CN1259135A - 9-oxime erythromycin derivatives - Google Patents

9-oxime erythromycin derivatives Download PDF

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CN1259135A
CN1259135A CN98805848A CN98805848A CN1259135A CN 1259135 A CN1259135 A CN 1259135A CN 98805848 A CN98805848 A CN 98805848A CN 98805848 A CN98805848 A CN 98805848A CN 1259135 A CN1259135 A CN 1259135A
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deoxy
methyl
oxo
desosaminyl
chek
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邬永金
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Pfizer Products Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • 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

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Abstract

The invention relates to compounds of formula (I), and to pharmaceutically acceptable salts thereof, wherein R<1>, R<2>, R<6> and X are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formula (I), methods of using said compounds of formula (I) in the treatment of bacterial and protozoa infections, and methods of preparing said compounds of formula (I).

Description

The 9-oxime erythromycin derivatives
Background of the present invention
The present invention relates to the new 3-ketone group-9-oxime-11 of 6-O-methyl-Erythromycin A, the derivative of 12-carbazates (carbazate) or carbamate.The compounds of this invention comprises the microbiotic of the mankind and fish and birds as Mammals.The compounds of this invention is the wide spectrum macrolide antibiotic, and they are effective for the infection that is caused by some gram-positive microorganism and Gram-negative bacteria and protozoon.
The present invention's general introduction
The present invention relates to the compound and the pharmacy acceptable salt thereof of following formula:
Figure A9880584800151
Wherein: X is-CR 7R 8-or-NR 7-; Or X and R 2Formation-N=CR together 4R 5Or X and R 2Form the heterocycle of formula XVI together:
Figure A9880584800161
Wherein, in the ring of described formula XVI, r and p independently are the integer of 1-3 separately, and q is 0 or 1, X 1For-CH 2-, O, S ,-C (O)-,-C (S)-,-SO 2-,-CH=CH-,-CH (OH) CH (OH)-or-NH-; (the CH of wherein said formula XVI ring 2) r(CH 2) pPart is optional to be replaced by 1-4 substituting group, wherein X 1Replaced by a substituting group for the nitrogen-atoms the among-NH-is optional, described optional substituting group independently is selected from-C (O) O (C 1-C 10Alkyl), C 1-C 10Alkoxyl group, C 1-C 10Alkanoyl, halo, nitro, cyano group, the heterocyclic radical of 5-10 unit, C 1-C 10Alkyl ,-NR 7R 8, C 6-C 10Aryl ,-S (O) n(C 1-C 10Alkyl) wherein n be 0-2 integer and-SO 2NR 7R 8R 1Be H or C 1-C 10Alkyl, the 1-3 of a wherein said alkyl carbon atom are selected from optional replacement of a heteroatoms of O, S and N, and described alkyl is optional independently to be selected from following substituting group replacement by 1-3 :-C (O) O (C 1-C 10Alkyl), C 1-C 10Alkoxyl group, C 1-C 10Alkanoyl, halo, nitro, cyano group, the heterocyclic radical of 5-10 unit, C 1-C 10Alkyl ,-NR 7R 8, C 6-C 10Aryl ,-S (O) n(C 1-C 10Alkyl) wherein n be 0-2 integer and-SO 2NR 7R 8When X is-NR 7-time, R 2Be (i) H, R 4,-C (O) R 4,-C (O) OR 4Or-(CR 7C 8) mR 3Perhaps working as X is-NR 7R 8-time, R 2Be (ii) H, R 4Or-(CR 7R 8) mR 3, wherein for (i) with (ii), m is the integer of 0-6, for each repetition, and R 7And R 8All can change, wherein m is greater than 1; Each R 3Independent is C 6-C 10Aryl or 5-10 unit heterocyclic radical, wherein said aryl and heterocyclic radical are optional independently to be selected from following substituting group replacement by 1-3 :-C (O) O (C 1-C 10Alkyl), C 1-C 10Alkoxyl group, C 1-C 10Alkanoyl, halo, nitro, cyano group, the heterocyclic radical of 5-10 unit, C 6-C 10Aryl, C 1-C 10Alkyl ,-NR 7R 8,-S (O) n(C 1-C 10Alkyl) wherein n be 0-2 integer and-SO 2NR 7R 8With each R 4And R 5Independently be selected from H and C 1-C 12Alkyl, one or two optional replacements of a heteroatoms that carbon atom is selected from O, S and N of wherein said alkyl, wherein said alkyl is optional independently to be selected from following substituting group replacement by 1-3 :-C (O) O (C 1-C 10Alkyl), C 1-C 10Alkoxyl group, C 1-C 10Alkanoyl, halo, nitro, cyano group, C 1-C 10Alkyl ,-NR 7R 8, C 6-C 10The heterocyclic radical of aryl, 5-10 unit ,-S (O) n(C 1-C 10Alkyl) wherein n be 0-2 integer and-SO 2NR 7R 8R 6For H ,-C (O) R 3Or C 1-C 18Alkanoyl, wherein in the moieties of described alkanoyl, one or two optional heteroatomss that can be selected from O, S and N of carbon atoms are replaced; With each R 7And R 8Independent is H or C 1-C 6Alkyl.
More specific embodiment of the present invention comprises wherein R 6Formula I compound for H.
Other more specific embodiment of the present invention comprises the formula I compound for-NH-of X wherein.
Other more specific embodiment of the present invention comprises wherein R 1Be H, benzyl or C 1-C 3Alkyl or-CH 2O (CH 2) 2OCH 3The compound of formula I.
Other more specific embodiment of the present invention comprises wherein R 2For-(CH 2) mR 3Formula I compound, wherein m is the integer of 0-6, R 3Be 5-10 unit's heterocyclic radical or C 6-C 10Aryl.R 3Particular comprise quinolyl-4,4-phenyl-imidazoles-1-base, imidazo (4,5-b) pyridin-3-yl, 4-pyridin-3-yl imidazoles-1-base and pyridin-3-yl.
The preferred compounds of the present invention include: 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - pyridin-3 - yl - imidazol-1 - yl) - Propyl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - pyridin-3 - yl - imidazol-1 - yl) - Propyl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-keto lactone red A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (imidazo (4,5-b) pyridin-3 - yl) - Propyl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (imidazo (4,5-b) pyridin-3 - yl) - Propyl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-keto lactone red A, 11,12 - carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - quinoline-4 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - quinoline-4 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (7 - methoxy - quinolin-4 - yl) - C Yl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (7 - methoxy - quinolin-4 - yl) - C Yl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - quinoline-4 - yl - propylene) Tristate ammonia -9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - quinoline-4 - yl - propylene) Tristate ammonia -9 - methoxy-imino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - quinoline-4 - yl - propyl) hydrazo - 9 - benzoyloxy imino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - ammonia Allophanate; 19 - deoxy-dioxo-1 - deoxy-5-O-desosaminyl -11 - (3 - benzimidazol-1 - yl - propyl) Tristate Amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 19 - deoxy-dioxo-1 - deoxy-5-O-desosaminyl -11 - (3 - benzimidazol-1 - yl - propyl) Tristate Amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - ammonia Allophanate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - indole-1 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - indole-1 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - indazol-1 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - indazol-1 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - carbazole triazol-1 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - carbazole triazol-1 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (5 - phenyl-1H-pyrrol-2 - yl) - C Yl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (5 - phenyl-1H-pyrrol-2 - yl) - C Yl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - phenyl - imidazol-1 - yl) - propyl) Tristate amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - Carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - phenyl - imidazol-1 - yl) - propyl) Tristate amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (3 - (4 - chlorophenyl) - (1,2,4) evil Oxadiazol-5 - yl) - propyl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-keto red Lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (3 - (4 - chlorophenyl) - (1,2,4) evil Oxadiazol-5 - yl) - propyl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-red one Acid lactone A, 11,12 - carbamate; 19 - deoxy-dioxo-1 - deoxy-5-O-desosaminyl -11 - (3 - (3 - (4 - methoxyphenyl) - (1,2,4) Oxadiazol-5 - yl) - propyl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-red one Acid lactone A, 11,12 - carbamate; 19 - deoxy-dioxo-1 - deoxy-5-O-desosaminyl -11 - (3 - (3 - (4 - methoxyphenyl) - (1,2,4) Oxadiazol-5 - yl) - propyl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-Chek Keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (3 - (4 - pyridin-4 - yl) - (1,2,4) evil Oxadiazol-5 - yl) - propyl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-keto red Lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (3 - (4 - pyridin-4 - yl) - (1,2,4) evil Oxadiazol-5 - yl) - propyl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-red one Acid lactone A, 11,12 - carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - naphthalene-1 - yl - propyl) amino-9 Tristate - Hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - naphthalene-1 - yl - propyl) amino-9 Tristate - Methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - benzotriazol-1 - yl - propyl) Tristate Amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - benzotriazol-1 - yl - propyl) Tristate Amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - ammonia Allophanate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - benzotriazol-2 - yl - propyl) Tristate Amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - benzotriazol-2 - yl - propyl) Tristate Amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - ammonia Allophanate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (1H-indole-3 - yl) - propyl) Tristate Amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (1H-indol-3 - yl) - propyl) imino -9 - methoxy-imino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyridine-4 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyridine-4 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyridine-3 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyridine-3 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyridine-2 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyridine-2 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - phenylpropyl) amino-9 Tristate - hydroxy Imino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - phenylpropyl) Tristate amino-9 - A Oxy amino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - bis - (3 - phenylpropyl) amino-9 Tristate - Hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - bis - (3 - phenylpropyl) amino-9 Tristate - Methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - methoxyphenyl) - propyl) Tristate Amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - methoxyphenyl) - propyl) Tristate Amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - ammonia Allophanate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (3 - methoxyphenyl) - propyl) Tristate Amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (3 - methoxyphenyl) - propyl)-linked Alkylene amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - Carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (2 - methoxy-phenyl) - propyl) Tristate Amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (2 - methoxy-phenyl) - propyl) Tristate Amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - ammonia Allophanate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - hydroxyphenyl) - propyl) amino Tristate -9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - hydroxyphenyl) - propyl) amino Tristate -9 - methoxy-imino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (3 - methoxyphenyl) - propyl) Tristate Amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (3 - methoxyphenyl) - propyl) Tristate Amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - ammonia Allophanate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (2 - phenylethyl) Tristate amino-9 - hydroxy Imino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (2 - phenylethyl) Tristate amino-9 - A Oxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (4 - phenylbutyl) Tristate amino-9 - hydroxy Imino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (4 - phenylbutyl) Tristate amino-9 - A Oxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - furan-2 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - furan-2 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - thiophene-2 ​​- yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - thiophene-2 ​​- yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyrrol-1 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyrrol-1 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyrazol-1 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyrazol-1 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (2 - pyridin-3 - yl - thiazol-4 - yl) - Propyl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (2 - pyridin-3 - yl - thiazol-4 - yl) - Propyl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-keto lactone red A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (2 - phenyl - thiazol-5 - yl) - propyl) Tristate amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - Carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (2 - phenyl - thiazol-5 - yl) - propyl) Tristate amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - phenyl-1H-imidazol-2 - yl) - C Yl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - phenyl-1H-imidazol-2 - yl) - C Yl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -10 - Table -11 - Tristate amino-9 - benzoyloxy Imino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -10 - Table -11 - Tristate amino-9 - hydroxy-imino Yl-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate;, and the Compound a pharmaceutically acceptable salt thereof. ...
The present invention also relates to be used for the treatment of the medicinal compositions of Mammals, fish or birds infectation of bacteria or protozoan infection, this medicinal compositions contains formula I compound or its pharmacy acceptable salt and the pharmaceutically acceptable carrier for the treatment of significant quantity.
The present invention also relates to be used for the treatment of the method for Mammals, fish or birds infectation of bacteria or protozoan infection, this method comprises formula I compound or its pharmacy acceptable salt that gives this Mammals, fish or birds treatment significant quantity.
Except that indicating in addition, comprise according to method treatment of the present invention or prevention infectation of bacteria or protozoan infection at this used term " treatment ".
