Journal of Medicinal Chemistry, 2008, Vol. 51, No. 7 2033 NNN-(1, 7-Heptylenej-bis-(-)-nor-MEP Hydrochloride(5f. Subsequent salt for gave5j2HC1(0.47g,84%):m 2HCI).(-)-nor-MEP 8(1.70 g, 7.76 mmol), acetonitrile(20 mL) 108-112°C;[alb 0.29,MeOH);IRv3423,3180,2927 mL, 3.88 mmol)were used to produce 5f(0.73 g, 35%). Subsequent 10.13, 10.02(br s, 7/5 H, NH), 9.58, 9.55, 947, 9.45(s, 2H, salt formation gave 5f. 2HCI(0.70 g, 84%0): mp 125-128C; [alD Ar-OH, 8.41, 8.37(br s, 3/5H, NH), 7. 18-7.10(m, 2H, Ar-H), 429601801Rp34订2H0AOd)973522m6H,AB38(351HJ=141 Hz. N-C田H 1600,1585,1447,1268,1232cm H,J=13.7Hz,N-CH2),3.42-3.26(m,3H,N-CH2), brs,2/3H,NH),9.52,9.50,942,941(s,2H,Ar-OH,8.253.14-3.03(m,7H,N-CH2),2.37-232(m,H,CH2),2.10-1.97(m brs,4/3H,NH+),7.22-714(m,2H,Ar-H,687-666(m,6H,3H,CH2),1.82-1.70(m,12H,CH2),1.54-1.37(m,4H,CH2 413813341326:15且1+1+19mxAC1M图 CH2),2.13(m,4/5H,CH2),2.00-1.73(m,14H,CH2),1.53-1.4 591.4884: found,591.4901.HPLC:R=15.30min,98.9% purity m,4H,CH2),1.30(m,6H,CH2),0.50(m,6H,CH3);MS(ESD) N, N-(1, 12-Dodecydene)-bis-(-)-nor-MEP Hydrochloride M +H 535.8, [M 2H] 268.4. HRMS m/z calcd for (5k. 2HCI).(-)-nor-MEP 8(0.69 g, 3.15 mmol), acetonitrile(10 C3sHsN2O2[M+H+,535.4258; found,535.4258.HPC:R= mL), triethylamine(0.9 mL, 6.47 mmol), and 1, 12-dibromodode- 9.67 min, 99.4% purity cane(0.53 mL, 1.58 mmol) were used to produce 5k(0.34 g, 36%0) N,N-(1, 8-Octylene)-bis-(-j-nor-MEP Hydrochloride(5g 2HCI).(-)-nor-MEP 8(0.94 g, 4.29 mmol), acetonitrile(10 mL), 0105Cab3720300340292128 triethylamine(1. 2 mL, 8.63 mmol), and 1, 8-dibromooctane(0.40 mL, 2.15 mmol)were used to produce 5g(0.43 g, 37%) Subsequent NH,), 9.49, 9.48, 9.40(s, 2H, Ar-OH), 8.23(br s, 2/3 H, NH), salt formation of 5g(0.31 g) gave 5g 2HCI(0. 29 g, 83%0): mp 7 19-7.11(m, 2H, Ar-H), 6.85-6.64(m, 6H, Ar-H), 3.82(d, 4/5 101-106°C;alb-37.8°(c0.099,MeOH;IRv3420.2936,H,J=13.7Hz,N-CH2),3.53(d,6/5H,J=13.3H2,N-CH2), 1600,1447,1269cm-1;HNMR①DMSO-d6)10.11,9.95(brs,3.37-3.30(m,3HN-CH2),3.15-305(m,7HN-CH),236-231 43H,NH,9.57,9.54,9.45,9.43(s,2H,Ar-OH,8.43,8.35(m,H,CH2),2.10(m,HCH2),1.81-1.70(m,14H,CH2),152-1.42 brs,23H,NH),719-7.11(m,2H,Ar-H,6.85-664(m,6H (m,4H,CH2),1.27-1.24(m,16H,CH2),0.48(m,6H,CHy);Ms Ar-H),3.8l(d,2/3H,J=14.1Hz,N-CH2),3.53(d,4/3H,J (ESD[M+ H+ 605.3. HRMS m/z caled for CaoH6sN2O2[M 13.7Hz,N-CH2),3.35-3.28(m,3H,N-CH2),3.15-3.05(m,7H,H,605.5041; found,605.5054.HPLC:lg=19.73min,96.1% N-CH2),2.38-2.33(m,H,CH2),2.11-1.96(m,3H,CH2), punty 80-1.70(m,12H,CH2),1.51-1.4l(m,4H,CH2),1.28-1.24(m, General Procedure for the Synthesis of Intermediate