Benzoyl-piperazine derivatives

Preparation of 1-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine

(a) 4-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester

A mixture of 20 mmol 1-bromo-2-fluoro-4-trifluoromethyl-benzene, 24.7 mmol n-Boc-piperazine, 0.1 mmol Tris(dibenzylideneacetone) dipalladium chloroform complex, 28.8 mmol sodium-t-butoxide and 0.4 mmol 2-(dicyclohexylphosphino)biphenyl in 50 ml toluene was heated for 16 h at 80° C. After cooling to RT the mixture was treated with 15 g Isolute HM—N and all volatiles were removed under vacuum. The residue was purified on silica eluting with a gradient of heptane/EtOAc to yield after evaporation the title compound.

(b) 1-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine

A mixture of 9 mmol 4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester in 20 ml dioxane was treated with 8.93 ml 4N HCl in dioxane for 2 h at 80° C. The mixture was concentrated and treated with 20 ml water, 20 ml 2M Na 2 CO 3 and extracted with 50 ml EtOAc. The organic phase was washed with 30 ml saturated NaCl. All aqueous phases were combined and extracted with 50 ml EtOAc. The combined organic phases were dried with MgSO 4 and evaporated to yield the title compound 1.1.

1-H-NMR (300 MHz, CDCl 3 ) δ=7.50 (d, J=13.3 Hz, 1H, H-3), 7.45 (d, J=8.8 Hz, 1H, H-5), 7.16 (dd, J 1 =8.8 Hz, J 2 =8.8 Hz, 1H, H-6), 3.5-3.2 (s, br, 1H, NH), 3.04 (m, 4H, piperazine), 2.87 (m, 4H, piperazine). MS (m/e): 249.2 (MH + , 100%)

Preparation of 2-isopropoxy-5-methanesulfonyl-benzoic acid

(a) 2-Chloro-5-methanesulfonyl-benzoic acid

To 99 mmol 2-chloro-5-(methylthio) benzoic acid in 400 ml methanol at 0° C. 296 mmol oxone® was added, and the mixture was allowed to stir at RT for 3.5 h. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was extracted 3× with 400 ml ethyl acetate, and the combined organic phases washed 2× with 300 ml 1N HCl and with 300 ml saturated aqueous NaCl solution and dried with MgSO 4 . Evaporation under reduced pressure yielded the title compound.

(b) 2-Isopropoxy-5-methanesulfonyl-benzoic acid

A mixture of 2.13 mmol 2-chloro-5-methanesulfonyl-benzoic acid, 0.64 mmol Cu(I)Br in 5 ml NEt 3 and 25 ml isopropanol was heated to 120° C. for 16 h in a sealed tube. The volatiles were removed under vacuum, and the residue was taken up in 70 ml 1N HCl. Extraction with ethyl acetate drying of the combined organic fractions and evaporation yielded a residue which was purified by reversed phase preparative HPLC eluting with an acetonitrile/water gradient. Evaporation of the product fractions yielded the title compound 1.2.

MS (m/e): 257.0 (MH − , 100%)

In analogy to Example 1.2(b) compounds 1.3 to 1.7 of the following table were prepared from 2-chloro-5-methanesulfonyl-benzoic acid and the appropriate alcohol:

Preparation of 1-{3-fluoro-4-[4-(2-fluoro-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone

A solution of 0.261 mmol 2-fluoro-5-nitro-benzoyl chloride [CAS: 7304-32-7; Feng and Burgess, Chem. Europ. J. EN, 5:3261-3272 (1999)] in 1 ml dioxane was treated with 0.522 mmol triethylamine and then with a solution of 0.261 mmol 1-(3-fluoro-4-piperazin-1-yl-phenyl)-ethanone (CAS: 189763-57-3; WO 97/14,690) in 1 ml dioxane. The mixture was stirred at RT for 30 min. The solvent was removed in vacuo. The crude oil was taken up in water. The aqueous layer was extracted 3 times with CH 2 Cl 2 . The combined extracts were dried over Na 2 SO 4 , filtered, and the solvent was removed in vacuo. The crude gum was purified on silica gel (eluent: heptane/ethylacetate 0%-20% (10 min) to provide the title compound 1.8.

MS (m/e): 390.2 (MH + , 100%)

Preparation of (2-iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

(a) 2-Amino-5-methanesulfonyl-benzoic acid

A mixture of 4.26 mmol 2-chloro-5-methanesulfonyl-benzoic acid, 0.39 mmol Copper powder and 10 ml ammonium hydroxide 25% was heated at 125-130° C. with stirring for 18 hours. Mixture was cooled to room temperature and filtered. The solid was washed with methanol. The filtrate was concentrated in vacuo. The residue was acidified with HCl 1N to pH=2. The obtained solid was washed with water and dried (HV, 50° C., 1 hour) to yield the title compound. MS (m/e): 214.1 (M−H, 100%)

(b) 2-Iodo-5-methanesulfonyl-benzoic acid

To a suspension of 3.0 mmol 2-amino-5-methanesulfonyl-benzoic acid in a mixture of 1.7 ml sulfuric acid and 1.7 ml water was added dropwise a solution of 3.92 mmol sodium nitrite in 1.7 ml water at such rate that the temperature did not exceed 3° C. The mixture was stirred at 0° C. for 1 hour. A solution of 3.0 mmol KI in 1.7 ml water was added dropwise at 0° C. The brown suspension was allowed to warm to rt and stirred for 30 minutes. Excess iodine was destroyed by addition of a few drops of a sodium hydrogenosulfite solution. The solid was filtered, washed with water and dried (HV, 50° C., 1 hour) to yield the title compound. MS (m/e): 325.0 (M−H, 100%)

(c) (2-iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]methanone

To a solution of 9.2 mmol 2-iodo-5-methanesulfonyl-benzoic acid in 20 ml dimethylformamide 11.5 mmol TBTU, 46.0 mmol N-ethyldiisopropylamine and 11.0 mmol 1-(4-trifluoromethylphenyl)piperazine (ABCR F07741NB, [30459-17-7]) were successively added. The reaction was then stirred at RT for two hours, concentrated in vacuo and purified by column chromatography (SiO 2 , 50 g, CH 2 Cl 2 /MeOH/NH 3 =100/0/0 to 95/4.5/0.5), to give the title compound 1.9. MS (m/e): 539.1 (M+H + )

Preparation of [4-(2-fluoro-4-trifluoromethyl-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone

A mixture of 0.05 mmol 2-isopropoxy-5-methanesulfonyl-benzoic acid (Compound 1.2), 0.06 mmol 1-(2-fluoro-4-trifluoromethyl-phenyl)-piperazine, 0.055 mmol TBTU and 0.25 mmol DIPEA in 1 ml DMF was stirred at RT for 16 h. 0.5 ml MeOH/HCOOH 1/1 was added and the mixture was subjected to reversed phase preparative HPLC separation eluting with an acetonitrile/water gradient yielding the title compound.

MS (m/e): 489.2 (MH + , 100%)

In analogy to Example 5 compounds 1 to 4, 6 to 46 and 52-54 of the following table were prepared from the acid derivatives and piperazine derivatives:

Preparation of 1-{3-fluoro-4-[4-(2-methoxy-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone

To a solution of 0.257 mmol 1-{3-fluoro-4-[4-(2-fluoro-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone (Compound 1.8) in 1.5 ml dioxane 102 mg sodium methoxyde was added portionwise. The mixture was stirred at 100° C. for 4 h. The reaction mixture was diluted with 10 ml water, neutralized with 1N HCl and then extracted with ethylacetate (3×10 ml). Combined organic phases were concentrated in vacuo. The residue was chromatographed on silica gel: eluent: heptane/ethylacetate 0%-30% (10 min) to provide compound 47.

MS (m/e): 402.2 (M+H + , 100%).

Preparation of (2-benzyloxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

A mixture of 0.19 mmol (2-iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (Compound 1.9), 0.037 mmol CuI, 0.37 mmol Cs 2 CO 3 , 0.074 mmol 1,10-phenanthroline and 0.4 ml benzylic alcohol was heated at 110° C. for 16 hours. The mixture was cooled to RT, diluted with ethylacetate and filtered. The organic layer was washed twice with water, dried over Na 2 SO 4 , filtered and the solvent was removed in vacuo. The crude oil was purified on silica gel, eluent: heptane/ethylacetate 0%-50% (25 min) to provide compound 48.

MS (m/e): 519.2 (M+H + , 100%)

In analogy to Example 48 compounds 49 to 51 of the following table were prepared from (2-iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (Compound 1.9) and alcohols:

Preparation of 5-Methanesulfonyl-2-(2-methoxy-ethoxy)-benzoic acid

(a) 2-Amino-5-methanesulfonyl-benzoic acid

A mixture of 4.26 mmol 2-chloro-5-methanesulfonyl-benzoic acid (compound 1.2a), 0.39 mmol Copper powder and 10 ml ammonium hydroxide 25% was heated at 125-130° C. with stirring for 18 hours. The mixture was cooled to room temperature and filtered. The solid was washed with methanol. The filtrate was concentrated in vacuo. The residue was acidified with HCl 1N to pH=2. The obtained solid was washed with water and dried (HV, 50° C., 1 hour) to yield the title compound. MS (m/e): 214.1 (, 100%)

(b) 2-Iodo-5-methanesulfonyl-benzoic acid

To a suspension of 3.0 mmol 2-amino-5-methanesulfonyl-benzoic acid in a mixture of 1.7 ml sulfuric acid and 1.7 ml water was added dropwise a solution of 3.92 mmol sodium nitrite in 1.7 ml water at such rate that the temperature did not exceed 3° C. The mixture was stirred at 0° C. for 1 hour. A solution of 3.0 mmol KI in 1.7 ml water was added dropwise at 0° C. The brown suspension was allowed to warm to rt and stirred for 30 minutes. Excess iodine was destroyed by addition of a few drops of a sodium hydrogenosulfite solution. The solid was filtered, washed with water and dried (HV, 50° C., 1 hour) to yield the title compound. MS (m/e): 325.0 (M−H, 100%)

(c) 5-Methanesulfonyl-2-(2-methoxy-ethoxy)-benzoic acid

To a solution of 1.6 mmol 2-iodo-5-methanesulfonyl-benzoic acid in 30 ml 2-methoxyethanol and 6 ml triethylamine were added 79 mg copper (I) bomide, and the reaction mixture heated to 120° C. for 4 h. The solvent was distilled off, and the residue dissolved in 90 ml 1N HCl. The aqueous phase was extracted twice with ethyl acetate, and the pooled organic extracts washed twice with water and once with brine. The organic layer was dried with Na 2 SO 4 , filtered and evaporated to yield the title compound 1.10. MS (m/e): 273.1 (MH − , 100%).

Preparation of 5-Cyano-2-(2-methoxy-ethoxy)-benzoic acid

(a) 2-Bromo-5-cyano-benzoic acid

To a suspension of 7.1 mmol copper (II) bromide in acetonitrile (30 ml) was added dropwise 8.63 mmol tert-butylnitrite at 0° C. within 2 minutes. 6.17 mmol 2-Amino-5-cyano-benzoic acid (CAS: 99767-45-0; WO9518097) was added portionwise within 10 minutes at 0° C. The mixture was stirred at 0° C. for 2 hours and then at room temperature overnight. Half of the solvent was removed in vacuo. The residue was taken in HCl 1N (15 ml) and ethyl acetate (30 ml). The organic layer was extracted with NaOH 1N (3×10 ml). The aqueous layer was acidified with HCl 2N. The resulting solid was filtered, washed with water and dried (high vacuum, 50° C.) to provide the title compound MS (m/e): 227.1 (M+H + , 100%)

(b) 5-Cyano-2-(2-methoxy-ethoxy)-benzoic acid

To a solution of 0.16 mmol 2-bromo-5-cyano-benzoic acid in 6 ml 2-methoxyethanol and 1.2 ml triethylamine were added 23 mg copper (I) bromide, and the reaction mixture heated to 120° C. for 4 h. The solvent was distilled off, and the residue dissolved in 20 ml 1N HCl. The aqueous phase was extracted twice with ethyl acetate, and the pooled organic extracts washed twice with water and once with brine. The organic layer was dried with Na 2 SO 4 , filtered and evaporated to yield the title compound 1.11. MS (m/e): 220.4 (MH − , 100%).

Preparation of 5-Cyano-2-(2,2,2-trifluoro-ethoxy)-benzoic acid

A mixture of 11.3 mmol sodium in 66 mmol 2,2,2-trifluoroethanol was heated to 100° C. until all sodium was dissolved (20 min.). Then a solution of 5.5 mmol 5-cyano-2-iodo-benzoic acid [CAS: 219841-92-6; WO9901455] in 2 ml N-methyl-2-pyrrolidone and 0.5 mmol copper(I)bromide were added, and the reaction mixture heated to 120° C. for 2 h. The reaction mixture was poured onto water, acidified to pH 2 with conc. HCl and extracted 3× with ethyl acetate. The pooled organic extracts were washed with brine, dried over Na 2 SO 4 and evaporated. Flash chromatography on silica gel with heptane/ethyl acetate provided the title compound 1.12. MS (EI) (m/e): 245.1 (M + , 94%), 146.0 ([M—CF 3 CH 2 O] + , 100%).

In analogy to Example 1.12 compounds 1.13 to 1.16 of the following table were prepared from 5-cyano-2-iodo-benzoic acid and the appropriate alcohol:

In analogy to Example 5 compounds 55 to 61 of the following table were prepared from the acid derivatives and piperazine derivatives:

Preparation of (2-Hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

Compound 2.1 was prepared in analogy to Example 5 using 2-hydroxy-5-nitrobenzoic acid [96-97-9] and 1-(4-trifluoromethyl-phenyl)-piperazine. MS (m/e): 394.0 (M−H, 100%)

Preparation of (2-Hydroxy-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

Compound 2.2 was prepared in analogy to Example 5 using 2-hydroxy-5-(methylsulfonyl)benzoic acid [68029-77-6] and 1-(4-trifluoromethyl-phenyl)-piperazine.

