NZ625402B2 - Antibacterial tylosin derivatives and methods for their preparation - Google Patents

Antibacterial tylosin derivatives and methods for their preparation Download PDF

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Publication number
NZ625402B2
NZ625402B2 NZ625402A NZ62540212A NZ625402B2 NZ 625402 B2 NZ625402 B2 NZ 625402B2 NZ 625402 A NZ625402 A NZ 625402A NZ 62540212 A NZ62540212 A NZ 62540212A NZ 625402 B2 NZ625402 B2 NZ 625402B2
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New Zealand
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compound
aryl
spp
substituted
formula
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NZ625402A
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NZ625402A (en
Inventor
Sugawara Akihiro
Julia Charlotte Dorner
Robrecht Froyman
Shiomi Kazuro
Gerd Kleefeld
Carolin Ludwig
Omura Satoshi
Hirose Tomoyasu
Sunazuka Toshiaki
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Bayer Intellectual Property Gmbh
The Kitasato Institute
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Priority claimed from PCT/EP2012/073277 external-priority patent/WO2013076169A1/en
Publication of NZ625402A publication Critical patent/NZ625402A/en
Publication of NZ625402B2 publication Critical patent/NZ625402B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Abstract

The present disclosure relates to new macrolide derivatives, in particular new tylosin derivatives of the formula (I); a pharmaceutical or veterinary composition comprising the derivatives; a method for preparation thereof; a method for treating and/or preventing bacterial infections in an animal, wherein the method comprises administering the derivatives or the composition; and a use of the derivatives for the manufacture of medicaments for treating and/or preventing bacterial infections in an animal. One example of the marcolide derivative is 20-(4-phenyl-1H-1,2,3-triazol-1-yl)-20-deoxo-23-(4-butyl-1H-1,2,3-triazol-1-yl)-23-deoxy-5-O-mycaminosyltylonolide. herein the method comprises administering the derivatives or the composition; and a use of the derivatives for the manufacture of medicaments for treating and/or preventing bacterial infections in an animal. One example of the marcolide derivative is 20-(4-phenyl-1H-1,2,3-triazol-1-yl)-20-deoxo-23-(4-butyl-1H-1,2,3-triazol-1-yl)-23-deoxy-5-O-mycaminosyltylonolide.

Description

ANTIBACTERIAL TYLOSIN DERIVATIVES AND METHODS FOR THEIR PREPARATION BACKGROUND OF THE ION The present invention relates to new ide derivatives, in particular new tylosin derivatives; a pharmaceutical or veterinary composition comprising any of the derivatives; a method for ation thereof; a method for treating and/or preventing ial infections in an animal, n the method comprises administering any of the derivatives or the composition; and a use of the tives for the manufacture of medicaments for treating and/or preventing bacterial infections in an animal.
Macrolides in generally have a chemical structure of 12-, 14- or l6-membered macrocyclic group (aglycone) substituted with l to 3 substituents such as neutral sugars, deoxy sugars or amino sugars. Macrolides have a wide spectrum of antibacterial activities against for e Pneumococcus spp, Streptococcus spp, Hemophilus influenzae, lococcus aureus, Actinobacillus spp, Pasteurella spp and atypical pathogen such as Mycoplasma, Legionella or Chlamydia that is resistant to other drugs. Consequently, macrolides have been used for the treatment of among others a variety of respiratory tract infections. A variety of macrolides have been discovered or synthesized until now, W0 2013/076169 _ 2 _ typically including tylosin represented by the following formula: mycaminose /CHO E \ . N— H\oZ\g\o OH 1 fiOH ""'OH O mycarose mycinose Tylosin has been used for the treatment of infections of Gram-positive bacterium and asma in farm animals.
In order to further expand the spectrum of tylosin and to improve its oral bioavailability, a number of tylosin derivatives have been tested. Examples of such tylosin derivatives lly include among others tilmicosin and tulathromycin (tulathromycin belongs to a ent class of compounds) represented by the following formulae, respectively: Tulathromycin H W0 2013/076169 _ 3 _ Tilmicosin and tulathromycin are useful for the treatment of pasteurellosis caused by Gram negative bacillus such as Pasteurella or Mannheimia. They are the most commonly used and important antibiotics in farm animals.
However, new antibiotics are inextricably associated with the emergence of resistant bacteria. Accordingly, there is still a need to e new otics.
[0005] The backgrounds may be reflected in the following Patent and Non-patent nces: Patent References: WO 2009-064953 WO 2005-118610 W0 2003-089447 WO 2003-089446 WO 2003-0393558 WO 2007-071370 WO 2005-118610 W0 2003-043642 WO 393558 WO 1996-009312 EP 606747 EP 240264 EP 124216 Non-patent References: W0 2013/076169 _ 4 _ \Voodward,R”13.AngeMA Chent 1957,69,50-58 Brockmann,I{g HenkeL “fl dssenshdfnni 1950,37,138.
Pinnert-Sindico, S.; Ninet, L.; Preud’honnne, J.; Cosar, C.
Rhone-Pouienc Research Labs” Pafis,i4nfibi0fics Ann. 1955, 2,1954-1955.
Iiansen, J.I;g Ippolfio, J A”; Ban, N]; Nissen, Pg hdoore, P. fiz,1C,A.Ahflecuhn‘CeU.2002,10,117.
Ducrubg A ;Pascard,CL; Nakagawa, A.;(hnura,S.tL Chem.
S00 Chent C0nnnun.1976,947. hdorin, R4 B.; Gornian, hi; l, R. L. Tetrahedron Lett 1970,11, 4737-4740.
Omura, S.; Nakagawa, A.; Neszmelyi, A.; Gero, S. D.; Sepuhne, A” Ni; Piflou, F; Lukacs, G. J.14m. Chem. Soc 1975, 97, 4001-4009. h4cGuire,J.h[ Antflfiot Chemothen I,320-327. o, h4.; KirsL 11. A”; Ornura, S. J. Antibiot. 1989, 42, 1253-1267.
Shokichi Tfiakajinuu Resistant to the drugs - fight against infections-,h4aruzen,'Tokyo (2000) Cattle death loss: the al Statistics Service (NASS).
United State department ongriculture, May, 5 (2006) Rogert A. Smith: Impact of disease on feedlot performance: A reVieW LL Anint Sci 1998, 76,276-274.
Maina, H.; John, D. B.; Ben A. FEMS Microbiol. Lett. 2006, 256, 1-10.
Yasuhnno Arashhna: NfisunderMending of"pasteurersi§'in Japan. _ 5 _ Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40, 2004-2021. tseV, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.
B. Angew. Chem., Int. Ed. 2002, 41, 2596-2599. a) Huisgen, R. Pure Apple Chem. 1989, 61, 613-628. b) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984, I, l-l76. a) RostovtseV, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K.
B. Angew. Chem., Int. Ed. 2002, 41, 2596-2599.
Macrolide antibiotics. Chemistry, biology, and practice.
Edited by Oniura, S. ical Press, Inc., Orlando, FL 32887. 1984.
, T.; Sunazuka, T.; Noguchi, Y.; Yamaguchi, Y.; Hanaki, H.; Sharpless, K. B.; Oniura, S. Heterocycles, 2006, 69, 55-61.
Kirst, H. A.; Toth, J. E.; Debono, M.; Willard, K. E.; Truedell, B. A.; Ott, J. L.; r, F. T.; Felty-Duckworth, A. M.; Pekarek, R. S. J. Med. Chem. 1988, 31, 1631-1641.
Mereu, A.; Moriggi, E.; Napoletano, M.; Regazzoni, C.; Manfredini, S.; Mercurio, T. P.; Pellacini, F. Bioorg. Med.
Chem. Lett. 2006, 16, 5801-5804.
RostovtseV, V. V.; Green, L. G.; Forkin, V. V.; Sharpless, K.
B. Angew. Chem., Int. Ed. 2002, 41, 2597.
Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org.
Lett. 2004, 6, 855.
Noboru Kagei: Journal of preventive medicine, 1985, 199, 32- W0 2013/076169 _ 6 _ Yoshio Ueno, Satoshi Omura: "Microbial Chemistry, 2nd. edition", Nankodo (1986).
Tsuyoshi Yamada: "Fight between bacterium and human", Ishiyaku hers, Inc. i Omura, Ruiko Oiwa: Chemistry and Biology, 1982, 20, -12.
Cassinelli, G.; Cotta, G.; D’Amico, G.; Della, B. C.; Grein, A.; Mazzoleni, R.; Ricciardi, M. L.; elli, R. Arch.
Mikrobiol. 1970, 70,197-210.
Bruna, D. C.; Ricciardi, M. L.; ippo, A. Antimicrob.
Agents. Chemother. 1973, 3, 708-710.
Hamill, R. L.; Hoehn, M. M. J. Antibiot. 1964, 17,100-103.
Probst, G. W.; Hoehn, M. M.; Woods, B. L. Antimicrob.
Agents. Chemother. 1966, 5.
Haneisi, T.; Arai, M.; Kitano, N.; Yamamoto, S. J. Antibiot. 1974, 27, 339-342.
Masatoshi Inukai, Hiroshi Mishima: Current Chemistry special 9 "Advanced antibiotics", Tokyo dojin, 1987, 37-43. a) Omura, S.; Otoguro, K.; Imamura, N.; Huga, H.; Takahashi, Y.; Masuma, R., Tanaka, Y.; Tanaka, H.; Xue-hui, S.; En-tai, Y. J. Antibio, 1987, 40, 623-629. b) Imamura, N.; Kuga, H.; Otoguro, K.; Tanaka, H.; Omura, S. J. Antibio. 1989, 42, 156- 158.
Giencke, W.; Ort, 0.; Stark, H. Liebz’gs. Ann. Chem. 1989. 671-676.
Moss, R. A.; Landon, M. J.; r, K. M.; Mamantov, A. J.
Am. Chem. Soc. 1972, 94, 4392-4394. 2012/073277 _ 7 _ Tsuzuki, K.; Yan, F.; Otoguro, K.; Omura, S. J. Antibiot. 1991, 44, 774-784.
Kar, A.; Argade, N. P. Tetrahedron, 2003, 59, 2991.
Nam, N. H.; Kim, Y.; You, Y. J.; Hong, D. H.; Kim, H. M.; Ahn, B. Z. Bioorg. Med. Chem. Lett. 2002, 12,1955-1958.
Naora, H.; , T.; Nakamura, A. Bull. Chem. Soc. Jpn. 1988, 61, 993-994.
Thakkalapally, A.; Benin, V. Tetrahedron. 2005, 61, 4939- 4948.
SUMMARY OF THE INVENTION The object of the present invention is to e new chemical entities effective in the treatment or prevention of infections in animals caused by bacteria such as: Staphylococcus spp, Streptococcus spp, Enterococcus spp, Neisseria spp, Moraxella spp, Corynebacterium spp, Lactobacillus spp, Bacillus spp, Listeria spp, Erysipelothrix spp, Arcanobacterium spp, Vibrio spp nas spp, Escherichia spp, Klebsiella spp, Proteus spp, Salmonella spp, Shigella spp, Morganella spp, Citrobacter spp, bacter spp, Serratia spp, Erwinia spp, Yersinia spp, Pseudomonas spp, Alcaligenes spp, Burkholderia spp, Phyllobacterium spp, Acinetobacter spp, Stenotrophomonas spp, Haemophilus spp, bacillus spp, Bordetella spp, Pasteurella spp, Brucella spp, Campylobacter spp, Capnytophaga spp, Francisella spp, Helicobacter Spp, Legionella Spp, Mycoplasma spp, Ureaplasma spp, Bartonella spp, Chlamydia spp, Coxiella spp, Ehrlichia spp, Rickettsia spp, Borrelia spp, pira spp, Treponema spp, Brachyspira spp, Veillonella spp, Peptostreptococcus spp, Peptococcus spp, Bacteroides spp, Porphyromonas spp, Prevotella spp, Fusobacterium spp, Clostridium spp, Actinomyces spp, Propionibacterium spp, Eubacterium spp, Lactobacillus spp, Bifidobacterium spp.
More ically the present compounds can be used in the treatment or tion of bacterial infections caused by gram-positive bacteria such as staphylococcal, streptococcal, Lactobacillus acidophilus, Corynebacterium diphtheriae, Propionibacterium acnes, myces bovis, Mycobacterium tuberculosis, Mycobacterium , Bacillus or Clostridium and gram-negative bacteria such as Pasteurella, Mannheimia or Mycoplasma in animals.
In one embodiment, the present invention provides compounds represented by the formula (I): (I) or a ceutically acceptable salt, ester, prodrug or solvate thereof; wherein, A is selected from the group ting of: (1)-CHO or a protected aldehyde; (2) CHz-X, wherein X is selected from the group consisting of: a. hydroxy or protected hydroxy; b. halogen; and 0. -N3 (3) -CN; (4) -CH=N-NR7R8, wherein R7 and R8 are each independently selected from hydrogen, Cl-C6-alkyl, optionally substituted with one or more tuents selected from the group consisting of halogen, aryl, tuted aryl, cyclic and tuted heterocyclic, C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic, C2-C6-alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic or R7 and R8 taken with the en atom to which they are connected form a 3- to 7-membered ring which may optionally contain a hetero function selected from the group consisting of -O-, -NH-, - N(Cl-C6-alkyl)-, -N(aryl) -, -N oaryl)-, -S-, -S(O)- and- S(O)2-; (5) -CH=N-OR7, wherein R7 is as preViously defined; (6) C3-Cl4-cycloalkyl; (7) substituted C3-C14-cycloalkyl; (8) aryl; (9) substituted aryl; (10) heterocyclic; (11) substituted heterocyclic; and (12) CHz-R'; R1 and R2 are each independently ed from the group consisting of: (1) hydrogen; (2) hydroxy; (3) protected hydroxy; (4) -OC(O)-C1-C12-alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic, tuted heterocyclic, -O-R7 and -NR7R8 Where R7 and R8 are as preViously defined; (5) -O-R7, Where R7 is as preViously defined; (6) n; (7) -NR7R8, Where R7 and R8 are as preViously defined; (8) R1 and R2 taken together are oxo; and (9) R1 and R2 taken together are =N-O-C0-C3-alkyl-R'; R3 is ed from the group consisting of: (1) en; (2) a hydroxy protecting group; (3) -C(O)-C1-C12-alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic, substituted _ 1 1 _ heterocyclic, -O-R7 and -NR7R8 where R7 and R8 are as previously defined; (4) Cl-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, - O-R7 and -NR7R8 where R7 and R8 are as previously defined; (5) C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, tuted aryl, heterocyclic, substituted cyclic, - O-R7 and -NR7R8 where R7 and R8 are as preViously d; (6) C2-C6-alkynyl, optionally tuted with one or more substitutents selected fron the group consisting of halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, - O-R7 and -NR7R8 where R7 and R8 are as preViously defined; R4 is -M-Y, where M is: (1) , (2) -C(0)-, (3) -C(O)N(R7)-, where R7 is as preViously defined, (4) -Cl-C6-alkyl-N(R7) -, where R7 is as preViously defined, (5)-C2-C6-allcenyl-N(R7) -, where R7 is as preViously defined, or (6) -C2-C6-alkynyl-N(R7) -, where R7 is as preViously defined; and where Y is: (1) hydrogen, (2) hydroxy protecting group, WO 76169 _ 1 2 _ (3) Cl-C6-alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, cyclic and substituted heterocyclic, -OR7 where R7 is as previously defined, (4) C2-C6-alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted hetreocyclic, -OR7 where R7 is as previously defined, (5) C2-C6-alkynyl, optionally substituted with one or more tuents selected from the group consisting of halogen, aryl, tuted aryl, heterocyclic and substituted heterocyclic, -OR7 where R7 is as previously defined, (6) aryl, (7) substituted aryl, (8) heterocyclic, or (9) substituted heterocyclic; R5 is selected from the group consisting of: (1) hydrogen; (2) hydroxy; (3) protected hydroxy; (4) halogen; (5) -O-R7, where R7 is as usly defined; (6) -N3 or R'; RP is en or a hydroxy protecting group; and each R' is independently [l,4]-epi-[l,2,3]-triazoro-R; and where each R is independently selected from the group consisting of: (l) Cl-C9-alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic, -OR7 where R7 is as previously d; (2) C2-C9-alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, tuted aryl, heterocyclic and substituted cyclic, -OR7 where R7 is as previously defined; (3) alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and tuted heterocyclic, -OR7 where R7 is as usly defined; (4) C3-Cl4-cycloalkyl; (S) substituted C3-Cl4-cycloalkyl; (6) aryl; (7) substituted aryl; (8) heterocyclic; (9) substituted heterocyclic; and (10) -COOR7, where R7 is as previously defined; provided that at least one of A, R1 and R2 and R5 comprise R'.
In one preferred embodiment, the present invention provides compounds of said formula (I), wherein; A is selected from halogen, CHz-Ng, hydroxy, CHO, hydroxyC1_6alkyl, haloC1_6alkyl, (3,5-di(Cl-C3-alkyl)- piperidino) and CHz-R'; R1 and R2 taken together are oxo or =N-O-C0-C3-alkyl-R'; R3 is H; R4 is H; R5 is selected from hydroxy, N3, halogen, 6-deoxy-2,3-di-O- methyl-b-d-allo-hexapyranosyloxy and R'; and R' is as defined above; provided that at least one of A, R1 and R2 and R5 comprises or a pharmaceutically acceptable salt, ester, g or solvate thereof.
In further preferred embodiment of the present invention, there are provided compounds of said formula (I), wherein; A is CHz-R'; R1 and R2 taken together are oxo; R3 is H; R4 is H; and R5 is 6-deoxy-2,3-di-O-methyl-b-d-allo-hexapyranosyloxy.
[0011] In r preferred embodiment of the present ion, there are provided compounds of said formula (I), Wherein; A is CHO or methyl(3,5-dimethylpiperidino); R1 and R2 taken together are oxo; R3 is H; R4 is H; and R5 is R'.
W0 2013/076169 In another preferred ment of the present invention, there are provided compounds of said formula (I), wherein; A is CHO or methyl(3,5-dimethylpiperidino); R1 and R2 taken together are 0-C3-alkyl-R'; and R3 is H; R4 is H; and R5 is 6-deoxy-2,3-di-O-methyl-b-d-allo-hexapyranosyloxy.
In the present invention, R is preferably selected from the group consisting of In another embodiment, the t invention provides a method for preparing a compound of the formula (1): Ray, VHE wherein A is CHz-R' and R1, R2, R3, R4, R5, R' and Rp are as defined above; which method comprises following steps: (i) reacting a compound of the formula (II): IIII:I wherein, A is CHz-hydroxy; and the other variable groups are as defined in the formula (I), with an azide selected from diphenylphosphoryl azide (DPPA) or sodium azide (NaNg) to form a compound of said formula (11) wherein A is CH2-N3 and the other variable groups are as defined in the formula (I); and (ii) reacting the resulting compound of the formula (11) wherein A is CH2-N3 and the other variable groups are as defined in the formula (I) with an R-CECH, wherein R is as d in the formula (1) above, in the presence of a copper st to form a compound of the formula (11), wherein A is CHz-R' and R3, R4, R5, R' and Rp are as d above.
[0016] In another embodiment, the present invention provides a method for preparing a nd of the formula (I): WO 76169 wherein R5 is R' and A, R1, R2, R3, R4, R' and Rp are as defined above; which method comprises following steps: (i) reacting a compound of the formula (II): IIII:I wherein, R5 is hydroxy; and the other variable groups are as defined in the formula (I), with an azide ed from diphenylphosphoryl azide (DPPA) or sodium azide (NaNg) to form a compound of said formula (11) wherein R5 is -N3 and the other variable groups are as defined in the formula (I); and (ii) reacting the resulting compound of the formula (11) wherein R5 is -N3 and the other variable groups are as defined in the a (I) with an R-CECH, wherein R is as defined in the formula (1) above, in the presence of a copper catalyst to form a compound of the formula (11), n R5 is R' and A, R3, R4, R' and Rp are as defined above.
In still r embodiment, the present invention provides a method for preparing a compound of the formula (I): (I) wherein R1 and R2 taken together are =N-O-C0-C3-alkyl-R' and A, R3, R4, R5, R' and R1) are as defined above; which method comprises following steps: (i) reacting a compound of the formula (II): IIII:I wherein, the variable groups are as defined in the formula (I), but A is not -CHO, with a CHEC-(CH2)n-O-NH2-HC1 wherein n is an integer from 1 to 3 to form a nd of the formula (III): wherein n is an integer from 1 to 3 and A, R3, R4, R5 and Rp are as defined in formula (I), but A is not -CH0; and (ii) reacting the compound of the formula (III) resulting from step (i) or (ii) with an R-N3, wherein R is as defined in formula (1) above, in the presence of a copper catalyst to form a compound of the formula (I): n R1 and R2 taken er are =N-O-C0-C3-alkyl-R' and A, R3, R4, R5, R' and R1) are as defined above. _ 2 1 _ In further embodiment, the present invention provides a pharmaceutical or nary composition comprising the compound of the present invention. Such composition may be used for the treatment or the prevention of bacterial infections or ers associated with bacterial infections in animals, which include among others mammal, fish or birds.
The pharmaceutical or veterinary composition may include or may be used simultaneously, sequentially or contiguously with one or more other antibiotics.
In further embodiment, the present invention provides use of the compound of the present invention for manufacturing a medicament for treatment or prevention of ial infections or disorders ated with bacterial infections in animals.
The compounds of the present invention has different chemical structure from tylosin or tilmicosin, while the present compounds may have antibacterial activities similar to or r than those of tylosin or tilmicosin. ore, the compounds of the present invention may be used as a substitute for tylosin or tilmicosin, particularly to treat infections or related disorders caused by tylosin- or osin-resistant ia. ingly, the compound of the present invention is useful in the treatment or prevention of bacterial infections or disorders associated with bacterial _ 2 2 _ infections in s.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The terms as used herein have the meaning as defined below or as understood by an artisan of ordinary skill in fields of organic chemistry, biochemistry, medical sciences, pharmaceutical sciences, bacteriology and the like.
The terms "Cl-C3-alkyl", "Cl-C6-alkyl", "Cl-ClZ-alkyl" or the like, as used herein, refer to saturated, straight- or branched-chain hydrocarbon radicals ning n one and three, one and six or one and twelve carbon atoms, respectively. The term "C0-C3-alkyl" means a bond or Cl- C3-alkyl. Examples of Cl-C3-alkyl radicals include methyl, ethyl, propyl and isopropyl, and examples of Cl-C6-alkyl radicals include, but are not limited to, methyl, ethyl, propyl, pyl, n- butyl, tert-butyl, neopentyl and n-hexyl, and examples of Cl-Cl2-alkyl radicals include, but are not limited to, methyl, ethyl, propyl, pyl, n-butyl, tert- butyl, neopentyl, n-hexyl, n-octyl, n-decyl and n-dodecyl.
The term "C2-C6-alkenyl" or the like, as used herein, refers to straight- or branched-chain hydrocarbon radicals containing n two and six carbon atoms with one or more double bonds in the chain. Examples of C2-C6-alkenyl e, but are not limited to, propenyl, isobutenyl, 1,3- hexadienyl, n-hexenyl and enyl.
The term "C2-C6-alkynyl" or the like, as used , refers to straight- or branched-chain hydrocarbon radicals containing between two and six carbon atoms with one or more triple bonds in the chain optionally containing one or more double bond. Examples of C2-C6- alkynyl include, but are not limited to, propynyl, isopentynyl, l,3-hexadiynyl, n- hexynyl, 3- pentynyl, and l-hexenynyl.
The term "aryl", as used herein, refers to unsubstituted carbocyclic mono-, di- or tri-cyclic aromatic groups including, but not limited to, phenyl, lor 2-naphthyl, anthracene, phenanthrene and the like.
The term, "C3-Cl4-cycloalkyl", as used herein refer to unsubstitued mono-, di- or clic groups where each carbocyclic ring consisting cycloalkyl comprises 3 to 7 carbon atoms, respectively, such as for example, ropyl, cyclobutyl, cyclopentyl, cyclohexyl, and eptyl.
The terms "halo" and "halogen", as used herein, refer to an atom selected from fluorine, chlorine, bromine and iodine.
The term "heteroaryl", as used herein, refers to a mono-, di- or tri-cyclic aromatic radical haVing from five to fourteen ring atoms of which one ring atom is selected from S, O and N; zero, one or more ring atoms are additional heteroatoms independently selected from S, O and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule Via any of the ring atoms, such as, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, azolyl, oxadiazolyl, thiophenyl, l, quinolinyl, nolinyl, and the like.
The term ocycloalkyl", as used herein, refers to a non- aromatic 3-, 4-, 5-, 6-or 7-membered ring or a bi-or tri-cyclic group comprising fused mbered rings haVing between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen and sulfur heteroatoms may optionally be ed, (iii) the nitrogen heteroatom may optionally be quaternized, and (iV) any of the above heterocyclic rings may be fused to one or two benzene ring.
Representative heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, lidinyl, isothiazolidinyl, and tetrahydrofuryl.
The term "heterocyclic", as used herein, refers to W0 2013/076169 heterocycloalkyl and heteroaryl.
The term "substituted heterocyclic", as used herein, refers to substituted heterocycloallcyl and substituted heteroaryl.
The term "substituted aryl", as used herein refers to an aryl group, as defined herein, tuted by independent replacement of one or more of the en atoms therein with, for example, but not limited to, F, Cl, Br, I, OH, N02, CN, C(O)-Cl-C6-alkyl, ryl, C(O)-heteroaryl, COz-alkyl COz-aryl, COz-heteroaryl, CONHz, CONH-Cl-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)-Cl-C6-alkyl, OC(O)- aryl, heteroaryl, OCOz-alkyl, OCOz-aryl, OCOz- heteroaryl, OCONHz, OCONH-Cl-C6-alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(O)-Cl-C6-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCOz-alkyl, NHCOz-aryl, NHCOz- heteroaryl, NHCONHz, NHCONH-Cl-C6-alkyl, NHCONH-aryl, NHCONH-heteroaryl, SOz-Cl-C6-alkyl, SOz-aryl, SOz- heteroaryl, SOzNHz, SOzNH-Cl-C6-alkyl, SOzNH-aryl, SOzNH-heteroaryl, Cl-C6-alkyl, C3-C7-cycloalkyl, CF3, CH2CF3, CHzClz, CHzOH, CHzCHzOH, CH2NH2, CH2502CH3, aryl, substituted aryl, heteroaryl, tuted heteroaryl, , benzyloxy, aryloxy, heteroaryloxy, Cl-C6-alkoxy, methoxymethoxy, yethoxy, amino, benzylamino, arylamino, heteroarylamino, Cl-C3-alkyl-amino, thio, aryl- thio, heteroarylthio, benzyl-thio, Cl-C6-alkyl-thio, or methylthiomethyl.
