The invention relates to piperazine derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to their medical use. The novel compounds are antagonists of tachykinins, including substance P and other neurokinins.
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30. A method for the treatment of emesis in a mammal comprising administering to said mammal an effective amount of 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide acetate. #5#
29. A method for the treatment of emesis in a mammal comprising administering to said mammal an effective amount of 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide methanesulphonate. #5#
28. A method for the treatment of emesis in a mammal comprising administering to said mammal an effective amount of 4-(2-Amino-acetyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride. #5#
31. A method for the treatment of emesis in a mammal comprising administering to said mammal an effective amount of #5# 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide #6# 2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide or an enantiomer or pharmaceutically acceptable salt or solvate thereof.
1. A method for the treatment of emesis in a mammal comprising administering to said mammal an effective amount of a compound of formula (I):
##STR00014##
#5#
#6# wherein
R is a halogen atom or a c1-4 alkyl group;
R1 is hydrogen or a c1-4 alkyl group;
R2 is hydrogen, a c1-4 alkyl, c2-6 alkenyl or a c3-7 cycloalkyl group; or R1 and R2 together with nitrogen and carbon atom to which they are attached respectively represent a 5-6 membered heterocyclic group;
R3 is a trifluoromethyl, a c1-4 alkyl, a c1-4 alkoxy, a trifluoromethoxy or a halogen group;
R4 is hydrogen, a (CH2)qR7 or a (CH2)rCO(CH2)pR7 group;
R5 is hydrogen, a c1-4 alkyl or a COR6 group;
R6 is hydrogen, hydroxy, amino, methylamino, dimethylamino, a 5 membered heteroaryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen or a 6 membered heteroaryl group containing 1 to 3 nitrogen atoms;
R7 is hydrogen, hydroxy or NR8R9 wherein R8 and R9 represent independently hydrogen or c1-4 alkyl optionally substituted by hydroxy or by amino;
R10 is hydrogen, a C1-4 alkyl group or R10 together with R2 represents a c3-7 cycloalkyl group;
m is zero or an integer from 1 to 3;
n is zero or an integer from 1 to 3;
both p and r are independently zero or an integer from 1 to 4;
q is an integer from 1 to 4;
provided that, when R1 and R2 together with nitrogen and carbon atom to which they are attached respectively represent a 5 to 6 membered heterocyclic group,
i) m is 1 or 2;
ii) when m is 1, R is not fluorine and
iii) when m is 2, the two substituents R are not both fluorine, or a pharmaceutically acceptable salt or solvate thereof.
12. A method for the treatment of emesis in a mammal comprising administering to said mammal an effective amount of a compound selected from the group consisting of
#5# 2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide; #6#
2-(2-Isopropyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;
2-(4-Fluoro-3-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;
2-(2,4-Difluoro-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;
2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methyl-amide;
2-(4-Fluoro-phenyl)-piperazine-1-carboxylic acid (3,4-bis-trifluoromethyl-benzyl)-methyl-amide;
2-Phenyl-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;
2-(2,4-dichloro-phenyl)-piperazine-1-carboxylic acid (3,5-bistrifluoro methyl-benzyl)-methyl-amide;
2-(3,4-dichloro-phenyl)-piperazine-1-carboxylic acid (3,5-bistrifluoro methyl-benzyl)-methyl-amide;
2-(4-Fluoro-2-methyl-phenyl)-3-methyl-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;
2-(2-Methyl-4-Fluoro-phenyl)-6-Methyl-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;
2-(4-fluoro-2-Methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methyl-amide;
4-(2-Amino-acetyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;
2-(S)-(4-Fluoro-2-methyl-phenyl)-4-(piperidine-4-carbonyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;
4-(2-Amino-ethyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;
2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [(1-3,5-bis-trifluoromethyl-phenyl)-cyclopropyl]-methyl-amide;
[2-(3,5-Bis-trifluoromethyl-phenyl)-pyrrolidin-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanone;
[2-(3,5-Bis-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridyn-1-yl]-(2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanone;
2-(3,5-Bis-trifluoromethyl-phenyl)-piperidin-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanone;
2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-but-3-enyl]-methyl-amide;
2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propyl]-methyl-amide;
2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [(3,5-bis-trifluoromethyl-phenyl)-cyclopropyl-methyl]-methyl-amide;
or an enantiomer, or pharmaceutically acceptable salt or solvate thereof.
2. The method according to 3. The method according to 4. The method according to 5. The method according to 6. The method according to 7. The method according to 8. The method according to 9. The method according to 10. The method according to 11. The method according to 13. The method according to 14. The method according to 15. The method according to 16. The method according to 17. The method according to 18. The method according to 19. The method according to 20. The method according to 21. The method according to 22. The method according to 23. The method according to 24. The method according to 25. The method according to 26. The method according to 0. 27. A method for the treatment of emesis in a mammal comprising administering to said mammal an effective amount of 2-(S)-(4-Fluoro-2-methyl-phenyl)-4-(piperidine-4-carbonyl)-piperazine-1carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride. #5#
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This Application is a continuation of U.S. patent application Ser. No. 10/089,964, filed May 8, 2002, (R)-3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine (R)-[(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine
To a solution of 3,5-bis-trifluoromethylacetophenone (300 g) in MeOH (1120 ml), a solution of methylamine 8M in EtOH (372 mL) was added dropwise during 15 min. at 25° C. under N2. The mixture was stirred for 24 hrs at 25° C. under N2. Then, NaBH4 was portionwise added over 30 min (27.9 g) at 0° C. A second amount of NaBH4 was added over 30 min (17.1 g) and the mixture stirred for further 1.5 hrs.
The mixture was concentrated by evaporating 600 mL of solvent under vacuum then it was slowly poured into a mixture of AcOEt (1500 mL)/NH4Cl sat (750 mL) and water (750 mL). The water phase was back-extracted with AcOEt (1500 mL). The combined organic phases were washed with Water/Brine (150 mL/150 mL) then evaporated to obtain 3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine (3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine (305 g) as a yellow oil. To a solution of 3,5-bis-trifluoromethyl-phenyl)ethyl]-methyl-amine (3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine (245.6 g) in EtOAc (2380 mL), L(+) malic L(−) malic acid was added portionwise (118 g). The suspension was stirred for 2 hrs at 25° C. then 3 hrs at 0° C. The suspension was filtered and the cake was washed with EtOAc (240 mL). The solid was dried under vacuum obtaining crude L(+)malate3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine L(−)malate[(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine (135.3 g) as a white solid which was suspended in Ethyl acetate (1760 mL) then heated to reflux till complete dissolution and then cooled at 25° C. The suspension was filtered, washed with Ethyl acetate (135 mL) then dried to obtain L(+)malate3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine L(−)malate[(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine (128.5 g). The solid was stirred in a mixture of NaOH 10% v/v (720 mL) and Ethyl acetate (650 mL). Organic phase was washed with water (720 mL), then concentrated to yield the title compound (82.2 g).
1H-NMR (DMSO) δ (ppm) 7.99 (s, 2H); 7.85 (s, 1H); 3.78 (q, 1H); 2.34 (s, 1H); 2.09 (s, 3H); 1.23 (d, 3H).
