WO1999021869A1 - Erythromycin a, 11,12-carbamate derivatives - Google Patents
Erythromycin a, 11,12-carbamate derivatives Download PDFInfo
- Publication number
- WO1999021869A1 WO1999021869A1 PCT/JP1998/004876 JP9804876W WO9921869A1 WO 1999021869 A1 WO1999021869 A1 WO 1999021869A1 JP 9804876 W JP9804876 W JP 9804876W WO 9921869 A1 WO9921869 A1 WO 9921869A1
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- WO
- WIPO (PCT)
- Prior art keywords
- group
- carbon atoms
- mmol
- pyridyl
- amino
- Prior art date
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- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 title claims abstract description 28
- 229960003276 erythromycin Drugs 0.000 title abstract description 14
- 229930006677 Erythromycin A Natural products 0.000 title description 8
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 44
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 15
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 claims abstract description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 84
- 238000000034 method Methods 0.000 claims description 76
- 125000004432 carbon atom Chemical group C* 0.000 claims description 66
- -1 dibenzofuranyl group Chemical group 0.000 claims description 58
- 125000004076 pyridyl group Chemical group 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 19
- 125000003277 amino group Chemical group 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000005493 quinolyl group Chemical group 0.000 claims description 10
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 208000035473 Communicable disease Diseases 0.000 claims description 5
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000000335 thiazolyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 claims description 2
- 125000001326 naphthylalkyl group Chemical group 0.000 claims description 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 2
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 241000894006 Bacteria Species 0.000 abstract description 9
- 125000004043 oxo group Chemical group O=* 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 178
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 112
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 106
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 87
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 69
- 239000000243 solution Substances 0.000 description 63
- 239000000460 chlorine Substances 0.000 description 58
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 51
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 238000005160 1H NMR spectroscopy Methods 0.000 description 43
- 238000006243 chemical reaction Methods 0.000 description 43
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 32
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- 238000003756 stirring Methods 0.000 description 22
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- 238000005481 NMR spectroscopy Methods 0.000 description 20
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 13
- 238000001816 cooling Methods 0.000 description 13
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
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- 239000012442 inert solvent Substances 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
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- CDRNYKLYADJTMN-UHFFFAOYSA-N pyridine-3-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CN=C1 CDRNYKLYADJTMN-UHFFFAOYSA-N 0.000 description 8
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- 238000000746 purification Methods 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
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- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 6
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- NXGKPRKPUCSEIL-UHFFFAOYSA-N 2-acetamido-4-methyl-1,3-thiazole-5-sulfonyl chloride Chemical compound CC(=O)NC1=NC(C)=C(S(Cl)(=O)=O)S1 NXGKPRKPUCSEIL-UHFFFAOYSA-N 0.000 description 5
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
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- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 239000002253 acid Substances 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
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- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
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- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
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- 125000001309 chloro group Chemical group Cl* 0.000 description 1
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- ULCKEERECJMLHP-UHFFFAOYSA-N dibenzofuran-2-sulfonyl chloride Chemical compound C1=CC=C2C3=CC(S(=O)(=O)Cl)=CC=C3OC2=C1 ULCKEERECJMLHP-UHFFFAOYSA-N 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
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- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- HDOUGSFASVGDCS-UHFFFAOYSA-N pyridin-3-ylmethanamine Chemical compound NCC1=CC=CN=C1 HDOUGSFASVGDCS-UHFFFAOYSA-N 0.000 description 1
- DVECLMOWYVDJRM-UHFFFAOYSA-N pyridine-3-sulfonic acid Chemical compound OS(=O)(=O)C1=CC=CN=C1 DVECLMOWYVDJRM-UHFFFAOYSA-N 0.000 description 1
- NRTYMEPCRDJMPZ-UHFFFAOYSA-N pyridine;2,2,2-trifluoroacetic acid Chemical compound C1=CC=NC=C1.OC(=O)C(F)(F)F NRTYMEPCRDJMPZ-UHFFFAOYSA-N 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
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- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- VNNLHYZDXIBHKZ-UHFFFAOYSA-N thiophene-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CS1 VNNLHYZDXIBHKZ-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- 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
Definitions
- the present invention relates to novel derivatives of antibiotic erythromycin A.
- Erythromycin A is an antibiotic clinically widely used as an agent for treating infectious diseases caused by Gram-positive bacteria, mycoplasmas, etc.
- erythromycin A is decomposed by the gastric acid due to instability to acids, and thereby has a drawback of no constancy of movement in the body.
- Hitherto many erythromycin A derivatives have been prepared for the purpose of the improvement of the biological or pharmacological properties. For example, it is reported that 6-O-methylerythromycin A derivatives have an improved stability to acids and have a superior in vivo antibacterial activity in comparison with erythromycin A when administered orally (U.S. Patent No. 4331803).
- An object of the present invention is to provide post-generational macrolide antibiotics having a strong antibacterial activity against not only known erythromycin-sensitive bacteria but also erythromycin- resistant bacteria which recently are showing a tendency to increase.
- the present inventors have found that the compounds which can be produced by introducing a sulfonamide group onto the alkyl group attached to the nitrogen atom of the 11,12-cyclic carbamate of erythromycin A and converting 3 -position of the erythromycin A have a strong antibacterial activity against not only erythromycin-sensitive bacteria but also erythromycin-resistant bacteria, and thus the present invention has been accomplished.
- the present invention relates to an erythromycin A derivative represented by the formula:
- R! is a group represented by the formula: -S ⁇ 2N(-R 7 )-R 8 wherein R 7 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a phenyl group, a phenyl group substituted by a nitro group or an alkoxy group having 1 to 3 carbon atoms, a pyridyl group, a pyridyl group substituted by 1 or 2 members selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; a halogen atom; an alkoxy group having 1 to 3 carbon atoms; a nitro group; an amino group; a cyano group and an amino group substituted by an alkyl group having 1 to 6 carbon atoms, a quinolyl group, or a c ⁇ uinolyl group substituted by 1 or 2 members selected from the group consisting of an alkyl group having 1 to 6 carbon atoms;
- a phenyl group a phenyl group substituted by 1 to 5 members selected from the group consisting of a hydroxyl group; a methylsulfonyl group; an alkyl group having 1 to 6 carbon atoms ; an alkoxy group having 1 to 3 carbon atoms; a nitro group; an amino group; a cyano group; a dimethylamino group; an acetylamino group; a pyridyl group; a trifluoromethyl group; a trifluoromethoxy group and a halogen atom, a pyridyl group, a pyridyl group substituted by 1 or 2 members selected from the group consisting of a hydroxyl group; an alkyl group having 1 to 6 carbon atoms; an alkoxy group having 1 to 3 carbon atoms; a nitro group; an amino group; a cyano group; a dimethylamino group; an acetylamino group;
- R3 is a group represented by the formula:
- R 1 ! is a pyridylmethyl group, a methylthiomethyl group, a quinolyl group, a phenyl group, a phenyl group substituted by 1 to 5 members selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; a nitro group; an alkoxy group having 1 to 3 carbon atoms and a halogen atom, a pyridyl group, or a pyridyl group substituted by 1 or 2 members selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; a nitro group; an alkoxy group having 1 to 3 carbon atoms and a halogen atom,
- R4 is a hydrogen atom, or R ⁇ and R ⁇ together form an oxo grou , and
- R5 and R ⁇ are the same or different, and are each a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof.
- examples of the alkyl group having 1 to 6 carbon atoms are a methyl group, an ethyl group, a propyl group, a butyl group, a 3- methylbutyl group and a cyclohexyl group;
- examples of the alkoxy group having 1 to 3 carbon atoms are a methoxy group, an ethoxy group, a propoxy group and an isopopoxy group;
- the halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
- the pharmaceutically acceptable salt refers to a salt used in chemotherapy or prophylaxis of bacterially infectious diseases, for example, a salt with acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethylsuccinic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, laurylsulfuric acid, malic acid, aspartic acid, glutaminic acid, adipic acid, cysteine, N-acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid,
- the compounds of the present invention can be prepared, for example, according to the following reaction scheme.
- the inert solvent to be used here are dichloromethane, dichloroethane, acetone and tetrahydrofuran.
- Step (2) The compound of Formula (a) is treated with a base in an inert solvent at a temperature of from room temperature to 120°C to give a compound of Formula (b) .
- the inert solvent to be used here are N,N-dimethylformamide, dimethyl sulfoxide, N- methylpiperidone, tetrahydrofuran and a mixture thereof, and examples of the base to be used here are 1,1,3,3- tetramethylguanidine and potassium carbonate.
- Step (3) The compound of Formula (b) is treated with a reagent of the following formula:
- a base such as 4-dimethylaminopyridine
- Examples of the activating agent to be used herein are 1, 3-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) - 3-ethylcarbodiimide hydrochloride and pivaloyl chloride.
- Examples of the inert solvent to be used here are dichloromethane, dichloroethane, acetone, pyridine, ethyl acetate and tetrahydrofuran.
- Step (4) The compound of Formula (c) is reacted with 1, 1 ' -carbonyldiimidazole in an inert solvent under the presence of a base such as sodium hydride to give a compound of Formula (d) .
- the inert solvent is the same as used in Step (3) .
- Step (5) The compound of Formula (d) is reacted in an inert solvent with an amine compound of the following formula:
- n, R ⁇ and R ⁇ are as defined above, and then is deprotected at the 2 '-position by an ordinary methanolysis to give a compound of Formula (e) .
- the inert solvent to be used here are acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, ethyl acetate, N-methylpyrrolidone, a mixture of the solvent and water and a mixture thereof .
- Step (6) The compound of Formula (e) is reacted with a reagent of the following formula: R 9 S0 2 C1 wherein R 9 is as defined above, in an inert solvent in the presence of a base such as pyridine, to give a compound of Formula (f) which is a compound of the present invention.
- the inert solvent is the same as used in Step (3).
- the compounds of the present invention can be administered orally or parenterally in the dosage form such as, for example, tablets, capsules, powders, troches, ointments, suspensions, suppositories and injections, all of which can be prepared according to conventional preparation techniques.
- the dose of the present compounds for treating an adult is from 100 to 1000 mg/day in single or several divided doses. This dose can be increased or decreased depending on the age, body weight and conditions of the patient.
- Example 1 11— T2- f (4-Acetaminophenyl) sulfonylaminol - ethyl! amino-11-deoxy-3-O- (2-pyridyl) acetyl-5-O- desosaminyl-6-O-methylervthronolide A 11.12-cvclic carbamate (1) To a solution of 1.38 g (2.1 mmol) of the compound obtained in Reference Example 1 in 30 ml of a mixture of methylene chloride and pyridine was added 0.59 g (2.5 mmol) of p-acetamidobenzenesulfonyl chloride under ice-cooling, followed by stirring for 1.5 hours at room temperature.
- the reaction solution was diluted with ethyl acetate, and washed with an aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution respectively.
- the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2.07 g of 11- [2- [ (4-acetaminophenyl) sulfonylamino] -ethyl] amino-11- deoxy-5-0-desosaminyl-6-0-methyl-erythronolide A 11,12- cyclic carbamate.
- the reaction solution was diluted with ethyl acetate, and washed with an aqueous sodium hydroxide solution, a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution successively.
- the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 1.06g of the residue, which was then dissolved in 20 ml of methanol and stirred at room temperature overnight.
- Example 7 11- r2- (Benzo-2.1.3-thiadiazole-4-sulfonyl- amino) ethyll amino-ll-deoxy-3-O- (2-pyridyl) acet ⁇ l-5-O- desosaminyl-6-O-methylervthronolide A 11,12-cvclic carbamate
- reaction solution was diluted with ethyl acetate and washed with distilled water and a saturated aqueous sodium chloride solution successively.
- the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give 7.1 g of 2 ' -O-acetyl-11- (2-aminoethyl) - amino-3 , ll-dideoxy-3-oxo-5-0-desosaminyl-6-0-methyl- erythronolide A 11,12-cyclic carbamate.
- Example 10(6) Following the same procedure as in Example 10(6) using 0.51 g (0.66 mmol) of the compound obtained in Example 10(5) and 0.06 ml (0.79 mmol) of methanesulfonyl chloride, there was obtained 0.45 g (yield: 80 %) of the title compound.
- Example 21 11- ⁇ 2- (2-Mesitylenesulfonylamino) ethyl! a ino- ll-deoxy-3-O- (2-Pyridyl) acetyl-5-0-desosamin ⁇ l-6-0- methylerythronolide A 11,12-cyclic carbamate
- Example 10(6) Following the same procedure as in Example 10(6) using 0.53 g (0.68 mmol) of the compound obtained in Example 10(5) and 0.21 g (0.82 mmol) of 2-(l- naphthyl) ethanesulfonyl chloride, there was obtained 0.38 g (yield: 56 %) of the title compound.
- Example 10(6) Following the same procedure as in Example 10(6) using 1.0 g (1.3 mmol) of the compound obtained in Example 10(5) and 0.69 g of pyridine-3-sulfonyl chloride described in the following Reference Example 2, there was obtained 0.20 g (yield: 17 %) of the title compound.
- Example 10(6) Following the same procedure as in Example 10(6) using 0.53 g (0.69 mmol) of the compound obtained in Example 10(5) and 0.15 g (0.80 mmol) of p-toluene- sulfonyl chloride, there was obtained 0.40 g (yield: 63 %) of the title compound.
- Example 10(6) Following the same procedure as in Example 10(6) using 0.65 g (0.84 mmol) of the compound obtained in Example 10(5) and 0.26 g (1.0 mmol) of 4- (trifluoro- methoxy) benzenesulfonyl chloride, there was obtained 0.36 g (yield: 43 %) of the title compound.
- Example 10(6) Following the same procedure as in Example 10(6) using 0.52 g (0.67 mmol) of the compound obtained in Example 10(5) and 0.20 g (0.82 mmol) of 4- (trifluoromethyl) benzenesulfonyl chloride, there was obtained 0.45 g (yield: 68 %) of the title compound.
- Example 34 11- ⁇ 2 - (N-Phenylsulfamoyl) ethyl lamino-3.11- dideoxy-3 -oxo-5-O-desosaminyl-6-O-methylervthronolide A
- Example 33 Following the same procedure as in Example 33 using 0.38 g (0.50 mmol) of the compound obtained in Example 12(3), 1.0 g (5.0 mmol) of 2-aminoethyl- sulfonanilide described in Reference Example 3 , there was obtained 0.34 g (yield: 85 %) of the title compound.
- Example 38 11- ⁇ 2 - (3-P ⁇ ridylsulfon ⁇ lamino) ethyll a ino-
- Example 10(6) Following the same procedure as in Example 10(6) using 0.55 g (0.71 mmol) of the compound obtained in Example 10(5) and 0.26 g (0.85 mmol) of 5- [2- (methylthio)pyrimidin-4-yl] thiophene-2-sulfonyl chloride, there was obtained 0.50 g (yield: 67 %) of the title compound.
- Example 41 11- ⁇ 2 - (5-Chloro-3-methylbenzo[b1 thiophene-2- sulfonylamino) ethyll amino-ll-deoxy-3-0- (2-pyridyl) - acetyl-5-0-desosaminyl-6-0-meth ⁇ lervthronolide A 11,12- cvclic carbamate
- Example 10(6) Following the same procedure as in Example 10(6) using 0.51 g (0.65 mmol) of the compound obtained in Example 10(5) and 0.22 g (0.78 mmol) of 5-chloro-3- methylbenzo [b] thiophene-2-sulfonyl chloride, there was obtained 0.45 g (yield: 67%) of the title compound.
- Example 48 11- ⁇ 2 - (4-Nitrobenzenesulfonylamino) butyll amino- ll-deoxy-3-O- (2-pyridyl) acetyl-5-0-desosamin ⁇ l-6-0- methylerythronolide A 11,12-cyclic carbamate
- Example 10(5) Following the same procedure as in Example 10(5) using 5.0 g (6.1 mmol) of the compound obtained in Example 10(4) and 6.1 ml (61 mmol) of 1, 4-diaminopropane, there was obtained 4.9 g of 11- (3-aminobutyl)amino-ll- deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-0- methylerythronolide A 11,12-cyclic carbamate.
- Example 53 11- ⁇ 2- (2-Methylsulfonylbenzenesulfonylamino) - ethyl! amino-3 , ll-dideoxy-3-oxo-5-0-desosaminyl-6-0- methylervthronolide A 11.12-cvclic carbamate
- Example 10(5) Following the same procedure as in Example 10(5) using 5.0 g (6.1 mmol) of the compound obtained in Example 10(4) and 4.5 g (61 mmol) of 1, 3-diaminopropane, there was obtained 4.5 g of 11- (3-aminopropyl) amino-11- deoxy-3-O- (2-pyridyl)acetyl-5-0-desosaminyl-6-0- methylerythronolide A 11,12-cyclic carbamate.
