Orvinol and thevinol derivatives useful in the treatment of drug and alcohol abuse, depression, anxiety, or a compulsive disorder
09890170 ยท 2018-02-13
Assignee
Inventors
Cpc classification
C07D489/12
CHEMISTRY; METALLURGY
International classification
C07D489/12
CHEMISTRY; METALLURGY
Abstract
The invention provides a method of treating drug and alcohol abuse, depression, anxiety, or a compulsive disorder in a subject comprising administering to the subject a compound having formula 2: ##STR00001##
or a pharmaceutically acceptable salt or solvate thereof, wherein R, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and X are as defined in the specification.
Claims
1. A compound of formula 2, or a pharmaceutically acceptable salt or solvate thereof, ##STR00054## wherein: R is H or alkyl R.sup.1 is alkyl or alkenyl; R.sup.2 is H; R.sup.4 and R.sup.5 are methyl; R.sup.3 is aryl or heteroaryl, either of which may be substituted or unsubstituted, and X is CH.sub.2CH.sub.2 or CHCH.
2. The compound of claim 1, wherein R is H.
3. The compound of claim 1, wherein R.sup.3 is unsubstituted or substituted phenyl, or unsubstituted or substituted pyridyl.
4. The compound of claim 3, wherein R.sup.3 is phenyl, optionally substituted with a halogen, methyl, hydroxyl or methoxy.
5. The compound of claim 3, wherein R.sup.3 is pyridyl, optionally substituted with a halogen, methyl, hydroxyl or methoxy.
6. The compound of claim 1, wherein R.sup.1 is n-propyl.
7. The compound of claim 1, wherein R.sup.1 is CH.sub.2CHCH.sub.2.
8. A composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or carrier.
9. A method of treating opiate abuse, alcohol abuse, cocaine abuse, depression, anxiety, or a compulsive disorder, the method comprising administering an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, to a human in need thereof.
10. The method of claim 9 for treating opiate abuse, alcohol abuse, or cocaine abuse.
11. The method of claim 10, wherein said treating prevents relapse of the opiate abuse, alcohol abuse, or cocaine abuse.
12. The method of claim 9 for treating depression.
13. The method of claim 9 for treating anxiety.
14. The method of claim 9 for treating a compulsive disorder.
15. A method of treating opiate abuse, alcohol abuse, cocaine abuse, depression, anxiety, or a compulsive disorder, the method comprising administering an effective amount of the composition of claim 8, or a pharmaceutically acceptable salt or solvate thereof, to a human in need thereof.
16. The method of claim 15 for treating opiate abuse, alcohol abuse, or cocaine abuse.
17. The method of claim 16, wherein said treating prevents relapse of the opiate abuse, alcohol abuse, or cocaine abuse.
18. The method of claim 15 for treating depression.
19. The method of claim 15 for treating anxiety.
20. The method of claim 15 for treating a compulsive disorder.
Description
EXPERIMENTAL
(1) The compounds can be prepared by, for example, the methods outlined in Schemes 1, 2, 3 and 4. These methods are illustrative of how secondary and tertiary alcohols are made in these series. The exact order of some the chemical steps may be varied (for example, when the nitrogen substituent is introduced).
(2) The compounds (structure 2), having R4=H, can be prepared as shown in Schemes 1 and 2 from N-cyclopropylmethyl-6,14-endoetheno-7-acetyltetrahydronorthebaine (5b) or N-cyclopropylmethyl-6,14-endoetheno-7-formyltetrahydronorthebaine (8b) by methods analogous to those described in British Patents GB969.263 and GB1.136.214. Thus the synthesis of series 1, with stereochemistry at C20 as depicted in 7, is shown in Scheme 1, with the equivalent compounds with opposite stereochemistry at C20 (Series 2, structure 15) shown in scheme 2. However an exception was found in the case of the synthesis of the C20-pryridyl analogues where instead of Grignard reagent the more reactive pyridyl lithium reagents had to be used. The result was that the predominant product had the stereochemistry of structure 15a instead of the expected structure 7a.
(3) The compounds of the invention, having R4=Me, are most readily prepared from N-cyclopropylcarbonyl northebaine (16) by a Diels-Alder reaction with methacrolein to give 17a and 17b. Addition of an aryl Grignard reagent to 17b provides secondary alcohols 18 and these can be converted to the diasteriomeric alcohols 20 by oxidation and reduction. The orvinol analogues 22 and 23 are then made by 3-O-demethylation using KOH, PrSNa or L-selectride (Scheme 3)
(4) Ethano bridged analogues are prepared by catalytic hydrogenation of adduct 17b and then equivalent chemistry to that described for the etheno series. (Scheme 4)
(5) ##STR00006##
(6) ##STR00007##
(7) ##STR00008##
(8) ##STR00009##
(9) Experimental Data on Compounds
(10) General Procedure A: Grignard Addition (Schemes 1 and 2)
(11) The Grignard reagents were prepared form the corresponding bromides (5 mmol) by reaction with magnesium (182 mg, 7.5 mmol) in anhydrous THF (5 ml) containing a crystal of iodine). The Grignard reagents were titrated prior to use by adding 1 ml of the Grignard solution to a flask containing 1,10-phenanthroline (2 mg) in anhydrous THF (2 ml) (purple solution) and titrating with 1M 2-butanol (anhydrous) in THF (end point pale yellow solution)]
(12) Grignard reagent (1 M in THF, 1.2 ml, 1.2 mmol) was treated dropwise at room temperature with a solution of 5 (500 mg) or 8 (500 mg) in anhydrous toluene (12 ml). After stirring at room temperature for 20 h, the reaction was quenched by addition of saturated aqueous ammonium chloride solution (20 ml). The phases were separated and the aqueous phase extracted with EtOAc. The combined organic phases were washed with saturated aqueous sodium bicarbonate, dried over MgSO.sub.4, filtered and evaporated in vacuo. The residue was purified by column chromatography over silica gel eluting with a gradient from 10% to 30% ethyl acetate in hexane. R.sub.f values are recorded from TLC eluted with 30:1:69 ethyl acetate/ammonia solution/hexane.
(13) General Procedure B. Grignard Addition (Schemes 3 and 4)
(14) To a solution of aldehyde 17b or 24 in dry THF (10 mL/mmol of aldehyde) were added 3 eq of Bu.sub.4NBr followed by 2 eq of arylmagnesium halide as solution in THF. The solution was then heated at reflux for 48 h, cooled to RT and quenched with 0.05 mL of water. The mixture was allowed to stir for 5 min then filtered over Celite. The solids were washed with hot THF, and the solution was removed of its solvent by rotary evaporation. The remaining residue was partitioned between EtOAc (20 mL) and water (10 mL). The water layer was extracted twice with 5 mL of EtOAc. The pooled organic solvent was washed twice with 5 mL of water, once with brine, dried over MgSO.sub.4, filtered and dried under reduced pressure. The residue was dissolved in a minimum amount of Et.sub.2O to induce crystallization. The crystals were collected by filtration, and dried under vacuum.
(15) General Procedure C. Swern Oxidation:
(16) A solution of oxalyl chloride (1.25 eq) in CH.sub.2Cl.sub.2 (3 mL/mmol) was cooled to 78 C. in a one neck flask. Into this flask was added dropwise, a solution of dry DMSO (2.6 eq) in CH.sub.2Cl.sub.2 (3 mL/mmol). The solution stirred for 5 min and then a solution 9, 18 or 25 in CH.sub.2Cl.sub.2 (2 mL/mmol) was added. The mixture stirred for 20 min and then Et.sub.3N (5 eq) was added. The reaction was removed from the cold bath, stirred for 1 h and water was added. The mixture was shaken, the organic layer was separated and washed with a saturated solution of NH.sub.4Cl, then with a concentrated solution of NaHCO.sub.3. The solution was washed once more with brine, dried over magnesium sulfate, filtered, and the solvents removed under reduced pressure to yield crude 11, 19 or 26 as a clear residue.
(17) General Procedure D. LiAlH.sub.4 Reduction
(18) Substrate (11, 18, 19, 25 or 26) was dissolved in dry THF (10 mL/mmol) and added to a stirring suspension of LiAlH.sub.4 (4 eq) in dry THF (5 mL/mmol) at 0 C. The suspension was allowed to warm up to RT and was stirred for 24 h. The reaction was cooled to 0 C. and quenched with water in THF. The mixture was filtered, rinsing the solids with hot THF. The solution was subjected to rotary evaporation to yield an oil that was subjected to silica gel column chromatography eluting with 15% EtOAc in petroleum ether to yield product.
(19) General Procedure E. O-Demethylation using NaSPr/HMPA:
(20) A solution of 6, 9, 12, 14, 20, 21, 27 or 28 in dry HMPA (6 mL/mmol) was added sodium propanethiolate (6 eq). The reaction was stirred for 3 h at 115 then cooled to RT and quenched with 7 mL/mmol of a concentrated solution of NH.sub.4Cl. The mixture was extracted three times with Et.sub.2O. The organic layer was then extracted five times with water, once with brine, dried over MgSO.sub.4, filtered and the solvents were removed under reduced pressure. The residue was then subjected to silica gel flash column chromatography eluting with a gradient of EtOAc in petroleum ether. The fractions containing the compound of Interest were then evaporated to dryness and dissolved in a 2 M solution of HCl in EtOH, and then induced to crystallize upon addition of EtOAc. The crystals were collected by filtration, and dried under vacuum.
(21) General Procedure F. O-Demethylation using L-Selectride:
(22) L-Selectride in THF (5 equivalents of a 1M solution) was added to the starting material (6, 9, 12, 14, 20, 21, 27 or 28) under nitrogen and the resulting solution heated to 80 C. and stirred for 14 hours, during which time a change from clear to white and opaque was observed. Excess L-Selectride was quenched with water and solvent removed under vacuum. The resulting residue was extracted into dichloromethane, washed with distilled water and saturated brine solution, dried (MgSO.sub.4) and solvents again removed under vacuum.
N-Cylcopropylmethyl-6,14-endo-ethanonorthevinone (5a) [Marton et al 1997]
(23) A solution of 4a (6 g, 14.8 mmol) in anhydrous DMF (36 ml) was treated sequentially at room temperature with sodium bicarbonate (5 g, 60 mmol) and (bromomethyl)cyclopropane (1.87 ml, 19.3 mmol). The resulting suspension was heated to 90 C. and stirred for 20 h. On cooling, the DMF was removed in vacuo and the residue dissolved in water and rendered basic with 2 M NaOH solution. The product was extracted into chloroform and the organic phases washed with brine, dried over MgSO.sub.4, filtered and evaporated to dryness. The resulting yellow solid was purified by column chromatography over silica gel (50% ethyl acetate in hexane, R.sub.f=0.50) affording 6.15 g 5a as a white solid (98%). Mp 105-106 C. .sup.1H NMR (270 MHz, CDCl.sub.3) 0.04-0.10 (2H, m), 0.43-0.49 (2H, m), 0.63-0.80 (1H, m), 1.22-1.34 (1H, m), 1.49-1.75 (4H, m), 1.96-2.08 (1H, m), 2.20-2.38 (4H, m), 2.25 (3H, s), 2.58-2.77 (2H, m), 2.93-3.11 (3H, m), 3.42 (3H, s), 3.86 (3H, s), 4.47 (1H, s), 6.55 (1H, d, J=8.0 Hz), 6.63 (1H, d, 8.0 Hz). .sup.13C NMR (68 MHz, CDCl.sub.3) 3.4, 4.2, 9.6, 17.6, 22.8, 28.8, 30.5, 33.9, 35.4, 35.5, 43.8, 46.6, 49.8, 52.4, 56.8, 58.4, 59.9, 77.8, 94.8, 113.9, 119.2, 128.9, 132.8, 141.8, 146.8, 211.1. HRMS (ESI.sup.+) calcd for C.sub.26H.sub.34NO.sub.4 (MH.sup.+), 424.2488. found 424.2485.
N-Cyclopropylmethyl-6,14-dihydronorthevinal (8a) and N-cyclopropylmethylnorthevinal (8b)
(24) N-CPMnorthebaine (3) (1 equlv.) and acrolein (1.2 equiv.) were heated to reflux in toluene (4 mL/mmol) overnight. The solvent and excess dienophile were removed in vacuo and the product purified by silica gel chromatography (8b: 74%), Rf (EtPAc:NH4OH, 99.5:0.5) 0.58, .sup.1H NMR (270 MHz, CDCl.sub.3) (0.14 (2H, m), 0.50 (2H, m), 0.83 (1H, m), 1.45 (1H, dd), 2.98 (1H, dd), 3.11 (1H, d), 3.57 (1H, d), 3.62 (3H, s), 3.82 (3H, s), 4.64 (1H, d), 5.59 (1H, d), 5.89 (1H, d), 6.52 (1H, d), 6.62 (1H, d), 9.43 (1H, d); .sup.13C NMR (68 MHz, CDCl.sub.3) 3.43, 4.17, 9.44, 23.21, 26.76, 33.45, 42.92, 43.97, 48.05, 49.87, 52.70, 56.56, 57.11, 59.80, 80.92, 93.62, 113.39, 119.51, 126.47, 128.15, 133.96, 137.45, 141.93, 147.93, 201.96; LRMS (EI) 407 (M+), HRMS found 407.2096, C.sub.25H.sub.29NO.sub.4 requires 407.2097.
(25) This adduct 8b (6.0 g, 14.7 mmol) was dissolved in EtOH (45 mL) and treated with 10% Pd/C (60 mg) under a H.sub.2 atmosphere at 65 psi at 50 C. for 24 h. After cooling to rt the catalyst was removed by filtration through Celite and the solvent removed in vacuo. 5.9 g (8a: 98%), Rf (Hexane: EtOAc: NH.sub.4OH, 33:66:1) 0.48; .sup.1H NMR (270 MHz, CDCl.sub.3) 0.09 (2H, m), 0.49 (2H, m), 0.76 (1H, m), 3.00 (1H, d), 3.51 (3H, s), 3.87 (3H, s), 4.58 (1H, d), 6.58 (1H, d), 6.72 (1H, d), 9.92 (1H, d); .sup.13C NMR (68 MHz, CDCl.sub.3) 3.40, 4.11, 9.46, 19.95, 22.79, 26.72, 28.64, 35.33, 35.46, 43.70, 46.02, 48.80, 51.67, 56.68, 58.45, 59.86, 77.37, 92.37, 113.86, 119.10, 119.32, 128.58, 132.39, 141.82, 203.33; m/z (EI) 409 (M.sup.+); HRMS (EI) found 409.2263, C.sub.25H.sub.31NO.sub.4 requires 409.2253.