Except that indicating in addition, this used term " infectation of bacteria " or " protozoan infection " be included in the infectation of bacteria that takes place in Mammals, fish and the birds and protozoan infection and with infectation of bacteria and protozoan infection diseases associated, they can be by giving microbiotic compounds for treating for example of the present invention or prevention.This bacterial infection and protozoan infection and infect diseases associated with this class and comprise; Relevant pneumonia, otitis media, sinusitis paranasal sinusitis, bronchitis, tonsillitis and the mastoiditis of infection that causes with the bacterial classification (Peptostreptococcus spp.) of streptococcus pneumoniae, hemophilus influenzae, morazella catarrhalis, streptococcus aureus or Peptostreptococcus; Relevant pharyngitis (pharynigitis), rheumatic fever and the glomerulonephritis of infection that causes with streptococcus pyogenes, C and G group streptococcus, Clostridium diptheriae or Actinobacillus haemolyticum; With mycoplasma pneumoniae, invade the relevant respiratory tract infection of infection that lung legionella, streptococcus pneumoniae, hemophilus influenzae or mycoplasma pneumoniae cause; Skin and soft tissue infection, abscess and osteomyelitis and the lochiopyra of the non-complication relevant with the bacterial classification (Clostridium spp.) of streptococcus aureus, coagulase-positive staphylococci (being staphylococcus epidermidis, staphylococcus haemolyticus (s.hemolyticus) etc.), streptococcus pyogenes, streptococcus agalactiae, hammer flora C-F (minute-colony streptococci), viridans streptococci, Corynebacterium minutissimum, fusobacterium or infection that the Han Shi bartonia bodies causes; The acute urinary tract infection of the non-complication that the infection that causes with the bacterial classification (Enterococcus spp.) of Staphylococcus saprophyticus or enterococcus spp is relevant; Urethritis and cervicitis; With sand holes chlamydozoan, Ducrey bacillus, Treponema pallidum, separate the relevant property transmission disease of infection that urea urine mycoplasma or Diplococcus gonorrhoeae (Neiserria gonorrheae) cause; The relevant toxic disorder of infection that causes with streptococcus aureus (food poisoning and toxic shock syndrome, TSS) or A, B and C group streptococcus; With the relevant ulcer of the microbial infection of helicobacter pylorus; The relevant systemic febrile syndrome of infection that causes with borrelia obermeyri; The relevant Lyme disease of infection that causes with B. burgdorferi; Relevant conjunctivitis, keratitis and the dacryocystitis of infection that causes with bacterial classification (Listeria spp.) that sand holes chlamydozoan, Diplococcus gonorrhoeae, streptococcus aureus, streptococcus pneumoniae, streptococcus pyogenes, hemophilus influenzae or Listera belong to; Relevant dispersivity bird mycobacterium syndrome (MAC) disease of infection that causes with mycobacterium in bird mycobacterium or the born of the same parents; The relevant gastro-enteritis of infection that causes with campylobacter jejuni jejunum subspecies; The relevant intestines protozoon of infection that causes with Cryptosporidium spp.; The relevant odontogenic infection of infection that causes with viridans streptococci; The persistence cough that the infection that causes with Bordetella pertussis is relevant; The relevant gas gangrene of infection that causes with the bacterial classification (Bacteroides spp.) of clostridium perfringens or Bacteroides; With helicobacter pylori or the relevant atherosclerosis of Chlamydia pneumoniae infection together.The infectation of bacteria that can in animal, treat or prevent and protozoan infection and infect diseases associated with this type of and comprise: the relevant cattle respiratory disease of infection that causes with the bacterial classification (Bordetella) of P.haem., P.multocida (multocida), Mycoplasma bovis or Bordetella; The intestinal disease of the ox that the infection that causes with intestinal bacteria or protozoon (being coccidium (coccidia), cryptosporidia etc.) is relevant; The relevant dairy cow mastitis of infection that causes with the bacterial classification (Enterococcus spp.) of bacterial classification (Klebsiella spp.), Corynebacterium or the enterococcus spp of streptococcus aureus, streptococcus uberis, streptococcus agalactiae, streptococcus dysgalactiae, Klebsiella; The relevant porcine respiratory disease of infection that causes with A.pleuro., multocida or Mycoplasma kind (Mycoplasma spp.); The relevant chitling tract disease of infection that causes with the little snake bacterium of intestinal bacteria, Lawsonia intracellularis, salmonella or swine dysentery (Serpulina hyodyisinteriae); The ox foot rotten sick (footrot) that the infection that causes with the bacterial classification (Fusobacterium spp.) of Fusobacterium is relevant; The relevant cattle metritis of infection that causes with intestinal bacteria; The Niu Duomao wart relevant with actinomyces pseudonecrophorus or the microbial infection of plethora artiodactyl; The ox acute conjunctivitis relevant with the microbial infection of ox Moraxella; The relevant ox premature labor (premature abortion) of infection that causes with protozoon (neosporium); Dog that the infection that causes with intestinal bacteria is relevant and the urinary tract infection of cat; Dog that the infection that causes with staphylococcus epidermidis, Staphylococcus intermedius, coagulase-negative Staph. or multocida is relevant and skin and the soft tissue infection of cat; Dog that the infection that causes with bacterial classification (Enterobacter spp.), eubacterium, Peptostreptococcus, porphyrin zygosaccharomyces or the prevotella of the bacterial classification (Clostridium spp.) of the bacterial classification (Bacteroides spp.) of the bacterial classification (Alcaligenes spp.) of Alkaligenes, Bacteroides, fusobacterium, enterobacter is relevant and tooth or the oral cavity infection of cat.Can the method according to this invention treatment or prevention other infectation of bacteria and protozoan infection and infect diseases associated with this type of can be referring to people's such as J.P.Sanford " The Sanford Guide To Antimicrobial Therapy ", 26 editions (Antimicrobial Therapy, Inc., 1996).
The present invention also relates to the method for preparation I compound and pharmacy acceptable salt thereof, R among the formula I 1, R 2, R 6As above define with X, this method is included under the existence of acid, for example uses formula R in methyl alcohol, ethanol or the Virahol at polar solvent 1ONH 2HCl or formula R 1ONH 2(R wherein 1Definition as described formula I compound) compound treatment following formula: compound: Wherein, X and R 2Definition as described formula I compound.Preferred described acid be PyHCl wherein Py be pyridine or Et 3NHCl.
In the chemical structure described herein, the stereochemistry that wavy line is represented chiral centre that this wavy line connects is configured as R or S configuration for carbon atom that this wavy line connected.In formula I compound, the wavy line on 10 of the macrolide ring represents that this methyl can be R or S configuration.In formula I compound, connect 9 wavy lines of going up the oxime nitrogen-atoms of macrolide ring and represent-OR 1Part is E or Z configuration.
Refer to fluoro, chloro, bromo or iodo at this used term " halo " outside except as otherwise noted.Preferred described halogeno-group is fluoro, chloro and bromo.
Comprise outside except as otherwise noted at this used term " alkyl " have straight chain, saturated monovalence alkyl or its mixture of ring-type or side chain.Described alkyl can comprise two keys of or two or triple bond.Be appreciated that for circular part in described alkyl, to have three carbon atoms at least.
Comprise-C (O)-alkyl that wherein alkyl as above defines at this used term " alkanoyl " outside except as otherwise noted.
Comprise the aromatic hydrocarbons deutero-organic group of removing a hydrogen atom at this used term " aryl " outside except as otherwise noted, for example phenyl or naphthyl.
Comprise outside except as otherwise noted at this used term " 5-10 unit heterocyclic radical " and to contain one or more heteroatomic aromatics and the non-aromatic heterocycle that is selected from O, S and N, wherein each heterocyclic radical has 5-10 atom in its ring system.Described heterocyclic radical comprises benzo-fused ring system and the ring system that is replaced by one or more oxo bases.The example of quinary heterocyclic radical is a thiazolyl, and the example of ten yuan of heterocyclic radicals is a quinolyl.The non-aromatic heterocycle example is pyrrolidyl, piperidino-(1-position only), morpholino, thiomorpholine generation and piperazinyl.The example of aromatic heterocyclic radical is pyridyl, imidazolyl, pyrimidyl, pyrazolyl, triazolyl, pyrazinyl, tetrazyl, furyl, thiophene phenyl, isoxazolyl and thiazolyl.Heterocyclic radical with fused benzene rings comprises benzimidazolyl-.
Comprise the acidic group that can in formula I compound, exist or the salt of base outside except as otherwise noted at this used term " pharmacy acceptable salt ".Formula I compound for alkalescence can form various salt with various mineral acids and organic acid in nature.The acid of pharmaceutically-acceptable acid addition of formula I compound that can be used to prepare this class alkalescence is for forming those acid of atoxic acid salt (promptly containing pharmaceutically acceptable anionic salt), hydrochloride for example, hydrobromate, hydriodate, nitrate, vitriol, hydrosulfate, phosphoric acid salt, acid phosphate, Yi Yansuan salt, acetate, lactic acid salt, salicylate, Citrate trianion, the acid Citrate trianion, tartrate, pantothenate, bitartrate, ascorbate salt, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharic acid salt, formate, benzoate, glutaminate, mesylate, esilate, benzene sulfonate, tosilate and pamoate [promptly 1,1 '-methylene radical-two-(2-hydroxyl-3-naphthoate)].
Be that those formulas of tart I compound can form alkali salt with various pharmaceutically acceptable positively charged ions in nature.The example of this class salt comprises basic metal or alkaline earth salt, particularly sodium salt and sylvite.
The present invention also comprises all formula I compound radio-labeling form and pharmacy acceptable salts thereof, and wherein said radioactively labelled substance is selected from 3H, 11C and 14C.These radio-labeled compounds are as the instrument of research or diagnosis.
Some formula I compound may have asymmetric center, thereby exists with the form of different enantiomorphs.The present invention relates to the purposes of all optically active isomers of formula I compound and steric isomer and composition thereof.The present invention especially comprise the methyl on the C-10 position of formula I macrolide ring be the oximido on the C-9 position of R and S configuration and connection mode I macrolide ring nitrogen-atoms-OR 1Group is E and Z configuration.Formula I compound also can exist with the form of tautomer.The present invention relates to the purposes of all these tautomers and composition thereof.
The present invention describes in detail
In the following preparation of introducing The compounds of this invention in graphic.
Graphic 1
Graphic 2
Figure A9880584800321
Graphic 2 is continuous
Figure A9880584800331
Graphic 2 is continuous
Figure A9880584800341
Graphic 3
Figure A9880584800351
Above graphic in, " Ac " represents ethanoyl.The compounds of this invention can easily prepare.The universal synthesis method of graphic 1 explanation The compounds of this invention.In graphic 1, can be as the starting compound of preparation formula II described in the United States Patent (USP) 5543400 (mandate on August 6th, 1996).Generally speaking, can be as asking " the 3-ketone group-11 of 6-O-erythromycin A; 12-carbazic acid ester derivative " (Journal of Antibiotics of people such as number 2288174 (October 11 nineteen ninety-five is open) and G.Griesgraber in United States Patent (USP) 5543400 (as mentioned above), United States Patent (USP) 5527780 (mandate on June 18th, 1996), the English Patent, the midbody compound of the formula III of preparation 49 (5), 465-477 (1996)).
In graphic 1 step 1, wherein X is-CR 7R 8-and R 2The formula III compound can be by using formula H as defined above 2N-X-R 2(wherein X and R 2Define in the formula III compound as described) compound treatment prepare, this treating processes is at solvent for example in acetonitrile, dimethyl formamide (DMF), tetrahydrofuran (THF) (THF), glycol dimethyl ether or the dimethyl sulfoxide (DMSO) (DMSO), in about 50 ℃ of-90 ℃ of scopes about 4-10 hour.Wherein X is-CR 7R 8-the preparation process of formula III in above-mentioned United States Patent (USP) 5543400 and 5527780, describe in detail.Wherein X is-NH-and R 2The formula III compound is by using formula H as defined above 2NNHR 2(R wherein 2Compound treatment as defined above) prepares, and this is handled at solvent and for example among acetonitrile, diox or the DMSO, carried out about 12 hours in about 40 ℃-90 ℃ temperature range.Wherein X is introduced in GB Patent Application No. 2288174 (as mentioned above) in further detail for the preparation of the formula III compound of-NH-.In graphic 1 step 2, by at acid for example PyHCl (wherein Py is a pyridine) or Et 3NHCl exists down, in polar solvent particular methanol, ethanol or Virahol, in about 65 ℃ of-95 ℃ of scopes, uses formula R 1ONH 2HCl or R 1ONH 2(R wherein 1Compound treatment formula III compound as defined above) about 10 hours-6 days can preparation I compound.
Graphic 2 have introduced another prepares the method for the formula I compound of-NH-of X wherein.In graphic 2, can preparation formula IV compound according to the described method of people such as Baker (Journal of Organic Chemistry, 53,2340 (1988)).In graphic 2 step 1, according to the above-mentioned method that is used to prepare X wherein for the formula III compound of-NH-, can preparation formula V compound by handling formula IV compound with hydrazine.Preferred formula V compound is by, in about 60 ℃-90 ℃, handling formula IV compound with anhydrous hydrazine and prepared in about 12 hours for example in acetonitrile or the dimethyl formamide at solvent.In graphic 2 step 2, by at solvent for example in methyl alcohol and the ethanol, with acid salt acid treatment formula V compound for example, can preparation formula VI compound.In graphic 2 step 3, by for example in dehydrated alcohol or the Virahol, in about 80 ℃ of-90 ℃ of scopes, using formula R at anhydrous solvent 3-(CH 2) M-1(wherein m is 1-7 and R to-C (O) H 3Compound treatment formula VI compound as defined above), compound that can preparation formula VII.
In graphic 2 step 4 and 5, by handling formula VII compound formation formula VIII compound with diacetyl oxide,, become carbonyl by the hydroxyl in 3 of the oxidations then with the hydroxyl on the C-2 ' position of the form protection VII compound of acetic ester.Preferred this process by with diacetyl oxide at solvent for example in the methylene dichloride, under envrionment temperature, handle formula VII compound and obtain formula VIII compound and carry out.By in solvent such as methylene dichloride, under envrionment temperature, handle formula VIII compound with dimethyl sulfoxide (DMSO), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide (EDAC) and trifluoroacetic acid pyridine (PyTFA), can preparation formula IX compound.By in solvent such as methyl alcohol, under envrionment temperature, with reductive agent such as NaBH 3CN handles formula IX compound, can preparation formula X compound.According to the method in graphic 1 the step 6, can preparation formula XI compound.
Graphic 3 explanations prepare another method for the formula I compound of-NH-of X wherein.In graphic 3, according to the described method of people such as Griesgraber (Journal of Antibiotics, 49 (5), 465-477 (1966)), compound that can preparation formula XII.In graphic 3 step 1, by at acid for example PyHCl (wherein Py is a pyridine) or Et 3NHCl exists down, in polar solvent particular methanol, ethanol or Virahol, in about 65 ℃ of-95 ℃ of scopes, uses formula R 1ONH 2HCl or R 1ONH 2Compound treatment formula XII compound about 10 hours-4 days, can preparation formula XII compound.In graphic 3 step 2, can formula XIII compound be converted into formula XIV compound according to the method for graphic 2 steps 3.In graphic 3 step 3, formula XIV compound can be converted into the compound of formula XV according to the method for graphic 2 step 6.
The compounds of this invention can have unsymmetrical carbon.According to the difference on its physical chemistry by with method known to those skilled in the art for example with chromatography or fractional crystallization, this class non-enantiomer mixture can be separated into independent diastereomer.By making described mixture of enantiomers be converted into non-enantiomer mixture, separating this diastereomer and diastereomer that will be independent and transform (for example hydrolysis) and come enantiomer separation for accordingly pure enantiomorph with compound (for example alcohol) reaction of suitable optically active.All these class isomer (comprising non-enantiomer mixture and pure enantiomorph) all are considered as a part of the present invention.
Character can form various salt with various inorganic and organic acids for the formula I compound of alkalescence.Although this class salt must be pharmaceutically acceptable for giving animal, but in the middle of the reality, to from reaction mixture, separate for the formula I compound of unacceptable salt pharmaceutically when usually needing to begin, by handling this salt is converted into free alkali compound then, subsequently this free alkali is converted into pharmaceutically-acceptable acid addition with alkaline reagents.By in water-containing solvent medium or appropriate organic solvent (for example methyl alcohol or ethanol), handling described basic cpd, can easily prepare the acid salt of The compounds of this invention with the selected mineral acid or the organic acid of equivalent basically.Evaporate described solvent carefully, can easily obtain required solid salt.Also can be settled out required hydrochlorate by in the solution of the organic solvent of free alkali, adding suitable mineral acid or organic acid.
