USOO961 0287B2 (12) United States Patent (10) Patent No.: US 9,610,287 B2 Holm et al. (45) Date of Patent: Apr. 4, 2017 (54) METHOD OF ADMINISTRATION OF (56) References Cited 4-((1R,3S)-6-CHLORO-3-PHENYL-INDAN 1-YL)-1.2.2-TRIMETHYL-PIPERAZINE AND U.S. PATENT DOCUMENTS THE SALTS THEREOF IN THE TREATMENT 7,767,683 B2 8/2010 Lopez de Diego et al. OF SCHIZOPHRENA 8,076.342 B2 12/2011 Lopez de Diego et al. 8,227,607 B2 7/2012 de Diego et al. (75) Inventors: René Holm, Jyllinge (DK); Lone Bruun, Solred Strand (DK) FOREIGN PATENT DOCUMENTS RU 2006140962 A 11 2006 (73) Assignee: H. Lundbeck A/S, Valby (DK) WO 2005102342 A1 11 2005 WO 200701 1955 A2 1, 2007 (*) Notice: Subject to any disclaimer, the term of this WO 2009 135495 A1 11, 2009 patent is extended or adjusted under 35 WO 2010/037398 A1 4/2010 WO 2010O37398 A1 4/2010 U.S.C. 154(b) by 57 days. WO 2010149727 A2 6, 2010 (21) Appl. No.: 14/126,499 OTHER PUBLICATIONS (22) PCT Fed: Jun. 20, 2012 International Search Report and Written Opinion issued Jul. 26. 2012 in International Application No. PCT/EP2012/061779. (86) PCT No.: PCT/EP2012/061779 Anonymous, Mar. 23, 2010, "Zicronapine”. New Drugs Online, XP002680825, Retrieved from the Internet: URL: http://www.ukmi. S 371 (c)(1), nhs.uk/applications/ndo/record view open. (2), (4) Date: Mar. 14, 2014 asp?newDrugID=5028 retrieved on Jul. 26, 2012). Clozapine Augmentation Article, Graylands Hospital Drug Bulletin (87) PCT Pub. No.: WO2012/175531 2004, vol. 12 No. 1, March ISSN 123-1251, Claramont, WA, 6 pageS. PCT Pub. Date: Dec. 27, 2012 Kito et al., “The Rehospitalization-reducing Effect of Supporting Self-administration According to Individual Cognitive Function of (65) Prior Publication Data Patients with Schizophrenia', Nippon Byolin Yakuzaishikai, vol. 46, No. 8, pp. 1114-1117 (2010). US 2014/O194409 A1 Jul. 10, 2014 New Pharmacology, 3rd revised edition, pp. 20-21, 268-278. Goffet al., “Once-weekly D-cycloserine effects on negative symp toms and cognition in Schizophrenia: An exploratory study’. Related U.S. Application Data Schizophrenia Research, vol. 106, pp. 320-327 (2008). Kane et al., “A Double-Blind, Randomized Study Comparing the (60) Provisional application No. 61/498,653, filed on Jun. Efficacy and Safety of Sertindole and Risperidone in Patients with 20, 2011. Treatment-Resistant Schizophrenia'. J. Clin. Psychiatry, vol. 72, No. 2, pp. 194-204 (2011). (30) Foreign Application Priority Data Manual of Diagnosis and Therapy, vol. II, Editor in Chief, Robert Berkow, D.M., pp. 57-65 (1997). Jun. 20, 2011 (DK) ................................. 2011 OO465 “The clinical phase III programme commenced on Zicronapine'. Corporate Release No. 423, 3 pages, (2011). (51) Int. C. Chemistry Database, Compound Summary for CID 11465618 A6 IK 3/495 Zicronapine. (2006.01) New Drugs Online XP-002680825. Online Report for Zicronapine. A 6LX 3/553 (2006.01) Japanese Office Action dated Dec. 20, 2016 issued in corresponding A6 IK 3L/4545 (2006.01) Japanese application. A6 IK3I/554 (2006.01) Partial English language translation of New General Pharmaceutics, A6 IK 3/496 (2006.01) Revised Third Edition, pp. 262-267 (1987). A6 IK 3L/455 (2006.01) New General Pharmaceutics, Revised Third Edition, pp. 262-267 A6 IK 3L/454 (2006.01) (1987). A 6LX 3/57 (2006.01) A 6LX 3/59 (2006.01) Primary Examiner — Sarah Pihonak (52) U.S. C. Assistant Examiner — Jason A Deck CPC .......... A6 IK3I/495 (2013.01); A61K 31/454 (74) Attorney, Agent, or Firm — Morgan, Lewis & (2013.01); A61K 31/4515 (2013.01); A61 K Bockius, LLP 31/4545 (2013.01); A61K 31/496 (2013.01); A6 IK3I/517 (2013.01); A61K 3 1/519 (57) ABSTRACT (2013.01); A61 K3I/554 (2013.01); A61 K The present invention relates to 4-((1R,3S)-6-chloro-3-phe 3I/5513 (2013.01) nyl-indan-1-yl)-1.2.2-trimethyl-piperazine and the salts (58) Field of Classification Search thereof with activity at dopamine D and D receptors as CPC .............. A61K 31/495; A61K 31/4515; A61 K well as the serotonin 5HT receptor for the treatment of 31/454: A61K 31/4545; A61K 31/496; diseases in the central nervous system in a once weekly A61K 3 1/517: A61K 3 1/519: A61 K dosing regime. 31/5513; A61K 31/554 See application file for complete search history. 7 Claims, 1 Drawing Sheet U.S. Patent Apr. 4, 2017 US 9,610,287 B2 Panel 1 Study Design Zicronapine 10 mg/day H - - - - Zicronapine 10 mg/day Previous treatment dow- ask tapered 1 week Zicronapine 45 mg Once-Weekly No--- dosing SCreenin Oper-label Oeriod DOuble-blind treatment Oeriod Safety follow-up 2 weeks My 3 weeks M 5 weeks ah 8 weeks Baseline Randomisation Completion US 9,610,287 B2 1. 