O-alkyl macrolide and azalide derivatives and regioselective process for their preparation
The present disclosure relates to new 11-O-alkyl macrolides and azalides and pharmaceutically acceptable salts and solvates thereof, and to pharmaceutical compositions thereof. The disclosure also relates to a process for the preparation of 11-O-alkyl macrolides and azalides by regioselective 11-O-alkylation of macrolides and azalides having a vicinal diol system, using diazoalkanes in the presence of transition-metal halides or boric acid as catalysts. In another aspect, the disclosure relates to uses of the 11-O-alkyl macrolides and azalides as antibacterial agents or intermediates for the synthesis of other antibacterial agents.
1. A process for the preparation of a compound of the formula
wherein:
A is a bivalent radical selected from —C(O)—, —C(O)NH—, —NHC(O)—, —N(R 11 )—CH 2 —, —CH 2 —N(R 11 )—, —CH(NR 11 R 12 )— and —C(═N—OR 13 )—;
R 1 is cladinosyl of formula (V), OH or together with R 2 forms a keto group provided that when R 1 together with R 2 forms a keto group R 4 is not H;
R 2 is H or together with R 1 forms a keto group;
R 3 is desosaminyl of formula (VI) or hydroxyl;
R 4 is hydrogen, C 1-4 alkyl, or C 2-6 alkenyl optionally substituted by 9 to 10 membered fused bicyclic heteroaryl;
R 5 is hydrogen or fluorine;
R 6 is hydroxyl, —NH 2 , or together with R 7 forms a keto group or ═NR 10;
R 7 is hydrogen, —NH 2 , or together with R 6 forms a keto group or ═NR 10;
R 8 is H or a carbobenzoxy group;
R 9 is H, CH 3 or a carbobenzoxy group;
R 10 is hydrogen or C 1-6 alkyl;
R 11 and R 12 are each independently hydrogen, C 1-6 alkyl, aryl, heteroaryl, heterocyclyl, sulfoalkyl, sulfoaryl, sulfoheterocyclyl or —C(O)R 10 , wherein the alkyl, aryl and heterocyclyl groups are optionally substituted by up to three groups independently selected from R 14 ;
R 13 is hydrogen, —C 1-6 alkyl, C 2-6 alkenyl, —(CH 2 ) a aryl, —(CH 2 ) a heterocyclyl, or —(CH 2 ) a O(CH 2 ) b OR 10 ;
R 14 is halogen, cyano, nitro, hydroxyl, C 1-6 alkyl, C1-6alkoxy or aryloxy, C1-6alkythio or arylthio, —NH 2 , —NH(C 1-6 alkyl) or —N(C 1-6 alkyl) 2 ; and
a and b are each independently integers from 1 to 4;
comprising the step of O-methylating at the 11 position a compound of formula (IV)
wherein A and R 1 -R 14 are as hereinbefore defined,
with a diazomethane of formula (III)
R 2 —CH N 2 (III)
wherein:
R 2 is hydrogen,
in the presence of a catalyst selected from the group consisting of TiCl 4 , SnCl 2 and boric acid, and in an inert organic solvent selected from the group consisting of acetone, ethanol, acetonitrile and N,N-dimethylformamide, wherein the molar ratio of a compound of formula (IV) to catalyst is 1: 0.25 to 1: 2, and wherein said methylating step results in substantial regioselectivity.
2. The process according to claim 1 , wherein a compound of formula (IV) is selected from the group consisting of azithromycin, 2′—O,3′—N-dicarbobenzoxy-azithromycin, 9-deoxo-9a-aza-9a-homoerythromycin, 3-decladinosyl-5-dedesosaminyl-9-deoxo-9a-aza-9a-homoerythromycin , 8a-aza-8a-homoerythromycin, roxithromycin, clarithromycin, 3-decladinosyl-5-desosaminyl-9-deoxo-9a-aza-9a-homoerythromycin, 3-decladinosyl-5-desosaminyl-8a-aza-8a-homoerythromycin and 3-decladinosyl-5-dedesosaminyl-8a-aza-8a-homoerythromycin.