- Example 58 11- [3- (3 -Pyridylsulfonyl) aminopropyll amino-11- deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-Q- methylervthronolide A 11,12-cvclic carbamate
- Example 59 11- r3 - r (2-Acetamido-4-methyl-5- thiazolesulfonyl) aminolprop l! amino-3. ll-dideoxy-3-oxo- 5-0-desosaminyl-6-0-methylervthronolide A 11.12-cvclic carbamate (1)
- Example 10(5) using 2.0 g (2.8 mmol) of the compound obtained in Example 12(3) and 2.1 g (28 mmol) of 1, 3-diaminopropane, there was obtained 2.0 g of 11- (3-aminopropyl) amino- 3 , ll-dideoxy-3-oxo-5-0-desosaminyl-6-0- methylerythronolide A 11,12-cyclic carbamate.
- Example 65 11- r2- r (2-Nitrophenyl) sulfonylamino1 - ethyl! amino-ll-deoxy-3-O- (3-pyridyloxy) carbonyl-5-O- desosaminyl-6-O-methylerythronolide A 11,12-cyclic carbamate
- a solution of 2.2 g (2.5 mmol) of the compound obtained in Example 3(1) in 10 ml of pyridine was added dropwise a solution of 0.74 g (2.5 mmol) of triphosgene in 10 ml of methylene chloride under ice- cooling, followed by stirring for 30 minutes.
- Example 13 The in vitro antibacterial activity of the compound obtained in Example 13 as an example of the compound of the present invention against various experimental bacteria was measured using sensitive disc media (produced by Eiken Chemical Co.) according to the MIC measuring method specified by the Japan Society of Chemotherapy. The results are expressed as MIC value
- the compounds of the present invention have a strong antibacterial activity against not only erythromycin-sensitive bacteria but also erythromycin- resistant bacteria. Therefore, the compounds of the present invention are useful as antibacterial agents for the treatment of bacterially infectious diseases in human beings and animals (including farm animals) .
Abstract
An erythromycin A derivative represented by formula (I) wherein n is an integer of 1 to 7, R1 is a group represented by the formula: -SO¿2?N(-R?7)-R8¿ or N-(R10)SO2R9, R2 is a hydrogen atom, an alkyl group or a cinnamyl group, R3 is a group represented by the formula: -OCO-CH¿2-R?11, -OCO-R11, -OCO-NH-R?11, -O-R11¿ or -OCO-O-R11, R4 is a hydrogen atom, or R?3 and R4¿ together form an oxo group, and R?5 and R6¿ are each a hydrogen atom or an alkyl group, or a pharmaceutically acceptable salt thereof has a strong antibacterial activity against not only known erythromycin-sensitive bacteria but also erythromycin-resistant bacteria.
Description
DESCRIPTION ERYTHROMYCIN A, 11,12-CARBAMATE DERIVATIVES
TECHNICAL FIELD
The present invention relates to novel derivatives of antibiotic erythromycin A.
BACKGROUND ART Erythromycin A is an antibiotic clinically widely used as an agent for treating infectious diseases caused by Gram-positive bacteria, mycoplasmas, etc. However, erythromycin A is decomposed by the gastric acid due to instability to acids, and thereby has a drawback of no constancy of movement in the body. Hitherto many erythromycin A derivatives have been prepared for the purpose of the improvement of the biological or pharmacological properties. For example, it is reported that 6-O-methylerythromycin A derivatives have an improved stability to acids and have a superior in vivo antibacterial activity in comparison with erythromycin A when administered orally (U.S. Patent No. 4331803). Recently, it is also reported that 11,12- cyclic carbamate derivatives are prepared from 6-0- methylerythromycin A as a starting material with the aim of expansion of antibacterial spectrum as well as stability to acids (EP. patent No. 487411 and US. Patent No. 4742049). In addition, the antibacterial activities
of the ester derivatives at the 3 -position are also reported by some of the present inventors (EP. patent No.619320) .
An object of the present invention is to provide post-generational macrolide antibiotics having a strong antibacterial activity against not only known erythromycin-sensitive bacteria but also erythromycin- resistant bacteria which recently are showing a tendency to increase.
DISCLOSURE OF THE INVENTION
The present inventors have found that the compounds which can be produced by introducing a sulfonamide group onto the alkyl group attached to the nitrogen atom of the 11,12-cyclic carbamate of erythromycin A and converting 3 -position of the erythromycin A have a strong antibacterial activity against not only erythromycin-sensitive bacteria but also erythromycin-resistant bacteria, and thus the present invention has been accomplished.
The present invention relates to an erythromycin A derivative represented by the formula:
R3 is a group represented by the formula:
-OCO-CH2-R11 a group represented by the formula: -OCO-R11 a group represented by the formula: -OCO-NH-R11 a group represented by the formula:
-O-R11 or a group represented by the formula: -OCO-O-R11 wherein R1! is a pyridylmethyl group, a methylthiomethyl group, a quinolyl group, a phenyl group, a phenyl group substituted by 1 to 5 members selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; a nitro group; an alkoxy group having 1 to 3 carbon atoms and a halogen atom, a pyridyl group, or a pyridyl group substituted by 1 or 2 members selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; a nitro group; an alkoxy group having 1 to 3 carbon atoms and a halogen atom,
R4 is a hydrogen atom, or R^ and R^ together form an oxo grou , and
R5 and R^ are the same or different, and are each a
hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof.
In the present invention, examples of the alkyl group having 1 to 6 carbon atoms are a methyl group, an ethyl group, a propyl group, a butyl group, a 3- methylbutyl group and a cyclohexyl group; examples of the alkoxy group having 1 to 3 carbon atoms are a methoxy group, an ethoxy group, a propoxy group and an isopopoxy group; and the halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
The pharmaceutically acceptable salt refers to a salt used in chemotherapy or prophylaxis of bacterially infectious diseases, for example, a salt with acetic acid, propionic acid, butyric acid, formic acid, trifluoroacetic acid, maleic acid, tartaric acid, citric acid, stearic acid, succinic acid, ethylsuccinic acid, lactobionic acid, gluconic acid, glucoheptonic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, laurylsulfuric acid, malic acid, aspartic acid, glutaminic acid, adipic acid, cysteine, N-acetylcysteine, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, hydroiodic acid, nicotinic acid, oxalic acid, picric acid, thiocyanic acid, undecanoic acid, polyacrylate or carboxyvinyl polymer .
The compounds of the present invention can be
prepared, for example, according to the following reaction scheme.
Step (2); The compound of Formula (a) is treated with a base in an inert solvent at a temperature of from room temperature to 120°C to give a compound of Formula (b) . Examples of the inert solvent to be used here are N,N-dimethylformamide, dimethyl sulfoxide, N- methylpiperidone, tetrahydrofuran and a mixture thereof, and examples of the base to be used here are 1,1,3,3- tetramethylguanidine and potassium carbonate.
Step (3); The compound of Formula (b) is treated with a reagent of the following formula:
R1:L-CH2C00H wherein RU is as defined above, and an activating agent thereof in an inert solvent in the presence of a base such as 4-dimethylaminopyridine at a temperature of from -30°C to 30°C to give a compound of Formula (c) . Examples of the activating agent to be used herein are 1, 3-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) - 3-ethylcarbodiimide hydrochloride and pivaloyl chloride. Examples of the inert solvent to be used here are dichloromethane, dichloroethane, acetone, pyridine, ethyl acetate and tetrahydrofuran.
Step (4) ; The compound of Formula (c) is reacted with 1, 1 ' -carbonyldiimidazole in an inert solvent under the presence of a base such as sodium hydride to give a compound of Formula (d) . The inert solvent is the same as used in Step (3) .
Step (5) ; The compound of Formula (d) is reacted in an inert solvent with an amine compound of the following formula:
R5
I H2N- (CH2) n-C-NH2
R«
wherein n, R^ and R^ are as defined above, and then is deprotected at the 2 '-position by an ordinary methanolysis to give a compound of Formula (e) . Examples of the inert solvent to be used here are acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, ethyl acetate, N-methylpyrrolidone, a mixture of the solvent and water and a mixture thereof .
Step (6) ; The compound of Formula (e) is reacted with a reagent of the following formula: R9S02C1 wherein R9 is as defined above, in an inert solvent in the presence of a base such as pyridine, to give a compound of Formula (f) which is a compound of the present invention. The inert solvent is the same as used in Step (3).
The compounds of the present invention can be administered orally or parenterally in the dosage form
such as, for example, tablets, capsules, powders, troches, ointments, suspensions, suppositories and injections, all of which can be prepared according to conventional preparation techniques. The dose of the present compounds for treating an adult is from 100 to 1000 mg/day in single or several divided doses. This dose can be increased or decreased depending on the age, body weight and conditions of the patient.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is illustrated in more detail by the following Examples and a Test Example.
Reference Example 1 Synthesis of 11- (2-aminoethyl) amino-ll-deoxy-5-
O-desosaminγl-6-O-methylervthronolide A 11,12-cvclic carbamate
(1) To a solution of 70.0 g (77 mmol) of 10, ll-anhydro-2 ' , 4"-di-0-acetyl-12-0-imidazolylcarbonyl- 6-O-methylerythromycin A described in European Patent No. 638584 in 1 L of acetonitrile was added 30.0 ml (0.23 mol) of ethylenediamine at room temperature, followed by stirring overnight. The reaction solution was evaporated under reduced pressure, and the residue was dissolved in 1 L of methanol and refluxed under heating for 4 hours. After evaporation of the solvent, purification by silica gel column chromatography (chloroform : methanol : aqueous ammonia =20:1:0.1) gave
67.0 g (yield: 97 %) of 4"-0-acetyl-ll- (2-aminoethyl) - amino-ll-deoxy-6-O-methylerythromycin A 11,12-cyclic carbamate .
(2) A solution of 20 g (24 mmol) of the compound obtained in the above (1) in 100 ml of IN aqueous hydrochloric acid solution was stirred at 70°C for an hour. The mixture was cooled to room temperature, and extracted with chloroform to remove the cladinose. The aqueous layer was made basic with an aqueous sodium hydroxide solution, extracted with chloroform and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was crystallized from 50 ml of ether to give 9.8 g (yield: 63 %) of the title compound. SIMS m/z: 658 [M+H] +
XH-NMR (500 MHz, CDC13) δ (ppm) : 2.25 (s, 6H, NMe2) , 3.00 (s, 3H, 6-OMe) , 4.40 (d, IH, J=7.3 Hz, H-l'), 5.22 (dd, IH, J=11.0, 2.4 Hz, H-13). 13C-NMR (125 MHz, CDC13) δ (ppm) : 40.3 (NMe2) , 49.6
(6-OMe), 106.9 (Cl ' ) , 157.9 (11, 12-carbamate) , 175.7 (CD, 215.6 (C9).
Example 1 11— T2- f (4-Acetaminophenyl) sulfonylaminol - ethyl! amino-11-deoxy-3-O- (2-pyridyl) acetyl-5-O- desosaminyl-6-O-methylervthronolide A 11.12-cvclic carbamate
(1) To a solution of 1.38 g (2.1 mmol) of the compound obtained in Reference Example 1 in 30 ml of a mixture of methylene chloride and pyridine was added 0.59 g (2.5 mmol) of p-acetamidobenzenesulfonyl chloride under ice-cooling, followed by stirring for 1.5 hours at room temperature. The reaction solution was diluted with ethyl acetate, and washed with an aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution respectively. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2.07 g of 11- [2- [ (4-acetaminophenyl) sulfonylamino] -ethyl] amino-11- deoxy-5-0-desosaminyl-6-0-methyl-erythronolide A 11,12- cyclic carbamate. (2) 2.07 g of the compound obtained in the above (1) was dissolved in 20 ml of acetone, and 0.3 ml (3.2 mmol) of acetic anhydride was added thereto at room temperature, followed by stirring overnight. After the reaction, the reaction solution was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution respectively. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 1.90 g of a 2 ' -O-acetyl compound.
(3) To a solution of 1.00 g (1.1 mmol) of the compound obtained in the above (2) in 20 ml of methylene chloride were successively added 0.58 g (3.3 mmol) of 2-
pyridylacetate hydrochloride, 0.64 g (3.3 mmol) of 1- ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 0.14 g (1.1 mmol) of 4-dimethylaminopyridine under ice-cooling, followed by stirring at room temperature overnight. After the reaction, the reaction solution was diluted with ethyl acetate, and washed with an aqueous sodium hydroxide solution, a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution successively. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 1.06g of the residue, which was then dissolved in 20 ml of methanol and stirred at room temperature overnight. After the reaction, the solvent was evaporated under reduced pressure, and purification by silica gel column chromatography (chloroform : methanol : aqueous ammonia =15:1:0.1) gave 0.85 g (yield: 78 %) of the title compound. IonSprayMS m/z: 974.5 [M+H] + XH-NMR (500 MHz, CDC13) δ (ppm) : 2.03 (s, 3H, -COCH2) , 2.28 (s, 6H, NMe2), 2.52 (s, 3H, 6-OMe) , 3.95 and 3.98 (each d, each IH, Jgem=16.2 Hz, -CH2 [2-Pyridine] ) , 4.07 (d, IH, J=7.3 Hz, H-l'), 4.91 (d, IH, J=11.0 Hz, H-3), 4.92 (dd, IH, J=11.2, 1.1 Hz, H-13), 5.49 (brs, IH, -NHS02-), 8.14 (brs, IH, -NHAc) .
13C-NMR (125 MHz, CDC13) δ (ppm) : 24.3 (-COCH3), 40.3 (NMe2) , 49.7 (6-OMe), 103.4 (Cl'), 157.5 (11,12- carbamate) , 168.7 (-COCH3), 171.1 (-COCH2[2-
Pyridine]), 175.0 (Cl) , 215.7 (C9).
Example 2
11- \ 2- \ (4-Acetaminophenγl) sulfonylaminol - ethyll amino-3. ll-dideoxy-3-oxo-5-Q-desosaminyl-6-0- methylervthronolide A 11.12-cγclic carbamate
To a solution of 0.87 g (0.97 mmol) of the compound obtained in Example 1(2) in 18 ml of methylene chloride were successively added 0.69 ml (9.7 mmol) of dimethyl sulfoxide, 0.56 g (2.9 mmol) of l-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride and 0.56 g (2.9 mmol) of pyridinium trifluoroacetate under ice- cooling, followed by stirring at room temperature overnight. After the reaction, the reaction solution was diluted with ethyl acetate, and washed with an a-queous sodium hydroxide solution and a saturated aqueous sodium chloride solution successively. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 0.99 g of the residue, which was then dissolved in 20 ml of methanol and stirred at room temperature overnight. After the reaction, the solvent was evaporated under reduced pressure, and purification by silica gel column chromatography (chloroform : methanol : aqueous ammonia =15:1:0.1) gave 0.55 g (yield: 66 %) of the title compound. IonSprayMS m/z: 853.5 [M+H]+ ^-NMR (500 MHz, CDC13) δ (ppm) ; 2.20 (s, 3H, -NHCOCH2) ,
2.26 (s, 6H, NMe2) , 2.54 (s, 3H, 6-OMe) , 3.83 (q, J=6.7 Hz, H-2) , 4.22 (d, IH, J=8.6 Hz, H-5) ,
4.27 (d, IH, J=7.3 Hz, H-l') , 4.88 (dd, IH, J=11.0, 2.4 Hz, H-13), 5.77 (brt, IH, J=5.5 Hz, -NHS02-) , 8.00 (s, IH, -NHCOCH3)
13C-NMR (125 MHz, CDCl3) δ (ppm) ; 24.6 (-NHCOCH3) , 40.2 (NMe2), 49.7 (6-OMe), 104.0 (Cl'), 158.0 (11,12- carbamate) , 168.8 (-NHCOCH3) , 170.KC1) , 203.5 (C3), 216.4 (C9) .
Example 3
11- \2- \ (2-Nitrophenyl) sulfonylaminol ethyl! - amino-ll-deoxγ-3-O- (2-pyridyl) acetyl-5-Q-desosaminyl-6- O-methylervthronolide A 11,12-cvclic carbamate (1) Following the same procedures as in
Example 1(1) and (2) using 1.57 g (2.4 mmol) of the compound obtained in Reference Example 1 and 0.63 g (2.8 mmol) of 2-nitrobenzenesulfonyl chloride, there was obtained 2.16 g of the 2 ' -O-acetyl compound. (2) Following the same procedure as in Example
1(3) using 1.03 g (1.2 mmol) of the compound obtained in the above (1), there was obtained 0.66 g (yield: 59 %) of the title compound. SIMS m/z: 962 [M+H]+ XH-NMR (500 MHz, CDC13) δ (ppm) ; 2.29 (s, 6H, NMe2) , 2.99 (s, 3H, 6-OMe) , 3.92 and 3.96 (each d, each IH, Jgem=16.2 Hz, -CI 2-Pyridine] ) , 4.06 (d, IH, J=7.3 Hz, H-l'), 5.02 (d, IH, J=11.0 Hz, H-3), 5.06 (dd, IH,
J=11.0, 2.1 Hz, H-13) , 6.26 (brs, IH, -NHS02-) 13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.3 (NMe2) , 50.3
(6-OMe) , 103.5 (Cl') , 157.5 (11, 12 -carbamate ) , 170.4 ( -COCH2[ 2 -Pyridine] ) , 174.8 (Cl) , 215.8 (C9) .
