WO2000037426A1 - Nouveaux composes d'oxo-aminotetraline s'utilisant pour soulager la douleur - Google Patents

Nouveaux composes d'oxo-aminotetraline s'utilisant pour soulager la douleur Download PDF

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Publication number
WO2000037426A1
WO2000037426A1 PCT/SE1999/002402 SE9902402W WO0037426A1 WO 2000037426 A1 WO2000037426 A1 WO 2000037426A1 SE 9902402 W SE9902402 W SE 9902402W WO 0037426 A1 WO0037426 A1 WO 0037426A1
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WO
WIPO (PCT)
Prior art keywords
compound
tetrahydro
amino
naphthalen
trans
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PCT/SE1999/002402
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English (en)
Inventor
Dilip Dixit
Krzysztof Bednarski
Jean-Francois Lavallée
Tiechao Li
Edward Roberts
Richard Storer
Wuyi Wang
Original Assignee
Astrazeneca Ab
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Publication date
Priority claimed from SE9804494A external-priority patent/SE9804494D0/xx
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to JP2000589498A priority Critical patent/JP2002533320A/ja
Priority to EP99965659A priority patent/EP1140790A1/fr
Priority to AU21349/00A priority patent/AU2134900A/en
Publication of WO2000037426A1 publication Critical patent/WO2000037426A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/68—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/70—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/52—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/93—Spiro compounds
    • C07C2603/94—Spiro compounds containing "free" spiro atoms

