Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-01-03
1996-08-13
Haley, Jacqueline
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514506, 5483241, 562499, C07D23332, A61K 31415
Patent
active
055456545
DESCRIPTION:
BRIEF SUMMARY
This application is a National Stage Application of PCT/EP93/01033, filed Apr. 29, 1993, published as WO 93/22288, Nov. 11, 1993.
This invention concerns pleuromutilin derivatives that are useful as stable propleuromutilin antibacterial agents and that are useful in the production of pleuromutilin antibacterial agents.
Pleuromutilin compounds of the formula II ##STR2## in which each of R.sub.3 and R.sub.4 is independently hydrogen, alkyl or substituted alkyl, are disclosed in European patent application EP 0 153 277. These compounds have useful biological properties; especially chemotherapeutic properties. For example the compounds of the formula II inhibit the growth of bacteria, Mycoplasms and Chlamydia and have antiparasitic properties (particularly against coccidia) and growth promoting activity. Hence these compounds can be used as medicaments and animal feeds.
However the compounds of the formula II could not previously be obtained in highly purified form since they are not available in crystalline form. As disclosed in EP 0 153 277, they could only be purified using chromatographic techniques.
Austrian Patent 392 272 discloses methods for the extraction and purification of compounds of the formula IV ##STR3## using specific solvents but analogous compounds with similar separation coefficients are not separated off and highly pure forms cannot be obtained.
Therefore there is a need for a route for preparing compounds of formula II that enables the compounds to be obtained in highly purified form (for example in crystalline form). There is also a need for stable compounds which may be used as pro-drugs for the compound of formula II.
Accordingly, in one aspect this invention provides compounds of the formula I ##STR4## in which each of R.sub.1 and R.sub.2 is independently hydrogen, alkyl or, together with the carbon atom to which it is bonded, a cycloalkyl group; and each of R.sub.3 and R.sub.4 is independently hydrogen, alkyl or substituted alkyl. The compounds of the formula I are easily isolated in crystal form and hence are easily purified. Therefore the compounds of the formula I are useful intermediates in the production of compounds of the formula II in that they enable the preparation and isolation of highly purified forms of the compounds of formula II.
Preferably each R.sub.1 and R.sub.2 is independently H or C.sub.1 to C.sub.6 alkyl, or forms, together with the carbon atom to which it is bonded, a cycloalkyl ring of up to 6 carbon atoms (for example a 5 membered ring). R.sub.1 and R.sub.2 are both preferably methyl.
Preferably each R.sub.3 and R.sub.4 is independently H or C.sub.1 to C.sub.6 alkyl.
The invention also provides a process for the production of the compounds of the formula I comprising reacting a compound of formula II as defined above with a carbonyl compound of the formula III ##STR5## in which R.sub.3 and R.sub.4 are as defined above, and isolating the compound of the formula I in tree base or acid addition salt form. The compound of formula I may be obtained in crystalline form.
The reaction may be carried out in a suitable solvent such as a lower alcohol (for example methanol, ethanol or isopropanol) or mixtures thereof.
The carbonyl compound of the formula III is preferably acetone, butan-2-one or cyclopentanone.
The invention also provides a method of producing compounds of the formula II as defined above in highly purified form (for example above 95% pure) comprising heating a compound of the formula I in the presence of an acid or a solvent, or both, and isolating the compound of the formula II in free base or acid addition salt form. Therefore, to produce compounds of the formula II in pure form, these compounds may be produced as conventionally produced to provide them in impure form. They may then be reacted with a carbonyl group of formula III as described above to provide the compounds of the formula I which may be readily purified since they are obtainable in crystalline form. The compounds of the formula I may then be convened to compounds of the formula II as d
REFERENCES:
patent: 4675330 (1987-06-01), Berner et al.
Fitzi, et al, Tetrahedron vol. 44, No. 17 pp. 5277-5292, (1988).
Kealy, et al, J. Organic Chemistry, vol. 26, No. 4, pp. 1097-1101 Apr., 1961.
Fitzi, et al, Angew. Chem. Int. Ed. Engl., vol. 25, No. 4, 1986, pp. 345-346.
Smissman, et al, J. Medicinal Chemistry, vol. 19, No. 1, (1976), pp. 161-163.
Biochemie Gesellschaft m.b.H.
Haley Jacqueline
Honor Robert S.
Kassenoff Melvyn M.
McGovern Thomas O.
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