Series 1, Scheme 1: R=Ph (1S, 5, 6R, 7R, 14)-1,-phenyl-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethano-morphinan-7-yl)-ethan-1-ol (BU127)
(26) 5 was treated as in procedure A with phenylmagnesium bromide followed by procedure E or F. White solid, (R.sub.f=0.21; 0.5% NH.sub.4OH, 30% EtOAc in hexane; column ran in 30% EtOAc in hexane). .sup.1H NMR (400 MHz, CDCl.sub.3) 0.10-0.00 (2H, m), 0.31-0.42 (2H, m), 0.55-0.62 (1H, m), 0.69-0.77 (1H, m), 0.91 (1H, dd, J=13.5 and 9.5 Hz), 1.02-1.10 (1H, m), 1.58 (1H, dd, J=12.5 and 2.5 Hz), 1.76-1.90 (3H, m), 1.80 (3H, s), 1.94-2.02 (1H, m), 2.10-2.20 (5H, m), 2.45 (1H, dd, J=11.5 and 5.0 Hz), 2.85-2.93 (2H, m), 3.57 (3H, s), 4.45 (1H, d, J=2.0 Hz), 5.49 (1H, s), 6.48 (1H, d, 7=8.0 Hz), 6.66 (1H, d, J=8.0 Hz), 7.23-7.26 (1H, m), 7.32-7.36 (2H, m), 7.51-7.53 (2H, m). .sup.13C NMR (100.6 MHz, CDCl.sub.3) 3.3, 4.2, 9.4, 18.0, 22.9, 23.7, 30.0, 32.7, 35.6, 36.2, 43.6, 47.3, 48.5, 52.9, 58.1, 59.6, 77.5, 80.9, 97.6, 116.4, 119.7, 126.2, 126.9, 128.0, 128.5, 132.5, 137.3, 145.5, 147.2. HRMS (ESI.sup.+) calcd for C.sub.31H.sub.38NO.sub.4 (MH.sup.+), 488.2795. found 488.2794 (100%).
Series 1, Scheme 1, R=2-thienyl: (1S, 5, 6R, 7R, 14)-1-(2-thienyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethano-morphinan-7-yl)-ethan-1-ol (BU08026)
(27) 5 was treated as in procedure A with 2-thienyl magnesiumbromide followed by procedure E or F. Rf (30% EtoAc-Pet.Ether-0.5% NH.sub.3) 0.5. .sub.H (270 MHz; CDCl.sub.3) 7.2 (1H, d, J 4.2, 12-thienyl.CH), 6.9 (1H, t, J 3.6, 12-thienyl.CH), 6.9 (1H, d, J 4.9, 12-thienyl.CH). 6.7 (1H, d, J 8.2, CH), 6.5 (1H, d, J 8.9, CH), 5.8 (1H, s, 21-OH), 4.4 (1H, s, 5-H), 3.9 (3H, s, 3-OCH.sub.3), 3.6 (3H, s, 6-OCH.sub.3), 2.9 (1H, d, J 19.0, 10-H), 2.9 (1H, d, J 7.2, 9-H), 0.6-0.7 (1H, m, NCH.sub.2CH(CH.sub.2CH.sub.2)), 0.3-0.4 (2H, m, NCH.sub.2CH(CH.sub.2CH.sub.2)), 0 (2H, m, NCH.sub.2CH(CH.sub.2CH.sub.2)).
(28) By a similar method the following ligands were prepared:
Series 1, Scheme 1, R=m-tolyl: (1S, 5, 6R, 7R, 14)-1-(3-methylphenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethano-morphinan-7-yl)-ethan-1-ol (BU10092)
(29) Rf (30% EtoAc-Pet.Ether-0.5% NH.sub.3) 0.8. .sub.H (270 MHz; CDCl.sub.3) 7.5-7.6 (1H, m, 4aryl.CH), 7.1 (3H, d, J 3.3, 2-methylphenyl), 6.7 (1H, d, J 8.3, CH). 6.6 (1H, d, J 8.2, CH), 5.9 (1H, s, 21-OH), 4.4 (1H, s, 5-H), 3.9 (3H, s, 3-OCH.sub.3), 3.3 (3H, s, 6-OCH.sub.3), 2.9 (2H, d, J 19.0, 10-H), 2.9 (1H, d, J 7.2, 9-H), 0.6-0.7 (1H, m, NCH.sub.2CH(CH.sub.2CH.sub.2)), 0.3-0.4 (2H, m, NCH.sub.2CH(CH.sub.2CH.sub.2)), 0.1-0 (2H, m, NCH.sub.2CH(CH.sub.2CH.sub.2)).
Series 1, Scheme 1, R=p-t-butylphenyl: (1S, 5, 6R, 7R, 14)-1-(4-t-butylphenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1-ol (BU08024)
(30) R.sub.f 0.33 .sup.1H NMR (400 MHz, CDCl.sub.3) 0.07 (2H, m), 0.31-0.33 (2H, d, J=8.0 Hz), 068-072 (1H, m), 0.73-0.86 (1H, m), 0.86-0.92 (1H, m), 0.99-1.03 (1H, m), 1.31 (10H, s), 1.52-1.55 (1H, d, J=12.5 Hz), 1.77 (5H, s), 1.81-1.84 (1H, m), 2.03-2.10 (1H, m), 2.13-2.20 (5H, m), 2.46-2.48 (1H, m), 2.77-278 (1H, m), 2.87-2.91 (1H, d, J=18.3 Hz), 3.54 (3H, s), 4.43 (1H, s), 5.44 (1H, s), 6.44-6.46 (2H, d, J=8.0 Hz), 6.61-6.63 (2H, d, J=8.0 Hz), 7.32-7.33 (2H, d, J=4.1 Hz), 7.34 (2H, d, J=4.7 Hz); .sup.13C NMR (100.6 MHz, CDCl.sub.3) 3.4, 3.5, 9.1, 17.8, 23.0, 23.4, 29.8, 31.3, 32.4, 34.3, 35.5, 36.0, 43.2, 47.0, 48.3, 52.7, 58.5, 59.2, 80.7, 97.2, 116.3, 119.4, 124.6, 125.6, 128.1, 132.3, 137.2, 144.0, 145.4, 149.3; ESIMS m/z: 544 [M+1].sup.+.
Series 1, Scheme 1, R=p-i-propylphenyl: (1S, 5, 6R, 7R, 14)-1-(4-isopropylphenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1-ol (BU10096)
(31) .sup.1H NMR (CDCl.sub.3) 0.09-0.04 (2H, m), 0.31-0.0.35 (2H, m), 0.57-0.60 (1H, m), 0.68-0.75 (1H, m), 0.86-0.92 (1H, m), 1.00-1.05 (1H, m), 1.24 (6H, d, J=6.88 Hz), 1.56 (1H, s), 1.78 (3H, s), 1.79-1.85 (3H, m), 1.98-2.04 (2H, m), 2.10-2.23 (4H, m), 2.45-2.49 (1H, m), 2.78 (1H, d, J=6.40 Hz), 2.88-2.93 (2H, m), 3.56 (3H, s), 4.45 (1H, s), 4.61 (1H, bd), 5.30 (1H, bd), 6.47 (1H, d, J=8.0 Hz), 6.66 (1H, d, J-8.0 Hz), 7.17 (2H, d, J-8.1 Hz), 7.40 (2H, d, J=8.1 Hz); .sup.13C NMR, 400 MHz, (CDCl.sub.3) 3.40, 3.65, 9.29, 17.92, 23.05, 23.59, 23.92, 24.12, 29.87, 32.60, 33.72, 35.61, 36.16, 43.35, 47.25, 48.53, 52.71, 58.56, 59.39, 80.80, 97.56, 116.22, 119.52, 125.81, 125.91, 128.51, 132.52, 137.12, 144.75, 145.48, 147.14. HRMS, m/z for (C.sub.34H.sub.44NO.sub.4) [MH].sup.+, calcd530.3270. found530.3285.
Series 1, Scheme 1, R=p-chlorophenyl: (1S, 5, 6R, 7R, 14)-1-(4-chlorophenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1-ol (BU10097)
(32) .sup.1H NMR (CDCl.sub.3) 0.03-0.02 (2H, m), 0.37-0.0.41 (2H, m), 0.58-0.62 (1H, m), 0.71-0.74 (1H, m), 0.85-0.90 (1H, m), 0.99-1.05 (1H, m). 1.54 (1H, m), 1.75 (3H, s), 1.77-1.84 (3H, m), 1.99-2.05 (2H, m), 2.14-2.22 (4H, m), 2.44-2.48 (1H, m), 2.86-2.90 (2H, m), 3.58 (3H, s), 4.42 (1H, s), 4.63 (1H, bd), 5.46 (1H, bd), 6.51 (1H, d, J=8.0 Hz), 6.69 (1H, d, J=8.0 Hz), 7.29 (2H, d, J=11.1 Hz), 7.43 (2H, d, J=11.1 Hz); .sup.13C NMR, 400 MHz, (CDCl.sub.3) 3.20, 4.03, 9.27, 17.83, 22.79, 23.48, 29.86, 32.60, 35.59, 36.09 43.45, 47.29, 48.52, 52.81, 57.99, 59.50, 80.85, 97.48, 116.32, 119.60, 127.60, 127.93, 128.49, 132.35, 132.54, 137.13, 145.44, 146.10; HRMS, m/z for (C.sub.31H.sub.37ClNO.sub.4): [MH].sup.+; calcd 522.2411. found522.2515.
Series 1, Scheme 1, R=m-chlorophenyl: (1S, 5, 6R, 7R, 14)-1-(3-chlorophenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1-ol (BU10098)
(33) .sup.1H NMR, 400 MHz, (CDCl.sub.3) 0.05-0.02 (2H, m), 0.36-0.0.42 (2H, m), 0.60-0.62 (1H, m), 0.70-0.76 (1H, m). 0.89-0.93 (1H, m). 1.02-1.07 (1H, m), 1.56 (1H, s). 1.75-1.85 (6H, m), 2.01-2.06 (2H, m), 2.15-2.23 (4H, m), 2.44-2.48 (1H, m), 2.87-2.94 (2H, m), 3.57 (3H, s), 4.43 (1H, s), 4.68 (1H, s), 5.48 (1H, bd), 6.48 (1H, d, J=8.0 Hz), 6.67 (1H, d, J=J=8.0 Hz), 7.21-7.28 (2H, m), 7.37 (1H, d, J=10.6 Hz), 7.53 (1H, s); .sup.13C NMR, 400 MHz, (CDCl.sub.3) 3.21, 4.03, 9.27, 17.87, 22.84, 23.54, 29.84, 32.53, 35.60, 36.10, 43.46, 47.27, 48.44, 52.81, 57.98, 59.44, 80.87, 97.42, 116.34, 119.62, 124.40, 126.50, 126.92, 128.47, 129.05, 132.37, 133.89, 137.14, 145.44, 149.68; HRMS, m/z for (C.sub.31H.sub.37FNO.sub.4) [MH].sup.+; calcd 522.2411. found522.2447.
Series 1, Scheme 1, R=3,5-dimethylphenyl: (1S, 5, 6R, 7R, 14)-1-(3,5-dimethylphenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1-ol (BU10100)
(34) .sup.1H NMR (CDCl.sub.3) 0.04-0.01 (2H, m), 0.34-0.0.42 (2H, m), 0.61-0.65 (1H, m), 0.70-0.76 (1H, m), 0.94-0.99 (1H, m), 1.04-1.11 (1H, m), 1.56 (1H, s), 1.76 (3H, s), 1.79-1.86 (3H, m), 2.00-2.07 (2H, m), 2.14-2.24 (4H, m), 2.33 (6H, s), 2.41-2.45 (1H, m), 2.90-2.94 (2H, m), 3.56 (3H, s), 4.45 (1H, s), 4.80 (1H, bd), 5.41 (1H, bd), 6.48 (1H, d, J=8.0 Hz), 6.66 (1H, d, J=8.0 Hz), 6.87 (1H, s), 7.10 (2H, s): .sup.13C NMR, 400 MHz, (CDCl.sub.3) 3.00, 4.23, 9.19, 18.12, 21.59, 22.78, 23.83, 29.87, 32.53, 35.52, 36.09, 43.67, 47.17, 48.16, 52.70, 57.81, 59.27, 80.87, 97.34, 116.29, 119.53, 123.90, 128.29, 128.45, 132.48, 136.93, 137.16, 145.47, 147.41; HRMS, m/z for (C.sub.33H.sub.42NO.sub.4) [MH].sup.+: calcd 516.3114. found516.3145.
Series 1, Scheme 1, R=o-tolyl: (1S, 5, 6R, 7R, 14)-1,-(2-methylphenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethy 1-6,14-ethanomorphinan-7-yl)-ethan-1-ol (BU10101)
(35) .sup.1H NMR (CDCl.sub.3) 0.08-0.03 (2H, m), 0.31-0.0.38 (2H, m), 0.56-0.58 (1H, m), 0.69-0.76 (1H, m), 0.83-0.89 (1H, m), 1.02-1.09 (1H, m), 1.59-1.63 (1H, m), 1.79-1.89 (6H, m), 1.98-2.05 (1H, m), 2.13-2.23 (4H, m), 2.45-2.49 (1H, m), 2.62-2.66 (1H, m), 2.75 (3H, s), 2.84-2.93 (2H, m), 3.56 (3H, s), 4.45 (1H, s), 4.62 (1H, bd), 5.06 (1H, bd), 6.48 (1H, d, J=8.0 Hz), 6.67 (1H, d, J=8.0 Hz), 7.07-7.17 (3H, m), 7.22-7.24 (1H, m): .sup.13C NMR, 400 MHz, (CDCl.sub.3) 3.17, 4.06, 9.22, 18.24, 22.76, 22.84, 25.93, 29.87, 32.66, 35.63, 36.11, 43.52, 43.72, 47.34, 52.68, 57.92, 59.47, 79.68, 80.85 97.80, 116.27, 119.55, 124.83, 126.84, 127.50, 128.56, 132.43, 132.81, 136.84, 137.11, 143.64, 145.49; HRMS, m/z for (C.sub.32H.sub.40NO.sub.4). [MH].sup.+, calcd502.2957. found502.3017.
