WO1996029074A1 - Procedes de traitement ou de prevention de la douleur ou de la nociception - Google Patents

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

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Publication number
WO1996029074A1
WO1996029074A1 PCT/US1996/004198 US9604198W WO9629074A1 WO 1996029074 A1 WO1996029074 A1 WO 1996029074A1 US 9604198 W US9604198 W US 9604198W WO 9629074 A1 WO9629074 A1 WO 9629074A1
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indol
pain
activity
serotonin
receptor antagonist
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PCT/US1996/004198
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English (en)
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Kirk W. Johnson
Lee A. Phebus
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Eli Lilly And Company
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Priority to AU55289/96A priority Critical patent/AU5528996A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • 5-HT has been implicated as being involved in the expression of a number of behaviors, physiological responses, and diseases which originate in the central nervous system. These include such diverse areas as sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, schizophrenia, and other bodily states.
  • Serotonin plays an important role in peripheral systems as well. For example, approximately 90% of the body's serotonin is synthesized in the gastrointestinal system, and serotonin has been found to mediate a variety of contractile, secretory, and electrophysiologic effects in this system. Serotonin may be taken up by the platelets and, upon platelet aggregation, be released such that the cardiovascular system provides another example of a peripheral network that is very sensitive to serotonin. Given the broad distribution of serotonin within the body, it is understandable that tremendous interest in drugs that affect serotonergic systems exists.
  • receptor-specific agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, compulsive disorders, schizophhrenia, autism, neurodegenerative disorders, such as Alzheimer's disease,
  • Serotonin produces its effects on cellular physiology by binding to specialized receptors on the cell surface. It is now recognized that multiple types of receptors exist for many neurotransmitters and hormones, including serotonin. The existence of multiple, structurally distinct serotonin receptors has provided the possibility that subtype- selective pharmacologic agents can be produced.
  • 5-HT 2 , 5-HT3, 5-HT 4 , 5-HT5, 5-HT 6 , and 5-HT contain some fourteen to eighteen separate receptors that have been formally classified based on their pharmacological or structural differences.
  • 5-HT receptor types ___. Glennon, et al.. Neuroscience and
  • 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. Between 1983 and 1984 several groups reported the isolation of two novel mammalian tachykinins, now termed neurokinin A (also known as substance K, neuromedin L, and neurokinin ⁇ ), and neurokinin B (also known as neuromedin K and neurokinin ⁇ ). See. J.E. Maggio, Peptides. 6 (Supplement 3):237-243 (1985) for a review of these discoveries.
  • 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
  • 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.
  • Recent publications have described novel classes of non- peptidyl tachykinin receptor antagonists which generally have greater oral bioavailability and metabolic stability than the earlier classes of tachykinin receptor antagonists.
  • This invention provides methods for the treatment or prevention of pain or nociception in a mammal which comprise administering to a mammal in need thereof an effective amount of a composition having both tachykinin receptor antagonist activity and either serotonin agonist activity or activity as a selective serotonin reuptake inhibitor.
  • the present invention provides methods for treating persons afflicted with, or with a heightened risk of contracting, one or more disorders selected from the group consisting of chronic pain, such as neuropathic pain, and post-operative pain, pain associated with arthritis, cancer-associated pain, chronic lower back pain, cluster 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, angina pain, and genitourinary tract-related pain including cystitis.
  • chronic pain such as neuropathic pain, and post-operative pain
  • pain associated with arthritis cancer-associated pain, chronic lower back pain, cluster 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,
  • This invention further provides methods for the treatment or prevention of pain or nociception in a mammal which comprise the sequential administration to a mammal in need thereof a composition having serotonin agonist activity (or selective serotonin reuptake inhibitor activity) followed by the administration of a composition having tachykinin receptor antagonist activity.
  • This invention also provides methods for the treatment or prevention of pain or nociception in a mammal which comprise the sequential administration to a mammal in need thereof a composition having tachykinin receptor antagonist activity followed by the administration of a composition having serotonin agonist activity (or selective serotonin reuptake inhibitor activity).
