[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

EP1047670A1 - Aminosulphonylbenzamide derivatives as modulators of the activity of neuronal calcium channels - Google Patents

Aminosulphonylbenzamide derivatives as modulators of the activity of neuronal calcium channels

Info

Publication number
EP1047670A1
EP1047670A1 EP99901722A EP99901722A EP1047670A1 EP 1047670 A1 EP1047670 A1 EP 1047670A1 EP 99901722 A EP99901722 A EP 99901722A EP 99901722 A EP99901722 A EP 99901722A EP 1047670 A1 EP1047670 A1 EP 1047670A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
cycloalkyl
benzamide
optionally substituted
substituted phenyl
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Withdrawn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
EP99901722A
Other languages
German (de)
French (fr)
Inventor
Sandra 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 EP1047670A1 publication Critical patent/EP1047670A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • 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

Definitions

  • This invention relates to novel chemical compounds and their use as pharmaceuticals .
  • the compounds of the invention have the following general formula:
  • R 2 is C ⁇ _ alkyl, C3_ ⁇ o cycloalkyl, C3_ ⁇ o cycloalkyl-
  • R3 and R ⁇ are each C]__g alkyl, C3_ ⁇ o cycloalkyl, C3_IQ
  • 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 diseases of the central nervous system.
  • a C ⁇ _6 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 C3_IQ cycloalkyl group is
  • cyclopropyl cyclobutyl, cyclopentyl or cyclohexyl and these groups may optionally be substituted by one or two C ⁇ _4 alkyl,
  • a C3_]_Q cycloalkyl- C ⁇ _4 alkyl group is one such cycloalkyl group attached
  • R-(CH2) n - where R is cycloalkyl and n is 1 to 4.
  • R ⁇ or R4 are C _ alkyl they are preferably C3_g alkyl.
  • the groups R ⁇ and R 2 , R3 and R ⁇ , and R ⁇ and R ⁇ 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
  • R1, R 2 , R3 and R ⁇ are each C ⁇ _6 alkyl, ⁇ - ⁇ Q cycloalkyl, C3_]_o cycloalkyl-C ⁇ __4 alkyl or optionally substituted phenyl-C ⁇ _4 alkyl, and
  • R-L is in addition hydrogen.
  • R! is hydrogen. Furthermore, R ⁇
  • R4 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
  • 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 glyco
  • 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:
  • 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
  • Amine reactants of the formula HNR ⁇ -R 2 are also well known and can be prepared readily by known methods.
  • R 2 is - (CH2 ) 2 NR ⁇ *R * ⁇
  • R 2 is - (CH2 ) 2 NR ⁇ *R * ⁇
  • Those in which R 2 is - (CH2 ) 2 NR ⁇ *R * ⁇ can, for example, be prepared by reductive amination, that is, by reacting the appropriate diamine with an aldehyde in reducing conditions .
  • the compounds of the invention are active in tests that indicate their utility in the treatment of diseases of the central nervous system.
  • the compounds modulate the activity of calcium channels and, in particular, they block voltage sensitive calcium channels as determined in a test based on Boot J. R. , et al . , Specificity of autoantibodies in the Lambert- Eaton Myasthenic Syndrome, Ann NY Acad. Sci . (1997), in which measurements of calcium flux using calcium sensitive dyes are made.
  • Compounds described in the following Examples were found to inhibit voltage- dependent calcium channels in cloned human cell lines expressing specific voltage-dependent calcium channels with an IC 50 of less than 10 ⁇ 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
  • 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 when it 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 .
  • Tablets each containing 10 mg of active ingredient are made up 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:
  • 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 : Active ingredient 20 mg Lactose 171 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:
  • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyrrole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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

