NEW PHENYLPIPERAZINES

Abstract: The invention relates to a group of phenylpiperazines having high affinity for the dopamine D2-receptor and are good serotonin reuptake inhibitors (SRI's). The invention relates to a group of phenylpiperazine derivatives of formula (I) wherein: a.o. x is 1) a group of formula (1) wherein: S1 is hydrogen or halogen; S2 and S3 are independently hydrogen, alkyl (1-6C), phenyl or benzyl; S4 represents two hydrogen atoms or an oxo group, S5 is H or alkyl (1-4C); and Y is C, O or S, and salts there of.

Description: New phenylpiperazines The invention relates to a group of novel phenylpiperazine derivatives of the formula (I): wherein: - X is 1 ) a group of the formula wherein - S, is hydrogen or halogen, - S 2 and S 3 are independently hydrogen, alkyl (1-6C), phenyl or benzyl, - S 4 represents two hydrogen atoms or an oxo group, - S 5 is H or alkyl (1-4C), and - Y is C, O or S, or 2) a group of the formula wherein Si has the above meaning and R is H, alkyl (1-4C), alkoxyalkyl (2-6C), alkenyl (2-4C) or alkynyl (2-4C), or 3) a group of the formula wherein S T has the above meaning and Z is C, O or N, or 4) a group of the formula wherein S., has the above meaning, or 5) a group of the formula wherein S T has the above meaning and A is O or N, linked to the piperazine ring with position 5 or 8, or 6) a group of the formula wherein S T has the above meaning and S 6 and S 7 represent hydrogen atoms or an oxo group, or 7) a group of the formula wherein one of the dotted lines can represent a double bond, S Ϊ has the above meaning, and P=T=Q=nitrogen or P=T=nitrogen and Q=C or P=Q=nitrogen and T=C or C-CH 3 or P=nitrogen, and T and Q are carbon or P=nitrogen, T is carbon and Q is sulphur - m has the value 2 to 6; - n has the value 0-2; - R 5 and R 6 are independently H or alkyl (1-3C); or R 5 +R 6 represent a group -(CH 2 )- P wherein p has the value 3-5, and - R 7 is alkyl (1-3C), alkoxy (1-3C), halogen or cyano; or Re+R 7 (R 7 at position 7 of the indole group) represent a group -(CH 2 ) q wherein q has the value 2-4, and salts thereof, which show high affinity for the dopamine D 2 -receptor and are good serotonin reuptake inhibitors (SRI's). Preferred compounds of the invention are compounds having formula (I) wherein X represents a group of the formula (1), (2) or (3), wherein the symbols have the meanings given above and the salts thereof. Especially preferred are compounds having formula (I) wherein X is the group with the formula (1 ) wherein S^H, S 2 =CH 3 , S 3 =H, S 4 =oxo, S 5 =H and Y is oxygen, m is 3, R 5 =R 6 = hydrogen, n is 0 or 1 and R 7 is 5-fluoro, and the salts thereof. It has been found that the compounds according to the invention show high affinity for both the dopamine D 2 receptor and the serotonin reuptake site. This combination is useful for the treatment of schizophrenia and other psychotic disorders which enables a more complete treatment of all disease symptoms (e.g. positive symptoms and negative symptoms). However, some of the compounds having formula (I) show (partial) agonist activity at dopamine receptors making them particularly suitable for the treatment of Parkinson's disease. The compounds show activity as antagonists at dopamine D 2 receptors as they potentially antagonize apomorphine-induced climbing behaviour in mice. The compounds also show activity as inhibitors of serotonin reuptake, as they potentiate 5-HTP induced behaviour in mice. The compounds are active in therapeutic models sensitive to clinically relevant antipsychotics (e.g. the conditioned avoidance response; Van der Heyden & Bradford, Behav. Brain Res., 1988, 31:61-67) and antidepressants or anxiolytics (e.g. suppression of stress-induced vocalization; van der Poel et al., Psychopharmacology, 1989, 97: 147- 148). In contrast to clinically relevant dopamine D 2 receptor antagonists the described compounds have a low propensity to induce catalepsy in rodents and as such are likely to induce less extrapyramidal side effects than existing antipsychotic agents. The inhibitory activity of serotonin reuptake inherent in these compounds may be responsible for the therapeutic effects observed in behavioural models sensitive to either antidepressants or anxiolytics. The compounds can be used for the treatment of affections or diseases of the central nervous system caused by disturbances in either the dopaminergic or serotonergic systems, for example: aggression, anxiety