Series 1, Scheme 1, R=4-dimethylphenyl: (1S, 5, 6R, 7R, 14)-1-(4-fluorophenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1-ol (BU10102)
(36) .sup.1H NMR (CDCl.sub.3) 0.06-0.03 (2H, m), 0.35-0.0.40 (2H, m), 0.58-0.62 (1H, m), 0.70-0.76 (1H, m), 0.84-0.89 (1H, m), 0.99-1.06 (1H, m), 1.59 (1H, s), 1.74-1.84 (6H, m), 1.94-2.07 (2H, m), 2.14-2.22 (4H, m), 2.44-2.48 (1H, m), 2.85-2.91 (2H, m), 3.58 (3H, s), 4.44 (1H, s), 4.59 (1H, s), 5.45 (1H, bd), 6.48 (1H, d, J=8.0 Hz), 6.67 (1H, d, J=8.0 Hz), 6.99-7.04 (2H, m), 7.41-7.46 (2H, m): .sup.13C NMR, 400 MHz, (CDCl.sub.3) 3.22, 3.99, 9.27, 17.80, 22.83, 23.58, 29.86, 32.64, 35.60, 36.09, 43.45, 47.29, 48.72, 52.81, 58.05, 59.48, 80.83, 97.54, 114.39, 114.60, 116.32, 119.59, 126.64, 127.70, 128.47, 128.98, 132.35, 137.13, 143.35, 145.45, 160.57; HRMS, m/z for (C.sub.31H.sub.37FNO.sub.4), [MH].sup.+: calcd 506.2707. found506.2749.
Series 1, Scheme 1, R=3-fluorophenyl: (1S, 5, 6R, 7R, 14)-1-(3-fluorophenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1-ol (BU10103)
(37) .sup.1H NMR (CDCl.sub.3) 0.05-0.03 (2H, m), 0.35-0.0.40 (2H, m), 0.58-0.63 (1H, m), 0.70-0.76 (1H, m), 0.87-0.93 (1H, m), 1.01-1.09 (1H, m), 1.60 (1H, s), 1.75-1.86 (6H, m), 1.97-2.14 (2H, m), 2.17-2.22 (4H, m), 2.45-2.49 (1H, m), 2.81-2.94 (2H, m), 3.58 (3H, s), 4.44 (1H, s), 4.64 (1H, s), 5.45 (1H, bd), 6.48 (1H, d, J=J=8.0 Hz), 6.67 (1H, d, J=J=8.0 Hz), 6.92-6.97 (1H, m), 7.24-7.29 (3H, m): .sup.13C NMR, 400 MHz, (CDCl.sub.3) 3.28, 3.94, 9.28, 17.83, 22.85, 23.51, 29.86, 32.51, 35.60, 36.09, 43.40, 47.28, 48.52, 52.81, 58.09, 59.49, 80.84, 97.48, 113.23, 113.45, 113.69, 116.31, 119.61, 121.76, 128.48, 129.17, 132.38, 137.13, 145.44, 150.23, 161.63; HRMS, m/z for (C.sub.31H.sub.37FNO.sub.4), [MH].sup.+: calcd 506.2707. found506.2749.
Series 1, Scheme 1, R=3-methyl-2-thienyl: (1S, 5, 6R, 7R, 14)-1-(3-methyl-2-thienyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1-ol (BU10093)
(38) Rf (30% EtOAc.Pet.Ether-0.5% NH.sub.3) 0.17. .sub.H (400 MHz; CDCl.sub.3) 7.03 (1H, d, J 5.04, 1 thienyl.CH), 6.76 (1H, d, J 5.12, 1 thienyl.CH), 6.68 (1H, d, J 8.04, 2-H), 6.50 (1H, d, J 8.08, 1-H), 5.30 (1H, s, 20-OH), 4.51 (1H, s, 3-OH), 4.46 (1H, s, 50-H), 3.56 (3H, s, 6-OCH.sub.3), 2.93 (1H, d, J 18.04, 10-H), 2.90 (1H, d, J 6.36, 9-H), 2.46-2.51 (2H, m, includes 15/16-NCH.sub.2, CH.sub.2), 2.48 (3H, s, 1 thienyl.CH.sub.3), 2.15-2.31 (5H, m, includes 7-H, 10-H, 15/16-NCH.sub.2, CH.sub.2), 1.79-1.89 (3H, m, 15/16-NCH.sub.2, CH.sub.2, 218/19-H), 1.87 (3H, s, 20-CH.sub.3), 1.60-1.64 (1H, m, 15/16-NCH.sub.2, CH.sub.2), 1.04-1.10 (1H, m, 8-H), 0.68-0.78 (1H, m, 18/19-H), 0.62-0.68 (1H, m, N CH.sub.2CH(CH.sub.2CH.sub.2)), 0.34-0.45 (2H, m, NCH.sub.2CH(CH.sub.2CH.sub.2)), 0.02-0.01 (2H, m, NCH.sub.2CH(CH.sub.2CH.sub.2)); .sub.C (100.56 MHz; CDCl.sub.3) 145.49, 144.06, 137.18, 133.14, 132.40, 131.75, 128.47, 121.22, 119.59, 116.35, 97.60, 80.53, 59.45 (NCH.sub.2CH(CH.sub.2).sub.2), 57.94, 52.78, 47.35, 43.54 (CH.sub.2), 36.09, 35.63 (CH.sub.2), 32.20 (CH.sub.2), 29.84 (CH.sub.2), 25.61, 22.80 (CH.sub.2), 21.03, 18.00 (CH.sub.2), 16.02, 14.20, 9.30, 4.10 (CH.sub.2), 3.22 (CH.sub.2). m/z 508 (M.sup.++1), (Found M.sup.++1, 508.2572. C.sub.30H.sub.38NO.sub.4S requires 508.2522).
Series 1, Scheme 1, R=p-Tolyl (1S, 5, 6R, 7R, 14)-1-(4-methyl-phenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1-ol (BU10135)
(39) Rf (30% EtOAc.Pet, Ether-0.5% NH.sub.3) 0.23. .sub.H (400 MHz; CDCl.sub.3) 7.39 (2H, d, J 8.20, 2 aryl.CH), 7.14 (2H, d, J 7.92, 2 aryl.CH), 6.68 (1H, d, J 8.04, 2-H), 6.49 (1H, d, J 8.08, 1-H), 5.42 (1H, s, 20-OH), 4.62 (1H, s, 3-OH), 4.51 (1H, s, 5-H), 3.57 (3H, s, 6-OCH.sub.3), 2.91 (1H, d, J 18.88, 10-H), 2.87 (1H, d, J 6.80, 9-H), 2.43-2.47 (1H, m, 15/16-NCH.sub.2, CH.sub.2), 2.35 (3H, s, 1 aryl.CH.sub.3), 2.12-2.21 (4H, m, includes 7-H, 10-H), 2.07-2.12 (1H, m, 15/16-NCH.sub.2, CH.sub.2), 1.95-2.02 (1H, m, 15/16-NCH.sub.2CH.sub.2), 1.82-1.88 (1H, m, 15/16-NCH.sub.2, CH.sub.2), 1.79-1.83 (1H, m, 8-H), 1.77 (3H, s, 20-CH.sub.3), 1.00-1.09 (1H, m, 18/19-H), 0.87-0.93 (1H, m, 8-H), 0.69-0.76 (1H m, 18/19-H), 0.56-0.64 (1H, m, NCH.sub.2CH(CH.sub.2CH.sub.2)), 0.32-0.43 (2H, m, NCH.sub.2CH(CH.sub.2CH.sub.2)), 0.09-0 (2H, m, NCH.sub.2CH(CH.sub.2CH.sub.2)); .sub.C (100.56 MHz; CDCl.sub.3) 145.34, 137.00, 136.03, 132.38, 128.45, 125.86, 119.45, 116.13, 80.71, 59.41 (NCH.sub.2CH(CH.sub.2).sub.2), 57.88, 52.72, 48.30, 47.14, 43.42 (CH2), 35.97 (CH.sub.2), 32.49, 22.64 (CH2), 20.98, 17.86 (CH2), 9.17, 4.00 (CH.sub.2), 3.13 (CH2). m/z 502 (M.sup.++1), (Found M.sup.++1, 502.3048. C.sub.32H.sub.40NaO.sub.4 requires 502.2957).
Series 1, Scheme 1, R=5-Chloro-2-Thienyl (1S, 5, 6R, 7R, 14)-1-(5-chloro-2-thienyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1-ol (BU10136)
(40) Rf (30% EtOAc.Pet.Ether-0.5% NH.sub.3) 0.12. .sub.H (400 MHz; CDCl.sub.3) 6.72 (1H, d, J 3.80, 1 thieny.CH), 6.68 (1H, d, J 8.04, 2-H), 6.61 (1H, d, J 3.84, 1 thienyl.CH), 6.50 (1H, d, J 8.08, 1-H), 5.69 (1H, s, 20-OH), 4.56 (1H, s, 3-OH), 4.42 (1H, s, 5-H), 3.57 (3H, s, 6-OCH.sub.3), 2.94 (1H, d, J 18.56, 10-H), 2.90 (1H, d, J 6.52, 9-H), 2.52-2.57 (1H, m, 15/16-NCH.sub.2, CH.sub.2), 2.15-2.35 (5H, m, includes 7-H, 10-H, 15/16-NCH.sub.2, CH.sub.2), 1.77-1.88 (3H, m, 15/16-NCH.sub.2, CH.sub.2), 218/19-H), 1.76 (3H, s, 20-CH.sub.3). 1.59-1.63 (1H, m, 15/16-NCH.sub.2, CH.sub.2), 1.00-1.10 (1H, m, 18/19-H), 0.86-0.95 (1H, m, 8-H), 0.67-0.77 (2H, m, 18/19-H, NCH.sub.2CH(CH.sub.2CH.sub.2)). 0.36-0.47 (2H, m, NCH.sub.2CH(CH.sub.2CH.sub.2)), 0.04-0.06 (2H, m, NCH.sub.2CH(CH.sub.2CH.sub.2)); .sub.5C (100.56 MHz; CDCl.sub.3) 151.81, 146.75, 141.55, 132.47, 129.06, 128.80, 124.93, 122.13, 119.10, 113.84, 96.91, 80.65, 59.52 (NCH.sub.2CH(CH.sub.2).sub.2), 57.84, 56.76, 52.99, 49.40, 47.00, 43.37 (CH.sub.2), 35.90, 35.53 (GHz), 32.59 (CH.sub.2), 29.81 (CH.sub.2), 23.41, 22.55 (CH.sub.2), 17.69 (CH.sub.2), 9.27, 4.07 (CH.sub.2), 3.25 (CH.sub.2). m/z550 (M.sup.++Na), (Found M.sup.++Na, 550.1774. C.sub.29H.sub.34ClNNaO.sub.4S requires 550.1795).
Series 1, Scheme 1, R=3-Thienyl (1S, 5, 6R, 7R, 14)-1-(3-thienyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1-ol (BU11001)
(41) Rf (30% EtOAc.Pet.Ether-0.5% NH.sub.3) 0.11, .sub.H (400 MHz; CDCl.sub.3) 7.26 (1H, d, J 2.96, 1 thienyl.CH), 7.20 (1H, d, J 5.00, 1 thienyl.CH), 7.16 (1H, d, J 2.88, 1 thienyl.CH), 6.68 (1H, d, J 8.04, 2-H), 6.50 (1H, d, J 8.00, 1-H), 5.32 (1H, s, 20-OH), 4.59 (1H, s, 3-OH), 4.46 (1H, s, 5-H), 3.58 (3H, s, 6-OCH.sub.3), 2.93 (1H, d, J 18.40, 10-H), 2.86 (1H, d, J 6.16, 9-H), 2.49-2.53 (1H, m, 15/16-NCH.sub.2, CH.sub.2), 2.12-2.28 (6H, m, 7-H, 8-H, 10a-H, 15/16-NCH.sub.2, CH.sub.2), 1.81-1.92 (3H, m, 15/16-NCH.sub.2, CH.sub.2, 218/19-H), 1.79 (3H, s, 20-CH.sub.3), 1.58-1.63 (1H, m, 15/16-NCH.sub.2, CH.sub.2), 1.04-1.07 (1H, m, 18/19-H), 0.89-0.97 (1H, m, 8-H), 0.70-0.80 (1H, m, 18/19-H), 0.60-0.70 (1H, m, NCH.sub.2CH(CH.sub.2CH.sub.2)), 0.34-0.45 (2H, m, NCH.sub.2CH(CH.sub.2CH.sub.2)),0.06-0.03 (2H, m, NCH.sub.2CH(CH.sub.2CH.sub.2)); .sub.c (100.56 MHz; CDCl.sub.3) 149.44, 137.04, 126.37, 124.94, 120.41, 119.48, 116.18, 97.52, 80.63, 59.47 (NCH.sub.2CH(CH2).sub.2), 58.22, 52.67, 48.22, 47.29, 43.33 (CH.sub.2), 36.05, 35.57 (CH.sub.2), 32.47 (CH.sub.2), 29.76 (CH.sub.2), 23.90, 22.85 (CH.sub.2), 17.79 (CH.sub.2), 9.27, 3.79 (CH.sub.2), 3.28 (CH.sub.2). m/z 494 (M.sup.++1), (Found M.sup.++1, 494.2411. C.sub.29H.sub.36NO.sub.4S requires 494.2365).
Series 1, Scheme 2, R=Ph: (1R, 5, 6R, 7R, 14)-1-phenyl-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1-ol (BU147)
(42) Using General Procedure A with methylmagnesium bromide on ketone 11a (R=Ph), followed by General Procedure E or F. White solid. R.sub.f=0.5 (MeOH:DCM, 1:10); .sup.1H NMR (270 MHz, CDCl.sub.3) 0.10 (2H, m), 0.51 (2H, m), 0.84 (1H, m), 1.55 (3H, s), 2.92 (1H, d), 2.95 (1H, d), 3.41 (3H, s), 4.33 (1H, d), 6.03 (1H, s), 6.41 (1H, d), 6.58 (1H, d), 7.25 (3h, m), 7.55 (2H, m); .sup.13C NMR (68 MHz, CDCl.sub.3) 3.90, 4.12, 9.73, 15.72, 22.97, 29.15, 31.02, 31.28, 35.80, 36.09, 43.98, 47.01, 49.94, 52.73, 59.02, 60.39, 80.86, 98.33, 116.73, 119.67, 126.90, 126.98, 127.70, 128.48, 132.79, 137.81, 145.98, 146.56. HRMS (EI) calcd for C.sub.31H.sub.44NO.sub.4 (M.sup.+), 487.2723. found 487.2323.