A solution of intermediate 13 (0.05 g) in EtOH (10 mL) was hydrogenated at atmospheric pressure for 3 hr, in the presence of 10% Pd/C (10 mg) as catalyst. The catalyst was filtered off and the solvent was evaporated. The crude residue dissolved in diethyl ether and then a 1M sol. of HCl in Et2O (0.1 mL) was added. The formed precipitate was filtered and washed with diethyl ether to obtain the title compound (0.02 g) as a white powder.
m.p. >220° C.
NMR (DDMSO) δ (ppm) 9.33 (bm, 1H), 9.18 (bm, 1H), 7.96 (s, 1H), 7.59 (s, 2H), 7.33 (dd, 1H), 6.99 (d, 1H), 6.85 (t, 1H), 4.63 (d, 1H), 4.53 (d, 1H), 4.37 (d, 1H), 3.52 (d, 1H), 3.4-3.2 (m, 2H), 3.25 (m, 1H), 3.04 (t, 1H), 3.0-2.8 (m, 1H), 2.93 (s, 3H), 2.38 (s, 3H).
IR (Nujol) (cm−1) 3200, 1659
MS (m/z) 478[M—Cl]+
To a solution of intermediate 14 (0.353 g) in anh. EtOH (5.7 mL), at r.t., under N2, Pd/C 10% (175 mg, 50% wt) was added. The black suspension was placed under an atmosphere of H2 and was stirred for 3 hr. The catalyst was then filtered on Celite and the Celite cake was rinsed with EtOH. HCl 1.0M in Et2O was then added (1.13 mL). The solvent was evaporated and the oil obtained was triturated with Et2O. The solid was filtered, rinsed with Et2O and dried under vacuum. The title compound was obtained as a grey solid (104 mg).
m.p. 77-80° C.
NMR (CDCl3): δ (ppm) 8.95 (bs, 2H), 7.97 (s, 1H), 7.75 (s, 1H), 7.22-7.08 (m, 4H), 4.584.41 (2d, 2H), 4.50 (dd, 1H), 3.44 (m, 1H), 3.4-3.1 (m, 5H), 2.84 (s, 3H), 2.80 (m, 1H), 1.12 (d, 3H), 1.07 (d, 3H).
IR (Nujol) (cm−1) 3437, 1653
MS (m/z) 488[M—Cl]+
To a solution of intermediate 15 (0.108 g) in anh. EtOH (2.0 mL), at r.t., under N2, Pd/C 10% (20 mg, 20% wt) was added. The black suspension was placed under an atmosphere of H2 and was stirred for 3 hr. The catalyst was then filtered on Celite and the Celite cake was rinsed with EtOH. HCl 1.0M in Et2O was then added (350 μL). The solvent was evaporated and the oil obtained was triturated with Et2O. The solid was filtered, rinsed with Et2O and dried under vacuum. The title compound was obtained as a brown solid (29 mg).
m.p. 108-110° C.
NMR (CDCl3): δ (ppm) 9.15 (bd, 1H), 8.92 (bd, 1H), 7.97 (s, 1H), 7.66 (s, 2H), 7.30 (m, 1H), 7.27 (m, 1H), 7.19 (dt, 1H), 7.03 (dt, 1H), 4.69 (dd, 1H), 4.55 (2d, 2H), 3,53 (m, 1H), 3.39 (m, 3H), 3.19 (bd, 1H), 3.04 (dt, 1H), 2.92 (m, 4H), 1.24 (d, 3H), 1.20 (d, 3H).
IR (Nujol) (cm−) 3441, 1662.
MS (m/z) 489[M—Cl]+.
To a solution of intermediate 16 (0.226 g) in anh. EtOH (3.7 mL), at r.t., under N2, Pd/C 10% (23 mg, 10% wt) was added. The black suspension was placed under an atmosphere of H2 and stirred for 3 hr. The catalyst was then filtered on Celite and the Celite cake was rinsed with EtOH. HCl 1.0M in Et2O was then added (740 μL). The solvent was evaporated and the oil obtained was treated with Et2O. The solid obtained was filtered, rinsed with Et2O and dried under vacuum to give the title compound as a white solid (112 mg).
m.p. 70-72° C.
NMR (CDCl3): δ (ppm) 9.08 (m, 2H), 7.97 (s, 1H), 7.67 (s, 2H), 7.19 (m, 1H), 7.14 (m, 1H), 7.01 (t, 1H), 4.59 (d, 1H), 4.43 (m, 1H), 4.40 (d, 1H), 3.1-3.5 (m, 6H), 2.92 (s, 3H), 2.14 (s, 3H).
IR (Nujol) (cm−1) 3406, 1653
MS (m/z) 478 [M—Cl]+
To a solution of intermediate 17 (0.134 g) in anh. EtOH (2.0 mL), at r.t., under N2, Pd/C 10% (27 mg, 20% wt) was added. The black suspension was placed under an atmosphere of H2 and was stirred for 3 hr. The catalyst was then filtered on Celite and the Celite cake was rinsed with EtOH. HCl 1.0M in Et2O was then added (436 μL). The solvent was evaporated and the oil obtained was triturated with Et2O. The solid was filtered, rinsed with Et2O and dried under vacuum. The title compound was obtained as a yellow solid (112 mg).
m.p. 220-230° C.
NMR (CDCl3): δ (ppm) 9.08-9.3 (m, 2H), 7.97 (s, 1H), 7.62 (s, 2H), 7.44 (m, 1H), 7.18 (m, 1H), 6.95 (m, 1H), 4.65 (m, 1H), 4.34.65 (dd, 2H), 3.2-3.6 (m, 4H), 3.07 (m, 2H), 2.92 (s, 3H).
IR (Nujol) (cm−1) 3400, 1656
MS (m/z) 482 [M—Cl]+.
A solution of intermediate 18 (0.086 g) in EtOH (10ml) was hydrogenated at atmospheric pressure for 2 hr, in the presence of 10% Pd/C (20mg) as catalyst. The catalyst was filtered off and the solvent was evaporated. The crude residue dissolved in Et2O and then a 1M sol. of HCl in Et2O (0.1 ml) was added. The solvent was evaporated to obtain the title compound (0.05 g) as a white solid.
NMR (DMSO) δ (ppm) 9.06 (m, 1H), 8.88 (m, 1H), 7.91 (s, 1H), 7.77 (s, 2H), 7.42 (t, 1H), 7.22 (dd, 1H), 7.03 (m, 1H), 6.94 (t, 1H), 5.22 (t, 1H), 4.34 (m, 2H), 3.98 (m, 1H), 3.64 (m, 1H), 3.4-3.2 (m, 2H), 3.22 (m, 2H), 2.32 (s, 3H).
IR (Nujol) (cm−1) 3360, 1645.
MS (m/z) 464 [M—Cl]+.