Definitions

  • the present invention is related to compounds that exhibit analgesic activity and in particular compounds exhibiting analgesia due to their opioid receptor affinity.
  • the third, K exhibits equal affinity for either group of the above ligands and preferential affinity for dynorphin.
  • the ⁇ receptors seem to be more involved with analgesic effects.
  • the ⁇ receptors appear to deal with behavioral effects, although the 6 and the K receptors may also mediate analgesia.
  • Each opioid receptor when coupled with an opiate, causes a specific biological response unique to that type of receptor.
  • an opiate activates more than one receptor, the biological response for each receptor is affected, thereby producing side effects.
  • the present invention provides novel oxo-aminotetralin compounds which are represented by formula (I):
  • R 7 and Re are independently selected from the group consisting of H , OH, halogen, CN, COOH, CONH 2 , amino, nitro, SH, C ⁇ -6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2 ⁇ alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2-6 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N; and COORc wherein R « is C 2 _6alkenyl or C 2- 6alkynyl; R 7 and Rg can also be connected to form C 3-8 cycloalkyl, a C 3 .
  • Ri is selected from the group consisting of H, C ⁇ . t2 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2 - ⁇ 2 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2- ⁇ alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 6 _ ⁇ 2 aryl,
  • R 2 and R 3 are independently selected from the group consisting of C ⁇ . 6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2 - ⁇ alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2-6 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 6 -i 2 aryl, C 6 - ⁇ 2 aralkyl, heteroaryl having from 6 to 12 atoms, and H; or
  • R 2 and R 3 may together form a saturated heterocycle of from 3 to 8 atoms
  • R and R5 are independently selected from the group consisting of C ⁇ _ 6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2-6 alkenyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2-6 alkynyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, and H; R4 and Rs can also be connected to form C 3-8 cycloalkyl, a C 3-8 cycloalkenyl or a saturated heterocycle of from 3 to 8 atoms; R$ is hydrogen, OH, C ⁇ _ 6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, C 2 .
  • R 2 and R 3 are H or C ⁇ . 6 alkyl.
  • the compounds of the present invention are useful in therapy, in particular as analgesics.
  • a method of treating pain in a mammal comprising administering to said mammal an analgesic amount of a compound or composition of the present invention.
  • Still another aspect of the invention is the use of a compound according to formula (I), for the manufacture of a medicament for the treatment of pain.
  • compositions comprising compounds of the present invention and pharmaceutically acceptable carriers, diluents or adjuvants.
  • X is preferably -CR Rg- wherein R 7 and Re are independently selected from the group consisting of OH, halogen, CN, COOH, CONH 2 , amino, nitro, SH, C ⁇ _ 6 alkyl where one or more of the carbon atoms may optionally be substituted by one or more heteroatoms selected from O, S and N, H, and COOR c wherein R e is C ⁇ . 6 alkyl; R 7 and Rg can also be connected to form a C 3 . 8 cycloalkyl.
  • X is more preferably -CR 7 Rs- wherein R 7 and Rg are independently selected from the group consisting of C ⁇ _ 6 alkyl, and H. X is most preferably -CH 2 -.
  • Ri is preferably selected from the group consisting of H, C 6 -i 2 aryl, and C 6- i2 aralkyl.
  • Ri is more preferably selected from the group consisting of C 1-6 alkyl, C 6 -i2 aryl, and C 6- i 2 aralkyl. Ri is most preferably C ⁇ -6 alkyl.
  • Ri can also be , wherein n is an integer between 1 to 5, Rx and Rxi are independentiy H, C 2- ⁇ alkenyl or C 2 - 6 alkynyl. More preferably, n is 1 or 2 and Rx and Rxi are C h alky!. Most preferably, Rx and R i are methyl or ethyl.
  • Ri is selected from the group consisting of CH , -(CH2) n -
  • n is an integer selected between 1 and 5
  • Ri is C 6 .i2 aryl or heteroaryl having from 6 to 12 atoms.
  • Ri is selected from the group consisting of
  • A is selected from the group consisting of C ⁇ -6 alkyl, C ⁇ . 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, O-C 1-6 alkyl, O-C 2 - 6 alkenyl, O-C 2- 6alkynyl, , S-C ⁇ -6 alkyl, S-C 2-6 alkenyl, S-C 2 - 6 alkynyl, N-C ⁇ -6 alkyl, N-C 2 - 6 alkenyl, N-C 2- 6alkynyl, CF 3 , fluoro, chloro, bromo, iodo, OH, SH, CN, nitro, amino, aminoamidino, amidino, guanido, COOH, and COOR z wherein R z is C 1-6 alkyl, C 2-6 alkenyl or C 2 -6 lkynyl.
  • Ri is C 6- i 2 aralkyl or heteroaryl having from 6 to 12 atoms. More preferably, Ri is selected from the group consisting of