The term "substituted heteroaryl", as used herein refers to a heteroaryl group as defined herein substituted by independent replacement of one or more of the hydrogen atoms therein with, for e, but not limited to, F, Cl, Br, I, OH, N02, CN, C(O)-Cl-C6-alkyl, C(O)-aryl, eteroaryl, COz-alkyl, COz-aryl, COz-heteroaryl, CONHz, CONH-Cl-C6-alkyl, ryl, CONH-heteroaryl, OC(O)-Cl-C6-alkyl, OC(O)- aryl, OC(O)-heteroaryl, lkyl, ryl, OCOz- heteroaryl, OCONHz, OCONH-Cl-C6-alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(O)-Cl-C6-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCOz-alkyl, NHCOz-aryl, NHCOz- heteroaryl, NHCONHz, NHCONH-Cl-C6-alkyl, NHCONH-aryl, NHCONH-heteroaryl, SOz-Cl-C6-alkyl, SOz-aryl, $02- heteroaryl, SOzNHz, SOzNH-Cl-C6-alkyl, SOzNH-aryl, SOzNH-heteroaryl, Cl-C6-alkyl, C3-C7-cycloallcyl, CF3, CH2CF3, CHzClz, CHzOH, CHzCHzOH, CH2NH2, CH2502CH3, aryl, aryl, benzyl, benzyloxy, aryloxy, heteroaryloxy, Cl-C6-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, Cl-C3-alkyl-amino, thio, aryl-thio, arylthio, benzyl-thio, Cl-C6-alkyl-thio, or methylthiomethyl.
The term "substituted heterocycloalkyl", as used herein, refers to a heterocycloalkyl group, as defined above, substituted by independent replacement of one or more of the hydrogen atoms therein with, for e, but not limited to, W0 2013/076169 F, Cl, Br, I, OH, N02, CN, l-C6-alkyl, C(O)-aryl, C(O)-heteroaryl, COz-alkyl, COz-aryl, COz-heteroaryl, CONHz, CONH-Cl-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)- Cl-C6-alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCOz-alkyl, OCOz-aryl, OCOz-heteroaryl, OCONHz, OCONH-Cl-C6-alkyl, OCONH-aryl, OCONH-heteroaryl, NHC(O)-Cl-C6-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCOz-alkyl, NHCOz-aryl, NHCOz-heteroaryl, z, NHCONH-Cl-C6-alkyl, NHCONH-aryl, NHCONH-heteroaryl, SOz-Cl-C6-alkyl, $02- aryl, teroaryl, SOzNHz, SOzNH-Cl-C6-alkyl, SOzNH- aryl, heteroaryl, Cl-C6-alkyl, C3-C7-cycloallcyl, CF3, CH2CF3, CHzClz, CHzOH, CHzCHzOH, CHzNHz, CH2802CH3, aryl, heteroaryl, benzyl, benzyloxy, aryloxy, heteroaryloxy, Cl-C6-alkoxy, methoxymethoxy, yethoxy, amino, amino, ino, heteroarylamino, Cl-C3-alkyl-amino, thio, aryl-thio, heteroarylthio, benzyl-thio, Cl-C6-alkyl-thio, or methylthiomethyl.
The term "substituted lkyl", as used herein, refers to a cycloalkyl group, as defined above, substituted by independent replacement of one or more of the hydrogen atoms therein with, for example, but not limited to, F, Cl, Br, I, OH, N02, CN, C(O)-Cl-C6-alkyl, C(O)-aryl, C(O)- heteroaryl, COz-alkyl, COz-aryl, COz-heteroaryl, CONHz, CONH-Cl-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)- Cl-C6-alkyl, OC(O)-aryl, OC(O)-heteroaryl, OCOz-alkyl, OCOz-aryl, OCOz-heteroaryl, OCONHz, OCONH-Cl-C6-alkyl, WO 76169 OCONH-aryl, OCONH-heteroaryl, -Cl-C6-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCOz-alkyl, NHCOz-aryl, NHCOz-heteroaryl, NHCONHz, NHCONH-Cl-C6-alkyl, NHCONH-aryl, NHCONH-heteroaryl, SOz-Cl-C6-alkyl, $02- aryl, SOz-heteroaryl, SOzNHz, SOzNH-Cl-C6-alkyl, SOzNH- aryl, SOzNH-heteroaryl, Cl-C6-alkyl, C3-C7-cycloallcyl, CF3, CH2CF3, CHzClz, CHzOH, CHzCHzOH, CHzNHz, CH2802CH3, aryl, heteroaryl, benzyl, benzyloxy, aryloxy, heteroaryloxy, Cl-C6-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, Cl-C3-alkyl-amino, thio, aryl-thio, arylthio, -thio, Cl-C6-alkyl-thio, or thiomethyl.
The term "amino" includes a group represented by - NHz. The term "substituted amino" indicates amino groups having one or two substituents in place of one or two hydrogen atoms attached to nitrogen atom of the amino group.
The term "azide" means a group represented by -N3, Which may comprise -N-NEN or -N=N=N.
"Hydroxy-protecting group", as used herein, refers to an easily removable group which is known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable. The use of y-protecting groups is well known in the art for protecting groups against rable reactions during a synthetic procedure and many such protecting groups are known. See, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic sis, 3rd edition, John Wiley & Sons, New York (1999). Examples of hydroxy- protecting groups include, but are not limited to, methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, acyl substituted with an aromatic group and the like.
The rotected-hydroxy", refers to a y group protected with a hydroxy protecting group, as defined above, including, for example, but not limited to, benzoyl, acetyl, trimethylsilyl, triethylsilyl, ymethyl groups.
"Aldehyde-protecting group", as used herein, refers to an easily removable group which is known to protect an aldehyde group against undesirable reaction during synthetic procedures and to be selectively removable. The use of aldehyde-protecting groups is well known in the art for protecting aldehyde groups against undesirable reactions during a tic procedure and many such protecting groups are known. See, for example, T. H. Greene and P. G, M, Wuts, tive Groups in Organic Synthesis, op. cit. Examples of aldehyde-protecting groups include, but are not limited to, acetals, ketals, O-substituted cyanohydrins, substituted hydrazones, imines and the like.
The term "protected aldehyde" refers to an aldehyde group protected with an aldehyde protecting group, as defined above, ing, for example, but not limited to, dimethyl acetyl, dimethoxy methyl, l,3-dioxolane, oxane and the like.
The compound ofthe present invention can be prepared, but is not limited to, by any conventional method known to an artisan of ordinary skill, for example according to any one of the methods described below, typically ous to the method detailed in Examples of the present specification.
[0031] The preparation of the present compound can be performed lly by using cycloaddition reaction between azide and acetylene derivative, what is called click chemistry (see, for example Kolb, H. C.; Finn, M. G.; Sharpless, K. B., Angew. Chem., Int. Ed. 2001, 40, 2004-2021 and Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B., Angew.
Chem., Int. Ed. 2002, 41, 2596-2599). The ism of the reaction is represented by the following scheme A: 2012/073277 -3]- RH. cuLn'l N~ ,N.
"N Rh I—‘x N‘ a“; ‘N R}, fl?uLn_2 N: ,N‘ N Rh [Ln'CI-I]+ Ra : cuan .N—Rh Ra : H Ra : CULn_1 NEfi—fi—Rh wherein Ra and Rb indicate any functional groups and LnCu indicates copper catalysis. The click chemistry may be typically characterized by sophisticated functional group selectivity and regio selectivity, mild reaction condition, high yield, and applicability for a Wide variety of substituents.
In one embodiment, the present invention es a method for preparing a compound of the formula (I): wherein A is CHz-R' and R1, R2, R3, R4, R5, R' and Rp are as defined above; which method comprises following steps : (i) reacting a nd of the formula (II): IIII:I wherein, A is CHz-hydroxy; and the other variable groups are as defined in the formula (I), with an azide selected from diphenylphosphoryl azide (DPPA) or sodium azide (NaNg) to form a compound of said formula (11) wherein A is CH2-N3 and the other variable groups are as defined in the a (I); and (ii) reacting the resulting compound of the formula (11) wherein A is CH2-N3 and the other variable groups are as _ 3 3 _ defined in the formula (I) with an R-CECH, wherein R is as defined in the formula (1) above, in the presence of a copper catalyst to form a nd of the formula (11), wherein A is CHz-R' and R3, R4, R5, R' and Rp are as defined above.
In another embodiment, the present invention provides a method for preparing a compound of the formula (I): wherein R5 is R' and A, R1, R2, R3, R4, R' and Rp are as d above; which method comprises following steps: (i) reacting a nd of the formula (II): IIII:I wherein, R5 is hydroxy; and the other variable groups are as defined in the formula (I), with an azide selected from ylphosphoryl azide (DPPA) or sodium azide (NaNg) to form a compound of said formula (11) wherein R5 is -N3 and the other variable groups are as defined in the formula (I); and (ii) reacting the resulting compound of the formula (11) wherein R5 is -N3 and the other variable groups are as d in the formula (I) with an R-CECH, wherein R is as defined in the formula (1) above, in the presence of a copper catalyst to form a compound of the formula (11), wherein R5 is R' and A, R3, R4, R' and Rp are as defined above.
[0034] In the step (i) of those methods for preparing the present compound of a (I), the starting materials are commercially ble or can be easily prepared a compound commercially available according to any know method. For example, the ng compound of the formula: [IIII wherein, _ 3 5 _ A is CHz-hydroxy; and the other variable groups are as defined in the a (I), can be prepared by performing following sub-steps: (a) deglycosylation of tylosin under acidic condition, for example in the presence of HCl aq.; (b) reducing aldehyde group at 20-position in the presence of a reducing agent, such as NaBH4; and (c) optionally ting the remaining functional groups to desired substituents according to any conventional process. 2O m caminose (CHO 5’ {CHO HOWE)o %o23 OMeOMe mycinose own; The ng compound of the formula: WO 76169 [IIII wherein, R5 is hydroxy; and the other variable groups are as defined in the formula (I), can be prepared by performing, for example following sub- steps: (a) deglycosylation of tylosin under acidic condition, for example in the ce of TFA aq. or HBr; and (b) optionally converting the remaining functional groups to desired substituents according to any conventional process. 2|] 2|} JCHO nosne III fCHO u 2.! I ll mu 2". I To enhance the vity of the 20- or 23-hydroxyl functional group, the starting compounds of formula (11) may, if desired, be halogenized, for example with a halogenating agent such as 12 or CCl4 in the presence of PPh3 in a solvent such as pyridine and/or dichloromethyl at -27 to 40°C, preferably 0°C _ 3 7 _ to rt, so that a compound of formula (11) n A is CH2- halo or R5 is halogen is formed.
By using a compound of formula (11) wherein either A is CH2- R' or R5 is R', which nd may be obtained from any of the ing methods described above as a starting material, ,23-bistriazole n derivative, that is a compound of the formula (I) wherein A is CHz-R' and R5 is R' may be prepared by carrying out the other preparing method as described above.
In a detailed embodiment, the azidation of step (i) in the preparing methods above can be d out by reacting azide such as diphenylphosphoryl azide (DPPA) or sodium azide (NaNg) with the starting material in the presence of solvent such as THF or DMSO at -27 to 100°C, preferably at 0 to 80°C.
The reaction of step (ii) in the preparing methods above can be d out in a solvent for example water, tert- butyl alcohol, ol or acetonitrile or combination thereof, preferably in acetonitrile, preferably in the presence of tris[(1-benzyl-1H-1,2,3-triazolyl)methyl]amine (TBTA), in the presence of a copper catalysis for example CuSO4'5H20, CuOTf-C6H6, [Cu(NCCH3)4][PF6] or CuI, preferably CuI at 0 to 100°C, preferably 10 to 40°C, more preferably rt.
In still another embodiment, the present invention _ 3 8 _ provides a method for preparing a compound of the formula (I): wherein R1 and R2 taken together are =N-O-C0-C3-alkyl-R' and A, R3, R4, R5, R' and R1) are as defined above; which method comprises ing steps: (i) reacting a compound of the formula (II): IIII:I wherein, the variable groups are as defined in the a (I), but A is not -CHO, with a CHEC-(CH2)n-O-NH2-HC1 wherein n is an integer from 1 to 3 to form a compound of the formula (III): _ 3 9 _ wherein n is an integer from 1 to 3 and A, R3, R4, R5 and Rp are as defined in formula (I), provided that A is not -CH0; (ii) reacting the compound of the formula (III) resulting from step (i) or (ii) with an R-N3, wherein R is as defined in a (1) above, in the presence of a copper catalyst to form a compound of the formula (I): n R1 and R2 taken together are =N-O-C0-C3-alkyl-R' and A, R3, R4, R5, R' and R1) are as defined above.
The starting compound of the formula (II): IIII:I wherein, the le groups are as defined in the formula (I), but A is not -CHO can be readily available or prepared according to any conventional process known to the skilled person.
In a detailed embodiment, the introduction of an acetylene moiety of step (i) can be carried out by reacting a CHEC-(CH2)n-O-NH2-HC1 (wherein n is as defined above) with the starting material in a solvent such as ne or methanol or combination thereof, preferably in the combination of pyridine and methanol, at 0 to 80°C, preferably rt to 65°C. If desired, an oxo or hydroxyl group which is d not to participate in the introduction of an acetylene moiety can be protected by any conventional process.
In a detailed embodiment, the reaction of step (ii) can be carried out in solvent, for example water, utyl l, methanol or acetonitrile or ation thereof, preferably in acetonitrile, preferably in the presence of tris[(1-benzyl-1H-1,2,3-triazolyl)methyl]amine (TBTA), in the presence of copper catalyst, for example CuSO4'5H20, CuOTf-C6H6, [Cu(NCCH3)4][PF6] or CuI, preferably CuI at 0 to 100°C, ably 10 to 40°C, more preferably rt.
The compounds represented by R-N3 and R-CiCH are commercially available or can be easily prepared by any tional procedure known to a d person.
[0035] The process steps to synthesize the compounds of the invention can be carried out under reaction conditions that are known per se, including those ned specifically, in the absence or, customarily, in the presence of solvents or diluents, including, for example, solvents or diluents that are inert towards the reagents used and dissolve them, in the absence or presence of catalysts, condensation or neutralizing agents, for example ion exchangers, such as cation gers, e.g., in the H+ form, depending on the nature of the reaction and/or of the reactants at d, normal or elevated temperature, for example in a temperature range of from about -100 °C to about 190°C, ing, for example, from approximately -80°C to approximately 150°C, for example at from -80 to -60°C, at room temperature, at from -20 to 40°C or at reflux temperature, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under argon or nitrogen atmosphere.
The solvents from which those solvents that are suitable for any particular reaction may be selected e those mentioned specifically or, for example, water, esters, such as lower alkyl-lower alkanoates, for example ethyl acetate, ethers, such as aliphatic ethers, for example diethyl ether, or cyclic ethers, for example ydrofurane or dioxane, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, such as methanol, ethanol or 1- or 2- propanol, nitriles, such as acetonitrile, halogenated hydrocarbons, such as ene chloride or chloroform, acid amides, such as dimethylformamide or dimethyl acetamide, bases, such as heterocyclic en bases, for example pyridine or N-methylpyrrolidinone, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic ide, cyclic, linear or branched arbons, such as cyclohexane, hexane or isopentane, or mixtures of those solvents, for example aqueous solutions, unless ise indicated in the description ofthe processes.
Such solvent mixtures may also be used in working up, for example by tography or partitioning.
Within the scope of this text, only a readily removable group that is not a tuent of the particular desired end product of the compounds of the present invention is designated a “protecting group,’ 3 unless the context indicates otherwise. The protection of functional groups by such ting groups, the protecting groups themselves, and their ge reactions are described for example in standard reference works, such as e.g., Science of Synthesis: - Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 pp. (URL: http://www.science-of—synthesis.com (Electronic Version, 48 Volumes)); J. F. W. , "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T.
W. Greene and P. G. M. Wuts, ctive Groups in Organic Synthesis", Third edition, Wiley, New York 1999, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in "Methoden der organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit, "Aminosauren, Peptide, Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie, im, eld Beach, and Basel 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of Carbohydrates: Monosaccharides and tives), Georg Thieme Verlag, Stuttgart 1974. A characteristic of protecting groups is that they can be removed readily (i.e., without the occurrence of undesired secondary reactions) for example by solvolysis, reduction, photolysis or alternatively under physiological conditions (e.g., by enzymatic cleavage).
Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known per se. For example, salts of compounds of the t ion having acid groups may be formed, for example, by treating the nds with metal compounds, such as alkali metal salts of suitable organic carboxylic acids, e.g., the sodium salt of 2-ethylhexanoic acid, with organic alkali metal or alkaline earth metal compounds, such as the corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or potassium hydroxide, carbonate or hydrogen ate, with ponding calcium compounds or with ammonia or a le organic amine, stoichiometric amounts or only a small excess of the orming agent preferably being used. Acid addition salts of compounds of the present invention are obtained in customary manner, e.g., by ng the compounds with an acid or a suitable anion exchange reagent. Internal salts of compounds of the present invention containing acid and basic salt-forming groups, e.g., a free carboxy group and a free amino group, may be formed, e.g., by the neutralisation of salts, such as acid addition salts, to the isoelectric point, e.g., with weak bases, or by treatment with ion exchangers.
Intermediates and final products can be worked up and/or purified according to standard methods, e.g., using chromatographic methods, distribution methods, (re-) crystallization, and the like. The compounds, including their salts, may also be obtained in the form of solvates, in W0 2013/076169 particular hydrates. In the context of the ion, solvates refer to those forms of the compounds according to the invention which, in the solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a specific form of the solvates in which the coordination is with water. Crystals of the present compounds may, for example, include the solvent used for crystallization. Different crystalline forms may be present.
[0044] The invention relates also to those forms of the process in which a compound obtainable as an intermediate at any stage of the process is used as ng material and the remaining process steps are d out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative, for e in a ted form or in the form of a salt, or a compound obtainable by the process according to the invention is produced under the process ions and processed further in situ.
[0045] This invention also encompasses pharmaceutical or veterinary compositions containing, and s of treating bacterial infections through administering, pharmaceutically acceptable prodrugs of the compounds of the invention. For example, nds of the invention haVing free amino, amido, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, 2012/073277 three or four) amino acid residues is covalently bound through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of compounds of the invention. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also es 4-hydroxyproline, hydroxylysine, ne, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methionine sulfone.
Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters. Free y groups may be derivatized using groups including but not limited to ccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of y and amino groups are also included, as are ate prodrugs, ate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may be an alkyl ester, optionally substituted with groups including but not limited to ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
Prodrugs of this type are described in J. Med. Chem. 1996,39, . Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug W0 2013/076169 moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
The compound of the present invention has valuable pharmacological properties and thus it can be used for the treatment of diseases. In one embodiment, the compound of the present invention may be used for the treatment or tion of bacterial infections or disorders associated With ial infections in animals, for example mammals, fish or birds.
The term "animal", "patient" or ct" as used herein is used interchangeably. The term animal typically includes, but is not limited to animals suffering from, at risk of suffering from, or potentially capable of suffering from a bacterial infection, for example humans, cattle, horses, chickens, pigs, sheep, goats, dogs, apes, cats, mice, rabbits, rats, etc.; especially farm animals such as cattle, pigs and poultry.
As used herein, the term "bacterial ion(s)" includes, but is not limited to, bacterial infections that occur in s, fish and birds as well as disorders related to bacterial ions that may be treated or prevented by administering antibiotics such as the compounds of the present ion. The compounds of the present invention are useful for ng infections caused by bacteria such as: Staphylococcus spp, Streptococcus spp, Enterococcus spp, Neisseria spp, Moraxella spp, Corynebacteriuni spp, Lactobacillus spp, Bacillus spp, Listeria spp, Erysipelothrix spp, Arcanobacterium spp, Vibrio spp nas spp, Escherichia spp, ella spp, Proteus spp, Salmonella spp, Shigella spp, Morganella spp, Citrobacter spp, Enterobacter spp, ia spp, Erwinia spp, Yersinia spp, Pseudonionas spp, Alcaligenes spp, lderia spp, Phyllobacteriuni spp, Acinetobacter spp, Stenotrophomonas spp, Haemophilus spp, Actinobacillus spp, Bordetella spp, rella spp, Brucella spp, Campylobacter spp, Capnytophaga spp, Francisella spp, Helicobacter spp, ella spp, Mycoplasnia spp, Ureaplasnia spp, Bartonella spp, Chlamydia spp, Coxiella spp, Ehrlichia spp, Rickettsia spp, Borrelia spp, Leptospira spp, Treponenia spp, Brachyspira spp, nella spp, treptococcus spp, Peptococcus spp, Bacteroides spp, Porphyronionas spp, ella spp, Fusobacterium spp, Clostridiuni spp, Actinoniyces spp, Propionibacteriuni spp, Eubacterium spp, Lactobacillus spp, Bifidobacterium spp.
More specifically the present compounds can be used in the treatment or prevention of bacterial infections caused by gram-positive bacteria such as staphylococcal, streptococcal, Lactobacillus acidophilus, Corynebacterium diphtheriae, Propionibacteriuni acnes, Actinomyces bovis, Mycobacterium tuberculosis, Mycobacteriuni leprae, Bacillus or Clostridium or gram-negative bacteria such as Pasteurella, Mannheimia or 2012/073277 Mycoplasma infections in animals.
Such ial infections and ers related to such infections include, but are not limited to, the following: acne, rosacea, skin ion, pneumonia, otitis media, tus, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Peptostreptococcus spp. or Pseudomonas spp.; pharynigitis, rheumatic fever, and glomerulonephritis related to infection by ococcus pyogenes, Groups C and G ococci, Clostridium diptheriae, or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; uncomplicated skin and soft tissue infections, abscesses and osteomyelitis, and puerperal fever related to infection by Staphylococcus aureus, coagulase- positive staphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), S. pyogenes, S. agalactiae, Streptococcal groups C-F (minute-colony streptococci), viridans streptococci, Corynebacterium spp., Clostridium spp., or Bartonella henselae; uncomplicated acute urinary tract infections related to infection by S. hyticus or Enterococcus spp.; urethritis and cervicitis; sexually transmitted diseases d to ion by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Nesseria _ 5 0 _ gonorrheae; toxin diseases d to infection by S. aureus (food poisoning and Toxic shock syndrome), or Groups A, S. and C streptococci; ulcers related to ion by Helicobacter pylori; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by C. trachomatis, N. gonorrhoeae, S. , S. pneumoniae, S. pyogenes, H. nzae, or ia spp.; disseminated cterium avium complex (MAC) disease related to infection by Mycobacterium avium, or Mycobacterium intracellulare; gastroenteritis related to infection by Campylobacter jejuni; inal protozoa related to infection by Cryptosporidium spp., odontogenic ion related to infection by viridans streptococci; persistent cough related to infection by Bordetella pertussis; gas gangrene related to infection by Clostridium ngens or Bacteroides spp.; Skin infection by S. aureus, Propionibacterium acne; atherosclerosis related to infection by Helicobacter pylori or Chlamydia pneumoniae; or the like.
Further bacterial infections and disorders related to such ions that may be treated or prevented in animals include, but are not limited to, the following: bovine respiratory disease related to infection by P. haemolytica., P. multocida, Mycoplasma bovis, or Bordetella spp.; cow enteric disease related to infection by E. coli or protozoa (i.e., W0 2013/076169 coccidia, cryptosporidia, eta), dairy cow mastitis related to infection by S. aureus, S. uberis, S. agalactiae, S. dysgalactiae, ella spp., Corynebacterium, or Enterococcus spp.; swine atory e related to infection by A. pleuropneumoniae., P. multocida, or Mycoplasma spp.; swine enteric disease related to infection by E. coli, Lawsonia intracellularis, Salmonella spp., or Serpulina hyodyisinteriae; cow footrot related to infection by Fusobacterium spp.; cow metritis related to infection by E. coli; cow hairy warts related to infection by Fusobacterium necrophorum or Bacteroides nodosus; cow pink-eye related to infection by lla bovis, cow premature on related to infection by protozoa (z'.e., neosporium); urinary tract infection in dogs and cats related to infection by E. coli; skin and soft tissue infections in dogs and cats related to infection by S. epidermidis, S. intermedius, coagulase neg.
Staphylococcus or P. multocida; dental or mouth ions in dogs and goats related to infection by Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium spp., Peptostreptococcus spp., Porphfyromonas spp., Campylobacter spp., Actinomyces spp., Erysipelothrix spp., Rhodococcus spp., Trypanosoma spp., dium spp., Babesia spp., Toxoplasma spp., cystis spp., Leishmania spp., Trichomonas spp. or Prevotella spp. Other bacterial infections and disorders related to such infections that may be treated or prevented in accord with the method of the present invention are referred to in J. P. Sanford at al., W0 2013/076169 “The Sanford Guide To Antimicrobial Therapy,” 26th Edition, (Antimicrobial Therapy, Inc., 1996). The compounds of the present invention is especially effective to respiratory diseases such as rellosis caused by Gram negative bacillus such as Pasteurella or imia in farm animals such as cows.
Accordingly, in a certain embodiment, the present invention provides a pharmaceutical or veterinary composition comprising any of the nd of the present invention.
The composition may comprise therapeutically effective amount of the compound of the present invention, and if desired one or more pharmaceutically acceptable excipients or carriers.
The language “therapeutically effective amount” of the compound is that amount necessary or sufficient to treat or prevent a bacterial infection, e.g. prevent the various morphological and somatic symptoms of a ial infection, and/or a disease or condition described herein. In an example, an effective amount of the compound of the ion is the amount sufficient to treat a ial infection in a subject.
The ive amount can vary ing on such factors as the size and weight of the subject, the type of illness, or the particular compound of the invention. For example, the choice of the compound of the invention can affect what constitutes an “effective amount.” One of ordinary skill in _ 5 3 _ the art would be able to study the factors contained herein and make the determination ing the effective amount of the compounds of the invention Without undue experimentation.
The regimen of administration can affect What constitutes an effective amount. The compound of the invention can be administered to the t either prior to or after the onset of a bacterial infection. Further, l divided dosages, as well as staggered s, can be administered daily or sequentially, or the dose can be continuously infused, or can be a bolus ion. Further, the dosages of the compound(s) of the invention can be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
Compounds of the invention may be used in the treatment of states, disorders or diseases as bed herein, or for the manufacture of pharmaceutical or veterinary compositions for use in the treatment of these diseases.
Methods of use of nds of the present invention in the treatment of these diseases, or pharmaceutical or veterinary preparations comprising compounds of the present invention for the treatment of these diseases are also included in embodiments of the present invention.
The language aceutical or veterinary W0 2013/076169 composition” includes preparations suitable for administration to mammals, e.g., farm animals such as cows.
When the compounds of the present invention are administered as pharmaceuticals to mammals, e.g., cows, they can be given per se or as a pharmaceutical or veterinary composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
[0056] The phrase “pharmaceutically acceptable carrier” is art recognized and includes a pharmaceutically acceptable material, composition or vehicle, le for stering compounds of the present invention to mammals. The carriers e liquid or solid filler, diluent, ent, solvent or encapsulating al, involved in ng or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
Formulations of the present ion include those known in the art. The formulations may conveniently be presented in unit dosage form and may be ed by any methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Methods _ 5 5 _ of preparing these formulations or compositions are also known in the art.
The term ,” “treated,” ing” or “treatment” includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated. In certain embodiments, the treatment comprises the induction of a bacterial infection, followed by the activation of the compound of the invention, which would in turn sh or ate at least one symptom ated or caused by the bacterial infection being treated. For example, treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder.
