SULFONAMIDE SUBSTITUTED BENZYLAMINE DERIVATIVES AND THEIR USE AS MEDICAMENTS

Abstract: A pharmaceutical compound of formula (I) in which the aminosulfonyl group is attached at the 3- or 4-position, and in which R<1> is hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl or optionally substituted phenyl-C1-4 alkyl, R<2> is C1-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, optionally substituted phenyl-C1-4 alkyl or -(CH2)2NR<5>R<6> where R<5> and R<6> are each hydrogen or C1-6 alkyl, and R<3> and R<4> are each C1-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, C3-6 alkenyl, optionally substituted phenyl or optionally substituted phenyl-C1-4 alkyl, or R<1> and R<2>, or R<3> and R<4>, or R<5> and R<6>, together with the nitrogen atom to which they are attached, form a carbocyclic group containing 4 to 7 carbon atoms optionally substituted with one to three methyl or ethyl groups and optionally containing an oxygen atom or a further nitrogen atom, said carbocyclic group being optionally fused to an optionally substituted phenyl group; or a salt thereof.

Description: SULFONAMIDE SUBSTITUTED BENZYLAMINE DERIVATIVES AND THEIR USE AS MEDICAMENTS This invention relates to novel chemical compounds and their use as pharmaceuticals. It is well known that chemical compounds which modulate the activity of neuronal calcium channels are potentially useful in treating disorders of the central nervous system. 10 The compounds of the invention have the following general formula: R 3 (I) in which the aminosulfonyl group is attached at the 3- or 4-position, and in which R is hydrogen, C]__g alkyl, C3_ ] _Q cycloalkyl, C3_ ] _Q cycloalkyl-C ] __4 alkyl or optionally substituted phenyl- C]__4 alkyl, R.2 is C__g alkyl, C3_IQ cycloalkyl, C3_IQ cycloalkyl- Cι__4 alkyl, optionally substituted phenyl-C ] __4 alkyl or -(CH2)2NR 5 R 6 where R 5 and R 6 are each hydrogen or Cι_5 alkyl, and R3 and R 4 are each C _5 alkyl, C3_IQ cycloalkyl, C3_χo cycloalkyl-C__4 alkyl, 03. alkenyl, optionally substituted phenyl or optionally substituted phenyl-C ] __4 alkyl, or R 1 and R 2 ; or R^ and R 4 t or R 5 and R^ , together with the nitrogen atom to which they are attached, form a carbocyclic group containing 4 to 7 carbon atoms optionally substituted with one to three methyl or ethyl groups and optionally containing an oxygen atom or a further nitrogen atom, said carbocyclic group being optionally fused to an optionally substituted phenyl group; or a salt thereof. The compounds of the invention have been found to be active in tests that show modulation of voltage- dependent calcium channels, and are thus indicated for use in the treatment of diseases in which such modulation is beneficial, in particular disorders of the central nervous system. Thus, the invention includes a method of treating a disorder of the central nervous system, which comprises administering an effective amount of a compound of formula (I) , or a pharmaceutically acceptable salt thereof . The invention also includes the use of a compound of formula (I) , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder of the central nervous system. The invention also includes the use of a compound of formula (I) , or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disorder of the central nervous system. In the above formula (I), a C]__ alkyl group includes methyl, ethyl, propyl, isopropyl, butyl, tert. butyl and hexyl, and is preferably methyl or ethyl. A substituted phenyl group is phenyl substituted with one or more, for example one to three, substituents selected from, for example C]__4 alkyl, especially methyl, Cχ_4 alkoxy, especially methoxy and ethoxy, hydroxy, nitro, cyano, halo, especially