NZ714071B2 - Tylosin derivatives and method for preparation thereof - Google Patents
Tylosin derivatives and method for preparation thereof Download PDFInfo
- Publication number
- NZ714071B2 NZ714071B2 NZ714071A NZ71407114A NZ714071B2 NZ 714071 B2 NZ714071 B2 NZ 714071B2 NZ 714071 A NZ714071 A NZ 714071A NZ 71407114 A NZ71407114 A NZ 71407114A NZ 714071 B2 NZ714071 B2 NZ 714071B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- mmol
- spp
- aryl
- substituted
- compound
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title abstract description 23
- WBPYTXDJUQJLPQ-VMXQISHHSA-N Tylosin Chemical class O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 WBPYTXDJUQJLPQ-VMXQISHHSA-N 0.000 title abstract description 19
- 239000000203 mixture Substances 0.000 claims abstract description 59
- 206010060945 Bacterial infection Diseases 0.000 claims abstract description 41
- 239000003814 drug Substances 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 230000003405 preventing Effects 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 168
- 125000000623 heterocyclic group Chemical group 0.000 claims description 96
- 125000001424 substituent group Chemical group 0.000 claims description 53
- 125000003118 aryl group Chemical group 0.000 claims description 48
- 229910052736 halogen Inorganic materials 0.000 claims description 43
- 125000003107 substituted aryl group Chemical group 0.000 claims description 43
- 150000002367 halogens Chemical class 0.000 claims description 40
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 34
- 201000010099 disease Diseases 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000011780 sodium chloride Substances 0.000 claims description 15
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 12
- 230000002265 prevention Effects 0.000 claims description 12
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- 239000012453 solvate Substances 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000005418 aryl aryl group Chemical group 0.000 claims description 3
- 239000003120 macrolide antibiotic agent Substances 0.000 abstract description 7
- 238000000034 method Methods 0.000 description 94
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- -1 and N Chemical group 0.000 description 53
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 48
- 201000009910 diseases by infectious agent Diseases 0.000 description 47
- ODUCDPQEXGNKDN-UHFFFAOYSA-N Nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 44
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- LKYXEULZVGJVTG-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH] LKYXEULZVGJVTG-UHFFFAOYSA-N 0.000 description 29
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- 239000002904 solvent Substances 0.000 description 25
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- 239000007858 starting material Substances 0.000 description 22
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- 239000010949 copper Substances 0.000 description 21
- 241000283690 Bos taurus Species 0.000 description 20
- 239000011734 sodium Substances 0.000 description 18
- 238000003818 flash chromatography Methods 0.000 description 17
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- 230000002401 inhibitory effect Effects 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
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- 239000000460 chlorine Substances 0.000 description 15
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 15
- 229910052802 copper Inorganic materials 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- 229960004059 Tylosin Drugs 0.000 description 14
- 239000004182 Tylosin Substances 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 235000019375 tylosin Nutrition 0.000 description 14
- MKRTXPORKIRPDG-UHFFFAOYSA-N Diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 13
- 230000002829 reduced Effects 0.000 description 13
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 12
- 125000001072 heteroaryl group Chemical group 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 229960000223 tilmicosin Drugs 0.000 description 12
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- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 10
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- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
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- 239000008267 milk Substances 0.000 description 8
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 230000000202 analgesic Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 229940077747 antacids containing calcium compounds Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 201000001320 atherosclerosis Diseases 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- UDLLFLQFQMACJB-UHFFFAOYSA-N azidomethylbenzene Chemical compound [N-]=[N+]=NCC1=CC=CC=C1 UDLLFLQFQMACJB-UHFFFAOYSA-N 0.000 description 1
- 201000008680 babesiosis Diseases 0.000 description 1
- 230000000721 bacterilogical Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 229940000635 beta-Alanine Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 150000001674 calcium compounds Chemical class 0.000 description 1
- 229940043430 calcium compounds Drugs 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000005591 charge neutralization Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000001808 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- CRRYCJOJLZQAFR-UHFFFAOYSA-N cyclohexane;pentane Chemical compound CCCCC.C1CCCCC1 CRRYCJOJLZQAFR-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 150000008266 deoxy sugars Chemical class 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- RYPWQHONZWFXBN-UHFFFAOYSA-N dichloromethyl(methylidene)-$l^{3}-chlorane Chemical compound ClC(Cl)Cl=C RYPWQHONZWFXBN-UHFFFAOYSA-N 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 230000002255 enzymatic Effects 0.000 description 1
- 230000001586 eradicative Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940013945 gamma-Aminobutyric Acid Drugs 0.000 description 1
- 201000000628 gas gangrene Diseases 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- CJNBYAVZURUTKZ-UHFFFAOYSA-N hafnium(IV) oxide Inorganic materials O=[Hf]=O CJNBYAVZURUTKZ-UHFFFAOYSA-N 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 230000002140 halogenating Effects 0.000 description 1
- LMYQAZODCDGPSE-UHFFFAOYSA-N hexa-1,2,3,4-tetraene Chemical group [CH2+][C]=C=C=C=C LMYQAZODCDGPSE-UHFFFAOYSA-N 0.000 description 1
- 239000008079 hexane Substances 0.000 description 1
- XBFMJHQFVWWFLA-UHFFFAOYSA-N hexane;pentane Chemical compound CCCCC.CCCCCC XBFMJHQFVWWFLA-UHFFFAOYSA-N 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000266 injurious Effects 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 229940079867 intestinal antiinfectives Sulfonamides Drugs 0.000 description 1
- 230000003834 intracellular Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000000877 morphologic Effects 0.000 description 1
- IJUPCLYLISRDRA-ULAWRXDQSA-N mycaminose Chemical compound C[C@@H](O)[C@@H](O)[C@H](N(C)C)[C@@H](O)C=O IJUPCLYLISRDRA-ULAWRXDQSA-N 0.000 description 1
- JYAQWANEOPJVEY-LYFYHCNISA-N mycarose Chemical compound C[C@H](O)[C@H](O)[C@](C)(O)CC=O JYAQWANEOPJVEY-LYFYHCNISA-N 0.000 description 1
- QGQQTJFIYNGSEU-CWKFCGSDSA-N mycinose Chemical compound CO[C@@H](C=O)[C@H](OC)[C@H](O)[C@@H](C)O QGQQTJFIYNGSEU-CWKFCGSDSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000006916 nutrient agar Substances 0.000 description 1
- 229940005938 ophthalmologic antiinfectives Sulfonamides Drugs 0.000 description 1
- 230000036220 oral bioavailability Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 238000002559 palpation Methods 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- HPUOAJPGWQQRNT-UHFFFAOYSA-N pentoxybenzene Chemical compound CCCCCOC1=CC=CC=C1 HPUOAJPGWQQRNT-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 description 1
- 125000005541 phosphonamide group Chemical group 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 230000015843 photosynthesis, light reaction Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001184 polypeptide Chemical group 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 201000010153 skin papilloma Diseases 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 230000000392 somatic Effects 0.000 description 1
- 210000001082 somatic cell Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000002522 swelling Effects 0.000 description 1
- 201000010874 syndrome Diseases 0.000 description 1
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 229940026752 topical Sulfonamides Drugs 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N trans-L-hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical group CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WBPYTXDJUQJLPQ-VMXQISHHSA-O tylosin(1+) Chemical class O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1[NH+](C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 WBPYTXDJUQJLPQ-VMXQISHHSA-O 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 238000010518 undesired secondary reaction Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Abstract
The present invention relates to new macrolide derivatives, in particular new tylosin derivatives of the formula (Ila), 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. 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.
Description
TYLOSIN DERIVATIVES AND METHOD FOR PREPARATION THEREOF
BACKGROUND OF THE INVENTION
The present invention relates to new macrolide derivatives, in particular new tylosin derivatives; a
pharmaceutical or veterinary composition comprising any of the derivatives; a method for preparation
thereof; a method for treating and/or preventing bacterial infections in an animal, wherein the method
comprises administering any of 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.
Macrolides in generally have a chemical structure of 12-, 14- or 16-membered macrocyclic group
(aglycone) substituted with 1 to 3 substituents such as neutral sugars, deoxy sugars or amino sugars.
Macrolides have a wide spectrum of antibacterial activities against for example Pneumococcus spp,
Streptococcus spp, Hemophilus influenzae, Staphylococcus 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, typically including
tylosin represented by the following formula:
mycaminose
HO O
3 OH O
mycarose
1'''
mycinose
Tylosin has been used for the treatment of infections of Gram-positive bacterium and Mycoplasma 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 typically include among
others tilmicosin and tulathromycin (tulathromycin belongs to a different class of compounds)
represented by the following formulae, respectively:
HO O O
HO
O OMe
1'''
Tulathromycin
OMe Tilmicosin H
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 provide new antibiotics.
The backgrounds may be reflected in the following Patent and Non-patent References:
Patent References:
EP 124216 WO 2003-089446
EP 240264 WO 2003-089447
EP 606747 WO 2005-118610
WO 1996-009312 WO 2005-118610
WO 2003-039558 WO 2007-071370
WO 2003-039558 WO 2009-064953
WO 2003-043642
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SUMMARY OF THE INVENTION
The object of the present invention is to provide 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 Aeromonas spp, Escherichia spp, Klebsiella spp, Proteus spp,
Salmonella spp, Shigella spp, Morganella spp, Citrobacter spp, Enterobacter spp, Serratia spp, Erwinia
spp, Yersinia spp, Pseudomonas spp, Alcaligenes spp, Burkholderia spp, Phyllobacterium spp,
Acinetobacter spp, Stenotrophomonas spp, Haemophilus spp, Actinobacillus 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, Leptospira 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; and/or to at least provide the public with a
useful choice.
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, Propionibacterium acnes, Actinomyces bovis,
Mycobacterium tuberculosis, Mycobacterium leprae, Bacillus or Clostridium and gram-negative bacteria
such as Pasteurella, Mannheimia or Mycoplasma in animals.
In one embodiment, the present invention provides a compound represented by the formula (IIa):
or a pharmaceutically acceptable salt, ester or solvate thereof;
wherein,
R is hydroxyl;
11 12
R and R are each independently selected from
hydrogen;
-CHO;
C -C -X, wherein X is selected from the group consisting of hydroxyl or protected hydroxyl, halogen, and
CN;
C -C -alkyl, optionally substituted with one or more substituents selected from the group consisting of
halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
C -C -alkenyl, optionally substituted with one or more substituents selected from the group consisting of
halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
C -C -alkynyl, optionally substituted with one or more substituents selected from the group consisting of
halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic;
C -C - cycloalkyl;
3 14
substituted C -C -cycloalkyl;
3 14
aryl;
substituted aryl;
heterocyclic;
substituted heterocyclic;
11 12
and wherein at least R or R is C -C -alkyl, substituted with a 1,2,3-triazole substituted at position 4 with
one substituent selected from the group consisting of heterocyclic and substituted heterocyclic.
Described are compounds represented by the formula (IIa):
R O O N
O OH O
(IIa)
or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof;
11 12
wherein, R and R are each independently selected from hydrogen;
CHO;
C -C -X, wherein X is selected from the group consisting of hydroxyl or protected hydroxyl,
halogen, and N ,
C1-C6-alkyl, optionally substituted with one or more substituents selected from the group
consisting of halogen, aryl, substituted aryl, heterocyclic and substituted 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;
C3-C14-cycloalkyl;
substituted C3-C14-cycloalkyl;
aryl;
substituted aryl;
heterocyclic;
substituted heterocyclic;
11 12
or R and R taken with the nitrogen atom to which they are connected form N or a 3- to 7-
membered ring which may optionally contain a hetero function selected from the group consisting of -
O-, -NH-, -N(C1-C6-alkyl)-, -N(aryl) -, -N (heteroaryl)-, -S-, -S(O)- and-S(O) -;C3-C14 cycloalkyl; and
wherein R is
hydrogen;
hydroxyl;
protected hydroxyl;
halogen;
-N ; or
N-Y2, wherein each Y is independently selected from the group consisting of hydrogen and C1-
C6-alkyl, or the two Y taken with the nitrogen atom to which they are connected form a 3- to 7-
membered ring.
In a further embodiment, the present invention provides compounds of said formula (IIa), wherein:
R is hydroxy.
In another embodiment, the present invention provides compounds of said formula (IIa), wherein:
11 12
at least R or R is C1-C6-alkyl, optionally substituted with one or more substituents selected from the
group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic, and
wherein preferably
11 12
at least R or R is C1-C6-alkyl, substituted with one substituent selected from the group consisting of
heterocyclic and substituted heterocyclic, and wherein more preferably
11 12
at least R or R is C1-C3-alkyl, substituted with one substituent selected from the group consisting of
heterocyclic and substituted heterocyclic, and wherein even more preferably
11 12
at least R or R is C1-C3-alkyl, substituted with a 1,2,3-triazole substituted at position 4 with one
substituent selected from the group consisting of heterocyclic and substituted heterocyclic.
In still another embodiment the present invention provides compounds of said formula (IIa), wherein:
11 12
one of R and R is C1-C6-alkyl, substituted with one substituent selected from the group consisting of
11 12
heterocyclic and substituted heterocyclic, and the other one of R and R is
hydrogen or
C1-C6-alkyl, optionally substituted with one or more substituents selected from the group
consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic; wherein
preferably
11 12
one of R or R is C1-C3-alkyl, substituted with one substituent selected from the group consisting of
heterocyclic and substituted heterocyclic, and the other one of R11 and R12 is
hydrogen or
C1-C3-alkyl, optionally substituted with one or more substituents selected from the group
consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic, wherein even
more preferably
11 12
one of R and R is C1-C2-alkyl, substituted with a 1,2,3-triazole substituted at position 4 with one
substituent selected from the group consisting of heterocyclic and substituted heterocyclic, and the other
11 12
one of R and R is
hydrogen or
C1-C2-alkyl, optionally substituted with one substituent selected from the group consisting of
aryl and substituted aryl.
Also described is a method for preparing a compound of the formula (IIa):
R O O N
O OH O
(IIa)
11 12
wherein R , R and R are as defined above;
which method comprises at least one of the following steps following steps (i), (ii), (iii) and/or (iv):
(i) reacting O-mycaminosyltylonolide (OMT):
with an amine of the general formula NR R to form a compound of the following formula (IIb)
(IIb)
wherein
1 11 12
R is as defined for R and R in the formula (IIa) above, and
R is 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
(ii) reacting the resulting compound of the formula (IIb),
wherein
1 11 12
R is as defined for R and R in the formula (IIa) above, and
R is C2-C6-alkynyl, optionally substituted with one or more substituents selected from the
group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic
11 12
with an R-N , wherein R is as defined for R or R in the formula (IIa) above, in the presence of a
copper catalyst to form a compound of the formula (IIa); or
(iii) reacting O-mycaminosyltylonolide (OMT):
with an amine of the general formula NR R to form a compound of the following formula (IIb)
(IIb)
wherein
1 11 12
R is as defined for R and R in the formula (IIa) above, and
R is C1-C6-alkyl, bearing one N -substituent and being optionally substituted with one or more
substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and
substituted heterocyclic; or
(iv) reacting the resulting compound of the formula (IIb), wherein
1 11 12
R is as defined for R and R in the formula (IIa) above, and
R is C1-C6-alkyl, bearing one N -substituent and being optionally substituted with one or more
substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and
substituted heterocyclic
11 12
with an R-C≡CH, wherein R is as defined for R or R in the formula (IIa) above, in the presence of a
copper catalyst to form a compound of the formula (IIa).
Described is a pharmaceutical or veterinary composition comprising the compound of the present
invention. In one embodiment, the present invention provides a pharmaceutical or veterinary
composition comprising a compound of the present invention and at least one pharmaceutically
acceptable carrier. Such composition may be used for the treatment or the prevention of bacterial
infections or disorders 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.
Preferred in this context are pharmaceutical or veterinary compositions comprising the compound of
formula (IIa) as mentioned before. These compositions, as well as the compounds of formula (IIa) as
mentioned before, may preferably be used for the treatment of mastitis in non-human mammals, such as
cattle, camel, buffalo, goat or sheep, more preferably in ruminants that are used for milk production for
human consumption, such as cattle, buffalo, sheep, and goat.
In further embodiment, the present invention provides use of the compound of the present invention in
the manufacture of a medicament for use in the treatment or prevention of bacterial infections or
disorders associated with bacterial infections in a human.
In further embodiment, the present invention provides a method for treating or preventing bacterial
infections or disorders associated with bacterial infections in a non-human animal, wherein the method
comprises administering to the non-human animal a therapeutically effective amount of the compound
of the present invention.
Also described are uses of the compounds of the present invention for manufacturing a medicament for
treatment or prevention of bacterial infections or disorders associated with bacterial infections in
animals.
In still further embodiments, the present invention provides compounds according to the embodiments
as mentioned before for use as a medicament, preferably the compounds of formula (IIa) as mentioned
before.
In yet another embodiments, the present invention provides compounds or pharmaceutical or veterinary
compositions according to the embodiments as mentioned before for use in the treatment or prevention
of bacterial infections or disorders associated with bacterial infections in an animal, preferably the
compounds of formula (IIa) as mentioned before.
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 greater than those of tylosin
or tilmicosin. Therefore, 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 tilmicosin-resistant
bacteria. Accordingly, the compound of the present invention is useful in the treatment or prevention of
bacterial infections or disorders associated with bacterial infections in animals.
In the description in this specification reference may be made to subject matter which is not within the
scope of the appended claims. That subject matter should be readily identifiable by a person skilled in
the art and may assist in putting into practice the invention as defined in the appended claims.
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 "C1-C3-alkyl", "C1-C6-alkyl", "C1-C12-alkyl" or the like, as used herein, refer to saturated,
straight- or branched-chain hydrocarbon radicals containing between one and three, one and six or one
and twelve carbon atoms, respectively. The term "C0-C3-alkyl" means a bond or C1-C3-alkyl.
Examples of C1-C3-alkyl radicals include methyl, ethyl, propyl and isopropyl, and examples of C1-C6-
alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n- butyl, tert-butyl,
neopentyl and n-hexyl, and examples of C1-C12-alkyl radicals include, but are not limited to, methyl,
ethyl, propyl, isopropyl, 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 between two and six carbon atoms with one or more double bonds in the chain.
