WO1997025988A1 - Procedes de traitement ou de prevention de la douleur ou nociception - Google Patents

Procedes de traitement ou de prevention de la douleur ou nociception Download PDF

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WO1997025988A1
WO1997025988A1 PCT/US1997/000788 US9700788W WO9725988A1 WO 1997025988 A1 WO1997025988 A1 WO 1997025988A1 US 9700788 W US9700788 W US 9700788W WO 9725988 A1 WO9725988 A1 WO 9725988A1
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mol
mixture
piperidin
solution
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PCT/US1997/000788
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Smriti Iyengar
Lee A. Phebus
Harlan E. Shannon
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Eli Lilly And Company
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine

Definitions

  • Tachykinins are a family of peptides which share a common amidated carboxy terminal sequence.
  • Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970 * s.
  • neurokinin A also known as substance K, neuromedin L, and neurokinin ⁇
  • neurokinin B also known as neuromedin K and neurokinin ⁇
  • Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.
  • NK-1 The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.
  • Substance P is believed inter alia to be involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease. Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra.
  • Tachykinins play a major role in mediating the sensation and transmission of pain or nociception, especially migraine headaches, see, e.g.. S.L. Shepheard, et al.. British Journal of Pharmacologv. 108:11-20 (1993); S.M. Moussaoui, etal, Euronean Journal of Pharmacology. 238:421-424 (1993); and W.S. Lee, et al.. BrJM ⁇ h Journal of Pharmacology. 112:920-924 (1994).
  • tachykinin receptor antagonists In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions.
  • the earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability.
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, methyl, methoxy, chloro, and trifluoromethyl, with the proviso that no more than one of R 1 and R 2 can be hydrogen;
  • N-Ra or CH-NRbRc
  • R a , R b , and R c are independently selected from the group consisting of hydrogen and Ci-C ⁇ alkyl;
  • C 1 -C 6 alkyl refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl.
  • the term "Ci-C ⁇ alkyl” includes within its definition the term “C1-C3 alkyl”.
  • Halo represents chloro, fluoro, bromo or iodo.
  • haloformate refers to an ester of a haloformic acid, this compound having the formula
  • X is halo
  • Rd is Ci-C ⁇ alkyl.
  • Preferred haloformates are bromoformates and chloroformates. Especially preferred are chloroformates. Those haloformates wherein Rd is C3-C6 alkyl are especially preferred. Most preferred is isobutylchloroformate.
  • the compounds prepared in the processes of the present invention have an asymmetric center.
  • the compounds produced in the present invention may occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. Processes for preparing such asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
  • R and S are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
  • the term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the term “S” (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the priority of groups is based upon their atomic number (in order of decreasing atomic number).
  • the older D-L system is also used in this document to denote absolute configuration, especially with reference to amino acids.
  • a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top.
  • the prefix "D” is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and "L", that of the isomer in which it is on the left.
  • Patent Cooperation Treaty Publication WO 95/14017 published May 26, 1995, teaches, inter alia, a series of tachykinin receptor antagonists of Formula II
  • n are independently 0-6;
  • Z is -(CHR ) p -(CHR 6 ) q -, where,
  • p is 0 or 1;
  • q is 0 or 1
  • R 4 and R 6 are independently selected from the group consisting of hydrogen and C1-C 3 alkyl
  • N-R a or CH-NRbRc
  • R a , R b , and R c are independently selected from the group consisting of hydrogen and C1-C 6 alkyl; and R 1 and R 2 are independently hydrogen, halo, Ci-C ⁇ alkoxy, Ci-C ⁇ alkylthio, nitro, trifluoromethyl, or Ci- C 6 alkyl;
  • Particularly preferred compounds are those of Formula II in which m and n are both 1; R 1 and R 2 are independently hydrogen, methoxy, ethoxy, chloro, fluoro, trifluoromethyl, methyl, and ethyl; Z is methylene; and Y, when combined with the heterocyclic group to which it is attached, forms 4-(piperidin-l-yl)piperidin-l-yl, 4- (cyclohexyl)piperazin-l-yl, 4-(phenyl)piperazin-l-yl, or 4- (phenyl)piperidin-l-yl.
