GB2352240A - Novel sulphonamides useful in treating CNS disorders - Google Patents
Novel sulphonamides useful in treating CNS disorders Download PDFInfo
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Abstract
A pharmaceutical compound of the formula <EMI ID=1.1 HE=66 WI=36 LX=1284 LY=410 TI=CF> <PC>in which the aminosulfonyl group is attached at the 3- or 4-position, and in which<BR> R<SB>1</SB> is hydrogen, C<SB>1-6</SB> alkyl, C<SB>3-10</SB> cycloalkyl, C<SB>3-10</SB> cycloalkyl-C<SB>1-4</SB> alkyl or optionally substituted phenyl-C<SB>1-4</SB> alkyl,<BR> R<SP>2</SP> is C<SB>1-6</SB> alkyl, C<SB>3-10</SB> cycloalkyl, C<SB>3-10</SB> cycloalkyl-C<SB>1-4</SB> alkyl, optionally substituted phenyl-C<SB>1-4</SB> alkyl or -(CH<SB>2</SB>)<SB>2</SB>NR<SP>5</SP>R<SP>6</SP> where R<SP>5</SP> and R<SP>6</SP> are each hydrogen or C<SB>1-6</SB> alkyl, and<BR> R<SP>3</SP> and R<SP>4</SP> are each C<SB>1-6</SB> alkyl, C<SB>3-10</SB> cycloalkyl, C<SB>3-10</SB> cycloalkyl-C<SB>1-4</SB> alkyl, C<SB>3-6</SB> alkenyl, optionally substituted phenyl or optionally substituted phenyl-C<SB>1-4</SB> alkyl,<BR> or R<SP>1</SP> and R<SP>2</SP>, or R<SP>3</SP> and R<SP>4</SP>, or R<SP>5</SP> and R<SP>6</SP>, 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;<BR> or a salt thereof.
Description
PHARMACEUTICAL COMPOUNDS This invention relates to novel chemical
compounds and their use as pharmaceuticals. 5 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:
R1 R2 N I CH 2 3 // 0 4 S \ 0 N-R4 I R3 in which the aminosulfonyl group is attached at the 3or 4-position, and in which R1 is hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-CI-4 alkyl or optionally substituted phenyl- C1-4 alkyl, R2 is C1-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl- C1-4 alkyl, optionally substituted phenyl-Cl-4 alkyl or -(CH2)2 NR5R6 where R5 and R6 are each hydrogen or C1-6 alkyl, and R3 and R4 are each CI-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-Cl-4 alkyl, C3-6 alkenyl, optionally substituted phenyl or optionally substituted phenyl-CI-4 alkyl, or R1 and R2 I or R3 and R4 I or R5 and R6, 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. 5 The compounds of the invention have been found to be active in tests that show modulation of voltagedependent calcium channels, and are thus indicated for use in the treatment of diseases in which such modulation is beneficial, in particular diseases of the central nervous system.
In the above formula (1), a Cl-6 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 Cl-4 alkyl, especially methyl, Cl- 4 alkoxy, especially methoxy and ethoxy, hydroxy, nitro, cyano, halo, especially chloro, or fluoro, trihalomethyl, especially trifluoromethyl, carboxy and C1-4 alkoxycarbonyl. A halo atom is preferably chlorine, bromine or fluorine. A substituted phenyl group preferably has one to three substituents selected from hydroxy, Cl-4 alkyl, halo, nitro and trifluoromethyl. An optionally substituted phenyl-Cl-4 alkyl group is preferably of the formula R-(CH2)nwhere R is optionally substituted phenyl and n is 1 to 4, but the linking chain can also be branched alkylene. A C3-10 cycloalkyl group is preferably, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and these groups may optionally be substituted by one or two CI-4 alkyl, especially methyl, substituents. A C3-10 cycloalkylC1-4 alkyl group is one such cycloalkyl group attached to a C1-4 alkyl, and is preferably of the formula R-(CH2)n- where R is cycloalkyl and n is 1 to 4. When R3 or R4 is C1-6 alkyl it is preferably C3-6 alkyl.