chloro or fluoro, trihalomethyl , especially trifluoromethyl, carboxy and C]__4 alkoxy- carbonyl . A halo atom is preferably chlorine, bromine or fluorine. A substituted phenyl group preferably has one to three substituents selected from hydroxy, C^_4 alkyl, halo, nitro and trifluoromethyl . An optionally substituted phenyl-C]__4 alkyl group is preferably of the formula R-(CH2) n - where R is optionally substituted phenyl and n is 1 to 4, but the linking chain can also be branched alkylene. A ^ - ± Q cycloalkyl group is preferably, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and these groups may optionally be substituted by one or two C]__4 alkyl, especially methyl, substituents. A C3_ o cycloalkyl- C]__4 alkyl group is one such cycloalkyl group attached to a Cι_4 alkyl, and is preferably of the formula R-(CH2) n - where R is cycloalkyl and n is 1 to 4. When R3 or R 4 is C]__g alkyl it is preferably ^ - ζ alkyl. The groups R 1 and R 2 , R 3 and R 4 , and R 5 and R 6 , can form a carbocyclic ring with the nitrogen to which they are attached and optionally also contain an oxygen atom or an additional nitrogen. Preferred examples, including the nitrogen of the amino sulfonyl group, are pyrrolidino, piperazino, morpholino and especially 3 , 5-dimethylpiperidino . A particular group of compounds of the invention is one of formula (I) in which R 1 , R2 , R3 and R4 are each Cι_g alkyl, C3_IQ cycloalkyl, C3_]_Q cycloalkyl-Ci-4 alkyl or optionally substituted phenyl-Cι_4 alkyl, and R^ can in addition be hydrogen, or R^ and R 2 , or R 3 and R^ together with the nitrogen atom to which they are attached, form a carbocyclic group as defined above. In a preferred group of compounds R^, R 2 , R3 and R^ are each Cι_5 alkyl, C3_IQ cycloalkyl, C3_I_Q cycloalkyl-C__4 alkyl or optionally substituted phenyl-C__4 alkyl, and R! is in addition hydrogen. It is preferred that R^ is hydrogen. Furthermore, R 3 and R^ , which can be the same or different, are preferably C]__4 alkyl. It is further preferred that R 2 is optionally substituted phenyl-Cι_4 alkyl. A further preferred group of compounds is one of formula (I) in which R 2 is - (CH 2 ) 2NR 5 R 6 . A further preferred group of compounds is one of formula (I) in which R 3 or R^ is C3_ alkyl or when R 3 and R^ are taken together with the nitrogen atom they form a piperidine ring which is substituted at the 3- and/or 5-positions with one or two methyl or ethyl substituents. It will be appreciated that the compounds of the invention can contain one or more asymmetric carbon atom which gives rise to enantiomers . The compounds can be prepared as racemates or can be made from enantiomeric intermediates. Both racemates and enantiomers form part of the present invention. It will also be understood that salts of the compounds of the invention can be prepared and such salts are included in the invention. They can be any of the well known acid addition salts. Acid addition salts are preferably the pharmaceutically acceptable non-toxic addition salts with suitable acids, such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids, or with organic acids, such as organic carboxylic acids, for example glycollic, maleic, fumaric, malic, oxalic, tartaric, citric, salicylic or o-acetoxybenzoic acids, or organic sulfonic acids, methane sulfonic, 2-hydroxyethane sulfonic, toluene-p-sulfonic or naphthalene-2-sulfonic acids . In addition to pharmaceutically-acceptable salts, other salts are included in the invention. They may serve as intermediates in the purification of compounds or in the preparation of other, for example pharmaceutically- acceptable, salts, or are useful for identification, characterisation or purification. The