  • serotonin binding receptors have been identified. These receptors are generally grouped into seven classes on the basis of their structure and the pharmacology of the receptor as determined by the binding efficiency and drug-related characteristics of numerous serotonin receptor-binding compounds. In some of the groups several subtypes have been identified. [For a relatively recent review of 5- hydroxytryptamine receptors, __&, E. Zifa and G. Fillion, PharamcologJcal Reviews. 44:401-458 (1992); D. Hoyer, ⁇ La ,
  • Table I Pharam ⁇ nlogjcal Reviews. 46:157-203 (1994).] Table I, infra, lists the seven classes of serotonin receptors as well as several known subtypes. This table also provides the physiological distribution of these receptors as well as biological responses mediated by the receptor class or subtype, if any such response is known. This table is derived from D. Hoyer, e_t al.. "VII. International Union of Pharmacology Classification of Receptors for 5-Hydroxytryptamine (Serotonin)", Pharamcolo Jcal Reviews. 46:157-203 (1994), a publication of the Serotonin Club Receptor Nomenclature Committee of the IUPHAR Committee for Receptor Nomenclature. The Hoyer, et al.. reference describes for each class or subtype one or more compounds which have efficacy as antagonists or agonists for the receptor.
  • the 5-HT ⁇ family includes subtypes which can be grouped together based on the absence of introns in the cloned genes, a common G-coupled protein transduction system (inhibition of adenylate cyclase), and similar operational characteristics.
  • the 5-HT ⁇ family of inhibitory receptors includes subtypes A, B, D, E, and F.
  • the 5-HT ⁇ G protein- linked receptors general inhibit the production of cyclic adenosine monophosphate (cAMP), while the 5-HT2 G protein linked receptors stimulate phosphoinosytol hydrolysis.
  • the 5-HTIA receptor was the first cloned human serotonin receptor. Activated 5-HTIA receptors expressed in HeLa cells inhibit forskolin-stimulated adenylate cyclase activity.
  • the 5-HTID receptor was originally identified in bovine brain membrane by Heuring and
  • the 5-HTID receptors are the most common 5-HT receptor subtype in the human brain and may be identical to the 5-HT ⁇ . like receptor in the cranial vasculature. S.D. Silberstein, Headache. 34:408-417 (1994). Sumatriptan and the ergot alkaloids have high affinity for both the human 5-HTID and the 5-HTIB receptors. __..
  • the 5-HTIF subtype of receptor has low affinity for 5- carboxamidotryptamine (5-CT) unlike the other 5-HT receptors, except for the 5-HTIE subtype. Unlike the 5-HTIE receptors, however, the 5- HTIF receptors do show affinity for sumatriptan.
  • 5-CT 5- carboxamidotryptamine
  • 5-HT 2 5-HT 2A Vascular smooth Vasoconstriction, platelet muscle, platelets, aggregation, lung, CNS, bronchoconstriction gastrointestinal tract
  • 5-HT7 CNS Activation of adenylyl cyclase The biological efficacy of a compound believed to be effective as a serotonin agonist may be confirmed by first employing an initial screening assay which rapidly and accurately measures the binding of the test compound to one or more serotonin receptors. Once the binding of the test compound to one or more serotonin receptors is established, the in vivo activity of the test compound on the receptor is established. Assays useful for evaluating serotonin agonists are well known in the art. See, e.g.. E. Zifa and G. Fillion, supra: D. Hoyer, et al.. supra, and the references cited therein.
  • binding to the 5-HTIF receptor The ability of a compound to bind to a serotonin receptor was measured using standard procedures. For example, the ability of a compound to bind to the 5-HTip receptor substype was performed essentially as described in N. Adham, et al.. Proceedings of the National Academy of Sciences (USA). 90:408-412 (1993). The cloned 5-HTIF receptor was expressed in stably transfected LM(tk”) cells. Membrane preparations were made by growing these transfected cell lines to confluency.