[0059] These compounds may be administered to humans and other animals for therapy by any le route of administration.
Regardless ofthe route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical or veterinary itions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
Actual dosage levels of the active ingredients in the pharmaceutical or veterinary compositions of this invention _ 5 6 _ may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a ular patient, composition, and mode of administration, without being toxic to the patient.
The selected dosage level will depend upon a y of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
A physician or veterinarian having ry skill in the art can readily determine and prescribe the effective amount of the pharmaceutical or veterinary composition required. For example, the physician or veterinarian could start doses of the nds of the invention employed in the pharmaceutical or nary composition at levels lower than that required in order to achieve the d therapeutic effect and gradually increase the dosage until the d effect is achieved. _ 5 7 _ In l, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, intravenous and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day, more preferably from about 0.01 to about 50 mg per kg per day, and still more preferably from about 1.0 to about 100 mg per kg per day. An effective amount is that amount treats a bacterial infection.
If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, ally, in unit dosage forms.
While it is possible for a nd of the present invention to be administered alone, it is preferable to administer the compound as a ceutical or veterinary composition.
The antibacterial activity by the compounds of the present invention may be measured using a number of assays available in the art. An e of such an assay is the standard minimum inhibitory concentration (MIC) test 2012/073277 _ 5 8 _ ted according to CSLI guidelines or paper disc test conducted according to Examples below.
The invention is further illustrated by the following examples, which should not be construed as further ng.
The practice of the present invention will employ, unless otherwise ted, conventional techniques of cell biology, cell culture, molecular biology, transgenic biology, microbiology and immunology, which are within the skill of the art.
EXAMPLES All ng materials, building blocks, reagents, acids, bases, solvents, and catalysts, etc. utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21).
Analytical methods Infrared (IR) absorption spectra were determined by using Horiba FT-210 spectrometer. 1H NMR spectra were determined by using JEOL JNM-EX270 (270 MHz), VALIAN-400 NMR System (400 MHz). 13C NMR _ 5 9 _ spectra were determined by using JEOL JNM-EX270 (67.5 MHz) \ VARIAN-400 NMR system (100 MHz). Chemical shifts are indicated in 5 (ppm) and coupling patterns are indicated by using following abbreviations: s : t; d ; dd : double doublet; t : triplet; q : quartet; m multiplet; br.d : broad doublet; br.dd : broad double doublet; br.dt : broad double triplet.
Low-resolution mass spectra (LC-MS) were determined by using JEOL JMS-DX300 Mass Spectrometer. High-resolution mass spectra (HRMS) were deteremined by using JEOL JMS- 700 V Mass Spectrometer.
A ayer chromatography (TLC) was performed by using silica gel 60 F254 ) and compounds were detected by using UV irradiation (254nm) or color development of phosphomolybden.
Column chromatography was performed by flash chromatography on silica gel 60 (Art. 1.09385) (Mark).
Thirty % of ammonium purchased from Kanto Chemical Co.
Ltd. was used as NH4OH
[0071] Preparation of azoledeoxodesmycosins (1) Preparation of desmycosin (YT6) /CHO - \ O ..... O OH 0.2N HCI O IIIII 1 , I38, 2 h """ OH quant.
HOW0O1!" HOW0 1!" 23 OMeOMe TYL OMeOMe YT6 Tylosin (20.0g, 21.8 mmol) was ved in 0.2N HCl aq. (340 mL) and then the mixture was stirred at 35°C for 2 hours.
After confirming complete consumption of the starting material, the reaction mixture was neutralized by adding 1N NaOH aq., extracted with CHC13 and dried over NazSO4. The solvent was removed under reduced-pressure to obtain quantitative amount of desmycosin (YT6).
Rf: 0.53 (CHC13 : MeOH : NH4OH = 5 : l : 0.005).
HRFABMS : calcd. for 014N : 772.4483 [M+H], found m/z : 772.4424 [M+H]+.
IR (KBr)vcm'1 : 3450 (-OH), 2933 (C-H), 1720 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm):9.67 (s, 1H, H-20), 7.27 (d, .1 =15.5 Hz, 1H, H-ll), 6.23 (d, J = 15.5 Hz, 1H, H-10), .87 (d, J = 10.2 Hz, 1H, H-l3), 4.94 (br. dt, .1 = 9.4 Hz, 1H, H-15), 4.52 (d, .1 = 7.6 Hz, 1H, H-1”’), 4.22 (d, .1 = 7.3 Hz, 1H, H-l’), 3.96 (dd, J = 9.4, 3.5 Hz, 1H, H-23), 3.80 (d, J = .3 Hz, 1H, H-3), .67 (m, 2H, H-5, H-3”’), 3.58 (s, 3H, 3”’-OCH3), 3.53-3.48 (m, 3H, H-23, H-2’, H-5”’), 3.45 (s, 3H, H3), 3.24 (m, 1H, H-5’), 3.14 (dd, J = 9.9, 3.0 Hz, 1H, H-4”’), 3.07-2.85 (m, 4H, H-l4, H-l9, H-4’, H-2”’), 2.50 (m, 1H, H-8), 2.49 (s, 6H, 3’-N(CH3)2), 2.41—2.33 (m, 4H, H-2, H- 19, H-3’), 2.13 (m, 1H, H-6), 1.94-1.80 (m, 2H, H-2, H-16), 1.76 (s, 3H, H-22), 1.60-1.40 (m, 4H, H-4, H-7, H-16), 1.23— 1.21 (m, 6H, H-6’, H-6”’), 1.17 (d, 1 = 6.6 Hz, 3H, H-21), 0.97 (d, 1 = 6.6 Hz, 3H, H-18), 0.90 (t, 1 = 6.7 Hz, 3H, H-l7). 13C NMR (67.5 MHz, CDCl3) 5 (ppm):203.l (C-9), 202.9 (C- ), 173.8 (C-l), 148.0 (C-ll), 142.2 (013), 134.8 (012), 118.5 (C-lO), 104.0 (C-l’), 101.0 (C-l”’), 81.9 (C-2”’), 81.2 (C-5), 79.8 (C-3”’), 75.1 (C-15), 73.3 (C-5’), 72.6 (C-4”’), 71.0 ), 70.7 (C-4’), 70.6 (C-2’), 70.1 (C-3’), 69.2 (C- 23), 67.4 (03), 61.7 (C-8”’), 597 (C-7”’), 45.0 (C-14), 44.6 (08), 43.8 (C-19), 41.7 (2C, C-7’, 8’), 40.3 (C-4), 39.4 (C-2), 32.8 (C-7), 31.9 (C-6), 25.4 , 17.8 (C-6”’), 17.7 , 17.4 (021), 12.9 , 9.6 (C-17), 8.9 (C-18).
[0072] (2) Preparation of 20-dihydrodesmycosin (YT7) o NaBH4 i-PrOH-HZO rt, 30 min How0OMe OMe YT6 OMe YT7 To a solution of Desmycosin (16.8 g, 21.8 mmol) in i-PrOH : H20 = 3 : 2 (300 mL) was added NaBH4 (0.206 g, 5.45 mmol) and then the mixture was stirred at rt for 30 minutes. The reaction mixture was concentrated, neutralized by adding sat.
NaHC03 aq., extracted with CHC13 and dried over Na2SO4.
The solvent was removed under reduced pressure to obtain YT7 (Yield: 95%). 2012/073277 Rf: 0.50 (CHC13 : MeOH : NH4OH = 5 : 1 : 0.005) S : calcd. for C39H68014N : 774.4640 [M+H], found m/z : 774.4657 [M+H]+.
IR (KBr)vcm'1 : 3446 (-OH), 2935 (C-H), 1724 (C=O) 1H NMR (270 MHz, CDC13) 6 (ppm):7.27 (d, J = 15.5 Hz,1H, H-11), 6.23 (br. d, 1H, H-10), 5.85 (br. d, 1H, H-13), 4.97 (br. dt, J = 9.7 Hz, 1H, H-15), 4.54 (d, J = 7.6 Hz, 1H, H-1”’), 4.31 (d, J = 7.0 Hz, 1H, H-1’), 3.97 (dd, J = 9.6, 3.6 Hz,1H, H-23), 3.78-3.73 (m, 5H, H-3, H-5, H-20, H-3”’), 3.60 (s, 3H, 3”’-OCH3), 3.55-3.49 (m, 3H, H-23, H-2’, H-5”’), 3.47 (s, 3H, 2”’-OCH3), 3.33 (m, 1H, H-5’), 3.17 (dd, J = 9.5, 3.1 Hz, 1H, H-4”’), 3.08-2.99 (m, 2H, H-4’, H-2”’), 2.95 (m, 1H, H-14), 2.74 (m, 1H, H-8), 2.49 (s, 6H, 3’-N(CH3)2), 2.47-2.33 (m, 2H, H-2, H-3’), 1.95 (d, 1H, H-2), 1.89-1.80 (m, 2H, H-6, H-16), 1.77 (s, 3H, H-22), 1.65-1.54 (m, 5H, H-4, H-7, H-19, H-16), 1.25-1.23 (m, 6H, H-6’, H-6”’), 1.17 (d, J = 6.6 Hz, 3H, H- 21), 1.00 (d, J = 6.2 Hz, 3H, H-18), 0.91 (t, J = 7.3 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDCl3) 5 (ppm): 204.2 (C-9), 174.2 (C- 1), 148.0 (C-11), 142.6 (C-13), 135.4 (C-12), 118.5 (C-10), 104.4 (C-1’), 101.0 (C-1”’), 82.1 (C-2”’), 80.5 (C-5), 80.1 (C-3”’), 75.5 (C-15), 73.3 (C-5’), 72.6 (C-4”’), 70.3 (4C, C- 2’, C-3’, C-4’ 69.3 67.4 62.1 , C-5”’), (C-23), (C-3), (C-20), 60.6 (C-8”’), 59.8 (C-7”’), 45.0 (2C, C-8, C-14), 42.0 (2C, C-7’, 8’), 41.0 (C-4), 39.4 (C-2), 32.8 (C-7), 32.4 (C-6), 31.5 (C-19), 25.4 , 17.5 (3C, C-21, C-6’, C-6”’), 13.1 (C- 22), 10.0 (2C, C-17, C-18). 2012/073277 _ 6 3 _ (3) Preparation of 20-chlorodeoxodesmycosin 1YT8! OH CCI4, PPh3 pyridine CHZCIZ n, 16 h OMe YT8 To a solution of YT7 (16.9 g, 21.8 mmol) in CH2C12 pyridine = 1 : 1 (330 mL) were added PPh3 (17.2 g, 65.4 mmol) and CCl4 (3.2 g, 32.7 mmol) under N2 atmosphere and the mixture was stirred for 16 hours at rt. The reaction mixture was diluted with CHCl3, washed sequentially with sat.
NaHC03 aq., brine. The organic layer was dried over NazSO4 and then the solvent was removed under reduced pressure.
The resulting products were purified by flash column chromatography to obtain YT8 (Yield: 83%).
Rf: 0.51 (CHC13 : MeOH : NH4OH = 5 : 1 : 0.005) S : calcd. for C39H67013NC1 : 792.4301 [M+H], found m/z : 792.4300 [M+H]+.
IR (KBr)vcm'1 : 3460 (-OH), 2933 (C-H), 1718 (C=O) 1H NMR (270 MHz, CDC13) 6 (ppm): 7.30 (d, J = 15.2 Hz, 1H, H-11), 6.24 (d, J =15.2 Hz, 1H, H-10), 5.87 (d, J = 10.9 Hz, 1H, H-13), 4.95 (br. dt, J = 8.7 Hz, 1H, H-15), 4.54 (d, J = 7.9 Hz, 1H, H-1”’), 4.29 (d, J = 7.3 Hz, 1H,H-1’), 3.98 (dd, .1 = 9.4, 3.5 Hz, 1H, H-23), 3.74-3.67 (m, 3H, H-3, H-5, H- 3’”), 3.60 (s, 3H, fl3), 3.60—3.47 (m, 5H, H-20, H-23, H-2’, H-5”’), 3.47 (s, 3H, 2”’-0Cfl3), 3.29 (m, 1H, H-5’), 3.17 (d, 1 = 8.6 Hz, 1H, H-4”’), 3.07 (d, 1 =95, H-4’), 3.01(dd, 1 =6.9, 2.6,1H, H-2”’), 2.94 (m, 1H, H-14), 2.73 (m, 1H, H-8), 2.49 (s, 6H, 3’-N(Cfl3)2), 2.40 (d, 1 = 4.9 Hz, 1H, H-2), 2.34 (d, 1 = 9.9 Hz, 1H, H-3’), 2.14 (m, 1H, H-6), 1.96- 1.83 (m, 2H, H-2, H-16), 1.77 (s, 3H, H-22), 1.62-1.51 (m, 5H H-4, H-7, H-16, H-19), 1.30 (d, 1 = 5.9 Hz, 3H, H-6’), 1.25 (d 1 = 6.9 Hz, 3H, H-6”’), (d, 1 = 6.6 Hz, 3H, H-21), 1.01 (d, 1 = 6.6 Hz, 3H, H-18), 0.91 (t, 1 = 7.1 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDC13) 5 (ppm): 203.5 (C-9), 174.2 (C- 1), 147.7 (C-ll), 141.9 (C—13), 134.9 (C-12), 118.5 (C-lO), 103.9 (C-l’), 101.0 (C-l”’), 81.8 ), 79.7 (C—5), 77.2 (C-3”’), 75.2 (C-15), 73.3 (C-S’), 72.6 (C-4”’), 70.7 (4C, C- 2’, C-3’, C-4’ , C-S’”), 70.1 (C—23), 68.8 (C—3), 61.7 (C-8”’), 59.6 (C-7”’), 44.9 (2C, C—8, C-14), 43.1 (C-20), 41.7 (2C, C- 7’, 8’), 41.0 (C-4), 39.4 (C-2), 32.8 (C-7), 31.8 (C-6), 27.6 (C-19), 25.4 (C-16), 17.8 (3C, C-21, C-6’, , 12.9 (C- 22), 9.6 (C-17), 9.4 (C—18). (4) Preparation of 20-azidodeoxodesmycosin (YTll) HO OH 0 NaN3 1' —> DMSO 80 I38, 20 h YT8 YTH _ 6 5 _ To a solution onT8 (12.4 g, 15.7 mmol) in DMSO (160 mL, 0.100 M) was added NaN3 (5.10 g, 78.3 mmol) and then the mixture was stirred for 20 hours at 800C. The reaction mixture was diluted with AcOEt and water. The organic layer was separated, the aqueous layer was extracted with AcOEt and the combined organic layer was washed with water, brine, and then dried over Na2SO4 and trated. The resulting products were ed by flash column chromatography to obtain YT11 (Yield: 90%).
Rf: 0.51 (CHC13 : MeOH : NH4OH = 5 : 1 : 0.005) HRFABMS : calcd. for C39H67013N4 : 799.4705 [M+H], found m/z : 799.4684 [M+H]+.
IR (KBr)vcm'1 : 3458 (-OH), 2933 (C-H), 2096 (-N3), 1716 (C=O) 1H NMR (270 MHz, CDCl3) 5 (ppm): 7.30 (d, 1 = 15.5 Hz, 1H, H-11), 6.24 (d, 1 = 15.5 Hz, 1H, H-10), 5.87 (d, 1 = 9.9 Hz, 1H, H-13), 4.95 (br. dt, 1 = 8.4 Hz, 1H, H-15), 4.54 (d, 1 = 7.9 Hz, 1H, H-1”’), 4.29 (d, 1 = 7.3 Hz, 1H,H-1’), 3.98 (dd, 1 = 9.6, 3.6 Hz, 1H, H-23), 3.74-3.66 (m, 3H, H-3, H-5, H- 3’”), 3.60 (s, 3H, H3), 3.56-3.49 (m, 3H, H-23, H-2’, H-5”’), 3.47 (s, 3H, 2”’—ocH3), 3.32—3.20 (m, 3H, H-20, H- ’), 3.16 (dd, 1 = 9.2, 3.0 Hz, 1H, H-4”’), 3.07 (d, 1 = 9.6 Hz, 1H, H-4’), 3.01 (dd, 1 = 7.7, 2.8 Hz, 1H, H-2”’), 2.94 (m, 1H, H-14), 2.73 (m, 1H, H-8), 2.48 (s, 6H, 3’-N(Cfis)2), 2.42 (d, 1 = 12.2 Hz, 1H, H-2), 2.34 (d, 1 = 9.9 Hz, H-3’), 1.96-1.83 (m, 3H, H-2, H-6, H-16), 1.77 (s, 3H, H-22), 1.63-1.49 (m, 5H, H- _ 6 6 _ 4, H-7, H-9, H-16), 1.29 (d, 1 = 6.3 Hz, 3H, H-6’), 1.24 (d, 1 = 5.9 Hz, 3H, H-6”’), 1.18 (d, 1 = 6.6 Hz, 3H, H-21), 1.01 (d, 1 = 6.6 Hz, 3H, H—18), 0.92 (t, 1 = 7.2 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDC13) 5 (ppm):203.3 (C-9), 174.1 (C- 1), 147.8 (C-11), 141.9 (C—13), 134.7 (C-12), 118.5 (C-10), 103.8 (C-1’), 100.8 (C-1”’), 81.6 (C-2”’), 79.7 (05), 77.3 ), 75.1 (015), 73.1 (C-S’), 72.5 (C-4”’), 70.7 (4C, C- 2’, C-3’, C-4’ , C-S’”), 70.0 (C—23), 68.8 (C—3), 61.5 (C-8”’), 59.4 (C-7”’), 49.3 (C-20), 44.7 (2C, C—8, C-14), 41.5 (2C, C- 7’, 8’), 41.5 (C-4), 39.2 (C-2), 32.8 (C-7), 32.4 (C-6), 27.6 (C-19), 25.1 (C-16), 17.6 (3C, C-21, C-6’, C-6”’), 12.8 (C- 22), 9.4 (C-17), 9.2 (C-18). (5) Preparation of 20-triazoledeoxodesmycosins _ _ R - Cul, TBTA CchN or MeOH O O HO 1"! HO 1"! O O OMe OMe 1 5 OMe YT11 OMe To a solution of YTll (0.24 g, 0.30 mmol) in CH3CN or MeOH (3.0 mL) were added copper catalyst (2.9 mg, 0.015 mmol), TBTA (1.6 mg, 3.0 umol) or 2,6-lutidine (0.01 eq.) and acetylene compound wherein R is p-ethynyl (pentyloxy)benzene or phenyl (0.33 mmol) and the mixture was stirred at rt until the on was completed. After tion, the on mixture was diluted with CHClg, washed with 10% NH3 aq.. After removing copper catalyst, the filtrate was washed with brine. The organic layer was dried over Na2804 and concentrated. The resulting ts were purified by flash column chromatography to obtain the triazole compounds.
The results ofthe step (5) are shown in Table 1 below. :aIbl Reaction times* t R = p-ethynyl Entry Conditions s (0.1 (pentyloxy)benzen R = Ph M) e CuI (0.05 eq.) 1 2,6-lutidine CH3CN 2days 2 days (0.01 eq.), rt Cu(CH3CN)4PF 6 (0.05 eq.) 2 MeOH 2days 2days TBTA (0.01 eq.), rt Cu(CH3CN)4PF 6 (0.05 eq.) 3 CH3CN 30 min. 30min.
TBTA (0‘01 eq.), rt CuI (0.05 eq.) . 4 TBTA (0.01 MeOH 50 min 3120““ eq.), rt CuI (0.05 eq.) .
TBTA (0.01 CH3CN 90 min 3120““ eq.), rt * Time for consumption ofthe starting material.
[0077] Under the conditions of Entry 4 or 5 above, with the following nineteen compounds: 2012/073277 yt13 yt14 yt19 yt29 yt30 yt32 as the acetylene compound, the step (5) above was repeated to obtain the 20-triazo1edeoxodesn1ycosins, which are shown below. 20-(4-(pyridiney1)-III-1,2,3-triazolyl) deoxodesmycosin (YT12) _ 6 9 _ YT12 Yield: 85% HRFABMS : calcd. for C46H72013N5 : 902.5127 [M+H], found m/z : 902.5132 .
IR (KBr)vcm'1 : 3436 (-OH), 2933 (C-H), 1722 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm) : 8.62 (d, J = 2.8 Hz, 1H Htriazole -pyridine), 8.23 (m, 2H, Htriazole pyridine, Htriazole- 2-pyridine), 7.79 (dt, J = 5.5, 2.0 Hz, 1H, Htriaz0lepyridine), 7.23 (dd, J = 5.9, 5.0 Hz, 1H, Htriazole- 2-pyridine), 7.12 (d, J = 15.5 Hz, 1H, H-11), 6.19 (d, J =15.5 Hz, 1H, H-10), 5.62 (d, J = 10.2 Hz,1H,H- 13), 4.89 (br. dt, J = 9.2 Hz, 1H, H-15), 4.57 (d, J = 7.9 Hz, 1H, H-1”’), 4.48 (m, 2H, H-20), 4.37 (d, J = 7.6 Hz, 1H, H- 1’), 3.97 (dd, J = 9.2, 4.0 Hz, 1H, H-23), 3.82 (d, J = 9.2 Hz, 1H, H-5), 3.76 (t, J = 3.1 Hz, 1H, H-3”’), 3.64 (s, 3H, 3”’- OCHg), 3.61-3.48 (m, 4H, H-3, H-23, H-2’, H-5”’), 3.46 (s, 3H, 2”’-OCH3), 3.35 (m, 1H, H-5’), 3.18 (dd, J = 9.4, 3.1 Hz, 1H, H-4”’), 3.09 (d, J =9.6, 1H, H-4’), 3.01(dd, J = 7.9, 3.0, 1H, , 2.94 (m, 1H, H-14), 2.67 (m, 1H, H-8), 2.51 (s, 6H, 3’-N(CH3)2), 2.46-2.36 (m, 3H, H-2, H-6, H-3’), 2.04 (m, 1H, H-19), 1.90-1.85 (m, 2H, H-2, H-16), 1.61 (s, 3H, H-22), 1.62-1.51 (m, 4H, H-4, H-7, H-16), 1.27 (d, J = 6.3 Hz, 3H, H-6’), 1.24 (d, J = 6.3 Hz, 3H, H-6”’), 1.18 (d, J = 6.6 Hz, 3H, H-21), 1.04 (d, J = 6.6 Hz, 3H, H-18), 0.92 (t, J = 7.3 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.4 (C-9), 174.2 (C- 1), 150.8 (C triazolepyridine), 149.7 (Ctriaz01e-2_— pyridine), 148.2 (C-11), 142.5 (C-13), 137.1 (Ctriaz01e-2_- pyridine), 135.2 (C-12), 122.9 (Ctriaz01epyridine), 122.5 (2C, C-20 -triaz01epyridine), 120.7 (Ctriaz01e-2_— pyridine), 118.6 (C-10), 104.2 (C-1’), 101.4 ), 82.0 (C- 2”’), 80.3 (C-5), 78.1 (C-3”’), 75.4 (C-15), 73.6 (C-5’), 73.1 (C-4”’), 70.7 (4C, C-2’, C-3’, C-4’, C-5”’), 69.5 , 67.1 (C-3), 62.0 (C-8”’), 59.8 (C-7”’), 48.8 (C-20), 45.2 (2C, C-8, C-14), 39.7 (2C, C-7’, 8’), 41.5 (C-4), 39.7 (C-2), 32.8 (C-7), 32.4 (C-6), 27.6 (C-19), 25.6 (C-16), 18.1 (2C, C-6’, C-6”’), 17.6 (C-21), 13.2 , 9.9 (C-17), 95 (C-18). 20-(4-phenyl-1H-1,2,3-triazolyl) deoxodesmycosin (YT13) HOWO 23 OMe Yield:98% W0 2013/076169 2012/073277 HRFABMS : calcd. for C47H73013N4 : 901.5174 [M+H], found m/z : 902.5157 [M+H]+.
IR (KBr)vcm'1 : 3442 (-OH), 2933 (C-H), 1720 (C=O). 1H NMR (270MHz, CDCl3) 6 (ppm): 8.00 (d, J = 7.3 Hz, 2H, Htriazole-pheny1), 7.90 (s, 1H, Htriazole-pheny1), 7.46 (t, J = 7.6 Hz, 2H, Htriazole-pheny1), 7.32 (t, J = 6.9 Hz, 1H, Htriazole-pheny1), 6.92 (d, J = 15.5 Hz, 1H, H- 11), 6.14 (d, J = 15.2 Hz, 1H, H-10), 5.23 (d, J = 9.6 Hz,1H, H-13), 4.80 (br. dt, J = 9.6 Hz,1H, H-15), 4.57 (d, J = 7.6 Hz, 1H, H-1”’), 4.48 (m, 2H, H-20), 4.35 (d, J = 7.2 Hz, 1H, H- 1’), 3.92 (dd, J = 9.2, 4.3 Hz, 1H, H-23), 3.81 (d, J = 9.9 Hz, 1H, H-5), 3.76 (t, J = 2.6 Hz, 1H, H-3”’), 3.64 (s, 3H, 3”’- OCHg), 3.60-3.36 (m, 5H, H-3, H-23, H-2’, H-5”’, H-5’), 3.40 (s, 3H, 2”’-OCH3), 3.16 (dd, J = 9.4, 3.1 Hz, 1H, H-4”’), 3.08 (d, J = 9.6, H-4’), 2.98(dd, J = 7.8, 2.4, 1H, , 2.86 (m, 1H, H-14), 2.67 (m, 1H, H-8), 2.50 (s, 6H, 3’-N(Cfl3)2), 2.44- 2.37 (m, 2H, H-2, H-3’), 2.20 (m, 1H, H-6), 2.02 (m, 1H, H- 19), 1.90-1.75 (m, 2H, H-2, H-16), 1.66 (s, 3H, H-22), 1.62- 1.51 (m, 4H, H-4, H-7, H-16), 1.28 (d, J = 6.0 Hz, 3H, H-6’), 1.27 (d, J = 6.0 Hz, 3H, , 1.17 (d, J = 6.9 Hz, 3H, H- 21), 1.00 (d, J = 6.6 Hz, 3H, H-18), 0.90 (t, J = 7.3 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.8 (C-9), 173.7 (C- 1), 148.1 (C-11), 147.7 (Ctriazole-pheny1), 142.7 (C-13), 134.9 (C-12), 131.1 (Ctriazole-pheny1), 129.2 (C triazole-phenyl), 128.9 (Ctriazole-pheny1), 128.1 (C triazole- phenyl), 126.1 (2C, Ctriazole-pheny1), 119.7 (C- -triazole-pheny1), 118.2 (010), 103.8 (C-1’), 101.3 (C-1”’), 81.9 (C-2”’), 80.1 (C-S), 78.0 (C-3”’), 75.1 (C-15), 73.4 (C- ’), 73.0 ), 705 (4C, C-2’, C-3’, C-4’, C-S’”), 69.6 (C- 23), 66.9 (C-3), 61.8 (C-8”’), 597 (C-7”’), 48.1 (C-20), 450 (2C, C-8, C-14), 41.9 (2C, C-7’, 8’), 41.5 (C-4), 395 (C-2), 32.8 (C-7), 32.4 (C-6), 27.7 (C-19), 25.6 (C-16), 18.0 (2C, C- C-6”’), 17.5 (C-21), 13.1 (C-22), 9.8 (C-17), 9.3 (C-18).