disorders, autism, vertigo, depression, disturbances of cognition or memory, Parkinson's disease, and in particular schizophrenia and other psychotic disorders. Pharmacologically acceptable acids with which the compounds of the invention can form suitable acid addition salts are for example hydrochloric acid, sulphuric acid, phosphoric acid, nitric acid, and organic acids such as citric acid, fumaric acid, maleic acid, tartaric acid, acetic acid, benzoic acid, p-toluene sulphonic acid, methanesulphonic acid and naphthalene sulphonic acid. When the compounds comprise a centre of chirality both the racemic mixture and the individual enantiomers belong to the invention. The compounds and their acid addition salts can be brought into forms suitable for administration by means of suitable processes using auxiliary substances such as liquid and solid carrier materials. The compounds having formula (I) can be prepared by reaction of a compound of the formula X-N NH (II) under basic conditions with a compound of the formula in which formulae the symbols have the meanings given above, and L is a so-called leaving group such as a halogen atom or a mesylate group. The piperazine compounds having formula (II) can be obtained as described in EP 0138280, EP 0189612 and/or EP 0900792, or in an analogous manner. The preparation of the piperazines having formula (II) can be carried out as indicated in schemes (i)-(iv) below. Some of the routes result in optically pure piperazine derivatives. Scheme (i) Scheme (ii) Scheme (iii) Scheme (iv) The starting compounds having formula (III) can be prepared according to methods known for analogues compounds, as described for example in Organic Process Res. and Dev. 1997 (1 ), 300-310. The invention will now be illustrated by means of the following Examples: Example 1 : preparation of compound a,i (see scheme i) Step 1 (scheme i): To a solution of chloronitrocatechol (6.45 g , 34 mmol) in dry DMSO (50 ml) was added powdered NaOH (2.72 g , 68 mmol). After stirring for 30 minutes a solution was added of R-glycerolketal mesylate (8.0 g, 38 mmol) in DMSO (20 ml) and this mixture was heated at 80°C during 24 hours. After cooling to room temperature the reaction mixture was poured into water (200 ml), acidified with 1N HCI and extracted with methyl t-butylether. The organic fraction was washed with water and dried on MgSO 4 . After removal of the drying agent and the solvent in vacuo, the resulting oil was subjected to flash chromatografy (SiO 2 , eluent PE/aceton=3/1 ). Yield 9.29 g (90%) of the S-ketal. Step 2 (scheme i): To a solution of the S-ketal (31 g, 102 mmol) in acetic acid (120 ml) was added 35% HBr in acetic acid (80 ml) and this mixture was rotated for 2 hours on a rotavapor in a waterbath of 50°C. The reaction mixture was diluted with ethanoi (96%, 250 ml), cooled in a salt ice mixture and then NaOH (50% in water, 250 ml) was added slowly, keeping the temperature below 15°C. After adding ethanoi (250 ml) and water (250 ml) the reaction mixture was stirred at room temperature for 16 hours. Then concentrated HCI (about 300 ml) and water were added and the mixture extracted with ethyl acetate. After washing the organic fraction with 5% NaHCO 3 (4x500 ml), the solvent was removed in vacuo and the resulting oil was subjected to flash chromatografy (SiO 2 , eluent PE/aceton=3/1). Yield 20.5 g (81%) of the R-benzodioxane as a yellow oil. Step 3 (scheme i): To a solution of R-benzodioxane (20 g, 81 mmol) in DMF (200 ml) was added KOH (4.56 g, 81 mmol). After cooling the red solution in ice/aceton dimethyl sulfate (23 ml) was added and the reaction mixture was stirred for 1.5 hours at room temperature. Then more KOH (4.56 g, cooling) was added and the mixture was stirred at room temperature for 16 hours. After adding water (700 ml), the product was extracted with ethyl acetate. The ethyl acetate was removed in vacuo and the resulting oil was subjected to flash chromatografy (SiO 2 , eluent PE/aceton=4/1 ) yielding R- methoxymethylbenzodioxane (12.3 g, 58%) as a yellow oil. [α] D 25 = -97° ( methanol). Step 4 (scheme i): To a solution of R- methoxymethylbenzodioxane (5 g, 19 mmol) in ethanoi (100 ml) and ethyl acetate (50 ml) was added a catalytic amount of 10% Pd/C and the solution was shaken under atmospheric H 2 pressure at room temperature. After the calculated amount of H 2 was taken up by the reaction mixture, the catalyst was removed by filtration and the filtrate was concentrated in vacuo. Yield 