Examples of C2-C6-alkenyl include, but are not limited to, propenyl, isobutenyl, 1,3-hexadienyl, n-
hexenyl and 3-pentenyl.
The term "C2-C6-alkynyl" or the like, as used herein, 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, 1,3-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, 1-or 2-naphthyl, anthracene, phenanthrene and the like.
The term, "C3-C14-cycloalkyl", as used herein refer to unsubstitued mono-, di- or tri-cyclic groups
where each carbocyclic ring consisting cycloalkyl comprises 3 to 7 carbon atoms, respectively, such as
for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
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, triazolyl, tetrazolyl, thiazolyl,
oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and the
like.
The term "heterocycloalkyl", 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 six-membered 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 oxidized, (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, thiazolidinyl,
isothiazolidinyl, and tetrahydrofuryl.
The term "heterocyclic", as used herein, refers to 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, substituted by
independent replacement of one or more of the hydrogen atoms therein with F, Cl, Br, I, OH, NO , CN,
C(O)-C1-C6-alkyl, C(O)-aryl, C(O)-heteroaryl, CO -alkyl, CO -aryl, CO -heteroaryl, CONH , CONH-
2 2 2 2
C1-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)-C1-C6-alkyl, OC(O)-aryl, OC(O)-heteroaryl,
OCO -alkyl, OCO -aryl, OCO -heteroaryl, OCONH , OCONH-C1-C6-alkyl, OCONH-aryl, OCONH-
2 2 2 2
heteroaryl, NHC(O)-C1-C6-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO -alkyl, NHCO -aryl,
NHCO -heteroaryl, NHCONH , NHCONH-C1-C6-alkyl, NHCONH-aryl, NHCONH-heteroaryl, SO -
2 2 2
C1-C6-alkyl, SO -aryl, SO -heteroaryl, SO NH , SO NH-C1-C6-alkyl, SO NH-aryl, SO NH-heteroaryl,
2 2 2 2 2 2 2
C1-C6-alkyl, C3-C7-cycloalkyl, CF , CH CF , CH Cl , CH OH, CH CH OH, CH NH , CH SO CH ,
3 2 3 2 2 2 2 2 2 2 2 2 3
aryl, substituted aryl, heteroaryl, substituted heteroaryl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C1-
C6-alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C1-
C3-alkyl-amino, thio, aryl-thio, heteroarylthio, benzyl-thio, C1-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 F, Cl, Br, I,
OH, NO , CN, C(O)-C1-C6-alkyl, C(O)-aryl, C(O)-heteroaryl, CO -alkyl, CO -aryl, CO -heteroaryl,
2 2 2 2
CONH , CONH-C1-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)-C1-C6-alkyl, OC(O)-aryl,
OC(O)-heteroaryl, OCO -alkyl, OCO -aryl, OCO -heteroaryl, OCONH , OCONH-C1-C6-alkyl,
2 2 2 2
OCONH-aryl, OCONH-heteroaryl, NHC(O)-C1-C6-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO -
alkyl, NHCO -aryl, NHCO -heteroaryl, NHCONH , NHCONH-C1-C6-alkyl, NHCONH-aryl,
2 2 2
NHCONH-heteroaryl, SO2-C1-C6-alkyl, SO2-aryl, SO2-heteroaryl, SO2NH2, SO2NH-C1-C6-alkyl,
SO NH-aryl, SO NH-heteroaryl, C1-C6-alkyl, C3-C7-cycloallcyl, CF , CH CF , CH Cl , CH OH,
2 2 3 2 3 2 2 2
CH CH OH, CH NH , CH SO CH , aryl, heteroaryl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C1-C6-
2 2 2 2 2 2 3
alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C1-C3-
alkyl-amino, thio, aryl-thio, heteroarylthio, benzyl-thio, C1-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 F, Cl,
Br, I, OH, NO , CN, C(O)-C1-C6-alkyl, C(O)-aryl, C(O)-heteroaryl, CO -alkyl, CO -aryl, CO -
2 2 2 2
heteroaryl, CONH , CONH-C1-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)-C1-C6-alkyl, OC(O)-
aryl, OC(O)-heteroaryl, OCO -alkyl, OCO -aryl, OCO -heteroaryl, OCONH , OCONH-C1-C6-alkyl,
2 2 2 2
OCONH-aryl, OCONH-heteroaryl, NHC(O)-C1-C6-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO -
alkyl, NHCO -aryl, NHCO -heteroaryl, NHCONH , NHCONH-C1-C6-alkyl, NHCONH-aryl,
2 2 2
NHCONH-heteroaryl, SO -C1-C6-alkyl, SO -aryl, SO -heteroaryl, SO NH , SO NH-C1-C6-alkyl,
2 2 2 2 2 2
SO NH-aryl, SO NH-heteroaryl, C1-C6-alkyl, C3-C7-cycloallcyl, CF , CH CF , CH Cl , CH OH,
2 2 3 2 3 2 2 2
CH CH OH, CH NH , CH SO CH , aryl, heteroaryl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C1-C6-
2 2 2 2 2 2 3
alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C1-C3-
alkyl-amino, thio, aryl-thio, heteroarylthio, benzyl-thio, C1-C6-alkyl-thio, or methylthiomethyl.
The term "substituted cycloalkyl", 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 F, Cl, Br, I,
OH, NO , CN, C(O)-C1-C6-alkyl, C(O)-aryl, C(O)-heteroaryl, CO -alkyl, CO -aryl, CO -heteroaryl,
2 2 2 2
CONH , CONH-C1-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(O)-C1-C6-alkyl, OC(O)-aryl,
OC(O)-heteroaryl, OCO -alkyl, OCO -aryl, OCO -heteroaryl, OCONH , OCONH-C1-C6-alkyl,
2 2 2 2
OCONH-aryl, OCONH-heteroaryl, NHC(O)-C1-C6-alkyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHCO -
alkyl, NHCO -aryl, NHCO -heteroaryl, NHCONH , NHCONH-C1-C6-alkyl, NHCONH-aryl,
2 2 2
NHCONH-heteroaryl, SO -C1-C6-alkyl, SO -aryl, SO -heteroaryl, SO NH , SO NH-C1-C6-alkyl,
2 2 2 2 2 2
SO NH-aryl, SO NH-heteroaryl, C1-C6-alkyl, C3-C7-cycloallcyl, CF , CH CF , CH Cl , CH OH,
2 2 3 2 3 2 2 2
CH2CH2OH, CH2NH2, CH2SO2CH3, aryl, heteroaryl, benzyl, benzyloxy, aryloxy, heteroaryloxy, C1-C6-
alkoxy, methoxymethoxy, methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino, C1-C3-
alkyl-amino, thio, aryl-thio, heteroarylthio, benzyl-thio, C1-C6-alkyl-thio, or methylthiomethyl.
The term "amino" includes a group represented by -NH . 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 -N , which may comprise -N-N≡N
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 hydroxy-protecting groups is well known in the art for protecting
groups against undesirable 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 Synthesis, 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 term "protected-hydroxy", refers to a hydroxy group protected with a hydroxy protecting group, as
defined above, including, for example, but not limited to, benzoyl, acetyl, trimethylsilyl, triethylsilyl,
methoxymethyl 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 synthetic procedure and many such protecting groups are
known. See, for example, T. H. Greene and P. G, M, Wuts, Protective 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, including, for example, but not limited to, dimethyl acetyl, dimethoxy methyl, 1,3-
dioxolane, 1,3-dioxane and the like.
The term “comprising” as used in this specification and claims means “consisting at least in part of”.
When interpreting statements in this specification and claims which include the term “comprising”,
other features besides the features prefaced by this term in each statement can also be present. Related
terms such as “comprise” and “comprises” are to be interpreted in similar manner.
The compound of the 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 analogous to the method detailed in Examples of the present specification.
The preparation of the present compound can be performed typically 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
mechanism of the reaction is represented by the following scheme A:
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.
One embodiment for a method for preparing a compound of the formula (IIa):
R O O N
O OH O
(IIa)
11 12
wherein R , R and R are as defined above;
which method comprises following steps :
(i) reacting O-mycaminosyltylonolide (OMT):
with an amine of the general formula NR R to form a compound of the following formula (IIb)
(IIb)
wherein
1 11 12
R is as defined for R and R in the formula (IIa) above, and
R is C2-C6-alkynyl, optionally substituted with one or more substituents selected from the
group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic; and
(ii) reacting the resulting compound of the formula (IIb) with an R-N , wherein R is as defined for R or
R in the formula (IIa) above, in the presence of a copper catalyst to form a compound of the formula
(IIa); or
(iii) reacting O-mycaminosyltylonolide (OMT):
with an amine of the general formula NR R to form a compound of the following formula (IIb)
(IIb)
wherein
1 11 12
R is as defined for R and R in the formula (IIa) above, and
R is C1-C6-alkyl, bearing one N -substituent and being optionally substituted with one or more
substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and
substituted heterocyclic; and
(iv) reacting the resulting compound of the formula (IIb) with an R-C≡CH, wherein R is as defined for
11 12
R or R in the formula (IIa) above, in the presence of a copper catalyst to form a compound of the
formula (IIa).
The starting compound of the formula:
can be prepared by performing, for example following sub-steps:
(a) deglycosylation of tylosin under acidic condition, for example in the presence of TFA aq. or HBr;
and
(b) optionally converting the remaining functional groups to desired substituents according to any
conventional process.
One example for a method for preparing a compound of the formula (I):
wherein A is CH -R' and R1, R2, R3, R4, R5, R' and R are as defined above;
which method comprises following steps :
(i) reacting a compound of the formula (II):
wherein,
A is CH -hydroxy; and
the other variable groups are as defined in the formula (I), with an azide selected from
diphenylphosphoryl azide (DPPA) or sodium azide (NaN ) to form a compound of said formula (II)
wherein A is CH -N and the other variable groups are as defined in the formula (I); and
(ii) reacting the resulting compound of the formula (II) wherein A is CH -N and the other variable
groups are as defined in the formula (I) with an R-C≡CH, wherein R is as defined in the formula (I)
above, in the presence of a copper catalyst to form a compound of the formula (II),
wherein A is CH -R' and R3, R4, R5, R' and R are as defined above.
Further example, for a method for preparing a compound of the formula (I):
wherein R5 is R' and A, R1, R2, R3, R4, R' and R are as defined above;
which method comprises following steps:
(i) reacting a compound of the formula (II):
wherein,
R5 is hydroxy; and
the other variable groups are as defined in the formula (I), with an azide selected from
diphenylphosphoryl azide (DPPA) or sodium azide (NaN ) to form a compound of said formula (II)
wherein R5 is -N and the other variable groups are as defined in the formula (I); and
(ii) reacting the resulting compound of the formula (II) wherein R5 is -N and the other variable groups
are as defined in the formula (I) with an R-C≡CH, wherein R is as defined in the formula (I) 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 R are as defined above.
In the step (i) of those methods for preparing the present compound of formula (I), the starting materials
are commercially available or can be easily prepared a compound commercially available according to
any know method. For example, the starting compound of the formula:
wherein,
A is CH -hydroxy; and
the other variable groups are as defined in the formula (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 NaBH ; and
(c) optionally converting the remaining functional groups to desired substituents according to any
conventional process.
To enhance the reactivity of the 20- or 23-hydroxyl functional group, the starting compounds of formula
(II) may, if desired, be halogenized, for example with a halogenating agent such as I or CCl in the
presence of PPh in a solvent such as pyridine and/or dichloromethyl at -27 to 40 C, preferably 0 C to rt,
so that a compound of formula (II) wherein A is CH -halo or R5 is halogen is formed.
By using a compound of formula (II) wherein either A is CH -R' or R5 is R', which compound may be
obtained from any of the preparing methods described above as a starting material, 20,23-bistriazole
tylosin derivative, that is a compound of the formula (I) wherein A is CH -R' and R5 is R' may be
prepared by carrying out the other preparing method as described above.
In a detailed example for formula (I), the azidation of step (i) in the preparing methods above can be
carried out by reacting azide such as diphenylphosphoryl azide (DPPA) or sodium azide (NaN ) 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) and (iv) in the preparing methods for formula (I) and (IIb) above can be carried
out in a solvent for example water, tert-butyl alcohol, methanol or acetonitrile or combination thereof,
preferably in acetonitrile, preferably in the presence of tris[(1-benzyl-1H-1,2,3-triazol
yl)methyl]amine (TBTA), in the presence of a copper catalysis for example CuSO ·5H O, CuOTf·C H ,
4 2 6 6
[Cu(NCCH ) ][PF ] or CuI, preferably CuI at 0 to 100 C, preferably 10 to 40 C, more preferably rt.
3 4 6
Still further example for 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 R are as
defined above;
which method comprises following steps:
(i) reacting a compound of the formula (II):
wherein,
the variable groups are as defined in the formula (I), but A is not -CHO, with a CH≡C-(CH ) -O-
NH ·HCl wherein n is an integer from 1 to 3 to form a compound of the formula (III):
wherein n is an integer from 1 to 3 and A, R3, R4, R5 and R are as defined in formula (I), provided that
A is not -CHO; and
(ii) reacting the compound of the formula (III) resulting from step (i) or (ii) with an R-N , wherein R is
as defined in formula (I) above, in the presence of a copper catalyst to form 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 R are as
defined above.
The starting compound of the formula (II):
wherein,
the variable 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 CH≡C-(CH )n-O-NH ·HCl (wherein n is as defined above) with the starting material in a
solvent such as pyridine 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 desired
not to participate in the introduction of an acetylene moiety can be protected by any conventional
process.
In a detailed example, the reaction of step (ii) and (iv) for formula (I) and (IIb) can be carried out in
solvent, for example water, tert-butyl alcohol, methanol or acetonitrile or combination thereof,
preferably in acetonitrile, preferably in the presence of tris[(1-benzyl-1H-1,2,3-triazol
yl)methyl]amine (TBTA), in the presence of copper catalyst, for example CuSO ·5H O, CuOTf·C H ,
4 2 6 6
[Cu(NCCH ) ][PF ] or CuI, preferably CuI at 0 to 100 C, preferably 10 to 40 C, more preferably rt.
3 4 6
The compounds represented by R-N and R-C=CH are commercially available or can be easily prepared
by any conventional procedure known to a skilled person.
The process steps to synthesize the compounds of the invention can be carried out under reaction
conditions that are known per se, including those mentioned 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 exchangers, e.g., in the H form,
depending on the nature of the reaction and/or of the reactants at reduced, normal or elevated
temperature, for example in a temperature range of from about -100 ºC to about 190ºC, including, for
example, from approximately -80ºC to approximately 150ºC, for example at from -80 to -60ºC, at room
temperature, at from -20 to 40ºC 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
include 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 tetrahydrofurane 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 methylene chloride or chloroform, acid amides, such as dimethylformamide or
dimethyl acetamide, bases, such as heterocyclic nitrogen bases, for example pyridine or N-
methylpyrrolidinone, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for
example acetic anhydride, cyclic, linear or branched hydrocarbons, such as cyclohexane, hexane or
isopentane, or mixtures of those solvents, for example aqueous solutions, unless otherwise indicated in
the description of the processes. Such solvent mixtures may also be used in working up, for example by
chromatography or partitioning.
Within the scope of this text, only a readily removable group that is not a constituent of the particular
desired end product of the compounds of the present invention is designated a “protecting group,” unless
the context indicates otherwise. The protection of functional groups by such protecting groups, the
protecting groups themselves, and their cleavage reactions are described for example in standard
reference works, such as e.g., Science of Synthesis: Houben-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. McOmie, "Protective Groups in Organic
Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts,
"Protective 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/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit, "Aminosäuren,
Peptide, Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and
Basel 1982, and in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate"
(Chemistry of Carbohydrates: Monosaccharides and Derivatives), 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 present invention having acid groups
may be formed, for example, by treating the compounds 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 carbonate, with
corresponding calcium compounds or with ammonia or a suitable organic amine, stoichiometric
amounts or only a small excess of the salt-forming agent preferably being used. Acid addition salts of
compounds of the present invention are obtained in customary manner, e.g., by treating 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 particular hydrates. In the context
of the invention, 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.
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 starting material and the remaining process steps are
carried out, or in which a starting material is formed under the reaction conditions or is used in the form
of a derivative, for example in a protected form or in the form of a salt, or a compound obtainable by the
process according to the invention is produced under the process conditions and processed further in situ.
This invention also encompasses pharmaceutical or veterinary compositions containing, and methods of
treating bacterial infections through administering, pharmaceutically acceptable prodrugs of the
compounds of the invention. For example, compounds 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, 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 includes 4-hydroxyproline,
hydroxylysine, demosine, 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 hydroxy groups may be derivatized using groups including but not limited to
hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as
outlined in Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and
amino groups are also included, as are carbonate prodrugs, sulfonate 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, 10.
Free amines can also be derivatized as amides, sulfonamides or phosphonamides. All of these prodrug
moieties may incorporate groups including but not limited to ether, amine and carboxylic acid
functionalities.
The compounds of the present invention have valuable pharmacological properties and thus they can be
used for the treatment of diseases. In one embodiment, the compound of the present invention may be
used for the treatment or prevention of bacterial infections or disorders associated with bacterial
infections in animals, for example mammals, fish or birds.
The term "animal", "patient" or "subject" 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 infection(s)" includes, but is not limited to, bacterial infections that
occur in mammals, fish and birds as well as disorders related to bacterial infections that may be treated
or prevented by administering antibiotics such as the compounds of the present invention. The
compounds of the present invention are useful for treating infections 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 Aeromonas spp, Escherichia spp, Klebsiella spp, Proteus spp,
Salmonella spp, Shigella spp, Morganella spp, Citrobacter spp, Enterobacter spp, Serratia spp, Erwinia
spp, Yersinia spp, Pseudomonas spp, Alcaligenes spp, Burkholderia spp, Phyllobacterium spp,
Acinetobacter spp, Stenotrophomonas spp, Haemophilus spp, Actinobacillus 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, Leptospira 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 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, Propionibacterium acnes, Actinomyces bovis,
Mycobacterium tuberculosis, Mycobacterium leprae, Bacillus or Clostridium or gram-negative bacteria
such as Pasteurella, Mannheimia or Mycoplasma infections in animals.
