Macrolide compound
09765105 · 2017-09-19
Assignee
Inventors
Cpc classification
C07H17/00
CHEMISTRY; METALLURGY
A61K31/706
HUMAN NECESSITIES
A61P33/02
HUMAN NECESSITIES
C07H17/08
CHEMISTRY; METALLURGY
International classification
C07H17/08
CHEMISTRY; METALLURGY
A61K31/706
HUMAN NECESSITIES
C07H17/00
CHEMISTRY; METALLURGY
Abstract
The present disclosure relates to a macrolide compound as shown by formula I and pharmaceutically acceptable salt thereof. The compound of the present disclosure is an antibacterial agent, and can be used to treat various bacterial and protozoal infections. The present disclosure further relates to the preparation method of the compound and a pharmaceutical composition thereof. ##STR00001##
Claims
1. A macrolide compound having a structural general formula as shown by formula (I), ##STR00028## wherein R′ is H or n-propyl, R.sub.1 is selected from a group consisting of H, hydroxyl, methoxyl, propargyl, aryl, and a nitrogen-containing heterocycle, R.sub.2 is hydroxyl, R.sub.3 is —CH.sub.2R, wherein R is H or an organic group that contains or does not contain a heteroatom, the heteroatom being selected from a group consisting of O, N, S, and halogen, and R.sub.4 is selected from a group consisting of H, acetyl, and carbobenzoxy.
2. The compound according to claim 1, wherein R.sub.3 is —CH.sub.2NR.sub.20R.sub.30 or —CH.sub.2SR.sub.40, wherein each R.sub.20, R.sub.30, and R.sub.40 is independently H or an organic group that contains or does not contain a heteroatom, the heteroatom being selected from a group consisting of O, N, S, and halogen, and R.sub.20 and R.sub.30 being optionally bonded to each other to form a ring.
3. The compound according to claim 1, wherein R.sub.3 is —CH.sub.2NHR.sub.50, and R.sub.50 is an organic group that contains or does not contain heteroatom, the heteroatom being selected from a group consisting of O, N, S, and halogen.
4. The compound according to claim 3, wherein R.sub.50 is selected from a group consisting of n-propyl, n-butyl, cyclopropyl, ethyl, isopropyl, isobutyl, tert-butyl, cyclopropylmethyl, 2-methoxyethyl, cyclopentyl, 2,4-difluorobenzyl, 3-methoxybenzyl, n-pentyl, 2-methyl-pyrazine-5-yl-methyl, 3-methoxypropyl, cyclohexylmethyl, and 4-methoxyphenethyl.
5. The compound according to claim 2, wherein R.sub.3 is —CH.sub.2NR.sub.20R.sub.30, and each R.sub.20 and R.sub.30 is independently selected from C1-C6 alkyl.
6. The compound according to claim 5, wherein each R.sub.20 and R.sub.30 is independently methyl or ethyl.
7. The compound according to claim 1, wherein R in R.sub.3 is a nitrogen-containing heterocyclic compound, in which the nitrogen atom is directly attached to the carbon atom of methylene in R.sub.3.
8. The compound according to claim 7, wherein R in R.sub.3 is morpholinyl, piperidinyl, or piperazinyl.
9. The compound according to claim 2, wherein R.sub.20 and R.sub.30 together form a 4 to 10-membered monocyclic ring, or a 5 to 10-membered heteroaryl ring optionally substituted by one or two alkyls.
10. The compound according to claim 2, wherein one of R.sub.20 and R.sub.30 is H, and the other thereof is an organic group containing phenyl or benzyl.
11. The compound according to claim 1, wherein the compound is: 1) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(propylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 2) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(butylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 3) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(diethylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 4) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(phenylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 5) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(morpholinyl)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 6) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(cyclopropylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 7) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(pyrryl)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 8) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(4-fluorobenzylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 9) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(imidazolyl)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 10) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(ethylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 11) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(isopropylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 12) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(isobutylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 13) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[tert-butylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 14) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[piperidinylmethyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 15) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(cyclopropylmethylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 16) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(4-methoxybenzylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 17) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(4-chlorolbenzylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 18) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-pyridinylmethylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 19) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[((3-ethoxypropyl)amino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 20) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-methoxyethyl)amino-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 21) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[2-methoxybenzyl-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 22) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[(2-[(N-methyl)amino]-ethyl)amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 23) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(cyclopentylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 24) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[2,4-difluorobenzyl-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 25) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2,6-chloro-pyridazin-3-yl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 26) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[(1-methyl-3-phenyl)propyl-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 27) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[3-methoxybenzyl-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 28) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[2,2,2-trifluoroacetyl-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 29) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[[(2-chloro-pyridin-4-yl-amino)-methyl]-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 30) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[[(4-formyl-benzyl-amino)-methyl]-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 31) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[propargyl-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 32) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[butyrate-2-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[(3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 33) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[butyrate-4-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 34) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-hydroxy-propylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 35) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[n-pentyl-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 36) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(morpholin-4-yl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 37) 3-({(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-6-[-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-1-oxa-7-azacyclopentadecan-15-one-13-yl-oxy]-3-hydroxy-4-methoxy-2,4-dimethyl-tetrahydropyran-3-yl-methyl}-amino)-butyric acid; 38) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(1-hydroxymethyl-propylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 39) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-hydroxy-2-phenyl-ethylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 40) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(4-dimethoxy-butylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 41) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3,4-dichloro-benzylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 42) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(1-methyl-4-dimethylaminobutylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 43) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[(3-cyclohexylamino)propylamino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 44) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[(4-mesylphenylethylamino)propylamino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 45) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[(1-methyl-but-1-en-3-yne-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 46) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[(1-methyl-butyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 47) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[(2-pyridin-4-yl-ethylamine)-methyl]]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 48) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-{[(5-methyl-pyrazin-2-yl-methyl)-amino]-methyl}-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 49) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[(3-methoxy-propyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 50) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[cyclohexyl-methyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 51) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-fluoro-phenyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 52) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-morpholinyl-propyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 53) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-furfuryl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 54) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-aminobenzyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 55) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(phenylhydrazono)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 56) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 57) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-chloropropyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 58) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3,5-dimethoxyphenyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 59) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(thienylformyloxymethyl-2-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 60) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(5-methylfurfurylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 61) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(4-fluoro-phenylhydrazono)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 62) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(benzyloxy-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 63) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(p-methoxyphenyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 64) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3,4-dimethylphenyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 65) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(5-fluoropyridin-2-yl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[(3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 66) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-pyrrolyl-ethyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 67) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-pyridin-4-yl-ethylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 68) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-fluorobenzyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 69) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-piperidin-4-yl-methyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 70) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(5-chloro-o-methylphenyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 71) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-fluoro-phenyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(methylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 72) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-fluoro-5-methylphenyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 73) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-methyl-4-chloro-phenyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 74) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(N-methyl-butyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 75) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(quinolin-6-yl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 76) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(1,2,2-trimethyl-propylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 77) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(n-propyl-amino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 78) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(n-butyl-amino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 79) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(pentylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 80) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(diethylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 81) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(phenylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 82) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(morpholinyl)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 83) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-{[(5-amino-1,3,3-trimethyl-cyclohexylmethyl)-amino]-methyl}-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 84) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[piperonylamino-methyl)]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 85) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(4-fluorobenzylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 86) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(1,2,3-triazolyl)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 87) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(ethylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 88) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(isopropylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 89) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(isobutylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 90) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-chlorophenylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 91) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(tert-butylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 92) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(n-hexylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 93) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(4-trifluoromethylbenzylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 94) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(cyclopropyl-methylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 95) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(4-methoxy-benzylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 96) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[(4-nitro-benzyl)amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 97) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[4-chloro-benzyl-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 98) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-pyridinyl-methyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 99) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[(3-ethyoxyl-propyl)-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 100) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-methoxyethyl)-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 101) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-methyl-2-hydroxy-ethyl)amino-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 102) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-methoxy-benzyl)-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 103) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(cyclopentyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 104) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2,4-difluorobenzyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 105) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2,6-chloro-pyridazin-3-yl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 106) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(4-hydroxy-butyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 107) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(1-methyl-3-phenyl-propylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 108) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-methoxy-benzylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 109) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[piperazinyl-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 110) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[trifluoroacetylamino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 111) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[[(2-chloro-pyridin-4-yl-amino)-methyl]-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 112) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[4-formylbenzylamino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 113) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[propargyl-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 114) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[1-butyrate2-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-1H[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 115) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[1-butyrate4-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)+D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 116) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[diglycol-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 117) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-hydroxy-1-hydroxyethyl-ethylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 118) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-hydroxy-propylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 119) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[n-pentyl-amino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 120) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(morpholin-4-yl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 121) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-amino-butyrate)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 122) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(1-hydroxymethyl-propylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 123) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-hydroxy-2-phenyl-ethylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 124) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3,4-difluorophenylmethylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 125) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3,5-difluorophenylmethylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 126) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-methoxyethylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 127) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(1-methyl-4-diethylaminobutylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 128) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[4-sulphonylamino-phenylethylamino]-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 129) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[(1-methyl-but-1-ene-3-yne-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 130) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[(1-methyl-butyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 131) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[(2-pyridin-4-yl-ethylamino)-methyl]α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 132) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-{[(5-methyl-pyrazin-2-yl-methyl)-amino]-methyl}-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 133) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[[(cyclohexyl-methyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 134) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-fluoro-phenyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 135) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-morpholinyl-propyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 136) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-chloro-phenylmethyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 137) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-furyl-methyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 138) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-aminobenzyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 139) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(phenylhydrazono)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 140) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-{[2-(1H-indol-3-yl)-ethylamino]-methyl}-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 141) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-chloro-propyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 142) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3,5-dimethoxyphenyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 143) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(5-methyl-furan-2-yl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 144) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(4-fluoro-phenylhydrazono)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 145) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(benzyloxy-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 146) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(p-methoxyphenyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 147) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3,4-dimethylphenyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 148) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(4-fluorothiophenol)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 149) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(5-fluoropyridinyl-2-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 150) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(diethyl-methyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 151) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-morpholinyl-propyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 152) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-pyrrolyl-ethyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 153) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-pyridin-4-yl-ethylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 154) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-fluorobenzyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 155) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-piperidin-4-yl-methyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 156) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-methyl-4-chloro-phenyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 157) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(N-methyl-butyl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 158) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(4,6-dichloro-pyrimidin-2-yl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 159) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(cycloheptylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 160) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-(morpholinyl-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 161) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(4,4-dimethoxy-butylamino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 162) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-(piperidin-4-yl-amino-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 163) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2,6-chloro-pyridin-3-yl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 164) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-(tetrahydropyrrolyl-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 165) (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(5-hydrosulphonyl-1H-[1,2,4]triazol-3-yl-amino)-methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one; 166) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-amino-5-chloropyridinyl)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 167) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(N-ethylmethylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 168) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(diallylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 169) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2,2,2-trifluoroacetamido)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 170) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-amino-2 chloropyridinyl)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 171) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(benzamido)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 172) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-trifluoromethylbenzylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 173) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-bromophenylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 174) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3-methoxyphenylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 175) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(p-iodophenylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 176) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2,4-dinitrophenylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 177) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2,4-dimethylphenylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 178) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(3,5-di(trifluoromethyl)phenylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 179) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2,4-dichlorophenylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 180) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-chlorophenylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 181) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(allopurinol)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 182) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(1,2,4-triazolyl)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; 183) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(2-methylimidazolyl)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one; or 184) 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(N-methyl-2-hydroxyethylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-(2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-1-oxa-7-azacyclopentadecan-15-one.
