Title of Invention

NOVEL PHENYLPIPERAZINE DERIVATIVES

Abstract

The invention relates to a novel group of phenylpiperazines having interesting pharmacological properties. The invention relates to a group of novel phenylpiperazine derivatives of formula (I): wherein: X is 1) a group of formula (1) wherein: S<sub>1</sub> is hydrogen or halogen, S<sub>2</sub> and S<sub>3</sub> are independently hydrogen, alkyl (1- 6C), phenyl or benzyl, S<sub>4</sub> represents two hydrogen atoms or an oxo group, S<sub>5</sub> is H or alkyl (1-4C), and Y is C, 0 or 8, qr 2) a group of formula (2) wherein S<sub>1</sub> 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 formula (3) wherein 81 has the above meaning and Z is C, 0 or N, or 4) a group of formula (4) wherein S<sub>1</sub> has the above meaning, or 5) a group of formula (5)' wherein S<sub>1</sub> 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 formula (6) wherein <sub></sub> has the above meaning and S<sub>6</sub> and <sub>7</sub> represent hydrogen atoms or an oxo group, or 7) a group of formula (7) wherein one of the dotted lines can represent a double bond, 81 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<sub>3</sub> 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<sub>5</sub> and R<sub>6</sub> are independently H or alkyl (1-3C); or R<sub></sub>+R<sub>6</sub> represent a group -(CH<sub>2</sub>-p wherein p has the value 3-5, and R<sub>7</sub> is alkyl (1-3C), alkoxy (1-3C), halogen or cyano; or R<sub>6</sub>+R<sub>7</sub> (R<sub>7</sub> at position 7 of the indole group) represent a group -(CH<sub>2</sub>)<sub>q</sub>, wherein <sub>q</sub> has the value 2-4, and salts thereof.