  • A is selected from the group consisting of C ⁇ alkyl, C ⁇ .6alkyl, C 2 ⁇ alkenyl, C 2-6 alkynyl, O-C 2-6 alkynyl, , S-d -6 alkyl, S-C 2- 6alkenyl, S-C 2 ⁇ alkynyl, N-C ⁇ alkyl, N-C ⁇ - ⁇ alkenyl, N-C - 6 alkynyl, CF 3 , fluoro, chloro, bromo, iodo, OH, SH, CN, nitro, amino, aminoamidino, amidino, guanido, COOH, and COOR z wherein R z is wherein m is an integer selected between 1 and 5.
  • Ri is preferably or wherein A and Y are as defined above.
  • A is preferably selected from the group consisting of C ⁇ . 6 alkyl, O-C ⁇ -6 alkyl,
  • R a is C ⁇ . 6 alkyl, C 2 - 6 alkenyl or C 2 - 6 alkynyl.
  • A is more preferably selected from the group consisting of C ⁇ -6 alkyl, OH, nitro, amino, aminoamidino, amidino, guanido, and
  • COOH is most preferably selected from the group consisting of amidino, guanido, and
  • R 2 and R 3 are preferably H.
  • R 4 and R 5 are preferably C M alkyl substituted by a hydroxyl.
  • R4 and R 5 are preferably C alkyl.
  • R 4 and R 5 are independently selected from the group consisting of methyl, ethyl, isopropyl, propyl, butyl, and isobutyl.
  • R4 and R 5 are preferably ethyl.
  • R4 and R 5 are preferably methyl.
  • R can be substituted at any position on the aromatic ring. More preferably R$ is adjacent to the carbon bearing the OH.
  • the present invention provides compounds of the formula (II) or (HI)
  • R is preferably, H, methyl, halogen or OR b wherein R t , is C ⁇ . 6 alkyl, C2- 6 alkenyl or
  • R « is most preferably H.
  • the compounds of the present invention contains at least 2 chiral centers which are marked by an asterik (*) on the general formula (I).
  • the compounds of formula (I) thus exist in the form of different geometric( i.e. trans and cis) and optical isomers (i.e. (+) or (-) enantiomers).
  • the compounds may be therefore be in the form of cis isomers or trans isomers.
  • Each cis or trans isomers also exists as a (+) and (-) enantiomer. All such isomers, enantiomers and mixtures thereof including racemic mixtures are included within the scope of the invention.
  • the compounds of the present invention are in the form of the trans isomers (between the centers marked by an asteriks on the general formula (I)). More preferably the compounds of the present invention are present in the form of trans- (+) enantiomers and trans (-) enantiomers.
  • Preferred compounds of the invention include:
  • More Preferred compounds of this invention are selected from the group consisting of: compound#l, compound#2, compound#3, compound#4, compound#5, compound#6, compound#7, compound#8, compound#9, compound#12, compound#16, compound#17, compound#18 and compound#19.
  • Most preferred compounds of the present invention are selected from the group consisting of compound#l, compound#2, compound#5, compound#8, compound#9, compound#16, compound#17, compound#18 and compound#19.
  • pain represents "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.
  • pain also includes “acute pain” and chronic pain.
  • Acute pain is usually immediate and of a short duration. Acute pain can be present further to an injury, short-term illness, or surgical/medical procedure.
  • Examples of acute pain include a burn, a fracture, an overused muscle, or pain after surgery. Cancer pain may be long-lasting but acute due to ongoing tissue damage.
  • Some chronic pain is due to damage or injury to nerve fibers themselves (neuropathic pain).
  • Chronic pain can result from diseases, such as shingles and diabetes, or from trauma, surgery or amputation (phantom pain). It can also occur without a known injury or disease.
  • alkyl represents an unsubstituted or substituted (by a halogen, nitro, aminoamidino, amidino, guanido, CONH 2 , COOH, O-C ⁇ . 6 alkyl, O-C 2 - 6 alkenyl, O-C 2 - 6 alkynyl, amino, hydroxyl or COOQ, wherein Q is C ⁇ _6 alkyl, C 2 - 6 alkenyl, a C 2 . 6 alkynyl) straight chain, branched chain, or cyclic hydrocarbon moiety (e.g.
  • alkyl is also meant to include alkyls in which one or more hydrogen atoms is replaced by an halogen, more preferably, the halogen is fluoro (e.g., CF 3 -, or CF 3 CH 2 -).
  • saturated heterocycle represents a carbocyclic ring in which one or more of the from 3 to 8 atoms of the ring are elements other than carbon, such as N, S and O;
  • aryl represents an aromatic ring having from 6 to 12 carbon atoms, which may be substituted by a C 1-6 alkyl, C 2-6 alkenyl, a C2-6 alkynyl, halogen, nitro, aminoamidino, amidino, guanido, CONH 2 .
  • aralkyl represents an aryl group attached to the adjacent atom by a C ⁇ -6 alkyl, or C ⁇ - 6 alkynyl(e.g., benzyl).
  • aryloxy represents an aryl or aralkyl moiety covalently bonded through an oxygen atom (e.g., phenoxy).
  • heteroaryl represents an aromatic ring in which one or more of the from
  • acyl refers to a radical derived from a carboxylic acid, substituted (by halogen(F, Cl, Br, I), C ⁇ - 2 o aryl or C ⁇ -6 alkyl) or unsubstituted, by replacement of the OH group.
  • an acyl radical may be aliphatic or aromatic, substituted (by halogen, C 1 .
