EP1047670A1 - Derives aminosulphonylbenzamides utilises comme inhibiteurs de l'activite des canaux calcium neuronaux - Google Patents

Derives aminosulphonylbenzamides utilises comme inhibiteurs de l'activite des canaux calcium neuronaux

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Withdrawn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)
English (en)
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/fr
Withdrawn legal-status Critical Current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.

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  • 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

L'invention se rapporte à un composé pharmaceutique représenté par la formule (I) dans laquelle le groupe aminosulfonyle est attaché en position 3 ou 4 et où R1 est hydrogène, alkyle C¿1?-C6, cycloalkyle C3-C10, cycloalkyle C3-C10-alkyle C1-C4 ou phényle-alkyle C1-C4, R?2¿ est alkyle C¿1?-C6, cycloalkyle C3-C10, cycloalkyle C3-C10-alkyle C1-C4 ou phényle-alkyle C1-C4 ou (CH2)2NR?5R6 où R5 et R6¿ sont chacun hydrogène ou alkyle C¿1?-C6, et R?3 et R4¿ sont chacun alkyle C¿1?-C6, cycloalkyle C3-C10, cycloalkyle C3-C10-alkyle C1-C4, alcényle C3-C6, phényle éventuellement substitué ou phényle-alkyle C1-C4 éventuellement substitué, ou bien R?1 et R2, ou R3 et R4, ou R5 et R6¿ forment conjointement à l'atome d'azote auquel ils sont attachés, un groupe carbocyclique contenant 4 à 7 atomes de carbone éventuellement substitués par un à trois groupes méthyle ou éthyle et contenant éventuellement un atome d'oxygène ou un autre atome d'azote, ledit groupe carbocyclique étant éventuellement fusionné à un groupe phényle éventuellement substitué. L'invention se rapporte également à un sel de ce composé.
EP99901722A 1998-01-14 1999-01-13 Derives aminosulphonylbenzamides utilises comme inhibiteurs de l'activite des canaux calcium neuronaux Withdrawn EP1047670A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9800750 1998-01-14
GBGB9800750.3A GB9800750D0 (en) 1998-01-14 1998-01-14 Pharmaceutical compound
PCT/GB1999/000099 WO1999036398A1 (fr) 1998-01-14 1999-01-13 Derives aminosulphonylbenzamides utilises comme inhibiteurs de l'activite des canaux calcium neuronaux

Publications (1)

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

Family

ID=10825269

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99901722A Withdrawn EP1047670A1 (fr) 1998-01-14 1999-01-13 Derives aminosulphonylbenzamides utilises comme inhibiteurs de l'activite des canaux calcium neuronaux

Country Status (6)

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

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2812198B1 (fr) * 2000-07-28 2008-07-18 Sod Conseils Rech Applic DERIVES D'AMIDINES INHIBITEURS DE PHOSPHATASES cdc25
WO2003027068A2 (fr) * 2001-09-24 2003-04-03 Elan Pharmaceuticals, Inc. Amines substituees pour le traitement de la maladie d'alzheimer
TW200302717A (en) * 2002-02-06 2003-08-16 Schering Corp Novel gamma secretase inhibitors
WO2004058679A2 (fr) 2002-12-20 2004-07-15 Migenix Corp. Ligands d'adenine nucleotide translocase (ant) et compositions et methodes associees
KR20080019693A (ko) * 2005-06-09 2008-03-04 버텍스 파마슈티칼스 인코포레이티드 이온 채널 조절인자로서의 인단 유도체
US8357711B2 (en) * 2007-03-23 2013-01-22 Pfizer Limited Heterocyclic sulfonamides as inhibitors of ion channels
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
CN103889953B (zh) 2011-07-01 2016-06-08 巴鲁﹒S﹒布隆伯格研究所 作为防乙型肝炎病毒感染的抗病毒剂的氨磺酰苯甲酰胺衍生物
AU2019207491A1 (en) 2018-01-10 2020-07-30 Cura Therapeutics, Llc Pharmaceutical compositions comprising phenylsulfonamides, and their therapeutic applications
WO2021007474A1 (fr) * 2019-07-11 2021-01-14 Cura Therapeutics, Llc Composés de phényle et compositions pharmaceutiques associées, et leurs applications thérapeutiques

Family Cites Families (1)

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Publication number Priority date Publication date Assignee Title
DK0589336T3 (da) * 1992-09-22 1997-06-16 Hoechst Ag Benzylguanidiner, fremgangsmåde til deres fremstilling samt deres anvendelse som antiarytmetika

Non-Patent Citations (1)

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

Also Published As

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

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