Such bacterial infections and disorders related to such infections include, but are not limited to, the
following: acne, rosacea, skin infection, pneumonia, otitis media, sinusitus, 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 Streptococcus pyogenes, Groups C and
G streptococci, 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. saprophyticus or Enterococcus spp.; urethritis and cervicitis; sexually transmitted
diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum,
Ureaplasma urealyticum, or Nesseria gonorrheae; toxin diseases related to infection by S. aureus (food
poisoning and Toxic shock syndrome), or Groups A, S. and C streptococci; ulcers related to infection 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. aureus, S. pneumoniae, S. pyogenes, H. influenzae, or
Listeria spp.; disseminated Mycobacterium avium complex (MAC) disease related to infection by
Mycobacterium avium, or Mycobacterium intracellulare; gastroenteritis related to infection by
Campylobacter jejuni; intestinal protozoa related to infection by Cryptosporidium spp., odontogenic
infection related to infection by viridans streptococci; persistent cough related to infection by Bordetella
pertussis; gas gangrene related to infection by Clostridium perfringens 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 infections 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., coccidia, cryptosporidia, etc.), dairy cow mastitis related to
infection by S. aureus, S. uberis, S. agalactiae, S. dysgalactiae, Klebsiella spp., Corynebacterium, or
Enterococcus spp.; swine respiratory disease 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 Moraxella bovis, cow
premature abortion related to infection by protozoa (i.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
infections 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., Plasmodium spp.,
Babesia spp., Toxoplasma spp., Pneumocystis 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., “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 pasteurellosis caused by
Gram negative bacillus such as Pasteurella or Mannheimia in farm animals such as cows.
Still further bacterial infections and disorders related to such infections that may be treated or prevented
in animals especially by compounds of formula (IIa) as mentioned before include, but are not limited to,
mastitis in all non-human milk-producing mammals, such as cattle, camel, buffalo, goat or sheep, and
which may be associated with several pathogens including E. coli, Klebsiella spp., Enterobacter spp.,
Salmonella spp., Citrobacter spp., Serratia spp., Shigella spp., Edwardsiella spp., Hafnia spp.,
Morganella spp., Providencia spp., Yersinia spp., Staphylococcus aureus, Staphylococcus spp.,
Pseudomonas spp., Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus spp.,
Enterococci, Corynebacterium spp., Arcanobacterium spp., Actinomyces spp., Mycobacterium spp.,
Prototheca spp., Mycoplasma spp., and Erwinia spp., among others and in addition to the above
mentioned pathogens related to mastitis. Of the mentioned non-human milk-producing mammals,
ruminants that are used for milk production for human consumption, such as cattle, buffalo, sheep, and
goat, are especially important.
Accordingly, in a certain embodiment, the present invention provides a pharmaceutical or veterinary
composition comprising any of the compounds 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 bacterial infection, and/or a disease or condition described herein. In an example, an effective amount
of the compound of the invention is the amount sufficient to treat a bacterial infection in a subject. The
effective amount can vary depending 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 the art would be
able to study the factors contained herein and make the determination regarding 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 subject either prior to or after the onset of a bacterial infection.
Further, several divided dosages, as well as staggered dosages, can be administered daily or sequentially,
or the dose can be continuously infused, or can be a bolus injection. 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 described
herein, or for the manufacture of pharmaceutical or veterinary compositions for use in the treatment of
these diseases. Methods of use of compounds 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 “pharmaceutical or veterinary 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.
The phrase “pharmaceutically acceptable carrier” is art recognized and includes a pharmaceutically
acceptable material, composition or vehicle, suitable for administering compounds of the present
invention to mammals. The carriers include liquid or solid filler, diluent, excipient, solvent or
encapsulating material, involved in carrying 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 invention include those known in the art. The formulations may
conveniently be presented in unit dosage form and may be prepared 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 of preparing these formulations or compositions are also known in the art.
The term “treat,” “treated,” “treating” 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 diminish or alleviate at least one symptom
associated 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.
Especially treatment of mastitis is curing or ameliorating an animal that has contracted mastitis, i.e.
reducing at least one symptom of mastitis. Mastitis refers to inflammation of the mammary gland.
Physical, chemical and usually bacteriological changes in the milk and pathological changes in the
glandular tissue characterize it. The glandular changes often result in a number of symptomatic
conditions such as, discoloration of the milk, the presence of clots and the presence of large numbers of
leukocytes. Clinically, mastitis is seen as swelling, heat, pain and induration in the mammary gland
often resulting in deformation of the udder. An inflamed udder can be visibly seen or determined
through palpation of the udder. In many cases the diagnosis of subclinical infections has come to depend
largely on indirect tests which depend on the leukocyte content of the milk (flakes, clots, or serous milk),
at least 1 bacterium is detected in at least 100 μL of milk from the udder, elevated somatic cell count
(SCC) usually higher than 300,000 cells/mL and/or the electrical conductivity of the milk is increased
from normal. Prevention of mastitis means preventing the occurrence of the infection. Prevention also
includes treatment of cows that do not exhibit any signs of mastitis but are in the presence of other cows
that do have at least one sign of mastitis to minimize or prevent the transmission or potential
transmission of mastitis from one cow to another.
These compounds may be administered to humans and other animals for therapy by any suitable route of
administration.
Regardless of the 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 compositions 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 may be varied so as to obtain an amount of the active ingredient which is effective to achieve
the desired therapeutic response for a particular patient, composition, and mode of administration,
without being toxic to the patient.
The selected dosage level will depend upon a variety 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 ordinary 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 compounds of the invention employed in the pharmaceutical or
veterinary composition at levels lower than that required in order to achieve the desired therapeutic
effect and gradually increase the dosage until the desired effect is achieved.
In general, 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, optionally, in
unit dosage forms.
While it is possible for a compound of the present invention to be administered alone, it is preferable to
administer the compound as a pharmaceutical 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 example of such an assay is the standard minimum inhibitory
concentration (MIC) test conducted according to CSLI guidelines or paper disc test conducted according
to Examples below.
Further disclosed are embodiments of compounds represented by the formula (I):
or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof;
wherein, A is selected from the group consisting of:
(1) -CHO or a protected aldehyde;
(2) CH -X, wherein X is selected from the group consisting of:
a. hydroxy or protected hydroxy;
b. halogen; and
c. -N
(3) -CN;
(4) -CH=N-NR7R8, wherein R7 and R8 are each independently selected from hydrogen, C1-C6-alkyl,
optionally substituted with one or more substituents selected from the group consisting of halogen, aryl,
substituted aryl, heterocyclic and substituted 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 nitrogen 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(C1-C6-alkyl)-, -N(aryl) -, -N (heteroaryl)-, -S-, -S(O)- and-S(O) -;
(5) -CH=N-OR7, wherein R7 is as previously defined;
(6) C3-C14-cycloalkyl;
(7) substituted C3-C14-cycloalkyl;
(8) aryl;
(9) substituted aryl;
(10) heterocyclic;
(11) substituted heterocyclic;
(12) CH -R';and
(13) -CH -NR7R8, where R7 and R8 are as previously defined;
R1 and R2 are each independently selected 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, substituted heterocyclic, -O-R7 and -NR7R8
where R7 and R8 are as previously defined;
(5) -O-R7, where R7 is as previously defined;
(6) halogen;
(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 selected from the group consisting of:
(1) hydrogen;
(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 heterocyclic, -O-R7 and -NR7R8
where R7 and R8 are as previously defined;
(4) C1-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, substituted aryl, heterocyclic, substituted heterocyclic, -O-R7 and -NR7R8
where R7 and R8 are as previously defined; and
(6) C2-C6-alkynyl, optionally substituted 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) absent,
(2) -C(O)-,
(3) -C(O)N(R7)-, where R7 is as previously defined,
(4) -C1-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,
(3) C1-C6-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 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 substituents selected from the group
consisting of halogen, aryl, substituted 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 previously defined;
(6) -N or R';
R is hydrogen or a hydroxy protecting group;
and each R' is independently [1,4]-epi-[1,2,3]-triazoro-R; and where each R is independently selected
from the group consisting of:
(1) C1-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 defined;
(2) C2-C9-alkenyl, 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 defined;
(3) C2-C9-alkynyl, 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 defined;
(4) C3-C14-cycloalkyl;
(5) substituted C3-C14-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'.
Furthermore, compounds of said formula (I) are disclosed, wherein;
A is selected from halogen, CH -N , hydroxy, CHO, hydroxyC alkyl, haloC alkyl, methyl(3,5-di(C1-
2 3 1-6 1-6
C3-alkyl)-piperidino), CH -R', and –CH -NR7R8;
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, N , halogen, 6-deoxy-2,3-di-O-methyl-b-d-allo-hexapyranosyloxy and R';
R' is as defined above;
provided that at least one of A, R1 and R2 and R5 comprises R';
or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof.
Furthermore, compounds of said formula (I) are disclosed, wherein;
A is CH -R'or –CH -NR7R8;
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.
Furthermore, compounds of said formula (I) are disclosed, wherein;
A is CHO or methyl(3,5-dimethylpiperidino)or –CH NR7R8;
R1 and R2 taken together are oxo;
R3 is H;
R4 is H; and
R5 is R'.
Furthermore, compounds of said formula (I) are disclosed, wherein;
A is –CH -NR7R8;
R1 and R2 taken together are oxo;
R3 is H;
R4 is H; and
R5 is hydroxy.
Furthermore, compounds of said formula (I) are disclosed, wherein;
A is CHO, methyl(3,5-dimethylpiperidino), or –CH -NR7R8;
R1 and R2 taken together are =N-O-C0-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 mentioned disclosure of compounds according to formula (I), R is preferably selected from the
group consisting of
Further disclosed is a method for preparing a compound of the formula (I):
wherein A is CH -R' and R1, R2, R3, R4, R5, R' and R are as defined above;
which method comprises following steps:
(i) reacting a compound of the formula (II):
wherein,
A is CH -hydroxy; and
the other variable groups are as defined in the formula (I), with an azide selected from
diphenylphosphoryl azide (DPPA) or sodium azide (NaN ) to form a compound of said formula (II)
wherein A is CH -N and the other variable groups are as defined in the formula (I); and
(ii) reacting the resulting compound of the formula (II) wherein A is CH -N and the other variable
groups are as defined in the formula (I) with an R-C≡CH, wherein R is as defined in the formula (I)
above, in the presence of a copper catalyst to form a compound of the formula (II),
wherein A is CH -R' and R3, R4, R5, R' and R are as defined above.
Furthermore, a method for preparing a compound of the formula (I) is disclosed:
wherein R5 is R' and A, R1, R2, R3, R4, R' and R are as defined above;
which method comprises following steps:
(i) reacting a compound of the formula (II):
wherein,
R5 is hydroxy; and
the other variable groups are as defined in the formula (I), with an azide selected from
diphenylphosphoryl azide (DPPA) or sodium azide (NaN ) to form a compound of said formula (II)
wherein R5 is -N and the other variable groups are as defined in the formula (I); and
(ii) reacting the resulting compound of the formula (II) wherein R5 is -N and the other variable groups
are as defined in the formula (I) with an R-C≡CH, wherein R is as defined in the formula (I) 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 R are as defined above.
Furthermore, a method for preparing a compound of the formula (I) is disclosed:
wherein R1 and R2 taken together are =N-O-C0-C3-alkyl-R' and A, R3, R4, R5, R' and R are as
defined above;
which method comprises following steps:
(i) reacting a compound of the formula (II):
wherein,
the variable groups are as defined in the formula (I), but A is not -CHO, with a CH≡C-(CH ) -O-
NH ·HCl wherein n is an integer from 1 to 3 to form a compound of the formula (III):
wherein n is an integer from 1 to 3 and A, R3, R4, R5 and R are as defined in formula (I), but A is not -
CHO; and
(ii) reacting the compound of the formula (III) resulting from step (i) or (ii) with an R-N , wherein R is
as defined in formula (I) above, in the presence of a copper catalyst to form 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 R are as
defined above.
The invention is further illustrated by the following examples, which should not be construed as further
limiting. The practice of the present invention will employ, unless otherwise indicated, conventional
techniques of cell biology, cell culture, molecular biology, transgenic biology, microbiology and
immunology, which are within the skill of the art.
EXAMPLES
All starting 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.
H NMR spectra were determined by using JEOL JNM-EX270 (270 MHz), VALIAN-400 NMR System
(400 MHz). C NMR spectra were determined by using JEOL JNM-EX270 (67.5 MHz) 、VARIAN-
400 NMR system (100 MHz). Chemical shifts are indicated in δ (ppm) and coupling patterns are
indicated by using following abbreviations: s : singlet; d : double; 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 thin-layer chromatography (TLC) was performed by using silica gel 60 F (Merck) 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 NH OH
Preparation of Compounds of Formula (I)
Preparation of 20-triazoledeoxodesmycosins
(1) Preparation of desmycosin (YT6)
20
CHO CHO
HO HO
O OH OH
O 9 O O 9 O
0.2N HCl
1' 1'
3 OH O 3 OH
Þ C, 2 h
quant.
HO HO
1''' 1'''
23 23
OMe OMe
OMe OMe YT6
Tylosin (20.0g, 21.8 mmol) was dissolved in 0.2N HCl aq. (340 mL) and then the mixture was stirred at
C for 2 hours. After confirming complete consumption of the starting material, the reaction mixture
was neutralized by adding 1N NaOH aq., extracted with CHCl and dried over Na SO . The solvent was
3 2 4
removed under reduced-pressure to obtain quantitative amount of desmycosin (YT6).
(2) Preparation of 20-dihydrodesmycosin (YT7)
O 9 OH
O O 9
O NaBH
i-PrOH-H O
3 2 OH
rt, 30 min
1''' HO
1'''
OMe YT6
OMe YT7
To a solution of Desmycosin (16.8 g, 21.8 mmol) in i-PrOH : H O = 3 : 2 (300 mL) was added NaBH
(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. NaHCO aq., extracted with CHCl and dried over Na SO . The
3 3 2 4
solvent was removed under reduced pressure to obtain YT7 (Yield: 95%).
(3) Preparation of 20-chlorodeoxodesmycosin (YT8)
OH Cl
20
HO CCl , PPh HO
OH 4 3 OH
9 5 O 9 5 O
pyridine
1' 1'
OH OH
CH Cl
rt, 16 h
O 83% O
HO HO
1''' 1'''
23 23
OMe OMe
YT7 YT8
OMe OMe
To a solution of YT7 (16.9 g, 21.8 mmol) in CH Cl : pyridine = 1 : 1 (330 mL) were added PPh (17.2
2 2 3
g, 65.4 mmol) and CCl (3.2 g, 32.7 mmol) under N atmosphere and the mixture was stirred for 16
hours at rt. The reaction mixture was diluted with CHCl , washed sequentially with sat. NaHCO aq.,
brine. The organic layer was dried over Na SO and then the solvent was removed under reduced
pressure. The resulting products were purified by flash column chromatography to obtain YT8 (Yield:
83%).
(4) Preparation of 20-azidodeoxodesmycosin (YT11)
HO OH
O 9 O
OH NaN O
O 9 O
3 DMSO
80 Þ C, 20 h
90% O
1'''
1'''
23 O
YT11
To a solution of YT8 (12.4 g, 15.7 mmol) in DMSO (160 mL, 0.100 M) was added NaN (5.10 g, 78.3
mmol) and then the mixture was stirred for 20 hours at 80 C. 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 Na SO and concentrated.
The resulting products were purified by flash column chromatography to obtain YT11 (Yield: 90%).
(5) Preparation of 20-triazoledeoxodesmycosins
20
HO HO
OH OH
O 9 O 9
O 5 O
CuI, TBTA
1' 1'
OH OH
3 CH CN or MeOH 3
HO HO
1''' 1'''
23 23
OMe OMe
OMe OMe
YT11
To a solution of YT11 (0.24 g, 0.30 mmol) in CH CN or MeOH (3.0 mL) were added copper catalyst
(2.9 mg, 0.015 mmol), TBTA (1.6 mg, 3.0 μmol) 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 reaction was completed. After completion, the reaction mixture was diluted with CHCl3, washed
with 10% NH aq.. After removing copper catalyst, the filtrate was washed with brine. The organic
layer was dried over Na SO and concentrated. The resulting products were purified by flash column
chromatography to obtain the triazole compounds.
The results of the step (5) are shown in Table 1 below.
Table 1 Reaction times*
Solvents (0.1 R = p-ethynyl
Entry Conditions R = Ph
M) (pentyloxy)benzene
CuI (0.05 eq.)
1 CH CN 2days 2 days
2,6-lutidine (0.01 eq.), rt
Cu(CH CN) PF (0.05 eq.)
3 4 6
2 MeOH 2days 2days
TBTA (0.01 eq.), rt
Cu(CH CN) PF (0.05 eq.)
3 4 6
3 CH CN 30 min 30min
TBTA (0.01 eq.), rt
CuI (0.05 eq.)
4 MeOH 50 min 120min
TBTA (0.01 eq.), rt
CuI (0.05 eq.)
CH CN 90 min 120min
TBTA (0.01 eq.), rt
* Time for consumption of the starting material.
Under the conditions of Entry 4 or 5 above, with the following nineteen compounds:
yt12
yt13 yt14 yt16
yt18 yt19 yt20
yt17
yt21
yt22 yt23
yt24
OC H
11
yt25 yt26 yt27 yt28
N N OH
yt29
yt30 yt32
as the acetylene compound, the step (5) above was repeated to obtain the 20-triazole
deoxodesmycosins, which are shown below.
