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WO1998041523A1 - Procede de preparation d'octanes dibenzo-1- carboxamido-1,4-azabicyclo(3.2.1.) - Google Patents

Procede de preparation d'octanes dibenzo-1- carboxamido-1,4-azabicyclo(3.2.1.) Download PDF

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Publication number
WO1998041523A1
WO1998041523A1 PCT/US1998/005501 US9805501W WO9841523A1 WO 1998041523 A1 WO1998041523 A1 WO 1998041523A1 US 9805501 W US9805501 W US 9805501W WO 9841523 A1 WO9841523 A1 WO 9841523A1
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formula
carbon atoms
alkyl
process according
groups
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Philip D. Magnus
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Neurogen Corp
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Neurogen Corp
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Priority to AU67655/98A priority Critical patent/AU6765598A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/12—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
    • C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes

Definitions

  • This invention relates to the field of pharmaceutical chemistry, and provides an advantageous process for preparing dibenzo-l-carboxamido-l,4-azabicyclo[3.2.1]octanes.
  • U.S. Patent No. 5,196,415 discloses various dibenzo-l-carboxamido-1,4- azabicyclo[3.2.1]octanes (5-aminocarbonyl-5H-dibenzo[a,d]-cyclohepten-5,10-imines) and methods for preparing such compounds.
  • the methods disclosed there involve conversion of C5-unsubstituted-10,l l-dihydro-5H-dibenzo[a.d]cyclohepten-5.10-imines into their N-tert- butylformamidine derivatives followed by formation of the C5-substituted ethyl ester.
  • the ester functionality is replaced with an amide group by warming the ester in methanol with the appropriate amine derivative.
  • the secondary amine is allowed to react with the appropriate alkyl halide in the presence of a suitable base.
  • This series of reactions produces a racemic mixture of dibenzo-l-carboxamido-1,4- azabicyclo[3.2.1]octanes. i.e., a racemic mixture of 5-aminocarbonyl-5H- dibenzo[a,d]cyclohepten-5, 10-imines.
  • Racemic mixtures of 5-aminocarbonyl-5H-dibenzo[a,d]cyclohepten-5,l 0-imines are known to have pharmacological activity as anticonvulsant agents. See, for example, Rogawski et al., 1991, J. Pharmacology and Experimental Therapeutics, 259: 30-37; and Grant et al., 1992, J. Pharmacology and Experimental Therapeutics, 260: 1017-1022.
  • the present invention provides a novel method for preparing dibenzo-1-carboxamido- l,4-azabicyclo[3.2.1]octanes, i.e., 5-aminocarbonyl-5H-dibenzo[a,d]cyclohepten-5,l 0-imines, in good yield.
  • the invention provides a process for preparing 5-aminocarbonyl-5H- dibenzo[a,d]cyclohepten-5,10-imines comprising replacing the 5-hydroxy group in a compound of formula I with a hydroxyamino group to yield a compound of formula II, a 5- hydroxyaminodibenzocy cloheptene :
  • R a is lower alkyl and R ⁇ and R 2 are as defined below for Formula A.
  • the invention also provides novel compounds of formula II.
  • the invention provides compounds of formula III and a process involving heating a solution of a compound of formula II to yield a 12-hydroxy-10,l l- dihydrodibenzocy cloheptene of formula III.
  • Another aspect of the invention provides process wherein the 12-hydroxy group of the compound of formula III is reduced to yield a compound of formula IV.
  • R a is lower alkyl and R, and R 2 are as defined below for Formula A.
  • the invention provides a process for producing a 4- hydroxyphenyl compound of formula V, which process involves cleaving the alkyl portion of alkoxy group OR a .
  • R a is lower alkyl and R, and R 2 are as defined below for Formula A.
  • the invention also provides a method for preparing an N-formyl compound of formula VI which entails treating a compound of formula V with an alkyl formate.
  • R, and R 2 are as defined below for Formula A.
  • the invention provides a process for removing the 4- hydroxyphenyi group from a compound of formula VI to yield a 12-Formyl-10,ll-dihydro- dibenzo cycloheptene imine carboxylate of formula VII.
  • R b is lower alkyl and R* and R 2 are as defined below for Formula A.
  • the invention further provides a process for reducing the aminoformyl group to yield a cycloheptene imine carboxylate of formula VIII.
