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G Proteinactivation US 20200079745A1 INI (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No .: US 2020/0079745 A1 Kruegel et al. (43 ) Pub . Date : Mar. 12 , 2020 (54 ) CARBOXYLIC DIARYTHIAZEPINEAMINES Publication Classification AS MIXED MU - AND DELTA -OPIOID (51 ) Int. Ci. RECEPTOR AGONISTS C07D 281/02 ( 2006.01 ) (71 ) Applicants :Andrew Kruegel, New York , NY (US ) ; (52 ) U.S. CI. Dalibor Sames , New York , NY (US ) ; CPC CO7D 281/02 (2013.01 ) ; A61K 45/06 Jonathan A. Javitch , Dobbs Ferry , NY (2013.01 ) (US ) (57 ) ABSTRACT ( 72 ) Inventors : Andrew Kruegel , New York , NY (US ) ; The present invention provides a compound having the Dalibor Sames , New York , NY (US ) ; structure : Jonathan A. Javitch , Dobbs Ferry , NY (US ) Rg Ri (73 ) Assignee : The Trustees of Columbia University in the City of New York , New York , Ro R4 NY (US ) -R5, (21 ) Appl. No .: 16 /493,992 R10 ( 22 ) PCT Filed : Mar. 15 , 2018 R11 N R2 R7 Ro ( 86 ) PCT No .: PCT/ US2018 /022650 R3 $ 371 ( c ) ( 1 ) , or a pharmaceutically acceptable salt or ester thereof , and a (2 ) Date : Sep. 13 , 2019 method of treating a subject afflicted with a pain , a depres sive disorder , a mood disorder, an anxiety disorder , border Related U.S. Application Data line personality disorder, opioid addiction , or opioid with (60 ) Provisional application No. 62 /471,745 , filed on Mar. drawal symptoms by administering the compound to the 15 , 2017 subject . hDOR + GOB - Luc + B1 + y2 - Venus 150 DPDPE 100 GProteinActivation(%) Www Wewe os des . 9c IT Most 12 DI -50 Log (drug ] (M ) Patent Application Publication Mar. 12 , 2020 Sheet 1 of 2 US 2020/0079745 A1 Fig . 1 hDOR + GOB -Luc + B1 + y2 - Venus 150 DPDPE GProteinActivation(%) 50 9c .L DI 3 -2 HH Log ( drug ] ( M ) 50 Patent Application Publication Mar. 12 , 2020 Sheet 2 of 2 US 2020/0079745 A1 Fig . 2 30 TW 25-1 Tianeptine (15 min ) ED50 = 15 mg/ kg Latency(s) 9b ( 15 min ) 20 ED50 = 5.1 mg/ kg 9k ( 15 min ) ED50 1.7 mg/ kg 15 10 0.1 1 10 Baseline Drug (mg /kg ) US 2020/0079745 A1 Mar. 12 , 2020 1 CARBOXYLIC DIARYTHIAZEPINEAMINES [0006 ] Long - acting prescription opioids may also be used AS MIXED MU - AND DELTA -OPIOID as maintenance ( replacement ) therapies in the treatment of RECEPTOR AGONISTS opioid addiction . In this case , a prescription opioid is provided to the patient chronically and under medical super [ 0001 ] This application claims priority of U.S. Provisional vision to substitute for the use of illicit opioids (e.g. heroin ), Application No. 62/ 471,745 , filed Mar. 15 , 2017 , the con thus reducing cravings for , and abuse of, the illicit drug . tents of each of which are hereby incorporated by reference. Opioid maintenance therapy is considered a standard [ 0002 ] Throughout this application , certain publications method of care for opioid addiction and is more successful are referenced in parentheses. Full citations for these pub than behavioral or antagonist interventions (Bart , G. 2012 ) . lications may be found immediately preceding the claims. The disclosures of these publications in their entireties are SUMMARY OF THE INVENTION hereby incorporated by reference into this application