Example 4
11— T2— f (2-Nitrophenyl) sulfonylaminol ethyl! - amino-3. ll-dideoxy-3-oxo-5-Q-desosaminγl-6-0- methylerythronolide A 11.12-cvclic carbamate Following the same procedure as in Example 2 using 1.06 g (1.2 mmol) of the compound obtained in Example 3(1), there was obtained 0.88 g (yield: 88 %) of the title compound. IonSprayMS m/z: 841.4 [M+H]+ ^-NMR (300 MHz, CDC13) δ (ppm) ; 2.26 (s, 6H, NMe2) , 2.58 (s, 3H, 6-OMe) , 3.84 (q, J=6.7 Hz, H-2), 4.24 (d, IH, J=9.0 Hz, H-5), 4.27 (d, IH, J=7.3Hz, H-l"), 4.96 (dd, IH, J=10.8, 2.3 Hz, H-13)
Example 5
11- T2- T ri- ( 5-Dimethylamino) naphthyl! sulfonyl- aminol ethyll amino-ll-deoxy-3-O- (2-pyridyl) acetyl-5-O- desosaminyl-6-O-methylervthronolide A 11.12-cvclic carbamate (1) Following the same procedures as in
Example 1(1) and (2) using 1.44 g (2.2 mmol) of the compound obtained in Reference Example 1 and 0.71 g (2.6 mmol) of l-dimethylaminonaphthalene-5-sulfonyl chloride,
there was obtained 2.18 g of the 2 ' -O-acetyl compound.
(2) Following the same procedure as in Example 2(3) using 1.02 g (1.1 mmol) of the compound obtained in the above (1), there was obtained 0.95 g (yield: 86 %) of the title compound.
IonSprayMS m/z: 1010.6 [M+H]+
XH-NMR(300MHz, CDC13) δ (ppm) ; 2.29 (s, 6H, NMe2) , 2.71
(s, 3H, 6-OMe) , 2.86 (s, 6H, [Naphthalene] -NMe2) , 3.95 (s, 2H, -CH2[2-Pyridine] ) , 4.05 (d, IH, J=7.3 Hz, H-l'), 4.99 - 5.06 (m, 2H, H-3 and H-13), 6.23 (brt, IH, J=6.0 Hz, -NHS02-) .
Example 6
11- \2- r ri- (5-Dimethylamino) naphthyl! sulfonyl- amino! ethyll amino-3 , ll-dideoxy-3-oxo-5-0-desosaminγl-6- O-methylervthronolide A 11.12-cγclic carbamate
Following the same procedure as in Example 2 using 1.19 g (1.3 mmol) of the compound obtained in Example 5(1), there was obtained 0.91 g (yield: 79 %) of the title compound. SIMS m/z: 889 [M+H]+
^-NMR (500 MHz, CDC13) δ (ppm) ; 2.26 (s, 6H, NMe2) , 2.44 (s, 3H, 6-OMe) , 2.88 (s, 6H, [Naphthalene] -NMe2) , 3.83 (q, J=6.7Hz, H-2), 4.20 (d, IH, J=8.5Hz, H-5) , 4.27 (d, IH, J=7.3 Hz, H-l'), 4.91 (dd, IH, J=11.0, 2.4 Hz, H-13), 6.11 (brt, IH, J=5.5Hz, -NHS02-) 13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.2 (NMe2) , 45.4
( [Naphthalene] -NMe2) , 49.6 (6-OMe), 103.9 (Cl"),
157.9 (11, 12-carbamate) , 170.0 (Cl) , 203.4 (C3), 216.3 (C9).
Example 7 11- r2- (Benzo-2.1.3-thiadiazole-4-sulfonyl- amino) ethyll amino-ll-deoxy-3-O- (2-pyridyl) acetγl-5-O- desosaminyl-6-O-methylervthronolide A 11,12-cvclic carbamate
(1) Following the same procedures as in Example 1(1) and (2) using 1.21 g (1.8 mmol) of the compound obtained in Reference Example 1 and 0.52 g (2.2 mmol) of benzo-2 , 1, 3-thiadiazole-4-sulfonyl chloride, there was obtained 1.75 g of the 2 ' -O-acetyl compound.
(2) Following the same procedure as in Example 1(3) using 0.85 g (0.95 mmol) of the compound obtained in the above (1), there was obtained 0.78 g (yield:
85 %) of the title compound.
SIMS m/z: 975 [M+H]+
XH-NMR (500 MHz, CDC13) δ (ppm) ; 2.29 (s, 6H, NMe2) , 2.91 (s, 3H, 6-OMe) , 3.92 and 3.98 (each d, each IH,
Jgem=16.1 Hz , -CH2 [2-Pyridine]) , 4.06 (d, IH, J=7.4 Hz, H-l"), 5.01 (d, IH, J=11.2 Hz, H-3), 5.04 (dd, IH, J=11.0, 2.1 Hz, H-13), 6.28 (brs, IH, -NHS02-)
13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.3 (NMe2) , 50.2 (6-OMe), 103.6 (Cl ' ) , 157.3 (11, 12-carbamate) , 170.4 ( -C_OCH2 [2-Pyridine] ) , 174.8 (Cl) , 215.7 (C9).
Example 8
11- \2- (Benzo-2 , 1.3-thiadiazole-4- sulfonylamino) ethyll amino-3 , ll-dideoxγ-3-oxo-5-0- desosaminyl-6-O-methylervthronolide A 11.12-cvclic carbamate
Following the same procedure as in Example 2 using 0.85 g (0.94 mmol) of the compound obtained in Example 7(1), there was obtained 0.67 g (yield: 84 %) of the title compound. SIMS m/z: 854 [M+H]+
XH-NMR (500 MHz, CDCl3) δ (ppm) ; 2.26 (s, 6H, NMe2) , 2.51 (s, 3H, 6-OMe) , 3.83 (q, J=6.7 Hz, H-2), 4.22 (d, IH, J=9.2 Hz, H-5), 4.27 (d, IH, J=7.3 Hz, H-l'), 4.93 (dd, IH, J=11.0, 2.4 Hz, H-13), 6.15 (brs, IH, -NHS02-)
13C-NMR (125 MHz, CDC13) δ (ppm) ; 24.6 (-NHCOCH3), 40.2 (NMe2), 49.8 (6-OMe), 104.0 (Cl ' ) , 157.3 (11,12- carbamate) , 170.0 (Cl) , 203.4 (C3), 216.3 (C9) .
Example 9
11- \ 2 - \ (8-Ouinolyl) sulfonylaminol ethyll amino- 3. ll-dideoxy-3-oxo-5-0-desosaminyl-6-0-methylervthro- nolide A 11, 12-cyclic carbamate
(1) Following the same procedures as in Example 1(1) and (2) using 2.02 g (3.1 mmol) of the compound obtained in Reference Example 1 and 0.84 g (3.7 mmol) of quinoline-8-sulfonyl chloride, there was obtained 3.08 g of the 2 ' -O-acetyl compound.
(2) Following the same procedure as in Example 2 using 3.08 g of the compound obtained in the above (1) , there was obtained 2.45 g (yield: 94 %) of the title compound. IonSpray MS m/z: 847.4 [M+H]+
^-NMR (500 MHz, CDC13) δ (ppm) ; 2.26 (s, 6H, NMe2) , 2.43 (s, 3H, 6-OMe) , 3.80 (q, J=7.0 Hz, H-2), 4.18 (d, IH, J=8.8 Hz, H-5), 4.27 (d, IH, J=7.4 Hz, H-l'), 4.93 (dd, IH, J=10.6, 2.4 Hz, H-13), 6.73 (brt, IH, J=6.4 Hz, -NHS02-)
13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.2 (NMe2) , 49.6 (6-OMe) , 104.0 (Cl') , 157.4 (11, 12 -carbamate ) , 169.4(C1) , 203.8 (C3) , 216.0 (C9) .
Example 10
11— T2— r (8-Ouinolyl) sulfonylamino! ethyll amino- ll-deoxγ-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-0- methγlerγthronolide A 11,12-cvclic carbamate
(1) To a solution of 53.6 g (0.09 mol) of 2 ' - 0-acetyl-5-0-desosaminyl-6-0-methylerythronolide A in 500 ml of methylene chloride was added 54.9 ml (0.70 mol) of pyridine. 16.8 g (0.06 mol) of triphosgene was added to the mixture under ice-cooling, followed by stirring at room temperature for 2 hours. After the reaction, water was added to the reaction mixture under ice-cooling to decompose the excess triphosgene, and the mixture was diluted with chloroform and washed with water and a saturated a-queous sodium chloride solution
successively. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 56.0 g of the 11,12-cyclic carbonate compound. (2) To a solution of 56.0 g of the compound obtained in the above (1) in 500 ml of N, N- dimethyIformamide was added 23.7 ml (0.23 mol) of 1, 1, 3 , 3-tetramethylguanidine, followed by stirring at 100°C for 3 hours. After the reaction, the reaction solution was diluted with ethyl acetate and washed with distilled water and a saturated aqueous sodium chloride solution successively. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 50.27 g of 10 , ll-anhydro-2 ' -0-acetyl-5-0-desosaminyl-6-0- methylerythronolide A.
(3) Following the same procedure as in Example 2(3) using 50.3 g (0.08 mol) of the compound obtained in the above (2), there was obtained 41.95 g of 10,11- anhydro-2 ' -O-acetyl-3-O- (2-pyridyl) acetyl-5-O- desosaminyl-6-O-methylerythronolide A.
(4) To a solution of 31.0 g (0.04 mol) of the compound obtained in the above (3) in a mixture of 180 ml of N,N-dimethylformamide and 120 ml of tetrahydrofuran were successively added 20.6 g (0.13 mol) of carbonyldiimidazole and 3.38 g (0.08 mol) of sodium hydride under ice-cooling, followed by stirring under ice-cooling for 40 minutes. After the reaction,
the reaction solution was diluted with ethyl acetate and washed with distilled water and a saturated aqueous sodium chloride solution successively. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 32.7 g of 10 , ll-anhydro-2 ' -O-acetyl-12-O- imidazolylcarbonyl-3-O- (2-pyridyl ) acetyl-5-0- desosaminyl-6-O-methylerythronolide A.
(5) To a solution of 11.5 g (14.6 mmol) of the compound obtained in the above (4) in 100 ml of acetonitrile was added 9.8 ml (0.15 mol) of ethylenediamine, followed by stirring for 2 days. After the reaction, the reaction solution was diluted with ethyl acetate and washed with distilled water and a saturated aqueous sodium chloride solution successively. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in 100 ml of methanol, followed by stirring at room temperature overnight. After the reaction, the reaction solution was evaporated under reduced pressure, and the precipitated crystals were washed with ether to give 3.98 g of 11- (2-aminoethyl) amino-ll-deoxy-3-O- (2- pyridyl)acetyl-5-0-desosaminyl-6-0-methylerythronolide A 11,12-cyclic carbamate.
(6) To a solution of 0.62 g (0.8 mmol) of the compound obtained in the above (5) in 10 ml of a mixture of methylene chloride and pyridine was added 0.22 g (1.0
mmol) of quinoline-8-sulfonyl chloride under ice-cooling, followed by stirring at room temperature for 2 hours. After the reaction, the reaction solution was diluted with ethyl acetate and washed with an aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution successively. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and purification by silica gel column chromatography (chloroform : methanol : aqueous ammonia =20:1:0.1) gave 0.62 g (yield: 80 %) of the title compound. IonSprayMS m/z: 968.5 [M+H]+ i-NMR (500 MHz, CDC13) δ (ppm) ; 2.29 (s, 6H, NMe2) , 2.81 (s, 3H, 6-OMe) , 3.93 and 3.97 (each d, each IH, Jgem=16.2 Hz, -CH2[2-Pyridine] ) , 4.06 (d, IH, J=7.3 Hz, H-l'), 5.04 (d, IH, J=11.0 Hz, H-3), 5.11 (dd, IH, J=11.0, 2.4 Hz, H-13), 6.79 (brt, IH, J=6.4 Hz, -NHS02-) 13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.3 (NMe2) , 49.9 (6-OMe), 103.6 (Cl ' ) , 157.5 (11, 12-carbamate) , 170.4 (-C_OCH2 [2-Pyridine] ) , 174.1 (Cl) , 215.7 (C9).
Example 11
11- \2 - r (3-Nitrophenγl) sulfonylamino! ethyll - amino-ll-deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6- O-methylervthronolide A 11,12-cyclic carbamate
Following the same procedure as in Example 10(6) using 0.53 g (0.68 mmol) of the compound obtained
in Example 10(5) and 0.18 g (0.23 mmol) of 3-nitro- benzenesulfonyl chloride, there was obtained 0.55 g
(yield: 85 %) of the title compound.
SIMS m/z: 962 [M+H]+ ^-NMR (500 MHz, CDC13) δ (ppm) ; 2.29 (s, 6H, NMe2) , 2.87 (s, 3H, 6-OMe) , 3.93 and 3.96 (each d, each IH, Jgeιn=16.2 Hz, -CH2[2-Pyridine] ) , 4.06 (d, IH, J=7.3 Hz, H-l'), 4.92 (dd, IH, J=11.0, 2.4Hz, H-13), 4.99 (d, IH, J=11.0 Hz, H-3), 6.31 (brs, IH, -NHS02-) 13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.3 (NMe2), 50.1
(6-OMe), 103.5 (Cl ' ) , 157.7 (11, 12-carbamate) , 170.4 ( -COCH2 [2-Pyridine] ) , 175.5 (Cl) , 216.0 (C9).
Example 12 11- 12- T (3-Nitrophenyl) sulfonylamino! ethyll -
.amino-3 , ll-dideoxy-3-oxo-5-0-desos.aminyl-6-0- methylervthronolide A 11,12-cvclic carbamate
(1) Following the same procedure as in Example 1 for oxidation using 72.0 g of the compound obtained in Example 10(2), there was obtained 67.0 g of 2 ' -O-acetyl- 3 , ll-dideoxy-3-oxo-5-0-desosaminyl-6-0-methylerythro- nolide A 11,12-cyclic carbonate.
(2) Following the same procedure as in Example 10(2) using 67.0 g of the compound obtained in the above (1), there was obtained 19.8 g of the 10 , 11-anhydro compound.
(3) Following the same procedure as in Example 10(4) using 19.8 g of the compound obtained in the above
(2), purification by silica gel column chromatography (acetone : n-hexane : triethylamine =10:20:0.2) gave 15.5 g (yield: 68 %) of the 12-0-imidazolylcarbonyl compound. (4) To a solution of 8.4 g (12 mmol) of the compound obtained in the above (3) in 60 ml of acetonitrile was added 8.0 ml (0.12 mol) of ethylenediamine, followed by stirring at room temperature for 2 days. After the reaction, the reaction solution was diluted with ethyl acetate and washed with distilled water and a saturated aqueous sodium chloride solution successively. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give 7.1 g of 2 ' -O-acetyl-11- (2-aminoethyl) - amino-3 , ll-dideoxy-3-oxo-5-0-desosaminyl-6-0-methyl- erythronolide A 11,12-cyclic carbamate.
(5) To a solution of 0.52 g (0.75 mmol) of the compound obtained in the above (4) in 10 ml of a mixture of methylene chloride and pyridine was added 0.20 g (0.9 mmol) of 3-nitrobenzenesulfonyl chloride under ice- cooling, followed by stirring at room temperature overnight. After the reaction, the reaction solution was diluted with ethyl acetate and washed with an aqueous sodium hydroxide solution and a saturated aqueous sodium chloride solution successively. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 20 ml of methanol, followed
by stirring at room temperature overnight . After the reaction, the solvent was evaporated under reduced pressure, and purification by silica gel column chromatography (chloroform : methanol : aqueous ammonia =27:1:0.1) gave 0.26 g (yield: 41 %) of the title compound.
