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(12) Patent Application Publication (10) Pub. No.: US 2003/0171347 A1 Matsumoto (43) Pub US 2003.0171347A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0171347 A1 Matsumoto (43) Pub. Date: Sep. 11, 2003 (54) SIGMA RECEPTOR ANTAGONISTS HAVING Publication Classification ANT-COCANE PROPERTIES AND USES THEREOF (51) Int. Cl." ......................... A61K 31/55; A61K 31/33; A61K 31/397; A61K 31/445; (76) Inventor: Rae R. Matsumoto, Edmond, OK (US) A61K 31/40; A61K 31/137 (52) U.S. Cl. .............. 514/183; 514/210.01; 514/217.12; Correspondence Address: 514/317; 514/408; 514/649 DUNLAP, CODDING & ROGERS PC. PO BOX 16370 OKLAHOMA CITY, OK 73114 (US) (57) ABSTRACT (21) Appl. No.: 10/178,859 The present invention relates to novel Sigma receptor antagonist compounds that have anti-cocaine properties. (22) Filed: Jun. 21, 2002 These Sigma receptor antagonists are useful in the treatment Related U.S. Application Data of cocaine overdose and addiction as well as movement disorders. The Sigma receptor antagonists of the present (63) Continuation of application No. 09/715,911, filed on invention may also be used in the treatment of neurological, Nov. 17, 2000, now abandoned, which is a continu psychiatric, gastrointestinal, cardiovascular, endocrine and ation of application No. 09/316,877, filed on May 21, immune System disorders as well as for imaging procedures. 1999, now abandoned. The present invention also relates to novel pharmaceutical compounds incorporating Sigma receptor antagonists which (60) Provisional application No. 60/086,550, filed on May can be used to treat overdose and addiction resulting from 21, 1998. the use of cocaine and/or other drugs of abuse. Patent Application Publication Sep. 11, 2003 Sheet 1 of 24 US 2003/0171347 A1 J. mACh CORTICAL, LIMBIC MESOCORTICOLIMBIC CARDIOVASCULAR COLLAPSE RESIRATORY DISTRESS MEDULLARY ADDICTION DEATH Fig. 1 . 20028N0W0 7.5 1 O 1600|2000TECHCENTER COCAINE DOSE (mg/kg, i.p.) RECEIVED Fig. 3 Patent Application Publication Sep. 11, 2003 Sheet 3 of 24 US 2003/0171347 A1 100 -O- BD1008 -H BD1060 80 - - A - BD1067 60 40 20 1 O 1 OO PRETREATMENT DOSE (mg/kg, i.p.) Fig. 4 100 -O- BD1047 -- LR172 80 60 40 20 ... 1 1 1 O 1 OO PRETREATMENT DOSE (mg/kg, i.p.) Fig. 5 Patent Application Publication Sep. 11, 2003 Sheet 4 of 24 US 2003/0171347 A1 OO -O- BD1018 -- BD1063 80 - A - LR132 - A - LR176 PRETREATMENT DOSE (mg/kg, i.p.) Fig. 6 -- YZ011 - A - YZ06 -O- YZ.018 -H YZO27 -O- YZ028 - A YZ029 ... 1 1 O 1 OO PRETREATMENT DOSE (mg/kg, i.p.) Fig. 7 Patent Application Publication Sep. 11, 2003 Sheet 5 of 24 US 2003/0171347 A1 -O- RED HAL -- HALOPERIDOL -- BMY14802 -A RIMCAZOLE ----O-- NALOXONE 1 1 O 1 OO PRETREATMENT DOSE (mg/kg, i.p.) Fig. 8 Patent Application Publication Sep. 11, 2003 Sheet 6 of 24 US 2003/0171347 A1 100 80 - +BD 1052 - A - +(+)PENT 2 - A - +BD1031 2 60 2 40 O & 20 O O 1 O 2 O 3 O 4 O 5 O 6 O 70 COCAINE DOSE (mg/kg, i.p.) Fig. 9 100 80 >- 3 60 ir 40 & 20 -O- BD1008 -- BD1060 -- BD1067 ... 1 1 O 1 OO PRETREATMENT DOSE (mg/kg, i.p.) Fig. 10 Patent Application Publication Sep. 11, 2003 Sheet 7 of 24 US 2003/0171347 A1 -O- BD1047 -- LR172 ... 1 1 O PRETREATMENT DOSE (mg/kg, i.p.) Fig. 11 -O- BD1018 -- BD1063 -- LR132 - A - LR176 ... 1 1 1 O 1 OO PRETREATMENT DOSE (mg/kg, i.p.) Fig. 12 Patent Application Publication Sep. 11, 2003 Sheet 8 of 24 US 2003/0171347 A1 100 80 40 ... 1 1 1 O PRETREATMENT DOSE (mg/kg, i.p.) Fig. 13 -- HALOPERDOL -O-RED HAL - A - BMY14802 -A-RIMCAZOLE ----O---. NALOXONE 1 1 O OO PRETREATMENT DOSE (mg/kg, i.p.) Fig. 14 w? CDCOCO<†CN 3 CDOCDC)CDCD TIME OF TREATMENT Fig. 18 Patent Application Publication Sep. 11, 2003 Sheet 13 of 24 US 2003/0171347 A1 HORIZONTAL LOCOMOTOR ACTIVITY (30 minute) A S 2 Z. s ss O O O O O O O O O O O U C) N vo HORIZONTAL LOCOMOTOR ACTIVITY (per 5 minute interval) Patent Application Publication Sep. 11, 2003 Sheet 14 of 24 US 2003/0171347 A1 HORIZONTAL LOCOMOTORACTIVITY S O : s s e O O O O O O O O O O O ur C CN an HORIZONTAL LOCOMOTOR ACTIVITY (per 5 minute interval) Patent Application Publication Sep.11, 2003 Sheet 15 of 24 US 2003/0171347 A1 HORIZONTAL LOCOMOTORACTIVITY (30 minute) O O O O O v GN ON ve v O O O O l V () N vm HORIZONTAL LOCOMOTORACTIVITY (per 5 minute interval) Patent Application Publication Sep. 11, 2003 Sheet 16 of 24 US 2003/0171347 A1 HORIZONTAL LOCOMOTORACTIVITY (30 minute) 3 8 3 3 3 3 3 3V C 3C CN 3CN y 3o 3 C. CO CNs s: s e O O O O O O O O O O V C CN vo