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WO2003011828A2 - Nouveaux analgesiques - Google Patents

Nouveaux analgesiques Download PDF

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Publication number
WO2003011828A2
WO2003011828A2 PCT/US2002/023686 US0223686W WO03011828A2 WO 2003011828 A2 WO2003011828 A2 WO 2003011828A2 US 0223686 W US0223686 W US 0223686W WO 03011828 A2 WO03011828 A2 WO 03011828A2
Authority
WO
WIPO (PCT)
Prior art keywords
salt
formula
compound
attached
nitrogen
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.)
Ceased
Application number
PCT/US2002/023686
Other languages
English (en)
Other versions
WO2003011828A3 (fr
Inventor
Richard A. Glennon
Billy R. Martin
Malgozata Dukat
Imad M. Damaj
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.)
Virginia Commonwealth University
Original Assignee
Virginia Commonwealth University
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 Virginia Commonwealth University filed Critical Virginia Commonwealth University
Priority to AU2002327340A priority Critical patent/AU2002327340A1/en
Publication of WO2003011828A2 publication Critical patent/WO2003011828A2/fr
Publication of WO2003011828A3 publication Critical patent/WO2003011828A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07D213/60—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 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • the present invention relates to novel compounds having activity at nicotinic acetylcholine receptors.
  • the compounds have particular utility as peripheral analgesics, with advantage that they have relatively limited access to the central nervous system.
  • R 1 and R 2 are lower alkyl, are known actives at the nicotinic acetylcholine receptor (nACh) (see Cheng et al (1999) J. Med. Chem 34 177-190 incorporated herein by reference) with potential in therapy of anxiety, appetite disorder, pain and impaired cognition.
  • nACh nicotinic acetylcholine receptor
  • N,N-dimethyl-AXP (formula A wherein R and R are both methyl) has been found by the present inventors to be active in the tail flick pain assay.
  • R , R , R and A together with the carbon and nitrogen to which they are attached form a heterocyclic ring this is most preferably a 4, 5, 6 or 7 membered ring comprising only carbon and nitrogen, although oxygen and sulphur may also be present as preferred ring members.
  • compounds of Formulae I and II may exist as optical isomers which may be prepared in forms other than the 50:50 racemate by selection of chirally pure starting materials or by resolution of racemic forms using, eg. column chromatography eg. using chiral columns.
  • a method of treating a patient in need of therapy for pain comprising administering a therapeutically effect amount of a compound as described in the first aspect.
  • a compound of the first aspect for use in therapy, and particularly to treat pain.
  • a compound of the first aspect for use in therapy, and particularly to treat pain.
  • a compound of the first aspect in the manufacture of a medicament for the treatment of pain.
  • an analgesic composition comprising a compound of the first aspect.
  • compositions are sterile and pyrogen free if for parenteral administration.
  • parenteral administration and further for non-parenteral administration, ie. via oral, buccal, rectal, topical or transdermal routes, the composition will preferably comprise a pharmaceutically acceptable carrier, excipient or diluent.
  • a method for synthesising a compound of the first aspect of formula II comprising reacting a 2-(3-pyridoxyl)- ethan-halide, preferably chloride, with a tertiary amme of formula NR R R , where
  • R , R and R are as defined above to yield the halide salt of a compound of the invention.
  • the compounds of the invention may be formulated into the compositions of the invention by associating them, eg. by mixing or enclosing them, with a physiologically acceptable diluent or carrier for use as pharmaceuticals for veterinary, for example in a mammalian context, and particularly for human use, by a variety of methods. For instance, they may be applied as a composition incorporating a liquid diluent or carrier, for example an aqueous or oily solution, suspension or emulsion, which may often be employed in injectable form for parenteral administration and therefore may conveniently be sterile and pyrogen free. Oral administration is preferred for the preferred compounds of the invention.
  • compositions for this purpose may incorporate a liquid diluent or carrier, it is more usual to use a solid, for example a conventional solid carrier material such as starch, lactose, dextrin or magnesium stearate.
