Patent Application
20080070924
a) A mixture of (±)-1,1-dimethyl 7-(phenylmethyl)-1,4-dioxa-8-azaspiro[4,5]decane-8-carboxylate (13 g; prepared according to the method described in EP-A-532,456) in HCl (6 N; 130 ml) was stirred and refluxed for 3 hours. The reaction mixture was cooled, alkalized with aqueous NaOH (50%) and extracted with DCM. The organic layer was separated, dried, filtered, and the filtrate, which contained (±)-2-(phenyl-methyl)-4-piperidinone (intermediate 1), was used in next reaction step.
b) A mixture of the filtrate obtained in the previous reaction step, 3,5-dimethylbenzoyl chloride (7.4 g) and triethylamine (11 ml) was stirred overnight at RT. The reaction mixture was extracted with dilute NaOH solution. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 7.44 g (58%) of (±)-1-(3,5-dimethyl-benzoyl)-2-(phenylmethyl)-4-piperidinone (intermediate 2; mp. 107.8° C.).
a) A mixture of (±)- 1,1-dimethyl 7-(phenylmethyl)-1,4-dioxa-8-azaspiro[4,5]decane-8-carboxylate (33.34 g; prepared according to the method described in EP-A-532,456) in HCl (6 N; 250 ml) was stirred at 70° C. for 1 hour and 30 minutes. The mixture was cooled, alkalized with NaOH while cooling to 25° C., and extracted with DCM (100 ml). The organic layer was separated and the aqueous layer was extracted with CH2Cl2. Triethylamine (20.2 g), followed by 3,5-bis(trifluoromethyl)benzoyl chloride (27.7 g) dissolved in a little DCM were added and the mixture was stirred for 2 hours. The mixture was extracted with water, and the layers were separated. The organic layer. was dried, filtered and the solvent evaporated. The residue was crystallized from DIPE, the precipitate was filtered off and dried, yielding 18.34 g product. The mother layer was evaporated and the residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 6.51 g of product. The two fractions were put together and taken up in water and DCM, NaOH was added and the mixture was extracted. The organic layer was dried, filtered and the solvent evaporated, yielding 16.14 g (38%) of (±)- 1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinone (intermediate 3; mp.102.5° C).
A mixture of pyrrolidine (2.13 g) and triethylamine (6.06 g) in DCM (100 ml) was stirred at −10° C. 2-chloro-2-phenylacetylchloride (5.67 g) was added slowly and dropwise. The mixture was allowed to warm to RT and was then stirred overnight. The mixture was extracted with water and K2CO3. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE and the precipitate was filtered off and dried, yielding 3.25 g (48%) of fraction 1. The mother layer was separated and the solvent was evaporated. The residue was crystallized from DIPE and the precipitate was filtered off and dried, yielding 0.29 g (5%) of fraction 2. Both fractions were combined, thus yielding 3.54 g (53%) of (±)- 1-(2-chloro-2-phenylacetyl)pyrrolidine (intermediate 4; mp. 88.5° C.).
Sodium hydride (2 g) was added portionwise to a solution of 3,5-dimethylphenol (6.1 g) in DMF (50 ml). The mixture was stirred for 30 minutes and added dropwise at a temperature below 30° C. to a solution of 2-chloro-2-phenylacetylchloride (9.45 g) in DMF (50 ml). The mixture was stirred overnight, decomposed with water (5 ml) and the solvent was evaporated. Water was added and the mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent:hexane/DIPE 100/0, 98/2 and 95/5). The pure fractions were collected and the solvent was evaporated [residue; yielding 10.82 g (79%)]. A small amount of the obtained residue was crystallized from DIPE, the precipitate was filtered off and the solvent was evaporated, yielding 1 g of (±)-3,5-dimethylphenyl α-chlorobenzeneacetate (intermediate 5; mp. 79.0° C.).
a) A mixture of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-(1-piperazinyl)piperidine (0.0127 mol), chloroacetonitrile (0.013 mol) and sodium carbonate (0.013 mol) in methylisobutyl keton (100 ml) was stirred and refluxed. The mixture was cooled and water was added. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99.5/0.5 and 99/1). The pure fractions were collected and the solvent was evaporated, yielding 3.64g (53%) of (±)-cis-1-[3,5-bis-(trifluoromethyl)benzoyl]-4-[4-(cyanomethyl)-1-piperazinyl]-2-(phenylmethyl)-piperidine (intermediate 6).
b) A mixture of intermediate 6 (0.0067 mol) in THF (150 ml) was hydrogenated at 20° C. with Raney Nickel (1 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated, yielding 3.77 g of (±)-cis-4-[4-(2-aminoethyl)-1-piperazinyl]-1-[3,5-(trifluoromethyl)benzoyl]-2-(phenylmethyl)-piperidine (intermediate 7).