2 METHOD OF ADMINISTRATION OF vitro. The compound is also described as a potent 5-HT 4-((1R,3S)-6-CHLORO-3-PHENYL-INDAN antagonist. It is also mentioned that the compound does not 1-YL)-1.2.2-TRIMETHYL-PIPERAZINE AND induce catalepsy in rats. THE SALTS THEREOF IN THE TREATMENT The aetiology of schizophrenia is not known, but the OF SCHIZOPHRENA dopamine hypothesis of Schizophrenia formulated in the early 1960s, has provided a theoretical framework for under CROSS-REFERENCE TO RELATED standing the biological mechanisms underlying this disorder APPLICATIONS (Carlsson, Am. J. Psychiatry 1978, 135, 164-173). In its simplest form, the dopamine hypothesis states that schizo The present application is a National Stage Application 10 phrenia is associated with a hyperdopaminergic state, a which claims priority of International Application No. PCT/ notion which is supported by the fact that all antipsychotic EP12/061779, filed Jun. 20, 2012, which claims priority of drugs on the market today exert some dopamine D receptor U.S. Provisional Application No. 61/498,653, filed Jun. 20, antagonism (Seeman Science and Medicine 1995, 2, 28-37). 2011 and Danish Application No. PA201100465, filed Jun. However, whereas it is generally accepted that antagonism 20, 2011. Each of these applications is hereby incorporated 15 of dopamine D receptors in the limbic regions of the brain by reference in its entirety. plays a key role in the treatment of positive symptoms of Schizophrenia, the blockade of D receptors in striatal FIELD OF THE INVENTION regions of the brain causes extrapyramidal symptoms (EPS). As described in EP 638 073 a profile of mixed dopamine The present invention relates to 4-((1R,3S)-6-chloro-3- D/D receptor inhibition has been observed with some phenyl-indan-1-yl)-1.2.2-trimethyl-piperazine and the salts so-called "atypical antipsychotic compounds, in particular thereof with activity at dopamine D and D receptors as with clozapine (8-chloro-11-(4-methylpiperazin-1-yl)-5H well as the serotonin 5HT, receptor for the treatment of dibenzob.e. 1.4 diazepine), used in treatment of Schizo diseases in the central nervous system in a once weekly phrenic patients. dosing regime. 25 Further, selective Dantagonists have been connected to treatment of sleep disorders and alcohol abuse (D. N. Eder, BACKGROUND OF THE INVENTION Current Opinion in Investigational Drugs, 2002 3(2):284 288). 4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1.2.2-trim Dopamine may also play an important role in the aetiol ethyl-piperazine and the salts thereof, pharmaceutical com 30 ogy of affective disorders (P. Willner, Brain. Res. Rev. 1983, positions containing these salts and the medical use thereof, 6, 211-224, 225-236 and 237-246; Bogese et al., J. Med. including treatment of schizophrenia or other diseases Chem., 1985, 28, 1817-1828). involving psychotic symptoms, is disclosed in WO2005/ In EP 638 073 is described how compounds having 0.16900. 4-((1R,3S)-6-chloro-3-phenyl-indan-1-yl)-1.2.2- affinity for 5-HT, receptors, in particular 5-HT, receptor trimethyl-piperazine is hereinafter referred to as Compound 35 antagonists, have been suggested for treatment of different (I) diseases, such as Schizophrenia including the negative symptoms in Schizophrenic patients, depression, anxiety, sleep disturbance, migraine attacks and neuroleptic-induced (I) parkinsonism. 5-HT2 receptor antagonism has also been 40 Suggested to reduce the incidence of extrapyramidal side effects induced by classical neuroleptics (Balsara et al. Psychopharmacology 1979, 62, 67-69). Psychotic patients, and in particular schizophrenic patients, are often unwilling or unable to take their medi 45 cation regularly; several studies have shown that a less frequent dosing results in higher degree of compliance and thus eventually better treatment of the patients. Therefore there is an unmet need for long acting preparations of antipsychotic medicine. In particular there is a need for long 50 acting preparations of antipsychotic medicine in non-inva sive form that represent an alternative to intra muscular depot formulations in order to make change in dosing regime, frequency of medication or type of medication, more flexible. Compound (I) is also known as Zicronapine. 55 EP 638 073 covers a group of trans isomers of 3-aryl-1- SUMMARY OF THE INVENTION (1-piperazinyl)indanes Substituted in the 2- and/or 3-posi tion of the piperazine ring. The compounds are described as The inventors of the present invention have Surprisingly having high affinity for dopamine D and D receptors and found that the elimination half life of Compound (I) in the 5-HT, receptor and are suggested to be useful for 60 human is about 150 hours. The long elimination half life in treatment of several diseases in the central nervous system, combination with affinity for both dopamine D1 and D2 including Schizophrenia.