MS (m/e): 427.5 (M−H, 100%)

Preparation of (2-Butoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

A solution of (2-Hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (50 mg), potassium carbonate (87 mg) and 1-bromobutane (0.15 mL) in dimethylacetamide (0.3 mL) was heated at 150° C. for 15 minutes in a microwave oven. The reaction mixture was then concentrated and purified by column chromatography (SiO 2 ) to give the title compound (55 mg).

In analogy to Example 66, compounds 62 to 97 of the following table were prepared from the acid derivatives and piperazine derivatives:

Preparation of (2-Difluoromethoxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

In analogy to a procedure published in WO9749710, a solution of (2-Hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (50 mg), potassium carbonate (1 eq), and ethyl chlorofluoroacetate (1 eq) in DMF (1 mL) was stirred at 65° C. for 16 hours. After such time the reaction mixture was concentrated in vacuo and purified by column chromatography (SiO 2 ) to yield the title compound (26 mg). MS (m/e): 446.0 (M+H + , 100%).

Preparation of 5-Nitro-2-(2,2,3,3-tetrafluoro-cyclobutylmethoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

Example 99 was prepared in analogy to Example 66 using 1-(chloromethyl)-2,2,3,3-tetrafluorocyclobutane [356-80-9]. MS (m/e): 536.3 (M+H + , 100%).

Preparation of [5-Nitro-2-(2,2,3,3,3-pentafluoro-propoxy)-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

To a refluxing solution of 50 mg of (2-hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone in acetone (2 mL) containing potassium carbonate (35 mg) was added 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (54 mg) over 10 min. The reaction mixture was refluxed for 20 hours before being concentrated in vacuo and purified by column chromatography (SiO 2 , CH 2 Cl 2 /MeOH) to yield the title compound as a colorless solid (66 mg). MS (m/e): 569.0 (M+H + , 100%).

Preparation of [2-(2-Fluoro-1-fluoromethyl-ethoxy)-5-nitro-phenyl]-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

A solution of (2-hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (50 mg), 1,3-difluoro-2-propanol [453-13-4] (27 mg), triphenylphosphine (76 mg) and diisopropylazodicarboxylate (48 mg) was refluxed overnight, concentrated in vacuo and purified by column chromatography (SiO 2 ) to yield the title compound as a colorless solid (68 mg). MS (m/e): 474.1 (M+H + , 100%).

In analogy to Example 48, compounds 102 to 104 of the following table were prepared from (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound 1.9) and an alcohol:

Preparation of (2-Fluoro-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone

Compound 2.3 was prepared in analogy to Example 5 using 2-fluoro-5-(methylsulfonyl)benzoic acid [247569-56-8] and 1-(5-trifluoromethyl-2-pyridyl)piperazine [132834-58-3]. MS (m/e): 432.4 (M+H + , 100%).

Preparation of [5-Methanesulfonyl-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone

A solution of (2-fluoro-5-methanesulfonyl-phenyl)-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone (compound 2.3) (20 mg), 2-trifluoromethyl-2-propanol (0.053 mL), potassium carbonate or cesium carbonate (3 equivalents) in dimethylacetamide was heated at 150° C. for 30 min and then at 180° C. for 1 h in a microwave oven. After such time the reaction mixture was concentrated and purified by column chromatography (SiO 2 ) to yield the title compound as a light yellow solid (4.9 mg). MS (m/e): 540.3 (M+H + , 100%).

Preparation of (2-Isopropoxy-5-methanesulfonyl-phenyl)-piperazin-1-yl-methanone trifluoro-acetic acid

A solution of 2-isopropoxy-5-methanesulfonyl-benzoic acid (compound 1.2, 1.0 g), tert-butyl 1-piperazinecarboxylate (0.78 g), TBTU (1.4 g) and N-ethyldiisopropylamine (4 mL) was stirred at room temperature for 2 hours. After such time, the reaction mixture was concentrated in vacuo and purified by column chromatography (SiO 2 ) to give 4-(2-Isopropoxy-5-methanesulfonyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester as a colorless foam (1.6 g). The latter was dissolved in dichloromethane (11 mL) and treated with trifluoroacetic acid (4.2 mL) for 30 minutes. After such time the reaction mixture was concentrated in vacuo to yield the title compound (1.6 g) as light yellow oil. MS (m/e): 327.1 (M+H + , 100%).

Preparation of 4-Chloro-6-trifluoromethyl-pyrimidine

6-Trifluoromethyl-pyrimidin-4-ol ([1546-78-7], 5 g) was refluxed in phosphorus oxychloride (17 mL) for 2 hours. The reaction mixture was carefully concentrated in vacuo and the residue was distilled (Kugelrohr) under reduced pressure (bp=30-55° C.@10 mbar) to yield the title compound ([37552-81-1], 1.4 g). MS (EI): 182.0 (M).

Preparation of (2-Isopropoxy-5-methanesulfonyl-phenyl)-[4-(5-nitro-pyridin-2-yl)-piperazin-1-yl]-methanone

A solution of (2-isopropoxy-5-methanesulfonyl-phenyl)-piperazin-1-yl-methanone trifluoro-acetic acid (compound 2.4, 80 mg) 2-chloro-5-nitro-pyridine (29 mg), potassium carbonate (50 mg) in 1-butanol (3 mL) was stirred at 120° C. for 20 hours. After such time the solution was concentrated in vacuo, and purified by column chromatography (SiO2) to yield the title compound as white foam (81 mg). MS (m/e): 449.1 (M+H + , 100%).

Preparation of (2-Isopropoxy-5-methanesulfonyl-phenyl)-[4-(6-trifluoromethyl-pyrimidin-4-yl)-piperazin-1-yl]-methanone

Example 107 was prepared in analogy to example 106 using 4-chloro-6-trifluoromethyl-pyrimidine [37552-81-1]. MS (m/e): 473.1 (M+H + , 100%).

Preparation of 2-(4-fluorophenoxy)-5-nitrobenzoic acid

2-(4-Fluoro-phenoxy)-5-nitro-benzoic acid can be prepared by a similar method to that described in the literature (e.g. WO9938845) by reaction of 2-Chloro-5-nitro-benzoic acid ethyl ester [16588-17-3] with 4-Fluoro-phenol [371-35-7] yielding 2-(4-Fluoro-phenoxy)-5-nitro-benzoic acid ethyl ester. 2-(4-Fluoro-phenoxy)-5-nitro-benzoic acid ethyl ester can then be hydrolysed with sodium hydroxide for example to yield the title compound. MS (m/e): 276.1 (M+H + , 100%).

Preparation of 2,3-Difluoro-4-piperazin-1-yl-benzonitrile-trifluoro-acetic acid

(a) 4-(4-Cyano-2,3-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester

To a solution of N-Boc-piperazine (0.65 g) in DMA (20 mL) was slowly added a solution of 2,3,4-trifluorobenzonitrile (0.49 g) in DMA (10 mL). The reaction mixture was stirred for 2 hours at 80° C. After such time the solvent was removed in vacuo and purified by column chromatography (SiO 2 ) to yield the title compound as white solid (0.76 g).

(b) 2,3-Difluoro-4-piperazin-1-yl-benzonitrile-trifluoro-acetic acid

To a solution of 4-(4-Cyano-2,3-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.72 g) in dichloromethane (5 mL) was added trifluoroacetic acid, and the reaction mixture was stirred at room temperature for 30 minutes. After such time the reaction mixture was concentrated in vacuo to yield the title compound (0.63 g). MS (m/e): 224.3 (M+H + , 100%).

Preparation of 2,5-Difluoro-4-piperazin-1-yl-benzonitrile-trifluoro-acetic acid

Example 2.8 was prepared in analogy to Example 2.7 using 2,4,5-trifluorobenzonitrile. MS (m/e): 224.3 (M+H + , 100%).

Preparation of 5-Methylsulfamoyl-2-trifluoromethoxy-benzoic acid

(a) 5-Chlorosulfonyl-2-trifluoromethoxy-benzoic acid

A solution of 2-trifluoromethoxy benzoic acid [1979-29-9] (1.0 g) was added in small batches to chlorosulfonic acid (3.2 mL) at 0° C. After completion of the addition, the reaction mixture was stirred at 70° C. for 4 hours then left at room temperature overnight and heated at 75° C. for another 3 hours. After such time the reaction was slowly poured onto ice, and the precipitate was then filtered, washed with water and dried to yield the title compound as a white solid (1.2 g). MS (m/e): 303.3 (M−H, 100%).

(b) 5-Methylsulfamoyl-2-trifluoromethoxy-benzoic acid

To a solution of 5-Chlorosulfonyl-2-trifluoromethoxy-benzoic acid (0.15 g) in dichloromethane (1.5 ml) was added a solution of methylamine in methanol (8M, 0.31 mL), and the reaction mixture was stirred for 2 minutes after precipitation was complete. The reaction mixture was then concentrated in vacuo and the residue was dissolved in 1N NaOH (2 mL) and extracted with diethylether. The aqueous phase was then acidified using 3 N hydrochloric acid solution (2 mL), and the solution was extracted with dichloromethane (2×10 mL). The combined organic phases were dried with sodium sulfate and concentrated in vacuo to yield the title compound as a white solid (0.12 g). MS (m/e): 298.0 (M−H, 100%).

Preparation of 5-Methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-benzoic acid

(a) 5-Methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-benzoic acid methyl ester

A solution of methyl 5-(methanesulfonyl)-salicylate [101371-44-2] (50 mg), triphenylphosphine (65 mg) 3,3,3-trifluoro-1-propanol and di-tert-butyl azodicarboxylate (55 mg) in THF (3 mL) was stirred at room temperature for 1 hour. The reaction mixture was then concentrated in vacuo and purified by column chromatography (SiO 2 ) to yield the title compound as a white solid (65 mg). MS (m/e): 327.5 (M+H + , 100%).

(b) 5-Methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-benzoic acid

To 5-methanesulfonyl-2-(3,3,3-trifluoro-propoxy)-benzoic acid methyl ester (620 mg) in ethanol at 60° C. was added 1N NaOH solution (3.8 mL), and the reaction mixture was stirred for 15 minutes. After such time, 3.8 ml of 1N HCl was slowly added to the reaction mixture, and the ethanol was evaporated in vacuo. The precipitate was then washed with water several times to give the title compound (497 mg). MS (m/e): 311.0, M−H + , 100%).

Preparation of 5-Methanesulfonyl-2-(tetrahydro-pyran-4-yloxy)-benzoic acid

Compound 2.11 was prepared in analogy to compound 2.10 using tetrahydro-2H-pyran-4-ol. MS (m/e): 299.4 (M−H, 100%).

Preparation of 2-Cyclobutylmethoxy-5-methanesulfonyl-benzoic acid

Compound 2.12 was prepared in analogy to compound 2.10 using cyclobutyl methanol. MS (m/e): 299.4 (M−H, 100%).

Preparation of 3,5-Difluoro-4-piperazin-1-yl-benzonitrile trifluoro-acetic acid

Compound 2.13 was prepared in analogy to compound 2.7 using 3,4,5-trifluorobenzonitrile. MS (m/e): 224.1 (M+H + , 100%).

Preparation of 2,6-Difluoro-4-piperazin-1-yl-benzonitrile trifluoro-acetic acid

Compound 2.14 was prepared in analogy to compound 2.7 using 2,4,6-trifluorobenzonitrile. MS (m/e): 224.1 (M+H + , 100%).

Preparation of 5-Methanesulfonyl-2-trifluoromethoxy-benzoic acid

(a) 5-Sulfino-2-trifluoromethoxy-benzoic acid

5-chlorosulfonyl-2-trifluoromethoxy-benzoic acid (1.0 g, compound 2.9.a) was added portionwise onto a solution of sodium sulfite (3.1 g) in 16 mL of water. The reaction mixture was kept under basic conditions by the addition of the proper amount of 20% NaOH and was stirred at room temperature for 45 minutes. After such time the reaction mixture was cooled down with an ice bath and was then acidified by the addition of 20% H 2 SO 4 solution until reaching pH 2. The solution was then extracted several times with diethyl ether and ethyl acetate. The combined organic phases were dried (sodium sulfate) and concentrated in vacuo to yield the title compound as a white solid (0.88 g).

(b) 5-Methanesulfonyl-2-trifluoromethoxy-benzoic acid

To 5-Sulfino-2-trifluoromethoxy-benzoic acid (0.82 g) in DMF (5 mL) was added 1.3 g of potassium carbonate, and the reaction mixture was stirred for 5 minutes before methyl iodide (0.66 mL) was added. The reaction mixture was then stirred at room temperature for 60 hours. After such time the reaction mixture was concentrated in vacuo, and the residue was treated with 1N NaOH (10 mL) and THF (4 mL). The reaction mixture was stirred for a further 2 hours at room temperature. After such time the solution was acidified with concentrated HCl solution. THF was then removed in vacuo, and the precipitate was isolated by filtration and washed several times with water to yield the title compound. MS (m/e): 283.0 (M−H, 100%).

Preparation of 2,4-Difluoro-6-piperazin-1-yl-benzonitrile trifluoro-acetic acid

Compound 2.16 was prepared in analogy to compound 2.7 using 2,4,6-trifluorobenzonitrile of. MS (m/e): 224.1 (M+H + , 100%).

Preparation of 2-(2-Fluoro-1-fluoromethyl-ethoxy)-5-methanesulfonyl-benzoic acid

Compound 2.17 was prepared in analogy to compound 2.10 using 1,3-difluoro-2-propanol. MS (m/e): 293.1 (M−H, 100%).

Preparation of 5-Methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoic acid

(a) 5-Methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoic acid methyl ester

A solution of methyl 5-(methanesulfonyl)salicylate [101371-44-2] (0.50 g), trifluoro-methanesulfonic acid 2,2,3,3,3-pentafluoro-propyl ester (0.67 g) and potassium carbonate (0.60 g) in acetone was stirred at 60° C. for 5 hours. The reaction mixture was then concentrated in vacuo and purified by column chromatography (SiO 2 ) to yield the title compound as a white solid (0.44 g). MS (m/e): 363.1 (M+H + , 100%).

