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WO1998049158A1 - Kappa agonistes opioides peripheriquement selectifs - Google Patents

Kappa agonistes opioides peripheriquement selectifs Download PDF

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Publication number
WO1998049158A1
WO1998049158A1 PCT/US1998/006485 US9806485W WO9849158A1 WO 1998049158 A1 WO1998049158 A1 WO 1998049158A1 US 9806485 W US9806485 W US 9806485W WO 9849158 A1 WO9849158 A1 WO 9849158A1
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Prior art keywords
methyl
ethyl
pyrrolidin
phenyl
benzofuran
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Ceased
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PCT/US1998/006485
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English (en)
Inventor
David Christopher Horwell
Simon Osborne
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Warner Lambert Co LLC
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Warner Lambert Co LLC
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Priority to AU68782/98A priority Critical patent/AU6878298A/en
Priority to US09/331,753 priority patent/US6057357A/en
Publication of WO1998049158A1 publication Critical patent/WO1998049158A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the compounds of the instant invention are polar compounds designed to have a low log D and thereby have a limited ability to cross the blood-brain barrier. This means that the side effects associated with centrally acting kappa opioid agonists are greatly reduced upon administration of these compounds to a mammal, preferably a human, in need of treatment. Such side effects are various CNS problems and dysphoria.
  • Preferred compounds of the invention are those of Formula I wherein Z is 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 4-(methylsulphonyl)phenyl, 3-(methylsulphonyl)phenyl,
  • Other preferred compounds are those of Formula I wherein Z is diphenylcyclopropene or diphenylmethyl, and n is zero.
  • More preferred compounds are those selected from: (S)-(3 - ⁇ 1 - [(Benzofuran-2-yl-acetyl)-methyl-amino] -2-pyrrolidin- 1 -yl- ethyl ⁇ -phenoxy)-acetic acid;
  • Other compounds are: [S-(R*,R*)]- ⁇ 3-[l-[(Benzofuran-4-yl-acetyl)-methyl-amino]-2-(3-fluoro- pyrrolidin-l-yl)-ethyl]-phenoxy ⁇ -acetic acid,
  • a pharmaceutical composition comprising a compound of Formula I in a therapeutically effective amount in combination with a pharmaceutically acceptable carrier in unit dosage form is another aspect of the instant invention.
  • the compounds of the invention are useful in the treatment of pain, inflammation, migraine, inflammatory disorders of the gastrointestinal tract, psoriasis, and irritable bowel syndrome (IBS).
  • IBS irritable bowel syndrome
  • the compounds covered below are selective kappa opioid agonists. They are polar compounds designed to have a low log D and hence a limited ability to cross the blood-brain barrier. The side effects associated with centrally acting kappa agonists are thus reduced. This reduction in side effects is of great value in the treatments provided in this invention.
  • X CO2H, SO3H, or tetrazole; m is an integer of from 1 to 3;
  • Y is hydrogen, fluoro, or OR wherein R is hydrogen or methyl; n is an integer of from 0 to 1 ; and Z is 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 4-(methylsulphonyl)phenyl, 3-(methylsulphonyl)phenyl, 2-thianaphthene, 3-thianaphthene, 4-thianaphthene, 5-thianaphthene, 6-thianaphthene, or 7-thianaphthene when n is 1 and
  • Z is diphenylcyclopropene or diphenylmethyl when n is 0.
  • Compounds of the present invention contain one or more asymmetric carbon atoms and therefore exist in various stereoisomeric forms. Additionally, the compounds of this invention exist in different geometric isomeric forms. The instant invention is all geometric and stereoisomeric forms.
  • the compounds of the present invention and/or their nontoxic, pharmaceutically acceptable acid addition salts may be administered to mammals in pharmaceutical compositions which comprise one or more compounds of this invention and/or salts thereof in combination with a pharmaceutically acceptable nontoxic carrier.
