CA2317536A1 - Aminosulphonylbenzamide derivatives as modulators of the activity of neuronal calcium channels - Google Patents

Aminosulphonylbenzamide derivatives as modulators of the activity of neuronal calcium channels Download PDF

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CA2317536A1
CA2317536A1 CA002317536A CA2317536A CA2317536A1 CA 2317536 A1 CA2317536 A1 CA 2317536A1 CA 002317536 A CA002317536 A CA 002317536A CA 2317536 A CA2317536 A CA 2317536A CA 2317536 A1 CA2317536 A1 CA 2317536A1
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alkyl
cycloalkyl
benzamide
optionally substituted
substituted phenyl
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Robin George Simmonds
Sandra Ginette Milutinovic
David Edward Tupper
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Eli Lilly and Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

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Abstract

A pharmaceutical compound of formula (I) in which the aminosulfonyl group is attached at the 3- or 4-position, and in which R1 is hydrogen, C1-6 Alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 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-C1-4 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-C1-4 alkyl, C3-6 alkenyl, optionally substituted phenyl or optionally substituted phenyl-C1-4 alkyl, or R1 and R2, 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.

Description

AMINOSULPHONYLBENZAMIDE DERIVATIVES AS MODULATORS OF THE ACTIVITY OF NEURONAL
CALCIUM
CHANNELS
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.
The compounds of the invention have the following general formula:
R~

4/ S,O
O~
~N- Ra in which the aminosulfonyl group is attached at the 3-or 4-position, and in which R1 is hydrogen, C1_6 alkyl, C3_10 cYcloalkyl, C3_10 cycloalkyl-C1_4 alkyl or optionally substituted phenyl-C1_4 alkyl, R2 is C1_6 alkyl, C3_10 cycloalkyl, C3_10 cYcloalkyl-C1_g alkyl, optionally substituted phenyl-C1_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-C1_4 alkyl, C3_6 alkenyl, optionally substituted phenyl or optionally substituted phenyl-C1_4 alkyl, or R1 and R2 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;

WO_99/36398 PCT/G~99/00099 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 diseases of the central nervous system.
In the above formula (I), a C1_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 C1_4 alkyl, especially methyl, C1_4 alkoxy, especially methoxy and ethoxy, hydroxy, nitro, cyano, halo, especially chloro or fluoro, trihalomethyl, especially trifluoromethyl, carboxy and C1_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, C1_4 alkyl, halo, nitro and trifluoromethyl. An optionally substituted phenyl-C1_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 WO_99/36398 PCT/GB99/00099 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 C1_4 alkyl, especially methyl, substituents. A C3-10 cycloalkyl-C1_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 R~ are C1_6 alkyl they are 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 Rl, R2, R3 and R4 are each C1_6 alkyl, C3_10 cycloalkyl, C3_10 cycloalkyl-C1_4 alkyl or optionally substituted phenyl-C1_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 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-C1-4 alkyl or optionally substituted phenyl-C1_4 alkyl, and R1 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-C1_4 alkyl.
A further preferred group of compounds is one of formula (I) in which R2 is -(CH2)2NR5R6.
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 3-and/or 5-positions with one or two methyl or ethyl substituents.

WO 99136398 PCT/G~99/00099 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, malefic, 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 also includes a process for producing the compounds of formula (I) above which comprises reacting a compound of the formula:
O X
~O
O~ S~
Ra ~ Nv s R
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 0° C. to 100° C.
such as, for example, ambient temperature.
Intermediate compounds of formula (II) are known in the art and can be prepared readily by known methods. When WQ 99!36398 PCT/GB99/00099 _ g _ 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.
Amine reactants of the formula HNR1R2 are also well known and can be prepared readily 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, such compounds in which R 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 WQ 99/3b398 PCT/GB99/00099 _ g _ 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 ICSp of less than 10 ~M.
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.

