WO2014187957A1 - Tylosin derivatives and method for preparation thereof - Google Patents
Tylosin derivatives and method for preparation thereof Download PDFInfo
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- WO2014187957A1 WO2014187957A1 PCT/EP2014/060665 EP2014060665W WO2014187957A1 WO 2014187957 A1 WO2014187957 A1 WO 2014187957A1 EP 2014060665 W EP2014060665 W EP 2014060665W WO 2014187957 A1 WO2014187957 A1 WO 2014187957A1
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- 0 CC(C[C@]1C)*C*1=* Chemical compound CC(C[C@]1C)*C*1=* 0.000 description 4
- PIKIOCLIZVRQTQ-UHFFFAOYSA-N CC(C(C[O]=C)C1[O]=C)OC1OC Chemical compound CC(C(C[O]=C)C1[O]=C)OC1OC PIKIOCLIZVRQTQ-UHFFFAOYSA-N 0.000 description 1
- XLTWPGIJBQABAC-JMXKONFFSA-N CCCCc1c[n](CC[C@H](C[C@@H](C)CCC(O[C@H](CC)[C@@H](CO[C@@H](C([C@H]2OC)OC)OC(C)[C@H]2O)/C=C(\C)/C=C2)=O)C[C@@H](C)C2=O)nn1 Chemical compound CCCCc1c[n](CC[C@H](C[C@@H](C)CCC(O[C@H](CC)[C@@H](CO[C@@H](C([C@H]2OC)OC)OC(C)[C@H]2O)/C=C(\C)/C=C2)=O)C[C@@H](C)C2=O)nn1 XLTWPGIJBQABAC-JMXKONFFSA-N 0.000 description 1
- VBVAINWXDGUYPN-TZXDXTJFSA-N CCCN(CCC(C)(C[C@@H](C)C(/C=C/C(C)C[C@H](CO)C(CC)O1)=O)/C=C(\C)/CCC1=O)CC1=CCCC=C1 Chemical compound CCCN(CCC(C)(C[C@@H](C)C(/C=C/C(C)C[C@H](CO)C(CC)O1)=O)/C=C(\C)/CCC1=O)CC1=CCCC=C1 VBVAINWXDGUYPN-TZXDXTJFSA-N 0.000 description 1
- YURIUWFXFUJYTR-WONSXVRQSA-N CC[C@H]([C@@H](C[n]1nnc(CNc2ccccc2N=N)c1)/C=C(\C)/C=C/C([C@H](C)C[C@H](CC=O)C([C@@H](C)[C@@H](C1)O)S[O](C(C)[C@@H]2O[C@H](C)[C@H]3O)OC2C3N(C)C)=O)OC1=O Chemical compound CC[C@H]([C@@H](C[n]1nnc(CNc2ccccc2N=N)c1)/C=C(\C)/C=C/C([C@H](C)C[C@H](CC=O)C([C@@H](C)[C@@H](C1)O)S[O](C(C)[C@@H]2O[C@H](C)[C@H]3O)OC2C3N(C)C)=O)OC1=O YURIUWFXFUJYTR-WONSXVRQSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
Definitions
- 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:
- Tylosin has been used for the treatment of infections of Gram-positive bacterium and Mycoplasma in farm animals.
- tylosin derivatives typically include among others tilmicosin and tulathromycin (tulathromycin belongs to a different class of compounds) represented by the following formulae, respectively:
- 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.
- Huisgen R. Pure Apple Chem. 1989, 61, 613-628.
- Huisgen R. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984, 1, 1-176.
- 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 s
- 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.
- the present invention provides compounds represented by the formula (Ila):
- R 11 andR 12 are each independently selected from hydrogen
- Ci-Ce- ⁇ wherein X is selected from the group consisting of hydroxyl or protected hydroxyl, halogen, and N3,
- Cl -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;
- R 11 and R 12 taken with the nitrogen atom to which they are connected form N3 or a 3- to 7- membered ring which may optionally contain a hetero function selected from the group consisting of - ⁇ -, -NH-, -N(Cl-C6-alkyl)-, -N(aryl) -, -N (heteroaryl)-, -S-, -S(O)- and-S(0) 2 -;C3-C14 cycloalkyl; and wherein R 5 is
- each Y is independently selected from the group consisting of hydrogen and Cl- C6-alkyl, or the two Y taken with the nitrogen atom to which they are connected form a 3- to 7- membered ring.