  • the compounds of this invention may be administered with conventional injectable liquid carriers such as sterile, pyrogen- free water, sterile peroxide-free ethyl oleate, dehydrated alcohols, polypropylene glycol, and mixtures thereof.
  • Suitable pharmaceutical adjuvants for the injectable solutions include stabilizing agents, solubilizing agents, buffers, and viscosity regulators. Examples of these adjuvants include ethanol, ethylenediamine tetraacetic acid (EDTA), tartrate buffers, citrate buffers, and high molecular weight polyethylene oxide viscosity regulators.
  • These pharmaceutical formulations may be injected intramuscularly, intraperitoneally, or intravenously.
  • the compounds of the present invention may be administered to mammals orally in combination with conventional compatible carriers in solid or liquid form.
  • These orally administered pharmaceutical compositions may contain conventional ingredients such as binding agents such as syrups, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, and mixtures thereof.
  • the compositions may further include fillers such as lactose, mannitol, starch, calcium phosphate, sorbitol, methylcellulose, and mixtures thereof.
  • compositions may also contain lubricants such as magnesium stearate, high molecular weight polymers such as polyethylene glycol, high molecular weight fatty acids such as stearic acid, silica, or agents to facilitate disintegration of the solid formulation such as starch, and wetting agents such as sodium lauryl sulfate.
  • lubricants such as magnesium stearate, high molecular weight polymers such as polyethylene glycol, high molecular weight fatty acids such as stearic acid, silica, or agents to facilitate disintegration of the solid formulation such as starch, and wetting agents such as sodium lauryl sulfate.
  • the oral pharmaceutical compositions may take any convenient form such as tablets, capsules, lozenges, aqueous or oily suspensions, emulsions, or even dry powders which may be reconstituted with water or other suitable liquids prior to use.
  • the solid or liquid forms may contain fiavorants, sweeteners, and/or preservatives such as alkyl p-hydroxybenzoates.
  • the liquid forms may further contain suspending agents such as sorbitol, glucose, or other sugar syrups, methyl-, hydroxymethyl-, or carboxymethylcellulose, and gelatin, emulsifying agents such as lecithin or sorbitol monooleate, and conventional thickening agents.
  • the liquid compositions may be encapsulated in, for example, gelatin capsules.
  • the compounds of the present invention may be administered in the form of ointments or creams containing from about 0.1% to about 10% by weight of the active component in a pharmaceutical ointment or cream base.
  • Compounds of the present invention may be rectally administered in the form of suppositories.
  • a low-melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously in the melt. The mixture is then poured into convenient-sized molds and allowed to cool and solidify.
  • the pharmaceutical compositions of this invention are in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate amounts of the active component.
  • the unit dosage can be a packaged preparation with the package containing discrete quantities of the preparation.
  • the package may take the form of packaged tablets, capsules, and powders in envelopes, vials, or ampoules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself or can be the appropriate number of any of these packaged forms.
  • the quantity of active compound in the unit dosage form may be varied or adjusted from about 0.5 mg to about 350 mg according to the particular application and the potency of the active ingredient.
  • the compounds When employed systematically in therapeutic use as analgesic agents in the pharmaceutical method of this invention, the compounds are administered at doses of from about 0.05 mg to about 2.0 mg of active compound per kilogram of body weight of the recipient.
  • the rabbit vas deferens is a specific test for activity at the K-receptor and allows comparison of potency and efficacy of a test ligand and its parent K-agonist. Rabbit vas deferens assay (Oka T., Negiski K et al., Eur. J. Pharmacol, 1981 ;73:235) was used to test the compounds of the invention.