  • the cells were washed twice with phosphate-buffered saline, scraped into 5 ml of ice- cold phosphate-buffered saline, and centrifuged at 200 x g for about five minutes at 4°C.
  • the pellet was resuspended in 2.5 ml of cold Tris buffer (20 mM Tris-HCl, pH 7.4 at 23°C, 5 mM EDTA) and homogenized.
  • the lysate was centrifuged at 200 x g for about five minutes at 4°C to pellet large fragments.
  • the supernatant was then centrifuged at 40,000 x g for about 20 minutes at 4°C.
  • the membranes were washed once in the homogenization buffer and resuspended in 25 mM glycylclycine buffer, pH 7.6 at 23°C.
  • Radioligand binding studies were performed using [ H]5- HT (20-30 Ci/mmol). Competition experiments were done by using various concentrations of drug and 4.5-5.5 nM [ 3 H]5-HT. Nonspecific binding was defined by 10 ⁇ M 5-HT. Binding data were analyzed by nonlinear- regression analysis. IC50 values were converted to Kj values using the Cheng-Prusoff equation.
  • binding affinities of compounds for various serotonin receptors may be determined essentially as described above except that different cloned receptors are employed in place of the 5-HTIF receptor clone employed therein.
  • Adenylate cyclase activity was determined in initial experiments in LM(tk-) cells, using standard techniques. See, e.g.. N.
  • Intracellular levels of cAMP were measured using the clonally derived cell line described above. Cells were preincubated for about 20 minutes at 37°C in 5% carbon dioxide, in Dulbecco's modified Eagle's medium containing 10 mM HEPES, 5 mM theophylline, and 10 ⁇ M pargyline. Varying concentrations of the test compounds were added to ths medium to determine inhibition of forskolin-stimulated adenylate cyclase.
  • Some compounds that bind serotonin receptors show no receptor selectively, i.e. they bind different receptor subtypes with comparable affinity.
  • One example of such a non-selective serotonin receptor binding compound is dihydroergotamine, a compound having the structure 10
  • a compound having a high affinity for one (or a few) receptor subtype and low affinity for other receptor subtypes using studies analogous to the binding assays supra, is considered to be subtype-selective. Such compounds are especially preferred in the methods of the present invention.
  • An additional serotonin agonist which is specific for the 5- HTi class of receptors is a compound of the structure
  • 311C90 having the designation 311C90 and the chemical name (S)-4-[[3-[2- (dimethylamino)ethyl]- lH-indol-5-yl]methyl]-2-oxazolidinone.
  • This compound may be synthesized as described in Patent Cooperation Treaty Publication WO 91/18897, published December 12, 1991. Unlike sumatriptan, 311C90 is believed capable of crossing the blood-brain barrier. Scrip. September 7, 1994.
  • Especially preferred serotonin agonists employed in the methods of this invention are those compounds with a high affinity for the 5-HTIF subtype of receptor.
  • One such class of compounds is typified by the compound
  • the dichloromethane phase was separated, washed sequentially with water and saturated aqueous sodium chloride solution and then dried over sodium sulfate to give 4.0 g of a brown oil.
  • the brown oil was chromatographed over silica gel, eluting with 95:5 dichloromethane:methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to give 5-fluoro-3-[l-[2-[l-methyl-lH-pyrazol-4-yl]ethyl]-4- piperidinyl]-lH-indole as a yellow oil.
  • the oil was dissolved in a minimal volume of methanol and to it were added 1.21 ml (0.006 mole) 5N hydrochloric acid.
  • the starting materials described herein are either commercially available or may be synthesized from commercially available materials using known methods.
  • Also especially preferred compounds employed in the methods of the present invention are those compounds which have a high affinity for the 5-HT 2 subtypes of receptors. Such compounds are well known to those skilled in the art. See, e.g.. Hoyer, et al.. supra, at 174-179.