A mixture of 1-(phenylmethyl)-4-piperidinone (0.2 mol) and 1-methylpiperazine (0.2 mol) in methanol (500 ml) was hydrogenated for 8 hours with palladium on activated carbon (10%, 2.5 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. A mixture of di-tert -butyl dicarbonate (0.2 mol) in THF (500 ml) was added to the residue and hydrogenated again with palladium on activated carbon (10%, 2.5 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 45.3 g (80%) of 1,1-dimethylethyl 4-(4-methyl- 1-piperazinyl)- 1-piperidinecarboxylate (intermediate 8).
a) A mixture of 4-methoxypyridine (0.4 mol) in THF (1000 ml) was stirred and cooled in a 2-propanol/CO2 bath. Ethyl chloroformate (0.4 mol) was added dropwise and the mixture was stirred for 3 hours while cooling (mixture I). In another round-bottom flask, the Grignard-reagent was prepared: Mg (0.44 mol) was stirred in a small amount of (C2H5)2O. Some 12 was added. A small amount of 1,2-dichloro-4-(chloromethyl)-benzene was added. Then, 1,2-dichloro-4-(chloromethyl)benzene (0.4 mol) in (C2H5)2O (600 ml) was added dropwise at reflux temperature. The mixture was stirred for one hour (mixture II). The Grignard-reagent was decanted off, added to mixture I at <−40° C., and the resulting reaction mixture was stirred, allowing the temperature to reach RT. The reaction mixture was stirred for one hour at RT. HCl (10%, 800 ml) was added and the mixture was stirred for 30 minutes, then CH2Cl2 was added. The organic layer was separated, dried, filtered and the solvent evaporated, yielding 57.8 g (44%) of (±)-ethyl 6-[(3,4-dichlorophenyl)methyl]-1,2,3,4-tetrahydro-4-oxo- 1-pyridine-carboxylate (intermediate 9).
b) Intermediate 9 (0.176 mol) in THF (880 ml) was stirred under a N2 flow, and cooled to −78° C. L-selectride (0.264 mol) was added dropwise at −78° C. The reaction mixture was stirred for 1 hour, then poured out into water. DIPE was added. The organic layer was separated, washed with an aqueous NaHCO3 solution, with an aqueous NaCl solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 90/10). The desired fractions were collected and the solvent was evaporated, yielding 20.2 g (34.8%) of (±)-ethyl 2-[(3,4-dichlorophenyl)methyl]-4-oxo-1-piperidinecarboxylate (intermediate 10).
c) Titanium(IV)isopropoxide (0.0269 mol) was added to a mixture of intermediate 10 (0.0224 mol) and intermediate 10 (0.0224 mol) in DCM (11 ml). The mixture was stirred at RT for 3 hours. Sodium cyanoborohydride (0.0224 mol) and then ethanol (10 ml) were added. The mixture was stirred at RT for 48 hours. Water was added and the mixture was stirred. CH2Cl2 was added and the mixture was stirred. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by HPLC over silica gel (eluent: CH2Cl2/CH3OH 100/0 and 98/2). The pure fractions were collected and the solvent was evaporated. The residue was purified by reversed phase chromatography (eluent: NH4OAc(0.5% in H2O)/CH3OH 20/80). Two pure fractions were collected and their solvents were evaporated. The residue was dried and ground, yielding 2 g (1 6%) of (±)-ethyl trans-2-[(3,4-dichlorophenyl)methyl]-4-[4-[2-[(2,6-dimethylphenyl)amino]-2-oxoethyl]-1-piperazinyl]- 1-piperidinecarboxylate (intermediate 11) and 3.5g (28%) of (±)-ethyl cis-2-[(3,4-dichlorophenyl)methyl]-4-[4-[2-[(2,6-dimethylphenyl)amino]-2-oxoethyl]-1-piperazinyl]-1-piperidinecarboxylate (intermediate 12).
d) A mixture of intermediate 11 (0.0034 mol) and potassium hydroxide (0.034 mol) in 2-propanol (150 ml) was stirred and refluxed for 4 days. The solvent was evaporated. The residue was taken up in CH2Cl2/water. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The pure fractions were collected and the solvent was evaporated, yielding 0.5 g (30%) of (±)-trans-4-[2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (intermediate 13).