Am- 8H, CH2), 0.47(t, 6H,J=7.4 Hz, CH3): MS(ESI)[M+ HI ide Compounds 9c, d. Triethylamine(2 equiv) was added to a 5494, [M+2H]275.2. HRMS m/z calcd for C36Hs7 IM+ solution of (-)-nor-MEP 8 in dry CH2Cl. Then a, o-alkanediacyl dihalide(0.5 equiv) in dry CH2Cl2 was added dropwise at 0 The mixture was stirred for 15 min at oC. The mixture was washed NNN-(1,9-Nonylene)-bis-(-)-nor-MEP Hydrochloride(5h. with H20 (5 mL), 2 M HCI(8 mL), and then H2o (5 mL). The 2HCI(-)-nor-MEP 8(0.89 g, 4.06 mmol), acetonitrile(10 mL), combined water layers were back-extracted with CH2C1z(10 mL triethylamine(1. 2 mL, 8.62 mmol), and 1, 9-dibromononane(0.42 x 3). All the CH2Cl2 layers were combined and dried with mL, 2.03 mmol) were used to produce 5h(0.71 g, 62%0) Subsequent anhydrous Na2SO4. Evaporation of the solvent under reduced salt formation of sh(0.67 g) gave 5h 2HCI(0.62 g, 82%o): mp pressure gave a yellowish foam. Purification by chromatography 118-124C; aI-3913( 0.32, MeOH); IR v 3423, 2934, 1600. on silica gel eluted with petroleum ether/EtOAc (1: 3) afforded the 1585,1446,1268cm-; H NMR(DMSO-d6)10.10,995brs, mide intermediates 9c.d as a white foan 43H,NH,9.56,9.54,9.44(s,2H,Ar-OH,8.41,8.34(brs, N, N-(1,, 4-Succinyl)-bis-(-j-nor-MEP (9c).(-)-nor-MEP 8 2/3H,NH,7.19-7.11(m,2H,Ar-H),6846.64(m,6H,Ar-H (1.45 g, 6.63 mmol), CH2Cl2(35 mL), triethylamine(1.84 mL. 12.2 3.82(d, 2/3 H, J= 14.1 Hz, N-CH2), 3.53(d, 4/3 H, J=13.7 mmol), and succinyl chloride(0.382 mL, 3.30 mmol) were used to Hz,N-CH2),3.38-3.27(m,3H,N-CH2),3.15-3.04m,阻H, produce 9e(0.73g,41%).IRv3170.2966,2936,1737,1614 N-CH2),2.38-2.32(m,H,CH2),2.10-2.01(m,3H,CH2),1596,145,1427,1266,1238,1202cm-1;HNMR(DMSO-d6) 1.79-1.70(m,12H,CH2),1.541.41(m,4H,CH2),1.29-1.27(m,8.79(s,2H,Ar-OH),7.19(t,2H,Ar-H),678-6.70(m,6H, 10H,CH2),O.47(t,6H,J=74Hz,CH);MS(ESD[M+HAr-H,4.88(d,2H,J=14.7Hz,N-CH2),3.59(d,2H,J1= 563.5, M+ 2H]- 282.3 HRMS m/z caled for C37HsgN2O M 117Hz,2=7.0Hz,N一CH2),3.08(d,2H,J=15.0Hz,N-CH2 H+,5634571; found,5634553.HPC:k=15.98min,98.4%21(t,2H,J=1.7Hz,CH2),283(d,2H,J=136Hz,N-CH2), 2.39(dm,2H,J=77Hz,N-CH2),2.33(d,2H,J=13.2Hz, N, N-(1, 10-Decylene-bis-(-)-nor-MEP Hydrochloride (5i N-CH2),1.82-1.48(m,14H,CH2),0.68(t,6H,J=73Hz,CH3); 2HCI(-)-nor-MEP 8(0.83 g, 3.78 mmol), acetonitrile(10 mL), MS (ESD)[M+ H 521.3 triethylamine(1. 1 mL, 7.91 mmol), and 1, 10-dibromodecane(043 NNN-(1, 5-Glutaryl)-bis-(-)-nor-MEP (9d).