- the present invention provides compounds of said formula (Ila), wherein: R 5 is hydroxy. In another embodiment, the present invention provides compounds of said formula (Ila), wherein:
- R 11 or R 12 is Cl-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
- R 11 or R 12 is Cl-C6-alkyl, substituted with one substituent selected from the group consisting of heterocyclic and substituted heterocyclic, and wherein more preferably
- R 11 or R 12 is Cl-C3-alkyl, substituted with one substituent selected from the group consisting of heterocyclic and substituted heterocyclic, and wherein even more preferably
- R 11 or R 12 is Cl-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.
- the present invention provides compounds of said formula (Ila), wherein: one of R 11 and R 12 is Cl-C6-alkyl, substituted with one substituent selected from the group consisting of heterocyclic and substituted heterocyclic, and the other one of R 11 and R 12 is
- Cl-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
- R 11 or R 12 is Cl-C3-alkyl, substituted with one substituent selected from the group consisting of heterocyclic and substituted heterocyclic, and the other one of Rl 1 and R12 is
- Cl-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
- R 11 and R 12 is Cl-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 one of R 11 and R 12 is
- Cl-C2-alkyl optionally substituted with one substituent selected from the group consisting of aryl and substituted aryl.
- the present invention provides a method for preparing a compound of the formula (Ila):
- R 1 is as defined for R 11 and R 12 in the formula (Ila) above, and
- R 2 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
- R 1 is as defined for R 11 and R 12 in the formula (Ila) above, and
- R 2 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
- R-N3 wherein R is as defined for R 11 or R 12 in the formula (Ila) above, in the presence of a copper catalyst to form a compound of the formula (Ila); or (iii) reacting O-mycaminosyltylonolide (OMT):
- R 1 is as defined for R 11 and R 12 in the formula (Ila) above, and
- R 2 is Cl-C6-alkyl, bearing one N3-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
- R 1 is as defined for R 11 and R 12 in the formula (Ila) above, and
- R 2 is Cl-C6-alkyl, bearing one N3-substituent and being optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic
- the present invention provides a pharmaceutical or veterinary composition comprising the compound of the present invention.
- 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.
- compositions comprising the compound of formula (Ila) as mentioned before.
- These compositions, as well as the compounds of formula (Ila) 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.
- the present invention provides 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.
- the present invention provides compounds according to the embodiments as mentioned before for use as a medicament, preferably the compounds of formula (Ila) as mentioned before.
- 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 (Ila) 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.
- Cl-C3-alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals containing between one and three, one and six or one and twelve carbon atoms, respectively.
- C0-C3-alkyl means a bond or Cl-C3-alkyl.
- Cl-C3-alkyl radicals include methyl, ethyl, propyl and isopropyl
- C1-C6- alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n- butyl, tert-butyl, neopentyl and n-hexyl
- examples of Cl-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.
- C2-C6-alkenyl 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.
- 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.
- C2-C6- alkynyl examples include, but are not limited to, propynyl, isopentynyl, 1,3-hexadiynyl, n-hexynyl, 3- pentynyl, and l-hexen-3-ynyl.
- aryl 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.
- C3-C14-cycloalkyl 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.
- heteroaryl 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.
- heterocycloalkyl 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.
- heterocycles include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
- heterocyclic refers to heterocycloalkyl and heteroaryl.
- substituted heterocyclic refers to substituted heterocycloallcyl and substituted heteroaryl.