  • phosphoryl represents a radical derived from a phosphono moeity in which the hydrogen atom of at least one of the -OH can be replaced by C ⁇ . 6 alkyl, C 2-6 alkenyl, C 2- 6alkynyl, C 6- ⁇ 2 aryl, C 6- ⁇ 2 aralkyl, and C 6 . ⁇ 2 heteroaryl(e.g., diethoxyphosphorylmethyl).
  • halogen encompasses chloro, fluoro, bromo and iodo.
  • the sulfur atom can be at different oxydation level, S, SO, or SO 2 . All such oxydation level are within the scope of the present invention.
  • the starting ketone AA was dissolved in a suitable solvent such as DMF, acetonitrile, THF, DME and was treated with sodium hydride or any other base such as potassium t- butoxide, sodium bis(trimethylsilyl)amide.
  • a suitable solvent such as DMF, acetonitrile, THF, DME
  • sodium hydride or any other base such as potassium t- butoxide, sodium bis(trimethylsilyl)amide.
  • the resulting mixture was then treated with ethyl iodide or any other alkyl halide such as methyl iodide, allyl bromide, diiodobutane to produce the compound A.
  • the compound A was dissolved in a suitable solvent such as pyridine, DMF, ethanol and was treated with hydroxylamine hydrochloride or any other hydroxylamine salt such as hydroxylamine sulfate, hydroxylamine bromide to produce the compound B.
  • a suitable solvent such as pyridine, DMF, ethanol
  • hydroxylamine hydrochloride or any other hydroxylamine salt such as hydroxylamine sulfate, hydroxylamine bromide
  • the compound B was dissolved in a suitable solvent as THF, dioxane, DME, and was treated with LAH or any other reducing agent such as red-Al in presence of diethylamine or any other amine such as methylbutylamine, dipropylamine. The mixture was then heated to 50°C or at any higher temperature to produce the compound C.
  • a suitable solvent as THF, dioxane, DME, and was treated with LAH or any other reducing agent such as red-Al in presence of diethylamine or any other amine such as methylbutylamine, dipropylamine.
  • the compound C in was dissolved in a suitable solvent as dichloromethane (CH 2 C1 2 ) or in any other solvent such as dichloroethane, and was treated with BBr 3 or any other demethylating agent such as BC1 3 , HBr, to produce the compound D.
  • a suitable solvent as dichloromethane (CH 2 C1 2 ) or in any other solvent such as dichloroethane
  • BBr 3 any other demethylating agent such as BC1 3 , HBr
  • the compound E was dissolved in a suitable solvent such as ethanol or in any other alcohol such as methanol, propanol, butanol and was treated with pyridinium p-toluenesulfonate (PPTS) or any other acid or Lewis acid such as HC1, BF 3 .OEt 2 , PTS A, to produce the compound F.
  • a suitable solvent such as ethanol or in any other alcohol such as methanol, propanol, butanol and was treated with pyridinium p-toluenesulfonate (PPTS) or any other acid or Lewis acid such as HC1, BF 3 .OEt 2 , PTS A, to produce the compound F.
  • PPTS pyridinium p-toluenesulfonate
  • HC1, BF 3 .OEt 2 , PTS A pyridinium p-toluenesulfonate
  • a non alcoholic solvent can be used in combination with
  • the protecting groups of the compound F were removed under appropriate conditions e.g. with TFA or with any other acid such as HC1, PTS A, to produce the compound I.
  • a method of agonizing or activating opioid receptors in a mammal comprising administering to said mammal an opioid receptor agonizing or activating amount of a compound or composition of the invention.
  • compositions comprising compounds of the present invention and derivatives thereof, in combination with pharmaceutically acceptable carriers diluents or adjuvants.
  • derivative is meant any pharmaceutically acceptable salt, ester, or salt of such ester, of compounds of formula (I) or (II) or any other compound which, upon administration to the recipient, is capable of providing (directly or indirectly) compounds of formula (I) or (II) or an active metabolite or residue thereof.
  • compositions which comprise a pharmaceutically effective amount of a compound of the invention, or pharmaceutically acceptable salts thereof, and preferably, a pharmaceutically acceptable carrier, diluent or adjuvant.
  • pharmaceutically effective amount is the amount of compound required upon administration to a mammal in order to induce analgesia.
  • opioid receptor agonizing amount refers to the amount of compound administered to a mammal necessary to bind and/or activate opioid receptors in vivo.
  • Therapeutic methods of this invention comprise the step of treating patients in a pharmaceutically acceptable manner with those compounds or compositions.
  • Such compositions may be in the form of tablets, capsules, caplets, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • a composition of the invention is in the form of a unit dose.
  • the unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients.
  • binding agents such as acacia, gelatin, sorbitol, or polyvinylpyrolidone
  • fillers such as lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants such as magnesium stearate