  • the potency of the compounds listed below is the EC50 compared to the EC 50 of [5R-(5 ⁇ ,7 ⁇ ,8 ⁇ )]-N-methyl-N-[7-(l-pyrrolidinyl)-l-oxaspiro-[4,5]dec-8- yl]-4-benzofuranacetamide, monohydrochloride.
  • Nociceptive reaction number of times left paw is licked during the observation period.
  • Ataxic reaction time taken for mouse to fall off the rotarod (maximum time 120 seconds).
  • the starting aldehyde is converted into the corresponding styrene by means of a Wittig reaction in a suitable solvent.
  • Asymmetric dihydroxylation gives a diol, and this is converted into an epoxide.
  • Opening the epoxide with pyrrolidine or a substituted pyrrolidine leads to an amino alcohol which can then be transformed into a diamine.
  • Coupling the diamine with an acid using a suitable coupling reagent leads to an amide.
  • the benzyl protecting group is removed by hydrogenation with a catalyst in a suitable solvent.
  • the phenol is then etherified with a suitable base and t-butylbromoacetate. Conversion of the ester into the carboxylic acid by means of a strong acid leads to the salts of the final compound.
  • the starting aldehyde is converted into the corresponding styrene by means of a Wittig reaction in a suitable solvent.
  • Asymmetric dihydroxylation gives a diol, and this is converted into an epoxide.
  • Opening the epoxide the hydroxy protected pyrrolidine leads to an amino alcohol which can then be transformed into a diamine.
  • Coupling the diamine with an acid using a suitable coupling reagent leads to an amide.
  • the benzyl protecting group is removed by hydrogenation with a catalyst in a suitable solvent.
  • the phenol is then etherified with a suitable base and t-butylbromoacetate.
  • the protecting group is removed from the hydroxy pyrrolidine. Conversion of the ester into the carboxylic acid by means of a strong acid leads to the salts of the final compound.
  • AD-mix- ⁇ (42 g).
  • Example 1 (6.4 g, 30 mmol) was added and stirred for 3.5 hours. The reaction was refrigerated overnight (15.5 hours), stirred for 8 hours, refrigerated for another 16 hours, and stirred for a further 1 hour. Sodium sulphite (45 g, 36 mmol) was added and the reaction stirred for 2 hours at room temperature. The mixture was poured into ethyl acetate (300 mL) and the aqueous extracted with ethyl acetate (3 x 150 mL). The organics were dried (MgSO- and the solvent removed in vacuo.
  • Example 2 To a solution of Example 2 (16.22 g, 66 mmol) in dichloromethane (150 mL), trimethylorthoacetate (10.0 mL, 79 mmol) and chlorotrimethylsilane (10.0 mL, 79 mmol) were added. The reaction was stirred at room temperature under argon for 2 hours, then the solvent removed in vacuo. Potassium carbonate (11.59 g, 84 mmol) and methanol (260 mL) were added, and the reaction was stirred at room temperature under argon for 2 hours then poured into saturated ammonium chloride solution (550 mL) and extracted with dichloromethane (1650 mL). The organics were dried (MgSO4) and the solvent removed in vacuo.
  • Example 3 To a stirred solution of Example 3 (2.80 g, 12.4 mmol) in ethanol (45 mL), pyrrolidine (3.3 mL, 39.5 mmol) was added. The reaction was heated to reflux for
  • Example 11 To a stirred solution of Example 3 (7.65 g, 38 mmol) in ethanol (120 mL) was added Example 11 (7.85 g, 35 mmol). This was heated to reflux for 3.5 hours, stood at room temperature overnight (17 hours), and heated to reflux for a further
  • Example 6 A solution of Example 6 (6.23 g, 33 mmol) and lithium hydroxide monohydrate (1.45 g, 35 mmol) in tetrahydrofuran (50 mL), water (35 mL), and methanol (14 mL) was stirred for 6.5 hours at room temperature. Water (70 mL) was added, and the reaction mixture was acidified to pH 4 using 2 M HCl and extracted with dichloromethane (5 x 200 mL). The organics were dried (MgSO- and the solvent removed in vacuo to give a brown solid. This was dissolved in diethyl ether, heptane was added, and the mixture was stirred overnight. Solvent was removed by syringe to give product as a pale brown solid, 27 mmol, 80%.