  • R b is lower alkyl and R, and R 2 are as defined below for Formula A. Also encompassed within the invention are compounds of formula VIII.
  • the invention provides a process for converting the ester functionality of compounds of formula VIII to an aminocarbonyl group (formula IX) and, optionally, for alkylating the secondary nitrogen in a compound of formula IX.
  • R, R 2 , R 4 and R 5 are as defined below for Formula A.
  • the invention further encompasses novel intermediates involved in the inventive process for preparing compounds of formula I. It also encompasses methods for preparing those intermediates.
  • the invention further provides a process for converting compounds of Formula I into final product, i.e., a 5-aminocarbonyl-5H-dibenzo[a,d]cyclohepten-5,10-imine of Formula A.
  • the invention provides processes and intermediates for preparing dibenzo-l-carboxamido-l,4-azabicyclo[3.2.1]octanes. These compounds can also be referred to as 5-aminocarbonyl-5H-dibenzo[a,d]cyclohepten-5,l 0-imines. These compounds are encompassed by general formula A:
  • Rl and R2 independently represent hydrogen, linear or branched alkyl of from one to about
  • alkenyl having from two to about ten carbon atoms
  • alkynyl having from two to about ten carbon atoms
  • hydroxyl amino, alkylamino, alkoxy, cyano, nitro, haloalkyl, or mercapto
  • R3 is hydrogen, linear or branched alkyl having from one to about ten carbon atoms, alkenyl
  • R 4 and R 5 independently represent hydrogen, linear or branched alkyl groups of from one to about twenty carbon atoms, alkenyl groups from two to about twenty carbon atoms, alkynyl groups from two to about twenty carbon atoms, cycloalkyl groups of three to about eight carbon atoms, cycloalkenyl groups of from three to about eight carbon atoms, and wherein R4 and R5 may be taken together to form a N-containing cyclic
  • any of the said groups being optionally substituted with one or more substituents selected from alkyl, haloalkyl, hydroxyalkyl, alkenyl, oxo, hydroxyl, alkoxy, thio, alkoxyalkyl, amino, halo, cyano, or mercapto.
  • Particularly preferred compounds that are prepared according to the invention are those where R quarantine R 2 , R 3 , R 4 and R 5 are hydrogen.
  • the subsituents Renfin and R b are methyl groups.
  • X is NHOH
  • R c is H or alkyl
  • R, and R 2 are independently hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, amino, alkylamino, alkoxy, cyano, nitro, haloalkyl, or mercapto.
  • R, and R 2 are independently hydrogen or alkyl.
  • the invention also encompasses intermediates of formula INT-II:
  • R c is H or alkyl
  • R, and R 2 are independently hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, amino, alkylamino, alkoxy, cyano, nitro, haloalkyl, or mercapto.
  • R, and R 2 are independently hydrogen or alkyl.
  • the invention also provides compounds of the formula INT-III
  • R c is H or alkyl
  • R, and R 2 are independently hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, amino, alkylamino, alkoxy, cyano, nitro, haloalkyl, or mercapto.
  • R, and R 2 are independently hydrogen or alkyl.
  • the invention also encompasses intermediates of formula INT-IV:
  • R c is H or alkyl
  • R, and R 2 are independently hydrogen, alkyl, alkenyl, alkynyl, hydroxyl, amino, alkylamino, alkoxy, cyano, nitro, haloalkyl, or mercapto.
  • R, and R 2 are independently hydrogen or alkyl.
  • 'alkyl' embraces linear or branched radicals having one to about ten carbon atoms.
  • Preferred alkyl radicals are "lower alkyl" radicals having from one to about five carbon atoms.
  • 'cycloalkyl' embraces radicals having from three to about ten carbon atoms, such as cyclopropyl and cyclobutyl.
  • haloalkyl embraces radicals wherein one or more of the alkyl carbon atoms is substituted with one or more halogens atoms, preferably selected from fluoro, chloro and bromo. Specifically embraced by the term 'haloalkyl' are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups. Examples of a polyhaloalkyl are trifluoromethyl, 2,2,2-trifluoroethyl and perfluoroethyl.
  • alkenyl embraces linear or branched radicals having from two to about ten carbon atoms and containing at least one double bond.
  • alkynyl embraces linear or branched radicals having from two to about ten carbon atoms containing at least one carbon-carbon triple bond.