WO_99/36398 PCT/GB99/00099 4-(N,N-dipropylaminosulfonyl)-N-benzyl-benzamide To 50-100 mg polyvinylpyridine was added a 25 mM
solution of benzylamine in chloroform (1 ml), followed by a 37.5 mM solution of 4-(N,N-dipropylaminosulfonyl)-benzoyl chloride in chloroform (1 ml). The mixture was shaken at room temperature for 4 hours.
Aminomethylpolystyrene (100 mg, 0.1 mmole) was added and shaking continued for a further 16.5 hours. The mixture was then filtered and the resin washed with chloroform (2 x 2 ml). The combined filtrates were vacuum evaporated to give the required product. (TS-MS: m/z 375, [M+H]+) The following compounds were similarly prepared (mass spectrum values are given in brackets).
Thermospray Mass Spectrum values 4-(N,N-Dipropylaminosulfonyl)-N,N-dibenzyl-benzamide (465) WO_99/36398 PCT/GB99/00099 4-(N,N-Dipropylaminosulfonyl)-N-3,4-dimethoxybenzyl-benzamide(435) 4-(N,N-Dipropylaminosulfonyl)-N-3,5-dimethoxybenzyl-benzamide(435) 4-(N,N-Dipropylaminosulfonyl)-N-3-methoxybenzyl-benzamide(405) 4-(N,N-Dipropylaminosulfonyl)-N-3,4,5-trimethoxybenzyl-benzamide(465) 4-(N,N-Dipropylaminosulfonyl)-N-4-chlorobenzyl-benzamide (409/410) 4-{N,N-Dipropylaminosulfonyl)-N-4-trifluoromethylbenzyl-benzamide(443) 4-(N,N-Dipropylaminosulfonyl)-N-4-dimethylaminobenzyl-benzamide(418) 4-(N,N-Dipropylaminosulfonyl)-N-4-methylbenzyl-benzamide0389) 4-(N,N-Dipropylaminosulfonyl)-N-3-chlorobenzyl-benzamide (409/410) 4-(N,N-Dipropylaminosulfonyl)-N-3-methylbenzyl-benzamide(389) 4-(N,N-Dipropylaminosulfonyl)-N-3-trifluoromethylbenzyl-benzamide(443) 4-(N,N-Dipropylaminosulfonyl)-N-3.5-difluoromethylbenzyl-benzamide(411) 4-(N,N-Dipropylaminosulfonyl)-N-2,6-dimethoxybenzyl-benzamide(435) 4-(N,N-Dipropylaminosulfonyl)-N-2-methylbenzyl-benzamide(389) 4-(N,N-Dipropylaminosulfonyl)-N-2-chlorobenzyl-benzamide9/410) (40 4-(N,N-Dipropylaminosulfonyl)-N-2-methoxybenzyl-benzamide(405) 4-(N,N-Dipropylaminosulfonyl)-N-2-trifluoromethylbenzyl-benzamide(443) 4-(N,N-Dipropylaminosulfonyl)-N-3,4-dimethylbenzyl-benzamide(403) 4-(N,N-Dipropylaminosulfonyl)-N-2,6-dichlorobenzyl-benzamide(444) 2 4-(N,N-Dipropylaminosulfonyl)-N-4-methoxyphenethyl-benzamide(419) 4-(N,N-Dipropylaminosulfonyl)-N-phenethyl-benzamide (389) 4-(N,N-Dipropylaminosulfonyl)-N-3-methoxyphenethyl-benzamide(419) 4-(N,N-Dipropylaminosulfonyl)-N-4-nitrophenethyl-benzamide(434) 4-(N,N-Dipropylaminosulfonyl)-N-2-phenylpropyl-benzamide(403) 2 4-(N,N-Dipropylaminosulfonyl)-N-4-chlorophenethyl-benzamide3/424) 5 (42 4-(N,N-Dipropylaminosulfonyl)-N-4-methylphenethyl-benzamide(403) 4-(N,N-Dipropylaminosulfonyl)-N-2-methoxyphenethyl-benzamide(419) 4-(N,N-Dipropylaminosulfonyl)-N-2-chlorophenethyl-benzamide/424) (423 4-(N,N-Dipropylaminosulfonyl)-N-3-trifluoromethylphenethyl-benzamide(457) 3 4-(N,N-Dipropylaminosulfonyl)-N-hexyl-benzamide {369) 4-(N,N-Dipropylaminosulfonyl)-N-2-methylbutyl-benzamide(355) krB