[0080] 20-(4-(thi0pheneyl)-1H-1,2,3-triazolyl) deoxodesmycosin (YT14) Yield:81% HRFABMS : calcd. for C45H71O13N4S : 907.4738 [M+H], found m/z : 907.4730 .
IR (KBr)vcm'1 : 3437 (-OH), 2933 (C-H), 1720 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm): 7.84 (s, 1H, H triazole-thiophene), 7.81 (s, 1H, riazole-thiophene), 7.65 (d, J = 4.6 Hz, 1H, Htriazole-thiophene), 7.42 (m, 1H, Htriazole-thiophene), 6.91 (d, J = 15.5 Hz, 1H, H-11), 6.15 (d, J = 15.5 Hz,1H, H-10), 5.31 (d, J = 11.2 Hz,1H, H- 13), 4.84 (dt, J = 9.2, 7.0 Hz, 1H, H-15), 4.57 (d, J = 7.9 Hz, 1H, H-1”’), 4.48 (m, 2H, H-20), 4.35 (d, J = 7.6 Hz, 1H, H- 1’), 3.95 (dd, J = 9.2, 4.2 Hz, 1H, H-23), 3.81 (d, J = 9.9 Hz, 1H, H-5), 3.75 (t, J = 3.0 Hz, 1H, H-3”’), 3.64 (s, 3H, 3”’- OCHg), 3.60-3.35 (m, 5H, H-3, H-23, H-2’, H-5”’, H-5’), 3.43 (s, 3H, 2”’-OCH3), 3.17 (dd, J = 9.2, 3.1 Hz, 1H, , 3.10 (br. dd, J = 9.4, H-4’), 3.01 (dd, J = 7.9, 2.8, 1H, H-2”’), 2.89 (m, 1H, H-14), 2.65 (m, 1H, H-8), 2.53 (s, 6H, 3’- N(Cfl3)2), 2.49-2.39 (m, H-2, H-3’), 2.25 (m, 1H, H-6), 2.08 (m, 1H, H-19), 1.85-1.75 (m, 2H, H-2, H-16), 1.68 (s, 3H, H- 22), 1.56-1.54 (m, 4H, H-4, H-7, H-16), 1.29 (d, J = 6.0 Hz, 3H, H-6’), 1.27 (d, J = 6.2 Hz, 3H, H-6”’), 1.18 (d, J = 6.9 Hz, 3H, H-21), 1.01 (d, J = 6.6 Hz, 3H, H-18), 0.90 (t, J = 7.3 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 204.0 (C-9), 174.0 (C- 1), 148.3 (C-11), 144.4 (Ctriaz0le-thiophene), 143.1 (C- 13), 135.1 (C-12), 132.5 (Ctriazole hene), 126.6 (C- -triazole-thiophene), 121.4 (Ctriazole-thiophene), 119.7 triazole-thiophene), 118.5 (C-10), 104.0 (C-1’), 101.5 (C-1”’), 82.2 (C-2”’), 80.2 (C-5), 78.0 (C-3”’), 75.1 (C-15), 73.6 (C-5’), 73.1 (C-4”’), 70.8 (4C, C-2’, C-3’, C-4’, C-5”’), 69.8 (C-23), 66.9 (C-3), 62.1 (C-8”’), 59.9 ), 48.3 (C-20), 45.3 (2C, C-8, C-14), 42.1 (2C, C-7’, 8’), 41.5 (C-4), 39.8 (C-2), 32.8 (C-7), 32.4 (C-6), 26.7 (C-19), 25.6 (C-16), 18.2 (2C, C-6’, C-6”’), 17.5 (C-21), 13.3 (C-22), .0 (C-17), 9.5 (C-18).
W0 2013/076169 (pyridineyl)-1H-1,2,3-triazolyl) deoxodesmycosin (YT16) Yield:82% HRFABMS : calcd. for C46H72013N5 : 902.5127 [M+H], found m/z : 902.5106 [M+H]+.
IR (KBr)vcm'1 : 3438 (-OH), 2931 (C-H), 1722 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm): 9.22 (s, 1H, H lepyridine ), 8.59 (d, J = 4.0 Hz, 1H, Htriazole- 3-pyridine), 8.34 (d, 1H, Htriazolepyridine), 8.02 (s, 1H, Htriazolepyridine), 7.43 (dd, J = 7.9, 5.1 Hz, 1H, Htriazole pyridine), 6.88 (d, J = 15.2 Hz, 1H, H-11), 6.16 (d, J =15.2 Hz, 1H, H-10), 5.30 (d, J = 10.2 Hz,1H,H- 13), 4.87 (br. dt, J = 9.2 Hz, 1H, H-15), 4.58 (d, J = 7.6 Hz, 1H, H-1”’), 4.48 (m, 2H, H-20), 4.37 (d, J = 7.6 Hz, 1H, H- 1’), 3.97 (dd, J = 9.6, 4.0 Hz, 1H, H-23), 3.83 (d, J = 9.9 Hz, 1H, H-5), 3.76 (t, J = 2.7 Hz, 1H, H-3”’), 3.65 (s, 3H, 3”’- OCflg), 3.61-3.35 (m, 4H, H-3, H-23, H-2’, H-5”’), 3.41 (s, 3H, 2”’-OCH3), 3.35 (m, 1H, H-5’), 3.18 (dd, J = 9.3, 3.2 Hz, 1H, H-4”’), 3.11 (t, J = 9.4, H-4’), 3.01(dd, J = 7.9,2.7,1H, H'2”,), 291 (m, 1H, H-14), 2.65 (1’11, 1H, H'8), 2.53 (S, 6H9 _ 7 5 _ 3’-N(Cfl3)2), 2.46-2.39 (m, 2H, H-2, H-3’), 2.28 (m, 1H, H-6), 2.05, (m, 1H, H-19), .79 (m, 2H, H-2, H-16), 1.69 (s, 3H, H-22), 1.60-1.55 (m, 4H, H-4, H-7, H-16), 1.27 (d, J = 6.3 Hz, 3H, H-6’), 1.24 (d, J = 6.3 Hz, 3H, H-6”’), 1.18 (d, J = 6.9 Hz, 3H, H-21), 1.03 (d, J = 6.6 Hz, 3H, H-18), 0.91 (t, J = 7.3 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.7 (C-9), 174.1 (C- 1), 149.0 (Ctriaz01e idine), 148.1 (Ctriaz01e-3_— pyridine), 147.4 (C-11), 144.8 (Ctriaz01e pyridine), 143.0 (C-13), 135.0 (C-12), 133.6 (Ctriaz01e- 3-pyridine), 127.5 (C triazolepyridine), 124.0 (Ctriaz01e-3_— pyridine), 120.4 (Ctriaz01epyridine), 118.3 (C-10), 104.0 (C-1’), 101.5 (C-1”’), 82.0 (C-2”’), 80.3 (C-5), 77.7 (C-3”’), 75.3 (C-15), 73.6 (C-5’), 73.1 (C-4”’), 70.5 (4C, C- 2’, C-3’, C-4’, C-5”’), 69.7 (C-23), 67.0 (C-3), 62.0 (C-8”’), 59.8 (C-7”’), 48.4 (C-20), 45.2 (2C, C-8, C-14), 42.0 (2C, C- 7’, 8’), 40.7 (C-4), 39.7 (C-2), 32.8 (C-7), 31.8 (C-6), 25.8 (C-19), 25.8 (C-16), 18.1 (2C, C-6’, C-6”’), 17.6 (C-21), 13.2 , 9.9 (C-17), 9.5 . 20-(4-(3-amin0phenyl-1H-1,2,3-triazolyl) deoxodesmycosin (YT17) _ 7 6 _ Yield:91% HRFABMS : calcd. for C47H74013N5 : 916.5283 [M+H], found n1/z : 916.5309 [M+H]+.
IR (KBr)vcm'1 : 3463 (-OH), 2933 (C-H), 1720 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm) : 7.84 (s, 1H, H triazoleani1ine), 7.33-7.29 (m, 2H, Htriazoleani1ine), 7.18 (t, J = 7.6 Hz,1H, Htriazole- 3-ani1ine), 6.84 (d, J = .2 Hz, 1H, H-11), 6.61 (d, J = 7.0 Htriazole- 3_- aniline), 6.08 (d, J = 15.5 Hz,1H, H-10), 5.17 (d, J = 9.6 Hz, 1H, H-13), 4.76 (br. dt, J = 8.9 Hz, 1H, H-15), 4.52 (d, J = 7.9 Hz, 1H, H-1”’), 4.48 (m, 2H, H-20), 4.30 (d, J = 7.2 Hz, 1H, H-1’), 3.90 (dd, J = 9.6, 4.3 Hz, 1H, H-23), 3.75 (d, J = 9.9 Hz, 1H, H-5), 3.71 (t, J = 2.8 Hz, 1H, H-3”’), 3.58 (s, 3H, 3”’-OCH3), 3.55-3.23 (m, 5H, H-3, H-23, H-2’, H-5’, H-5”’), 3.34 (s, 3H, 2”’-OCH3), 3.14 (dd, J = 9.6, 3.0 Hz,1H,H-4”’), 3.06 (d, J = 9.6, H-4’), 2.94(dd, J = 7.9, 2.7, 1H, H-2”’), 2.86 (m, 1H, H-14), 2.67 (m, 1H, H-8), 2.47 (s, 6H, 3’-N(CH3)2), .34 (m, 2H, H-2, H-3’), 2.18 (m, 1H, H-6), 1.99 (m, 1H, H-19), 1.77-1.71 (m, 2H, H-2, H-16), 1.61 (s, 3H, H-22), 1.57-1.44 (m, 4H, H-4, H-7, H-16), 1.23 (d, J = 6.3 Hz, 3H, H-6’), 1.22 (d, J = 6.0 Hz, 3H, H-6”’), 1.11 (d, J = 6.6 Hz, 3H, H-21), 0.97 (d, J = 6.6 Hz, 3H, H-18), 0.85 (t, J = 7.1 Hz, 3H, H-17). 13C NMR (67.5 MHZ, C13) 6 (ppm): 203.9 (C-9), 173.9 (C-1), 148.4 (C-11), 148.0 (Ctriazoleani1ine), 147.3 (C triazoleani1ine), 142.9 (C-13), 135.2 (C-12), 132.0 (C triazoleani1ine), 130.0 (Ctriaz016ani1ine), 120.0 (C- -triazole aniline), 118.3 (C-10), 116.3 (Ctriazole-3_- aniline), 115.0 triazole aniline), 112.8 (C triazoleani1ine), 104.0 (C-1’), 101.4 (C-1”’), 81.9 (C-2”’), 80.3 (C-5), 77.7 (C-3”’), 75.3 (C-15), 73.5 (C-5’), 73.0 (C- 4”’), 70.5 (4C, C-2’, C-3’, C-4’ , , 69.9 (C-23), 67.1 (C-3), 62.0 (C-8”’), 59.8 (C-7”’), 47.9 (C-20), 45.1 (2C, C-8, C-14), 41.9 (2C, C-7’, 8’), 40.9 (C-4), 39.7 (C-2), 33.2 (C-7), 32.8 (C-6), 27.8 (C-19), 25.9 (C-16), 18.1 (2C, C-6’, C-6”’), 17.7 (C-21), 13.2 (C-22), 9.9 (C-17), 9.4 (C-18). (3-amin0phenyl-1H-1,2,3-triazolyl) deoxodesmycosin (YT18) _ 7 8 _ Yield:67% HRFABMS : calcd. for C47H74013N5 : 916.5283 [M+H], found m/z : 916.5266 [M+H]+.
IR (KBr)vcm'1 : 3448 (-OH), 2933 (C-H), 1720 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm): 7.83 (d, J = 7.9 Hz,1H, Htriazole- 4-ani1ine), 7.77 (s, 1H, Htriazole aniline), 7.73 (d, J = 8.9 Hz, 1H, Htriazole- 4-ani1ine), 6.90 (d, J = 15.5 Hz, 1H, H-11), 6.80-6.77 (m, 2H, H triazoleani1ine), 6.11 (d, J = 15.5 Hz, 1H, H-10), 5.12 (br. d, 1H, H-13), 4.75 (br. dt, .1 = 8.9 Hz, 1H, H-15), 4.61 (d, J = 7.9 Hz, 1H, H-1”’), 4.53 (m, 2H, H-20), 4.35 (d, J = 7.3 Hz, 1H, H-1’), 3.96 (dd, J = 9.0, 3.5 Hz,1H,H-23),3.79-3.72(n1, 2H, H-5, H-3”’), 3.64 (s, 3H, 3”’-OCH3), 3.50-3.45 (m, 5H, H-3, H-23, H-2’, H-5”’), 3.42 (s, 3H, 2”’-OCH3), 3.32 (m, 1H, H-5’), 3.20-3.12 (m, 2H, H-4’, H-4”’), 3.00 (dd, J = 7.9, 2.6, 1H, H-2”’), 2.86 (m, 1H, H-14), 2.60 (m, 1H, H-8), 2.59 (s, 6H, 3’-N(CH3)2), 2.45-2.35 (m, 2H, H-2, H-3’), 2.18-1.14 (m, 2H, H-6, H-19), 1.74-1.64 (m, 2H, H-2, H-16), 1.61 (s, 3H, H- 22), 1.56-1.45 (m, 4H, H-4, H-7, H-16), 1.27 (d, J = 6.3 Hz, 3H, H-6’), 1.26 (d, J = 6.0 Hz, 3H, H-6”’), 1.16 (d, J = 6.9 Hz, 3H, H-21), 0.98 (d, J = 6.9 Hz, 3H, H-18), 0.88 (t, J = 7.2 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.9 (C-9), 173.1 (C- 1), 148.2 (2C, C-11, riazoleani1ine), 146.6 (C triazoleani1ine), 142.9 , 134.9 , 127.2 (2C, C- -triazoleani1ine), 121.0 (Ctriaz016ani1ine), 118.0 (2C, C-10, riazoleani1ine), 115.2 (2C, Ctriazole- WO 76169 _ 7 9 _ 4-ani1ine, Ctriazoleani1ine), 103.5 (C-1’), 101.2 (C- 1”’), 81.5 (C-2”’), 80.3 (C-5), 77.3 (C-3”’), 74.5 (C-15), 73.2 (C-5’), 73.1 (C-4”’), 70.2 (4C, C-2’, C-3’, C-4’, C-5”’), 69.8 (C-23), 66.5 (C-3), 61.9 (C-8”’), 60.0 (C-7”’), 47.5 (C-20), 44.7 (2C, C-8, C-14), 41.7 (2C, C-7’, 8’), 40.6 (C-4), 39.5 (C-2), 33.2 (C-7), 32.8 (C-6), 27.1 (C-19), 25.5 (C-16), 17.8 (2C, C-6’, , 17.7 (C-21), 12.8 (C-22), 9.6 (C-17), 9.0 (C-18).
[0084] (4-chlor0butyl)-1H-1,2,3-triazolyl) deoxodesmycosin (YT19) Yield:54% HRFABMS : calcd. for C45H76013N4C1 : 915.5097 [M+H], found m/z : 915.5129 [M+H]+.
IR (KBr)vcm'1 : 3433 (-OH), 2933 (C-H), 1722 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm): 7.35 (s, 1H, H triazole-l-chlorobutyl), 7.14 (d, J = 15.2 Hz, 1H, H-11), 6.19 (d, J =15.2 Hz, 1H, H-10), 5.83 (d, J = 10.2 Hz,1H,H-13), 4.94 (br. dt, J = 8.6 Hz, 1H, H-15), 4.54 (d, J = 7.9 Hz,1H, H-1”’), 4.33-4.31 (m, 3H, H-20, H-1’), 3.97 (dd, J = 9.4, 3.7 Hz, 1H, H-23), 3.77-3.67 (m, 2H, H-5, H-3”’), 3.59 (s, 3H, _ 8 0 _ 3”’-OCH3), 3.57-3.49 (m, 6H, H-3, H-23, H-2’, H-5”’, H triazole ch10r0buty1), 3.45 (s, 3H, 2”’-OCH3), 3.32 (m, 1H, H-5’), 3.16 (d, J = 8.9 Hz, 1H, H-4”’), 3.08 (t, J = 9.4 Hz,1H, H-4’), 3.00 (dd, J = 7.9, 2.6, 1H, H-2”’), 2.93 (m, 1H, H-14), 2.76 (m, 2H, riazolech10robuty1), 2.60 (m, 1H, H-8), 2.49 (s, 6H, 3’-N(CH3)2), 2.43-2.35 (m, 2H, H-2, H-3’), 2.26- 2.15(rn,2H,H-6,H-19),1.83-1.88(m,2H,H-2,H-16), 1.73 (s, 3H, H-22), 1.65-1.45 (m, 4H, H-4, H-7, H-16), 1.23 (d, J = 6.3 Hz, 3H, H-6’), 1.20 (d, J = 6.0 Hz, 3H, H-6”’), 1.16 (d, J = 6.6 Hz, 3H, H-21), 1.01 (d, J = 6.6 Hz, 3H, H-18), 0.90 (t, J = 7.3 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDCl3) 6 (ppm) : 203.3 (C-9), 173.7 (C-1), 148.0 (C-11), 147.3 (Ctriazolech10r0buty1), 141.9 (C-13), 134.5 (C-12), 120.5 (Ctriazole chlorobutyl), 118.0 (C-10), 103.8 (C-1’), 100.9 (C-1”’), 81.7 (C-2”’), 79.7 (C-5), 77.2 (C-3”’), 75.0 (C-15), 73.2 (C-5’), 72.6 (C-4”’), 70.7 (4C, C-2’, C-3’, C-4’, C-5”’), 70.0 (C-23), 66.0 (C-3), 61.6 (C-8”’), 59.5 ), 48.0 (C-20), 45.0 (C- 14), 44.7 (C-8), 41.6 (2C, C-7’, 8’), 40.6 (C-4), 39.4 (C-2), 33.8 (C-7), 33.0 (C-6), 31.9 (2C, riazolech10robuty1), 28.7 (C-19), 26.5 (Ctriazolech10robuty1), 25.2 (C-16), 24.7 (Ctriazolech10r0buty1), 17.6 (2C, C-6’, C-6”’), 17.3 (C-21), 12.8 , 9.5 (C-17), 9.2 (C-18).
[0085] 20-(4-butyl-1H-1,2,3-triazolyl) deoxodesmycosin (YT20) Yield:83% HRFABMS : calcd. for C45H77013N4: 881.5487 [M+H], found m/z : 881.5443 [M+H]+.
IR (KBr)vcm'1 : 3440 (-OH), 2933 (C-H), 1722 (C=O). 1H NMR (270 MHz, CDC13) 6 (ppm) : 7.33 (s, 1H, H le-butyl), 7.18 (d, J = 15.5 Hz, 1H, H-11), 6.20 (d, J = .5 Hz, 1H, H-10), 5.86 (d, J = 10.2 Hz, 1H, H-13), 4.96 (br. dt, J = 9.2 Hz, 1H, H-15), 4.55 (d, J = 7.9 Hz, 1H, H-1”’), 4.38-4.33 (m, 3H, H-20, H-1’), 4.01-3.93 (m, 4H, H-23, H triazole-Mfl), 3.78-3.73 (m, 2H, H-5, , 3.61 (s, 3H, 3”’-OCH3), 3.56-3.50 (m, 4H, H-3, H-23, H-2’, H-5”’), 3.47 (s, 3H, 2”’-OCH3), 3.38 (m, 1H, H-5’), 3.24 (d, J = 9.9 Hz,1H, H-4”’), 3.17 (dd, J = 9.6, 3.1 Hz, 1H, H-4’), 3.01 (dd, J = 7.7, 2.8, 1H, H-2”’), 2.94 (m, 1H, H-14), 2.76-2.70 (m, 9H, H-8, 3’-N(Cfl3)2, Htriazole-Mfl), 2.50—2.33 (m, 3H, H-2, H- 3’), 2.23 (m, 1H, H-6), 2.02 (m, 3H, H-19, Htriazole- M), 1.91-1.85 (m, 2H, H-2, H-16), 1.76 (s, 3H, H-22), 1.73-1.54 (m, 4H, H-4, H-7, H-16), 1.40 (m,2H, H le-Mfl), 1.26-1.24 (m, 6H, H-6’, H-6”’), 1.17 (d, J = 6.9 Hz, 3H, H-21), 1.01 (d, .1 = 6.6 Hz, 3H, H-18), 0.90 (t, .1 = 7.3 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDCl3) 6 (ppm) : 203.3 (C-9), 173.6 (C-l), 148.1 (C-ZO-triazole-butyl), 147.8 (C-ll), 142.4 (C-13), 134.6 (C-12), 120.3 (Ctriazole -buty1), 118.1 (C-lO), 103.8 (C-l’), 100.9 (C-l”’), 81.6 (C-2”’), 79.7 (C—5), 77.2 (C-3”’), 74.9 (C-15), 73.2 (C-S’), 72.6 (C-4”’), 70.7 (4C, C- 2’, C-3’, C-4’, C-S’”), 69.0 (023), 66.5 (C-3), 61.5 (C-8”’), 59.4 (C-7”’), 47.9 (C-20), 44.9 (C-14), 44.7 (C—8), 41.5 (2C, C-7’, 8’), 39.4 (2C, C-2, C-4), 33.8 (C-7), 33.0 (C-6), 31.4 triaz016 -M), 28.9 (C-19), 25.1 (Ctriazole-Mfl), 22.2 (3C, C-16, C—20—triazole-MLI), 17.6 (2C, C-6’, C-6”’), 17.2 (C-21), 13.7 (Ctriazole-Mfl), 12.8 (C-22), 9.5 (C- 17), 9.1 .
[0086] 20-(4-phenyl-1H-1,2,3-triazolyl) deoxodesmycosin (YT21) Yield:86% HRFABMS : calcd. for C53H77O13N4 : 977.5487 [M+H], found m/z : 64 [M+H]+. _ 8 3 _ IR (KBr)vcm'1 : 3440 (-OH), 2931 (C-H), 1718 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm): 8.06 (m, 2H, H le-biphenyl), 7.94 (s, 1H, Htriazole-bipheny1), 7.72- 7.63 (m, 4H, Htriazole-bipheny1), 7.48-7.42 (m, 2H, H- 20-triazole-bipheny1), 7.35 (d, J = 7.3 Hz, 1H, Htriazole- biphenyl), 6.99 (d, J = 15.5 Hz, 1H, H-11), 6.17 (d, J = 15.2 Hz, 1H, H-10), 5.36 (d, J = 8.9 Hz, 1H, H-13), 4.80 (br. dt, J = 8.7 Hz, 1H, H-15), 4.47 (m, 2H, H-20), 4.38-4.35 (m, 2H, H-1’, H-1”’), 3.84-3.81 (m, 2H, H-5, H-23), 3.67 (t, J = 2.8 Hz, 1H, H-3”’), 3.59 (s, 3H, 3”’-OCH3), 3.53-3.47 (m, 4H, H- 3, H-23, H-2’, H-5”’), 3.38 (s, 3H, 2”’-OCH3), 3.27 (m, 1H, H-5’), 3.13-3.07 (m, 2H, H-4’, H-4”’), .89 (m, 2H, H- 14, H-2”’), 2.70 (m, 1H, H-8), 2.51 (s, 6H, 3’-N(Cfl3)2), 2.45- 2.37 (m, 2H, H-2, H-3’), 2.28 (m, 1H, H-6), 2.10 (m, 1H, H- 19), 1.83-1.75 (m, 2H, H-2, H-16), 1.68 (s, 3H, H-22), 1.59- 1.54 (m, 4H, H-4, H-7, H-16), 1.28 (d, J = 6.0 Hz, 3H, H-6’), 1.24-1.18 (m, 6H, H-6”’, H-21), 1.02 (d, J = 6.9 Hz, 3H, H- 18), 0.89 (t, J = 7.4 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.9 (C-9), 174.0 (C- 1), 148.2 (Ctriazole ny1), 147.4 (C-11), 142.8 (C- 13), 140.8 (Ctriazole-bipheny1), 135.1 (C-12), 130.1 (C- -triazole-bipheny1), 129.1 (4C, Ctriazole-bipheny1), 127.6 (2C, C-20 -triazole-bipheny1), 127.2 (2C, Ctriazole- biphenyl), 126.6 (2C, Ctriazole -bipheny1), 120.0 (C triazole-biphenyl), 118.4 , 103.8 (C-1’), 101.2 (C-1”’), 82.1 (C-2”’), 80.1 (C-5), 78.0 (C-3”’), 75.6 (C-15), 73.5 (C- ’), 72.9 (C-4”’), 70.5 (4C, C-2’, C-3’, C-4’, C-5”’), 69.4 (C- 23), 67.0 (C-3), 61.9 (C-8”’), 59.8 (C-7”’), 48.3 (C-20), 45.2 (2C, C-8, C-14), 42.0 (2C, C-7’, 8’), 41.5 (C-4), 39.6 (C-2), 32.8 (C-7), 32.4 (C-6), 28.1 (C-19), 25.8 (C-16), 18.2 (2C, C- 6’, C-6”’), 17.7 (C-21), 13.2 (C-22), 9.8 (C-17), 9.3 (C-18). eth0xycarb0ny1-1H-1,2,3-triazolyl) deoxodesmycosin (YT22) Yield:86% HRFABMS : calcd. for C44H72015N4Na : 919.4892 [M+Na], found m/z : 919.4877 [M+Na]+.