in order to describe more fully the state of the art to which this [0007 ] The present invention provides a compound having invention relates . the structure : BACKGROUND OF THE INVENTION Rg [0003 ] The mu opioid receptor (MOR ) has been the major molecular target for treatment of pain for several decades . R9 R4 However, the vast majority of MOR agonists used clinically today are structurally related to or derived from morphine -R5, ( and other poppy alkaloids ). These compounds suffer from R10 many serious problems, including development of tolerance Ril ( increased dosing is required to achieve the same analgesic R7 Ro effects ) , high addiction liability , and other side effects (e.g. R? R3 respiratory depression , nausea , and constipation ) (Williams , J. T. et al. 2013) . Therefore , there is a continuing interest in the development of new pain medications , including new [0008 ] wherein MOR agonists with improved therapeutic profile ( Corbett , [0009 ] Riis1 -H or - (alkyl ) ; A. D. et al. 2006 ) . [ 0010 ] R2 is (Cz - C20 alkyl) -CO2H or — (C3 -C20 alkyl) [ 0004 ] There is also both historical and growing interest in CO2- alkyl) ; the use of MOR agonists as medicaments for depression . [0011 ] R , is - H or -alkyl) ; Prior to the adoption of tricyclic antidepressants and elec [ 0012 ] R4 , R5, R. and R , are each independently —H , troshock therapy as favored treatments for depression , opi Ci, —Br, -F , -1, CN , CF3, — OCF3, - (alkyl ) , oids were among the only options available , with the “ opium -( alkenyl) , - ( alkynyl ), -( aryl ) , -NH2, -NH-( alkyl) , -NH cure " being an accepted treatment modality in the early 20th (alkenyl ) , -NH-( alkynyl) -NH - Caryl) , -NH-(heteroaryl ) , century (Berrocoso , E. et al. 2009 ) . More recently , studies in OH , OAc , O C ( O ) ( alkyl) , O - alkyl) , O - alky both rodents (Besson , A. et al. 1996 ) and humans (Bodkin , laryl) , O-( alkenyl) , O-( alkynyl ) , O - Caryl) , O-( het J. A. et al. 1995 ) have suggested that MOR activation may eroaryl ), S- (alkyl ), —S- ( alkenyl) , —S-( alkynyl) , S lead to antidepressant and / or anxiolytic effects . The antide ( aryl ), S- (heteroaryl ) , -SS ( O ) -( alkyl) ), S ( O )-aryl ), pressant tianeptine has also been reported to act as a full S ( O ) - (heteroaryl ) , SO2- ( alkyl ), -SO2- ( aryl) , or agonist of the MOR (Gassaway , M.M. et al. 2014 ) . On the -SO-(heteroaryl ) ; molecular level , MORs are extensively expressed in the hippocampus and have been shown to exert a variety of [0013 ] Ry, Ry, Rio and Rui are each independently —H , indirectmodulatory effects on glutamatergic neurons in this C1, —Br, —F, —I, CN , CF39 OCF3, - ( alkyl) , brain region ( Xie , C. W. et al . 1997 ; Svoboda, K. R. et al. -aryl ), -( heteroaryl) - (alkenyl ) , - (alkynyl ), -NH2, -NH 1999 ) . Normalization and modulation of glutamate signaling ( alkyl) , NH-( alkenyl) , -NH-( alkynyl ) -NH -Caryl ) , has been strongly associated with the actions of antidepres NH-( heteroaryl ) , OH , -OA , 0_C ( O ) (alkyl ) , sants (Paul , I. A. and Skolnick , P. 2003 ) and indeed , the O - alkyl) , O-( alkenyl ) , O-( alkynyl ) , O - aryl ) , NMDA receptor antagonist ketamine , shows rapid and effi O-( heteroaryl ) , S - alkyl) , -S - alkenyl) , -S - alkynyl) , cacious antidepressant activity in human clinical trials S - aryl) , S-( heteroaryl ) , -S ( O ) - (alkyl ) , -S ( O ) - (aryl ), ( Zarate , C. A. Jr et al. 2006 ) . Further , agonists of the related S ( O )- (heteroaryl ) , SO2- ( alkyl) , -SO2- ( aryl ) , or delta opioid receptor ( DOR ) have been demonstrated to SOZ- (heteroaryl ) ; show robust antidepressant efficacy in animals ( Jutkiewicz , [0014 ] wherein when R , is (C3-6 alkyl) -CO H , then E. M. 2006 ) . one of Rs or Ro is - ( alkynyl) or S-( alkyl ) , or R , and [0005 ] Opioid receptor dysfunction may also be associ Ro are each independently — Cl, —Br, —F, or —I, ated with borderline personality disorder (BPD ) . Patients [0015 ] wherein when R , is – (C3-6 alkyl) -CO2- (alkyl ) , afflicted with BPD exhibit alterations in both basal MOR then one of R , or Rois - ( alkynyl ) , or R , and Roare each binding potential and endogenous opioid responses to nega independently C1, -Br, —F, or —I, tive stimuli (Prossin , A. R. et al. 2010 ) . There is also a high 10016 ] wherein when R , is CH , Rz, R4 , R., Rz, Rg, prevalence of BPD among patients seeking buprenorphine R9, R10 and Ru1 are each H , and R , is Cl, then R2 is treatment for opioid addiction (Sansone , R. A. et al . 2008 ) . other than ( CH2) , CO H , ( CH2) 1.CO2H , CH Accordingly , MOR modulators may be useful medicaments (CH ) ( CH2) CO , H or ( CH2) 2CH (CH3 ) ( CH2) for BPD . 3CO2H , and US 2020/0079745 A1 Mar. 12 , 2020 2 [ 0017 ] wherein when R , is CH3, R3, R4, R6 R7, R8, R9, other than ( CH ) CO2H , (CH2 ) 1.CO H , CH R10 and Rui are each -H , and R , is SCH3, then R2 is other (CH ) (CH ) COZH or - ( CH2) 2CH (CH3 ) (CH2 ) than ( CH2) .CO , H , 3CO , H , and [ 0018 ] or a pharmaceutically acceptable salt or ester [0031 ] wherein when R , is CH3, R3, R4, R6, R7, Rg, thereof . R9, R10 and R11 are each — H , and R , is SCHz, then R2 is other than (CH ).CO , H , BRIEF DESCRIPTION OF THE FIGURES [0032 ] or a pharmaceutically acceptable salt or ester [ 0019 ] FIG . 1 : Compound 9c activates DOR to a lesser thereof. Emax than the control agonist DPDPE . [0033 ] In some embodiments , a compound having the [0020 ] FIG . 2 : Dose - response curves of analgesic activity structure : of tianeptine, 9b and 9k in the hot plate assay. DETAILED DESCRIPTION OF THE Rg R1 INVENTION R9 R4 [0021 ] The present invention provides a compound having the structure : R5, Rió Rg Ri R11 R2 R Ro Ro Lo R4 R3 .R5, [ 0034 ] wherein Rio (0035 ] Ri is -H or - ( alkyl) ; Ru1 [0036 ] R2 is (Co - C20 alkyl) -CO H or (Co - C20 R7 R6 R R3 alkyl) -C02- (alkyl ) ; [0037 ] Rz is -H or - ( alkyl ) ; [ 0038 ] R4, R5, R. and R , are each independently —H , [0022 ] wherein C1, —Br, —F, — I , -CN , –CF3, -OCF3, - (alkyl ) , [0023 ] R1 is H or - ( alkyl) ; - (alkenyl ), - (alkynyl ) , - ( aryl) , —NH2, —NH - alkyl) , [0024 ] R2 is – (Cz - C20 alkyl) -CO , H or —Cz- C20 NH-( alkenyl) , -NH-( alkynyl) -NH - Caryl ) , -NH alkyl) -CO2- (alkyl ) ; ( heteroaryl) , OH , OA , O C ( O ) (alkyl ) , O [0025 ] Rz is –H or - (alkyl ) ; ( alkyl) , O - alkylaryl) , O - alkenyl) , O - alkynyl) , [0026 ] R4, R5, R.
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