SIMS m/z: 841 [M+H]+ XH-NMR (500 MHz, CDC13) δ (ppm) ; 2.26 (s, 6H, NMe2) , 2.49
(s, 3H, 6-OMe) , 3.83 (q, J=7.0 Hz, H-2), 4.21 (d, IH, J=8.8 Hz, H-5), 4.26 (d, IH, J=7.3 Hz, H-l'), 4.82
(dd, IH, J=10.9, 2.4 Hz, H-13), 6.12 (brs, IH,
-NHS02-) 13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.2 (NMe2) , 50.0
(6-OMe) , 104.0 (Cl') , 158.0 (11, 12 -carbamate ) , 170.4 (Cl) , 203.1 (C3) , 216.6 (C9) .
Example 13
11- \2- f (4-Nitrophenyl) sulfonylamino! ethyl! - amino-ll-deoxy-3-O- (2-pyridyl) acetyl-5-Q-desosaminyl-6- O-methylervthronolide A 11,12-cyclic carbamate
Following the same procedure as in Example 10(6) using 0.51 g (0.66 mmol) of the compound obtained in Example 10(5) and 0.17 g (0.77 mmol) of 4-nitro- benzenesulfonyl chloride, there was obtained 0.51 g (yield: 80 %) of the title compound. SIMS m/z: 962 [M+H]+
XH-NMR (500 MHz, CDC13) δ (ppm) ; 2.29 (s, 6H, NMe2) , 2.89 (s, 3H, 6-OMe) , 3.93 and 3.96 (each d, each IH,
Jgem= 16.5Hz, -CH2[ 2 -Pyridine] ) , 4.06(d, IH, J=7.3 Hz, H-l') , 4.91 (dd, IH, J=11.0, 1.8 Hz, H-13) , 5.00 (d, IH, J=11.0 Hz, H-3) , 6.32 (brs, IH, -NHS02-) 13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.2 (NMe2) , 50.1 (6-OMe) , 103.5 (Cl ' ) , 157.9 (11, 12 -carbamate ) , 170.4
( -COCH2 [2 -Pyridine] ) , 175.3 (Cl) , 216.1 (C9) .
Example 14
11- \2- \ (4-Nitrophenyl) sulfonylamino! ethyl! - amino-3 , ll-dideoxy-3-oxo-5-Q-desos.aminyl-6-0- methylervthronolide A 11,12-cyclic carbamate
Following the same procedure as in Example 12(5) using 0.83 g (1.2 mmol) of the compound obtained in Example 12(4) and 0.35 g (1.6 mmol) of 4-nitro- benzenesulfonyl chloride, there was obtained 0.41 g (yield: 41 %) of the title compound. SIMS m/z: 841 [M+H]+
^-NMR (500 MHz, CDC13) δ (ppm) ; 2.26 (s, 6H, NMe2) , 2.51 (s, 3H, 6-OMe) , 3.83 (q, J=6.7 Hz, H-2), 4.22 (d, IH, J=9.2 Hz, H-5), 4.27 (d, IH, J=7.3 Hz, H-l'), 4.82 (dd, IH, J=11.0, 2.4 Hz, H-13), 6.14 (brs, IH, -NHS02-) 13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.2 (NMe2) , 49.7
(6-OMe), 104.0 (Cl ' ) , 158.2 (11, 12-carbamate) , 170.3 (Cl), 203.2 (C3), 216.7 (C9).
Example 15
11- \2- (Pentafluorophenylsulfonylamino) -
ethyl! amino-ll-deoxy-3-O- (2-pyridyl) acetyl-5-O- desosaminyl-6-O-methylervthronolide A 11,12-cyclic carbamate
Following the same procedure as in Example 10(6) using 0.53 g (0.68 mmol) of the compound obtained in Example 10(5) and 0.22 g (0.83 mmol) of pentafluoro- benzenesulfonyl chloride, there was obtained 0.29 g (yield: 42 %) of the title compound. SIMS m/z: 1007 [M+H] + ^-NMR (500 MHz, CDC13) δ (ppm) ; 2.29 (s, 6H, NMe2) ,
3.04 (s, 3H, 6-OMe) , 3.78 (d, IH, J=4.3 Hz, H-5), 3.92 and 3.96 (each d, each IH, Jgem=15.9 Hz, -CH2 [2-Pyridine] ) , 4.07 (d, IH, J=7.3 Hz, H-l'), 4.99 (dd, IH, J=11.0, 2.4 Hz, H-13), 5.03 (d, IH, J=11.0 Hz, H-3)
13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.3 (NMe2), 50.4
(6-OMe), 103.5 (Cl'), 157.7 (11, 12-carbamate) , 170.5 (-COCH2 [2-Pyridine] ) , 175.5 (Cl) , 216.0 (C9) .
Example 16
11- \ 2 - (Pentafluorophenylsulfonylamino) - ethyll amino-3 , ll-dideoxy-3-oxo-5-0-desosaminγl-6-0- methylerythronolide A 11,12-cyclic carbamate
Following the same procedure as in Example 12(5) using 0.83 g (1.2 mmol) of the compound obtained in Example 12(4) and 0.38 g (1.4 mmol) of pentafluoro- benzenesulfonyl chloride, there was obtained 0.49 g (yield: 46 %) of the title compound.
SIMS m/z: 886 [M+H]+
XH-NMR (500 MHz, CDC13) δ (ppm) ; 2.26 (s, 6H, NMe2) , 2.62
(s, 3H, 6-OMe) , 3.86 (q, J=6.7 Hz, H-2) , 4.25 (d, IH,
J=9.2 Hz, H-5) , 4.27 (d, IH, J=7.3 Hz, H-l') , 4.90 (dd, IH, J=11.0, 2.4 Hz, H-13)
13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.2(NMe2), 49.9 (6-OMe),
104.0 (Cl*), 157.7 (11, 12-carbamate) , 170.7 (Cl) ,
203.0 (C3) , 216.5 (C9) .
Example 17
11- \2- (Methanesulfonylamino) ethyll amino-11- deoxy-3-0- (2-pyridyl) acetyl-5-0-desosaminyl-6-Q- methylerythronolide A 11,12-cyclic carbamate
Following the same procedure as in Example 10(6) using 0.51 g (0.66 mmol) of the compound obtained in Example 10(5) and 0.06 ml (0.79 mmol) of methanesulfonyl chloride, there was obtained 0.45 g (yield: 80 %) of the title compound. SIMS m/z: 855 [M+H]+ ^-NMR (500 MHz, CDC13) δ (ppm) ; 2.29 (s, 6H, NMe2) , 2.98 (s, 3H, -S02Me), 3.05 (s, 3H, 6-OMe) , 3.92 and 3.96 (each d, each IH, Jgern=15.9 Hz, -CH2[2-Pyridine] ) , 4.06 (d, IH, J=7.3Hz, H-l'), 5.03 (d, 2H, J=10.9 Hz, H-3 and H-13), 5.51 (brt, IH, J=5.5 Hz, -NHS02-) 13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.3 (NMe2) , 41.2
(-S02Me), 50.3 (6-OMe), 103.5 (Cl'), 157.9 (11,12- carbamate) , 170.4 (-COCH2 [2-Pyridine] ) , 175.1 (Cl) , 216.0 (C9).
Example 18
11- F2- (methanesulfonylamino) ethyll amino-3 , 11- dideoxy-3-oxo-5-0-desosaminyl-6-0-methγlervthronolide A 11,12-cyclic carbamate Following the same procedure as in Example
12(5) using 0.83 g (1.2 mmol) of the compound obtained in Example 12(4) and 0.11 ml (1.4 mmol) of methanesulfonyl chloride, there was obtained 0.18 g (yield: 21 %) of the title compound. FABMS m/z: 734 [M+H]+
XH-NMR (500 MHz, CDC13) δ (ppm) ; 2.27 (s, 6H, NMe2) , 2.66 (s, 3H, 6-OMe) , 2.99 (s, 3H, -S02Me) , 3.86 (q, J=6.7 Hz, H-2), 4.25 (d, IH, J=9.2 Hz, H-5), 4.28 (d, IH, J=7.3 Hz, H-l'), 4.95 (dd, IH, J=11.0, 2.4 Hz, H-13), 5.33 (brs, IH, -NHS02-)
13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.2 (NMe2) , 41.0
(-S02Me), 49.9 (6-OMe) , 104.0 (Cl'), 157.9 (11,12- carbamate) , 170.3 (Cl) , 203.3 (C3), 216.5 (C9).
Example 19
11- [2- (Phenylsulfonylamino) ethyl! amino-11- deoxγ-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-0- methylervthronolide A 11,12-cyclic carbamate
Following the same procedure as in Example 10(6) using 0.54 g (0.69 mmol) of the compound obtained in Example 10(5) and 0.15 g (0.85 mmol) of benzenesulfonyl chloride, there was obtained 0.52 g (yield: 82 %) of the title compound.
IonSpray MS m/z: 917.4 [M+H]+
XH-NMR (500 MHz, CDC13) δ (ppm) ; 2.28 (s, 6H, NMe2) , 2.80
(s, 3H, 6-OMe) , 3.92 and 3.96 (each d, each IH,
Jgem=15.8 Hz, -CH2 [2 -Pyridine] ) , 4.05 (d, IH, J=7.3 Hz, H-l') , 4.95 (dd, IH, J=11.0, 2.2 Hz, H-13) , 4.99
(d, IH, J=11.0 Hz, H-3) , 5.93 (brt, IH, J=5.8 Hz,
-NHSO2-) 13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.3 (NMe2) , 50.1
(6-OMe) , 103.5 (Cl') , 157.7 (11, 12 -carbamate ) , 170.4 (-COCH2 [2 -Pyridine] ) , 175.1 (Cl) , 215.9 (C9) .
Example 20
11- \2- (1-Naphthalenesulfonylamino) ethyll amino- ll-deoxy-3-O- (2-pyridyl) acetγl-5-Q-desosaminyl-6-0- methylervthronolide A 11,12-cvclic carbamate
Following the same procedure as in Example 10(6) using 0.54 g (0.69 mmol) of the compound obtained in Example 10(5) and 0.19 g (0.84 mmol) of naphthalenesulfonyl chloride, there was obtained 0.58 g (yield: 87 %) of the title compound. IonSpray MS m/z: 967.4 [M+H]+
^-NMR (500 MHz, CDC13) δ (ppm) ; 2.28 (s, 6H, NMe2) , 2.67 (s, 3H, 6-OMe) , 3.93 and 3.97 (each d, each IH, Jgem=16.2 Hz, -CH2[2-Pyridine] ) , 4.04 (d, IH, J=7.3 Hz, H-l'), 5.02(dd, IH, J=11.2, 2.2 Hz, H-13), 5.00 (d, IH, J=11.0 Hz, H-3), 6.31 (brt, IH, J=5.8 Hz, -NHSO2-) 13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.3 (NMe2) , 50.0
(6-OMe), 103.6 (Cl ' ) , 157.7 (11, 12-carbamate) , 170.4 ( -COCH2[2-Pyridine] ) , 175.1 (Cl) , 215.8 (C9) .
Example 21 11- \ 2- (2-Mesitylenesulfonylamino) ethyl! a ino- ll-deoxy-3-O- (2-Pyridyl) acetyl-5-0-desosaminγl-6-0- methylerythronolide A 11,12-cyclic carbamate
Following the same procedure as in Example 10(6) using 0.53 g (0.68 mmol) of the compound obtained in Example 10(5) and 0.18 g (0.82 mmol) of 2-mesityl- enesulfonyl chloride, there was obtained 0.55 g (yield: 84 %) of the title compound. IonSpray MS m/z: 959.5 [M+H] +
^-NMR (500 MHz, CDC13) δ (ppm) ; 2.27 and 2.63 (each s, 9H, -PhMe3) , 2.29 (s, 6H, NMe2) , 2.93 (s, 3H, 6-OMe) , 3.92 and 3.95 (each d, each IH, Jgem=16.2 Hz, -CH2 2- Pyridine] ) , 4.05 (d, IH, J=7.3 Hz, H-l'), 5.00-5.03 (m, 2H, H-3 and H-13), 5.92 (brt, IH, J=6.0 Hz, -NHSO2-) 13C-NMR (125 MHz, CDC13) δ (ppm) ; 20.8 and 22.9 (-PhMe3), 40.3 (NMe2), 50.2 (6-OMe), 103.5 (Cl'), 157.8 (11, 12-carbamate) , 170.4 (-COCH2 [2-Pyridine] ) , 174.8 (Cl) , 215.8 (C9) .
Example 22
11- T2- F2- (1-Naphthyl) ethanesulfonylamino! - ethyll amino-ll-deoxy-3-O- (2-pyridyl) acetyl-5-O- desosaminyl-6-O-methylervthronolide A 11,12-cvclic
carbamate
Following the same procedure as in Example 10(6) using 0.53 g (0.68 mmol) of the compound obtained in Example 10(5) and 0.21 g (0.82 mmol) of 2-(l- naphthyl) ethanesulfonyl chloride, there was obtained 0.38 g (yield: 56 %) of the title compound. IonSpray MS m/z: 995.5 [M+H] + XH-NMR (500 MHz, CDC13) δ (ppm) ; 2.31 (s, 6H, NMe2) ,
3.04(s, 3H, 6-OMe) , 3.91 and 3.96 (each d, each IH, Jgem=15.9 Hz, -CH2 2-Pyridine] ) , 4.06 (d, IH, J=7.3 Hz, H-l'), 5.03 (d, IH, J=11.0 Hz, H-3 ) , 5.04 (dd, IH, J=11.0, 2.2 Hz, H-13), 5.60 (brs, IH, -NHS02-) 13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.3 (NMe2) , 50.3
(6-OMe), 103.5 (Cl ' ) , 158.0 (11 , 12-carbamate) , 170.4 ( -COCH2[2-Pyridine] ) , 175.0 (Cl) , 216.0 (C9).
Example 23
11- f2- (2-Acetamido-4-methyl-5-thiazolesulfonyl- amino) ethyll amino-ll-deoxy-3-O- (2-pyridyl) acetyl-5-O- desosaminyl-6-O-methylervthronolide A 11,12-cyclic carbamate
Following the same procedure as in Example
10(6) using 0.57 g (0.73 mmol) of the compound obtained in Example 10(5) and 0.22 g (0.86 mmol) of 2-acetamido- 4-methyl-5-thiazolesulfonyl chloride, recrystallization from ethyl acetate/n-hexane gave 0.19 g (yield: 26 %) of the title compound as the first crystals.
FABMS m/z: 995 [M+H]+
XH-NMR (500MHz, CDC13) δ (ppm) ; 2.21 (s, 3H, ' -NHCOCIfc) ,
2.29 (s, 6H, NMe2), 2.49 (s, 3H, [Thiazole] -Me) , 2.91 (s, 3H, 6-OMe) , 3.91 and 3.95 (each d, each IH, Jgem=15.8 Hz, -CH2 [ -Pyridine] ) , 4.05 (d, IH, J=7.4 Hz, H-l') , 4.97 (d, 2H, J=11.3 Hz, H-3 and H-13) , 6.08
(brs, IH, -NHSO2-) 13C-NMR (125 MHz, CDC13) 5 (ppm) ; 16.3 ( [Thiazole] -Me) , 23.0 (-NHCOC_H3) , 40.3 (NMe2) , 50.2 (6-OMe) , 103.6 (Cl') , 157.8 (11, 12 -carbamate ) , 168.1 (-NHCOCH3) , 170.5 ( -COCH2 [2 -Pyridine] ) , 175.1 (Cl) , 215.9 (C9) .
Example 24
11- \2- \2 , 5-Dimethylisoxazole-4-sulfonγl- amino! ethyll amino-ll-deoxy-3-O- (2-Pyridγl) acetyl-5-O- desosaminyl-6-O-methylervthronolide A 11,12-cvclic carbamate
Following the same procedure as in Example 10(6) using 0.54 g (0.69 mmol) of the compound obtained in Example 10(5) and 0.16 g (0.82 mmol) of 3,5- dimethylisoxazole-4-sulfonyl chloride, there was obtained 0.28 g (yield: 44 %) of the title compound. FABMS m/z: 936 [M+H]+
^-NMR (500 MHz, CDC13) δ (ppm) ; 2.29 (s, 6H, NMe2) , 2.41 and 2.64 (each s, each 3H, [Isoxazole] -Me) , 2.96 (s, 3H, 6-OMe) , 3.92 and 3.96 (each d, each IH, Jgem=16.2 Hz, -CH.2 [2-Pyridine] ) , 4.06 (d, IH, J=7.3 Hz, H-l'), 4.95 (dd, IH, J=11.0, 2.1 Hz, H-13), 5.02 (d, IH, J=11.0 Hz, H-3), 6.31 (brs, IH, -NHS02-)
13C-NMR (125 MHz, CDC13) ό" (ppm) ; 10.7 and 12.6 ( [Isoxazole]-Me) , 40.3 (NMe2) , 50.1 (6-OMe), 103.6 (Cl') , 158.1 (11, 12 -carbamate ) , 170.5 (-£OCH2[ 2 -Pyridine] ) , 175.2 (Cl) , 216.1 (C9) .