12. A pharmaceutically acceptable salt of the compound according to claim 1.
13. The pharmaceutically acceptable salt according to claim 12, wherein the salt is prepared from the compound and an acid, and the acid is selected from one or more of a group consisting of hydrochloric acid, oxalic acid, maleic acid, fumaric acid, citric acid, malic acid, isethionic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, benzoic acid, and p-toluenesulfonic acid.
14. A pharmaceutical composition for use in treatment of bacterial infections or protozoal infections in mammals, birds, or fish, comprising a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof.
15. A method of using the compound according to claim 1 or a pharmaceutically acceptable salt thereof, the method comprising: treating bacterial infections or protozoal infections in mammals, birds, or fish with the compound or pharmaceutically acceptable salt thereof.
Description
DETAILED DESCRIPTION OF THE EMBODIMENTS
(1) Examples are provided to further illustrate the process and intermediates according to the present disclosure. Nevertheless, the following examples are not intended to limit the scope of the present disclosure.
(2) A synthetic route involved in examples 1 to 80 of the present disclosure is shown as follows.
(3) ##STR00004##
Example 1
(4) A cryostat was turned on, and the temperature was set at −12° C. 500 ml dichloromethane was measured with a 1 L graduated cylinder and added into a 1.0 L three-necked bottle. The three-necked bottle was placed in the cryostat to be cooled under agitation. 50 g (0.068 mol) of compound 2 was weighed with a counter balance and added into the reaction flask, and 300 ml of dichloromethane was measured with the 1 L graduated cylinder and added therein. The mixture was stirred, dissolved and cooled. An inner temperature of the reaction flask was cooled to 0-5° C. To the reaction solution, the temperature of which is kept at 0-5° C., was slowly added dropwise a mixed solution of 11.98 ml of benzyl chloroformate and 60 ml of dichloromethane. After the addition of the mixed solution, the reaction was carried out under the same temperature for 1 h. The reaction progress was monitored through thin layer chromatography (developing solvent: dichloromethane/methanol=10:1, with addition of two drops of ammonia). After the reaction was completed, the resulting reaction solution was concentrated under vacuum (with a temperature being ≦50° C. and a vacuum degree being ≦−0.086 Mpa) to give about 300 ml of compound 3.
(5) TLC Rf=0.42 (dichloromethane:methanol=7:1).
(6) ESI/MS: m/z 869[M+H].sup.+.
Example 2
(7) A low temperature cooling device was turned on, and the temperature was set at −75° C. Temperature was cooled to a range from −70 to −60° C. The 300 ml compound 3 liquid obtained from the concentration according to example 1 was transferred to a 1.0 L three-necked reaction flask. 106.46 ml (117.11 g or 1.498 mol) of dimethyl sulfoxide was added into the reaction flask under room temperature (25-30° C.). After dimethyl sulfoxide was added, the reaction flask was placed in the cryostat to be cooled under agitation to a temperature in a range from −70 to 60° C. 21.55 ml (0.152 mol or 31.865 g) of trifluoroacetic anhydride was slowly added dropwise, a dropping speed thereof being controlled, so that a temperature of the reaction solution can be maintained in a range from −65 to −60° C. The reaction was carried out under the same temperature for 0.5 h. Under the condition that the temperature of the reaction solution was maintained in the range from −65 to −60° C., 47.3 ml (0.339 mol, 34.35 g) of triethylamine was slowly added dropwise, and then stirred for 0.5 h under the same temperature. After the completion of the reaction, the reaction solution was warmed to the room temperature. The reaction liquid at room temperature (20-30° C.) was transferred to a 2.0 L separating funnel, into which 350 ml of purified water was added. After extraction, a water layer was discarded and an organic layer was obtained. The organic layer was extracted again with 250 ml of saturated sodium bicarbonate solution, from which an organic layer was obtained and a water layer was discarded. The organic layer obtained was extracted again with 350 ml of purified water, from which a water layer was discarded and an organic layer is obtained. The organic layer was transferred to a 1.0 L beaker, into which 20 g of anhydrous magnesium sulfate was added. After agitation for 20 minutes, the mixture in the beaker is dried and dehydrated. Then, magnesium sulfate was filtered out, and pale yellow filtrate was obtained. The pale yellow filtrate was concentrated to a volume of 125 ml under vacuum, with a temperature being ≦60° C. and a vacuum degree being ≦−0.086 Mpa. To the concentrate, was added 135 ml of isopropanol, and concentrated again to a volume of 135 ml. The liquid finally obtained from the concentration was transferred into the 1.0 L three-necked reaction flask. 700 ml of tert-butyl methyl ether was added into the reaction flask, and 11.2 ml (0.1497 mol, 17.07 g) of trifluoroacetic acid was slowly added therein dropwise at room temperature. The resulting mixture was crystallized under stirring at room temperature. After suction filtration, the filter cake was washed with n-heptane (200 ml×2) by stirring for 30 min. The filter cake was dried by forced air at 30° C., to afford 8.2 g of compound 4, with a yield of 82.2% and HPLC purity of 91% (applying HPLC-Waters Symmetry C8, 15 cm×3.9 mm column, Mobile Phase:methanol:ammonium acetate (25:75), Flow rate: 2.0 mL/min, Residence time: 5.07 min).
(8) TLC Rf=0.39 (dichloromethane:methanol=7:0).
(9) ESI/MS: m/z 867[M+H].sup.+.
Example 3
(10) To a 3.0 L beaker were added 50 g (0.0456 mol) of compound 4 of example 2 and 80 ml of dichloromethane. After uniform mixing, the solution was dried with 15 g of anhydrous magnesium sulfate for 20 min and then filtered by suction filtration. The filtrate was dried for the second time with 7 g of anhydrous magnesium sulfate for 20 min and then filtered by suction filtration. The filter residue, which was washed with dichloromethane, and the filtrate, which was refilled with dichloromethane to a volume of 160 ml (the measured content of moisture in the filtrate should be less than 0.3%) were reserved for later use. A low temperature cooling device was turned on and set at −8° C. 170 ml of tetrahydrofuran (dried with anhydrous magnesium sulfate for 30 min and filtered by suction filtration) was added into a 1.0 L three-necked bottle. The three-necked bottle was placed in a cryostat to be cooled under agitation to a temperature in a range from −5 to 0° C. 20 g (0.1273 mol) of trimethylsulfonium bromide was added into the three-necked bottle, and 20 g (0.11.786 mol) of potassium tert-butoxide was added therein at −5-0° C. After being vacuumized by a circulating water pump, the three-necked bottle was filled with nitrogen. The reaction mixture was stirred for for 15 min under nitrogen atmosphere. The temperature of the low temperature cooling device was adjusted to −75° C., and an inner temperature thereof was reduced to a range from −65 to −60° C. The solution, which has been deoxidized and dried, was slowly added into the reaction flask dropwise, meanwhile timekeeping begun. In this course, the temperature of the reaction solution was kept in a range from −65 to −60° C. After the addition of the solution, the reaction was carried out at −65 to −60° C. till the timekeeping reached 3 h. Reaction progress was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol=10:1, with addition of two drops of ammonia). After the reaction was completed, to the reaction mixture was added a solution of 21.5 g (0.405 mol) of ammonium chloride in 120 ml of water. The resulting mixture was stirred for 15 min at 5-10° C. After stratification, the water layer was extracted once with 200 ml of dichloromethane; and organic phases were combined, and washed with water for four times (4×100 ml). The organic layer was concentrated under vacuum until no more distillate was observed. Remaining solvent was vaporized by being substituted with 200 ml methanol. After two substitutions, the solution was concentrated, thereby obtaining compound 5.
(11) TLC Rf=0.55(dichloromethane:methanol=8:1).
(12) ESI/MS: m/z 881 [M+H].sup.+.
Example 4
(13) Compound 5 prepared in example 3 was dissolved in 350 ml of methanol and transferred to a 1.0 L three-necked bottle. 16 g of palladium and 142 g (0.2246 mol) of ammonium formate were added into the three-necked bottle. The reaction was carried out at 50° C. for 2 h. Reaction progress was monitored by thin layer chromatography (developing solvent: dichloromethane/methanol=10:1, with addition of two drops of ammonia). After the reaction was completed, the reaction solution was cooled to lower than 30° C., and then filtered by suction. The filtrate was concentrated under vacuum until about 200 ml of mixture remained, and the filter cake was kept sealed with water. The concentrate was slowly added into 550 ml of water dropwise within 20 min, and crystallized under stirring for 1 h. After suction filtration, the filter cake was washed with methanol/water (1:3), and then dried, to afford compound 6 (applying WATERS ACQUITY UPLC BEH C18 chromatographic column (2.1×50 mm, 1.7 μm); Mobile phase: acetonitrile-0.01 moL/L ammonium acetate in water (55:45), Flow rate: 0.20 mL/min, Residence time: 2.77 min, Detecting wavelength: 210 nm, Column temperature: 40° C., and Inj. Vol: 2.5 μl).
(14) TLC Rf=0.45(dichloromethane:methanol=7:1).
(15) ESI/MS: m/z 747[M+H].sup.+.
Example 5
(16) General Preparation Process 1
(17) Preparation of (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(cyclopropylamino)methyl]-α-L- ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one.