  • disintegrants such as starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose
  • pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • the compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like.
  • the compounds may be administered orally in the form of solutions which may contain coloring and/or flavoring agents.
  • the compounds may also be administered sublingually in the form of tracheas or lozenges in which each active ingredient is mixed with sugar or corn syrups, flavoring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form.
  • the solid oral compositions may be prepared by conventional methods of blending, filling, tableting, or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • Liquid oral preparations may be in the form of emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may or may not contain conventional additives.
  • suspending agents such as sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, or hydrogenated edible fats
  • emulsifying agents such as sorbitan monooleate or acaci
  • non-aqueous vehicles which may include edible oils), such as almond oil, fractionated coconut oil, oily esters selected from the group consisting of glycerine, propylene glycol, ethylene glycol, and ethyl alcohol
  • preservatives for instance methyl para-hydroxybenzoate, ethyl para-hydroxybenzoate, n- propyl parahydroxybenzoate, or n-butyl parahydroxybenzoate of sorbic acid
  • the compounds may be injected parenterally; this being intramuscularly, intravenously, or subcutaneously.
  • the compound may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic.
  • fluid unit dosage forms may be prepared by utilizing the compound and a sterile vehicle, and, depending on the concentration employed, may be either suspended or dissolved in the vehicle.
  • the compound Once in solution, the compound may be injected and filter sterilized before filling a suitable vial or ampoule and subsequently sealing the carrier or storage package.
  • Adjuvants such as a local anesthetic, a preservative or a buffering agent, may be dissolved in the vehicle prior to use.
  • Stability of the pharmaceutical composition may be enhanced by freezing the composition after filling the vial and removing the water under vacuum, (e.g., freeze drying the composition).
  • Parenteral suspensions may be prepared in substantially the same manner, except that the compound should be suspended in the vehicle rather than being dissolved, and, further, sterilization is not achievable by filtration.
  • the compound may be sterilized, however, by exposing it to ethylene oxide before suspending it in the sterile vehicle.
  • a surfactant or wetting solution may be advantageously included in the composition to facilitate uniform distribution of the compound.
  • compositions of this invention comprise a pharmaceutically effective amount of a compound of this invention and a pharmaceutically acceptable carrier. Typically, they contain from about 0.01% to about 99% by weight, preferably from about 10% to about 60% by weight, of a compound of this invention, depending on which method of administration is employed.
  • the compounds of the present invention can be administered in combination with one or more further therapeutic agents.
  • the one or more further therapeutic agent is selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, narcotics, antidepressants, anticonvulsants, corticosteroid, tramadol, sumatriptan, and capsaicin.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • acetaminophen acetaminophen
  • narcotics antidepressants
  • anticonvulsants corticosteroid
  • tramadol tramadol
  • sumatriptan sumatriptan
  • capsaicin capsaicin.
  • NSAIDs include aspirin (Anacin, Bayer, Bufferin), ibuprofen (Motrin, Advil, Nuprin), naproxen sodium (Aleve) and ketoprofen (Orudis KT)
  • narcotics include drugs derived from opium (opiates), such as morphine and codeine, and synthetic narcotics (opioids), such as oxycodone, methadone and meperidine (Demerol).
  • antidepressants include amitriptyline (Elavil), trazodone (Desyrel) and imipramine (Tofranil) may be used with other analgesics. These drugs are especially useful for neuropathic, head and cancer pain.
  • anticonvulsants include drugs developed for epilepsy, these drugs, such as phonation (Dilantin) and carbamazepine (Tegretol), can also help control chronic nerve pain.
  • Tramadol (Ultram) is a synthetic analgesic used primarily for chronic pain, but is also prescribed for acute pain.
  • Sumatriptan (Imitrex),may reduce pain from migraine headache by constricting blood vessels.
  • Capsaicin (Zostrix), a topical cream made from an extract of red peppers, can help relieve skin sensitivity resulting from shingles. Capsaicin can also be used to treat pain from arthritis, cluster headaches, diabetic neuropathy and pain after mastectomy.
  • compounds may be used to identify opioid receptors from non-opioid receptors.