Example 25
11- r2- \2- (Pyrid-2-yl) thiophene-5- sulfonylamino! ethyll amino-11-deoxy-3-O- (2-pyridyl) - acetyl-5-0-desosaminyl-6-0-methylervthronolide A 11,12- cyclic carbamate
Following the same procedure as in Example 10(6) using 0.53 g (0.69 mmol) of the compound obtained in Example 10(5) and 0.21 g (0.81 mmol) of 2-(pyrid-2- yl) thiophene-5-sulfonyl chloride, there was obtained 0.47 g (yield: 68 %) of the title compound. FABMS m/z: 1000 [M+H]+
^-NMR (500 MHz, CDC13) δ (ppm) ; 2.29 (s, 6H, NMe2) , 2.94 (s, 3H, 6-OMe) , 3.92 and 3.96 (each d, each IH, Jgem=15.9 Hz, -CH2[2-Pyridine] ) , 4.05 (d, IH, J=7.3 Hz, H-l'), 5.01 (dd, IH, J=11.0, 2.4 Hz, H-13), 5.02 (d, IH, J=11.0 Hz, H-3), 6.14 (brs, IH, -NHS02-) 13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.3 (NMe2) , 50.2
(6-OMe), 103.5 (Cl'), 157.8 (11, 12-carbamate) , 170.4 (-C_OCH2[2-Pyridine] ) , 175.0 (Cl) , 215.9 (C9).
Example 26
11- F2— f (3-Pyridγl) sulfonylamino! ethyll amino-11- deoxy-3 -O- (2-pyridyl ) acetv1-5-O-desosaminyl-6-O-methyl-
ervthronolide A 11,12-cvclic carbamate
Following the same procedure as in Example 10(6) using 1.0 g (1.3 mmol) of the compound obtained in Example 10(5) and 0.69 g of pyridine-3-sulfonyl chloride described in the following Reference Example 2, there was obtained 0.20 g (yield: 17 %) of the title compound. IonSprayMS m/z: 918.4 [M+H]+
^-NMR (500 MHz, CDCl3) δ (ppm) ; 2.29 (s, 6H, NMe2) , 2.86 (s, 3H, 6-OMe) , 3.93 and 3.96 (each d, each IH, Jgem=15.9 Hz, -CH2 [2-Pyridine] ) , 4.06 (d, IH, J=7.3 Hz, H-l'), 4.93 (dd, IH, J=11.0, 2.4 Hz, H-13), 5.00 (d, IH, J=11.0 Hz, H-3), 6.21 (brs, IH, -NHS02-) 13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.3 (NMe2) , 50.1
(6-OMe), 103.5 (Cl ' ) , 157.8 (11, 12-carbamate) , 170.4 ( -£OCH2[2-Pyridine] ) , 175.3 (Cl) , 216.0 (C9).
Reference Example 2
Preparation of pyridine-3-sulfonyl chloride 1.6 g (0.01 mol) of pyridine-3-sulfonic acid and 4.2 g (0.02 mol) of phosphorus pentachloride together were stirred at 200°C for 2.5 hours. After the reaction, chloroform was added to the reaction system, the insoluble matter was removed by filtration, and the filtrate was evaporated under reduced pressure to give 2.41 g of pyridine-3-sulfonyl chloride.
Example 27
11— r2— T (4-Methylphenyl) sulfonylamino! ethyll -
amino-11-deoxy-3-0- (2-pyridyl) acetyl-5-0-desosaminyl-6- O-methylervthronolide A 11.12-cvclic carbamate
Following the same procedure as in Example 10(6) using 0.53 g (0.69 mmol) of the compound obtained in Example 10(5) and 0.15 g (0.80 mmol) of p-toluene- sulfonyl chloride, there was obtained 0.40 g (yield: 63 %) of the title compound. IonSprayMS m/z: 931.5 [M+H] +
^-NMR (500 MHz, CDC13) δ (ppm) ; 2.29 (s, 6H, NMe2) , 2.39 (s, 3H, Ph-Me) , 2.83 (s, 3H, 6-OMe) , 3.93 and 3.96 (each d, each IH, Jgem=15.9 Hz, -CH2 [2 -Pyridine] ) , 4.06 (d, IH, J=7.3 Hz, H-l'), 4.96 (dd, IH, J=11.0, 2.4 Hz, H-13), 5.00 (d, IH, J=11.0 Hz, H-3), 5.83 (brt, IH, J=6.1 Hz, -NHS02-) 13C-NMR (125 MHz, CDC13) δ (ppm) ; 21.4 (Ph-Me), 40.3 (NMe2) , 50.0 (6-OMe), 103.5 (Cl ' ) , 157.7 (11,12- carbamate) , 170.4 (-COCH2 [2 -Pyridine] ) , 175.0 (Cl) , 215.9 (C9) .
Example 28
11- \2 - f4- (4-Dimethylaminophenylazo)phenyl- sulfonylamino! ethyll amino-ll-deoxy-3-O- (2-pyridyl) - acetyl-5-0-desosaminyl-6-0-methylerγthronolide A 11.12- cvclic carbamate Following the same procedure as in Example
10(6) using 0.52 g (0.67 mmol) of the compound obtained in Example 10(5) and 0.26 g (0.80 mmol) of 4-(4- dimethylaminophenylazo) benzenesulfonyl chloride, there
was obtained 0.54 g (yield: 76 %) of the title compound.
IonSprayMS m/z: 1064.6 [M+H] +
^-NMR (500 MHz, CDC13) δ (ppm) ; 2.29 (s, 6H, NMe2) , 2.93
(s, 3H, 6-OMe) , 3.11 (s, 6H, Ph-NMe2) , 3.92 and 3.96 (each d, each IH, J=15.9 Hz, -CH2[2-Pyridine] ) , 4.05
(d, IH, J=7.3 Hz, H-l'), 4.98 (dd, J=11.0, 1.8 Hz,
H-13), 5.04 (d, IH, J=11.0 Hz, H-3), 6.03 (brt, IH,
J=6.1 Hz, -NHSO2-) 13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.2 (NMe2) , 40.3 (NMe2) , 50.2 (6-OMe), 103.5 (Cl') , 157.9 (11, 12 -carbamate ) ,
170.3 ( -COCH2[ 2 -Pyridine] ) , 174.9 (Cl) , 215.9 (C9) .
Example 29
11- \2- r (4-Methoxyphenγl) sulfonylaminol ethyll - amino-ll-deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminγl-6- O-methylervthronolide A 11,12-cvclic carbamate
Following the same procedure as in Example 10(6) using 0.57 g (0.74 mmol) of the compound obtained in Example 10(5) and 0.18 g (0.87 mmol) of 4-methoxy- benzenesulfonyl chloride, there was obtained 0.45 g (yield: 64 %) of the title compound. FABMS m/z: 947 [M+H]+
^-NMR (500 MHz, CDC13) δ (ppm) ; 2.29 (s, 6H, NMe2) , 2.83 (s, 3H, 6-OMe) , 3.83 (s, 3H, Ph-OMe) , 3.92 and 3.96 (each d, each IH, J=15.9 Hz, -Ok [2-Pyridine] ) , 4.06 (d, IH, J=7.3 Hz, H-l'), 4.96 (dd, IH, J=11.0, 1.8 Hz, H-13), 5.01 (d, IH, J=11.0 Hz, H-3), 5.79 (brt, IH, J=6.1 Hz, -NHSO2-)
13C-NMR (125 MHz, CDC13) δ (ppm) ; 40.3 (NMe2 ") , 50.1
(6-OMe), 55.5 (Ph-OMe) , 103.5 (Cl'), 157.7 (11,12- carbamate) , 170.4 (-COCH2 [2-Pyridine] ) , 175.0 (Cl) , 215.8 (C9).
Example 30
11- r2- r (4-Cvanophenyl ) sulfonylamino1 ethyl1 - amino-ll-deoxγ-3-O- (2-pyridyl) acetyl-5-Q-desosaminyl-6- O-methylervthronolide A 11.12-cvclic carbamate Following the same procedure as in Example
10(6) using 0.54 g (0.69 mmol) of the compound obtained in Example 10(5) and 0.17 g (0.84 mmol) of 4-cyano- benzenesulfonyl chloride, there was obtained 0.48 g (yield: 74 %) of the title compound. FABMS m/z: 942 [M+H]+
XH-NMR (300 MHz, CDC13) δ (ppm) ; 2.29 (s, 6H, NMe2) , 2.86 (s, 3H, 6-OMe) , 3.95 (s, 2H, -CH2 [2-Pyridine] ) , 4.07(d, IH, J=7.3 Hz, H-l'), 4.91 (dd, IH, J=11.0, 2.1 Hz, H-13), 5.01 (d, IH, J=11.2 Hz, H-3).
Example 31
11- \ 2- \ (4-Trifluoromethoxyphenyl) sulfonyl- amino! ethyl! amino-ll-deoxy-3-O- (2-pyridγl) acetyl-5-O- desosaminyl-6-O-methylerythronolide A 11,12-cvclic carbamate
Following the same procedure as in Example 10(6) using 0.65 g (0.84 mmol) of the compound obtained in Example 10(5) and 0.26 g (1.0 mmol) of 4- (trifluoro-
methoxy) benzenesulfonyl chloride, there was obtained 0.36 g (yield: 43 %) of the title compound. XH-NMR (300 MHz, CDC13) δ (ppm) ; 2.29 (s, 6H, NMe2) , 2.84 (s, 3H, 6-OMe) , 3.94 (s, 2H, -CH2[2-Pyridine] ) , 4.06 (d, IH, J=7.1 Hz, H-l'), 4.93 (dd, IH, J=11.0, 1.9 Hz, H-13), 5.01 (d, IH, J=10.8 Hz, H-3).
Example 32
11- \ 2 - r (4-Trifluoromethylphenyl) sulfonyl- amino! ethyl! amino-11-deoxy-3-0- (2 -pyridyl) acetyl-5-O- desosaminγl-6-O-methylervthronolide A 11,12-cyclic carbamate
Following the same procedure as in Example 10(6) using 0.52 g (0.67 mmol) of the compound obtained in Example 10(5) and 0.20 g (0.82 mmol) of 4- (trifluoromethyl) benzenesulfonyl chloride, there was obtained 0.45 g (yield: 68 %) of the title compound.
XH-NMR (300 MHz, CDC13) δ (ppm) ; 2.29 (s, 6H, NMe2) , 2.85 (s, 3H, 6-OMe) , 3.94 (s, 2H, -CH2 [2-Pyridine] ) , 4.06 (d, IH, J=7.3 Hz, H-l'), 4.91 (dd, IH, J=11.0, 2.1 Hz, H-13), 5.01 (d, IH, J=11.2 Hz, H-3).
Example 33
11- [2- (N-Phenylsulfamoyl) ethyl! amino-11- deoxy-3-O- (2-Pyridγl) acetγl-5-0-desosaminyl-6-0- methylerythronolide A 11,12-cyclic carbamate
To a solution of 0.15 g (0.17 mmol) of the compound obtained in Example 10(4) in 10 ml of a mixture
of N,N-dimethylformamide and distilled water [10:3] was added 0.34 g (1.7 mmol) of 2-aminoethylsulfonanilide described in the following Reference Example 3 at room temperature, followed by stirring for 7 days. After the reaction, chloroform was added to the reaction solution, and the mixture was successively washed with distilled water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 10 ml of methanol and stirred at room temperature overnight. After the reaction, the solvent was evaporated under reduced pressure, and purification by silica gel column chromatography (chloroform : methanol : aqueous ammonia =19:1:0.1 - 9:1:0.1) gave 0.05 g (yield: 32 %) of the title compound. FABMS m/z: 917 [M+H]+ ^-NMR (500MHz, CDC13) δ (ppm) ; 0.84 (t, 3H, J=7.3 Hz,
14-Me) , 2.29 (s, 6H, NMe2) , 2.95 (s, 3H, 6-OMe) , 5.06 (d, IH, J=11.0 Hz, H-3 ) , 5.48 (dd, IH, J=11.0, 1.8 Hz, H-13) .
Reference Example 3
Preparation of 2-aminoethylsulfonanilide (1) To a solution of 8.0 g (64 mmol) of 2- aminoethylsulfonic acid (taurine) in 35 ml of distilled water were added 11.2 g (0.13 mol) of sodium bicarbonate and 19.8 g (0.12 mol) of carbobenzoxychloride under ice-
cooling, followed by stirring at room temperature for 4 hours. After the reaction, the reaction solution was washed with ether, the aqueous layer was made acidic with an aqueous hydrochloric acid solution, and the solution was concentrated under reduced pressure. The solution was allowed to stand overnight, and the precipitated crystals were recrystallized from water/methanol (1:10) to give 15.5 g (yield: 86 %) of carbobenzoxytaurine . (2) To a suspension of 15.0 g (53.3 mmol) of the compound obtained in the above (1) in 150 ml of benzene was added 15.0 g (72 mmol) of phosphorus pentachloride, followed by refluxing under heating for 25 minutes. After the reaction, the reaction solution was evaporated under reduced pressure, and 150 ml of benzene was added thereto, followed by removal of the insoluble matter by filtration. The filtrate was evaporated under reduced pressure to give 15.0 g of sulfonyl chloride. (3) To a solution of 3.7 g (13.2 mmol) of the compound obtained in the above (2) in 100 ml of methylene chloride were added 1.8 ml (19.0 mmol) of aniline, 4.0 ml (51.6 mmol) of pyridine and 0.16 g (1.3 mmol) of 4-dimethylaminopyridine, followed by stirring overnight. After the reaction, the reaction solution was washed with IN aqueous hydrochloric acid solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced
pressure. The residue was dissolved in 100 ml of methanol, and 0.5 g of palladium carbon was added thereto, followed by stirring under a hydrogen stream overnight. After the reaction, the catalyst in the reaction solution was removed by filtration, and the filtrate was concentrated under reduced pressure to give 1.7 g of 2-aminoethylsulfonanilide.
Example 34 11- \ 2 - (N-Phenylsulfamoyl) ethyl lamino-3.11- dideoxy-3 -oxo-5-O-desosaminyl-6-O-methylervthronolide A
11,12-cyclic carbamate
Following the same procedure as in Example 33 using 0.38 g (0.50 mmol) of the compound obtained in Example 12(3), 1.0 g (5.0 mmol) of 2-aminoethyl- sulfonanilide described in Reference Example 3 , there was obtained 0.34 g (yield: 85 %) of the title compound.
FABMS m/z: 796 [M+H] +
XH-NMR (500 MHz, CDC13) δ (ppm) ; 0.87 (t, 3H, J=7.3 Hz, 14-Me) , 2.26 (s, 6H, NMe2) , 2.60 (s, 3H, 6-OMe) , 4.23 (d, IH, J=8.5 Hz, H-5) .
Example 35
11- \ 2 - TN- (4-Methoxγphenyl) sulfamoyl! ethyll - .amino-ll-deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6- O-methylervthronolide A 11,12-cyclic carbamate
Following the same procedure as in Example 33 using 0.50 g (0.57 mmol) of the compound obtained in
Example 10(4), 4-methoxyaniline in place of aniline and 1.30 g (5.7 mmol) of 4 ' -methoxy-2-aminoethyl- sulfonanilide prepared in the same manner as in Reference Example 3, there was obtained 0.06 g (yield: 11 %) of the title compound. FABMS m/z: 947 [M+H] + ^-NMR (300 MHz, CDC13) δ (ppm) ; 0.83 (t, 3H, J=7.3 Hz,
14-Me) , 2.29 (s, 6H, NMe2) , 2.97 (s, 3H, 6-OMe) , 3.79 (s, 3H, Ph-OMe) , 5.06 (d, IH, J=10.6 Hz, H-3), 5.48 (dd, IH, J=11.0, 2.0 Hz, H-13), 6.87 ( , 2H) , 7.29 (m, 2H) .
Example 36
11- \ 2 - TN- (3-Pyridyl) sulfamoyll ethyll amino-11- deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-0- methylervthronolide A 11,12-cyclic carbamate
Following the same procedure as in Example 33 using 0.35 g (0.40 mmol) of the compound obtained in Example 10(4), 3 -aminopyridine in place of aniline and 0.80 g (3.98 mmol) of 3- (2-aminoethyl) sulfonamidopyridine prepared in the same manner as in Reference Example 3 , there was obtained 0.05 g (yield: 14 %) of the title compound.