invention includes a process for producing the compounds of formula (I) above which comprises reducing a compound of the fomula: R R 3 (II) The reaction is preferably carried out in an organic solvent, for example, at a temperature of 0° C. to 100° C, employing a reducing agent, for example lithium aluminium hydride . Compounds of formula (II) can readily be prepared by conventional methods, for example, by reacting a compound of the formula: (III) where X is a leaving group such as, for example, halo or hydroxy, with an amine of the formula HNR^R 2 . The reaction is preferably carried out in an organic solvent such as, for example, chloroform or acetonitrile, at a temperature of from 0° C. to 100° C. such as, for example, ambient temperature. Intermediate compounds of formula (III) are known in the art and can be readily prepared by known methods. When an acid halide is employed (X is halo such as, for example, chloro) , the reaction is preferably carried out in the presence of a solid phase scavenger to absorb the acid liberated by the reaction. When the free acid is employed (X is hydroxy) , a condensing reagent such as, for example, dimethylaminopropyl-ethylcarbodiimide can be employed. A further route to the compounds of the invention, which is also included in the invention, involves the reduction of the imine corresponding to the compound of formula (III) : R 1 R 3 (iv) employing a reducing agent as, for example, sodium borohydride. Compounds of formula (IV) can readily be prepared by reacting an amine of formula R!R 2 NH with the appropriate benzaldehyde derivative, which can, in its turn, be prepared by reducing the corresponding benzoic acid derivative to the alcohol, followed by oxidation to the required benzaldehyde intermediate . Amine reactants of the formula H R 1 R 2 are well known and can be readily prepared by known methods. Those in which R 2 is -(CH2)2 NR ^ R ^ can, for example, be prepared by reductive amination, that is, by reacting the appropriate diamine with an aldehyde in reducing conditions . Alternatively, compounds of formula (I) in which R 2 is -(CH2)2 NR 5R6 can be prepared by alkylation of the corresponding compound of formula (I) in which R^ is hydrogen. As mentioned above, the compounds of the invention are active in tests that indicate their utility in the treatment of diseases of the central nervous system. The compounds modulate the activity of calcium channels and, in particular, they block voltage sensitive calcium channels as determined in a test based on Boot J. R. , et al . , Specificity of autoantibodies in the Lambert- Eaton Myasthenic Syndrome, Ann NY Acad. Sci. (1997), in which measurements of calcium flux using calcium sensitive dyes are made. Compounds described in the following Examples were found to inhibit voltage- dependent calcium channels in cloned human cell lines expressing specific voltage-dependent calcium channels with an IC 50 of less than 10 μM. The compounds of the invention are thus indicated for use in the treatment of anoxia, ischaemia, stroke and heart failure, migraine, diabetes, cognitive impairment, pain, epilepsy, traumatic head or spinal injury, AIDS related dementia and blindness, amnesia, neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases and age-related memory disorders, Down's syndrome, mood disorders, drug or alcohol addition withdrawal, nausea from chemotherapy, and carbon monoxide or cyanide poisoning. The invention also includes a pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier in association with the compound of the invention or a pharmaceutically acceptable salt or ester thereof . The compound may be administered by various routes, for example by the oral or rectal route, topically or parenterally, for example by injection or infusion, being usually employed in the form of a pharmaceutical composition. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, and/or enclosed within a carrier which may, for example, be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient or medium for the active ingredient. Thus, the composition may be in the form of tablets, lozenges, sachets, cachets, elixirs, suspensions, ointments containing, for example, up to 10% by weight of the compound, soft and hard gelatin capsules, suppositories, injection solutions and suspensions and sterile packaged powders. Some examples of suitable carriers are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propyl- hydrobenzoate, talc magnesium stearate and mineral oil. The compositions of the injection may, as is well known in the art, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient. Where the compositions are formulated in unit dosage form, it is preferred that each unit dosage form contains from 5 mg to 500 mg. The term 'unit dosage form' refers to physically discrete units suitable as unit dosages for human subjects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. The active compound is effective over a wide dosage range and, for example, dosages per day will normally fall within the range of from 0.5 to 300 mg/kg, more usually in the range of from 5 to 100 mg/kg. However, it will be understood that the amount administered will be determined by the physician in the light of the relevant circumstances including the conditions to be treated, the choice of compound to be administered and the chosen route of administration, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. The invention is illustrated by the following Preparations and Examples . EXAMPLE 1 4- [ (N,N-di-n-propylamino) sulfonyl] -benzoic acid To a stirred solution of di-n-propylamine (3.03 g, 0.03 mole) in dry tetrahydrofuran (20 ml) at 0° C. (ice/salt bath) , was added 4-chlorosulfonylbenzoic acid (2.2 g, 0.01 mole). Stirring was continued for 1 hour. Ice water was added cautiously and the reaction made acid with 2NHC1. The 4- [ (N,N-di-n- propylamino) sulfonyl] -benzoic acid was collected by filtration as a white solid which was dried in vacuo at 40° C. EXAMPLE 2 4- [ (N-di-n-propylamino) sulfonyl] -N-4-methoxybenzyl- benzamide To a solution of 4- [ (N, N-di-n-propylamino) sulfonyl] - benzoic acid (2.85 g, 0.01 mole) in dry dichloromethane (ml) at 0° C. was added oxalyl chloride (2.54 g, 0.02 mole) and dimethylformamide (4 drops). The reaction mixture was stirred for 2 hours . The reaction was evaporated to dryness in vacuo . The resulting acid chloride was added to a stirred solution of p-methoxybenzylamine (1.51 g, 0.011 mole) and triethylamine (1.11 g, 0.011 mole) in dry tetrahydrofuran (25 ml) at 0-5° C. After stirring for 4 hours the reaction was poured into ice water and extracted with ethyl acetate. The solvent was washed with brine, dried and evaporated to dryness in vacuo . Chromatography on flash silica using 10% ethyl acetate/dichloromethane gave 4-{ (N,N-di-n- propylamino) sulfonyl] -N-4-methoxybenzyl-benzamide as a white solid. M.p. 132-134° C. EXAMPLE 3 N, N-di-n-propyl-4- { [ ( 4-methoxybenzyl) amino] methyl} benzenesulfonamide To a stirred solution of 4- [ (N,N-di-n- propylamino) sulfonyl] -N-4-methoxybenzyl-benzamide (1.87g, 4.62mmole) in dry ether (50ml) was added a solution of 2M lithium aluminium hydride in tetrahydrofuran (4.63ml, 9.24mmole) . The reaction was heated at reflux for 2 hours. After cooling to room temperature water (1ml) was added dropwise with caution followed by 2NNaOH (lml) . When gas evolution