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Ep 0790250 A2 Patentamt Europaisches || || 1 1| || || || 1 1| || 1 1|| 1 1 1| (19) J European Patent Office Office europeen des brevets (11) EP 0 790 250 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication:ation: (51) |nt. ci.6: C07D 471/08, A61 K 31/435 20.08.1997 Bulletin 1997/34 (21) Application number: 97107218.6 (22) Date of filing: 11.08.1994 (84) Designated Contracting States: • RESEARCH TRIANGLE INSTITUTE AT BE CH DE DK ES FR GB GR IE IT LI LU MC NL Research Triangle Park, NC 27709-21 94 (US) PTSE (72) Inventor: (30) Priority: 12.08.1993 US 105747 The designation of the inventor has not yet bee 28.02.1 994 US 203222 n filed (62) Document number(s) of the earlier application(s) in (74) Representative: VOSSI US & PARTNER accordance with Art. 76 EPC: Siebertstrasse 4 94925860.2 / 0 71 3 484 81 675 Munchen (DE) (71) Applicants: Remarks: This application was filed on 30 - 04 - 1 997 as a THE GOVERNMENT OF THE UNITED STATES O divisional application to the application mentioned F AMERICA, as represented by THE SECRETAR under INID code 62. Y, DEPARTMENT OF HEALTH AND HUMAN SER VICES Rockville, MD 20852 (US) (54) Inhibitors of biogenic amine transporters (57) The present invention provides a compound having the following structure CM The present invention also provides a pharmaceutical composition comprising the compound above and a pharma- ^ ceutically acceptable carrier. The present invention further provides a method for treating a disease characterized by a q dopamine deficiency which comprises administering to a subject in need of such treatment an amount of the pharma- lO ceutical composition above effective to treat the disease. CM O <7> o Q_ LU Printed by Rank Xerox (UK) Business Services 2.14.12/3.4 EP 0 790 250 A2 Description This is a continuation-in-part of copending application Serial No. 08/105,747, filed August 12, 1993, the contents of which is hereby incorporated by reference. Background of the Invention [3H]1-[1-(2-thienyl)cyclohexyl]cyclohexyl]piperidine (TCP), an analog of the dissociative anesthetic phencyclidine (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 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., etal. Synapse 8: 289-300 (1991); Rothman, R.B., etal., In: Multiple Sigma and PCP Receptor Ligands: Mechanisms for Neuromodulation and Protection, pp. 137-146 (Domino, E.F. and Kamenka, J.M., eds., 1992); Akunne, H.C., et al. Neurochem. Res. 17: 261-264 (1992)). Based upon the association of PCP site 2 with BATs, drugs with high affinity for PCP site 2 would be ejected to inhibit the reuptake of biogenic amines. The present invention is directed to classes of compounds which bind selectively and potently to PCP site 2 and also have activity as biogenic amine transport blockers. (2RS, 3aSR, 8aRS)-1 ,2,3a,8,8a-Hexahydro-2-benzyl-1 -methyl- indeno[1 ,2-b]pyrrole (RTI-4793-14) represents the first of these compounds which bind with high affinity to biogenic amine transporters but are relatively less potent amine reuptake blockers than classical BAT ligands. This compound has been shown to increase the levels of dopamine in the brain and thus would be useful for treating diseases or disor- ders characterized by dopamine deficiency such as Parkinson's Disease and depression. The compound also would be useful in radioligand binding studies to label the PCP site 2 because of its high affinity and selectively for PCP 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 (see also Chemical Abstracts, vol. 62, No. 528(g) (1965)). Some of these compounds have antispasmatic or tranquilizing properties. HN R2 R1 De and Saha disclosed ideno [1 ,2-b]pyrroles having the structure below wherein R is an alkyl group such as methyl, ethyl, propyl, butyl, orpentyl (De, A.U. and Saha, B.R. J. Pharm. Sci.62(8): 1363-1364 (1973); De, A.U. and Saha, B.R, J. Pharm. Sci. 64(2): 249-252 (1975)). These compounds were screened as possible oral hypoglycemic agents. Summary of the Invention The present invention provides a compound having the structure: EP 0 790 250 A2 H H R2 R1 10 wherein X, Y, and Z are independently H, CI, Br, F, OCH3, I, or an alkyl group having 1 to 6 carbon