A solution of intermediate 20a (0.120 g) in EtOH (5 mL) was hydrogenated at atmospheric pressure for 4 hr, in the presence of 10% Pd/C (25 mg). Then the catalyst was filtered off and the solvent was evaporated. The crude product was dissolved in Et2O and then a solution 1M of HCl in Et2O (0.3 mL) was added. Then the precipitate was filtered and washed with Et2O to obtain the title compound (0.057 g) as a white solid.
m.p.>220° C.
NMR (DMSO) δ (ppm) 9.11 (m, 1H); 8.83 (m, 1H); 7.96 (s, 1H); 7.59 (s, 2H); 7.34 (dd, 1H); 6.94 (dd, 1H); 6.86 (m, 1H); 4.65-4.35 (dd, 2H); 4.49 (m, 1H); 3.54 (m, 1H); 3.44-3.01(m, 4H); 2.93 (s, 3H); 2.90 (m, 1H); 2.38 (s, 3H). MS (m/z) 479 [MH—Cl]+
[α]D20=+69.5 C.=0.27(g/100 ml) CHCl3
A solution of intermediate 20b (0.110 g) in EtOH (5 mL) was hydrogenated at atmospheric pressure for 4 hr, in the presence of 10% Pd/C (25 mg). Then the catalyst was filtered off and the solvent was evaporated. The crude product was dissolved in Et2O and then a solution 1M of HCl in Et2O (0.3 mL) was added. Then the precipitate was filtered and washed with diethyl ether to obtain the title compound (0.045 g) as a white solid.
A solution of intermediate 37a (0.24 g) in EtOH (4 mL) was hydrogenated at atmospheric pressure for 3 hr. in the presence of 10% Pd/C (73 mg) as catalyst. The catalyst was filtered off and the solvent was evaporated. The crude residue was dissolved in Et2O and then a 1M sol. of HCl in Et2O (0.58 mL) was added. The formed precipitate was filtered and washed with diethyl ether to obtain the title compound (0.04 g) as a white powder.
To Intermediate 39 (2.37 g) TEA (3.15 mL) in dry DCM (57 mL) was added dropwise, at 0° C. Then a solution of triphosgene (1.502 g) in dry DCM (12 mL) under inert atmosphere was added. The temperature was maintained at 0° C. for 3 hr. before the addition of DIPEA (4 mL) followed by 3,5-bis-trifluoromethylbenzyl-N-methyl amine (4.62 g) in acetonitrile (142 mL). The reaction mixture was heated to reflux for 3 hr then cooled to room temperature diluted with DCM (25 mL) and washed with a 1N solution of HCl (25 mL), H2O (25 mL) and brine (25 mL) in sequence. The organic phase was dried and the crude product obtained after evaporation of the solvent was purified by flash chromatography (from AcOEt/CH 4:1 to pure AcOEt) to give 2-(4-Fluoro-2-methyl-phenyl)-3-oxo-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a foam (1.79 g).
This compound was reduced with BH3.THF (17.6 mL) following the standard procedure (4 hr reflux in 10 ml of THF, then work-up with 6 mL of HCl 37% and subsequent neutralisation with 5 g of solid NaHCO3) to give the title compound (1.16 g).
m.p.>220° C.
NMR (DMSO) δ (ppm) 9.11 (m, 1H); 8.83 (m, 1H); 7.96 (s, 1H); 7.59 (s, 2H); 7.34 (dd, 1H); 6.94 (dd, 1H); 6.86 (m, 1H); 4.654.35 (dd, 2H); 4.49 (m, 1H); 3.54 (m, 1H); 3.44-3.01(m, 4H); 2.93 (s, 3H); 2.90 (m, 1H); 2.38 (s, 3H).
MS (m/z) 479 [MH—Cl]+
[α]D20=−72.6 C.=0.27 (g/100 ml) CHCl3
A solution of intermediate 22a (0.05 g) in EtOH (5 mL) was hydrogenated at atmospheric pressure for 1½ hr. in the presence of 10% Pd/C (15 mg). Then the catalyst was filtered off and the solvent was evaporated. The crude product was dissolved in Et2O and then a solution 1M of HCl in Et2O (0.5 mL) was added. Then the precipitate was filtered and washed with Et2O to obtain the title compound (0.025 g) as a white powder.
NMR (CDCl3) δ (ppm) 10.2 (b, 1H); 7.78 (s, 1H); 7.54 (s, 2H); 7.13 (dd, 1H); 6.88 (dd, 1H); 6.82 (m, 1H); 5.48 (q, 1H); 4.57 (m, 1H); 3.6-3.5 (m, 2H); 3.38 (m, 2H); 3.3-3.0 (m, 2H); 2.71 (s, 3H); 2.48 (s, 3H); 1.44 (d, 3H).
IR (CDCl3) 1663
MS (m/z) 491 [M—Cl]+
A solution of intermediate 22b (0.05 g) in EtOH (5 mL) was hydrogenated at atmospheric pressure for 1½ hr. in the presence of 10% Pd/C (15 mg). Then the catalyst was filtered off and the solvent was evaporated. The crude product was dissolved in Et2O and then a solution 1M of HCl in Et2O (0.5 mL) was added. Then the precipitate was filtered and washed with Et2O to the title compound (0.057 g) as a white powder.
NMR (CDCl3) δ (ppm) 10.2 (b, 1H); 7.74 (s, 1H); 7.41 (s, 2H); 7.10 (m, 1H); 6.88 (m, 1H); 6.80 (m, 1H); 5.58 (q, 1H); 4.85 (m, 1H); 3.7-2.9 (m, 6H); 2.80 (s, 3H); 2.49 (s, 3H); 1.44 (d, 3H).
IR (CDCl3) 1662
MS (m/z) 491 [M—Cl]+
To a solution of intermediate 32 (813 mg) in anh. THF (6.6 mL), at r.t., under N2, BH3-THF 1M in THF (9.9 mL) was added. The solution was heated at reflux for 3 hr. It was then brought back to r.t. and 1N HCl (4 mL) was added slowly in order to destroy the borane complexes. The reaction mixture was stirred at r.t. for 18 hr. The THF was evaporated and the aqueous phase was basified with 10% NaOH. It wash then extracted with EtOAc (3×). The combined organic extracts were dried, the solids were filtered and the solvent evaporated. The title compound was used in the next step (790 mg) without any further purification.
NMR (CDCl3): δ (ppm) 7.77 (s, 1H), 7.49 (s, 2H), 7.33 (m, 1H), 6.86 (m, 1H), 6.82 (m, 1H), 4.65-4.46 (2d (AB), 2H), 4.46 (m, 1H), 3.40-2.85 (m, 6H), 2.97 (s, 3H), 2.66 (s, 3H).
IR (CDCl3, cm−1): 1653.
MS (m/z): 478 [MH]+
A 1M solution of BH3.in THF (1.88 mL) was added very carefully to a solution of intermediate 33 (0.180 g) in dry THF (8 mL) under inert atmosphere; and the reaction mixture was refluxed 3 hr. After completion of the reduction, HCl 37% was added (3 mL) and the reaction mixture was refluxed 2 hr. THF was removed under reduced pressure, water was added (3 mL) and the aqueous solution was basified using Na2CO3; next, it was extracted with DCM, washed with brine and dried. The crude product was purified by flash chromatography (AcOEt/MeOH 8:2) affording the free amine which was treated with a 1M solution of HCl in Et2O (0.3 mL) to yield the title compound (0.05 g) as a white solid.
mp>200° C.