(b) 5-Methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoic acid

To 5-methanesulfonyl-2-(2,2,3,3,3-pentafluoro-propoxy)-benzoic acid methyl ester (414 mg) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (72 mg) in water (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After such time 1.72 mL of 1N aqueous hydrochloric acid solution was added. The reaction mixture was then concentrated in vacuo, and the resulting precipitate was then washed several times with water to yield the title compound as a white solid (367 mg). MS (m/e): 347.1 (M−H, 100%).

Preparation of 2-tert-Butoxy-5-methanesulfonyl-benzoic acid

(a) 2-tert-Butoxy-5-methanesulfonyl-benzoic acid methyl ester

To a solution of methyl 5-(methanesulfonyl)-salicylate [101371-44-2] (0.50 g) in toluene (5 mL) was added N,N-dimethylformamide-di-tert-butylacetal, and the reaction mixture was stirred at 80° C. for 1 hour. After such time the reaction mixture was concentrated in vacuo and purified by column chromatography to yield the title compound as colourless oil (258 mg). MS (m/e): 304.4 (M+NH 4 + , 100%).

(b) 2-tert-Butoxy-5-methanesulfonyl-benzoic acid

To 2-tert-Butoxy-5-methanesulfonyl-benzoic acid methyl ester (1.58 g) in THF (25 mL) was added a solution lithium hydroxide monohydrate (0.35 g) in water (25 mL), and the reaction mixture was stirred at room temperature for 4 hours. After such time, the THF was removed in vacuo and to the remaining aqueous solution was added 8 mL of 1N HCl solution, leading to precipitation of the compound. The precipitate was filtered off and washed several times with water to yield the title compound (1.00 g) as a white solid. MS (m/e): 289.9 (M+NH 4 + ).

Preparation of 1-(2,5-Difluoro-4-methanesulfonyl-phenyl)-piperazine trifluoro-acetic acid

(a) 2,4,5-Trifluoro-benzenesulfinic acid

2,4,5-Trifluoro-benzenesulfonyl chloride ([220227-21-4], 2.5 g) was added portionwise onto a solution of sodium sulfite (10.3 g) in 50 mL of water. The reaction mixture was kept under basic conditions by the addition of the proper amount of 20% NaOH and was stirred at room temperature for 1 hour. Methanol was added to the reaction mixture, and the reaction mixture was stirred at room temperature for another hour. After such time, the reaction mixture was cooled down with an ice bath and was then acidified by the addition of 20% H 2 SO 4 solution until reaching pH 2. The aqueous solution was then extracted several times with diethyl ether and ethyl acetate. The aqueous solution was further extracted with ethyl acetate using a Kutscher-Steudel apparatus (continuous extraction). The combined organic phases were dried (sodium sulfate) an concentrated in vacuo to yield the title compound as a white solid (2.1 g).

(b) 1,2,4-Trifluoro-5-methanesulfonyl-benzene

To 2,4,5-trifluoro-benzenesulfinic acid (2.0 g) in DMF (17 mL) was added 4.3 g of potassium carbonate, and the reaction mixture was stirred for 5 minutes before methyl iodide (2.2 mL) was added. The reaction mixture was then stirred at room temperature for 60 hours. After such time, water (30 mL) was poured onto the reaction mixture, and the reaction mixture was extracted with diethylether several times. The combined organic phases were dried with sodium sulfate, and the remaining mixture was distilled to yield the title compound as a light yellow oil (2.1 g).

(c) 1-(2,5-Difluoro-4-methanesulfonyl-phenyl)-piperazine trifluoro-acetic acid

The title compound was obtained in analogy to example 2.7 using 1,2,4-Trifluoro-5-methanesulfonyl-benzene. MS (m/e): 277.1 (M+H + ).

Preparation of 1-(3,5-Difluoro-4-methanesulfonyl-phenyl)-piperazine trifluoro-acetic acid

Compound 2.21 was prepared in analogy to compound 2.20 using 2,4,6-trifluoro-benzenesulfonyl chloride [172326-59-9]. MS (m/e): 277.1 (M+H + ).

Preparation of 5-Methanesulfonyl-2-(2,2,3,3-tetrafluoro-propoxy)-benzoic acid

Compound 2.22 was prepared in analogy to compound 2.18 using 2,2,3,3-tetrafluoro-1-propyl triflate. MS (m/e): 329.1 (M−H).

Preparation of 1-(2,6-Difluoro-4-methanesulfonyl-phenyl)-piperazine trifluoro-acetic acid

Compound 2.23 was prepared in analogy to compound 2.20 using 3,4,5-trifluoro-benzenesulfonyl chloride [351003-43-5]. MS (m/e): 277.1 (M+H + ).

Preparation of 4-piperazin-1-yl-6-trifluoromethyl-pyrimidine trifluoro-acetic acid

Compound 2.24 was prepared in analogy to compound 2.7 using 4-chloro-6-trifluoromethyl-pyrimidine [37552-81-1]. MS (m/e): 233.1 (M+H + ).

Preparation of 2-piperazin-1-yl-5-trifluoromethyl-pyrimidine

(a) 2-(4-Benzyl-piperazin-1-yl)-5-trifluoromethyl-pyrimidine

To a solution of (3-Dimethylamino-2-trifluoromethyl-allylidene)-dimethyl-ammonium chloride ([176214-18-9], 0.60 g) in acetonitrile (10 mL) was added 4-Benzyl-piperazine-1-carboxamidine hydrochloride ([7773-69-5], 0.66 g) and triethylamine (0.87 mL), and the reaction mixture was stirred for 3 hours at room temperature. After such time, the reaction mixture was concentrated in vacuo and purified by column chromatography to yield the title compound as a light yellow solid (0.79 g). MS (m/e): 323.4 (M+H + ).

(b) 2-piperazin-1-yl-5-trifluoromethyl-pyrimidine

To a solution of 2-(4-Benzyl-piperazin-1-yl)-5-trifluoromethyl-pyrimidine (0.63 g) in methanol was added Palladium-C (Degussa E101N; 5%), and the reaction mixture was heated at 60° C. under hydrogen atmosphere. The reaction mixture was then allowed to cool down to room temperature, the catalyst was filtered off, and solvent was removed in vacuo to yield the title compound as a colorless solid (0.41 g). MS (m/e): 233.1 (M+H + ).

In analogy to Example 5 compounds 108 to 280 of the following table were prepared from the acid derivatives and piperazine derivatives:

In analogy to Example 1.2(b) compounds 3.1 to 3.5 of the following table were prepared from 2-chloro-5-methanesulfonyl-benzoic acid and the appropriate alcohol:

In analogy to Example 5 compounds 281 to 326 of the following table were prepared from the acid derivatives and piperazine derivatives.

Preparation of 6-Ethoxy-2-fluoro-3-methanesulfonyl-benzoic acid

(a) 3-Chlorosulfonyl-2,6-difluoro-benzoic acid

95 mmol of 2,6-difluorobenzoic acid in 19 ml of chlorosulfonic acid was stirred for 2 h at 150°. The mixture was poured into 200 ml of ice and stirred for 20 min. The resulting slurry was filtered, washed with water and dried (20° overnight in the dessicator) to yield the title compound as a colorless solid. MS (m/e): 279.4 (MNa + , 81%)

(b) 2,6-Difluoro-3-sulfino-benzoic acid

41 mmol of 3-chlorosulfonyl-2,6-difluoro-benzoic acid was slowly added over 20 min. to a solution of 310 mmol sodium sulfite in 200 ml of water. The resulting mixture was stirred for one hour at room temperature, cooled to 0° C. and acidified with 20% aqueous sulfuric acid. The sulfinic acid was extracted with ethyl acetate, dried over MgSO 4 and concentrated to yield the title compound as a colorless solid. MS (m/e): 220.9 (M−H, 100%)

(c) 6-Ethoxy-2-fluoro-3-methanesulfonyl-benzoic acid

A mixture of 27 mmol 2,6-difluoro-3-sulfino-benzoic acid and 9 mmol Na 2 CO 3 in 110 ml methanol was treated with 72 mmol of methyl iodide. The resulting mixture was stirred overnight at 60°, concentrated and the dark residue dissolved in 100 ml of ethanol. 100 ml of 2 molar aqueous NaOH was added, and the mixture was refluxed for 2 hours. Concentration to about 100 ml precipitated a yellowish solid which was filtered and triturated with diethyl ether to give the crude title compound, which was used without further purification.

Preparation of 1-(4-Trifluoromethanesulfonyl-phenyl)-piperazine

A mixture of 1 mmol 1-Bromo-4-trifluoromethanesulfonyl-benzene [Nodiff et al., J. Org. Chem. 25, 60 (1960)], 3 mmol of piperazine and 2 mmol of potassium carbonate in 5 ml of acetonitrile was refluxed for 2 hours. The resulting mixture was poured into water, extracted with ethyl acetate, dried, concentrated and purified by column chromatography (SiO 2 ; Et2O/cyclohexane) to yield the title compound as a colorless solid. MS (m/e): 295.2 (MH + , 100%)

Preparation of 1-(2,4-Bis-trifluoromethyl-phenyl)-piperazine hydrochloride

(a) 4-(2,4-Bis-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester

A mixture of 5 mmol 2,4-bis(trifluoromethyl)bromobenzene, 6 mmol N-BOC-piperazine, 8 mmol NaOtBu, 0.5 mmol rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 1 mmol tris-(dibenzylideneacetone)dipalladium chloroform complex in 20 ml toluene was stirred at 80° C. for 3 hours. The mixture was then diluted with water, extracted with ethyl acetate, dried and purified by column chromatography (SiO 2 ; cyclohexane/ethyl acetate 9:1) to yield the title compound as a yellowish oil.

MS (m/e): 399.1 (MH + , 100%)

(b) 1-(2,4-Bis-trifluoromethyl-phenyl)-piperazine hydrochloride

3 mmol of 4-(2,4-Bis-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester was stirred in 10 ml of 1,4-dioxane saturated with gaseous HCl. After 4 h at room temperature, the reaction mixture was evaporated to dryness to yield the title compound as a colorless solid. MS (m/e): 299.3 (MH + , 100%)

Preparation of 1-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-piperazine hydrochloride

(a) 4-[14-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester

A well stirred mixture of 0.015 mmol of bis(tri-t-butylphosphine)palladium, 0.01 mmol of cetyltrimethylammonium bromide, 2 mmol of powdered potassium hydroxide, 2 mmol of 3-(4-bromo-phenyl)-5-methyl-[1,2,4]oxadiazole and 2.1 mmol of N-BOC-piperazine in 1 ml of toluene was heated under Ar to 90° C. for 17 hours. The resulting reaction mixture was diluted with water, extracted with ethyl acetate and the product purified by column chromatography (SiO 2 ; cyclohexane/ethyl acetate 7:3) to yield the title compound as a yellowish solid. MS (m/e): 345.3 (MH + , 100%)

(b) 1-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-piperazine hydrochloride

1 mmol of 4-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester was stirred in 3 ml of 1,4-dioxane saturated with gaseous HCl. After 2 h at room temperature, the reaction mixture was evaporated to dryness to yield the title compound as a colorless solid. MS (m/e): 245.1 (MH + , 100%)

Preparation of 1-(4-Oxazol-2-yl-phenyl)-piperazine hydrochloride

(a) 4-Bromo-N-(2,2-dimethoxy-ethyl)-benzamide

A solution of 24 mmol aminoacetaldehyde dimethylacetal was dissolved in 30 ml of water and treated with 25 mmol of potassium hydrogencarbonate. A solution of 23 mmol of 4-bromobenzoyl chloride in 50 ml of acetone was slowly added under stirring over a period of 30 min. The acetone was evaporated and the aqueous phase was extracted 3 times with ethyl acetate to yield the crude title compound as a slightly brown solid.

MS (m/e): 287.1 (M−H, 43%)

(b) 2-(4-Bromo-phenyl)-oxazole

A solution of 21 mmol of phosphorous pentoxide in 20 ml of methylsulfonic acid was treated with 7 mmol of 4-Bromo-N-(2,2-dimethoxy-ethyl)-benzamide. The reaction mixture was heated for 5 hours at 130°, cooled to room temperature and poured into ice-water. The resulting solid was filtered off and dried to yield the crude title compound as a brownish solid. MS (m/e): 224.0 (MH + , 24%)

(c) 4-(4-Oxazol-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester

Prepared in analogy to example 4.4(a) from 2-(4-Bromo-phenyl)-oxazole and N-BOC-piperazine. MS (m/e): 330.3 (MH + , 100%)

(d) 1-(4-Oxazol-2-yl-phenyl)-piperazine hydrochloride

Prepared in analogy to example 4.4(b) from 4-(4-Oxazol-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and hydrochloric acid in dioxane. MS (m/e): 230.1 (MH + , 100%)

Preparation of 1-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-piperazine hydrochloride

(a) 2-(4-Bromo-phenyl)-[1,3,4]oxadiazole

12.3 mmol of 4-bromo-benzoic acid hydrazide were dissolved in 26 ml of triethyl orthoformate. The reaction mixture was stirred overnight at 140°, evaporated and the residue crystallized from ethanol to give the title compound as a colorless solid. MS (m/e): 225.0 (MH + , 100%)

(b) 4-(4-[1,3,4]Oxadiazol-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester

Prepared in analogy to example 4.4(a) from 2-(4-Bromo-phenyl)-[1,3,4]oxadiazole and N-BOC-piperazine.