  • Chlorotrimethylsilane (70.0 ml, 0.527 mol) was added at a moderate rate to a stirred slurry of D-tryptophan (100.0 g, 0.490 mol) in anhydrous methylene chloride (800 ml) under a nitrogen atmosphere. This mixture was continuously stirred for 4.25 hours. Triethylamine (147.0 ml, 1.055 mol) was added, followed by the addition of a solution of triphenylmethyl chloride (147.0 g, 0.552 " mol) in methylene chloride (400 ml) using an addition funnel. The mixture was stirred at room temperature, under a nitrogen atmosphere for at least 20 hours. The reaction was quenched by the addition of methanol (500 ml).
  • the solution was concentrated on a rotary evaporator to near dryness and the mixture was redissolved in methylene chloride and ethyl acetate. .An aqueous work-up involving a 5% citric acid solution (2X) and brine (2X) was then performed. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness on a rotary evaporator. The solid was dissolved in hot diethyl ether followed by the addition of hexanes to promote crystallization.
  • the mixture was allowed to warm to room temperature under a nitrogen atmosphere for at least 20 hours.
  • the mixture was concentrated on a rotary evaporator and then redissolved in methylene chloride and an aqueous work-up of 5% citric acid solution (2X), saturated sodium bicarbonate solution (2X), and brine (2X) was performed.
  • the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness on a rotary evaporator.
  • the desired product was then recrystallized from hot ethyl acetate to yield 215.8 g (0.381 mol, 95%) of analytically pure material.
  • the reaction was quenched after at least 20 hours by the slow addition of excess saturated Rochelle's salt solution (potassium sodium tartrate tetrahydrate).
  • the organic layer was isolated, washed with brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to an oil on a rotary evaporator. No further purification was done and the product was used directly in the next step.
  • Cyclohexylpiperazine (10.0 g, 0.059 mol) was added to ten volumes of methylene chloride at room temperature. To this mixture was added sodium hydroxide (36 ml of a 2N solution, 0.072 mol) and tetrabutylammonium bromide (1.3 g, 0.004 mol). After the addition of the sodium hydroxide and tetrabutylammonium bromide, methyl bromoacetate (7.0 ml, 0.073 mol) was added and the reaction mixture was stirred for four to six hours. The progress of the reaction was monitored by gas chromatography.
  • the organic fraction was separated and the aqueous phase was back-extracted with methylene chloride.
  • the organic phases were combined and washed twice with deionized water, once with saturated sodium bicarbonate solution, and then with brine.
  • the organic phase was dried over magnesium sulfate and the solvents were removed in vacuo to yield methyl 2-((4-cyclohexyl)piperazin-l-yl)acetate as a yellowish oil.
  • the title compound was prepared by dissolving the methyl 2-((4-cyclohexyl)piperazin-l-yl)acetate (10.0 g, 0.042 mol) in ten volumes of diethyl ether. This solution was cooled to 15°C and then potassium trimethylsilanoate (5.9 g, 0.044) was added. This mixture was then stirred for four to six hours. The reaction product was removed by filtration, washed twice with five volumes of diethyl ether, then washed twice with five volumes of hexanes, and then dried in a vacuum oven for 12-24 hours at 50°C. Analysis for C 1 2H 21 KN2O2 • 1.5 H 2 0: Theory: C, 49.63; H, 7.98; N, 9.65. Found: C, 49.54; H, 7.72; N, 9.11.
  • the title compound was prepared by first cooling 2-((4- cyclohexyl)piperazin-l-yl)acetic acid potassium salt to a temperature between -8°C and -15°C in 5 volumes of anhydrous methylene chloride. To this mixture was added isobutylchloroformate at a rate such that the temperature did not exceed -8°C. The resulting reaction mixture was stirred for about 1 hour, the temperature being maintained between -8°C and -15°C.
  • the reaction was quenched by the addition of 5 volumes of water.
  • the organic layer was washed once with a saturated sodium bicarbonate solution.
  • the organic phase was then dried over anhydrous potassium carbonate and filtered to remove the drying agent.
  • To the filtrate was then added 2 equivalents of concentrated hydrochloric acid, followed by 1 volume of isopropyl alcohol.
  • the methylene chloride was then exchanged with isopropyl alcohol under vacuum by distillation.