HORIZONTAL LOCOMOTOR ACTIVITY (per 5 minute interval) Patent Application Publication Sep.11, 2003 Sheet 17 of 24 US 2003/0171347 A1 O. O. O. O. O. O. O. O O. O. O. O. O. O. O. O L O L O O. O. S C C CN N P vs O : ss s s s O O O O O O O O O O O V N HORIZONTAL LOCOMOTORACTIVITY (per 5 minute interval) O O f HORIZONTAL LOCOMOTOR ACTIVITY (per 5 minute interval) O Sep. 11, 2003 Sheet 19 of 24 US 20 03/0171347 A1 HORIZONTAL LOCOMOTOR ACTIVITY (30 minute) D V d S y HORIZONTAL LOCOMOTOR ACTIVITY (per 5 minute interval) Patent Application Publication Sep. 11, 2003 Sheet 20 of 24 US 2003/017 1347 A1 O O. O. O. O. O. O. O O. O. O. O. O. O. O. O O ) O L O O U () () (N ON v L. O. s Ns s N O O O O O O O O O O t C) CN O HORIZONTAL LOCOMOTORACTIVITY (per 5 minute interval) m). SNOISTQANOC)9% lae”) encaer)CNON!:-)- INE Nº ANTISENSE ICV TREATMENT Patent Application Publication Sep. 11, 2003. Sheet 23 of 24 US 2003/0171347 A1 700 600 500 400 300 200 -O- SALINE 100 - - - SENSE - A - ANTISENSE O 1 O 2 O 3 O 40 MINUTE Fig. 32 700 -O- SALINE 600 -- SENSE - A - ANTISENSE 500 400 300 200 100 O 1 O 20 3 O 4 O MINUTE Fig. 33 Patent Application Publication Sep. 11, 2003 Sheet 24 of 24 US 2003/0171347 A1 1 O 1 OO 1 OOO 1 OOOO AFFINITY (Ki in Nm) Fig. 34 US 2003/0171347 A1 Sep. 11, 2003 SIGMA RECEPTOR ANTAGONSTS HAVING in those instances where previously tested compounds have ANT-COCANE PROPERTIES AND USES attenuated Some of the actions of cocaine, major problems THEREOF have persisted: ineffectiveness against the lethal effects of cocaine, ineffectiveness when administered after cocaine CROSS-REFERENCE TO RELATED ingestion, unacceptable Side effects, and/or a narrow thera APPLICATIONS peutic margin. 0001. This application is a continuation of U.S. patent application Ser. No. 09/715,911, filed Nov. 17.2000, entitled 0008 Cocaine is generally thought of as a dopamine “SIGMA RECEPTOR ANTAGONISTS HAVING ANTI uptake inhibitor. However, it can also inhibit the reuptake of COCAINE PROPERTIES AND USES THEREOF;” which Serotonin and norepinephrine and bind to a number of is a continuation of U.S. patent application Ser. No. 09/316, neurotransmitter receptors. Of the myriad of sites with 877, filed May 21, 1999, entitled “SIGMA RECEPTOR which cocaine interacts, the ones that are thought to be most ANTAGONISTS HAVING ANTI-COCAINE PROPER relevant in terms of its psychological and physiological TIES AND USES THEREOF,” now abandoned; and claims properties are the monoamine transporters, muscarinic priority under 35 U.S.C. S.119(e) of U.S. Provisional Patent receptors, and Sigma receptors. It is at these sites that the Application Serial No. 60/086,550, filed May 21, 1998, affinity of cocaine corresponds to concentrations that are entitled “NOVEL SIGMA RECEPTOR LIGANDS FOR achievable in vivo. THE TREATMENT OF COCAINE ABUSE. 0009 Sigma receptor antagonists attenuate the behav ioral toxic effects of cocaine, even when administered after BACKGROUND OF THE INVENTION an overdose and may also have prophylactic effects against 0002) 1. Field of the Invention the psychomotor Stimulant effects of cocaine. These novel 0003. The present invention relates to novel sigma recep Sigma receptor antagonists ("sigma ligands') also have few tor antagonist compounds that have anti-cocaine properties. Side effects, wide therapeutic margins, and remain effective These Sigma receptor antagonists are useful in the treatment even when administered after a cocaine overdose. of cocaine overdose and addiction as well as movement 0010 Sigma receptors were first proposed in 1976 based disorders. The Sigma receptor antagonists of the present on the actions of SKF 10,047 and related benzomorphans. invention may also be used in the treatment of neurological, The name “sigma' is in fact derived from the first letter “S” psychiatric, gastrointestinal, cardiovascular, endocrine and in SKF 10,047 which was thought to be the prototypic ligand immune System disorders as well as for imaging procedures. for these binding sites. Unfortunately, SKF 10,047 is now The present invention also relates to novel pharmaceutical recognized as a very non-Selective ligand and Some of the compounds incorporating Sigma receptor antagonists which binding sites with which it interacts are shown in FIG.1. In can be used to treat overdose and addiction resulting from the very earliest experiments, investigators used racemic the use of cocaine and/or other drugs of abuse.
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