  • Example 8 A solution of Example 8 (5.32 g, 28 mmol) and lithium hydroxide monohydrate (1.24 g, 30 mmol) in tetrahydrofuran (45 mL), water (30 mL), and methanol (12 mL) was stirred for 5 hours at room temperature. Water (60 mL) was added, and the reaction mixture was acidified to pH 4 using 2 M HCl and extracted with dichloromethane (5 x 150 mL). The organics were dried (MgSO-i) and the solvent removed in vacuo. Column chromatography (ethyl acetate: heptane 4:1 — ⁇ ethyl acetate:methanol) gave a brown solid. This was dissolved in ethyl acetate, heptane was added, and the mixture was stirred overnight. Solvent was removed by syringe to give product as a pale brown solid, 17 mmol, 61%.
  • Example 10 To a solution of Example 10 (24.78 g, 85 mmol) in ethanol (200 mL) was added palladium catalyst (10% on carbon) (6.0 g) and HCl (4 M in dioxane) (4.5 mL, 18 mmol). This was hydrogenated at 30°C for 6 hours and then filtered through Celite. The solvent was removed in vacuo, and column chromatography
  • Example 12 A solution of Example 12 (1.970 g, 4.20 mmol) in absolute ethanol (50 mL) with Pearlman's catalyst (0.88 g) was hydrogenated at 30°C and 50 psi for 5.5 hours. The catalyst was removed by filtration through Celite and concentrated in vacuo to give the product, 1.391 g, 87%. This was used without further purification.
  • Example 13 To a solution of Example 13 (1.390 g, 3.67 mmol) in DMF (20 mL) was added powdered potassium carbonate (1.528 g, 11.07 mmol) followed by t-butylbromoacetate (0.65 mL, 4.03 mmol). After stirring for 22 hours, the solution was diluted with water (50 mL) and extracted with dichloromethane (3 x 100 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. Purification by column chromatography in ethyl acetate :methanol: aqueous ammonia (90:9:1) gave an inseparable mixture of product and an unidentified side product. This was used in the next step without any further attempt at purification.
  • Example 14 To a solution of crude Example 14 (0.482 g, 0.98 mmol) in dichloromethane (2 mL) was added HCl (2 mL of 4 M solution in dioxan). After stirring for 16 hours, all volatiles were removed in vacuo and the resulting solid dissolved dichloromethane. A small amount of diethyl ether was added and the suspension left for 5 minutes, in which time a beige solid precipitated out. The resulting supernatant was removed and diluted 100 times with diethyl ether to give a white suspension, which was allowed to settle. This solid was filtered and dried to give pure product, 0.305 g.
  • Example 17 To a solution of Example 17 (1.460 g, 3.86 mmol) in DMF (25 mL) was added powdered potassium carbonate (1.51 g, 22.5 mmol) followed by t-butylbromoacetate (0.80 mL, 4.95 mmol). After stirring for 24 hours, the solution was diluted with water (50 mL) and extracted with dichloromethane (4 x 100 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. Purification by column chromatography in 9:1 ethyl acetate :methanol gave the product as an oil, 1.272 g. 67%. l H NMR (400 MHz, CDC1 3 ): ⁇ 7.79 (IH, s); 7.57 (IH, m); 7.46 (IH, m);
  • Example 18 To a solution of Example 18 (1.272 g, 2.58 mmol) in dichloromethane (10 mL) was added HCl (2.5 mL of 4 M solution in dioxan). After stirring for
  • Example 20 To a solution of Example 20 (1.79 g, 3.5 mmol) in ethanol (85 mL) was added palladium hydroxide (20% on carbon) (0.15 g). This was hydrogenated at
  • Example 21 To a solution of Example 21 (1.41 g, 3.4 mmol) in dimethylformamide (22 mL) was added potassium carbonate (1.48 g, 10.7 mmol) and, under argon, t-butylbromoacetate (0.5 mL, 3.4 mmol). After stirring at room temperature for 22.5 hours, the reaction was poured into water (170 mL), extracted with dichloromethane (170 mL), dried (MgSO4), and the solvent removed in vacuo.
  • potassium carbonate 1.48 g, 10.7 mmol
  • t-butylbromoacetate 0.5 mL, 3.4 mmol
  • Example 24 A solution of Example 24 (3.00 g, 5.01 mmol) in absolute ethanol (50 mL) with palladium on charcoal (0.34 g) was hydrogenated at 30°C and 50 psi for
  • iH NMR 400 MHz, CDCI3: ⁇ 7.72 (IH, s); 7.61 (IH, m); 7.48 (IH, m);
  • Example 27 To a solution of Example 27 (0.79 g, 1.55 mmol) in dichloromethane (12 mL) and water (0.5 mL) was added HCl (2.5 mL of 4 M solution in dioxan). After stirring for 24 hours, all volatiles were removed in vacuo to give a pale pink solid. The solid was stirred with ethyl acetate (75 mL) for 2 hours, then the solvent removed by pipette. This was repeated. The resulting solid was dissolved in acetonitrile (50 mL) and all solids removed by filtration. Ethyl acetate was added until the solution became cloudy, and the precipitate was allowed to settle. All supernatant was then removed and the resulting solid dried. Yield 0.25 g.
