9A-N-(N'-carbamoyl)and 9A-N-(N'-thiocarbamoyl) derivatives of 9-deoxo-9A-aza-9A-homoerythromycin A
AssigneePliva farmaceutiska, kemijska, prehrambena i kozmeticka industrija, dionicko drustvo Zagreb
InventorsNedjeliko Kujund zi c, Gabrijela Kobrehel, Zeljko Kelneri c
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Abstract
The invention relates to 9a-N-(N'-carbamoyl) and 9a-N-(N'-thiocarbamoyl) derivatives of 9-deoxo-9a-aza-9a-homoerythromycin A, novel semisynthetic macrolide antibiotics of the azalide series, of the formula (I) ##STR1## wherein R represents a C.sub.1 -C.sub.3 alkyl, aryl or aralkyl group and X represents O or S, and pharmaceutically acceptable addition salts thereof with inorganic or organic acids, to the intermediates and processes for the preparation thereof, to a process for the preparation of pharmaceutical compositions as well as to the use of pharmaceutical compositions in the treatment of bacterial infections.
Claims17
A compound of the general formula (I) ##STR4## wherein R is a C.sub.1 -C.sub.3 alkyl, or
- R is a mono- or bicyclic aryl group of up to 10 carbon atoms, or
- R is an aralkyl wherein aryl group of said aralkyl is a mono- or bicyclic aromatic hydrocarbon of up to 10 carbon atoms and the alkyl group of said aralkyl contains 1 carbon atom, or
- R is unsubstituted or substituted 5- to 6-membered heterocyclic group containing one or two hetero atoms wherein said hetero atom is N or O, or both
- and X is O or S,
- and a pharmaceutically acceptable addition salt with an acid selected from the group consisting of inorganic acid and organic acid.
A process for preparation of the compound of the general formula (I) ##STR5## wherein R is a C.sub.1 -C.sub.3 alkyl, or
- R is a mono- or bicyclic aryl group of up to 10 carbon atoms, or
- R is an aralkyl wherein aryl portion of said aralkyl is a mono- or bicyclic aromatic hydrocarbon of up to 10 carbon atoms and the portion of said aralkyl contains 1 carbon atom, or
- R is unsubstituted or substituted 5- to 6-membered heterocyclic group containing one or two hetero atoms wherein said hetero atom is N or O, or both
- and X is O or S,
- and their pharmaceutically acceptable addition salt with inorganic or organic acid, characterized in that 9-deoxo-9a-aza-9a-homoerythromycin A is reacted with isocyanates or isothiocyanates of the general formula (II)
- R-N.dbd.C.dbd.X(II)
- wherein R and X have the meaning as defined above, in an aprotic solvent selected from the group consisting of toluene and xylene, at a temperature from 20.degree. to 100.degree. C., characterized in that the compounds of the general formula (II) wherein R represents aryl or heteroaryl group as defined above and X represents O being prepared in situ by means of Curtius rearrangement of the corresponding acid azide at elevated temperature, which are then optionally subjected to reaction with inorganic acid or organic acid to give corresponding acid addition salt.
A pharmaceutical composition useful for treating bacterial infections in humans and animals which comprises an antibacterially effective amount of the compound of the formula (I) or a pharmaceutically acceptable acid addition salt thereof:
- ##STR6## wherein R is a C.sub.1 -C.sub.3 alkyl, or
- R is a mono- or bicyclic aryl group of up to 10 carbon atoms, or
- R is an aralkyl wherein aryl group of said aralkyl is a mono- or bicyclic aromatic hydrocarbon of up to 10 carbon atoms and alkyl group of said aralkyl contains 1 carbon atom, or
- R is unsubstituted or substituted 5- to 6-membered heterocyclic group containing one or two hetero atoms wherein said hetero atom is N or O, or both
- and X is O or S,
- in combination with a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.