The groups R1 and R2, R3 and R4, and R5 and R6, 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 R1, R2, R3 and R4 are each CI-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-Cl-4 alkyl or optionally substituted phenyl-Cl-4 alkyl, and Rl can in addition be hydrogen, or Rl and R2, or R3 and R4 together with the nitrogen atom to which they are attached, form a carbocyclic group as defined above.
In a preferred group of compounds R1, R2, R3 and R4 are each C1-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-Cl-4 alkyl or optionally substituted phenyl-Cl-4 alkyl, and Rl is in addition hydrogen.
It is preferred that R1 is hydrogen. Furthermore, R3 and R4, which can be the same or different, are preferably C1-4 alkyl. It is further preferred that R2 is optionally substituted phenyl-Cl-4 alkyl.
A further preferred group of compounds is one of formula (I) in which R2 is -(CH2)2 NR5R6.
A further preferred group of compounds is one of formula (I) in which R3 or R4 is C3-6 alkyl or when R3 and R4 are taken together with the nitrogen atom they form a piperidine ring which is substituted at the 3and/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 pharmaceuticallyacceptable, 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:
R1 I 0 J- R2 3 // 0 4 '// S \ 0 N-R4 I R3 The reaction is preferably carried out in an organic solvent, for example, at a temperature of 00 C. to 100' C., employing a reducing agent, for example lithium aluminium hydride. 15 Compounds of formula (II) can readily be prepared by conventional methods, for example, by reacting a compound of the formula:
0 X"- X 3 '/ 0 4 S 0 N R4 R3 where X is a leaving group such as, for example, halo or hydroxy, with an amine of the formula HNR1R2.
The reaction is preferably carried out in an organic solvent such as, for example, chloroform or acetonitrile, at a temperature of from 00 C. to 1000 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 5 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 10 formula (III):
R1 I R2 3 0 4 // S \ 0 N -R4 I R3 (IV) employing a reducing agent as, for example, sodium borohydride. Compounds of formula (IV) can readily be prepared by reacting an amine of formula R1R2NH 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. 5 Amine reactants of the formula HNR1R2 are well known and can be readily prepared by known methods. Those in which R2 is -(CH2)2NR5R6 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 R2 is -(CH2)2NR5R6 can be prepared by alkylation of the corresponding compound of formula (I) in which R1 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 IC50 Of less than 10 pM.
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 propylhydrobenzoate, 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. 5 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)sulfonyll-benzoic acid To a stirred solution of di-n-propylamine (3.03 g, 0.03 mole) in dry tetrahydrofuran (20 ml) at 00 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-npropylamino)sulfonyll-benzoic acid was collected by filtration as a white solid which was dried in vacuo at 400 C.
EXAMPLE 2
4-[(N-di-n-propylamino)sulfonyll-N-4-methoxybenzylbenzamide To a solution of 4-[(N,N-di-n-propylamino)sulfonyllbenzoic 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 dimethy1formamide (4 drops). The reaction mixture was stirred for 2 hours. The reaction was evaporated to dryness in vacuo. The resulting acid 5 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 0-50 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-npropylamino)sulfonyl]N-4-methoxybenzyl-benzamide as a white solid. M.p. 132-1340 C.