Be that those formulas of tart I compound can form alkali salt with various pharmaceutically acceptable positively charged ions in nature.The example of this class salt comprises the salt of basic metal or alkaline-earth metal, especially is sodium salt and sylvite.These salt can prepare by ordinary method.The alkali that can be used for preparing the reagent of pharmaceutically acceptable alkali salt of the present invention can form the alkali of atoxic alkali salt with the acidic cpd of formula I for those.The atoxic alkali salt of this class comprises those alkali salts derived from pharmaceutically acceptable positively charged ion such as sodium, potassium, calcium and magnesium etc.These salt can be by the required pharmaceutically acceptable cationic aqueous solution is handled corresponding acidic cpd with containing, the solution that evaporates gained then prepares to doing (preferred decompression down).Perhaps, they also can be by the lower alkane acid solution of described acidic cpd is mixed with required alkali metal alcoholates, and are with foregoing same way as that the solution evaporation of gained is extremely dried then.In either case, preferably use the reagent of stoichiometric quantity so that assurance reacts completely and the maximum yield of required end product.
Suppress by The compounds of this invention human (measuring I) or animal (measuring II and III) pathogenic agent the ability of given strain growth prove the activity of The compounds of this invention antibacterium and protozoal disease substance.
Measure I
Mensuration I as described below uses ordinary method and criteria for interpretation, and designs the guidance that is used to provide chemically modified, and this chemically modified can obtain getting around the compound of known macrolide resistance mechanism.In measuring I, collected one group of bacterial isolates so that comprising all types of target pathogenic agent belongs to, it has comprised the representative of the macrolide resistance mechanism of having identified.Use this group can be with regard to effectiveness, activity profile and textural factor or modification mensuration chemical structure/activity relationship, may avoid resistance mechanism essential.Provide the bacterial pathogens that comprises the screening group in the following table.In many cases, can utilize to the parent bacterial strain of macrolide sensitivity and from its macrolide resistant strain so that the evaluation more accurately that The compounds of this invention is got around the ability of resistance mechanism is provided.Contain a bacterial strain of the gene that is called ermA/ermB/ermC for macrolide, lincosamides and chain sun mycin B microbiotic are had resistance, this is because the Erm methylase has been modified 23S rRNA molecule (methylating), has therefore prevented the combination of all three kinds of structure types generally speaking.By the agency of the efflux of two kinds of macrolides; As if the component of the efflux system in the msrA coding staphylococcus stop entering of macrolide and chain sun mycin, and the mefA/E coding only flows out the transmembrane protein of macrolide.The inactivation of macrolide antibiotic can occur and be subjected to 2 '-hydroxyl phosphorylation (mph) or the mediation of macrolide cracking (esterase).Use conventional polymerase chain reaction (PCR) technology and/or can identify this bacterial strain by the order-checking RD.In using, this use round pcr to be illustrated in people such as J.Sutcliffe " detecting the determinant of erythromycin resistance by PCR ", Antimicrobial Agents and Chemotherapy, 40 (11), 2562-2566 (1996).Described being determined in the microtiter plates carried out, and according to Performance Standards for Antimicrobial Disk Susceptibility Tests-SixthEdition; Approved Standard (open by The National Committee for ClinicalLaboratory Standards (NCCLS) guidelines) makes an explanation; Use relatively bacterial strain of minimum inhibitory concentration (MIC).Begin compound is dissolved in the dimethyl sulfoxide (DMSO) (DMSO) storing solution as 40mg/ml.
Strain name macrolide resistance mechanism
Streptococcus aureus 1116 responsive parents
Streptococcus aureus 1117 ermB
Streptococcus aureus 0052 responsive parent
Streptococcus aureus 1120 ermC
Streptococcus aureus 1032 msrA, mph, esterase
Staphylococcus haemolyticus 1006 msrA, mph
Streptococcus pyogenes 0203 responsive parent
Streptococcus pyogenes 1079 ermB
Streptococcus pyogenes 1062 responsive parents
Streptococcus pyogenes 1061 ermB
Streptococcus pyogenes 1064 ermB
Streptococcus agalactiae 1024 responsive parents
Streptococcus agalactiae 1023 ermB
Streptococcus pneumoniae 1016 sensitivities
Streptococcus pneumoniae 1046 ermB
Streptococcus pneumoniae 1095 ermB
Streptococcus pneumoniae 1175 mefE
Streptococcus pneumoniae 0085 sensitivity
Hemophilus influenzae 0131 sensitivity
Morazella catarrhalis 0040 sensitivity
Morazella catarrhalis 1055 erythromycin intermediate resistances
Intestinal bacteria 0266 sensitivity
Utilize and measure the activity that II detects anti-multocida, utilize and measure the activity that III detects the anti-hemolysis pasteurella.
Measure II
This measures the liquid diluting method based on microlitre size (format).The single colony inoculation of multocida (bacterial strain 59A067) is gone in 5ml brain heart infusion (BHI) substratum.The described compound of 1mg is dissolved in preparation test-compound in the 125 μ l dimethyl sulfoxide (DMSO) (DMSO).Use the diluent of nonvaccinated BHI medium preparation test-compound.The concentration range of used test-compound is two times of serial dilutions of 200 μ g/ml-0.098 μ g/ml.Inoculate the BHI of multocida so that per 200 μ l are 10 with nonvaccinated BHI substratum dilution 4The suspension of cell.Described BHI cell suspending liquid is mixed with the test-compound of each serial dilution, and under 37 ℃, hatch 18 hours.Minimum inhibitory concentration (MIC) equal described compound to multocida growth show 100% concentration that suppresses (by with the nonvaccinated mensuration of comparing).
Measure III
This mensuration is based on the agar dilution that adopts Steers reproducer (Replicator).Will be in the BHT substratum by the isolated 2-5 of an agar plate colony inoculation, (200rpm) is in 37 ℃ of overnight incubation under the jolting.In morning next day, the pre-culture of haemolysis pasteurella that 300 μ l are grown fully is inoculated in the new BHI substratum of 3ml, and (200rpm) hatches in 37 ℃ under jolting.The test-compound of appropriate amount is dissolved in the ethanol, and prepares two times of serial dilutions.The BHT agar that each serial dilutions of 2mlg and 18ml are melted mixes and solidifies.When the haemolysis pasteurella culture of inoculation reaches 0.5 McFarland standard density, adopt the Steers reproducer that the haemolysis pasteurella of about 5 μ l is inoculated in the BHI agar culture plate of the test-compound that contains various concentration, and hatched 18 hours in 37 ℃.The starting point concentration scope of test-compound is at 100-200 μ g/ml.Its MIC equal to haemolysis pasteurellaceae bacteria growing show 100% test-compound that suppresses concentration (by with the nonvaccinated mensuration of comparing).
The activity in vivo of formula (I) compound can be measured by conventional animal protection research method well known to those skilled in the art, carries out in mouse usually.
When mouse one arrives, just it is assigned to by (10 in every cage) in the cage, and before use, makes it adapt to minimum 48 hours.Give animal intraperitoneal inoculation 0.5ml 3 * 10 3CFU/ml bacterial suspension (multocida bacterial strain 59A006).Each experiment has and comprises that one is infected and two three non-administration control groups with the control group of 1x challenge dose infection with the 0.1x challenge dose at least; May also use 10x to attack data set.Generally speaking, all mouse in the research that one determines all can be attacked 30-90 minute, especially adopted duplicate injection device (Cornwall for example Syringe) gives this attack thing.After 30 minutes commence firings, give compounds for treating for the first time.If all animals were not all attacked at final 30 minutes, may need second people to begin administration so.The approach of administration is subcutaneous or oral.Subcutaneous dosage administration and oral dosage is raised the syringe needle administration by feeding under the loose skin of nape portion.In both cases, every used administration volume of mouse is 0.2ml.Gave compound in back 30 minutes, 4 hours and 24 hours in attack.The control compound that in each test, comprises the known effectiveness that gives according to same approach.Observe animal every day, write down every group of survival quantity.This multocida model monitoring is continued 96 hours (4 die young) after attack.
PD 50Calculating dosage for test-compound (this infectation of bacteria do not have be can be fatal under the pharmacological agent) death that causes of protecting in one group 50% mouse to avoid because infectation of bacteria.
Formula I compound and pharmacy acceptable salt thereof (after this being called active compound) can be by oral, parenteral, part or rectum administrations, so that treatment or pre-bacteriological protection or protozoan infection.Although can be according to patient race, body weight and the disease condition of being treated, especially selected route of administration and carry out necessary variation, but generally speaking, these compounds preferably according to dosage range per kilogram of body weight, about 0.2mg every day (mg/kg/ days) by about 200mg/kg/ days, give with single dose or divided dose (be every day 1-4 time).Yet, most preferably use the dosage level in about 4mg/kg/ days-Yue 50mg/kg/ days scope.Yet,, can change described dosage according to the kind of the Mammals of being treated, fish or birds with to the individual reaction of described medicine and according to selected medicinal preparations type and time of administration length and delivery time.In some cases, the dosage level that is lower than above-mentioned scope lower limit is more suitable, then can use bigger dosage in other cases and can not cause any toxic side effect, if at first that this is bigger dosage be divided in dying young that several little dosage give can.
Described active compound can be separately or with pharmaceutically acceptable carrier or mixing diluents, according to above-mentioned administration, this administration can divide single dose or multiple doses to carry out.Especially compound of the present invention can be according to various formulation administration, promptly they can be mixed with various pharmaceutically acceptable inert supports, use with forms such as tablet, capsule, lozenge, lozenge, boiled sweet (hard candies), pulvis, sprays, ointment, ointment, suppository, frozen glue, gelifying agent, paste, lotion, paste, aq suspension, injection liquid, elixir, syrups.This class carrier comprises solid diluent or weighting agent, sterile aqueous media and various non-toxic organic solvent etc.In addition, composition for oral liquid can suitably add sweeting agent and/or correctives.Generally speaking, the concentration range of described active compound in this class formulation is in about 70% (weight) of about 5.0%-.
For oral administration, can use and contain for example for example starch (preferred W-Gum, yam starch or tapioca (flour)), alginic acid and some composition silicate of Microcrystalline Cellulose, Trisodium Citrate, lime carbonate, Lin Suanergai and glycine and various disintegrating agent of various vehicle, and the granulation binders tablet of polyvinylpyrrolidone, sucrose, gelatin and gum arabic for example.In addition, for example Magnesium Stearate, Sodium Lauryl Sulphate BP/USP and talcum powder are usually used in compressing tablet to lubricant.Similarly solids composition also can be as the weighting material of gelatine capsule; Preferred in this respect material also comprises lactose and high molecular weight polyethylene glycol.When needs are used for oral administration with aq suspension and/or elixir, described active compound and various sweeting agent or correctives, coloring material or dyestuff and (as needs) can be comprised emulsifying agent and/or suspension agent, also have thinner such as water, ethanol, propylene glycol, glycerine and various similar mixture to be mixed together use.
For parenteral admin, can use active compound in sesame oil or peanut oil or the solution in aqueous propylene glycol.If desired, this aqueous solution suitably should be cushioned (preferred pH greater than 8), and liquid diluent etc. is oozed.These aqueous solutions are suitable for intravenous administration.Oil-soluble solution is applicable to intraarticular, intramuscular and subcutaneous injection purpose.The preparation of these solution under aseptic condition can easily be finished according to standard pharmaceutical technology well known by persons skilled in the art.
In addition, also can topical administration active compound of the present invention, this can be according to standard pharmacy practice, waits by ointment, frozen glue, gelifying agent, paste, patch, paste and carries out.
For except that the animal human for example ox (cattle) or domestic animal, can give described active compound with the feed of animal or with the form of drencs composition.
Also can give described active compound with for example little unilamellar vesicle of liposome transfer system, big unilamellar vesicle and multilamellar vesicles.Liposome can for example cholesterol, stearylamine or phosphatidylcholine form by various phosphatide.
Described active compound also can with the soluble polymer coupling as the carrier of targeted medicine.This base polymer comprises the polylysine of polyvinylpyrrolidone, pyran co-polymer, poly-hydroxypropyl MAAm phenyl, Polyhydroxyethylaspartamide-Phenol or polyethylene oxide-replaced by the palmityl residue.In addition, described active compound Biodegradable polymeric for example multipolymer, poly-epsilon-caprolactone, polyhydroxybutyrate, poe, polyacetal, poly-dihydropyrane, polybutylcyanoacrylate and the water-setting crosslinked or amphiphilic block copolymer of poly(lactic acid), polyglycolic acid, poly(lactic acid) and polyglycolic acid that can be used for medicine controlled releasing with a class.
The embodiment that below provides illustrates specific embodiment of the present invention, yet the present invention is not limited to the scope of listed embodiment.
Embodiment 1
4 "-and ethanoyl-11-deoxidation-11-hydrazo--6-O-erythromycin A, 11, the 12-carbamate
Under room temperature; to 10; 11-dehydration-2 '; (460mg is 0.51mmol) (according to people's such as Baker method preparation (J.Org.Chem., 1988 for 4 '-two-O-ethanoyl-12-O-imidazolyl carbonyl-6-O-erythromycin A; 53; 2340) add in the acetonitrile solution) anhydrous hydrazine (0.16ml, 5.1mmol), with the solution of gained in 60 ℃ of heating 12 hours.Vacuum is removed acetonitrile, adds salt solution and ethyl acetate, uses ethyl acetate extraction water layer three times.With the organic layer of salt water washing merging, through anhydrous magnesium sulfate drying, vacuum concentration.Crude product is through flash chromatography on silica gel purifying (1.5% triethylamine-1.5% methyl alcohol-97% t-butyl methyl ether); obtain title compound (261mg for white solid; 62%) and be white solid 4 "-ethanoyl-10-table-11-deoxidation-11-hydrazo--6-O-erythromycin A; 11; 12-carbamate (38mg, 10%).
Title compound: 1H NMR (400MHz, CDCl 3) δ: 5.02 (1H, dd, J=1.6,10.8Hz), 4.94 (1H, d, J=4.8Hz), 4.65 (1H, d, J=10.0Hz), 4.53 (1H, d, J=7.2Hz), 4.33 (1H, m), 3.82-3.30 (m), 3.29 (3H, s), 3.20-3.00 (m), 3.00 (3H, s), 2.92-2.31 (m), 2.27 (6H, s), 2.08 (3H, s), 2.0-1.4 (m), 0.82 (3H, t, J=7.2Hz); MS:m/z830 (M+H).