Series 2, R=2-pyridyl: (1R, 5, 6R, 7R, 14)-1-(2-pyridyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1-ol (BU11005)
(43) 2-Bromopyridine (0.11 ml, 0.1.13 mmol) was taken in dry diethylether and solution was cooled to 78 C. with dry ice under nitrogen atmosphere. Thereafter a solution of n-butyllithium (1.13 mmol) was dropwise added to it. The reaction mixture was stirred for 10 min. then 5a dissolved in dry THF was added to it. The reaction mixture was allowed to warm to room temperature and stirred for 20 h. After completion, the reaction mixture was quenched with saturated ammonium chloride solution (aqueous) and extracted with ethylacetate. Organic layer was washed with brine, dried over sodium sulfate and vacuum evaporated to obtained crude product which was purified by flash chromatography using methanol:dichloromethane (0.5:99.5).
(44) White Solid; .sup.1H NMR (CDCl.sub.3) 0.08-0.11 (2H, m), 0.40-0.51 (2H, m), 0.80-0.88 (2H, m), 1.20-1.27 (2H, m), 1.62 (1H, d, J=2.68 Hz), 1.67 (3H, s), 2.02-2.41 (8H, m), 2.61 (1H, dd, J-11.72, J=5.12 Hz), 2.78 (1H, dt, J-112.16, J=3.92 Hz), 2.91 (1H, d, J=18.24 Hz), 3.02 (1H, d, J-6.40 Hz), 3.35 (3H, s), 4.39 (1H, s), 4.55 (1H, bd), 5.83 (1H, s), 6.43 (1H, d, J=8.0 Hz), 6.61 (1H, d, J=8.0 Hz), 7.10-7.14 (1H, m), 7.62-7.64 (2H, m), 8.48 (1H, d, J=4.76 Hz), .sup.13C NMR, 400 MHz, (CDCl.sub.3) 3.21, 4.33, 9.35, 16.42, 22.45, 28.39, 28.86, 29.92, 35.24, 35.65, 43.81, 46.78, 49.36, 52.28, 57.95, 59.89, 80.1, 97.70, 116.01, 119.37, 120.54, 121.55, 128.54, 132.45, 135.78, 136.93, 145.30, 147.32, 166.46; HRMS, m/z for (C.sub.30H.sub.36N.sub.2O.sub.4), [MH].sup.+: calcd 489.2753. found489.2821.
Series 2, R=4-pyridyl: (1R, 5, 6R, 7R, 14)-1-(4-pyridyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-ethan-1-ol (BU11006)
(45) 4-Bromopyridine (0.11 ml, 0.1.13 mmol) was taken in dry diethylether and solution was cooled to 78 C. with dry ice under nitrogen atmosphere. Thereafter a solution of n-butyllithium (1.13 mmol) was dropwise added to it. The reaction mixture was stirred for 10 min. then 5a dissolved in dry THF was added to it. The reaction mixture was allowed to warm to room temperature and stirred for 20 h. After completion, the reaction mixture was quenched with saturated ammonium chloride solution (aqueous) and extracted with ethylacetate. Organic layer was washed with brine, dried over sodium sulfate and vacuum evaporated to obtained crude product which was purified by flash chromatography using methanol:dichloromethane (0.5:99.5). White Solid; .sup.1H NMR (CDCl.sub.3) 0.10-0.12 (2H, m), 0.24-0.55 (5H, m), 0.82-0.84 (1H, m), 1.49 (1H, dd, J-12.88, J=9.04 Hz), 1.58 (3H, s), 1.65 (1H, dd, J=12.92, J=5.60 Hz), 2.01-2.40 (7H, m), 2.62-2.68 (2H, m), 2.92-3.01 (3H, m), 3.41 (3H, s), 4.33 (1H, s), 6.06 (1H, s), 6.43 (1H, d, J=&0 Hz), 6.63 (1H, d, J=8.0 Hz), 7.48 (2H, dt J=6.16 Hz), 8.52 (2H, d, Hz); .sup.13C NMR, 400 MHz, (CDCl.sub.3) 3.47, 4.11, 9.38, 15.58, 22.49, 28.52 29.22, 31.02, 35.33, 35.66, 36.80, 43.60, 46.75, 49-50, 52.61, 58.24, 59.92, 80.35, 97.62, 116.53, 119.50, 121.97, 127.87, 131.92, 137.41, 145.45, 148.76, 149.21, 155.79; HRMS, m/z for (C.sub.30H.sub.36N.sub.2O.sub.4), [MH].sup.+: calcd 489.2753. found489.2756.
Series 3, Scheme 2, R=Ph: (1S, 5, 6R, 7R, 14)-1-phenyl-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (BU126)
(46) From reduction of 11a (R=Ph) followed by general procedure B or F.
(47) .sup.1H NMR (CDCl.sub.3) 0.04-0.06 (2H, m), 0.45 (2H, m), 0.7 (1H, m), 2.93 (1H, d, J 18.5). 3.07 (1H, d, J 6.3). 3.48 (3H, s). 4.46 (1H, d, J 1.8), 5.28 (1H, s), 6.50 (1H, d, J 8.1), 6.68 (1H, d, J 8.1), 7.26-7.40 (5H, m); .sup.13C NMR (CDCl.sub.3) 3.36, 4.17, 9.32, 20.6, 22.7, 25.6, 29.1, 35.3, 35.9, 42.1, 43.8, 46.1, 50.6, 58.5, 59.9, 70.1, 77.3, 92.3, 116.6, 119.5, 125.7, 127.0, 128.2, 128.3, 132.6, 137.4, 145.0, 145.5; m/z 473.
13b, Scheme 2, R=Phenyl: (1S, 5, 6R, 7R, 14)-1-phenyl-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (BU125)
(48) From the treatment of 11b (R=Ph) as per General Procedure D, followed by General Procedure E or F.
(49) NMR (CDCl.sub.3) 0.4 (2H, m), 0.45 (2H, m), 0.65 (1H, m), 3.01 (1H, d, J 18.7), 3.35 (1H, d. J 6.7). 3.80 (3H, s), 4.35 (1H, d, J 9.0), 4.65 (1H, d, J 1.3), 5.43 (1H, s). 5.56 (1H, d, J 8.9), 6.00 (1H, d, J 9.0), 6.43 (1H, d, J 8.1), 6.55 (1H, d, J 8.1), 7.28 (5H, m); .sup.13C NMR (CDCl.sub.3) 3.5, 4.0, 9.2, 23.0, 30.4, 33.0, 42.6, 43.8, 43.9, 47.8, 54.9, 57.0, 59.9, 77.7, 84.5, 97.8, 116.3, 119.8, 124.4, 125.8, 127.7, 128.1, 128.2, 134.3, 137.5, 137.8, 141.7, 146.3; m/z 471.
Series 4, Scheme 2, R=Ph: (1R, 5, 6R, 7R, 14)-1-phenyl-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol BU106)
(50) As the major product of phenylmagnesium bromide addition to aldehyde 8 (General procedure A) followed by General Procedure E or F. White solid. R.sub.f=0.48 (Hexane:EtOAc, 1:1, 0.5% NH4OH), .sup.1H NMR (270 MHz, CDCl.sub.3) 0.05 (2H, m), 0.45 (2H, m), 0.71 (1H, m), 2.93 (1H, d), 3.07 (1H, d), 3.48 (3H, s), 4.46 (1H, d), 5.28 (1H, s), 6.50 (1H, d), 6.68 (1H, d), 7.26-7.40 (2H, m), 7.36-7.43 (3H, m). .sup.13C NMR (68 MHz, CDCl.sub.3) 3.4, 4.2, 9.4, 20.4, 22.6, 25.7, 29-3, 35.5, 35.8, 42.5, 43.8, 46.0, 51.0, 56.6, 58.5, 59.9, 70.1, 77.3, 92.3, 116.6, 119.5, 125.7, 127.0, 128.2, 128.3, 132.6, 137.4, 145.0, 145.5. HRMS (ES) calcd for C.sub.31H.sub.44NO.sub.4 (M.sup.+), 473.2566. found 473.2558.
N-Cyclopropylcarbonyl-7-formyl-7-methyl-6, 14-endo-ethenotetrahydronorthebaine (17b)
(51) To a suspension of 13.61 g (37.29 mmol) N-CPCnorthebaine (16) in 20 mL of methacrolein was added 3.49 g of LiBF.sub.4. The resulting solution was stirred for 16 h at RT. Into this solution were added 30 mL of CH.sub.2Cl.sub.2 and the mixture was extracted with water (10 mL3) and brine (5 mL). The solution was dried, filtered and removed of solvent on a rotary evaporator to afford a dark red syrup. This material was subjected to silica gel flash column chromatography eluting with 50% EtOAc in petroleum ether to afford 5.91 g of the faster running component 17a (N-Cyclopropylcarbonyl-7-formyl-7-methyl-6,14-endo-ethenotetrahydronorthebaine) as white solid .sup.1H NMR (CDCl.sub.3) 9.85 (s, 1H); 6.67 (d, 1H, J=6 Hz); 6.57 (d, 1H, J=6 Hz); 6.14-6.07 (2d, 1H); 5.57 (d, 1H, J=9 Hz); 5.33 (d, 1H, J=6 Hz); 4.76 (d, 1H, 0.4H); 4.57-4.53 (m, 1.6H); 4.15-4.10 (m, 1H); 3.85 (s, 3H); 3.72 (s, 3H); 3.42 (dt, 1H, J.sub.a=9 Hz, J.sub.b=3 Hz); 3.11-3.05 (dd, 1H, J.sub.a=6 Hz, J.sub.b=3 Hz); 2.88-2.83 (m, 2H); 2.43-2.35 (dt, 1H, J.sub.a=9 Hz, J.sub.b=6 Hz), 1.85-1.76 (m, 1H); 1.69-1.65 (m, 1H); 1.09-1.03 (m, 5H); 0.91-0.76 (m, 2H). ESIMS: m/z 436 (M+H.sup.+, 100) and 4.11 g of a slower running component N-Cyclopropylcarbonyl-7-formyl-7-methyl-6,14-endo-ethenotetrahydronorthebaine (17b) as a white solid.
(52) .sup.1H NMR (CDCl.sub.3) 9.54 (s, 0.5H); 9.45 (s, 0.5H); 6.69 (d, 1H, J=6 Hz); 6.59 (d, 1H, J=6 Hz); 6.14 (t, 1H); 5.57 (dd, 1H, J.sub.a=9 Hz, J.sub.b=6 Hz); 5.35 (d, 0.5H, J=3 Hz); 4.93 (s, 1H); 4.80 (d, 0.5H, J=6 Hz); 4.64 (dd, 1H, J.sub.a=6 Hz, J.sub.b=3 Hz); 4.15 (dd, 1H, J.sub.a=6 Hz, J.sub.b=3 Hz); 3.85 (s, 3H); 3.72 (2s, 3H); 3.49 (dt, 1H); 3.21-3.31 (m, 2H), 2.37-2.26 (dt, 0.5H), 2.27-2.15 (dt, 0.5H); 2.06-1.72 (m, 3H); 1.35 (s, 3H); 1.08 (m, 2H); 0.82 (m, 2H). At RT the .sup.1H NMR spectra of this compound in d.sub.6-DMSO has two signals at 9.408 (s, 0.5H) and 9.375 (s, 0.5H) which coalesce when running the .sup.1H NMR experiment at 360 K. ESIMS: m/z 436 (M+H.sup.30, 100).
N-Cyclopropylcarbonyl-6, 14-endo-etheno-7-methyl-nornepenthol (18)
(53) General procedure B was followed using 500 mg of 17b to yield 442 mg of 18 as a white solid: .sup.1H NMR (CDCl.sub.3) 7.26-7.19 (m, 5H); 6.68-6.63 (2d, 1H); 6.55-6.49 (2d, 1H); 6.19 (d, 0.55H, J=9 Hz); 5.98 (d, 0.45H, J=6 Hz); 5.41 (d, 0.55H, J=9 Hz); 5.29-5.22 (m, 1H); 5.01 (s, 1H), 4.80 (d, 1H, J=3 Hz); 4.66-4.53 (m, 1H); 4.12 (dd, 0.45H, J=3 Hz, J=6 Hz); 3.84 (2s, 3H); 3.72 (2s, 3H); 3.49-3.39 (m, 0.45H); 3.20-3.11 (dd, 0.55H, J=3 Hz, J=6 Hz); 3.08-2.89 (m, 2H); 2.82-2.78, (d, 0.55H); 2.46 (d, 0.45H); 2.39 (dt, 0.45H); 2.24 (dt, 0.55H); 2.10 (d, 0.55H, J=9 Hz); 2.03 (d, 0.45H, J=9 Hz); 1.89-1.69 (m, 3H); 1.27 (s, 1.35H); 1.12 (s, 1.65H); 1.10-0.91 (m, 2H); 0.88-0.78 (m, 2H). ESIMS: m/z 514 (M+H.sup.+, 100).
N-Cyclopropylmethy 1-6,14-endo-etheno-7-methyl-norisonepenthol (20: R=Ph)
(54) General procedures C and D were followed using 439 mg of 18 to yield, after chromatography, 201 mg of the faster eluting component 20a as a colorless oil
(55) .sup.1H NMR (CDCl.sub.3) 7.29-7.20 (m, 5H); 6-64 (d, 1H, J=6 Hz); 6.50 (d, 1H, J=6 Hz); 6.20 (dd, 1H, J.sub.a=6 Hz, J.sub.b=3 Hz); 5.58 (d, 1H, J=6 Hz); 5.28 (s, 1H); 5.08 (s, 1H); 4.69 (s, 1H); 3.85 (s, 6H); 3.40 (d, 1H, J=6 Hz); 3.07 (d, 1H, J=15 Hz); 2.66 (m, 1H); 2.39 (dd, 1H, J.sub.a=6 Hz, J.sub.b=15 Hz); 2.35-2.22 (m, 4H); 2.01 (d, 1H, J=12 Hz); 1.75-1.71 (m, 1H); 1.53 (s, 1H); 1.41 (s, 3H); 1.32-1.28 (d, 1H, J=12 Hz); 0.73-0.68 (m, 1H); 0.52-0.42 (m, 2H); 0.09-0.02 (m, 2H). ESIMS: m/z 500 (M+H.sup.+, 100).