(18) Compound 6 (0.5 g, 0.6698 mmol), potassium iodide (1.11 g, 0.698 mmol) and cyclopropylamine (2.43 mL, 2.00 g, 35 mmoL) were dissolved under vibration at 50° C. in 5 ml isopropanol in a 50 ml round-bottom flask, and the resulting mixture was stirred at 50° C. Reaction progress was monitored by TLC. After the reaction was completed, the resulting reaction mixture was concentrated, and the residue was dissolved in water (50 ml) and ethyl acetate (100 ml). After standing stratification, the water layer was washed with ethyl acetate (3×50 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution (50 ml) and brine (40 ml), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford crude product. The crude product was purified by silica gel chromatograph (gradient of eluents of methanol:dichloromethane:ammonia water from 4:95.6:0.4 to 6:93.5:04) to afford 0.38 g of the titled compound (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(cyclopropylamino)methyl]-α-L- ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one.
(19) TLC Rf=0.47(dichloromethane:methanol=5:1).
(20) ESI/MS: m/z 805[M+H].sup.+.
(21) General Preparation Process 2
(22) Preparation of (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(butylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one,
(23) Compound 6 (0.5 g, 0.6698 mmol), tetrabutylammonium iodide (0.74, 2.0 mmoL) and n-butylamine (0.395 mL, 0.2938, 4 mmoL) were dissolved under vibration in 5 ml methanol at 50° C., and the resulting mixture was stirred at the same temperature. Reaction progress was monitored by TLC. After the reaction was completed, the resulting reaction mixture was concentrated, and residue was dissolved in 20 ml of water and 20 ml of ethyl acetate. After standing stratification, the water layer was washed with ethyl acetate (3×20 ml). The organic extractants were combined and washed with 40 ml of brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, thereby obtaining crude product. The crude product was purified by silica gel chromatograph (gradient of eluents of methanol:dichloromethane:ammonia water from 4:95.6:0.4 to 6:93.5:0.4) to afford 0.0888 g of the titled compound (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(butylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one.
(24) TLC Rf=0.47(dichloromethane:methanol=5:1).
(25) ESI/MS: m/z 819 [M+H].sup.+.
(26) General Preparation Process 3
(27) Preparation of (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(propylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one.
(28) Compound 6 (0.5 g, 06694 mmol) and n-propylamine (0.5 g) were dissolved under vibration in isopropanol (10 ml) at 50° C., and the resulting mixture was stirred at the same temperature for 48 h. Reaction progress is monitored by TLC. After the reaction was completed, the resulting reaction mixture was concentrated, and residue was added into saturated sodium bicarbonate solution (50 ml) and dichloromethane (80 ml). The mixture was vibrated uniformly, and stood to be stratified. The organic phase dichloromethane was washed with water (3×50 ml), dried with MgSO.sub.4, and concentrated under vacuum to dryness. The resulting substance was dissolved in dichloromethane, and applied on GF254 silica gel. Thin layer chromatography separation was performed with an eluent of 4/1 cyclohexane/diethylamine or 4/1/0.01 dichloromethane/methanol/ammonia water. The chromatographic band corresponding to the desired product was scraped off and further purified by silica gel chromatography eluted with a mixture of dichloromethane/methanol/ammonia in a ratio of 4/1/0.01. The mobile phase was concentrated at 50° C. under vacuum and dried, thereby obtaining 0.16 g of (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(propylamino)methyl]-α-L-ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one as pure amine.
(29) TLC Rf=0.47(dichloromethane:methanol=5:1).
(30) ESI/MS: m/z 807[M+H].sup.+.
(31) Compounds according to examples 5 to 80 have structures shown by the following general formula 1.
(32) ##STR00005##
(33) In examples 5 to 80, R is a group shown by Table 1, and nitrogen or sulfur in R is directly attached to methylene of R.sub.3. R′ in each of examples 5 to 80 is H. Specific reaction time for each of compounds of examples 6 to 80 prepared according to the above general preparation process 1, general preparation process 2 and general preparation process 3 of example 5 is shown in Table 1. In Table 1, data relating to structures, yields and mass spec are the data of the final compounds.
(34) TABLE-US-00001 TABLE 1 Mass Compound Preparation Reaction Yield spec Example No. R process time, h % M + H 5 (general syzx-1 n-propylamino general 48 50 807 preparation preparation process 3) process 3 5 (general syzx-2 n-butylamino general 53 45 819 preparation preparation process 2) process 2 6 syzx-3 diethylamino general 36 60 820 preparation process 1 7 syzx-4 phenylamino general 36 58 840 preparation process 1 8 syzx-5 morpholinyl general 36 42 834 preparation process 1 5 (general syzx-6 cyclopropylamino general 36 46 805 preparation preparation process 1) process 1 9 syzx-7 pyrryl general 36 59 814 preparation process 1 10 syzx-8 4-fluorobenzylamino general 36 58 872 preparation process 1 11 syzx-9 1-imidazolyl general 36 32 815 preparation process 2 12 syzx-10 ethylamino general 36 40 792 preparation process 2 13 syzx-11 isopropylamino general 48 33 806 preparation process 2 14 syzx-12 isobutylamino general 48 35 820 preparation process 2 15 syzx-14 tert-butylamino general 48 51 820 preparation process 1 16 syzx-15 piperidinylamino general 48 55 832 preparation process 1 17 syzx-17 cyclopropylmethylamino general 48 70 818 preparation process 3 18 syzx-18 4-methoxybenzylamino general 48 55 884 preparation process 2 19 syzx-20 4-chlorobenzylamino general 48 52 888 preparation process 3 20 syzx-21 3-pyridinylmethylamino general 48 60 855 preparation process 3 21 syzx-22 (3-ethoxypropyl)amino general 48 33 850 preparation process 3 22 syzx-24 dimethylamino general 48 33 792 preparation process 1 23 syzx-25 (2-methoxyethyl)amino general 48 44 822 preparation process 3 24 syzx-27 2-methoxybenzyl-amino general 72 50 884 preparation process 3 25 syzx-29 2-[(N-methyl)amino]-ethyl)amnino general 72 33 821 preparation process 3 26 syzx-30 cyclopentylamino general 72 35 832 preparation process 1 27 syzx-31 2,4-difluoro-benzyl-amino general 72 36 890 preparation process 3 28 syzx-32 6-chloro-pyridazin-3-yl-amino general 72 44 876 preparation process 1 29 syzx-34 (1-methyl-3-phenyl)propyl-amino general 72 23 896 preparation process 1 30 syzx-35 3-methoxybenzyl-amino general 72 26 884 preparation process 3 31 syzx-37 2,2,2-trifluoroacetyl-amino general 72 56 860 preparation process 2 32 syzx-38 2-chloro-pyridin-4-yl-amino general 72 60 875 preparation process 1 33 syzx-39 4-formyl-benzyl-amino general 72 23 898 preparation process 1 34 syzx-40 propargyl-amino general 72 45 802 preparation process 1 35 syzx-41 butyrate-2-amino general 72 56 850 preparation process 1 36 syzx-42 butyrate-4-amino general 72 60 850 preparation process 1 37 syzx-46 3-hydroxy-propylamino general 72 56 822 preparation process 3 38 syzx-47 n-pentyl-amino general 72 57 834 preparation process 3 39 syzx-48 morpholin-4-yl-amino general 72 23 849 preparation process 1 40 syzx-50 butyrate-3-amino general 72 26 850 preparation process 2 41 syzx-51 1-hydroxymethyl-propylamino general 72 66 836 preparation process 1 42 syzx-52 2-hydroxy-2-phenyl-ethylamino general 72 77 884 preparation process 1 43 syzx-56 4-dimethoxy-butylamino general 72 50 880 preparation process 1 44 syzx-57 3,4-dichloro-benzylamino general 72 45 923 preparation process 1 45 syzx-58 2-methoxyethylamino general 48 44 822 preparation process 1 46 syzx-59 1-methyl-4-dimethylamino- general 72 36 905 butylamino preparation process 1 47 syzx-60 (3-cyclohexylamino)propylamino general 72 37 903 preparation process 3 48 Syzx-61 4-sulfamido-phenethylamino general 72 38 947 preparation process 3 49 syzx-62 1-methyl-but-1-en-3-yne-amino general 72 44 828 preparation process 1 50 syzx-63 1-methyl-butyl-amino general 72 25 834 preparation process 1 51 syzx-64 2-pyridin-4-yl-ethylamino general 72 27 869 preparation process 3 52 syzx-65 (2-methyl-pyrazin-5-yl-methyl)- general 72 28 870 amino preparation process 1 53 syzx-66 3-methoxy-propyl-amino general 72 29 836 preparation process 1 54 syzx-67 cyclohexyl-methyl-amino general 72 30 860 preparation process 1 55 syzx-68 2-fluoro-phenyl-amino general 72 33 858 preparation process 1 56 syzx-69 3-morpholinyl-propyl-amino general 72 63 891 preparation process 2 57 syzx-71 2-furfuryl-amino general 72 38 844 preparation process 1 58 syzx-72 3-aminobenzyl-amino general 72 39 869 preparation process 1 59 syzx-73 phenylhydrazono general 72 50 855 preparation process 1 60 syzx-74 2-(1H-indol-3-yl)-ethylamino general 72 23 907 preparation process 1 61 syzx-75 3-chloropropyl-amino general 72 46 840 preparation process 3 62 syzx-76 3,5-dimethoxyphenyl-amino general preparation 72 44 900 process 1 63 syzx-77 thienylformyloxymethyl-2-amino general 72 43 904 preparation process 1 64 syzx-78 5-methylfurfurylamino general 72 48 858 preparation process 1 65 syzx-81 4-fluoro-phenylhydrazono general 72 25 873 preparation process 1 66 syzx-82 benzyloxy-amino general 72 30 870 preparation process 1 67 syzx-83 p-methoxyphenyl-amino general 72 21 870 preparation process 1 68 syzx-84 3,4-dimethylphenyl-amino general 72 25 868 preparation process 1 69 syzx-86 5-fluoropyridin-2-yl-amino general 72 16 859 preparation process 1 70 syzx-90 2-pyrrolyl-ethyl-amino general 72 33 861 preparation process 3 71 syzx-91 2-pyridin-4-yl-ethylamino general 72 32 869 preparation process 1 72 syzx-92 2-fluorobenzyl-amino general 72 33 872 preparation process 1 73 syzx-93 2-piperidin-4-yl-methyl-amino general 72 36 861 preparation process 3 74 syzx-94 5-chloro-o-methylphenyl-amino general 72 11 888 preparation process 1 75 syzx-95 2-fluoro-phenyl-amino general 72 10 858 preparation process 1 76 syzx-96 2-fluoro-5-methylphenyl-amino general 72 10 872 preparation process 1 77 syzx-97 2-methyl-4-chloro-phenyl-amino general 72 13 888 preparation process 1 78 syzx-98 N-methyl-butyl-amino general 72 23 834 preparation process 1 79 syzx-99 quiriolin-6-yl-amino general 72 12 891 preparation process 1 80 syzx-100 1,2,2-trimethyl-propylamino general 72 18 848 preparation process 1
(35) The following examples relate to compounds and preparation thereof when R′ in formula (I) is n-propyl,
(36) ##STR00006##
Example 81
(37) 600 ml of dichloromethane was added into a 2 L three-necked bottle. The three-necked bottle was placed in the cryostat to be cooled under agitation. 30 g (0.3861 mol) of compound 11, which was prepared according to the process as described in Chinese patent CN102239174A, was measured and added into the reaction flask to be dissolved under stirring, and then cooled to 0-5° C. To the reaction solution, the temperature of which is kept at 0-5° C., was slowly added dropwise a mixed solution of 6.8 ml (0.424 mol, 82.32 g) of benzyl chloroformate and 60 ml of dichloromethane. After the addition of the mixed solution, the reaction was carried out under 0-5° C. for 1 h. The reaction solution was concentrated under vacuum, with a temperature being ≦50° C. and a vacuum degree being ≦−0.086 Mpa, to give 180 ml of concentrate of compound 7. The concentrate of compound 7 was transferred to the 2 L three-necked reaction flask, into which 60.6 ml (66.6 g, 8.532 mol) of dimethyl sulfoxide was added at room temperature (20-30° C.). After dimethyl sulfoxide was added, the reaction flask was placed in the cryostat to be cooled under agitation to a temperature in a range from −70 to −60° C. 12.18 ml (0.864 mol, 181.32 g) of trifluoroacetic anhydride was slowly added dropwise, a dropping speed thereof being controlled, so that a temperature of the reaction solution can be maintained in a range from −65 to −60° C. The reaction was carried out at the same temperature for 0.5 h. Under the condition that the temperature of the reaction solution was maintained in the range from −65 to −60° C., 26.88 ml (1.932 mol, 195.3 g) of triethylamine was slowly added dropwise, and then stirred for 0.5 h at the same temperature.