  • OH having the chemical name 17 ⁇ -hydroxy-20 ⁇ -yohimban-16 ⁇ -carboxylic acid methyl ester.
  • This compound also known as ⁇ -yohimbine, can be prepared as described in T ⁇ ke, et al.. Journal of Organic Chemistry. 38:2496 (1973) or can be purchased commercially from many sources.
  • this invention also encompasses methods for the treatment or prevention of pain or nociception in a mammal which comprise administering to a mammal in need thereof an effective amount of a composition having both tachykinin receptor antagonist activity and selective serotonin reuptake inhibition activity.
  • This invention further provides methods for the treatment or prevention of pain or nociception in a mammal which comprise the sequential administration to a mammal in need thereof a composition having selective serotonin reuptake inhibition activity followed by the administration of a composition having tachykinin receptor antagonist activity.
  • This invention also provides methods for the treatment or prevention of pain or nociception in a mammal which comprise the sequential administration to a mammal in need thereof a composition having tachykinin receptor antagonist activity followed by the administration of a composition having selective serotonin reuptake inhibition activity.
  • the selective serotonin reuptake inhibitors are a series of compounds which selectively inhibit the serotonin transporter on membranes of serotonin neurons. These uptake inhibitors increase the concentration of serotonin within the synaptic cleft by blocking its removal via the membrane transporter.
  • Inhibitors of serotonin uptake increase serotonin action on postsynaptic receptors on target neuron, and increase serotonergic neurotransmission, resulting in functional consequences that are mostly subtle, i.e., not detectable by gross observation, but are detectable by various specific techniques.
  • serotonin uptake inhibitors reduce aggressive behavior, decrease food uptake, decrease alcohol drinking in reats, decrease rapid-eye-movememt sleep, potentiate morphine analgesia, and the like.
  • Serotonin uptake inhibitors are used clinically in the treatment of mental depression, bulimia, and obsessive-compulsinve disorder. They are also reported to be effective as appetite suppressant drugs in the treatment of obesity, in borderline personality disorder, trichotillomania, panic disorder, and attention deficit hyperactivity disorder. See, e.g.. R.W. Fuller, Advances in Biosciences. 85:255-270 (1992).
  • serotonin uptake inhibitors have been reported to have therapeutic benefit in premenstrual syndrome, diabetic neuropathy, certain non-cognitive symptoms of Alzheimer's Disease, chrome pain, and in postanoxic intention myoclonus.
  • fluoxetine a compound having the structure
  • Another selective serotonin reuptake inhibitor which may be employed in the methods of the present invention is citalopram, a compound having the structure
  • Another compound belonging to this class of therapeutics is femoxetine, a compound having the structure
  • Another SSRI which may be employed in the methods of the present invention is fluvoxamine, a compound having the structure
  • indalpine a compound having the structure
  • Another such compound is paroxetine, a compound having the structure
  • Sertraline is another SSRI which may be employed in the methods of the present invention.
  • This compound having the chemical name (lS-cis)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l- naphthalenamine, has the following structure.
  • Sertraline may be prepared as described in United States Patent 4,536,518, the entire contents of which are herein incorporated by reference.
  • An additional SSRI which may be employed in the methods of the present invention is zimeldine, a compound of the structure
  • the methods of the present invention in addition to the serotonin agonists and selective serotonin reuptake inhibitors, examples of which are described above, also employ various tachykinin receptors.
  • Patent Cooperation Treaty publication WO 94/01402 published January 20, 1994, describes a series of compounds best typified by the following compound.
  • A is a pharmaceutically acceptable anion
  • Patent Cooperation Treaty publication WO 94/07843 describes a series of cyclohexylamine derivatives typified by the following compound
  • Another group of compounds useful as tachykinin receptor antagonists is typified by the following compound.
  • a most preferred class of tachykinin receptor antagonists are those compounds of the following structure
  • 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; and Y is
  • R a , R b , and R c are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
  • 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.
  • 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
  • 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.
  • 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.