  • Deionized water (1.2 L) was then added to the mixture and the layers separated. The aqueous layer was back-extracted with methylene chloride (2.4 L). The organic fractions were combined and washed with deionized water (3 x 1.2 L), a saturated sodium bicarbonate solution (1.1 L) and a saturated sodium chloride solution (1.1 L). The organic fraction was then dried over anhydrous magnesium sulfate and concentrated to an oil on a rotary evaporator to yield 1.613 kg (93.5%) of methyl 2-(4-(piperidin-l-yl)piperidin-l-yl)acetate.
  • the title compound was prepared by first admixing (R)-2- amino-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)acetylamino]propane dihydrochloride (50.0 g, 0.118 mol) with 100 ml of methylene chloride under a nitrogen atmosphere.
  • 2-(4- (piperidin-l-yl)piperidin-l-yl)acetic acid potassium salt (62.3 g, 0.236 mol) was added to 600 ml of methylene chloride. This mixture was cooled to about -10°C and stirring was continued. To this mixture isobutylchloroformate (23 ml, 0.177 mol) was added dropwise such that the temperature of the 2-(4-(piperidin-l-yl)piperidin-l-yl)acetic acid potassium salt mixture never rose appreciably.
  • This reaction mixture was stirred at about -10°C for about 1.5 hours at which time the (R)-2-amino-3-(lH-indol-3-yl)-l-[N-(2- methoxybenzyl )acetylamino]propane dihydrochloride/methylene chloride mixture prepared supra was slowly added to the 2-(4-(piperidin- l-yl)piperidin-l-yl)acetic acid potassium salt isobutylchloroformate/methylene chloride solution. The resulting mixture was then stirred for about 1 hour at a temperature between - 15°C and -8°C.
  • reaction mixture was removed from the ice bath and allowed to warm to 15-20°C and the reaction was quenched by the addition of 200 ml of water.
  • the pH of the solution was adjusted to 2.3-2.7 by the additon of IN sulfuric acid.
  • the layers were separated and the aqueous layer was washed with 100 ml of methylene chloride.
  • D-tryptophan 40.0 g, 0.196 mol
  • acetonitrile 240 ml
  • 1,1,1,3,3,3-hexamethyldisilazane 39.5 g, 0.245 mol
  • the resulting mixture was heated to 50-60°C and stirred until homogeneous.
  • trityl chloride 60.06 g, 0.215 mol
  • acetonitrile 120 ml
  • N-trityl-D-tryptophan N-methylmopholine salt 108.0 g, 0.196 mol
  • acetonitrile 800 ml
  • 2-chloro-4,6-dimethoxy-l,3,5-triazine 38.63 g, 0.22 mol
  • N-methylmorpholine 29.1 ml
  • RED-AL® [a 3.4 M, solution of sodium bis(2- methoxyethoxy)aluminum hydride in toluene] (535 ml, 1.819 mol), dissolved in anhydrous tetrahydrofuran (400 ml) was slowly added using an addition funnel to a refluxing solution of the acylation product, (R)-3- (lH-indol-3-yl)-N-(2-methoxybenzyl)-2-(N- triphenylmethylamino)propanamide (228.6 g, 0.404 mols) produced supra, in anhydrous tetrahydrofuran (1.0 L) under a nitrogen atmosphere. The reaction mixture became a purple solution.
  • the reaction was quenched after at least 20 hours by the slow addition of excess saturated Rochelle's salt solution (potassium sodium tartrate tetrahydrate).
  • the organic layer was isolated, washed with brine (2X), dried over anhydrous sodium sulfate, filtered, and concentrated to an oil on a rotary evaporator. No further purification was done and the product was used directly in the next step.
  • Cyclohexylpiperazine (10.0 g, 0.059 mol) was added to ten volumes of methylene chloride at room temperature. To this mixture was added sodium hydroxide (36 ml of a 2N solution, 0.072 mol) and tetrabutylammonium bromide (1.3 g, 0.004 mol). After the addition of the sodium hydroxide and tetrabutylammonium bromide, methyl bromoacetate (7.0 ml, 0.073 mol) was added and the reaction mixture was stirred for four to six hours. The progress of the reaction was monitored by gas chromatography.
  • the organic fraction was separated and the aqueous phase was back-extracted with methylene chloride.
  • the organic phases were combined and washed twice with deionized water, once with saturated sodium bicarbonate solution, and then with brine.
  • the organic phase was dried over magnesium sulfate and the solvents were removed in vacuo to yield methyl 2-((4-cyclohexyl)piperazin-l-yl)acetate as a yellowish oil.