(-)-nor-MEP 8 mL, 1.89 mmol) were used to produce 5i(0.51 g, 47%) Subsequent (1.59 g, 7.26 mmol), CH2Cl>(35 mL), triethylamine(2.02 mL, 14.4 salt formation of 5i(0.47 g) gave 5i 2HCI(0.45 g, 85%): mp mmol), and glutaryl chloride(0.481 mL, 3.63 mmol) were used to 2856,2733,1600,1585,1447,1269,1230cm-; H NMR(DMSO-1443,1264cm-;HNMR(CDCl3)8.54,8.10,7.777.52brs d6)10.09,9.94(brs,4/3H,NH),9.57,9.54,946,945(s,2H,4,2H,Ar-OH,7.17(t,2H,Ar-H,7.05-693(m,2H,Ar-H Ar-OH,841,8.34(brs,2/3H,NH+),7.18-7.11(m,2H,Ar-H),6.82-6.70(m,4H,Ar-H,4.53(d,H,J=149Hz,N-CH2) 6846.64(m,6H,Ar-H),3.82(d,2/3H,J=14.5Hz,N-CH2),3.75-349(m,3H,N-CH2),3.41-3.18(m,2HN-CH2),299-294 3.52(d,4/3H,J=14.1Hz,N-CH2),3.36-3.27(m,3H,N一CH2),(m,H,N-CH2),2.54-2.46(m,H,N-CH2),2.34-2.17(m,4H, 3.14-3.03(m,7H,N-CH2),2.38-2.32(m,H,CH2),2.13-1.95(m,CO-CH2),1.93-1.50(m,18H,CH2),0.62-0.51(m,6H,CH3);MS H,CH2,1.79-1.70(m,12H,CH2),1.54-1.41(m,4H,CH2),( ESDM+H]+5353 1.28-1.25(m,12H,CH2),0.47(t,6H,J=7.0Hz,CH3);MS(ESD General Procedure for the Synthesis of Bis-(-)-nor-MEP [M H+ 577.5, [M 2H]2+ 289.3. HRMS m/z calcd for C Compounds 5e, d. A solution of ge, d in dry THF was added C3sH6IN202 [M+ H, 577.4728: found, 577. 4747. HPLC: IR dropwise to lithium aluminum hydride (5 equiv) in dry THF at 22 13 min, 98.9% purity room temperature. The mixture was refluxed for 1 h, and then H2O NNN-(1,11'-Undecydene)-bis-(-)-nor-MEP Hydrochloride 15% NaOH. and H,O were added. The mixture was stirred for 15 (5j 2HCI(-)-nor-MEP 8(0.78 g, 3.56 mmol), acetonitrile (10 min at room temperature. The mixture was filtered, and the solid mL), triethylamine(1.0 mL, 7.20 mmol), and 1, 1l-dibromounde- material was washed with THF. The combined THF solution was cane(0.418 mL, 1.78 mmol) were used to produce 5j(0.50 g, 48%0). evaporated to remove solvents. The residue was treated with H2ON,N′-(1′,7′-Heptylene)-bis-(-)-nor-MEP Hydrochloride (5f· 2HCl). (-)-nor-MEP 8 (1.70 g, 7.76 mmol), acetonitrile (20 mL), triethylamine (2.2 mL, 15.8 mmol), and 1,7-dibromoheptane (0.674 mL, 3.88 mmol) were used to produce 5f (0.73 g, 35%). Subsequent salt formation gave 5f· 2HCl (0.70 g, 84%): mp 125-128 °C; [R]D -44.29° (c 0.218, MeOH); IR ν 3417, 3186, 2938, 2866, 2740, 1600, 1585, 1447, 1268, 1232 cm-1 ; 1 H NMR (DMSO-d6) 9.70 (br s, 2/3 H, NH+), 9.52, 9.50, 9.42, 9.41 (s, 2H, Ar-OH), 8.25 (br s, 4/3 H, NH+), 7.22–7.14 (m, 2H, Ar-H), 6.87–6.66 (m, 6H, Ar-H), 3.85 (d, 4/5 H, J ) 14.1 Hz, N-CH2), 3.56 (d, 6/5 H, J ) 14.1 Hz, N-CH2), 3.39–3.01 (m, 10H, N-CH2), 2.40 (m, 6/5 H, CH2), 2.13 (m, 4/5 H, CH2), 2.00–1.73 (m, 14H, CH2), 1.53–1.45 (m, 4H, CH2), 1.30 (m, 6H, CH2), 0.50 (m, 6H, CH3); MS (ESI) [M + H]+ 535.8, [M + 2H]2+ 268.4. HRMS m/z calcd for C35H55N2O2 [M + H]+, 535.4258; found, 535.4258. HPLC: tR ) 9.67 min, 99.4% purity. N,N′-(1′,8′-Octylene)-bis-(-)-nor-MEP Hydrochloride (5g · 2HCl). (-)-nor-MEP 8 (0.94 g, 4.29 mmol), acetonitrile (10 mL), triethylamine (1.2 mL, 8.63 mmol), and 1,8-dibromooctane (0.406 mL, 2.15 mmol) were used to produce 5g (0.43 g, 37%). Subsequent salt formation of 5g (0.31 g) gave 5g · 2HCl (0.29 g, 83%): mp 101-106 °C; [R]D -37.8 ° (c 0.099, MeOH); IR ν 3420, 2936, 1600, 1447, 1269 cm-1 ; 1 H NMR (DMSO-d6) 10.11, 9.95 (br s, 4/3 H, NH+), 9.57, 9.54, 9.45, 9.43 (s, 2H, Ar-OH), 8.43, 8.35 (br s, 2/3 H, NH+), 7.19–7.11 (m, 2H, Ar-H), 6.85–6.64 (m, 6H, Ar-H), 3.81 (d, 2/3 H, J ) 14.1 Hz, N-CH2), 3.53 (d, 4/3 H, J ) 13.7 Hz, N-CH2), 3.35–3.28 (m, 3H, N-CH2), 3.15–3.05 (m, 7H, N-CH2), 2.38–2.33 (m, H, CH2), 2.11–1.96 (m, 3H, CH2), 1.80–1.70 (m, 12H, CH2), 1.51–1.41 (m, 4H, CH2), 1.28–1.24 (m, 8H, CH2), 0.47 (t, 6H, J ) 7.4 Hz, CH3); MS (ESI) [M + H]+ 549.4, [M + 2H]2+ 275.2. HRMS m/z calcd for C36H57N2O2 [M + H]+, 549.4415; found, 549.4428. HPLC: tR ) 12.25 min, 97.9% purity. N,N′-(1′,9′-Nonylene)-bis-(-)-nor-MEP Hydrochloride (5h · 2HCl). (-)-nor-MEP 8 (0.89 g, 4.06 mmol), acetonitrile (10 mL), triethylamine (1.2 mL, 8.62 mmol), and 1,9-dibromononane (0.423 mL, 2.03 mmol) were used to produce 5h (0.71 g, 62%). Subsequent salt formation of 5h (0.67 g) gave 5h · 2HCl (0.62 g, 82%): mp 118-124 °C; [R]D -39.13° (c 0.32, MeOH); IR ν 3423, 2934, 1600, 1585, 1446, 1268 cm-1 ; 1 H NMR (DMSO-d6) 10.10, 9.95 (br s, 4/3 H, NH+), 9.56, 9.54, 9.44 (s, 2H, Ar-OH), 8.41, 8.34 (br s, 2/3 H, NH+), 7.19–7.11 (m, 2H, Ar-H), 6.84–6.64 (m, 6H, Ar-H), 3.82 (d, 2/3 H, J ) 14.1 Hz, N-CH2), 3.53 (d, 4/3 H, J ) 13.7 Hz, N-CH2), 3.38–3.27 (m, 3H, N-CH2), 3.15–3.04 (m, 7H, N-CH2), 2.38–2.32 (m, H, CH2), 2.10–2.01 (m, 3H, CH2), 1.79–1.70 (m, 12H, CH2), 1.54–1.41 (m, 4H, CH2), 1.29–1.27 (m, 10H, CH2), 0.47 (t, 6H, J ) 7.4 Hz, CH3); MS (ESI) [M + H]+ 563.5, [M + 2H]2+ 282.3. HRMS m/z calcd for C37H59N2O2 [M + H]+, 563.4571; found, 563.4553. HPLC: tR ) 15.98 min, 98.4% purity. N,N′-(1′,10′-Decylene)-bis-(-)-nor-MEP Hydrochloride (5i · 2HCl). (-)-nor-MEP 8 (0.83 g, 3.78 mmol), acetonitrile (10 mL), triethylamine (1.1 mL, 7.91 mmol), and 1,10-dibromodecane (0.438 mL, 1.89 mmol) were used to produce 5i (0.51 g, 47%). Subsequent salt formation of 5i (0.47 g) gave 5i · 2HCl (0.45 g, 85%): mp 104-108 °C; [R]D -38.43° (c 0.27, MeOH); IR ν 3417, 3176, 2932, 2856, 2733, 1600, 1585, 1447, 1269, 1230 cm-1 ; 1 H NMR (DMSO￾d6) 10.09, 9.94 (br s, 4/3 H, NH+), 9.57, 9.54, 9.46, 