  • alkoxy' embraces linear or branched oxy-containing radicals having alkyl portions of from one to about ten carbon atoms, such as methoxy group.
  • the alkoxy radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo to provide haloalkoxy groups.
  • 'alkylamino' embraces linear or branched nitrogen containing radicals where the nitrogen atom may be substituted with from one to three alkyl radicals of from one to about ten carbon atoms, such as N-methylamino and N,N-dimethylamino.
  • alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, neopentyl and n-pentyl.
  • Typical alkenyl groups may have one unsaturated double bond, such as allyl or may have a plurality of double bonds.
  • racemic mixture as used herein is meant a 50:50 by weight mixture of two enantiomers.
  • the compounds preparable by the inventive methods are useful for treatment of patients with generalized epilepsy or partial (symptomatic) epilepsy. These compounds are also useful for treating drug craving in patients addicted to cocaine.
  • Administration of compounds within Formula I to humans can be by any technique capable of introducing the compounds into the bloodstream of a human patient, including oral administration, and by intraveneous, intramuscular and subcutaneous injections.
  • Compounds indicated by prophylactic therapy will preferably be administered in a daily dose generally in the range of 0.1 mg to 100 mg per kilogram of body weight per day. A more preferred dosage will be in the range of 1.0 to 50 mg per kilogram of body weight.
  • a suitable dose can be administered in suitable sub-doses per day.
  • the active compound is usually administered in a pharmaceutically acceptable formulation, although in some acute-care situations a compound of Formula I may be administered alone.
  • Such formulations may comprise the active compound with one or more pharmaceutically acceptable carriers or diluents. Other therapeutic agents may also be present in the formulation.
  • a pharmaceutically acceptable carrier or diluent provides an appropriate vehicle for delivery of the active compound without undesirable side effects. Delivery of the active compound in such formulations may be by various routes such as oral, nasal, buccal or sublingual, or by parenteral administration such as subcutaneous, intramuscular, intravenous or intradermal routes. Delivery of the active compound may also be through the use of controlled release formulations in subcutaneous implants.
  • Formulations for oral administration may be in the form of capsules containing the active compound dispersed in a binder such as gelatin or hydroxypropylmethyl cellulose, together with one or more of a lubricant, preservative, surface acting or dispersing agent.
  • Such capsules or tablets may contain controlled release formulation as may be provided in a disposition of active compound in hydroxypropylmethyl cellulose.
  • Formulations for parental administration may be in the form of aqueous or non- aqueous isotonic sterile injection solutions or suspensions. These solutions or suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration.
  • R,-R 5 are as defined above for Formula A and It, and R b represent lower alkyl.
  • the compounds of formula I are prepared according to the invention by Grignard addition of a suitable phenyl Grignard reagent to a dibenzosuberenone derivative. See Scheme I below.
  • a 4-haloanisole such as 4-bromoanisole may be converted into a suitable Grignard reagent in the typical manner in a solvent such as tetrahydrofuran (THF) or diethylether (ether).
  • This reagent may then, as shown in Scheme I and Example 1, be reacted according to well-known procedures with an appropriate ketone to afford the desired 5-hydroxy-5-(4-alkoxyphenyl) dibenzocycloheptene 1.
  • Preferred R a groups are ethyl and, most preferably, methyl.
  • the 5-hydroxy-5-(4-methoxyphenyl) dibenzocycloheptene I is conveniently converted into the corresponding 5-hydroxyamino 2 compound by treating the hydroxy compound 1 with hydroxylamine in a solvent such as, for example, dichloromethane, preferably with a buffer such as sodium acetate.
  • a solvent such as, for example, dichloromethane
  • a buffer such as sodium acetate
  • This reaction shown in Scheme I, is carried out at ambient temperature in the presence of an acid.
  • a suitable acid is trifluoroacetic acid, used in excess.
  • dibenzocycloheptene 1 is added to the hydroxylamine solution.
  • the resulting mixture is preferably mixed for about three hours followed by aqueous workup. Chromatography can then be carried out on the crude product; gradient elution with a solvent such as 30-50% v/v ethe ⁇ hexanes affords the desired product 2 in about 80% yield.
  • Also isolated are starting material and imine 9.
  • hydroxyamino compound 2 is heated, preferably refluxed, in a solvent such as toluene to afford hydroxyimine 3.