atoms; R1 is H, an alkyl or alkenyl group having 1 to 6 carbon atoms, or 15 CH3; and R2 is 20 -<CH2)n or 25 wherein n is 0 to 6, X' and Y' are independently H, CI, F, CH3, C2H5, C3H7, C4H9, OCH3, OH, CF3, OCF3, N02, NH2, 30 N(CH3)2, NHCOCH3, NCS, NHCOCH2Br, or N3, and (CH2)n, if present, may be substituted with OH, OCH3, or an alkyl or alkenyl group having 1 to 3 carbon atoms. The present invention also provides a compound having the structure: 35 40 wherein X, Y, and Z are independently H, CI, Br, F, OCH3, I, or an alkyl group having 1 to 6 carbon atoms; and R is 45 •(CH2)n or 50 wherein n is 0 to 6, X' and Y' are independently H, CI, F, CH3, C2H5, C3H7, C4H9, OCH3, OH, CF3, OCF3, N02, NH2, N(CH3)2, NHCOCH3, NCS, NHCOCH2Br, or N3, and (CH2)n, if present, may be substituted with OH, OCH3, or an alkyl 55 or alkenyl group having 1 to 3 carbon atoms. The present invention further provides a compound having the structure: 3 EP 0 790 250 A2 X wherein X is H, CI, Br, F, OCH3, I, or an alkyl group having 1 to 6 carbon atoms; and R is -<CH2)n r wherein n is 0 to 6, X' and Y' are independently H, CI, F, CH3, C2H5, C3H7, C4H9, OCH3, OH, CF3, OCF3, N02, NH2, N(CH3)2, NHCOCH3, NCS, NHCOCH2Br, or N3, and (CH2)n, if present, may be substituted with OH, OCH3, or an alkyl or alkenyl group having 1 to 3 carbon atoms. The present invention also provides a pharmaceutical composition comprising one of the compounds above and a pharmaceutical^ acceptable carrier. Lastly, the present invention provides a method for treating a disease characterized by a dopamine deficiency which comprises administering to a subject in need of such treatment an amount of the pharmaceutical composition above effective to treat the disease. Brief Description of the Figures Figure 1. Schematic diagram for the synthesis of o-allylbenzaldehyde. Figure 2. Schematic diagram for the synthesis of hexahydro-1 -methylindeno[1 ,2-b]pyrroles. Figure 3. Jn vivo microdialysis of ertracellular dopamine in the nucleus accumbens at concentrations of 1 , 10, and 1 00 nM of RTI-4793-1 4. All values are mean + SEM (n=4). Group comparisons are made with one-way ANOVA and the Dunnetts t-test * p<0.05 and ** p<0.01. Figure 4. Effects of systemic RTI-4793-1 4 (5 mg/kg, i.v.) on extracellular dopamine in the nucleus accumbens. All values are mean + SEM (n=3). Group comparisons are made with one-way ANOVA and the Dunnetts t-test * p<0.05 and ** p<0.01. Figure 5. Schematic diagram for the synthesis of RTI-4793-41 and RTI-4793-48 compounds and analogs thereof. Detailed Description of the Invention The present invention provides a compound having the structure: X R1 wherein X, Y, and Z are independently H, CI, Br, F, OCH3, I, or an alkyl group having 1 to 6 carbon atoms; R1 is H, an alkyl or alkenyl group having 1 to 6 carbon atoms, or EP 0 790 250 A2 CH \7 2 ' 5 and R2 is 10 -(CH2) n or -CI 75 wherein n is 0 to 6, X' and Y' are independently H, CI, F, CH3, C2H5, C3H7, C4H9, OCH3, OH, CF3, OCF3, N02, NH2, N(CH3)2, NHCOCH3, NCS, NHCOCH2Br, or N3, and (CH2)n, if present, may be substituted with OH, OCH3, or an alkyl or alkenyl group having 1 to 3 carbon atoms. The compounds of the present invention may exist in (2R, 3aS, 8aR)-, (2S, 3aS, 8aR)-, (2R, 3aR, 8aS)-, or (2S, 3aR, 8aS)-isomers, or mixtures thereof. In the preferred embodiment, R2 is a substituted or unsubstituted benzyl group. The benzyl group may be substi- 20 tuted with one or more of the following: H, CI, F, CH3, C2H5, C3H7, C4H9, OCH3, OH, CF3, OCF3, N02, NH2, N(CH3)2, NHCOCH3, NCS, NHCOCH2Br, or N3. In the more preferred embodiment, R1 is methyl and R2 is benzyl. Most prefer- ably, R1 is methyl, R2 is benzyl, and X, Y, and Z are hydrogen. The present invention also provides a compound having the structure: 30 35 wherein X, Y, and Z are independently H, CI, Br, F, OCH3, I, or an alkyl group having 1 to 6 carbon atoms; and R is or 40 45 wherein n is 0 to 6, X' and Y' are independently H, CI, F, CH3, C2H5, C3H7, C4H9, OCH3, OH, CF3, OCF3, N02, NH2, N(CH3)2, NHCOCH3, NCS, NHCOCH2Br, or N3, and (CH2)n, if present, may be substituted with OH, OCH3, or an alkyl or alkenyl group having 1 to 3 carbon atoms.
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