  • the title compound was prepared by dissolving the methyl 2-((4-cyclohexyl)piperazin-l-yl)acetate (10.0 g, 0.042 mol) in ten volumes of diethyl ether. This solution was cooled to 15°C and then potassium trimethylsilanoate (5.9 g, 0.044) was added. This mixture was then stirred for four to six hours. The reaction product was removed by filtration, washed twice with five volumes of diethyl ether, then washed twice with five volumes of hexanes, and then dried in a vacuum oven for 12-24 hours at 50°C. Analysis for C12H2 1 KN2O2 • 1.5 H2O:
  • the title compound was prepared by first cooling 2-((4- cyclohexyl)piperazin-l-yl)acetic acid potassium salt to a temperature between -8°C and -15°C in 5 volumes of anhydrous methylene chloride. To this mixture was added isobutylchloroformate at a rate such that the temperature did not exceed -8°C. The resulting reaction mixture was stirred for about 1 hour, the temperature being maintained between -8°C and -15°C.
  • the reaction was quenched by the addition of 5 volumes of water.
  • the organic layer was washed once with a saturated sodium bicarbonate solution.
  • the organic phase was then dried over anhydrous potassium carbonate and filtered to remove the drying agent.
  • To the filtrate was then added 2 equivalents of concentrated hydrochloric acid, followed by 1 volume of isopropyl alcohol.
  • the methylene chloride was then exchanged with isopropyl alcohol under vacuum by distillation.
  • Deionized water (1.2 L) was then added to the mixture and the layers separated. The aqueous layer was back-extracted with methylene chloride (2.4 L). The organic fractions were combined and washed with deionized water (3 x 1.2 L), a saturated sodium bicarbonate solution (1.1 L) and a saturated sodium chloride solution (1.1 L). The organic fraction was then dried over anhydrous magnesium sulfate and concentrated to an oil on a rotary evaporator to yield 1.613 kg (93.5%) of methyl 2-(4-(piperidin- l-yl)piperidin- 1-yl )acetate .
  • reaction mixture was then cooled to -35°C and solid (R)- 2-amino-3-(lH-indol-3-yl)-l-[N-(2-methoxybenzyl)amino]propane dihydrochloride (0.60 kg, 1.14 mol) was added at such a rate that the reaction temperature was maintained at less than -20°C.
  • the reaction mixture was stirred for about one hour with the temperature being maintained between -37°C and -20°C.
  • the reaction was quenched by the addition of deionized water (7.5 L).
  • the reaction mixture was basified to pH 12.8-13.2 by the addition of 5 N sodium hydroxide.
  • the aqueous fraction was removed and retained. Additional deionized water (3.75 L) was added to the organic fraction as was sufficient 5 N sodium hydroxide to re-adjust the pH to 12.8-13.2.
  • the organic fraction was dried over anhydrous magnesium sulfate, filtered, and solvent exchanged from methylene chloride to acetone (3.75 L) on a rotary evaporator.
  • An aqueous solution of hydrochloric acid (0.48 L of 6 N solution, 2.88 mol) and seed crystals (2 g) were added and mixture was stirred for .30-90 minutes.
  • Acetone (13.2 L) was then added and the slurry stirred for one hour.
  • the resulting mixture is then cooled to 0°C, stirred for about ten minutes, and then permitted to warm to room temperature.
  • the progress of the reaction was monitored by chromatography. High performance liquid chromatography showed 99% conversion of the reactants after ninety minutes.
  • the reaction mixture was partitioned between ethyl acetate (375 ml) and a saturated sodium bicarbonate solution (375 ml).
  • the aqueous layer was back extracted with 375 ml of ethyl acetate.
  • the organic fractions were combined, washed with water (3 x 375 ml), and then dried over magnesium sulfate.
  • Potassium hydroxide is then added to the aqueous fraction from above and this resulting basified solution is extracted with ethyl acetate. This organic fraction is then dried over magnesium sulfate.
  • the mixed anhydride process will work in a number of organic solvents, in addition to the anhydrous N,N-dimethylformamide depicted above.
  • solvents which may be employed include acetonitrile, tetrahydrofuran, dichloromethane.
  • the mixed anhydride process can be performed at temperatures below 0°C.
  • the oxalate can be isolated from ethyl acetate as well as from other solvents, probably including acetone, acetonitrile, and t-butyl methyl ether.