AMINOSULPHONYLBENZAMIDE DERIVAΗVES AS MODULATORS OF THE ACΗVITY 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.
10
The compounds of the invention have the following general formula:
R1
R3
(I)
15 in which the aminosulfonyl group is attached at the 3- or 4-position, and in which R1 is hydrogen, C]__6 alkyl, C3_χo cycloalkyl, C3_IQ
cycloalkyl-Cι_4 alkyl or optionally substituted phenyl- Cχ_4 alkyl,
R2 is Cχ_ alkyl, C3_χo cycloalkyl, C3_χo cycloalkyl-
C^_4 alkyl, optionally substituted phenyl-C]__4 alkyl or
-(CH2)2NR R where R^ and R^ are each hydrogen or C]__6
alkyl , and
R3 and R^ are each C]__g alkyl, C3_χo cycloalkyl, C3_IQ
cycloalkyl-C]__4 alkyl, C3_ alkenyl, optionally
substituted phenyl or optionally substituted phenyl-Cχ_4
alkyl ,
or R1 and R2 t or R3 and R4 t 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.
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 Cχ_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 C]__4 alkyl, especially methyl, C]__4 alkoxy,
especially methoxy and ethoxy, hydroxy, nitro, cyano, halo, especially chloro or fluoro, trihalomethyl, especially trifluoromethyl , carboxy and Cχ_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 C3_IQ cycloalkyl group is
preferably, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and these groups may optionally be substituted by one or two Cχ_4 alkyl,
especially methyl, substituents. A C3_]_Q cycloalkyl- Cι_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. When
R^ or R4 are C _ alkyl they are preferably C3_g alkyl.
The groups R^ and R2 , R3 and R^ , and R^ and R^ , 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 C]__g
alkyl, C3_χo cycloalkyl, C3_ιo cycloalkyl-Cχ_4 alkyl or
optionally substituted phenyl-C]__4 alkyl, and R! 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 R^ are each Cχ_6 alkyl, ^ -^Q cycloalkyl, C3_]_o cycloalkyl-Cι__4 alkyl or optionally substituted phenyl-Cι_4 alkyl, and
R-L is in addition hydrogen.
It is preferred that R! is hydrogen. Furthermore, R^
and R4 , which can be the same or different, are
preferably Cχ_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 - (CH ) 2NR5R6 •
A further preferred group of compounds is one of
formula (I) in which R^ or R4 is C3_g alkyl or when R^
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 also includes a process for producing the compounds of formula (I) above which comprises reacting a compound of the formula:
(II)
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 (II) are known in the art and can be prepared readily 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, dimethyla inopropyl-ethylcarbodiimide can be employed.
Amine reactants of the formula HNR^-R2 are also well known and can be prepared readily 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, such compounds in which R is - (CH2 ) 2NR~IR^ 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-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) - ( N , N- ■Dipropylaminosulfonyl -N-3 , 4-dimethoxybenzyl-benzamide (435) - ( N N- ■Dipropylaminosulfonyl -N-3 , 5-dimethoxybenzyl-benzamide (435 ) - N , N- ■Dipropylaminosulfonyl -N-3-methoxybenzyl-benzamide (405) - N N- •Dipropylaminosulfonyl -N-3 , 4, 5-trimethoxybenzyl-benzamide (465) - N , N- •Dipropylaminosul fonyl -N-4-chlorobenzyl-benzamide (409/410) - N N- •Dipropylaminosulfonyl -N-4-trifluoromethylbenzyl-benzamide ( 443 ) - N N Dipropylaminosul fonyl -N-4-dimethylaminobenzyl-benzamide ( 418 ) - N N -Dipropylaminosulfonyl -N-4-methylbenzyl-benzamide (389 ) - N N ■Dipropylaminosul fonyl -N-3-chlorobenzyl-benzamide (409/410) - N N -Dipropylaminosulfonyl -N-3-methylbenzyl-benzamide (389 ) - N N -Dipropylaminosulfonyl -N-3 -trifluoromethylbenzyl-benzamide (443 ) - N N -Dipropylaminosul onyl -N-3.5-difluoromethylbenzyl-benzamide ( 411 ) - N N -Dipropylaminosulfonyl -N-2, 6-dimethoxybenzyl-benzamide (435) - N N -Dipropylaminosulfonyl -N-2-methylbenzyl-benzamide (389) - N N -Dipropylaminosulfonyl -N-2-chlorobenzyl-benzamide (409/410) - N N -Dipropylaminosulfonyl -N-2-methoxybenzyl-benzamide ( 405 ) - N N -Dipropylaminosulfonyl -N-2-trifluoromethylbenzyl-benzamide ( 443 ) - N N -Dipropylaminosulfonyl -N-3 , 4-dimethylbenzyl-benzamide ( 403 ) - N N -Dipropylaminosulfony1 -N-2 , 6-dichlorobenzyl-benzamide ( 444 ) - N N -Dipropylaminosulfonyl -N-4-methoxyphenethyl-benzamide (419 ) - N N -Dipropylaminosulfonyl -N-phenethyl-benzamide (389) - N N -Dipropylaminosulfonyl -N-3-methoxyphenethyl-benzamide (419 ) - N N -Dipropylaminosulfonyl -N-4-nitrophenethyl-benzamide (434) - N N -Dipropylaminosulfonyl -N-2-phenylpropyl-benzamide (403 ) - N N -Dipropylaminosulfonyl -N-4-chlorophenethyl-benzamide ( 423 /424 ) - N N -Dipropylaminosulfonyl -N-4-methylphenethyl-benzamide (403 ) - N N -Dipropylaminosulfonyl -N-2-methoxyphenethyl-benzamide ( 419 ) - (N N -Dipropylaminosulfonyl -N-2-chlorophenethyl-benzamide (423/424) - (N N -Dipropylaminosulfonyl -N-3 -trifluoromethylphenethyl-benzamide (457 " - (N N -Dipropylaminosulfonyl -N-hexyl-benzamide (369) - (N N -Dipropylaminosulfonyl -N-2-methylbutyl-benzamide (355) 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-eye1ohexy1-benzamide (367) 4- (N,N-Dipropylaminosulfonyl -N-cyclopentyl-benzamide (353) 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 (403) 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-eyelopropylmethy1-benzamide (339) 4- (N,N-Dipropylaminosulfonyl -N-buty1-benzamide (341)
EXAMPLE 2
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]+) .
EXAMPLE 3
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.
Thermospray Mass
Spectrum values
4- (N-pentylaminosulfonyl) -N-4-methoxybenzyl-benzamide (391) 4- [N- (3-methylcyclohexyl) aminosulfonyl] -N-4-methoxybenzyl-benzamide (417)
4- [ (N-butyl-N-propyl) aminosulfonyl] -N-4-methoxybenzyl-benzamide (419)
4- [N- (3 , 5-dimethylpiperidin-l-yl) aminosulfonyl] -N-4-methoxybenzyl-benzamide (417 )
4- [ (N-diisobutyl) aminosulfonyl] -N-4-methoxybenzyl-benzamide (433 )
4- [N- (3-methylpiperidin-l-yl) aminosulfonyl] -N-4-methoxybenzyl-benzamide (403 ) 4-[ (N-methylbutyl) aminosulfonyl] -N-4-methoxybenzyl-benzamide (405)
4- [ (4-methylpiperidin-l-yl) aminosulfonyl] -N-4-methoxybenzyl-benzamide (403 )
4- [ (3 , 3-dimethylpiperidin-l-yl) aminosulfonyl] -N-4-methoxybenzyl-benzamide (41 )
4- [ (N-cyclopropyl-N-propylmethyl) aminosulfonyl] -N-4-methoxybenzyl-benzamide (41 )
EXAMPLE 4
3 - (N, N-dipropylaminosulf onyl ) -N-3 , 4 -dimethoxyphenethyl - benzamide 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]+)
EXAMPLE 5
(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-l-yl) sulfonyl] -benzoic acid 4- [N- (3 , 3-dimethylpiperidin-l-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-l-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 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.
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. 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-l-yl) sulfonyl] -N-4- fluorobenzyl-benzamide . M.p. 125° C.
4- [N- (3 , 3-dimethylpiperidin-l-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-l-yl) sulfonyl] -N-4- fluorobenzyl-benzamide . M.p. <50° C.
