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Ie-O-JY -CH2 S (56) References Cited Wherein N Is 0 to 6, X" and Y Are Independently H, Cl, F, CH, CH, CH, CH, OCH, OH, CF, OCF, NO, U.S

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Ie-O-JY -CH2 S (56) References Cited Wherein N Is 0 to 6, X US005574060A United States Patent (19) 11) Patent Number: 5,574,060 Rothman et al. (45) Date of Patent: Nov. 12, 1996 54 SELECTIVE INHIBITORS OF BIOGENIC "Hydrindene Derivatives as Potential Oral Hypoglycemic AMINE TRANSPORTERS Agents: N-Alkyl 1,2,3,3a,4,8b-Hexahydroindeno1,2-b) pyrroles', De et al., Journal of Pharmaceutical Sciences, vol. (75) Inventors: Richard Rothman, Silver Spring, Md.; 62, No. 8, Aug. 1973, pp. 1363-1364. Frank J. Carroll, Durham, N.C.; Bruce Blough, Raleigh, N.C.; Samuel (List continued on next page.) W. Mascarella, Hillsborough, N.C. Primary Examiner-Mark L. Berch (73) Assignees: The United States of America as Attorney, Agent, or Firm-Morgan & Finnegan LLP represented by the Department of 57) ABSTRACT Health and Human Services, Washington, D.C.; Office of Technology The present invention provides a compound having the Transfer, Bethesda, Md.; Research Structure: Triangle Institue, Research Triangle Park, N.C. (21) Appl. No.: 203,222 22 Filed: Feb. 28, 1994 Related U.S. Application Data H 63 Continuation-in-part of Ser. No. 105,747, Aug. 12, 1993, abandoned. wherein X, Y, and Z are independently H, Cl, Br, F, OCH, I, or an alkyl group having 1 to 6 carbon atoms; and R is (51) Int. Cl." .......................... A61K 31/40; A61K 31/47; C07D 403/06; C07D 471/08 X (52) U.S. Cl. ............................ 514/411; 546/94; 546/146; 54.6/150; 548/427: 548/428 58) Field of Search .............................. 548/427; 514/411 -ie-O-JY -CH2 S (56) References Cited wherein n is 0 to 6, X" and Y are independently H, Cl, F, CH, CH, CH, CH, OCH, OH, CF, OCF, NO, U.S. PATENT DOCUMENTS NH, N(CH4), NHCOCH, NCS, NHCOCHBr, or N, and 9/1993 DeBernardis et al. .................. 514/41 (CH), if present, may be substituted with OH, OCH oran 5,244,888 alkyl or alkenyl group having 1 to 3 carbon atoms. The OTHER PUBLICATIONS present invention also provides a pharmaceutical composi Ordway, J. Pharm. Exp. Therapeutics 247, 379(1988). tion comprising the compound above and a pharmaceuti "Synthesis and Ligand Binding at PCT Sites 1 and 2 for cally acceptable carrier. The present invention further pro Hexahydro-2-Substituted-l-Methylindeno1,2-bPyr vides a method for treating a disease characterized by a roles' Carroll et al., Med. Chem. Res (1993) 3:178-182. dopamine deficiency which comprises administering to a "RTI-4793-14, a New Ligand with High Affinity and Selec subject in need of such treatment an amount of the pharma tivity for the (+)-MK801-Insensitive (H)1-1-(2-thienyl) ceutical composition above effective to treat the disease. cyclohexyl)piperidine Binding Site (PCP Site 2) of Guinea Pig Brain", Goodman et al., Synapse 16:59-65 (1994). 36 Claims, 5 Drawing Sheets H AH HF, oc H NYCoch225 |N1-OH 3d CH 6 CH 1. Dess-Martin's CHNHCHCOCH reagent, CHC Cl toluene. 