ceased the reaction mixture was filtered through a pad of celite which was well washed with ether. After removal of the solvent in- vacuo the product was purified by chromatography on flash silica eluting with 10% methanol/ethyl acetate. The resulting amine was converted to the maleic acid salt and re-crystallised from ethanol/ether to give N, N- di-n-propyl-4-{ [ (4-methoxybenzyl) amino]methyl} benzenesulfonamide maleate. mp. 133-135°C Similarly prepared were: N, N-di-n-propyl-3 - { [ (4-methoxybenzyl) amino] methyl} benzenesulfonamide maleate. mp. 160-162°C N, N-di-n-propyl-4- { [ (3 , 4-dimethoxyphenethyl) amino]methyl}benzenesulfonamide maleate. mp. 130-132°C N- (3 , 3-dimethylpiperidino) -3- { [ (4-fluorobenzyl) amino]methyl}benzenesulfonamide maleate. mp. 169-171°C N- (3 , 3-dimethylpiperidino) -4-{ [ (4-fluorobenzyl) amino] methyl}benzenesulfonamide maleate. mp. 196-198°C N, W-di-n-propyl-3-{ [ (4-fluorobenzyl) amino]methyl} benzenesulfonamide maleate. mp. 168-170°C N-pheny1-W-n-propy1-4- { [dimethylamino] methyl} benzenesulfonamide maleate. mp. 154-156°C N- (3, 3-dimethylpiperidino) -3-{ [ (4-fluorobenzyl) -N- methylamino]methyl}benzenesulfonamide maleate. Mass spectrum:MH + =405 (TSP+) N- (3, 3-dimethylpiperidino) -3-{ [ (4-fluorobenzyl) -N- benzylamino]methyl}benzenesulfonamide maleate. mp. 183- 185°C N-phenyl-N-methyl-3 - { [ (4-fluorobenzyl) amino] methyl} benzenesulfonamide maleate. mp. 194-196°C N-pheny1 -N-n-buty1-4- { [hexylamino] methyl} benzenesulfonamide maleate. mp. 106-108°C N- (3-ethylpiperidino) -3-{ [ (4-fluorobenzyl) amino] methyl}benzenesulfonamide maleate. mp. 140-142°C N- (3, 3-dimethylpiperidino) -3- { [ (cyclohexylmethyl) amino]methyl}benzenesulfonamide hydrochloride. mp. 147- 149°C N- (3-methylpiperidino) -4-{ [ ( 4-chlorophenethy1) amino] methyl}benzenesulfonamide maleate. mp. 176-178°C N- (3-methylpiperidino) -4- { [ (4-chlorophenethyl) -N- methylamino]methyl}benzenesulfonamide maleate. mp. 168- 170°C 3-{ [ [2- (dimethylamino) ethyl] (4-fluorobenzyl) amino]methyl} -N-3 , 3-dimethylpiperidino- benzenesulfonamide maleate as an oil. Mass spectrum(MH + =462 (10%) ) (TSP+) 3- {[ [2- (dimethylamino) ethyl] (cyclohexylmethyl) amino] methyl} -N-3 , 3-dimethylpiperidino- benzenesulfonamide maleate. mp. 149-151°C EXAMPLE 4 4-{ [ [2- (piperidino) ethyl] (2- [3, 4- dimethoxy] phenylethyl) amino] methyl} -N, N-di-n- propylbenzene sulfonamide dihydrochloride To solution of N, N-di-n-propyl-4- { [ (3 , 4- dimethoxyphenethyl) amino]methyl}benzene sulfonamide (550 mg, Immole) in dry acetonitrile (lOOml) was added sodium carbonate ( 440mg, 4.4mmole), potassium iodide (166mg, Immole) and 2-chloroethylpiperidine hydrochloride (184mg, Immole) . The reaction was stirred and heated at reflux for 18 hours. The reaction was poured into ice water and extracted with ethyl acetate, washed with brine, dried and evaporated to dryness in-vacuo . Chromatography on flash silica by elution with 10%methanol/dichloromethane gave 4-{[[2- (piperidino) ethyl] (2- [3 , 4-dimethoxy]phenylethyl) amino] methyl } -N, N-di-n-propylbenzenesulfonamide which was crystallised as its dihydrochloride salt. mp. 135-137°C EXAMPLE 5 N- { 3 - [ (3, 3-dimethylpiperidin-l-yl) sulfonyl] benzyl } -N- (4- methylbenzyl ) amine A mixture of a 0.15 M solution of 3— [ (3,3- dimethylpiperidin-1-yl) sulfonyl] benzaldehyde in methanol (0.25 ml) and a 0.1 M solution of 4-methylbenzylamine in methanol (0.25 ml) was stirred at room temperature for 1 hour. A 0.15 M solution of sodium borohydride in methanol (0.25 ml) was added and stirring continued for a further 16 hours. The mixture was then applied to a methanol-washed 500 mg SCX solid phase extraction (SPE) cartridge and