WO1997020556A9 - Methode de traitement de la douleur - Google Patents

Methode de traitement de la douleur

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Publication number
WO1997020556A9
WO1997020556A9 PCT/US1996/019390 US9619390W WO9720556A9 WO 1997020556 A9 WO1997020556 A9 WO 1997020556A9 US 9619390 W US9619390 W US 9619390W WO 9720556 A9 WO9720556 A9 WO 9720556A9
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WO
WIPO (PCT)
Prior art keywords
thiadiazol
tetrahydro
methylpyridine
azabicyclo
octane
Prior art date
Application number
PCT/US1996/019390
Other languages
English (en)
Other versions
WO1997020556A1 (fr
Filing date
Publication date
Priority to NZ324594A priority Critical patent/NZ324594A/en
Application filed filed Critical
Priority to CA002239732A priority patent/CA2239732A1/fr
Priority to HU0000110A priority patent/HUP0000110A3/hu
Priority to PL96327144A priority patent/PL327144A1/xx
Priority to EA199800535A priority patent/EA199800535A1/ru
Priority to IL12478696A priority patent/IL124786A0/xx
Priority to KR1019980704268A priority patent/KR19990071977A/ko
Priority to EP96942906A priority patent/EP0866702A4/fr
Priority to AU11476/97A priority patent/AU715645B2/en
Priority to JP09521436A priority patent/JP2000501711A/ja
Publication of WO1997020556A1 publication Critical patent/WO1997020556A1/fr
Publication of WO1997020556A9 publication Critical patent/WO1997020556A9/fr
Priority to NO982582A priority patent/NO982582L/no

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Definitions

  • the present invention relates to a method for using azacyclic, azabicyclic, or tetrahydropyridine compounds for treating pain.
  • This invention relates to a therapeutic combination of compounds to provide analgesic activity.
  • More active analgesic combinations effects are in constant demand because they offer the attractive possibility of relieving pain with reduced dosages, thereby diminishing the expected side effects and toxicity that would otherwise result from higher dosages. It would be particularly desirable to acquire a synergistic combination effect.
  • Such a composition is the subject of the present invention.
  • the present invention provides a method for treating pain comprising administering to a patient in need thereof, an anagesic composition comprising a compound of Formula I
  • X is oxygen or sulphur
  • R is hydrogen, amino, halogen, -CHO, -NO 2 , -OR 4 , -SR 4 , -SOR 4 ,
  • R 4 is straight or branched C ⁇ - 1 5-alkyl, straight or branched C 2 - 15 - alkenyl, straight or branched C 2 -i 5 -alkynyl, each of which is optionally substituted with one or more halogens, -CF 3 , -CN, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, C ⁇ - 4 -alkyl, C ⁇ - 4 -alkoxy, -OCF 3 , -CONH 2 or -CSNH 2 ; or R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with
  • Y is a 5 or 6 membered heterocyclic group containing one to four N, O or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched C ⁇ _ 6 -alkyl, phenyl or benzyl, or which heterocyclic group is optionally fused with a phenyl group; and G is selected from one of the following azabicyclic rings
  • R 1 and R 2 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C ⁇ _ 5 -alkyl, straight or branched C 2 - 5 alkenyl, straight or branched C 2 - 5 -alkynyl, straight or branched C ⁇ - 10 -alkoxy, straight or branched C 1 - 5 - alkyl substituted with -OH, OR 4 , halogen, -NH 2 or carboxy;
  • R 3 is H, straight or branched C ⁇ _ 5 -alkyl, straight or branched C 2 - 5 -alkenyl or straight or branched C 2 - 5 -alkynyl; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2;
  • the present invention provides a method for treating pain comprising administering to a patient in need thereof, an anagesic composition comprising a compound of Formula II
  • Z 1 ' is oxygen or sulphur
  • R' is hydrogen, halogen, amino, -NHCO-R 2 ', C 3 - 7 -cycloalkyl, C 4 - ⁇ o ⁇ (cycloalkylalkyl) , -Z 2 ' -C 3 _ 7 -cycloalkyl optionally substituted with C ⁇ _6-alkyl, -Z 2 '-C 4 -. 10 - (cycloalkylalkyl) , -Z 2 '-C4_ ⁇ o- (cycloalkenylalkyl) , -Z 2 '-C4_ ⁇ o- (methylenecycloalkyl-alkyl) ,
  • Z 2 ', Z 3 ', and Z 4 ' independently are oxygen or sulphur
  • R 2 ' , R 3 ' and R 4 ' independently are straight or branched C ⁇ _i 5 -alkyl, straight or branched C -i 5 -alkenyl, straight or branched C 2 -i5-alkynyl, each of which is optionally substituted with halogen(s), -OH, -CN, -CF 3 , -SH, -COOH, -NH-R 2 ' , -NR 2 'R 3 ', C ⁇ _ 6 alkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wherein each aromatic group is optionally substituted with one or two halogen, -CN, C ⁇ - 4 -alkyl or
  • R 5 ' and R 6 ' may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C 1 - 5 - alkyl, straight or branched C 2 - 5 -alkenyl, straight or branched C 2 - 5 -alkynyl, straight or branched Cj 10 -alkoxy, straight or branched C ⁇ - 5 -alkyl substituted with -OH, -OH, halogen, -NH 2 or carboxy;
  • R 1 ' is hydrogen, straight or branched C ⁇ - 5 -alkyl, straight or branched C 2 - 5 ⁇ alkenyl or straight or branched C 2 - 5 -alkynyl; or a pharmaceutically acceptable salt or solvate thereof; and one or more nonsteroidal anti-inflammatory drug in a weight ratio of Formula II to nonsteroidal anti- inflammatory drug of from about 1 to about 1000.