MS (m/e): 342.2 (MH + , 100%)

(c) 1-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-piperazine hydrochloride

Prepared in analogy to example 4.4(b) from 4-(4-[1,3,4]Oxadiazol-2-yl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester and hydrochloric acid in dioxane. MS (m/e): 245.3 (MH + , 100%)

Preparation of 1-[4-(2-Methyl-2H-tetrazol-5-yl)-phenyl]-piperazine hydrochloride

(a) 5-(4-Bromo-phenyl)-2-methyl-2H-tetrazole

A mixture of 3.5 mmol of 5-(4-bromo-phenyl)-2H-tetrazole, 0.2 mmol of tetrabutyl ammonium bromide, 4.4 mmol of methyl iodide, 6 ml of 1M aqueous sodium hydroxide and 6 ml of dichloromethane were stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried, evaporated and the product purified by column chromatography (SiO 2 ; cyclohexane/ethyl acetate 7:3). MS (m/e): 239.1 (MH + , 29%)

(b) 4-[4-(2-Methyl-2H-tetrazol-5-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester

Prepared in analogy to example 4.4(a) from 5-(4-Bromo-phenyl)-2-methyl-2H-tetrazole and N-BOC-piperazine. MS (m/e): 345.1 (MH + , 41%)

(c) 1-[4-(2-Methyl-2H-tetrazol-5-yl)-phenyl]-piperazine hydrochloride

Prepared in analogy to example 4.4(b) from 4-[4-(2-Methyl-2H-tetrazol-5-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester and hydrochloric acid in dioxane. MS (m/e): 245.1 (MH + , 100%)

Preparation of 3,4,5,6-Tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester hydrochloride

(a) 2,3,5,6-Tetrahydro-[1,2′]bipyrazinyl-4,5′-dicarboxylic acid 4-tert-butyl ester 5′-methyl ester

A mixture of 17 mmol methyl-5-chloropyrazine-2-carboxylate, 18 mmol of N-BOC-piperazine and 20 mmol of K 2 CO 3 in 20 ml of acetonitrile was heated under reflux for 3 hours. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The title compound was recrystallized from ethyl acetate to yield a colorless solid. MS (m/e): 323.4 (MH + , 100%)

(b) 3,4,5,6-Tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester hydrochloride

Prepared in analogy to example 4.4(b) from 2,3,5,6-Tetrahydro-[1,2′]bipyrazinyl-4,5′-dicarboxylic acid 4-tert-butyl ester 5′-methyl ester and 1,4-dioxane saturated with gaseous HCl. MS (m/e): 223.1 (MH + , 100%)

Preparation of 6′-Chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl trifluoroacetate

(a) 6′-Chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester

A mixture of 10 mmol 2,6-dichloropyrazine and 21 mmol of N-BOC-piperazine in 15 ml acetonitrile was heated under reflux for 1.5 hours. The reaction mixture was concentrated and purified by chromatography (SiO 2 ; dichloromethane/methanol 95:5) to yield the title compound as a colorless solid. MS (m/e): 299.2 (MH + , 100%)

(b) 6′-Chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl trifluoroacetate

A solution of 2 mmol 6′-Chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester in 10 ml of dichloromethane was treated with 3 mmol of trifluoroacetic acid and stirred at room temperature for 17 hours. Concentration and crystallisation from diethylether yielded the title compound as a colorless solid. MS (m/e): 198.0 (M + , 100%)

Preparation of 3,4,5,6-Tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid amide hydrochloride

(a) 5′-Carbamoyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester

3 mmol of 2,3,5,6-Tetrahydro-[1,2′]bipyrazinyl-4,5′-dicarboxylic acid 4-tert-butyl ester 5′-methyl ester (example 1.13(a)) was dissolved in a 7 molar solution of gaseous ammonia in methanol. The reaction vessel was tightly closed and heated overnight at 60° C. Cooling of the reaction mixtures led to crystallisation of the title compound. MS (m/e): 308.4 (MH + , 100%)

(b) 3,4,5,6-Tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid amide hydrochloride

0.25 mmol of 5′-Carbamoyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester was stirred for 1 hour in 1 ml of dioxane saturated with gaseous HCl. Concentration of the reaction mixture led to the title compound, as a colorless solid. MS (m/e): 208.3 (MH + , 100%)

Preparation of Dimethyl-(4-piperazin-1-yl-[1,3,5]triazin-2-yl)-amine

(a) 4-(4-Chloro-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester

A solution of 11 mmol of 2,4-dichlorotriazine (WO 02/083654) in 20 ml of acetonitrile was chilled and treated with 11 mmol of triethylamine and 11 mmol of N-BOC-piperazine. The reaction mixture was stirred for 2 hours at 0° C. then for 2 hours at room temperature. Addition of 100 ml brine and extraction with ethyl acetate yielded the crude product which was purified through trituration in ethyl acetate. MS (m/e): 300.3 (MH + , 100%)

(b) 4-(4-Dimethylamino-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester

A solution of 2 mmol of 4-(4-Chloro-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 15 ml of 2M dimethylamine in methanol was stirred at room temperature for 1 hour. Concentration and purification by chromatography (SiO 2 ; ethyl acetate/cyclohexane 1:1) yielded the title compound as a colorless solid. MS (m/e): 309.1 (MH + , 100%)

(c) Dimethyl-(4-piperazin-1-yl-[1,3,5]triazin-2-yl)-amine

A solution of 1 mmol of 4-(4-Dimethylamino-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in 10 ml dichloromethane was chilled and treated with 14 mmol of trifluoroacetic acid. The reaction mixture was heated to 40° C. for 30 min. After cooling, 50 ml of 2M aqueous sodium hydroxide was added. The organic layer was separated, dried and concentrated to yield the title compound as a yellowish oil. MS (m/e): 267.0 (M+CH 3 COO + , 100%)

Preparation of 6′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl

(a) 6′-Methoxy-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester

1 mmol of 6′-Chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester [example 4.9(a)] was dissolved in a solution of sodium methanolate (prepared by dissolving 1 mmol of sodium in 10 ml of methanol). The mixture was heated overnight to 70°, concentrated and the product purified by chromatography (SiO 2 ; dichloromethane/methanol 99:1) to yield the title compound as a colorless foam. MS (m/e): 295.3 (MH + , 100%)

(b) 6′-Methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl

Prepared in analogy to example 4.10(c) from 6′-Methoxy-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester and trifluoroacetic acid. MS (m/e): 195.1 (MH + , 80%)

Preparation of 2-Methoxy-4-piperazin-1-yl-[1,3,5]triazine

(a) 4-(4-Methoxy-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester

1 mmol of 4-(4-Chloro-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester [example 4.11(a)] was dissolved in a solution of sodium methanolate (prepared by dissolving 1 mmol of sodium in 5 ml of methanol). The mixture was stirred at room temperature for 1 hour, concentrated and the title compound purified by recrystallisation from ethyl acetate/cyclohexane. MS (m/e): 296.3 (MH + , 100%)

(b) 2-Methoxy-4-piperazin-1-yl-[1,3,5]triazine

Prepared in analogy to example 4.10(c) from 4-(4-Methoxy-[1,3,5]triazin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester and trifluoroacetic acid. MS (m/e): 196.4 (MH + , 100%)

Preparation of 2-Dimethylcarbamoyloxy-5-methanesulfonyl-benzoic acid

(a) 2-Hydroxy-5-methanesulfonyl-benzoic acid benzyl ester

5 mmol of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochloride was slowly added to a stirred suspension of 5 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid, 5 mmol of benzyl alcohol and 0.5 mmol of 4-dimethylaminopyridine in 10 ml acetonitrile. The mixture was stirred overnight at room temperature, concentrated and treated with 10 ml of water. A few drops of diluted hydrochloric acid were added to acidify the solution. The resulting solid was filtered and then purified by chromatography (SiO 2 ; ethyl acetate/cyclohexane 3:7) to yield the title compound as a colorless solid. MS (m/e): 305.0 (M−H, 100%)

(b) 2-Dimethylcarbamoyloxy-5-methanesulfonyl-benzoic acid benzyl ester

A mixture of 1 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid benzyl ester, 1.5 mmol of N-methylmorpholine and 0.2 mmol of 4-dimethylaminopyridine in 4 ml of dimethylformamide was treated with 1.3 mmol of N,N-dimethyl-carbamoylchloride. The reaction mixture was stirred at 60° for 48 hours, concentrated in vacuo and the residue taken up in 5 ml of water. Acidification with diluted hydrochloric acid and extraction with ethyl acetate yielded a crude product which was purified by chromatography (SiO 2 ; ethyl acetate/cyclohexane 1.1). MS (m/e): 378.3 (MH + , 100%)

(c) 2-Dimethylcarbamoyloxy-5-methanesulfonyl-benzoic acid

1 mmol of 2-dimethylcarbamoyloxy-5-methanesulfonyl-benzoic acid benzyl ester was dissolved in 5 ml of methanol. 25 mg of palladium 10% on charcoal was added and the reaction mixture hydrogenated at room temperature to yield the title compound as a slightly yellowish solid. MS (m/e): 288.0 (MH + , 66%)

In analogy to Example 5 compounds 327 to 355 of the following table were prepared from the acid derivatives and piperazine derivatives:

Preparation of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone oxime

0.12 mmol of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone was dissolved in 1 ml of a 1:1 mixture of ethanol and water. 0.8 mmol of hydroxylamine hydrochloride was added, followed by 8.4 mmol of sodium acetate. The resulting mixture was stirred overnight at room temperature, diluted with water, filtered, washed and dried to yield the title compound as a colorless solid.

MS (m/e): 478.2 (MH + , 100%)

Preparation of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone O-methyl-oxime

0.12 mmol of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone was dissolved in 1 ml of a 1:1 mixture of ethanol and water. 0.8 mmol of O-methyl-hydroxylamine hydrochloride was added, followed by 8.4 mmol of sodium acetate. The slurry was stirred overnight at room temperature, diluted with water, extracted with ethyl acetate, dried and concentrated. The resulting gum was triturated with diethyl ether/heptane to yield the title compound as a colorless solid. MS (m/e): 492.3 (MH + , 100%)

Preparation of (2,6-Difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone

(a) 3-Chlorosulfonyl-2,6-difluoro-benzoic acid

77 mmol of 2,6-difluorobenzoic acid were dissolved in 15.5 ml of chlorosulfonic acid and stirred for 2 h at 150° C. The reaction mixture was cooled to room temperature and poured into 100 ml of ice/water. The solid was filtered and dried to yield the title compound as a colorless solid. MS (m/e): 255.1 (M−H, 44%)

(b) 2,6-Difluoro-3-sulfino-benzoic acid

240 mmol of sodium sulfite were dissolved in 150 ml of water. 32 mmol of 3-Chlorosulfonyl-2,6-difluoro-benzoic acid was added under stirring over a period of about 20 min. After stirring for an additional hour at room temperature, the mixture was chilled and acidified with 20% aqueous sulfuric acid. The product was extracted with ethyl acetate to yield the title compound as a colorless solid. MS (m/e): 221.3 (M−H, 34%)

(c) 2,6-Difluoro-3-methanesulfonyl-benzoic acid

A suspension of 18 mmol sodium carbonate and 9 mmol 2,6-Difluoro-3-sulfino-benzoic acid in 30 ml of methanol was stirred at room temperature for 30 min, then heated to 60° C. 24 mmol of methyl iodide were added and the reaction mixture heated overnight at 60° C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was discarded and the aqueous phase acidified by addition of concentrated hydrochloric acid. Extraction with ethyl acetate yielded the title compound as a slightly brownish solid. MS (m/e): 235.1 (M−H, 16%)

(d) (2,6-Difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone

This compound was prepared in analogy to example 5 from 1-(2-fluoro-4-methanesulfonyl-phenyl)-piperazine and 2,6-difluoro-3-methanesulfonyl-benzoic acid. MS (m/e): 477.0 (MH + , 67%)

Preparation of 4-[4-(2,6-Difluoro-3-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile

Prepared in analogy to example 5 from 4-piperazin-1-yl-benzonitrile and 2,6-difluoro-3-methanesulfonyl-benzoic acid. MS (m/e): 406.3 (MH + , 84%)

Preparation of (2-Cyclopentyloxy-6-ethoxy-3-methanesulfonyl-phenyl)-[4-(4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone

0.12 mmol of (6-Ethoxy-2-fluoro-3-methanesulfonyl-phenyl)-[4-(4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone (example 55) was added to a solution of sodium cyclopentanolate (prepared from 1 mmol sodium dissolved in 1 ml of cyclopentanol). The mixture was heated for 1 hour at 80° C., poured on ice/water and extracted with ethyl acetate. Chromatography (SiO 2 ; ethyl acetate) yielded the title compound as a slightly yellow solid. MS (m/e): 551.1 (MH + , 29%)

Preparation of (2,6-diisopropoxy-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone

0.27 mmol of 2,6-difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone (example 4.15) was added to a solution of sodium isopropanolate (prepared by dissolving 3 mmol of sodium in 2 ml of isopropanol). The reaction mixture was heated under reflux for 5 hours, cooled, diluted with water and extracted with ethyl acetate, yielding the title compound as a slightly yellow solid. MS (m/e): 557.3 (MH + , 66%)

Preparation of (2-Fluoro-6-isopropoxy-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone

0.2 mmol of (2,6-difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone were dissolved in a solution of sodium isopropanolate (prepared by dissolving 0.2 mmol of sodium in 1 ml of isopropanol). The reaction mixture was heated to 50° C. for 2 hours, then stirred at room temperature for 48 hours. The solution was diluted with water and extracted with ethyl acetate. The product was purified by chromatography (SiO 2 , ethyl acetate/cyclohexane 9:1) to yield the title compound as a colorless solid. MS (m/e): 517.1 (MH + , 100%)

Preparation of (6-Cyclopentyloxy-2-fluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone

The compound was prepared in analogy to example 358 from (2,6-difluoro-3-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone and sodium cyclopentanolate. MS (m/e): 560.5 (MNH 4 + , 43%)

Preparation of 4-[4-(2-Fluoro-6-isopropoxy-3-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile

The compound was prepared in analogy to example 359 from 4-[4-(2,6-difluoro-3-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile and sodium isopropanolate. MS (m/e): 446.0 (MH + , 49%)

Preparation of 1-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine

(a) 4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester

A mixture of 4.9 mmol 4-chloro-2-fluorobenzotrifluoride, 5.9 mmol n-Boc-piperazine, 0.05 mmol palladium acetate, 6.9 mmol sodium-t-butoxide and 0.49 mmol 2-(di-t-butylphosphino)biphenyl in 10 ml toluene was heated for 16 h at 80° C. After cooling to RT, the mixture was diluted with ether; the suspension was filtered over decalite; and the filtrate evaporated. The residue was purified on silica eluting with a gradient of heptane/EtOAc to yield after evaporation the title compound.