  • the final volume of isopropyl alcohol was then concentrated to three volumes by vacuum.
  • the reaction mixture was cooled to 20°C to 25°C and the product was allowed to crystallize for at least one hour.
  • the desired product was then recovered by filtration and washed with sufficient isopropyl alcohol to give a colorless filtrate.
  • the crystal cake was then dried under vacuum at 50°C. MS 560 (M+l + ).
  • 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.
  • the 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.
  • the organic fractions were combined and washed with water (100 ml).
  • the water wash was back extracted with methylene chloride (50 ml) and combined with the aqueous fraction from above.
  • Methylene chloride 500 ml was added to the combined aqueous layers and the mixture was stirred at room temperature for 15 minutes as basification with 2N sodium hydroxide to a final pH of 9.8 to 10.2 was achieved.
  • the organic and aqueous fractions were separated.
  • the aqueous fraction was washed with methylene chloride and the methylene chloride was added to the organic fraction.
  • the organic fraction was then washed with a mixture of saturated sodium bicarbonate solution (100 ml) and water (50 ml).
  • the bicarbonate wash was separated from the organic fraction and back extracted with methylene chloride (50 ml).
  • the back extraction was combined with the methylene chloride fraction and the combined fractions were dried over magnesium sulfate.
  • the magnesium sulfate was removed by filtration and the volatiles were removed by vacuum distillation to yield the title product as a foam. (72.5 g, >98% yield).
  • 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 i-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- 1,2-cyclohexane dicarboxylic, succinic, phthalic, trans- l,2-diaminocyclohexane-N,N,N',N'-naphthalenedisulfonic, and 5- sulfosalicylic acids. Only oxalic acid 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 acid 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.
  • a compound believed to be effective as a tachykinin receptor antagonist may be confirmed by employing an initial screening assay which rapidly and accurately measured the binding of the tested compound to known NK-1 and NK-2 receptor sites.
  • Assays useful for evaluating tachykinin receptor antagonists are well known in the art. See, e.g.. J. Jukic, et al.. Life Sciences. 49:1463-1469 (1991); N. Kucharczyk, et al.. Journal of Medicinal Chemistry. 36:1654-1661 (1993); N. Rouissi, et al.. Biochemical and Biophysical Research Communications. 176:894-901 (1991).
  • Radioreceptor binding assays were performed using a derivative of a previously published protocol.
  • 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 Academv of Science. 190: 221-234 (1972); Nature (London).
  • 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, et al.. Journal of Biological Chemistry. 265:20455-20462 (1990).
  • CHO-hNK-2R membrane preparation was suspended in 40 ml of assay buf er 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 [ 1 5 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. All samples and standards were added to the incubation in
  • DMSO dimethylsulfoxide
  • IC50 10 ⁇ l dimethylsulfoxide
  • 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.
  • Co-pending United States Patent Application 08/318,330, filed October 5, 1994 clearly demonstrates that those compounds having an affinity for the 5-HT ⁇ p receptor subtype are most advantageous for the treatment of migraine.
  • Co-pending United States Patent Application Serial Number 08/318,391, filed October 5, 1994 clearly demonstrates that a combination of a serotonin agonist and a tachykinin receptor antagonist are superior to either class of compound alone in the treatment of migraine, the combination demonstrating a synergistic efficacy profile.
  • any synergistic combination therapy greatly increases the therapeutic index of a composition in treating these nociceptive disorders.
  • a markedly decreased amount of a serotonin agonist 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 especially 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 associated with arthritis, cancer-associated pain, chronic lower back pain, cluster 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, angina pain, and genitourinary tract-related pain including cystitis.
  • chronic pain such as neuropathic pain, and post-operative pain, pain associated with arthritis, cancer-associated pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, neuropathic pain, opioid-resistant pain, visceral pain
  • compositions comprising a pharmaceutically acceptable excipient 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 PHARMACEUTICAL SCIENCES, (16th ed. 1980).
  • the active ingredient is usually mixed with an excipient, diluted by an excipient 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 excipient 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.
  • suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium 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.
  • lubricating agents such as talc, magnesium stearate, and mineral oil
  • wetting agents such as talc, magnesium stearate, and mineral oil
  • emulsifying and suspending 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 association with a suitable pharmaceutical excipient.
  • 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 especially preferred.
  • 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 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:
  • Quantity Ingredient (mg/capsule)
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • a dry powder inhaler formulation is prepared containing the following components:
  • 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:
  • Quantity Ingredient (mg/capsule)
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • the active ingredient(s) is passed through a No. 60 mesh
  • Suspensions each containing 50 mg of medicament per 5.0 ml dose are made as follows:
  • Capsules each containing 15 mg of medicament, are made as follows:
  • Quantity Ingredient (mg/capsule)
  • 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:
  • the white soft paraffin is heated until molten.
  • the liquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the mixture is then cooled until solid.
  • 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 serotonin agonist may be simultaneous with, before, or after the administration of the tachykinin receptor antagonist. If it is desired to administer the serotonin agonist 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.

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Abstract

Cette invention concerne des procédés destinés au traitement ou à la prévention de la douleur ou de la nociception. Ces procédés consistent à administrer à un mammifère justifiant de ce traitement une combinaison d'un antagoniste des récepteurs de la tachykinine et, soit d'un agoniste de la sérotonine, soit d'un inhibiteur sélectif de la réabsorption de la sérotonine. Cette administration peut se faire de façon simultanée ou séquentielle, l'une ou l'autre des deux activités pouvant être administrée en premier.
PCT/US1996/004198 1995-03-22 1996-03-20 Procedes de traitement ou de prevention de la douleur ou de la nociception WO1996029074A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
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WO1998031354A2 (fr) * 1997-01-17 1998-07-23 Smithkline Beecham Plc Nouveau traitement
WO2000016761A2 (fr) * 1998-09-18 2000-03-30 Alcon Laboratories, Inc. Agonistes de 5ht2 serotoninergiques utiles pour traiter le glaucome
US6056715A (en) * 1995-12-12 2000-05-02 Omeros Medical Systems, Inc. Surgical irrigation solution and method for inhibition of pain and inflammation
WO2000042071A2 (fr) * 1999-01-12 2000-07-20 Cambridge University Technical Services Ltd. Composes et procedes destines a inhiber ou renforcer une reaction inflammatoire
EP1082958A2 (fr) * 1996-11-15 2001-03-14 Eli Lilly And Company Agonistes 5-HT1F dans la douleur chronique
WO2001032178A1 (fr) * 1999-10-29 2001-05-10 Novo Nordisk A/S Utilisation de piperidines 3,4-substituees
US6413961B1 (en) 1995-12-12 2002-07-02 Omeros Medical Systems, Inc. Irrigation solution and method for inhibition of pain and inflammation
WO2003011272A1 (fr) * 2001-07-31 2003-02-13 Pharmacia & Upjohn Company Traitement des douleurs chroniques au moyen de 3-aryloxy-3-phenylpropanamines
US6989435B2 (en) 1997-09-11 2006-01-24 Cambridge University Technical Services Ltd. Compounds and methods to inhibit or augment an inflammatory response