NMR (DMSO) δ (ppm): 9.08 (bs, 2H), 7.97 (s, 1H), 7.66 (s, 2H), 7.35 (m, 2H), 7.10 (m, 2H), 4.60 (d, 1H), 4.46 (dd, 1H), 4.39 (d, 1H), 3.50-3.10 (m, 6H), 2.92 (s, 3H).
IR (Nujol) (cm−1) 3437, 1653
MS: 464 [M—Cl]+.
To a stirred solution of intermediate 34 (0.382 g) in THF (10 mL) a 1M solution of BH3 in THF (1.66 mL) was added. The mixture was then refluxed for 3 hr. The temperature was then cooled, and the reaction was quenched with a solution of HCl 37% (5 mL) and stirred at room temperature overnight. The solution was then basified with NaOH and the product was extracted with DCM, dried and concentrated under reduced pressure to give an oil. The oil was then dissolved in Et2O and a 1M solution of HCl in Et2O (1.6 mL) was added. After a few minutes the solution was concentrated, and the product was triturated from petroleum ether to give the title compound (0.300 g) as a solid.
NMR(CDCl3): δ (ppm): 10.15(b, 2H); 7.75(s, 1H); 7.44(s, 2H); 7.3(m, 5H); 4.80-4.34(m, 3H); 3.80-3.00(m, 6H); 2.93(s, 3H).
MS (m/z):446 [M—Cl]+.
To a solution of intermediate 35 (0.22 g) in THF (15 mL) a 1M solution of borane in THF (1.2 mL) was added and the reaction mixture was stirred at reflux for 3 hr, then cooled to r.t. 37% HCl (3 mL) was added drop-wise and the reaction mixture stirred for 3 hr. The solvent was evaporated and the crude residue was diluted with AcOEt and washed with a saturated solution of NaHCO3 and brine. The organic phase was dried and concentrated to give the crude product. The latter was dissolved in Et2O (2ml), then a 1M sol of HCl in Et2O (1 mL) was added. The obtained solution was added dropwise in petroleum (30 mL) and the formed precipitate was filtered to obtain the title compound (0.06 g, white solid).
NMR (DMSO) δ (ppm) 9.25, 9.15 (m+m, 2H), 7.98 (m, 1H), 7.64 (s, 2H), 7.60 (d, 1H), 7A45 (d, 1H), 7.29 (dd, 1H), 4.78 (dd, 1H), 4.63 (d, 1H), 4.35 (d, 1H), 3.59 (d, 1H), 3.40-3.25 (m, 3H), 3.07 (t, 3H), 2.95, 2.93 (s+m, 4H).
IR (Nujol) (cm−1) 3442, 1654
MS (m/z) 515 [M—Cl]+.
To a solution of intermediate 36 (0.13 g) in THF (20 mL) a 1M solution of borane in THF (1.96 mL) was added and the reaction mixture was stirred at reflux for 3 hr, then cooled to r.t. 37% HCl (5 mL) was added drop-wise and the reaction mixture was stirred for 3 hr. The solvent was evaporated and the crude residue was diluted with AcOEt and washed with a saturated solution of NaHCO3 and brine. The organic phase was dried and concentrated to give the crude product. The latter was dissolved in Et2O (2 mL), then a 1M sol of HCl in diethyl ether (1 mL) was added. The obtained solution was added drop-wise in petroleum (30 mL) and the formed precipitate was filtered to obtain the title compound (0.016 g, white solid).
NMR (DMSO) δ (ppm) 8.99 (broad, 2H), 7.98 (s, 1H), 7.70 (s, 2H), 7.56 (d+d, 2H), 7.31 (dd, 1H), 4.58 (d, 1H), 4.50 (d, 1H), 4.41 (d, 1H), 3.5-3.1 (m, 4H), 2.93 (s, 3H).
IR (Nujol) (cm−1) 3436, 1653
MS (m/z) 515 [M—Cl+.
A solution of intermediate 38a (0.08 g) in EtOH (5 mL) was hydrogenated at atmospheric pressure for 4 hr, in presence of 10% Pd/C (50 mg). The catalyst was filtered off and the solvent was evaporated. The crude product was dissolved in Et2O and then a solution of 1M of HCl in Et2O (0.5 mL) was added. The precipitate was filtered and washed with Et2O to obtain the title compound (0.023 g).
NMR (CDCl3) δ (ppm) 10.5-10.0 (b, 2H); 7.74 (s, 1H); 7.41 (s, 2H); 7.09 (m, 1H); 6.88 (m, 1H); 6.80 (m, 1H); 5.58 (q, 1H); 4.85 (m, 1H); 3.80-3.00 (m, 6H); 2.80 (s, 3H); 2.49 (s, 3H); 1.53 (d, 3H).
MS (m/z) 492
[α]D20=−164.9, 0.12(g/100 ml) CHCl3
(+)-2-(R)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide hydrochloride
A solution of intermediate 38 b (0.08 g) in EtOH (5 mL) was hydrogenated at atmospheric pressure for 4 hr, in presence of 10% Pd/C (50 mg). The catalyst was filtered off and the solvent was evaporated. The crude product was dissolved in Et2O and then a solution 1M of HCl in Et2O (0.5 ML) was added. The precipitate was filtered and washed with Et2O to obtain the title compound (0.020 g).
NMR (CDCl3) δ (ppm) 10.5-10.0 (b, 2H); 7.74 (s, 1H); 7.41 (s, 2H); 7.09 (m, 1H); 6.88 (m, 1H); 6.80 (m, 1H); 5.58 (q, 1H); 4.85 (m, 1H); 3.80-3.00 (m, 6H); 2.80 (s, 3H); 2.49 (s, 3H); 1.53 (d, 3H).
MS (m/z) 492
[α]D20=+207, 0.11 (g/100 ml) CHCl3
To a solution of intermediate 40a (8.8 9) in dry THF (33 mL) under N2 BH3.THF (1M solution in THF—87 mL) was added and the reaction mixture was stirred at reflux for 3 hr, then cooled to r.t. and HCl (37%, 30 mL) was added drop-wise maintaining the reaction mixture in an icebath. The reaction mixture was stirred at r.t. for 1 hr. Water was then added (70 mL) and solid NaHCO3 (35.2 g) was added portion-wise until a pH of 6.5. The THF was evaporated and the aqueous phase was extracted with Et2O (3×88 mL). The combined organic phases were dried, and evaporated to leave a colourless oil (7.37 g).
This crude oil was purified by flash chromatography (AcOEt/MeOH 7:3). The product obtained was suspended in Et2O (125 mL) and washed with NaHCO3 sat. (2×20 mL). The clear combined organic phases were dried and evaporated to obtain the 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide as white foam (5.27 g). This material (5.27 g) was dissolved in Et2O (79 mL) and acetic acid (613 μL) was added drop-wise. The mixture was stirred at r.t. for 1 h and then at 0° C. for 1 h. The suspension was filtered to give the title compound (4.366 g) as a white solid.