a) Sec-butyllithium (0.066 mol) was added to a mixture of 1,1-dimethylethyl 1,4-dioxo-8-azaspiro[4.5]-8-carboxylate (0.06 mol) in N,N,N′N′-tetramethylethylenediamine (22.6 ml) and (C2H5)2O (100 ml). The mixture was stirred at −70° C. for 3 hours. 3,5-difluorobenzaldehyde (0.07 mol) was added dropwise at −70° C. The mixture was allowed to warm to RT. Water (50 ml) and DIPE were added. The aqueous layer was separated and extracted with CH2Cl2. The combined organic layer was dried, filtered and the solvent was evaporated. Toluene was added and evaporated again, yielding 23 g of (±)- 1,1-dimethylethyl 7-[(3,5-difluorophenyl)hydroxymethyl]-1,4-dioxo-8-azaspiro[4.5]-8-carboxylate (intermediate 14)
b) A mixture of intermediate 14 (0.06 mol) and 2-methyl-2-propanol, potassium salt (0.72 g) in toluene (110 ml) was stirred and refluxed for 2 hours. The solvent was evaporated. The residue was stirred in petroleum ether and a small amount of water, and decanted. The residue was dissolved in CH2Cl2, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0, 99/1 and 98/2). Two pure fractions were collected and their solvents were evaporated, yielding 9.2 g (49%) of (±)-3-(3,5-difluorophenyl)-tetrahydrospiro[1,3-dioxolan-2,5′(3′H)- 1H-oxazolo[3,4-a]pyridin]-1-one (intermediate 15)
c) A mixture of intermediate 15 (0.03 mol) in methanol (250 ml) was hydrogenated at 50° C. with palladium on activated carbon (10%, 2 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 98/2 and 95/5 and CH2Cl2/(CH3OH/NH3) 95/5). The desired fractions were collected and the solvent was evaporated, yielding 1.9 g (39%) of (±)-7-[(3,5-difluorophenyl)methyl]-1,4-dioxo-8-azaspiro[4.5]decane (intermediate 16).
d) A mixture of intermediate 16 (0.012 mol) in HCl 6N (30 ml) was stirred at 75° C. for 2 hours. The mixture was cooled, poured out into ice and a NaOH solution and extracted with CH2Cl2. The organic layer was separated, dried and filtered, yielding 2.7 g of (±)-2-[(3,4-difluorophenyl)methyl]-4-piperidinone (intermediate 17).
e) A mixture of 3,5-trifluoromethylbenzoyl chloride (0.012 mol) in a small amount of CH2Cl2 was added dropwise to a stirred mixture of intermediate 17 (0.012 mol) and N,N-diethylethanamine (0.024 mol). The mixture was stirred at RT for 1 hour and water was added. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0 and 99.5/0.5). The pure fractions were collected and the solvent was evaporated, yielding 2.7g (48%) of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,5-difluorophenyl)methyl]-4-piperidinone (intermediate 18).
Sec-butyllithium (0.63 mol) was added at −78° C. under N2 flow to a solution of 1,1-dimethylethyl 1,4-dioxo-8-azaspiro[4.5]-8-carboxylate (0.57 mol) and N,N,N′N′-tetramethylethylenediamine (1.14 mol) in (C2H5)2O (1000 ml). One hour after complete addition, a mixture of 3-(trifluoromethyl)benzaldehyde (0.57 mol) in (C2H5)2O (200 ml) was added. The mixture was allowed) to warm to RT and then stirred at RT for 16 hours. The solvent was evaporated. A mixture of 2-methyl-2-propanol, potassium salt (0.2 mol) in toluene (500 ml) was added. The mixture was stirred. at 80° C. for 5 hours. The solvent was evaporated. The residue was heated with a saturated NH4Cl solution and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was suspended in DIPE, filtered off and dried. This fraction was dissolved in CH3OH (250 ml) and the mixture was hydrogenated with palladium on activated carbon (10%, 3 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. This fraction was dissolved in HCl (6 N, 100 ml) and CH3OH (100 ml) and the mixture was stirred at 50° C. for 8 hours. The organic solvent was evaporated. The concentrate was washed with a saturated K2CO3 solution and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated, yielding 48.5 g (70%) of (±)-2-[[4-(trifluoromethyl)phenyl]methyl]-4-piperidinone (intermediate 19).
a) A mixture of ethyl β-oxobenzenebutanoate (0.5 mol) and benzenemethanamine (0.5 mol) in toluene (500 ml) was hydrogenated at 120° C. (pressure=100 kg) overnight in the presence of Cu2Cr2O5 (5 g) and CaO (10 g). After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated, yielding 29.7 g of (±)-ethyl N,2-bis(phenylmethyl)-β-alanine (intermediate 20).
b) Ethyl chloroacetate (0.3 mol) was added to a mixture of intermediate 20 (0.2 mol) in DMF (250 ml). The mixture was stirred and triethylamine (0.4 mol) was added. The mixture was stirred at 60° C. overnight. The solvent was evaporated and the residue was taken up in water/CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 76.6 g of (±)-ethyl 3-[(2-ethoxy-2-oxoethyl)(phenylmethyl)amino]benzenebutanoate (intermediate 21).
c) Intermediate 21 (0.2 mol) was heated to 80° C. under N2 flow. NaOCH3 (44 g) was added. The mixture was stirred at 80° C. for 30 minutes. The solvent was evaporated and water (170 ml) and HCl (6 N, 60 ml) were added. The mixture was stirred and refluxed for 1 hour, then cooled, alkalized with NaOH and extracted with CH2Cl2. The organic layer was separated, washed with water and a saturated NaCl solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3CN 100/0 to 96/4). The pure fractions were collected and the solvent was evaporated, yielding 7.8 g of (±)-1,5-bis(phenylmethyl)-3-pyrrolidinone (intermediate 22).
d) A mixture of intermediate 22 (0.027 mol) and CH3SO3H (0.03 mol) in THF (200 ml) was hydrogenated with palladium on activated carbon (10%, 2 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off, yielding (±)-5-(phenylmethyl)-3-pyrrolidinone methanesulfonate(1:1) (intermediate 23).