  • compounds of the invention are radiolabeled e.g.
  • radiolabeled forms can be used directly to identify the presence of opioid receptors and in particular ⁇ opioid receptors in a receptor population. This can be achieved by incubating membrane preparations with a radiolabeled compound of the invention. The presence and or amount of opioid receptors in the preparation is determined from the difference in membrane-bound radioactivity against a control preparation devoid of opioid receptors. Furthermore, radiolabeled forms of the present compounds can be exploited to screen for more potent opioid ligands, by determining the ability of the test ligand to displace the radiolabeled compound of the present invention.
  • Step 1 l,l-DiethyI-7-methoxy-3,4-dihydro-lH-naphthalen-2-one (A)
  • Step 2 l,l-Diethyl-7-methoxy-3,4-dihydro-lH-naphthalen-2-one oxime (B)
  • Step 4 7,7-DiethyI-la,2,7,7a-tetrahydro-lH-l-aza-cyclopropa[b]naphthalen-5-oI(D)
  • Step 5 5-tert-Butoxycarbonyloxy-7,7-diethyI-la,2,7,7a-tetrahydro-l-aza- cyclopropa[b]naphthalene-l-carboxylic acid tert-butyl ester (E)
  • Step 6 Carbonic acid 7-tert-butoxycarbonyIamino-trans-6-ethoxy-8,8-diethyl- 5,6,7,8-tetrahydro-naphthalen-2-yl ester tert-butyl ester (F)
  • Step 7 Carbonic acid 7-tert-butoxycarbonyIamino-trans-6-ethoxy-8,8-diethyU 5,6,7,8-tetrahydro-naphthalen-2-yl ester tert-butyl ester
  • Step 8 Trans-3-Ethoxy-l,l-diethyI-7-hydroxy-1 ⁇ 2 ,4-tetrahydro-naphthalen-2-yl- ammonium chloride (compound #1)
  • Carbonic acid 7-tert-butoxycarbonylamino-trans-6-ethoxy-8,8-diethyl-5,6,7,8-tetrahydro- naphthalen-2-yl ester tert-butyl ester (200mg ; 0.43mmol) placed under nitrogen at room temperature was dissolved in tetrahydrofuran (5.0mL) and trifluoroacetic acid (3.0mL) was then added and the reaction mixture was stirred for about an hour. The solvents were then evaporated by vacuo and a solution of hydrochloric acid in ether (1.0M) (50mL) was then added. The reaction mixture thus obtained was then stirred for another hour. The solvents were removed by vacuo and the isolated solid washed several times with ether than dichloromethane. The isolated product is a yellow powder (145mg, >99%).
  • Trans-7-Amino-6-ethoxy-8,8-diethyl-5,6,7,8-tetrahydro-naphthalen-2-ol (23 lmg ; 0.88mmol) is placed under nitrogen at room temperature and dissolved with anhydrous acetonitrile (20 mL). Triethylamine 0.25mL (1.75mmol) and the chiral auxiliary reagent 504mg (1.75mmol) are then added. The reaction mixture thus obtained was heated overnight at reflux. The following day, the reaction mixture is cooled back to room temperature and it is then poured into an aqueous solution of sodium bicarbonate and extracted using dichloromethane.
  • (+)Trans-3-Ethoxy-l,l-diethyl-7-hydroxy-1 ⁇ 3?4-tetrahydro-naphthaIen-2-yI-ammonium chloride (compound #16) Carbonic acid trans-6-ethoxy-8,8-diethyl-7-(l-phenyl-ethoxycarbonylamino)-5,6,7,8-tetrahydro- naphthalen-2-yl ester 1-phenyl-ethyl ester (more polar isomer) (32mg ; 0.057mmol) placed unde nitrogen at room temperature was dissolved in dichloromethane (5.0mL) and trifluoroacetic acid (3.0mL) was then added and the reaction mixture was stirred for about an hour.
  • Affinity for ⁇ and ⁇ opioid receptors was assessed in vitro using radioligand binding assay employing rat brain membrane preparations as described in Schiller et al., Biophys. Res. Commun., 85, p.1322 (1975) incorporated herein by reference.
  • Male Sprague-Dawley rats weighing between 350-450g were sacrificed by inhalation of CO2.
  • the rats were decapitated and the brains minus cerebellum were removed and place in ice-cold saline solution and then homogenized in ice-cold 50 mM Tris buffer pH 7.4 (lOml/brain).
  • the membranes were centrifuged at 14000 rpm for 30 min. at 4°C.
  • the pellets were re- suspended in approximately 6ml/brain of ice-cold Tris buffer 50mM pH 7.4 and stored at - 78°C until ready for use. Protein quantification of the brain homogenate was conducted according to protein assay kit purchased (Bio-Rad).
  • Radioligand 50 ⁇ l, membranes 100 ⁇ l and serially diluted test compound were incubated for 1 hr at 22°C. Non specific binding was determined using 500 fold excess of unlabeled ligand in the presence of tracer and membranes. Free ligand was separated from bound by filtration through Whatman GF/B paper (presoaked in polyethylenimine 1% aqueous solution) and rinsing with ice-cold 50mM Tris pH 7.4 using a Brandel cell harvester.
  • PBQ phenyl-p-benzoquinone
  • ED50 values dose of compound which induced a 50% reduction in the number of writhes observed compared to the control
  • PBQ solution was prepared by dissolving 20mg of PBQ in 5ml ethanol 90% (sigma, reagent, alcohol). The dissolved PBQ was slowly added to 95ml of distilled water continuously shaken and preheated (not boiled). The PBQ solution was left 2 hours before use, and at all times, protected from light. A new solution was prepared every day for the test.