N-Cyclopropylmethyl-6,14-endo-etheno-7-methyl-nornepenthol (21: R=Ph)
(56) General procedure D was followed using 439 mg of 18 to yield, after chromatography, 139 mg of the slower eluting component 21 as a colourless oil .sup.1H NMR (CDCl.sub.3) 7.29-7.17 (m, 5H); 6.59 (d, 1H, J=6 Hz); 6.46 (d, 1H, J=6 Hz); 6.02 (d, 1H, J=6 Hz); 5.35 (d, 1H, J=6 Hz); 5.01 (s, 1H); 4.78 (s, 1H); 3.82 (s, 3H); 3.70 (s, 3H); 3.52 (d, 1H, J=3 Hz); 3.08 (d, 1H, 15 Hz); 2.78-2.68 (m, 2H); 2.44-2.25 (m, 6H); 1.94 (d, 1H, J=12 Hz); 1.75-1.72 (m, 1H); 1.21 (s, 3H) 0.85 (m, 1H); 0.54 (m, 2H); 0.14 (m, 2H). ESIMS: m/z 500 (M+H.sup.+, 100).
22, R=Ph: (1R, 5, 6R, 7R, 14)-1-phenyl-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (BU128)
(57) General procedure E or F was followed using 184 mg of 20 to yield 103 mg of 22 as a white solid: .sup.1H NMR (CD.sub.3OD) 7.37 (d, 1H, J=6 Hz); 7.32-7.23 (m, 3H); 6.62 (d (AB system), 1H); 6.56 (d (AB system), 1H); 6.22 (d, 1H, J=6 Hz); 5.61 (d, 1H, J=9 Hz); 5.22 (s, 1H), 4.47 (s, 1H); 4.35 (d, 1H, J=6 Hz); 3.86 (s, 3H); 3.40-3.30 (m, 3H); 3.15 (dt, 1H, J.sub.a=9 Hz, J.sub.b=3 Hz); 3.09-2.97 (m, 2H); 2.47 (dt, 1H, J.sub.b=9 Hz, J.sub.a=3 Hz); 2.10 (dd, 1H, J.sub.a=12 Hz, J.sub.b=3 Hz); 1.87 (d (AB system), 1H); 1.67 (d, (AB system), 1H); 1.50 (s, 3H); 1.07 (m, 1H); 0.83 (m, 1H); 0.74 (m, 1H); 0.51-0.43 (m, 2H). ESIMS: m/z 486 (M+H.sup.+, 100).
23, R=Ph: (1R, 5, 6R, 7R, 14)-1-phenyl-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (BU129)
(58) General procedure E or F was followed using 161 mg of 21 to yield 56 mg of 23 as a white solid: .sup.1H NMR (CD.sub.3OD) 7.30-7.18 (m, 5H); 6.59 (AB system, 2H); 6.31 (d, 1H, J=6.7 Hz); 5.51 (d, 1H, J=6.7 Hz); 5.02 (s, 1H); 4.66 (s, 1H); 4.45 (d, 1H, J=5.1 Hz); 3.50-3.40 (m, 3H); 3.38-3.32 (m, 1H); 3.20 (dt, 1H, J.sub.a=10.5 Hz, J.sub.b=7.3 Hz); 3.16-3.04 (m, 2H); 2.53 (dt, 1H, J.sub.a=11.0 Hz, J.sub.b=3.9 Hz); 2.16 (AB system, 2H); 2.11 (dd, 1H); 1.28 (s, 3H); 1.21-1.13 (m, 1H); 0.92-0.84 (m, 1H); 0.84-77 (m, 1H); 0.57 (m, 2H). ESIMS: m/z 486 (M+H.sup.+, 100).
(59) By a similar method, the following ligands were prepared:
22, R=o-tolyl: (1R, 5, 6R, 7R, 14)-1-(2-methylphenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (BU10111)
(60) .sup.1H NMR (CD.sub.3OD) 7.65 (d, 1H, J=5.5 Hz); 7.25-7.15 (m, 3H); 6.67-6.47 (AB system, 2H); 5.80 (d, 1H. J=6.7 Hz); 5.26 (s, 1H). 5.08 (s, 1H): 4.23 (d, 1H, J=4.8 Hz); 3.94 (s, 3H); 3.43-3.33 (m, 3H); 3.12 (m, 1H); 3.03-2.83 (m, 1H); 2.52 (dt, 1H, J.sub.b=10.3 Hz, J.sub.a=4.1 Hz); 2.27 (s, 3H); 2.16-2.04 (bd, 1H); 1.95 (d, 1H, J=10.2 Hz); 1.61 (s, 3H); 1.23 (d, 1H, J=10.2 Hz); 1.07 (m, 1H); 0.82 (m, 1H); 0.72 (m, 1H); 0.49-0.37 (m, 2H). ESIMS: m/z 500 (M+H.sup.+, 100).
23, R=o-tolyl (1R, 5, 6R, 7R, 14)-1-(2-methylphenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (BU10121)
(61) .sup.1H NMR (CD.sub.3OD) 7.16 (d, 2H, J=6.0 Hz); 7.08 (d, 2H, J=6.0 Hz); 6.59 (d, 1H, J=6.1 Hz); 6.54 (d, 1H, J=6.1 Hz); 6.29 (d, 1H, J=6.5 Hz); 5.49 (s, 1H J=6.8 Hz); 5.02 (s, 1H); 4.63 (s, 1H); 4.45 (bd, 1H); 3.47 (s, 3H); 3.46-3.31 (m, 2H); 3.32-3.06 (m, 3H); 2.52 (dt, 1H, J.sub.a=13.8 Hz, J.sub.b=3.8 Hz); 2.30 (s, 3H); 2.14 (s, 2H); 2.10-2.06 (m, 1H); 1.24 (s, 3H); 1.18 (m, 1H); 0.89-0.78 (m, 2H); 0.51 (m, 2H). ESIMS: m/z 500 (M+H.sup.+, 100).
23, R=m-tolyl: (1R, 5, 6R, 7R, 14)-1-(3-methylphenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (BU10112)
(62) .sup.1H NMR (CD.sub.3OD) 7.45 (d, 1H, J=5.6 Hz); 7.18-7.13 (m, 3H); 6.64-6.57 (AB system, 2H); 6.33 (d, 1H, 6.7 Hz); 5.54 (d, 1H, J=6.7 Hz); 5.35 (s, 1H), 5.11 (s, 1H); 4.52 (d, 1H, J=5.1 Hz); 3.72 (s, 3H); 3.51-3.32 (m, 3H); 3.29-3.20 (dt, 1H, J.sub.b=9.8 Hz, J.sub.a=3.1 Hz); 3.17-3.09 (m, 2H); 2.59 (dt, 1H, J.sub.b=10.3 Hz, J.sub.a=4.1 Hz); 2.45 (d, 1H, J=11.1 Hz); 2.39 (s, 3H); 2.22 (d, 1H, 11.1 Hz); 2.11 (bd, 1H); 1.23 (m, 1H); 1.11 (s, 3H); 0.92-0.85 (m, 2H); 0.57 (m, 1H). ESIMS: m/z 500 (M+H.sup.+, 100).
23, R=m-tolyl: (1R, 5, 6R, 7R, 14)-1-(3-methylphenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (BU10113)
(63) .sup.1H NMR (CD.sub.3OD) 7.17-7.06 (m, 3H); 6.59 (d, 1H, J=6.0 Hz); 6.54 (d, 1H, J=6.0 Hz); 6.31 (d, 1H, J=6.9 Hz); 5.50 (d, 1H, J=6.6 Hz); 5.02 (s, 1H J=6.8 Hz); 4.64 (s, 1H); 4.44 (bd, 1H); 3.45 (s, 3H); 3.46-3.31 (m, 2H); 3.23-3.05 (m, 3H); 2.52 (dt, 1H, J.sub.a=11.7 Hz, J.sub.b=4.4 Hz); 2.32 (s, 3H); 2.11 (m, 2H); 1.25 (s, 3H); 1.18 (m, 1H); 0.93-0.77 (m, 2H); 0.53 (m, 2H). ESIMS: m/z 500 (M+H.sup.+, 100).
22, R=p-tolyl: (1R, 5, 6R, 7R, 14)-1-(4-methylphenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (BU10117)
(64) .sup.1H NMR (CD.sub.3OD) 7.25 (d, 1H, J=6.0 Hz): 7.12 (d, 1H, J=5.7 Hz); 6.59 (AB system, 2H); 6.23 (d, 1H, J=6.6 Hz): 5.62 (d, 1H, J=6.6 Hz); 5.21 (s, 1H), 4.69 (s, 1H); 4.34 (d, 1H, J=4.8 Hz); 3.87 (s, 3H); 3.40-3.32 (m, 3H); 3.14 (dt, J.sub.a=9.9 Hz, J.sub.a=1.8 Hz); 3.12-2.99 (m, 2H); 2.48 (dt, 1H, J.sub.b=3.9 Hz, J.sub.a=10.8 Hz); 2.30 (s, 3H); 2.10 (dd, J.sub.a=10.8 Hz, J.sub.b=2.4 Hz); 1.87 (d, AB system, 1H); 1.64 (d, AB system, 1H); 1.50 (s, 3H); 1.07 (m, 1H); 0.83 (m, 1H); 0.74 (m, 1H); 0.52-0.40 (m, 2H). ESIMS: m/z 500 (M+H.sup.+, 100).
23, R=p-tolyl: (1R, 5, 6R, 7R, 14)-1-(4-methylphenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (BU10099)
(65) .sup.1H NMR (CD.sub.3OD) 7.16 (d, 2H, J=6.0 Hz); 7.08 (d, 2H, J=6.0 Hz); 6.59 (d, 1H, J=6.1 Hz); 6.54 (d, 1H, J=6.1 Hz); 6.29 (d, 1H, J=6.5 Hz); 5.49 (s, 1H J=6.8 Hz); 5.02 (s, 1H); 4.63 (s, 1H); 4.45 (bd, 1H); 3.47 (s, 3H); 3.46-3.31 (m, 2H); 3.32-3.06 (m, 3H); 2.52 (dt, 1H, J.sub.a=13.8 Hz, J.sub.b=3.8 Hz); 2.30 (s, 3H); 2.14 (s, 2H); 2.10-2.06 (m, 1H); 1.24 (s, 3H); 1.18 (m, 1H); 0.89-0.78 (m, 2H); 0.51 (m, 2H). ESIMS: m/z 500 (M+H.sup.+, 100).
22, R=p-fluorophenyl: (1R, 5, 6R, 7R, 14)-1-(4-fluorophenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (BU10120)
(66) .sup.1H NMR (maleate) (400 MHz, CDCl.sub.3) 0.40-0.49 (2H, m), 0.72-0.84 (2H, m), 1.00-1.12 (1H, m) 1.48 (3H, s), 1.61 (1H, d, J=13.6 Hz), 1.88 (1H, d, J=13.2 Hz), 2.08 (1H, d, J=14.4 Hz), 2.46 (1H, td, J=14.1, 4.9 Hz), 2.93-3.15 (3H, m), 3.85 (3H, s), 4.29 (1H, s), 5.20 (1H, s), 5.58 (1H, d, J=8.0 Hz), 6.16 (1H, d, J=8.0 Hz), 6.24 (2H, s), 6.54 (1H, d, J=8.0 Hz), 6.61 (1H, d, J=8.4 Hz), 7.01-7.05 (2H, m), 7.36-7.38 (2H, m).
23, R=p-fluorophenyl: (1R, 5, 6R, 7R, 14)-1-(4-fluorophenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (BU10118)
(67) .sup.1H NMR (maleate) (CD.sub.3OD) 7.31-7.27 (m, 2H); 7.01-6.96 (m, 2H); 6.59 (d, 1H, J=6.0 Hz); 6.55 (d, 1H, J=6.0 Hz); 6.31 (d, 1H, J=6.7 Hz); 5.53 (d, 1H, J=6.9 Hz); 5.00 (s, 1H); 4.63 (s, 1H); 4.45 (d, 1H, J=5.1 Hz); 3.48-3.28 (m, 5H); 3.24 (dt, 2H, J.sub.a=10.2 Hz, J.sub.b=3.3 Hz); 3.11 (d, (d, 1H, J=5.4 Hz); 3.07 (t, J=5.4 Hz); 2.53 (dt, 1H, J.sub.a=10.5 Hz, J.sub.b=3.9 Hz); 2.21 (d, 1H, J=9.9 Hz); 2.12-2.06 (m, 2H); 1.29 (s, 3H); 1.17 (m, 1H); 0.93-0.78 (m, 2H); 0.53 (m, 2H). ESIMS: m/z 504 (M+H.sup.+, 100).
22, R=4-PrSPh (1R, 5, 6R, 7R, 14)-1-(4-propylthiophenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (BU11020)
(68) .sup.1H NMR (maleate) (400 MHz, CDCl.sub.3) 0.38-0.51 (2H, m), 0.70-0.89 (2H, m), 1.01 (3H, t, J=7.1 Hz), 1.03-1.12 (1H, m), 1.44-1.51 (4H, m), 1.59-164 (3H, m), 1.87 (1H, d, J=13.0 Hz), 2.10 (1H, dd, J=14.8, 3.7 Hz), 2.47 (1H, td, J=13.9, 4.9 Hz), 2.89 (2H, t, J=6.8 Hz), 2.98-3.18 (3H, m), 3.32-3.40 (3H, m). 3.85 (3H, s), 4.34 (1H, d, J=7.2 Hz), 4.68 (1H, s), 5.21 (1H, s), 5.60 (1H, d, J=9.0 Hz), 6.20 (1H, d, J=8.9 Hz), 6.26 (2H, s), 6.56 (1H, d, J=8.1 Hz), 6.61 (1H, d, J=8.1 Hz), 7.25-7.30 (4H, m).