WO_99/36398 PCT/GB99/00099 4-(4-N,N-Dipropylaminosulfonyl)benzoylmorpholine (355) 2-(4-N,N-Dipropylaminosulfonyl)benzoyl-6,7-dimethoxy-tetra-hydroisoquinoline (461) 4-(N,N-Dipropylaminosulfonyl)-N-3-methoxypropyl-benzamide (357) 4-(N,N-Dipropylaminosulfonyl)-N-2-methylpropyl-benzamide (355) 4-(N,N-Dipropylaminosulfonyl)-N-cyclohexylmethyl-benzamide (381) 4-(N,N-Dipropylaminosulfonyl)-N-cyclohexyl-benzamide (367) 4-(N,N-Dipropylaminosulfonyl)-N-cyclopentyl-benzamide 0353) 4-(N,N-Dipropylaminosulfonyl)-N-pentyl-benzamide (355) 4-(N,N-Dipropylaminosulfonyl)-N-3-methylbutyl-benzamide (355) 4-(N,N-Dipropylaminosulfonyl)-N-3-phenylpropyl-benzamide (4~3) 4-(N,N-Dipropylaminosulfonyl)-N-4-tert.butylcyclohexyl-benzamide (423) 4-(N,N-Dipropylaminosulfonyl)-N-4-phenylbutyl-benzamide (417) 4-(N,N-Dipropylaminosulfonyl)-N-1-aminopropylpyrrolidine(396) 4-(N,N-Dipropylaminosulfonyl)-N-3-methylcyclohexyl-benzamide(381) 4-(N,N-Dipropylaminosulfonyl)-N-1-benzyl-4-aminopoperidine(458) 4-(N,N-Dipropylaminosulfonyl)-N-cyclopropylmethyl-benzamide(339) 4-(N,N-Dipropylaminosulfonyl)-N-butyl-benzamide (341) 4-(N,N-dipropylaminosulfonyl)-N-4-methoxybenzyl-benzamide A mixture of a 75 mM solution of 4-methoxybenzylamine in chloroform (0.5 ml), a 75 mM solution of N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in chloroform (0.5 ml) and a 50 mM