  • Preferred NSAIDS include, but are in no way limited to salicylates such as aspirin, indomethacin, ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac.
  • salicylates such as aspirin, indomethacin, ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac.
  • Especially preferred NSAIDS include aspirin, ibuprofen, and naproxen.
  • Alternative preferred NSAIDS include ibuprofen and naproxen.
  • Alternative particularly preferred NSAIDS include ibuprofen.
  • the invention further provides a composition for treating pain comprising a compound selected from the group consisting of Formula I and Formula II; or a pharmaceutically acceptable salt or solvate thereof; and a a nonsteroidal anti-inflammatory drug in a weight ratio of Compound to a nonsteroidal anti-inflammatory drug of from about 1 to about 1000.
  • the present invention provides a method for treating pain comprising administering to a patient in need thereof, an anagesic composition comprising a compound selected from the group consisting of Formula I and Formula II; or a pharmaceutically acceptable salt or solvate thereof; and acetaminophen in a weight ratio of Compound to acetaminophen of from about 1 to about 1000.
  • composition for treating pain comprising an analgesic dose of a compound selected from the group consisting of Formula I
  • X is oxygen or sulphur;
  • R is hydrogen, amino, halogen, -CHO, -NO 2 , -OR 4 , -SR 4 , -SOR 4 , -SO2R 4 , C3-7-cycloalkyl, C 4 - 8 -(cycloalkylalkyl) , -Z-C 3 - 7 - cycloalkyl, and -Z-C 4 -8- (cycloalkylalkyl) wherein R 4 is straight or branched C ⁇ _i5-alkyl, straight or branched C 2 - 15 - alkenyl, straight or branched C 2 -i 5 -alkynyl, each of which is optionally substituted with one or more halogens, -CF 3 , -CN, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, C ⁇ - 4 -alkyl, C ⁇ -
  • Y is a 5 or 6 membered heterocyclic group containing one to four N, 0 or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched C ⁇ - 6 -alkyl, phenyl or benzyl, or which heterocyclic group is optionally fused with a phenyl group; and G is selected from one of the following azabicyclic rings
  • R 1 and R 2 may be present at any position, including the point of attachment of the thiadiazole or oxadiazole ring, and independently are hydrogen, straight or branched C 1 - 5 - alkyl, straight or branched C 2 - B alkenyl, straight or branched C 2 - 5 -alkynyl, straight or branched C ⁇ - 10 -alkoxy, straight or branched C ⁇ _ 5 -alkyl substituted with -OH, OR 4 , halogen, -NH 2 or carboxy;
  • R 3 is H, straight or branched C ⁇ _ 5 -alkyl, straight or branched C 2 - 5 -alkenyl or straight or branched C 2 - 5 -alkynyl; n is 0, 1 or 2; m is 0, 1 or 2; p is
  • Z 1 ' is oxygen or sulphur
  • R' is hydrogen, halogen, amino, -NHCO-R 2 ', C 3 - 7 -cycloalkyl, C 4 - 10 - (cycloalkylalkyl) , -Z 2 ' -C 3 _ 7 -cycloalkyl optionally substituted with C _ 6 -alkyl, -Z 2 ' -C 4 - 10 - (cycloalkylalkyl) , -Z 2 '-C _ ⁇ o-(cycloalkenylalkyl) , -Z 2 '-C 4 - ⁇ 0 - (methylenecycloalkyl-alkyl) ,
  • Z 2 ' , Z 3 ' , and Z 4 ' independently are oxygen or sulphur
  • R 2 ', R 3 ' and R 4 ' independently are straight or branched C ⁇ - 1 5-alkyl, straight or branched C 2 -i 5 ⁇ alkenyl, straight or branched C 2 -i 5 -alkynyl, each of which is optionally substituted with halogen(s), -OH, -CN, -CF 3 , -SH, -COOH, -NH-R 2 ', -NR 2 'R 3 ', C ⁇ _ 6 alkyl ester, one or two phenyl, phenoxy, benzoyl or benzyloxycarbonyl wherein each aromatic group is optionally substituted with one or two halogen, -CN, C ⁇ - 4 -alkyl
  • a preferred composition is a weight ratio of Compound to acetaminophen of from about 1 to about 100.