FABMS m/z: 918 [M+H] + XH-NMR (300 MHz, CDC13) δ (ppm) ; 0.84 (t, 3H, J=7.3 Hz,
14-Me) , 2.29 (s, 6H, NMe2) , 2.99 (s, 3H, 6-OMe) , 5.06 (d, IH, J=11.0 Hz, H-3), 5.48 (dd, IH, J=11.2, 2.0 Hz, H-13), 6.87 ( , 2H) , 7.29 (m, 2H) .
Example 37
11- \2 - r (4-Nitrophenylsulfonyl)aminol ethyl! - amino-ll-deoxy-3-Q-methylthiomethyl-5-0-desosaminyl-6-0- methylervthronolide A 11,12-cyclic carbamate (1) Following the same procedures as in
Example 1(1) and (2) using 5.06 g (7.69 mmol) of the compound obtained in Reference Example 1 and 2.3 g (10.4 mmol) of 4-nitrobenzenesulfonyl chloride, there was obtained 7.31 g of the 2 ' -O-acetyl compound. (2) Following the same procedure as in Example
2 using 4.02 g (4.54 mmol) of the compound obtained in the above (1), there were obtained 1.33 g (yield: 35 %) of the same compound as obtained in Example 14 and 0.15 g (yield: 4 %) of the title compound. IonSpray MS m/z: 903.4 [M+H] +
1 H-NMR (500MHz, CDCl 3 ) { (ppm) 2.28 (s , 6H, NMe _ ) , 2.29(s, 3H, SMe) , 2.94(s, 3H, 6-OMe) , 4.44(d, IH, J=7.3Hz, H-l'), 4.68 and 4.92 (each d, each IH, J=11.0Hz, -OCH_2_SMe) - 4.86 (dd, IH, J=11.0, 1.8Hz, H-13) 13C-NMR(125MHz, CDCl 3 ) (ppm) 15.8 (SMe) , 40.2 (NMe 2),
50.2(6-OMe), 77.7 (-OCH 2 SMe) , 101.7(C1'), 158.0(11, 12-carbamate) , 176.5(C1), 216.2 (C9) .
Example 38 11- \ 2 - (3-Pγridylsulfonγlamino) ethyll a ino-
3 , ll-dideoxy-3-oxo-5-0-desosaminyl-6-0-methyl- ervthronolide A 11,12-cvclic carbamate
(1) Following the same procedures as in
Example 1(1) and (2) using 1.00 g (1.52 mmol) of the compound obtained in Reference Example 1 and 0.60 g (3.4 mmol) of 3-pyridylsulfonyl chloride obtained in Reference Example 2 , there was obtained 0.42 g of the 2 ' -O-acetyl compound.
(2) Following the same procedure as in Example 2 using 0.42 g (0.5 mmol) of the compound obtained in the above (1), there was obtained 0.21 g (yield: 17 %) of the title compound. IonSpray MS m/z: 797.4 [M+H] +
1 H-NMR (500MHz, CDCl 3 ) -5 (ppm) 2.26 (s , 6H, NMe _ ) , 2.51(s, 3H, 6-OMe) , 3.84(q, IH, J=6.7Hz, H-2), 4.22 (d, IH, J=9.2Hz, H-5), 4.27(d, IH, J=7.3Hz, H-l'), 4.86(dd, IH, J=11.0, 2.4Hz, H-13), 6.12 (brs, IH, -NHS02-) ■ C-NMR( 125MHz, CDCl 3 ) i (ppm) 40.2 (NMe _ ) , 49.7(6-OMe), 103.9(C1'), 158.0(11, 12-carbamate) , 170.2(C1), 203.2(C3), 216.6(C9).
Example 39 11- \ 2- r (5- T2- (Methylthio)pyrimidin-4- yl! thiophene-2-sulfonylamino! ethyll amino-11-deoxy-3-0- (2-pyridyl) -acetyl-5-0-desosaminyl-6-0- methylervthronolide A 11.12-cvclic carbamate
Following the same procedure as in Example 10(6) using 0.55 g (0.71 mmol) of the compound obtained in Example 10(5) and 0.26 g (0.85 mmol) of 5- [2- (methylthio)pyrimidin-4-yl] thiophene-2-sulfonyl chloride, there was obtained 0.50 g (yield: 67 %) of the title
compound.
FABMS m/z: 1047 [M+H] +
1 H-NMR (500MHz, CDCl 3 ) J (ppm)2.30 (s, 6H, NMe _ ) , 2.60(s,
3H, SMe), 2.91(s, 3H, 6-OMe) , 3.92 and 3.96 (each d, each IH, J=15.9Hz, -CH_2_ [2-Pyridine] ) , 4.26(d, IH,
J=7.3Hz, H-l'), 4.98(dd, IH, J=11.0, 1.8Hz, H-13),
5.00(d, IH, J=11.6Hz, H-3), 6.24(brs, IH, -NHSO 2-) 13C-NMR( 125MHz, CDCl 3 ) δ (ppm) 14.1 (SMe) , 40.3 (NMe 2),
50.1(6-OMe), 103.5(C1'), 157.6 (11, 12-carbamate) , 170.4(-COCH 2 [2-Pyridine] ) , 175.2(C1), 216.0(C9).
Eχ.ample 40
11- [2- (6-Chloroimidazor2, 1-bl thiazole-5- sulfonylamino) ethyll amino-ll-deoxy-3-O- (2- pyridyl) acetyl-5-0-desosaminyl-6-Q-methylerythronolide A 11,12-cyclic carbamate
Following the same procedure as in Example 10(6) using 0.62 g (0.80 mmol) of the compound obtained in Example 10(5) and 0.26 g (1.0 mmol) of 6- chloroimidazo [2 , 1-b] thiazole-5-sulfonyl chloride, there was obtained 0.16 g (yield: 19 %) of the title compound. FABMS m/z: 997 [M+H] +
1 H-NMR (500MHz, CDCl 3 ) (ppm) 2.30 (s , 6H, NMe _ ) , 2.85(s, 3H, 6-OMe) , 3.92 and 3.96 (each d, each IH, J=15.9Hz, -CH_2_[2-Pyridine] ) , 4.06(d, IH, J=7.3Hz, H-l'),
4.99(d, IH, J=11.0Hz, H-3), 5.00(dd, IH, J=11.0, 2.4Hz, H-13), 6.65 (brs, IH, -NHS02-) 13C-NMR( 125MHz, CDCl 3 ) I (ppm) 40.3 (NMe 2 ) , 50.0(6-OMe),
103.5(C1'), 157.8 (11, 12-carbamate) , 170.4 (-COCH _ [2 - Pyridine]), 175.3(d), 215.9 (C9) .
Example 41 11- \ 2 - (5-Chloro-3-methylbenzo[b1 thiophene-2- sulfonylamino) ethyll amino-ll-deoxy-3-0- (2-pyridyl) - acetyl-5-0-desosaminyl-6-0-methγlervthronolide A 11,12- cvclic carbamate
Following the same procedure as in Example 10(6) using 0.51 g (0.65 mmol) of the compound obtained in Example 10(5) and 0.22 g (0.78 mmol) of 5-chloro-3- methylbenzo [b] thiophene-2-sulfonyl chloride, there was obtained 0.45 g (yield: 67%) of the title compound. FABMS m/z: 1021 [M+H] + 1 H-NMR (500MHz, CDCl 3 ) $ (ppm) 2.29 (s , 6H, NMe _ ) , 2.66(s, 3H, benzothiophene-Me) , 2.88 (s, 3H, 6-OMe) , 3.93 and 3.96(each d, each IH, J=15.9Hz, -CH_2_ [2 -Pyridine] ) , 4.05(d, IH, J=6.7Hz, H-l'), 4.97-5.00(m, IH, H-13), 5.01(d, IH, J=11.6Hz, H-3 ) , 6.48(brs, IH, -NHSO 2-) 13C-NMR( 125MHz, CDCl 3 ) (ppm) 12.2 (benzothiophene-Me) , 40.3(NMe2), 50.1(6-OMe), 103.5(C1'), 157.9(11,12- carbamate) , 170.4 (-COCH 2 [2-Pyridine] ) , 175.2 (Cl), 215.9(C9) .
Example 42
11- \ 2 - (4-Methylsulfonylbenzenesulfonylamino) - ethyll amino-ll-deoxy-3-O- (2-pyridγl) acetyl-5-O- desosaminyl-6-O-methylervthronolide A 11,12-cyclic
carbamate
Following the same procedure as in Example 10(6) using 0.53 g (0.68 mmol) of the compound obtained in Example 10(5) and 0.23 g (0.90 mmol) of 4- methylsulfonylbenzenesulfonyl chloride, there was obtained 0.36 g (yield: 53 %) of the title compound. FABMS m/z: 995 [M+H] + 1 H-NMR (500MHz, CDCl 3 ) <5 (ppm) 2.29 ( s , 6H, NMe _ ) , 2.87 (s,
3H, 6-OMe) , 3.08(s, 3H, S02Me), 3.93 and 3.96 (each d, each IH, J=15.9Hz, -CH.^ [2-Pyridine] ) , 4.07 (d, IH, J=7.3Hz, H-l'), 4.92(dd, IH, J=11.0, 1.8Hz , H-13), 5.00(d, IH, J=11.0Hz, H-3), 6.30(brs, IH, -NHS02-) 13C-NMR( 125MHz, CDCl 3 ) * (ppm) 40.3 (NMe _ ) , 44.2 (SO _ Me), 50.1(6-OMe), 103.5(C1'), 157.8 (11, 12-carbamate) , 170.6(-C_OCH _ [2-Pyridine] ) , 175.5(d), 216.0(C9).
Example 43
11- \2 - (2-Thiophenesulfonylamino) ethyll amino-11- deoxy-3-O- (2-pyridyl) acetyl-5-0-desosamιnyl-6-0- methylerythronolide A 11,12-cyclic carbamate
Following the same procedure as in Example 10(6) using 0.52 g (0.66 mmol) of the compound obtained in Example 10(5) and 0.15 g (0.82 mmol) of 2- thiophenesulfonyl chloride, there was obtained 0.46 g (yield: 75 %) of the title compound. FABMS m/z : 923 [M+H] +
1 H-NMR (500MHz, CDCl 3 ) t (ppm) 2.29 (s , 6H, NMe _ ) , 2.88(s, 3H, 6-OMe) , 3.92 and 3.96 (each d, each IH, J=15.9Hz,
-CH_2_ [2-Pyridine] ) , 4.06(d, IH, J=7.3Hz, H-l'), 4.98(dd, IH, J=11.0, 1.8Hz, H-13), 5.01(d, IH, J=11.0Hz, H-3), 6.10 (brs, IH, -NHS02-) 13C-NMR( 125MHz, CDCl 3 ) . (ppm) 40.3 (NMe 2 ) , 50.1(6-OMe), 103.5(C1'), 157.7 (11, 12-carbamate) , 170.5 (-COCH _ [2- Pyridine]), 175.KC1), 215.9 (C9).
Example 44
11- T2- T5- (Isoxazol-3-yl) thiophene-2- sulfonylamino1 ethyll amino-ll-deoxy-3-0- (2- pyridyl) acetγl-5-0-desosaminyl-6-0-methylervthronolide A 11, 12-cyclic carbamate
Following the same procedure as in Example 10(6) using 0.58 g (0.75 mmol) of the compound obtained in Example 10(5) and 0.22 g (0.88 mmol) of 5-(isoxazol- 3-yl) thiophene-2-sulfonyl chloride, there was obtained 0.36 g (yield: 48 %) of the title compound. FABMS m/z : 990 [M+H] +
Η-NMR(500MHz, CDC13) $ (ppm) 2.29 (s, 6H, NMe 2 ) , 2.93(s, 3H, 6-OMe) , 3.91 and 3.95 (each d, each IH, J=15.9Hz, -CH_2_ [2-Pyridine] ) , 4.05 (d, IH, J=7.3Hz, H-l'), 4.95(dd, IH, J=11.0, 2.2Hz , H-13), 5.01(d, IH, J=10.9Hz, H-3), 6.30(brs, IH, -NHS02-) 13C-NMR(125MHz, CDCl 3 ) S (ppm) 40.3 (NMe _ ) , 50.2(6-OMe), 103.5(C1'), 157.9 (11, 12-carbamate) , 170.4 (-COCH 2 [2- Pyridine] ) , 175.2(d), 216.0(C9).
Example 45
11- f2- (Benzofurazan-4-sulfonylamino) ethyll - amino-ll-deoxy-3-O- (2-pyridyl) acetyl-5-Q-desosaminyl-6- O-methylervthronolide A 11,12-cvclic carbamate Following the same procedure as in Example
10(6) using 0.58 g (0.75 mmol) of the compound obtained in Example 10(5) and 0.19 g (0.87 mmol) of benzofurazan- 4-sulfonyl chloride, there was obtained 0.47 g (yield: 66 %) of the title compound. FABMS m/z.-990 [M+H] +
1 H-NMR (500MHz, CDCl 3 ) J (ppm) 2.29 (s , 6H, NMe _ ) , 3.02 (s, 3H, 6-OMe) , 3.93 and 3.96 (each d, each IH, J=15.9Hz, -CH_2_ [2-Pyridine] ) , 4.08 (d, IH, J=7.3Hz, H-l'), 5.02 (dd, IH, J=11.0Hz, H-3), 5.11 (dd, IH, J=11.0, 1.8Hz, H-13), 6.48 (brs, IH, -NHS02-)
13C-NMR( 125MHz, CDCl 3 ) J (ppm) 40.3 (NMe 2 ) , 50.5(6-OMe), 103.5(C1'), 157.1 (11, 12-carbamate) , 170.4 (-C0CH _ [2- Pyridine] ) , 175.3 (Cl), 215.8(C9).
Example 46
11- \2 - (2-Methylsulfonylbenzenesulfonγlamino) - ethyl! amino-ll-deoxy-3-O- (2-pyridyl) acetyl-5-O- desosaminyl-6-O-methylerγthronolide A 11,12-cyclic carbamate Following the same procedure as in Example
10(6) using 0.52 g (0.67 mmol) of the compound obtained in Example 10(5) and 0.21 g (0.82 mmol) of 2- methylsulfonylbenzenesulfonyl chloride, there was
obtained 0.46 g (yield: 66 %) of the title compound.
FABMS m/z: 995 [M+H] +
1 H-NMR (500MHz, CDCl 3 ) $ (ppm) 2.29 (s , 6H, NMe _ ) , 2.92(s,
3H, 6-OMe) , 3.92 and 3.96 (each d, each IH, J=15.9Hz, -CH_2_ [2-Pyridine] ) , 3.39(s, 3H, S02Me), 4.05 (d, IH,
J=7.3Hz, H-l'), 5.00(d, IH, J=11.0Hz, H-3), 5.04(dd,
IH, J=11.0, 1.8Hz, H-13), 6.40(brt, IH, J=5.5Hz,
-NHSO 2-) 13C-NMR( 125MHz, CDCl 3 ) I (ppm) 40.3 (NMe _ ) , 50.1 (6-OMe) , 103.6(C1'), 157.2 (11, 12-carbamate) , 170.4 (-COCH 2 [2-
Pyridine] ) , 174.0(C1), 215.6 (C9).
Example 47
11- \ 2 - (4-Nitrobenzenesulfonylamino) butyll amino- 3 , ll-dideoxy-3-oxo-5-0-desosaminyl-6-0- methylervthronolide A 11,12-cvclic carbamate
(1) Following the same procedure as in Example 10(5) using 3.0 g (4.25 mmol) of the compound obtained in Example 12(3) and 4.3 ml (43 mmol) of 1,4- diaminobutane , there was obtained 3.2 g of 11- (3- aminobutyl) amino-3 , ll-dideoxy-3-oxo-5-0-desosaminyl-6-0- methylerythronolide A 11,12-cyclic carbamate.
(2) Following the same procedure as in Example 10(6) using 0.61 g (0.88 mmol) of the compound obtained in the above (1) and 0.26 g (1.2 mmol) of 4-nitro- benzenesulfonyl chloride, there was obtained 0.45 g (yield: 58 %) of the title compound. FABMS m/z: 869 [M+H] +
1 H-NMR (500MHz, CDCl 3 ) S (ppm) 2.27 (s , 6H, NMe _ ) , 2.60(s, 3H, 6-OMe) , 3.87 (q, IH, J=6.7Hz, H-2), 4.26(d, IH, J=8.6Hz, H-5), 4.29(d, IH, J=7.3Hz, H-l'), 4.88(dd, IH, J=11.0, 1.8Hz, H-13), 5.65 (brs, IH, -NHSO 2-) ' 3C-NMR( 125MHz, CDCl 3 ) J (ppm) 40.2 (NMe _ ) , 49.9(6-OMe), 104.0(C1'), 157.3 (11, 12-carbamate) , 170.1(C1), 203.4(C3) , 216.9(C9) .