IR (KBr)vcm'1 : 3452 (-OH), 2933 (C-H), 1726 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm): 8.15 (s, 1H, H triazole-COOEt), 7.23 (d, J = 15.5 Hz,1H, H-11), 6.21 (d, J = 15.5 Hz, 1H, H-10), 5.87 (d, .1 = 9.9 Hz, 1H, H-13), 4.95 (br. dt, J = 9.2 Hz, 1H, H-15), 4.54 (d, .1 = 7.6 Hz, 1H, H-1”’), 4.46-4.38 (m, 4H, H-20, Htriazole-COOEt), 4.32 (m, 1H, H-1’), 3.98 (d, .1 = 9.6 Hz, 1H, H-23), 3.55-3.65 (m, 2H, H-5, H-3”’), 3.59 (s, 3H, 3”’—0CH3), .46 (m, 4H, H-3, H-23, H-2’, H-5”’), 3.45 (s, 3H, H3), 3.30 (m, 1H, H-5’), 3.15 (d, J = 9.6 Hz,1H, H-4”’), 3.09-2.94 (m, 3H, H-14, H-4’, _ 8 5 _ H-2”’), 2.59 (m, 1H, H-8), 2.48 (s, 6H, 3’-N(Cfl3)2), 2.40— 2.33 (m, 4H, H-2, H-6, H-19, H-3’), .85 (m, 2H, H-2, H-16), 1.75 (s, 3H, H-22), 1.63-1.54 (m, 4H, H-4, H-7, H-16), 1.39 (dt, J = 7.3, 3.0 Hz, 2H, H-20 ole-COOEt), 1.24 (d, 1 = 5.0 Hz, 3H, H-6”’), 1.19—1.17 (m, 6H, H-21, H-6’), 1.01 (d, 1 = 6.3 Hz, 3H, H—18), 0.90 (t, 1 = 6.9 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDC13) 5 (ppm): 203.7 (C-9), 174.4 (C- 1), 161.1 (020 triazole-QOOEt), 148.3 (011), 142.8 (013), 140.3 (Ctriazole-COOEt), 135.2 (C-12), 127.6 (C triazole-COOEt), 118.3 (C-lO), 103.8 (C-l’), 101.8 (C-l”’), 82.1 (C-2”’), 80.1 (05), 77.3 (C-3”’), 75.6 (015), 73.7 (C- ’), 73.0 (C-4”’), 70.7 (4C, C-2’, C-3’, C-4’, C-S’”), 69.4 (C- 23), 67.2 (C-3), 62.0 (Ctriazole-COOEt), 61.3 (C-8”’), 59.9 (C-7”’), 49.1 , 45.3 (2C, C-8, C-14), 42.0 (2C, 0 7’, 8’), 39.5 (2C, C-2, C-4), 33.8 (C-7), 33.0 (C-6), 28.9 (C- 19), 25.7 (C-16), 18.1 (2C, C-6’, C-6”’), 17.6 (C-21), 14.6 (Ctriazole-COOEt), 13.2 (C-22), 10.0 (C-17), 9.6 (C-18). 20-(4-(phenanthrene-S-yD-1H-1,2,3-triazolyl) deoxodesmycosin (YT23) WO 76169 _ 8 6 _ Yield:93% HRFABMS : calcd. for 013N4 : 1001.5487 [M+H], found m/z : 1001.5475 [M+H]+.
IR (KBr)vcm'1 : 3444 (-OH), 2929 (C-H), 1720 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm):8.80-8.64 (m, 3H, H triazole-phenanthrene), 8.18 (s, 1H, Htriazole- phenanthrene), 8.02 (s, 1H, Htriaz0le-phenanthrene), 7.98 (d, J = 7.6 Hz, 1H, Htriaz0le-phenanthrene), 7.72-7.59 (m, 4H, Htriazole -phenanthrene), 6.95 (d, J = 15.2 Hz, 1H, H-11), 6.16 (d, J: 15.5 Hz, 1H, H-10), 5.18 (br. d, 1H, H-13), 4.67 (m, 1H, H-15), 4.56 (m, 2H, H-20), 4.45 (d, J = 7.9 Hz, 1H, H-1”’), 4.38 (d, J = 7.3 Hz, 1H, H-1’), 3.90 (d, J = 9.6 Hz, 1H, H-23), 3.74 (m, 1H, H-5), 3.76 (t, J = 3.0 Hz,1H,H- 3”’), 3.63 (s, 3H, 3”’-OCH3), 3.58-3.48 (m, 4H, H-3, H-23, H- 2’, H-5”’), 3.37 (m, 1H, H-5’), 3.26 (s, 3H, 2”’-OCH3), 3.16- 3.06 (m, 2H, H-4’, H-4”’), 2.88 (dd, J = 7.4, 2.2, 1H, H-2”’), 2.86 (m, 1H, H-14), 2.67 (m, 1H, H-8), 2.50 (s, 6H, 3’- N(Cfl3)2), 2.44-2.37 (m, 2H, H-2, H-3’), 2.20-2.00 (m, 2H, H- 6, H-19), 1.88-1.77 (m, 2H, H-2, H-16), 1.66 (s, 3H, H-22), .58 (m, 4H, H-4, H-7, H-16), 1.30-1.25 (m, 6H, H-6’, H-6”’), 1.18 (d, J = 6.6 Hz, 3H, H-21), 1.05 (d, J = 6.9 Hz, 3H, H-18), 0.87 (t, .1 = 7.2 Hz, 3H, H-17). 20-(4-(4-phen0xyphenyl)-1H-1,2,3-triazolyl) deoxodesmycosin (YT24) 2012/073277 _ 8 7 _ Yield:85% S : calcd. for C53H77014N4 : 993.5436 [M+H], found m/z : 993.5455 [M+H]+.
IR (KBr)vcm'1 : 3444 (-OH), 2931 (C-H), 1720 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm): 7.94 (d, J = 8.3 Hz, 2H, Htriazole- Ph-O-Ph), 7.85 (s, 1H, Htriazole-Ph-O-Ph), 7.37-7.31 (m, 2H, Htriazole- Ph-O-Ph), 7.13-7.03 (m, 5H, Htriazole-Ph-O-Ph), 6.99 (d, J = 15.5 Hz, 1H, H-11), 6.17 (d, J = 15.1 Hz, 1H, H-10), 5.45 (d, J = 10.4 Hz,1H,H-13), 4.86 (br. dt, J = 9.2 Hz, 1H, H-15), 4.57 (d, J = 7.9 Hz,1H, H-1”’), 4.46 (m, 2H, H-20), 4.35 (d, J = 7.2 Hz, 1H, H-1’), 3.95 (dd, J = 9.5, 4.2 Hz, 1H, H-23), 3.82 (d, J = 9.9 Hz,1H, H-5), 3.72 (t, J = 2.6 Hz, 1H, H-3”’), 3.59 (s, 3H, 3”’-OCH3), 3.53-3.45 (m, 5H, H-3, H-23, H-2’, H-5’, H-5”’), 3.43 (s, 3H, 2”’-OCH3), 3.14 (dd, J = 9.5, 3.1 Hz, 1H, , 3.08 (t, J =9.0, H-4’), 3.00(dd, J = 7.7, 2.8, 1H, H-2”’), 2.91 (m, 1H, H-14), 2.62 (m, 1H, H-8), 2.50 (s, 6H, 3’-N(CH3)2), 2.47-2.37 (m, 2H, H-2, H-3’), 2.26 (m, 1H, H-6), 2.08 (m, 1H, H-19), 1.86-1.76 (m, 2H, H-2, H-16), 1.71 (s, 3H, H-22), 1.57-1.42 (m, 4H, H-4, H-7, H-16), 1.27 (d, .1 = 5.9 Hz,3H,H-6’),1.23 (d, J = 5.9 Hz, 3H, H-6”’), 1.18 (d, J = 6.6 Hz, 3H, H-21), 1.02 (d, J = 6.6 Hz, 3H, H-18), 0.91 (t, J = 7.3 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.2 (C-9), 173.6 (C- 1), 156.9 (C triazole-Ph-O-Ph), 156.7 (Ctriazole-& O-Ph), 147.7 (011), 146.9 (Ctriazole -Ph-O-Ph), 142.3 (C-13), 134.6 (C-12), 134.6 (3C, Ctriazole-Ph-O-Ph), 127.3 (Ctriazole-Ph-O-Ph), 126.1 (Ctriazole-Ph-O-Ph), 123.1 (Ctriazole -Ph-O-Ph), 119.0 (2C, Ctriazole-Ph- O-Ph), 119.0 (3C, Ctriazole-Ph-O-Ph, Ctriazole -Ph- O-Ph), 118.6 (C-10), 103.8 (C-1’), 101.0 (C-1”’), 81.6 (C- 2’”), 79.6 (C-5), 77.2 (C-3”’), 75.1 (C-15), 73.1 (C-5’), 72.5 (C-4”’), 70.5 (4C, C-2’, C-3’, C-4’, C-5”’), 69.0 (C-23), 66.8 (C-3), 61.5 (C-8”’), 59.3 (C-7”’), 47.8 (C-20), 44.7 (2C, C-8, 014), 41.5 (2C, C-7’, 8’), 40.5 (C-4), 39.2 (C-2), 32.8 (C-7), 32.4 (C-6), 27.8 (C-19), 25.1 , 17.7 (2C, C-6’, C-6”’), 17.6 (C-21), 12.8 (C-22), 9.4 (C-17), 9.2 (C-18). (2,4,5-trimethylphenyl)-1H-1,2,3-triazolyl)- -de0x0desmycosin (YT25) Yield:73% _ 8 9 _ HRFABMS : calcd. for 013N4 : 943.5644 [M+H], found m/z : 943.5643 [M+H]+.
IR (KBr)vcm'1 : 3442 (-OH), 2931 (C-H), 1716 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm): 7.67 (s, 1H, H triazole-fl(CH3)3), 7.62 (s, 1H, Htriazole-Ph(CH3)3), 6.99 (s, 1H, Htriazole-fl(CH3)3), 6.96 (d, J = 15.5 Hz, 1H, H-11), 6.14 (d, J = 15.2 Hz, 1H, H-10), 5.39 (d, J = 9.2 Hz, 1H, H-13), 4.81 (br. dt, J = 9.2 Hz,1H, H-15), 4.49 (d, J = 7.6 Hz, 1H, H-1”’), 4.40 (m, 2H, H-20), 4.30 (d, J = 7.2 Hz, 1H, H-1’), 3.88 (dd, J = 9.3, 4.1 Hz, 1H, H-23), 3.76 (d, J = 9.6 Hz, 1H, H-5), 3.69 (s, 1H, H-3”’), 3.56 (s, 3H, 3”’-OCH3), 3.52-3.27 (m, 5H, H-3, H-23, H-2’, H-5’, H-5”’), 3.37 (s, 3H, 2”’-OCH3), 3.10 (dd, J = 8.9, 2.6 Hz, 1H, H-4”’), 3.05 (d, J = 8.9 Hz,1H, H-4’), 2.93 (dd, J = 8.0, 2.5, 1H, H-2”’), 2.85 (m, 1H, H-14), 2.59 (m, 1H, H-8), 2.45-2.43 (m, 9H, 3’-N(CH3)2, Htriazole-Ph(CH3)3), 2.37-2.33 (m, 2H, H-2, H-3’), 2.24- 2.22 (m, 7H, H-6, Htriazole-Ph(Cfl3)3), 2.01 (m, 1H, H- 19), 1.85-1.78 (m, 2H, H-2, H-16), 1.66 (s, 3H, H-22), 1.56- 1.51 (m, 4H, H-4, H-7, H-16), 1.20 (d, J = 6.3 Hz, 3H, H-6’), 1.18 (d, J = 7.6 Hz, 3H, H-6”’), 1.12 (d, J = 6.6 Hz, 3H, H- 21), 0.99 (d, J = 6.6 Hz, 3H, H-18), 0.86 (t, J = 7.1 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.7 (C-9), 173.7 (C- 1), 147.7 (C-11), 146.7 (Ctriazole-Ph(CH3)3), 142.0 (C- 13), 135.8 (C-12), 134.7 (Ctriazole )3), 133.5 (C- azole-fl(CH3)3), 132.5 (Ctriazole-fl(CH3)3), 132.0 (Ctriazole -fl(CH3)3), 130.0 (Ctriazole-fl(CH3)3), 127.3 (Ctriazole-L(CH3)3), 121.0 (C triazole- Ph(CH3)3), 118.1 (C-10), 103.5 (C-1’), 100.9 (C-1”’), 81.6 (C-2”’), 79.7 (C-5), 77.2 (C-3”’), 75.1 (C-15), 73.1 (C-5’), 72.5 ), 70.3 (4C, C-2’, C-3’, C-4’, C-5”’), 69.0 (C-23), 66.8 (C-3), 61.5 (C-8”’), 59.4 (C-7”’), 47.9 (C-20), 44.7 (2C, C-8, C-14), 41.5 (2C, C-7’, 8’), 40.5 (C-4), 39.2 (C-2), 33.2 (C-7), 32.8 (C-6), 27.9 (C-19), 25.2 , 20.6 (C triazole-Ph(CH3)3), 19.1 (2C, C-6’, C-6”’), 19.0 (C triazole -Ph(QH3)3), 17.6 triazole-Ph(CH3)3), 17.5 (C- 21), 12.8 (022), 9.4 (C-17), 93 (C-18). 20-(4-(4-t-butylphenyl)-1H-1,2,3-triazolyl) deoxodesmycosin (YT26) Yield:88% HRFABMS : calcd. for C51H81013N4: 957.5800 [M+H], found m/z : 957.5789 [M+H]+.
IR (KBr)vcm'1 : 3446 (-OH), 2967 (C-H), 1724 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm): 7.84-7.82 (m, 3H, H triazole-fl-C(CH3)3, Htriazole-Ph-C(CH3)3), 7.42 (d, 2H, H—20—triazole—m—C(CH3)3), 6.97 (d, .1 = 15.5 Hz, 1H, H-11), 6.15 (d, J = 15.5 Hz, 1H, H-10), 5.50 (d, J = 10.2 Hz,1H,H- 13), 4.84 (br. dt, .1 = 8.5 Hz,1H, H-15), 4.49 (d, J = 7.6 Hz, 1H, H-1”’), 4.39 (m, 2H, H-20), 4.32 (d, J = 7.3 Hz, 1H, H- 1’), 3.89 (dd, J = 9.4, 4.5 Hz, 1H, H-23), 3.76 (d, J = 9.6 Hz, 1H, H-5), 3.69 (s, 1H, H-3”’), 3.56 (s, 3H, 3”’-OCH3), 3.51- 3.29 (m, 5H, H-3, H-23, H-2’, H-5’, H-5”’), 3.40 (s, 3H, 2’”- OCHg), 3.15-3.08 (m, 2H, H-4’, H-4”’), 2.95 (dd, J = 7.9, 2.7, 1H, H-2”’), 2.89 (m, 1H, H-14), 2.64 (m, 1H, H-8), 2.47 (s, 6H, 3’-N(CH3)2), 2.43-2.37 (m, 2H, H-2, H-3’), 2.22 (m, 1H, H-6), 1.98 (m, 1H, H-19), 1.84-1.78 (m, 2H, H-2, H-16), 1.67 (s, 3H, H-22), 1.53-1.56 (m, 4H, H-4, H-7, H-16), 1.31 (s, 9H, Htriazole-Ph-C(Cfl3)3), 1.23—1.21 (m, 6H, H-6’, H-6”’), 1.13 (d, J = 6.6 Hz, 3H, H-21), 0.99 (d, J = 6.3 Hz, 3H, H-18), 0.87 (t, J: 7.1 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDC13) 5 (ppm): 203.5 (C-9), 173.6 (C- 1), 150.6 (C triazole-fl-C(CH3)3), 147.8 (C-11), 147.4 (Ctriazole-Ph-C(CH3)3), 142.0 (C-13), 134.6 (C-12), 127.9 triaz0le-fi-C(CH3)3), 125.4 (4C, Ctriazole- 3)3), 119.1 (Ctriazole-Ph-C(CH3)3), 118.1 (C-10), 103.5 (C-1’), 100.9 ), 81.7 (C-2”’), 79.6 (C-5), 77.2 (C-3”’), 75.2 (C-15), 73.2 (C-5’), 72.5 (C-4”’), 70.3 (4C, C- 2’, C-3’, C-4’, C-5”’), 69.3 (C-23), 66.7 (C-3), 61.5 (C-8”’), 59.4 (C-7”’), 47.9 , 44.8 (2C, C-8, C-14), 41.5 (2C, C- 7’, 8’), 40.5 (C-4), 39.2 (C-2), 34.4 (Ctriazole-Ph- C(CH3)3), 33.2 (C-7), 32.8 (C-6), 31.2 (3C, Ctriazole-Ph - C(QH3)3), 28.1 (C-19), 25.3 (C-16), 17.7 (2C, C-6’, C-6”’), 17.5 (C-21), 12.8 (C-22), 9.4 (C-17), 9.3 (C-18).
WO 76169 20-(4-(4-pentyloxyphenyl)-1H-1,2,3-triazolyl) deoxodesmycosin (YT27) OCSHH Yield:86% HRFABMS : calcd. for C52H83014N4: 987.5906 [M+H], found m/z : 987.5934 [M+H]+.
IR (KBr)vcm'1 : 3455 (-OH), 2933 (C-H), 1720 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm): 7.82 (d, J = 8.2 Hz, 2H, Htriazole -fl-O-C5H11), 7.76 (s, 1H, Htriazole-Ph-O- C5H11), 7.00-6.92 (m, 3H, riazole -fl-O-C5H11, H-11), 6.13 (d, J = 15.2 Hz, 1H, H-10), 5.39 (d, J = 9.9 Hz,1H,H- 13), 4.83 (br. dt, J = 9.4 Hz,1H, H-15), 4.51 (d, J = 7.6 Hz, 1H, H-1”’), 4.40 (m, 2H, H-20), 4.32 (d, J = 7.3 Hz, 1H, H- 1’), .88 (m, 3H, H-23, Htriazole -Ph-O-C5H11), 3.76 (d, J = 9.5 Hz, 1H, H-5), 3.70 (t, J = 2.8 Hz, 1H, H-3”’), 3.58 (s, 3H, 3”’-OCH3), 3.52-3.31 (m, 5H, H-3, H-23, H-2’, H-5’, H-5”’), 3.40 (s, 3H, 2”’-OCH3), 3.14 (dd, J = 9.3, 3.2 Hz,1H, H-4”’), 3.07 (t, J = 9.3, H-4’), 2.96 (dd, J = 8.0, 2.7, 1H, H- 2”’), 2.86 (m, 1H, H-14), 2.61 (m, 1H, H-8), 2.49 (s, 6H, 3’- N(Cfl3)2), 2.41-2.36 (m, 2H, H-2, H-3’), 2.24 (m, 1H, H-6), _ 9 3 _ 2.00 (m, 1H, H-19), 1.82-1.71 (m, 4H, H-2, H-16, H triazole -Ph-O-C5H11), 1.66 (s, 3H, H-22), 1.53-1.56 (m, 4H, H-4, H-7, H-16), 1.45-1.32 (m, 4H, Htriazole-Ph-O- Csflll), 1.24-1.22 (m, 6H, H-6’, H-6”’), 1.14 (d, J = 6.9 Hz, 3H, H-21), 0.99 (d, J = 6.7 Hz, 3H, H-18), 0.92-0.85 (m, 6H, H-17, Htriazole -Ph-O-C5H11). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.8 (C-9), 174.0 (C- 1), 159.1 (C triazole-fl-O-Can), 148.0 (C-11), 147.8 (Ctriazole-Ph-O-C5H11), 142.7 (C-13), 135.1 , 127.4 (2C, Ctriazole-fi-O-C5H11), 123.6 (Ctriazole- 5H11), 118.9 triazole-fl-O-C5H11), 118.4 (C-10), 114.9 (2C, Ctriazole-fl-O-C5H11), 103.8 (C-1’), 101.2 (C-1”’), 81.9 ), 80.0 (C-5), 77.6 (C-3”’), 75.4 (C-15), 73.5 (C-5’), 72.9 (C-4”’), 70.3 (4C, C-2’, C-3’, C-4’, C-5”’), 68.2 (C-23), 67.3 (C-3), 61.9 (C-8”’), 59.7 (C-7”’), 48.2 (C- ), 45.1 (2C, C-8, C-14), 41.9 (2C, C-7’, 8’), 40.8 (C-4), 39.6 (C-2), 33.2 (C-7), 32.8 (C-6), 29.1 (Ctriazole-Ph-O- Q5H11), 28.3 (2C, C-19, Ctriazole-Ph-O-Q5H11), 25.7 (C- 16), 22.6 (Ctriazole-Ph-O-Q5H11), 18.0 (2C, C-6’, C-6”’), 17.5 (021), 14.2 (Ctriazole-Ph), 13.1 (C-22), 9.8 (C-17), 9.3 (C-18). 20-(4-(l-methyl-1H-benz0triazole)-1H-1,2,3-triazol- 1-yl)de0x0desmyc0sin (YT28) Yield:96% HRFABMS : calcd. for C48H73013N7Na : 978.5164 , found m/z : 978.5139 [M+Na]+.
IR (KBr)vcm'1 : 3438 (-OH), 2931 (C-H), 1720 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm): 8.00 (d, J = 8.2 Hz,1H, Htriazole-CH2 -benz0triazole), 7.75 (d, J = 8.2 Hz, H triazole-CHz-benzotriazole), 7.58 (s, 1H, riazole-CH2- benzotriazole), 7.44 (t, 1H, J = 7.8 Hz, Htriazole-CH2 - benzotriazole), 7.32 (t, J = 7.8 Hz,1H, riazole-CH2- benzotriazole), 7.14 (d, J = 15.5 Hz, 1H, H-11), 6.16 (d, J = .5 Hz, 1H, H-10), 5.99 (s, 2H, Htriazole-CH2 - benzotriazole), 5.88 (d, J = 9.9 Hz, 1H, H-13), 4.96 (br. dt, J = 9.6 Hz, 1H, H-15), 4.53 (d, J = 7.9 Hz, 1H, H-1”’), 4.29- 4.26 (m, 3H, H-20, H-1’), 3.97 (dd, J = 9.3, 3.3 Hz, 1H, H- 23), 3.70-3.66 (m, 2H, H-5, H-3”’), 3.56 (s, 3H, 3”’-OCH3), 3.51-3.38 (m, 4H, H-3, H-23, H-2’, H-5”’), 3.43 (s, 3H, 2”’- OCHg), 3.22 (m, 1H, H-5’), 3.09 (dd, J = 9.4, 2.8 Hz, 1H, H- 4”’), 3.03 (t, J = 9.6, H-4’), 2.95 (dd, J = 7.9,3.0,1H,H-2”’), 2.86 (m, 1H, H-14), 2.50 (m, 1H, H-8), 2.48 (s, 6H, 3’- N(CH3)2), 2.42—2.32 (m, 2H, H-2, H-3’), 2.23 (m, 1H, H-6), _ 9 5 _ 1.89-1.83 (m, 2H, H-2, H-16, H-19), 1.72 (s, 3H, H-22), 1.60- 1.52 (m, 4H, H-4, H-7, H-16), 1.22 (d, J = 5.9 Hz, 3H, H-6’), 1.13 (d, J = 6.6 Hz, 3H, H-6”’), 1.00-0.97 (m, 6H, H-18, H- 21), 0.90 (t, J = 7.1 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.5 (C-9), 174.1 (C- 1), 148.2 (C-11), 146.1 (Ctriaz0le-CHz-benzotriazole), 142.8 (C-13), 141.9 (Ctriazole-CH2- benzotriazole), 134.9 triaz0le-CHz-benzotriazole), 132.9 (2C, C-12, C-20 - triazole-CHz-benzotriazole), 127.8 triazole-CH2- benzotriazole), 124.3 (Ctriaz0le-CHz-benzotriazole), 122.9 (Ctriaz0le-CHz-benzotriazole), 119.7 (C triazole-CHz-benzotriazole), 118.1 (C-10), 110.6 (C triazole-QHZ -benz0triazole), 103.5 (C-1’), 101.2 (C-1”’), 81.9 ), 80.1 (C-5), 77.7 (C-3”’), 75.4 (C-15), 73.4 (C- 5’), 72.9 (C-4”’), 70.3 (4C, C-2’, C-3’, C-4’ , C-5”’), 69.1 , 66.8 (C-3), 61.9 (C-8”’), 59.7 (C-7”’), 48.8 (C-20), 45.2 (C-14), 44.0 (C-8), 41.9 (2C, C-7’, 8’), 40.5 (C-4), 39.6 (C-2), 33.2 (C-7), 32.8 (C-6), 28.9 (C-19), 25.4 (C-16), 17.9 (2C, C-6’, C-6”’), 17.5 (C-21), 13.1 (C-22), 9.8 (C-17), 9.3 (C-18). 20-(4-(4-dimethylamin0phenyl)-1H-1,2,3-triazol yl)de0x0desmyc0sin (YT29) _ 9 6 _ Yield:89% HRFABMS : calcd. for C49H77013N5Na : 966.5416 [M+Na], found m/z : 966.5406 [M+Na]+.
IR cm'1 : 3442 (-OH), 2931 (C-H), 1722 (C=O). 1H NMR (270 MHz, CDC13) 6 (ppm): 7.83 (d, J = 8.2 Hz, 2H, Htriaz01€-&-N(CH3)2), 7.74 (s, 1H, Htriazole-Ph- N(CH3)2), 6.98 (d, J = 15.5 Hz, 1H, H-11), 6.79 (d, J = 8.6 Hz, 2H, Htriazole-fl-N(CH3)2), 6.15 (d, J = 15.2 Hz, 1H, H- 10), 5.28 (br. d, 1H, H-13), 4.82 (br. dt, J = 8.9 Hz, 1H, H- ), 4.50 (d, J = 7.6 Hz, 1H, H-1”’), 4.42 (m, 2H, H-20), 4.34 (d, J = 7.2 Hz, 1H, H-1’), 3.91 (dd, J = 9.3, 4.1 Hz, 1H, H- 23), 3.79 (d, J = 9.5 Hz, 1H, H-5), 3.71 (t, J = 2.8 Hz,1H,H- 3”’), 3.60 (s, 3H, 3”’-OCH3), 3.53-3.44 (m, 4H, H-3, H-23, H- 2’, H-5”’), 3.40 (s, 3H, 2”’-OCH3), 3.34 (m, 1H, H-5’), 3.15 (dd, J = 9.5, 3.1 Hz, 1H, H-4”’), 3.08 (t, J = 9.4, H-4’), 2.98- 2.95 (m, 7H, H-”2, riazole-Ph-N(Cfl3)2), 2.86 (m, 1H, H-14), 2.65 (m, 1H, H-8), 2.49 (s, 6H, 3’-N(CH3)2), 2.44-2.36 (m, 2H, H-2, H-3’), 2.24 (m, 1H, H-6), 2.02 (m, 1H, H-19), 1.85-1.76 (m, 2H, H-2, H-16), 1.68 (s, 3H, H-22), 1.58-1.53 (m, 4H, H-4, H-7, H-16), 1.26 (d, .1 = 5.9 Hz,3H,H-6’),1.25 (d, J = 6.3 Hz, 3H, H-6”’), 1.17 (d, J = 6.6 Hz, 3H, H-21), 1.00 (d, J = 6.6 Hz, 3H, H-18), 0.90 (t, J = 7.1 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.5 (C-9), 173.2 (C- 1), 150.0 (2C, C-11, Ctriaz0le-fl-N(CH3)2), 147.8 (C triazole-Ph-N(CH3)2), 142.4 , 134.6 (C-12), 126.7 (C- -triazole-Ph-N(CH3)2), 119.0 (Ctriaz0le-fl-N(CH3)2), 118.1 (C-10), 117.7 (Ctriazole-fl-N(CH3)2), 112.2 (3C, Ctriazole-fl-N(CH3)2), 103.5 (C-1’), 100.8 (C-1”’), 81.5 (C-2”’), 79.7 (C-5), 77.2 (C-3”’), 76.5 (C-15), 73.1 (C-5’), 72.5 (C-4”’), 70.3 (4C, C-2’, C-3’, C-4’, C-5”’), 69.1 , 66.5 (C-3), 61.5 (C-8”’), 59.3 (C-7”’), 47.7 (C-20), 44.7 (2C, C-14,C-8), 41.5 (2C, Ctriazole -Ph-N(CH3)2), 40.3 (3C, C-4, C-7’, 8’), 39.3 (C-2), 33.2 (C-7), 32.8 (C-6), 27.9 (C-19), .3 (C-16), 17.6 (2C, C-6’, C-6”’), 17.2 (C-21), 12.7 (C-22), 9.4 (C-17), 9.0 (C-18).