- substituted aryl refers to an aryl group, as defined herein, substituted by independent replacement of one or more of the hydrogen atoms therein with, for example, but not limited to, F, CI, Br, I, OH, N0 2 , CN, C(0)-Cl-C6-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 2 -alkyl, C0 2 - aryl, C0 2 -heteroaryl, CONH 2 , CONH-Cl-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(0)-Cl-C6- alkyl, OC(0)-aryl, OC(0)-heteroaryl, OC0 2 -alkyl, OC0 2 -aryl, OC0 2 -heteroaryl, OCONH 2 , OCONH- Cl-C6-alkyl, OCONH-aryl,
- substituted heteroaryl refers to a heteroaryl group as defined herein substituted by independent replacement of one or more of the hydrogen atoms therein with, for example, but not limited to, F, CI, Br, I, OH, N0 2 , CN, C(0)-Cl-C6-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 2 -alkyl, C0 2 -aryl, C0 2 -heteroaryl, CONH 2 , CONH-Cl-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(0)-Cl- C6-alkyl, OC(0)-aryl, OC(0)-heteroaryl, OC0 2 -alkyl, OC0 2 -aryl, OC0 2 -heteroaryl, OCONH 2 , OCONH-Cl-C6-alkyl, OCONH-aryl, OCONH-aryl, OCONH-
- substituted heterocycloalkyl refers to a heterocycloalkyl group, as defined above, substituted by independent replacement of one or more of the hydrogen atoms therein with, for example, but not limited to, F, CI, Br, I, OH, N0 2 , CN, C(0)-Cl-C6-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 2 -alkyl, C0 2 -aryl, C0 2 -heteroaryl, CONH 2 , CONH-Cl-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(0)-Cl-C6-alkyl, OC(0)-aryl, OC(0)-heteroaryl, OC0 2 -alkyl, OC0 2 -aryl, OC0 2 -heteroaryl, OCONH 2 , OCONH-Cl-C6-alkyl,
- substituted cycloalkyl refers to a cycloalkyl group, as defined above, substituted by independent replacement of one or more of the hydrogen atoms therein with, for example, but not limited to, F, CI, Br, I, OH, N0 2 , CN, C(0)-Cl-C6-alkyl, C(0)-aryl, C(0)-heteroaryl, C0 2 -alkyl, C0 2 -aryl, C0 2 -heteroaryl, CONH 2 , CONH-Cl-C6-alkyl, CONH-aryl, CONH-heteroaryl, OC(0)-Cl- C6-alkyl, OC(0)-aryl, OC(0)-heteroaryl, OC0 2 -alkyl, OC0 2 -aryl, OC0 2 -heteroaryl, OCONH 2 , OCONH-Cl-C6-alkyl,
- amino includes a group represented by -NH 2 .
- 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.
- “Hydroxy-protecting group” 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).
- hydroxy-protecting groups include, but are not limited to, methylthiomethyl, tert-dimethylsilyl, tert-butyldiphenylsilyl, acyl substituted with an aromatic group and the like.
- 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 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.
- aldehyde-protecting groups are 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.
- aldehyde-protecting groups include, but are not limited to, acetals, ketals, O-substituted cyanohydrins, substituted hydrazones, imines and the like.
- 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 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).
- 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.
- N i3 ⁇ 4-N-R b
- 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.
- R 5 , R 11 and R 12 are as defined above;
- R 1 is as defined for R 11 and R 12 in the formula (Ha) above, and
- R 2 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
- R 1 is as defined for R 11 and R 12 in the formula (Ha) above, and
- R 2 is Cl-C6-alkyl, bearing one N3-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
- A is CH2-hydroxy
- variable groups are as defined in the formula (I), with an azide selected from diphenylphosphoryl azide (DPPA) or sodium azide (NaNs) to form a compound of said formula (II) wherein A is CH2-N3 and the other variable groups are as defined in the formula (I); and
- DPPA diphenylphosphoryl azide
- NaNs sodium azide
- A is CH2-R' and R3, R4, R5, R' and R p are as defined above.
- R5 is R' and A, Rl, R2, R3, R4, R' and R p are as defined above;
- R5 is hydroxy
- the other variable groups are as defined in the formula (I), with an azide selected from diphenylphosphoryl azide (DPPA) or sodium azide (NaNs) to form a compound of said formula (II) wherein R5 is -N3 and the other variable groups are as defined in the formula (I); and (ii) reacting the resulting compound of the formula (II) wherein R5 is -N3 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),
- DPPA diphenylphosphoryl azide
- NaNs sodium azide
- R5 is R' and A, R3, R4, R' and R p are as defined above.
- the starting materials are commercially available or can be easily prepared a compound commercially available according to any know method.