9.45 (s, 2H, Ar-OH), 8.41, 8.34 (br s, 2/3H, NH+), 7.18–7.11 (m, 2H, Ar-H), 6.84–6.64 (m, 6H, Ar-H), 3.82 (d, 2/3 H, J ) 14.5 Hz, N-CH2), 3.52 (d, 4/3 H, J ) 14.1 Hz, N-CH2), 3.36–3.27 (m, 3H, N-CH2), 3.14–3.03 (m, 7H, N-CH2), 2.38–2.32 (m, H, CH2), 2.13–1.95 (m, 3H, CH2), 1.79–1.70 (m, 12H, CH2), 1.54–1.41 (m, 4H, CH2), 1.28–1.25 (m, 12H, CH2), 0.47 (t, 6H, J ) 7.0 Hz, CH3); MS (ESI) [M + H]+ 577.5, [M + 2H]2+ 289.3. HRMS m/z calcd for C38H61N2O2 [M + H]+, 577.4728; found, 577.4747. HPLC: tR ) 22.13 min, 98.9% purity. N,N′-(1′,11′-Undecydene)-bis-(-)-nor-MEP Hydrochloride (5j· 2HCl). (-)-nor-MEP 8 (0.78 g, 3.56 mmol), acetonitrile (10 mL), triethylamine (1.0 mL, 7.20 mmol), and 1,11-dibromounde￾cane (0.418 mL, 1.78 mmol) were used to produce 5j (0.50 g, 48%). Subsequent salt formation gave 5j· 2HCl (0.47 g, 84%): mp 108-112 °C; [R]D -38.53° (c 0.29, MeOH); IR ν 3423, 3180, 2927, 2856, 1600, 1585, 1446, 1267, 1232 cm-1 ; 1 H NMR (DMSO-d6) 10.13, 10.02 (br s, 7/5 H, NH+), 9.58, 9.55, 9.47, 9.45 (s, 2H, Ar-OH), 8.41, 8.37 (br s, 3/5 H, NH+), 7.18–7.10 (m, 2H, Ar-H), 6.84–6.64 (m, 6H, Ar-H), 3.81 (d, 3/5 H, J ) 14.1 Hz, N-CH2), 3.52 (d, 7/5 H, J ) 13.7 Hz, N-CH2), 3.42–3.26 (m, 3H, N-CH2), 3.14–3.03 (m, 7H, N-CH2), 2.37–2.32 (m, H, CH2), 2.10–1.97 (m, 3H, CH2), 1.82–1.70 (m, 12H, CH2), 1.54–1.37 (m, 4H, CH2), 1.27–1.24(m, 14H, CH2), 0.47 (t, 6H, J ) 7.4 Hz, CH3); MS (ESI) [M + H]+ 591.3. HRMS m/z calcd for C39H63N2O2 [M + H]+, 591.4884; found, 591.4901. HPLC: tR ) 15.30 min, 98.9% purity. N,N′-(1′,12′-Dodecydene)-bis-(-)-nor-MEP Hydrochloride (5k · 2HCl). (-)-nor-MEP 8 (0.69 g, 3.15 mmol), acetonitrile (10 mL), triethylamine (0.9 mL, 6.47 mmol), and 1,12-dibromodode￾cane (0.53 mL, 1.58 mmol) were used to produce 5k (0.34 g, 36%). Salt formation of 5k (0.58 g) gave 5k · 2HCl (0.49 g, 80%): mp 100-105 °C; [R]D -35.77° (c 0.30, MeOH); IR ν 3419, 2927, 2855, 1600, 1585, 1446, 1269; 1 H NMR (DMSO-d6) 10.00 (br s, 4/3 H, NH+), 9.49, 9.48, 9.40 (s, 2H, Ar-OH), 8.23 (br s, 2/3 H, NH+), 7.19–7.11 (m, 2H, Ar-H), 6.85–6.64 (m, 6H, Ar-H), 3.82 (d, 4/5 H, J ) 13.7 Hz, N-CH2), 3.53 (d, 6/5 H, J ) 13.3 Hz, N-CH2), 3.37–3.30 (m, 3H, N-CH2), 3.15–3.05 (m, 7H, N-CH2), 2.36–2.31 (m, H, CH2), 2.10 (m, H, CH2), 1.81–1.70 (m, 14H, CH2), 1.52–1.42 (m, 4H, CH2), 1.27–1.24 (m, 16H, CH2), 0.48 (m, 6H, CH3); MS (ESI) [M + H]+ 605.3. HRMS m/z calcd for C40H65N2O2 [M + H]+, 605.5041; found, 605.5054. HPLC: tR ) 19.73 min, 96.1% purity. General Procedure for the Synthesis of Intermediate Am￾ide Compounds 9c,d. Triethylamine (2 