-(4-(pyridineyl)-1H-1,2,3-triazolyl)deoxodesmycosin (YT12)
HO OH
O 9 O
1'''
YT12
Yield: 85%
20-(4-phenyl-1H-1,2,3-triazolyl)deoxodesmycosin (YT13)
HO OH
O 9 O
3 OH
HO 1'''
O 23
Yield:98%
-(4-(thiopheneyl)-1H-1,2,3-triazolyl)deoxodesmycosin (YT14)
HO OH
3 OH
HO 1'''
Yield:81%
20-(4-(pyridineyl)-1H-1,2,3-triazolyl)deoxodesmycosin (YT16)
9 HO OH
O 5 O
3 OH
HO 1'''
O 23
Yield:82%
-(4-(3-aminophenyl-1H-1,2,3-triazolyl)deoxodesmycosin (YT17)
9 HO OH
3 OH
HO 1'''
Yield:91%
20-(4-(3-aminophenyl-1H-1,2,3-triazolyl)deoxodesmycosin (YT18)
HO OH
3 OH
HO 1'''
Yield:67%
-(4-(4-chlorobutyl)-1H-1,2,3-triazolyl)deoxodesmycosin (YT19)
9 HO OH
3 OH
HO 1'''
Yield:54%
20-(4-butyl-1H-1,2,3-triazolyl)deoxodesmycosin (YT20)
HO OH
1'''
Yield:83%
-(4-phenyl-1H-1,2,3-triazolyl)deoxodesmycosin (YT21)
HO OH
3 OH
1'''
O 23
Yield:86%
20-(4-ethoxycarbonyl-1H-1,2,3-triazolyl)deoxodesmycosin (YT22)
HO OH
9 5 O
HO 1'''
Yield:86%
-(4-(phenanthreneyl)-1H-1,2,3-triazolyl)deoxodesmycosin (YT23)
HO OH
9 5 O
1'''
Yield:93%
20-(4-(4-phenoxyphenyl)-1H-1,2,3-triazolyl)deoxodesmycosin (YT24)
O HO OH
1'''
Yield:85%
-(4-(2,4,5-trimethylphenyl)-1H-1,2,3-triazolyl)deoxodesmycosin (YT25)
HO OH
O 9 O
1'''
Yield:73%
20-(4-(4-t-butylphenyl)-1H-1,2,3-triazolyl)deoxodesmycosin (YT26)
HO OH
1'''
Yield:88%
-(4-(4-pentyloxyphenyl)-1H-1,2,3-triazolyl)deoxodesmycosin (YT27)
OC H
11
HO OH
O 9 5 O
HO 1'''
Yield:86%
20-(4-(1-methyl-1H-benzotriazole)-1H-1,2,3-triazolyl)deoxodesmycosin (YT28)
HO OH
O 9 O
1'''
Yield:96%
-(4-(4-dimethylaminophenyl)-1H-1,2,3-triazolyl)deoxodesmycosin (YT29)
HO OH
9 5 O
HO 1'''
Yield:89%
20-(4-(N-methy-methylamine)-1H-1,2,3-triazolyl)deoxodesmycosin (YT30)
9 HO OH
HO 1'''
Yield:80%
-(4-(1-methyhydroxylethyl)-1H-1,2,3-triazolyl)deoxodesmycosin (YT32)
HO OH
HO 1'''
Yield:92%
20-(4-(2-methy-propyl)-1H-1,2,3-triazolyl)deoxodesmycosin (YT33)
HO OH
O 9 O
1'''
Yield:89%
-(4-nonyl-1H-1,2,3-triazolyl)deoxodesmycosin (YT34)
HO OH
O 9 O
HO 1'''
Yield:97%
-(4-(3-quinoline)-1H-1,2,3-triazolyl)deoxodesmycosin (YT35)
HO OH
O 9 O
HO 1'''
Yield:93%
20-(4-(4-butanol)-1H-1,2,3-triazolyl)deoxodesmycosin (YT36)
HO OH
O 9 O
1'''
Yield:97%
-(4-(methanol)-1H-1,2,3-triazolyl)deoxodesmycosin (YT37)
HO OH
O 9 O
3 OH
1'''
Yield:100%
Preparation of 23-triazoledeoxoO-mycaminosyltylonolides
(1) Preparation of 5-O-mycaminosyltylonolide (YT106)
HO O
O OH
9 5 O HO OH
O 9 O
0.5 M TFA aq.
OH O
3 OH
100 Þ C, 5 h
1''' 23
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 NaHCO sat. aq., extracted with CHCl and dried over
Na SO . The solvent was removed under reduced-pressure. The resulting products were purified by
flash column chromatography to obtain YT106 (Yield: 39%).
(2) Preparation of 23-azidodeoxoO-mycaminosyltylonolide (YT107)
1) PPh , I
3 2 N
Pyridine
HO OH
HO OH
O 9 O
O 9 O 5
rt, 46%
OH 3
2) NaN , DMSO
60 Þ C, 84%
23 23
YT106
YT107
To a solution of PPh (787 mg, 3.0 mmol) and I (381 mg, 3.0 mmol) in pyridine (4.0 mL) was added
YT106 (300 mg, 0.50 mmol) under N atmosphere and then stirred for 4 hours at rt. After confirming
complete consumption of the starting material, the reaction mixture was diluted with CHCl . The
organic layer was washed with Na2S2O3 sat. aq. and dried over Na2SO4. The solvent was then removed
under reduced pressure. The resulting products were purified by flash column chromatography to obtain
23-IdeoxoO-mycaminosyltylonolide (Yield: 46%).
To a solution of 23-IdeoxoO-mycaminosyltylonolide (155 mg, 0.22 mmol) in DMSO (2.0 mL)
was added NaN (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 CHCl . The organic layer was washed with water and dried over Na SO . The solvent
3 2 4
was removed under reduced pressure. The resulting products were purified by flash column
chromatography to obtain YT107 (Yield: 84%).
(3) Preparation of 23-triazoledeoxyO- mycaminosyltylonolides
To a solution of YT107 (0.24 g, 0.30 mmol) in CH CN or MeOH (3.0 mL) were added CuI (2.9 mg,
0.015 mmol), TBTA (1.6 mg, 3.0 μmol) 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
CHCl , and washed with 10% NH aq.. After removing CuI, the filtrate was washed with brine. The
organic layer was dried over Na SO and concentrated. The resulting products were purified by flash
column chromatography to obtain the following triazole compounds:
23-(4-phenyl-1H-1,2,3-triazolyl)DeoxyO-mycaminosyltylonolide (YT101)
HO OH
9 5 O
3 OH
YT101
Yield: 64%
Rf : 0.5 (CHCl3 : MeOH : NH4OH = 8 : 1 : 0.008).
23-(4-butyl-1H-1,2,3-triazolyl)DeoxoO-mycaminosyltylonolide (YT102)
HO OH
YT102
Yield: 77%
23-(4-(3-quinolineyl)-1H-1,2,3-triazolyl)DeoxoO-mycaminosyltylonolide (YT103)
HO OH
3 OH
YT103
Yield: 100%
23-(4-biphenyl-1H-1,2,3-triazolyl)DeoxyO-mycaminosyltylonolide (YT104)
HO OH
3 OH
YT104
Yield: 100%
23-(4-(pyridineyl)-1H-1,2,3-triazolyl)DeoxoO-mycaminosyltylonolide (YT109)
HO OH
O 9 O
YT109
Yield: 94%
23-(4-(methyl-1H-benzotriazolyl)-1H-1,2,3-triazolyl)deoxoO-mycaminosyltylonolide
(YT110)
HO OH
9 5 O
YT110
Yield: 94%
Preparation of 20-(4-phenyl-1H-1,2,3-triazolyl)deoxotriazoledeoxyO-mycaminosylt-
ylonolides
(1) Preparation of 20-(4-phenyl-1H-1,2,3-triazolyl)deoxoO-mycaminosyltylonolide (YT112)
HO OH
O HO OH
9 O O
9 O
3 OH
50ºC, 30min
1''' 23
OMe YT112
YT13
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 confirming complete consumption of the starting material, the reaction mixture was
neutralized by adding NaHCO sat. aq., extracted with CHCl and dried over Na SO . The solvent was
3 3 2 4
removed under reduced pressure. The resulting products were purified by flash column chromatography
to obtain YT112 (Yield: 39%).
(2) Preparation of 20-(4-phenyl-1H-1,2,3-triazolyl)deoxoazidodeoxyO-mycaminosylt-
ylonolide (YT114)
1) PPh , I
Pyridine
HO OH
O HO OH
9 5 O O
rt, 64% 9 O
3 OH
2) NaN , DMSO
60ºC, 96%
YT114
YT112
To a solution of PPh (144 mg, 0.55 mmol) and I (70 mg, 0.55 mmol) in pyridine (1.0 mL) was added
YT112 (80 mg, 0.11 mmol) under N atmosphere and then the mixture was stirred for 4 hours at rt.
After confirming complete consumption of the starting material, the reaction mixture was diluted with
CHCl 3. The organic layer was washed with Na2S2O3 sat. aq. and dried over Na2SO4. The solvent was
removed under reduced pressure. The resulting products were purified by flash column chromatography
to obtain 20-(4-phenyl-1H-1,2,3-triazolyl)deoxoIdeoxyO-mycaminosyltylonolide
(Yield: 64%).
To a solution of 20-(4-phenyl-1H-1,2,3-triazolyl)deoxoIdeoxyO-mycaminosyltyl-
onolide (57 mg, 0.068 mmol) in DMSO (0.6 mL) was added NaN (13 mg, 0.20 mmol) and then the
mixture was stirred for 30 minutes at 60 C. After confirming complete consumption of the starting
material by LC Mass, the reaction mixture was diluted with CHCl . The organic layer was washed with
water and dried over Na SO . The solvent was removed under reduced pressure. The resulting products
were purified by flash column chromatography to obtain YT114 (Yield: 96%).
(3) Preparation of 20-(4-phenyl-1H-1,2,3-triazolyl)deoxotriazoledeoxyO-mycamino-
syltylonolides
To a solution of YT114 (0.24 g, 0.30 mmol) in CH CN or MeOH (3.0 mL) were added CuI (2.9 mg,
0.015 mmol), TBTA (1.6 mg, 3.0 μmol) 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
CHCl , washed with 10% NH aq.. After removing CuI, the filtrate was washed with brine. The organic
layer was dried over Na SO and concentrated. The resulting products were purified by flash column
chromatography to obtain the following triazole compounds:
20-(4-phenyl-1H-1,2,3-triazolyl)deoxo(4-phenyl-1H-1,2,3-triazolyl)deoxyO-
mycaminosyltylonolide (YT115)
HO OH
YT115
Yield: 85%
-(4-phenyl-1H-1,2,3-triazolyl)deoxo(4-butyl-1H-1,2,3-triazolyl) deoxyO-
mycaminosyltylonolide (YT116)
HO OH
YT116
Yield: 92%
Preparation of Compounds of Formula (IIa)
General procedure for reductive amination from O-mycaminosyltylonolide (OMT)
To a solution of O-mycaminosyltylonolide (OMT) in 1,2-dichloroethane (0.1 M) at room temperature
was added amines (1.5 to 2.0 equiv.), NaBH(OAc) (1.5 equiv.), and AcOH (3.0 equiv.). The reaction
mixture was stirred at room temperature until OMT was consumed. After the reaction was quenched
with sat. NH Cl aq., the resulting mixture was extracted with CHCl (3 times). The combined organic
layers were dried over Na SO and concentrated in vacuo. The crude product was purified by silica gel
chromatography (CHCl3/MeOH/NH4OH=100/1/0.1 to 10/1/0.1) to afford desired compounds.
YT615
According to the general procedure for reductive amination with OMT, OMT (200.0 mg, 0.335 mmol)
with 2-azidoethylamine in 1.0 M solution of H O (669.0 mL, 0.669 mmol) was converted to YT615
(124.3 mg, 56%) as a colorless solid.
HRMS (ESI) m/z :690.4041 [M+Na] , calcd for C H N O Na: 690.4054.
33 57 5 9
YT646
According to the general procedure for reductive amination with OMT, OMT (1.0 g, 1.67 mmol) with
N-methylpropargyl amine (209.0 mL, 2.51 mmol) was converted to YT646 (1.01 g, 93%) as a colorless
solid. HRMS (ESI) m/z :651.4202 [M+H] , calcd for C H N O : 651.4221.
59 2 9
YT649
According to the general procedure for reductive amination with OMT, OMT (100 mg, 0.167 mmol)
with N-(2-azidoethyl)benzylamine (32.6 µL, 0.251 mmol) was converted to YT649 (98.7 mg, 82%) as a
colorless solid. HRMS (ESI) m/z :758.4700 [M+H] , calcd for C H N O : 758.4704.
40 64 5 9
YT699
According to the general procedure for reductive amination with OMT, OMT (1.99 g, 3.33 mmol) with
N-(2-azidoethyl)iodobenzylamine (1.51 g, 5.00 mmol) was converted to YT699 (2.44 g, 83 %) as a
colorless solid. HRMS (ESI) m/z :884.3669 [M+H] , calcd for C H IN O : 884.3670.
40 63 5 9
YT711
According to the general procedure for reductive amination with OMT, OMT (1.63 g, 2.72 mmol) with
N-benzylpropargyl amine (1.66 g, 4.08 mmol) was converted to YT711 (1.49 g, 75%) as a colorless
solid. HRMS (ESI) m/z :727.4532 [M+H] , calcd for C H N O : 727.4534.
41 63 2 9
YT712
According to the general procedure for reductive amination with OMT, OMT (100.0 mg, 0.167 mmol)
with N-propargyl amine (16.1 mL, 0.251 mmol) was converted to YT712 (50.4 mg, 47%) as a colorless
solid. HRMS (ESI) m/z :637.4073 [M+H] , calcd for C H N O : 637.4064.
34 57 2 9
Synthesis of YT616
To a solution of OMT (500.0 mg, 0.836 mmol) in pyridine (5 mL) was added AcOH (2.4 mL, 41.8
mmol). The reaction was stirred at room temperature for 1h. After to the reaction mixture was added
water, the solvent was evaporated with toluene. The residue was dissolved in CHCl (10 mL), the
organic layer was washed with water (5 mL). The organic layer was dried over Na SO and concentrated
in vacuo. The crude product was used next step without further purification. To a solution of the crude
product in MeOH (6.2 mL) was added NaBH (15.8 mg, 0.418 mmol). The reaction was stirred at room
temperature for 30 min. After addition of water (3 mL), the mixture was extracted with EtOAc (10 mL,
x3). The combined organic layers were dried over Na SO and concentrated in vacuo. The crude product
was used next step without further purification. To a solution of the crude product in toluene (10 mL)
was DPPA (215.0 mL, 1.00 mmol) and DBU (140.9 mL, 1.00 mmol). The reaction was stirred at 0 ˚C
for 1 h 15 min. After addition of brine (3 mL), the mixture was extracted with EtOAc (10 mL, x3). The
combined organic layers were dried over Na SO and concentrated in vacuo. The crude product was
used next step without further purification. To a solution of the crude product in DMF (6.8 mL) was
added NaN (108.7 mg, 1.672 mmol). The reaction was stirred at 80 ˚C for 19 h. After the reaction was
cooled to room temperature and diluted with EtOAc, the reaction mixture was washed with H O. The
organic layer was dried over Na SO and concentrated in vacuo. The crude product was used next step
without further purification. To a solution of the crude product in MeOH (5.0 mL) was added a solution
of 10 % K CO in water (3.0 mL). The reaction was stirred at room temperature for 16 h. The reaction
mixture was extracted with AcOEt (10 mL, x3). The combined organic layers were dried over Na SO
and concentrated in vacuo. The crude product was purified by silica gel chromatography
(CHCl /MeOH/NH OH=100/1/0.1 to 10/1/0.1) to afford YT616 (91.7 mg, 18% over 6 steps) as a
colorless solid. HRMS (ESI) m/z :625.3803 [M+H] , calcd for C H N O : 625.3813.
31 53 4 9
General procedure for triazole reaction.
Method A) To a solution of azide- or acetylene-tylosin analogues in MeOH (0.1 M) at room temperature
was added acetylenes or azide building blocks (1.0-2.0 equiv.), tetrakis(acetonitrile)copper(I)
hexafluorophosphate (Cu(MeCN) PF , 0.1-0.5 mol%), and tris[(1-benzyl-1H-1,2,3-triazol
yl)methyl]amine (TBTA, 0.1-0.5 mol%). The reaction mixture was stirred at room temperature until a
starting material was consumed. After the reaction was added sat. NH Cl aq., the resulting mixture was
extracted with CHCl (3 times). The combined organic layers were dried over Na SO and concentrated
3 2 4
in vacuo. The crude product was purified by silica gel chromatography
(CHCl /MeOH/NH OH=100/1/0.1 to 10/1/0.1) to afford desired compounds.
Method B) To a solution of azide- or acetylene-tylosin analogues in MeOH (0.1 M) at room temperature
was added acetylenes or azide building blocks (1.0-2.0 equiv.), tetrakis(acetonitrile)copper(I)
hexafluorophosphate (Cu(MeCN) PF , 0.1-0.5 mol%), and tris[(1-benzyl-1H-1,2,3-triazol
yl)methyl]amine (TBTA, 0.1-0.5 mol%). The reaction mixture was stirred at 70 ˚C for 15 to 30 min
under microwave irradiation until a starting material was consumed. After the reaction was cooled to
room temperature and added sat. NH Cl aq., the resulting mixture was extracted with CHCl (3 times).
The combined organic layers were dried over Na SO and concentrated in vacuo. The crude product was
purified by silica gel chromatography (CHCl /MeOH/NH OH=100/1/0.1 to 10/1/0.1) to afford desired
compounds.
Method C) To a solution of azide- or acetylene-tylosin analogues in t-BuOH/H O (0.03 M) at room
temperature was added acetylenes or azide building blocks (1.0-2.0 equiv.), CuSO (0.1 mol%), and
sodium ascorbate (0.5 equiv.). The reaction mixture was stirred at room temperature until a starting
material was consumed. After the reaction was added sat. Rochelle salt aq., the resulting mixture was
extracted with AcOEt (3 times). The combined organic layers were dried over Na SO and concentrated
in vacuo. The crude product was purified by silica gel chromatography
(CHCl /MeOH/NH OH=100/1/0.1 to 10/1/0.1) to afford desired compounds.
YT617
According to the general procedure (method A) for synthesis of triazole analogues, YT615 (67.5 mg,
0.101mmol) with ethynylbenzene (25.0 µL, 0.228 mmol) was converted to YT617 (41.8 mg, 53%) as a
colorless solid. HRMS (ESI) m/z :770.4676 [M+H] , calcd for C H N O : 770.4704.
41 64 5 9
YT620
According to the general procedure (method A) for synthesis of triazole analogues, YT616 (47.0 mg,
0.0752 mmol) with 2-propynol (9.0 µL, 0.155 mmol) was converted to YT620 (30.5 mg, 61%) as a
colorless solid. HRMS (ESI) m/z :703.3891 [M+Na] , calcd for C H N O Na: 703.3894.