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  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne de nouveaux composés d'oxo-aminotétraline de formule (I), dans laquelle X, R1, R2, R3, R4, R5, et R6 sont définis dans la description. Ces composés de formule (I) s'utilisent pour soulager la douleur.
PCT/SE1999/002402 1998-12-22 1999-12-17 Nouveaux composes d'oxo-aminotetraline s'utilisant pour soulager la douleur WO2000037426A1 (fr)

Priority Applications (3)

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JP2000589498A JP2002533320A (ja) 1998-12-22 1999-12-17 疼痛管理に有用な新規なオキソ−アミノテトラリン化合物
EP99965659A EP1140790A1 (fr) 1998-12-22 1999-12-17 Nouveaux composes d'oxo-aminotetraline s'utilisant pour soulager la douleur
AU21349/00A AU2134900A (en) 1998-12-22 1999-12-17 Novel oxo-aminotetralin compounds useful in pain management

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US11354198P 1998-12-22 1998-12-22
SE9804494A SE9804494D0 (sv) 1998-12-22 1998-12-22 Novel compounds
US60/113,541 1998-12-22
SE9804494-4 1998-12-22

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7547713B2 (en) * 2002-08-23 2009-06-16 Lianquan Gu O-pyridinequinone derivatives, the composition containing the derivatives, the process for preparation of the derivatives and the use of the derivatives
WO2009076399A2 (fr) 2007-12-11 2009-06-18 Theravance, Inc. Composés d'aminotétraline en tant qu'agonistes de récepteur opioïde mu
WO2009076408A2 (fr) 2007-12-11 2009-06-18 Theravance, Inc. Dérivés de 3-carboxypropyl-aminotétraline et composés associés en tant qu'antagonistes du récepteurs mu-opioïde
WO2009124022A1 (fr) * 2008-04-01 2009-10-08 Theravance, Inc. Dérivés de 2-aminotétraline en tant qu'antagonistes du récepteur mu-opioïde

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JPS4857962A (fr) * 1971-11-26 1973-08-14
GB1377356A (en) * 1972-08-14 1974-12-11 Eisai Co Ltd Tetrahydronaphthalene derivatives useful as pharmaceuticals
JPS5037764A (fr) * 1973-08-10 1975-04-08
EP0378456A1 (fr) * 1989-01-09 1990-07-18 Merrell Dow Pharmaceuticals Inc. Dérivés de tétraline

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JPS4857962A (fr) * 1971-11-26 1973-08-14
GB1377356A (en) * 1972-08-14 1974-12-11 Eisai Co Ltd Tetrahydronaphthalene derivatives useful as pharmaceuticals
JPS5037764A (fr) * 1973-08-10 1975-04-08
EP0378456A1 (fr) * 1989-01-09 1990-07-18 Merrell Dow Pharmaceuticals Inc. Dérivés de tétraline

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CHEMICAL ABSTRACTS, vol. 84, no. 7, 16 February 1976, Columbus, Ohio, US; abstract no. 43700E, COLUMBUS, OHIO, USA XP002947888 *
DATABASE CAPLUS [online] CHRISTOVA, K. ET. AL.: "Derivaties of 2-amino-1,2,3,4-tetrahydronaphthalene. VII. Aroyl esters of cis- and trans-2-dimethylamino-3-hydroxy-5,8-dimethoxy. 1,2,3,4-tetrahydronaphtphalenes", XP002947837, retrieved from 97:197950 accession no. STN Int., File CAPLUS Database accession no. 1982:597950 *
DATABASE CAPLUS [online] HIROSE, NORIYASU ET. AL.: "Synthesis and analgesic activities of some 2-amino-1, 1-dialky1-7-methoxy-1,2,3,4-tetrahydronaphthalenes and related compounds", XP002947835, retrieved from 85:142882 accession no. STN Int., File Caplus Database accession no. 1976:542882 *
DATABASE CAPLUS [online] RAINOVA, L. ET. AL.: "Neuropharmacological profile of an amninotet-ralin derivatie", XP002947838, retrieved from 88:182828 accession no. STN Int, File CAPLUS Database accession no. 1978:182828 *
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EKSP. MED. MORFOL., vol. 16, no. 4, 1977, pages 211 - 216 *
SOFIA, FARMATSIYA, vol. 34, no. 3, 1984, pages 15 - 19 *
YAKUGAKU ZASSHI, vol. 96, no. 2, 1976, pages 185 - 194 *