- A is CH2-hydroxy
- the starting compounds of formula (II) may, if desired, be halogenized, for example with a halogenating agent such as h or CCLt in the presence of PPI13 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 CH2-halo or R5 is halogen is formed.
- a halogenating agent such as h or CCLt
- a solvent such as pyridine and/or dichloromethyl at -27 to 40°C, preferably 0°C to rt
- step (i) in the preparing methods above can be carried out by reacting azide such as diphenylphosphoryl azide (DPPA) or sodium azide (NaNs) 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.
- azide such as diphenylphosphoryl azide (DPPA) or sodium azide (NaNs)
- solvent such as THF or DMSO
- step (ii) and (iv) in the preparing methods for formula (I) and (lib) 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[(l-benzyl-lH-l,2,3-triazol-4- yl)methyl] amine (TBTA), in the presence of a copper catalysis for example CuSO r5H20, CuOTf- CeH6, [Cu(NCCH 3 ) 4 ] [PF 6 ] or Cul, preferably Cul at 0 to 100°C, preferably 10 to 40°C, more preferably rt.
- a solvent for example water, tert-butyl alcohol, methanol or acetonitrile or combination thereof, preferably in acetonitrile, preferably in the presence of tris[(l-benzyl-lH-l,2,3-triazol
- variable groups are as defined in the formula (I), but A is not -CHO, with a CH ⁇ C-(CH2) n -0- NH2-FIC1 wherein n is an integer from 1 to 3 to form a compound of the formula (III):
- n is an integer from 1 to 3 and A, R3, R4, R5 and R p are as defined in formula (I), provided that A is not -CHO; and
- step (ii) reacting the compound of the formula (III) resulting from step (i) or (ii) with an R-N3, wherein R is as defined in formula (I) above, in the presence of a copper catalyst to form a compound of the formula (I):
- 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.
- the introduction of an acetylene moiety of step (i) can be carried out by reacting a CH ⁇ C-(CH2)n-0-NH2-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.
- a solvent such as pyridine or methanol or combination thereof, preferably in the combination of pyridine and methanol
- reaction of step (ii) and (iv) for formula (I) and (lib) 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[(l-benzyl-lH-l,2,3-triazol-4- yl)methyl] amine (TBTA), in the presence of copper catalyst, for example CuSO r5H20, CuOTf-CeH6, [Cu(NCCH 3 ) 4 ][PF 6 ] or Cul, preferably Cul at 0 to 100°C, preferably 10 to 40°C, more preferably rt.
- solvent for example water, tert-butyl alcohol, methanol or acetonitrile or combination thereof, preferably in acetonitrile, preferably in the presence of tris[(l-benzyl-lH-l,2,3-triazol-4- yl)methyl]
- R-N3 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 °C to about 190°C, including, for example, from approximately -80°C to approximately 150°C, for example at from -80 to -60°C, at room temperature, at from -20 to 40°C or at reflux temperature, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, for example under argon or nitrogen
- 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- methylpyrrolidin-2-one, carboxylic acid anhydrides, such as lower alkanoic acid anhydrides, for example acetic anhydride
- Such solvent mixtures may also be used in working up, for example by chromatography or partitioning.
- protecting group 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.
- Salts of compounds of the present invention having at least one salt-forming group may be prepared in a manner known per se.
- 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.
- metal compounds such as alkali metal salts of suitable organic carboxylic acids, e.g., the sodium salt of 2-ethylhexanoic acid
- organic alkali metal or alkaline earth metal compounds such as the corresponding hydroxides, carbonates or hydrogen carbonates, such
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 s
- 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.
- 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.
- 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
- saprophyticus or Enterococcus spp. 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.
- MAC Mycobacterium avium complex
- 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.
- atherosclerosis related to infection by Helicobacter pylori or Chlamydia pneumoniae; or the like.
- 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 enteric disease related to infection by E. coli, Lawsonia intracellularis, Salmonella spp., or Serpulina hyodyisinteriae
- cow footrot related to infection by Fusobacterium spp.
- 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 (Ila) 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.
- 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.
- an effective amount of the compound of the invention 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.
- 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.
- pharmaceutical or veterinary composition includes preparations suitable for administration to mammals, e.g., farm animals such as cows.