  • the use of oxalic acid is, however, very important for the precipitation as a large number of acids do not give a precipitate.
  • acids attempted, but found not satisfactory for the processes of the present invention are citric, anhydrous hydrochloric, tartaric, mandelic, trifluoroacetic, p-nitrobenzoic, phenoxyacetic, maleic, fumaric, glutaric, adipic, methanesulfonic, p-toluenesulfonic, pamoic, trans-l,2-cyclohexane dicarboxylic, succinic, phthalic, trans- l,2-diaminocyclohexane-N,N,N',N'-naphthalenedisulfonic, and 5- sulfosalicylic acids. Only oxalic arid and 1,5-naphthalene disulfonic acid reproducibly produced a solid.
  • the phases were separated and the organic phase was back extracted with water (101.44 ml).
  • the organic fraction was transferred to a jacketed round bottom flask and a solvent exchange was performed using about 23 volumes of acetone. Portions of the acetone were added to the product solution and the amount added was distilled away. The progress of the solvent exchange was monitored by NMR. The amount of desired product was monitored by high performance liquid chromatography .
  • Enough water was added to bring the water concentration to eleven percent and the resulting mixture was heated to 55°C.
  • Enough concentrated hydrochloric arid was added to lower the pH to 2.0 and the reaction mixture was then permitted to cool to 37°C over 45 minutes.
  • the product solution was seeded and permitted to stir for 10-30 minutes.
  • the product solution was cooled to 19°C over two hours and acetone (ten equivalent volumes) was added over three hours, after which time the reaction mixture was stirred for one to three hours, maintaining the temperature at 19°C.
  • the product solution was filtered and the residue was washed with 6.67 equivalents of acetone. The residue was then dried in a vacuum oven at 42 °C to give the desired title product.
  • NK-1 Receptor Binding Assay useful for evaluating tachykinin receptor antagonists are well known in the art. See, e,g Berry J. Jukic, ⁇ LaL, Life Sciences.49:1463-1469 (1991); N. Kucharczyk, sLs . Journal of Medicinal Chemistry. 36:1654-1661 (1993); N. Rouissi, s s Biochemical and Biophysical Research Cnm ⁇ m ⁇ ninat.inn R . 176:894-901 (1991). NK-1 Receptor Binding Assay
  • Radioreceptor binding assays were performed using a derivative of a previously published protocol. D.G. Payan, et al. t Journal of Immunolo y. 133:3260-3265 (1984). In this assay an aliquot of IM9 cells (1 x 10 6 cells/tube in RPMI 1604 medium supplemented with 10% fetal calf serum) was incubated with 20 pM 125 I-labeled substance P in the presence of increasing competitor concentrations for 45 minutes at 4°C.
  • the IM9 cell line is a well-characterized cell line which is readily available to the public. See, e.g.. Annals of the New York Academy of Sdence. 190: 221-234 (1972); Nature (London).251:443-444 (1974); Proceedings of the National Academy of Sdences (USA). 71:84-88 (1974). These cells were routinely cultured in RPMI 1640 supplemented with 50 ⁇ g/ml gentamirin sulfate and 10% fetal calf serum.
  • reaction was terminated by filtration through a glass fiber filter harvesting system using filters previously soaked for 20 minutes in 0.1% polyethylenimine. Spedfic binding of labeled substance P was determined in the presence of 20 nM unlabeled ligand.
  • the CHO-hNK-2R cells a CHO-derived cell line transformed with the human NK-2 receptor, expressing about 400,000 such receptors per cell, were grown in 75 cm 2 flasks or roller bottles in minimal essential medium (alpha modification) with 10% fetal bovine serum.
  • minimal essential medium alpha modification
  • the gene sequence of the human NK-2 receptor is given in N.P. Gerard, fi aL, Journal of Biological Chemistry.265:20455-20462 (1990).
  • Membranes were prepared by homogenization of the cell pellets in 300 ml 50 mM Tris buffer, pH 7.4 with a Tekmar® homogenizer for 10-15 seconds, followed by centrifugation at 12,000 RPM (20,000 x g) for 30 minutes using a Beckman JA-14® rotor. The pellets were washed once using the above procedure, and the final pellets were resuspended in 100-120 ml 50 mM Tris buffer, pH 7.4, and 4 ml aliquots stored frozen at -70°C. The protein concentration of this preparation was 2 mg/ml.