N-benzyl-3- [N- (3 , 3-dimethylpiperidin-l-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-l-yl) sulfonyl] -N- ( 2 - { [ (4- fluorophenyl) methyl] amino} ethyl) benzamide . Maleate.
M.p. 132-134° C.
3- [Ν- (3-ethylpiperidin-l-yl) sulfonyl] -Ν-4-fluorobenzyl-
benzamide. 405(M+H)+
N- [2- (dimethylamino) ethyl] -3- [ (3 , 3-dimethylpiperidin-l- yl) sulfonyl] -N-4-fluorobenzyl-benzamide maleate. M.p.
126° C. N- [2- (dimethylamino) ethyl] -3- [ (3 , 3-dimethylpiperidin-l- yl) sulfonyl] -N-cyclohexylmethyl-benzamide . M.p. 122° C. N- [2- (dimethylamino) ethyl] -4- [ (Ν-phenyl-Ν-n- propylamino) sulfonyl] -N-cyclohexylmethyl-benzamide maleate. M.p. 140-142° C.
N- [2- (pyrrolidino) ethyl] -3- [ (3 , 3-dimethylpiperidin-l- yl) sulfonyl] -N-isoamyl-benzamide hydrochloride . M.p. 179° C. N- [2- (pyrrolidino) ethyl] -4- [ (3-ethylpiperidin-l- yl) sulfonyl] -N-isoamyl-benzamide malea. M.p. 166- 168° C.
N- [3- (pyrrolidino) propyl] -3- [ (3 , 3-dimethylpiperidin-l- yl) sulfonyl] -N-isoamyl-benzamide hydrochloride. M.p. 155° C. N- [3- (pyrrolidino) propyl] -3- [ (3 , 3-dimethylpiperidin-l- 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- ( iperidin-1-yl) ethyl] -3- [ (3-methylpiperidin-l- yl) sulfonyl] -N- (2-4-methoxyphenethyl) -benzamide . M.p. 210° C.
N- [2- (piperidin-1-yl) ethyl] -3- [ (3-methylpiperidin-l- yl) sulfonyl] -N- (2-4-methoxyphenethyl) -benzamide hydrochloride. M.p. 205° C. The following Examples illustrate typical formulations containing a compound of the invention.
EXAMPLE 6
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 7
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 8
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 9
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 3 00 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^-ζ alkyl, C3_χo cycloalkyl, C3_ιo cycloalkyl-Cχ_4 alkyl or optionally substituted
phenyl-Cχ_4 alkyl,
R2 is Cχ_g alkyl, C3_IQ cycloalkyl, C3_ιg cycloalkyl-Cχ_4 alkyl, optionally substituted
phenyl-C!_4 alkyl or -(CH2)2NR5R6 where R5 and R6 are each hydrogen or Cχ_g alkyl, and R3 and R"4 are each Cχ_g alkyl, C3_IQ cycloalkyl,
C3_ o cycloalkyl-C _4 alkyl, C3_g alkenyl,
optionally substituted phenyl or optionally substituted phenyl-Cχ_4 alkyl,
or R1 and R2 r 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, R , R^
and R4 are each Cχ_g alkyl, C3_IQ cycloalkyl, C3_χo cycloalkyl-C]__4 alkyl or optionally substituted
phenyl-C^-4 alkyl, and R! can in addition be
hydrogen, or R! and R , or R^ and R*4 together with the nitrogen atom to which they are attached, form a carbocyclic group.
3. A compound according to Claim 2 in which R^, R2 , R^
and R are each Cχ_g alkyl, C3_]_Q cycloalkyl, C3_χo cycloalkyl-C _4 alkyl or optionally substituted
phenyl-C]__4 alkyl, and R1 can in addition be
hydrogen .
4. A compound according to Claim 3 in which R! is
hydrogen, R2 is optionally substituted phenyl-C╬╣_4
alkyl and R3 and R4 are C╬╣_ 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_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.
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
(II)
where X is a leaving group, with an amine of the
formula HNR^-R2.
EP99901722A 1998-01-14 1999-01-13 Aminosulphonylbenzamide derivatives as modulators of the activity of neuronal calcium channels Withdrawn EP1047670A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9800750.3A GB9800750D0 (en) 1998-01-14 1998-01-14 Pharmaceutical compound
GB9800750 1998-01-14
PCT/GB1999/000099 WO1999036398A1 (en) 1998-01-14 1999-01-13 Aminosulphonylbenzamide derivatives as modulators of the activity of neuronal calcium channels