(b) 1-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine

A mixture of 2.87 mmol 4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester in 10 ml dichloromethane was treated with 14.4 mmol trifluoroacetic acid and refluxed for 3 h. The mixture was concentrated and treated with 10 ml water, NaOH and extracted with dichloromethane. The combined organic phases were dried with MgSO 4 and evaporated to yield the title compound 5.1. MS (m/e): 249.2 (MH + , 100%)

Preparation of 2-piperazin-1-yl-5-trifluoromethyl-benzonitrile

The compound was prepared in analogy to compound 5.1 from 2-Chloro-5-trifluoromethyl-benzonitrile (DE2550262). MS (m/e): 256.0 (MH + , 100%)

Preparation of 1-(2,3-Difluoro-4-methanesulfonyl-phenyl)-piperazine

The compound was prepared in analogy to compound 2.20 from 2,3,4-Trifluoro-benzenesulfonyl chloride (commercial). MS (m/e): 277.2 (MH + , 100%)

Preparation of 1-(2-Fluoro-4-methyl-phenyl)-piperazine

The compound was prepared in analogy to compound 1.1 from 4-bromo-3-fluorotoluene (commercial). MS (m/e): 195.3 (MH + , 100%)

Preparation of 1-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazine

The compound was prepared in analogy to compound 2.7 from 2,3-Difluoro-5-trifluoromethyl-pyridine (EP0104715). MS (m/e): 250.2 (MH + , 100%)

Preparation of 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid

(a) rac-5-Methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester

A mixture of 21.7 mmol 2-Hydroxy-5-methanesulfonyl-benzoic acid methyl ester [68029-77-6], 32.5 mmol trifluoro-methanesulfonic acid 2,2,2-trifluoro-1-methyl-ethyl ester [212556-43-9], 43.4 mmol potassium carbonate in 87 ml DMF was stirred at 80° C. for 48 hours. After cooling to RT, the mixture was concentrated in vacuo, taken in water and stirred for 1 hour. Filtration yielded the title compound.

(b) 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester

The title compound was obtained by separation of rac-5-Methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester by chiral HPLC (Chiralcel OD, 15% ethanol/Heptane, flow 35 ml, 220 nm, retention time: 86 min.).

(c) 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid

The compound was prepared in analogy to compound 2.10(b) from 5-Methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester MS (m/e): 311.0 (M−H, 100%)

Preparation of 5-Methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid

(a) 5-Methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester

The title compound was obtained by separation of rac-5-Methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester by chiral HPLC (Chiralcel OD, 15% ethanol/Heptane, flow 35 ml, 220 nm, retention time: 74 min.).

(b) 5-Methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid

The compound was prepared in analogy to compound 2.10(b) from 5-Methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester MS (m/e): 311.0 (M−H, 100%)

Preparation of 2-Chloro-4-piperazin-1-yl-benzonitrile

A mixture of 7.0 mmol 2-chloro-4-fluorobenzonitrile (commercial), 10.5 mmol piperazine in 4 ml N,N-dimethylacetamide was heated for 1 h at 85° C. After cooling to RT and evaporation in vacuo, the mixture was diluted with dichloromethane and purified on silica, eluting with a gradient of dichloromethane/MeOH to yield after evaporation the title compound. MS (m/e): 222.1 (MH + , 100%)

Preparation of 1-(2-Fluoro-4-piperazin-1-yl-phenyl)-ethanone

The compound was prepared in analogy to compound 5.8 from 2,4-difluoroacetophenone (commercial). MS (m/e): 223.2 (M−H, 100%)

Preparation of 1-(3-Fluoro-4-methanesulfonyl-phenyl)-piperazine

The compound was prepared in analogy to compound 2.20 from 2,4-difluorobenzenesulfonylchloride (commercial). MS (m/e): 259.1 (MH + , 100%)

Preparation of 1-(4-Fluoro-2-piperazin-1-yl-phenyl)-ethanone

The compound was prepared in analogy to compound 5.8 from 2,4-difluoroacetophenone (commercial). MS (m/e): 223.2 (M−H, 100%)

Preparation of 6-Isopropoxy-isophthalamic acid

The compound was prepared in analogy to compound 2.10 from 6-Hydroxy-isophthalamic acid methyl ester [89366-34-7]. MS (m/e): 222.1 (M−H, 100%)

Preparation of 5-Ethanesulfonyl-2-isopropoxy-benzoic acid

(a) 5-Ethanesulfonyl-2-hydroxy-benzoic acid methyl ester

The compound was prepared in analogy to compound 2.20(b) from 2-Hydroxy-5-sulfino-benzoic acid [19479-88-0] and ethyliodide

(b) 5-Ethanesulfonyl-2-isopropoxy-benzoic acid

The compound was prepared in analogy to compound 2.10 from 5-Ethanesulfonyl-2-hydroxy-benzoic acid methyl ester. MS (m/e): 271.1 (M−H, 100%)

Preparation of 1-(4-Difluoromethyl-2-fluoro-phenyl)-piperazine

(a) 1-Chloro-4-difluoromethyl-2-fluoro-benzene

24.7 mmol 4-Chloro-3-fluorobenzaldehyde was dissolved in DAST (5.1 ml) under nitrogen. The mixture was stirred at room temperature for 3 hours, at 50° C. for 2 hours and then at room temperature for 65 hours. The solution was added dropwise to a saturated bicarbonate solution (150 ml) under cooling. The aqueous layer was extracted 3 times with ethyl acetate. The combined extracts were dried over Na 2 SO 4 , filtered and the solvent was removed in vacuo. The residue was purified on silica eluting with heptane to yield after evaporation the title compound.

(b) 1-(4-Difluoromethyl-2-fluoro-phenyl)-piperazine

The compound was prepared in analogy to compound 1.1 from 1-Chloro-4-difluoromethyl-2-fluoro-benzene. MS (m/e): 231.2 (M+H + , 100%)

Preparation of 1-(6-Trifluoromethyl-pyridin-3-yl)-piperazine

The compound was prepared in analogy to compound 1.1 from 5-Bromo-2-trifluoromethyl-pyridine [436799-32-5]. MS (m/e): 232.1 (M+H + , 100%)

Preparation of 3-Fluoro-4-piperazin-1-yl-benzoic acid ethyl ester

The compound was prepared in analogy to compound 5.8 from Ethyl-3,4-difluorobenzoate (commercial). MS (m/e): 253.2 (M+H + , 100%)

Preparation of 1-(2-Trifluoromethyl-pyridin-4-yl)-piperazine

The compound can be prepared from 4-Nitro-2-trifluoromethyl-pyridine 1-oxide [147149-97-1] in analogy to the procedure used for the preparation of 4-Bromo-2-methyl-6-trifluoromethyl-pyridine [615579-78-1] (WO03087056). MS (m/e): 227 (M+H + , 100%)

Preparation of 1-(6-Methyl-pyridin-3-yl)-piperazine

The compound was prepared in analogy to compound 1.1 from 5-Bromo-2-methyl-pyridine (commercial). MS (m/e): 178.1 (M+H + , 100%)

In analogy to Example 5 compounds 363 to 461 of the following table were prepared from the acid derivatives and piperazine derivatives:

Preparation of rac-{4-[2-Fluoro-4-(1-hydroxy-ethyl)-phenyl]-piperazin-1-yl}-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone

0.086 mmol of 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone was dissolved in 1 ml ethanol and 0.26 mmol sodium borohydride was added. The mixture was refluxed for 40 min., cooled to room temperature, quenched with water, acidified with HCl 1N and extracted with ethyl acetate. The combined extracts were dried over Na 2 SO 4 , filtered and the solvent was removed in vacuo. The residue was purified on silica eluting with heptane/ethylacetate to yield after evaporation the title compound. MS (m/e): 465.4 (M+H + , 100%)

Preparation of {4-[2-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-piperazin-1-yl}-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone

To a solution of 0.173 mmol 1-{3-Fluoro-4-[4-(2-isopropoxy-5-methanesulfonyl-benzoyl)-piperazin-1-yl]-phenyl}-ethanone in tetrahydrofuran (2 ml) was added dropwise 0.190 mmol 1.6M Methyllithium solution in ether at −75° C. The mixture was stirred for 2 hours and then allowed to warm to 0° C. The mixture was quenched with a 20% NH 4 Cl solution and extracted 3 times with ethyl acetate. The combined extracts were dried over Na 2 SO 4 , filtered and the solvent was removed in vacuo. The residue was purified on silica, eluting with dichloromethane/MeOH to yield after evaporation the title compound.

MS (m/e): 479.5 (M+H + , 100%)

The examples 464-471 have been prepared by separation of the racemic material by chiral HPLC:

Preparation of 2-isobutoxy-5-methylsulfamoyl-benzoic acid

(a) 5-Chlorosulfonyl-2-hydroxy-benzoic acid

To 3.26 mol chlorosulfonic acid at 0° C. was added 652 mmol salicylic acid in small portions, and the mixture was then allowed to stir at RT for 1 h, then at 50° C. for 1 h, and finally at 70° C. for 1 h. The mixture was then added dropwise to 1000 ml ice-water with stirring and stirring continued for an additional 30 min. The ensuing white crystals were collected by filtration, washed three times with water, and then dried in vacuo at 45° C. for 16 h to yield the title compound. MS (m/e): 236.8 ([{ 37 Cl}M−H] − , 33%), 235.0 ([{ 37 Cl}M−H] − , 100%)

(b) 2-Hydroxy-5-methylsulfamoyl-benzoic acid

To 63 mmol 5-chlorosulfonyl-2-hydroxy-benzoic acid in 120 ml dichloromethane at RT was added dropwise 317 mmol methylamine (8 M solution in ethanol), and the mixture was allowed to stir at RT for 1 h. The mixture was then concentrated in vacuo. The residue was suspended in 1 M aq NaOH solution and extracted twice with ether. The aqueous phase was acidified with 5 M aq HCl, saturated with NaCl, and extracted 3 times with THF. The combined THF extracts were washed twice with saturated aqueous NaCl solution and dried with Na 2 SO 4 . Evaporation in vacuo yielded the title compound. MS (m/e): 249.0 (M+NH 4 + , 100%), 231.9 (M+H + , 63%)

(c) 2-Hydroxy-5-methylsulfamoyl-benzoic acid methyl ester

To 77 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid in 300 ml THF was added 85 mmol CDI, and the mixture heated at 70° C. for 1 h. 770 mmol methanol was then added, and the mixture was heated at 70° C. for 16 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane/dichloromethane 45:45:10) to afford the title compound.

MS (m/e): 244.1 ([M−H] − , 100%)

(d) 2-Isobutoxy-5-methylsulfamoyl-benzoic acid methyl ester

To 2.9 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester, 3.1 mmol 2-methyl-1-propanol and 3.3 mmol triphenylphosphine in 10 ml THF was added 3.1 mmol di-tert-butyl azodicarboxylate, and the mixture was stirred at RT for 2 h. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 2:3) to afford the title compound. MS (m/e): 300.2 ([M−H] − , 100%)

(e) 2-Isobutoxy-5-methylsulfamoyl-benzoic acid

To 3.3 mmol 2-isobutoxy-5-methylsulfamoyl-benzoic acid methyl ester in 10 ml THF was added 20 mmol 2 M aq NaOH, and the mixture was heated at 50° C. for 2 h. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 10% aq citric acid and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na 2 SO 4 . Evaporation in vacuo followed by trituration in ether afforded the title compound. MS (m/e): 286.2 ([M−H] − , 100%)

In analogy to Example 6.1(d) and (e), compounds 6.2 to 6.10 of the following table were prepared from 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and the appropriate alcohol, followed by hydrolysis with aqueous sodium hydroxide:

Preparation of 5-methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid

(a) 5-Methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid methyl ester

To 3.3 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and 3.3 mmol potassium carbonate in 50 ml acetone was added dropwise 4.9 mmol 2,2,2-trifluoro-ethyl trifluoromethanesulfonate, and the mixture was heated at 60° C. for 16 h. The mixture was then concentrated in vacuo. The residue was suspended in dichloromethane and filtered. The filtrate was concentrated in vacuo, and the residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 3:7) to afford the title compound. MS (m/e): 328.0 (M+H + , 100%)

(b) 5-Methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid

To 2.3 mmol 5-methylsulfamoyl-2-(2,2,2-trifluoro-ethoxy)-benzoic acid methyl ester in 10 ml THF was added 20 mmol 2 M aq NaOH, and the mixture was heated at 50° C. for 2 h. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 10% aq citric acid and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na 2 SO 4 . Evaporation in vacuo followed by trituration in ether afforded the title compound. MS (m/e): 312.0 ([M−H] − , 100%)

Preparation of rac-5-methylsulfamoyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid

(a) rac-5-Methylsulfamoyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester

To 4.1 mmol 2-hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and 4.1 mmol potassium carbonate in 5 ml DMF was added dropwise 6.1 mmol trifluoro-methanesulfonic acid 2,2,2-trifluoro-1-methyl-ethyl ester, and the mixture was heated at 90° C. for 16 h. The mixture was then cooled to RT, poured onto water and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na 2 SO 4 . Evaporation in vacuo followed by chromatography on silica gel (eluant: dichloromethane) afforded the title compound.