US7091181B2 (en) 1994-12-12 2006-08-15 Omeros Corporation Method of inhibition of pain and inflammation during surgery comprising administration of soluble TNF receptors

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US5292726A (en) * 1991-05-22 1994-03-08 Merck & Co., Inc. N,N-diacylpiperazines
US5307953A (en) * 1991-12-03 1994-05-03 Glaxo Group Limited Single dose dispenser having a piercing member
US5409941A (en) * 1992-02-03 1995-04-25 Pfizer Inc. 5-heteroyl indole derivatives

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US4804669A (en) * 1986-11-11 1989-02-14 A/S Ferrosan Treatment of pain with a piperidine
US5292726A (en) * 1991-05-22 1994-03-08 Merck & Co., Inc. N,N-diacylpiperazines
US5307953A (en) * 1991-12-03 1994-05-03 Glaxo Group Limited Single dose dispenser having a piercing member
US5409941A (en) * 1992-02-03 1995-04-25 Pfizer Inc. 5-heteroyl indole derivatives

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7091181B2 (en) 1994-12-12 2006-08-15 Omeros Corporation Method of inhibition of pain and inflammation during surgery comprising administration of soluble TNF receptors
US6413961B1 (en) 1995-12-12 2002-07-02 Omeros Medical Systems, Inc. Irrigation solution and method for inhibition of pain and inflammation
US6056715A (en) * 1995-12-12 2000-05-02 Omeros Medical Systems, Inc. Surgical irrigation solution and method for inhibition of pain and inflammation
US6420432B2 (en) 1995-12-12 2002-07-16 Omeros Corporation Surgical irrigation solution and method for inhibition of pain and inflammation
US6645168B2 (en) 1995-12-12 2003-11-11 Omeros Corporation Arthroscopic irrigation solution and method for inhibition of pain and inflammation
US6242447B1 (en) 1995-12-12 2001-06-05 Omeros Medical Systems, Inc. Surgical irrigation solution and method for inhibition of pain and inflammation
US6261279B1 (en) 1995-12-12 2001-07-17 Omeros Medical Systems, Inc. Surgical irrigation solution and method for inhibition of pain and inflammation
EP1082958A3 (fr) * 1996-11-15 2002-12-11 Eli Lilly And Company Agonistes 5-HT1F dans la douleur chronique
EP1082958A2 (fr) * 1996-11-15 2001-03-14 Eli Lilly And Company Agonistes 5-HT1F dans la douleur chronique
WO1998031354A3 (fr) * 1997-01-17 1998-09-17 Smithkline Beecham Plc Nouveau traitement
WO1998031354A2 (fr) * 1997-01-17 1998-07-23 Smithkline Beecham Plc Nouveau traitement
US6989435B2 (en) 1997-09-11 2006-01-24 Cambridge University Technical Services Ltd. Compounds and methods to inhibit or augment an inflammatory response
WO2000016761A3 (fr) * 1998-09-18 2000-05-25 Alcon Lab Inc Agonistes de 5ht2 serotoninergiques utiles pour traiter le glaucome
AU755119B2 (en) * 1998-09-18 2002-12-05 Alcon Laboratories, Inc. Serotonergic 5HT2 agonists for treating glaucoma
WO2000016761A2 (fr) * 1998-09-18 2000-03-30 Alcon Laboratories, Inc. Agonistes de 5ht2 serotoninergiques utiles pour traiter le glaucome
US6664286B1 (en) 1998-09-18 2003-12-16 Alcon Manufacturing, Ltd. Serotonergic 5ht2 agonists for treating glaucoma
WO2000042071A2 (fr) * 1999-01-12 2000-07-20 Cambridge University Technical Services Ltd. Composes et procedes destines a inhiber ou renforcer une reaction inflammatoire
JP2005506947A (ja) * 1999-01-12 2005-03-10 ケンブリッジ ユニバーシティ テクニカル サービシズ リミティド 炎症反応を阻害又は増強するための組成物及び方法
WO2000042071A3 (fr) * 1999-01-12 2001-05-31 Neorx Corp Composes et procedes destines a inhiber ou renforcer une reaction inflammatoire
JP4712975B2 (ja) * 1999-01-12 2011-06-29 ケンブリッジ エンタープライズ リミティド 炎症反応を阻害又は増強するための組成物及び方法
WO2001032178A1 (fr) * 1999-10-29 2001-05-10 Novo Nordisk A/S Utilisation de piperidines 3,4-substituees
WO2003011272A1 (fr) * 2001-07-31 2003-02-13 Pharmacia & Upjohn Company Traitement des douleurs chroniques au moyen de 3-aryloxy-3-phenylpropanamines

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