Example 48 11- \ 2 - (4-Nitrobenzenesulfonylamino) butyll amino- ll-deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminγl-6-0- methylerythronolide A 11,12-cyclic carbamate
(1) Following the same procedure as in Example 10(5) using 5.0 g (6.1 mmol) of the compound obtained in Example 10(4) and 6.1 ml (61 mmol) of 1, 4-diaminopropane, there was obtained 4.9 g of 11- (3-aminobutyl)amino-ll- deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-0- methylerythronolide A 11,12-cyclic carbamate.
(2) Following the same procedure as in Example 10(6) using 0.45 g (0.56 mmol) of the compound obtained in the above (1) and 0.14 g (0.63 mmol) of 4- nitrobenzenesulfonyl chloride, there was obtained 0.34 g
(yield: 62 %) of the title compound.
FABMS m/z: 990 [M+H] + ' H-NMR (500MHz, CDCl 3 ) I (ppm) 2.30(s, 6H, NMe _ ) , 3.00(s, 3H, 6-OMe) , 3.93 and 3.99 (each d, each IH, J=15.9Hz, -CH_2_[2-Pyridine] ) , 4.08(d, IH, J=7.3Hz, H-l'), 4.97 (dd, IH, J=11.0, 2.1Hz, H-13), 5.06(d, IH,
J=11 . 2Hz , H-3 ) .
Example 49
11- \ 2 - (2-Acetamido-4-methyl-5- thiazolesulfonylamino) butyll amino-ll-deoxy-3-0- (2- pyridyl) acetyl-5-0-desosaminyl-6-0-methylerythronolide A 11.12-cyclic carbamate
Following the same procedure as in Example 10(6) using 0.43 g (0.53 mmol) of the compound obtained in Example 48(1) and 0.16 g (0.63 mmol) of 2-acetamido- 4-methyl-5-thiazolesulfonyl chloride, there was obtained 0.38 g (yield: 70 %) of the title compound. FABMS m/z : 1023 [M+H] +
1 H-NMR (500MHz, CDCl 3 ) S (ppm) 2.23 (s, 3H, COCH 3 ) , 2.29 (s, 6H, NMe2), 2.98 (s, 3H, 6-OMe) , 3.93 and 3.98 (each d, each IH, J=15.9Hz, -CH__2_[2-Pyridine] ) , 4.08(d, IH, J=7.3Hz, H-l'), 4.98(dd, IH, J=11.0, 2.1Hz, H-13), 5.02(d, IH, J=11.3Hz, H-3), 5.63 (brt, IH, J=5.8Hz, -NHSO 2-) ' 3C-NMR( 125MHz, CDCl 3 ) $ (ppm) 22.9(COCH3), 40.3(NMe2), 50.2(6-OMe), 103.6(C1'), 157.5(11, 12-carbamate) , 168.2 (COCH 3) , 170.7 (-COCH 2 [2-Pyridine] ) , 174.5 (Cl), 216.4(C9) .
Example 50
11- \2 - ( 3-Pyridylsulfonylamino) butyll amino-11- deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-0- methylervthronolide A 11.12-cvclic carbamate
Following the same procedure as in Example 10(6) using 0.58 g (0.72 mmol) of the compound obtained in Example 48(1) and 0.38 g (2.14 mmol) of 3- pyridylsulfonyl chloride obtained in Reference Example 2, there was obtained 0.51 g (yield: 75 %) of the title compound.
FABMS m/z: 946 [M+H] +
1 H-NMR (500MHz, CDCl 3 ) S (ppm) 2.30(s, 6H, NMe 2 ) , 3.04 (s, 3H, 6-OMe) , 3.93 and 3.97 (each d, each IH, J=15.9Hz, -CH_2_[2-Pyridine] ) , 4.08(d, IH, J=7.3Hz, H-l'), 4.98(dd, IH, J=11.0, 1.8Hz , H-13), 5.06(d, IH, J=11.0Hz, H-3), 5.77 (brs, IH, -NHS02-) 13C-NMR( 125MHz, CDCl 3 ) t (ppm) 40.3 (NMe 2), 50.4(6-OMe), 103.6(C1'), 157.4(11, 12-carbamate) , 170.4 (-COCH 2 [2- Pyridine]), 174.8 (Cl), 216. (C9).
Example 51
11- \2 - ( 3 -Pyridylsulfonylamino) butyll amino-3 , 11- dideoxy-3-oxo-5-0-desosaminyl-6-0-methylervthronolide A 11, 12-cyclic carbamate
Following the same procedure as in Example
10(6) using 0.78 g (1.15 mmol) of the compound obtained in Example 47(1) and 0.61 g (3.43 mmol) of 3- pyridylsulfonyl chloride obtained in Reference Example 2, there was obtained 0.39 g (yield: 41 %) of the title compound.
FABMS m/z: 825 [M+H] +
1 H-NMR (500MHz, CDCl 3 ) . (ppm) 2.27 (s , 6H, NMe 2 ) , 2.63 (s,
3H, 6-OMe) , 3.87(q, IH, J=6.7Hz, H-2), 4.27 (d, IH, J=10.4Hz, H-5), 4.29(d, IH, J=7.3Hz, H-l'), 4.90(dd, IH, J=11.0, 1.8Hz, H-13), 5.68 (brs, IH, -NHS02-) 13C-NMR(125MHz, CDCl 3 ) & (ppm) 40.2 (NMe 2 ) , 50.0(6-OMe), 103.9(C1'), 157.3 (11, 12-carbamate) , 170.KC1), 203.4(C3) , 216.9(C9) .
Example 52
11- r2- (2-Dibenzofuransulfonylamino) ethyll amino- 3. ll-dideoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-0- methylerythronolide A 11.12-cvclic carbamate
Following the same procedure as in Example 10(6) using 0.33 g (0.42 mmol) of the compound obtained in Example 10(5) and 0.13 g (0.49 mmol) of 2- dibenzofuransulfonyl chloride, there was obtained 0.24 g (yield: 57 %) of the title compound. FABMS m/z: 1007 [M+H] +
1 H-NMR (300MHz, CDCl 3 ) δ (ppm) 2.29 (s, 6H, NMe _ ) , 2.88(s, 3H, 6-OMe) , 3.97 and 3.91 (each d, each IH, J=15.9Hz, -CH_2_ [2-Pyridine] ) , 4.05(d, IH, J=7.3Hz, H-l'), 4.96(dd, IH, J=11.0, 2.0Hz, H-13), 5.01(d, IH, J=11.2Hz, H-3), 6.00 (brt, IH, -NHS02-).
Example 53 11- \ 2- (2-Methylsulfonylbenzenesulfonylamino) - ethyl! amino-3 , ll-dideoxy-3-oxo-5-0-desosaminyl-6-0- methylervthronolide A 11.12-cvclic carbamate
Following the same procedure as in Example
12(5) using 0.51 g (0.73 mmol) of the compound obtained in Example 12(4) and 0.22 g (0.86 mmol) of 2- methylsulfonylbenzenesulfonyl chloride, there was obtained 0.46 g (yield: 72 %) of the title compound. IonSprayMS m/z:874.2 [M+H]+
1 H-NMR (300MHz, CDCl 3 ) i (ppm) 2.26 (s , 6H, NMe _ ) , 2.55(s, 3H, 6-OMe) , 3.40(s, 3H, S02Me), 4.96(dd, IH, J=10.6, 2.5Hz, H-13), 6.37 (brt, IH, J=6.2Hz, -NHS02-)
Example 54
11- T2- r2- (Pyrid-2-yl) thiophene-5- sulfonylamino! ethyl! amino-3. ll-dideoxy-3-oxo-5-0- desosaminyl-6-O-methylervthronolide A 11,12-cvclic carbamate Following the same procedure as in Example
12(5) using 0.51 g (0.73 mmol) of the compound obtained in Example 12(4) and 0.24 g (0.92 mmol) of 2-(pyrid-2- yl) thiophene-5-sulfonyl chloride, there was obtained 0.33 g (yield: 48 %) of the title compound. IonSprayMS m/z: 879.3 [M+H] +
1 H-NMR (300MHz, CDCl 3 ) I (ppm) 2.26 (s , 6H, NMe _ ) , 2.58(s, 3H, 6-OMe) , 4.22 (d, IH, J=8.7Hz, H-5) , 4.27 (d, IH, J=7.3Hz, H-l'), 4.92(dd, IH, J=10.6, 2.3Hz, H-13), 6.00 (brs, IH, -NHS02-).
Example 55
11- \ 2 - (2-Methylsulfonylbenzenesulfonylamino) ethyll amino-11-deoxy-3-0- (2-pyridyl) acetyl-5-O-
desosaminylervthronolide A 11,12-cvclic carbamate
(1) Following the same procedure as in Example 10(5) using 2.47 g of 2 ' -O-acetyl-10 , ll-anhydro-12-O- imidazolylcarbonyl-3-O- (2-pyridyl) acetyl-5-O- desosaminylerythronolide A, there was obtained 2.29 g of 11- (2-aminoethyl) amino-ll-deoxy-3-O- (2-pyridyl) acetyl-5- O-desosaminylerythronolide A 11,12-cyclic carbamate.
(2) Following the same procedure as in Example 10(6) using 0.52 g (0.68 mmol) of the compound obtained in the above (1) and 0.21 g (0.82 mmol) of 2- methylsulfonylbenzenesulfonyl chloride, there was obtained 0.38 g (yield: 57 %) of the title compound. FABMS m/z: 981 [M+H] +
1 H-NMR (500MHz, CDCl 3 ) 5 (ppm) 2.33 (s, 6H, NMe _ ) , 3.40(s, 3H, SO 2 Me), 3.91 and 3.95 (each d, each IH, J=15.3Hz, -CH_2_ [2-Pyridine] ) , 4.57 (d, IH, J=7.3Hz, H-l'), 4.99 and 5.48 (each brs, each IH, H-3 and H-13), 6.25 (brs, IH, -NHSO 2-) 13C-NMR(125MHz, CDCl 3 ) (ppm) 40.5 (NMe 2 ) , 44.3 (SO _ Me), 104.5(C1'), 156.5(11, 12-carbamate) , 170.0 (-COCH _ [2- Pyridine] ) , 174.6(d), 214.5 (C9).
Example 56
11- T2- r (2-Acetamido-4-methyl-5- thiazolesulfonyl) amino! ethyll amino-ll-deoxy-3-0- (2- pyridyl) acetyl-5-0-desosaminyl-6-0-methylervthronolide A 11,12-cvclic carbamate
(1) Following the same procedure as in Example
10(5) using 5.0 g (6.1 mmol) of the compound obtained in Example 10(4) and 4.5 g (61 mmol) of 1, 3-diaminopropane, there was obtained 4.5 g of 11- (3-aminopropyl) amino-11- deoxy-3-O- (2-pyridyl)acetyl-5-0-desosaminyl-6-0- methylerythronolide A 11,12-cyclic carbamate.
(2) Following the same procedure as in Example 10(6) using 0.50 g (0.63 mmol) of the compound obtained in the above (1) and 0.24 g (0.95 mmol) of 2-acetamido- 4-methyl-5-thiazolesulfonyl chloride, there was obtained 0.47 g (yield: 74 %) of the title compound. FABMS m/z: 1009 [M+H] +
1 H-NMR (500MHz, CDCl 3 ) i (ppm) 0.76 (t, 3H, J=7.3Hz, 14-Me) , 2.29(s, 6H, NMe2), 2.93(s, 3H, 6-OMe) , 4.07 (d, IH, J=7.3Hz, H-l'), 4.92 (dd, IH, J=11.0, 2.1Hz, H-13), 5.01(d, IH, J=11.0Hz, H-3).
13C-NMR(125MHz, CDCl 3 ) S (ppm) 40.3 (NMe _ ) , 50.0(6-OMe), 103.7(C1'), 157.9 (11, 12-carbamate) , 174.5(C1), 216.0(C9) .
Example 57
11- T3- (4-Nitrobenzenesulfonyl) aminopropyll - amino-ll-deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6- O-methylerythronolide A 11.12-cvclic carbamate
Following the same procedure as in Example 10(6) using 0.50 g (0.63 mmol) of the compound obtained in Example 56(1) and 0.21 g (0.95 mmol) of 4-nitrobenzenesulfonyl chloride, there was obtained 0.45 g (yield: 21 %) of the title compound.
FABMS m/z: 976 [M+H] +
1 H-NMR (500MHz, CDCl 3 ) -J (ppm) 2.29 (s, 6H, NMe _ ) , 2.98 (s, 3H, 6-OMe) , 4.06(d, IH, J=7.3Hz, H-l'), 4.83 (dd, IH, J=11.0, 1.8Hz, H-13), 5.02(d, IH, J=11.0Hz, H-3). 13C-NMR (125MHz, CDCl 3 ) (ppm) 40.3 (NMe _ ) , 50.0(6-OMe), 103.6(C1'), 158.1(ll,12-carbamate) , 174.7 (Cl), 216.KC9) .
Example 58 11- [3- (3 -Pyridylsulfonyl) aminopropyll amino-11- deoxy-3-O- (2-pyridyl) acetyl-5-0-desosaminyl-6-Q- methylervthronolide A 11,12-cvclic carbamate
Following the same procedure as in Example 10(6) using 0.50 g (0.63 mmol) of the compound obtained in Example 56(1) and 0.40 g (2.3 mmol) of pyridine-3- sulfonyl chloride obtained in Reference Example 2, there was obtained 0.24 g (yield: 21 %) of the title compound. FABMS m/z:932[M+H]+
1 H-NM (500MHz, CDCl 3 ) S (ppm) 2.29 (s , 6H, NMe 2 ) , 2.99(s, 3H, 6-OMe) , 4.06(d, IH, J=7.3Hz, H-l'), 4.86(dd, IH, J=11.0, 2.4Hz, H-13), 5.02(d, IH, J=11.6Hz, H-3), 5.89(brs, IH, -NHSO 2-) .
Example 59 11- r3 - r (2-Acetamido-4-methyl-5- thiazolesulfonyl) aminolprop l! amino-3. ll-dideoxy-3-oxo- 5-0-desosaminyl-6-0-methylervthronolide A 11.12-cvclic carbamate
(1) Following the same procedure as in Example 10(5) using 2.0 g (2.8 mmol) of the compound obtained in Example 12(3) and 2.1 g (28 mmol) of 1, 3-diaminopropane, there was obtained 2.0 g of 11- (3-aminopropyl) amino- 3 , ll-dideoxy-3-oxo-5-0-desosaminyl-6-0- methylerythronolide A 11,12-cyclic carbamate.
(2) Following the same procedure as in Example 10(6) using 0.40 g (0.56 mmol) of the compound obtained in the above (1) and 0.22 g (0.84 mmol) of 2-acetamido- 4-methyl-5-thiazolesulfonyl chloride, there was obtained 0.31 g (yield: 62 %) of the title compound. FABMS m/z: 888 [M+H] +
1 H-NMR (500MHz, CDCl 3 ) t (ppm) 2.27 (s , 6H, NMe _ ) , 2.62 (s, 3H, 6-OMe) , 4.23 (d, IH, J=9.2Hz, H-5), 4.28(d, IH, J=7.3Hz, H-l'), 4.84(dd, J=11.0, 2.4Hz, H-13), 5.89(brs, IH, -NHS02-) 13C-NMR( 125MHz, CDCl 3 ) J (ppm) 40.2 (NMe _ ) , 49.9(6-OMe), 104.0(C1'), 158.0(11, 12-carbamate) , 169.8(C1), 203.5(C3) , 216.4(C9) .
Example 60
11- [3- (3-Pyridylsulfonyl) aminopropyll amino- 3 , ll-dideoxy-3-oxo-5-0-desosaminyl-6-0- methylervthronolide A 11,12-cyclic carbamate Following the same procedure as in Example
10(6) using 0.39 g (0.58 mmol) of the compound obtained in Example 59(1) and 0.22 g (0.84 mmol) of 2-acetamido- 4-methyl-5-thiazolesulfonyl chloride, there was obtained
0.31 g (yield: 51 %) of the title compound. FABMS m/z: 811 [M+H] +
1 H-NMR (300MHz, CDCl 3 ) 6 (ppm) 0.76 ( t, IH, J=7.5Hz, 14-Me) , 2.27(s, 6H, NMe2), 2.60(s, 3H, 6-OMe) , 4.23(d, IH, J=8.6Hz, H-5), 4.28(d, IH, J=7.3Hz, H-l'), 4.78(dd, J=11.0, 2.4Hz, H-13), 5.82 (brs, IH, -NHS02-)
Example 61
11- \ 2 - TN- (2-Methylsulfonylbenzene) sulfonyl-N- methylamino! ethyl! amino-ll-deoxy-3-0- (2 -pyridyl) acetyl- 5-0-desosaminyl-6-0-methylerythronolide A 11,12-cyclic carbamate
(1) 8.0 g (9.14 mmol) of 11- [2- (N-methyl-N- benzylamino) ethyl] amino-ll-deoxy-3-O- (2-pyridyl) acetyl- 5-0-desosaminyl-6-0-methylerythronolide A 11,12-cyclic carbamate was hydrogenated in methanol using palladium- carbon in an ordinary manner. The reaction solution was filtered, and the solvent was evaporated under reduced pressure to give 5.0 g (yield: 69 %) of the debenzylated compound.