MS (m/e): 359.2 (M+NH 4 + , 80%), 342.0 (M+H + , 100%)

(b) rac-5-Methylsulfamoyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid

To 1.6 mmol 5-methylsulfamoyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid methyl ester in 10 ml THF was added 20 mmol 2 M aq NaOH, and the mixture was heated at 50° C. for 2 h. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 10% aq citric acid and extracted twice with ethyl acetate. The combined organic phases were dried with Na 2 SO 4 . Evaporation in vacuo followed by trituration in ether and hexane afforded the title compound. MS (m/e): 326.2 ([M−H] − , 100%)

Preparation of 5-cyclopropanesulfonyl-2-isopropoxy-benzoic acid

(a) 2-Hydroxy-5-sulfino-benzoic acid

To 317 mmol sodium sulfite in 200 ml water at RT was added dropwise over 30 min a solution of 42.3 mmol 5-chlorosulfonyl-2-hydroxy-benzoic acid in 80 ml dioxane and stirring continued for a further 30 min. 5 M aq NaOH was then added dropwise until the reaction mixture was pH 14, and the mixture was then allowed to stir at RT for a further 2 h. The mixture was then cooled to 0° C. and concentrated H 2 SO 4 added until the reaction mixture was pH 1. Ethyl acetate was added, and the phases were separated. The organic phase was dried with Na 2 SO 4 . Evaporation in vacuo yielded the title compound.

MS (m/e): 201.0 ([M−H] − , 100%)

(b) 5-(3-Chloro-propane-1-sulfonyl)-2-hydroxy-benzoic acid

To 16.7 mmol 2-hydroxy-5-sulfino-benzoic acid and 41.7 mmol triethylamine in 40 ml DMF was added 18.3 mmol 1-chloro-3-iodopropane, and the mixture heated at 40° C. for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: dichloromethane/methanol/acetic acid gradient) to afford the title compound. MS (m/e): 279.1 ([{ 37 Cl}M−H] − , 33%), 277.0 ([{ 35 Cl}M−H] − , 100%)

(c) 5-Cyclopropanesulfonyl-2-hydroxy-benzoic acid

To 8.0 mmol 5-(3-chloro-propane-1-sulfonyl)-2-hydroxy-benzoic acid in 30 ml THF at −78° C. was added dropwise over 30 min 23.9 mmol of a 0.9 M solution of potassium bis(trimethylsilyl)amide in toluene. The reaction mixture was then allowed to warm to RT and stirring continued for a further 30 min at RT. The mixture was then diluted with THF/ethyl acetate (1:1) and washed sequentially with 1 M aq HCl and saturated aqueous NaCl solution, dried with Na 2 SO 4 , and concentrated in vacuo. The residue was triturated in ether/pentane to afford the title compound. MS (m/e): 241.2 ([M−H] − , 100%)

(d) 5-Cyclopropanesulfonyl-2-hydroxy-benzoic acid methyl ester

To 7.2 mmol 5-cyclopropanesulfonyl-2-hydroxy-benzoic acid in 20 ml dichloroethane containing a few drops of DMF was added dropwise 8.7 mmol oxalyl chloride. After stirring for 90 min at RT, the reaction mixture was cooled to 0° C. and then 144 mmol methanol was added, followed by 72 mmol pyridine, and stirring continued at RT for 1 h. The mixture was then washed with 1 M aq HCl, dried with Na 2 SO 4 , and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 255.2 ([M−H] − , 100%)

(e) 5-Cyclopropanesulfonyl-2-isopropoxy-benzoic acid

To 0.6 mmol 5-cyclopropanesulfonyl-2-hydroxy-benzoic acid methyl ester, 3.7 mmol 2-propanol and 0.9 mmol diphenyl-2-pyridylphosphine in 8 ml THF was added 0.9 mmol di-tert-butyl azodicarboxylate, and the mixture was stirred at RT for 3 h. 4 mmol 5 M aq NaOH solution was then added, and the mixture heated at 60° C. for 1 h. The mixture was then concentrated in vacuo. The residue was resuspended in ethyl acetate and washed twice with 1 M aq NaOH solution. The combined aqueous phases were then acidified to pH 1 by addition of 25% aq HCl and extracted three times with ethyl acetate. The combined organic extracts were then dried with Na 2 SO 4 , and concentrated in vacuo to afford the title compound. MS (m/e): 282.9 ([M−H] − , 100%)

In analogy to Example 6.14 (e), compounds 6.15 to 6.18 of the following table were prepared from 5-cyclopropanesulfonyl-2-hydroxy-benzoic acid methyl ester and the appropriate alcohol, followed by hydrolysis with aqueous sodium hydroxide:

Preparation of 1-(4-ethanesulfonyl-2-fluoro-phenyl)-piperazine

(a) 3,4-Difluoro-benzenesulfinic acid

To 2.47 mol sodium sulfite in 1120 ml water at RT was added dropwise over 20 min a solution of 329 mmol 3,4-difluoro-benzenesulfonyl chloride in 560 ml dioxane and stirring continued for a further 30 min. 1 M aq NaOH was then added dropwise until the reaction mixture was pH 14, and the mixture was then allowed to stir at RT for a further 16 h. The mixture was then cooled to 0° C. and concentrated H 2 SO 4 added until the reaction mixture was pH 1. The mixture was extracted three times with ethyl acetate, and the combined organic phases washed with saturated aq NaCl solution and then dried with Na 2 SO 4 . Evaporation in vacuo yielded the title compound. MS (m/e): 177.1 ([M−H] − , 100%)

(b) 4-Ethanesulfonyl-1,2-difluoro-benzene

To 3.0 mmol 3,4-difluoro-benzenesulfinic acid and 3.0 mmol triethylamine in 10 ml DMF was added 7.5 mmol iodoethane and the mixture heated at 90° C. for 9 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed twice with saturated aq. NaCl solution, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:7) to afford the title compound. MS (m/e): 206.9 (M+H + , 100%)

(c) 1-(4-Ethanesulfonyl-2-fluoro-phenyl)-piperazine

To 2.0 mmol 4-ethanesulfonyl-1,2-difluoro-benzene in 5 ml N,N-dimethylacetamide was added 5.6 mmol piperazine and the mixture was heated at 80° C. for 45 min. The mixture was then concentrated in vacuo to afford the title compound. MS (m/e): 273.0 (M+H + , 100%)

In analogy to Example 6.12(b) and (c), compounds 6.13, and 6.21 to 6.23 of the following table were prepared from 3,4-difluoro-benzenesulfinic acid and the indicated alkyl halides, followed by reaction with piperazine:

Preparation of 1-(4-Cyclopropanesulfonyl-2-fluoro-phenyl)-piperazine

(a) 4-(3-Chloro-propane-1-sulfonyl)-1,2-difluoro-benzene

To 28.3 mmol 3,4-difluoro-benzenesulfinic acid and 36.8 mmol triethylamine in 100 ml DMF was added 70.7 mmol 1-chloro-3-iodopropane and the mixture stirred at RT for 1 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated aq. NaCl solution, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound.

MS (m/e): 257.2 ({ 37 Cl}M+H + , 33%), 255.1 ({ 35 Cl}M+H + , 100%),

(b) 4-Cyclopropanesulfonyl-1,2-difluoro-benzene

To 11.8 mmol 4-(3-chloro-propane-1-sulfonyl)-1,2-difluoro-benzene in 400 ml THF at −78° C. was added dropwise over 30 min 14.2 mmol of a 0.9 M solution of potassium bis(trimethylsilyl)amide in THF. The reaction mixture was then allowed to warm to RT and stirring continued for a further 30 min at RT. The mixture was then quenched by addition of 1 M aq HCl and extracted three times with ethyl acetate. The combined organic phases were dried with Na 2 SO 4 , and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:5) to afford the title compound. MS (m/e): 219.2 (M+H + , 100%)

(c) 1-(4-Cyclopropanesulfonyl-2-fluoro-phenyl)-piperazine

To 0.2 mmol 4-cyclopropanesulfonyl-1,2-difluoro-benzene in 5 ml N,N-dimethylacetamide was added 0.5 mmol piperazine and the mixture was heated at 80° C. for 90 min. The mixture was then concentrated in vacuo to afford the title compound. MS (m/e): 285.0 (M+H + , 100%)

Preparation of 1-(4-cyclobutanesulfonyl-2-fluoro-phenyl)-piperazine hydrochloride

(a) 4-Cyclobutanesulfonyl-1,2-difluoro-benzene

To 5.6 mmol 3,4-difluoro-benzenesulfinic acid and 6.2 mmol triethylamine in 10 ml DMF were added 8.4 mmol bromocyclobutane and 0.2 mmol sodium iodide and the mixture heated at 100° C. for 48 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated aq. NaCl solution, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 233.1 (M+H + , 100%)

(b) 1-(4-Cyclobutanesulfonyl-2-fluoro-phenyl)-piperazine hydrochloride

To 2.8 mmol 4-cyclobutanesulfonyl-1,2-difluoro-benzene in 20 ml N,N-dimethylacetamide was added 8.3 mmol piperazine, and the mixture was heated at 80° C. for 45 min. The mixture was then concentrated in vacuo, and the residue was chromatographed on silica gel (eluant: ethyl acetate/methanol gradient). The product-containing fractions were combined and concentrated in vacuo. The residue was resuspended in 100 ml dioxane, and 6.0 mmol HCl (as a 4 M solution in dioxane) was added. After stirring for 10 min, the ensuing white crystals were collected by filtration, washing twice with ether, to afford the title compound.

MS (m/e): 299.1 (M+H + , 100%)

In analogy to Example 6.24(a) and (b), compound 6.25 of the following table was prepared from the 3,4-difluoro-benzenesulfinic acid, bromocyclobutane and sodium iodide, followed by reaction with piperazine and subsequent treatment with HCl in dioxane.

Preparation of 1-[2-fluoro-4-(3,3,3-trifluoro-propane-1-sulfonyl)-phenyl]-piperazine

(a) 1,2-Difluoro-4-(3,3,3-trifluoro-propylsulfanyl)-benzene

To 3.4 mmol 3,4-difluoro-thiophenol and 5.1 mmol 1-iodo-3,3,3-trifluoropropane in 5 ml acetone was added 3.7 mmol potassium carbonate, and the mixture heated at 140° C. for 3 h under microwave irradiation. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed with saturated aq. NaCl solution, dried over Na 2 SO 4 , and concentrated in vacuo to afford the title compound. MS (m/e): 243.1 (M+H + , 100%)

(b) 1,2-Difluoro-4-(3,3,3-trifluoro-propane-1-sulfonyl)-benzene

To 3.0 mmol 1,2-difluoro-4-(3,3,3-trifluoro-propylsulfanyl)-benzene in 5 ml dichloromethane was added 8.3 mmol m-chloroperbenzoic acid, and the mixture heated at 50° C. for 48 h. The reaction mixture was then cooled to room temperature and diluted with dichloromethane and washed three times with saturated aq NaHCO3 solution. The organic phase was then washed with saturated aq. NaCl solution, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 275.1 (M+H + , 100%)

(c) 1-[2-Fluoro-4-(3,3,3-trifluoro-propane-1-sulfonyl)-phenyl]-piperazine

To 0.5 mmol 1,2-difluoro-4-(3,3,3-trifluoro-propane-1-sulfonyl)-benzene in 5 ml N,N-dimethylacetamide was added 1.5 mmol piperazine, and the mixture was heated at 80° C. for 90 min. The mixture was then concentrated in vacuo, and the residue was chromatographed on silica gel (eluant: methanol/dichloromethane gradient) to afford the title compound. MS (m/e): 341.2 (M+H + , 100%)

In analogy to Example 6.26(a) to (c), compounds 6.27 and 6.28 of the following table were prepared from 3,4-difluoro-thiophenol and the indicated alkylating agent, followed by oxidation with m-chloroperbenzoic acid and reaction with piperazine:

Preparation of 1-[2,3-difluoro-4-(propane-2-sulfonyl)-phenyl]-piperazine hydrochloride

(a) 1,2,3-Trifluoro-4-(propane-2-sulfonyl)-benzene

To 20.4 mmol 2,3,4-trifluoro-benzenesulfinic acid (prepared in analogy to example 2.20(a) from 2,3,4-trifluoro-benzenesulfonyl chloride) and 61.2 mmol triethylamine in 20 ml DMF was added 40.8 mmol 2-iodopropane, and the mixture stirred at room temperature for 16 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed twice with saturated aq. NaCl solution, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:4) to afford the title compound.

MS (m/e): 239.1 (M+H + , 100%)

(b) 4-[2,3-Difluoro-4-(propane-2-sulfonyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester

To 7.6 mmol 1,2,3-trifluoro-4-(propane-2-sulfonyl)-benzene in 20 ml N,N-dimethylacetamide was added 15.9 mmol tert-butyl-1-piperazine carboxylate, and the mixture was heated at 90° C. for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:2) to afford the title compound.

MS (m/e): 405.2 (M+H + , 100%)

(c) 1-[2,3-Difluoro-4-(propane-2-sulfonyl)-phenyl]-piperazine hydrochloride

To 7.5 mmol 4-[2,3-difluoro-4-(propane-2-sulfonyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester in 100 ml dioxane was added 30.2 mmol HCl (as a 4 M solution in dioxane), and the mixture was heated at 80° C. for 1 h. The mixture was then cooled to room temperature, and the ensuing white crystals were collected by filtration, washing twice with ether, to afford the title compound.