(38) After the reaction was completed, the reaction solution was warmed to the room temperature, and then transferred to a 2 L separating funnel, into which 210 ml of purified water was added. After extraction, an organic layer was obtained and a water layer was discarded. The organic layer was extracted again with 150 mL of saturated sodium bicarbonate solution, from which an organic layer was obtained and a water layer was discarded. Again, the organic layer obtained was extracted with 200 ml of purified water, from which a water layer was discarded and an organic layer was obtained.
(39) The organic layer was transferred to a 1.0 L beaker, into which 120 g of anhydrous magnesium sulfate was added. After agitation for 20 minutes, the mixture in the beaker is dried and dehydrated. Then, magnesium sulfate was filtered out, and pale yellow filtrate was obtained. The pale yellow filtrate was concentrated under vacuum to dryness, with a temperature being ≦60° C. and a vacuum degree being ≦−0.086 Mpa, to afford compound 8.
(40) TLC Rf=0.60 (dichloromethane:methanol=7:1).
(41) ESI/MS: m/z 909[M+H].sup.+.
Example 82
(42) 170 ml of tetrahydrofuran was added into a 1.0 L three-necked bottle. The three-necked bottle was placed in a cryostat to be cooled under agitation to a temperature in a range of −5-0° C. Trimethylsulfonium bromide (0.12256 mol, 19.25 g) was added into the three-necked bottle, and potassium tert-butoxide (0.17156 mol, 19.25 g) was added therein at −5-0° C. The reaction mixture was stirred for 15 min under nitrogen atmosphere. An inner temperature was reduced to −70° C., and a dichloromethane solution of compound 8 prepared according to example 81 was slowly added dropwise into the three-necked bottle, meanwhile timekeeping begun. In this course, the temperature of the reaction solution was kept in a range from −65 to −60° C. After the addition of the solution, the reaction was carried out under nitrogen atmosphere till the timekeeping reached 3 h.
(43) To the reaction solution was added a solution of 20.85 g (0.39 mol, 20.85 g) of ammonia chloride in 120 ml of water. The resulting mixture was stirred for 15 min at 5-10° C. After stratification, the water layer was extracted once with 200 ml of dichloromethane. The dichloromethane layer and the organic phase were combined, and washed with water (4×200 ml). The organic layer was concentrated under vacuum until no more distillate was observed. Remaining solvent was vaporized by being substituted with 200 ml methanol. After two substitutions, the solution was concentrated, thereby obtaining compound 9.
(44) TLC Rf=0.58(dichloromethane:methanol=7:1).
(45) ESI/MS m/z 923[M+H].sup.+.
Example 83
(46) Compound 9 prepared in example 82 was dissolved in 170 ml of methanol. 16 g of palladium and 13.63 g (0.2164 mol, 13.63 g) of ammonium formate were added into the resulting solution. The reaction was carried out at 50° C. for 2 h. After the reaction was completed, the reaction solution was cooled and then filtered. The filter cake was kept sealed with water, and the filtrate was concentrated under vacuum until about 80 ml of mixture remained. The concentrate was slowly added dropwise into 250 ml of water within 20 min. The concentrate was regulated with 10% sodium hydroxide solution until the pH thereof reached 10.5±0.5, and crystallized under stirring for 1 h. After suction filtration, the filter cake was washed with methanol/water (1:3), and then dried under forced air at 40° C., thereby affording compound 10.
(47) TLC Rf=0.33(dichloromethane:ethanol=7:1).
(48) ESI/MS: m/z 789[M+H].sup.+.
Example 84
(49) General Preparation Process (a)
(50) Preparation of (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(cyclopropylamino)-methyl]-α-L- ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one.
(51) In a 50 ml round-bottom flask, compound 10 (0.5 g, 0.6698 mmol) prepared according to example 83, potassium iodide (1.11 g, 0.698 mmol) and cyclopropylamine (2.43 mL, 2.00 g, 35 mmoL) were dissolved under vibration at 50° C. in 5 ml of isopropanol, and the resulting mixture was stirred at 50° C. Reaction progress was monitored by TLC. After the reaction was completed, the resulting reaction mixture was concentrated, and the residue was dissolved in water (50 ml) and ethyl acetate (100 ml). After stratification, the water layer was washed with ethyl acetate (3×50 mL). The organic phases were combined, washed with saturated sodium bicarbonate solution (50 ml) and brine (40 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to afford a crude product. The crude product was purified by silica gel chromatograph (gradient of eluents of methanol:dichloromethane:ammonia water from 4:95.6:0.4 to 6:93.5:0.4) to afford 0.38 g of the titled corn pound.
(52) TLC Rf=0.47(dichloromethane:methanol=5:1).
(53) ESI/MS: m/z 846[M+H].sup.+.
(54) General Preparation Process (b)
(55) Preparation of (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(n-butylamino)-methyl]-α-L- ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one.
(56) Compound 10 (0.5 g, 0.6698 mmol) prepared according to example 83, tetrabutylammonium iodide (0.74, 2.0 mmoL) and n-butylamine (0.395 mL, 0.2938, 4 mmoL) were dissolved under vibration in 5 ml methanol at 50° C., and the resulting mixture was stirred at the same temperature. Reaction progress was monitored by TLC. After the reaction was completed, the resulting reaction mixture was concentrated, and the residue was dissolved in water (20 ml) and ethyl acetate (20 ml). After stratification, the water layer was washed with ethyl acetate (3×20 ml). The organic extractants were combined and washed with 40 ml of brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum, thereby obtaining a crude product. The crude product was purified by silica gel chromatography (gradient of eluents of methanol:dichloromethane: ammonia water being in a range from 4:95.6:0.4 to 6:93.5:0.4) to afford 0.0888 g of the titled compound.
(57) TLC Rf=0.47(dichloromethane:methanol=5:1).
(58) ESI/MS: m/z 862 [M+H].sup.+.
(59) General Preparation Process c)
(60) Preparation of (2R,3S,4R,5S,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-4-C-[(n-propylamino)-methyl]-α-L- ribopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-7-propyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosy]oxy]-1-oxa-7-azacyclopentadecan-15-one.
(61) Compound 10 (0.5 g, 0.6694 mmol) prepared according to example 83 and n-propylamine (0.5 g, 25 nlmmol) were dissolved under vibration in isopropanol (10 ml) at 50° C., and the resulting mixture was stirred at the same temperature for 72 h. Reaction progress was monitored by TLC. After the reaction was completed, the resulting reaction mixture was concentrated, and the residue was added into saturated sodium bicarbonate solution (50 ml) and dichloromethane (80 ml). The mixture was vibrated uniformly, and stood to be stratified. The organic phase dichloromethane was washed with water (3×50 ml). The organic phases were combined, dried over MgSO.sub.4, and concentrated under vacuum to dryness. The resulting substance was dissolved in dichloromethane, and applied on GF254 silica gel. Thin layer chromatography separation was performed with an eluent of 4/1 cyclohexane/diethylamine or 4/1/0.01 dichloromethane/methanol/ammonia water. The chromatographic band corresponding to the desired product was scraped off and further purified by silica gel chromatography eluted with a mixture of dichloromethane/methanol/ammonia in a ratio of 4/1/0.01. The mobile phase was concentrated at 50° C. under vacuum and dried, thereby obtaining 0.16 g of the titled compound as a pure amine.
(62) TLC Rf=0.47(dichloromethane:methanol=5:1).
(63) ESI/MS: m/z 848[M+H].sup.+.
(64) Compounds of examples 85-187 each have a structure shown by the following general formula 1, in which substituent group R is as shown by Table 2. Compounds of examples 85-187 are prepared according to the general preparation process (a), general preparation process (b) and general preparation process (c) of the above example 84. Specific reaction time for preparation of each of compounds of examples 85 to 187 is shown in Table 2. In Table 2, structures, yields and mass spec are data of the final compounds.
(65) ##STR00007##
(66) In examples 84 to 187, R is a group shown by Table 2, and nitrogen or sulfur in R is directly attached to methylene of R.sub.3. R′ in each of examples 84 to 187 is n-propyl.