(N-methy-methylamine)-1H-1,2,3-triazolyl)- -de0x0desmyc0sin (YT30) Yield:80% HRFABMS : calcd. for C43H74O13N5: 868.5283 [M+H], found _ 9 8 _ m/z : 968.5269 [M+H]+.
IR (KBr)vcm-1 ; 3430 (-OH), 2933 (C-H), 1724 (C=0). 1H NMR (270 MHz, CDCl3) 6 (ppm): 7.58 (s, 1H, H triazole-CHzNHCHg), 7.15 (d, 1 = 15.2 Hz, 1H, H-ll), 6.18 (d, 1 = 15.5 Hz, 1H, H—10), 5.85 (d, 1 = 10.2 Hz, 1H, H-13), 4.93 (br. dt, 1 = 9.9 Hz, 1H, H—15), 4.53 (d, 1 = 7.9 Hz, 1H,H-1”’), 4.36 (m, 2H, H-20), 4.31 (d, 1 = 7.2 Hz, 1H, H—1’), 3.97 (dd, 1 = 9.6, 3.8 Hz, 1H, H—23), 3.92 (s, 1H, H—5), 3.73 (t, 1 = 3.1 Hz, 1H, , 3.59 (s, 3H, 3”’—0CH3), 3.55—3.49 (m, 4H, H- 3, H23, H-2’, H—5”’), 3.45 (s, 3H, fl3), 3.31 (m, 1H, H—5’), 3.15 (dd, 1 = 9.4, 3.1 Hz, 1H,H-4”’),3.10-2.85 (111,5H, H-14, H-4’, H2”, Htriazole-Cfl2NHCH3), 2.50 (m, 1H, H—8), 2.48 (s, 9H, 3’—N(CH3)2, Htriazole-CH2NHCfl3), 2.41—2.33 (m, 2H, H-2, H-3’), 2.24 (m, 1H, H-6), 1.88—1.83 (m, 3H, H-2, H-16, H-19), 1.73 (s, 3H, H-22), 1.60—1.54 (m, 4H, H-4, H-7, H-16), 1.23 (d, 1 = 6.3 Hz, 3H, H—6’), 1.21 (d, 1 = 6.3 Hz, 3H, H—6”’), 1.15 (d, 1 = 6.6 Hz, 3H, H-21), 1.00 (d, 1 = 6.6 Hz, 3H, H—18), 0.90 (t, 1 = 7.2 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDCls) 5 (ppm): 203.3 (C-9), 173.5 (C- 1), 148.0 (011), 145.8 (Ctriazole-CHzNHCHg), 142.4 (c— 13), 134.6 (012), 121.7 (Ctriazole -CH2NHCH3), 118.1 (C-lO), 103.8 (C—1’), 101.0 (C—1”’), 81.7 (C-2”’), 79.8 (05), 77.2 (2C, C—3”’, Ctriazole-Ph-QHzNHCHg), 75.0 (015), 73.2 (05’), 72.6 (C-4”’), 70.3 (4C, C-2’, C—3’, C-4’, , 69.0 (023), 66.3 (03), 61.7 (08”), 59.5 (C—7”’), 48.1 (C- ), 46.2 (C-14), 45.0 (08), 42.3 (2C, C-7’, 8’), 41.0 (C-4), 39.6 (C-2), 35.6 (Ctriazole-Ph-CHzNHQHg), 33.2 (C-7), _ 9 9 _ 32.8 (C-6), 27.9 (C-19), 25.2 (C-16), 17.7 (2C, C-6’, C-6”’), 17.3 (C-21), 12.8 (C-22), 9.6 (C-17), 9.2 (C-18). 20-(4-(1-methyhydr0xylethyl)-1H-1,2,3-triazol yl)de0x0desmyc0sin (YT32) HRFABMS : calcd. for C44H75014N4: 883.5280 [M+H], found m/z:883.5311[M+H]+.
IR (KBr)vcm'1 ; 3438 (-OH), 2931 (C-H), 1722 (c=0). 1H NMR (270 MHz, CDC13) 6 (ppm): 7.57 (s, 1H, H triazole-C(CH3)20H), 7.21 (d, 1 = 15.2 Hz, 1H, H-ll), 6.16 (d, 1 = 15.5 Hz, 1H, H-10), 5.90 (d, 1 = 10.5 Hz, 1H, H-13), 4.94 (br. dt, 1 = 9.2 Hz, 1H, H-15), 4.58-4.45 (m, 2H, H-20, H-l”’), 4.36-4.28 (m, 2H, H-20, H-l’), 3.99 (dd, 1 = 9.7, 3.8 Hz, H- 23), 3.79 (d, 1 = 11.6 Hz, 1H, H—5), 3.76 (t, 1 = 3.1 Hz, 1H, H-3”’), 3.62 (s, 3H, 3”’—ocH3), 3.56-3.44 (m, 4H, H-3, H-23, H-2’, , 3.47 (s, 3H, 2”’—ocH3), 3.35 (m, 1H, H-S’), 3.19 (dd, 1 = 9.0, 2.8 Hz, 1H, H-4’), 3.10 (t, 1 = 9.4 Hz, 1H, H-4”’), 3.02 (dd, 1 = 7.6, 2.7, 1H, H-2”’), 2.92 (m, 1H, H-14), 2.58 (m, 1H , H-8), 2.51 (s, 6H, H—3’—N(CH3)2), 2.44 (d, 1 = 9.9 Hz, 1H, H-2), 2.40 (t, 1 = 10.2 Hz, 1H, H-3’), 2.23 (m, 1H, - 1 0 0 - H-6), 2.00 (m, 1H, H-19), 1.87-1.81 (m, 2H, H-2, H-16), 1.73 (s, 6H, Htriazole-C(Cfl3)zOH), 1.70 (s, 3H, H-22), 1.65— 1.50 (m, 4H, H-4, H-7, H-16), 1.28-1.26 (m, 6H, H-6’, , 1.18 (d, 1 = 6.9 Hz, 3H, H-21), 1.03 (d, 1 = 6.9 Hz, 3H, H-18) 0.92 (t, 1 = 6.7 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDC13) 5 (ppm): 203.2 (C-9), 173.3 (C- 1), 155.8 (Ctriazole-C(CH3)20H), 148.1 (011), 143.1 (c— 13), 134.3 (012), 119.0 (020 -triazole-C(CH3)2OH), 117.3 (010), 103.5 (C-l’), 100.9 (C-l”’), 81.6 (C-2”’), 79.7 (05), 77.2 (C-3”’), 74.9 (015), 73.0 (C-S’), 72.5 (C-4”’), 70.7 (4C, C-2’, C-3’, C-4’, C-S’”), 68.7 (023), 67.8 (Ctriazole- Q(CH3)2OH), 66.1 (03), 61.5 (C-8”’), 59.5 (C-7”’), 47.4 (C- ), 45.0 , 44.7 (C-8), 41.5 (2C, C-7’, 8’), 40.7 (C-4), 39.4 (C-2), 32.8 (C-7), 32.6 (C-6), 30.0 (2C, Ctriazole- C(QH3)20H), 28.2 (C-19), 25.1 (C-16), 17.6 (2C, C-6’, C- 6’”), 17.2 (C-21), 12.8 (C-22), 9.5 (C-17), 9.0 (C-18). 20-(4-(2-methy-pr0pyl)-1H-1,2,3-triazolyl) deoxodesmycosin (YT33) HRFABMS : calcd. for C45H77O13N4: 881.5487 [M+H], found - 1 0 1 - m/z : 881.5516 [M+H]+.
IR (KBr)vcm'1 : 3438 (-OH), 2931 (C-H), 1722 (C=O). 1H NMR (270 MHz, CDC13) 6 (ppm): 7.31 (s, 1H, H triazole-CHzCH(CH3)2), 7.16 (d, J = 15.2 Hz, 1H, H-11), 6.19 (d, J = 15.5 Hz, 1H, H-10), 5.983 (d, J = 9.9 Hz,1H,H-13), 4.94 (br. dt, J = 9.3 Hz, 1H, H-15), 4.52 (d, J = 7.6 Hz, 1H, H-1”’), 4.37 (m, 2H, H-20), 4.31 (d, J = 7.3 Hz, 1H, H-1’), 3.95 (dd, J = 10.1, 4.0 Hz,H-23),3.76-3.71(m,2H,H-5,H- 3”’), 3.57 (s, 3H, 3”’-OCH3), 3.54-3.42 (m, 4H, H-3, H-23, H- 2’, , 3.44 (s, 3H, 2”’-OCH3), 3.30 (m, 1H, H-5’), 3.13 (d, J = 14.2 Hz, 1H, H-4’), 3.13 (t, J = 9.1 Hz, 1H, H-4”’), 2.97 (dd, J = 7.9, 2.8, 1H, H-2”’), 2.91 (m, 1H, H-14), 2.56 (d, J = 7.0 Hz, 2H, Htriazole-CH2CH(CH3)2), 2.54 (m, 1H, H- 8), 2.46 (s, 6H, H-3’-N(CH3)2), (d, J = 9.9 Hz, 1H, H-2), 2.40 (t, J = 10.2 Hz, 1H, H-3’), 2.23 (m, 1H, H-6), 1.97-1.83 (m, 3H, H-2, H-16, H-19), 1.72 (s, 3H, H-22), 1.59-1.56 (m, 4H, H-4, H-7, H-16), 1.22 (d, J = 6.2 Hz, H-6’), 1.16-1.14 (m, 7H, H-21, H-6”’, Htriazole (CH3)2), 1.00 (d, J = 6.6 Hz, 3H, H-18), 0.93-0.86 (m, 12H, H-17, H-18, Htriazole- CH2CH(CH3)2). 13C NMR (67.5 MHz, CDCl3) 5 (ppm): 203.3 (C-9), 173.7 (C- 1), 147.7 (C-11), 146.7 triazole-CH2CH(CH3)2), 142.2 (C-13), 134.6 (C-12), 120.8 triazole- CH2CH(CH3)2), 118.0 (C-10), 103.5 (C-1’), 100.9 (C-1”’), 81.6 (C-2”’), 79.7 (C-5), 77.2 (C-3”’), 74.9 (C-15), 73.2 (C-5’), 72.6 (C-4”’), 70.7 (4C, C-2’, C-3’, C-4’, C-5”’), 68.8 (C-23), 66.1 (C-3), 61.6 (C-8”’), 59.5 (C-7”’), 47.9 (C-20), 44.8 (C-14), 44.7 (c- WO 76169 8), 41.5 (2C, C-7’, 8’), 40.7 (C-4), 39.2 (C-2), 34.6 (C triazole-CH2QH(CH3)2), 32.8 (C-7), 32.6 (C-6), 28.5 (2C, C- 19, Ctriazole-QH2CH(CH3)2), 25.0 (C-16), 22.3 (C triazole-CHzCH(QH3)2), 22.2 (Ctriazole-CH2CH(QH3)2), 17.6 (2C, C-6’, C-6”’), 17.2 (C-21), 12.8 (C-22), 9.5 (C-17), 9.0 (C-18). 20-(4-n0nyl-1H-1,2,3-triazolyl) deoxodesmycosin (YT34) Yield:97% HRFABMS : calcd. for C50H87013N4: 951.6270 [M+H], found m/z : 951.6309 [M+H]+.
IR (KBr)vcm'1 : 3440 (-OH), 2933 (C-H), 1722 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm) : 7.25 (s, 1H, H triazole-nonyl), 7.12 (d, J = 14.8 Hz, 1H, H-11), 6.15 (d, J = .6 Hz, 1H, H-10), 5.78 (d, J = 10.2 Hz, 1H, H-13), 4.88 (br. dt, J = 9.7 Hz, 1H, H-15), 4.48 (d, J = 7.9 Hz, 1H, H-1”’), 4.20-4.40 (m, 3H, H-20, H-1’), 3.91 (dd, J = 9.2, 3.4 Hz, H- 23), 3.67-3.63 (m, 2H, H-5, H-3”’), 3.52 (s, 3H, 3”’-OCH3), 3.45-3.43 (m, 4H, H-3, H-23, H-2’, H-5”’), 3.40 (s, 3H, 2”’- WO 76169 - 1 0 3 - OCHg), 3.26 (m, 1H, H-5’), 3.11-3.06 (m, 2H, H-4’, H-4”’), 2.93 (dd, J = 7.6, 2.6, 1H, H-2”’), 2.85 (m, 1H, H-14), 2.66- 2.61 (m, 3H, H-8, Htriazole-M), 2.42 (s, 6H, H-3’- N(CH3)2,), 2.40-2.29 (m, 3H, H-2, H-3’), 2.22 (m, 1H, H-19), 2.08 (m, 1H, H-6), 1.84-1.78 (m, 2H, H-2, H-16), 1.68 (s, 3H H-22), 1.58-1.52 (m, 4H, H-4, H-7, H-16), 1.18-1.09 (m, 20H, H-6’, H-6”’, H0 triazole- non1), 0.96 (d, J: 6. 3 Hz, 3H, H- 21), 0.85 (d, J = 6.9 Hz, 3H, H-18), 0.79 (m, 6H, H-17, H triazole-M). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.2 (C-9), 173.7 (C- 1), 148.0 (Ctriazole-nony1), 147.7 (C-11), 142.2 (C-13), 134.5 (C-12), 120.1 (Ctriazole-nony1), 118.0 (C-10), 103.5 (C-1’), 100.8 (C-1”’), 81.6 (C-2”’), 79.7 (C-5), 77.5 ), 76.5 (C-15), 74.9 (C-5’), 73.2 (C-4”’), 70.7 (4C, C- 2’, C-3’, C-4’, C-5”’), 68.8 (C-23), 67.9 (C-3), 61.5 (C-8”’), 59.4 (C-7”’), 47.9 (C-20), 44.8 , 44.7 (C-8), 41.4 (2C, C-7’, 8’), 39.2 (2C, C-2, C-4), 33.8 (C-7), 33.0 (C-6), 31.6 triazole-M), 29.3 (Ctriazole-M), 29.1 (2c, C- 20- triazole- non_y_1), 29. 0 (2C, C- 20- triazole- non_y_), 28. 9 (C- 19), 25.4 (Ctriazole-M), 25.2 (C-16), 22.4 (C triazole-M), 17.6 (2C, C-6’, C-6”’), 17.5 (C-21), 13.9 (C- -triazole-nony1), 12.7 (C-22), 9.4 (C-17), 8.9 (C-18). 20-(4-(3-quinoline)-1H-1,2,3-triazolyl) deoxodesmycosin (YT35) — 1 0 4 — Yield:93% HRFABMS: calcd. for C50H74013N5 : 952.5283 [M+H], found m/z:952.5281[M+H]+.
IR (KBr)vcm'1 : 3436 (-OH), 2933 (C-H), 1722 (C=O). 1H NMR (270 MHz, CDCl3) 5 (ppm): 9.55 (s, 1H, H-triazole- guinoline), 8.83 (s, 1H, zole-guinoline), 8.19 (s, 1H, H- triazole-guinoline), 8.16 (s, 1H, H-triazole- quinoline), 7.97 (d, J = 7.6 Hz, 1H, H-triazole-guinoline), 7.72 (t, J = 7.1 Hz, 1H, H-triazole-guinoline), 7.59 (t, J = 7.1 Hz, 1H, H-triazole- ine), 6.87 (d, J = 15.5 Hz, 1H, H-11), 6.14 (d, J = 15.2 Hz, 1H, H-10), 4.98 (d, J = 9.2 Hz, 1H, H-13), 4.69 (br. dt, J = 8.9 Hz, 1H, H-15), 4.55 (m, 2H, H-20), 4.39 (d, J = 7.6 Hz, 1H, H-1”’), 4.38 (d, J = 7.6 Hz, 1H, H-1’), 3.82 (d, J = 9.9 Hz, 1H, H-5), 3.71 (m, 2H, H-23, H-3”’), 3.64 (s, 3H, 3”’- OCHg), 3.60-3.37 (m, 4H, H-3, H-23, H-2’, H-5”’), 3.33 (s, 3H, 2”’-OCH3), 3.25 (m, 1H, H-5’), 3.17-3.09 (m, 2H, H-4’, H-4”’), 2.90 (dd, J = 7.5, 2.3, 1H, H-2”’), 2.81 (m, 1H, H-14), 2.68 (m, 1H, H-8), 2.53 (s, 6H, H3)2), 2.47-2.39 (m, 3H, H-2, H-3’), 2.30 (m, 1H, H-6), 2.15 (m, 1H,H-19),1.82-1.76 (m, 2H, H-2, H-16), 1.64 (s, 3H, H-22), 1.62-1.51 (m, 4H, H-4, WO 76169 - 1 0 5 - H-7, H-16), 1.32 (d, J = 5.9 Hz, 3H, H-6’), 1.27 (d, J = 6.3 Hz, 3H, H-6”’), 1.16 (d, J = 6.9 Hz, 3H, H-21), 1.05 (d, J = 6.6 Hz, 3H, H-18), 0.89 (t, J = 7.1 Hz, 3H, H-17). 13C NMR (67.5 MHZ, CDCl3) 6 (ppm) : 203.3 (C-9), 173.5 (C-1), 150.8 (C triazole-quinoline), 147.6 (C-11), 147.2 (Ctriaz0le-guinoline), 144.5 (C triazole-guinoline), 142.4 (C-13), 134.5 (C-12), 131.9 (Ctriaz0le-guinoline), 129.2 (Ctriazole-guin01ine), 129.0 (Ctriazole- ine), 128.0 (Ctriazole 1ine), 127.8 (C triazole-guinoline), 126.9 (Ctriazole-guin01ine), 124.1 (Ctriaz0le-guinoline), 120.2 (Ctriazole -quin01ine), 117.6 (C-10), 103.5 (C-1’), 100.8 (C-1”’), 81.4 ), 79.7 (C-5), 77.5 (C-3”’), 75.0 (C-15), 73.1 (C-5’), 72.5 (C-4”’), 70.2 (4C, C-2’, C-3’, C-4’, C-5”’), 68.8 (C-23), 66.6 (C-3), 61.5 (C-8”’), 59.2 (C-7”’), 47.8 (C-20), 44.7 (2C, C-8, C-14), 41.5 (2C, C-7’, 8’), 40.3 (C-4), 39.1 (C-2), 32.8 (C-7), 32.4 (C-6), 27.4 (C-19), 25.2 (C-16), 17.7 (2C, C-6’, C-6”’), 17.1 (021), 12.7 (C-22), 9.4 (C-17), 9.0 (C-18).
[0100] 20-(4-(4-butanol)-1H-1,2,3-triazolyl) deoxodesmycosin (YT36) - 1 0 6 - Yield:97% HRFABMS: calcd. for 014N4 : 36 [M+H], found m/z : 897.5445 [M+H]+.
IR (KBr)vcm'1 : 3433 (-OH), 2933 (C-H), 1722 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm): 7.37 (s, 1H, H triazolebutan01), 7.12 (d, J = 15.5 Hz, 1H, H-11), 6.16 (d, J =15.5 Hz, 1H, H-10), 5.88 (d, J = 10.6 Hz, 1H, H-13), 4.91 (br. dt, J = 10.5 Hz, 1H, H-15), 4.53 (d, J = 7.9 Hz, 1H, H- 1”’), 4.40 (m, 2H, H-20), 4.32 (d, J = 7.3 Hz, 1H, H-1’), 3.98 (dd, J = 9.4, 3.5 Hz, 1H, H-23), 3.78 (d, J = 11.2 Hz,1H,H- ), 3.73 (t, J = 3.1 Hz, 1H, H-3”’), 3.68 (t, J = 6.4 Hz, 2H, H- -triazolebutan01), 3.58 (s, 3H, 3”’-OCH3), 3.56-3.39 (m, 6H, H-3, H-23, H-2’, H-5”’), 3.44 (s, 3H, 2”’-OCH3), 3.30 (m, 1H, H-5’), 3.15 (dd, J = 9.6, 3.0 Hz, 1H, H-4”’), 3.08 (t, J = 9.4 Hz, 1H, H-4’), 3.00 (dd, J = 7.9, 2.6 Hz, 1H, H-2”’), 2.99 (m, 3H, H-14, Htriazole- 4-butan01), 2.77 (t, J = 7.6 Hz, 4H, Htriazolebutan01), 2.60 (m, 1H, H-8), 2.48 (s, 6H, 3’-N(CH3)2), 2.44-2.35 (m, 2H, H-2, H-3’), 2.19-2.01 (m, 2H, H-6, H-19), 1.86-1.81 (m, 2H, H-2, H-16), 1.71 (s, 3H, H-22), 1.68-1.54 (m, 4H, H-4, H-7, H-16), 1.23 (d, J = 6.3 Hz, 3H, H-6’), 1.22 (t, J = 5.3 Hz, 3H, H-6”’), 1.14 (d, J = 6.6 Hz, 3H, H-21), 1.00 (d, J = 6.6 Hz, 3H, H-18), 0.89 (t, J = 7.2 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.2 (C-9), 173.5 (C- 1), 147.9 , 147.8 (Ctriazolebutan01), 142.7 (C- 13), 134.4 (C-12), 120.3 (Ctriaz016butan01), 18.0 (C- ), 103.5 (C-l’), 100.9 (C-l’”), 81.5 (C-2”’), 79.7 (C-5), 77.5 (C-3”’), 74.8 (C-15), 73.1 (C-5’), 72.6 (C-4”’), 70.7 (4C, C-2’, C-3’, C-4’, C-5”’), 69.0 (C-23), 66.0 (C-3), 61.9 (C triazolebutan01), 61.6 ), 59.4 (C-7”’), 47.6 (C-20), 44.9 (C-14), 44.9 (C-8), 41.5 (2C, C-7’, 8’), 40.6 (C-4), 39.3 (C-2), 33.8 (C-7), 33.0 (C-6), 32.0 (Ctriazolebutan01), 28.2 (C-19), 25.6 (Ctriaz016butan01), 25.1 (C-20 - triazolebutan01), 25.0 (C-16), 17.5 (2C, C-6’, C-6”’), 17.3 (021), 12.7 (C-22), 9.5 (C-17), 9.0 (C-18).
[0101] 20-(4-(methanol)-1H-1,2,3-triazolyl) deoxodesmycosin (YT37) Yield:100% HRFABMS: calcd. for C42H71014N4 : 855.4967 [M+H], found m/z : 72 [M+H]+.
IR (KBr)vcm'1 : 3433 (-OH), 2933 (C-H), 1722 (C=O). 1H NMR (270 MHz, CDCl3) 6 (ppm): 7.60 (s, 1H, H triazole-methanol), 7.16 (d, J = 15.2 Hz,1H, H-11), 6.12 (d, J = 15.5 Hz, 1H, H-10), 5.89 (d, J = 10.6 Hz, 1H, H-13), 4.89 (br. dt, J = 9.6 Hz, 1H, H-15), 4.77 (d, J = 7.9 Hz,1H,H triazole-methanol), 4.53 (d, J = 7.6 Hz, 2H, H-20, H-1”’), - 1 0 8 - 4.32 (d, J = 7.3 Hz, 2H, H-20, H-1’), 3.94 (dd, J = 9.6, 4.0 Hz, 1H, H-23), 3.72-3.69 (m, 2H, H-5, H-3”’), 3.57 (s, 3H, 3”’- OCHg), 3.52-3.38 (m, 6H, H-3, H-23, H-2’, H-5”’), 3.43 (s, 3H, 2”’-OCH3), 3.31 (m, 1H, H-5’), 3.15 (d, J = 8.9 Hz, 1H, H-4”’), 3.06 (t, J = 9.4 Hz, 1H, H-4’), 2.99 (dd, J = 7.7, 2.8 Hz, 1H, , 2.89 (m, 1H, H-14), 2.55 (m, 1H, H-8), 2.46 (s, 6H, 3’-N(Cfl3)2), 2.39 (d, J = 5.6 Hz, 1H, H-2), 2.35 (t, J = 10.2 Hz, 1H, H-3’), 2.18 (m, 1H, H-19), 1.96 (m, 1H, H-6), 1.81-1.75 (m, 2H, H-2, H-16), 1.68 (s, 3H, H-22), 1.45-1.55 (m, 4H, H-4, H-7, H-16), 1.23 (d, J = 3.3 Hz, 3H, H-6’), 1.21 (d, J = 3.6 Hz, 3H, H-6”’), 1.13 (d, J = 6.9 Hz, 3H, H-21), 0.90 (d, J = 6.6 Hz, 3H, H-18), 0.86 (t, J = 7.1 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.6 (C-9), 173.7 (C- 1), 148.3 (C-11), 148.2 triazole-methano1), 143.3 (C- 13), 134.4 (C-12), 121.8 (Ctriazole-methano1), 117.5 (C- ), 103.5 (C-1’), 100.9 (C-1”’), 81.7 (C-2”’), 79.7 (C-5), 77.5 (C-3”’), 75.2 (C-15), 73.2 , 72.6 (C-4”’), 70.9 (4C, C-2’, C-3’, C-4’, , 70.0 (C-23), 66.0 (C-3), 61.6 (C- 8”’), 59.5 (C-7”’), 56.3 (Ctriazole-methano1), 47.6 (C-20), 45.1 (C-14), 45.0 (C-8), 41.6 (2C, C-7’, 8’), 40.6 (C-4), 39.8 (C-2), 32.8 (C-7), 32.7 (C-6), 28.1 (C-19), 25.3 (C-16), 17.8 (2C, C-6’, C-6”’), 17.7 (C-21), 12.8 (C-22), 9.6 (C-17), 9.1 (C-18).
[0102] Preparation of 23-triazoledeoxoO- mycarninosyltylonolides WO 76169 - l 0 9 - (1) Preparation of 5-O-mycaminosyltylonolide (YT106) 0.5 M TFA aq. 100 hi), 5 h HO YT106 Tylosin (9.16 g, 10.0 mmol) was dissolved to 0.5 M TFA solution (300 mL) and then the mixture was stirred for 5 hours at 100°C. After confirming complete consumption of the starting material, the reaction mixture was neutralized by adding NaHC03 sat. aq., ted with CHC13 and dried over Na2SO4. The solvent was removed under reduced-pressure.
The resulting products were purified by flash column chromatography to obtain YT106 : 39%).
Rf: 0.3 (CHC13 : MeOH : NH4OH = 5 : l : 0.005).
