Sulfonamides Such dimethyl-5H-dibenzb.fazepine-5-propanamine), as (N-5-(aminosulfonyl)-1,3,4-thiadiazol-2- (3-(10,11-dihydro-5H-dibenzoa,dcyclohep yl)acetamide), (1.2-benzisoxazole-3-methane ten-5-ylidene)-N-methyl-1-propanamine), (10. sulfonamide), sulthiame (4-(tetrahydro-2H-1,2-thiazin-2- 11-dihydro-N.N.B-trimethyl-5H-dibenzb.fazepine-5-pro yl)-benzenesulfonamide S.S.-dioxide) etc., N- panamine), and (10,11-dihydro-N-methyl-5H derivatives such as (N-(aminocarbonyl)ben dibenzb.fazepine-5-propanamine), aS well aS Zene-acetamide), (N-(aminocarbonyl)-O-ethyl pharmaceutically suitable acid addition salts thereof. benzeneacetamide) etc. 0053 A further useful group of antidepressants includes 0057 Additional useful antiepileptics include lamot tetracyclic compounds such as (N-methyl-9,10 rigine (6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine), ethanoanthracene-9(10H)-propanamine) and pharmaceuti (2.3:4,5-bis-O-(1-methylethylidene)-B-D-fructo cally suitable acid addition salts thereof. pyranose Sulfamate), and ((R)-1-4.4-bis(3-me 0054) The term “antiepileptic” or “” refers thyl-2-thienyl)-3-butenyl-3-piperidinecarboxylic acid) and to a drug that prevents or reduces the severity and frequency pharmaceutically suitable metal salts thereof. of seizures in various types of epilepsy. A preferred group of 0.058 An especially preferred group of antiepileptics antiepileptics includes certain phenothiazine derivatives of includes valproic acid and pharmaceutically Suitable alkali formula IA such as (N,N-dimethyl-2-(trif metal . luoromethyl)-1OH-phenothiazine-10-propanamine) and 0059 A pharmaceutically suitable acid addition salt is a metofenazate (3,4,5-trimethoxybenzoic acid 2-4-3-(2- salt formed with an inorganic acid Such as hydrochloric acid, chloro-1 OH-phenothiazin-10-yl)propyl)-1-piperazinylethyl Sulfuric acid etc. or with an organic acid such as acetic acid, ester) which latter is typically administered as the difuma lactic acid, tartaric acid etc. Useful acid addition salts rate. Said phenothiazine derivatives possess, in addition to include hydrochlorides, acetates, maleates etc. A preferred antipsychotic, also antiepileptic activity. acid addition salt of O-(3-piperidino-2-hydroxy-1-propyl) 0055. A further preferred group of antiepileptics includes nicotinic amidoxime is the dihydrochloride thereof. benzodiazepine derivatives such as (5-(2-chlo 0060. In the context of the description and claims, the rophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepine-2- expression “metabolic side-effect” corresponds to the side one), (7-chloro-1-methyl-5-phenyl-1H-1,5-benzo effect experienced in antipsychotic, antidepressant or anti diazepine-2,4(3H,5H)-dione) etc., epileptic medication which leads to weight gain, overweight derivatives such as (5H-dibenzb.fazepine or obesity. 5-carboxamide) having also activity, oXcarba 0061 BGP-15 can be prepared by the process described Zepine (10,11-dihydro-10-oxo-5H-dibenzb.fazepine-5- in, e.g., U.S. Pat. No. 4,187.220. carboxamide) etc., barbituric acid derivatives having also 0062. In one embodiment, a conventional dose of a hypnotic and sedative activity Such as known antipsychotic or antidepressant or antiepileptic drug (5-ethyl-5-phenyl-2,4,6(1H.3H,5H)-pyrimidine-trione) and is administered to a patient requiring treatment with an pharmaceutically suitable metal salts thereof, antipsychotic or antidepressant or antiepileptic drug, and, (5-ethyl-1,3-bis(methoxy-methyl)-5-phenyl-2,4,6(1H.3H, simultaneously, a dose of BGP-15 or a pharmaceutically 5H)-pyrimidinetrione), proxibarbal (5-(2-hydroxy-propyl)- suitable acid addition salt thereof is administered. This 5-(2-propenyl)-2,4,6(1H.3H,5H)-pyrimidinetrione), primi non-toxic dose of BGP-15 prevents or reduces, effectively, done (5-ethyl-dihydro-5-phenyl-4,6(1H,5H)- the weight gain associated with the administration of the pyrimidinedione) etc., derivatives