100°C 2. (Css)P=CH N CoH H H Hmm. toluene, 10°C COCHO Côu N S 7 H N t 3c CH CHNHCH(R)COHC. to°C HCH-OHPdic O c H N R 3e N CH CH 5,574,060 Page 2 OTHER PUBLICATIONS the Biogenic Amine Reuptake Complex', Akunne et al., "Indolizines II: Search for Potential Oral Hypoglycemic Synapse 8:289-300 (1991). Agents”, Journal of Pharmaceutical Sciences, vol. 64, No. 2, “The Psychotomimetic Drug Phencyclidine Labels Two Feb. 1975, pp. 249-252. High Affinity Binding Sites in Guinea Pig Brain: Evidence "Structure Activity Studies on the Interaction of Biogenic for N-Methyl-D aspartate-Coupled and Dopamine Amine Reuptake Inhibitors and Potassium Channel Block Reuptake Carrier-Associated Phencyclidine Binding Sites', ers with MK-801 Sensitive (PCT Site 1) and Insensitive Rothman et al., Molecular Pharmacology, 36:887-896, (PCPSite 2) HTCP Binding Sites in Guinea Pig Brain", 1989. Rothman et al., Multiple Sigma and PCP Receptor Ligands: “MPTP Lesions of the Nigrostriatal Dopaminergic Projec Mechanisms for Neuromodulation and Neuroprotection, tion Decrease H)1-1-(2-Thienyl)Cyclohexyl)-Piperi NPP Books, 1992, pp. 137-146. dine Binding to PCTSite 2: Further Evidence that PCP Site “H1-2-(2-Thienyl)Cyclohexyl)Piperidine Labels Two 2 is Associated with the Biogenic Amine Reuptake Com High-Affinity Binding Sites in Human Cortex: Further plex', Akunne et al, Neurochemical Research, vol. 17, No. Evidence for Phencyclidine Binding Sites Associated with 3, 1992, pp. 261-264. U.S. Patent Nov. 12, 1996 Sheet 1 of 5 5,574,060 OHO Nonobe£,! IGIH[10IJI HO ?–??????????????????????????????~~ HO -:-)————————————.”?ingube€ +HL'o,Oz-OHO U.S. Patent Nov. 12, 1996 Sheet 2 of S 5,574,060 FIGURE 2 1. Dess-Martin's CHNHCHCOCH reagent, CHC toluene, 100°C 2. (CH)P=CH53 N COH H H H ammu toluene, 11 O°C COCHO C-fuN ea H N S H 3C 7 CH 3 CHNHCH(R)COH Pd/C ltoluene, 110°C HCHOH2'2' '5 H N R 3e ) l CH CH 3a, R-H b, R=CHCH U.S. Patent Nov. 12, 1996 Sheet 3 of 5 5,574,060 FIGURE 3 20 OO 80 60 40 20 -45 - 15 15 45 75 105 35 65 95 Time (min) U.S. Patent Nov. 12, 1996 Sheet 4 of 5 5,574,060 FIGURE 4 30 RTI 4793-14 20 10 -45 -30 -15 O 5 30 45 60 75 Time (min) 5,574,060 1. SELECTIVE INHIBITORS OF BIOGENIC AMINE TRANSPORTERS This is a continuation-in-part of application Ser. No. 5 08/105,747, filed Aug. 12, 1993, ABN the contents of which is hereby incorporated by reference. BACKGROUND OF THE INVENTION 10 SUMMARY OF THE INVENTION H)1-1-(2-thienyl)cyclohexylcyclohexyl)piperidine The present invention provides a compound having the (TCP), an analog of the dissociative anesthetic phencyclid Structure: ine (PCP), binds with high affinity to two sites in guinea pig brain membranes, one of which is MK-801 sensitive and one 15 of which is not. The MK-801-sensitive site (PCP site 1) is associated with NMDA receptors. The MK-801-insensitive site (PCP site 2) is thought to be associated with biogenic amine transporters (BAT) (Rothman, R. B., et al. Mol. 20 Pharmacol. 