  • An especially preferred ratio is from about 1 to about 30.
  • a further preferred ratio may be from about 1 to about 10.
  • a final preferred ratio may be from about 1 to about 3.
  • the invention further provides a composition for treating pain comprising a Compound selected from the group consisting of Formula I and Formula II or a pharmaceutically acceptable salt or solvate thereof and a acetaminophen in a weight ratio of Compound to acetaminophen of from about 1 to about 1000.
  • the present invention provides a composition for treating pain comprising a Compound selected from the group consisting of Formula I and Formula II; or a pharmaceutically acceptable salt thereof; and a central alpha-adrenergic active compound in a weight ratio of Compound to central alpha-adrenergic active compound of from about 1 to about 1000.
  • a preferred composition is a weight ratio of Compound to central alpha-adrenergic active compound of from about 1 to about 100.
  • An especially preferred ratio is from about 1 to about 30.
  • a further preferred ratio may be from about 1 to about 10.
  • a particularly preferred central alpha- adrenergic active compound is Clonidine or a pharmaceutically acceptable salt thereof.
  • the chemical name for clonidine is 2-(2, 6-dichlorophenylamino)-2- imidazoline.
  • the invention further provides a method for treating pain comprising administering an effective amount of a compound selected from the group consisting of Formula I and Formula II; or a pharmaceutically acceptable salt or solvate thereof; and a central alpha-adrenergic active compound in a weight ratio of Compound to central alpha- adrenergic active compound of from about 1 to about 1000.
  • the present invention provides a method for treating pain comprising administering to a patient in need thereof, an anagesic composition comprising a Compound selected from the group consisting of Formula I and Formula II; or a pharmaceutically acceptable salt or solvate thereof; and one or more opioid compounds in a weight ratio of Compound to an opioid active compound of from about 1 to about 1000.
  • an anagesic composition comprising a Compound selected from the group consisting of Formula I and Formula II; or a pharmaceutically acceptable salt or solvate thereof; and one or more opioid compounds in a weight ratio of Compound to an opioid active compound of from about 1 to about 1000.
  • a preferred composition is a weight ratio of
  • An especially preferred ratio is from about 1 to about 30.
  • a further preferred ratio may be from about 1 to about 10.
  • Preferred an opioid compounds are morphine, codeine, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, brompton's cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabuphine, and buprenorphine.
  • Especially preferred opioid compounds are selected from the group consisting of hydromorphone, hydrocodone, meperidone, buprenorphine, butorphenol, nalbuphine, pentazocine, oxymorphine, oxycodone, levorphanol, fentanyl, and alphaprodine.
  • Particularly preferred opioid compounds are selected from the group consisting of propoxyphene, methadone, morphine, hydrocodone, hydromorphine, and codeine.
  • the especially particularly preferred opioid compounds are selected from morphine and codeine.
  • the invention further provides a composition for treating pain comprising a Compound selected from the group consisting of Formula I and Formula II; or a pharmaceutically acceptable salt or solvate thereof; and a one or more opioid compounds in a weight ratio of Compound to opioid compound of from about 1 to about 1000.
  • NSAIDS represents a nonsteroidal anti-inflammatory drug which can be identified as such by the skilled artisan.
  • the Merck Manual, 16th Edition, Merck Research Laboratories (1990) pp 1308 - 1309 provide well known examples of NSAIDS.