3.7 g (100%) of the corresponding aniiino-compound. Step 5 (scheme i): The aniiino-compound (4 g, 2 mmol) and BCEA, i.e. HN(CH 2 CH 2 CI) 2 .HCI (3.7 g , 2 mmol) were dissolved in chiorobenzene (100 ml). The mixture was heated to 150°C for 16 hours, concentrated in vacuo and purified by flash chromatografy (SiO 2 , dichloromethane/methanol/ammonium hydroxide=92/7.5/0.5). Yield 3.67 g (68%) of the piperazine aj. Example 2: preparation of compound no. 126 The route is described above, i.e. reaction of compound (II) with compound (III). The mesylates of formula (III) were prepared from the corresponding alcohols by standard procedures, e.g. with MsCI/Et 3 N. A mixture of the piperazine aj (3,6 g , 13,6 mmol) , the 5-fluoro indoie-mesylate (4,1 g , 15,1 mmol), triethylamine (2 ml) and a catalytic amount of Kl in CH 3 CN (100 ml) was heated under reflux during 18 hours after which the reaction mixture was concentrated in vacuo and purified by chromatografy (Si0 2 , dichloromethane/methanol/ammonium hydroxide =92/7.5/0.5). Yield 3,77 of the free base (oil). The free base was dissolved in ethanoi and 1 equivalent of fumaric acid in ethanoi was added. After removal of the solvent compound no. 126 was obtained (4,3 g, 57%). [α] D 25 = -2° (methanol) Example 3 : preparation of compound b,ii (see scheme ii) Step 1 (scheme ii): A solution of the aminophenol (37.3 g, 198 mmol), S-lactic acid methyl ester (20 ml) and triphenylphosphine (58 g, 220 mmol) in THF (2000 ml) was cooled in ice/salt (temperature <10°C). Then a solution of azodicarboxic acid ester (DIAD, 43 ml , 218 mmol) in THF (400 ml) was added slowly. After stirring at room temperature for 18 hours the reaction mixture was concentrated in vacuo and ethanoi (500 ml) and 36% HCI (125 ml) were added to the residue. The mixture was heated to 100°C (development of gas). After cooling the compound was isolated by filtration and washed with 96% ethanoi (about 100 ml). Yield 42 g (87%). Step 2 (scheme ii): This step is similar to step 4 described in scheme i. Step 3 (scheme ii): This step is similar to step 5 described in scheme i, resulting in the formation of the piperazine b,ii. Example 4: preparation of compound no. 89 The route is described above, i.e. reaction of compound (II) with compound (III). The reaction is carried out as described in example 2, starting with the piperazine b,ii . Yield 58% of compound no. 89, [α] D 25 = -24° (methanol). Example 5: preparation of coumpound c.iii (see scheme iii) Step 1 (scheme iii): A solution of the benzomorpholinone (10 g , 41 mmol ; see scheme ii, step 1 ) and powdered KOH (2.3 g , 41 mmol) in DMF (100 ml) was cooled in ice (temperature <10°C). After adding 1 equivalent of Mel (2.55 ml, 41 mmol) the reaction mixture was stirred at room temperature for about 1.5 hours and then poured into water. The precipitate was filtered off, washed with water and dried. Yield 10 g (95%) of the NCH 3 .-compound, mp. 191-192; [α] D 25 = +7.5° (in THF) Step 2 (scheme iii): This step is similar to step 4 described in scheme i. Step 3 (scheme iii): This step is similar to step 5 described in scheme i, resulting in the formation of the piperazine cjii. Example 6 : preparation of compound no. 121 The route is described above, i.e. reaction of compound (II) with compound (III). The reaction is performed as described in example 2, starting with the piperazine cjii . Yield 44% of compound no. 121, [α] D 25 = -28° (methanol). Example 7: preparation of compound d,iv (see scheme iv) Step 1 (scheme iv): Pyridine (81ml, 1 mol) was added to a solution of 2-hydroxy-5- chloroaniline (143.5 g, 1 mol) in dry CH 2 CI 2 . The mixture was cooled in ice (temperature <10°C) and then a solution of 2-bromo-2-methyl-propionylbromide (163 ml, 1 mol) in CH 2 CI 2 (100 ml) was added slowly. The mixture was stirred at room temperature for 18 hours and was poured into CH 2 CI 2 (5000 ml) and water (2000 ml). The organic layer was washed with water, dried and concentrated in vacuo till about 1 litre. The precipitate was filtered off, washed with CH 2 CI 2 and dried. Yield 231 g (79%) of the bromocompound, mp. 172°C. Step 2 (scheme iv): To a suspension of the bromocompound (60 g , 205 mmol) in water (95 ml) was added slowly under ice cooling concentrated sulfuric acid (7 ml) followed by 70% HNO 3 (16 ml) and stirring was continued for 2 hours at room temperature. After cooling in ice water the precipitate was filtered off, washed with water and purified by