solution of 4-(N,N-dipropylaminosulfonyl)-benzoic acid in chloroform (0.5 ml) was stirred at room temperature for 17 hours. Methanol (0.5 ml) was added with stirring and the solution applied to a methanol-washed 500 mg SCX
solid phase extraction (SPE) cartridge. The cartridge was washed with methanol (4 ml) and the combined eluates vacuum evaporated to give the required product. (TS-MS:
m/z 405, (M+H]+) .
T V T wdTT r, 7 4-(N,N-dibutylaminosulfonyl)-N-4-methoxybenzyl-benzamide A mixture of a 200 mM solution of dibutylamine in acetonitrile (0.5 ml) and a 25 mM solution of 4-chlorosulfonylbenzoic acid in acetonitrile (1 ml) was stirred at room temperature for 18 hours. Methanol (1 ml) was then added with stirring and the solution applied to a methanol-washed 500 mg SCX SPE cartridge.
The cartridge was washed with methanol (4 ml) and the combined eluates vacuum evaporated. The residue was dissolved in dichloromethane (1 ml) and a 75 mM solution of 4-methoxybenzylamine in chloroform (0.5 ml) and a 75 mM solution of N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in chloroform (0.5 ml) added. This mixture was stirred at room temperature for 17 hours. Methanol (0.5 ml) was added with stirring and the solution applied to a methanol-washed 500 mg SCX SPE
cartridge. The cartridge was washed with methanol (4 ml) and the combined eluates vacuum evaporated to give the required product. (TS-MS: m/z 433, [M+H]+) The following compounds were prepared similarly.
1 ~ Thermospray Mass Spectrum values 4-(N-pentylaminosulfonyl)-N-4-methoxybenzyl-benzamide (391) 1 5 4-[N-(3-methylcyclohexyl)aminosulfonyl]-N-4-methoxybenzyl-benzamide(917) 4-((N-butyl-N-propyl)aminosulfonyl]-N-4-methoxybenzyl-benzamide(419) 4-[N-(3,5-dimethylpiperidin-1-yl)aminosulfonyl]-N-4-methoxybenzyl-benzamide(417) 4-((N-diisobutyl)aminosulfonyl]-N-4-methoxybenzyl-benzamide(433) 4-(N-(3-methylpiperidin-1-yl)aminosulfonyl]-N-4-methoxybenzyl-benzamide(403) 2 0 4-[(N-methylbutyl)aminosulfonyl]-N-4-methoxybenzyl-benzamide(405) 4-((4-methylpiperidin-1-yl)aminosulfonyl]-N-4-methoxybenzyl-benzamide(403) 4-((3,3-dimethylpiperidin-1-yl)aminosulfonyl]-N-4-methoxybenzyl-benzamide(417) 4-[(N-cyclopropyl-N-propylmethyl)aminosulfonyl]-N-4-methoxybenzyl-benzamide(417) TVTIITT T A
3-(N,N-dipropylaminosulfonyl)-N-3,4-dimethoxyphenethyl-benzamide WO_ 99/36398 PCT/GB99/00099 A mixture of a 200 mM solution of dipropylamine in acetonitrile (0.5 ml) and a 25 mM solution of 3-chlorosulfonylbenzoic acid in acetonitrile (1 ml) was stirred at room temperature for 18 hours. Methanol (1 ml) was then added with stirring and the solution applied to a methanol-washed 500 mg SCX SPE cartridge.
The cartridge was washed with methanol (4 ml) and the combined eluates vacuum evaporated. The residue was dissolved in dichloromethane (1 ml) and a 75 mM solution of 3,4-dimethoxyphenethylamine in chloroform (0.5 ml) and a 75 mM solution of N-(dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride in chloroform (0.5 ml) added. This mixture was stirred at room temperature for 17 hours. Methanol (0.5 ml) was added with stirring and the solution applied to a methanol-washed 500 mg SCX SPE
cartridge. The cartridge was washed with methanol (4 ml) and the combined eluates vacuum evaporated to give the required product. (TS-MS: m/z 449, [M+H]+) (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.
Similarly prepared were:
3-[(N,N-di-n-propylamino)sulfonyl]-benzoic acid 4-[(N-phenyl-N-n-propylamino)sulfonyl]-benzoic acid 4-[(N-phenyl-N-n-allylamino)sulfonyl]-benzoic acid 3-[N-(3,3-dimethylpiperidin-1-yl)sulfonyl]-benzoic acid 4-[N-(3,3-dimethylpiperidin-1-yl)sulfonyl]-benzoic acid 4-[(N-phenyl-N-n-butylamino)sulfonyl]-benzoic acid 3-[(N-phenyl-N-n-propylamino)sulfonyl]-benzoic acid 3-[N-(3-ethylpiperidin-1-yl)sulfonyl]-benzoic acid 3-[(N-phenyl-N-methyl)sulfonyl]-benzoic acid 4-[N-(3-methylpiperidin-1-yl)sulfonyl]-benzoic acid (2) 4-[(N-di-n-propylamino)sulfonyl]-N-4-methoxybenzyl-benzamide WO_99/36398 PCT/GB99/00099 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)sulfonylJ-N-4-methoxybenzyl-benzamide as a white solid. M.p. 132-134° C.
Similarly prepared were:
3-[(N,N-di-n-propylamino)sulfonyl]-N-4-methoxybenzyl-benzamide. M.p. 132-134° C.
4-[(N-phenyl-N-n-propylamino)sulfonyl]-N-4-methoxybenzyl-benzamide. M.p. 112-114° C.
4-[(N-phenyl-N-n-butylamino)sulfonyl]-N-n-hexyl-benzamide. M.p. 84-86° C.

WO_99136398 PCTIGB99/00099 4-[(N-phenyl-N-n-allylamino)sulfonyl]-N-n-hexyl-benzamide. M.p. 90-92° C.
4-[(N-phenyl-N-n-propylamino)sulfonyl]-N-n-hexyl-benzamide. M.p. 92-94° C.
3-[N-(3,3-dimethylpiperidin-1-yl)sulfonyl]-N-4-fluorobenzyl-benzamide. M.p. 125° C.
4-[N-(3,3-dimethylpiperidin-1-yl)sulfonyl]-N-4-fluorobenzyl-benzamide. M.p. 138-140° C.
3-[(N,N-di-n-propylamino)sulfonyl]-N-4-fluorobenzyl-benzamide. M.p. 84-86° C.
N-methyl-3-[N-(3,3-dimethylpiperidin-1-yl)sulfonyl]-N-4-fluorobenzyl-benzamide. M.p. <50° C.
N-benzyl-3-[N-(3,3-dimethylpiperidin-1-yl)sulfonyl]-N-4-fluorobenzyl-benzamide. M.p. 112° C.
4-[(N-phenyl-N-n-butylamino)sulfonyl]-N-4-fluorobenzyl-benzamide. M.p. 128-130° C.
3-[(N-phenyl-N-n-propylamino)sulfonyl]-N-4-fluorobenzyl-benzamide. M.p. 99° C.
4-[(3,3-dimethylpiperidin-1-yl)sulfonyl]-N-(2-{[(4-fluorophenyl)methyl] amino}ethyl)benzamide. Maleate.
M.p. 132-134° C.
3-[N-(3-ethylpiperidin-1-yl)sulfonyl]-N-4-fluorobenzyl-benzamide. 405(M+H)+
N-[2-(dimethylamino)ethyl]-3-[(3,3-dimethylpiperidin-1-yl)sulfonyl]-N-4-fluorobenzyl-benzamide maleate. M.p.
126° C.

