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United States Patent (19) 11 Patent Number: 5,747,503 Rothman Et Al

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United States Patent (19) 11 Patent Number: 5,747,503 Rothman Et Al IIIIUSOO5747503A United States Patent (19) 11 Patent Number: 5,747,503 Rothman et al. 45) Date of Patent: May 5, 1998 54). SELECTIVE INHIBITORS OF BIOGENIC Attorney, Agent, or Firin-Morgan & Finnegan, L.L.P. AMINE TRANSPORTERS 57 ABSTRACT 75) Inventors: Richard Rothman, Silver Spring, Md.; The present invention provides a compound having the Frank I. Carroll, Durham, N.C.; Bruce Structure: Blough, Raleigh, N.C.; Samuel W. Mascarella, Hillsborough, N.C. 73 Assignees: The United States of America as represented by the Department of Health and Human Services, Washington, D.C.; Research Triangle Institute. Research Triangle Park, N.C. 21 Appl. No.: 746,517 22 Filled: Nov. 12, 1996 wherein X, Y, and Z are independently H. C. Br. F. OCH Related U.S. Application Data I. or an alkyl group having 1 to 6 carbon atoms; and R is 60) Division of Ser. No. 203.222, Feb. 28, 1994, Pat. No. X 5,574,060, which is a continuation-in-part of Ser. No. 105, 747, Aug. 12, 1993, abandoned, -(CH2) or -CH S (51) Int. Cl. ...................... C07D 221/22; A61K 31f46 Y (52) U.S. Cl. ............................ 514/294: 514/299; 546/94: 546/95; 54.6/112:546/183 wherein n is 0 to 6, X and Y are independently H.C. F. 58) Field of Search ..................................... 54.6/112, 183, CH, CH, CH, CH, OCH, OH, CF. OCF. NO. 546/94, 95: 514/294, 299 NH, N(CH), NHCOCH, NCS. NHCOCHBr, or N, and (CH), if present, may be substituted with OH, OCH oran 56) References Cited alkyl or alkenyl group having 1 to 3 carbon atoms. The present invention also provides a pharmaceutical composi PUBLICATIONS tion comprising the compound above and a pharmaceuti Kametani et al., "Studies on . Benzazocine”, Journal of cally acceptable carrier. The present invention further pro Heterocyclic Chemistry, vol. 10 (1973), pp. 291-295. vides a method for treating a disease characterized by a Blough et. al., “Synthesis of . Benzazocine”, Journal of dopamine deficiency which comprises administering to a Chem. Soc., Chem. Comm., No. 9 (1993), pp. 758-760. subject in need of such treatment an amount of the pharma Primary Examiner-Matthew V. Grumbling ceutical composition above effective to treat the disease. Assistant Examiner Tamthom T. Ngo 70 Claims, 5 Drawing Sheets U.S. Patent 5,747,503 U.S. Patent May 5, 1998 Sheet 2 of 5 5,747,503 FIGURE 2 1. Dess-Martin's CHNHCHCOCH reagent, CHC toluene, 100°C 2. (CHS)P=CH l COH H H 21 H toluene,semimm 10°C CO CXu H N S / 3C 7 CH3 CHNHCH(R)COH. 10°C HCH-OHPo/C C. C H H n R 3e H y CH CH 3a, Rich b, R=CHCH U.S. Patent May 5, 1998 Sheet 3 of 5 5,747,503 FIGURE 3 120 00 80 60 40 20 -45 - 15 15 45 75 105 135 165 195 Time (min) U.S. Patent May 5, 1998 Sheet 4 of 5 5,747,503 FIGURE 4 30 R. 4793-4 20 O O -45 -30 - 15 0 15 30 45 60 75 Time (min) 5,747.503 1 SELECTIVE INHIBITORS OF BIOGENIC AMNE TRANSPORTERS This is a divisional of application Ser. No. 08/203.222 filed Feb. 28, 1994, U.S. Pat. No. 5,574,060 which is a continuation-in-part of Ser. No. 08/105.747, filed Aug. 12. 1993, now abandoned. SUMMARY OF THE INVENTION BACKGROUND OF THE INVENTION O The present invention provides a compound having the H1-1-(2-thienyl)cyclohexylcyclohexyl-piperidine Structure (TCP). an analog of the dissociative anesthetic phencyclid ine (PCP), binds with high affinity to two sites in guinea pig brain membranes, one of which is MK-801 sensitive and one of which is not. The MK-801-sensitive site (PCP site 1) is 5 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. Pharmacol. 36: 887-896 (1989); Akunne. H. C. et al. Synapse 8: 289-300 (1991); Rothman. R. B., et al. In: Multiple Sigma and PCP Receptor Ligands: Mechanisms for wherein X, Y, and Z are independently H, Cl, Br, F. OCH Neuromodulation and Protection, pp. 137-146 (Domino, E. I, or an alkyl group having 1 to 6 carbon atoms; R1 is H. an F. and Kamenka, J. M., eds., 1992); Akunne, H. C., et al. alkyl or alkenyl group having 1 to 6 carbon atoms, or Neurochen. Res. 17:261-264 (1992)). 