  • Example 5 a solution of Example 5 (5.30 g, 12.03 mmol) in THF (30 mL) was added. After stirring for 16 hours, all volatiles were removed in vacuo and the residue dissolved in ethyl acetate (400 mL). This solution was washed with saturated sodium hydrogencarbonate solution, then water, then saturated NaCl solution (100 mL of each). After drying (MgSO4) and concentration in vacuo, column chromatography (1 :1 ethyl acetate :heptane) gave the desired product, 4.721 g, 66%.
  • Example 29 A solution of Example 29 (4.72 g, 7.88 mmol) in absolute ethanol (50 mL) with 10% palladium on charcoal (0.37 g) added was hydrogenated at 30°C and approximately 50 psi for 6 hours, after which the palladium on charcoal was removed by filtration through Celite and the filtrate concentrated in vacuo to give the product, 3.00 g, 75%. This was used without further purification.
  • Example 30 To a solution of Example 30 (3.00 g, 5.91 mmol) in DMF (48 mL) was added potassium carbonate (1.50 g, 10.87 mmol) followed by tert-butyl bromoacetate (1.20, 7.43 mmol). After stirring for 15 hours, the reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (4 x 250 mL). The organic phases were dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (8:2 ethyl acetate :heptane) gave the product 1.659 g, 45%.
  • Example 31 To a solution of Example 31 (1.659 g, 2.66 mmol) in THF (25 mL) at room temperature was added TBAF (2.8 mL of a 1 M solution in THF, 2.8 mmol). The reaction was stirred for 2.5 hours, then diluted with saturated brine (100 mL) and extracted with dichloromethane (4 x 120 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. Purification by column chromatography in ethyl acetate :methanol (9:1) gave the product as an oil. 0.824 g, 61%.
  • Example 32 To a solution of Example 32 (0.824 g, 1.62 mmol) in dichloromethane (15 mL) was added HCl (3 mL of 4 M solution in dioxan). After stirring for 22 hours, all volatiles were removed in vacuo, and the resulting solid was washed with ethyl acetate (twice). The remaining solid was dissolved in acetonitrile and treated with diethyl ether. The precipitate was allowed to settle and the supernatant discarded. The solid was dried to give the product as an off-white solid.
  • Example 34 To a solution of Example 34 (1.97 g, 3.2 mmol) in methanol (70 mL) was added palladium hydroxide (20% on carbon) (0.10 g). This was hydrogenated at 30°C for 6 hours, filtered through Celite, and the solvent removed in vacuo to give a white foam, 3.2 mmol, 97%. This was used without further purification.
  • Example 36 To a solution of Example 36 (0.90 g, 1.45 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (1.0 M in tetrahydrofuran) (1.45 mL, 1.45 mmol). The reaction was stirred at room temperature under argon for 2.5 hours, then half the solvent was removed in vacuo. After stirring for a further 30 minutes, the reaction was poured into water (15 mL) and brine (70 mL), and extracted with dichloromethane (3 x 70 mL). The organics were dried (MgSO 4 ) and the solvent removed in vacuo. Column chromatography (ethyl acetate:methanol 4:1) gave the product as a clear oil, 1.32 mmol, 90%.
  • tetrabutylammonium fluoride 1.0 M in tetrahydrofuran
  • Example 37 A solution of Example 37 (0.64 g, 1.25 mmol) in dichloromethane (2.0 mL) was stirred with HCl in dioxane (4.0 M) (0.8 mL, 3.20 mmol) for 24 hours at room temperature under argon. The solvent was removed , and the residue dissolved in dichloromethane (1.5 mL) and stirred with HCl in dioxane (1.5 mL, 6.0 mmol) for 47 hours. The solvent was removed in vacuo, and the residue washed with diethyl ether.
  • Example 5 (1.92 g, 4.4 mmol) in tetrahydrofuran (10 mL) was added and the reaction stirred for 18 hours at room temperature under argon. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (170 mL) and washed with saturated sodium hydrogen carbonate solution (50 mL), water (50 mL) and brine (50 mL). The organics were dried (MgSO4) and the solvent removed in vacuo.
  • Example 41 To a solution of Example 41 (1.23 g, 1.86 mmol) in tetrahydrofuran