e) 3,5-di(trifluoromethyl)benzoyl chloride (0.03 mol) was added to intermediate 23 (0.027 mol). The mixture was stirred and triethylamine (0.1 mol) was added. The mixture was stirred at RT for 18 hours and then washed with water, NaOH and a saturated NaCl solution. The organic layer was separated, washed with a saturated NaCl solution, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated, yielding 1.4 g of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-5-(phenylmethyl)-3-pyrrolidinone (intermediate 24).
a) Titanium(IV)isopropoxide (16.5 g) was added to a mixture of intermediate 3 (21.5 g) and 1-(phenylmethyl)piperazine (8.81 g) in DCM (35 ml). The mixture was stirred for 3 hours at RT. Sodium cyanoborohydride (2.85 g) and ethanol (70 ml) were added and the resulting reaction mixture was stirred overnight at RT. Water (5 ml) and DCM were added. The biphasic mixture was filtered over dicalite, and the filter residue was washed with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from CH3CN and the precipitate was filtered off and dried, yielding 7.93 g (26.9%) of (±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidine (compound 16; mp. 143.8° C.).
b) The mother liquor was concentrated and the residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0, then 99/1, 98/2, 97/3). The desired fractions ((A) and (B)) were collected and their solvent was evaporated. The A-isomer was crystallized from CH3CN, filtered off and dried, yielding 1.11 g (4%) of compound 16. The pure fractions of the B-isomer were concentrated, yielding 5.9 g (20%) of (±)-trans-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-(phenylmethyl)-1-piperazinyl]piperidine. The impure fractions of the B-isomer were collected and the solvent was evaporated. The residue was converted into the fumaric acid salt (1:2) in ethanol. The precipitate was filtered off and dried, yielding 1.89 g (i)-trans-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-[4-(phenylmethyl)- 1-piperazinyl]piperidine (E)-2-butenedioate(1:2) (compound 17; mp. 240.3° C.).
A mixture of compound 16 (8.4 g) in methanol (250 ml) was hydrogenated at 50° C. with palladium on activated carbon (10%) (2 g) as a catalyst. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated, yielding 7 g (100%) of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-(1-piperazinyl)piperidine (compound 15).
a) Titanium(IV)isopropoxide (13.2 g) was added to a mixture of intermediate 3 (17.16 g) and N-(2,6-dimethylphenyl)-1-piperazineacetamide (9.88 g) in DCM (20 ml). This mixture was stirred for 3 hours at RT. Sodium cyanoborohydride (2.52 g) in ethanol (20 ml) was added and the resulting reaction mixture was stirred overnight at RT. Water (10 ml) was added and the reaction mixture was extracted with DCM (800 ml). The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was taken up into water and this mixture was extracted with DCM. The separated organic layer was dried, filtered, and the solvent evaporated. The residue was pre-purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The desired fractions were collected and the solvent was evaporated, giving 4 g of the trans-racemate. Resolution was obtained by purification over stationary phase Chiralcel OD (eluent: CH3OH 100%). Two desired trans-fraction groups were collected and their solvent was evaporated, yielding 1.75 g fraction 1 and 2 g fraction 2. Fraction 1 was dissolved in DCM, filtered and the filtrate was evaporated. The residue was dried, yielding 1.55 g (6%) (−)-(A)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenyl-methyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazine acetamide (compound 26; mp. 97.4° C.; [α]D°=−5.81° (c.=1% in DMF)). Fraction 2 was dissolved in DCM, filtered and the filtrate was evaporated. The residue was dried, yielding 1.70 g (6%) (+)-(B)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazine acetamide (compound 27; mp. 96.8° C.; [α]D20=+5.71° (c=1% in DMF)).
b) Compound 27 was dissolved in warm 2-propanol and converted into the (L)-malic acid salt with a solution of (L)-malic acid in 2-propanol. The mixture was stirred for 2 hours and the precipitate was filtered off and dried, yielding (+)-(B)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazine acetamide (L)-malic acid (1:1) (compound 95).
A mixture of compound 15 (2.5 g), intermediate 5 (1.65 g) and sodium carbonate (0.64 g) in methylisobutylketon (50 ml) was stirred and refluxed for 3 hours. The reaction mixture was washed and the separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0 and 99.5/0.5). The pure fractions were collected and the solvent was evaporated, yielding 1.59 g (43%) of (±)-3,5-dimethylphenyl cis-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-α-phenyl- 1-piperazine-acetate (compound 43; mp. 88.1° C.).
