Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-02-18
1995-01-24
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540456, A61K 3142, A61K 31435, C07D49822
Patent
active
053843169
DESCRIPTION:
BRIEF SUMMARY
This invention relates to macrocyclic compounds, processes for their preparation, their use as medicaments, and compositions containing them.
European Patent Application 184162 (to Fujisawa Pharmaceuticals Co Ltd) discloses a number of macrocyclic compounds isolated from microorganisms belonging to the genus Streptomyces. The compounds are numbered FR-900506, FR-900520, FR-900523 and FR-900525, and the preparation of some of their derivatives is also described. The compounds are indicated as immunosuppressive agents.
International Patent Applications Nos WO 89/05304 and WO 91/02736 and European Patent Application No 413532 (to Fisons plc), European Patent Application 353678 (to Fujisawa Pharmaceuticals Co Ltd), European Patent Applications 349049, 349061, 358508 and 388153 (to Merck & Co Inc) and European Patent Application 356399 and International Patent Application WO 90/15805 (to Sandoz AG) also disclose a number of macrocyclic compounds whose indications include immunosuppressive activity.
We have now found a new group of macrocyclic compounds which possess advantageous properties over those disclosed previously.
According to the invention, there is provided a compound of formula I, ##STR2## wherein R.sup.1 represents OH or OCH.sub.3 ; is 1, then R.sup.3 is allyl or propyl.
Compounds of formula I, and pharmaceutically acceptable derivatives thereof ("the compounds of the invention"), have the advantage that they are less toxic, are more efficacious, are longer acting, have a broader range of activity, are more potent, are more stable, produce fewer side effects, are more easily absorbed, are more soluble, or have other more useful physical or pharmacological properties, than compounds of the prior art.
Preferred groups of compounds are those in which: R.sup.1 represents OCH.sub.3 ; R.sup.2 represents OH; X represents O; m represents 1; and n represents 2.
Pharmaceutically acceptable derivatives of compounds of formula I include prodrugs of compounds of formula I, i.e. compounds which may be metabolised in vivo to compounds of formula I. These include compounds which differ from compounds of formula I in that some or all of the OH groups (for example those which R.sup.1 and R.sup.2 may represent) are derivatized to esters or carbamates. Such esters may be prepared by conventional methods, for example reaction with a carboxylic acid and a coupling agent, or an acyl chloride. Such carbamates may also be prepared by conventional methods, for example reaction with an isocyanate. Specific esters and carbamates are CH.sub.3 CO.sub.2 --, C.sub.6 H.sub.5 CO.sub.2 --, H.sub.2 NCO.sub.2 -- and CH.sub.3 NHCO.sub.2 --.
There is also provided a process for the production of a compound of the invention, which comprises cyclizing a compound of formula II, ##STR3## wherein R.sup.1, R.sup.2, R.sup.3, X and n are as defined above, or a pharmaceutically acceptable derivative thereof; by the action of an appropriate oxidizing agent, and where necessary converting the resulting compound of formula I to a pharmaceutically acceptable derivative thereof.
Compounds of the invention in which m is 0 may be prepared from a corresponding compound of formula II by the action of Martin's sulfurane reagent, in a solvent which does not adversely affect the reaction (e.g. dichloromethane), below room temperature (e.g. from 0.degree. to 10.degree. C.). Martin's sulfurane reagent produces compounds of the invention having S-stereochemistry at C14 (i.e. the same stereochemistry as FR-900506) from Z-oximes of formula II, and compounds having R-stereochemistry at C14 from E-oximes of formula II.
Compounds of the invention in which m is 1 may be prepared from a corresponding compound of formula II by the action of lead tetraacetate, in a solvent which does not adversely affect the reaction (e.g. dichloromethane), at or around room temperature. Lead tetraacetate produces compounds of the invention having S-stereochemistry at C14 from both E- and Z-oximes of formula II. Compounds of the invention having R-stereochemistry at C14 in which m is 1
REFERENCES:
patent: 4659389 (1987-04-01), Wumbles et al.
Jarrar et al, J. Heterocyclic Chem., 27, pp. 275-278 (1990).
Donald David K.
Furber Mark
Datlow Philip I.
Fisons plc
Shah Mukund J.
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