4 "-and ethanoyl-10-table-11-deoxidation-11-hydrazo--6-O-erythromycin A, 11, the 12-carbamate: 1H NMR (400MHz, CDCl 3) δ: 5.05 (1H, d, J=4.4Hz), 4.87 (1H, dd, J=1.6,10.8Hz), 4.64 (1H, d, J=10.0Hz), 4.43 (1H, d, J=7.6Hz), 4.33 (1H, m), 3.84-3.32 (m), 3.30 (3H, s), 3.18 (3H, s), 3.2-2.3 (m), 2.23 (6H, s), 2.08 (3H, s), 1.62 (3H, s), 1.30 (3H, s), 0.97 (3H, d, J=6.8Hz), 0.84 (3H, t, J=7.2Hz); MS:m/z830 (M+H).
Embodiment 2
11-deoxidation-5-O-deosaminyl-11-hydrazo--6-O-methyl erythronolactone A, 11, the 12-carbamate
With 4 "-ethanoyl-11-deoxidation-11-hydrazo--6-O-erythromycin A; 11; (solution stirs under room temperature and spends the night the 12-carbamate among the 40mg, ethanol 0.048mmol)-2N hydrochloric acid (1: 2), in the cold soln with this reaction mixture impouring saturated sodium bicarbonate.With this water layer of chloroform extraction three times.With the organic layer of salt water washing merging, through anhydrous magnesium sulfate drying, vacuum concentration.Through flash chromatography on silica gel (5% methyl alcohol-0.5% ammoniacal liquor-94.5% methylene dichloride) purifying crude product product, obtain title compound (26.1mg, 86%) into white solid:
1H?NMR(400MHz，CDCl 3)δ：5.09(1H，dd，J＝2.4，10.8Hz)，4.45(1H，s)，4.38(1H，d，J＝7.6Hz)，3.9-3.0(m)，2.95(3H，s)，2.75-2.45(m)，2.27(6H，s)，2.0-1.4(m)，1.40(3H，s)，1.34(3H，s)，1.24(3H，d，J＝6.8Hz)，1.23(3H，d，J＝6.0Hz)，1.12(3H，d，J＝7.2Hz)，1.09(3H，d，J＝7.2Hz)，1.07(3H，d，J＝6.8Hz)，0.80(3H，t，J＝7.6Hz)。
13C?NMR(100.6MHz，CDCl 3)δ：216.90，175.69，156.45，106.65，88.29，81.46，78.74，78.36，75.78，70.63，70.23，65.71，63.37，49.30，45.35，44.66，40.27(2C)，39.57，38.87，36.07，28.28，22.01，21.23，18.88，18.16，15.19，14.15，13.74，10.14，8.22。
MS：m/z?629(M+H)。
Embodiment 3
11-deoxidation-5-O-deosaminyl-11-(3-quinolyl-4-propylidene) hydrazo--6-O-methyl erythronolactone A, 11, the 12-carbamate
To 11-deoxidation-5-O-deosaminyl-11-hydrazo--6-O-methyl erythronolactone A, 11,12-carbamate (1.35g, 21.7mmol) the solution of dehydrated alcohol (20ml) in add 3-(4-quinolyl) propionic aldehyde (0.57g, 3.08mmol), in 86 ℃ formed solution was heated two days.Obtain title compound (1.84g, 97%) behind the vacuum-evaporation ethanol into white solid.
1H?NMR(400MHz，CDCl 3)δ：8.81(1H，d，J＝4.4Hz)，8.09(1H，d，J＝5.2Hz)，8.07(1H，d，J＝5.2Hz)，7.69(1H，t，J＝8.4Hz)，7.56(1H，t，J＝7.2Hz)，7.29(1H，d?J＝4.0Hz)，5.08(1H，dd，J＝2.0，10.8Hz)，4.53(1H，s)，4.41(1H，d，J＝7.6Hz)，4.2-3.2(m)，2.99(3H，s)，2.9-2.4(m)，2.25(6H，s)，2.0-1.5(m)，1.48(3H，s)，1.29(3H，s)，1.30(3H，d，J＝6.4Hz)，1.24(3H，d，J＝6.0Hz)，1.15(3H，d，J＝6.4Hz)，1.10(3H，d，J＝7.2Hz)，1.07(3H，d，J＝6.4Hz)，0.87(3H，t，J＝7.2Hz)。
MS：m/z?794(M+H)。
Embodiment 4
2 '-ethanoyl-11-deoxidation-5-O-deosaminyl-11-(3-quinolyl-4-propylidene) hydrazo--6-O-methyl erythronolactone A, 11, the 12-carbamate
To 11-deoxidation-5-O-deosaminyl-11-(3-quinolyl-4-propylidene) hydrazo--6-O-methyl erythronolactone A, 11,12-carbamate (2.07g, 2.60mmol) the solution of methylene dichloride (10ml) in add diacetyl oxide (0.49ml, 5.20mmol), under room temperature with formed solution stirring 5 hours.Add saturated sodium bicarbonate, use the dichloromethane extraction water layer, with the organic layer that the salt water washing merges, through anhydrous magnesium sulfate drying, vacuum-evaporation obtains the title compound (1.79g, 82%) into white solid.
1H?NMR(400MHz，CDCl 3)δ：8.80(1H，d，J＝4.4Hz)，8.08(1H，d，J＝8.4Hz)，8.05(1H，d，J＝9.2Hz)，8.01(1H，t，J＝4.8Hz)，7.68(1H，dt，J＝1.2，6.8Hz)，7.55(1H，dt，J＝1.2，6.8Hz)，7.27(1H，d，J＝4.4Hz)，5.02(1H，dd，J＝2.8，10Hz)，4.718(1H，t，J＝6.7Hz)，4.40(1H，s)，4.35(1H，d，J＝7.6Hz)，4.19(1H，d，J＝8.0Hz)，3.81(1H，q，J＝6.8Hz)，3.6-2.4(m)，2.71(3H，s)，2.24(6H，s)，1.9-1.5(m)，1.55(3H，s)，1.35(3H，d，J＝6.8Hz)，1.33(3H，s)，1.22(3H，d，J＝6.0Hz)，1.14(3H，d，J＝7.6Hz)，1.10(3H，d，J＝6.8Hz)，1.06(3H，d，J＝6.4Hz)，0.87(3H，t，J＝7.2Hz)。
MS：m/z?837(M+H)。
Embodiment 5
2 '-ethanoyl-11-deoxidation-5-O-deosaminyl-11-(3-quinolyl-4-propylidene) hydrazo--6-O-methyl erythronolactone A, 11, the 12-carbamate
To 2 '-ethanoyl-11-deoxidation-5-O-deosaminyl-11-(3-quinolyl-4-propylidene) hydrazo--6-O-methyl erythronolactone A; 11; 12-carbamate (1.69g; 2.02mmol) the solution of methylene dichloride (16ml) in add dimethyl sulfoxide (DMSO) (1.85ml; 8.06mmol; 10eq), 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide (EDAC) (1.55g; 8.06mmol; 3.1eq) and PyTFA (1.56g; 8.06mmol; 3.1eq) solution, under room temperature, formed suspension was stirred 2 hours.Add saturated sodium bicarbonate, use dichloromethane extraction water layer three times.With the organic layer of salt water washing merging, through anhydrous magnesium sulfate drying, vacuum concentration.Described crude product obtains the title compound (1.59g, 94%) into white solid through silica gel rapid column chromatography purifying (5% methyl alcohol-0.5% ammoniacal liquor-94.5% methylene dichloride).
1H?NMR(400MHz，CDCl 3)δ：8.79(1H，d，J＝3.6Hz)，8.08(1H，d，J＝8.8Hz)，8.05(1H，d，J＝8.4Hz)，8.00(1H，t，J＝4.8Hz)，7.69(1H，t，J＝8.4Hz)，7.55(1H，t?J＝7.2Hz)，7.27(1H，d，J＝4.4Hz)，5.03(1H，dd，J＝2.4，10.0Hz)，4.70(1H，dd，J＝7.6，10.4Hz)，4.39(1H，s)，4.34(1H，d，J＝7.6Hz)，4.18(1H，d，J＝8.0Hz)，3.82(1H，q，J＝6.8Hz)，3.6-1.6(m)，2.71(3H，s)，2.22(6H，s)，2.03(3H，s)，1.54(3H，s)，1.33(3H，d，J＝6.4Hz)，1.28(3H，s)，1.21(3H，d，J＝6.4Hz)，1.14(3H，d，J＝7.6Hz)，1.09(3H，d，J＝6.8Hz)，1.06(3H，d，J＝6.8Hz)，0.87(3H，t，J＝7.2Hz)。
MS：m/z?836(M+H)。
Embodiment 6
11-deoxidation-5-O-deosaminyl-11-(3-quinolyl-4-propyl group) hydrazo--6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
Under room temperature; to 2 '-ethanoyl-11-deoxidation-5-O-deosaminyl-11-(3-quinolyl-4-propylidene) hydrazo--6-O-methyl-3-oxo erythronolactone A; 11, (1.59g adds sodium cyanoborohydride (359mg in the solution of methyl alcohol 1.90mmol) (25ml) to the 12-carbamate; 5.70mmol; 3eq), add acetate (0.65ml, 11.4mmol then; 6eq), and under room temperature formed reaction mixture stirring is spent the night.After vacuum is removed methyl alcohol, residue is dissolved in the methylene dichloride.Add saturated sodium bicarbonate, with this water layer of dichloromethane extraction three times, the organic layer that merges with the salt water washing is through anhydrous magnesium sulfate drying and vacuum concentration.Described residue is dissolved in the methyl alcohol (50ml) and in refluxing descending to heat this solution 1 hour.Vacuum is removed methyl alcohol then, and by flash chromatography on silica gel (5%MeOH-5%NH 3H 2O-94.5%CH 2Cl 2) purifying crude product product obtains the title compound (1.13g, 75%) into white solid.
1H?NMR(400MHz，CDCl 3)δ：8.75(1H，d，J＝4.27Hz)，8.07(2H，t，J＝9.4Hz)，7.64(1H，dt，J＝1.6，6.8Hz)，7.50(1H，dt，J＝1.6，7.2Hz)，7.26(1H，d，J＝4.4Hz)，5.47(1H，t，J＝3.6Hz)，4.98(1H，d，J＝10.8Hz)，4.26(1H，s)，4.24(1H，s)，3.84(1H，q，J＝6.8Hz)，3.71(1H，s)，3.8-2.7(m)，2.62(3H，s)，2.6-2.3(m)，2.22(6H，s)，2.2-1.5(m)，1.44(3H，s)，1.33(3H，d，J＝6.8Hz)，1.31(3H，s)，1.29(3H，d，J＝7.6Hz)，1.21(3H，d，J＝6.0Hz)，1.16(3H，d，J＝6.0Hz)，1.04(3H，d，J＝6.8Hz)，0.78(3H，t，J＝7.2Hz)。
13C NMR (100.6MHz, CDCl 3) δ (H of connection): 217.82 (0), 203.63 (0), 169.72 (0), 156.10 (0), 150.18 (1), 148.20 (2C, 0), 130.05 (1), 128.85 (1), 127.58 (0), 126.19 (1), 123.81 (1), 120.97 (1), 103.96 (1), 80.69 (0), 79.37 (1), 78.12 (0), 77.35 (1), 70.33 (1), 69.63 (1), 65.84 (1), 58.14 (1), 51.04 (1), 50.13 (3), 48.41 (2), 47.31 (1), 44.55 (1), 40.19 (2C, 3), 39.60 (2C, 2 and 1), 29.49 (2), 28.47 (2), 28.14 (2), 22.03 (2), 21.14 (3), 19.82 (3), 18.50 (3), 15.31 (3), 14.55 (3), 14.38 (3), 14.21 (3), 10.35 (3).
MS：m/z?797(M+H)。
Embodiment 7
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-quinolyl-4-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
Method I:
To 11-deoxidation-5-O-deosaminyl-11-(3-quinolyl-4-propyl group) hydrazo--6-O-methyl-3-oxo erythronolactone A, 11,12-carbamate (654mg, 0.82mmol) the solution of Virahol (8.0ml) in add oxammonium hydrochloride (855mg, 12.3mmol, 15eq), under 90 ℃, described reaction mixture heating 6 is died young.Vacuum is removed Virahol,, residue is dissolved in the methylene dichloride.Add saturated sodium bicarbonate, with this water layer of dichloromethane extraction three times, the organic layer that merges with the salt water washing is through anhydrous magnesium sulfate drying and vacuum concentration.With described crude product through preparation property TLC purifying (10% methyl alcohol-1% ammoniacal liquor-89% methylene dichloride), the starting compound (107mg, 16%) that obtains title compound (224mg, 34%) and reclaim into white solid.
1H?NMR(400MHz，CDCl 3)δ：10.85(1H，brs)，8.39(1H，d，J＝4.4Hz)，8.00(1H，d，J＝8.4Hz)，7.90(1H，d，J＝8.0Hz)，7.60(1H，t，J＝7.2Hz)，7.42(1H，t，J＝7.6Hz)，6.82(1H，d，J＝4.8Hz)，5.05(1H，dd，J＝2.0，10.8Hz)，4.30(1H，dd，J＝5.6，7.2Hz)，3.89(1H，q，J＝6.4Hz)，3.92(1H，s)，3.55(1H，m)，3.27(1H，m)，3.15-2.50(m)，2.83(3H，s)，2.35(6H，s)，1.95(1H，m)，1.8-1.2(m)，1.55(3H，s)，1.49(3H，s)，1.35(3H，d，J＝6.8Hz)，1.29(3H，d，J＝7.6Hz)，1.26(3H，d，J＝6.0Hz)，1.15(3H，d，J＝6.8Hz)，1.03(3H，d，J＝6.8Hz)，0.825(3H，t，J＝7.2Hz)。
13C NMR (100.6MHz, CDCl 3) δ (H of connection): 203.73 (0), 169.85 (0), 166.52 (0), 156.35 (0), 149.22 (1), 147.06 (0), 129.35 (1), 128.85 (1), 127.36 (0), 126.41 (1), 123.77 (1), 120.24 (1), 103.91 (1), 81.28 (0), 79.77 (1), 78.66 (0), 77.37 (1), 70.34 (1), 69.40 (1), 65.95 (1), 59.68 (1), 51.16 (1), 50.52 (3), 48.08 (2), 47.52 (1), 40.26 (2C, 3), 38.26 (2), 33.66 (1), 29.40 (2), 28.5 1 (2), 27.93 (2), 25.59 (1), 22.17 (2), 21.18 (3), 20.09 (3), 19.15 (3), 17.40 (3), 15.37 (3), 14.52 (3), 14.36 (3), 10.44 (3).