such as antipsychotic or antidepressant or antiepileptic drug leading phenyloin (5.5-diphenyl-2,4-imidazolidinedione), mephe otherwise to overweight or even obesity. In some embodi nyloin (5-ethyl-3-methyl-5-phenyl-2,4-imidazolidinedione), ments, the antipsychotic medication or the antidepressant fosphenyloin (5,5-diphenyl-3-phosphonoyl-methyl-2,4-imi medication or the antiepileptic medication is not adminis dazolidinedione) etc. and pharmaceutically suitable metal tered simultaneously with BGP-15. Thus, while the two or salts thereof, derivatives such as more agents in the combination therapy, e.g., BGP-15 and (3-ethyl-5,5-dimethyl-2,4-oxazolidinedione) etc., succinim olanzapine, can be administered simultaneously, they need ide derivatives such as (3-ethyl-3-methyl-2,5- not be. For example, administration of a first agent (or pyrrolidine-dione), (1-methyl-3-phenyl-2,5- combination of agents) can precede administration of a pyrrolidinedione) etc., carboxylic acid derivatives Such as second agent (or combination of agents) by minutes, hours, valproic acid (2-propylpentanoic acid) and pharmaceutically days, or weeks. Thus, the two or more agents can be Suitable metal salts thereof, (2-propylpentana administered within minutes of each other or within 1, 2, 3, mide), (2-ethyl-3-methyl-pentanamide) etc. 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, US 2008/0108602 A1 May 8, 2008

4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, Such as magnesium Stearate, talc, poly(ethylene glycol), 5, 6, 7, 8, 9, or 10 weeks of each other. In some cases even silica etc.; wetting agents such as Sodium laurylsulfate etc. as longer intervals are possible. While in many cases it is desir the carrier. able that the two or more agents used in a combination 0071. The liquid pharmaceutical compositions suitable therapy be present in within the patient’s body at the same for peroral administration may be solutions, Suspensions or time, this need not be so. Combination therapy can also include two or more administrations of one or more of the emulsions and can comprise, e.g., Suspending agents such as agents used in the combination. For example, if agent X and gelatine, carboxymethylcellulose etc., emulsifiers such as agent Y are used in a combination, one could administer them Sorbitane monooleate etc.; Solvents such as , oils, glyc sequentially in any combination one or more times, e.g., in the erol, propylene glycol, ethanol etc.; preservatives such as order X Y X, X X Y.Y X Y.Y Y X, X-X methyl p-hydroxybenzoate etc. as the carrier. Y Y, etc. 0072 Pharmaceutical compositions suitable for 0063 Combination therapy can also include the adminis parenteral administration consist of sterile solutions of the tration of two or more agents via different routes or locations. active ingredients, in general. For example, (a) one agent is administered orally and another 0073 Dosage forms listed above as well as other dosage agents is administered intravenously or (b) one agent is forms are known perse, see e.g. Remington's Pharmaceutical administered orally and another is administered locally. In Sciences, 18th Edition, Mack Publishing Co., Easton, USA each case, the agents can either simultaneously or sequen tially. (1990). 0064 Generally, the daily dose of antipsychotic, antide 0074 The pharmaceutical composition contains dosage pressant orantiepileptic drugs for an adult person of about 70 unit, in general. The daily dose can be administered in one or kg body weight amounts to 1-1000 mg. The similar daily dose more portions. The actual dosage depends on many factors of BGP-15 (as dihydrochloride) is, in general, 5-1000 mg. and is determined by the doctor. preferably 50-500 mg. 0075. The pharmaceutical composition is prepared by 0065 According to certain embodiments, 10-20 mg of admixing the active ingredients to one or more carrier(s), and