N-Cyclopropylcarbonyl-7-formyl-7-methyl-6,14-endo-ethanotetrahydronorthebaine (24)
(69) The aldehyde 17b (500 mg) was dissolved in 15 mL of EtOH. Into this solution was added 30 mg of 10% Pd on carbon. The mixture was shaken in a Parr hydrogenator under 100 psi of H.sub.2 for 12 h. The mixture was filtered and the solvents removed under reduced pressure to yield 510 mg of 24 as a white solid.
(70) .sup.1H NMR (CDCl.sub.3) 9.69 (2s, 1H); 6.77 (d, 1H, J=6.1 Hz); 6.61 (d, 1H, J=6.1 Hz); 4.91 (d, 0.47H, J=4.9 Hz); 4.83 (2s, 1H); 4.52 (dd, 0.53H, J=10.6 Hz); 4.35 (d, 0.53H, J=5.2 Hz); 4.08-4.03 (m, 1H); 3.90 (s, 3H); 3.46 (2s, 3H); 3.39-3.30 (m, 0.47H); 3.08-2.95 (m, 1H); 2.90-2.69 (m, 2H); 2.41 (m, 1H); 2.28 (dt, 0.47H); 2.17 (dt, 0.53H); 1.70-1.60 (m, 4H); 1.31 (s, 3H); 1.19-1.1 (m, 1H); 1.01 (m, 2H); 0.77 (m, 2H). ESIMS: m/z 438 (M+H.sup.+, 100).
N-Cyclopropylcarbonyl-6,14-endo-ethano-7-methyl-nornepenthol (25)
(71) General procedure B was followed using 515 mg of 24 to yield 336 mg of 25 as white crystals:
(72) .sup.1H NMR (CDCl.sub.3) 7.36-7.23 (m, 5H); 6.78-6.75 (2d, 1H); 6.61-6.58 (2d, 1H); 5.06 (d, 0.55H, J=2.0 Hz); 4.99 (d, 0.45H, J=2.0 Hz); 4.91-4.87 (m, 1H); 4.51-4.46 (dd, 0.55H, J.sub.a=4.1 Hz, J.sub.b=10.3 Hz); 4.35-4.34 (d, 0.55H, J=5.1 Hz); 4.03-3.98 (d, 0.45H, J.sub.a=3.7 Hz, J.sub.b=10.2 Hz); 3.92-3.914 (2s, 3H); 3.53 (s, 1.65H); 3.48 (s, 1.35H); 3.38-3.30 (dt, 0.55H, J.sub.a=2.9 Hz, J.sub.b=6.5 Hz); 3.11-3.04 (dd, 0.55H, J.sub.a=5.2 Hz, J.sub.b=13.8 Hz); 3.02-2.96 (dd, 0.45H, J.sub.a=5.2 Hz, J.sub.b=13.9 Hz); 2.92-2.88 (d, 0.55H, J=13.8 Hz); 2.49-2.44 (m, 1H); 2.36-2.29 (dt, 0.45 Hz, J.sub.a=4.2 Hz, J.sub.b=9.7 Hz); 2.25-2.17 (dt, 0.55 Hz, J.sub.a=4.5 Hz, J.sub.b=9.9 Hz); 2.03-1.90 (m, 2H); 1.86-1.80 (m, 0.55 Hz); 1.76-1.51 (m, 5.45H); 1.10-0.69 (m, 7H).
(73) ESIMS: m/z 516 (M+H.sup.+, 100).
(1R, 5, 6R, 7R, 14)-1-phenyl-1-(4,5-epoxy-7,8-dihydro-3,6-dimethoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (28: R=Ph)
(74) General procedures C and D were followed using 473 mg of 25 to yield a clear residue after extraction. Crystallization from CH.sub.2Cl.sub.2/Et.sub.2O gave 133 mg of 28 as white crystals
(75) .sup.1H NMR (CDCl.sub.3) 7.45 (m, 2H); 7.34-7.30 (m, 2H); 7.27-7.24 (m, 1H); 6.73 (d, 1H, J=6.3 Hz); 6.57 (d, 1H, J=6.0 Hz); 5.76 (s, 1H); 5.03 (s, 1H); 4.96 (s, 1H); 3.91 (s, 3H); 3.64 (s, 3H); 3.01-2.94 (m, 2H); 2.57 (d, 1H, J=5.1 Hz); 2.29 (dd, 1H, J.sub.a=5.1 Hz, J.sub.b=13.8 Hz); 2.24-2.20 (m, 3H); 1.95 (dd, 1H, J.sub.a=3 Hz, J.sub.=10.8 Hz); 1.90-1.77 (m, 2H); 1.60-1.52 (m, 2H); 1.40-1.28 (m, 4H); 0.95 (m, 1H); 0.68 (m, 1H); 0.51-0.39 (m, 2H); 0.08-0.01 (m, 2H). ESIMS: m/z 502 (M+H.sup.+, 100).
(1S, 5, 6R, 7R, 14)-1-phenyl-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (BU10122)
(76) General procedure E or F was followed using 27 to yield 29 as a white solid:
(77) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.47-0.53 (2H, m), 0.77-0.89 (3H, m), 0.92 (3H, s), 1.12-1.20 (1H, m), 1.62-1.70 (1H, m), 1.79-1.90 (2H, m), 2.00 (1H, dd, J=12.6, 4.2 Hz), 2.15 (1H, t, J=12.2 Hz), 2.50 (1H, td, J=13.8, 5.6 Hz), 2.67 (1H, d, J=12.8 Hz), 2.95 (1H, dd, J=19.4, 7.0 Hz), 3.00-3.12 (2H, m), 3.22-3.39 (3H, m), 3.47 (3H, s), 4.00 (1H, d, J=7.2 Hz), 4.95 (1H, d, J=2.4 Hz), 5.02 (1H, s), 6.64 (1H, d, J=8.0 Hz), 6.74 (1H, d, J=8.4 Hz), 7.21-7.25 (1H, m), 7.27-7.31 (2H, m), 7.36-7.38 (2H, m). HMRS: calc for [C.sub.31H.sub.36N.sub.1O.sub.4].sup.+ ([M+H].sup.+) 488.2796. found 488.2949.
(1R, 5, 6R, 7R, 14)-1-phenyl-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (BU10119)
(78) General procedure E or F was followed using 133 mg of 28 to yield 75 mg of 30 as a white solid:
(79) .sup.1H NMR (CD.sub.3OD) 7.55 (d, 2H); 7.38-7.34 (m, 2H); 7.31-7.27 (m, 1H); 6.77 (d, 1H, J=6.0 Hz); 6.67 (d, 1H, J=6.0 Hz); 5.11 (s, 2H); 3.93 (d, 1H, J=5.4 Hz); 3.27-3.18 (m, 2H); 3.6-2.91 (m, 3H); 2.41 (dt, 1H, J.sub.a=10.5 Hz, J.sub.b=4.2 Hz); 1.95-1.90 (m 1H); 1.77 (dd, 1H, J.sub.a=10.2 Hz, J.sub.b=3.3 Hz); 1.66-1.58 (m, 1H); 1.38 (s, 3H); 1.05-1.01 (m, 1H); 0.80 (m, 1H); 0.72 (m, 1H); 0.4-0.34 (m, 2H). ESIMS: m/z 488 (M+H.sup.+, 100).
(80) By a similar method the following compounds were prepared:
(1R, 5, 6R, 7R, 14)-1-(2-methylphenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (BU12004)
(81) .sup.1H NMR (400 MHz, CDCl.sub.3) (0.02)-0.07 (2H, m), 0.38-0.48 (2H, m), 0.62-0.71 (1H, m), 0.83-0.95 (1H, m), 1.25 (1H, d, J=14.3 Hz), 1.33-1.43 (4H, m), 1.56 (1H, d, J=10.1 Hz), 1.83-1.87 (2H, m), 1.99 (1H, dd, J=14.3, 3.9 Hz), 2.18-2.31 (5H, m), 2.47 (3H, s), 2.57-2.61 (1H, m), 2.93 (1H, d, J=6.5 Hz), 2.94 (1H, d, J=18.1 Hz). 3.61 (3H, s), 4.83 (1H, bs), 5.04 (1H, s), 5.47 (1H, s), 5.49 (1H, s), 6.52 (1H, d, J=8.0 Hz), 6.69 (1H, d, J=8.0 Hz), 7.13 (1H, dd, J=7.5, 1.7 Hz), 7.17 (1H, td, J=7.3, 1.5 Hz), 7.22 (1H, td, J=7.4, 1.5 Hz), 7.69 (1H, dd, J=7.8, 1.2 Hz). .sup.13C NMR (101 MHz, CDCl.sub.3) 3.8, 4.3, 9.6, 17, 7, 18.3, 21.8, 23.1, 28.9, 33.6, 35.9, 38.6, 43.8, 44.5, 46.2, 53.5, 53.7, 59.3, 60.3, 73.8, 82.6, 94.8, 116.8, 119.9, 125.7, 127.4, 128.4, 130.6, 130.8, 133.4, 136.1, 137.7, 139.7, 145.4. HMRS: calc for [C.sub.32H.sub.40N.sub.1O.sub.4].sup.+ ([M+H].sup.+) 502.2952. found 502.3045.
(1R, 5, 6R, 7R, 14)-1-(4-methylphenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (30: R=3-MePh) (BU12005)
(82) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.00-0.08 (2H, m), 0.39-0.50 (2H, m), 0.64-0.74 (1H, m), 0.86-0.96 (1H, m), 1.26-1.35 (4H, m), 1.54-1.58 (2H, m), 1.76-1.87 (2H, m), 1.96 (1H, dd, J=14.3, 4.9 Hz), 2.19-2.30 (5H, m), 2.36 (3H, s), 2.54-2.62 (1H, m), 2.95 (1H, d, J=19.7 Hz), 2.99 (1H, d, J=6.9 Hz), 3.61 (3H, s), 4.75 (1H, bs), 5.00 (2H, s), 5.72 (1H, s), 6.53 (1H, d, J=8.0 Hz), 6.70 (1H, d, J=8.0 Hz), 7.07 (1H, d, J=6.8 Hz), 7.18-7.23 (2H, m), 7.29 (1H, s). .sup.13C NMR (101 MHz, CDCl.sub.3) 3.8, 4.4, 9.6, 17.2, 18.2, 21.9, 23.1, 29.7, 33.7, 35.9, 39.8, 43.4, 43.9, 46.2, 53.4, 59.3, 60.3, 80.4, 82.4, 94.8, 116.8, 120.0, 127.5, 127.6, 128.4, 128.5, 131.0, 133.4, 137.2, 137.7, 141.2, 145.4. HMRS: calc for [C.sub.32H.sub.40N.sub.1O.sub.4].sup.+ ([M+H].sup.+) 502.2952. found 502.3086.
(1R, 5, 6R, 7R, 14)-1-(4-methylphenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (30: R=4-MePh) (BU12006)
(83) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.00-0.07 (2H, m), 0.41-0.50 (2H, m), 0.64-0.72 (1H, m), 0.86-0.94 (1H, m), 1.25-1.32 (4H, m), 1.50-1.55 (2H, m), 1.76-1.84 (2H, m), 1.95 (1H, dd, J=14.0, 4.0 Hz), 2.18-2.28 (5H, m), 2.34 (3H, s), 2.55-2.61 (1H, m), 2.94 (1H, d, J=18.5 Hz), 2.98 (1H, d, J=6.5 Hz), 3.60 (3H, s), 4.97 (1H, s), 5.01 (1H, s), 5.47 (1H, bs), 5.85 (1H, s), 6.50 (1H, d, J=8.0 Hz). 6.66 (1H, d, J=8.0 Hz), 7.12 (2H, d, J=8.0 Hz), 7.33 (2H, d, J=8.0 Hz). .sup.13C NMR (125 MHz, CDCl.sub.3) 3.4, 4.0, 9.2, 16.8, 17.8, 21.0, 22.6, 23.8, 29.3, 33.3, 35.5, 39.4, 43.0, 43.5, 45.7, 53.0, 58.9, 60.0, 79.9, 81.9, 94.2, 116.5, 119.5, 127.8, 128.0, 129.9, 132.9, 136.8, 137.5, 137.7, 145.0. HMRS: calc for [C.sub.32H.sub.40N.sub.1O.sub.4].sup.+ ([M+H].sup.+) 502.2952. found 502.3104; calc for [C.sub.32H.sub.39N.sub.1O.sub.4Na.sub.1].sup.+ ([M+Na].sup.+) 524.2777. found 524.2812.
(1R, 5, 6R, 7R, 14)-1-(4-fluorophenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (30: R=4-FPh) (BU12007)
(84) .sup.1H NMR (400 MHz, CDCl.sub.3) 0.00-0.08 (2H, m), 0.40-0.50 (2H, m), 0.64-0.72 (1H, m), 0.87-0.97 (1H, m), 1.23-1.29 (4H, m), 1.46 (1H, d, J=14.5 Hz), 1.51-1.58 (1H, m), 1.73-1.85 (2H, m), 1.95 (1H, dd, J=14.0, 4.0 Hz), 2.19-2.28 (5H, m), 2.54-2.61 (1H, m), 2.94 (1H, d, J=18.5 Hz), 2.99 (1H, d, J=6.5 Hz), 3.59 (3H, s), 4.95 (1H, d, J=2.0 Hz), 5.03 (1H, s), 6.00 (1H, s), 6.49 (1H, d, J=8.5 Hz) 6.62 (1H, d, J=8.0 Hz), 7.00 (2H, t, J=8.8 Hz), 7.42 (2H, dd, J=8.5, 5.5 Hz). .sup.13C NMR (125 MHz, CDCl.sub.3) 3.4, 4.0, 9.1, 16.7, 17.7, 22.6, 29.3, 33.3, 35.4, 39.4, 42.9, 43.5, 45.6, 58.8, 59.9, 79.4, 81.9, 93.9, 114.0, 114.2, 116.62, 119.5, 127.6, 131.3, 131.4, 132.8, 137.6, 145.0, 161.1, 163.0. HMRS: calc for [Ca.sub.31H.sub.37N.sub.1O.sub.4F.sub.1].sup.+ ([M+H].sup.+) 506.2701. found 506.2682.