- mammals e.g., farm animals such as cows.
- 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.
- 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.
- treat includes the diminishment or alleviation of at least one symptom associated or caused by the state, disorder or disease being treated.
- 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.
- treatment can be diminishment of one or several symptoms of a disorder or complete eradication of a disorder.
- 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.
- 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 ⁇ L ⁇ 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.
- SCC somatic cell count
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- a compound of the present invention 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.
- A is selected from the group consisting of:
- R7 and R8 are each independently selected from hydrogen, Cl-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 -0-, -NH-, -N(Cl-C6-alkyl)-, -N(
- Rl and R2 are each independently selected from the group consisting of:
- R3 is selected from the group consisting of:
- Cl-C6-alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, -0-R7 and -NR7R8 where R7 and R8 are as previously defined;
- C2-C6-alkenyl optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, -0-R7 and -NR7R8 where R7 and R8 are as previously defined; and
- C2-C6-alkynyl optionally substituted with one or more substitutents selected fron the group consisting of halogen, aryl, substituted aryl, heterocyclic, substituted heterocyclic, -0-R7 and -NR7R8 where R7 and R8 are as previously defined;
- R4 is -M-Y, where M is:
- Cl-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,
- 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,
- R5 is selected from the group consisting of:
- R p is hydrogen or a hydroxy protecting group
- each R' is independently [l,4]-epi-[l ,2,3]-triazoro-R; and where each R is independently selected from the group consisting of:
- Cl-C9-alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heterocyclic and substituted heterocyclic, -OR7 where R7 is as previously defined;
- At least one of A, Rl and R2 and R5 comprise R'.
- A is selected from halogen, CH2-N3, hydroxy, CHO, hydroxyCi-6alkyl, haloCi-6alkyl, methyl(3,5-di(Cl- C3-alkyl)-piperidino), CH 2 -R, and -CH 2 -NR7R8;
- R3 is H
- R4 is H
- R5 is selected from hydroxy, N3, halogen, 6-deoxy-2,3-di-0-methyl-b-d-allo-hexapyranosyloxy and R';
- R' is as defined above;
- At least one of A, Rl and R2 and R5 comprises R';
- A is CH 2 -R'or -CH 2 -NR7R8; Rl and R2 taken together are oxo;
- R3 is H
- R4 is H
- R5 is 6-deoxy-2,3-di-0-methyl-b-d-allo-hexapyranosyloxy.
- A is CHO or methyl(3,5-dimethylpiperidino)or -CH 2 NR7R8;
- R3 is H
- R4 is H
- R5 is R'.
- R3 is H
- R4 is H
- R5 is hydroxy. Furthermore, compounds of said formula (I) are disclosed, wherein;
- A is CHO, methyl(3,5-dimethylpiperidino), or -CH 2 -NR7R8;
- R3 is H
- R4 is H
- R5 is 6-deoxy-2,3-di-0-methyl-b-d-allo-hexapyranosyloxy.
- R is preferably selected from the group consisting of
- A is CH 2 -R' and Rl, R2, R3, R4, R5, R' and R p are as defined above; which method comprises following steps:
- A is CH2-hydroxy
- variable groups are as defined in the formula (I), with an azide selected from diphenylphosphoryl azide (DPPA) or sodium azide (NaNs) to form a compound of said formula (II) wherein A is CH2-N3 and the other variable groups are as defined in the formula (I); and
- DPPA diphenylphosphoryl azide
- NaNs sodium azide
- A is CH 2 -R' and R3, R4, R5, R' and R p are as defined above.
- R5 is R' and A, Rl, R2, R3, R4, R' and R p are as defined above;
- R5 is hydroxy
- variable groups are as defined in the formula (I), with an azide selected from diphenylphosphoryl azide (DPPA) or sodium azide (NaNs) to form a compound of said formula (II) wherein R5 is -N3 and the other variable groups are as defined in the formula (I); and
- DPPA diphenylphosphoryl azide
- NaNs sodium azide
- R5 is R' and A, R3, R4, R and R p are as defined above.