HRFABMS : calcd. for C31H52010N : 598.3591 [M+H], found m/z : 598.3610 [M+H]+. 1H NMR (270 MHz, CDCl3) 6 (ppm): 9.69 (s, 1H, H-20), 7.32 (d, J = 15.5 Hz, 1H, H-ll), 6.29 (d, J =15.5 Hz,1H,H-10), .88 (d, J = 10.2 Hz, 1H, H-l3), 4.96 (br. dt, J = 9.6 Hz,1H, H-15), 4.25 (d, J = 7.2 Hz, 1H, H-l’), 3.84 (d, J = 10.6 Hz, 1H, H-3), 3.73 (d, J = 10.3 Hz, 1H, H-23), 3.48 (dd, J =10.0, 9.0 Hz, 1H, H-2’), 3.27 (m, 1H, H-5’), 3.27 (t, .1 = 7.4 Hz, 1H, H-4’), 3.09-3.02 (m, 3H, H-14, H-19), 2.55 (m, 1H, H-8), 2.50 (s, 6H, 3’-N(Cfl3)2), 2.40-2.32 (m, 4H, H-2, H-19, H-3’), 2.13 (m, 1H, H-6), 1.95 (d, .1 = 16.9 Hz, 1H, H-2), 1.87 (m, -llO- 1H, H-16), 1.83 (s, 3H, H-22), 1.68-1.48 (m, 4H, H-4, H-7, H- 16), 1.26 (d, .1 = 6.0 Hz, 3H, H-6’), 1.22 (d, .1 = 6.9 Hz, 3H, H-21), 1.01 (d, .1 = 6.6 Hz, 3H, H-18), 0.95 (t, .1 = 7.2 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDC13) 5 (ppm): 203.8 (C-9), 203.2 (C- ), 173.7 (C-l), 148.2 (C-ll), 142.3 (C-13), 135.3 (C-12), 118.5 (C-10), 103.0 (C-l’), 81.0 (05), 74.9 (015), 73.0 (C- ’), 70.7 (C-4’), 70.6 (C-2’), 69.9 , 67.4 (C-3), 61.9 (C-23), 46.9 (C-14), 44.6 (08), 43.5 (C-19), 41.5 (2C, C-7’, 8’), 40.3 (C-4), 39.3 (C-2), 32.8 (C-7), 31.9 (C-6), 25.2 (C- 16), 17.6 (C-6’), 17.2 (C-21), 12.9 , 9.5 (C-17), 8.8 (C- 18). (2) Preparation of 23-azidodeoxoO- mycaminosyltylonolide (YT107) 20 /CH0 /CH0 \N_ 1) PPh3, 12 5 \N— P ridine MOWOH “(46% 5 WOWOH u 3 "'"OH 2) NaN3, DMSO 60 to, 84% YT106 YT107 To a solution of PPh3 (787 mg, 3.0 mmol) and I2 (381 mg, 3.0 mmol) in pyridine (4.0 mL) was added YT106 (300 mg, 0.50 mmol) under N2 atmosphere and then stirred for 4 hours at rt.
After confirming complete consumption of the starting al, the reaction mixture was diluted with CHClg. The organic layer was washed with Na28203 sat. aq. and dried over Na2SO4. The solvent was then d under reduced pressure. The resulting products were purified by flash column tography to obtain 23-IdeoxoO- mycaminosyltylonolide (Yield: 46%).
To a on of 3-deoxoO-mycaminosyltylonolide (155 mg, 0.22 mmol) in DMSO (2.0 mL) was added NaNg (50 mg, 0.77 mmol) and then the mixture was stirred for 90 minutes at 60°C. After confirming complete consumption of the starting material by mass spectrometry, the reaction mixture was diluted with CHClg. The organic layer was washed with water and dried over NazSO4. The solvent was removed under reduced pressure. The resulting products were purified by flash column chromatography to obtain YT107 (Yield: 84%).
Rf: 0.5 (CHC13 : MeOH : NH4OH = 5 : l : 0.005).
HRFABMS : calcd. for C31H5109N4 : 623.3656 [M+H], found m/z : 623.3603 [M+H]+. 1H NMR (270 MHz, CDCl3) 6 (ppm): 9.69 (s, 1H, H-20), 7.31 (d, J = 15.5 Hz, 1H, H-ll), 6.31 (d, J =15.5 Hz,1H,H-10), .76 (d, J = 10.6 Hz, 1H, H-l3), 4.90 (dt, J = 9.6, 2.8 Hz,1H, H-15), 4.25 (d, J = 7.6 Hz, 1H, H-l’), 3.84 (d, J = 10.9 Hz, 1H, H-3), 3.72 (d, J = 8.9 Hz, 1H, H-5), 3.52-3.37 (m, 3H, H- 23, H-2’), 3.27 (m, 1H, H-5’), 3.06 (t, J = 9.4 Hz,1H,H-4’), 2.97-2.85 (m, 3H, H-14, H-19), 2.55 (m, 1H, H-8), 2.62 (s, 6H, H3)2), 2.70—2.33 (m, 4H, H-2, H-19, H-3’), 2.13 (m, 1H, - 1 1 2 - H-6), 1.94 (d, 1 = 16.0 Hz, 1H, H-2), 1.83 (s, 3H, H-22), 1.80 (m, 1H, H-16), 1.79—1.49 (m, 4H, H-4, H-7, H-16), 1.26 (d, 1 = 6.6 Hz, 3H, H-6’), 1.22 (d, 1 = 6.6 Hz, 3H, H-21), 1.01 (d, 1 = 6.6 Hz, 3H, H—18), 0.95 (t, 1 = 7.2 Hz, 3H, H-17). 13C NMR (67.5 MHz, CDC13) 5 (ppm): 203.2 (C-9), 203.1 (C- ), 173.5 (C—1), 147.3 (C-11), 142.3 (013), 135.9 (C-12), 118.5 (C-10), 104.0 (C-1’), 82.0 (05), 74.6 (015), 73.1 (C- ’), 70.7 , 70.6 (C-2’), 70.0 (C-3’), 68.0 (03), 51.0 (023), 46.0 , 44.3 (08), 43.5 (C-19), 41.5 (2C, C-7’, 8’), 40.6 (C-4), 39.3 (C-2), 32.8 (C-7), 31.9 (C-6), 25.1 (C- 16), 17.6 (C-6’), 17.2 (C-21), 12.9 (C-22), 9.4 (C-17), 8.8 (C- 18). (3) Preparation of 23-triazoledeoxy0- mycaminosyltylonolides To a solution of YT107 (0.24 g, 0.30 mmol) in CH3CN or MeOH (3.0 mL) were added CuI (2.9 mg, 0.015 mmol), TBTA (1.6 mg, 3.0 umol) and a suitable acetylene compound, and then the mixture was stirred at rt until the reaction was completed. After tion, the reaction mixture was diluted with CHC13, and washed with 10% NH3 aq.. After removing CuI, the filtrate was washed with brine. The organic layer was dried over NazSO4 and concentrated. The resulting products were purified by flash column chromatography to obtain the ing triazole compounds: 23-(4-phenyl-1H-1,2,3-triazolyl)De0xy O-mycaminosyltylonolide (YT101) _/CHO «OWOH -----'OH YT101 Yield: 64% Rf: 0.5 (CHC13 : MeOH : NH4OH = 8 : 1 : 0.008).
HRFABMS : calcd. for C39H5709N4 : 725.4126 [M+H], found m/z : 725.4158 [M+H]+. 1H NMR (270 MHz, CDC13) 6 (ppm): 9.68 (s, 1H, H-20), 7.80 (d, J = 9.6 Hz, 3H, H-triazole-phenyl), 7.66 (s, 1H, H- triazole-phenyl), 7.40 (m, 2H, H-triazole-phenyl), 7.19 (d, J = .5 Hz, 1H, H-11), 6.23 (d, J =15.5 Hz, 1H, H-10), 5.68 (d, J = 10.6 Hz, 1H, H-13), 4.94 (br. dt, J = 9.6, 1H, H-15), 4.66 (dd, J 3.6 Hz, 1H, H-23), 4.32 (dd, J = 13.5, 3.6 Hz, 1H, H-23), 4.23 (d, J = 7.3 Hz, 1H, H-1’), 3.83 (d, J = 10.5 Hz, 1H, H-3), 3.69 (d, J = 7.9 Hz, 1H, H-5), 3.43 (m, 1H, H- 2’), 3.25 (m, 1H, H-5’), 3.04 (t, J = 9.7 Hz, 1H, H-4’), 2.90 (m, 1H, H-19), 2.55 (m, 1H, H-8), 2.49 (s, 6H, 3’-N(CH3)2), 2.46-2.21 (m, 2H, H-14, H-3’), 2.10 (m, 1H, H-6), 1.93 (d, J = 7.2 Hz, 1H, H-2), 1.77 (m, 1H, H-16), 1.66 (s, 3H, H-22), 1.60-1.40 (m, 4H, H-4, H-7, H-16), 1.24 (d, J = 5.9 Hz, 3H, H-6’), 1.16 (d, J = 6.6 Hz, 3H, H-21), 0.99 (d, J = 6.6 Hz, 3H, H-18), 0.95 (t, .1 = 7.2 Hz, 3H, H-17). —114— 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.2 (C-9), 203.0 (C- ), 173.6 (C-1), 147.6 (Ctriazole-pheny1), 146.9 , 138.4 (C-13), 137.8 (C-12), 128.9 (2C, Ctriazole-pheny1), 128.4 (Ctriazole-pheny1), 125.8 (3C, Ctriazole- phenyl), 120.1 (Ctriazole-pheny1), 118.5 (C-10), 104.0 (C-1’), 81.0 (C-5), 74.5 (C-15), 73.4 (C-5’), 70.9 (C-4’), 70.8 (C-2’), 70.1 (C-3’), 68.0 (C-3), 51.1 (C-23), 46.0 (C-14), 44.3 (C-8), 43.8 (C-19), 41.8 (2C, C-7’, 8’), 40.2 (C-4), 39.5 (C-2), 32.8 (C-7), 31.9 (C-6), 25.5 , 18.0 (C-6’), 17.4 (C-21), 13.0 (C-22), 9.7 (C-17), 9.1 (C-18). 23-(4-butyl-1H-1,2,3-triazolyl)De0x0 O-mycaminosyltylonolide (YT102) YT102 Yield: 77% Rf: 0.5 (CHC13 : MeOH : NH4OH = 8 : 1 : 0.008).
HRFABMS : calcd. for C37H6109N4 : 39 [M+H], found m/z : 705.4457 [M+H]+. 1H NMR (270 MHz, CDCl3) 6 (ppm): 9.70 (s, 1H, H-20), 7.21 (d, J = 9.6 Hz,1H, H-11), 7.16 (s, 1H, H-triazole-butyl), 6.25 (d, J = 15.5 Hz, 1H, H-10), 5.63 (d, J = 10.2 Hz,1H,H-13), 4.91 (br. dt, .1 = 9.6, 1H, H-15), 4.59 (dd, .1 = 13.9, 3.6 Hz, - 1 1 5 - 1H, H-23), 4.24 (d, 1 = 7.6 Hz, 1H, H-l’), 4.19 (d, 1 = 9.9 Hz, 1H, H—23), 3.83 (d, 1 = 10.2 Hz, 1H, H—3), 3.71 (d, 1 = 9.2 Hz, 1H, H—5), 3.49 (dd, 1 = 9.5, 7.2 Hz, 1H, H-2’), 3.25 (m, 1H, H-S’), 3.05 (t, 1 = 9.6 Hz, 1H, H-4’), 2.96 (m, 1H, H-19), 2.70—2.53 (m, 2H, H-8, H-19), 2.50 (s, 6H, 3’-N(Cfl3)2), 2.40- 2.17 (m, 3H, H-8, H-14, H-3’), 2.10 (m, 1H, H-6), 1.93 (d, 1 = 16.5 Hz, 1H, H-2), 1.86-1.39 (m, 8H, H-4, H-7, H-16, H-22), 1.36—1.10 (m, 12H, H-21, H-6’, H—triazole—MLI), 1.02—0.97 (m, 6H, H-18, H-triazole Jim), 0.90 (t, 1 = 7.2 Hz, 3H, H- 17). 13C NMR (67.5 MHz, CDC13) 5 (ppm): 203.1 (C-9), 203.0 (C- ), 173.6 (C—1), 146.6 (011), 148.6 (Ctriazole-butyl), 138.0 (013), 137.6 , 121.3 (Ctriazole -buty1), 118.5 (C-lO), 104.0 (C-l’), 81.0 (05), 74.2 (015), 73.2 (C- 5’), 70.7 (C-4’), 70.6 (C-2’), 70.2 (C-3’), 68.0 (03), 50.8 (023), 46.0 (C-14), 44.3 (08), 43.8 (C-19), 41.8 (2C, C-7’, 8’), 40.2 (C-4), 39.5 (C-2), 32.8 (C-7), 31.9 (C-6), 31.6 (C- 23-triazole -M), 31.0 (Ctriazole-Mfl), 25.3 (C-16), 22.3 (Ctriazole-Mfl), 179 (C-6’), 17.4 , 13.9 (C- 23-triazole-butyl), 12.9 (C-22), 9.6 (C-17), 9.0 . 23-(4-(3-quinolineyl)-1H-1,2,3-triazolyl) De0X00-mycaminosyltylonolide (YT103) - 1 1 6 - YT103 Yield: 100% Rf: 0.4 (CHC13 : MeOH : NH4OH = 8 : 1 : 0.008).
HRFABMS : calcd. for 09N5 : 726.4235 [M+H], found m/z : 726.4196 [M+H]+. 1H NMR (270 MHz, CDC13) 6 (ppm): 9.67 (s, 1H, H-20), 9.29 (d, J = 2.0 Hz, 1H, H-triazole-guinoline), 8.59 (d, J = 2.0 Hz, 1H, H-triazole-guinoline), 8.09 (d, J = 7.6 Hz, 1H, H- triazole-guinoline), 7.92 (s, 1H, H-tiazole-quinoline), 7.86 (d, J = 7.9 Hz,1H, H-triazole-guinoline), 7.70 (t, J = 6.9 Hz,1H, zole-guinoline), 7.55 (d, J = 7.6 Hz, 1H, H-triazole- guinoline), 7.19 (d, J = 15.5 Hz, 1H, H-11), 6.24 (d, J =15.5 Hz, 1H, H-10), 5.71 (d, J = 10.6 Hz, 1H, H-13), 4.97 (br. dt, J = 9.6, 1H, H-15), 4.66 (dd, J = 13.5, 3.6 Hz, 1H, H-23), 4.32 (dd, J = 13.5, 3.6 Hz, 1H, H-23), 4.23 (d, J = 7.2 Hz,1H,H- 1’), 3.83 (d, J = 10.2 Hz, 1H, H-3), 3.68 (d, J = 7.9 Hz,1H, H-5), 3.44 (m, 1H, H-2’), 3.25 (m, 1H, H-5’), 3.04 (t, J = 9.4 Hz, 1H, H-4’), 2.95 (m, 1H, H-19), 2.55 (m, 1H, H-8), 2.48 (s, 6H, 3’-N(Cfl3)2), 2.46-2.31 (m, 2H, H-14, H-3’), 2.10 (m, 1H, H-6), 1.93 (d, J = 6.8 Hz, 1H, H-2), 1.76 (m, 1H, H-16), 1.67 (s, 3H, H-22), 1.58-1.41 (m, 4H, H-4, H-7, H-16), 1.23 (d, J = .9 Hz, 3H, H-6’), 1.13 (d, .1 = 6.6 Hz, 3H, H-21), 1.04—0.99 (m, 6H, H-17, H-18). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.2 (C-9), 203.0 (C- ), 173.8 (C-1), 148.4 (Ctriazole-guin01ine), 147.8 (C- 23-triazole-quin01ine), 146.8 (C-11), 145.0 (Ctriazole- ine), 138.4 (C-13), 137.8 (C-12), 132.2 (Ctriazole- guinoline), 129.8 triazole-guin01ine), 129.4 (C triazole-guinoline), 128.3 (Ctriazole -guin01ine), 128.0 (Ctriazole-guin01ine), 127.3 (C triazole-guinoline), 123.6 (Ctriazole-guin01ine), 120.8 (Ctriazole-quin01ine), 118.5 (C-10), 104.0 (C-1’), 81.0 (C-5), 74.5 (C-15), 73.4 (C-5’), 70.9 , 70.8 (C-2’), 70.2 (C-3’), 68.0 (C-3), 51.3 (C-23), 46.0 (C-14), 44.7 (C-8), 43.8 (C-19), 41.8 (2C, C-7’, 8’), 40.2 (C-4), 39.6 (C-2), 32.8 (C-7), 31.9 (C-6), 25.6 (C-16), 18.0 , 17.4 (C-21), 13.0 (C-22), 9.7 (C-17), 9.1 (C-18). 23-(4-biphenyl-1H-1,2,3-triazolyl)De0xy O-mycaminosyltylonolide (YT104) _/CHO «oww uuuuu 1 --'OH YT104 Yield: 100% Rf: 0.4 (CHC13 : MeOH : NH4OH = 8 : 1 : 0.008).
HRFABMS : calcd. for C45H6109N4 : 801.4439 [M+H], found - 1 1 8 - m/z : 801.4435 [M+H]+. 1H NMR (270 MHz, CDCl3) 6 (ppm): 9.67 (s, 1H, H-20), 7.86 (d, J = 6.9 Hz, 2H, H-triazole-biphenyl), 7.71 (s, 1H, H- tiazole-biphenyl), 7.63 (t, J = 8.3 Hz, 4H, H-triazole- biphenyl), 7.41 (m, 3H, H-triazole-biphenyl), 7.20 (d, J = .5 Hz, 1H, H-11), 6.24 (d, J = 15.5 Hz, 1H, H-10), 5.69 (d, J = 10.5 Hz, 1H, H-13), 4.96 (br. dt, J = 9.6, 1H, H-15), 4.66 (dd, J = 13.5, 3.6 Hz, 1H, H-23), 4.33 (dd, J =13.5,3.6 Hz, 1H, H-23), 4.23 (d, J = 7.5 Hz, 1H, H-1’), 3.84 (d, J = 10.2 Hz, 1H, H-3), 3.69 (d, J = 8.9 Hz, 1H, H-5), 3.46 (m, 1H, H- 2’), 3.25 (m, 1H, H-5’), 3.04 (t, J = 9.6 Hz, 1H, H-4’), 2.95 (m, 1H, H-19), 2.56 (m, 1H, H-8), 2.49 (s, 6H, 3’-N(CH3)2), 2.39-2.31 (m, 2H, H-14, H-3’), 2.10 (m, 1H, H-6), 1.95 (d, J = 7.1 Hz, 1H, H-2), 1.78 (m, 1H, H-16), 1.66 (s, 3H, H-22), 1.59-1.42 (m, 4H, H-4, H-7, H-16), 1.25 (d, J = 5.9 Hz, 3H, H-6’), 1.16 (d, J = 6.9 Hz,3H,H-21),1.04-0.99(rn,6H,H-17, H-18). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.2 (C-9), 203.0 (C- ), 173.8 (C-1), 147.6 triazole-bipheny1), 146.9 (C- 11), 141.2 (Ctr1azole-bipheny1), 140.6 (Ctriazole- biphenyl), 138.4 (C-13), 137.8 (C-12), 129.0 (Ctriazole- biphenyl), 128.9 (3C, Ctriazole-bipheny1), 127.6 (2C, C- 23-triazole-bipheny1), 127.1 (2C, Ctriazole-bipheny1), 126.2 (2C, Ctriazole-bipheny1), 120.2 (Ctr1azole- biphenyl), 118.5 (C-10), 104.0 , 81.0 (C-5), 74.5 (C-15), 73.4 (C-5’), 70.9 (C-4’), 70.8 , 70.1 (C-3’), 68.0 (C-3), 51.1 (C-23), 46.0 (C-14), 443 (C-8), 43.8 (C-19), 41.8 (2C, C-7’, 8’), 40.2 (C-4), 39.5 (C-2), 32.8 (C-7), 31.9 (C-6), 25.5 (C-16), 18.0 (C-6’), 17.4 (C-21), 13.0 (C-22), 9.7 (C-17), 9.1 (C-18). 23-(4-(pyridineyl)-1H-1,2,3-triazolyl) De0X00-mycaminosyltylonolide (YT109) {CHO YT109 Yield: 94% Rf: 0.5 (CHC13 : MeOH : NH4OH = 8 : 1 : 0.008).
MS (ESI+) : calcd. for C38H5609N5 : 97 [M+H], found m/z : 726.4078 [M+H]+. 1H NMR (270 MHz, CDCl3) 5 (ppm): 9.68 (s, 1H, H-20), 8.97 (s, 1H, H-triazole-3 -pyridine), 8.56 (s, 1H, H-triazole-3_— pyridine), 8.14 (d, J = 7.9 Hz, 1H, zole- 3-pyridine), 7.79 (s, 1H, H-tiazolepyridine), 7.35 (dd, J = 7.6, 4.7 Hz, 1H, H- triazolepyridine), 7.19 (d, J = 15.5 Hz, 1H, H-11), 6.25 (d, J =15.5 Hz, 1H, H-10), 5.68 (d, J = 10.5 Hz,1H,H- 13), 4.96 (br. dt, J = 9.6, 1H, H-15), 4.68 (dd, J = 13.5, 3.8 Hz, 1H, H-23), 4.37 (dd, J = 12.6, 9.6 Hz, 1H, H-23), 4.23 (d, J = 7.6 Hz, 1H, H-1’), 3.83 (d, J = 10.2 Hz, 1H, H-3), 3.68 (d, J = 8.9 Hz, 1H, H-5), 3.50-3.39 (m, 2H, H-14, H-2’), 3.25 (m, 1H, H-5’), 3.04 (t, .1 = 9.6 Hz, 1H, H-4’), 2.95 (m, 1H, H-19), 2.56 (m, 1H, H-8), 2.49 (s, 6H, 3’-N(CH3)2), .31 (m, 2H, H-9, H-3’), 2.10 (m, 1H, H-6), 1.93 (d, J = 6.8 Hz,1H,H-2), 1.75 (m, 1H, H-16), 1.67 (s, 3H, H-22), 1.60-1.45 (m, 4H, H-4, H-7, H-16), 1.24 (d, J = 5.9 Hz, 3H, H-6’), 1.15 (d, J = 6.9 Hz, 3H, H-21), 1.04-0.99 (m, 6H, H-17, H-18). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.2 (C-9), 203.0 (C- ), 173.6 (C-1), 149.4 (Ctriazolepyridine), 147.1 (C- 23-triazolepyridine), 146.8 (C-11), 144.8 (C-23 -triazole- 3-pyridine), 138.4 (C-13), 137.9 (C-12), 133.2 (2C, C triazole- 3-pyridine), 123.9 (Ctriazolepyridine), 120.6 (Ctriazolepyridine), 118.5 (C-10), 104.0 (C-1’), 81.0 (C-5), 74.4 (C-15), 73.4 (C-5’), 70.9 (C-4’), 70.8 (C-2’), 70.2 (C-3’), 68.0 (C-3), 51.2 (C-23), 45.9 (C-14), 44.3 (C-8), 43.8 (C-19), 41.8 (2C, C-7’, 8’), 40.2 (C-4), 39.6 (C-2), 32.8 (C-7), 31.9 (C-6), 25.5 (C-16), 17.9 , 17.4 (C-21), 13.0 (C-22), 9.7 (C-17), 9.1 (C-18). 23-(4-(methyl-1H-benz0triazolyl)-1H-1,2,3-triazol yl) X0O-mycaminosyltylonolide (YT109) /CH0 -----oWOH ---"OH Q»,flN’N YT110 N, Yield: 94% Rf: 0.5 (CHC13 : MeOH : NH4OH = 8 : 1 : 0.008). - 1 2 1 - MS (ESI+) : calcd. for C40H5809N7 : 780.4325 [M+H], found m/z : 780.4296 [M+H]+. 1H NMR (270 MHz, CDC13) 6 (ppm): 9.67 (s, 1H, H-20), 7.99 (d, J = 8.3 Hz, 1H, H-triazole-CHz-benzotriazole), 7.59 (d, J = 8.3 Hz, 1H, H-triazole-CHz-benzotriazole), 7.46 (s, 1H, H- tiazole-CHz-benzotriazole), 7.42 (d, J = 8.3 Hz, 1H, H- triazole-CHZ -benz0triazole), 7.32 (t, J = 7.3 Hz, 1H, H- triazole-CHz-benzotriazole), 7.05 (d, J = 15.5 Hz, 1H, H-11), 6.16 (d, J = 15.5 Hz,1H, H-10), 5.80 (s, 2H, H-triazole-Cflz - benzotriazole), 5.52 (d, J = 10.5 Hz, 1H, H-13), 4.89 (br. dt, 1 = 9.6, 1H, H-15), 4.52 (dd, 1 = 13.5, 3.6 Hz, 1H, H-23), 4.29 (d, 1 = 9.9 Hz, 1H, H-23), 4.22 (d, 1 = 7.3 Hz, 1H, H-1’), 3.79 (d, 1 = 10.2 Hz, 1H, H-3), 3.68 (d, 1 = 8.9 Hz, 1H, H-5), 3.46 (m, 1H, H-2’), 3.24 (m, 1H, H-5’), 3.05 (t, 1 = 9.6 Hz, 1H, H-4’), 2.95 (m, 1H, H-19), 2.56 (m, 1H, H-8), 2.49 (s, 6H, fl3)z), 2.35 (m, 1H, H-3’), 2.10 (m, 1H, H-6), 1.88 (d, 1 = 6.5 Hz, 1H, H-2), 1.75 (m, 1H, H-16), 1.81-1.57 (m, 4H, H-4, H-7, H-16), 1.49 (s, 3H, H-22), 1.25 (d, 1 = 6.0 Hz, 3H, H-6’), 1.20 (d, 1 = 6.9 Hz, 3H, H-21), 0.04—0.91 (m, 6H, H-17, H-18). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.1 (C-9), 203.0 (C- ), 173.6 (C-1), 146.6 (011), 146.2 (Ctriazole-CH2- benzotriazole), 142.3 (Ctriazole-CH2 -benz0triazole), 138.0 (C-13), 137.6 (C-12), 132.7 triazole-CH2- benzotriazole), 127.9 (2C, Ctriaz0le-CHz-benzotriazole), 124.3 (Ctriazole-CHz-benzotriazole), 123.4 (C triazole-CHz-benzotriazole), 120.0 (Ctriazole-CH2- benzotriazole), 118.5 (C-10), 110.0 triazole-QH2- benzotriazole), 104.0 (C-l’), 81.0 (C-5), 74.2 (C-l5), 73.2 (C-5’), 70.7 (C-4’), 70.6 (C-2’), 70.2 (C-3’), 68.0 (C-3), 51.0 (C-23), 45.7 (C-l4), 44.3 (C-8), 43.8 (C-l9), 41.8 (2C, C-7’, 8’), 40.2 (C-4), 39.5 (C-2), 32.8 (C-7), 31.9 (C-6), 25.5 (C- 16), 17.9 (C-6’), 17.4 (C-21), 12.7 (C-22), 9.6 (C-l7), 9.0 (C- 18).
Preparation of 20-(4-phenyl-lH-l,2,3-triazol-l-yl) deoxotriazoledeoxyO-mycaminosyltylonolides (1) Preparation of 20-(4-phenyl-lH-l,2,3-triazol-l-yl) deoxoO-mycaminosyltylonolide (YT112) "‘O‘WOH 50°C, 30min YT112 YT13 (0.5 g, 0.56 mmol) was dissolved in HBr (3.0 mL) and then the mixture was stirred for 30 minutes at 50°C. After ming complete consumption of the starting material, the reaction mixture was neutralized by adding NaHC03 sat. aq., extracted with CHC13 and dried over Na2SO4. The t was removed under reduced pressure. The ing products were ed by flash column chromatography to obtain YT112 (Yield: 39%). 2012/073277 - 1 2 3 - Rf: 0.5 (CHC13 : MeOH : NH4OH = 7 : 1 : 0.007).