equiv) was added to a solution of (-)-nor-MEP 8 in dry CH2Cl2. Then R,ω-alkanediacyl dihalide (0.5 equiv) in dry CH2Cl2 was added dropwise at 0 °C. The mixture was stirred for 15 min at 0 °C. The mixture was washed with H2O (5 mL), 2 M HCl (8 mL), and then H2O (5 mL). The combined water layers were back-extracted with CH2Cl2 (10 mL × 3). All the CH2Cl2 layers were combined and dried with anhydrous Na2SO4. Evaporation of the solvent under reduced pressure gave a yellowish foam. Purification by chromatography on silica gel eluted with petroleum ether/EtOAc (1:3) afforded the amide intermediates 9c,d as a white foam. N,N′-(1′,4′-Succinyl)-bis-(-)-nor-MEP (9c). (-)-nor-MEP 8 (1.45 g, 6.63 mmol), CH2Cl2 (35 mL), triethylamine (1.84 mL, 12.2 mmol), and succinyl chloride (0.382 mL, 3.30 mmol) were used to produce 9c (0.73 g, 41%). IR ν 3170, 2966, 2936, 1737, 1614, 1596, 1455, 1427, 1266, 1238, 1202 cm-1 ; 1 H NMR (DMSO-d6) 8.79 (s, 2H, Ar-OH), 7.19 (t, 2H, Ar-H), 6.78–6.70 (m, 6H, Ar-H), 4.88 (d, 2H, J ) 14.7 Hz, N-CH2), 3.59 (dd, 2H, J1 ) 11.7 Hz, J2 ) 7.0 Hz, N-CH2), 3.08 (d, 2H, J ) 15.0 Hz, N-CH2), 2.91 (t, 2H, J ) 11.7 Hz, CH2), 2.83 (d, 2H, J ) 13.6 Hz, N-CH2), 2.39 (dm, 2H, J ) 7.7 Hz, N-CH2), 2.33 (d, 2H, J ) 13.2 Hz, N-CH2), 1.82–1.48 (m, 14H, CH2), 0.68 (t, 6H, J ) 7.3 Hz, CH3); MS (ESI) [M + H]+ 521.3. N,N′-(1′,5′-Glutaryl)-bis-(-)-nor-MEP (9d). (-)-nor-MEP 8 (1.59 g, 7.26 mmol), CH2Cl2 (35 mL), triethylamine (2.02 mL, 14.4 mmol), and glutaryl chloride (0.481 mL, 3.63 mmol) were used to produce 9d (0.74 g, 38%). IR ν 3383, 2933, 2877, 1616, 1583, 1443, 1264 cm-1 ; 1 H NMR (CDCl3) 8.54, 8.10, 7.77, 7.52 (brs × 4, 2H, Ar-OH), 7.17 (t, 2H, Ar-H), 7.05–6.93 (m, 2H, Ar-H), 6.82–6.70 (m, 4H, Ar-H), 4.53 (d, H, J ) 14.9 Hz, N-CH2), 3.75–3.49 (m, 3H, N-CH2), 3.41–3.18 (m, 2H, N-CH2), 2.99–2.94 (m, H, N-CH2), 2.54–2.46 (m, H, N-CH2), 2.34–2.17 (m, 4H, CO-CH2), 1.93–1.50 (m, 18H, CH2), 0.62–0.51 (m, 6H, CH3); MS (ESI) [M + H]+ 535.3. General Procedure for the Synthesis of Bis-(-)-nor-MEP Compounds 5c,d. A solution of 9c,d in dry THF was added dropwise to lithium aluminum hydride (5 equiv) in dry THF at room temperature. The mixture was refluxed for 1 h, and then H2O, 15% NaOH, and H2O were added. The mixture was stirred for 15 min at room temperature. The mixture was filtered, and the solid material was washed with THF. The combined THF solution was evaporated to remove solvents. The residue was treated with H2O Bis-(-)-nor-meptazinols as Inhibitors Journal of Medicinal Chemistry, 2008, Vol. 51, No. 7 2033