Cited By (21)

* Cited by examiner, † Cited by third party
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US7547713B2 (en) * 2002-08-23 2009-06-16 Lianquan Gu O-pyridinequinone derivatives, the composition containing the derivatives, the process for preparation of the derivatives and the use of the derivatives
AU2008335210B2 (en) * 2007-12-11 2013-10-10 Theravance Biopharma R&D Ip, Llc 3 -carboxypropyl-aminotetralin derivatives as mu opioid receptor antagonists
US8497287B2 (en) 2007-12-11 2013-07-30 Theravance, Inc. Aminotetralin compounds as mu opioid receptor antagonists
WO2009076408A3 (fr) * 2007-12-11 2009-09-03 Theravance, Inc. Dérivés de 3-carboxypropyl-aminotétraline et composés associés en tant qu'antagonistes du récepteurs mu-opioïde
WO2009076399A3 (fr) * 2007-12-11 2009-09-17 Theravance, Inc. Composés d'aminotétraline en tant qu'agonistes de récepteur opioïde mu
US8969370B2 (en) 2007-12-11 2015-03-03 Theravance Biopharma R&D Ip, Llc 3-carboxypropyl-aminotetralin derivatives and related compounds as mu opioid receptor antagonists
CN101896455A (zh) * 2007-12-11 2010-11-24 施万制药 作为mu阿片类受体拮抗剂的3-羧基丙基-氨基四氢萘衍生物
US8101791B2 (en) 2007-12-11 2012-01-24 Theravance, Inc. Aminotetralin compounds as mu opioid receptor antagonists
US8318765B2 (en) 2007-12-11 2012-11-27 Theravance, Inc. 3-carboxypropyl-aminotetralin derivatives and related compounds as mu opioid receptor antagonists
KR101610165B1 (ko) 2007-12-11 2016-04-08 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 뮤 오피오이드 수용체 길항제로서의 3-카르복시프로필-아미노테트랄린 유도체
US8314128B2 (en) 2007-12-11 2012-11-20 Theravance, Inc. Aminotetralin compounds as mu opioid receptor antagonists
US8106232B2 (en) 2007-12-11 2012-01-31 Theravance, Inc. 3-carboxypropyl-aminotetralin derivatives and related compounds as mu opioid receptor antagonists
RU2482107C2 (ru) * 2007-12-11 2013-05-20 Тереванс, Инк. Производные 3-карбоксипропил-аминотетралина и родственные соединения в качестве антагонистов mu-опиоидного рецептора
US8492399B2 (en) 2007-12-11 2013-07-23 Theravance, Inc. 3-carboxypropyl-aminotetralin derivatives and related compounds as mu opioid receptor antagonists
WO2009076408A2 (fr) 2007-12-11 2009-06-18 Theravance, Inc. Dérivés de 3-carboxypropyl-aminotétraline et composés associés en tant qu'antagonistes du récepteurs mu-opioïde
WO2009076399A2 (fr) 2007-12-11 2009-06-18 Theravance, Inc. Composés d'aminotétraline en tant qu'agonistes de récepteur opioïde mu
TWI412360B (zh) * 2007-12-11 2013-10-21 Theravance Inc 作為ｍｕ類鴉片受體拮抗劑之３－羧基丙基－胺基四氫萘衍生物及相關化合物
US8703791B2 (en) 2007-12-11 2014-04-22 Theravance, Inc. 3-carboxypropyl-aminotetralin derivatives and related compounds as mu opioid receptor antagonists
US8952031B2 (en) 2008-04-01 2015-02-10 Theravance Biopharma R&D Ip, Llc Amino- and amido-aminotetralin derivatives and related compounds as mu opioid receptor antagonists
WO2009124022A1 (fr) * 2008-04-01 2009-10-08 Theravance, Inc. Dérivés de 2-aminotétraline en tant qu'antagonistes du récepteur mu-opioïde
US8153686B2 (en) 2008-04-01 2012-04-10 Theravance, Inc. Amino- and amido-aminotetralin derivatives and related compounds as mu opioid receptor antagonists

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