MS：m/z?812(M+H)。
Method II:
To 9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-quinolyl-4-propylidene) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11,12-carbamate (186mg, 0.23mmol) add acetate (212 μ l in the methanol solution of (according to the described methods preparation of embodiment 17), 3.7mmol) and sodium cyanoborohydride (158mg, 2.3mmol), under room temperature, formed mixture was stirred 12 hours.Vacuum is removed methyl alcohol, and residue is dissolved in the methylene dichloride.Add saturated sodium bicarbonate, use dichloromethane extraction water layer three times, with the organic layer of salt water washing merging, through anhydrous magnesium sulfate drying, and vacuum concentration.Crude product obtains the title compound (114mg, 61%) into white solid through flash chromatography on silica gel purifying (5% methyl alcohol-0.5% ammoniacal liquor-94.5% methylene dichloride).
Embodiment 8
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-quinolyl-4-propyl group) hydrazo--9-methoxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
Method I: to 11-deoxidation-5-O-deosaminyl-11-(3-quinolyl-4-propyl group) hydrazo--6-O-methyl-3-oxo erythronolactone A, 11, (50mg adds NH in the solution of Virahol 0.063mmol) (1.0ml) to the 12-carbamate 2(26mg, 0.31mmol's OMeHCl 5eq), die young described reaction mixture heating 3 under 90 ℃.Vacuum is removed Virahol, and residue is dissolved in the methylene dichloride.Add saturated sodium bicarbonate, with this water layer of dichloromethane extraction three times, the organic layer that merges with the salt water washing is through anhydrous magnesium sulfate drying and vacuum concentration.Described crude product through preparation property TLC purifying (10% methyl alcohol-1% ammoniacal liquor-89% methylene dichloride), is obtained title compound (27mg, 52%) and partially recycled starting compound into white solid.
1H?NMR(400MHz，CDCl 3)δ：8.75(1H，d，J＝4.4Hz)，8.12(1H，d，J＝6.8Hz)，8.06(1H，d，J＝8.8Hz)，7.65(1H，t，J＝6.8Hz)，7.50(1H，t，J＝6.8Hz)，7.27(1H，d，J＝4.4Hz)，6.04(1H，br?s)，5.01(1H，t，J＝9.6Hz)，4.3-1.4(m)，3.86(1H，q，J＝6.8Hz)，3.70(3H，s)，2.66(3H，m)，2.31(6H，s)，1.45(3H，s)，1.37(3H，s)，1.33(3H，d，J＝6.8Hz)，1.27(3H，d，J＝7.2Hz)，1.24(3H，d，J＝6.0Hz)，1.10(3H，d，J＝6.4Hz)，0.98(3H，d，J＝6.8Hz)，0.77(3H，t，J＝7.6Hz)。
Ms：m/z?826(M+H)。
Method II: according to embodiment 11 described methods, by 9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-hydrazo--9-methoxyimino-6-O-methyl-3-oxo erythronolactone A, 11,12-carbamate and 3-quinolyl-4-propionic aldehyde prepare title compound.
Embodiment 9
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-quinolyl-4-propyl group) hydrazo--9-benzoyloxy imino--6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
To 11-deoxidation-5-O-deosaminyl-11-(3-quinolyl-4-propyl group) hydrazo--6-O-methyl-3-oxo erythronolactone A, 11, (40mg adds NH in the solution of Virahol 0.050mmol) (1.0ml) to the 12-carbamate 2(32mg 0.20mmol), heats described reaction mixture 3 days under 90 ℃ OBnHCl.Vacuum is removed Virahol, and residue is dissolved in the methylene dichloride.Add saturated sodium bicarbonate, with this water layer of dichloromethane extraction three times, the organic layer that merges with the salt water washing is through anhydrous magnesium sulfate drying and vacuum concentration.Described crude product through preparation property TLC purifying (10% methyl alcohol-1% ammoniacal liquor-89% methylene dichloride), is obtained title compound (10mg, 22%) and partially recycled starting compound into white solid.
1H?NMR(400MHz，CDCl 3)δ：8.75(1H，d，J＝4.4Hz)，8.10(1H，d，J＝8.4Hz)，8.07(1H，d，J＝8.4Hz)，7.65(1H，t，J＝7.2Hz)，7.49(1H，t，J＝8.4Hz)，7.30(6H，m)，5.82(1H，br?s)，4.99(1H，d，J＝8.0Hz)，4.95(1H，d?J＝12.4Hz，AB)，4.85(1H，d?J＝12.4Hz，AB)，4.3-1.4(m)，3.86(1H，q，J＝6.8Hz)，2.67(3H，s)，2.30(6H，s)，1.44(3H，s)，1.40(3H，s)，1.33(3H，d，J＝6.8Hz)，1.28(3H，d，J＝7.6Hz)，1.25(3H，d，J＝6.0Hz)，1.07(3H，d，J＝7.2Hz)，0.95(3H，d，J＝6.8Hz)，0.75(3H，t，J＝7.2Hz)。
Ms：m/z?902(M+H)。
Embodiment 10
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-hydrazo--9-methoxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
To 11-deoxidation-5-O-deosaminyl-11-hydrazo--6-O-methyl-3-oxo erythronolactone A, 11, (600mg adds NH in the solution of ethanol 0.96mmol) (9.0ml) to the 12-carbamate 2(319mg, 3.83mmol 4.0eq), heat described reaction mixture 48 hours under 80 ℃ OMeHCl.Vacuum is removed ethanol, and residue is dissolved in the methylene dichloride.Add saturated sodium bicarbonate, with this water layer of dichloromethane extraction three times, the organic layer with the salt water washing merges through anhydrous magnesium sulfate drying and vacuum concentration, obtains the title compound (602mg) into white solid.
1H?NMR(400MHz，CDCl 3)δ：3.77(3H，s)，2.68(3H，s)，2.55(6H，s)，1.43(3H，s)，1.38(3H，s)，1.33(3H，d，J＝7.2Hz)，1.27(3H，d，J＝7.6Hz)，1.23(3H，d，J＝6.0Hz)，1.13(3H，d，J＝6.8Hz)，0.98(3H，d，J＝6.8Hz)，0.83(3H，t，J＝7.6Hz)。
MS：m/z?657(M+H)。
Embodiment 11
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-(4-pyridin-3-yl-imidazoles-1-yl)-propyl group) hydrazo--9-methoxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
To 9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-hydrazo--9-methoxyimino-6-O-methyl-3-oxo erythronolactone A, 11,12-carbamate (300mg, 0.45mmol) the solution of toluene (4.0ml) in add 3-(4-pyridin-3-yl-imidazoles-1-yl)-propionic aldehyde (100mg, 0.50mmol, 1.1eq), under 90 ℃, described reaction mixture was heated 18 hours.Vacuum is removed toluene, and residue is dissolved in the methyl alcohol (4ml).Add acetate (0.39ml, 6.8mmol) and sodium cyanoborohydride (427mg, 6.8mmol), under room temperature with the solution stirring of gained 14 hours.Vacuum-evaporation methyl alcohol adds saturated sodium bicarbonate in residue, with this water layer of dichloromethane extraction three times, the organic layer that merges with the salt water washing is through anhydrous magnesium sulfate drying and vacuum concentration.Described crude product through preparation property TLC purifying (10% methyl alcohol-1% ammoniacal liquor-89% methylene dichloride), is obtained the title compound into white solid.
1H?NMR(400MHz，CDCl 3)δ：8.94(1H，s)，8.42(1H)，8.03(1H)，7.58(1H，s)，7.36(1H，s)，7.25(1H)，6.11(1H，s)，3.69(3H，s)，2.64(3H，s)，2.23(6H，s)，1.45(3H，s)，1.36(3H，s)，1.30(3H，d，J＝5.6Hz)，1.26(3H，d，J＝6.8Hz)，1.21(3H，d，J＝4.8Hz)，1.09(3H，d，J＝6.8Hz)，0.97(3H，d，J＝6.4Hz)，0.80(3H，t，J＝6.4Hz)。
13C?NMR(100MHz，CDCl 3)δ：203.41，170.01，167.63，156.73，147.56，146.40，138.94，138.13，131.85，130.31，123.47，115.12，103.99，81.36，79.51，78.51，77.27，70.33，69.58，65.84，61.30，59.24，51.06，50.40，47.37，44.39，44.35，40.23(2C)，38.21，33.86，29.28，28.12，26.48，22.11，21.18，19.91，18.97，17.45，15.19，14.49，14.33，10.53。
MS：m/z?842(M+H)。
Embodiment 12
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-(imidazo (4,5-b) pyridin-3-yl)-propyl group) hydrazo--9-methoxyimino-6-O-methyl-3-oxo erythronolactone A, 11,12-carbamate
To 9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-hydrazo--9-methoxyimino-6-O-methyl-3-oxo erythronolactone A, 11,12-carbamate (2.0g, 3.05mmol) the solution of toluene (30ml) in add 3-(imidazo (4,5-b) pyridin-3-yl)-propionic aldehyde (910mg, 4.26mmol, 1.4eq), and under 90 ℃, this reaction mixture was heated 18 hours.Vacuum is removed toluene, and residue is dissolved in the methyl alcohol (30ml).Add acetate (2.8ml, 48.72mmol) and sodium cyanoborohydride (1.91g, 30.45mmol), the formed solution of stirring is 14 hours under room temperature.Vacuum-evaporation methyl alcohol adds sodium bicarbonate in this residue, uses its water layer of dichloromethane extraction three times, with the organic layer of salt water washing merging, and through anhydrous magnesium sulfate drying, vacuum concentration.Its crude product obtains the title compound into white solid through preparation property TLC (10% methyl alcohol-1% ammoniacal liquor-89% methylene dichloride) purifying.
1H?NMR(400MHz，CDCl 3)δ：8.35(1H)，8.22(1H，s)，8.02(1H)，7.20(1H)，7.36(1H，s)，6.10(1H，br?t)，3.47(3H，s)，2.62(3H，s)，2.24(6H，s)，1.46(3H，s)，1.37(3H，s)，1.30(3H，d，J＝6.8Hz)，1.27(3H，d，J＝7.6Hz)，1.22(3H，d，J＝6.0Hz)，1.12(3H，d，J＝6.8Hz)，0.99(3H，d，J＝7.2Hz)，0.84(3H，t，J＝7.6Hz)。
MS：m/z?816(M+H)。
Embodiment 13
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-(4-phenyl-imidazoles-1-yl)-propyl group) hydrazo--9-methoxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
To 9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-hydrazo--9-methoxyimino-6-O-methyl-3-oxo erythronolactone A, 11,12-carbamate (1.37g, 2.09mmol) the solution of toluene (14ml) in add 3-(4-phenyl-imidazoles-1-yl)-propionic aldehyde (583mg, 2.92mmol, 1.4eq), under 90 ℃, described reaction mixture was heated 18 hours.Vacuum is removed toluene, and residue is dissolved in the methyl alcohol (20ml).Add acetate (1.8ml, 31.35mmol) and sodium cyanoborohydride (1.97g, 31.35mmol), under room temperature with the solution stirring of gained 14 hours.Vacuum-evaporation methyl alcohol adds saturated sodium bicarbonate in residue, with this water layer of dichloromethane extraction three times, the organic layer that merges with the salt water washing is through anhydrous magnesium sulfate drying and vacuum concentration.Described crude product through preparation property TLC purifying (10% methyl alcohol-1% ammoniacal liquor-89% methylene dichloride), is obtained the title compound into white solid.
1H?NMR(400MHz，CDCl 3)δ：8.35(1H)，8.22(1H，s)，8.02(1H)，7.20(1H)，7.36(1H，s)，6.10(1H，br?t)，3.69(3H，s)，2.66(3H，s)，2.26(6H，s)，1.46(3H，s)，1.37(3H，s)，1.32(3H，d，J＝6.8Hz)，1.27(3H，d，J＝7.6Hz)，1.22(3H，d，J＝6.0Hz)，1.11(3H，d，J＝7.2Hz)，0.98(3H，d，J＝7.2Hz)，0.83(3H，t，J＝7.2Hz)。
MS：m/z?841(M+H)。
Embodiment 14
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-10-table-11-hydrazo--9-benzoyloxy imino--6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
To 11-deoxidation-5-O-deosaminyl-10-table-11-hydrazo--6-O-methyl-3-oxo erythronolactone A, 11, (202mg adds NH in the solution of methyl alcohol 0.322mmol) (3.0ml) to the 12-carbamate 2(225mg, 1.41mmol 4.4eq), heat described reaction mixture 16 hours under 72 ℃ OBn.HCl.Vacuum is removed methyl alcohol, and residue is dissolved in the methylene dichloride.Add saturated sodium bicarbonate, with this water layer of dichloromethane extraction three times, the organic layer that merges with the salt water washing is through anhydrous magnesium sulfate drying and vacuum concentration.Described crude product through preparation property TLC purifying (10% methyl alcohol-1% ammoniacal liquor-89% methylene dichloride), is obtained the title compound into white solid.
1H?NMR(400MHz，CDCl 3)δ：7.25(5H，m)，5.39(4H，br?s)，5.09(1H，d，J＝12.8Hz，AB)，4.99(1H，d，J＝12.8Hz，AB)，4.93(1H，dd，J＝3.2，9.2Hz)，4.30(1H，d，J＝7.2Hz)，3.98(3H，d，J＝10.8Hz)，3.54(1H，q，J＝6.8Hz)，3.9-1.3(m)，2.75(3H，s)，2.27(6H，s)，2.02(3H，d，J＝6.8Hz)，1.30(3H，s)，1.27(3H，d，J＝7.2Hz)，1.22(3H，s)，1.21(3H，d，J＝6.8Hz)，1.20(3H，d，J＝6.8Hz)，1.09(3H，d，J＝7.2Hz)，0.814(3H，t，J＝7.6Hz)。
MS：m/z?733(M+H)。
Embodiment 15
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-10-table-11-hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
To 11-deoxidation-5-O-deosaminyl-10-table-11-hydrazo--6-O-methyl-3-oxo erythronolactone A, 11,12-carbamate (499mg, 0.795mmol) the solution of Virahol (7.0ml) in add oxammonium hydrochloride (579mg, 8.33mmol, 10.5eq), under 80 ℃, described reaction mixture was heated three days.Vacuum is removed Virahol, and residue is dissolved in the methylene dichloride.Add saturated sodium bicarbonate, with this water layer of dichloromethane extraction three times, the organic layer that merges with the salt water washing is through anhydrous magnesium sulfate drying and vacuum concentration.Described crude product through preparation property TLC purifying (10% methyl alcohol-1% ammoniacal liquor-89% methylene dichloride), is obtained 3: 2 the mixture (157mg, 31%) into the title compound of white solid.