34 56 4 10
YT625
According to the general procedure (method A) for synthesis of triazole analogues, YT615 (121.3 mg,
0.182 mmol) with 2-propynol (21.0 µL, 0.361 mmol) was converted to YT625 (62.9 mg, 48%) as a
colorless solid. HRMS (ESI) m/z :724.4486 [M+H] , calcd for C H N O : 724.4497.
36 62 5 10
YT647
According to the general procedure (method A) for synthesis of triazole analogues, YT646 (100.0 mg,
0.154 mmol) with tetra-OAc-β-D-glucopyranosyl azide (86.0 mg, 0.230 mmol) was converted to YT647
(92 mg, 58%) as a colorless solid. HRMS (ESI) m/z :1024.5336 [M+H] , calcd for C H N O :
49 78 5 18
1024.5342.
YT648
According to the general procedure (method A) for synthesis of triazole analogues, YT646 (100.0 mg,
0.154 mmol) with tri-OAcN -β-D-methylglucopyranoside (79.0 mg, 0.229 mmol) was converted to
YT647 (51.8 mg, 50%) as a colorless solid. HRMS (ESI) m/z :996.5378 [M+H] , calcd for C H N O :
48 78 5 17
996.5393.
YT650
According to the general procedure (method B) for synthesis of triazole analogues, YT646 (1.0 g, 1.54
mmol) with 3-azidoquinoline (392.0 mg, 2.30 mmol) using method B) was converted to YT650 (1.21 g,
31 1
95%) as a colorless solid. [a] –114.1 (c 1.0, CHCl ); H NMR (500 MHz, CD OD) δ (ppm) : 9.49 (d, J
D 3 3
= 2.3 Hz, 1H), 8.90 (d, J = 2.3 Hz, 1H), 8.89 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H),
7.89 (app t, J = 8.0 Hz, 1H), 7.75 (app t, J = 7.7 Hz, 1H), 7.14 (d, J = 15.5 Hz, 1H), 6.47 (d, J = 15.5 Hz,
1H), 5.51 (d, J = 10.3 Hz, 1H), 4.51 (app t, J = 8.9 Hz, 1H), 4.23 (d, J = 8.0 Hz, 1H), 3.94 (d, J = 14.3
Hz, 1H), 3.85 (dd, J = 1.7, 9.7 Hz, 1H), 3.59 (d, J = 10.3 Hz, 1H), 3.52 (d, J = 13.8 Hz, 1H), 3.42 (dd, J
= 4.0, 10.9 Hz, 1H), 3.35 (dd, J = 8.0, 10.9 Hz, 1H), 3.26-3.19 (complex m, 2H), 3.13 (app t, J = 9.5 Hz,
1H), 2.86 (m, 1H), 2.76 (m, 1H), 2.66 (m, 1H), 2.50 (s, 6H), 2.45-2.29 (complex m, 3H), 2.23 (s, 3H),
2.05 (d, J = 17.2 Hz, 1H), 1.88-1.73 (complex m, 3H), 1.80 (s, 3H), 1.72-1.63 (complex m, 2H), 1.59-
1.42 (complex m, 3H), 1.24 (d, J = 5.7 Hz, 3H), 1.21 (d, J = 6.9 Hz, 3H), 1.20 (d, J = 6.9 Hz, 3H), 0.84
(t, J = 7.5 Hz, 3H). C NMR (125 MHz, CD OD) δ (ppm) : 206.5, 174.3, 149.6, 148.4, 146.8, 145.2,
144.9, 136.5, 132.2, 132.0, 129.9, 129.7, 129.4, 129.1, 128.9, 124.3, 119.4, 105.7, 80.6, 76.1, 74.3, 72.6,
71.73, 71.66, 68.4, 62.4, 56.0 52.7, 48.3, 46.7, 43.1, 42.7, 42.2 (2C), 40.3, 34.9, 34.1, 26.2, 26.1, 18.3,
17.9, 13.2, 9.9, 9.7; HRMS (ESI) m/z :821.4812 [M+H] , calcd for C H N O : 821.4813.
44 65 6 9
YT651
According to the general procedure (method C) for synthesis of triazole analogues, YT646 (100.0 mg,
0.154 mmol) with azidomethyl benzene (30.8 mg, 0.230 mmol) was converted to YT651 (86.1 mg,
71%) as a pale yellow solid. HRMS (ESI) m/z :784.4851 [M+H] , calcd for C H N O : 784.4861.
42 66 5 9
YT652
According to the general procedure (method A) for synthesis of triazole analogues, YT646 (100.0 mg,
0.154 mmol) with 2-acetamido-4,6-O-benzylidenedeoxy-β -D-glucopyranosylazide (62.0 mg, 0.185
mmol) was converted to YT652 (117.8 mg, 78%) as a pale yellow solid. HRMS (ESI) m/z :985.5477
[M+H] , calcd for C50H77N6O14: 985.5498.
YT653
According to the general procedure (method C) for synthesis of triazole analogues, YT646 (100.0 mg,
0.154 mmol) with N-(2-azidoethyl)-benzylamine (40.6 mg, 0.230 mmol) was converted to YT653
(103.9 mg, 82%) as a pale yellow solid. HRMS (ESI) m/z :827.5277 [M+H] , calcd for C H N O :
44 71 6 9
827.5283.
YT654
According to the general procedure (method C) for synthesis of triazole analogues, YT649 (100.0 mg,
0.132 mmol) with ethynylbenzene (21.7 µL, 0.198 mmol) was converted to YT654 (106.6 mg, 94%) as
a pale yellow solid. HRMS (ESI) m/z :860.5157 [M+H] , calcd for C H N O : 860.5174.
48 70 5 9
YT657
According to the general procedure (method A) for synthesis of triazole analogues, YT649 (100.0 mg,
0.132 mmol) with m-ethynylaniline (30.0 µL, 0.264 mmol) was converted to YT657 (71.4 mg, 62%) as
a pale yellow solid. HRMS (ESI) m/z :875.5262 [M+H] , calcd for C H N O : 875.5283.
48 71 6 9
YT664
According to the general procedure (method A) for synthesis of triazole analogues, YT649 (100.0 mg,
0.132 mmol) with 3-ethynylpyridine (27.0 mg, 0.262 mmol) was converted to YT664 (46.9 mg, 41%) as
a pale yellow solid. HRMS (ESI) m/z :861.5110 [M+Na] , calcd for C45H70N6O9Na: 861.5102.
YT665
According to the general procedure (method A) for synthesis of triazole analogues, YT649 (100.0 mg,
0.132 mmol) with 1-ethynylpentylbenzene (51.0 µL, 0.263 mmol) was converted to YT665 (46.6 mg,
38%) as a pale yellow solid. HRMS (ESI) m/z :952.5767 [M+Na] , calcd for C H N O Na: 952.5776.
53 79 5 9
YT666
According to the general procedure (method A) for synthesis of triazole analogues, YT649 (100.0 mg,
0.132 mmol) with cyclopropylacetylene (22.0 µL, 0.260 mmol) was converted to YT666 (30.4 mg,
28%) as a pale yellow solid.HRMS (ESI) m/z :846.4986 [M+Na] , calcd for C45H69N5O9Na: 846.4993.
YT674
According to the general procedure (method A) for synthesis of triazole analogues, YT649 (100 mg,
0.132 mmol) with 3-ethynylthiophene (19.5µL, 0.198 mmol) was converted to YT674 (49.2 mg, 43%)
as a pale yellow solid. HRMS (ESI) m/z :866.4738 [M+H] , calcd for C H N O S: 866.4738.
46 68 5 9
YT680
According to the general procedure (method A) for synthesis of triazole analogues, YT649 (100 mg,
0.132 mmol) with 4-ethynylbiphenyl (35.3 mg, 0.198 mmol) was converted to YT680 (48.2 mg, 39%)
as a pale yellow solid. HRMS (ESI) m/z :936.5478 [M+H] , calcd for C H N O : 936.5487.
54 74 5 9
YT687
According to the general procedure (method C) for synthesis of triazole analogues, YT649 (100 mg,
0.132 mmol) with 1-ethynylphenoxybenzene (35.9 µL, 0.198 mmol) was converted to YT687 (57.6
mg, 46%) as a pale yellow solid. HRMS (ESI) m/z :952.5444 [M+H] , calcd for C H N O : 952.5434.
54 74 5 10
YT696
According to the general procedure (method A) for synthesis of triazole analogues, YT649 (100 mg,
0.132 mmol) with p-t-butylphenylacetylene (47.0 µL, 0.264 mmol) was converted to YT696 (55.7 mg,
46%) as a pale yellow solid. HRMS (ESI) m/z :916.5784 [M+H] , calcd for C52H78N5O9: 916.5800.
YT700
According to the general procedure (method B) for synthesis of triazole analogues, YT699 (100.0 mg,
0.133 mmol) with ethynyl benzene (18.7 µL, 0.170 mmol) was converted to YT700 (92.7 mg, 83%) as a
pale yellow solid. HRMS (ESI) m/z :986.4143 [M+H] , calcd for C H IN O : 986.4140.
48 69 5 9
YT701
According to the general procedure (method B) for synthesis of triazole analogues, YT699 (100.0 mg,
0.133 mmol) with 4-ethynyl biphenyl (30.3 mg, 0.170 mmol) was converted to YT701 (102.9 mg, 86%)
as a pale yellow solid. HRMS (ESI) m/z :1062.4446 [M+H] , calcd for C54H73IN5O9: 1062.4453.
YT705
According to the general procedure (method B) for synthesis of triazole analogues, YT699 (100.0 mg,
0.133 mmol) with 3-ethynylthiophene (17.4 µL, 0.170 mmol) was converted to YT705 (100.5 mg, 71%)
as a pale yellow solid. HRMS (ESI) m/z :992.3687 [M+H] , calcd for C H IN O S: 992.3704.
46 67 5 9
YT706
According to the general procedure (method B) for synthesis of triazole analogues, YT699 (100.0 mg,
0.133 mmol) with 1-ethynylphenoxybenzene (31.8 µL, 0.170 mmol) was converted to YT706 (97.2
mg, 68%) as a pale yellow solid. HRMS (ESI) m/z :1078.4388 [M+H] , calcd for C H IN O :
54 73 5 10
1078.4402.
YT707
According to the general procedure (method B) for synthesis of triazole analogues, YT699 (100.0 mg,
0.133 mmol) with 1-ethynyl-2,4,5-trimethyl benzene (25.3 mg, 0.170 mmol) was converted to YT707
(99.8 mg, 73%) as a pale yellow solid. HRMS (ESI) m/z :1028.4588 [M+H] , calcd for C H IN O :
51 75 5 9
1028.4609.
YT708
HRMS (ESI) m/z :694.4379 [M+H] , calcd for C H N O : 694.4391.
60 5 9
YT709
According to the general procedure (method B) for synthesis of triazole analogues, YT711 (100.0 mg,
0.138 mmol) with 3-azidoquinoline (30.4 mg, 0.179 mmol) was converted to YT709 (113.9 mg, 92%)
31 1
as a colorless solid. [a] –124.7 (c 1.0, CHCl ); H NMR (500 MHz, CD OD) δ (ppm) : 9.49 (d, J = 2.3
D 3 3
Hz, 1H), 8.95 (s, 1H), 8.89 (d, J = 2.3 Hz, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.12 (d, J = 8.6 Hz, 1H), 7.88
(app t, J = 8.0 Hz, 1H), 7.74 (app t, J = 8.0 Hz, 1H), 7.44 (d, J = 7.5 Hz, 2H), 7.38 (app t, J = 7.5 Hz,
2H), 7.27 (t, J = 7.5 Hz, 1H), 7.10 (d, J = 15.5 Hz, 1H), 6.48 (d, J = 15.5 Hz, 1H), 5.72 (d, J = 10.9 Hz,
1H), 4.78 (m, 1H), 4.01-3.67 (complex m, 3H), 3.94 (d, J =7.5 Hz, 1H), 3.57-3.43 (complex m, 4H),
3.26 (dd, J = 10.3, 8.0 Hz, 1H), 3.20 (d, J = 12.6 Hz, 1H), 3.02 (t, 9.7 Hz, 1H), 2.97 (m, 1H), 2.87-2.78
(complex m, 2H), 2.67 (m, 1H), 2.54 (dd, J = 17.2, 10.3 Hz, 1H), 2.45 (s, 6H), 2.22-2.15 (complex m,
2H), 2.08 (d, J = 17.2 Hz, 1H), 1.94 (m, 1H), 1.84 (s, 3H), 1.83-1.46 (complex m, 7H), 1.21 (d, J = 6.9
Hz, 3H), 1.04 (d, J = 6.3 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H), 0.91 (t, J = 7.5 Hz, 3H). C NMR (125 MHz,
CD OD) δ (ppm) : 206.7, 174.6, 149.5, 148.4, 147.7, 144.7, 144.5, 139.6, 136.6, 132.2, 131.9, 130.8
(2C), 129.8, 129.6, 129.5 (2C), 129.4, 129.0, 128.4, 128.2, 124.2, 119.6, 105.6, 80.5, 76.3, 74.2, 72.5,
71.7, 71.6, 68.6, 62.5, 59.8, 52.4, 50.4, 48.3, 46.5, 42.9, 42.1 (2C), 40.5, 34.9, 34.2, 26.2 (2C), 18.1, 17.9,
13.3, 10.0, 9.8. HRMS (ESI) m/z :897.5111 [M+H] , calcd for C H N O : 897.5126.
50 69 6 9
YT710
According to the general procedure (method B) for synthesis of triazole analogues, YT650 (100.0 mg,
0.154 mmol) with 6-azidoquinoline (39.1 mg, 0.230 mmol) was converted to YT710 (115.3 mg, 91%)
as a pale yellow solid.
H NMR (500 MHz, CD3OD) δ (ppm) : 8.96 (dd, J = 1.7, 4.0 Hz, 1H), 8.85 (s, 1H), 8.56-8.53 (m, 2H),
8.42 (dd, J = 2.3, 9.2 Hz, 1H), 8.27 (d, J = 9.2 Hz, 1H), 7.66 (dd, J = 4.3, 8.0 Hz, 1H), 7.18 (d, J = 14.9
Hz, 1H), 6.49 (d, J = 15.5 Hz, 1H), 5.63 (d, J = 10.9 Hz, 1H), 4.68 (m, 1H), 4.21 (d, J = 7.5 Hz, 1H),
3.91 (d, J = 13.8 Hz, 1H), 3.86 (d, J = 9.7 Hz, 1H), 3.59-3.53 (complex m, 2H), 3.47 (dd, J = 3.4 , 10.9
Hz, 1H), 3.36-3.30 (complex m, 2H), 3.20 (m, 1H), 3.12 (app t, J = 9.5 Hz, 1H), 2.87-2.76 (complex m,
2H), 2.67 (m, 1H), 2.50 (s, 6H), 2.47-2.26 (complex m, 3H), 2.24 (s, 3H), 1.82 (s, 3H), 2.06 (d, J =16.6
Hz, 1H), 1.82-1.67 (complex m, 5H), 1.58-1.50 (complex m, 3H), 1.22 (app d, J = 6.3 Hz, 6H), 1.02 (d,
J = 6.9 Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H). C NMR (125 MHz, CD OD) δ (ppm) : 206.6, 174.3, 152.4,
149.6, 148.2, 146.5, 144.7, 138.8, 136.5, 136.4, 131.3, 129.9, 124.6, 123.9, 123.8, 120.4, 119.5, 105.7,
80.6, 76.1, 74.3, 72.6, 71.7 (2C), 68.4, 62.4, 55.8, 52.9, 48.2, 46.6, 43.1, 42.5, 42.2 (2C), 40.5, 35.0, 34.2,
26.2, 26.0, 18.2, 17.9, 13.2, 10.0, 9.7. HRMS (ESI) m/z :821.4815 [M+H] , calcd for C H N O :
44 65 6 9
821.4813.
YT713
According to the general procedure (method B) for synthesis of triazole analogues, YT699 (100.0 mg,
0.133 mmol) with propargyl benzoate (24.6 µL, 0.170 mmol) was converted to YT713 (93.3 mg, 67%)
as a pale yellow solid. HRMS (ESI) m/z :1044.4190 [M+H] , calcd for C H IN O : 1044.4195.
50 71 5 11
YT714
According to the general procedure (method A) for synthesis of triazole analogues, YT699 (100.0 mg,
0.113 mmol) with 3-ethynylquinoline (26.0 mg, 0.170 mmol) was converted to YT714 (64.8 mg, 56%)
as a pale yellow solid. HRMS (ESI) m/z :1037.4252 [M+H] , calcd for C H IN O : 1037.4249.
51 70 6 9
YT715
According to the general procedure (method B) for synthesis of triazole analogues, YT615 (100.0 mg,
0.150 mmol) with m-ethynyl aniline (35.1 mg, 0.299 mmol) was converted to YT715 (33.0 mg, 28%) as
a pale yellow solid. HRMS (FAB, NBA matrix) m/z :785.4808 [M+H] , calcd for C41H65N6O9: 785.4813.
YT716
According to the general procedure (method A) for synthesis of triazole analogues, YT615 (100.0 mg,
0.150 mmol) with 2-ethynylpyridine (30.8 mg, 0.299 mmol) was converted to YT716 (50.9 mg, 44%) as
a pale yellow solid. HRMS (FAB, NBA matrix) m/z :771.4676 [M+H] , calcd for C H N O : 771.4657.
40 63 6 9
YT717
According to the general procedure (method A) for synthesis of triazole analogues, YT615 (100.0 mg,
0.150 mmol) with 3-ethynylthiophene (29.5 µL, 0.299 mmol) was converted to YT717 (65.9 mg, 57%)
as a colorless solid. HRMS (FAB, NBA matrix) m/z :776.4270 [M+H] , calcd for C H N O S:
39 62 5 9
776.4268.
YT718
According to the general procedure (method A) for synthesis of triazole analogues, YT615 (100.0 mg,
0.150 mmol) with 1-ethynylnitrobenzene (44.0 mg, 0.299 mmol) was converted to YT718 (55.4 mg,
45%) as a pale yellow solid. HRMS (FAB, NBA matrix) m/z :815.4567 [M+H] , calcd for C H N O :
41 63 6 11
815.4555.