MS (m/e): 305.2 (M+H + , 100%)

In analogy to Example 6.29(a) to (c), compounds 6.30, 6.32 and 6.33 of the following table were prepared from the indicated sulfinic acids and alkyl halides, followed by reaction with tert-butyl-1-piperazine carboxylate and hydrolysis with HCl in dioxane:

Preparation of 1-(4-cyclopropanesulfonyl-2,3-difluoro-phenyl)-piperazine hydrochloride

(a) 1-(3-Chloro-propane-1-sulfonyl)-2,3,4-trifluoro-benzene

To 30.6 mmol 2,3,4-trifluoro-benzenesulfinic acid (acid (prepared in analogy to example 2.20(a) from 2,3,4-trifluoro-benzenesulfonyl chloride) and 91.8 mmol triethylamine in 20 ml DMF was added 61.2 mmol 1-chloro-3-iodopropane, and the mixture stirred at room temperature for 1 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed twice with saturated aq. NaCl solution, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:4) to afford the title compound. MS (m/e): 275.2 ({ 37 Cl}M+H + , 33%), 273.1 ({ 35 Cl}M+H + , 100%),

(b) 1-Cyclopropanesulfonyl-2,3,4-trifluoro-benzene

To 5.9 mmol 1-(3-chloro-propane-1-sulfonyl)-2,3,4-trifluoro-benzene in 200 ml THF at −78° C. was added dropwise over 30 min 7.0 mmol of a 0.9 M solution of potassium bis(trimethylsilyl)amide in THF. The reaction mixture was then allowed to warm to RT, and stirring continued for a further 30 min at RT. The mixture was then quenched by addition of 1 M aq HCl and extracted three times with ethyl acetate. The combined organic phases were dried with Na 2 SO 4 , and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:4) to afford the title compound. MS (m/e): 237.2 (M+H + , 100%)

(c) 4-(4-Cyclopropanesulfonyl-2,3-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester

To 4.2 mmol 1-cyclopropanesulfonyl-2,3,4-trifluoro-benzene in 20 ml N,N-dimethylacetamide was added 8.9 mmol tert-butyl-1-piperazine carboxylate, and the mixture was heated at 90° C. for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: dichloromethane/ethyl acetate gradient) to afford the title compound. MS (m/e): 403.3 (M+H + , 100%)

(d) 1-(4-Cyclopropanesulfonyl-2,3-difluoro-phenyl)-piperazine hydrochloride

To 3.7 mmol 4-(4-Cyclopropanesulfonyl-2,3-difluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester in 100 ml dioxane was added 14.9 mmol HCl (as a 4 M solution in dioxane), and the mixture was heated at 80° C. for 1 h. The mixture was then cooled to room temperature, and the ensuing white crystals were collected by filtration, washing twice with ether, to afford the title compound. MS (m/e): 303.2 (M+H + , 100%)

In analogy to Example 6.31(a) to (d), compound 6.34 of the following table was prepared from the indicated sulfinic acid and alkyl halide, followed by treatment with potassium bis(trimethylsilyl)amide, reaction with tert-butyl-1-piperazine carboxylate and deprotection with HCl in dioxane:

Preparation of rac-2-Methyl-1-(4-trifluoromethyl-phenyl)-piperazine hydrochloride

(a) rac-3-Methyl-4-(4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester

To 1-bromo-4-trifluoromethyl-benzene (1 g), rac-3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (1 g), in toluene (10 mL) was added sodium tert-butylate (0.6 g), 2-(dicyclohexylphosphino)biphenyl (31 mg), and tris(dibenzylideneacetone)Pd—CHCl 3 (23 mg). The reaction mixture was then stirred at 80° C. overnight. Ethyl acetate was then added to the reaction mixture. Solids were filtered off. The filtrate was then concentrated in vacuo, and the residue was purified by column chromatography to yield 0.46 g of the title compound. MS (m/e): 345.2 (M+H + , 100%)

(b) rac-2-Methyl-1-(4-trifluoromethyl-phenyl)-piperazine hydrochloride

To 0.58 mmol rac-3-methyl-4-(4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester in 3 ml dioxane was added 8.7 mmol HCl (as a 4 M solution in dioxane), and the mixture was heated at 90° C. for 3 h. The mixture was then cooled 0° C. and diluted with 10 ml ether. The ensuing white crystals were collected by filtration, washing with ether, and dried in vacuo to afford the title compound.

MS (m/e): 245.1 (M+H + , 100%)

Preparation of 5-Acetyl-2-isopropoxy-benzoic acid

(a) 5-Acetyl-2-isopropoxy-benzoic acid methyl ester

To 25.8 mmol methyl-5-acetyl-2-hydroxybenzoate, 28.3 mmol 2-propanol and 29.6 mmol triphenylphosphine in 100 ml THF was added 28.3 mmol di-tert-butyl azodicarboxylate, and the mixture was stirred at RT for 90 min. The mixture was then concentrated in vacuo to afford the title compound. MS (m/e): 237.1 (M+H + , 100%)

(b) 5-Acetyl-2-isopropoxy-benzoic acid

To 25.8 mmol 5-acetyl-2-isopropoxy-benzoic acid methyl ester in 100 ml THF was added 400 mmol 2 M aq NaOH, and the mixture was heated at 80° C. for 2 h. The mixture was then cooled to RT and extracted twice with ether. The aqueous phase was acidified with 15% aq hydrochloric acid and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na 2 SO 4 . Evaporation in vacuo followed by trituration in ether afforded the title compound. MS (m/e): 221.2 ([M−H] − , 100%)

In analogy to Example 5 compounds 472 to 619 of the following table were prepared from the acid derivatives and piperazine derivatives:

Preparation of 4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzoic acid

(a) 4-Isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzonitrile

To a solution of 3.6 mmol 5-cyano-2-isopropoxy-benzoic acid (compound 1.13) in 20 ml THF were added 4.0 mmol TBTU, 21.6 mmol N-ethyldiisopropylamine and 4.0 mmol 1-(4-trifluoromethyl-phenyl)-piperazine (commercial). The reaction was then stirred at RT for 16 h, concentrated in vacuo, and purified by chromatography on silica gel (eluant: ethyl acetate/heptane 1:1) to afford the title compound. MS (m/e): 418.3 (M+H + , 100%)

(b) 4-Isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzoic acid

To 3.2 mmol 4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzonitrile in 15 ml ethanol was added 30 mmol 2 M aq NaOH and the mixture was heated at 85° C. for 16 h. The mixture was then cooled to RT, diluted with water and acidified to pH 1 with conc HCl, and then extracted three times with ethyl acetate. The combined organic phases were dried with Na 2 SO 4 , concentrated in vacuo, and the residue purified by chromatography on silica gel (eluant: methanol/dichloromethane 5:95) to afford the title compound. MS (m/e): 435.3 ([M−H] − , 100%)

Preparation of 4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzoic acid methyl ester

To 0.3 mmol 4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzoic acid in 2 ml DMF was added 0.4 mmol CDI, and the mixture heated at 50° C. for 30 min. 5.2 mmol methanol was then added, and the mixture was stirred at RT for 16 h. The mixture was then cooled to room temperature, concentrated in vacuo, and the residue chromatographed on silica gel (eluant: ethyl acetate/heptane 1:4) to afford the title compound. MS (m/e): 451.2 (M+H + , 100%)

Preparation of 4-isopropoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzamide

To 0.3 mmol 4-isopropoxy-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzoic acid in 2 ml DMF was added 0.4 mmol CDI, and the mixture heated at 50° C. for 30 min. 5.2 mmol methylamine (41% aq solution) was then added, and the mixture was stirred at RT for 16 h. The mixture was then cooled to room temperature, concentrated in vacuo, and the residue chromatographed on silica gel (eluant: ethyl acetate) to afford the title compound. MS (m/e): 450.1 (M+H + , 100%)

Preparation of 3-[4-(4-Cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-hydroxy-benzenesulfonamide

(a) 2-Hydroxy-5-sulfamoyl-benzoic acid

Ammonia gas was bubbled through a solution of 107 mmol 5-chlorosulfonyl-2-hydroxy-benzoic acid in 250 ml acetone at 0° C. for 2 h. Argon gas was then bubbled through the reaction mixture for 1 h to purge excess ammonia. The mixture was then diluted with water, the pH adjusted to pH 14 by addition of 5 M aq NaOH solution, and the mixture was then extracted with ether/ethyl acetate (1:1). The aqueous phase was acidified with concentrated HCl, saturated with NaCl, and extracted twice with THF. The combined THF extracts were dried with Na 2 SO 4 . Evaporation of the solvent in vacuo followed by drying of the residue by heating at 60° C. overnight in vacuo yielded the title compound.

MS (m/e): 216.1 ([M−H] − , 100%)

(b) 2-Hydroxy-5-sulfamoyl-benzoic acid methyl ester

To 62 mmol 2-hydroxy-5-sulfamoyl-benzoic acid in 80 ml THF was added 80 mmol CDI and the mixture heated at 50° C. for 1 h. 616 mmol methanol was then added, and the mixture was heated at 50° C. for 16 h. The mixture was then cooled to room temperature, concentrated in vacuo, and the residue chromatographed on silica gel (eluant: dichloromethane/methanol 20:1). The product containing fractions were concentrated in vacuo and the residue suspended in ethyl acetate and washed with aq NaHCO3 solution. The organic phase was dried with Na 2 SO 4 and concentrated in vacuo to afford the title compound. MS (m/e): 230.2 ([M−H] − , 100%)

(c) 2-(4-Methoxy-benzyloxy)-5-sulfamoyl-benzoic acid methyl ester

To 4.8 mmol 2-hydroxy-5-sulfamoyl-benzoic acid methyl ester, 5.2 mmol 4-methoxybenzyl alcohol and 5.2 mmol triphenylphosphine in 8 ml THF was added 5.2 mmol di-tert-butyl azodicarboxylate, and the mixture was stirred at RT for 2 h. The mixture was then concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 350.2 ([M−H] − , 100%)

(d) 2-(4-Methoxy-benzyloxy)-5-sulfamoyl-benzoic acid

To 2.5 mmol 2-(4-methoxy-benzyloxy)-5-sulfamoyl-benzoic acid methyl ester in 6 ml THF was added 5 mmol 2 M aq NaOH, and the mixture was heated at 60° C. for 30 min. The mixture was then cooled to RT and extracted twice with ethyl acetate. The aqueous phase was acidified to pH 1 with 5 M aq HCl and extracted with ethyl acetate. The combined organic phases were washed with saturated aq NaCl and dried with Na 2 SO 4 . Evaporation in vacuo afforded the title compound. MS (m/e): 336.1 ([M−H] − , 100%)

(e) (3-[4-(4-Cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-(4-methoxy-benzyloxy)-benzenesulfonamide

To a solution of 3.5 mmol 2-(4-methoxy-benzyloxy)-5-sulfamoyl-benzoic acid in 4 ml dimethylformamide and 12 ml THF were added 5.3 mmol TBTU, 17.5 mmol N-ethyldiisopropylamine and 3.5 mmol 3-fluoro-4-piperazin-1-yl-benzonitrile (WO9625414). The reaction was then stirred at RT for 1 h, concentrated in vacuo, and purified by chromatography on silica gel (eluant: ethyl acetate/heptane gradient) to afford the title compound. MS (m/e): 525.1 (M+H + )

(f) (3-[4-(4-Cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-hydroxy-benzenesulfonamide

Hydrogen gas was bubbled through a solution of 1.0 mmol (3-[4-(4-Cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-(4-methoxy-benzyloxy)-benzenesulfonamide in 40 ml THF containing 50 mg 10% palladioum on charcoal and a few drops of acetic acid for 6 h at RT. The reaction mixture was then purged with argon, filtered through celite, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (eluant: methanol/dichloromethane gradient) to afford the title compound. MS (m/e): 403.1 ([M−H] − , 100%)

In analogy to Example 6.38(e) and (f), compounds 6.39 and 6.40 of the following table were prepared from 2-(4-methoxy-benzyloxy)-5-sulfamoyl-benzoic acid and the appropriate piperazine, followed by hydrogenolysis with catalytic palladium on charcoal:

Preparation of 3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-isobutoxy-benzenesulfonamide

To 0.1 mmol (3-[4-(4-cyano-3-fluoro-phenyl)-piperazine-1-carbonyl]-4-hydroxy-benzenesulfonamide (compound 6.38), 0.5 mmol 2-methyl-1-propanol and 0.3 mmol diphenyl-2-pyridylphosphine in 4 ml THF was added 0.3 mmol di-tert-butyl azodicarboxylate, and the mixture was stirred at 60° C. for 4 h. The mixture was then diluted with ethyl acetate and washed twice with 5 M aq HCl and then with saturated aq NaCl solution. The organic phase was then dried with Na 2 SO 4 , and concentrated in vacuo. The residue was triturated in ether to afford the title compound. MS (m/e): 459.2 ([M−H] − , 100%)

In analogy to Example 622, compounds 623 to 632 of the following table were prepared from compounds 6.38 to 6.40 and the appropriate alcohol:

Preparation of 3-piperazin-1-yl-5-trifluoromethyl-pyridazine

(a)-3-Chloro-5-trifluoromethyl-pyridazine

5-Trifluoromethyl-pyridazin-3-ol [244268-34-6 (1 g) was added to a stirred solution of phosphoryloxychloride, and the reaction mixture was stirred at 80° C. for 1 hour. After such time, the reaction mixture was allowed to cool to room temperature, poured onto ice and after 5 minutes was extracted twice from the aqueous solution with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The residue was distilled in a Kugelrohr apparatus (bp=80-100° C.@12 mBar) to yield the title compound (0.26 g). MS (m/e): 182.0

(b) 4-(5-Trifluoromethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester

3-Chloro-5-trifluoromethyl-pyridazine (200 mg) was added to piperazine-1-carboxylic acid tert-butyl ester (231 mg) in dimethylacetamide (3 mL), and the reaction mixture was stirred at 100° C. for 3 hours. After such time, the reaction mixture was allowed to cool down to room temperature and diluted with ethyl acetate. The solid was filtered off and washed with ethyl acetate. The filtrate was then concentrated in vacuo and then purified by column chromatography (SiO 2 , Heptane/EtOAc) to yield the title compound as a white solid (364 mg). MS (m/e): 333.4 (M+H + , 100%)

(c) 3-piperazin-1-yl-5-trifluoromethyl-pyridazine

4-(5-Trifluoromethyl-pyridazin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (45 mg) was dissolved in dichloromethane (0.5 mL), and trifluoroacetic acid was added (0.5 mL). The reaction mixture was stirred for 30 minutes before being concentrated in vacuo to afford the crude title compound which was used directly in the next step without further purification or analysis.