chromatografy (SiO 2 , methyl t-butylether). Yield 49 g (71%) of the nitrocompound. Step 3 (scheme iv): To a solution of the nitrocompound (49 g , 145 mmol) in DMF (500ml) was added K 2 C0 3 . This mixture was heated for one hour at 150°C, then cooled and poured into a mixure water / ethyl acetate. The organic fraction was washed with sodium bicarbonate (5% in water) , HCI (2N) and water respectively. The solvent was removed in vacuo and the residue was purified by flash chromatografy (Si0 2 , methyl t-butylether / PE = 1 / 1 ). Yield 23 g (62%). Step 4 (scheme iv): This step is similar to step 4 described in scheme i. Step 5 (scheme iv): This step is similar to step 5 described in scheme i, leading to the formation of the piperazine d,iv. Example 8: preparation of compound no. 115 The route is described above, i.e. reaction of compound (II) with compound (III). The reaction is performed as described in example 2, starting with the piperazine d,iv . Yield 20% of compound no. 115. The compounds listed in the following tables have been prepared according to the method of the above examples. LD LO

Claims: Claims 1. The invention relates to a group of novel phenylpiperazine derivatives of the formula (I): wherein: - X is 1 ) a group of the formula wherein - Si is hydrogen or halogen, - S 2 and S 3 are independently hydrogen, alkyl (1-6C), phenyl or benzyl, - S 4 represents two hydrogen atoms or an oxo group, - S 5 is H or alkyl (1-4C), and - Y is C, O or S, or 2) a group of the formula wherein S Ϊ has the above meaning and R is H, alkyl (1-4C), alkoxyalkyl (2-6C), alkenyl (2-4C) or alkynyl (2-4C), or 3) a group of the formula wherein Si has the above meaning and Z is C, O or N, or 4) a group of the formula wherein S, has the above meaning, or 5) a group of the formula wherein Si has the above meaning and A is O or N, linked to the piperazine ring with position 5 or 8, or 6) a group of the formula wherein Si has the above meaning and S 6 and S 7 represent hydrogen atoms or an oxo group, or 7) a group of the formula wherein one of the dotted lines can represent a double bond, S 1 has the above meaning, and P=T=Q=nitrogen or P=T=nitrogen and Q=C or P=Q=nitrogen and T=C or C-CH 3 or P=nitrogen, and T and Q are carbon or P=nitrogen, T is carbon and Q is sulphur - m has the value 2 to 6; - n has the value 0-2; - R 5 and R 6 are independently H or alkyl (1-3C); or R 5 +R 6 represent a group -(CH 2 )- P wherein p has the value 3-5, and - R 7 is alkyl (1-3C), alkoxy (1-3C), halogen or cyano; or R 6 +R 7 (R 7 at position 7 of the indole group) represent a group -(CH 2 ) q wherein q has the value 2-4, and salts thereof. 2. A compound as claimed in claim 1 , wherein X represents a group of the formula (1 ), (2) or (3), wherein the symbols have the meanings given in claim 1. 3. A compound as claimed in claim 1 , wherein X is the group having formula (I), wherein S 1 =S 3 =S 5 =H, S 4 =oxo and S 2 =CH 3 , m is 3, R 5 =R 6 =H, n is 0 or 1 , and R 7 is 5-fluoro, and salts thereof. 4. Method for the preparation of compounds as claimed in claim 1 , characterised in that a compound having formula (II) / \ -N NH (H) \ / is reacted under basic conditions with a compound having formula (III) in which formulae the symbols having the meanings given in claim 1 , and L is a so-called leaving group. 5. A pharmaceutical composition containing at least one compound as claimed in claim 1 as an active component. 6. A method of preparing a composition as claimed in claim 5, characterised in that a compound of claim 1 is brought into a form suitable for administration. 7. A method of treating CNS disorders, characterised in that a compound as claimed in claim 1 is used.

Inventors: KRUSE CORNELIS G, TIPKER JACOBUS, TULP MARTINUS T M, VAN DER HEIJDEN JOHANNES A M, VAN HES ROELOF, VAN VLIET BERNARD J, VISSER GERBEN M, KRUSE, CORNELIS, G., TIPKER, JACOBUS, TULP, MARTINUS, T., M., VAN DER HEIJDEN, JOHANNES, A., M., VAN HES, ROELOF, VAN VLIET, BERNARD, J., VISSER, GERBEN, M.
Applicants: HEIJDEN JOHANNES A M V D, HES ROELOF VAN, KRUSE CORNELIS G, SOLVAY PHARM BV, TIPKER JACOBUS, TULP MARTINUS T M, VISSER GERBEN M, VLIET BERNARD J VAN, KRUSE, CORNELIS, G., SOLVAY PHARMACEUTICALS B.V., TIPKER, JACOBUS, TULP, MARTINUS, T., M., VAN DER HEIJDEN, JOHANNES, A., M., VAN HES, ROELOF, VAN VLIET, BERNARD, J., VISSER, GERBEN, M.
Application year: 2000
Main classification: C07D209
IPC codes: A61K31, A61P1, A61P25, C07D209, C07D401, C07D403, C07D405, C07D413, C07D417