(67) TABLE-US-00002 TABLE 2 Mass Compound Preparation Reaction Yield spec Examples No. R process time, h % M + H 84 (general syzx-217 cyclopropylamino general 72 76 846 preparation preparation process (a)) process (a) 84 (general syzx-102 n-butylamino general 72 20 862 preparation preparation process (b)) process (b) 84(general syzx-101 n-propylamino general 72 32 848 preparation preparation process (c)) process (c) 85 syzx-103 diethylamino general 72 60 862 preparation process (a) 86 syzx-104 phenylamino general 72 58 882 preparation process (a) 87 syzx-105 morpholinyl general 72 42 876 preparation process (a) 88 syzx-106 (5-amino-1,3,3-trimethyl- general 72 59 959 cyclohexylmethyl)-amino preparation process (a) 89 syzx-107 piperonylamino general 72 58 926 preparation process (a) 90 syzx-108 4-fluorobenzylamino general 72 32 914 preparation process (c) 91 syzx-109 1,2,3-triazolyl general 72 40 858 preparation process (a) 92 syzx-110 ethylamino general 72 33 834 preparation process (a) 93 syzx-111 isopropylamino general 72 35 848 preparation process (a) 94 syzx-112 isobutylamino general 72 56 862 preparation process (a) 95 syzx-113 3-chlorophenylamino general 72 51 914 preparation process a 96 syzx-114 tert-butylamino general 72 55 862 preparation process (a) 97 syzx-115 n-hexylamino general 72 60 890 preparation process (a) 98 syzx-116 4-trifluoromethylbenzylamino general 72 70 964 preparation process (a) 99 syzx-117 cyclopropyl-methylamino general 72 55 860 preparation process (c) 100 syzx-118 4-methoxy-benzylamino general 72 51 926 preparation process (a) 101 syzx-119 4-nitro-benzyl-amino general 72 52 941 preparation process (a) 102 syzx-120 4-chloro-benzyl-amino general 72 60 930 preparation process (a) 103 syzx-121 3-pyridinylmethylamino general 72 33 897 preparation process (a) 104 syzx-122 3-ethoxyl-propyl-amino general 72 36 892 preparation process (c) 105 syzx-125 2-methoxyethyl-amino general 72 45 864 preparation process (c) 106 syzx-126 (N-methyl-2-hydroxy-ethyl)-amino general 72 50 864 preparation process (a) 107 syzx-127 3-methoxy-benzyl-amino general 72 24 926 preparation process (c) 108 syzx-130 cyclopentyl-amino general 72 36 874 preparation process (a) 109 syzx-131 2,4-difluorobenzyl-amino general 72 44 932 preparation process(c) 110 syzx-132 6-chloro-pyridazin-3-yl-amino general 72 58 918 preparation process (a) 111 syzx-133 4-hydroxy-butylamino general 72 23 878 preparation process (c) 112 syzx-134 1-methyl-3-phenyl-propylamino general 72 26 938 preparation process (c) 113 syzx-135 3-methoxy-benzylamino general 72 55 926 preparation process (c) 114 syzx-136 piperazinyl general 72 56 875 preparation process (c) 115 syzx-137 trifluoroacetylamino general 72 20 902 preparation process (a) 116 syzx-138 2-chloro-pyridin-4-yl-amino general 72 23 917 preparation process (a) 117 syzx-139 4-formylbenzylamino general 72 45 940 preparation process (a) 118 syzx-140 propargyl-amino general 72 56 844 preparation process(a) 119 syzx-141 1-butyrate 2-amino general 72 60 892 preparation process (a) 120 syzx-142 1-butyrate 4-amino general 72 50 892 preparation process (a) 121 syzx-143 diglycol-amino general 72 45 894 preparation process (a) 122 syzx-145 2-hydroxy-1-hydroxyethyl- general 72 56 880 ethylamino preparation process (a) 123 syzx-146 3-hydroxy-propylamino general 72 57 864 preparation process (a) 124 syzx-147 n-pentyl-amino general 72 23 876 preparation process (c) 125 syzx-148 morpholin-4-yl-amino general 72 60 891 preparation process (a) 126 syzx-150 3-amino-butyrate general 72 66 892 preparation process (a) 127 syzx-151 1-hydroxymethyl-propylamino general 72 77 878 preparation process (a) 128 syzx-153 ethyl sulfate-amino general 72 25 930 preparation process 1 129 syzx-154 3,4-difluorophenylmethylamino general 72 28 932 preparation process (a) 130 syzx-155 3,5-difluorophenylmethylamino general 72 50 932 preparation process (a) 131 syzx-158 2-methoxyethylamino general 72 36 864 preparation process a 132 syzx-159 1-methyl-4- general 72 37 947 diethylaminobutylamino preparation process (a) 133 Syzx-161 4-sulphonylamino- general 72 5 989 phenylethylamino preparation process (a) 134 syzx-162 1-methyl-but-1-ene-3-yne-amino general 72 25 870 preparation process (b) 135 syzx-163 1-methyl-butyl-amino general 72 27 876 preparation process (a) 136 syzx-164 (2-pyridin-4-yl-ethylamino general 72 28 911 preparation process (a) 137 syzx-165 (5-methyl-pyrazin-2- general 72 29 912 yl-methyl)-amino preparation process (a) 138 syzx-167 cyclohexyl-methyl-amino general 72 33 902 preparation process (a) 139 syzx-168 2-fluoro-phenyl-amino general 72 63 900 preparation process (a) 140 syzx-169 3-morpholinyl-propyl-amino general 72 55 933 preparation process (b) 141 syzx-170 2-chloro-phenylmethyl-amino general 72 38 947 preparation process (b) 142 syzx-171 2-furyl-methyl-amino general 72 39 902 preparation process (a) 143 syzx-172 3-aminobenzyl-amino general 72 50 930 preparation process (a) 144 syzx-173 phenylhydrazono general 72 23 897 preparation process (b) 145 syzx-174 2-(1H-indol-3-yl)-ethylamino general 72 46 949 preparation process (a) 146 syzx-175 3-chloro-propyl-amino general 72 44 882 preparation process (c) 147 syzx-176 3,5-dimethoxyphenyl-amino general 72 43 942 preparation process (a) 148 syzx-178 5-methyl-furan-2-yl-amino general 72 50 886 preparation process (a) 149 syzx-181 4-fluoro-phenylhydrazono general 72 30 915 preparation process (b) 150 syzx-182 benzyloxy-amino general 72 21 912 preparation process (a) 151 syzx-183 p-methoxyphenyl-amino general 72 25 912 preparation process (a) 152 syzx-184 3,4-dimethylphenyl-amino general 72 20 910 preparation process (a) 153 syzx-187 diethyl-methyl-amino general 72 28 876 preparation process (a) 154 syzx-188 3-morpholinyl-propyl-amino general 72 29 933 preparation process (a) 155 syzx-190 2-pyrrolyl-ethyl-amino general 72 32 903 preparation process (b) 156 syzx-191 2-pyridin-4-yl-ethylamino general 72 33 911 preparation process (a) 157 syzx-192 2-fluorobenzyl-amino general 72 36 914 preparation process (a) 158 syzx-193 2-piperidin-4-yl-methyl-amino general 72 11 903 preparation process (a) 159 syzx-197 2-methyl-4-chloro-phenyl-amino general 72 23 930 preparation process (a) 160 syzx-198 N-methyl-butyl-amino general 72 12 876 preparation process (a) 161 Syzx-202 4,6-dichloro-pyrimidin-2-yl-amino general 72 42 952 preparation process (a) 162 Syzx-203 cycloheptylamino general 72 59 902 preparation process (a) 163 Syzx-204 morpholinyl general 72 58 876 preparation process (a) 164 Syzx-205 4,4-dimethoxy-butylamino general 72 32 922 preparation process (a) 165 Syzx-206 piperidinyl-1-amino general 72 40 889 preparation process (a) 166 Syzx-208 6-chloro-pyridin-3-yl-amino general 72 35 917 preparation process (a) 167 Syzx-209 tetrahydropyrrolyl general 72 56 860 preparation process (a) 168 Syzx-210 5-hydrosulphonyl-1H-[1,2,4] general 72 51 905 triazol-3-yl-amino preparation process (a) 169 Syzx-211 5-chloropyridinyl-2-amino general 72 55 917 preparation process (a) 170 Syzx-213 N-ethylmethylamino general 72 70 848 preparation process (a) 171 Syzx-214 diallylamino general 72 55 886 preparation process (a) 172 Syzx-215 2,2,2-trifluoroacetamido general 72 51 902 preparation process (a) 173 Syzx-218 2-chloropyridinyl-3-amino general 72 33 917 preparation process (a) 174 Syzx-219 benzamido general 72 36 910 preparation process (a) 175 Syzx-222 4,6-dimethoxypyrimidinyl- general 72 45 944 2-amino preparation process (a) 176 Syzx-223 3-bromophenylamino general 72 50 960 preparation process (a) 177 Syzx-226 5-fluoro-2-nitrophenylamino general 72 12 945 preparation process (a) 178 Syzx-227 p-iodophenylamino general 72 9 1008 preparation process (a) 179 Syzx-228 2,4-dinitrophenylamino general 72 5 972 preparation process (a) 180 Syzx-229 2,4-dimethylphenylamino general 72 6 910 preparation process (a) 181 Syzx-230 3,5-di(trifluromethyl) general 72 8 1018 phenylamino preparation process (a) 182 Syzx-231 2,4-dichlorophenylamino general 72 10 950 preparation process (a) 183 Syzx-234 5-chloro o-methylphenylamino general 72 6 930 preparation process (a) 184 Syzx-235 allopurinol general 72 5 925 preparation process (a) 185 Syzx-237 2,6-dichloropyrimidinyl-4-amino general 72 10 953 preparation process (a) 186 Syzx-238 2-methylimidazolyl general 72 11 871 preparation process (a) 187 Syzx-239 N-methyl-2-hydroxyethylamino general 72 26 864 preparation process (c)
(68) Although the present disclosure is described based on specific examples, certain changes and equivalents are obviously understandable for a person skilled in the art, which fall within the scope of the present disclosure.
(69) Table 3 shows structural formulas of some compounds in Table 1 and Table 2.
(70) TABLE-US-00003 TABLE 3 Compound Example No. Name of amine Structural formula of the compound 5 (general preparation process 3) syzx-1 n-propylamine 1 5 (general preparation process 2) syzx-2 n-butylamine
Example 188
(71) in vitro tests of susceptibility of the compounds according to the present disclosure against bacterial strains commonly used in laboratories.
