Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
• • 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
  • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
  • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
  • C07C211/16—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings
  • C07C211/17—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of a saturated carbon skeleton containing rings other than six-membered aromatic rings containing only non-condensed rings
• • 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
  • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
  • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
  • C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• the present invention relates to methods and compositions for the amelioration of pain. Description of the Prior Art:
• the opioids are a group of drugs, both natural and synthetic, that are employed primarily as centrally-acting analgesics and are opium or morphine-like in their properties (Gilman et al., 1980, GOODMAN AND GILMAN 1 S. THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, Chapter 24:494-534, Pub. Pergamon Press; hereby incorporated herein by reference).
• the opioids include morphine and morphine-like homologs, including, e.g., the semisynthetic derivatives codeine (methylmorphine) and hydrocodone (dihydrocodeinone) among many other such derivatives.
• Morphine and related opioids exhibit agonist activity at the central nervous system or CNS (referring to the brain and spinal cord) (mu) opioid receptors as well as showing affinity for the delta and kappa opioid receptors, to produce a range of effects including analgesia, drowsiness, changes in mood and mental clouding.
• CNS central nervous system
• the morphine-related opioids may also cause a number of undesirable side effects, including, for example, respiratory depression, nausea, vomiting, dizziness, mental clouding, dysphoria, pruritus, constipation, increased biliary tract pressure, urinary retention and hypotension.
• the development of tolerance to the opioid drugs and the risk of chemical dependence and abuse for these drugs is another undesirable side effect.
• Morphine which has been considered the prototypic opioid analgesic, has been available in many dosage forms, including immediate release oral dosage forms, and more recently, formulated into 12 hour controlled release formulations (e.g., MS Contin.RTM. tablets, commercially available from Purdue Frederick Company).
• Other opioid analgesics have been available as immediate release oral dosage forms, such as hydromorphone (e.g., Dilaudid.RTM., commercially available from Knoll Pharmaceuticals).
• hydromorphone e.g., Dilaudid.RTM., commercially available from Knoll Pharmaceuticals
• oxycodone More recently, another controlled release opioid analgesic, oxycodone, has become available (OxyContin.RTM., commercially available from Purdue Pharma).
• OxyContin.RTM commercially available from Purdue Pharma
• US patent 6,710,087 discloses the treatment of neuropathic pain with sibutramine, [N-l-[l-(4- chloropheny ⁇ cyclobuty ⁇ -S-methylbutylJ-NjN-dimethylamine]. It is disclosed in US patent 6,376,553 to treat lower back pain with N ⁇ N-dimethyl-l-fl- ⁇ -chloropheny ⁇ cyclobutyl] ⁇ - methylbutyl amine hydrochloride. US patent 5,688 830 indicates that 2 -(2,6- dimethylphenoxy)-l-methylethyl-ethylamine is useful for the treatment of pain.
• Other US patents disclosing the use of monoamine compounds to alleviate pain include 6,642,257; 5,843,942 and 5,063,231.
• One embodiment of the invention relates to a method for ameliorating pain in a human or non-human mammal suffering therefrom comprising administering to the mammal an effective amount of an antinociceptive amine having the formula: wherein: Z is H or OH,
• R and R 1 are the same or different and may be H or linear or branched chain alkyl having 1 to 8 carbon atoms, m is an integer from 0 to 10, inclusive and wherein the amine exhibits a mean reduction in abdominal writhings exhibited by mice in the standard acetic acid-induced visceral pain mouse model of at least 20%; a mixture of the amines; a derivative, salt or complex of the amine wherein the derivative, salt or complex former is physiologically acceptable and the formation of said salt, derivative or complex does not materially affect the pain amelioration properties of the amine; a mixture of the derivatives, salts and/or complexes or a prodrug that provides the amine, mixture of the amines, the derivative, salt or complex, or a mixture of the derivatives, salts and/or complexes.
• compositions for the for ameliorating pain in a human or non-human mammal suffering therefrom comprising (1) an effective amount of an antinociceptive amine having the formula: wherein: Z is H or OH,
• R and R 1 are the same or different and may be H or linear or branched chain alkyl having 1 to 8 carbon atoms, m is an integer from 0 to 10, inclusive and wherein the amine exhibits a mean reduction in abdominal writhings exhibited by mice in the standard acetic acid-induced visceral pain mouse model of at least 20%; a mixture of the amines; a derivative, salt or complex of the amine wherein the derivative, salt or complex former is physiologically acceptable and the formation of said salt, derivative or complex does not materially affect the pain amelioration properties of the amine; a mixture of the derivatives, salts and/or complexes or a prodrug that provides the amine, mixture of the amines, the derivative, salt or complex, or a mixture of the derivatives, salts and/or complexes and (2) a pharmacologically acceptable carrier therefore.
• Figure 1 sets forth the structural formulas of 6 monoamines tested for their effectiveness as pain-relief agents.
• FIGS 2 and 3 set forth reaction schemes for the preparation of monoamines described in the application.
• Figures 4-10 set forth the results of the standard acetic acid-induced visceral pain mouse test employing various of the monoamines described herein.