NMR (1H, DMSO-d6): δ (ppm) 7.98 (s, 1H), 7.70 (s, 2H), 7.87 (m, 1H), 6.91 (m, 1H), 6.77 (m, 1H), 5.29 (q, 1H), 4.23 (dd, 1H), 3.2-2.6 (m, 6H), 2.68 (s, 3H), 2.3 (s, 3H), 1.89 (s, 3H), 1.48 (d, 3H).
MS (m/z): 492 [M—CH3COO]+.
[α]D=−20.4° C. Solvent (CHCl3); Source: Na; Cell volume [mL]: 1; Cell pathlength [dm]: 1; Cell temperature [° C.]: 20; Wavelength [nm]: 589
To a solution of intermediate 40b (2.57 g) in dry THF (15.5 mL), at 0° C., under N2, was added BH3.THF (1M solution in THF) then heated at reflux for 3 hr. It was then brought back to r.t. and HCl 37% (9 mL) was added slowly maintaining the reaction mixture in an ice-bath. The reaction mixture was stirred at r.t. for 1 hr. Water was then added (20.5 mL) and solid NaHCO3 (10.3 g) was added portionwise until a pH of 7.
The THF was evaporated and the aqueous phase was extracted with Et2O (3×25.7 mL). The combined organic phases were dried and evaporated to leave a yellow oil (2.34 g). This crude oil was dissolved in Et2O (35 mL) and glacial ACOH (0.245 mL) was added dropwise. The mixture was stirred 2 hr at 0° C., then it was filtered, washed with Et2O (10 mL) and dried under vacuum to obtain the title compound as a white solid (1 349 gr).
NMR (1H, DMSOd6): δ (ppm) 7.92 (s, 1H), 7.58 (s, 1H), 7.29 (m, 1H), 6.90 (m, 1H), 6.77 (m, 1H), 5.33 (q, 1H), 4.19 (m, 1H), 3.2-2.6 (m, 6H), 2.79 (s, 3H), 2.32 (s, 3H), 1.89 (s, 3H), 1.48 (d, 3H).
MS (m/z): 492 [M—CH3COO]+.
[α]D=+2.2° C.
Solvent (CHCl3); Source:Na; Cell volume [mL]: 1; Cell pathlength [dm]: 1; Cell temperature [° C.]: 20; Wavelength [nm]: 589
Example 8 (0.05 g) was dissolved in dry DMF (2 mL), DIPEA (0.019 mL) was added and the solution thus obtained was added to a solution of N-(tert-butoxycarbonyl)glycine (0.0192 g), 1-(3dimethylaminopropyl)-3-ethylcarbodiimide (0.0214 g) and 1-hydroxybenzotriazole (0.015 g) in dry DMF (5 mL). The reaction mixture was stirred 18hr at room temperature, then diluted with AcOEt (30 mL), washed with water (30 mL), sodium bicarbonate (30 mL) and brine (30 mL). The separated organic layer was dried and evaporated to give a crude, which was purified by flash chromatography (AcOEt). The compound obtained (0.043 g) was dissolved in 1M solution of HCl in Et2O (5 mL), stirred 0.5 hr at room temperature and evaporated to obtain the title compound (0.046 g) as a yellow foam.
NMR (DMSO) δ (ppm) 8.01 (bs, 3H), 7.88 (s, 1H), 7.67 (s, 2H), 7.33 (m, 1H), 6.95 (m, 1H), 6.83 (m, 1H), 4.60 (m, 1H), 4.604.42 (dd, 2H), 4.2-3.3 (m, 6H), 3.2 (m, 2H), 2.89 (s, 3H), 2.4 (s, 3H).
IR (Nujol) (cm−1) 3410, 1660.
MS (m/z) 535 [M—Cl]+.
Palladium on charcoal (10%—17.5 mg) was added to a solution of intermediate 73 (145 mg) in ethanol (2 mL). The resulting mixture was stirred at 1 atm and r.t. under hydrogen atmosphere for 2 hrs. The mixture was filtered and concentrated in vacuo. The residue was dissolved in Et2O (2 mL) and treated with HCl 1M in Et2O (1 mL), the mixture was stirred at r.t. for 10 min, then concentrated in vacuo and the residue triturated with Et2O/petroleum to give the title compound (27 mg) as white solid.
NMR (d6-DMSO): δ (ppm) 9.15 (bs, 1H); 8.9 (bs, 1H); 7.77 (s, 1H); 7.71 (s, 2H); 7.31 (dd, 1H); 6.95-6.87 (m, 2H); 4.39 (dd, 1H); 3.71 (dt, 1H); 3.35-2.9 (m, 5H); 3.24 (s, 3H); 2.23 (s, 3H); 1.49 (s, 3H); 1.46 (s, 3H).
MS: m/z=506 [MH]+.
To a solution of intermediate 41 (25 mg) in absolute EtOH (1 mL), at room temperature, was added methylamine 8.03M in EtOH (48 μL). The reaction mixture was stirred at r.t. for 5 hr. The solvent was evaporated and the crude product purified by flash chromatography (AcOEt/MeOH/NH4OH conc. 90:5:5). The fractions were collected and the solvent was evaporated. The residue was dissolved in Et2O and HCl 1.0M in Et2O (150 μL) was added. The yellow precipitate was filtered and dried to give the title compound (19 mg) as a yellow solid.
NMR (DMSO) δ (ppm) 8.12 (bs, 2H), 7.90 (s, 1H), 7.62 (s, 2H), 7.33 (t, 1H), 6.95 (dd, 1H), 6.83 (td, 1H), 4.69 (m, 1H), 4.62 (d, 1H), 4.41 (d, 1H), 3.60-3.10 (m, 10H), 2.94 (s, 3H), 2.40 (s, 3H).
IR (Nujol) (cm−1) 3433-3300, 1651.
MS (m/z) 521 [M—2HCl+H]+.
To a solution of intermediate 45 (100 mg) in anh. MeOH (3 mL), under N2, at room temperature, was added Pd/C 10% (20 mg). The reaction mixture was placed under an H2 atmosphere and stirred at room temperature for 2 hr. The catalyst was filtered on Celite, and the Celite cake was rinsed with AcOEt. The solvent was evaporated and the residue was dissolved in Et2O. HCl 1.0N in Et2O (240 μl) was added and the white precipitate was filtered and rinsed with Et2O. The title compound was obtained (73 mg) as a white solid.
NMR (CDCl3) δ (ppm) 9.31+9.01 (m, 2H), 7.99 (s, 1H), 7.70 (s, 2H), 7.02 (m, 2H), 6.78 (m, 1H), 4.63 (d, 1H), 4.74.3 (dd, 2H), 3.66 (m, 1H), 3.5-2.9 (m, 4H), 3.05 (s, 3H), 2.34 (s, 3H), 1.09 (d, 3H).
IR (Film) (cm−1) 1659.
MS (m/z) 692 [MH—Cl]+.