(72) In accordance with the Performance Standards for Antimicrobial Disk Susceptibility Tests: Approved Standard published by the US National Committee for Clinical Laboratory Standards, the antibacterial activities of compounds prepared according to examples 5 to 187 were tested. The MICs (minimum inhibitory concentration) of the medicaments prepared according to the examples on the following bacterial strains were measured through mini broth dilution technique.
(73) 1. Bacterial Strains
(74) Staphylococcus aureus CVCC26003, Streptococcus equines CVCC556. Actinobacillus pleuropneumoniae CVCC262, Haemophilus parasuis, and Pasteurella multocida CVCC399, which were purchased from the Control Institute of Veterinary Bioproducts and Pharmaceuticals, China.
(75) 2. Test Medicaments (as Controls)
(76) Gamithromycin prepared by a process referring to that described in CN102239174A, the content thereof being 95.2%; and
(77) Tulathromycin prepared by a process referring to that described in CN1530370A, the content thereof being 96.4%.
(78) 3. Test Apparatus
(79) An SW-CJ-2FD model clean bench manufactured by Suzhou Anti Airtech Co., Ltd,
(80) a DNP-9272BS-III model electro-thermal incubator manufactured by Shanghai Xinmiao Medical Instruments Manufacturing Co., Ltd,
(81) a 6132 model nucleic acid analyser manufactured by Eppendorf Germany,
(82) ABC-265 model double-range electronic scales manufactured by METTLER TOLEDO,
(83) MBA of batch No. 20120921 manufactured by Qingdao Hope Bio-Technology Co., Ltd,
(84) MHB of batch No. 20120229 manufactured by Qingdao Hope Bio-Technology Co., Ltd,
(85) new-born calf serum of batch No. 20120824 manufactured by Weikesheng Biotech Co., Ltd,
(86) plastic culture dishes manufactured by Yangzou Guanghua Medical Instrument Factory,
(87) a 96-channel pipetting workstation manufactured by METTLER TOLEDO, and
(88) a single-channel pipettor and a multi-channel pipettor manufactured by Eppendorf Germany.
(89) 4. Test Process
(90) 4.1 Preparation of Culture Medium
(91) 4.1.1 Culture Medium for Staphylococcus aureus CVCC26003
(92) Liquid culture medium: CAMHB. To MHB (prepared according to the specification of the final product) were added CaCl.sub.2 and MgCl.sub.2, so that a final concentration of Ca.sup.2+ in the culture medium was 20 mg/L and that of Mg.sup.2+ therein was 10 mg/L.
(93) Solid culture medium: NINA prepared according to the specification of the final product.
(94) 4.1.2 Culture Media for the Rest Four Bacterial Strains.
(95) Liquid culture medium: CAMHB with 10% calf serum and 0.005% NAD+.
(96) Solid culture medium: MHA with 10% calf serum and 0.005% NAD+.
(97) 4.2 Strain Revival
(98) The strains were taken out of a refrigerator at −20° C. to be revived, and were spreaded by streaking on the solid culture medium with an inoculating loop. The inoculated culture medium was cultured at 35° C. in a constant temperature incubator for 20 h. Monoclonal antibodies were selected from a well-grown culture plate and streaked on the solid culture medium. The inoculated culture medium was cultured at 35° C. in the constant temperature incubator for 20 h.
(99) 4.3 Dilution of the Compounds
(100) The compounds of examples 5 to 80 and the compounds of examples 84 to 187 each were prepared with 100% DMSO into a solution having a concentration of 8.8 mg/mL. A 96-well plate was used, and 100 μl of DMSO was added into each of wells 2 to 11, and 200 μl of ready-prepared medicament solution was added into the 1.sup.st well, 100 μl of the medicament solution was extracted from the 1.sup.st well and added into the 2.sup.nd well. Double dilution was performed until the 11.sup.th well, thereby forming 11 gradients. In this case, compound of parent plate was prepared. 3 μl of double diluted medicament solution was extracted with a 12-channel pipettor and added into wells 1-11 of a new disposable 96-well culture plate. The 12.sup.th well thereof is a control well. For each medicament, there are two adjacent rows which are parallel. The transferred compound plate was reserved for later use.
(101) 4.4 Preparation of Bacterial Liquid
(102) Representative bacterial colony was selected from the plate prepared in the above section 4.2 and added into normal saline, an OD.sub.600 value being adjusted to a range of 0.14-0.15. The dilution ratio was recorded, and the bacterial liquid for the tests was diluted according to the recorded dilution ratio. Subsequently, the bacterial suspension and the liquid culture medium were diluted in the proportion of 1:200. The diluted solution was reserved for later use.
(103) 4.5 Test Operations
(104) The medicaments and bacterial liquid were added into the compound plates from section 4.3, two rows for each medicament, and one plate for one bacterium. The test results are as shown in Table 5. The MICs of partial compounds failed to be determined in one test, thus further tests were performed under new diluted concentration, so as to further determine the MICs of the compounds.
(105) TABLE-US-00004 TABLE 4 Schematic diagram of additives in the 96-well plate cmd 1 2 3 4 5 6 7 8 9 10 11 12 A ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ .square-solid. B ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ .square-solid. C ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ .square-solid. D ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ .square-solid. E ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ .box-tangle-solidup. F ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ .box-tangle-solidup. G ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ .box-tangle-solidup. H ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ ∘ .box-tangle-solidup. ∘ represents 3 μl compound + 100 μl bacterial liquid; .square-solid. represents positive control, the well contains 100 μl bacterial liquid; .box-tangle-solidup. represents negative control, the well contains 100 μl culture medium.
(106) TABLE-US-00005 TABLE 5 MIC values (ug/mi) of the compounds Actinobacillus Staphylococcus Pasteurella Streptococcus pleuropneumoniae aureus multocida equines Haemophilus Example Compound No. CVCC262 CVCC26003 CVCC399 CVCC556 parasuis Comparison Gamithromycin 0.25 0.25 0.25 0.5 0.25 example 1 0.25 0.25 0.25 0.5 0.25 Comparison Tulathromycin 0.25 0.25 0.25 0.25 0.25 example 2 0.25 0.25 0.25 0.25 0.25 5 general syzx-6 0.125 0.125 0.125 0.125 0.125 preparation process 1 5 general syzx-1 0.125 0.125 1 0.125 0.125 preparation process 3 5 general syzx-2 1 4 2 2 2 preparation process 2 6 syzx-3 1 0.5 0.125 0.125 0.125 7 syzx-4 32 1 1 ≦0.25 0.5 8 syzx-5 16 0.5 0.5 ≦0.25 0.5 9 syzx-7 2 ≦0.25 0.25 ≦0.25 ≦0.25 10 syzx-8 0.5 ≦0.25 0.25 ≦0.25 ≦0.25 11 syzx-9 0.5 ≦0.25 ≦0.25 ≦0.25 ≦0.25 12 syzx-10 0.5 0.5 ≦0.25 0.5 1 13 syzx-11 0.5 ≦0.25 ≦0.25 ≦0.25 0.5 14 syzx-12 ≦0.25 ≦0.25 ≦0.25 ≦0.25 ≦0.25 15 syzx-14 0.5 ≦0.25 0.25 ≦0.25 ≦0.25 16 syzx-15 0.5 ≦0.25 ≦0.25 ≦0.25 ≦0.25 17 syzx-17 2 ≦0.25 0.25 ≦0.25 ≦0.25 18 syzx-18 16 0.5 2 — 0.5 19 syzx-20 2 ≦0.25 0.25 ≦0.25 ≦0.25 20 syzx-21 32 0.5 ≦0.25 ≦0.25 ≦0.25 21 syzx-22 8 1 0.5 0.5 ≦0.25 22 syzx-24 0.25 0.5 0.25 0.25 0.5 23 syzx-25 16 ≦0.25 ≦0.25 ≦0.25 ≦0.25 24 syzx-27 4 0.5 0.5 ≦0.25 ≦0.25 25 syzx-29 16 1 2 0.5 0.5 26 syzx-30 0.5 ≦0.25 ≦0.25 ≦0.25 0.5 27 syzx-31 1 ≦0.25 ≦0.25 ≦0.25 ≦0.25 28 syzx-32 0.5 0.5 1 0.25 0.25 29 syzx-34 8 8 16 0.5 4 30 syzx-35 0.25 0.25 1 0.5 0.25 31 syzx-37 32 0.5 1 ≦0.25 0.5 32 syzx-38 32 1 0.5 0.5 0.5 33 syzx-39 0.25 0.25 0.5 0.5 0.25 34 syzx-40 16 0.5 1 0.5 0.5 35 syzx-41 1 2 4 0.5 1 36 syzx-42 1 2 2 1 1 37 syzx-46 32 1 4 2 ≦0.25 38 syzx-47 0.5 1 ≦0.25 ≦0.25 0.5 39 syzx-48 16 0.5 1 0.5 ≦0.25 40 syzx-50 0.5 1 1 1 0.5 41 syzx-51 1 0.5 0.5 1 2 42 syzx-52 32 0.5 0.5 0.5 ≦0.25 43 syzx-56 0.25 0.5 1 0.25 0.5 44 syzx-57 ≦0.25 ≦0.25 32 4 ≦0.25 45 syzx-58 16 ≦0.25 ≦0.25 ≦0.25 ≦0.25 46 syzx-59 32 1 2 2 0.5 47 syzx-60 8 1 2 2 1 48 syzx-61 32 ≦0.25 1 0.5 ≦0.25 49 syzx-62 8 0.5 0.5 ≦0.25 ≦0.25 50 syzx-63 0.5 0.5 ≦0.25 ≦0.25 ≦0.25 51 syzx-64 0.5 ≦0.25 0.25 0.25 ≦0.25 52 syzx-65 32 ≦0.25 1 ≦0.25 ≦0.25 53 syzx-66 8 1 ≦0.25 0.5 ≦0.25 54 syzx-67 0.5 ≦0.25 ≦0.25 ≦0.25 ≦0.25 55 syzx-68 8 ≦0.25 8 ≦0.25 ≦0.25 56 syzx-69 1 1 0.5 0.5 1 57 