  • the solvent is degassed and the reaction allowed to proceed for at least 24 hours.
  • that compound is treated with zinc and an excess of a weak acid to afford imine 4.
  • the reaction producing the imine is preferably conducted at reflux using glacial acetic acid in a solvent such as ether or, more preferably, tetrahydrofuran.
  • the zinc used in this process is preferably powdered.
  • the alkoxy protecting group is subsequently removed from imine 4 to yield the 4-hydroxyphenyl compound 5.
  • the protecting group may be conveniently removed using an excess of, for example, boron tribromide in a solvent such as dichloromethane at ambient temperature.
  • the boron tribromide is typically added to a solution of alkoxyphenylimine 4. Reaction times of from about 5-24 hours are suitable.
  • the deprotection is followed by treatment with an aqueous base, e.g., aqueous ammonia, for at least about 15 minutes, and preferably for about one hour.
  • the pH is then adjusted to about 7 with an aqueous buffer such as, for example, phosphate.
  • Extraction with an organic solvent affords 4-hydroxyphenyl imine 5.
  • a preferred extraction solvent is ethyl acetate.
  • the yield for the deprotection is generally in excess of 90%.
  • 4-Hydroxyphenyl imine 5 may be converted into formyl compound 6 in either of two convenient reactions.
  • phenolic imine 5 is heated with ethyl formate in a sealed tube to about 100°C.
  • the reaction may be monitored for completion using, as an example, thin layer chromatography.
  • concentration, preferably in vacuo formyl compound 6 is obtained in excess of 90% yield.
  • phenolic imine 5 is dissolved in a solvent such as dimethylformamide (DMF) containing an excess of methyl formate, and the resulting mixture is then heated in a sealed tube for an amount of time suitable to allow complete conversion to formyl compound 6. Heating to about 100°C for approximately 10-24 hours is appropriate. After cooling and concentration in vacuo, aqueous workup, preferably using ethyl acetate as an extraction solvent, affords 6 in about 70% yield.
  • a solvent such as dimethylformamide (DMF) containing an excess of methyl formate
  • the 4-hydroxyphenyl moiety is cleaved from formyl compound 6 using sodium periodate and ruthenium trichloride.
  • sodium periodate and ruthenium trichloride Preferably, to a mixture of formyl compound 6 in acetonitrile, carbon tetrachloride and water, is added disodium hydrogen phosphate and sodium periodate. Generally, large excesses of the phosphate and periodate salts are employed. Then, an aqueous solution of a catalytic amount of ruthenium trichloride is added, most preferably dropwise, and the resulting mixture heated to reflux. The reaction is typically complete in about 10-15 hours. However, the reaction may be allowed to reflux for a longer period, e.g., more than 20 hours. After cooling, the mixture may be filtered and extracted with an organic solvent. A preferred solvent is dichloromethane.
  • aqueous phase is then adjusted to acidic pH using, for example, hydrochloric acid and re-extracted, preferably with dichloromethane.
  • Aqueous washing of the organic extracts followed by concentration in vacuo yields a crude acid-formamide as an oil.
  • the crude acid-formamide is dissolved in, preferably, methanol and treated with an excess of diazomethane.
  • the treating is carried out in ethereal solution at ambient temperature for a short time, such as, for example, about 15 minutes.
  • the reaction is quenched with, for example, 10% aqueous acetic acid.
  • the 12- formyl-dibenzo[ ⁇ ,cT]cyclohepten-5,10-imine-5-carboxylate product 7 may be further purified using, for example, chromatography.
  • a presently preferred extraction solvent for the workup is dichloromethane.
  • a preferred elution solvent for the chromatography is 50-75% ether in hexanes.
  • the formyl group is then removed from imine carboxylate 7 by treating 7 with a strong acid, e.g., sulfuric acid, in an alcoholic solvent such as methanol.
  • a strong acid e.g., sulfuric acid
  • an alcoholic solvent such as methanol.
  • the reaction proceeds at ambient temperature and is generally complete in about 5-15 hours.
  • the acid is then neutralized and the pH adjusted to about 8 with, for example, bicarbonate. Extraction with a solvent such as dichloromethane and removal of solvent under reduced pressure affords imine carboxylate S.