  • the term is intended to include, but is not limited to salicylates such as aspirin, indomethacin, ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac.
  • NSAIDS include aspirin, ibuprofen, and naproxen.
  • NSAIDS are indomethacin, ibuprofen, naproxen, fenoprofen, tolmetin, sulindac, meclofenamate, keoprofen, piroxicam, flurbiprofen, and diclofenac.
  • Particularly preferred NSAIDS include aspirin and ibuprofen.
  • the salicylates may include acetylsalicylic acid, sodium acetylsalicylic acid, calcium acetylsalicylic acid, salicylic acid, and sodium salicylate.
  • An especially preferred NSAID is ibuprofen.
  • acetaminophen shall have the art accepted meaning and refers to N-(4- Hydroxyphenyl)acetamide and ' -hydroxyacetanilide.
  • the compound is claimed in U.S. Patent No. 2,998,450 and is known to the skilled artisan.
  • central alpha-adrenergic active compounds represents a compound having central alpha-adrenergic receptor activity.
  • the most preferred central alpha-adrenergic active compound is clonidine or a pharmaceutically acceptable salt thereof having the chemical name: 2- (2, 6-dichlorophenylamino) -2- imidazoline. Clonidine is known to be useful for treating hypertension. see Physicians' Desk Reference, 45th Ed. (1991) p. 673.
  • opioid represents opioid analgesics and antagonists including natural opioid analgesics, synthetic opioid analgesics, opioid antagonists and opioid agonist-antagonists.
  • Preferred an opioid compounds are selected from the group consisting of morphine, codeine, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, brompton's cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabuphine, and buprenorphine. More preferred opioid compounds are selected from the group consisting of codeine, nabuphine, naloxone, and naltrexone.
  • Preferred an opioid compounds are morphine, codeine, meperidine, methadone, propoxyphene, levorphanol, hydromorphone, oxymorphone, oxycodone, brompton's cocktail, naloxone, naltrexone, pentazocine, butorphanol, nabuphine, and buprenorphine.
  • Especially preferred opioid compounds are selected from the group consisting of hydromorphone, hydrocodone, meperidone, buprenorphine, butorphenol, nalbuphine, pentazocine, oxymorphine, oxycodone, levorphanol, fentanyl, and alphaprodine.
  • Particularly preferred opioid compounds are selected from the group consisting of propoxyphene, methadone, morphine, hydrocodone, hydromorphine, and codeine.
  • the especially particularly preferred opioid compounds are selected from morphine and codeine.
  • a group of compounds having muscarinic cholinergic activity can be particular useful for treating pain when used in combination with non-steroidal antiinflammatory agents (NSAIDS) . More specifically, the invention provides a method of treating pain in humans using a specified azacyclic, azabicyclic or tetrahydropyridine compounds (collectively referred to herein as "selected muscarinic compounds") in combination with a NSAIDS to provide a synergistic effect.
  • NSAIDS non-steroidal antiinflammatory agents
  • the invention provides a method of treating pain in humans using a specified Selected Muscarinic Compounds in combination with acetaminophen to provide a synergistic effect.
  • the invention provides a method of treating pain in humans using Selected Muscarinic Compounds in combination with a central alpha-adrenergic active compound to provide a synergistic effect.
  • composition of this invention a compound of Formula I or Formula II or a pharmaceutically acceptable salt thereof and NSAIDS compound are combined in a weight ratio of Compound to NSAIDS of from about 1 to about 1000.
  • a preferred composition is a weight ratio of Compound to NSAIDS of from about 1 to about 100.
  • An especially preferred ratio is from about 1 to about 30.
  • a further preferred ratio may be from about 1 to about 10.
  • a final preferred ratio may be from about 1 to about 3.
  • composition of this invention a Compound of Formula or Formula II and acetaminophen are combined in a weight ratio of Formula I or Formula II to acetaminophen of from about 1 to about 1000.
  • a preferred composition is a weight ratio of Formula I or Formula II to acetaminophen of from about 1 to about 100.
  • An especially preferred ratio is from about 1 to about 30.
  • a further preferred ratio may be from about 1 to about 10.
  • a final preferred ratio may be from about 1 to about 3.
  • the compounds of Formula I and Formula II are effective over a wide dosage range; however, it is desirable to administer a dosage that is as low as possible.
  • the amount of NSAIDS present in the composition is adjusted as described above in ratio to the Formula I or Formula II dosage.