  • CHO-hNK-2R membrane preparation For the receptor binding assay, one 4-ml aliquot of the CHO-hNK-2R membrane preparation was suspended in 40 ml of assay buffer containing 50 mM Tris, pH 7.4, 3 mM manganese chloride, 0.02% bovine serum albumin (BSA) and 4 ⁇ g/ml chymostatin. A 200 ⁇ l volume of the homogenate (40 ⁇ g protein) was used per sample.
  • the radioactive ligand was [ 125 I]iodohistidyl-neurokinin A (New England Nuclear, NEX-252), 2200 Ci mmol.
  • the ligand was prepared in assay buffer at 20 nCi per 100 ⁇ l; the final concentration in the assay was 20 pM. Non-specific binding was determined using 1 ⁇ M eledoisin. Ten concentrations of eledoisin from 0.1 to 1000 nM were used for a standard concentration-response curve.
  • DMSO dimethylsulfoxide
  • IC5 IC5 0 determinations.
  • the order of additions for incubation was 190 or 195 ⁇ l assay buffer, 200 ⁇ l homogenate, 10 or 5 ⁇ l sample in DMSO, 100 ⁇ l radioactive ligand.
  • the samples were incubated 1 hr at room temperature and then filtered on a cell harvester through filters which had been presoaked for two hours in 50 mM Tris buffer, pH 7.7, containing 0.5% BSA. The filter was washed 3 times with approximately 3 ml of cold 50 mM Tris buffer, pH 7.7. The filter circles were then punched into 12 x 75 mm polystyrene tubes and counted in a gamma counter.
  • the methods of the present invention may employ any analgesic whose primary mechanism of action is not as a tachykinin receptor antagonist in combination with the compounds of Formula I.
  • analgesic refers to an agent which relieves pain by acting centrally to elevate pain threshold without disturbing consiousness or altering other sensory modalities. Many drugs used to relieve pain are not analagesics.
  • analgesic whose primary mode of action is not as a tachykinin receptor antagonist classical analgesic, “traditional analgesic”, and like terms are used interchangeably herein and refer to an agent having analgesic properties, the primary mechanism of which is not as a tachykinin receptor antagonist.
  • An agent may be considered as an "analgesic whose primary mode of action is not as a tachykinin receptor antagonist” even if it exhibits some activity as a tachykinin receptor antagonist, if the primary mode of action of the agent is by means of another biological activity.
  • Classical agents used primarily for symptomatic relief of pain may be divided into four major groups: (1) opiate analgesics; (2) nonopiate analgesics; (3) analgesics and antipyretics; and (4) nonsteroidal antiinflammatory drugs.
  • Illustrative examples of commercially available analgesics include the following. These examples are designed to be illustrative and the present invention is not limited to these particular compounds.
  • NSAIDS non-steroidal anti ⁇ inflammatory drugs
  • analgesics and antipyretics are classified as analgesics and antipyretics. Representative examples of this class include:
  • Another class of commercially available analgesic agents is classified as nonopiate analgesics. Representative examples of this class include: Butorphanol
  • analgesic agents is classified as opiates.
  • Representative examples of commerdally available narcotic analgesic agents include: Hvdrocodone
  • analgesic agents are in advanced stages of pharmaceutical development.
  • the present invention encompasses all such analgesic agents that do not primarily function as tachykinin receptor antagonists.
  • Some such agents include: the opioids tramadol, meptazinol, propiram fumarate, carfentanil, remifentanil, mirfentanil, endaoline, RP 60180, GR 94839, and tonazocine; 5-HTID agonists zolmitriptan, MK-462, BMS 180048, naratriptan, CP 122288, eletriptan, SB 209509, and LAS 31416; COX II Inhibitors SC 58635, SC 57666, SC 58125, BF 389, L 745337, L 761066, NS 398, and meloxicam; 5- lipoxygenase/cyclo-oxygenase inhibitors tenidap, tepoxalin,
  • any synergistic combination therapy greatly increases the therapeutic index of a composition in treating these nociceptive disorders.
  • a markedly decreased amount of a traditional analgesic may now be administered to a patient, presumably greatly lessening the likelihood and severity of any adverse events.
  • the reduced amount of active ingredient necessary for a therapeutic effect makes possible other routes of formulation than those currently employed. Rapid onset formulations such as buccal or sublingual may now be developed. Sustained release formulations are now more feasible due to the lower amounts of active ingredient necessary.