A mixture of intermediate 2 (3.2 g), 1-(diphenylmethyl)piperazine (2.5 g) and aluminum tributoxide (2 g) in toluene (250 ml) was hydrogenated for 48 hours at 50° C., with palladium on activated carbon (10%; 2 g) as a catalyst in the presence of thiophene (4% solution; 1 ml). After uptake of hydrogen (1 equiv), the catalyst was filtered off and the filtrate was evaporated. The residue was purified by high-performance liquid chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0, upgrading to 90/10). Two pure fractions were collected and their solvent was evaporated, resulting in residue 1 and residue 2. Residue 1 was suspended in DIPE. The precipitate was filtered off and dried, yielding 0.94 g (17%) of (±)-cis-1-(dimethylbenzoyl)-4-[4-(diphenylmethyl)-1-piperazinyl]-2-(phenylmethyl)piperidine (compound 12; mp. 100.8° C.). Residue 2 was dried, yielding 0.2 g (3.6%) of (±)-trans-1-(dimethylbenzoyl)-4-[4-(diphenylmethyl)-1-piperazinyl]-2-(phenylmethyl)piperidine (compound 13).
A mixture of compound 15 (0.005 mol) and 1,2-epoxyethylbenzene (0.006 mol) in methanol (50 ml) was stirred at RT for 1 hour. The mixture was stirred and refluxed for 3 hours. The solvent was evaporated and the residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99/1 and 98/2). The pure fractions were collected and the solvent was evaporated. The residue was purified by HPLC over silica gel (eluent: CH2Cl2/CH3OH 98/2 to 95/5). Two pure fractions were collected and their solvents were evaporated. Each residue was dried, yielding 0.7 g (23%) of (±)-cis- 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(2-hydroxy-2-phenylethyl)-1-piperazinyl]-2-(phenylmethyl)piperidine (compound 60) and 0.23 g (7%) of (±)-cis- 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(2-hydroxy- 1-phenylethyl)-1-piperazinyl]-2-(phenylmethyl)piperidine (compound 61).
Compound 15 (0.005 mol), 2-chloro-1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazole (0.005 mol) and Cupper (0.005 mol) were stirred at 140° C. for 2 hours. The mixture was cooled, dissolved in CH2Cl2, filtered and washed with CH2Cl2 and a diluted NH4OH solution. The organic layer was separated, washed with a diluted NH4OH solution, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99.5/0.5, 99/1, 98.5/1.5 and 98/2). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 1.42 g (40%) (±)-cis-1-[3,5-bis(trifluoromethyl)-benzoyl]-4-[4-[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]- 1-piperazinyl]-2-(phenylmethyl)piperidine (compound 70).
A mixture of intermediate 7 (0.0033 mol) and 3,5-dimethylbenzoyl chloride (0.0035 mol) in DCM (50 ml) was stirred at RT for 15 minutes. Triethylamine (0.007 mol) was added and the mixture was stirred at RT for 1 hour. Water was added. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was converted into the fumaric acid salt (1:1) with 2-propanol. The precipitate was filtered off and dried. The residue was converted into the free base with NaOH. The precipitate was filtered off and dried. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99.5/0.5, 99/1, 98/2 and 97/3). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 0.8 g (36%) (±)-cis-N-[2-[4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]- 1-piperazinyl]ethyl]-3,5-dimethylbenzamide (compound 116).
A mixture of compound 74, prepared according to example B.4, (0.004 mol) in methanol (150 ml) was hydrogenated at 50° C. with palladium on activated carbon (10%; 1 g) as a catalyst in the presence of thiophene (4% solution, 1 ml). After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off, washed with DIPE and dried. This fraction was dissolved in toluene. The mixture was filtered and the solvent was evaporated. The residue was suspended in DIPE. The precipitate was filtered off and dried. This fraction was converted into the fumaric acid salt (1:2) with a warm solution of fumaric acid (0.52g) in ethanol. The mixture was stirred for 6 hours. The precipitate was filtered off and dried, yielding 0.91 g (25%) of (±)-cis-N-(4-amino-2,6-dimethylphenyl)-4-[1-[3,5-(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-1-piperazineacetamide (E)-2-butenedioate(1:2) (compound 129).
Sec-butyllithium (0.055 mol) was added at −78° C. under N2 flow to a solution of 1,1-dimethylethyl 4-(4-methyl-1-piperazinyl)-1-piperidinecarboxylate (0.05 mol) and N,N,N,N′-tetramethylethylenediamine (0.1 mol) in (C2H5)2O (50 ml). 2 hours after complete addition, a mixture of benzaldehyde (0.05 mol) in (C2H5)2O (50 ml) was added. The mixture was allowed to warm to RT and then stirred at 25° C. for 16 hours. The solvent was evaporated and the residue was washed with a saturated NH4Cl solution and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. A solution of 2-methyl-2-propanol, potassium salt (0.02 mol) in toluene (100 ml) was added to this fraction and the mixture was stirred at 100° C. for 2 hours. The solvent was evaporated. The residue was washed with a saturated NH4Cl solution, extracted with CH2Cl2 and decanted. The organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. This fraction was dissolved in methanol (150 ml) and hydrogenated with palladium on activated carbon (10%, 3 g) as a catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. This fraction was dissolved in DCM (20 ml) and Triethylamine (2 ml). 3,5-di(trifluoromethyl)benzoyl chloride (0.0087 mol) was added at 0° C. 1 hour after complete addition, water was added and the mixture was extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 95/5). The pure fractions were collected and the solvent was evaporated. This fraction was converted into the (E)-2-butenedioic acid salt (1:2) with ethanol. The precipitate was filtered off and dried, yielding 4.7 g (74%) of (±)-cis-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-methyl- 1-piperazinyl)-2-(phenylmethyl)-piperidine (E)-2-butenedioate(1:2) (compound 130).