Main isomer 1H NMR (400MHz, CDCl 3) δ: 2.77 (3H, s, 6-OMe), 2.26 (6H, s, NMe 2), 0.84 (3H, t, J=7.0Hz, 15-Me); MS:m/z 610 (M+H).
Less important isomer 1H NMR (400MHz, CDCl 3) δ: 2.68 (3H, s, 6-OMe), 2.25 (6H, s, NMe 2), 0.81 (3H, t, J=7.0Hz, 15-Me); MS:m/z 610 (M+H).
Embodiment 16
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
To 11-deoxidation-5-O-deosaminyl-11-hydrazo--6-O-methyl-3-oxo erythronolactone A, 11,12-carbamate (20g, 31.8mmol) the solution of ethanol (210ml) in add oxammonium hydrochloride (33.1g, 477mmol, 15eq) and pyridine (38.4ml, 477mmol, 15eq), under 80 ℃, formed solution was heated 38 hours.Vacuum is removed ethanol, and residue is dissolved in the methylene dichloride.Add saturated sodium bicarbonate, with this water layer of dichloromethane extraction three times, the organic layer that merges with the salt water washing is through anhydrous magnesium sulfate drying and vacuum concentration.Described crude product through flash chromatography on silica gel purifying (3% methyl alcohol-0.3% ammoniacal liquor-96.7% methylene dichloride), is obtained the title compound (7.3g) into white solid.
1H?NMR(400MHz，CDCl 3)δ：9.81(1H，br.s)，2.67(3H，s)，2.57(1H，q，J＝6.8Hz)，2.25(6H，s)，1.47(3H，s)，1.43(3H，s)，1.32(3H，d，J＝6.8Hz)，1.25(3H，d，J＝7.6Hz)，1.21(3H，d，J＝6.4Hz)，1.11(3H，d，J＝6.8Hz)，0.97(3H，d，J＝7.2Hz)，0.83(3H，t，J＝7.2Hz)。
13C?NMR(100MHz，CDCl 3)δ：203.81，169.80，165.97，156.68，103.91，81.53，79.85，78.49，76.74，70.35，69.48，65.85，64.33，51.10，49.66，47.73，40.24，38.42，33.73，28.19，25.55，22.11，21.15，19.98，18.64，16.96，15.68，14.25，13.71，10.39。
MS：m/z?643(M+H)。
Embodiment 17
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-quinolyl-4-propylidene) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
To 9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11,12-carbamate (150mg, 0.23mmol) the solution of dry toluene (2.3ml) in add 3-(4-quinolyl) propionic aldehyde (85mg, 0.46mmol), under 90 ℃, formed solution was heated 18 hours.Vacuum is removed ethanol, and described crude product obtains title compound through flash chromatography on silica gel (5% methyl alcohol-0.5% ammoniacal liquor-94.5% methylene dichloride) purifying.
1H?NMR(400MHz，CDCl 3)δ：2.84(3H，s)，2.30(6H，s)，1.58(3H，s)，1.54(3H，s)，1.34(3H，d，J＝6.8Hz)，1.32(3H，d，J＝7.2Hz)，1.28(3H，d，J＝6.0Hz)，1.25(3H，d，J＝6.0Hz)，1.05(3H，d，J＝7.2Hz)，0.86(3H，t，J＝7.2Hz)。
MS：m/z?810(M+H)。
Embodiment 18
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-benzoglyoxaline-1-base-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
To 9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11,12-carbamate (100mg, 0.16mmol) the solution of dry toluene (1.6ml) in add 3-(benzoglyoxaline-1-yl) propionic aldehyde (62mg, 0.36mmol), under 90 ℃, formed solution was heated 18 hours.Vacuum-evaporation ethanol is dissolved in crude product in the methyl alcohol (1.5ml).In this solution, add acetate (137 μ l, 2.4mmol) and sodium cyanoborohydride (103mg 1.5mmol), stirs formed mixture 12 hours under room temperature.Remove methyl alcohol under the vacuum, and its residue is dissolved in the methylene dichloride.Add saturated sodium bicarbonate, with this water layer of dichloromethane extraction three times, the organic layer that merges with the salt water washing is through anhydrous magnesium sulfate drying and vacuum concentration.Described crude product through preparation property TLC purifying (10% methyl alcohol-1% ammoniacal liquor-89% methylene dichloride), is obtained the title compound (57mg, 46%) into white solid.
1H?NMR(400MHz，CDCl 3)δ：11.00(1H，br.s)，2.71(3H，s)，2.30(6H，s)，1.49(3H，s)，1.47(3H，s)，1.34(3H，d，J＝6.8Hz)，1.28(3H，d，J＝7.6Hz)，1.23(3H，d，J＝6.0Hz)，1.11(3H，d，J＝7.2Hz)，0.99(3H，d，J＝6.8Hz)，0.824(3H，t，J＝7.2Hz)。2.84(3H，s)，2.30(6H，s)，1.58(3H，s)，1.54(3H，s)，1.34(3H，d，J＝6.8Hz)，1.32(3H，d，J＝7.2Hz)，1.28(3H，d，J＝6.0Hz)，1.25(3H，d，J＝6.0Hz)，1.05(3H，d，J＝7.2Hz)，0.86(3H，t，J＝7.2Hz)。
13C?NMR(100MHz，CDCl 3)δ：203.45，169.92，166.21，156.74，143.31，142.85，133.53，122.90，122.12，119.47，110.23，103.93，81.33，79.87，78.59，77.24，70.29，69.38，65.97，59.68，51.09，50.62，47.45，44.45，42.34，40.26，38.23，33.59，28.49，27.40，25.55，22.18，21.15，20.10，19.11，17.32，15.28，14.53，14.39，10.51。
MS：m/z?801(M+H)。
Use aforesaid method, by 9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11,12-carbamate and suitable aldehyde prepare following compounds.
Embodiment 19
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-(4-phenyl-imidazoles-1-yl)-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：2.69(3H，s)，2.29(6H，s)，1.49(3H，s)，1.47(3H，s)，1.32(3H，d，J＝6.8Hz)，1.27(3H，d，J＝7.6Hz)，1.24(3H，d，J＝6.0Hz)，1.10(3H，d，J＝6.8Hz)，1.00(3H，d，J＝6.8Hz)，0.83(3H，t，J＝7.2Hz)。
MS：m/z?801(M+H)。
Embodiment 20
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-benzotriazole-2-base-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：9.95(1H，br.s)，1.44(3H，s)，1.39(3H，s)，1.25(6H，d，J＝6.8Hz)，1.23(3H，d，J＝6.0Hz)，1.09(3H，d，J＝6.8Hz)，1.03(3H，d，J＝6.8Hz)，0.81(3H，t，J＝7.6Hz)。
MS：m/z?802(M+H)。
Embodiment 21
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-benzotriazole-1-base-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：9.02(1H，br.s)，6.23(1H，br.s)，2.58(3H，s)，2.32(6H，s)，1.47(6H，s)，1.29(3H，d，J＝6.8Hz)，1.26(3H，d，J＝7.6Hz)，1.23(3H，d，J＝6.0Hz)，1.10(3H，d，J＝6.8Hz)，1.01(3H，d，J＝6.8Hz)，0.81(3H，t，J＝7.2Hz)。
MS：m/z?802(M+H)。
Embodiment 22
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-phenyl propyl) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：9.59(1H，br.s)，7.10(5H，m)，6.55(1H，br.s)，2.67(3H，s)，2.24(6H，s)，1.43(6H，s)，1.33(3H，d，J＝6.8Hz)，1.25(3H，d，J＝7.2Hz)，1.21(3H，d，J＝6.0Hz)，1.00(3H，d，J＝6.8Hz)，0.92(3H，d，J＝6.4Hz)，0.82(3H，t，J＝7.2Hz)。
13C?NMR(100MHz，CDCl 3)δ：203.70，169.59，166.73，156.24，142.12，128.42(2C)，128.20(2C)，125.62，103.94，81.35，79.63，78.56，77.11，70.36，69.48，65.87，59.50，51.13，50.40，48.02，47.52，40.24(2C)，38.21，33.60，33.14，29.77，28.21，25.57，22.19，21.15，20.13，19.05，17.13，15.41，14.46，14.29，10.49。
MS：m/z?761(M+H)。
Embodiment 23
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-(4-hydroxy phenyl)-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：6.91(2H)，6.68(2H)，6.43(1H，br.s)，2.67(3H，s)，2.30(6H，s)，1.44(3H，s)，1.43(3H，s)，1.33(3H，d，J＝6.8Hz)，1.25(3H，d，J＝7.2Hz)，1.21(3H，d，J＝6.0Hz)，1.01(3H，d，J＝6.8Hz)，0.92(3H，d，J＝6.4Hz)，0.80(3H，t，J＝7.2Hz)。
MS：m/z?778(M+H)。
Embodiment 24
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-(4-p-methoxy-phenyl)-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：9.38(1H，br.s)，7.04(2H，d，J＝8.4Hz)，6.74(2H，d，J＝8.4Hz)，6.44(1H，br.s)，3.74(3H，s)，2.67(3H，s)，2.30(6H，s)，1.44(6H，s)，1.33(3H，d，J＝6.8Hz)，1.25(3H，d，J＝7.6Hz)，1.22(3H，d，J＝6.0Hz)，1.01(3H，d，J＝6.8Hz)，0.93(3H，d，J＝6.8Hz)，0.82(3H，t，J＝7.2Hz)。
13C?NMR(100MHz，CDCl 3)δ：203.71，169.58，167.06，157.64，156.30，134.23，129.29(2C)，113.68(2C)，103.84，81.33，79.61，78.51，77.16，70.27，69.34，65.98，59.51，55.19，51.12，50.44，47.95，47.45，40.26(2C)，38.19，33.64，32.29，30.06，28.46，25.55，22.19，21.12，20.09，19.05，17.17，15.34，14.49，14.33，10.49。
MS：m/z?792(M+H)。
Embodiment 25
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-(2-p-methoxy-phenyl)-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：8.66(1H，br.s)，7.13(2H)，6.82(2H)，3.80(3H，s)，2.68(3H，s)，2.30(6H，s)，1.45(3H，s)，1.43(3H，s)，1.32(3H，d，J＝6.8Hz)，1.26(3H，d，J＝7.6Hz)，1.22(3H，d，J＝6.4Hz)，1.06(3H，d，J＝6.8Hz)，0.98(3H，d，J＝6.4Hz)，0.83(3H，t，J＝7.2Hz)。
13C?NMR(100MHz，CDCl 3)δ：203.78，169.59，167.39，157.04，156.14，130.36，129.29，126.96，120.82，110.49，103.86，81.19，79.16，78.42，77.24，70.27，69.37，65.94，59.88，55.54，51.10，50.56，48.26，47.34，40.24(2C)，38.22，33.70，28.44，27.83，27.45，25.58，22.19，21.13，20.01，19.07，17.29，15.21，14.50，14.43，10.37。
MS：m/z?792(M+H)。
Embodiment 26
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(benzyl) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：7.95(1H，br.s)，6.23(1H，br.s)，2.88(3H，s)，2.29(6H，s)，1.51(3H，s)，1.44(3H，s)，1.36(3H，d，J＝6.8Hz)，1.29(3H，d，J＝7.6Hz)，1.25(3H，d，J＝6.0Hz)，1.05(3H，d，J＝6.8Hz)，0.97(3H，d，J＝7.2Hz)，0.75(3H，t，J＝7.6Hz)。
MS：m/z?733(M+H)。
Embodiment 27
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(pyridin-4-yl-methyl) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：8.07(2H)，7.25(2H)，6.39(1H，br.s)，2.87(3H，s)，2.27(6H，s)，1.54(3H，s)，1.46(3H，s)，1.34(3H，d，J＝6.8Hz)，1.29(3H，d，J＝7.2Hz)，1.24(3H，d，J＝6.0Hz)，1.13(3H，d，J＝6.8Hz)，1.01(3H，d，J＝7.2Hz)，0.76(3H，t，J＝7.2Hz)。
13C?NMR(100MHz，CDCl 3)δ：203.72，169.91，166.50，155.76，148.16(2C)，147.70，123.71(2C)，103.99，81.17，79.75，78.71，77.26，70.34，69.50，65.92，60.30，51.69，51.15，50.74，47.62，40.26(2C)，38.25，33.69，28.29，25.54，22.02，21.16，20.16，19.14，17.36，15.42，14.50，14.29，10.27。
MS：m/z?733(M+H)。
Embodiment 28
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-3-(pyridin-4-yl-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：11.62(1H，s)，8.24(2H)，6.91(2H)，6.20(1H，br.s)，2.76(3H，s)，2.31(6H，s)，1.51(3H，s)，1.46(3H，s)，1.33(3H，d，J＝6.4Hz)，1.27(3H，d，J＝7.2Hz)，1.23(3H，d，J＝6.0Hz)，1.10(3H，d，J＝6.8Hz)，1.00(3H，d，J＝6.8Hz)，0.83(3H，t，J＝7.2Hz)。
13C?NMR(100MHz，CDCl 3)δ：203.71，169.78，166.30，156.35，152.39，140.45，124.10(2C)，124.10(2C)，103.86，3，79.71，78.59，77.24，70.27，69.34，65.98，59.50，51.15，50.44，47.55(2C)，40.27(2C)，38.21，33.60，32.50，28.54，27.90，25.51，22.14，21.13，20.11，19.11，17.33，15.42，14.48，14.32，10.44。
MS：m/z?762(M+H)。
Embodiment 29
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-3-(pyridin-3-yl-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H NMR (400MHz, CDCl 3) δ: 10.96 (1H, s), 8.30 (1H, d, J=4.4Hz), 8.21 (1H, s), 7.40 (1H, d, J=8.0Hz), 7.10 (1H, dd, J=5.2 and 7.6Hz), 6.16 (1H, br.s), 2.70 (3H, s), 2.27 (6H, s), 1.48 (3H, s), 1.44 (3H, s), 1.31 (3H, d, J=7.2Hz), 1.25 (3H, d, J=7.6Hz) 1.21 (3H, d, J=6.0Hz), 1.06 (3H, d, J=6.8Hz), 0.96 (3H, d, J=6.8Hz), 0.80 (3H, t, J=7.6Hz).