• the present invention is predicated on the discovery that certain of the monoamines having the structure:
• R and R 1 are the same or different and may be H or linear or branched chain alkyl having 1 to 8 carbon atoms, m is an integer from 0 to 10, inclusive and wherein the amine exhibits a mean reduction in abdominal writhings exhibited by mice in the standard acetic acid-induced visceral pain mouse model of at least 20%; a mixture of the amines; a derivative, salt or complex of the amine wherein the derivative, salt or complex former is physiologically acceptable and the formation of said salt, derivative or complex does not materially affect the pain amelioration properties of the amine; a mixture of the derivatives, salts and/or complexes or a prodrug that provides the amine, mixture of the amines, the derivative, salt or complex, or a mixture of the derivatives, salts and/or complexes effectively ameliorate the effects of neuropathic pain.
• the drugs are identified below as Monoamine #1-6.
• Five groups of five mice male Harlan ICR, weight 35-50 g were used to test each of the drugs. Control animals were tested as part of each experiment as well. The mice in each group were weighed and identified with a tail marking and were given a single dose of one of the drugs at ImI/ lOOg SC. The first group served as controls and was given only saline; the other five groups were given a drug at five doses ranging from 0.37 mg/kg up to 30.0 mg/kg.
• mice were allowed to acclimate for one-half hour and were then given an IP injection of 0.75% Glacial acetic acid at a volume of 1 ml/100g. Once the acid was injected, the mice were put into individual clear containers for observation. The mice were then watched continuously for one-half hour and the number of "stretches" or writhes were counted. The animal was considered to be stretching when its front legs stepped forward and at least one hind leg was extended out behind them. At the end of the thirty-minute observational period the mice were sacrificed with CO 2 . The same procedure was followed for all of the different compounds examined. The results of the tests are set forth in Figs. 4- 10.
• mice typically stretch 65-70 times/30 minutes.
• mice that were dosed with 10 mg/kg of Monoamine #1 only writhed 25.9 ⁇ 14.8 times (P ⁇ 0.001 vs. controls).
• the number of stretches decreased further at a dose of 30 mg/kg, with 13.1 ⁇ 11.7 stretches/30 minutes (P ⁇ 0.001 vs. controls).
• the P-values show a statistical significance at all doses tested, confirming that there is an effect on inhibiting visceral pain at 0.37 mg/kg that continues through 30 mg/kg.
• mice were injected with Monoamine #2 at doses ranging from 0.37 mg/kg to 30.0 mg/kg.
• Several doses of Monoamine #3 were administered to five groups of mice in hopes of eliciting a nociceptive response. The lowest dose was 0.37 mg/kg and the highest was 30.0 mg/kg. All of the doses were found to result in significantly fewer stretches than the control mice, indicating that this drug also has an effect on visceral pain.
• Monoamine #4 Multiple doses of Monoamine #4 were administered to five groups of mice. The lowest dose was 0.37 mg/kg and the highest was 30.0 mg/kg. Although several doses of the test drug resulted in fewer stretches than those observed in the control group, the number of stretches in these groups were within error of those of groups that were not significant, suggesting that the compound is not effective against visceral pain.
• morphine was used as a positive control. It was administered to the mice at doses ranging from 0.37 mg/kg to 30.0 mg/kg SC. The most effective doses for the morphine were 10.0 or 30 mg/kg at which point the mice completely stopped writhing, i.e., the average was 0.
• 2-Hydroxyphenylacetic acid (7) was activated using carbonyldiimidazole (CDI) in CH 2 Cl 2 ; treatment with a 20% excess of ethylamine in THF afforded 8. Reduction of amide 8 with borane-tetrahydrofuran complex in THF and acidification gave the secondary amine salt 1. (Scheme 1 , Fig. 2). 2-Hydroxy-N-ethylbenzeneacetamide (8).
• CDI (5.86 g, 36.1 mmol) was added to a solution of 7 (5.0 g, 33 mmol) in CH 2 CI 2 (40 mL) under nitrogen. After 30 min.
• reaction solution was cooled in an ice bath, and ethylamine (2 M in THF, 20 mL, 40 mmol) was added dropwise over 30 min.
• ethylamine 2 M in THF, 20 mL, 40 mmol
• the reaction was quenched with H 2 O (50 mL) and 1 N HCl (25 mL), the layers were separated, and the aqueous phase extracted further with CH 2 Cl 2 (2 X 50 mL).
• the organic extracts were washed with H 2 O (50 mL) and saturated NaCl (50 mL, dried over Na 2 SO 4 , and concentrated in vacuo.
• Cyclohexylamine (18) was derivatized as sulfonamide 19, which was heated with 1- iodohexane (NaH, DMF) to give 20. Removal of the amine protecting group of 20 provided N-hexylcyclohexanamine 6 [Ganguly et al., polyhedron (1990), 9(20), 2517-26; Yoon et al, Synthetic Communications, (1993), 23(11), 1595-9] as its HCI salt (Scheme 5, Fig. 3).

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• 2005
  • 2005-01-18 WO PCT/US2005/001503 patent/WO2006078239A1/en active Application Filing
  • 2005-01-18 JP JP2007552098A patent/JP2008527035A/ja active Pending
  • 2005-01-18 AU AU2005325292A patent/AU2005325292A1/en not_active Abandoned
  • 2005-01-18 EP EP05711557A patent/EP1851190A4/de not_active Withdrawn
  • 2005-01-18 CA CA002595184A patent/CA2595184A1/en not_active Abandoned

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