A mixture of compound 15 (0.005 mol), N-[2-(3,4-dichlorophenyl)-4-[(methylsulfonyl)-oxy]butyl]-N-methyl benzamide (0.0055 mol) and NaHCO3 (0.0055 mol) in ethanol (50 ml) was stirred and refluxed for 6 hours. The solvent was evaporated, the residue was taken up in water and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99/1, 98/2 and 97/3). The pure fractions were collected and the solvent was evaporated. The residue was converted into the fumaric acid salt (1:2) with ethanol. The precipitate was filtered off and dried, yielding 1.42 g (27%) of (±)-cis-N-[4-[4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-1-piperazinyl]-2-(3,4-dichlorophenyl)butyl]-N-methyl-benzamide (E)-2-butenedioate(1:2) (compound 93).
A mixture of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,5-difluorophenyl)methyl]-4-piperidinone (0.0058 mol), N-(2,6-dimethylphenyl)-1-piperazineacetamide (0.0058 mol) and titanium(IV)isopropoxide (0.0064 mol) in 2-propanol (5 ml) was stirred at RT overnight. NaBH4 (0.0116 mol) and ethanol (15 ml) were added. The mixture was stirred for 2 days. Water (5 ml) was added and the mixture was stirred for 10 minutes. CH2Cl2 (200 ml) was added. The organic layer was separated, dried, filtered and the solvent was evaporated. This fraction was purified by HPLC over silica gel (eluent: CH2Cl2/CH3OH 98/2 to 90/10 over a 30-minute period). Two pure fractions (F1 and F2) were collected and their solvents were evaporated. F1 was purified by column chromatography over RP18 (eluent: NH4OAc (0.5% in H2O)/CH3CN 40/60). The pure fractions were collected and the solvent was evaporated. The residue was dried, yielding 0.33 g (8%) of (±)-cis-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,5-difluorophenyl)-methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 132). F2 was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 100/0 to 92/8 over a 30-minute period). The pure fractions were collected and the solvent was evaporated. The residue was dissolved in CH2Cl2, filtered and the solvent was evaporated. The residue was dried, yielding 0.24 g (6%) of (±)-trans-4-[1-[3,5-bis-(trifluoromethyl)benzoyl]-2-[(3,5-difluorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 133).
3,5 di(trifluormethyl)benzoyl chloride (0.0011 mol) was added to a mixture of (±)-trans-4-[2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (0.001 mol) in DCM (20 ml). The mixture was stirred for 5 minutes. Triethylamine (2 ml) was added. The mixture was stirred at RT for 3 hours, washed with a diluted NaOH solution and with water, and then dried. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 96/4). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.32 g (44%) of (±)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(3,4-dichlorophenyl)methyl]-4-piperidinyl] -N-(2,6-dimethylphenyl)- 1-piperazine-acetamide (compound 139).
A mixture of compound 15 (0.01 mol) and imidazo[1,2-a]pyridin-2-carboxaldehyde (0.01 mol) in methanol (250 ml) was hydrogenated at RT overnight with palladium on activated carbon (10%, 2 g) as a catalyst in the presence of thiophene (4% solution, 2 ml). After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0, 99/1, 98/2, 97/3 and 96/4). The pure fractions were collected and the solvent was evaporated. The residue was converted into the fumaric acid salt (1:2) from ethanol. The precipitate was filtered off and dried, yielding 2.8 g (32%) of (±)-cis- 1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-(imidazo[1,2-a]pyridin-2-ylmethyl)-1-piperazinyl]-2-(phenylmethyl)piperidine (E)-2-butenedioate(1:2) (compound 111).
(+)-(B-trans)-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (0.003 mol) was dissolved in ethanol (20 ml). A solution of fumaric acid (0.003 mol) in ethanol (15 ml) was added and the mixture was stood for 7 days. The precipitate was filtered off and dried, yielding 1.2 g of (B-trans)-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (E)-2-butenedioate(1:1) (compound 128).
A mixture of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-5-(phenylmethyl)-3-pyrrolidinone (0.0037 mol) and N-(2,6-dimethylphenyl)-l-piperazineacetamide (0.0037 mol) in methanol (150 ml) was hydrogenated at 50° C. with palladium on activated carbon (10%, 1 g) as a catalyst in the presence of tiophene solution (1 ml). After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 95/5). The desired fractions were collected and the solvent was evaporated. The residue was dried and then crystallized from DIPE. The precipitate was filtered off and dried, yielding 0.35 g (15%) of (±)-cis-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-5-(phenylmethyl)-3-pyrrolidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 131).