  • Imine carboxylate 8 can be conveniently converted into the desired 1 -carboxamido- 1 ,4-azabicyclo [3.2.1] octane of Formula A by any of a variety of methodologies known in the art.
  • the ester functionality can be replaced with an amide group by warming the ester in methanol with the appropriate amine derivative.
  • the secondary amine (A, where R 3 is H) is allowed to react with the appropriate alkyl halide (e.g., R 3 X where R 3 is defined above and X is a halide) in the presence of a suitable base to afford a compound of Formula A.
  • Imine 18 is also isolated (28 mg, 3%) as is starting material (194 mg, 18%>).
  • the title compound may be prepared by either of two methods as described below.
  • Method B A solution of the crude phenol-amine J (359 mg, -1.2 mmol) in DMF (10 mL) and methyl formate (20 mL, 320 mmol) is heated to 100°C in a sealed tube for 19 hours. The mixture is allowed to cool and subsequently concentrated in vacuo to yield a yellow solution. To the solution water is added (40 mL), and the resulting mixture is extracted into ethyl acetate (3x60 mL). The combined organic phases are washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to ⁇ 20 mL of a yellow solution. Dilution with an equal volume of ether and standing at 0°C affords J_5 (285 mg, 73% from 13) as colorless cubes.
  • the title compound 15_ has a melting point of 320-325°C (decomp). ⁇ (300M ⁇ z,
  • the aqueous phase is adjusted to pH 2 with 2N hydrochloric acid and re-extracted
  • Amino-ester 17 is converted into 2,3,6,7-Dibenzo-l-carboxamido-l,4- azabicyclo[3.2.1]octane F9 (5-aminocarbonyl-10, l l-dihydro-5H-dibenzo[a,d]cyclohepten- 5,10-imine) by heating the ester in methanolic ammonia as follows.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé et de nouveaux composés s'utilisant pour préparer des composés de la formule (A) dans laquelle R1 et R2 sont indépendamment un hydrogène, des substituants inorganiques ou organiques éventuellement substitués; R3 est un hydrogène, ou un groupe organique éventuellement substitué; et R4 et R5 sont comme défini ici; le procédé consiste: (a) à convertir un dibenzocycloheptène en un 5-hydroxyaminodibenzocycloheptène; (b) à convertir le 5-hydroxyaminodibenzocycloheptène en un 12-hydroxy-10,11-dihydrodibenzocycloheptène; et (c) à extraire le groupe 12-hydroxy pour obtenir un 10,11-dihydro-dibenzocycloheptène.
PCT/US1998/005501 1997-03-20 1998-03-20 Procede de preparation d'octanes dibenzo-1- carboxamido-1,4-azabicyclo(3.2.1.) Ceased WO1998041523A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU67655/98A AU6765598A (en) 1997-03-20 1998-03-20 Process for preparing dibenzo-1-carboxamido-1,4-azabicyclo(3.2.1.) octanes

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US82136597A 1997-03-20 1997-03-20
US08/821,365 1997-03-20

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WO1998041523A1 true WO1998041523A1 (fr) 1998-09-24

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990013297A1 (fr) * 1989-05-09 1990-11-15 The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce 5-AMINOCARBONYLE-5H-DIBENZO[a,d]CYCLOHEPTENE-5,10-IMINES POUR LE TRAITEMENT DE L'EPILEPSIE ET DE LA COCAINOMANIE
WO1993025203A1 (fr) * 1992-06-17 1993-12-23 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Procede de traitement et de protection contre l'ischemie, l'hypoxie, la degenerescence et les traumas du systeme nerveux central au moyen d'une 5-aminocarbonyl-sh-dibenzo[a,d]cyclohepten-5,10-imine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990013297A1 (fr) * 1989-05-09 1990-11-15 The United States Of America, As Represented By The Secretary, U.S. Department Of Commerce 5-AMINOCARBONYLE-5H-DIBENZO[a,d]CYCLOHEPTENE-5,10-IMINES POUR LE TRAITEMENT DE L'EPILEPSIE ET DE LA COCAINOMANIE
WO1993025203A1 (fr) * 1992-06-17 1993-12-23 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Procede de traitement et de protection contre l'ischemie, l'hypoxie, la degenerescence et les traumas du systeme nerveux central au moyen d'une 5-aminocarbonyl-sh-dibenzo[a,d]cyclohepten-5,10-imine

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