washed through with methanol (2.5 ml). The cartridge was then eluted with a 2 M solution of ammonia in methanol (2.5 ml) . The eluate was vacuum evaporated to give the required product. (TS-MS: m/z 387, [M+H] + ). The following compounds were similarly prepared (mass spectrum values are given in brackets) . N- { 3- [ (3, 3-dimethylpiperidin-l-yl) sulfonyl] benzyl } -N- [3- (4-methylpiperazin-l-yl) propyl] amine (423 ) N-{3- [ (3, 3-dimethylpiperidin-l-yl) sulfonyl] benzyl} -N- (3- morpholin-4-ylpropyl) amine (410) N- (4-chlorobenzyl) -N-{3- [ (3, 3-dimethylpiperidin-l- yl) sulfonyl] benzyl}amine (407/408) N- (cyclohexylmethyl) -N-{3- [ (3 , 3-dimethylpiperidin-l- yl) sulfonyl] benzyl}amine (379) N-{3- [ (3 , 3-dimethylpiperidin-l-yl) sulfonyl] benzyl } -N- [3- (lE-imidazol-1-yl) propyl] amine (391) N-butyl-N-{3- [ (3, 3-dimethylpiperidin-l- yl) sulfonyl] benzyl}amine (339) N-(tert-butyl)-N-{3- [ (3 , 3-dimethylpiperidin-l- yl) sulfonyl] benzyl}amine (339) N- (2-chlorobenzyl) -N-{3- [ (3 , 3-dimethylpiperidin-l- yl) sulfonyl] benzyl}amine (407/408) N- (4-chlorophenethyl) -N-{3- [ (3 , 3-dimethylpiperidin-l- yl) sulfonyl] enzyl}amine (421/422) N- (2-chlorophenethyl) -N-{3- [ (3 , 3-dimethylpiperidin-l- yl) sulfonyl] benzyl}amine (421/422) N- (2 , 4-dichlorobenzyl) -N-{3- [ (3 , 3-dimethylpiperidin-l- yl) sulfonyl] benzyl} amine (442) N-{3- [ (3 , 3-dimethylpiperidin-l-yl) sulfonyl] benzyl} -N- isopentylamine (353) N-{3- [ (3 , 3-dimethylpiperidin-l-yl) sulfonyl] benzyl } -N- (3- methoxypropyl) amine (355) N-{3- [ (3 , 3-dimethylpiperidin-l-yl) sulfonyl] benzyl }-N- (2- methylbenzyl) amine (387) N-{3- [ (3 , 3-dimethylpiperidin-l-yl) sulfonyl] benzyl } -N- (3- methylcyclohexyl) amine (379) N-{3- [ (3 , 3-dimethylpiperidin-l-yl) sulfonyl] benzyl} -N- hexylamine (367) N-{3- [ (3 , 3-dimethylpiperidin-l-yl) sulfonyl] benzyl }-N- propylamine (325) N-{3- [ (3 , 3-dimethylpiperidin-l-yl) sulfonyl] benzyl }-N- (4- methylphenethyl) amine (401) N- { 3 - [ (3 , 3-dimethylpiperidin-l-yl) sulfonyl] benzyl} -N- [3- (trifluoromethyl) benzyl] amine (441) N- { 3 - [ (3 , 3-dimethylpiperidin-l-yl) sulfonyl] benzyl} -N- [3- (trifluoromethyl ) phenethy1] amine (455) EXAMPLE 6 1- ( {3- [ (4-benzylpiperidin-l-yl)methyl]phenyl}sulfonyl) - 3 , 3-dimethylpiperidine A mixture of a 0.15 M solution of 3- [(3,3- dimethylpiperidin-1-yl) sulfonyl] benzaldehyde in dichloromethane (0.25 ml), a 0.1 M solution of 4- benzylpiperidine in dichloromethane (0.25 mi) and a 0.15 M solution of sodium tri-acetoxyborohydride in dichloromethane (0.25 ml) was stirred at room temperature for 22 hours. Methanol (1 ml) was added and the mixture applied to a methanol-washed 500 mg SCX solid phase extraction (SPE) cartridge and washed through with methanol (2.5 ml). The cartridge was then eluted with a 2 M solution of ammonia in methanol (2.5 ml) . The eluate was vacuum evaporated to give the required product. (TS-MS: m/z 441, [M+HD . The following compounds were similarly prepared (mass spectrum values are given in brackets) . 2- (butyl{3- [ (3, 3-dimethylpiperidin-l- yl) sulfonyl] benzyl}amino) ethan-1-ol (383) 2- (benzyl{3- [ (3 , 3-dimethylpiperidin-l- yl) sulfonyl] benzyl}amino) ethan-1-ol (417) iV-{3- [ (3, 3-dimethylpiperidin-l-yl) sulfonyl] benzyl } -N, N- bis (2-methoxyethyl)amine (399) 1- (3, 4-dichlorophenyl) -4- {3- [ (3, 3-dimethylpiperidin-l- yl) sulfonyl] benzyl}piperazine (497) N- { 3- [ (3 , 3-dimethylpiperidin-l-yl) sulfonyl] benzyl } -N- ethyl-N- (pyridin-4-ylmethyl) amine (402) l-{3- [ (3, 3-dimethylpiperidin-l-yl) sulfonyl] benzyl} -4- (4- fluorophenyl)piperazine (446) 4-{3- [ (3 , 3-dimethylpiperidin-l- yl) sulfonyl] benzyl}piperazine-1-carbaldehyde (380) 4-{3- [ (3 , 