YT721
According to the general procedure (method A) for synthesis of triazole analogues, YT615 (100.0 mg,
0.150 mmol) with 4-ethynylbiphenyl (53.5 mg, 0.30 mmol) was converted to YT721 (79.6 mg, 63%) as
a colorless solid. H NMR (500 MHz, CD3OD) δ (ppm) : 8.51 (s, 1H), 7.95 (d, J = 8.6 Hz, 2H), 7.71 (d,
J = 8.6 Hz, 2H), 7.66 (m, 2H), 7.45 (m, 2H), 7.35 (m, 1H), 7.32 (d, J = 15.5 Hz, 1H), 6.48 (d, J = 15.5
Hz, 1H), 5.94 (d, J = 10.9 Hz, 1H), 4.95 (m, 1H), 4.60 (m, 2H), 4.23 (d, J = 7.5 Hz, 1H), 3.80 (d, J = 9.7
Hz, 1H), 3.67 (complex m, 2H), 3.62 (d, J = 10.3 Hz, 1H), 3.33 (m, 1H), 3.20-3.06 (complex m, 4H),
2.86 (m, 1H), 2.74-2.62 (complex m, 3H), 2.49 (s, 6H), 2.47 (m, 1H), 2.36 (m, 1H), 2.07 (d, J = 16.6 Hz,
1H), 1.93-1.42 (complex m, 8H), 1.86 (s, 3H), 1.21 (d, J = 6.9 Hz, 3H), 1.16 (d, J = 5.7 Hz, 3H), 1.04 (d,
J = 6.9 Hz, 3H), 0.94 (t, J = 7.5 Hz, 3H); HRMS (ESI) m/z :846.5011 [M+H] , calcd for C H N O :
47 68 5 9
846.5017.
YT722
According to the general procedure (method B) for synthesis of triazole analogues, YT615 (100.0 mg,
0.150 mmol) with 1-ethynylpentylbenzene (51.5 mg, 0.299 mmol) was converted to YT722 (57.6 mg,
46%) as a colorless solid. HRMS (ESI) m/z :840.5508 [M+H] , calcd for C H N O : 840.5487.
46 74 5 9
YT723
According to the general procedure (method B) for synthesis of triazole analogues, YT615 (36.0 mg,
0.054 mmol) with 1-ethynyl-2,4,5-trimethylbenzene (15.5 mg, 0.108 mmol) was converted to YT723
(31 mg, 71%) as a colorless solid. HRMS (ESI) m/z :834.4984 [M+Na] , calcd for C H N O Na:
44 69 5 9
834.4993.
YT724
According to the general procedure (method B) for synthesis of triazole analogues, YT615 (100.0 mg,
0.150 mmol) with p-t-butylphenylacetylene (53.4 µL, 0.299 mmol) was converted to YT724 (70.5 mg,
57%) as a colorless solid. HRMS (FAB, NBA matrix) m/z :826.5333 [M+H] , calcd for C H N O :
45 72 5 9
826.5330.
YT726
According to the general procedure (method A) for synthesis of triazole analogues, YT616 (20.0 mg,
0.0321 mmol) with 3-ethynylthiophene (4.7 µL, 0.0481 mmol) was converted to YT726 (18.8 mg, 80%)
as a colorless solid. HRMS (ESI) m/z :733.3838 [M+H] , calcd for C H N O S: 733.3846.
37 57 4 9
YT727
According to the general procedure (method A) for synthesis of triazole analogues, YT616 (70.0 mg,
0.112 mmol) with ethynylbenzene (18.5 µL, 0.168 mmol) was converted to YT727 (54.6 mg, 67%) as a
colorless solid. HRMS (ESI) m/z :749.4109 [M+Na] , calcd for C39H58N4O9Na: 749.4102.
YT728
According to the general procedure (method A) for synthesis of triazole analogues, YT616 (70.0 mg,
0.112 mmol) with 4-ethynylquinoline (25.8 mg, 0.168 mmol) was converted to YT728 (67.7 mg, 73%)
as a colorless solid. HRMS (ESI) m/z :800.4222 [M+H] , calcd for C H N O Na: 800.4211.
42 59 5 9
YT731
According to the general procedure (method B) for synthesis of triazole analogues, YT699 (100.0 mg,
0.150 mmol) with propargyl benzoate (47.9 mg, 0.299 mmol) was converted to YT731 (64.0 mg, 52%)
as a colorless solid. HRMS (FAB, NBA matrix) m/z :828.4774 [M+H] , calcd for C H N O :
43 66 5 11
828.4779.
YT732
According to the general procedure (method A) for synthesis of triazole analogues, YT615 (100.0 mg,
0.149 mmol) with 1-ethynylquinoline (45.8 mg, 0.299 mmol) was converted to YT732 (66.0 mg,
54%) as a colorless solid. H NMR (500 MHz, CD OD) δ (ppm) : 9.39 (d, J = 2.3 Hz, 1H), 8.81 (d, J =
2.3 Hz, 1H), 8.75 (s, 1H), 8.06 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.79 (m, 1H), 7.65 (app. t, J
= 7.5 Hz, 1H), 7.28 (d, J = 15.5 Hz, 1H), 6.47 (d, J = 15.5 Hz, 1H), 5.92 (d, J = 10.3 Hz, 1H), 4.92 (m,
1H), 4.65 (m, 2H), 4.23 (d, J = 7.5 Hz, 1H), 3.79 (d, J = 9.7 Hz, 1H), 3.65-3.61 (complex m, 3H), 3.33
(m, 1H), 3.23-3.08 (complex m, 4H), 2.85 (m, 1H), 2.75 (m, 1H), 2.69-2.63 (complex m, 2H), 2.50 (s,
6H), 2.48-2.35 (complex m, 2H), 2.06 (d, J = 16.6 Hz, 1H), 1.91-1.43 (complex m, 8H), 1.85 (s, 3H),
1.21 (d, J = 6.9 Hz, 3H), 1.18 (d, J = 6.3 Hz, 3H), 1.03 (d, J = 6.3 Hz, 3H), 0.93 (t, J = 7.5 Hz, 3H);
HRMS (ESI) m/z :821.4808 [M+H] , calcd for C H N O : 821.4813.
44 65 6 9
YT733
According to the general procedure (method A) for synthesis of triazole analogues, YT616 (70.0 mg,
0.112 mmol) with 3-ethynylquinoline (25.8 mg, 0.168 mmol) was converted to YT733 (55.1 mg, 58%)
as a colorless solid. HRMS (ESI) m/z :800.4220 [M+Na] , calcd for C H N O Na: 800.4211.
42 59 5 9
YT734
According to the general procedure (method A) for synthesis of triazole analogues, YT616 (77.0 mg,
0.123 mmol) with 2-ethynylquinoline (28.4 mg, 0.185 mmol) was converted to YT734 (90.2 mg, 94%)
as a colorless solid. HRMS (ESI) m/z :800.4221 [M+Na] , calcd for C42H59N5O9Na: 800.4211.
YT735
According to the general procedure (method A) for synthesis of triazole analogues, YT616 (66.6 mg,
0.107 mmol) with 4-ethynylpyridine (16.5 mg, 0.160 mmol) was converted to YT735 (52.4 mg, 68%) as
a colorless solid. HRMS (ESI) m/z :750.4058 [M+Na] , calcd for C H N O Na: 750.4054.
38 57 5 9
YT736
According to the general procedure (method A) for synthesis of triazole analogues, YT616 (70 mg,
0.112 mmol) with 3-ethynylpyridine (17.4 mg, 0.168 mmol) was converted to YT736 (61.2 mg, 69%) as
a colorless solid. C NMR (125 MHz, CD OD) δ (ppm) : 206.4, 175.6, 150.2, 150.0, 148.4, 146.0,
144.8, 137.3, 136.1, 129.6, 126.5, 123.7, 120.3, 105.8, 80.2, 79.3, 77.1, 75.1, 73.3, 72.5, 72.4, 68.8, 63.4,
50.0, 49.0, 47.0, 43.0 (2C), 41.5, 35.4, 34.3, 30.0, 27.0, 19.0, 18.4, 14.0, 10.8, 10.2.
YT737
According to the general procedure (method B) for synthesis of triazole analogues, YT711 (100.0 mg,
0.138 mmol) with 6-azidoquinoline (35.1 mg, 0.206 mmol) was converted to YT737 (92.5 mg, 75%) as
a pale yellow solid. HRMS (ESI) m/z :897.5116 [M+H] , calcd for C H N O : 897.5126.
50 69 6 9
YT738
According to the general procedure (method B) for synthesis of triazole analogues, YT646 (100.0 mg,
0.154 mmol) with 5-azidoisoquinoline (39.1 mg, 0.230 mmol) was converted to YT738 (89.2 mg, 71%)
as a pale yellow solid. H NMR (500 MHz, CD3OD) δ (ppm) : 9.44 (d, J = 1.2 Hz, 1H), 8.71 (s, 1H),
8.57 (d, J = 6.3 Hz, 1H), 8.40 (d, J = 8.6 Hz, 1H), 8.13 (dd, J = 1.2, 7.5 Hz, 1H), 8.13 (t, J = 7.7 Hz, 1H),
7.74 (d, J = 5.7 Hz, 1H), 7.07 (d, J = 15.5 Hz, 1H), 6.44 (d, J = 15.5 Hz, 1H), 5.21 (d, J = 10.3 Hz, 1H),
4.25 (d, J = 7.5 Hz, 1H), 4.15 (m, 1H), 3.95 (dd, J = 1.7, 9.7 Hz, 1H), 3.86 (d, J = 13.8 Hz, 1H), 3.80 (d,
J = 10.3 Hz, 1H), 3.58-3.53 (m, 2H), 3.49 (dd, J = 4.0 , 10.9 Hz, 1H), 3.38-3.23 (complex m, 2H), 3.14
(app t, J = 9.5 Hz, 1H), 2.86 (m, 1H), 2.74-2.63 (complex m, 2H), 2.51 (s, 6H), 2.42-2.28 (complex m,
3H), 2.25 (s, 3H), 1.97 (d, J =17.2 Hz, 1H), 1.91-1.42 (complex m, 8H), 1.76 (s, 3H), 1.26 (d, J = 6.3 Hz,
3H), 1.21 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 6.9 Hz, 3H), 0.74 (t, J = 7.2 Hz, 3H). C NMR (125 MHz,
CD OD) δ (ppm) : 206.5, 173.9, 153.7, 149.6, 145.8, 145.0, 144.8, 136.2, 134.3, 132.7, 131.4, 130.5,
129.9, 128.6, 128.1, 119.2, 117.6, 105.7, 80.7, 76.1, 74.3, 72.6, 71.7 (2C), 68.3, 62.4, 56.1, 52.5, 48.3,
46.7, 43.0, 42.7, 42.2 (2C), 40.1, 35.0, 34.1, 26.2, 25.9, 18.3, 17.9, 13.1, 9.9, 9.6. HRMS (ESI)
m/z :821.4813 [M+H] , calcd for C H N O : 821.4813.
44 65 6 9
YT739
According to the general procedure (method B) for synthesis of triazole analogues, YT712 (100.0 mg,
0.157 mmol) with 3-azidoquinoline (40.1 mg, 0.236 mmol) was converted to YT739 (97.9 mg, 77%) as
26 1
a colorless solid. [a] –111.2 (c 1.0, CHCl ); H NMR (500 MHz, CD OD) δ (ppm) : 9.48 (d, J = 2.9
D 3 3
Hz, 1H), 8.89 (d, J = 2.3 Hz, 1H), 8.82 (s, 1H), 8.16 (d, J = 8.6 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 7.88
(dt, J = 1.2, 8.0 Hz, 1H), 7.74 (dt, J = 1.2, 8.0 Hz, 1H), 7.23 (d, J = 14.9 Hz, 1H), 6.48 (d, J = 15.5 Hz,
1H), 5.70 (d, J = 10.3 Hz, 1H), 4.63 (app t, J = 8.6 Hz, 1H), 4.26 (d, J = 7.5 Hz, 1H), 4.00 (d, J = 14.3
Hz, 1H), 3.86 (d, J = 13.8 Hz, 1H), 3.80 (d, J = 10.3 Hz, 1H), 3.65 (d, J = 10.3 Hz, 1H), 3.51 (dd, J =
3.4 , 11.2 Hz, 1H), 3.41-3.22 (complex m, 3H), 3.14 (t, J = 9.2, 9.7 Hz, 1H), 2.92 (m, 1H), 2.83-2.73
(complex m, 2H), 2.66 (m, 1H), 2.51 (s, 6H), 2.45-2.38 (complex m, 2H), 2.04 (d, J =17.2 Hz, 1H),
1.89-1.66 (complex m, 5H), 1.82 (s, 3H), 1.60-1.45 (complex m, 3H), 1.24 (d, J = 6.3 Hz, 3H), 1.22 (d, J
= 6.9 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H), 0.84 (t, J = 7.5 Hz, 3H). C NMR (125 MHz, CD OD) δ
(ppm) : 206.7, 174.6, 149.7, 148.4, 148.3, 144.8 (2C), 136.6, 132.2, 131.9, 129.8, 129.6, 129.4, 129.0,
128.4, 123.2, 119.6, 105.7, 80.6, 76.2, 74.3, 72.6, 71.73, 71.69, 68.3, 62.5, 48.3, 47.1, 46.6, 44.5, 42.8,
42.2 (2C), 40.4, 34.7, 34.1, 27.8, 26.1, 18.2, 17.9, 13.2, 10.0, 9.7. HRMS (ESI) m/z :829.4478 [M+Na] ,
calcd for C H N O Na: 829.4476.
43 62 6 9
YT740
According to the general procedure (method A) for synthesis of triazole analogues, YT699 (100.0 mg,
0.113 mmol) with 1-ethynylnitrobenzene (33.3 mg, 0.226 mmol) was converted to YT740 (62.2 mg,
53%) as a colorless solid. HRMS (ESI) m/z :1053.3832 [M+Na] , calcd for C48H67IN6O11Na: 1053.3810.
YT741
According to the general procedure (method A) for synthesis of triazole analogues, YT699 (100.0 mg,
0.113 mmol) with 3-ethynylpyridine (23.3 mg, 0.226 mmol) was converted to YT741 (71.7 mg, 64%) as
a colorless solid. HRMS (ESI) m/z :1009.3934 [M+H] , calcd for C H IN O : 1009.3936.
49 66 6 9
YT742
According to the general procedure (method A) for synthesis of triazole analogues, YT699 (100.0 mg,
0.113 mmol) with m-ethynylaniline (25.5 mL, 0.226 mmol) was converted to YT742 (75.6 mg, 67%) as
a colorless solid. HRMS (ESI) m/z :1023.4071 [M+Na] , calcd for C48H69IN6O9Na: 1023.4068.
YT743
According to the general procedure (method B) for synthesis of triazole analogues, YT646 (100.0 mg,
0.154 mmol) with 5-azidoquinoline (39.1 mg, 0.230 mmol) was converted to YT743 (113.2 mg, 90%)
as a pale yellow solid. H NMR (500 MHz, CD OD) δ (ppm) : 9.00 (dd, J = 1.7, 4.0 Hz, 1H), 8.69 (s,
1H), 8.30 (d, J = 8.6 Hz, 1H), 8.25 (d, J = 8.6 Hz, 1H), 8.02 (app t, J = 8.0 Hz, 1H), 7.94 (d, J = 7.5 Hz,
1H), 7.66 (dd, J = 4.0, 8.6 Hz, 1H), 7.06 (d, J = 15.5 Hz, 1H), 6.43 (d, J = 15.5 Hz, 1H), 5.11 (d, J =
.3 Hz, 1H), 4.25 (d, J = 7.5 Hz, 1H), 4.03 (m, 1H), 3.95 (d, J = 13.8 Hz, 1H), 3.79 (dd, J = 1.2, 9.7 Hz,
1H), 3.58-3.47 (complex m, 3H), 3.36 (dd, J = 7.5, 10.9 Hz, 1H), 3.30-3.23 (complex m, 2H), 3.14 (app
t, J = 9.5 Hz, 1H), 2.86 (m, 1H), 2.72-2.62 (complex m, 2H), 2.51 (s, 6H), 2.41-2.26 (complex m, 3H),
2.25 (s, 3H), 1.95 (d, J =17.2 Hz, 1H), 1.92-1.40 (complex m, 8H), 1.75 (s, 3H), 1.26 (d, J = 6.3 Hz, 3H),
1.20 (d, J = 6.9 Hz, 3H), 0.99 (d, J = 6.9 Hz, 3H), 0.76 (t, J = 7.2 Hz, 3H). C NMR (125 MHz,
CD OD) δ (ppm) : 206.4, 173.8, 152.5, 149.6, 148.9, 145.7, 136.2, 135.2, 133.9, 131.7, 130.4, 128.2,
125.8, 125.5, 124.1, 119.1, 105.7, 80.7, 76.0, 74.3, 72.3, 72.6, 71.72, 71.65, 68.2, 62.3, 56.0, 52.4, 48.4,
46.7, 42.9, 42.8, 42.2 (2C), 40.1, 35.0, 34.0, 26.1, 28.9, 18.3, 17.9, 13.1, 10.0, 9.6. HRMS (ESI)
m/z :821.4814 [M+H] , calcd for C H N O : 821.4813.