syzx-71 16 8 ≦0.25 ≦0.25 8 58 syzx-72 16 1 1 ≦0.25 0.25 59 syzx-73 1 1 2 0.5 1 60 syzx-74 1 1 1 0.5 2 61 syzx-75 64 4 8 4 4 62 syzx-76 64 2 4 2 1 63 syzx-77 16 0.25 0.5 0.5 0.25 64 syzx-78 2 0.25 0.5 0.25 0.25 65 syzx-81 2 ≦0.25 0.25 ≦0.25 ≦0.25 66 syzx-82 16 0.5 1 ≦0.25 ≦0.25 67 syzx-83 2 0.5 0.25 0.5 0.25 68 syzx-84 2 ≦0.25 0.25 ≦0.25 ≦0.25 69 syzx-86 2 ≦0.25 0.25 ≦0.25 ≦0.25 70 syzx-90 0.5 2 2 0.5 2 71 syzx-91 2 4 2 1 2 72 syzx-92 0.5 1 2 0.25 0.5 73 syzx-93 16 32 64 1 8 74 syzx-94 0.5 1 2 0.25 0.5 75 syzx-95 2 2 2 0.5 2 76 syzx-96 0.5 1 2 0.25 0.5 77 syzx-97 128 1 4 0.5 1 78 syzx-98 0.5 1 2 0.25 0.5 79 syzx-99 128 4 8 2 4 80 syzx-100 1 1 0.5 2 2 84 general syzx-217 0.25 0.25 0.5 0.25 0.25 preparation process (a) 84 general syzx-102 0.25 0.25 0.5 0.25 0.25 preparation process (b) 84 general syzx-101 0.125 0.125 0.125 0.125 0.125 preparation process (c) 85 syzx-103 0,25 0.25 1 0.25 0.25 86 syzx-104 0.25 0.25 1 0.25 0.25 87 sync-105 1 0.25 2 0.25 0.5 88 syzx-106 0.5 2 2 0.25 0.5 89 syzx-107 0.25 0.25 1 1 0.25 90 syzx-108 0.25 0.25 1 0.25 0.25 91 syzx-109 0.25 0.25 1 0.25 0.25 92 syzx-110 0.25 0.25 0.5 0.25 0.25 93 syzx-111 0.25 0.25 0.5 0.25 0.25 94 syzx-112 0.25 0.25 0.5 0.25 0.25 95 syzx-113 0.25 0.25 1 0.25 0.25 96 syzx-1 14 0.25 0.25 0.25 0.25 0.25 97 syzx-115 0.25 0.25 0.5 0.25 0.25 98 syzx-116 0.25 0.25 1 0.25 0.25 99 syzx-117 0.25 0.25 0.5 0.25 0.25 100 syzx-118 0.25 0.25 0.25 0.25 0.25 101 syzx-119 0.25 0.25 1 0.25 0.25 102 syzx-120 0.25 0.25 0.5 0.25 0.25 103 syzx-121 0.25 0.25 0.5 0.5 0.25 104 syzx-122 1 1 1 0.25 0.5 105 syzx-125 0.5 1 2 0.25 0.5 106 syzx-126 4 4 2 0.5 4 107 syzx-127 1 4 8 0.25 1 108 syzx-130 0.5 0.25 0.5 0.25 8 109 syzx-131 0.25 0.25 0.5 0.25 0.25 110 syzx-132 0.5 1 2 0.25 0.5 111 syzx-133 1 1 2 0.5 0.5 112 syzx-134 0.25 0.25 0.5 0.25 0.25 113 syzx-135 1 1 2 0.5 0.5 114 syzx-136 0.5 0.25 0.5 0.25 0.25 115 syzx-137 0.5 0.5 2 1 0.5 116 syzx-138 2 2 8 0.5 2 117 syzx-139 0.25 0.25 0.5 0.25 0.25 118 syzx-140 0.25 0.25 1 0.25 0.25 119 syzx-141 0.25 0.25 1 0.25 0.25 120 syzx-142 0.25 0.25 0.5 0.5 0.25 121 syzx-143 0.25 0.25 1 0.25 0.25 122 syzx-145 64 1 2 0.5 0.5 123 syzx-146 0.25 0.25 0.5 0.25 0.25 124 syzx-147 0.25 0.25 0.5 0.25 0.25 125 syzx-148 0.5 0.25 1 0.25 0.5 126 syzx-150 1 0.5 2 0.25 0.5 127 syzx-151 0.25 0.25 0.5 0.25 0.25 128 syzx-153 0.25 0.25 1 0.25 0.25 129 syzx-154 0.25 0.25 0.5 0.5 0.25 130 syzx-155 0.25 0.25 0.5 0.25 0.25 131 syzx-158 4 2 2 0.25 4 132 syzx-159 0.25 0.5 0.5 0.25 0.25 133 syzx-161 0.25 0.25 0.5 0.25 0.25 134 syzx-162 0.25 0.25 1 0.25 0.25 135 syzx-163 0.25 0.25 1 0.25 0.25 136 syzx-164 0.25 0.25 2 0.5 0.25 137 syzx-165 0.25 0.25 1 0.25 0.25 138 syzx-167 2 2 4 0.25 2 139 syzx-168 0.25 0.25 1 0.25 0.25 140 syzx-169 0.25 0.25 0.5 0.25 0.25 141 syzx-170 0.25 0.25 0.5 0.25 0.25 142 syzx-171 0.25 0.25 0.5 0.25 0.25 143 syzx-172 0.25 0.25 0.25 0.25 0.25 144 syzx-173 1 2 4 0.25 1 145 syzx-174 4 4 8 0.25 2 146 syzx-175 0.25 0.5 0.5 0.5 0.25 147 syzx-176 0.25 0.5 2 0.25 0.5 148 syzx-178 2 4 4 0.5 4 149 syzx-181 0.5 0.25 1 0.25 0.25 150 syzx-182 0.5 1 4 0.5 0.5 151 syzx-183 0.5 0.25 2 0.25 0.25 152 syzx-184 2 2 4 0.5 2 153 syzx-187 0.5 1 2 0.25 0.25 154 syzx-188 0.5 0.5 1 0.25 0.5 155 syzx-190 0.5 0.25 1 0.25 0.25 156 syzx-191 0.5 1 4 0.5 0.5 157 syzx-192 4 4 4 0.5 4 158 syzx-193 4 4 2 0.25 2 159 syzx-197 0.5 0.25 1 0.25 0.25 160 syzx-198 0.5 1 4 0.5 0.5 161 syzx-202 2 2 2 0.25 4 162 syzx-203 1 1 0.25 1 0.5 163 syzx-204 4 4 4 0.5 4 164 syzx-205 4 4 4 0.5 4 165 syzx-206 0.25 0.5 0.5 0.25 0.25 166 syzx-208 4 4 4 0.5 4 167 syzx-209 0.25 0.25 0.25 0.25 0.25 168 syzx-210 0.5 2 4 0.25 0.5 169 syzx-211 4 2 8 0.5 4 170 syzx-213 0.25 0.25 0.25 0.25 0.25 171 syzx-214 2 4 8 0.25 2 172 syzx-215 0.25 0.25 0.5 0.25 0.25 173 syzx-218 4 2 8 0.25 4 174 syzx-219 4 2 8 0.5 4 175 syzx-222 2 4 8 0.25 2 176 syzx-223 0.25 0.25 0.5 0.25 0.25 177 syzx-226 4 2 8 0.25 4 178 syzx-227 4 2 8 0.5 4 179 syzx-228 1 2 2 0.25 1 180 syzx-229 4 4 16 0.25 4 181 syzx-230 2 4 8 0.25 2 182 syzx-231 0.25 0.25 0.5 0.25 0.25 183 syzx-234 4 2 8 0.25 4 184 syzx-235 4 2 8 0.5 4 185 syzx-237 4 2 8 0.25 4 186 syzx-238 1 1 4 0.25 1 187 syzx-239 4 4 8 0.25 2
(107) The in vivo antibacterial activity was measured by conventional animal experiment process well known to the person skilled in the art, and the test animals were BALB/c mice.
(108) Test materials: standard strain of Streptococcus pneumoniae, under Accession Number CMCC 31203, purchased from the National Center for Medical Culture Collections; and Tulathromycin prepared by a process referring to that described in CN1530370A.
(109) Test medicaments: compounds (syzx-1, syzx-2, syzx-6) prepared according to the three general preparation processes of example 5, and compounds prepared in example 6 (syzx-3), example 8 (syzx-5), example 12 (syzx-10), example 13 (syzx-11), example 14 (syzx-12), example 15 (syzx-14), example 16 (syzx-15), example 17 (syzx-17), example 18 (syzx-101 prepared according to the general preparation process (c)), example 26 (syzx-30), example 30 (syzx-35), example 38 (syzx-47), example 45 (syzx-58), example 52 (syzx-65), example 53 (syzx-66), example 54 (syzx-67), and example 170 (syzx-213). In the meantime, Tulathromycin was used for comparison. The compounds each were dissolved in absolute ethyl alcohol. The mixture was supplemented until the volume reached a required level, and sufficiently mixed to afford solution with a concentration of 1 mg/mL.
(110) Test Process
(111) Mice each weighed in a range of 18-20 g were selected from 350 mice of 5 to 6 weeks and divided into different cages, with 10 mice in each cage. The mice were breeded for 72 h, and entered into tests if observations turned out normal. Before the tests started, Streptococcus pneumoniae was cultured in a blood plate for 24 h, and then added into a sterility broth containing serum for shaking culture (120 r/min) at 37° C., for 20 h, so that an enriched culture can be conducted. Viable count was performed. The bacteria were diluted to 5×10.sup.8 cfu/mL, with sterilized saline water. The mice each were infected with 0.5 ml of the bacterial liquid by intraperitoneal injection. The day after the infection, compounds prepared according to the above examples and the medicament for comparison were administered to the mice by subcutaneous injection via neck at a dose of 5 mg per kg of body weight for 3 consecutive days. In the meantime, control groups, such as blank control groups and medicament control groups, were arranged. The blank control groups were not administered with any medicament after being infected. The mice in the medicament control groups each were injected with Tulathromycin at a dose of 10 mg per kg of body weight after being infected. After infection and administration, the mice were observed every day, and the death count in each group was recorded until the seventh day, Table 6 shows the influence of the compounds shown in the general formula of the present disclosure on the survival rate of mice infected by Streptococcus pneumoniae.
(112) 1. Test Results
(113) TABLE-US-00006 TABLE 6 Results of in vivo antibacterial tests of certain compounds Test Animal Test Animal Test Animal medicament survival rate medicament survival rate medicament survival rate Blank control group 100% (10/10) syzx-5 70% (7/10) syzx-101 90% (9/10) Tulathromycin control group 70% (7/10) syzx-10 90% (9/10) syzx-30 80% (8/10) Negative control group 30% (3/10) syzx-11 70% (8/10) syzx-35 70% (7/10) syzx-1 80% (8/10) syzx-12 70% (8/10) syzx-47 90% (9/10) syzx-2 80% (8/10) syzx-14 70% (8/10) syzx-58 80% (8/10) syzx-6 80% (8/10) syzx-15 70% (8/10) syzx-65 90% (9/10) syzx-3 70% (8/10) syzx-17 70% (8/10) syzx-66 80% (8/10) syzx-67 70% (8/10) syzx-213 90% (9/10)
2. Results
(114) As shown in Table 6, administration of the compounds shown by the formula of the present disclosure at a dose of 5 mg per kg of body weight can reduce deaths of the mice due to infection by Streptococcus pneumoniae. As compared with the control groups, the compounds of the present disclosure can significantly improve the survival rate of the infected mice, and have manifested evident in vivo antibacterial activity.