  • the methods of the present invention are particularly advantageous in the treatment or prevention of pain. These methods are espedally preferred in the treatment or prevention of types of pain generally considered refractory to standard non-sedating, non-addictive therapies.
  • pains include chronic pain, such as neuropathic pain, and post-operative pain, pain assodated with arthritis, cancer-assoriated pain, chronic lower back pain, duster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, neuropathic pain, opioid-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, including sunburn, post partum pain, migraine, angina pain, and genitourinary tract-related pain including cystitis.
  • compositions comprising a pharmaceutically acceptable exdpient and at least one active ingredient.
  • These compositions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • Many of the compounds employed in the methods of this invention are effective as both injectable and oral compositions.
  • Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. See, e. g .. REMINGTON'S PH_ ⁇ RMACEUTIC_ ⁇ L SCIENCES, (16th ed. 1980).
  • the active ingredient is usually mixed with an exdpient, diluted by an exdpient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the exdpient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • exdpients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, caldum phosphate, alginates, tragacanth, gelatin, caldum silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.05 to about 100 mg, more usually about 1.0 to about 30 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in assodation with a suitable pharmaceutical exdpient.
  • the active compounds are generally effective over a wide dosage range.
  • dosages per day normally fall within the range of about 0.01 to about 30 mg kg of body weight.
  • the range of about 0.1 to about 15 mg/kg/day, in single or divided dose is espedally preferred.
  • the amount of the compound actually administered will be determined by a physidan, in the light of the relevant rircumstances, including the condition to be treated, the chosen route of administration, the actual compound or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • Quantity Ingredient (mg/tablet)
  • a dry powder inhaler formulation is prepared containing the following components:
  • the active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
  • Tablets each containing 30 mg of active ingredient, are prepared as follows:
  • Quantity Ingredient (mg/tablet)
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • Capsules each containing 40 mg of medicament are made as follows:
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • the active ingredient(s) is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty add glycerides previously melted using the minimum heat necessary.
  • the mixture is then poured into a suppository mold of nominal 2.0 g capadty and allowed to cool.
  • Suspensions each containing 50 mg of medicament per 5.0 ml dose are made as follows:
  • Purified water to 5.0 ml The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Suffident water is then added to produce the required volume.
  • Capsules each containing 15 mg of medicament, are made as follows:
  • Quantity Ingredient (mg/cansule)
  • the active ingredient(s), cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
  • An intravenous formulation may be prepared as follows:
  • a topical formulation may be prepared as follows:
  • Sublingual or buccal tablets each containing 10 mg of active ingredient, may be prepared as follows:
  • the glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrolidone are admixed together by continuous stirring and maintaining the temperature at about 90 °C.
  • the solution is cooled to about 50-55°C and the medicament is slowly admixed.
  • the homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See. e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • the type of formulation employed for the administration of the compounds employed in the methods of the present invention may be dictated by the particular compounds employed, the type of pharmacokinetic profile desired from the route of administration and the compound(s), and the state of the patient.
  • the administration of the non-tachykinin receptor antagonist analgesic may be simultaneous with, before, or after the administration of the tachykinin receptor antagonist. If it is desired to administer the non-tachykinin receptor, antagonist analgesic simultaneously with the tachykinin receptor antagonist, the two active ingredients may be combined into one pharmaceutical formulation or two formulations may be administered to the patient.
  • non-tachykinin receptor antagonist analgesic analgesic and the tachykinin receptor antagonist.
  • Some of these considerations include: the particular compounds employed; the manner in which each active ingredient is formulated; whether the adminstration is prophylactic or curative in nature; and the condition of the patient.

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Abstract

Cette invention se rapporte à des procédés de traitement ou de prévention de la douleur ou nociception chez un mammifère nécessitant une quantité efficace d'un composé de la formule (I) dans laquelle R1 et R2 sont indépendamment sélectionnés dans le groupe constitué par hydrogène, méthyle, méthoxy, chloro, et trifluorométhyle, à condition que pas plus d'un R1 et d'un R2 puisse représenter hydrogène; et Y représente la formule (II), N-Ra ou CH-NRbRc dans laquelle R?a, Rb et Rc¿ sont indépendamment sélectionnés dans le groupe constitué par hydrogène et alkyle en C¿1?-C6. Cette invention se rapporte également à un sel pharmaceutiquement acceptable ou un solvant de celui-ci, en combinaison avec un analgésique dont le mécanisme d'action primaire ne ressemble pas à celui d'un antagoniste du récepteur de la tachykinine. Cette invention se rapporte d'autre part à des formulations pharmaceutiques comprenant un composé de la formule (I) en combinaison avec un analgésique traditionnel, un ou plusieurs supports pharmaceutiquement acceptables, des diluants ou des excipients de celui-ci.