Publications (1)

Publication Number Publication Date
EP1047670A1 true EP1047670A1 (en) 2000-11-02

Family

ID=10825269

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99901722A Withdrawn EP1047670A1 (en) 1998-01-14 1999-01-13 Aminosulphonylbenzamide derivatives as modulators of the activity of neuronal calcium channels

Country Status (6)

Country Link
EP (1) EP1047670A1 (en)
JP (1) JP2002509135A (en)
AU (1) AU2172899A (en)
CA (1) CA2317536A1 (en)
GB (1) GB9800750D0 (en)
WO (1) WO1999036398A1 (en)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2812198B1 (en) * 2000-07-28 2008-07-18 Sod Conseils Rech Applic AMIDINE DERIVATIVES INHIBITORS OF PHOSPHATASES cdc25
WO2003027068A2 (en) * 2001-09-24 2003-04-03 Elan Pharmaceuticals, Inc. Substituted amines for the treatment of neurological disorders
TW200302717A (en) * 2002-02-06 2003-08-16 Schering Corp Novel gamma secretase inhibitors
EP1581472A2 (en) 2002-12-20 2005-10-05 MIGENIX Corp. Ligands of adenine nucleotide translocase (ant) and compositions and methods related thereto
RU2007148504A (en) * 2005-06-09 2009-06-27 Вертекс Фармасьютикалз Инкорпорейтед (Us) INDIAN DERIVATIVES AS ION CHANNEL MODULATORS
JP5361857B2 (en) * 2007-03-23 2013-12-04 ファイザー・リミテッド Ion channel inhibitors
GB201007789D0 (en) * 2010-05-10 2010-06-23 Glaxo Group Ltd Novel Compound
GB201007791D0 (en) * 2010-05-10 2010-06-23 Glaxo Group Ltd Novel compounds
US9399619B2 (en) * 2011-07-01 2016-07-26 Baruch S. Blumberg Institute Sulfamoylbenzamide derivatives as antiviral agents against HBV infection
EP3737382A1 (en) 2018-01-10 2020-11-18 Cura Therapeutics, LLC Pharmaceutical compositions comprising phenylsulfonamides, and their therapeutic applications
EP3996813A1 (en) * 2019-07-11 2022-05-18 Cura Therapeutics, LLC Phenyl compounds and pharmaceutical compositions thereof, and their therapeutic applications

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK0589336T3 (en) * 1992-09-22 1997-06-16 Hoechst Ag Benzylguanidines, methods for their preparation and their use as antiarrhythmics

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9936398A1 *

Also Published As

Publication number Publication date
JP2002509135A (en) 2002-03-26
AU2172899A (en) 1999-08-02
CA2317536A1 (en) 1999-07-22
GB9800750D0 (en) 1998-03-11
WO1999036398A1 (en) 1999-07-22

Similar Documents

Publication Publication Date Title
KR0142417B1 (en) Tertiary alkyl functionalized piperazine derivatives
US6617325B1 (en) Biphenyl derivatives, production thereof and uses as medicines
US7365077B2 (en) Piperazine bis-amide derivatives and their use as antagonists of the orexin receptor
EP0158775B1 (en) Substituted sulfonamidobenzamides, antiarrythmic agents and compositions thereof
CA1235122A (en) Substituted trans-1,2-diaminocyclohexyl amide compounds
WO1996041802A1 (en) Novel heteroaromatic piperazines for use as drugs
HU221315B1 (en) Alkyl-substituted piperazine derivatives, pharmaceutical compositions containing them, and process for producing them
WO2004013100A2 (en) N-[phenyl(piperidin-2-yl)methyl]benzamide derivatives, preparation thereof, and use thereof in therapy
NO338104B1 (en) Tetrahydroisoquinoline-sulfonamide derivatives, pharmaceutical compositions containing them and their use as therapeutic agents
WO1999036398A1 (en) Aminosulphonylbenzamide derivatives as modulators of the activity of neuronal calcium channels
EP0290377B1 (en) Substituted 4-[1H-Imidazol-1-yl] benzamides as antiarrhythmic agents
WO1995029152A1 (en) Benzamide derivatives as vasopressin antagonists
KR20010070997A (en) Biphenyl derivatives
EP0324791B1 (en) Aryl-n-aminoalkyl-4-(sulfonamido)benzamides, antiarrhytmic agents and compositions thereof
CA2244940A1 (en) Novel piperidines derived from 1-/(piperazin-1-yl)aryl(oxy/amino)carbonyl/-4-aryl-piperidine as selective 5-ht1db receptor antagonists
GB2352240A (en) Novel sulphonamides useful in treating CNS disorders
HUT73526A (en) Benzazepine derivative, pharmaceutical composition containing the same, and intermediate for the same
FR2740134A1 (en) CYCLIC AMINE DERIVATIVES OF ARYL-PIPERAZINES, PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
US5486518A (en) 4-indolylpiperazinyl derivatives
WO1998031669A1 (en) Novel arylpiperazine derived from piperidine as antidepressant medicines
KR20040007672A (en) Novel Phenylalkyl Diamine and Amide Analogs
AU3964393A (en) Novel amidoalkyl- and imidoalkyl-piperazines
KR20030024919A (en) N-(3,5-dichloro-2-methoxyphenyl)-4-methoxy-3-piperazin-1-yl-benzenesulfonamide
CA2173693A1 (en) 4-indolylpiperazinyl derivatives
CA1133495A (en) Cis and trans-3-aryloxy-4- hydroxypyrrolidines and derivatives thereof

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20000620

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU NL PT SE

17Q First examination report despatched

Effective date: 20011123

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20020404