44 65 6 9
YT744
According to the general procedure (method B) for synthesis of triazole analogues, YT646 (100.0 mg,
0.154 mmol) with 1-azidonaphthalene (39.1 mg, 0.230 mmol) was converted to YT744 (110 mg, 87%)
as a pale yellow solid. H NMR (500 MHz, CD OD) δ (ppm) : 8.62 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H),
8.07 (m, 1H), 7.76 (dd, J = 1.2, 7.5 Hz, 1H), 7.70 (m, 1H), 7.66-7.58 (complex m, 3H), 7.09 (d, J = 15.5
Hz, 1H), 6.43 (d, J = 14.9 Hz, 1H), 5.06 (d, J = 10.3 Hz, 1H), 4.25 (d, J = 7.5 Hz, 1H), 4.15 (app t, J =
8.6 Hz, 1H), 3.96 (dd, J = 1.2, 9.7 Hz, 1H), 3.58 (d, J = 10.3 Hz, 1H), 3.52 (d, J = 13.8 Hz, 1H), 3.45 (dd,
J = 4.6 , 10.9 Hz, 1H), 3.35 (dd, J = 7.5 , 10.3 Hz, 1H), 3.28-3.20 (complex m, 2H), 3.14 (app t, J = 9.5
Hz, 1H), 2.87 (m, 1H), 2.72-2.63 (complex m, 2H), 2.51 (s, 6H), 2.41-2.26 (complex m, 3H), 2.25 (s,
3H), 1.95 (d, J =17.2 Hz, 1H), 1.91-1.38 (complex m, 8H), 1.74 (s, 3H), 1.26 (d, J = 5.7 Hz, 3H), 1.20 (d,
J = 6.9 Hz, 3H), 0.99 (d, J = 6.9 Hz, 3H), 0.76 (t, J = 7.2 Hz, 3H). C NMR (125 MHz, CD OD) δ
(ppm) : 206.4, 173.7, 149.7, 145.4, 145.2, 136.2, 135.5, 135.3, 131.6, 130.1, 129.4, 129.0, 128.4, 128.3,
126.3, 125.4, 123.7, 119.0, 105.7, 80.7, 76.0, 74.3, 72.6, 71.74, 71.65, 68.3, 62.4, 56.0, 52.5, 48.4, 46.7,
42.9, 42.8, 42.2 (2C), 40.1, 35.0, 34.0, 26.2, 26.0, 18.3, 17.9, 13.1, 10.0, 9.6. HRMS (ESI) m/z :820.4868
[M+H] , calcd for C H N O : 820.4861.
44 66 5 9
YT745
According to the general procedure (method B) for synthesis of triazole analogues, YT712 (100.0 mg,
0.157 mmol) with 6-azidonaphthalene (40.1 mg, 0.236 mmol) was converted to YT745 (100.2 mg, 79%)
as a colorless solid. H NMR (500 MHz, CD3OD) δ (ppm) : 8.95 (dd, J = 1.7, 8.0 Hz, 1H), 8.77 (s, 1H),
8.53 (m, 2H), 8.42 (dd, J = 2.3, 9.2 Hz, 1H), 8.25 (d, J = 9.2, 1H), 7.65 (dd, J = 4.3, 8.3 Hz, 1H), 7.25
(d, J = 15.5 Hz, 1H), 6.49 (d, J = 15.5 Hz, 1H), 5.76 (d, J = 10.3 Hz, 1H), 4.76 (m, 1H), 4.25 (d, J = 7.5
Hz, 1H), 3.99 (d, J = 13.8 Hz, 1H), 3.86 (d, J = 13.8 Hz, 1H), 3.81 (d, J = 9.7 Hz, 1H), 3.66 (dd, J = 10.3
Hz, 1H), 3.53 (dd, J = 3.4 , 11.5 Hz, 1H), 3.46 (m, 1H), 3.35 (dd, J = 8.0, 10.9 Hz, 1H), 3.23 (m, 1H),
3.13 (app t, J = 9.5 Hz, 1H), 2.90 (m, 1H), 2.84-2.74 (complex m, 2H), 2.67 (m, 1H), 2.51 (s, 6H), 2.47-
2.36 (complex m, 2H), 2.06 (d, J =17.2 Hz, 1H), 1.88-1.68 (complex m, 5H), 1.83 (s, 3H), 1.60-1.51
(complex m, 3H), 1.23 (d, J = 6.3 Hz, 3H), 1.22 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H), 0.88 (t, J =
7.5 Hz, 3H). C NMR (125 MHz, CD OD) δ (ppm) : 206.4, 173.7, 149.7, 145.4, 145.2, 136.2, 135.5,
135.3, 131.6, 130.1, 129.4, 129.0, 128.4, 128.3, 126.3, 125.4, 123.7, 119.0, 105.7, 80.7, 76.0, 74.3, 72.6,
71.74, 71.65, 68.3, 62.4, 56.0, 52.5, 48.4, 46.7, 42.9, 42.8, 42.2 (2C), 40.1, 35.0, 34.0, 26.2, 26.0, 18.3,
17.9, 13.1, 10.0, 9.6. HRMS (ESI) m/z :829.4480 [M+Na] , calcd for C H N O Na: 829.4476.
43 62 6 9
YT747
According to the general procedure (method B) for synthesis of triazole analogues, YT646 (100.0 mg,
0.154 mmol) with 1-azidoadamantane (40.9 mg, 0.230 mmol) was converted to YT747 (110.6 mg, 87%)
as a colorless solid. HRMS (ESI) m/z :828.5474 [M+H] , calcd for C H N O : 828.5487.
45 74 5 9
YT749
According to the general procedure (method A) for synthesis of triazole analogues, YT699 (80.0 mg,
0.0905 mmol) with cyclopropylacetylene (30.4 mg, 0.181 mmol) was converted to YT749 (54.4 mg,
63%) as a colorless solid. HRMS (ESI) m/z :972.3968 [M+Na] , calcd for C H IN O Na: 972.3959.
45 68 5 9
YT750
According to the general procedure (method A) for synthesis of triazole analogues, YT699 (80.0 mg,
0.0905 mmol) with 4-ethynylbiphenyl (32.3 mg, 0.181 mmol) was converted to YT750 (53.5 mg, 56%)
as a colorless solid. HRMS (ESI) m/z :1084.4274 [M+Na] , calcd for C H IN O Na: 1084.4272.
54 72 5 9
YT751
According to the general procedure (method A) for synthesis of triazole analogues, YT699 (100.0 mg,
0.113 mmol) with p-t-butylacetylene (40.0 µL, 0.225 mmol) was converted to YT751 (60.8 mg, 65%) as
a pale yellow solid. HRMS (ESI) m/z :1042.4772 [M+H] , calcd for C H IN O : 1042.4766.
52 77 5 9
YT752
According to the general procedure (method A) for synthesis of triazole analogues, YT699 (100.0 mg,
0.113 mmol) with 1-ethynyln-pentylbenzene (44 µL, 0.227 mmol) was converted to YT752 (60.7 mg,
64%) as a pale yellow solid. HRMS (ESI) m/z :1056.4936 [M+H] , calcd for C H IN O : 1056.4922.
53 79 5 9
YT755
According to the general procedure (method B) for synthesis of triazole analogues, YT711 (100.0 mg,
0.138 mmol) with 5-azidoquinoline (30.4 mg, 0.179 mmol) was converted to YT755 (96.5 mg, 78%) as
a colorless solid. HRMS (ESI) m/z :897.5115 [M+H] , calcd for C H N O : 897.5126
50 69 6 9
YT756
According to the general procedure (method B) for synthesis of triazole analogues, YT711 (100.0 mg,
0.138 mmol) with 5-azidoisoquinoline (30.4 mg, 0.179 mmol) was converted to YT756 (75.1 mg, 61%)
as a pale yellow solid. HRMS (ESI) m/z :897.5121 [M+H] , calcd for C H N O : 897.5126.
50 69 6 9
YT757
According to the general procedure (method B) for synthesis of triazole analogues, YT711 (100.0 mg,
0.138 mmol) with 1-azidonaphthalene (30.4 mg, 0.179 mmol) was converted to YT757 (110.2 mg, 89%)
as a pale yellow solid. HRMS (ESI) m/z :896.5176 [M+H] , calcd for C H N O Na: 896.5174.
51 70 5 9
YT758
According to the general procedure (method B) for synthesis of triazole analogues, YT712 (100.0 mg,
0.157 mmol) with 5-azidoquinoline (40.1 mg, 0.236 mmol) was converted to YT758 (88.2 mg, 70%) as
a pale brown solid. HRMS (ESI) m/z :829.4479 [M+Na] , calcd for C43H62N6O9Na: 829.4476.
YT759
According to the general procedure (method B) for synthesis of triazole analogues, YT712 (100.0 mg,
0.157 mmol) with 1-azidonaphthalene (40.1 mg, 0.236 mmol) was converted to YT759 (97.3 mg, 77%)
as a pale yellow solid. HRMS (ESI) m/z :828.4515 [M+Na] , calcd for C H N O Na: 828.4524.
44 63 5 9
YT760
According to the general procedure (method B) for synthesis of triazole analogues, YT646 (100.0 mg,
0.154 mmol) with 2-azidonaphthalene (34.5 mg, 0.204 mmol) was converted to YT760 (95.0 mg, 76%)
as a colorless solid. HRMS (ESI) m/z :820.4858 [M+H] , calcd for C H N O : 820.4861.
45 66 5 9
YT761
According to the general procedure (method B) for synthesis of triazole analogues, YT712 (100.0 mg,
0.157 mmol) with 5-azidoisoquinoline (40.1 mg, 0.236 mmol) was converted to YT761 (87.8 mg, 69%)
as a pale yellow solid. HRMS (ESI) m/z :807.4652 [M+H] , calcd for C H N O : 807.4657.
43 63 6 9
YT762
According to the general procedure (method B) for synthesis of triazole analogues, YT711 (100.0 mg,
0.138 mmol) with 2-azidonaphthalene (30.4 mg, 0.179 mmol) using was converted to YT762 (120.0 mg,
97%) as a pale brown solid. C NMR (125 MHz, CD OD) δ (ppm) : 206.7, 174.6, 149.4, 147.2, 147.2,
144.3, 139.7, 135.8, 134.6, 134.3, 131.0, 130.7 (2C), 129.6, (2C), 129.5, 129.0, 128.4, 128.15, 128.06,
123.7, 120.1, 119.6 (2C), 105.5, 80.2, 76.2, 74.1, 72.5, 71.6 (2C), 68.6, 62.5, 59.7, 52.1, 50.6, 48.2, 46.5,
42.8, 42.1 (2C), 40.5, 34.8, 34.0, 26.3, 26.1, 18.1, 17.9, 13.4, 10.1, 9.9. HRMS (ESI) m/z :896.5177
[M+H] , calcd for C H N O : 896.5174
51 70 5 9
YT763
According to the general procedure (method B) for synthesis of triazole analogues, YT712 (100.0 mg,
0.157 mmol) with 2-azidonaphthalene (34.5 mg, 0.204 mmol) was converted to YT763 (92.1 mg, 73%)
as a pale brown solid. HRMS (ESI) m/z: 806.4704 [M+H] , calcd for C H N O : 806.4704
44 64 5 9
Synthesis of amine analogues at C23 position
YT729
To a solution of YT650 (300 mg, 0.365 mmol) in anhydrous pyridine (5.3 mL) was added DPPA (94.3
µL, 0.438 mmol) and DBU (65.5 µL, 0.438 mmol) at 0 ℃ and the reaction mixture was stirred at 0 ℃
for 2 hr. Then DPPA (175 µL, 0.814 mmol) and DBU (109 µL, 0.718 mmol) were added again to the
reaction mixture and the reaction was further performed at 80 ℃ for 4 hr. The reaction was quenched
with saturated NaHCO aq. (2 mL), the reaction mixture was concentrated under reduced pressure. The
residue was added CHCl (8 mL) and washed with saturated NaHCO aq. The organic layer was dried
over Na SO , and concentrated in vacuo. The crude product was used for the next step without further
purification. To the solution of the crude product (182 mg, 0.173 mmol) in anhydrous DMF (1.9 mL)
was added NaN (33.7 mg, 0.519 mmol), and the reaction mixture was stirred at 80 ℃ for 22 hr. The
solution was extracted with Hexane/EtOAc (v/v 1/1, 5 mL × 2), and washed with H O (15 mL). The
organic layer was dried over Na SO and concentrated in vacuo. The residue was purified by flash
column chromatography on silica gel (CHCl /MeOH/NH , 60/1/0.15) to give YT729 (115mg, 79%) as a
colorless solid. HRMS (ESI) m/z: 846.4877 [M+H] , calcd for C H N O : 846.4878.
44 64 9 8
YT768
To a solution of YT650 (300 mg, 0.365 mmol) and PPh (288 mg, 1.10 mmol) in anhydrous pyridine
(5.3 mL) was added iodine (186 mg, 0.731 mmol) in anhydrous pyridine (2 mL), and the reaction
mixture was stirred at 0 ℃ for 2 hr. The reaction was quenched with MeOH (0.2 mL), added toluene (15
mL) and concentrated in vacuo. The residue was added CHCl3 (8 mL) and washed with saturated
NaS O aq. The organic layer was dried over Na SO , and concentrated in vacuo. The residue was
2 3 2 4
purified by flash column chromatography on silica gel (CHCl /MeOH/NH , 70/1/0.15) to give
compound YT768 (290 mg, 85%) as a colorless solid. H NMR (500 MHz, CD OD) d (ppm) : 9.49 (d, J
= 2.3 Hz, 1H), 8.91 (d, J = 1.7 Hz, 1H), 8.89 (s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H),
7.90 (m, 1H), 7.76 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 15.5 Hz, 1H), 6.49 (d, J = 14.9 Hz, 1H), 5.10 (d, J =
.3 Hz, 1H), 4.32 (m, 1H), 4.25 (d, J = 7.5 Hz, 1H), 3.92 (d, J = 14.3 Hz, 1H), 3.81 (dd, J = 1.2, 9.7 Hz,
1H), 3.58 (d, J = 10.7 Hz, 1H), 3.51 (d, J = 13.8 Hz, 1H), 3.35 (dd, J = 7.5, 10.3 Hz, 1H), 3.29-3.22
(complex m, 2H), 3.14 (t, J = 9.5, 1H), 3.09 (dd, J = 3.2, 10.0 Hz, 1H), 2.84 (m, 1H), 2.74 (m, 1H), 2.67
(m, 1H), 2.50 (s, 6H), 2.44-2.30 (complex m, 3H), 2.25 (s, 3H), 2.02 (d, J =16.6 Hz, 1H), 1.90-1.77
(complex m, 3H), 1.77 (s, 3H), 1.70-1.62 (complex m, 2H), 1.58-1.41 (complex m, 3H), 1.24 (d, J = 6.3
Hz, 3H), 1.22 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.3 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H). C NMR (125 MHz,
CD OD) d (ppm) : 206.3, 174.1, 148.9, 148.4, 147.2, 146.9, 145.4, 145.3, 136.7, 132.3, 132.1, 129.9,
129.8, 129.5, 129.3, 129.0, 124.3, 120.0, 105.7, 80.7, 77.8, 74.3, 72.6, 71.72, 71.66, 68.3, 56.0, 47.2,
46.6, 43.0, 42.9, 42.2 (2C), 40.3, 34.9, 34.1, 26.2, 25.4, 18.3, 17.8, 13.2, 9.8, 9.7, 5.1. HRMS (ESI) m/z:
931.3828 [M+H] , calcd for C H IN O : 931.3830.
44 64 6 8
YT769
To a solution of YT768 (20.0 mg, 21.5 µmol) in anhydrous acetonitrile (0.3 mL) was added piperidine
(21.5 µL, 0.215 mmol). The mixture was heated in a microwave reactor at 120 ℃ for 1.5 hours. Then
piperidine (42.0 µL, 0.430 mmol) was added again to the reaction mixture and the reaction was further
performed in a microwave reactor at 80 ℃ for 1 hour. The reaction mixture was concentrated in vacuo,
and the residue was purified by flash column chromatography on silica gel (CHCl /MeOH/NH ,
60/1/0.15) to give compound YT769 (17.0 mg, 89%) as a pale yellow solid. HRMS (FAB, NBA matrix)
m/z: 888.5588 [M+H] , calcd for C H N O : 888.5599.
49 74 7 8
YT770
To a solution of YT768 (80.0 mg, 85.9 µmol) in anhydrous acetonitrile (1.1 mL) was added
dimethylamine (40 wt% in water, 0.8 mL). The mixture was heated in a microwave reactor at 80 ℃ for 1
hour. The solvent mixture was concentrated in vacuo, and the residue was purified by flash column
chromatography on silica gel (CHCl /MeOH/NH , 60/1/0.15) to give YT770 (69.2 mg, 95%) as a pale
yellow solid. H NMR (500 MHz, CD OD) d (ppm) : 9.51(d, J = 2.9 Hz, 1H), 8.91 (d, J = 2.3 Hz, 1H),
8.19 (d, J = 8.6 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H) , 7.91 (m, 1H), 7.77 (m, 1H), 7.03 (d, J = 14.9 Hz, 1H),
6.44 (d, J = 15.5 Hz, 1H), 5.12 (d, J = 10.3 Hz, 1H), 4.26 (d, J = 7.5 Hz, 1H), 4.19 (m, 1H), 3.97 (d, J =
14.3 Hz, 1H), 3.85 (m, 1H), 3.60 (d, J = 10.3 Hz, 1H), 3.43 (d, J = 14.3 Hz, 1H), 3.36 (dd, J = 7.5 , 10.3
Hz, 1H), 3.26 (m, 1H), 3.26 (m, 1H), 3.15 (d, J = 9.5 Hz, 1H), 2.89 (m, 1H), 2.78-2.62 (complex m, 2H),
2.52 (s, 6H), 2.45-2.39 (complex m, 2H), 2.31 (m, 1H), 2.25 (s, 3H), 2.06-2.02 (m, 1H), 2.02(s, 6H),
1.94-1.74 (complex m, 4H), 1.78 (s, 3H), 1.73-1.66 (complex m, 2H), 1.63-1.40 (complex m, 3H), 1.25
(d, J = 6.3 Hz, 3H), 1.20 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.3 Hz, 3H), 0.84 (t, J = 7.5 Hz, 3H). C NMR
(125 MHz, CD OD) d (ppm) : 206.2, 174.3, 149.3, 148.6, 147.2, 146.1, 145.7, 135.9, 132.3, 132.1,
130.0, 129.9, 129.5 (2C), 129.0, 124.1, 119.3, 105.7, 80.5, 76.9, 74.3, 72.6, 71.73, 71.70, 68.4, 61.1,
56.1, 52.4, 46.7, 45.8 (2C), 44.0, 43.2, 43.0, 42.2 (2C), 40.2, 34.8, 33.8, 26.2, 26.1, 18.2, 17.8, 13.1, 9.8,
9.7. HRMS (FAB, NBA matrix) m/z: 848.5277 [M+H] , Calcd for C H N O : 848.5286.
46 70 7 8
YT771
To a solution of YT729 (90.0 mg, 0.106 mmol) in THF/H O (1.2/0.12 mL) was added PPh (94.4 mg,
0.361 mmol), and the reaction mixture was stirred at room temperature for 25 hr. The reaction mixture
was concentrated in vacuo and the residue was extracted with CHCl (5 mL × 2). The organic layers
were washed with brine (3 mL x 1), and dried over Na SO , and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (CHCl /MeOH/NH , 60/1/0.15) to give
compound YT771 (57.0 mg, 65%) as a colorless solid. HRMS (FAB, NBA matrix) m/z: 820.4973
[M+H] , calcd for C H N O : 820.4973.