(±)-cis-1-(phenylmethyl)-4-[2-(phenylmethyl)-1-piperidinyl]piperazine (0.00043 mol) was added to 3,4-dichlorobenzeneacetic acid (±) 0.0004 mol) and 1-hydroxybenzo-triazole hydrate (0.080 g) in DCM (5 ml). The mixture was stirred and cooled on an ice/ethanol-bath, under N2 flow. Triethylamine was added dropwise. A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.120 g) in DCM (5 ml) was added and the reaction mixture was allowed to warm to RT, under N2. The reaction mixture was stirred overnight. The mixture was diluted with CH2Cl2, until a 15-ml total volume was obtained. Then, the compound was isolated and purified by HPLC over silica gel (eluent: CH2Cl2 to CH2Cl2/CH3OH 90/10 over 20 minutes at 125 ml/minute). The desired fractions were collected and the solvent was evaporated, yielding 0.020 g of (±)-cis-1-[(3,4-dichlorophenyl)acetyl]-2-(phenylmethyl)-4-[4-(phenylmethyl)- 1-piperazinyl]piperidine (compound 181).
3,5-di(trifluoromethyl)-1-isocyanatobenzene (0.0025 mol) in DCM (10 ml) was added to a mixture of (±)-trans-N-(2,6-dimethylphenyl)-4-[2-(phenylmethyl)-4-piperidinyl]-1-piperazineacetamide (0.0025 mol) in DCM (15 ml). The mixture was stirred at RT overnight. The precipitate was filtered off and dried, yielding 0.66 g (40%) of (±)-trans-4-[1-[[[3,5-bis(trifluoromethyl)phenyl]amino]carbonyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)- 1-piperazineacetamide (compound 143).
A mixture of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[[3-fluoro-5-(trifluoromethyl) phenyl]methyl]-4-piperidinone (0.01 mol) and N-(2,6-dimethylphenyl)-1-piperazine-acetamide (0.01 mol) in 2-propanol (150 ml) was hydrogenated at 50° C. with platinum on activated carbon (5%; 2 g) as a catalyst in the presence of titanium(IV)isopropoxide (2.84 g) and thiophene solution (1 ml). After uptake of hyrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in CH2Cl2 and H2O. The organic layer was separated, washed several times with H2O, dried, filtered over dicalite and the solvent was evaporated. This fraction was purified by HPLC over silica gel (eluent: CH2Cl2/CH3OH 98/2). Two pure fractions were collected and their solvents were evaporated. The residue was dried, yielding 0.72 g (10%) of (±)-cis-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[[3-fluoro-5-(trifluoromethyl)phenyl]methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 140) and 0.88 g (12%) of (±)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-[[3-fluoro-5-(trifluoro-methyl)phenyl]methyl]-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 141).
The NK1-antagonistic activity of the compounds in the Tables 1 to 4 has been disclosed in WO 97/16440-A1 which is disclosed herein by reference. Unless otherwise specified, all tests were performed with Compound 95: ((±)-(B)-trans-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazine acetamide, (L)-malic acid (1:1)).
In order to test whether a NK1, antagonist was also able to overcome emesis when co-administered with a centrally acting opioid, ascending doses of Compound 95 were tested against different concentrations of morphine in non food-deprived ferrets after i.p. administration.
Based on preliminary data, doses of 0.4 and 0.8 mg/kg morphine were selected. Increasing the dose from 0.4 to 0.8 mg/kg morphine resulted in more animals with emesis and increased frequencies of periods of emesis, retches and vomiting (Table 5). Doses>0.8 mg/kg morphine caused central side-effects.
At 0.8 mg/kg morphine, a more robust drug-induced emesis was present. Doses of 10 and 40 mg/kg i.p. Compound 95 significantly reduced the number of retches. The number (frequency) of vomits diminished significantly in the presence of 10 mg/kg Compound 95 i.p. In terms of periods of emesis, activity was seen at doses>2.5 mg/kg Compound 95.
In order to evaluate the effects of combinations of opioids with NK1 antagonists on respiratory depression, experiments were performed in gerbils, guinea pigs and rats, measuring arterial blood gases, and especially opioid-induced PCO
On the day of testing, male gerbils were equipped with a catheter in the arteria femoralis. After full recovery from surgery and habituation to the test conditions, pre-drug baselines were taken. Only animals with PCO
Opioids resulted in an increase in PCO
These data indicate that Compound 95 can reduce part of the respiratory depression induced by opioids. Furthermore, a role of SP in the respiratory system is suggested in the literature. If the effects of Compound 95 reflect here an antagonism of the opioid-induced excitation, this can be beneficial because opioid-induced excitation is sometimes seen at overdosing.
Guinea pigs were chronically catheterized with an intra-arterial line into the arteria carotis. In order to keep the lines patent, the animals were connected to chronic infusion pumps in their home cages and minimal amounts of heparine in saline were administered daily. After full recovery of the animals and habituation to the chronic housing conditions, the animals were disconnected from the pumps and after s.c. drug treatment, samples were taken in their home cages at repeated time intervals.