  • a solid carrier material such as starch, lactose, dextrin or magnesium stearate.
  • Such solid compositions may conveniently be of a formed type, for example as tablets, capsules (including spansules), powders etc.
  • compositions may be formulated in unit dosage form, i.e. in the form of discrete portions each comprising a unit dose, or a multiple or sub-multiple of a unit dose.
  • Typical dosages for use in human therapy will usually lie in the region of about 0.1 to 50g daily, preferably 0.5 g to 20 g daily, particularly from about 1 or 2 g to 10 or 15 g daily, for example about 5 g, veterinary doses being on a similar g/kg body weight ratio. However, it will be appreciated that it may be appropriate under certain circumstances to give daily dosages either below or above these levels. Where desired, more than one compound according to the present invention may be administered in the pharmaceutical composition, when the total dosage will usually correspond to those discussed.
  • APX of Formula A
  • ED50 1.5 mg/kg
  • the antinociceptive actions of APX are blocked by the nACh receptor antagonist mecamylamine.
  • Formula II Chemical structures of APX and APX-Q.
  • APX-Q Being a quaternary amine, APX-Q might not be expected to readily penetrate the blood brain barrier upon systemic administration. Consistent with this concept, the antinociceptive effects of APX-Q were blocked by hexamethonium (a nicotinic antagonist that does not readily penetrate the blood-brain barrier) at doses of 1 and 10 mg/kg. However, the locomotor effects of APX-Q were not blocked by hexamethonium.
  • APX-Q does not readily penetrate the blood-brain barrier, it could represent a novel type of nicotinic agonist with reduced central activity relative to nicotine; that is, it might be a mechanistically novel "peripherally-acting" analgesic.
  • preferred compounds of the invention may be compared with the existing prior art compounds as set out below.
  • Ethyl 3-pyridoxyacetate (APX-325). Ethyl bromoacetate (16.5 g, 0.1 mol) was added in a dropwise manner to a solution of 3-pyridinol sodium salt [prepared from 3- pyridinol (9.5 g, 0.1 mole) and 60% NaH (4.0 g, 0.1 mol) in DMSO (80 mL) at 0 °C] at 25 °C. The reaction was stirred at room temperature for 1 h. About 40 mL of DMSO was added and evaporated in vacuo. The residue was dissolved in H 2 O (150 mL), extracted with CHC1 3 (3 x 150 mL).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte à un sel représenté par la formule I dans laquelle R?1, R2 et R3¿ sont indépendamment choisis dans le groupe consistant en groupes alkyles C¿1-6? ou n'importe lequel des R?1, R2 et R3¿ peuvent, ensemble avec l'atome de nitrogène auquel ils sont attachés, former un noyau hétérocyclique. R4 est choisi dans le groupe des fractions qui sont capables de modifier la solubilité du composé dans des fluides physiologiques et dans des supports pharmaceutiques, n est un chiffre entier compris entre 0 et 5, A est choisi dans le groupe hydrogène ou peut, avec le carbone auquel il est attaché et avec n'importe lequel des R?1, R2 et R3¿ et l'atome de nitrogène auquel ils sont attachés, former un noyau hétérocyclique. X est un contre-ion chargé négatif et p représente le nombre de charges négatives, le nombre de molécules de l'ion amino tertiaire chargé positif égal au chiffre entier p dans n'importe quel sel. De préférence, ce sel est représente par la formule II.
PCT/US2002/023686 2001-07-31 2002-07-25 Nouveaux analgesiques Ceased WO2003011828A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002327340A AU2002327340A1 (en) 2001-07-31 2002-07-25 3-pyridylether rerivatives and their use as analgesics

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US30855701P 2001-07-31 2001-07-31
US60/308,557 2001-07-31

Publications (2)

Publication Number Publication Date
WO2003011828A2 true WO2003011828A2 (fr) 2003-02-13
WO2003011828A3 WO2003011828A3 (fr) 2003-10-16

Family

ID=23194447

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/023686 Ceased WO2003011828A2 (fr) 2001-07-31 2002-07-25 Nouveaux analgesiques

Country Status (2)

Country Link
AU (1) AU2002327340A1 (fr)
WO (1) WO2003011828A2 (fr)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL118279A (en) * 1995-06-07 2006-10-05 Abbott Lab Compounds 3 - Pyridyloxy (or Thio) Alkyl Heterocyclic Pharmaceutical Compositions Containing Them and Their Uses for Preparing Drugs to Control Synaptic Chemical Transmission

Also Published As

Publication number Publication date
AU2002327340A1 (en) 2003-02-17
WO2003011828A3 (fr) 2003-10-16

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