36:887-896 (1989); Akunne, H. C., et al. Syn Z. H N R2 apse 8:289-300 (1991); Rothman, R. B., et al., In: Multiple Sigma and PCP Receptor Ligands: Mechanisms for Neuro modulation and Protection, pp. 137-146 (Domino, E. F. and wherein X, Y, and Z are independently H, Cl, Br, F, OCH Kamenka, J. M., eds., 1992); Akunne, H. C., et al. Neuro 25 I, or an alkyl group having 1 to 6 carbon atoms; R1 is H, an chem. Res. 17:261-264 (1992)). alkyl or alkenyl group having 1 to 6 carbon atoms, or Based upon the association of PCP site 2 with BATs, drugs with high affinity for PCP site 2 would be expected to r/- CH2; inhibit the reuptake of biogenic amines. 30 The present invention is directed to classes of compounds and R2 is which bind selectively and potently to PCP site 2 and also have activity as biogenic amine transport blockers. (2RS, X" 3aSR, 8aRS)-1,2,3a,8,8a-Hexahydro-2-benzyl-1-methyl-in -(CH2) O 35 deno1,2-bipyrrole (RTI-4793-14) represents the first of Y -CH2 N these compounds which bind with high affinity to biogenic amine transporters but are relatively less potent amine wherein n is 0 to 6, X and Y are independently H, Cl, F, reuptake blockers than classical BAT ligands. This com CH, CH, CH, CH, OCH, OH, CF, OCF, NO, pound has been shown to increase the levels of dopamine in 40 NH, N(CH), NHCOCH, NCS, NHCOCHBr, or N, and the brain and thus would be useful for treating diseases or (CH), if present, may be substituted with OH, OCH or an disorders characterized by dopamine deficiency such as alkyl or alkenyl group having 1 to 3 carbon atoms. Parkinson's Disease and depression. The compound also The present invention also provides a compound having would be useful in radioligand binding studies to label the the structure: PCPsite 2 because of its high affinity and selectively for PCP 45 site 2. Hungarian Patent No. 151,567 disclosed ideno (1,2-b) pyrroles having the structure below wherein R1 is hydrogen, aryl, or a heteroaryl group and R2 is a H or an alkyl group 50 (see also Chemical Abstracts, vol. 62, No. 528(g) (1965)). Some of these compounds have antispasmatic or tranquil izing properties. H 55 wherein X, Y, and Z are independently H, Cl, Br, F, OCH, I, or an alkyl group having 1 to 6 carbon atoms; and R is X -(CH2) 60 Y -CH2 S De and Saha disclosed ideno (1,2-bpyrroles having the structure below wherein R is an alkyl group such as methyl, wherein n is 0 to 6, X and Y are independently H, C, F, ethyl, propyl, butyl, or pentyl (De, A.U. and Saha, B. P., J. CH, CH, CH, CH, OCH, OH, CF, OCF, NO, Pharm. Sci. 62(8): 1363-1364 (1973); De, A.U. and Saha, 65 NH, N(CH4), NHCOCH, NCS, NHCOCHBr, or N, and B. P. J. Pharm. Sci. 64(2): 249-252 (1975)). These com (CH), if present, may be substituted with OH, OCH, or an pounds were screened as possible oral hypoglycemic agents. alkyl or alkenyl group having 1 to 3 carbon atoms. 5,574,060 3 4. The present invention further provides a compound hav wherein X, Y, and Z are independently H, Cl, Br, F, OCH, ing the structure: I, or an alkyl group having 1 to 6 carbon atoms; Rl is H, an alkyl or alkenyl group having 1 to 6 carbon atoms, or sy- CH: and R2 is wherein X is H, Cl, Br, F, OCH, I, or an alkyl group having X 1 to 6 carbon atoms; and R is 10 -(CH2) O Y -CH N -(CH2) Y 15 wherein n is 0 to 6, X" and Y are independently H, Cl, F.
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