BH3.THF complex (1.25 mL) was added very carefully to a solution of intermediate 47 (0.080 g) in dry THF (5 ml) under inert atmosphere and the reaction mixture was refluxed for 3 hr. After completion of the reduction, HCl 37% was added (3 mL) and the reaction mixture was refluxed for 2 hr. THF was removed under reduced pressure, water was added (3 mL) and the aqueous solution was basified by means of Na2CO3, extracted with DCM, washed with brine and dried. The crude product was purified by flash chromatography (AcOEt/MeOH 8:2) to afford a product which was dissolved in Et2O and treated with HCl 1.0M in Et2O. (0.3 mL) to give the title compound (0.03 mg).
1H-NMR (DMSO) δ (ppm) 9.12 (bs, 1H), 8.88 (bs, 1H), 7.93 (s, 1H), 7.56 (s, 2H), 7.37 (m, 1H), 6.74 (m, 2H), 4.71 (d, 1H), 4.35 (dd, 1H), 4.36-4.10 (bm, 1H), 3.35-2.9 (m, 5H), 2.99 (s, 3H), 2.28 (s, 3H), 1.05 (d, 3H).
MS (m/z) 492 [M—Cl]+.
mp>200° C.
Conc. HCl (0.27 mL) was added to a solution of intermediate 53 (90 mg) in methanol (9 mL) and the mixture was refluxed for 15 min. The mixture was concentrated in vacuo and the residue triturated with Et2O to give the title compound (32 mg) as white solid.
IR (nujol): 3405 (NH2+), 1653 (C═O) cm−1.
NMR (DMSO) δ (ppm) 9.42 (bs, 1H), 9.27 (bs, 1H); 7.79 (bs, 1H), 7.45 (dd, 1H), 7.25 (bs, 2H), 6.94 (m, 2H), 4.52 (dd, 1H), 3.5-3.06 (m, 9H); 2.33 (s, 3H), 1.34 (m, 2H); 1.22 (m, 2H).
MS: m/z=504 [M—Cl]+.
Conc. HCl (0.3 mL) was added to a solution of intermediate 58a (15 mg) in methanol (5 mL) and the mixture was refluxed for 2 hrs. The mixture was concentrated in vacuo to give the title compound (7 mg) as white solid.
IR (nujol): 1654 (C═O) cm−1.
NMR (DMSO) δ (ppm) 9.17 (bs, 1H); 8.88 (bs, 1H); 7.93 (s, 1H), 7.86 (s, 2H); 7.23 (m, 1H); 6.94 (m, 2H); 4.78 (t, 1H), 4.46 (dd, 1H); 3.88-3.83 (m, 2H); 3.79 (m, 1H); 3.4 (m, 1H); 3.28 (m, 1H); 3.2 (d, 1H); 3.06 (t, 1H); 2.84 (m, 1H); 2.31 (m, 1H), 2.27 (s, 3H); 1.96 (m, 1H); 1.74 (m, 1H); 1.62 (m, 1H).
MS: m/z=504 [MH—HCl]+.
Conc. HCl (0.3 mL) was added to a solution of intermediate 58b (20 mg) in methanol (5 mL) and the mixture was refluxed for 2 hrs. The mixture was concentrated in vacuo to give the title compound (11 mg) as white solid.
IR (nujol): 1659 (C═O) cm−1.
NMR (DMSO) δ (ppm) 9.09 (bm, 1H); 8.89 (bm, 1H); 7.83 (s, 1H), 7.52 (s, 2H); 7.45 (dd, 1H); 6.97 (td, 1H), 6.9 (dd, 1H); 4.93 (dd, 1H), 4.39 (dd, 1H); 3.88-3.22 (m, 6H); 3.07 (t, 1H); 2.99 (m, 1H); 2.3 (m, 1H), 2.25 (s, 3H); 1.80 (m, 1H); 1.75 (m, 1H); 1.63(m, 1H).
MS: m/z=504 [MH—HCl]+.
Trifluoroacetic acid (5 mL) was added to a solution of intermediate 62 (172 mg) in DCM (5 mL) and the resulting solution was stirred at r.t. for 30 minutes. The mixture was concentrated in vacuo, then partitioned between 10% potassium carbonate solution and AcOEt. The organic layer was dried and concentrated in vacuo: the residue was dissolved in Et2O and treated with HCl 1M in Et2O (5 mL) the mixture was stirred at r.t. for 30 min, then concentrated in vacuo and the residue triturated with Et2O to give the title compound (90 mg) as white solid.
IR (nujol): 1656 (C═O) cm−1.
NMR (DMSO) δ (ppm) 9.4-9.2 (bs, 2H); 7.95 (s, 1H); 7.54 (s, 2H); 7.32 (dd, 1H); 6.98 (dd, 1H), 6.85 (dt, 1H); 5.9 (bm, 1H); 5.72 (m, 1H); 5.47 (d, 1H); 4.57 (dd, 1H); 4.41 (bd, 1H); 3.4-3.25 (m, 5H); 3.14 (t, 1H); 2.91 (t, 1H); 2.72 (dd, 1H); 2.55 (m, 1H), 2.37 (s, 3H).
Palladium on charcoal (10%—14 mg) was added to a solution of intermediate 62 (145 mg) in AcOEt (5 mL). The resulting mixture was stirred at 1 atm and r.t. under hydrogen atmosphere for 3 hrs. The mixture was filtered and concentrated in vacuo. DCM (5 mL) and trifluoroacetic acid (5 mL) were added to the residue and the resulting solution was stirred at r.t. for 30 minutes. The mixture was concentrated in vacuo, then partitioned between 10% potassium carbonate solution and AcOEt. The organic layer was dried and concentrated in vacuo: the residue was dissolved in Et2O and treated with HCl 1M in Et2O (5 mL), the mixture was stirred at r.t. for 15 min, then concentrated in vacuo and the residue triturated with Et2O to give the title compound (42 mg) as white solid.
IR (nujol) 3200-2500 (NH2+), 1656 (C═O) cm−1.
NMR (DMSO) δ (ppm) 9.4 (bs, 2H); 7.92 (bs, 1H); 7.48 (bs, 2H); 7.43 (dd, 1H); 6.97 (dd, 1H), 6.93 (m, 1H); 5.25 (bm, 1H); 4.61 (dd, 1H); 4.15 (bd, 1H); 3.5-3.2 (bm, 5H); 2.92 (t, 1H); 2.79 (m, 1H); 2.36-2.42 (m, 4H); 1.78-1.58 (m, 4H); 1.17 (m, 1H).
DCM (2 mL) and trifluoroacetic acid (5 mL) were added to intermediate 65 (44 mg) and the resulting solution was stirred at r.t. for 30 minutes. The mixture was concentrated in vacuo, then partitioned between 10% sodium carbonate solution and AcOEt. The organic layer was dried and concentrated in vacuo: the residue was dissolved in Et2O and treated with HCl 1M in Et2O (5 mL). The mixture was stirred at r.t. for 10 min, then concentrated in vacuo to give the title compound (43 mg) as white solid.