3-dimethylpiperidin-l- yl) sulfonyl]benzyl}morpholine (353 ) 1- [4- (4-{3- [ (3 , 3-dimethylpiperidin-l- yl) sulfonyl] benzyl}piperazin-1-yl ) phenyl] ethan-1-one (470) 3 , 3-dimethyl-l- { [3- (pyrrolidin-1- ylmethyl) phenyl] sulfonyl}piperidine (337) 2-{3- [ (3 , 3-dimethylpiperidin-l-yl) sulfonyl] benzyl}- 1, 2, 3 , 4-tetrahydroisoquinoline (399) N- { 3- [ (3 , 3-dimethylpiperidin-l-yl) sulfonyl] benzyl } -N, N- dipropylamine (367) l-benzhydryl-4-{3- [ (3 , 3-dimethylpiperidin-l- yl) sulfonyl] benzyl}piperazine (518) N- { 3 - [ (3 , 3-dimethylpiperidin-l-yl) sulfonyl] benzyl} -N- (2- methoxyethy1 ) -N-propylamine (383) EXAMPLE 7 l-{3- [ (3 , 3-dimethylpiperidin-l- yl) sulfonyl] benzyl}piperidine-4-carboxamide A mixture of a 0.15 M solution of 3- [(3, 3- dimethylpiperidin-1-yl) sulfonyl] benzaldehyde in methanol (0.25 ml), a 0.1 M solution of piperidine-4-carboxamide in methanol/acetic acid 4:1 v/v (0.25 ml) and a 0.15 M solution of sodium cyanoborohydride in methanol (0.25 ml) was stirred at room temperature for 18 hours. The mixture applied to a methanol-washed 500 mg SCX solid phase extraction (SPE) cartridge and washed through with methanol (2.5 ml) . The cartridge was then eluted with a 2 M solution of ammonia in methanol (2.5 ml) and the eluate vacuum evaporated. The residue was dissolved in chloroform (2 ml) and the solution added to isocyanatomethyl-polystyrene (loading 1 mmole/g, 100 mg) . The suspension was shaken at room temperature for 16 hours, then filtered. The resin was washed with chloroform (2 x 2 ml) and the combined filtrates vacuum evaporated to give the required product. (TS-MS: m/z 394, [M+H] + ). The following Examples illustrate typical formulations containing a compound of the invention. EXAMPLE 8 Tablets each containing 10 mg of active ingredient are made UD as follows: Active ingredient 10 mg Starch 160 mg Microcrystalline cellulose 100 mg Polyvinylpyrrolidone (as 10% solution in water) 13 mg Sodium carboxymethyl starch 14 mg Magnesium stearate 3 mg Total 300 mg The active ingredient, starch and cellulose are mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders and passed through a sieve. The granules so produced are dried and re-passed through a sieve. The sodium carboxymethyl starch and magnesium stearate are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 300 mg. EXAMPLE 9 Capsules each containing 20 mg of active ingredient are made as follows : Active ingredient 20 mg Dried starch 178 mg Magnesium stearate 2 mg Total 200 mg The active ingredient, starch and magnesium stearate are passed through a sieve and filled into hard gelatine capsules in 200 mg quantities. EXAMPLE 10 Capsules each containing 20 mg of medicament are made as follows : Active ingredient 20 mg Lactose 171 mg Sodium lauryl sulphate 2 mg Sodium starch glycollate 6 mg Magnesium stearate 1 mg 200 mg The active ingredient, lactose, sodium lauryl sulphate and sodium starch glycollate are mixed thoroughly. The blend is mixed with the magnesium stearate and filled into hard gelatine capsules in 200 mg quantities. EXAMPLE 11 Tablets each containing 20 mg and medicaments are made as follows: Active ingredient 20 mg Lactose 103 mg Microcrystalline cellulose 150 mg Hydroxypropylmethylcellulose 15 mg Sodium starch glycollate 9 mg Magnesium stearate 3 mg 300 mg The active ingredient, lactose, microcrystalline cellulose, sodium starch glycollate and hydroxypropylmethylcellulose are passed through a sieve and blended together. Water is added to the blended powders to form a damp mass. The damp mass is passed through a coarse screen, dried, then re-screened. The dried granules are mixed with the magnesium stearate and compressed into tablets of 300 mg weight.