  • the amount of acetaminophen present in the composition is adjusted as described above in ratio to the Formula I or Formula II dosage.
  • dosages per day of the Formula II compounds will normally fall within the range of about 0.005 to about 100 mg/kg of body weight and the acetaminophen in the composition would be from 3 to 1000 times this amount.
  • dosages per day of the Formula I compounds will normally fall within the range of about 0.005 to about 100 mg/kg of body weight and the NSAIDS in the composition would be from 3 to 1000 times this amount.
  • composition of this invention a Compound selected from the group consisting of Formula I and Formula II; or a pharmaceutically acceptable salt thereof and one or more opioid compounds are combined in a weight ratio of Compound to opioid compound of from about 1 to about 1000.
  • a preferred composition is a weight ratio of Compound to opioid compound of from about 1 to about 100.
  • An especially preferred ratio is from about 1 to about 30.
  • a further preferred ratio may be from about 1 to about 10.
  • a final preferred ratio may be from about 1 to about 3.
  • the Compounds are effective over a wide dosage range; however, it is desirable to administer a dosage that is as low as possible.
  • the amount of opioid compound present in the composition is adjusted as described above in ratio to the Compound dosage. For example, dosages per day of the Formula I compounds will normally fall within the range of about 0.005 to about 100 mg/kg of body weight and the opioid compound in the composition would be from 3 to 1000 times this amount.
  • the amount of the Compound actually administered will be determined by a physician, in the light of the relevant circumstances including the condition to be treated, the choice of Compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, 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 present compounds are preferably administered orally to humans susceptible to or suffering from pain, the compounds may also be administered by a variety of other routes such as the transdermal, parenterally, subcutaneous, intranasal, intramuscular and intravenous routes.
  • Such formulations may be designed to provide delayed or controlled release using formulation techniques which are known in the art.
  • Transdermal formulations containing the composition claimed herein most preferably deliver the active substances in an effective amount for from about three days to about seven days. However, for chronic pain such as arthritis or cancer pain, a transdermal delivery of from about three days to up to about two weeks is desirable. Alternatively, it may be preferred to deliver the claimed compositions transdermally in an effective amount for from about one day to about three days.
  • treating includes prophylaxis of a physical and/or mental condition or amelioration or elimination of the developed physical and/or mental condition once it has been established or alleviation of the characteristic symptoms of such condition.
  • the compounds of Formula I and Formula II employed in the invention are not believed to act via the GABA/benzodiazepine, 5HT1A, or Dl receptor systems in humans. Rather, the activity of the present Formula I and Formula II compounds as analgesic agents is believed to be based upon modulation of muscarinic cholinergic receptors. However, the mechanism by which the present compounds function is not necessarily the mechanism stated supra . , and the present invention is not limited by any mode of operation.
  • Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically-acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceu ical Science. 66, 2 (1977) which are known to the skilled artisan.
  • the compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, depot, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred.
  • oral or parenteral e.g. rectal, transdermal, depot, subcutaneous, intravenous, intramuscular or intranasal, the oral route being preferred.
  • the dosage administered will, of course, vary depending on known factors such as the pharmacodynamic characteristics of the particular agent, and it smode and route of administration; age, health, and weight of the recipient; nature and extent of the symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired.
  • the daily dosage can be such that the active ingredient is administered at a daily dosage of from about 0.2 mg/kg to about 100 mg/kg of body weight Formula I or Formula II compound and from about 0.6 to about 200 mg/kg of NSAIDS.
  • Compositions suitable for internal administration contain from about one half (0.5) milligrams to about 600 milligrams of active ingredient per unit.
  • the active ingredient will ordinarily be present in an amount of from about 0.5% to about 95% by weight based on the total weight of the composition.
  • the daily dosage can be such that the active ingredient is administered at a daily dosage of from about 0.2 mg/kg to about 100 mg/kg of body weight Formula II compound and from about 0.6 to about 200 mg/kg of acetaminophen.
  • compositions include a compound of Formula I or Formula II or a pharmaceutically acceptable acid addition salt thereof and one or more NSAIDSs, associated with a pharmaceutically acceptable excipient which may be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper, or other container.
  • a pharmaceutically acceptable excipient which may be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper, or other container.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • Typical compositions include a compound of Formula I or Formula II or a pharmaceutically acceptable acid addition salt thereof and acetaminophen, associated with a pharmaceutically acceptable excipient which may be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper, or other container.