WO_99/36398 PCT/GB99/00099 N-[2-(dimethylamino)ethyl]-3-[(3,3-dimethylpiperidin-1-yl)sulfonyl]-N-cyclohexylmethyl-benzamide. M.p. 122° C.
N-[2-(dimethylamino)ethyl]-4-[(N-phenyl-N-n-propylamino)sulfonyl]-N-cyclohexylmethyl-benzamide maleate. M.p. 140-142° C.
N-[2-(pyrrolidino)ethyl]-3-[(3,3-dimethylpiperidin-1-yl)sulfonyl]-N-isoamyl-benzamide hydrochloride. M.p.
179° C.
N-[2-(pyrrolidino)ethyl]-4-[(3-ethylpiperidin-1-yl)sulfonyl]-N-isoamyl-benzamide malea. M.p. 166-168° C.
N-[3-(pyrrolidino)propyl]-3-[(3,3-dimethylpiperidin-1-y1)sulfonyl]-N-isoamyl-benzamide hydrochloride. M.p.
155° C.
N-[3-(pyrrolidino)propyl]-3-[(3,3-dimethylpiperidin-1-yl)sulfonyl]-N-cyclohexylmethyl-benzamide. M.p. 124° C.
N-[2-(N-methyl-pyrrolidin-2-yl)ethyl]-3-[(3,3-dimethylpiperidin-1-yl)sulfonyl]-N-isoamyl-benzamide maleate. M.p. 115-117° C.
N-[2-(piperidin-1-yl)ethyl]-3-[(3-methylpiperidin-1-yl)sulfonyl]-N-(2-4-methoxyphenethyl)-benzamide. M.p.
210° C.
N-j2-(piperidin-1-yl)ethyl]-3-[(3-methylpiperidin-1-yl)sulfonyl]-N-(2-4-methoxyphenethyl)-benzamide hydrochloride. M.p. 205° C.

WO_99/3b398 PCT/GB99/00099 The following Examples illustrate typical formulations containing a compound of the invention.
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, WO_99/36398 PCT/GB99/00099 after mixing, are compressed on a tablet machine to yield tablets each weighing 300 mg.
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.
Capsules each containing 20 mg of medicament are made as follows:

WO_99/36398 PCT/GB99l00099 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.

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 WO_99/36398 PCT/GB99/00099 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 (10)

1. A compound of the formula in which the aminosulfonyl group is attached at the 3- or 4-position, and in which R1 is hydrogen, C1-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 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-C1-4 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-C1-4 alkyl, C3-6 alkenyl, optionally substituted phenyl or optionally substituted phenyl-C1-4 alkyl, or R1 and R2 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 C1-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl or optionally substituted phenyl-C1-4 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 R1, R2, R3 and R4 are each C1-6 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl or optionally substituted phenyl-C1-4 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-C1-4 alkyl and R3 and R4 are C1-6 alkyl.
5. A compound according to Claim 1 in which R2 is -(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 piperidine ring which is substituted at the 3- and/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.
10. A process for producing a compound according to Claim 1, which comprises reacting a compound of the formula where X is a leaving group, with an amine of the formula HNR1R2.
CA002317536A 1998-01-14 1999-01-13 Aminosulphonylbenzamide derivatives as modulators of the activity of neuronal calcium channels Abandoned CA2317536A1 (en)

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