Preparation of 5-Methanesulfonyl-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-benzoic acid

To 2-Fluoro-5-methanesulfonyl-benzoic acid (247569-56-8) (600 mg) in dimethylacetamide (10 mL) was added cesium carbonate at 170° C. 2-trifluoromethyl-propanol (0.94 mL) was first added to the reaction mixture followed by additionally 0.47 mL every 24 hours. After a total of 72 hours, the reaction mixture was acidified by addition of formic acid, concentrated in vacuo and purified by preparative HPLC to yield the title compound as a light brown solid (897 mg). MS (m/e): 325.3. (M−H, 100%)

Preparation of 5-Methanesulfonyl-2-piperazin-1-yl-pyrimidine

(a) 3-Dimethylamino-2-methanesulfonyl-allylidene-dimethyl-ammonium; chloride

To sulfonyl-acetic acid (1.5 g) in dimethylformamide was slowly added phosphorus oxychloride over 5 minutes, and the reaction was then stirred at 70° C. for 1 hour and then at room temperature overnight. The reaction mixture was then directly poured over a short column chromatography (SiO 2 , 100 g), eluting successively with 500 mL of EtOAc, THF, EtOAc/EtOH (50/50), EtOH and finally MeOH to yield the title compound (1.58 g). MS (m/e): 204.9 (M + ).

(b) 5-Methanesulfonyl-2-piperazin-1-yl-pyrimidine

The title compound was prepared in analogy to Example 2.25 using 3-Dimethylamino-2-methanesulfonyl-allylidene-dimethyl-ammonium; chloride as starting material. MS (m/e): 243.1 (M+H + , 100%).

Preparation of 1-(5-Methanesulfonyl-pyridin-2-yl)-piperazine trifluoro-acetic acid

The title compound was prepared in analogy to Example 7.1(b-c) from 2-bromo-5-(methanesulfonyl)pyridine and piperazine-1-carboxylic acid tert-butyl ester. MS (m/e): 242.1 (M+H + , 100%)

In analogy to Example 5, compounds 633 to 644 of the following table were prepared from the acid derivatives and piperazine derivatives:

Preparation of (2-Allyloxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone

The title compound was prepared in analogy to example 62 from (2-Hydroxy-5-nitro-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound 2.1) and cyclopropyl bromide. MS (m/e): 436.5 (MH + , 100%)

Preparation of 2-Benzyloxy-5-methanesulfonyl-benzoic acid

The title compound was prepared in analogy to example 2.10 from methyl 5-(methanesulfonyl)salicylate and benzylalcohol. MS (m/e): 305.3 (M−H, 100%)

Preparation of (2-Benzyloxy-5-methanesulfonyl-phenyl)-[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-methanone

The title compound was prepared in analogy to example 5 from 1-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazine (compound 5.5) and 2-Benzyloxy-5-methanesulfonyl-benzoic acid (compound 7.5). MS (m/e): 538.4 (MH + , 100%)

Preparation of (2-Benzyloxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone

The title compound was prepared in analogy to example 5 from 1-(2-Fluoro-4-methanesulfonyl-phenyl)-piperazine (commercial) and 2-Benzyloxy-5-methanesulfonyl-benzoic acid (compound 7.5). MS (m/e): 547.4 (MH + , 100%)

Preparation of [4-(2-Fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-(2-hydroxy-5-methanesulfonyl-phenyl)-methanone

A mixture of 0.915 mmol (2-benzyloxy-5-methanesulfonyl-phenyl)-[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-methanone, 0.05 mmol palladium on charcoal (10%) in 12.5 ml methanol was hydrogenated at atmospheric pressure at room temperature for 2 hours. After addition of chloroform, the mixture was filtered, and the solvent was evaporated to provide the title compound. MS (m/e): 474.3 (M+NH4 + , 100%)

Preparation of 5-piperazin-1-yl-2-trifluoromethyl-pyrimidine

(a) 5-Chloro-2-trifluoromethyl-pyrimidine

To a solution of 38 mmol trifluoroacetamidine in 70 ml acetonitrile was added 37.92 mmol ((Z)-2-Chloro-3-dimethylamino-allylidene)-dimethyl-ammonium hexafluoro phosphate (CAS: 291756-76-8) followed by 45.5 mmol triethylamine. The yellow solution was stirred at room temperature for 5 hours, then poured onto water and extracted 3 times with ether. The combined extracts were dried over sodium sulfate, filtered and distilled at 760 mm Hg to provide the title compound. MS (m/e): 182.2 (M + , 100%)

(b) 4-(2-Trifluoromethyl-pyrimidin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester

0.26 mmol 5-Chloro-2-trifluoromethyl-pyrimidine was added to 0.26 mmol piperazine-1-carboxylic acid tert-butyl ester in 1.5 ml dimethylacetamide, and the reaction mixture was stirred at 150° C. for 10 min. in a microwave oven. After such time, the reaction mixture was concentrated and the residue was then purified by column chromatography (SiO 2 , Heptane/EtOAc) to yield the title compound. MS (m/e): 333.2 (M+H + , 100%)

(c) 5-piperazin-1-yl-2-trifluoromethyl-pyrimidine

The title compound was prepared in analogy to Example 7.1(c) from 4-(2-trifluoromethyl-pyrimidin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester MS (m/e): 233.0 (M+H + , 100%)

Preparation of 5′-Trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl

(a) 2-Bromo-5-trifluoromethyl-pyrazine

To a suspension of 0.423 mmol copper (II) bromide in THF (1 ml) was added dropwise 0.51 mmol tert-butylnitrite at 0° C. within 2 minutes. 0.37 mmol 5-Trifluoromethyl-pyrazin-2-ylamine (CAS: 69816-38-2; WO9518097) in solution in THF (0.5 ml) was added dropwise within 5 minutes at 0° C. The mixture was stirred at 0° C. for 1 hour, at room temperature for 21 hours and quenched with water. The aqueous phase was extracted with ether. The combined extracts were dried over sodium sulfate and filtered and concentrated at atmospheric pressure. The residue was then purified by column chromatography (SiO 2 , ether) to yield the title compound.

(b) 5′-Trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl

The title compound was prepared in analogy to Example 7.6(b-c) from 2-Bromo-5-trifluoromethyl-pyrazine MS (m/e): 233.0 (M+H + , 100%)

Preparation of 3-piperazin-1-yl-6-trifluoromethyl-pyridazine

The title compound was prepared in analogy to Example 7.6(b-c) from 3-Chloro-6-trifluoromethyl-pyridazine (CAS: 258506-68-2). MS (m/e): 233.0 (M+H + , 100%)

In analogy to Example 5, compounds 649 to 660 of the following table were prepared from the acid derivatives and piperazine derivatives:

The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention are good inhibitors of the glycine transporter I (GlyT-1).

The compounds were investigated in accordance with the test given hereinafter.

Solutions and Materials

DMEM complete medium: Nutrient mixture F-12 (Gibco Life-technologies), fetal bovine serum (FBS) 5%, (Gibco life technologies), Penicillin/Streptomycin 1% (Gibco life technologies), Hygromycin 0.6 mg/ml (Gibco life technologies), Glutamine 1 mM Gibco life technologies)

Uptake buffer (UB): 150 mM NaCl, 10 mM Hepes-Tris, pH 7.4, 1 mM CaCl 2 , 2.5 mM KCl, 2.5 mM MgSO 4 , 10 mM (+) D-glucose. Flp-in™-CHO (Invitrogen Cat n o R758-07) cells stably transfected with mGlyT1b cDNA.

Glycine Uptake Inhibition Assay (mGlyT-1b)

On day 1 mammalian cells, (Flp-in™-CHO), transfected with mGlyT-1b cDNA, were plated at the density of 40,000 cells/well in complete F-12 medium, without hygromycin in 96-well culture plates. On day 2, the medium was aspirated, and the cells were washed twice with uptake buffer (UB). The cells were then incubated for 20 min at 22° C. with either (i) no potential competitor, (ii) 10 mM non-radioactive glycine, (iii) a concentration of a potential inhibitor. A range of concentrations of the potential inhibitor was used to generate data for calculating the concentration of inhibitor resulting in 50% of the effect (e.g. IC 50 , the concentration of the competitor inhibiting glycine uptake of 50%).

A solution was then immediately added containing [ 3 H]-glycine 60 nM (11-16 Ci/mmol) and 25 μM non-radioactive glycine. The plates were incubated with gentle shaking, and the reaction was stopped by aspiration of the mixture and washing (three times) with ice-cold UB. The cells were lysed with scintillation liquid, shaken 3 hours and the radioactivity in the cells counted using a scintillation counter.

The prepared compounds show an IC 50 (μM) at GlyT-1 in the range of 0.006-5.0.

The preferred compounds show an IC 50 (μM) at GlyT-1 in the range of 0.006-0.05, as shown in the table below.

The present invention also provides pharmaceutical compositions containing compounds of formula I or pharmaceutically acceptable salts of the compounds of formula I and a pharmaceutically acceptable carrier. Such pharmaceutical compositions can be in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. The pharmaceutical compositions also can be in the form of suppositories or injectable solutions.

The pharmaceutical compositions of the invention, in addition to one or more compounds of the invention, contain a pharmaceutically acceptable carrier. Suitable pharmaceutical acceptable carriers include pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are however usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical compositions can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.

Thus, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.

The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of schizophrenia, cognitive impairment and Alzheimer's disease.

Thus, the invention also provides a method of inhibiting glycine uptake comprising administering to an individual a glycine inhibiting amount of one or more compounds of formula I. The invention further provides a method of inhibiting glycine uptake which comprises administering to an individual a glycine inhibiting amount of one of the following compounds

1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine, 1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine, 1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine, 4-(3-amino-4-nitrophenyl)-1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-piperazine, 1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-4-(4-nitrophenyl)-piperazine, 4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-1-(4-nitrophenyl)-piperazine, 1-(2-chloro-4-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine, 1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-4-(2,4-dinitrophenyl)-2-methyl-piperazine, 1-(4-chloro-2-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine

or

4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-1-(2,4-dinitrophenyl)-2-methyl-piperazine.

The invention provides a method of treating an illness selected from the group consisting of psychoses, pain, disfunction in memory and learning, schizophrenia, dementia, attention deficit disorders, and Alzheimer's disease, which method comprises administering to an individual an effective amount of one or more compounds of formula I. The invention further provides a method of treating an illness selected from the group consisting of psychoses, pain, disfunction in memory and learning, schizophrenia, dementia, attention deficit disorders, and Alzheimer's disease, which method comprises administering to an individual an effective amount of one or more compounds of the following compound 1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine,

1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine, 1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine, 4-(3-amino-4-nitrophenyl)-1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-piperazine, 1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-4-(4-nitrophenyl)-piperazine, 4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-1-(4-nitrophenyl)-piperazine, 1-(2-chloro-4-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine, 1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-4-(2,4-dinitrophenyl)-2-methyl-piperazine, 1-(4-chloro-2-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine

or

4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-1-(2,4-dinitrophenyl)-2-methyl-piperazine.

In particular, the method provides a method of treating schizophrenia, which method comprises administering to an individual an effective amount of one or more compounds of formula I. The invention further provides a method of treating schizophrenia, which method comprises administering to an individual an effective amount of one or more compounds of the following compounds

1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine, 1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine, 1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine, 4-(3-amino-4-nitrophenyl)-1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-piperazine, 1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-4-(4-nitrophenyl)-piperazine, 4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-1-(4-nitrophenyl)-piperazine, 1-(2-chloro-4-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine, 1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-4-(2,4-dinitrophenyl)-2-methyl-piperazine, 1-(4-chloro-2-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine

or

4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-1-(2,4-dinitrophenyl)-2-methyl-piperazine.

In particular, the method provides a method of treating Alzheimer's disease, which method comprises administering to an individual an effective amount of one or more compounds of formula I. The invention further provides a method of treating Alzhemier's disease, which method comprises administering to an individual an effective amount of one or more compounds of the following compounds

1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(3-chlorophenyl)-piperazine, 1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-(4-fluorophenyl)-piperazine, 1-[5-(aminosulfonyl)-2-methoxybenzoyl]-4-[3-(trifluoromethyl)phenyl]-piperazine, 4-(3-amino-4-nitrophenyl)-1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-piperazine, 1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-4-(4-nitrophenyl)-piperazine, 4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-2-methyl-1-(4-nitrophenyl)-piperazine, 1-(2-chloro-4-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine, 1-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-4-(2,4-dinitrophenyl)-2-methyl-piperazine, 1-(4-chloro-2-nitrophenyl)-4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-piperazine

or

4-[4-(dimethylamino)-2-methoxy-5-nitrobenzoyl]-1-(2,4-dinitrophenyl)-2-methyl-piperazine.

The compounds and compositions of the present invention can be administered in a conventional manner, for example, orally, rectally, or parenterally. The pharmaceutical compositions of the invention can be administered orally, for example, in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. The pharmaceutical compositions also can be administered rectally, for example, in the form of suppositories or parenterally, for example, in the form of injectable solutions.

The dosage at which a compound of the invention can be administered can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.

Tablet Formulation (Wet Granulation) mg/tablet Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167 167 831

Manufacturing Procedure

1. Mix items 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50° C. 3. Pass the granules through suitable milling equipment. 4. Add item 5 and mix for three minutes; compress on a suitable press.

Capsule Formulation mg/capsule Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Hydrous Lactose 159 123 148 — 3. Corn Starch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5 Total 200 200 300 600

Manufacturing Procedure

1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add items 4 and 5 and mix for 3 minutes. 3. Fill into a suitable capsule.