EP1200397A1 - Sulfonamide substituted benzylamine derivatives and their use as medicaments - Google Patents

Sulfonamide substituted benzylamine derivatives and their use as medicaments

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Publication number
EP1200397A1
EP1200397A1 EP00938940A EP00938940A EP1200397A1 EP 1200397 A1 EP1200397 A1 EP 1200397A1 EP 00938940 A EP00938940 A EP 00938940A EP 00938940 A EP00938940 A EP 00938940A EP 1200397 A1 EP1200397 A1 EP 1200397A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
cycloalkyl
optionally substituted
substituted phenyl
sulfonyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00938940A
Other languages
German (de)
French (fr)
Inventor
Sandra Ginette Milutinovic
Robin George Simmonds
David Edward Tupper
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co Ltd
Eli Lilly and Co
Original Assignee
Eli Lilly and Co Ltd
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly and Co Ltd, Eli Lilly and Co filed Critical Eli Lilly and Co Ltd
Publication of EP1200397A1 publication Critical patent/EP1200397A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • This invention relates to novel chemical compounds and their use as pharmaceuticals.
  • the compounds of the invention have the following general formula:
  • R is hydrogen, C]__g alkyl, C3_ ] _Q cycloalkyl, C3_ ] _Q
  • R.2 is C__g alkyl, C3_IQ cycloalkyl, C3_IQ cycloalkyl-
  • R3 and R 4 are each C _5 alkyl, C3_IQ cycloalkyl, C3_ ⁇ o
  • 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;
  • 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.
  • 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.
  • a C]__ alkyl group includes
  • 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, C ⁇ _4 alkoxy,
  • a halo atom is preferably chlorine, bromine or fluorine.
  • a substituted phenyl group preferably has one to three substituents selected from hydroxy, C ⁇ _4
  • An optionally substituted phenyl-C]__4 alkyl group is preferably of the
  • phenyl and n is 1 to 4, but the linking chain can also be branched alkylene.
  • a ⁇ - ⁇ Q cycloalkyl group is
  • cyclopropyl cyclobutyl, cyclopentyl or cyclohexyl and these groups may optionally be substituted by one or two C]__4 alkyl,
  • C]__4 alkyl group is one such cycloalkyl group attached to a C ⁇ _4 alkyl, and is preferably of the formula
  • R-(CH2) n - where R is cycloalkyl and n is 1 to 4.
  • R3 or R 4 is C]__g alkyl it is preferably ⁇ - ⁇ 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
  • R ⁇ , R 2 , R3 and R ⁇ are each C ⁇ _5 alkyl, C3_IQ cycloalkyl, C3_I_Q cycloalkyl-C__4
  • R! is in addition hydrogen. It is preferred that R ⁇ is hydrogen. Furthermore, R 3
  • R ⁇ which can be the same or different, are
  • a further preferred group of compounds is one of
  • a further preferred group of compounds is one of
  • 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.
  • 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.
  • 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 .
  • suitable acids such as those with inorganic acids, for example hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids
  • organic acids such as organic carboxylic acids, for example glycol
  • 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
  • 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 .
  • a reducing agent for example lithium aluminium hydride .
  • X is a leaving group such as, for example, halo or
  • 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.
  • organic solvent such as, for example, chloroform or acetonitrile
  • 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) :
  • Amine reactants of the formula H R 1 R 2 are well known and can be readily prepared by known methods. Those in
  • R 2 is -(CH2)2 NR ⁇ R ⁇
  • R ⁇ can, for example, be prepared
  • reductive amination that is, by reacting the appropriate diamine with an aldehyde in reducing conditions .
  • -(CH2)2 NR 5R6 can be prepared by alkylation of the
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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 .
  • EXAMPLE 8 Tablets each containing 10 mg of active ingredient are made UD as follows:
  • 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.
  • Capsules each containing 20 mg of active ingredient are made as follows : Active ingredient 20 mg Dried starch 178 mg Magnesium stearate 2 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 :
  • Tablets each containing 20 mg and medicaments are made as follows:
  • 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.

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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, C¿1-6? alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl or optionally substituted phenyl-C1-4 alkyl, R?2¿ is C¿1-6? alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl, optionally substituted phenyl-C1-4 alkyl or -(CH2)2NR?5R6¿ where R?5 and R6¿ are each hydrogen or C¿1-6? alkyl, and R?3 and R4¿ are each C¿1-6? 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 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

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:
R3
(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)2NR5R6 where R5 and R6 are each hydrogen or Cι_5
alkyl, and
R3 and R4 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 R1 and R2 ; or R^ and R4 t or R5 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 R4 is C]__g alkyl it is preferably ^ -ζ 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 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 R2 , or R3 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^, R2 , 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, R3
and R^ , which can be the same or different, are
preferably C]__4 alkyl. It is further preferred that R2
is optionally substituted phenyl-Cι_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 R^ is C3_ alkyl or when R3
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
R3
(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^R2.
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) :
R1
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 R!R2NH 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 R1R2 are well known and can be readily prepared by known methods. Those in
which R2 is -(CH2)2NR^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 R2 is
-(CH2)2NR5R6 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 IC50 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

1. A compound of the formula
R3
(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,
R2 is C]__ alkyl, C3_IQ cycloalkyl, C3_ o
cycloalkyl-C]__4 alkyl, optionally substituted phenyl-C]__4 alkyl or -(CH2)2N 5Rβ where R5 and R6
are each hydrogen or Cχ_g alkyl, and
R3 and R4 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 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.
A compound according to Claim 1 in which R^ , R2 , R3
and R4 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 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 R^, R2 , R3
and R4 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, R2 is optionally substituted phenyl-Cχ_4
alkyl and R3 and R4 are Cι_ alkyl.
5. A compound according to Claim 1 in which R2 is
-(CH2)2NR5Rβ.
6. A compound according to Claim 1 or 5 in which R3 or
R4 is C3_g 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 .
. 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.
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Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2407088A1 (en) * 2000-05-19 2001-11-22 Takeda Chemical Industries, Ltd. Beta-secretase inhibitors
MXPA05006798A (en) 2002-12-20 2006-03-09 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
TW200630337A (en) 2004-10-14 2006-09-01 Euro Celtique Sa Piperidinyl compounds and the use thereof
WO2007110449A1 (en) 2006-03-29 2007-10-04 Euro-Celtique S.A. 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
WO2008124118A1 (en) 2007-04-09 2008-10-16 Purdue Pharma L.P. Benzenesulfonyl compounds and the use therof
WO2009040659A2 (en) * 2007-09-28 2009-04-02 Purdue Pharma L.P. Benzenesulfonamide compounds and the use thereof
AU2013254657B2 (en) * 2012-04-27 2015-12-24 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

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
AU3276793A (en) * 1991-12-20 1993-07-28 Agouron Pharmaceuticals, Inc. Antifolate quinazolines
JPH08208595A (en) * 1994-11-21 1996-08-13 Takeda Chem Ind Ltd Sulfonamide compound, its production and agent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0104087A1 *

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AU5416000A (en) 2001-01-30

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