EXAMPLE 3
N,IV-di-n-propyl-4-{[(4-methoxybenzyl)aminolmethyl) benzenesulfonamide To a stirred solution of 4-[(N,N-di-n propylamino)sulfonyl]-N-4-methoxybenzyl-benzamide(l.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 (Iml). 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 invacuo 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,Ndi-n-propyl-4-([(4methoxybenzyl)aminolmethylI benzenesulfonamide maleate. mp. 133-135'C Similarly prepared were:
N,N-di-n-propyl-3-{[(4-methoxybenzyl)amino]methylI benzenesulfonamide maleate. mp. 160-162'C N,N-di-n-propyl-4-{[(3,4-dimethoxyphenethyl) amino]methyllbenzenesulfonamide maleate. mp. 130-132'C 20 N-(3,3dimethylpiperidino)-3-{[(4-fluorobenzyl) aminolmethyl}benzenesulfonamide maleate. mp. 169-171'C N-(3,3-dimethylpiperidino)-4-{[(4-fluorobenzyl) amino]methyl)benzenesulfonamide maleate. mp. 196-198'C N,N-di-n-propyl-3-([(4-fluorobenzyl)aminolmethyl) benzenesulfonamide maleate. mp. 168-1700C N-phenyl-N-n-propyl-4-{[dimethylamino]methyl) benzenesulfonamide maleate. mp. 154-1560C N-(3,3-dimethylpiperidino)-3{[(4-fluorobenzyl)-Nmethylaminolmethyllbenzenesulfonamide maleate. mass spectrum:MHI=405 (TSP+) 5 N-(3,3-dimethylpiperidino)-3-{[(4-fluorobenzyl)Nbenzylaminolmethyl)benzenesulfonamide maleate. mp. 183185('C N-phenyl-Nmethyl-3-{[(4-fluorobenzyl)amino]methyl) benzenesulfonamide maleate. mp. 194-1960C N-phenyl-N-n-butyl-4-{[hexylaminolmethylI benzenesulfonamide maleate. mp. 106-1080C N-(3-ethylpiperidino)-3-([(4-fluorobenzyl)aminoI methyl)benzenesulfonamide maleate. mp. 140-142'C N-(3,3dimethylpiperidino)-3-{[(cyclohexylmethyl) amino]methyl)benzenesulfonamide hydrochloride. mp. 147149"C N-(3methylpiperidino)-4-{[(4-chlorophenethyl)amino] methyl)benzenesulfonamide maleate. mp. 176-1780C N-(3-methylpiperidino)-4-([(4-chlorophenethyl)-Nmethylamino]methyl}benzenesulfonamide maleate. mp. 168- 1700C 3-{[[2-(dimethylamino)ethyl](4-fluorobenzyl) aminolmethyl)-N-3,3-dimethylpiperidino- benzenesulfonamide maleate as an oil. mass spectrum(MH+=462(10%)) (TSP+) 3-{[[2-(dimethylamino)ethyl](cyclohexylmethyl) aminolmethyl)-N-3,3dimethylpiperidinobenzenesulfonamide maleate. mp. 149-151'C EXAMPLE 4
4-([[2-(piperidino)ethyl](2-[3,4dimethoxylphenylethyl)aminolmethyll-N,Ndi-n10 propylbenzene sulfonamide dihydrochloride To solution of N,N-di-n-propyl-4-{[(3, 4dimethoxyphenethyl)aminolmethyl)benzene sulfonamide(550 mg, lmmole) in dry acetonitrile (100ml) was added sodium carbonate ( 440mg, 4.4mmole), potassium iodide (166mg, 1mmole) and 2-chloroethylpiperidine hydrochloride (184mg, lmmole). 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-dimethoxylphenylethyl)amino] methyll-N,N-di-n-propylbenzenesulfonamide which was crystallised as its dihydrochloride salt. mp. 135-137'C 19 - EXAMPLE 5
1V-(3-[(3,3-dimethylpiperidin-1-yl)sulfonyllbenzyl)-N-(45 methylbenzyl)amine A mixture of a 0.15 M solution of 3-[(3,3dimethylpiperidin-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-f3-[(3,3-dimethylpiperidin-1-yl)sulfonyl]benzyl}-N-[3(4-methylpiperazin-1-yl)propyllamine (423) N-f3-[(3,3-dimethylpiperidin-1-yl)sulfonyl]benzyl)-N-(3morpholin-4ylpropyl)amine (410) N-(4-chlorobenzyl)-N-f3-[(3,3-dimethylpiperidin-lyl)sulfonyllbenzyl)aLmine (407/408) N-(cyclohexylmethyl)-N-(3-[(3,3-dimethylpiperidinlyl)sulfonyl]benzyl)amine (379) N-(3-[(3,3-dimethylpiperidin-1-yl)sulfonyllbenzyl)-N-[3(lH-imidazol-1yl)propyllamine (391) N-butyl-N-f3-[(3,3-dimethylpiperidinlyl)sulfonyl]benzyl}amine (339) 15 N-(tert-butyl)-N-{3-[(3,3dimethylpiperidin-lyl)sulfonyllbenzyl)amine (339) N-(2-chlorobenzyl)-N-(3[(3,3-dimethylpiperidin-l20 yl)sulfonyllbenzyl)amine (407/408) N-(4-chlorophenethyl)-N-(3-[(3,3-dimethylpiperidinlyl)sulfonyllbenzyllamine (421/422) N-(2-chlorophenethyl)-N-(3-[(3,3-dimethylpiperidinlyl)sulfonyllbenzyl)amine (421/422) N-(2,4-dichlorobenzyl)-N-{3-[(3,3-dimethylpiperidin-l5 yl)sulfonyl]benzyllamine (442) N-(3-[(3,3-dimethylpiperidin-1-yl)sulfonyl]benzyl)-Nisopentylamine (353) N-f3-[(3,3-dimethylpiperidin-1-yl)sulfonyl]benzyl)-AT-(3methoxypropyl)amine (355) N-t3-[(3,3-dimethylpiperidin-1-yl)sulfonyllbenzyl)-N-(2methylbenzyl)amine (387) 15 N-{3-[(3,3-dimethylpiperidin-1-yl)sulfonyllbenzyl)-N(3methylcyclohexyl)amine (379) N-{3-[(3,3-dimethylpiperidin-1-yl)sulfonyllbenzyl)-N20 hexylamine (367) N-(3-[(3,3-dimethylpiperidin-1-yl)sulfonyllbenzyl)-Npropylamine (325) N-{3-[(3,3-dimethylpiperidin-1-yl)sulfonyljbenzyl}-N(4methylphenethyl)amine (401) N-t3-[(3,3-dimethylpiperidin-1-yl)sulfonyllbenzyl}-N[3(trifluoromethyl)benzyllamine (441) N-{3-((3,3-dimethylpiperidin-1-yl)sulfonyllbenzyl)-N[3(trifluoromethyl)phenethyllamine (455) EXAMPLE 6
1-({3-[(4-benzylpiperidin-1-yl)methyl]phenyl}sulfonyl)3,3dimethylpiperidine A mixture of a 0.15 M solution of 3-[(3,3 dimethylpiperidin-1-yl)sulfonyllbenzaldehyde in dichloromethane (0.25 ml), a 0.1 M solution of 4- benzylpiperidine in dichloromethane (0.25 ml) 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+H]+).
The following compounds were similarly prepared (mass spectrum values are given in brackets).
2-(butyl{3-[(3,3-dimethylpiperidin-l5 yl)sulfonyllbenzyl)amino)ethan-l-o1 (383) 2-(benzyl(3-[(3,3-dimethylpiperidin-lyl)sulfonyllbenzyl)amino)ethan-l-o1 (417) N-{3-[(3,3-dimethylpiperidin-1-yl)sulfonyllbenzyl)-N,Nbis(2methoxyethyl)amine (399) 1-(3,4-dichlorophenyl)-4-(3-[(3,3-dimethylpiperidinlyl)sulfonyl]benzyllpiperazine (497) 15 N-{3-[(3,3-dimethylpiperidin-1yl)sulfonyllbenzyl}-Nethyl-N-(pyridin-4-ylmethyl)amine (402) 1-(3-[(3,3-dimethylpiperidin-1-yl)sulfonyllbenzyl)-4-(420 fluorophenyl)piperazine (446) 4-{3-[(3,3-dimethylpiperidin-lyl)sulfonyl]benzyllpiperazine-lcarbaldehyde (380) 4-{3-[(3,3-dimethylpiperidin-lyl)sulfonyllbenzyllmorpholine (353) 1-[4-(4-{3-[(3,3-dimethylpiperidin-lyl)sulfonyllbenzyl)piperazin-1yl)phenyllethan-l-one (470) 5 3,3-dimethyl-l-{[3-(pyrrolidinlylmethyl)phenyllsulfonyl)piperidine (337) 2-{3-[(3,3-dimethylpiperidin-1-yl)sulfonyl]benzyl)1,2,3,4-tetrahydroisoquinoline (399) N-{3-[(3,3-dimethylpiperidin-1-yl)sulfonyllbenzyl)-N,Ndipropylamine (367) 1-benzhydryl-4-{3-[(3,3-dimethylpiperidin-l- yl)sulfonyl]benzyllpiperazine (518) N-{3-[(3,3-dimethylpiperidin-1-yl)sulfonyllbenzyl)-N-(2methoxyethyl)-Npropylamine (383) 20 EXAMPLE 7 1-{3-[(3,3-dimethylpiperidin-lyl)sulfonyllbenzyl)piperidine-4-carboxamide 25 A mixture of a 0.15 M solution of 3 - [ (3, 3dimethylpiperidin-1yl)sulfonyl]benzaldehyde in methanol (0.25 ml), a 0.1 M solution of piper idine - 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 up 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 15
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 5 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 20 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 (9)
1. A compound of the formula R1 / R2 N I CH2 3 0 4 S \ 0 N-R4 I H3 in which the aminosulfonyl group is attached at the 3- or 4-position, and in which R1 is hydrogen, Cl-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-Cl-4 alkyl or optionally substituted phenyl-Cl-4 alkyl, R2 is Cl-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-CI-4 alkyl, optionally substituted phenyl-CI-4 alkyl or -(CH2)2NR5R6 where R5 and R6 are each hydrogen or C1-6 alkyl, and R3 and R4 are each C1-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-Cl-4 alkyl, C3-6 alkenyl, optionally substituted phenyl or optionally substituted phenyl-Cl-4 alkyl, or RI and R2 I or R3 and R4, or R5 and R6, 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.