(2) Following the same procedure as in Example 10(6) using 0.40 g (0.51 mmol) of the compound obtained in the above (1) and 0.16 g (0.61 mmol) of 2- methylsulfonylbenzenesulfonyl chloride, there was obtained 0.39 g (yield: 76 %) of the title compound. SIMS m/z: 1009 [M+H] +
1 H-NMR (300MHz, CDCl 3 ) (ppm) 0.82 ( t , 3H, J=7.3Hz, 14-Me) , 2.29(s, 6H, NMe2), 2.99(s, 3H, 6-OMe) , 4.06(d, IH,
J=7.3Hz, H-l"), 5.03-5.11(m, 2H, H-3 and H-13).
Example 62
11- r2-TN- (6-Chloroimidazor2, 1.61 thiazole-5- sulfonyl ) -N-methγlaminol ethyl! amino-ll-deoχy-3-O- (2- pyridyl) acetγl-5-Q-desosaminyl-6-0-methylervthronolide A 11,12-cyclic carbamate
Following the same procedure as in Example 10(6) using 0.40 g (0.51 mmol) of the compound obtained in Example 61 and 0.16 g (0.61 mmol) of 6-chloroimidazo- [2 , 1, 6] thiazole-5-sulfonyl chloride, there was obtained 0.38 g (yield: 74 %) of the title compound. SIMS m/z : 1011 [M+H] +
1 H-NMR (300MHz, CDCl 3 ) -J (ppm) 0.81 (t, 3H, J=7.3Hz, 14-Me) , 2.30(s, 6H, NMe2), 3.03(s, 3H, 6-OMe) , 4.06(d, IH, J=7.3Hz, H-l'), 5.03-5.11(m, 2H, H-3 and H-13).
Example 63
11- Ϊ2 - TN- (3 -Pyridylsulfonyl) -N-methylaminol - ethyl! amino-ll-deoxy-3-O- (2-pyridyl) acetyl-5-O- desosaminyl-6-O-methylervthronolide A 11,12-cyclic carbamate
Following the same procedure as in Example
10(6) using 0.40 g (0.51 mmol) of the compound obtained in Example 61 and 0.18 g (1.02 mmol) of pyridine-3- sulfonyl chloride, there was obtained 0.25 g (yield:
53 %) of the title compound.
SIMS m/z : 932 [M+H] +
1 H-NMR (300MHz, CDCl 3 ) $ (ppm) 0.83 ( t , 3H, J=7.3Hz, 14-Me) , 2.30(s, 6H, NMe2), 2.97(s, 3H, 6-OMe) , 4.07 (d, IH, J=7.3Hz, H-l'), 5.04 (dd, IH, J=11.0, 2.3Hz, H-13), 5.05(d, IH, J=11.2Hz, H-3).
Example 64
11- f2- T (2-Nitrophenyl) sulfonylamino1 ethyll - amino-ll-deoxy-3-0- f (3-pyridylmethyl) aminol carbonyl-5-O- desosaminyl-6-O-methylerγthronolide A 11,12-cvclic carbamate
To a solution of 2.2 g (2.5 mmol) of the compound obtained in Example 3(1) in 10 ml of pyridine was added dropwise a solution of 0.74 g (2.5 mmol) of triphosgene in 10 ml of methylene chloride under ice- cooling, followed by stirring for 30 minutes. To the mixture was added 1.25 ml (12.3 mmol) of 3- (aminomethyl) pyridine, followed by stirring for 1.5 hours. After completion of the reaction, the same working-up and removal of the acetyl group at the 2 ' - position as in Example 1(3) gave 1.6 g of the title compound. FABMS m/z: 977 [M+H] +
Example 65 11- r2- r (2-Nitrophenyl) sulfonylamino1 - ethyl! amino-ll-deoxy-3-O- (3-pyridyloxy) carbonyl-5-O- desosaminyl-6-O-methylerythronolide A 11,12-cyclic carbamate
To a solution of 2.2 g (2.5 mmol) of the compound obtained in Example 3(1) in 10 ml of pyridine was added dropwise a solution of 0.74 g (2.5 mmol) of triphosgene in 10 ml of methylene chloride under ice- cooling, followed by stirring for 30 minutes. To the mixture was added 1.18 g (12.4 mmol) of 3- hydroxypyridine , followed by stirring for 1.5 hours. After completion of the reaction, the same working-up and removal of the acetyl group at the 2 ' -position as in Example 1(3) gave 1.2 g of the title compound. FABMS m/z: 964 [M+H] +
Test Example
The in vitro antibacterial activity of the compound obtained in Example 13 as an example of the compound of the present invention against various experimental bacteria was measured using sensitive disc media (produced by Eiken Chemical Co.) according to the MIC measuring method specified by the Japan Society of Chemotherapy. The results are expressed as MIC value
(Minimum Inhibitory Concentration, μg/ml) , and shown in Table 1.
[Table 1] In Vitro Antibacterial Activity: MIC (μg/ml)
INDUSTRIAL APPLICABILITY
The compounds of the present invention have a strong antibacterial activity against not only erythromycin-sensitive bacteria but also erythromycin- resistant bacteria. Therefore, the compounds of the present invention are useful as antibacterial agents for the treatment of bacterially infectious diseases in human beings and animals (including farm animals) .
Claims
CLAIMS 1. An erythromycin A derivative represented by the formula:
R! is a group represented by the formula:
-Sθ2N(-R7)-R8 wherein R7 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a phenyl group, a phenyl group substituted by a nitro group or an alkoxy group having 1 to 3 carbon atoms , a pyridyl group , a pyridyl group substituted by 1 or 2 members selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; a halogen atom; an alkoxy group having 1 to 3 carbon atoms; a nitro group, an amino group; a cyano group and an amino group substituted by an alkyl group having 1 to 6 carbon atoms, a quinolyl group, or a quinolyl group substituted by 1 or 2 members selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; a halogen atom; an alkoxy group having 1 to 3 carbon atoms; a nitro group; an amino group; a cyano group and an amino group substituted by an alkyl group having 1 to 6 carbon atoms, R8 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms , or a group represented by the formula: -N-(Rl°)S02R9 wherein R9 is an alkyl group having 1 to 6 carbon atoms, a dibenzofuranyl group, a thienyl group, a thienyl group substituted by a group selected from the group consisting of a pyridyl group; an isoxazolyl group; a pyrimidinyl group and a pyrimidinyl group substituted by an alkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms, an isoxazolyl group, an isoxazolyl group substituted by 1 or 2 alkyl groups having 1 to 6 carbon atoms, an imidazolyl group, an imidazolyl group substituted by 1 to 3 alkyl groups having 1 to 6 carbon atoms, a benzothienyl group, a benzothienyl group substituted by 1 to 5 members selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and a halogen atom, a thiazolyl group, a thiazolyl group substituted by 1 or 2 members selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; an amino group and an acetamino group, an imidazo [2,1- b] thiazolyl group, an imidazo [2 , 1-b] thiazolyl group substituted by 1 to 3 members selected from the group consisting of an alkyl group having 1 to 6 carbon atoms and a halogen atom, a phenylalkyl group having 7 to 10 carbon atoms, a cϊuinolyl, a pyridyl, a naphthyl group, a naphthylalkyl group having 11 to 15 carbon atoms, a dimethylaminonaphthyl group, a group represented by the formula:
R2 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cinnamyl group,
R^ is a group represented by the formula:
-OCO-CH2-R11 a group represented by the formula:
-OCO-R11 a group represented by the formula:
-OCO-NH-R11 a group represented by the formula: -O-RH or a group represented by the formula: -OCO-O-R11 wherein R11 is a pyridylmethyl group, a methylthiomethyl group, a quinolyl group, a phenyl group, a phenyl group substituted by 1 to 5 members selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; a nitro group; an alkoxy group having 1 to 3 carbon atoms and a halogen atom, a pyridyl group, or a pyridyl group substituted by 1 or 2 members selected from the group consisting of an alkyl group having 1 to 6 carbon atoms; a nitro group; an alkoxy group having 1 to 3 carbon atoms and a halogen atom,
R^ is a hydrogen atom, or R^ and R4 together form an oxo grou , and
R5 and R^ are the same or different, and are each a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising an effective amount of the erythromycin A derivative or the pharmaceutically acceptable salt thereof according to Claim 1.
3. An antibacterial preparation comprising the erythromycin A derivative or the pharmaceutically acceptable salt thereof according to Claim 1 as an effective component.
4. A method for the treatment of a bacterially infectious disease which comprises administering a pharmaceutically effective amount of the erythromycin A derivative or the pharmaceutically acceptable salt thereof according to Claim 1 to a patient.
5. Use of the erythromycin A derivative or the pharmaceutically acceptable salt thereof according to Claim 1 for the treatment of a bacterially infectious disease.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000517978A JP2003527301A (en) | 1997-10-29 | 1998-10-28 | Erythromycin A derivative |
| AU96495/98A AU9649598A (en) | 1997-10-29 | 1998-10-28 | Erythromycin a, 11,12-carbamate derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9/296822 | 1997-10-29 | ||
| JP29682297 | 1997-10-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999021869A1 true WO1999021869A1 (en) | 1999-05-06 |
Family
ID=17838611
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP1998/004876 WO1999021869A1 (en) | 1997-10-29 | 1998-10-28 | Erythromycin a, 11,12-carbamate derivatives |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP2003527301A (en) |
| AU (1) | AU9649598A (en) |
| WO (1) | WO1999021869A1 (en) |
| ZA (1) | ZA989835B (en) |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002005837A1 (en) * | 2000-07-17 | 2002-01-24 | Intrabiotics Pharmaceuticals, Inc. | Antimicrobial sulfonamide derivatives of lipopeptide antibiotics |
| WO2002050091A1 (en) * | 2000-12-21 | 2002-06-27 | Glaxo Group Limited | Macrolide antibiotics |
| US6511962B1 (en) | 2000-07-17 | 2003-01-28 | Micrologix Biotech Inc. | Derivatives of laspartomycin and preparation and use thereof |
| WO2003102010A1 (en) * | 2002-05-31 | 2003-12-11 | Janssen Pharmaceutica N.V. | 3-descladinosyl-6-o-carbamoyl and 6-o-carbonoyl macrolide antibacterial agents |
| US6737403B2 (en) | 2000-07-17 | 2004-05-18 | Micrologix Biotech Inc. | Derivatives of laspartomycin and preparation and use thereof |
| US6750199B2 (en) | 2000-07-17 | 2004-06-15 | Micrologix Biotech Inc. | Antimicrobial sulfonamide derivatives of lipopeptide antibiotics |
| WO2004101584A1 (en) * | 2003-05-13 | 2004-11-25 | Glaxo Group Limited | Macrolides substituted at the 3-position having antimicrobial activity |
| US6833444B2 (en) | 1999-01-27 | 2004-12-21 | Pfizer, Inc. | Ketolide antibiotics |
| US6849608B2 (en) | 2000-08-07 | 2005-02-01 | Pfizer, Inc. | Macrolide antibiotics |
| WO2006067589A1 (en) | 2004-12-21 | 2006-06-29 | Pfizer Products Inc. | Macrolides |
| US9487485B2 (en) | 2013-02-28 | 2016-11-08 | Takeda Pharmaceutical Company Limited | Method for producing sulfonyl chloride compound |
| CN106432067A (en) * | 2016-09-18 | 2017-02-22 | 北京天弘天达医药科技有限公司 | Environment-friendly chemical synthetic method for 3-pyridine sulfonyl chloride |
| CN108610388A (en) * | 2016-12-12 | 2018-10-02 | 浙江京新药业股份有限公司 | A kind of preparation method of macrolide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0596802A1 (en) * | 1992-11-05 | 1994-05-11 | Roussel Uclaf | Erythromycin derivatives, their process of preparation and their application as medicaments |
| WO1997031929A1 (en) * | 1996-02-28 | 1997-09-04 | Hoechst Marion Roussel | Novel erythromycin derivatives, method for preparing same, and use thereof as drugs |
-
1998
- 1998-10-28 WO PCT/JP1998/004876 patent/WO1999021869A1/en active Application Filing
- 1998-10-28 ZA ZA989835A patent/ZA989835B/en unknown
- 1998-10-28 AU AU96495/98A patent/AU9649598A/en not_active Abandoned
- 1998-10-28 JP JP2000517978A patent/JP2003527301A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0596802A1 (en) * | 1992-11-05 | 1994-05-11 | Roussel Uclaf | Erythromycin derivatives, their process of preparation and their application as medicaments |
| WO1997031929A1 (en) * | 1996-02-28 | 1997-09-04 | Hoechst Marion Roussel | Novel erythromycin derivatives, method for preparing same, and use thereof as drugs |
Cited By (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6833444B2 (en) | 1999-01-27 | 2004-12-21 | Pfizer, Inc. | Ketolide antibiotics |
| US6511962B1 (en) | 2000-07-17 | 2003-01-28 | Micrologix Biotech Inc. | Derivatives of laspartomycin and preparation and use thereof |
| WO2002005837A1 (en) * | 2000-07-17 | 2002-01-24 | Intrabiotics Pharmaceuticals, Inc. | Antimicrobial sulfonamide derivatives of lipopeptide antibiotics |
| US6737403B2 (en) | 2000-07-17 | 2004-05-18 | Micrologix Biotech Inc. | Derivatives of laspartomycin and preparation and use thereof |
| US6750199B2 (en) | 2000-07-17 | 2004-06-15 | Micrologix Biotech Inc. | Antimicrobial sulfonamide derivatives of lipopeptide antibiotics |
| US6849608B2 (en) | 2000-08-07 | 2005-02-01 | Pfizer, Inc. | Macrolide antibiotics |
| WO2002050091A1 (en) * | 2000-12-21 | 2002-06-27 | Glaxo Group Limited | Macrolide antibiotics |
| JP2005531603A (en) * | 2002-05-31 | 2005-10-20 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 3-Descradinosyl-6-O-carbamoyl and 6-O-carbonoyl macrolide antibacterial agents |
| US6825172B2 (en) | 2002-05-31 | 2004-11-30 | Janssen Pharmaceutica, Nv | 3-descladinosyl-6-O-carbamoyl and 6-O-carbonoyl macrolide antibacterial agents |
| WO2003102010A1 (en) * | 2002-05-31 | 2003-12-11 | Janssen Pharmaceutica N.V. | 3-descladinosyl-6-o-carbamoyl and 6-o-carbonoyl macrolide antibacterial agents |
| WO2004101584A1 (en) * | 2003-05-13 | 2004-11-25 | Glaxo Group Limited | Macrolides substituted at the 3-position having antimicrobial activity |
| WO2006067589A1 (en) | 2004-12-21 | 2006-06-29 | Pfizer Products Inc. | Macrolides |
| US7462600B2 (en) | 2004-12-21 | 2008-12-09 | Pfizer Inc | Macrolides |
| EP2233493A1 (en) | 2004-12-21 | 2010-09-29 | Pfizer Products Inc. | Macrolides |
| US9487485B2 (en) | 2013-02-28 | 2016-11-08 | Takeda Pharmaceutical Company Limited | Method for producing sulfonyl chloride compound |
| US9932322B2 (en) | 2013-02-28 | 2018-04-03 | Takeda Pharmaceutical Company Limited | Method for producing sulfonyl chloride compound |
| US10370357B2 (en) | 2013-02-28 | 2019-08-06 | Takeda Pharmaceutical Company Limited | Method for producing sulfonyl chloride compound |
| CN106432067A (en) * | 2016-09-18 | 2017-02-22 | 北京天弘天达医药科技有限公司 | Environment-friendly chemical synthetic method for 3-pyridine sulfonyl chloride |
| CN108610388A (en) * | 2016-12-12 | 2018-10-02 | 浙江京新药业股份有限公司 | A kind of preparation method of macrolide |
| CN108610388B (en) * | 2016-12-12 | 2020-11-06 | 浙江京新药业股份有限公司 | Preparation method of macrolide |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2003527301A (en) | 2003-09-16 |
| ZA989835B (en) | 1999-05-05 |
| AU9649598A (en) | 1999-05-17 |
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