  • conventional techniques for the preparation of pharmaceutical compositions may be used, as described above.
  • a preferred composition is a weight ratio of Compound to central alpha-adrenergic active compound of from about 1 to about 100.
  • An especially preferred ratio is from about 1 to about 30.
  • a further preferred ratio may be from about 1 to about 10.
  • a final preferred ratio may be from about 1 to about 3.
  • the compounds of Formula I and Formula II are effective over a wide dosage range; however, it is desirable to administer a dosage that is as low as possible.
  • the amount of central alpha-adrenergic active compound present in the composition is adjusted as described above in ratio to the Formula I or Formula II dosage. For example, dosages per day of the Formula I compounds will normally fall within the range of about 0.005 to about 100 mg/kg of body weight and the central alpha-adrenergic active compound in the composition would be from 3 to 1000 times this amount.
  • the daily dosage can be such that the active ingredient is administered at a daily dosage of from about 0.2 mg/kg to about 100 mg/kg of body weight Formula I or Formula II compound and from about 0.6 to about 200 mg/kg of central alpha-adrenergic active compound.
  • compositions include a compound of formula I or Formula II or a pharmaceutically acceptable acid addition salt thereof; and one or more central alpha- adrenergic active compounds, associated with a pharmaceutically acceptable excipient which may be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper, or other container.
  • a pharmaceutically acceptable excipient which may be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper, or other container.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • the Formula I or Formula II compounds are dispensed in unit form comprising from about 0.1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage.
  • compositions of this invention may be suitable for administration to an animal.
  • animals include both domestic animals, for example livestock, laboratory animals, and household pets, and non-domestic animals such as wildlife. More preferredly, the animal is a vertebrate.
  • a compound of this invention shall be administered to a mammal. It is especially preferred that the animal is a domestic mammal or a human. The most preferred mammal is a human. For such purposes, a compound of this invention may be administered as a feed additive.
  • Acetic acid-induced writhing A standard procedure for detecting and comparing the analgesic activity of different classes of analgesic drugs for which there is a good correlation with human analgesic activity is the prevention of acetic acid-induced writhing in mice.
  • Mice are subcutaneously administered various doses of the claimed composition and are injected injected intraperitoneally with acetic acid (0.5% solution, 10 ml/kg) 5 min prior to a designated observation period.
  • acetic acid (0.5% solution, 10 ml/kg
  • a "writhe" is indicated by whole body stretching or contraction of the abdomen during the observation period beginning 5 min after receiving the acetic acid. Inhibition of writhing behavior is demonstrative of analgesic activity.
  • Sciatic nerve ligation model Rats are anesthetized and a nerve ligation procedure performed. The common sciatic nerve is exposed and 4 ligatures tied loosely around it with about 1 mm spacing'. One day to 10 weeks after surgery, the nociceptive testing is performed. Responses to noxious heat are determined by placing the rats in a chamber with a clear glass floor and aiming at the plantar surface of the affected foot a radiant heat source from beneath the floor. Increased latency to withdraw the hindpaw is demonstrative of analgesic activity. Responses to normally innocuous mechanical stimuli is determined by placing the rats in a chamber with a screen floor and stimulating the plantar surface of the hind paw with graduated von Frey hairs which are calibrated by the grams of force required to bend them.
  • Rats with sciatic nerve ligation respond to lower grams of mechanical stimulation by reflexive withdrawal of the foot than unoperated rats.
  • This response to stimuli which are normally innocuous is termed allodynia.
  • increases in the grams of mechanical force required to produce foot withdrawal is demonstrative of antiallodynic activity.
  • Bennett, G.J. and Xie, Y.-K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 33 (1988) 87-107.
  • Lee, Y.-W. Chaplan, S.R. and Yaksh, T.L. :
  • Rats are anesthetized and when there is a loss of spontaneous movement the rats are injected subcutaneously in the dorsal surface of the hindpaw with 50 ul of 5% formalin solution using a 30 gauge needle. Rats are then individually placed in an open Plexiglas chamber for observation, and within a maximum interval of 1 to 2 min, the animal displays recovery from anesthesia with spontaneous activity and normal motor function. Pain behavior is quantified by periodically counting the incidents of spontaneous flinching/shaking of the injected paw. The flinches are counted for 1-min periods at 1- to 2-, 5- to 6- and 5min intervals during the interval from 10 to 60 min. Inhibition of the pain behavior is demonstrative of an analgesic activity.