2. A compound according to Claim 1 in which R1, R2, R3 and.R4 are each C16 alkyl, C3-10 cycloalkylf C3-10 cycloalkyl-Cl-4 alkyl or optionally substituted phenyl-Cl-4 alkyl, and R1 can in addition be hydrogen, or R1 and R2, or R3 and R4 together with the nitrogen atom to which they are attached, form a carbocyclic group.
3. A compound according to Claim 2 in which Rl, R2, R3 5 and R4 are each C1-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-CI-4 alkyl or optionally substituted phenyl-CI-4 alkyl, and R1 can in addition be hydrogen.
4. A compound according to Claim 3 in which R1 is hydrogen, R2 is optionally substituted phenyl-CI-4 alkyl and R3 and R4 are C1-6 alkyl.
5. A compound according to Claim 1 in which R2 is 15 -(CH2)2NR5R6.
6. A compound according to Claim 1 or 5 in which R3 or R4 is C3-6 alkyl or when R3 and R4 are taken together with the nitrogen atom they form a 20 piperidine ring which is substituted at the 3and/or 5-positions with one or two methyl or ethyl substituents.
7. 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 disease of the central nervous system.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9916434A GB2352240A (en) | 1999-07-13 | 1999-07-13 | Novel sulphonamides useful in treating CNS disorders |
| EP00938940A EP1200397A1 (en) | 1999-07-13 | 2000-06-15 | Sulfonamide substituted benzylamine derivatives and their use as medicaments |
| AU54160/00A AU5416000A (en) | 1999-07-13 | 2000-06-15 | Sulfonamide substituted benzylamine derivatives and their use as medicaments |
| PCT/GB2000/002361 WO2001004087A1 (en) | 1999-07-13 | 2000-06-15 | Sulfonamide substituted benzylamine derivatives and their use as medicaments |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9916434A GB2352240A (en) | 1999-07-13 | 1999-07-13 | Novel sulphonamides useful in treating CNS disorders |
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| Publication Number | Publication Date |
|---|---|
| GB9916434D0 GB9916434D0 (en) | 1999-09-15 |
| GB2352240A true GB2352240A (en) | 2001-01-24 |
Family
ID=10857182
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| GB9916434A Withdrawn GB2352240A (en) | 1999-07-13 | 1999-07-13 | Novel sulphonamides useful in treating CNS disorders |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1200397A1 (en) |
| AU (1) | AU5416000A (en) |
| GB (1) | GB2352240A (en) |
| WO (1) | WO2001004087A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007118854A1 (en) * | 2006-04-13 | 2007-10-25 | Euro-Celtique S.A. | Benzenesulfonamide compounds and the use thereof |
| US8247442B2 (en) | 2006-03-29 | 2012-08-21 | Purdue Pharma L.P. | Benzenesulfonamide compounds and their use |
| US8399486B2 (en) | 2007-04-09 | 2013-03-19 | Purdue Pharma L.P. | Benzenesulfonyl compounds and the use thereof |
| US8765736B2 (en) | 2007-09-28 | 2014-07-01 | Purdue Pharma L.P. | Benzenesulfonamide compounds and the use thereof |
| US8791264B2 (en) | 2006-04-13 | 2014-07-29 | Purdue Pharma L.P. | Benzenesulfonamide compounds and their use as blockers of calcium channels |