olanzapine or 100-800 mg of clozapine and 50-500 mg of converting the mixture obtained to a pharmaceutical compo BGP-15 dihydrochloride are administered to an adult, daily. sition in a manner known perse. Useful methods are known 0066. In case of pharmaceutical compositions either or from the literature, e.g. Remington's Pharmaceutical Sci both of the two active agents (i.e. the known antipsychotic or ences mentioned above. antidepressant or antiepileptic drug and BGP-15) has been 0076. In some embodiments the pharmaceutical composi converted, one by one, to separate pharmaceutical composi tion contains an antipsychotic drug selected from the group tions using one or more conventional carrier(s) and any of the consisting of olanzapine, clozapine, risperidone, quetiapine usual processes of drug manufacture, and in this case the two and Sulpiride in addition to BGP-15 or a pharmaceutically sorts of pharmaceutical composition obtained are adminis suitable acid addition salt thereof. tered to the patient simultaneously or one after the other. 0067. Alternatively, the two active agents have been con EXAMPLE 1. Verted to one single pharmaceutical composition that can be administered to the patient being in need thereof. In the latter Effect of BGP-15 on the Body Weight Gain Induced case, the pharmaceutical composition may contain a mixture by Olanzapine in Rats of the two active agents, or each of the active agents may be present at a different site in the pharmaceutical composition, (0077 Groups of female Wistar rats were treated with e.g., one of them in the tablet core and the other in a coating vehicle (control group) and the compounds to be tested for 28 of the tablet core. Of course, one or more conventional carri days. Each group consisted of 6 animals fed with normal ers and any of the usual processes of drug manufacture are laboratory chow and tap water ad libitum. The compounds to used to prepare this single pharmaceutical composition. be tested were administered twice daily, at 8 h and 18 h, 0068. The pharmaceutical compositions described herein perorally. The antipsychotic olanzapine was administered in a contain an effective non-toxic amount of an antipsychotic or dose of 1 mg/kg to induce body weight gain. BGP-15 was antidepressant or antiepileptic drug or a pharmaceutically administered in a dose of 10 mg/kg, alone and together with suitable acid addition salt or metal salt thereof and an effec olanzapine. The oral antidiabetics metformin (100 mg/kg) tive non-toxic amount of BGP-15 or a pharmaceutically suit and rosiglitaZone (3 mg/kg) were employed as reference able acid addition salt thereof in addition to one or more compounds, alone and together with olanzapine. The average pharmaceutically acceptable carrier(s). The pharmaceutical starting weight of the animals was 171 g. The weights of the composition may include any dosage form Suitable for per animals at the end of the test on the 28 day are listed in Table oral, parenteral or rectal administration or for local treatment, 1. and can be solid or liquid. 0069. In principle, the pharmaceutical composition of the TABLE 1 invention may contain more then one antipsychotic, antide Body weight pressant and/or antiepileptic drug. Treatment (average in the group) ing 0070 The solid pharmaceutical compositions suitable for Control 255 peroral administration may be powders, capsules, tablets, Olanzapine, 1 mg/kg 330 film-coated tablets, microcapsules etc., and can comprise BGP-15 dihydrochloride, 10 mg/kg 242 binding agents such as gelatine, Sorbitol, poly(vinylpyrroli Metformin, 100 mg/kg 266 done) etc.; filling agents such as lactose, glucose, starch, RosiglitaZone, 3 mg/kg 284 calcium phosphate etc.; auxiliary Substances for tabletting US 2008/0108602 A1 May 8, 2008

side effect thereof and even further reduced the body weight TABLE 1-continued change relative to the control group.

