Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Silicon containing doai
Patent
1997-03-13
1999-11-30
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Silicon containing doai
514279, 546 14, 546 35, A61K 31695, A61K 3144, C07D49112, C07F 702
Patent
active
059943270
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention is directed to a new process for the preparation of 14-alkoxyindolomorphinans and 14-alkoxybenzofuranomorphinans.
BACKGROUND OF THE INVENTION
Opioid antagonists have been indispensable as tools in opioid research. For example, 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.
In addition to their uses as pharmacological tools, selective, non-peptide opioid antagonists have been described as having potential clinical applications in the treatment of a variety of disorders where endogenous opioids play a modulatory role. These include for instance disorders of food intake, shock, constipation, mental disorders, CNS injury, alcoholism, and immune function (P. S. Portoghese at al., J. Med. Chem., Vol. 34: 1757-1762, 1991).
Non-peptide, competitive, .delta.-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).
In U.S. Pat. No. 5,223,507 and U.S. Pat. No. 5,225,417 the synthesis of 14-O-substituted indolomorphinans and benzofuranomorphinans have been disclosed. According to the process used for preparing the compounds claimed and disclosed in U.S. Pat. No. 5,223,507, only a 3,14-dimethoxy substituted benzofuranomorphinan was prepared. According to the process used for preparing compounds claimed and disclosed in U.S. Pat. No. 5,225,417, two 14-O-alkyl substituted benzofuranomorphinans have been prepared. According to the methods used for preparing the compounds of both the two mentioned prior art documents, the 3-hydroxy group was protected by a methyl group which is not easily removed without having a loss in yield.
According to the processes known from the prior art, the variations of the substituents at the oxygen in position 14 are very much limited when a 3-hydroxy group is supposed to be present in the molecule. It is for instance not possible to prepare compounds with a substituent at the oxygen in 14-position, as this position is labile to the conditions used for the cleavage of the 3-methoxy group.
Thus, 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.
OUTLINE OF THE INVENTION
The present invention is directed to a new process for the preparation of compounds of the general formula (I) ##STR1## wherein R.sub.1 represents allyl, cyclopropylmethyl or methyl; C.sub.7 -C.sub.16 arylalkyloxy wherein aryl is C.sub.6 -C.sub.10 aryl and alkyloxy is C.sub.1 -C.sub.6 alkyloxy, C.sub.7 -C.sub.16 arylalkenyloxy wherein aryl is C.sub.6 -C.sub.10 aryl and alkenyloxy is C.sub.1 -C.sub.6 alkenyloxy, C.sub.1 -C.sub.6 alkanoyloxy, C.sub.7 -C.sub.16 arylalkanoyloxy wherein aryl is C.sub.6 -C.sub.10 aryl and alkanoyloxy is C.sub.1 -C.su
REFERENCES:
patent: 4816586 (1989-03-01), Portoghese
patent: 5223507 (1993-06-01), Dappen et al.
patent: 5225417 (1993-07-01), Dappen et al.
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patent: 5436249 (1995-07-01), Dappen et al.
Arakawa, et al., "Immunosuppression by Delta Opioid Receptor Antagonist," Transplant.Proc. 25:738-740 (1993).
Arakawa, et al., "Immunosuppressive Effect of .delta.-Opioid Receptor Antagonist on Xenogeneic Mixed Lymphocyte Reaction," Transplant. Proc. 24:696-697 (1992).
Arakawa, et al., "The Immunosuppresive Effect of .delta.-Opioid Receptor Antagonist on Rat Renal Allograft Survival," Transplantation 53:951-953 (1992).
Chem. Abstr. vol. 122, , pp. 1086-1087, abstr. #187841c, "Synthesis of N1'-([.sup.11 C]methyl)naltrindole . . . " (1995).
Portoghese, "An Approach to the Design of Receptor-Type-Selective Non-Peptide Antagonists of Peptidergic Receptors: .delta. Opioid Antagonists," J. Med. Chem. 34:1757-1762 (1991).
Schmidhammer Helmut
Schwarz Peter
Wei Zhong-Yong
Astra AB
Rotman Alan L.
Sanzo Michael A.
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