MS：m/z?762(M+H)。
Embodiment 30
9-deoxidation generation-11-deoxidation-5-0-deosaminyl-11-(styroyl) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：7.25(5H，m)，2.59(3H，s)，2.28(6H，s)，1.40(3H，s)，1.32(3H，d，J＝6.8Hz)，1.30(3H，s)，1.25(3H，d，J＝7.6Hz)，1.22(3H，d，J＝6.0Hz)，0.98(3H，d，J＝6.8Hz)，0.88(3H，d，J＝6.8Hz)，0.83(3H，t，J＝7.6Hz)。
MS：m/z?747(M+H)。
Embodiment 31
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-(4-p-methoxy-phenyl)-(1,2,4) oxadiazole-5-yl)-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：9.65(1H，br.s)，7.87(2H，d，J＝8.4Hz)，6.92(2H，d，J＝9.2Hz)，6.16(1H，br.s)，3.80(3H，s)，2.46(3H，s)，2.24(6H，s)，1.03(3H，d，J＝7.2Hz)，0.96(3H，d，J＝7.2Hz)，0.81(3H，t，J＝7.2Hz)。
MS：m/z?859(M+H)。
Embodiment 32
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-(4-chlorophenyl)-(1,2,4) oxadiazole-5-base-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11,12-carbamate
1H?NMR(400MHz，CDCl 3)δ：7.89(2H，d，J＝8.8Hz)，7.39(2H，d，J＝8.8Hz)，6.20(1H，br.s)，2.49(3H，s)，2.24(6H，s)，1.42(3H，s)，1.03(3H，d，J＝7.2Hz)，0.96(3H，d，J＝6.8Hz)，0.82(3H，t，J＝7.2Hz)。
MS：m/z?863(M+H)。
Embodiment 33
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-indoles-1-base-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：8.63(1H，br.s)，8.02(1H)，7.28(1H)，7.12(1H)，7.04(1H)，6.89(1H)，6.23(1H，br.s)，2.60(3H，s)，2.30(6H，s)，1.44(3H，s)，1.39(3H，s)，1.34(3H，d，J＝6.8Hz)，1.25(3H，d，J＝7.6Hz)，1.22(3H，d，J＝6.4Hz)，1.02(3H，d，J＝7.2Hz)，0.92(3H，d，J＝6.8Hz)，0.82(3H，t，J＝7.2Hz)
MS：m/z?800(M+H)。
Embodiment 34
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-indazole-1-base-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：10.53(1H，br.s)，7.91(1H)，7.68(1H)，7.44(1H)，7.26(1H)，7.12(1H)，6.40(1H，br.s)，2.54(3H，s)，2.25(6H，s)，1.48(3H，s)，1.44(3H，s)，1.08(3H，d，J＝6.8Hz)，1.02(3H，d，J＝7.2Hz)，0.79(3H，t，J＝7.2Hz)
MS：m/z?801(M+H)。
Embodiment 35
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-(5-phenyl-1H-pyrroles-2-yl)-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：9.36(1H，br.s)，7.49(2H)，7.30(2H)，7.10(1H)，6.35(1H)，5.88(1H)，2.66(3H，s)，2.25(6H，s)，1.45(3H，s)，1.38(3H，s)，1.32(3H，d，J＝6.8Hz)，1.25(3H，d，J＝7.6Hz)，1.18(3H，d，J＝6.4Hz)，1.05(3H，d，J＝6.8Hz)，0.93(3H，d，J＝7.2Hz)，0.72(3H，t，J＝7.2Hz)。
13C?NMR(100MHz，CDCl 3)δ：203.54，169.84，167.07，156.85，133.90，133.21，130.84，128.58，125.11，123.35，106.83，105.41，103.89，81.18，79.60，78.52，77.17，70.27，69.37，65.90，59.84，51.12，50.52，47.76，47.49，40.23，38.17，33.64，28.56，28.36，25.57，25.01，22.22，21.12，20.00，19.04，17.19，15.37，14.48，14.28，10.39。
MS：m/z?826(M+H)。
Embodiment 36
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-carbazole-9-base-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：7.98(2H)，7.46(2H)，7.38(2H)，7.12(2H)，2.55(3H，s)，2.23(6H，s)，1.44(3H，s)，1.40(3H，s)，1.35(3H，d，J＝7.2Hz)，1.03(3H，d，J＝6.8Hz)，0.94(3H，d，J＝6.8Hz)，0.76(3H，t，J＝7.2Hz)。
MS：m/z?851(M+H)。
Embodiment 37
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-(1H-indol-3-yl)-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：8.75(1H，br.s)，7.98(1H)，7.55(1H)，7.25(1H)，7.12(1H)，7.05(1H)，6.86(1H)，6.21(1H，br.s)，2.58(3H，s)，2.26(6H，s)，1.44(3H，s)，1.39(3H，s)，1.34(3H，d，J＝6.0Hz)，1.01(3H，d，J＝6.4Hz)，0.92(3H，d，J＝6.8Hz)，0.81(3H，t，J＝7.2Hz)。
MS：m/z?800(M+H)。
Embodiment 38
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-furans-2-base-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：9.18(1H，br.s)，7.21(1H)，5.93(1H，s)，6.42(1H，br.s)，5.93(1H，s)，2.68(3H，s)，2.25(6H，s)，1.45(3H，s)，1.44(3H，s)，1.32(3H，d，J＝6.4Hz)，1.26(3H，d，J＝7.2Hz)，1.21(3H，d，J＝6.4Hz)，1.01(3H，d，J＝6.8Hz)，0.93(3H，d，J＝6.8Hz)，0.83(3H，t，J＝7.2Hz)。
13C?NMR(100MHz，CDCl 3)δ：203.71，169.61，167.70，156.30，155.74，140.73，110.02，104.94，103.94，81.34，79.65，78.51，77.11，70.34，69.51，65.86，59.55，51.11，50.44，47.61，47.50，40.25(2C)，38.20，33.60，28.16，26.22，25.58，25.22，22.19，21.17，20.14，19.07，17.13，15.39，14.47，14.33.10.47。
MS：m/z?751(M+H)。
Embodiment 39
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-pyrroles-1-base-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：8.51(1H，br.s)，7.21(1H，s)，6.64(1H)，6.05(1H)，2.68(3H，s)，2.33(6H，s)，1.45(3H，s)，1.43(3H，s)，1.32(3H，d，J＝6.4Hz)，1.26(3H，d，J＝7.2Hz)，1.23(3H，d，J＝6.0Hz)，1.01(3H，d，J＝6.8Hz)，0.93(3H，d，J＝7.2Hz)，0.84(3H，t，J＝7.2Hz)。
MS：m/z?750(M+H)。
Embodiment 40
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-pyrazol-1-yl-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：10.83(1H，br.s)，7.40(1H)，7.28(1H)，6.20(1H)，6.05(1H)，2.52(3H，s)，2.24(6H，s)，1.45(3H，s)，1.43(3H，s)，1.28(3H，d，J＝6.4Hz)，1.24(3H，d，J＝7.6Hz)，1.19(3H，d，J＝6.4Hz)，1.05(3H，d，J＝6.8Hz)，0.99(3H，d，J＝6.8Hz)，0.80(3H，t，J＝7.2Hz)。
MS：m/z?751(M+H)。
Embodiment 41
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-naphthalene-1-base-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate
1H?NMR(400MHz，CDCl 3)δ：9.32(1H，br.s)，8.04(1H)，7.76(1H)，7.61(1H)，7.40(2H)，7.24(2H)，2.65(3H，s)，2.3?1(6H，s)，1.44(3H，s)，1.42(3H，s)，1.34(3H，d，J＝6.8Hz)，1.25(3H，d，J＝7.6Hz)，1.23(3H，d，J＝6.0Hz)，1.02(3H，d，J＝6.8Hz)，0.94(3H，d，J＝6.8Hz)，0.79(3H，t，J＝7.6Hz)。
MS：m/z?811(M+H)。
According to aforesaid method, by 9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11,12-carbamate and suitable aldehyde prepare following compounds:
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-(4-phenyl-1H-imidazoles-2-yl)-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate;
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-(2-pyridin-3-yl-thiazole-4-yl)-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate;
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-(2-phenyl-thiazole-5-yl)-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate;
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-thiophene-2-base-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate;
9-deoxidation generation-11-deoxidation-5-O-deosaminyl-11-(3-(7-methoxyl group-quinolyl-4)-propyl group) hydrazo--9-oxyimino-6-O-methyl-3-oxo erythronolactone A, 11, the 12-carbamate.

Claims (14)

1. following formula: compound or its pharmacy acceptable salt:
Figure A9880584800021
Wherein: X is-CR 7R 8-or-NR 7-; Or X and R 2Formation-N=CR together 4R 5Or X and R 2Form the heterocycle of formula XVI together:
Figure A9880584800022
Wherein, in the ring of described formula XVI, r and p independently are the integer of 1-3 separately, and q is 0 or 1, X 1For-CH 2-, O, S ,-C (O)-,-C (S)-,-SO 2-,-CH=CH-,-CH (OH) CH (OH)-or-NH-; (the CH of wherein said formula XVI ring 2) r(CH 2) pPart is optional to be replaced by 1-4 substituting group, wherein X 1Replaced by a substituting group for the nitrogen-atoms the among-NH-is optional, described optional substituting group independently is selected from-C (O) O (C 1-C 10Alkyl), C 1-C 10Alkoxyl group, C 1-C 10Alkanoyl, halo, nitro, cyano group, the heterocyclic radical of 5-10 unit, C 1-C 10Alkyl ,-NR 7R 8, C 6-C 10Aryl ,-S (O) n(C 1-C 10Alkyl) wherein n be 0-2 integer and-SO2NR 7R 8R 1Be H or C 1-C 10Alkyl, the 1-3 of a wherein said alkyl carbon atom are selected from optional replacement of a heteroatoms of O, S and N, and described alkyl is optional independently to be selected from following substituting group replacement by 1-3 :-C (O) O (C 1-C 10Alkyl), C 1-C 10Alkoxyl group, C 1-C 10Alkanoyl, halo, nitro, cyano group, the heterocyclic radical of 5-10 unit, C 1-C 10Alkyl ,-NR 7R 8, C 6-C 10Aryl ,-S (O) n(C 1-C 10Alkyl) wherein n be 0-2 integer and-SO 2NR 7R 8When X is-NR 7-time, R 2Be (i) H, R 4,-C (O) R 4,-C (O) OR 4Or-(CR 7C 8) mR 3Perhaps working as X is-NR 7R 8-time, R 2Be (ii) H, R 4Or-(CR 7R 8) mR 3, wherein for (i) with (ii), m is the integer of 0-6, for each repetition, and R 7And R 8All can change, wherein m is greater than 1; Each R 3Independent is C 6-C 10Aryl or 5-10 unit heterocyclic radical, wherein said aryl and heterocyclic radical are optional independently to be selected from following substituting group replacement by 1-3 :-C (O) O (C 1-C 10Alkyl), C 1-C 10Alkoxyl group, C 1-C 10Alkanoyl, halo, nitro, cyano group, the heterocyclic radical of 5-10 unit, C 6-C 10Aryl, C 1-C 10Alkyl ,-NR 7R 8,-S (O) n(C 1-C 10Alkyl) wherein n be 0-2 integer and-SO 2NR 7R 8With each R 4And R 5Independently be selected from H and C 1-C 12Alkyl, one or two optional replacements of a heteroatoms that carbon atom is selected from O, S and N of wherein said alkyl, wherein said alkyl is optional independently to be selected from following substituting group replacement by 1-3 :-C (O) O (C 1-C 10Alkyl), C 1-C 10Alkoxyl group, C 1-C 10Alkanoyl, halo, nitro, cyano group, C 1-C 10Alkyl ,-NR 7R 8, C 6-C 10The heterocyclic radical of aryl, 5-10 unit ,-S (O) n(C 1-C 10Alkyl) wherein n be 0-2 integer and-SO 2NR 7R 8R 6For H ,-C (O) R 3Or C 1-C 18Alkanoyl, wherein in the moieties of described alkanoyl, one or two optional heteroatomss that can be selected from O, S and N of carbon atoms are replaced; With each R 7And R 8Independent is H or C 1-C 6Alkyl.
The compound of 2 claims 1, wherein R 6Be H.
3. the compound of claim 1, wherein X is-NH-.
4. the compound of claim 3, wherein R 2Be H.
5. the compound of claim 1, wherein R 1Be H, benzyl, C 1-C 3Alkyl or-CH 2O (CH 2) 2OCH 3
6. the compound of claim 3, wherein R 2For-(CH 2) mR 3, wherein m and R 3As defined in claim 1.
7. the compound of claim 6, wherein R 3Heterocyclic radical for 5-10 unit.
8. the compound of claim 7, wherein R 3For quinolyl-4,4-phenyl-1-imidazoles-1-base, imidazo (4,5-b) pyridin-3-yl, 4-pyridin-3-yl-imidazoles-1-base and pyridin-3-yl.