Both fentanyl and morphine resulted in an increase in PCO
Rats were acutely equipped with a catheter in the arteria femoralis. After full recovery from surgery and habituation to the test conditions, predrug baseline values were taken. Only animals with PCO
As in the other species, the opioids fentanyl and morphine both resulted in increased levels of PCO
Thus, the data in rats confirm the observations in guinea pigs and gerbils that the NK1 antagonist Compound 95 can reduce the opioid-induced increases in PCO
In order to evaluate the constipatory effects of opioids in combination with NK1, antagonists, a castor oil test was performed in gerbils and rats. In both species, and one hour after s.c. pretreatment with the test compounds, animals were challenged with 0.25 (gerbils) or 1 ml (rats) ricinus oil, and the number of animals showing diarrhea were measured every hour up to 8 hours after the challenge. Because, in control animals (treated with vehicle), >95% revealed diarrhea within 4 (rats) and 8 h (gerbils), respectively, these time points were used to calculate ED50s for opioid-induced constipation (opioid-induced inhibition of diarrhea).
All opioids tested (morphine, fentanyl, codeine and oxycodone in gerbils and morphine and fentanyl in rats) resulted in a dose-dependent inhibition of the ricinus oil-induced diarrhea (Table 6). Compound 95, at doses up to 40 mg/kg s.c., had minimal effects on constipation in both rats and gerbils.
Adding Compound 95 to the opioids did not alter the ED50s of the opioids, neither in gerbils nor in rats (Table 6).
In order to evaluate the effects of adding an NK1, antagonist to the effects of opioids on gastrointestinal transit, a charcoal test was performed in male gerbils and rats. For testing, the animals were pretreated s.c. with the test compound, 1 h prior to the oral administration of 1 ml (gerbil) or 2 ml (rat) charcoal (10% in 5% Arabic gum) per 100 g body weight. After 20 min (gerbil) and 30 min (rat), the animals were sacrificed, the charcoal propulsion was measured throughout the small intestine and the peristalsis ratio was calculated. This is the ratio between the distance attained by the charcoal in the small intestines (as measured from the end of the stomach (pylorus)) and the total length of the small intestines (up to the beginning of the caecum). Because, in control rats (n=30) and gerbils (n=155), a peristalsis ratio<60% was never observed, this level was used as an all or nothing criterion to calculate GI tract inhibition.
In gerbils, all opioids resulted in a dose-dependent inhibition of the charcoal propulsion while Compound 95 was inactive. Adding Compound 95 to the opioids did not affect the outcome of the opioids (Table 7).
In rats, comparable results were obtained with morphine and Compound 95. With fentanyl, tested up to 0.16 mg/kg s.c., no inhibition of the charcoal transit was observed, also when combined with 40 mg/kg s.c. Compound 95 (Table 7).
In order to evaluate the effects of adding a NK1 antagonist on the opioid-induced tolerance over time in a chronic pain model, experiments were performed in gerbils with a chronic constrictive injury (CCI) using the acetone spray test. In CCI gerbils, acetone is demonstrated to produce an increased pain reactivity (cold/chemical hyperalgesia). This pain reactivity can be acutely antagonized by opioids, but not by NK1, antagonists.
To test whether Compound 95 could prevent the loss of efficacy of morphine over time in this model, CCI gerbils were tested over an 11 days period receiving twice daily i.p. injections of either vehicle, 2.5 mg/kg morphine, 2.5 mg/kg Compound 95 or the combination of 2.5 mg/kg morphine with 2.5 mg/kg Compound 95.
As was seen, morphine acutely reduced the acetone-induced lifting behaviour but reductions of activity became apparent from the second day onwards. At day 7, no differences with the controls were present anymore. With Compound 95, limited activity was present during some days of the experiment. The combination of Compound 95 with morphine resulted in an initial activity at the first day similar to morphine alone, and as opposed to morphine, the activity remained present over the entire testing period.
In order to evaluate whether a NK1, antagonist could interfere with the abuse potential, and especially the central narcotic properties of opioids, the effects of Compound 95 on the discriminative stimulus properties of fentanyl were studied in rats trained to discriminate 0.04 mg/kg s.c. fentanyl from saline in a two lever food reinforced test procedure.
The ED50 (95% CL) values of fentanyl for stimulus generalization in fentanyl trained rats injected s.c. 30 and 60 min prior to testing were 0.018 (0.012-0.028) and 0.021 (0.016-0.029) mg/kg, respectively.
Pretreatment with 10 or 40 mg/kg Compound 95 did not affect the stimulus generalization of fentanyl in the fentanyl trained rats. No shifts in the dose response curves of fentanyl were observed, neither was there a change in the ED50 values for stimulus generalization (Table 8).
These results clearly indicate that, in rats, Compound 95 does not interfere with the discriminative stimulus properties of the opioid fentanyl.
| Number | Date | Country | Kind |
|---|---|---|---|
| PCT/EP03/06118 | Jun 2003 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP04/51050 | 6/7/2004 | WO | 00 | 12/12/2005 |