HRFABMS : calcd. for C39H5909N4 : 724.4282 [M+H], found m/z : 727.4307 [M+H]+. 1H NMR (270MHz, CDCl3) 6 (ppm): 8.00 (d, J = 7.3 Hz, 2H, Htriazole-pheny1), 7.90 (s, 1H, riazole-pheny1), 7.46 (t, J = 7.6 Hz, 2H, Htriazole-pheny1), 7.32 (t, J = 6.9 Hz, 1H, Htriazole-pheny1), 6.92 (d, J = 15.5 Hz, 1H, H- 11), 6.14 (d, J = 15.2 Hz, 1H, H-10), 5.22 (d, J = 9.6 Hz,1H, H-13), 4.82 (br. dt, J = 9.6 Hz,1H, H-15), 4.50 (m, 2H, H-20), 4.35 (d, J = 7.2 Hz, 1H, H-1’), 3.82 (d, J = 10.2 Hz,1H,H-3) 3.58-3.68 (m, 3H, H-5, H-14, H-23), 3.46 (m, 1H, H-2’), 3.34 (m, 1H, H-5’), 3.09 (t, J = 9.6 Hz, 1H, H-4’), 2.72 (m, 1H, H- 19), 2.56 (m, 1H, H-8), 2.49 (s, 6H, 3’-N(CH3)2), 2.35 (m, 1H H-3’), 2.10 (m, 1H, H-6), 1.88 (d, J = 6.5 Hz, 1H, H-2), 1.75 (m, 1H, H-16), .57 (m, 4H, H-4, H-7, H-16), 1.49 (s, 3H H-22), 1.25 (d, J = 6.0 Hz, 3H, H-6’), 1.20 (d, J = 6.9 Hz, 3H H-21), 0.04-0.91 (m, 6H, H-17, H-18). 13C NMR (67.5 MHz, CDCl3) 6 (ppm): 203.7 (C-9), 173.5 (C- 1), 148.1 (C-11), 147.7 (Ctriazole-pheny1), 140.7 (C-13), 136.0 (C-12), 131.0 (Ctriazole-pheny1), 129.2 (C triazole-phenyl), 128.9 (Ctriazole-pheny1), 128.1 (C triazole -pheny1), 126.1 (2C, Ctriazole-pheny1), 119.9 (C- -triazole-pheny1), 118.2 (C-10), 103.7 (C-1’), 80.1 (C-5), 75.1 (C-15), 73.4 (C-5’), 71.1 (C-4’), 71.0 (C-2’), 69.9 (C-3’) 66.9 (C-3), 62.7 (C-23), 48.0 (C-20), 47.9 (C-8), 47.0 (C-14), 45.0 (C-19), 41.8 (2C, C-7’, 8’), 40.8 (C-4), 39.8 (C-2), 32.3 — 1 2 4 — (C-7), 319 (C-6), 25.7 (C-16), 18.0 (C-6’), 17.7 (C-21), 13.4 (C-22), 9.8 (C-17), 9.4 (C-18). (2) Preparation of 20-(4-phenyl-1H-1,2,3-triazolyl)- 20-deoxoazidodeoxyO-mycaminosyltylonolide (YT114) ¥ \N_ 1) PPh3, 12 $ \ --IOWOH Pyridine rt, 64% 5 «OWOH 2) NaN3, DMSO -"OH 60°C, 96% YT112 YT114 To a solution of PPh3 (144 mg, 0.55 mmol) and 12 (70 mg, 0.55 mmol) in pyridine (1.0 mL) was added YT112 (80 mg, 0.11 mmol) under N2 atmosphere and then the mixture was d for 4 hours at rt. After ming complete consumption of the starting material, the reaction mixture was diluted with CHClg. The organic layer was washed with Na28203 sat. aq. and dried over Na2804. The solvent was d under reduced pressure. The resulting products were purified by flash column chromatography to obtain 20-(4- -1H-1,2,3-triazolyl)deoxoIdeoxyO- mycaminosyltylonolide (Yield: 64%).
To a solution of 20-(4-phenyl-1H-1,2,3-triazolyl) deoxoIdeoxyO-mycaminosyltylonolide (57 mg, 0.068 mmol) in DMSO (0.6 mL) was added NaN3 (13 mg, 0.20 - 1 2 5 - mmol) and then the e was stirred for 30 minutes at 60 0C. After confirming complete consumption of the ng material by LC Mass, the reaction mixture was d with CHClg. The organic layer was washed with water and dried over Na2SO4. The solvent was removed under reduced pressure. The resulting products were ed by flash column chromatography to obtain YT114 (Yield: 96%).
Rf: 0.5 (CHC13 : MeOH : NH4OH = 5 : 1 : 0.005).
HRFABMS : calcd. for C39H5808N7 : 752.4347 [M+H], found m/z : 752.4354 [M+H]+. 1H NMR (270MHz, CDCls) 5 (ppm): 8.00 (d, J = 7.3 Hz, 2H, Htriazole-phenyl), 7.90 (s, 1H, Htriazole-phenyl), 7.46 (t, J = 7.6 Hz, 2H, Htriazole-phenyl), 7.32 (t, J = 6.9 Hz, 1H, Htriazole-phenyl), 6.92 (d, J = 15.5 Hz, 1H, H- 11), 6.14 (d, J = 15.2 Hz, 1H, H-10), 4.92 (d, J = 9.6 Hz,1H, H-13), 4.72 (br. dt, J = 9.6 Hz, 1H, H-15), 4.60 (m, 2H, H-20), 4.33 (d, J = 7.2 Hz, 1H, H-1’), 3.82 (d, J = 10.2 Hz,1H,H-3), 3.50 (m, 1H, H-5), 3.42-3.35 (m, 4H, H-23, H-2’, H-5’), 3.22 (m, 1H, H-14), 3.09 (t, J = 9.6 Hz, 1H, H-4’), 2.72 (m, 1H, H- 19), 2.56 (m, 1H, H-8), 2.49 (s, 6H, 3’-N(CH3)2), 2.35 (m, 1H, H-3’), 2.10 (m, 1H, H-6), 1.88 (d, J = 6.5 Hz, 1H, H-2), 1.75 (m, 1H, H-16), 1.81-1.57 (m, 4H, H-4, H-7, H-16), 1.49 (s, 3H, H-22), 1.25 (d, J = 6.0 Hz, 3H, H-6’), 1.20 (d, J = 6.9 Hz, 3H, H-21), 0.04-0.91 (m, 6H, H-17, H-18). 13C NMR (67.5 MHz, CDCls) 5 (ppm): 203.7 (C-9), 173.5 (C- 1), 148.1 (C-11), 147.6 (Ctriazole-phenyl), 140.7 (C-13), - 1 2 6 - 136.0 (C-12), 131.0 (Ctriazole-phenyl), 129.2 (C triazole-phenyl), 128.9 triazole-phenyl), 128.1 (C triazole- phenyl), 126.1 (2C, Ctriazole-phenyl), 119.5 (C- azole-phenyl), 118.2 (C-10), 103.7 (C-l’), 80.1 (C-5), 75.1 (C-15), 73.4 (C-5’), 71.1 (C-4’), 71.0 (C-2’), 69.9 (C-3’), 66.9 (C-3), 51.9 (C-23), 48.0 (C-20), 47.9 (C-8), 47.0 (C-14), 45.0 (C-19), 41.8 (2C, C-7’, 8’), 40.8 (C-4), 39.6 (C-2), 32.3 (C-7), 31.5 (C-6), 25.5 (C-16), 18.0 (C-6’), 17.7 (C-21), 13.1 (C-22), 9.7 (C-17), 9.3 (C-18). (3) Preparation of phenyl-1H-1,2,3-triazolyl)- -deoxotriazoledeoxyO-mycaminosyltylonolides To a solution of YT114 (0.24 g, 0.30 mmol) in CH3CN or MeOH (3.0 mL) were added CuI (2.9 mg, 0.015 mmol), TBTA (1.6 mg, 3.0 umol) and a suitable acetylene compound, and then the mixture was stirred at rt until the reaction was completed. After completion, the reaction mixture was diluted with CHClg, washed with 10% NH3 aq.. After removing CuI, the te was washed with brine. The c layer was dried over NazSO4 and concentrated. The resulting products were purified by flash column chromatography to obtain the following triazole compounds:
[0114] 20-(4-phenyl-1H-1,2,3-triazolyl)de0x0(4- phenyl-1H-1,2,3-triazolyl)de0xy0- mycaminosyltylonolide (YTl 15) - 1 2 7 - YT115 Yield: 85% Rf: 0.6 (CHC13 : MeOH : NH4OH = 6 : 1 : 0.006).
HRFABMS : calcd. for C47H6308N7Na : 36 [M+Na], found m/z : 876.4662 +. 1H NMR (400MHz, CDCl3) 6 (ppm): 8.10 (s, 2H, H triazole-phenyl), 7.90 (s, 2H, Htriazole-phenyl), 7.72 (d, J = 7.6 Hz, 3H, Htriazole-pheny1), 7.50 (t, J = 7.6 Hz, 4H, Htriazole-pheny1), 7.32 (t, J = 6.9 Hz, 1H, Htriazole- phenyl), 6.65 (d, J = 15.5 Hz, 1H, H-11), 6.09 (d, J = 15.2 Hz, 1H, H-10), 4.80 (br. (1, J = 9.6 Hz, 1H, H-13), 4.67 (br. dt, J = 9.6 Hz, 1H, H-15), 4.60 (m, 2H, H-23), 4.33 (d, J = 7.2 Hz, 1H, H-1’), 4.01 (m, 2H, H-20), 3.84 (d, J = 10.2 Hz,1H,H-3), 3.50 (m, 1H, H-5), 3.45-3.35 (m, 2H, H-2’, H-5’), 3.18 (m, 1H, H-14), 3.09 (t, J = 9.6 Hz, 1H, H-4’), 2.64 (m, 1H, H-19), 2.63 (m, 1H, H-8), 2.49 (s, 6H, 3’-N(CH3)2), 2.45 (m, 1H, H- 3’), 2.15 (rn, 1H, H-19), 1.85 (m, 1H, H-6), 1.88 (d, J = 6.5 Hz, 1H, H-2), 1.75 (m, 1H, H-16), 1.81-1.57 (m, 4H, H-4, H-7, H-16), 1.49 (s, 3H, H-22), 1.25 (d, J = 6.0 Hz, 3H, H-6’), 1.20 (d, J = 6.9 Hz, 3H, H-21), 0.04-0.91 (m, 6H, H-17, H-18). 20-(4-phenyl-1H-1,2,3-triazolyl)de0x0(4- butyl-1H-1,2,3-triazolyl) de0xy0- mycaminosyltylonolide (YTl 16) YT116 Yield: 92% Rf: 0.6 (CHC13 : MeOH : NH4OH = 6 : 1 : 0.006).
HRFABMS : calcd. for C45H6708N7Na : 857.0588 [M+Na], found m/z : 856.4954 [M+Na]+. 1H NMR z, CDCl3) 6 (ppm): 8.10 (s, 2H, H triazole-phenyl), 7.90 (s, 2H, Htriazole-pheny1, H-& triazole-butyl), 7.72 (d, J = 7.6 Hz, 3H, Htriazole - phenyl), 7.50 (t, J = 7.6 Hz, 4H, Htriazole-pheny1), 7.32 (t, J = 6.9 Hz, 1H, H-20 -triazole-pheny1), 6.62 (d, J = 15.5 Hz, 1H, H-11), 6.09 (d, J = 15.2 Hz, 1H, H-10), 4.78 (br. (1, J = 9.6 Hz, 1H, H-13), 4.64 (br. dt, J = 9.6 Hz, 1H, H-15), 4.60 (m, 2H, H-23), 4.33 (d, J = 7.2 Hz, 1H, H-1’), 3.90 (m, 2H, H-20), 3.84 (d, J = 10.2 Hz, 1H, H-3), 3.50 (m, 1H, H-5), 3.45-3.35 (m, 2H, H-2’, H-5’), 3.09 (t, J = 9.6 Hz,1H,H-4’), 3.07 (m, 1H, H-14), 2.64 (m, 1H, H-19), 2.63 (m, 1H, H-8), 2.49 (s, 6H, fl3)2), 2.45 (m, 1H, H-3’), 2.15 (m, 1H, H- 19), 1.85 (m, 1H, H-6), 1.65 (m, 1H, H-2), 1.86-1.39 (m, 8H, - 1 2 9 - H-4, H-7, H-16, H-22), 1.36-1.10 (m, 12H, H-21, H-6’, H- triazole-butyl), 1.02-0.97 (m, 6H, H-18, H-triazole-butyl), 0.90 (t, .1 = 7.2 Hz, 3H, H-17).
[0116] Paper disc assays (1) Antibacterial activities t Mannheimia and Pasteurella were determined by the following steps: 1) M.hemolytica KB345 (Tilmicosin-sensitivity strain) and M.hem01ytica KB346 (Tilmicosin-low sensitivity strain) were provided. KB 345 strain stored at -80 0C was seeded to BHIB agar medium (10 mL) by using Microbank beads (Pro- Lab) and um nail. After statically incubating the KB 345 strain for 24 hours at 37°C, it was seeded to maintaining slant BHIB agar medium (7 mL) by using platinum loop, further statically incubated for 24 hours at 37°C to obtain slant. One platinum loop of KB 345 strain stored at the slant was inoculated into a large test tube charged with BHIB liquid medium (10 mL) and then incubated for 24 hours at 37 0C with shaking. 2) A paper disc (ADVANTEC, (13:6 mm) was impregnated with a solution of test compound and dried under d re. 3) To a melted BHIB agar medium was inoculated 1% of WO 76169 the broth obtained from step 1) above to prepare a test plate.
After the medium set, the paper disc prepared in step 2) above was put on the plate and it was incubated at 37°C. 4) After 0116 day, the inhibition zone diameter and clarity (A to E) were determined.
For KB346 strain, the same ures were repeated.
[0117] The results ofthe assays are shown in Tables below: Table 2. Mannhemia hemolytica KB345: Inhibition zone (mm) and clarity (A to E) 100 30 10 3 mg/ 1 mg/ -pos1tion. . mg/ mg/ mg/ - 6mm 6mm subst1tuent 6mm 6mm 6mm di S k di S k disk disk disk Tylosin - 11.0A 10.5B - - - Tilmicosin kw? m m 16.0A 13.5A 10.7A Tulathromycin - MT MT 18.0A 16.0A 12.5A YT6 .g—CHO NT 10.5A — — — YT7 EACH - - - - - WO 76169 YT8 .EACI 20.0A 18.0A 12.5A — — YTll —§/\N3 18.0A 16.0A 13.0A 10.0A — YT12 3L; \N/ 22.0A 19.0A 17.0A 13.0A 9.0A YT13 '§’\N\NW 21.0A 18.0A 16.0A 15.0A 11.0A I/\3 KwS YT14 22.0A 19.5A 16.5A 14.0A 11.0A /§AN\ I YT16 NW 19.0A 16.5A 14.5A 11.5A — YT17 gmw 19.5A 18.0A 14.0A 12.0A _ /§“N\ YT18 NWNH2 19.5A 17.0A 14.5A 11.0A — E KEY/V“ YT19 21.0A 18.0A 16.0A 14.0A MT g EW/\ YTZO 20.0A 17.5A 16.0A 11.5A 9.013 YT21 E“VF.'1‘; O O 19.0A 18.0A 15.5A 13.5A 11.5A YT22 a““IN/MOE 21.0A 18.0A 14.5A 11.5A 7.513 :N t YT23 EA“ 09 16.5A 14.5A 13.5A 10.0A 7.513 YT24 :Wo@ 18.0A 17.0A 14.5A 12.0A 8.5B YT25 “KW 18.5A 17.0A 14.0A 12.0A 8.0A YT26 FEW 16.0A 14.0A 11.5A 9.0A — YT27 QMEWOCSHH 16.0A 13.0A 11.0A 9.0A — _/\g “EVNQ YT28 19.0A 16.0A 13.0A 11.0A _ Table 3. Mannheniia hemolytica KB346 Inhibition zone (mm) and clarity (A to E) iti0n substituent - 1 3 3 - Tilmicosin Tulathrornycin —134— YT21 —H 17'0 14 0A 12 5A 90A . . .
N=N A ;«N\ 16.0 11.0 YT22 $19,403 9013 _ A A ' O 11 YT23 'EAN ' 0 \ 9.0 A — — [LN 00 A YT24 TEE—@043 9 0 B - - _ “NS—Q 12.5 YT25 8.5 A - - N=N A YT26 ‘EANW - _ _ _ YT27 “WOCSHH\ — — _ _ E [hng 15.0 10.0 YT28 _ _ ‘N A A .EAN / \ 11.0 ‘EAN \ / 10.0 YT30 M N 80 B _ _ YT32 N’R’é 8.0 B A A .gAN \ 14.5 14.0 YT33 NW _ _ A A YT34 EAE/W - - _ _ A _ 14.5 13.5 YT35 E 71%;} — — A A ‘N N - 1 3 5 - YT36 'EANN/WOH “'0 8.0A - - _ YT 3 7 ‘EARh‘l/VOH - _ _ _ _ Table 4. Mannhernia hemolytica KB345 Inhibition zone clarity (A to E) nig/ 6mm disk) - 23- 100 30 10 position on mg/ mg/ mg/ substitu substituen 6mm 6mm 6mm ent t disk disk disk Tilniico 18.0 16.0 12.0 _ _ NT sin A A A Tylos1n. 11.0 10.5 - - _ _ _ A B .CHO 150 12.5 85 YT106 —E E/\OH - - A A A .CHO 25.0 20.0 15.5 11.5 YT111 E /\E | NT A A A A 215 18.0 16.0 12.0 YT107 .g.CHO EN./\ A A A A .gAN\NW 17.0 14.0 11.0 YT101 ‘_CHOg _ _ A A A YT102 .g-CHO ”CHO IEAWQ 16.0 14.0 12.0 YT103 E “‘11:; _ _ \N/ A A A ,CHO mx 12.5 10.0 10.0 9.0 YT104 E Mm _ A A A A “NW- 12.5 9.5 YT109 ECHO .A - - - A A YTl 10 'E’CHO Emil/YEN lAl .5 1.0 _ _ _ YT112 flaw $0.4 :90 :50 :00 [:70 NT YT113 WNW 0 -§’\| [:95 1:80 [:1 - NT YT114 $wa-§“N3 :10 :10 27.5 1131.5 NT YT115 flaw FEW [1&60 [1X40 [1&20 _ NT YT116 $wa pm”? [:70 [:70 [13.0 _ NT Table 5.Mannhen1ia hemolytica KB346 Inhibition zone (mm) and y (A to 23-position position substituent substituent Tilmicosin -—-—F 1LT -— Tylosin -—-— 1LTW -— YT106 .g—CHO .§’\OH MT MT 9T -— YT111 .g—CHO .E’N WW -— YT107 .g—CHO .gANg MT 10.7 -— —137— YT102 .g—CHO FEW .—— YT103 .g-CHO— .EAEW .———_—— YT 1 0 4 .g-CHO rm- - _ _ _ YT 1 0 9 g-CHO “gm 9 - - - _ . 0A YTllO .g—CHO éAEYENQ 8 0A - - _ _ YT112 FEW —§’\OH 11.5A — - - _ YT113 5“th -§’\| - - - _ _ YT114 FEW .§“N3 - - - _ _ YT115 WNW FEW - - _ _ _ YT116 FEW EAL; 3 - - _ _ _ (2) Antibacterial activities against other bacteria were determined with Micrococcus luteus ATCC934l (l), Bacillus subtilis ATCC663 (S), Escherichia coli NIHJ (C), Xanthomonas campestris KB88 (X), Mucor racemosus IFO 4581 (Mu) and a albicans ATCC 64548 (Ca).
Bacillus subtilis ATCC6633 was incubated in DaVis tic medium and then the seed broth was combined with the medium in the ratio of 1:99 to obtain a test plate. -l38- Micrococcus luteus ATCC934l, Escherichia coli NIH] and monas campestris KB88 were respectively incubated in Nutrient agar medium and inoculated at 0.2%\ 0.5% and 1.0%.
Mucor racemosus IFO 4581 and Candida albicans ATCC 64548 were respectively incubated in GY agar medium and then ated at 0.3% and 0.2%.
A paper disc (ADVANTEC, (13:6 mm) was impregnated with a on of test compound and dried under reduced pressure.
The paper disc was put on the test plate and it was incubated for 24 hours at 37°C. After incubation, the inhibition zone diameter and clarity (A to E) were determined.
The results ofthe assays are shown in Table 6 below: Table 6. Six bacteria Inhibition zone(mm) and clarity Sample 20- mg/ S l c X Ca Mu position 6mm substituent disc Tilmicosin CE 10 18 A 27.5 20 30 C — — if“ A C 1 11A 19 A 13 20 C — — 0.1 14 C 12 A — 12 C — — YT12 'E’w \ f“w 10 14 A 25 A — 27 B — — 1 12.5 18.5 — 12.5 — — A A B 0.1 7 A 12 A — 7 B — — YT13 -§’\1\1’§\_< > 10 15.5 27.5 — 23.5 — — N=N A A B l 12 A 21.5 — 17 B — — 0.1 9.5 15 A — 8 B — — YT14 i “11%/\ S 10 15 A :65 173 22 B 1 11A 20.5 — 16B — 0.1 8A 13.5 — 7B — YT19 5 EWC' 10 15A 26A — 23B — 1 10.5 19A — 14.5 — A B 0.1 7A 13A — 7B — YT29 .AEEWN/ 10 15A :55 _ 24B _ 1 10A 19.5 — 15B — 0.1 7A 11A — 7B — Minimal inhibitory concentrations (MICS) were determined against the most prevalent ens in cattle (Mannheimia Haemolytica, 3 isolates) and swine (A. pleuro- pneumoniae, 6 isolates).The results are summarized in Table 7.
Table 7. MICs (ug/ml) M.haemolytica pleuropneumoniae e isolates Compound 1 2 3 l 2 3 4 5 6 YT104 8 4 8 >16 >16 >16 >16 >16 >16 YT112 8 4 8 4 4 4 8 4 8
[0124] All references, patent applications and publications cited herein are hereby incorporated by reference in its entirety.

Claims (17)

Claims
1. A nd represented by the formula (I): 5 or a pharmaceutically acceptable salt, ester or solvate thereof; wherein, A is selected from halogen, CH2-N3, hydroxy, CHO, CH2-OH, CH2-halogen and CH2-R'; R1 and R2 taken er are oxo; R3 is hydrogen; 10 R4 is hydrogen; R5 is selected from hydroxy, N3, halogen, 6-deoxy-2,3-di-O- methyl-b-d-allo-hexapyranosyloxy and R'; R7 is selected from hydrogen, C1-C6-alkyl, optionally substituted with one or more tuents selected from the group consisting 15 of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic, C2-C6-alkenyl, ally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic, C2-C6-alkynyl, ally substituted with one or more 20 substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted cyclic; RP is hydrogen; and each R' is independently 4-R-1,2,3-triazolyl; and where each R is independently selected from the group consisting of: 5 (1) C1-C9-alkyl, optionally substituted with one or more tuents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic, -OR7 where R7 is as previously defined; (2) C2-C9-alkenyl, optionally substituted with one or more 10 substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic, -OR7 where R7 is as previously defined; (3) C2-C9-alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, 15 substituted aryl, heterocyclic and tuted heterocyclic, -OR7 where R7 is as usly defined; (4) C3-C14-cycloalkyl; (5) substituted C3-C14-cycloalkyl; (6) aryl; 20 (7) substituted aryl; (8) heterocyclic; (9) substituted cyclic; and (10) , where R7 is as previously defined; provided that at least one of A and R5 is defined as A = CH2-R’ 25 and/or R5 = R'.
2. The compound of claim 1 n; A is CH2-R'; R1 and R2 taken together are oxo; 5 R3 is H; R4 is H; and R5 is 6-deoxy-2,3-di-O-methyl-b-d-allo-hexapyranosyloxy.
3. The compound of claim 1 wherein; 10 A is CHO; R1 and R2 taken together are oxo; R3 is H; R4 is H; and R5 is R'.
4. The compound of any one of claims 1 to 3 wherein; R is selected from the group consisting of
5. A method for preparing a compound of the a (I): 5 wherein A is CH2-R' and R1, R2, R3, R4, R5, R' and Rp are as defined in claim 1; which method comprises following steps: (i) reacting a compound of the formula (II): wherein, 5 A is CH2-hydroxy; and the other variable groups are as d in claim 1, with an azide ed from diphenylphosphoryl azide (DPPA) or sodium azide (NaN3) to form a compound of said formula (II) wherein A is CH2- N3 and the other variable groups are as defined in claim 1; and 10 (ii) reacting the resulting compound of the formula (II) n A is CH2-N3 and the other variable groups are as defined in claim 1 with an R-C≡CH, wherein R is as defined in claim 1 above, in the presence of a copper catalyst to form a compound of the formula (II), 15 wherein A is CH2-R' and R3, R4, R5, R' and Rp are as defined above.
6. A method for preparing a compound of the formula (I): wherein R5 is R' and A, R1, R2, R3, R4, R' and Rp are as defined in claim 1; which method comprises following steps: 5 (i) reacting a compound of the formula (II): wherein, R5 is y; and the other variable groups are as defined in claim 1, with an azide 10 selected from diphenylphosphoryl azide (DPPA) or sodium azide (NaN3) to form a compound of said formula (II) wherein R5 is - N3 and the other variable groups are as defined in claim 1; and (ii) ng the resulting compound of the formula (II) wherein R5 is -N3 and the other variable groups are as defined in claim 1 with an R-C≡CH, n R is as defined in claim 1 above, in the presence of a copper catalyst to form a compound of the formula (II), wherein R5 is R' and A, R3, R4, R' and Rp are as defined above.
7. A pharmaceutical or veterinary composition comprising a compound ing to any one of claims 1 to 4 and at least one of pharmaceutically acceptable carriers. 10
8. The pharmaceutical or veterinary composition of claim 7 for the treatment or the prevention of bacterial infections or disorders associated with bacterial infections in an animal.
9. Use of the compound of any one of claims 1 to 4 for 15 manufacturing a medicament for the treatment or the prevention of bacterial infections or disorders ated with bacterial infections in an animal.
10. A compound of any one of claims 1 to 4 for use in the treatment 20 or the prevention of bacterial infections or disorders associated with bacterial infections in an animal.
11. A method for treating or preventing ial ions or disorders associated with ial infections in a non-human 25 animal, wherein the method comprises administering to the non- human animal a therapeutically effective amount of the compound ing to any one of claims 1 to 4.
12. A compound ing to claim 1 substantially as herein 5 described with nce to any of the examples.
13. A method according to claim 5 substantially as herein described or exemplified. 10
14. A method according to claim 6 substantially as herein described or exemplified.
15. A pharmaceutical or veterinary composition according to claim 7 substantially as herein described or exemplified.
16. A use according to claim 9 substantially as herein described or exemplified.
17. A method according to claim 11 substantially as herein 20 described or exemplified.
NZ625402A 2011-11-25 2012-11-21 Antibacterial tylosin derivatives and methods for their preparation NZ625402B2 (en)

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