  • Brewer's yeast-induced hyperalgesia (Randall-Selitto Test) : To assess nociceptive threshold in rats, ascending pressure is applied gradually to the paw with a motor driven weight of a Ugo Basile Analgesy Meter. Rats respond to the pressure by either pulling free of the device, struggling or vocalizing. Hyperalgesia is induced by a hind paw subplantar injection of 0.1 ml of 1% suspension of brewer's yeast in 0.9% saline. The composition of this invention is administered at varying times ( 0 - 4 hr) after injection of brewer's yeast and pressure threshold for the inflamed paw again determined at varying times.
  • mice Male mice are fasted for 16-22 hours and weighed. Mice weighing from about 18-22 grams at the time of testing are used for the following studies. All mice are dosed sequentially by the oral route with suspensions of a composition of this invention. Doses are coded using a code unknown to the observer.
  • a stock suspension of the test composition is prepared by mixing the active ingredients with about 40 mL of an aqueous vehicle containing about 2% Tween 80 (R) , a pharmacological dispersant and containing 100% polysorbate 80, and 1% by weight Methocel (R) MC powder, and containing 100% methylcellulose, in distilled water. The mixture may be sonicated for about 10 to about 15 seconds using an ultrasound sytem. All dosing suspensions are prepared by dilution of the stock suspension with Methocel/Tween 80. All suspensions are used within two hours of preparation.
  • mice treated with various doses of compound of Formula I or Formula II, composition or vehicle are injected intraperitoneally with a standard challenge dose of phenyl-p-benzoquinone 5 minutes prior to a designated observation period.
  • the pheyl-p-benzoquinone is prepared as about 0.1 mg/ml solution in about 5% by volume of ethanol in water.
  • the writhing dose is 1.25 mg/kg injected at a volume of about 0.25ml/10g.
  • a "writhe" is indicated by whole body stretching or contracting of the abdomen during an observation period beginning about five minutes after the phenyl-p- benzoquinone dose.
  • the solid line connecting the ED50 dosages of Formula I or Formula II (alone) and classical analgesic as claimed herein (alone) represents the "ED50 addition line" which indicates the expected location of the ED50' s for Formula I or Formula II and classical analagesic combinations if simple additivity were to describe their combined effects.
  • the 95% confidence range for the ED50 addition line is shown by the area between the broken lines above and below the ED50 addition line.
  • Formula II and classical analgesic component of each fixed dosage ratio would be contained within or overlap the region of the ED50 addition line.
  • Combination ED50's located significantly below the ED50 addition line would represent unexpectedly enhanced analgesic activity and combination ED50 's located above the line would represent unexpected diminished analgesic effect.
  • One method to establish the significance of such unexpected enhanced or diminished activity is to calculate the best fitting polynomial regression line to the observed ED50's using standard mathematical techniques.
  • compositions comprised of a compound of Formula I or Formula II and one or more classical analgesics provides a statistically significant synergistic analgesic effect.
  • Preferred compounds of Formula I for use in the analesic compositions are selected from the following:
  • Particularly preferred compounds of Formula I include:
  • More preferred compounds include the following: 3- (3-BUTYLTHIO-1,2, 5-THIADIAZOL-4-YL) -1- AZABICYCLO(2.2.2)OCTANE
  • the most especially preferred compound of Formula I is 3-(3-BUTYLTHIO-l,2,5-THIADIAZOL-4-YL)-l- AZABICYCLO [2.2.2]OCTANE; or a pharmaceutically acceptable salt or solvate thereof.
  • Preferred compounds of Formula II for the analgesic composition are selected from the following:
  • TRANS-3- (3- (2-HEXENYLOXY) -1, 2, 5-THIADIAZOL-4-YL) -1,2, 5, 6- TETRAHYDRO-1-METHYLPYRIDINE
  • Especially preferred compounds include the following:
  • TETRAHYDRO-1-METHYLPYRIDINE or a pharmaceutically acceptable salt or solvate thereof.
  • Compound which are particularly preferred include:
  • METHYLPYRIDINE or a pharmaceutically acceptable salt or solvate thereof .

Abstract

Méthode et composition de traitement de la douleur au moyen d'une composition comprenant un composé azabicyclique ou tétrahydropyridine et un composé analgésique classique.
