Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
  • C07D491/18—Bridged systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

• the present invention is directed to a new process for the preparation of 14-alkoxyindolomorphinans and 14-alkoxybenzofuranomorphinans.
• Opioid antagonists have been indispensable as tools in opioid research.
• the chief criterion for the classification of an agonist effect as being opioid receptor mediated is the ability of known opioid antagonists naloxone or naltrexone to reversibly antagonize this effect in a competitive fashion.
• the usefulness of naloxone and naltrexone for this purpose stems from the fact that they are universal opioid antagonists; that is, they are capable of antagonizing the agonist effects mediated by multiple opioid receptor types.
• Non-peptide, competitive, ⁇ -selective opioid antagonists have been found to have immunosuppressive potency and less toxicity than the presently used immunosuppressive compound cyclosporin (EP 456 833; EP 485 636; EP 614 898; K. Arakawa et al., Transplantation, Vol. 53: 951-953, 1992; K. Arakawa et al., Transplant Proc, Vol. 24: 696-697, 1992; K. Arakawa et al., Transplant Proc, Vol. 25: 738-740, 1993).
• Such immunosuppressive agents can be used after organ transplantation to suppress the rejection of the foreign organ and also in the treatment of autoimmune diseases (e.g. rheumatoid arthritis).
• the object of the present invention was to find a new process which would facilitate the preparation of 14-O-substituted indolomorphinans and benzofuranomorphinans.
• the present patent application discloses a process whereby naloxone, naltrexone or oxymorphone is used as the starting material, whereby the 14-alkoxy group is introduced after the protection of the oxygen in 3-position with an easily removable protecting group, preferably benzyl, methoxymethyl, ethoxymethyl, trityl or silyl, thereby providing a process enabling the synthesis of compounds involving 14-O-substitution.
• an easily removable protecting group preferably benzyl, methoxymethyl, ethoxymethyl, trityl or silyl
• the present invention is directed to a new process for the preparation of compounds of the general formula (I)
• Ri represents allyl, cyclopropylmethyl or methyl
• R2 represents -C6 alkoxy, Cj-Cg alkenyloxy, C7-C16 arylalkyloxy wherein aryl is C ⁇ -Cio aryl and alkyloxy is Ci-C ⁇ alkyloxy, C7-C16 arylalkenyloxy wherein aryl is C6-C10 aryl and alkenyloxy is Ci-C ⁇ alkenyloxy, C ⁇ -C( > alkanoyloxy, C7-C16 arylalkanoyloxy wherein aryl is C ⁇ -Cio aryl and alkanoyloxy is -C6 alkanoyloxy;
• R3 represents hydroxy, Ci-C ⁇ alkoxy, C7-C16 arylalkyloxy wherein aryl is Cg-Cio aryl and alkyloxy is C1-C6 alkyloxy, C1-C6 alkenyloxy, Ci-C ⁇ alkanoyloxy, C7-C16 arylalkanoyloxy wherein the aryl is C ⁇ -C ⁇ Q aryl and the alkanoyloxy is C1 -C6 alkanoyloxy, C2-C10 alkyloxyalkoxy wherein alkyloxy is C1-C4 alkyloxy and alkoxy is C1-C6 alkoxy; and
• X represents O, NH or NR4 wherein R4 is Cj-C ⁇ alkoxy, Cj-C ⁇ alkenyloxy, C7-C16 arylalkyloxy wherein aryl is C -Cio aryl and alkyloxy is Cj-Cg alkyloxy, C7-C16 arylalkenyloxy wherein the aryl is C6-C10 aryl and alkenyloxy is C1-C6 alkenyloxy, C j -C6 alkanoyloxy, C7-C16 arylalkanoyloxy wherein aryl is C ⁇ -Cirj aryl and alkanoyoloxy is C1-C6 alkanoyloxy.
• the process for the preparation of the compounds of the general formula (I) comprises the following steps:
• naloxindole NLI
• NKI naltrindole
• OMI oxymorphindole
• naloxone (II), naltrexone(III) or oxymorphone is reacted with O-phenyl-hydroxyl amine hydrochloride in the presence of an acid, preferably methanesulfonic acid, sulfuric acid or hydrochloric acid, giving the benzofurane derivatives NLB, naltriben (NTB; P. S. Portoghese et al., J. Med. Chem., Vol. 34: 1715-1720, 1991) or OMB (US 5 223 507) of the formula
• the 3-hydroxy group is protected by alkylation with benzyl bromide, methoxymethyl bromide, ethoxymethyl bromide, trityl chloride or a silylating agent, preferably dimethyl isobutyl-silyl chloride, trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride or tri-i-propylsilyl chloride, in a solvent, preferably N,N-dimethylformamide, dichloromethane or tetrahydrofurane, in the presence of a base which may not be a weak base, preferably potassium carbonate, potassium hydroxide, sodium hydride, sodium amide or diisopropyl ethylamine, giving a compound of the formula (IV)