25 Based upon the association of PCP site 2 with BATs. a 7- CH2; drugs with high affinity for PCP site 2 would be expected to inhibit the reuptake of biogenic amines. and R2 is The present invention is directed to classes of compounds 30 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 -(CH2) indeno. 1.2-blpyrrole (RTI-4793-14) represents the first of -CH N these compounds which bind with high affinity to biogenic 35 y amine transporters but are relatively less potent amine reuptake blockers than classical BAT ligands. This com wherein n is 0 to 6, X and Y are independently H. Cl, F, pound has been shown to increase the levels of dopamine in CH, CH5, CH, CH, OCH, OH. CF. OCF, NO. NHN(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: PCP site 2 because of its high affinity and selectively for PCP site 2. 45 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 (see also Chemical Abstracts, vol. 62, No. 528(g) (1965)). Some of these compounds have antispasmatic or tranquil 50 izing properties. R2 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 -(CH), or -CH S De and Saha disclosed ideno 1.2-blpyrroles having the structure below wherein R is an alkyl group such as methyl, Y ethyl, propyl, butyl, or pentyl (De, A.U. and Saha, B. P. J. wherein n is 0 to 6, X and Y are independently H. C. F. Pharm. Sci. 62(8): 1363-1364 (1973); CH, CH, CH, CH, OCH, OH, CF. OCF, NO. De, A.U. and Saha, B. P. J. Pharm. Sci. 64(2): 249-252 65 NHN(CH). NHCOCH NCS. NHCOCHBr, or N. and (1975)). These compounds were screened as possible oral (CH), if present, may be substituted with OH, OCH or an hypoglycemic agents. alkyl or alkenyl group having 1 to 3 carbon atoms. 5,747,503 3 4 The present invention further provides a compound hav alkyl or alkenyl group having 1 to 6 carbon atoms, or ing the structure: a 7- CH; and R2 is wherein X is H. Cl, Br, FOCH, I, or an alkyl group having 10 1 to 6 carbon atoms; and R is -(CH2) o -CH Y -(CH), wherein n is 0 to 6. X and Y are independently H. Cl, F. 15 CH, CH, CH, CH, OCH, OH. CF. OCF, NO. Y NHN(CH). NHCOCH NCS. NHCOCHBr, or N, and (CH2) if present, may be substituted with OH, OCH oran wherein n is 0 to 6, X and Y are independently H. Cl. F. alkyl or alkenyl group having 1 to 3 carbon atoms. The CH, CH, CH, CH, OCH, OH. CF. OCF, NO. compounds of the present invention may exist in (2R, 3aS, NH, N(CH,) NHCOCH, NCS, NHCOCHBr, or N, and 20 8aR)-, (2S. 3aS. 8aR)-. (2R, 3aR. 8aS)-, or (2S, 3aR, (CH), if present, may be substituted with OH. OCH oran 8aS)-isomers, or mixtures thereof. alkyl or alkenyl group having 1 to 3 carbon atoms. In the preferred embodiment, R2 is a substituted or The present invention also provides a pharmaceutical unsubstituted benzyl group. The benzyl group may be sub composition comprising one of the compounds above and a stituted with one or more of the following: H. C1. F. CH. pharmaceutically acceptable carrier. 25 CH, CH, CH, OCH, OH, CF. OCF, NO. NH2. N(CH), NHCOCH. NCS. NHCOCHBr, or N. In the Lastly, the present invention provides a method for treat more preferred embodiment, R1 is methyl and R2 is benzyl. ing a disease characterized by a dopamine deficiency which Most preferably, R1 is methyl. R2 is benzyl, and X, Y, and comprises administering to a subject in need of such treat Z are hydrogen. ment an amount of the pharmaceutical composition above The present invention also provides a compound having effective to treat the disease. the structure: BRIEF DESCRIPTION OF THE FIGURES FIG. 1. Schematic diagram for the synthesis of o-allylbenzaldehyde. FIG. 2. Schematic diagram for the synthesis of 35 hexahydro-1-methylindeno. 1.2-blpyrroles. FIG. 3. In vivo microdialysis of extracellular dopamine in the nucleus accumbens at concentrations of 1, 10, and 100 M of RTI-4793-14.
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