Body weight EXAMPLE 3 Treatment (average in the group) ing Olanzapine, 1 mg/kg -- 262 Effect of BGP-15 on the Body Weight Gain Induced BGP-15 dihydrochloride, 10 mg/kg by Risperidone in Rats Olanzapine, 1 mg/kg -- 331 metformin, 100 mg/kg I0081. The experiments were carried out in eight-week-old Olanzapine, 1 mg/kg -- 359 female Wistar rats. Each test group consisted of 10 animals rosiglitaZone, 3 mg/kg fed with normal laboratory chow and tap water ad libitum. The animals were treated with vehicle (control group) and the 0078. The weight gain of the control group relative to the compounds to be tested for 21 days. The antipsychotic ris starting weight during the test period of 28 days can be con peridone was injected Subcutaneously once daily in doses of 0.005 and 0.05 mg/kg, respectively to induce body weight sidered as normal in case of rats. The group treated with gain. BGP-15 dihydrochloride was administered in a dose of olanzapine had a significantly greater average weight than the 20 mg/kg, perorally, once daily, alone and together with ris control group. This is consistent with the obesity inducing peridone. effect of olanzapine observed in patients treated with this drug. Treatment with BGP-15 alone produced somewhat I0082. The average starting weight of the animals was 195 lower average weight, while treatment with metformin and g.The weight gains of the animals at the end of the test on the rosiglitaZone, respectively, produced somewhat higher aver 21 day are listed in Table 3 age weight relative to the control group. Treatment with met TABLE 3 formin did not reduce, while treatment with rosiglitazone increased the weight gain induced by olanzapine. However, Treatment Body weight gain (g) treatment with BGP-15 dihydrochloride prevented the weight Control 27 gain induced by olanzapine. BGP-15 dihydrochloride 20 mg/kg p.o. 22.7 Risperidone 0.005 mg/kg, s.c. 39.7 Risperidone 0.05 mg/kg. s.c. 41 EXAMPLE 2 Risperidone 0.005 mg/kg s.c. + 25.8 BGP-15 dihydrochloride 20 mg/kg p.o. Effect of BGP-15 on the Body Weight Gain Induced Risperidone 0.05 mg/kg. s.c. -- 28.7 by Olanzapine or Clozapine in Mice BGP-15 dihydrochloride 20 mg/kg p.o. 0079 Groups of female NMRI mice were treated with I0083. Both doses of the antipsychotic drug risperidone vehicle (control group) and the compounds to be tested for 15 caused increased body weight gain relative to the control days, perorally. Each group consisted of 10 animals fed with group. BGP-15 alone reduced body weight gain somewhat. In normal laboratory chow and tap water ad libitum. Treatments combination with the antipsychotic drug, BGP-15 prevented were performed between 5 and 6 pm, shortly before the dark the weight increasing side effect thereof in both doses. 0084. Thus, the above tests indicate that BGP-15 can phase, the primary feeding period of the day. The antipsy effectively reduce the weight gain induced by antipsychotics, chotic olanzapine was administered in a dose of 0.5 mg/kg, while the known oral antidiabetic drugs having also insulin while the antipsychotic clozapine was administered in a dose sensitizing effect metformin and rosiglitaZone used as refer of 1 mg/kg to induce body weight gain. BGP-15 was admin ence agents were of no useful effect. Consequently, BGP-15 istered in a dose of 10 mg/kg, alone and together with olan can be used to effectively prevent or reduce weight gain, Zapine and clozapine, respectively. The weights of the ani overweight or obesity. mals were recorded twice weekly and the change in the body 0085. A number of embodiments of the invention have weights of the animals between the first and 15" days are been described. Nevertheless, it will be understood that vari given in Table 2. ous modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodi TABLE 2 ments are within the scope of the following claims. Body weight gain (average Treatment in the group) ing What is claimed is: 1. A method for preventing or reducing the side effect Control 2.98 leading to weight gain or obesity in a patient requiring a Olanzapine, 0.5 mg/kg 3.5 Clozapine, 1 mg/kg 4.11 treatment with an antipsychotic antidepressant or antiepilep BGP-15 dihydrochloride, 10 mg/kg 2.85 tic drug comprising administering an effective amount of a Olanzapine, 0.5 mg/kg -- 2.33 known antipsychotic, antidepressant orantiepileptic drug and BGP-15 dihydrochloride, 10 mg/kg Clozapine, 1 mg/kg -- 2.19 an effective non-toxic amount of O-(3-piperidino-2-hydroxy BGP-15 dihydrochloride, 10 mg/kg 1-propyl)-nicotinic amidoxime or a pharmaceutically accept able acid addition salt thereof to the patient, wherein the administration of the O-(3-piperidino-2-hydroxy-1-propyl)- 0080. Both antipsychotic drugs caused increased body nicotinic amidoxime or a pharmaceutically acceptable acid weight gain relative to the control group. BGP-15 alone addition salt thereof prevents or reduces the metabolic side reduced body weight gain somewhat. In combination with the effect experienced by the patient requiring treatment with an antipsychotic drugs, BGP-15 prevented the weight increasing antipsychotic, antidepressant or antiepileptic drug. US 2008/0108602 A1 May 8, 2008