NMR (DMSO) δ (ppm) 9.05 (bs, 1H); 8.81 (bs, 1H); 7.96 (bs, 1H); 7.55 (bs, 2H); 7.25 (dd, 1H); 6.97 (dd, 1H); 6.78 (dt, 1H); 5.7 (m, 1H); 5.35 (dd, 1H); 5.25-5.06 (2m, 2H), 4.47 (dd, 1H); 3.5-2.37 (m, 15H).
DCM (2 mL) and trifluoroacetic acid (5 mL) were added to intermediate 66 (44 mg) and the resulting solution was stirred at r.t. for 30 minutes. The mixture was concentrated in vacuo, then partitioned between 10% sodium carbonate solution and AcOEt. The organic layer was dried and concentrated in vacuo: the residue was dissolved in Et2O and treated with HCl 1M in Et2O (5 mL). The mixture was stirred at r.t. for 10 min, then concentrated in vacuo to give the title compound (39 mg) as white solid.
IR (nujol): 3422 (NH2+), 1726 (C═O) cm−1
NMR (DMSO) δ (ppm) 9.24 (bm, 1H); 9.02 (bm, 1H); 7.99 (s, 1H); 7.78 (s, 2H); 7.26 (dd, 1H); 6.97 (dd, 1H), 6.87 (dt, 1H); 5.47 (m, 1H); 5.2 (t, 1H); 5.03 (dd, 1H); 4.89 (d, 1H); 4.49 (dd, 1H); 3.36 (m, 2H); 3.24 (m, 2H); 2.97 (m, 2H); 2.85 (s, 3H); 2.74 (t, 2H), 2.37 (s, 3H).
Trifluoroacetic acid (1 mL) was added to a solution of intermediate 77a (35 mg) in DCM (1.5 mL) and the resulting solution was stirred at r.t. for 30 minutes. The mixture was concentrated in vacuo, then partitioned between 10% potassium carbonate solution and AcOEt. The organic layer was dried and concentrated in vacuo: the residue was dissolved in Et2O and treated with HCl 1M in Et2O (1 mL). The mixture was stirred at r.t. for 10 min, then concentrated in vacuo and the residue triturated with Et2O to give the title compound (20 mg) as white solid.
NMR (d6-DMSO): δ (ppm) 8.87 (bs, 2H); 8.02 (s, 1H); 7.88 (s, 1H); 7.26 (m, 1H); 6.96 (m, 1H); 6.86 (m, 1H); 4.71 (bm, 1H); 4.42 (dd, 1H); 3.4-3.0 (m, 4H); 2.88-2.79 (m, 5H); 2.63-2.38 (m, 4H); 0.62 (d, 3H); 0.58 (d, 3H).
MS: m/z=520 [M—Cl]+.
Trifluoroacetic acid (1 mL) was added to a solution of intermediate 77b (37 mg) in DCM (1.5 mL) and the resulting solution was stirred at r.t. for 30 minutes. The mixture was concentrated in vacuo, then partitioned between 10% potassium carbonate solution and AcOEt. The organic layer was dried and concentrated in vacuo: the residue was dissolved in Et2O and treated with HCl 1M in Et2O (1 mL). The mixture was stirred at r.t. for 10 min, then concentrated in vacuo and the residue triturated with Et2O to give the title compound (20 mg) as white solid.
NMR (d6-DMSO): δ (ppm) 9.14-8.89 (bs, 2H); 7.96 (s, 1H); 7.69 (s, 2H); 7.02-6.95 (dd, 2H); 6.58 (m, 1H); 4.71 (d, 1H); 4.45 (dd, 1H); 3.5-3.2 (m, 4H); 2.95-2.80 (m, 5H); 2.6-2.38 (m, 4H); 0.87 (d, 3H); 0.72 (d, 3H).
MS: m/z=520 [M—Cl]+.
Conc. HCl (50 μL) was added to a solution of intermediate 80 (10 mg) in methanol (1 mL) and the mixture was refluxed for 15 min. The mixture was concentrated in vacuo and the residue triturated with Et2O to give the title compound (4 mg) as white solid.
NMR (DMSO) δ (ppm) 9.33 (bm, 1H); 9.16 (m, 1H); 8.0 (bs, 1H), 7.79 (bs, 2H); 7.3 (dd, 1H); 6.95 (m, 2H), 4.48 (dd, 1H), 4.27 (d, 1H); 3.5-2.8 (m, 9H); 2.34 (s, 3H), 1.47 (m, 1H); 0.64 (m, 1H); 0.45 (m, 1H); 0.38 (m, 1H); 0.08 (m, 1H).
Trifluoroacetic acid (5 mL) was added to a solution of intermediate 68 (172 mg) in DCM (5 mL) and the resulting solution was stirred at r.t. for 30 minutes. The mixture was concentrated in vacuo, then partitioned between 10% potassium carbonate solution and AcOEt. The organic layer was dried and concentrated in vacuo: the residue was dissolved in Et2O and treated with HCl 1M in Et2O (5 mL). The mixture was stirred at r.t. for 30 min, then concentrated in vacuo and the residue triturated with Et2O to give the title compound (90 mg) as white solid.
IR (nujol) 1656 (C═O) cm−1.
NMR (DMSO) δ (ppm) 9.23 (bs, 1H); 9.17 (bs, 2H); 7.89 (s, 1H); 7.56 (s, 2H); 7.32 (dd, 1H); 6.95 (dd, 1H), 6.82 (dt, 1H); 5.9 (m, 1H); 5.72 (d, 1H); 5.47 (d, 1H); 4.6 (dd, 1H); 4.4 (m, 1H); 3.4-3.2 (m, 6H); 2.94 (m, 1H); 2.7 (dd, 1H); 2.56 (m, 1H), 2.36 (s, 3H).
To a suspension of intermediate 81 (4.9 Kg) in AcOEt (137.2L), triethylamine (5.63L) was added. The mixture was cooled to 0° C. then a solution of diterbuthyl dicarbonate (3.134 Kg) in AcOEt (24.5L) was added in 35 min, maintaining the temperature between 0 and 5° C. The suspension was stirred at 0° C. for 15 min, at 20/250° C. for 1 hr, then washed with water (3×39.2L), concentrated to 24.5L and then added to a solution of triphosgene (1.97 Kg) in AcOEt (24.5L) cooled to 0° C. Triethylamine (3.28L) was then added in 40 min, maintaining the temperature between 0 and 8° C. The suspension was stirred for 1 h and 45 min at 20/25° C. and 30 min at 7° C. and then the solution of intermediate 82 diluted with AcOEt (49L) and triethylamine (2.6L) was added in 30 min. The mixture was refluxed for 15 hrs.