Example 189: Acute Toxicity Test of Compound Syzx-24
(115) 1. Test Materials
(116) 1.1 Test Medicaments
(117) Name of the medicaments: compound No. Syzx-24, and tulathromycin having a content of 96.4% prepared by the process referring to that described in Chinese patent CN1530370A.
(118) 1.2 Test Animals
(119) Balb/c mice, each weighed 16.0-19.0 g, were selected. The mice were half male and half female. Before the tests started, the mice were fed in different cages and observed for 3 days. 12 (half male and half female) healthy and brisk mice were selected for tests. The mice were prohibited from feeding, but not water, for 14 h (from 6 pm to 8 am the next morning) before administration.
(120) 1.3 Test Articles
(121) A mice gavage device, a 1 ml disposable syringe, a 50 mL beaker and a 100 mL beaker, individual ventilated cages (IVC), ophthalmologic operating scissors, tweezers, a medical tray, 0.5% basic fuchsin dye liquor, medical rubber gloves, an analytical balance, and electronic scales.
(122) 2. Test Process
(123) 2.1 Test Animals Grouping
(124) Three groups were arranged for the tests, each having four mice (half male and half female). The three groups were respectively tulathromycin group, Syzx-24 group, and solvent control group. The mice were marked with 0.5% basic fuchsin dye liquor. The marked parts of mice in the tulathromycin group were respectively left upper shoulders (female), left ribs (female), right upper shoulders (male) and right ribs (male). The marked parts of mice in the Syzx-24 group were respectively left hinder limbs (female), necks (female), right hinder limbs (male), and necks (male). The mice in the solvent control group were not marked.
(125) Mice in the administered group were administered at a dose of 2000 mg/kg.Math.d-1 (it was reported that the minimum lethal dose of tulathromycin in orally intoxicated mice is higher than 2000 mg/kg.Math.d-1).
(126) 2.2 Preparation of Medicament
(127) 0.2 g of sodium carboxymethylcellulose was added into 40 ml of purified water and dissolved therein under stirring at 80° C., thereby forming 0.5% sodium carboxymethylcellulose solution as solvent for preparing the medicament. The test medicament was added into the 0.5% sodium carboxymethylcellulose solution according to the dosage of administration, which gave 170 mg/ml suspension. 0.5% sodium carboxymethylcellulose solution of the same volume was added into the suspension and screened through a 100 mesh, whereby a suspension having a concentration of 85 mg/ml was prepared.
(128) 2.3 Administration Process
(129) The medicaments were formulated into 85 mg/ml suspensions and administered by gastric perfusion once at a dose of 2000 Ing/kg.Math.d-1. In other words, the medicament was administered to each mouse at a dose of 0.47 ml per 20 g of body weight. Specific grouping and administration are shown in Table 7.
(130) TABLE-US-00007 TABLE 7 Grouping of test animals Number of Group animals (n) Dosage Tulathromycin 4 85 mg/ml tulathromycin group suspension, at a dose of 0.47 ml/20 g by gastric perfusion Syzx-24 group 4 85 mg/ml Syzx-24 suspension, at a dose of 0.47 ml/20 g by gastric perfusion Solvent control 4 0.5% sodium group carboxymethylcellulose solution, at a dose of 0.47 ml/20 g by gastric perfusion
(131) After administration of the medicaments, toxic symptoms and deaths of the animals within 6 h after administration were observed and recorded. The animals were continuously observed for 30 min after administration, and observed once from 1 h to 4 h after administration. Subsequently, the animals were observed once a day until recovery. Toxic symptoms and deaths were recorded, and dead animals were dissected without delay, so that organs, such as heart, liver, spleen, lungs, kidneys, stomach and intestines, can be observed.
(132) 3. Test Results and Analysis
(133) 3.1 Death rates after 6 h upon infection were compared. Table 8 shows the death status and death rates of the groups.
(134) TABLE-US-00008 TABLE 8 Results of deaths of animals Number of dead animals/total Group number of animals Death rate Tulathromycin group 3/4 (2 female and 1 male) 75% Syzx-24 group 0/4 0% Solvent control group 0/4 0%
(135) Acute toxicity tests indicate that toxicities of the compounds according to the present disclosure were obviously lower than that of tulathromycin.
Example 190: Acute Toxicity of Orally Administered Compounds of the Present Disclosure
(136) 1. Test Materials
(137) 1.1 Appliances and Materials
(138) 1 ml disposable plastic sterile syringe, small operating scissors, disposable rubber gloves, a WKZ-4 model pulverizer, a mortar, a measuring cylinder, a beaker, TIANYIJA2003 electronic scales, a medical tray, carbazotic acid dye, medical rubber gloves, a mice gavage device (No. 12), sodium carboxymethylcellulose (Tianjin Kemiou Chemical Reagent Co., Ltd), and the like.
(139) 1.2 Test Medicaments
(140) Compounds (syzx-, syzx-2, syzx-6) prepared through the three general preparation processes according to example 5, compound of example 6 (syzx-3), compound of example 8 (syzx-5), compound of example 12 (syzx-10), compound of example 13 (syzx-11), compound of example 14 (syzx-12), compound of example 15 (syzx-14), compound of example 16 (syzx-15), compound of example 17 (syzx-17), compound of example 45 (syzx-58), compound (syzx-101) prepared in general preparation process (c) of example 84, and compound of example 170 (syzx-213).
(141) Solvent for the medicaments: 0.2% sodium carboxymethylcellulose solution.
(142) 1.3 Test Animals
(143) SPF level Konmin mice purchased from Henan Provicial Laboratory Animal Center, license number being SCXK ()2010-0002. The mice comprise half male and half female, each weighed 18-22 g. The female mice and the male mice are separated and fed in individual ventilated cages. Rearing condition of the mice include sterilized complete teed, free choice feeding and drinking, room temperature in a range of 10-24° C., and relative humidity in a range of 40-60%.
(144) 2. Test Process
(145) 2.1 Preparation of Medicaments
(146) 2.1.1 Preparation of a 0.2% Sodium Carboxymethylcellulose Solution
(147) 0.2 g of sodium carboxymethylcellulose was dissolved in 100 ml of purified water, placed overnight for swelling, and then stirred uniformly for later use.
(148) 2.1.2 The compounds of some examples were powdered using a mortar, and sifted through mesh (100-mesh) for later use.
(149) 2.2 Test Process
(150) Trial tests were performed repeatedly, so that an interval range between LD.sub.0 and LD.sub.100 can be determined and divided into groups, thereby grouping and determining the difference between the groups.
(151) In official tests, 60 mice each weighed in a range of 18-22 g were selected for each medicament. Male mice and female mice were separated and respectively weighed. Mice of the same weight range (for example a range of 18.0-18.9 g or a range of 19.0-19.9 g) were marked and fed in the same cage. The male mice and the female mice were respectively divided into 6 groups at random based on weight, so that mice of different gender and different weight can be evenly distributed in each group, and each group included 10 mice, in which half were male and half were female. Before the mice were infected, the medicament was prepared with 0.2% sodium carboxymethylcellulose solution based on a predetermined concentration. The mice each were gavaged once at a dose of 0.2 ml per 10 g of body weight. The mice were prohibited from feeding, but not from water, within 12-16 h before gavaging. The general health conditions, toxic symptoms, and the death process of the mice were minutely observed and recorded right after the gavaging. The dead mice were roughly dissected without delay, and continuously observed for 7 days.
(152) Per os LD.sub.50 and 95% fiducial limit (FL) were calculated according to improved karber method. The calculation equations are as follows:
(153)
The 95% fiducial limit: FL=lg.sup.−1(lgLD.sub.50±1.96×S.sub.x50)
(154) In the above equations, X.sub.m—logarithmic value of the maximum dosage,
(155) i—logarithm of ratio between two adjacent dosages,
(156) p—death rate at each dosage (represented by decimals),
(157) q—survival rate at each dosage, q=−p,
(158) Σp—sum of death rates of the groups,
(159) n—number of animals in each group,
(160) P.sub.m—maximum death rate,
(161) P.sub.n—minimum death rate,
(162) S.sub.x50—standard error of lgLD.sub.50.
(163) 3. Test Results
(164) TABLE-US-00009 TABLE 9 Results of acute oral toxicity test on partial compounds of the present disclosure LD.sub.50 95% fiducial LD.sub.50 95% fiducial Compound (mg/kg) limit (mg/kg) Compound (mg/kg) limit (mg/kg) syzx-1 2584.8 2156.3-3098.4 syzx-11 4196.0 3535.6-4979.8 syzx-2 2547.8 2231.2-2909.2 syzx-12 4313.5 3753.3-4957.4 syzx-6 2611.7 2229.0-3060.0 syzx-14 2589.5 2099.5-3139.8 syzx-3 2487.1 2162.2-2860.9 syzx-15 2662.0 2243.0-3159.3 syzx-5 2734.4 2219.4-3368.8 syzx-17 2673.5 2322.3-3077.7 syzx-10 2809.6 2291.0-3445.7 syzx-58 3549.4 2990.7-4212.4 syzx-213 2794.8 2375.7-3287.9 syzx-101 3760.6 2334.8-3263.9 Tulathromycin 2379.2 1608.1-2818.7 Gamithromycin 2165.2 1793.8-2613.6
(165) According to the LD.sub.50 dosage grading stardards for acute toxicity of chemicals in the Guidelines for Acute Toxicity of Veterinary Drugs, a drug, the LD.sub.50, of which is in a range of 501-5000 mg/kg body weight, is assessed as low toxic. Obviously, the compounds prepared according to the present disclosure have lower toxicity. It is known to the person skilled in the art that the higher the value of LD.sub.50, the lower the toxicity.
(166) The above embodiments are described only for better understanding, rather than restricting, the present disclosure. Various modifications and variants to the present disclosure may be made by anyone skilled in the art, without departing from the scope and spirit of the present disclosure. The scope of the present disclosure should still be subjected to the scope defined in the claims.