(1R, 5, 6R, 7R, 14)-1-(3-thiophenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (30: R=3-thiophenyl-) (BU12015)
(85) White Solid; .sup.1H NMR (CDCl.sub.3) 0.04-0.06 (2H, m), 0.44-0.49 (2H, m), 0.69-0.73 (1H, m), 0.88-0.93 (1H, m), 1.18-1.21 (1H, m), 1.30 (3H, s), 1.49-1.56 (2H, m), 1.71-1.83 (2H, m), 2.08 (1H, dd, J=14.20 Hz & J=4.04 Hz), 2.16-2.30 (5H, m), 2.58 (1H, d, J=6.72 Hz), 2.93 (1H, d, J=18.40 Hz), 2.98 (1H, d, J=6.36 Hz), 3.60 (3H, s), 4.68 (1H, bd), 4.98 (1H, s), 5.14 (1H, s), 5.64 (1H, s), 6.52 (1H, d, J=3.08 Hz), 6.69 (1H, d, J=8.08 Hz), 7.17-7.19 (1H, m), 7.22-7.25 (2H, m); .sup.13C NMR, 400 MHz, (CDCl.sub.3) 3.28, 4.09, 9.21, 16.89, 17.81, 22.66, 29.34, 33.35, 35.54, 40.09, 42.97, 43.56, 45.72, 53.03, 58.79, 59.92, 76.62, 81.78, 94.21, 116.38, 119.58, 123.55, 123.96, 128.06, 128.81, 132.90, 137.26, 142.54, 145.11. HRMS, m/z for (C.sub.29H.sub.35NO.sub.4SNa) [MNa].sup.+, calcd516.2184. found516.2212. Anal. (C.sub.29H.sub.35NO.sub.4S.HCl) C, H, N.
(1R, 5, 6R, 7R, 14)-1-(3-methyl-2-thiophenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (30: R=(3-methyl-2-thiophenyl) (BU12016)
(86) White Solid; .sup.1H NMR (CDCl.sub.3) 0.02-0.04 (2H, m), 0.41-0.46 (2H, m), 0.66-0.72 (1H, m), 0.87-0.97 (1H, m), 1.24-1.28 (2H, m), 1.52 (3H, s), 1.55-1.61 (1H, m), 1.77-1.85 (2H, m), 2.11 (1H, dd, J=14.20 Hz & J=4.04 Hz), 2.21-2.29 (8H, m), 2.59 (1H, m), 2.92-2.96 (2H, m), 3.58 (3H, s), 4.80 (1H, bd), 5.01 (1H, s), 5.45 (2H, s), 6.51 (1H, d, J=8.08 Hz), 6.68 (1H, d, J=8.08 Hz), 6.76 (1H, d, J=5.72 Hz), 7.20 (1H, d, J=5.12 Hz) .sup.13C NMR, 400 MHz, (CDCl.sub.3) 3.38, 3.93, 9.18, 15.67, 17.09, 17.94, 22.68, 29.01, 33.33, 35.50, 39.27, 43.43, 44.10, 45.87, 53.08, 58.90, 59.91, 73.50, 81.90, 94.22, 116.40, 119.57, 124.09, 127.99, 128.75, 132.87, 134.55, 137.29, 138.41, 144.92. HRMS, m/z for (C.sub.30H.sub.38NO.sub.4S) [MH].sup.+, calcd508.2521. found508.2571. Anal. (C.sub.30H.sub.37NO.sub.4S.HCl) C, H, N.
(1R, 5, 6R, 7R, 14)-1-(5-chloro-2-thiophenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (30: R=(5-chloro-2-thiophenyl) (BU12018)
(87) White Solid; .sup.1H NMR (CDCl.sub.3) 0.06-0.07 (2H, m), 0.46-0.50 (2H, m), 0.73-0.75 (1H, m), 0.87-0.94 (1H, m), 1.14-1.19 (1H, m), 1.32 (3H, s), 1.44-1.52 (2H, m), 1.65-1.68 (1H, m), 1.77-1.80 (1H, m), 2.23-2.28 (6H, m), 2.61 (1H, d, J=7.08 Hz), 2.93 (1H, d, J=18.40 Hz), 2.98 (1H, d, J=6.36 Hz), 3.57 (3H, s), 4.63 (1H, bd), 4.96 (1H, s), 5.16 (1H, s). 5.87 (1H, s), 6.52 (1H, d, J=8.08 Hz), 6.69 (1H, d, J=8.08 Hz), 6.76 (1H, d, J=3.80 Hz), 6.79 (1H, d, J=3.80 Hz); .sup.13C NMR, 400 MHz, (CDCl.sub.3) 3.39, 3.98, 9.25, 16.80, 17.69, 22.85, 29.27, 33.38, 35.58, 40.39, 42.99, 43.45, 45.73, 53.05, 58.82, 59.94, 77.58, 81.67, 94.04, 116.44, 119.67, 124.82, 125.23, 128.05, 129.14, 132.76, 137.25, 144.32, 144.87. HRMS, m/z for (C.sub.29H.sub.34NO.sub.4SClNa) [MNa].sup.+, calcd550.1795. found550.1823. Anal. (C.sub.29H.sub.34NO.sub.4SCl.HCl) C, H, N.
(1R, 5, 6R, 7R, 14)-1-(2-thiophenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (30: R=(2-thiophenyl) (BU12025)
(88) White Solid; .sup.1H NMR (CDCl.sub.3) 0.05-0.06 (2H, m), 0.42-0.51 (2H, m), 0.70-0.75 (1H, m), 0.86-0.95 (1H, m), 1.17-1.21 (2H, m), 1.35 (3H, s), 1.47-1.52 (1H, m), 1.71-1.84 (2H, m), 2.18-2.31 (6H, m), 2.59 (1H, d, J=6.72 Hz), 2.93 (1H, d, J=18.40 Hz), 2.99 (1H, d, J-6.36 Hz), 3.59 (3H, s), 4.68 (1H, bd), 4.98 (1H, s), 5.31 (1H, s), 5.85 (1H, s), 6.52 (1H, d, J=8.08 Hz), 6.69 (1H, d, J=8.08 Hz), 6.95-6.98 (1H, m). 7.03-7.04 (1H, m), 7.24-7.26 (1H, m); .sup.13C NMR, 400 MHz, (CDCl.sub.3) 3.34, 4.04, 9.23, 16.77, 17.77, 22.70, 29.28, 33.38, 35.59, 40.39, 43.10, 43.51, 45.74, 53.05, 58.79, 59.92, 76.62, 81.75, 94.15, 116.40, 119.62, 124.66, 125.71, 126.22, 128.08, 132.86, 137.25, 144.90, 145.27. HRMS, m/z for (C.sub.29H.sub.35NO.sub.4SNa) [MNa].sup.+, calcd516.2184. found519.2155. Anal. (C.sub.29H.sub.35NO.sub.4S.HCl.1.4H.sub.2O) C, H, N.
(1R, 5, 6R, 7R, 14)-1-(4-methoxyphenyl)-1-(4,5-epoxy-7,8-dihydro-3-hydroxy-6-methoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (30: R=(4-methoxyphenyl) (BU12027)
(89) White Solid; .sup.1H NMR (CDCl.sub.3) 0.02-0.05 (2H, m), 0.42-0.47 (2H, m), 0.64-0.67 (1H, m), 0.91-0.94 (1H, m), 1.23-1.29 (4H, m), 1.48 (1H, d, J=14.10 Hz), 1.51-1.53 (1H, m), 1.78-1.82 (2H, m), 1.91-1.94 (1H, m), 2.20-2.30 (5H, m), 2.56 (1H, d, J=5.88 Hz), 2.93-2.99 (2H, m), 3.59 (3H, s), 3.81 (3H, s), 4.98-5.01 (2H, m), 5.77 (1H, s), 6.50 (1H, d, J=8.00 Hz), 6.68 (1H, d, J=8.00), 6.84 (2H, d, J=&68), 7.34 (2H, d, J=8.68); .sup.13C NMR, 400 MHz, (CDCl.sub.3) 3.42, 4.02, 9.18, 16.72, 17.78, 22.60, 29.28, 33.29, 35.47, 39.42, 43.09, 43.46, 45.71, 53.06, 55.20, 58.86, 59.96, 79.55, 81.89, 94.27, 112.70, 116.40, 119.54, 127.94, 130.91, 132.92, 137.33, 144.91, 158.76. HRMS, m/z for (C.sub.32H.sub.39NO.sub.5Na) [MNa].sup.+, calcd540.2726. found540.2731.
(1R, 5, 6R, 7R, 14)-1-(4-methoxyphenyl)-1-(4,5-epoxy-7,8-dihydro-3,6-dimethoxy-7-methyl 17-cyclopropylmethyl-6,14-ethanomorphinan-7-yl)-methan-1-ol (28: R=(4-methoxyphenyl
(90) White Solid; .sup.1H NMR (CDCl.sub.3) 0.01-0.05 (2H, m), 0.42-0.47 (2H, m), 0.66-0.69 (1H, m), 0.91-0.94 (1H, m), 1.23-1.29 (4H, m), 1.47 (1H, d, J=14.10 Hz), 1.53 (1H, d, J=9.88 Hz), 1.79-1.85 (2H, m), 1.91 (1H, dd, J=14.20 Hz & J=3.88 Hz), 2.20-2.30 (5H, m), 2.56 (1H, d, J=5.88 Hz), 2.93 (1H, d, J=19.44 Hz), 2.97 (1H, d, J=7.08 Hz), 3.62 (3H, s), 3.81 (3H, s), 3.90 (3H, s), 4.95 (1H, s), 4.96 (1H, s), 5.75 (1H, s), 6.56 (1H, d, J=6.08 Hz), 6.71 (1H, d, J=8.08)%), 6.84 (2H, d, J=8.68), 7.35 (2H, d, J=8.68); .sup.13C NMR, 400 MHz, (CDCl.sub.3) 3.41, 4.05, 9.18, 16.71, 17.80, 22.53, 29.37, 33.38, 35.38, 39.43, 43.02, 43.46, 45.38, 53.09, 55.21, 56.88, 58.84, 59.98, 79.57, 81.80, 93.74, 112.67, 114.14, 119.13, 128.51, 130.92, 133.08, 133.24, 141.75, 146.38, 158.72. HRMS, m/z for (C.sub.33H.sub.41NO.sub.5Na) [MNa].sup.+, calcd554.2882. found554.2916.
(91) Receptor Binding and [.sup.35S]GTPS Assays
(92) Cell Culture:
(93) C6 glioma cells stably expressing the rat MOR (C6) or DOR (C6) were grown in Dulbecco's modified eagle medium (DMEM) supplemented with 10% fetal bovine serum (FBS), 90 units/ml penicillin, 90 g/ml streptomycin, and 0.5 mg/ml geneticin. Chinese hamster ovary cells stably expressing the human KOR (CHO) or human NOP receptor CHO-NOP were maintained similarly, except that DMEM-F12 medium was used. All cells were grown under 5% CO.sub.2 at 37 C.
(94) Preparation of Cell Membranes:
(95) Cells were washed three times with PBS and detached from plates using harvesting buffer (20 mM HEPES, pH 7.4, 150 mM NaCl, and 0.68 mM EDTA). After centrifugation at 200 g for 3 min, the cell pellet was resuspended in 50 mM Tris-HCl, pH 7.4 and homogenized with a Tissue Tearor (Biospec Products, Inc). The homogenate was pelleted at 20,000 g for 20 min at 4 C. and the pellet resuspended in 50 mM Tris-HCl, pH 7.4 and re-homogenized. The final pellet was resuspended in 50 mM Tris-HCl, pH 7.4 and frozen in aliquots at 80 C. Protein concentration was determined using the BCA protein assay.
(96) Ligand Binding Assays:
(97) As Alt et al 2002. Membranes (20 g) are incubated in 50 mM Tris-HCl, pH 7.4 with [.sup.3H]diprenorphine or [.sup.3H]nociceptin in the absence or presence of varying concentrations of test compounds for 60 min in a shaking water bath at 25 C. Nonspecific binding is measured using 10 M naloxone (MOR, DOR, KOR) or N/OFQ (NOP). Samples are filtered through GF/C glass-fiber filtermats mounted on a Brandel cell harvester and rinsed four times with 4 C. 50 mM Tris-HCl, pH 7.4 buffer. Filtermats are dried and 0.1 ml EcoLume scintillation cocktail added to each sample area to soak the filter. Each filtermat in a heat-sealed bag, is counted in a Wallac 1450 MicroBeta Liquid Scintillation and Luminescence Counter. IC50 values for test compounds are determined from concentration effect curves and converted to K.sub.i values using Graph Pad Prism.
(98) [.sup.35 S]GTPS Binding Assays:
(99) As described previously (Traynor and Nahorski, 1995), membranes (20 g) from cells expressing MOR, DOR, KOR or NOP receptors are incubated in 20 mM Tris-HCl, pH 7.4, 5 mM MgCl.sub.2, 100 mM NaCl, 2.2 mM dithiothreitol (prepared freshly), 30 M GDP, 0.1 nM [.sup.35S]GTPS, with or without 10 M of test compound or 10 M standard (DAMGO, SNC80, U50488H or N/OFQ as appropriate) or H.sub.2O for 60 min at 25 C. Samples are filtered through GF/C glass-fiber filtermats mounted on a Brandel cell harvester and rinsed four times with ice-cold 50 mM Tris-HCl, pH 7.4 containing 5 mM MgCl.sub.2, and 100 mM NaCl. Filtermats are processed as described for ligand binding above.
(100) Mouse Warm Water Tall Withdrawal Assay.
(101) For all of the tail-withdrawal data a minimum of five mice is used in each group. Each mouse (is placed in a cylindrical restraint (Harvard Apparatus, South Natick, Mass., USA) with the tail fully exposed. Approximately one-third of the tall is Immersed in water at 48 C. and latency to tail-withdrawal is measured (Janssen et al, 1963). The low temperature is to ensure that compounds with at delta or kappa agonism can be identified. Standards, test compounds or vehicle (usually sterile water) are be administered i.p. and tail-withdrawal latencies measured 25 min later. For antagonist studies compounds are administered 30 min before the first agonist dose. Baseline latencies vehicle Injected mice) are typically 2-4 s. A cut-off latency of 20 s is used to prevent injury to the tail. Mice that do not respond within this time are removed and assigned a score of 20 s.
(102) TABLE-US-00001 Binding affinities (Ki/nm) at opioid and NOP receptors Mu Kappa Delta NOP 7a, R = Ph - BU127
(103) Binding affinities at MOPr, KOPr, DOPr and NOPr were measured using [.sup.3H]diprenorphine (MOP, KOP, DOP) and [.sup.3H]N/OFQ (NOP) binding to membranes derived from CHO cells transfected with human receptors (KOP and NOP receptors) and C6 glioma cells stably expressing rat receptors (MOP and DOP). All compounds tested have high affinity at opioid receptors and selected compounds display affinity at NOP receptors.