The reaction mixture, cooled at 20/25° C. was treated with aqueous solution of NaOH 10%v/v (36.75L). Organic phase was washed with HCl 4%v/v (46.55L) and NaCl 11.5% p/p (4×24.5L) then concentrated to 14.7L. and diluted with Ciclohexane (39.2L). The mixture was filtered through a silica pad (4.9 Kg) that was washed twice with a mixture of CH/AcOEt 85/15 (2×49L). To the Eluted phases (14.7L) cooled at 20/25° C., methyl tertbutyl ether (49L) and methansulphonic acid (4.067L) were added. The mixture was washed with NaOH 10%v/v (31.85L) then with water (4×31.85L). Organic phase was concentrated to 9.8L, methyl tertbutyl ether (49L) was added and the solution filtered through a 5 micron filter then concentrated to 9.8L. At 20/25° C. MTBE (29.4L) and metansulphonic acid (1.098L) were added. The suspension was refluxed for 10 min, stirred at 20/25° C. for 10 hrs and 2 hrs at 0° C. Then the precipitate was filtered, washed with methyl tertbutyl ether (4.9L) dried under vacuum at 20/25° C. for 24 hrs to obtain the title compound (5.519 Kg.) as white solid.
1H-NMR (DMSO) δ (ppm) 8.99 (bm, 1H); 8.66 (bm, 1H); 8.00 (bs, 1H); 7.69 (bs, 2H); 7.27 (dd, 1H); 7.00 (dd, 1H); 6.83 (m, 1H); 5.32 (q, 1H); 4.47 (dd, 1H); 3.50-3.20 (m, 4H); 2.96 (m, 2H); 2.72 (s, 3H); 2.37 (s, 3H); 2.28 (s, 3H); 1.46 (d, 3H). ES+: m/z 492 [MH—CH3SO3H]+ES−; m/z 586 [M—H]−; 95 [CH3SO3]−
To a solution of intermediate 40a (15.6 g) in anhydrous THF (94 ml), at 0° C., under N2, BH3.THF 1M/THF (154 ml) was added. The solution was heated at reflux for 3 hr. HCl 37% (54 ml) was slowly added maintaining the reaction mixture in an ice-bath and the reaction mixture was stirred at rt for 1 hr. Water was then added (125 ml) and solid NaHCO3 (62.4 g) was added portionwise until a pH of 6.5. The aqueous phase was extracted with Et2O (4×160 ml) and the combined organic extracts were dried over Na2SO4, the solids were filtered and evaporated to leave a colourless oil which was purified by flash chromatography (silica gel, EtOAc/Methanol 7/3). The obtained product was suspended in Et2O (220 ml) and washed with NaHCO3 sat. (2×36 ml). The combined organic phases were dried (Na2SO4) and evaporated to give the title compound as white foam (8.7 g).
1H NMR (CDCl3) δ (ppm) 7.78 (s, 1H); 7.60 (s, 2H); 7.28 (m, 1H); 6.85 (dd, 1H); 6.79 (td, 1H); 5.53 (q, 1H); 4.43 (dd, 1H); 2.9-3.5 (m, 5H); 2.78 (m, 1H); 2.71 (s, 3H); 2.43 (s, 3H); 1.47 (d, 3H).
Example 37 (0.1 g) was dissolved in Ethyl Ether (0.8 ml) at room temperature, then 1M HCl solution in Ethyl Ether (0.6 ml) was added. The suspension was stirred at 3° C. for 3 hour, then filtered and washed with Ethyl Ether (1 ml) to afford the title compound (0.01 5 g) as a white solid.
1H NMR (DMSO) δ (ppm) 9.31 (bm, 1H); 9.11 (bm, 1H); 8.02 (bs, 1H); 7.72 (bs, 2H); 7.28 (dd, 1H); 7.00 (dd, 1H); 6.84 (m, 1H); 5.34 (q, 1H); 4.54 (dd, 1H); 3.50-3.20 (m, 4H); 3.08 (m, 1H); 2.93 (m, 1H); 2.73 (s, 3H); 2.38 (s, 3H); 1.48 (d, 3H).
A. Capsules/Tablets
Active ingredient
20.0
mg
Starch 1500
2.5
mg
Microcrystalline Cellulose
200.0
mg
Croscarmellose Sodium
6.0
mg
Magnesium Stearate
1.5
mg
The active ingredient is blended with the other excipients. The blend can be used to fill gelatin capsules or compressed to form tablets using appropriate punches. The tablets can be coated using conventional techniques and coatings.
B. Tablets
Active ingredient
20.0
mg
Lactose
200.0
mg
Microcrystalline Cellulose
70.0
mg
Povidone
25.0
mg
Croscarmellose Sodium
6.0
mg
Magnesium Stearate
1.5
mg
The active ingredient is blended with lactose, microcrystalline cellulose and part of the croscarmellose sodium. The blend is granulated with povidone after dispersing in a suitable solvent (i.e. water). The granule, after drying and comminution is blended with the remaining excipients. The blend can be compressed using appropriate punches and the tablets coated using conventional techniques and coatings.
c) Bolux
Active ingredient
2-60
mg/ml
Sodium phosphate
1.0-50.0
mg/ml
water for injection
qs to 1
ml
The formulation may be packed in glass ampoules or vials and syringes with a rubber stopper and a plastic/metal overseal (vials only).
D) Infusion
Active ingredient
2-60
mg/ml
Infusion solution (NaCl 0.9% or 5% dextrose)
qs to 100
ml
The formulation may be packed in glass vials or plastic bag.
The affinity of the compound of the invention for NK1 receptor was determined using the NK1-receptor binding affinity method measuring in vitro by the compounds' ability to displace [3H]—substance P (SP) from recombinant human NK1 receptors expressed in Chinese Hamster Ovary (CHO) cell membranes. The affinity values are expressed as negative logarithm of the inhibition constant (Ki) of displacer ligands (pKi).
The pKi values obtained as the average of at least two determinations with representative compounds of the invention are given in the following table:
Example No
pki
1
8.97
4
8.36
5
8.67
8
9.37
9
8.81
10
9
12
8.7
14
8.7
16
9.4
18
9.56
19
9.27
20
9.46
21
8.95
22
9.39
23
9.32
24
9.18
25
9.32
28
9.31
29
8.87
30
8.78
32
8.99
34
9.10
36
9.81
The ability of the compounds of the invention at the nk1 receptor may be determined using the gerbil foot tapping model as described by Rupniak & Williams, Eur. Jour. of Pharmacol., 1994.
The compound was administered orally and one hour later an NK1 agonist (e.g. delta-Aminovaleryl6[Pro9,Me-Leu10]-substance P (7-11)) (3 pmol in 5 μL, icv) was infused directly in the cerebral ventricules of the animals. The duration of hind foot tapping induced by the NK1 agonist (e.g. delta-Aminovaleryl6[Pro9,Me-Leu10]-substance P (7-11)) was recorded continuously for 3 min using a stopclock. The dose of the test compound required to inhibit by 50% the tapping induced by the NK1 agonist (e.g. delta-Aminovaleryl6[Pro9,Me-Leu10]-substance P (7-11)) expressed as mg/kg was referred as the ID50 values. Alternatively the compounds may be administered subcutaneously or intraperitoneally.
Representative results obtained for compounds of the invention when given by oral administration are given in the following table
Ex No
ED50(mg/dg po)
19
0.04
20
0.065
21
0.4
36
0.05
No untoward effects have been observed when compounds of the invention have been administered to the gerbil at the pharmacological active doses.
Giovannini, Riccardo, Alvaro, Giuseppe, St-Denis, Yves, Guercio, Giuseppe, Ursini, Antonella, DiFabio, Romano
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