PCT/US1997/000788 1996-01-17 1997-01-17 Procedes de traitement ou de prevention de la douleur ou nociception WO1997025988A1 (fr)

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AU22438/97A AU2243897A (en) 1996-01-17 1997-01-17 Methods of treating or preventing pain or nociception

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US60/010,133 1996-01-17

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999022730A1 (fr) * 1997-10-31 1999-05-14 Vanguard Medica Limited Utilisation de (+)-6-carboxamido-3-methylamino-1,2,3,4-tetrahydrocarbazole pour le traitement de l'hyperalgie
WO1999059635A1 (fr) * 1998-05-21 1999-11-25 Merck Sharp & Dohme Limited Utilisation d'un inhibiteur de cox-2 et d'un antagoniste du recepteur nk-1 dans le traitement de l'inflammation
US6552031B1 (en) 1997-09-17 2003-04-22 Euro-Celtique S.A. Synergistic analgesic combination of oxycodone and rofecoxib
WO2004110415A2 (fr) 2003-06-10 2004-12-23 Janssen Pharmaceutica N.V. Nouvelles formulations destinees au traitement a base d'opioides, contre la douleur, renfermant des derives di-piperidin-4-yl-piperazine a substitution 1,4
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques
US8604200B2 (en) 2005-03-08 2013-12-10 Janssen Pharmaceutica N.V. Diaza-spiro-{4,4}-nonane derivatives as neurokinin (NK1) antagonists

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995014017A1 (fr) * 1993-11-17 1995-05-26 Eli Lilly And Company Antagonistes non peptidiques des recepteurs a la tachykinine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995014017A1 (fr) * 1993-11-17 1995-05-26 Eli Lilly And Company Antagonistes non peptidiques des recepteurs a la tachykinine

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6552031B1 (en) 1997-09-17 2003-04-22 Euro-Celtique S.A. Synergistic analgesic combination of oxycodone and rofecoxib
US8143267B2 (en) 1997-09-17 2012-03-27 Purdue Pharma L.P. Analgesic combination of oxycodone and nimesulide
US8168629B2 (en) 1997-09-17 2012-05-01 Purdue Pharma L.P. Analgesic combination of tramadol and meloxicam
US8188107B2 (en) 1997-09-17 2012-05-29 Purdue Pharma L.P. Analgesic combination of oxycodone and N-[3-(formylamino)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl] methanesulfonamide
US8193209B2 (en) 1997-09-17 2012-06-05 Purdue Pharma L.P. Analgesic combination of oxycodone and meloxicam
US8685994B2 (en) 1997-09-17 2014-04-01 Purdue Pharma, L.P. Analgesic combination of oxycodone and celecoxib
WO1999022730A1 (fr) * 1997-10-31 1999-05-14 Vanguard Medica Limited Utilisation de (+)-6-carboxamido-3-methylamino-1,2,3,4-tetrahydrocarbazole pour le traitement de l'hyperalgie
WO1999059635A1 (fr) * 1998-05-21 1999-11-25 Merck Sharp & Dohme Limited Utilisation d'un inhibiteur de cox-2 et d'un antagoniste du recepteur nk-1 dans le traitement de l'inflammation
WO2004110415A2 (fr) 2003-06-10 2004-12-23 Janssen Pharmaceutica N.V. Nouvelles formulations destinees au traitement a base d'opioides, contre la douleur, renfermant des derives di-piperidin-4-yl-piperazine a substitution 1,4
US8604200B2 (en) 2005-03-08 2013-12-10 Janssen Pharmaceutica N.V. Diaza-spiro-{4,4}-nonane derivatives as neurokinin (NK1) antagonists
WO2008090117A1 (fr) 2007-01-24 2008-07-31 Glaxo Group Limited Nouvelles compositions pharmaceutiques

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