44 66 7 8
Paper disc assays
(1) Antibacterial activities against Mannheimia and Pasteurella were determined by the following steps:
1) M.hemolytica KB345 (Tilmicosin-sensitivity strain) and M.hemolytica KB346 (Tilmicosin-
low sensitivity strain) were provided. KB 345 strain stored at -80 C was seeded to BHIB agar medium
(10 mL) by using Microbank beads (Pro-Lab) and platinum 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 C with shaking.
2) A paper disc (ADVANTEC, Φ:6 mm) was impregnated with a solution of test compound and
dried under reduced pressure.
3) To a melted BHIB agar medium was inoculated 1% of 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 one day, the inhibition zone diameter and clarity (A to E) were determined.
For KB346 strain, the same procedures were repeated.
The results of the assays are shown in Tables below:
Table 2. Mannhemia hemolytica KB345:
Inhibition zone (mm) and clarity (A to E)
mg/ 10 mg/ 3 mg/ 1 mg/
Sample 20-position substituent 6mm 6mm 6mm 6mm
disk disk disk disk
disk
Tylosin - 11.0A 10.5B - - -
Tilmicosin NT NT 16.0A 13.5A 10.7A
Tulathromycin - NT NT 18.0A 16.0A 12.5A
YT6 NT 10.5A - - -
YT7 - - - - -
Inhibition zone (mm) and clarity (A to E)
mg/ 10 mg/ 3 mg/ 1 mg/
Sample 20-position substituent 6mm 6mm 6mm 6mm
disk disk disk disk
disk
YT8 20.0A 18.0A 12.5A - -
YT11 18.0A 16.0A 13.0A 10.0A -
YT12 22.0A 19.0A 17.0A 13.0A 9.0A
YT13 21.0A 18.0A 16.0A 15.0A 11.0A
YT14 22.0A 19.5A 16.5A 14.0A 11.0A
YT16 19.0A 16.5A 14.5A 11.5A -
YT17 19.5A 18.0A 14.0A 12.0A -
N NH
YT18 19.5A 17.0A 14.5A 11.0A -
YT19 21.0A 18.0A 16.0A 14.0A NT
YT20 20.0A 17.5A 16.0A 11.5A 9.0B
YT21 19.0A 18.0A 15.5A 13.5A 11.5A
YT22 21.0A 18.0A 14.5A 11.5A 7.5B
N OEt
YT23 16.5A 14.5A 13.5A 10.0A 7.5B
YT24 18.0A 17.0A 14.5A 12.0A 8.5B
YT25 18.5A 17.0A 14.0A 12.0A 8.0A
YT26 16.0A 14.0A 11.5A 9.0A -
OC H
YT27 5 11 16.0A 13.0A 11.0A 9.0A -
YT28 19.0A 16.0A 13.0A 11.0A -
YT29 20.0A 17.5A 16.0A 13.5A -
YT30 10.0A - - - NT
Inhibition zone (mm) and clarity (A to E)
mg/ 10 mg/ 3 mg/ 1 mg/
Sample 20-position substituent 6mm 6mm 6mm 6mm
disk disk disk disk
disk
YT32 16.0A 14.0A 9.0A - NT
YT33 20.0A 17.0A 16.0A 13.0A NT
YT34 8 15.0A 14.0A 13.0A 11.0B NT
YT35 21.0A 19.0A 17.0A 14.0A NT
YT36 9.0A - - - NT
YT37 12.5A 9.0A - - NT
Table 3. Mannhemia hemolytica KB346
Inhibition zone (mm) and clarity (A to E)
mg/ 10 mg/ 3 mg/ 1 mg/
Sample 20-position substituent 6mm 6mm 6mm 6mm
disk disk disk disk
disk
Tylosin - 9.5 B - - - -
Tilmicosin NT NT 11.0 A - -
Tulathromycin - NT NT 14.0 A 12.0 A 9.5 A
YT6 21.0 A 17.5 A 13.5 A 8.5 A -
YT7 - - - - -
YT8 14.5 A 11.0 A - - -
YT11 11.0 A - - - -
YT12 16.0 A 12.0 A 9.0 B - -
YT13 15.0 A 12.0 A 8.0 B - -
YT14 17.0 A 12.0 A 9.0 B - -
YT16 14.0 A 11.0 A 7.0 B - -
YT17 13.0 A 9.0 A - - -
YT18 12.5 A 8.5 A - - -
Inhibition zone (mm) and clarity (A to E)
mg/ 10 mg/ 3 mg/ 1 mg/
Sample 20-position substituent 6mm 6mm 6mm 6mm
disk disk disk disk
disk
YT19 16.5 A 14.0 A 11.0 A 7.0 A -
YT20 17.5 A 14.0 A 10.5 A - -
YT21 17.0 A 14.0A 12.5A 9.0 A -
YT22 16.0 A 11.0 A 9.0 B - -
YT23 N 11.0 A 9.0 A - - -
YT24 9.0 B - - - -
YT25 12.5 A 8.5 A - - -
YT26 - - - - -
OC H
YT27 5 11 - - - - -
YT28 15.0 A 10.0 A - - -
YT29 11.0 A - - - -
YT30 10.0 A 8.0 B - - -
YT32 13.5 A 12.0 A 8.0 B - -
YT33 14.5 A 14.0 A - - -
YT34 8 - - - - -
YT35 14.5 A 13.5 A - - -
YT36 11.0 A 8.0 A - - -
YT37 - - - - -
Table 4. Mannhemia hemolytica KB345
Inhibition zone (mm) and clarity (A to E)
mg/6mm disk)
100 mg/ 30 mg/ 10 mg/ 3 mg/
-position 23-position 1 mg/
Sample 6mm 6mm 6mm 6mm
substituent substituent 6mm disk
disk disk disk disk
Tilmicosin - - NT 18.0 A 16.0 A 12.0 A
Tylosin - - 11.0 A 10.5 B - - -
YT106 15.0 A 12.5 A 8.5 A - -
YT111 I 25.0 A 20.0 A 15.5 A 11.5 A NT
YT107 N 21.5 A 18.0 A 16.0 A 12.0 A
CHO N
YT101 17.0 A 14.0 A 11.0 A - -
CHO N
YT102 15.0 A 11.5 A 9.0 A - -
YT103 16.0 A 14.0 A 12.0 A - -
CHO N
YT104 12.5 A 10.0 A 10.0 A 9.0 A -
CHO N
YT109 12.5 A 9.5 A - - -
YT110 11.5 A 9.0 A - - -
YT112 OH 29.0 A 25.0 A 20.0 A 17.0 A NT
YT113 I 19.5 A 18.0 A 11.0 A - NT
YT114 N 21.0 A 21.0 A 17.5 A 11.5 B NT
YT115 16.0 A 14.0 A 12.0 A - NT
YT116 17.0 A 17.0 A 13.0 A - NT
Table 5. Mannhemia hemolytica KB346
Inhibition zone (mm) and clarity (A to E)
mg/
100 mg/ 10 mg/ 3 mg/ 1 mg/
-position 23-position
Sample 6mm 6mm 6mm
substituent substituent
disk disk disk
6mm disk
disk
Tilmicosin
- - NT 11.0A - -
Tylosin
- - 11.0A 10.5B - - -
YT106 OH 17.0A 13.0A 9.0A - -
YT111
I 13.0A 8.5A - - -
YT107 N 15.0A 10.5A - - -
CHO N
YT101 - - - - -
CHO N
YT102 - - - - -
Inhibition zone (mm) and clarity (A to E)
mg/
100 mg/
mg/ 3 mg/ 1 mg/
-position 23-position
Sample 6mm 6mm 6mm
substituent substituent
disk disk disk
6mm disk
disk
YT103 - - - - -
CHO N
YT104 - - - - -
CHO N
YT109 9.0A - - - -
YT110 8.0A - - - -
YT112 OH 11.5A - - - -
YT113 - - - - -
YT114 N - - - - -
YT115 - - - - -
YT116 3 - - - - -
(2) Antibacterial activities against other bacteria were determined with Micrococcus luteus ATCC9341
(l), Bacillus subtilis ATCC663 (s), Escherichia coli NIHJ (c), Xanthomonas campestris KB88 (X),
Mucor racemosus IFO 4581 (Mu) and Candida albicans ATCC 64548 (Ca).
Bacillus subtilis ATCC6633 was incubated in Davis synthetic medium and then the seed broth was
combined with the medium in the ratio of 1:99 to obtain a test plate. Micrococcus luteus ATCC9341,
Escherichia coli NIHJ and Xanthomonas 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 inoculated at 0.3% and 0.2%.
A paper disc (ADVANTEC, Φ:6 mm) was impregnated with a solution 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 of the assays are shown in Table 6 below:
Table 6. Six bacteria
Inhibition zone(mm) and clarity
Sample 20-position mg/ S l c X Ca Mu
substituent 6mm disc
Tilmicosin 10 18 A 27.5 A 20 C 30 C − −
1 11 A 19 A 13 C 20 C − −
0.1 14 C 12 A − 12 C − −
YT12 N 10 14 A 25 A − 27 B − −
1 12.5 A 18.5 A − 12.5 B − −
0.1 7 A 12 A − 7 B − −
YT13 N 10 15.5 A 27.5 A − 23.5 B − −
1 12 A 21.5 A − 17 B − −
0.1 9.5 A 15 A − 8 B − −
YT14 10 15 A 26.5 A 7 B 22 B − −
1 11 A 20.5 A − 16 B − −
0.1 8 A 13.5 A − 7 B − −
YT19 10 15 A 26 A − 23 B − −
1 10.5 A 19 A − 14.5 B − −
0.1 7 A 13 A − 7 B − −
YT29 10 15 A 25.5 A − 24 B − −
1 10 A 19.5 A − 15 B − −
0.1 7 A 11 A − 7 B − −
Minimal inhibitory concentrations (MICs) were determined against the most prevalent pathogens in
cattle (Mannheimia Haemolytica, 3 isolates) and swine (A. pleuropneumoniae, 6 isolates).The results are
summarized in Table 7.
Table 7. MICs (µg/ml)
M.haemolytica pleuropneumoniae
isolate isolates
Compound 1 2 3 1 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
(3) Activity against bacterial mastitis pathogens
The activity of several compounds against bacterial mastitis pathogens has been tested under in-vitro
conditions according to a recognized procedure (CLSI, document M31-A3, 2008). In this test 7 to 12
representative bacteria belonging to 7 bacterial species that typically cause mastitis in dairy cattle, i.e.
Staphylococcus aureus, coagulase negative staphylococci (CNS), Streptococcus uberis, Streptococus
dysgalactiae, Streptococcus agalactiae, Arcanobacterium pyogenes and Escherichia coli, were exposed
to two-fold dilutions of the test compounds. After 24 hours of incubation the concentration that inhibited
the growth of this bacteria was determined. The results are shown in table 8 below. It could be shown
that all these bacterial mastitis pathogens were highly susceptible to the test compounds.
Table 8. Minimum inhibitory concentration (broth dilution method) inhibiting 50 % of a population
(MIC50, µg/mL) of 7 to 12 isolates belonging to 7 distinct mastitis-causing bacterial species
(Staphylococcus aureus, coagulase negative staphylococci [CNS], Streptococcus uberis, Streptococus
dysgalactiae, Streptococcus agalactiae, Arcanobacterium pyogenes and Escherichia coli)
S. Str Str Str A.
Compound aureus CNS uberis dysgalactiae agalactiae pyogenes E. coli
YT650 0.25 0.25 0.03 0.03 0.008 0.004 8
YT709 ≤0.03 ≤0.03 0.06 0.06 0.06 0.008 16
YT721 0.5 0.5 0.12 0.25 0.125 0.06 8
YT732 0.5 0.25 0.03 0.12 0.03 0.008 8
YT739 0.5 0.25 0.03 0.12 0.03 0.008 8
YT762 1 0.25 0.03 0.12 0.03 0.015 8
YT769 0.25 0.25 ≤0.015 ≤0.015 ≤0.015 ≤0.015 4
YT770 0.25 0.25 0.03 0.03 ≤0.015 ≤0.015 4
YT773 0.25 0.12 ≤0.015 ≤0.015 ≤0.015 ≤0.015 16
YT794 0.25 0.25 0.12 0.06 0.12 ≤0.015 ≥16
In addition the activity of several compounds was tested against two bacterial species, i.e. Mannheimia
haemolytica and Actinobacillus pleuropneumoniae, which are considered as the most important bacterial
respiratory pathogens in cattle and swine, respectively. As shown in table 9 below these compounds
were highly active against these respiratory pathogens.
Table 9. Range of minimum inhibitory concentrations (MIC, µg/mL, broth dilution method) against 3
Mannheimia haemolytica isolates and 6 Actinobacillus pleuropneumoniae isolates
Compound M. haemolytica A. pleuropneumoniae
YT617 2-8 4
YT653 1-8 4-8
YT657 2-4 2
YT664 4-8 2-8
YT674 2-4 2
YT679 4-8 2-4
YT700 4-8 8
YT705 8 8
YT709 2-4 2-4
YT710 2-4 4
YT717 2-8 4
YT718 2-8 8
YT721 1-4 8
YT723 2-8 8
YT726 8 8
YT732 1-4 2-4
YT733 2-4 4
YT734 2-4 2-4
The clinical efficacy of compound YT709 against mastitis caused by S. aureus was shown in lactating
mice according to a recognized published procedure (E. Brouillette, G. Grondin, C. Lefebvre, B.G.
Talbot, F. Malouin, Mouse mastitis model of infection for antimicrobial compound efficacy studies
against intracellular and extracellular forms of Staphylococcus aureus, Veterinary Microbiology, 101,
(2004), 253-262). Into the glands of lactating mice S. aureus bacteria (strain Newbould) were instilled
and allowed to multiply. Bacterium S. aureus Newbould is an isolate which was isolated from a clinical
case of bovine mastitis and which also causes typical mastitis infection in dairy cattle upon experimental,
intramammary infection. Four hours after the intramammary infection of lactating mice with S. aureus
Newbould, compound YT709 was instilled into the infected glands. Different intramammary dosages of
YT709 were tested and their efficacy compared to an infected, untreated control group. Fourteen hours
after intramammary application of YT709, the glands of the treated and untreated mice were removed,
homogenized and the number of S. aureus bacteria counted in 10-fold dilutions of the homogenized
8.64
glands. The mean S. aureus count of 8 untreated glands was 10 (8.64 log10) bacteria. The mean S.
.10
aureus count in 6 glands that had been treated with 200 microgram YT709 was 10 bacteria (5.10
log10). Hence in the glands treated with 200 microgram YT709 the number of bacteria was reduced
about 3500 fold. The mean S. aureus count in the 5 glands that had been treated with 400 microgram
2.34
YT709 was 10 bacteria (2.34 log10). Hence in the glands treated with 400 microgram YT-709 the
number of bacteria was reduced about two million fold. In the mice from which the lactating glands had
been treated with 400 microgram YT709, S. aureus bacteria could not be counted anymore in
measurable numbers and hence in 2 out of 5 glands the infection was cleared.
All references, patent applications and publications cited herein are hereby incorporated by reference in
its entirety.
In this specification where reference has been made to patent specifications, other external documents,
or other sources of information, this is generally for the purpose of providing a context for discussing the
features of the invention. Unless specifically stated otherwise, reference to such external documents is
not to be construed as an admission that such documents, or such sources of information, in any
jurisdiction, are prior art, or form part of the common general knowledge in the art.
Claims (11)
1. A compound represented by the formula (IIa): or a pharmaceutically acceptable salt, ester or solvate thereof; 5 wherein, R is hydroxyl; 11 12 R and R are each independently selected from hydrogen; -CHO; 10 C -C -X, wherein X is selected from the group consisting of hydroxyl or protected hydroxyl, halogen, and C -C -alkyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic; 15 C -C -alkenyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic; C -C -alkynyl, optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic; C -C - cycloalkyl; 3 14 20 substituted C -C -cycloalkyl; 3 14 aryl; substituted aryl; heterocyclic; substituted heterocyclic; 11 12 and wherein at least R or R is C -C -alkyl, substituted with a 1,2,3-triazole substituted at position 4 with one substituent selected from the group consisting of heterocyclic and substituted heterocyclic.
2. The compound of claim 1, wherein: 11 12 the other one of R or R is hydrogen or a C -C -alkyl, optionally substituted with one substituent selected from the group consisting of aryl and substituted aryl. 11 12 10
3. The compound of claim 2, wherein the other R or R is C -C -alkyl, optionally substituted with one substituent selected from the group consisting of aryl and substituted aryl. 11 12
4. The compound of claim 2, wherein the other R or R is hydrogen. 15
5. Use of the compound of any one of claims 1 to 4 in the manufacture of a medicament for use in the treatment or prevention of bacterial infections or disorders associated with bacterial infections in a human.
6. A method for treating or preventing bacterial infections or disorders associated with bacterial infections in a non-human animal, wherein the method comprises administering to the non-human animal a 20 therapeutically effective amount of the compound according to any one of claims 1 to 4.
7. A pharmaceutical or veterinary composition comprising a compound according to any one of claims 1 to 4 and at least one pharmaceutically acceptable carrier. 25
8. The compound of any one of claims 1 to 4, substantially as herein described with reference to any example thereof.
9. Use of claim 5, substantially as herein described with reference to any example thereof.
10. The method of claim 4, substantially as herein described with reference to any example thereof.
11. The pharmaceutical or veterinary composition of claim 5, substantially as herein described with 5 reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13169009.1 | 2013-05-23 | ||
EP13169009 | 2013-05-23 | ||
PCT/EP2014/060665 WO2014187957A1 (en) | 2013-05-23 | 2014-05-23 | Tylosin derivatives and method for preparation thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ714071A NZ714071A (en) | 2020-12-18 |
NZ714071B2 true NZ714071B2 (en) | 2021-03-19 |
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