(104) TABLE-US-00002 TABLE 2 Efficacy (% stimulation.sup.a) and/or antagonist potency (Ke/nM) at mu, kappa and NOP receptors Mu Kappa NOP % stim.sup.a Ke/nM % stim.sup.a Ke/nM % stim.sup.a 7a, R = Ph 0.47 0.27 14 22, R = Ph 4 0.47 3 0.41 39 22, R = 3-MePh 22 6 43 30, R = Ph 2 0.28 0 0.09 57 15a, R = 4-pyridyl 1 17 4 30, 3-MePh 9 1 21 30, 4-FPh 17 5 13 .sup.a% stimulation at a single concentration (10 M) versus the standards DAMGO (MOP), U69,593 (KOP) and nocicepitn (NOP)
(105) In a measure of functional activity, selected compounds have been evaluated in the [.sup.35S]GTPS assay in the same cell lines used for the binding assays (Table 2). Assays were performed as previously described by Traynor and Nahorski..sup.21 Agonist efficacy at MOR, KOR and NOP receptors was determined at a single concentration (10 M) in comparison to the standard selective agonists DAMGO (MOR), and U69593 (KOR) and nociceptin (NOP) and antagonist Ke values determined against these standard agonists. For example, both 22, R=Ph (Ke.sub.(MOR) 0.47 nM, Ke.sub.(KOR) 0.41 nM) and 7a, R=Ph (Ke.sub.(MOR) 0.47 nM, Ke.sub.(MOR) 0.27 nM) are antagonists at MOR and KOR and have partial agonist activity at NOP receptors (40% and 14% of nociceptin's efficacy). 30, R=Ph also has no efficacy at MOR and KOR and is a partial agonist (57% of nociceptin) at NOP receptors.
(106) Furthermore, it has been confirmed that 7a, R=Ph, 22, R=Ph and 30, R=Ph display no opioid agonist actions in vivo, in assays where even a low efficacy opioid agonist would be expected to be active. Thus they display no agonist activity in the anti-writhing assay (abdominal stretch assay) or in the 50 C. tail withdrawal assay.
REFERENCES
(107) Alt, A., Clark., M., Woods, J. H., and Traynor, J. R. Brit J Pharmacol. 2002, 135, 217-225 Auriacombe, M.; Fatseas, M.; Dubernet, J.; Daulouede, J. P.; Trignol, J. French field experience with buprenorphine. Am. J. Addict., 2004, 13, Suppl 1, S17-28. Beardsley, P. M., Howard, J. L, Shelton, K. L Carroll, F. I. Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats. Psychopharmacology (Berl.) 2005, 183, 118-126. Bloms-Funke P, Gillen C, Schuettler A J and Wnendt S. Agonistic effects of the opioid buprenorphine on the nociceptin/OFQ receptor. Peptides 2000, 21, 1141-1146. Ciccocioppo R, Economidou D, Rimondini R, Sommer W, Massi M and Heilig M. Buprenorphine Reduces Alcohol Drinking Through Activation of the Nociceptin/Orphanin FQ-NOP Receptor System. Biol Psychiatry. 2007, 61, 4-12. Comer, S. D.; Sullivan, M. A.; Yu, E.; Rothenberg, J. L.; Kleber, H. D.; Kampman, K.; Dackis, C.; O'Brien, C. P. Injectable, sustained release naltrexone for the treatment of opioid dependence: a randomized, placebocontrolled trial. Archives of General Psychiatry, 2006, 63, 210-218. Corkery, J. M.; Schifano, F.; Ghodse, A. H.; Oyefeso, A. The effects of methadone and its role in fatalities. Hum. Psychopharmacol., 2004, 19, 565-576. Cowan A, Lewis J W and Macfarlane I R. Agonist and antagonist properties of buprenorphine, a new antinociceptive agent. Br J Pharmacol. 1977b, 60, 537-545. Cowan A.; Doxey J. C.; Harry E. J, The animal pharmacology of buprenorphine, an oripavine analgesic agent. Br J Pharmacol., 1977a, 60, 547-554. Cowan, A. Update on the general pharmacology of buprenorphine. In 'Buprenorphine: Combating drug abuse with a unique opioid. Eds. Cowan and Lewis, Wiley-Liss, New York, 1995, 31-47. Cowan, A.; Friderichs, E.; Strasburger, W.; Raffa, R. B. Basic pharmacology of buprenorphine, in Buprenorphinethe unique opioid analgesic ed.s. Budd, K.; Raffa, R., Thieme, New York, 2005. DAWNDrug Abuse Warning Network, 2003: Area Profiles of Drug-Related Mortality, DAWN Series D-27, DHHS Publication No. (SMA) 05-4023, Rockville, Md., March 2005. Gerra, G., Fantoma, A. & Zaimovic, A. Naltrexone and buprenorphine combination in the treatment of opioid dependence. J. Psychopharmacol. 2006, 20, 806-814. Gonzalez G, Oliveto A, Kosten T R. Combating opiate dependence: a comparison among the available pharmacological options. Expert Opinion On Pharmacotherapy, 2004, 5, 713-725. Gorelick, D. A. Regarding Buprenorphine reduces alcohol drinking through activation of the nociceptin/orphanin FQ-NOP receptor system. Biol. Psychiatry 2007, 62, 702. Huang, P.; Kehner, G. B.; Cowan, A.; Liu-Chen, L-Y. Comparison of pharmacological activities of buprenorphine and norbuprenorphine; norbuprenorphine is a potent opioid agonist. J. Pharmacol. Exp. Ther., 2001, 297, 688-695. Knoll, A. T.; Meloni, E. G.: Thomas, J. B.; Carroll, F. I.; Carlezon Jr, W. A. Anxiolytic-like effects of kappa-opioid receptor anagonists in models of unlearned and learned fear in rats. J. Pharmacol. Exp. Ther., 2007, 323, 838-845. Kosten, T. R., Kleber, H. D. & Morgan, C. Treatment of cocaine abuse with buprenorphine. Biol. Psychiatry 1989, 26, 637-639. Kotlinska, J., Wichmann, J., Legowska, A., Rolka, K. & Silberring, J. Orphanin FQ/nociceptin but not Ro 65-6570 inhibits the expression of cocaine-induced conditioned place preference. Behav. Pharmacol. 2002, 13, 229-235. Kovacs, K. M.; Szakall I.; O'Brien D.; Wang R.; Vinod K. Y.; Saito M.; Simonin F.; Kieffer B. L.; Vadasz C.; Decreased oral self administration of alcohol in KOR knockout mice. Alcohol Clin. Exp. Res., 2005, 29, 730-738. Lewis, J. W. Ring C-bridged derivatives of thebaine and oripavine. Adv. Biochem. Psychopharmacol., 1973, 8, 123-36 Lewis, J. W.; Bentley, K. W.; Cowan, A. Narcotic analgesics and antagonists. Ann. Rev. Pharmacol., 1971, 11, 241-270. Lewis, J. W.; Husbands, S. M. The Orvinols and Related OpioidsHigh Affinity Ligands with Diverse Efficacy Profiles. Current Pharmaceutical Design, 2004, 10, 717-732. Lobmaier, P.; Kornor, H.; Kunoe, N.; Bjorndal, A. Sustained-release naltrexone for opioid dependence (Cochrane review). The Cochrane Library, 2008, Issue 3, pp1-58. Lutfy K, Eitan S, Bryant C D, Yang Y C, Saliminejad N, Walwyn W, Kieffer B L, Takeshima H, Carroll F I, Maldment N T and Evans C J. Buprenorphine-induced antinociception is mediated by mu-opiold receptors and compromised by concomitant activation of opioid receptor-like receptors. J Neurosci 2003, 23:10331-10337. Mague, S. D.; Pliakas, A. M.; Todtenkopf, M. S.; Tomasiewicz, H. C.; Zhang, Y.; Stevens, W. C.; Jones, R. M.; Portoghese, P. S.; Carlezon, W. A. Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats. J. Pharmacol. Exp. Ther., 2003, 305, 323-330. Marquez, P.; Nguyen, A. T.; Hamid, A.; Lutfy, K. The endogenous OFQ/N/ORL-1 receptor system regulates the rewarding effects of acute cocaine. Neuropharmacology, 2008, 54, 564-568. Marton, J.; Simon, C.; Hosztafi, S.; Szab, Z.; Mrkij {dot over (A)}.; Borsodi, A.; Makleit, S. New nepenthone and thevinone derivatives. Bioorg. Med. Chem., 1997, 369-382 McAleer, S. D.; Mills, R. J.; Polack, T.; Hussain, T.; Rolan, P. E.; Gibbs, A. D.; Mullins, F. G. P.; Hussein, Z. Pharmacokinetics of high dose buprenorphine following single administration of sublingual tablet formulations in opioid naive healthy male volunteers under a naltrexone block. Drug and Alcohol Dependence, 2003, 72, 75-83. McCann, D. J. Potential of buprenorphine/naltrexone in treating polydrug addiction and co-occurring psychiatric disorders. Clinical Pharmacology & Therapeutics. 2008, 83, 627-630. McLaughlin, J. P., Marton-Popovici M. & Chavkin C. Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses. J. Neurosci. 2003, 23, 5674-5683. Mello, N. K., Mendeison, J. H. Buprenorphine treatment of cocaine and heroin abuse, in Buprenorphine: Combatting drug abuse with a unique opioid. eds Lewis and Cowan, New York, N.Y., US: Wiley-Liss, 1995, 241-287. Mello, N. K., Mendeison, J. H., Bree, M. P. & Lukas, S. E. Buprenorphine suppresses cocaine self-administration by rhesus monkeys. Science 1989, 245, 859-862. Minozzi, S.; Amato, L.; Vecchi, S.; Davoli, M.; Kirchmayer, U.; Verster, A. Oral naltrexone maintenance treatment for opioid dependence (Cochrane review). The Cochrane Library. 2006, Issue 1, pp1-27. Montoya, I. D.; Gorelick, D. A.; Preston, K. L.; Schroeder, J. R.; Umbricht, A.; Cheskin, L. J.; Lange, W. R.; Contoreggi, C.; Johnson, R. E.; Fudala, P. J. Randomized trial of buprenorphine for treatment of concurrent opiate and cocaine dependence. Clin. Pharmacol. Ther., 2004, 75, 34-48. Negus, S. S.; Woods, J. H. Reinforcing effects, discriminative stimulus effects and physical dependence liability of buprenorphine, in Buprenorphinecombating drug abuse with a unique opioid ed.s. Cowan, A and Lewis, J. W. Wiley-Liss, New York, 1995, p 71-101. Redila, V. A.; Chavkin, C. Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system. Psychopharmacology, 2008, 200, 59-70. Rothman, R. B. A review of the role of anti-opioid peptides in morphine tolerance and dependence. Synapset 1992, 12, 129-138. Rothman, R. B. Gorelick, D. A.; Helshman, S. J.; Eichmiller, P. R.; Hill, B. H.; Norbeck, J.; Liberto, J. G. I. An openlabel study of a functional opioid kappa antagonist in the treatment of opioid dependence. J. Subst. Abuse Treat. 2000, 18, 277-281. Rothman, R. B.; Long, J. B.; Bykov, V.; Xu, H.; Jacobson, A. E.; Rice, K. C.; Holaday, J. W. Upregulation of the opioid receptor complex by the chronic administration of morphine: A biochemical marker related to the development of tolerance and dependence. Peptides, 1991, 12, 151-160. Rothman, R. B. Gorelick, D. A.; Heishman, S. J.: Eichmiller, P. R.; Hill, B. H.; Norbeck, J.; Liberto, J. G. I. An openlabel study of a functional opioid kappa antagonist in the treatment of opioid dependence. J. Subst. Abuse Treat. 2000, 18, 277-281. Schottenfeld. R. S., Pakes, J., Ziedonis, D & Kosten. T. R. Buprenorphine: dose-related effects on cocaine and opioid use in cocaine-abusing optoid-dependent human, Biol. Psychiatry 1993, 34, 66-74. Shoblock, J. R; Wichmann. J.; Maidment, N. T. The effect of a systematically active ORL-1 agonist. Ro64-6198, on the acquisition, expression, extinction and reinstatement of morphine conditioned place preference. Neuropharmacology, 2005, 49, 439-446. Shoblock J. R. The pharmacology of Ro-64-6198, a systematically active, nonpeptide NOP receptor (opiate receptor-like 1, ORL-1) agonist with diverse preclinical therapeutic activity. CNS Drug. Reviews. 2007, 13, 107 136. Spagnolo, B.; Calo. G.; Polgar, W t., Jianng, F.; Olsen, C M.; Berzatel-Gurske, I.; Khroyan, T. V.: Husbands. S. M.; Lewis. J. W.: Toll. L; Zaveri, N T. Activities of mixed NOP and -opioid receptor ligands. Br. J. Pharmacol, 2008, 153, 609-619. Srisuraponont. M.; Jarusuraraisin, N. Opiod antagonists tor alcohol dependence (Cochrane review), The Cochrane Library, 2008, issue 3, pp1-92. Traynor. J. R., and Nahorski, S. R. Modulation by mu-opioid agonists of guanosine-5-O-(3-[35S]thio)triphosphate binding to membranes from human neuroblastoma SH-SY5Y cell. Mol. Pharmacol. 1995, 47, 848-864. Walker, B. M.; Koob. G. F. Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence. Neuropsychopharmacology, 2006, 33, 643-652. Wnendt S, Kruger T, Janocha E, Hildebrandt D and Englberger W, Agonistic effect of buprenorphine in a nociception/OFQ receptor-triggered reporter gene assay. Mol Pharmacol 1999, 56, 334-338. Zaveri N, Polgar W E, Olsen C M, Kelson A B, Grundt P, Lewis J W and Toll L. Characterization of opiates, neuroleptics and synthetic analogs at ORL1 and opioid receptors. Eur J Pharmacol 2001, 428, 29-36. Zhao. R-J.; Woo. R-S.; Jeong, M-S.; Shin. B-S.; Kim, D-G.; Kim. K-W. Orphanin FQ/noclecleptin block methamphetamine place reference in rats. Molecular Neuroscience. 2003, 14, 2383-2385.