| US9000174B2 (en) | 2004-10-14 | 2015-04-07 | Purdue Pharma L.P. | 4-phenylsulfonamidopiperidines as calcium channel blockers |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| AU2001258771A1 (en) * | 2000-05-19 | 2001-11-26 | Takeda Chemical Industries Ltd. | -secretase inhibitors |
| WO2004058679A2 (en) | 2002-12-20 | 2004-07-15 | Migenix Corp. | Ligands of adenine nucleotide translocase (ant) and compositions and methods related thereto |
| GB0420424D0 (en) * | 2004-09-14 | 2004-10-20 | Ionix Pharmaceuticals Ltd | Therapeutic compounds |
| WO2006038594A1 (en) * | 2004-10-04 | 2006-04-13 | Ono Pharmaceutical Co., Ltd. | N-type calcium channel inhibitor |
| CA2871534A1 (en) * | 2012-04-27 | 2013-10-31 | Glaxo Group Limited | Novel compounds |
| CN107033038B (en) * | 2017-05-03 | 2019-03-22 | 北京康正康仁生物科技有限公司 | The preparation method of probenecid |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08208595A (en) * | 1994-11-21 | 1996-08-13 | Takeda Chem Ind Ltd | Sulfonamide compound, its production and agent |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE726386C (en) * | 1939-01-28 | 1942-10-13 | Ig Farbenindustrie Ag | Process for the preparation of sulfonamide compounds |
| US3954830A (en) * | 1972-04-28 | 1976-05-04 | American Aniline Products, Inc. | Yellow methine dyes for hydrophobic textile material |
| IE914218A1 (en) * | 1991-09-11 | 1993-03-24 | Mcneilab Inc | Novel 4-arylpiperazines and 4-arylpiperidines |
| WO1993013079A1 (en) * | 1991-12-20 | 1993-07-08 | Agouron Pharmaceuticals, Inc. | Antifolate quinazolines |
-
1999
- 1999-07-13 GB GB9916434A patent/GB2352240A/en not_active Withdrawn
-
2000
- 2000-06-15 WO PCT/GB2000/002361 patent/WO2001004087A1/en not_active Application Discontinuation
- 2000-06-15 EP EP00938940A patent/EP1200397A1/en not_active Withdrawn
- 2000-06-15 AU AU54160/00A patent/AU5416000A/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08208595A (en) * | 1994-11-21 | 1996-08-13 | Takeda Chem Ind Ltd | Sulfonamide compound, its production and agent |
Non-Patent Citations (1)
| Title |
|---|
| WPI Abstract Accession No 1996-421952/42 & JP8208595A (TAKEDA CHEM IND LTD) * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9000174B2 (en) | 2004-10-14 | 2015-04-07 | Purdue Pharma L.P. | 4-phenylsulfonamidopiperidines as calcium channel blockers |
| US8247442B2 (en) | 2006-03-29 | 2012-08-21 | Purdue Pharma L.P. | Benzenesulfonamide compounds and their use |
| WO2007118854A1 (en) * | 2006-04-13 | 2007-10-25 | Euro-Celtique S.A. | Benzenesulfonamide compounds and the use thereof |
| US8791264B2 (en) | 2006-04-13 | 2014-07-29 | Purdue Pharma L.P. | Benzenesulfonamide compounds and their use as blockers of calcium channels |
| US8937181B2 (en) | 2006-04-13 | 2015-01-20 | Purdue Pharma L.P. | Benzenesulfonamide compounds and the use thereof |
| US8399486B2 (en) | 2007-04-09 | 2013-03-19 | Purdue Pharma L.P. | Benzenesulfonyl compounds and the use thereof |
| US8765736B2 (en) | 2007-09-28 | 2014-07-01 | Purdue Pharma L.P. | Benzenesulfonamide compounds and the use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| GB9916434D0 (en) | 1999-09-15 |
| AU5416000A (en) | 2001-01-30 |
| WO2001004087A1 (en) | 2001-01-18 |
| EP1200397A1 (en) | 2002-05-02 |
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