- variable groups are as defined in the formula (I), but A is not -CHO, with a CH ⁇ C-(CH2) n -0- NH 2 -HC1 wherein n is an integer from 1 to 3 to form a compound of the formula (III):
- step (ii) reacting the compound of the formula (III) resulting from step (i) or (ii) with an R-N3, wherein R is as defined in formula (I) above, in the presence of a copper catalyst to form a compound of the formula (I):
- Infrared (IR) absorption spectra were determined by using Horiba FT-210 spectrometer. 3 ⁇ 4 NMR spectra were determined by using JEOL JNM-EX270 (270 MHz), VALIAN-400 NMR System (400 MHz). 13 C NMR spectra were determined by using JEOL JNM-EX270 (67.5 MHz), VARIAN- 400 NMR system (100 MHz).
- TLC thin-layer chromatography
- Tylosin (20. Og, 21.8 mmol) was dissolved in 0.2N HCl aq. (340 mL) and then the mixture was stirred at 35°C for 2 hours. After confirming complete consumption of the starting material, the reaction mixture was neutralized by adding IN NaOH aq., extracted with CHCI3 and dried over Na2S04. The solvent was removed under reduced-pressure to obtain quantitative amount of desmycosin (YT6).
- the step (5) above was repeated to obtain the 20-triazole-20- deoxodesmycosins, which are shown below.
- Tylosin (9.16 g, 10.0 mmol) was dissolved to 0.5 M TFA solution (300 mL) and then the mixture was stirred for 5 hours at 100°C. After confirming complete consumption of the starting material, the reaction mixture was neutralized by adding NaHC03 sat. aq., extracted with CHCI3 and dried over Na2S04. 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-azido-23-deoxo-5-Q-mycaminosyltylonolide (YT107)
- YT13 (0.5 g, 0.56 mmol) was dissolved in HBr (3.0 niL) 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 NaHC03 sat. aq., extracted with CHCI3 and dried over Na2SO i. The solvent was removed under reduced pressure. The resulting products were purified by flash column chromatography to obtain YTl 12 (Yield: 39%).
- YT711 (100.0 mg, 0.138 mmol) with 3-azidoquinoline (30.4 mg, 0.179 mmol) was converted to YT709 (113.9 mg, 92%) as a colorless solid.
- 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.
- 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.
- 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 a colorless solid.
- 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.
- 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.
- YT768 a solution of YT768 (80.0 mg, 85.9 ⁇ ) 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°C for 1 hour. The solvent mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (CHCl 3 /MeOH/NH 3 , 60/1/0.15) to give YT770 (69.2 mg, 95%) as a pale yellow solid.
- 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
- a paper disc (ADVANTEC, ⁇ :6 mm) was impregnated with a solution of test compound and dried under reduced pressure.
- step 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.
- Micrococcus luteus ATCC9341 (1), 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, ⁇ :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.
- MICs Minimal inhibitory concentrations 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.
- 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.
- 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 glands. The mean S.
- aureus count of 8 untreated glands was 10 8'64 (8.64 loglO) bacteria.
- the mean S. aureus count in 6 glands that had been treated with 200 microgram YT709 was lO 5 10 bacteria (5.10 log 10). 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 YT709 was lO 2 34 bacteria (2.34 loglO). 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.
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Priority Applications (21)
Application Number | Priority Date | Filing Date | Title |
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NZ714071A NZ714071B2 (en) | 2013-05-23 | 2014-05-23 | Tylosin derivatives and method for preparation thereof |
DK14725726.5T DK2999707T3 (en) | 2013-05-23 | 2014-05-23 | Tylosin derivatives and process for their preparation. |
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US10758623B2 (en) | 2013-12-09 | 2020-09-01 | Durect Corporation | Pharmaceutically active agent complexes, polymer complexes, and compositions and methods involving the same |
WO2023230702A1 (en) * | 2022-06-03 | 2023-12-07 | University Of Manitoba | Novel antimicrobial compounds isolated using a machine learning model trained on a high-throughput antibacterial screen |
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CN110590885A (en) * | 2019-09-30 | 2019-12-20 | 郑州大学 | 20-substituted-5-O-mycaminosyl-tylonolide derivatives |
CN112898361A (en) * | 2021-02-01 | 2021-06-04 | 郑州大学 | 5-O-mycylamine glycosyl tylosin lactone derivative and preparation method and application thereof |
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