• Rl is allyl, cyclopropylmethyl or methyl
• R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl, preferably dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl; and X is NH, O, N-benzyl, N-methoxymethyl, N-ethoxymethyl, N-trityl or N-silyl, preferably dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl; (iii) the compound of the formula (IV) is treated with Ci -C2 dialkyl sulfates, Cj-C ⁇ alkyl halides, Ci-C alkenyl halides, C7-C16 aralkyl halides wherein the aryl is C ⁇ -Cio
• Rj is allyl or cyclopropylmethyl
• R2 is benzyl, methoxymethyl, ethoxymethyl, trityl or silyl, preferably dimethyl isobutyl silyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl or tri-i-propylsilyl; and
• R3 is C1-C6 alkyl, Cj-Cg alkenyl; C7-C16 arylalkyl wherein the aryl is C -Cio aryl and the alkyl is C1-C6 alkyl; C7-C16 arylalkenyl wherein the aryl C ⁇ -Cjo aryl and the alkenyl is C1 - C alkenyl; C]-C alkanoyl, C7-C16 arylalkanoyl wherein the aryl is Cg-Cjo aryl and the alkyl is Ci-C ⁇ alkyl;
• X is as defined in the formula (IV) above; and optionally the following step (iv) whereby
• Ri , and R3 are as defined above in formula (V), and X is NH, O or N-benzyl;
• Sodium hydride (492 mg, 20.5 mmol; obtained from 820 mg of 60% dispersion in oil by o washings with n-hexane) was added to a solution of naltrindole hydrochloride (1.5 g, 3.3 mmol) in 30 ml of anhydrous N,N-dimethyl formamide at 0° C. After stirring at 0° C for 15 min and additional 30 min at room temperature, the mixture was cooled again to 0° C and methoxymethyl bromide (1.27 g, 10.2 mmol) was added. After stirring at 0° C for 30 min, stirring was continued for another 120 min at room temperature. Methanol and H2O were added to destroy excess of sodium hydride.
• Sodium hydride (144 mg, 6 mmol; obtained from 240 mg of 60% sodium hydride dispersion in oil by washings with n-hexane) was added to a solution of naltriben methane-sulfonate (500 mg, 0.97 mmol) in 10 ml of anhydrous N,N-dimethylformamide at 0° C. The resulting mixture was stirred at 0° C for 15 min and then at room temperature for another 30 min. After cooling to 0° C, dimethyl sulfate (380 ⁇ l, 4 mmol) was added and stirring was continued first at 0° C for 30 min and then at room temperature for 3 h. Excess sodium hydride was destroyed by addition of MeOH and H2O.
• Dimethyl isobutylsilyl chloride (114 mg, 0.75 mmol) was added at 0° C to a stirred solution of naltrindole methanesulfonate (255 mg, 0.5 mmol) and diisopropyl ethylamine (260 mg, 2.0 mmol) in anhydrous N,N-dimethyl formamide (10 ml). The resulting solution was stirred at 20° C for 1 h and then cooled to 0° C prior to the addition of sodium hydride (60% dispersion in oil, 120 mg, 3.0 mmol). After 1 h, dimethyl isobutylsilyl chloride (114 mg, 0.75 mmol) was added to the mixture.
• the resulting mixture was stirred for 2 h at 20° C, and then 5 ml methanol and 5 ml ethyl acetate were slowly added at 0° C. After 30 min the mixture was extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to a yellow oil, which was dissolved in MgSO4, and concentrated to a yellow oil, which was dissolved in 10 ml ethanol 2.0 ml IN hydrochloric acid and refluxed for 5 hrs. The reaction mixture was alkalized with IN aqueous NH4OH solution, extracted with ethyl acetate (3x50 ml).
• the resulting mixture was stirred for 2 h at 20° C, and then 5 ml methanol and 5 ml ethyl acetate were slowly added at 0° C. After 30 min the mixture was extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with brine, dried over MgSO4, and concentrated to a yellow oil, which was dissolved in 10 ml ethanol/2 ml 1 N hydrochloric acid and refluxed for 5 hrs. The reaction mixture was alkalized with IN aqueous NH4OH solution, extracted with ethyl acetate (3x50 ml).

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• 1996
  • 1996-11-19 WO PCT/SE1996/001497 patent/WO1998022467A1/en not_active Application Discontinuation
  • 1996-11-19 CA CA002269910A patent/CA2269910A1/en not_active Abandoned
  • 1996-11-19 AU AU14024/97A patent/AU1402497A/en not_active Abandoned
  • 1996-11-19 EP EP96944151A patent/EP0946564A1/en not_active Withdrawn
  • 1996-11-19 JP JP52353998A patent/JP2001504829A/ja active Pending

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