2. The method of claim 1 in which the antipsychotic agent pine, clozapine, risperidone, quetiapine, Sulpiride, Ziprasi is selected from the group consisting of olanzapine, cloZap done, aripiprazole, sertindole, Zotepine, amisulpride and ine, risperidone, quetiapine and Sulpiride. N-desmethylclozapine. 3. The method of claim 1 in which O-(3-piperidino-2- 15. The method of claim 10 wherein the pharmaceutically hydroxy-1-propyl)-nicotinic amidoxime dihydrochloride is acceptable salt of O-(3-piperidino-2-hydroxy-1-propyl)- administered. nicotinic amidoxime is O-(3-piperidino-2-hydroxy-1-pro 4. The method of claim 1 in which the antiepileptic medi pyl)-nicotinic amidoxime dihydrochloride. cation is valproic acid or pharmaceutically acceptable addi 16. The method of claim 10 wherein the medication is an tion salt thereof. antidepressant. 5. A pharmaceutical composition having antipsychotic, 17. The method of claim 10 wherein the patient has suf antidepressant antiepileptic activity with reduced side effect fered weight gain after being administered the antipsychotic, comprising a known antipsychotic, antidepressant or antiepi antidepressant or antiepileptic medication. leptic drug and O-(3-piperidino-2-hydroxy-1-propyl)-nico 18. The method of claim 10 wherein the medication is an tinic amidoxime or a pharmaceutically acceptable acid addi antiepileptic medication. tion salt thereof in admixture with one or more conventional 19. The method of claim 18 wherein the antiepileptic medi carrier(s). cation is valproic acid or pharmaceutically acceptable addi 6. The pharmaceutical composition of claim 5 in which the tion salt thereof. known antipsychotic agent is selected from the group con 20. The method of claim 10 wherein the patient has a body sisting of olanzapine, clozapine, risperidone, quetiapine and mass index greater than 25 kg/m. Sulpiride. 21. The method of claim 10 wherein the patient has a body 7. The pharmaceutical composition of claim 6 comprising mass index greater than 30 kg/m. olanzapine and O-(3-piperidino-2-hydroxy-1-propyl)-nico 22. The method of claim 10 wherein the antipsychotic tinic amidoxime or a pharmaceutically acceptable acid addi medication is olanzapine, risperidone or clozapine. tion salt thereof. 23. A pharmaceutical composition comprising an antipsy 8. The pharmaceutical composition of claim 6 comprising chotic, antidepressant or antiepileptic medication and O-(3- clozapine and O-(3-piperidino-2-hydroxy-1-propyl)-nico piperidino-2-hydroxy-1-propyl)-nicotinic amidoxime or a tinic amidoxime or a pharmaceutically acceptable acid addi pharmaceutically acceptable acid addition salt thereof. tion salt thereof. 24. The composition of claim 23 wherein the antipsychotic 9. The pharmaceutical composition of claim 5 wherein the medication is selected from the group consisting of olanza known antiepileptic drug is selected from Valproic acid and pine, clozapine, risperidone, quetiapine and Sulpiride, pharmaceutically acceptable addition salts thereof. Ziprasidone, and aripiprazole. 10. A method for treating a patient being treated with an 25. The composition of claim 24 wherein the antipsychotic antidepressant medication, antipsychotic medication or anti medication is selected from the group consisting of olanza epileptic medication, the method comprising administering pine and clozapine. to the patient being treated with an antidepressant medication, 26. The composition of claim 24 wherein the antiepileptic antipsychotic medication or antiepileptic medication, a com medication is selected from valproic acid and pharmaceuti position comprising O-(3-piperidino-2-hydroxy-1-propyl)- cally acceptable addition salts thereof. nicotinic amidoxime or a pharmaceutically acceptable acid 27. Packaging containing a first pharmaceutical composi addition salt thereof to the patient. tion comprising an antipsychotic medication, an antidepres sant medication or an antiepileptic medication and a second 11. The method of claim 10 wherein the patient is being pharmaceutical composition comprising O-(3-piperidino-2- treated with an antipsychotic medication. hydroxy-1-propyl)-nicotinic amidoxime or a pharmaceuti 12. The method of claim 11 wherein the antipsychotic cally acceptable acid addition salt thereof. medication is an atypical antipsychotic medication. 28. The composition of claim 24 wherein the antipsychotic 13. The method of claim 11 wherein the antipsychotic medication is selected from the group consisting of olanza medicine causes weight gain in at least some patients. pine, clozapine, risperidone, quetiapine and Sulpiride. 14. The method of claim 10 wherein the antipsychotic medication is selected from the group consisting of olanza c c c c c