PCT/US1996/019390 1995-12-07 1996-12-05 Methode de traitement de la douleur WO1997020556A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
IL12478696A IL124786A0 (en) 1995-12-07 1996-12-05 Method for treating pain
CA002239732A CA2239732A1 (fr) 1995-12-07 1996-12-05 Methode de traitement de la douleur
HU0000110A HUP0000110A3 (en) 1995-12-07 1996-12-05 Pharmaceutical compositions comprising azacyclic, azabicyclic or tetrahydro-pyridine-derivatives suitable for treating pain
PL96327144A PL327144A1 (en) 1995-12-07 1996-12-05 Method of relieving paints
EA199800535A EA199800535A1 (ru) 1995-12-07 1996-12-05 Способ лечения боли
NZ324594A NZ324594A (en) 1995-12-07 1996-12-05 A method and composition for treating pain using a composition comprising an azacyclic azabicyclic or tetrahydropyridine compound and an analgesic
KR1019980704268A KR19990071977A (ko) 1995-12-07 1996-12-05 통증 치료 방법
JP09521436A JP2000501711A (ja) 1995-12-07 1996-12-05 疼痛を処置する方法
AU11476/97A AU715645B2 (en) 1995-12-07 1996-12-05 Method for treating pain
EP96942906A EP0866702A4 (fr) 1995-12-07 1996-12-05 Methode de traitement de la douleur
NO982582A NO982582L (no) 1995-12-07 1998-06-05 Fremgangsmaate for behandling av smerte

Applications Claiming Priority (14)

Application Number Priority Date Filing Date Title
US831895P 1995-12-07 1995-12-07
US830695P 1995-12-07 1995-12-07
US831295P 1995-12-07 1995-12-07
US831395P 1995-12-07 1995-12-07
US829895P 1995-12-07 1995-12-07
US831995P 1995-12-07 1995-12-07
US829595P 1995-12-07 1995-12-07
US60/008,312 1995-12-07
US60/008,318 1995-12-07
US60/008,319 1995-12-07
US60/008,306 1995-12-07
US60/008,298 1995-12-07
US60/008,295 1995-12-07
US60/008,313 1995-12-07

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WO1997020556A9 true WO1997020556A9 (fr) 1997-10-02

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JP (1) JP2000501711A (fr)
KR (1) KR19990071977A (fr)
CN (1) CN1208348A (fr)
AU (1) AU715645B2 (fr)
CA (1) CA2239732A1 (fr)
CZ (1) CZ174598A3 (fr)
EA (1) EA199800535A1 (fr)
HU (1) HUP0000110A3 (fr)
IL (1) IL124786A0 (fr)
NO (1) NO982582L (fr)
NZ (1) NZ324594A (fr)
PL (1) PL327144A1 (fr)
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WO2000075140A1 (fr) 1999-06-04 2000-12-14 Eli Lilly And Company 7-oxo-2-azabicyclo[2.2.1]heptanes servant d'antagonistes selectifs du recepteur muscarinique
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
JP6371463B2 (ja) 2014-07-17 2018-08-08 ファーマシューティカル マニュファクチュアリング リサーチ サービシズ，インコーポレーテッド 即時放出性乱用抑止性液体充填剤形
EP3209282A4 (fr) 2014-10-20 2018-05-23 Pharmaceutical Manufacturing Research Services, Inc. Forme galénique anti-abus de remplissage de liquide à libération prolongée
AU2020226870A1 (en) * 2019-02-22 2021-09-09 Karuna Therapeutics, Inc. Compounds and methods of deuterated xanomeline for treating neurological disorders
WO2021097427A1 (fr) 2019-11-15 2021-05-20 Karuna Therapeutics, Inc. Dérivés de xanoméline et méthodes de traitement de troubles neurologiques
CN115974863A (zh) * 2021-10-14 2023-04-18 南京迈诺威医药科技有限公司 占诺美林衍生物的苹果酸盐、a晶型及其制备方法和用途

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US5043345A (en) * 1989-02-22 1991-08-27 Novo Nordisk A/S Piperidine compounds and their preparation and use
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US5527813A (en) * 1990-08-21 1996-06-18 Novo Nordisk A/S Heterocyclic compounds and their preparation and use
US5376668A (en) * 1990-08-21 1994-12-27 Novo Nordisk A/S Heterocyclic compounds
WO1993014089A1 (fr) * 1992-01-13 1993-07-22 Novo Nordisk A/S Composes heterocycliques, leur preparation et leur utilisation
US5605701A (en) * 1995-02-17 1997-02-25 Eli Lilly And Company Transdermal formulation

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