Full Text

New DhenvlDiperazines The invention relates to a group of novel phenyipiperazine derivatives of the formula (1): wherein Si is hydrogen or halogen, - S2 and S3 are independently hydrogen, alkyi (1-6C), phenyl or benzyl, - S4 represents two hydrogen atoms or an 0x0 group. - S5 is H or alkyl (1-4C), and - Y is C, O or S, wherein S1 has the above meaning and R is H, alkyI (1-4C), alkoxyalkyl! (2-6C), alkenyl (2-4C) or alkynyl (2 ), or 3) a group of the funnier wherein S1 has the above meaning and Z is C, O or N, or 4) a group of the formula wherein S1 has the above meaning, or 5) a group of the formula wherein S1 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 Vv'hereip. ST h3s the above meaning and S and Sy 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, S1 has the above meaning, and P=7=Q=n[train or P=T=nitrogen and Q=C or P=Q=nitrogen and T=C or C-CH3 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; - R5 and Re are independently H or alky! (1-3C); or Rs-1Re represent a group -(CH2)-p wherein p has the value 3-5, and - R7 is alkyl (1-3C), alkoxy (1-3C), halogen or cyano; or R1+Ry (R7 at position 7 of the indole group) represent a group -(CH2)q wherein q has the value 2-4, and salts thereof, which show high affinity for the dopamine Do-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 fonn ia (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 Si=H, S2=CH3, S3=H. 84=0x0, S5=H and Y is oxygen, m is 3, R5=R6=hydrogen, n is 0 or 1 and R7 is 5-fiuoro, and the sails thereof. It has been found that the compounds according to the invention show high affinity for both the dopamine D2 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 cf the compounds having fonn ia (!) show (partial) acnes activity/ at dopamine receptors making them particularly suitable for the tr3atment cf Parkinson's disease. The compounds show activity as antagonists at camions D1 receptors as they potentially antagonize apomcrphine-induced climbing behaviour in mice. The compounds also show activity as inhibitors cf serotonin reuptake, as they potentiate 5-HTP induced behaviour in mice. The compounds are active in therapeutic models sensitive to relevant antipsychotics (e.g. the conditioned avoidance response; Van 6er Hoyden & Bradford, Behave. Brain Res., 1988, 31:61-67) and antidepressants or anxiolytic (e.g. suppression of stress-induced vocalization; van deer Pole et a!., Psychopharmacoiogy, 1989, 97: 147-148). In contrast to clinically relevant dopamine D2 receptor antagonists the described compounds have a low propensity to induce catalepsy in rodents and as such are likely to induce less extrapyramida! 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 behavioral models sensitive to either antidepressants or anxiolytic. 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 add, 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’s 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 (1) can be prepared by reaction of a compound of the formula under basic conditions with a compound of the formula the symbols have the meanings given above, and L is a so-coiled leaving group such as a halogen atom or a mesylate group. The piperazine compounds having formula (11) can be obtained as described in EP 0138280, EP 0189612 and/or EP 0900792, or in an analogous manner. The preparation of the piperazine having formula (II) can be carried out as indicated in schemes (i)-(Jv) below. Some of the routes result in optically pure piperazine derivatives- j 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 mi) and this mixture was rotated for 2 hours on a rotavapor in a waterbath of 50°C. The reaction mixture was diluted with ethanol (96%, 250 ml), cooled in a salt/ice mixture and then NaOH (50% in water, 250 mi) was added slowly, keeping the temperature below 15°C. After adding ethanol (250 mi) 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% NaHCOa (4x500 m.i), the solvent was removed in vacuo and the resulting oil was subjected to flash chromatografy (SiOj, eiuant 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 with ethyl acetate. The ethyl acetate was removed in vacuo and the resulting oil was subjected to flash chromatografy (SiO1, eiuent PE/aceton=4/1) yielding R-methcx11methylbenzodioxane (12.3 g, 58%) as a yellow oil. [a]o11= -97° ( methanol). Step 4 (scheme i): To a solution of R- methoxymethylbenzodioxane (5 g, 19 mmol!) in ethanol (100 ml) and ethyl acetate (50 ml) was added a catalytic amount of 10% Pd/C and the solution was shaken under atmospheric H2 pressure at room temperature. After the calculated amount of H2 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 anilino-compound. Step 5 (scheme i): The anilino-compound (4 g, 2 mmol) and BCEA, i.e. HN(CH2CH2C1)2.HCI (3.7 g , 2 mmol) were dissolved in chlorobenzene (100 ml). The mixture was heated to 150°C for 16 hours, concentrated in vacuo and purified by flash chromatografy (SiOs, dichloromethane/methanol/ammonium hydroxide=92/7.5/0.5). Yield 3.67 g (68%) of the piperazine Example 2: preparation of compound no. 126 The route is described above, i.e. reaction of compound (II) with compound (ill). The mesylate of formula (111) were prepared from the corresponding alcohols by standard procedures, e.g. with MsCl/EtaN. A mixture of the piperazine (3,6 g , 13,6 mmol), the 5-fluoro indole-mesylate (4,1 g , 15,1 mmol), triethylamine (2 mi) and a catalytic amount of K! in CH3CN (100 ml) was heated under reflux during 18 hours after which the reaction mixture was concentrated in vacuo and purified by chromatografy (Si02, dichloromethane/methanol/ammonium hydroxide =92/7.5/0.5). Yield 3,77 of the free base (oil). The free base was dissolved in ethanol and 1 equivalent of fumaric acid in ethanol was added. After removal of the solvent compound no. 126 was obtained (4,3 g, 57%). [a]o11 - -2° (methanol) example 3 : preparation of compound b.ii (see scheme ii) Step 3 (scheme ii): This step is similar to step 5 described in scheme i, resulting in the formation of the piperazine . Example 4: preparation of compound no. 89 The route is described above, i.e. reaction of compound (11) with compound (111). The reaction is carried out as described in example 2, starting with the piperazine Yield 58% of compound no. 89, c"= -24° (mechanic). bramble 5: preparation of compound kii (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 mi) was cooled in ice (temperature 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 Example 6 : preparation of compound no. 121 The route is described above, i.e. reaction of compound (I!) with compound (111). The reaction is performed as described in example 2, starting with the piperazine chi. Yield 44% of compound no. 121, [a]o11 = -28° (methanol). *—V amole 7: preparation of compound dive (see scheme iv) Step 1 (scheme iv): Pyridine (S1m!, 1 mol) Vvas added to a solution of 2-hydrcxy-5-chloroaniline (143.5 g, 1 moil) in dry CH2CI2. The mixture was cooled in ice (temperature 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% HNO3 (16 ml) and stoning 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 (Si02, methyl t-butyl ether). Yield 49 g (71%) of the nitro compound. 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 dive. Example 8: preparation of compound no. 115 The route is described above, i.e. reaction of compound (il) with compound (HI). The reaction is performed as described in example 2, starting the piperazine . Yield 20% cf compound nc. 115. Claims 1. The invention relates to a group of novel phenyipiperazine derivatives of the formula (I): wherein - Si is hydrogen or halogen, - S2 and S3 are independently hydrogen, alkyl (1-6C), phenyl or benzyl, - S4 represents two hydrogen atoms or an 0x0 group, - S5 is H or alkyl (1-4C), and - Y is C, O or S, wherein one of the dotted lines can represent a double bond, S, 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-CH3 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; - Re and Rg are independently H or alky! {1-3C); or Rs+Rg represent a group -(CH2)-p wherein p has the value 3-5, and - R7 is alkyl (1-3C), alkoxy (1-3C), halogen or cyano; or Rg+Rr (R7 at position 7 of the indole group) represent a group -(CHs)^ wherein q has the value 2-4, and salts thereof. 2. A compound as claimed in claim i, wherein A represents a group or me Tomtit (1), (2) or (3), wherein the symbols rave the meanings given in claim 1. 3. A compound as claimed in claim 1, wherein X is the group having fonn fA (I), wherein Si=S3=S5=H, 84=0x0 and S2=CH3, m is 3, R5=R5=H, n is 0 or 1, and R7 is 5-fIuoro, and salts thereof. 4. Method for the preparation of compounds as claimed in claim 1, characterised in that a compound having formula (II) in which formulae the symbols having the meanings given in claim 1, and L is a so-coiled 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. Claims 1. The invention relates to a group of novel phenyipiperazine derivatives of the formula (I): wherein - Si is hydrogen or halogen, - S2 and S3 are independently hydrogen, alkyl (1-6C), phenyl or benzyl, - S4 represents two hydrogen atoms or an 0x0 group, - S5 is H or alkyl (1-4C), and - Y is C, O or S, wherein one of the dotted lines can represent a double bond, S, 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-CH3 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; - Re and Rg are independently H or alky! {1-3C); or Rs+Rg represent a group -(CH2)-p wherein p has the value 3-5, and - R7 is alkyl (1-3C), alkoxy (1-3C), halogen or cyano; or Rg+Rr (R7 at position 7 of the indole group) represent a group -(CHs)^ wherein q has the value 2-4, and salts thereof. 2. A compound as claimed in claim i, wherein A represents a group or me Tomtit (1), (2) or (3), wherein the symbols rave the meanings given in claim 1. 3. A compound as claimed in claim 1, wherein X is the group having fonn fA (I), wherein Si=S3=S5=H, 84=0x0 and S2=CH3, m is 3, R5=R5=H, n is 0 or 1, and R7 is 5-fIuoro, and salts thereof. 4. Method for the preparation of compounds as claimed in claim 1, characterised in that a compound having formula (II) in which formulae the symbols having the meanings given in claim 1, and L is a so-coiled 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.

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