9 A compound according to claim 1, wherein said compound is selected from the following compounds: 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - pyridin-3 - yl - imidazol-1 - yl) - Propyl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - pyridin-3 - yl - imidazol-1 - yl) - Propyl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-keto lactone red A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (imidazo (4,5-b) pyridin-3 - yl) - Propyl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (imidazo (4,5-b) pyridin-3 - yl) - Propyl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-keto lactone red A, 11,12 - carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - quinoline-4 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - quinoline-4 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (7 - methoxy - quinolin-4 - yl) - C Yl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (7 - methoxy - quinolin-4 - yl) - C Yl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - quinoline-4 - yl - propylene) Tristate ammonia -9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - quinoline-4 - yl - propylene) Tristate ammonia -9 - methoxy-imino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - quinoline-4 - yl - propyl) hydrazo - 9 - benzoyloxy imino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - ammonia Allophanate; 19 - deoxy-dioxo-1 - deoxy-5-O-desosaminyl -11 - (3 - benzimidazol-1 - yl - propyl) Tristate Amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 19 - deoxy-dioxo-1 - deoxy-5-O-desosaminyl -11 - (3 - benzimidazol-1 - yl - propyl) Tristate Amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - ammonia Allophanate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - indole-1 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - indole-1 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - indazol-1 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - indazol-1 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - carbazole triazol-1 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - carbazole triazol-1 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (5 - phenyl-1H-pyrrol-2 - yl) - C Yl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (5 - phenyl-1H-pyrrol-2 - yl) - C Yl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - phenyl - imidazol-1 - yl) - propyl) Tristate amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - Carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - phenyl - imidazol-1 - yl) - propyl) Tristate amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (3 - (4 - chlorophenyl) - (1,2,4) evil Oxadiazol-5 - yl) - propyl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-keto red Lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (3 - (4 - chlorophenyl) - (1,2,4) evil Oxadiazol-5 - yl) - propyl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-red one Acid lactone A, 11,12 - carbamate; 19 - deoxy-dioxo-1 - deoxy-5-O-desosaminyl -11 - (3 - (3 - (4 - methoxyphenyl) - (1,2,4) Oxadiazol-5 - yl) - propyl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-red one Acid lactone A, 11,12 - carbamate; 19 - deoxy-dioxo-1 - deoxy-5-O-desosaminyl -11 - (3 - (3 - (4 - methoxyphenyl) - (1,2,4) Oxadiazol-5 - yl) - propyl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-Chek Keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (3 - (4 - pyridin-4 - yl) - (1,2,4) evil Oxadiazol-5 - yl) - propyl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-keto red Lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (3 - (4 - pyridin-4 - yl) - (1,2,4) evil Oxadiazol-5 - yl) - propyl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-red one Acid lactone A, 11,12 - carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - naphthalene-1 - yl - propyl) amino-9 Tristate - Hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - naphthalene-1 - yl - propyl) amino-9 Tristate - Methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - benzotriazol-1 - yl - propyl) Tristate Amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - benzotriazol-1 - yl - propyl) Tristate Amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - ammonia Allophanate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - benzotriazol-2 - yl - propyl) Tristate Amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - benzotriazol-2 - yl - propyl) Tristate Amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - ammonia Allophanate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (1H-indole-3 - yl) - propyl) Tristate Amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (1H-indol-3 - yl) - propyl) imino -9 - methoxy-imino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyridine-4 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyridine-4 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyridine-3 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyridine-3 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyridine-2 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyridine-2 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - phenylpropyl) amino-9 Tristate - hydroxy Imino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - phenylpropyl) Tristate amino-9 - A Oxy amino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - bis - (3 - phenylpropyl) amino-9 Tristate - Hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - bis - (3 - phenylpropyl) amino-9 Tristate - Methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - methoxyphenyl) - propyl) Tristate Amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - methoxyphenyl) - propyl) Tristate Amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - ammonia Allophanate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (3 - methoxyphenyl) - propyl) Tristate Amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (3 - methoxyphenyl) - propyl) Tristate Amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - ammonia Allophanate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (2 - methoxy-phenyl) - propyl) Tristate Amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (2 - methoxy-phenyl) - propyl) Tristate Amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - ammonia Allophanate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - hydroxyphenyl) - propyl) amino Tristate -9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - hydroxyphenyl) - propyl) amino Tristate -9 - methoxy-imino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (3 - methoxyphenyl) - propyl) Tristate Amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino Methyl ester; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - (3 - methoxyphenyl) - propyl) Tristate Amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - ammonia Allophanate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (2 - phenylethyl) Tristate amino-9 - hydroxy Imino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (2 - phenylethyl) Tristate amino-9 - A Oxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (4 - phenylbutyl) Tristate amino-9 - hydroxy Imino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (4 - phenylbutyl) Tristate amino-9 - A Oxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - furan-2 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - furan-2 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - thiophene-2 ​​- yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - thiophene-2 ​​- yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyrrol-1 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyrrol-1 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyrazol-1 - yl - propyl) hydrazo - 9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - amino acid Esters; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -11 - (3 - pyrazol-1 - yl - propyl) hydrazo - 9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate Esters; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (2 - pyridin-3 - yl - thiazol-4 - yl) - Propyl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (2 - pyridin-3 - yl - thiazol-4 - yl) - Propyl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-keto lactone red A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (2 - phenyl - thiazol-5 - yl) - propyl) Tristate amino-9 - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - Carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (2 - phenyl - thiazol-5 - yl) - propyl) Tristate amino-9 - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - phenyl-1H-imidazol-2 - yl) - C Yl) amino-9 Tristate - hydroxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy substituting -11 - deoxy-5-O-desosaminyl -11 - (3 - (4 - phenyl-1H-imidazol-2 - yl) - C Yl) amino-9 Tristate - methoxyimino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -10 - Table -11 - Tristate amino-9 - benzoyloxy Imino-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate; 9 - deoxy-generation -11 - deoxy-5-O-desosaminyl -10 - Table -11 - Tristate amino-9 - hydroxy-imino Yl-6-O-methyl-3 - oxo-Chek keto lactone A, 11,12 - carbamate;, and the Compound a pharmaceutically acceptable salt thereof. ...
10. be used for the treatment of the medicinal compositions of infectation of bacteria in Mammals, fish or the birds or protozoan infection, said composition comprises the compound and the pharmaceutically acceptable carrier of the claim 1 for the treatment of significant quantity.
11. the method for infectation of bacteria or protozoan infection in treatment Mammals, fish or the birds, this method comprise the compound of the claim 1 that gives described Mammals, fish or birds treatment significant quantity.
12. prepare the method for following formula: compound or its pharmacy acceptable salt: Wherein: X is-CR 7R 8-or-NR 7-; Or X and R 2Formation-N=CR together 4R 5Or X and R 2Form the heterocycle of formula XVI together:
Figure A9880584800131
Wherein, in the ring of described formula XVI, r and p independently are the integer of 1-3 separately, and q is 0 or 1, X 1For-CH 2-, O, S ,-C (O)-,-C (S)-,-SO 2-,-CH=CH-,-CH (OH) CH (OH)-or-NH-; (the CH of wherein said formula XVI ring 2) r(CH 2) pPart is optional to be replaced by 1-4 substituting group, wherein X 1Replaced by a substituting group for the nitrogen-atoms the among-NH-is optional, described optional substituting group independently is selected from-C (O) O (C 1-C 10Alkyl), C 1-C 10Alkoxyl group, C 1-C 10Alkanoyl, halo, nitro, cyano group, the heterocyclic radical of 5-10 unit, C 1-C 10Alkyl ,-NR 7R 8, C 6-C 10Aryl ,-S (O) n(C 1-C 10Alkyl) wherein n be 0-2 integer and-SO 2NR 7R 8R 1Be H or C 1-C 10Alkyl, the 1-3 of a wherein said alkyl carbon atom are selected from optional replacement of a heteroatoms of O, S and N, and described alkyl is optional independently to be selected from following substituting group replacement by 1-3 :-C (O) O (C 1-C 10Alkyl), C 1-C 10Alkoxyl group, C 1-C 10Alkanoyl, halo, nitro, cyano group, the heterocyclic radical of 5-10 unit, C 1-C 10Alkyl ,-NR 7R 8, C 6-C 10Aryl ,-S (O) n(C 1-C 10Alkyl) wherein n be 0-2 integer and-SO 2NR 7R 8When X is-NR 7-time, R 2Be (i) H, R 4,-C (O) R 4,-C (O) OR 4Or-(CR 7C 8) mR 3Perhaps working as X is-NR 7R 8-time, R 2Be (ii) H, R 4Or-(CR 7R 8) mR 3, wherein for (i) with (ii), m is the integer of 0-6, R 7And R 8All can change, wherein m is greater than 1; Each R 3Independent is C 6-C 10Aryl or 5-10 unit heterocyclic radical, wherein said aryl and heterocyclic radical are optional independently to be selected from following substituting group replacement by 1-3 :-C (O) O (C 1-C 10Alkyl), C 1-C 10Alkoxyl group, C 1-C 10Alkanoyl, halo, nitro, cyano group, the heterocyclic radical of 5-10 unit, C 6-C 10Aryl, C 1-C 10Alkyl ,-NR 7R 8,-S (O) n(C 1-C 10Alkyl) wherein n be 0-2 integer and-SO 2NR 7R 8With each R 4And R 5Independently be selected from H and C 1-C 12Alkyl, one or two optional replacements of a heteroatoms that carbon atom is selected from O, S and N of wherein said alkyl, wherein said alkyl is optional independently to be selected from following substituting group replacement by 1-3 :-C (O) O (C 1-C 10Alkyl), C 1-C 10Alkoxyl group, C 1-C 10Alkanoyl, halo, nitro, cyano group, C 1-C 10Alkyl ,-NR 7R 8, C 6-C 10The heterocyclic radical of aryl, 5-10 unit ,-S (O) n(C 1-C 10Alkyl) wherein n be 0-2 integer and-SO 2NR 7R 8R 6For H ,-C (O) R 3Or C 1-C 18Alkanoyl, wherein in the moieties of described alkanoyl, one or two optional heteroatomss that can be selected from O, S and N of carbon atoms are replaced; With each R 7And R 8Independent is H or C 1-C 6Alkyl; This method comprises: in the presence of acid, use wherein R in polar solvent 1Formula R as the definition of described formula I compound 1ONH 2HCl or formula R 1ONH 2The compound treatment following formula: compound:
Figure A9880584800141
Wherein X and R 2Definition as described formula I compound.
13. the method for claim 12, wherein said solvent are methyl alcohol, ethanol or Virahol.
14. the method for claim 12, wherein said acid be PyHCl wherein Py be pyridine, perhaps Et 3NHCl wherein Et is an ethyl.
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HN1998000159A (en) * 1997-10-29 1999-02-09 Monsanto Co DERIVATIVES OF 9- AMINO - 3 CETO ERITROMICINA
ES2243066T3 (en) * 1998-09-22 2005-11-16 Pfizer Products Inc. CARBAMATE AND CETOLID CARBAZATE ANTIBIOTICS.
FR2786188B1 (en) * 1998-11-24 2002-10-31 Hoechst Marion Roussel Inc NOVEL ERYTHROMYCIN DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS
US6258785B1 (en) 1998-12-02 2001-07-10 Pfizer Inc. Crystalline 9-E-(O-methyl)oxime of 11, 12-dideoxy-3-de(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyloxy)-6-O-methyl-12,11-(iminocarbonyl-(2-(3-(4-(3-pyridinyl)1H-imadazol-1-yl)propyl)hydrazono))-3-oxoerythromycin
EP1298138B1 (en) * 1998-12-10 2006-11-02 Pfizer Products Inc. Carbamate and Carbazate Ketolide Antibiotics
US6284732B1 (en) * 1998-12-18 2001-09-04 Bio-Rad Laboratories, Inc. Peptides and peptide analogues designed from HFE protein and their uses in the treatment of iron overload diseases
ES2272273T3 (en) * 1999-04-16 2007-05-01 Kosan Biosciences, Inc. MACROLID ANTI-INFECTIVE AGENTS.
WO2000071557A1 (en) 1999-05-24 2000-11-30 Pfizer Products Inc. 13-methyl-erythromycin derivatives
EP1181300B1 (en) * 1999-06-07 2003-09-17 Abbott Laboratories 6-o-carbamate ketolide derivatives
ID27331A (en) * 1999-09-29 2001-03-29 Pfizer Prod Inc MAKING ANTIBIOTIC-ANTIBIOTIC KETOLIDA CARBAMATE
EP1114826A3 (en) * 1999-12-29 2001-10-31 Pfizer Products Inc. Novel antibacterial and prokinetic macrolides
EP1439186A3 (en) * 1999-12-29 2004-11-03 Pfizer Products Inc. Intermediates for novel antibacterial and prokinetic macrolides
US6946446B2 (en) 2000-02-24 2005-09-20 Abbott Laboratories Anti-infective agents useful against multidrug-resistant strains of bacteria
US6403776B1 (en) 2000-07-05 2002-06-11 Pfizer Inc. Synthesis of carbamate ketolide antibiotics
WO2003090761A1 (en) * 2002-04-25 2003-11-06 Abbott Laboratories 9-oxime macrolide antibacterials
TW200420573A (en) 2002-09-26 2004-10-16 Rib X Pharmaceuticals Inc Bifunctional heterocyclic compounds and methods of making and using same
CA2529817C (en) * 2003-03-10 2013-02-12 Optimer Pharmaceuticals, Inc. Novel antibacterial agents
JP5383037B2 (en) 2004-02-27 2014-01-08 リブ−エックス ファーマシューティカルズ，インコーポレイテッド Macrocyclic compounds and methods of making and using them
CN101917850B (en) 2007-10-25 2016-01-13 森普拉制药公司 Macrolide antibacterial agent and its preparation method
WO2010048599A1 (en) 2008-10-24 2010-04-29 Cempra Pharmaceuticals, Inc. Methods for treating gastrointestinal diseases
US9937194B1 (en) 2009-06-12 2018-04-10 Cempra Pharmaceuticals, Inc. Compounds and methods for treating inflammatory diseases
JP5914335B2 (en) 2009-09-10 2016-05-11 センプラ ファーマシューティカルズ，インコーポレイテッド Method for treating malaria, tuberculosis and MAC disease
CN102146085B (en) * 2010-02-09 2014-03-26 北京理工大学 9-oxime-ether ketolide derivative, and preparation method and medical composite thereof
NZ602544A (en) 2010-03-22 2014-11-28 Cempra Pharmaceuticals Inc Crystalline forms of a macrolide, and uses therefor
US9051346B2 (en) 2010-05-20 2015-06-09 Cempra Pharmaceuticals, Inc. Process for preparing triazole-containing ketolide antibiotics
JP6042334B2 (en) 2010-09-10 2016-12-14 センプラ ファーマシューティカルズ，インコーポレイテッド Hydrogen bond forming fluoroketolides for disease treatment
SG11201405895UA (en) 2012-03-27 2014-10-30 Cempra Pharmaceuticals Inc Parenteral formulations for administering macrolide antibiotics
US9861616B2 (en) 2013-03-14 2018-01-09 Cempra Pharmaceuticals, Inc. Methods for treating respiratory diseases and formulations therefor
JP6675973B2 (en) 2013-03-15 2020-04-08 センプラ ファーマシューティカルズ，インコーポレイテッド Focused method for preparing macrolide antimicrobial agents

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL99995A (en) * 1990-11-21 1997-11-20 Roussel Uclaf Erythromycin derivatives, their preparation and pharmaceutical compositions containing them
US5527780A (en) * 1992-11-05 1996-06-18 Roussel Uclaf Erythromycin derivatives
FR2718450B1 (en) * 1994-04-08 1997-01-10 Roussel Uclaf New erythromycin derivatives, their preparation process and their use as drugs.

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