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Abstract

L'invention concerne de nouveaux composés représentés par la formule (I). Ces composés sont des kappa agonistes opioïdes périphériquement sélectifs, utiles pour le traitement des affections suivantes: arthrite, hypertension, douleur, inflammation, migraine, troubles inflammatoires du tube digestif, colon irritable et psoriasis. L'invention concerne à la fois les composés considérés, de nouveaux intermédiaires entrant dans leur élaboration, et des compositions pharmaceutiques les renfermant.
PCT/US1998/006485 1997-04-30 1998-04-02 Kappa agonistes opioides peripheriquement selectifs Ceased WO1998049158A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU68782/98A AU6878298A (en) 1997-04-30 1998-04-02 Peripherally selective kappa opioid agonists
US09/331,753 US6057357A (en) 1997-04-30 1998-04-02 Peripherally selective kappa opioid agonists

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US4698697P 1997-04-30 1997-04-30
US60/046,986 1997-04-30
US7454798P 1998-02-12 1998-02-12
US60/074,547 1998-02-12

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WO1998049158A1 true WO1998049158A1 (fr) 1998-11-05

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CN103180299A (zh) * 2010-08-13 2013-06-26 Abbvie德国有限责任两合公司 四氢化萘和二氢化茚衍生物、含其的药物组合物及其在治疗中的用途
CN103237788A (zh) * 2010-08-13 2013-08-07 Abbvie德国有限责任两合公司 苯烷基胺衍生物、包含所述苯烷基胺衍生物的药物组合物及其在治疗中的用途
WO2015168010A1 (fr) 2014-04-29 2015-11-05 E. I. Du Pont De Nemours And Company Herbicides à base de pyridazinone
WO2017074992A1 (fr) 2015-10-28 2017-05-04 E. I. Du Pont De Nemours And Company Nouveaux herbicides à base de pyridazinone
WO2018183432A1 (fr) 2017-03-28 2018-10-04 Fmc Corporation Nouveaux herbicides à base de pyridazinone
CN111362814A (zh) * 2020-04-22 2020-07-03 暨明医药科技（苏州）有限公司 一种卡巴拉汀手性中间体的合成方法

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EP0207773A2 (fr) * 1985-07-01 1987-01-07 Warner-Lambert Company 7-(Amino substitué)-8-[(carbonyl substitué)-méthylamino]-1-oxaspiro[4.5]décanes comme agents analgésiques
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EP0325406A2 (fr) * 1988-01-21 1989-07-26 Imperial Chemical Industries Plc Composés diamine
WO1997020831A1 (fr) * 1995-12-05 1997-06-12 Regents Of The University Of Minnesota Agonistes des recepteurs morphiniques kappa

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EP0147085A2 (fr) * 1983-12-06 1985-07-03 Warner-Lambert Company Composés trans-1,2-diaminocyclohexylamide substitués
EP0207773A2 (fr) * 1985-07-01 1987-01-07 Warner-Lambert Company 7-(Amino substitué)-8-[(carbonyl substitué)-méthylamino]-1-oxaspiro[4.5]décanes comme agents analgésiques
EP0254545A2 (fr) * 1986-07-25 1988-01-27 Imperial Chemical Industries Plc Composés diamines
EP0325406A2 (fr) * 1988-01-21 1989-07-26 Imperial Chemical Industries Plc Composés diamine
WO1997020831A1 (fr) * 1995-12-05 1997-06-12 Regents Of The University Of Minnesota Agonistes des recepteurs morphiniques kappa

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103180299A (zh) * 2010-08-13 2013-06-26 Abbvie德国有限责任两合公司 四氢化萘和二氢化茚衍生物、含其的药物组合物及其在治疗中的用途
CN103237788A (zh) * 2010-08-13 2013-08-07 Abbvie德国有限责任两合公司 苯烷基胺衍生物、包含所述苯烷基胺衍生物的药物组合物及其在治疗中的用途
WO2015168010A1 (fr) 2014-04-29 2015-11-05 E. I. Du Pont De Nemours And Company Herbicides à base de pyridazinone
EP3865480A1 (fr) 2014-04-29 2021-08-18 FMC Corporation Dérivés d'hydrazine
WO2017074992A1 (fr) 2015-10-28 2017-05-04 E. I. Du Pont De Nemours And Company Nouveaux herbicides à base de pyridazinone
WO2018183432A1 (fr) 2017-03-28 2018-10-04 Fmc Corporation Nouveaux herbicides à base de pyridazinone
CN111362814A (zh) * 2020-04-22 2020-07-03 暨明医药科技（苏州）有限公司 一种卡巴拉汀手性中间体的合成方法
CN111362814B (zh) * 2020-04-22 2022-09-13 暨明医药科技（苏州）有限公司 一种卡巴拉汀手性中间体的合成方法

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