Claims: CLAIMS 1. A compound of the formula R 3 (I) in which the aminosulfonyl group is attached at the 3- or 4-position, and in which R! is hydrogen, C]__ alkyl, C3_]_Q cycloalkyl, C3_IQ cycloalkyl-C]__4 alkyl or optionally substituted phenyl-C]__4 alkyl, R 2 is C]__ alkyl, C3_IQ cycloalkyl, C3_ o cycloalkyl-C]__4 alkyl, optionally substituted phenyl-C ] __4 alkyl or -(CH2)2N 5 R β where R 5 and R 6 are each hydrogen or Cχ_g alkyl, and R3 and R 4 are each C]_-g alkyl, C3_IQ cycloalkyl, C3_ιo cycloalkyl-C]__4 alkyl, C3_g alkenyl, optionally substituted phenyl or optionally substituted phenyl-C]__4 alkyl, or R 1 and R 2 or R 3 and R 4 or R 5 and R 6 , together with the nitrogen atom to which they are attached, form a carbocyclic group containing 4 to 7 carbon atoms optionally substituted with one to three methyl or ethyl groups and optionally containing an oxygen atom or a further nitrogen atom, said carbocyclic group being optionally fused to an optionally substituted phenyl group; or a salt thereof. A compound according to Claim 1 in which R^ , R 2 , R 3 and R 4 are each C]__g alkyl, C3_χo cycloalkyl, C3_-[_o cycloalkyl-C]__4 alkyl or optionally substituted phenyl-C ] __4 alkyl, and R^ can in addition be hydrogen, or R^ and R , or R 3 and R 4 together with the nitrogen atom to which they are attached, form a carbocyclic group. 3. A compound according to Claim 2 in which R^, R 2 , R 3 and R 4 are each C]__g alkyl, C3_]_Q cycloalkyl, C3_-[o cycloalkyl-C]__4 alkyl or optionally substituted phenyl-Cι_4 alkyl, and R^ can in addition be hydrogen . 4. A compound according to Claim 3 in which R^ is hydrogen, R 2 is optionally substituted phenyl-Cχ_4 alkyl and R 3 and R 4 are Cι_ alkyl. 5. A compound according to Claim 1 in which R 2 is -(CH 2 )2NR 5 R β . 6. A compound according to Claim 1 or 5 in which R 3 or R 4 is C3_g alkyl or when R 3 and R 4 are taken together with the nitrogen atom they form a piperidine ring which is substituted at the 3- and/or 5-positions with one or two methyl or ethyl substituents . . A pharmaceutical formulation comprising a compound according to any of Claims 1 to 6 or a pharmaceutically acceptable salt thereof, together with a diluent or carrier therefor. 8. A compound according to any of Claims 1 to 6, for use as a pharmaceutical . 9. Use of a compound according to any of Claims 1 to 6, in the manufacture of a medicament for treating a disorder of the central nervous system. 10. A method of treating a disorder of the central nervous system which comprises administering an effective amount of a compound according to Claim 1, or a pharmaceutically acceptable salt thereof.

Inventors: MILUTINOVIC SANDRA GINETTE, SIMMONDS ROBIN GEORGE, TUPPER DAVID EDWARD, MILUTINOVIC, SANDRA, GINETTE, SIMMONDS, ROBIN, GEORGE, TUPPER, DAVID, EDWARD
Applicants: LILLY CO ELI, MILUTINOVIC SANDRA GINETTE, SIMMONDS ROBIN GEORGE, TUPPER DAVID EDWARD, ELI LILLY AND COMPANY LIMITED, MILUTINOVIC, SANDRA, GINETTE, SIMMONDS, ROBIN, GEORGE, TUPPER, DAVID, EDWARD
Application year: 2000
Main classification: C07C311
IPC codes: C07C311, C07D211, C07D213, C07D217, C07D521