CN101759599B

CN101759599B - Tetracycline compound with amino oxime group

Info

Publication number: CN101759599B
Application number: CN2008101402321A
Authority: CN
Inventors: 黄振华
Original assignee: Xuanzhu Pharma Co Ltd
Current assignee: Hainan Sihuan Pharmaceutical Co Ltd
Priority date: 2008-09-17
Filing date: 2008-09-17
Publication date: 2012-05-30
Anticipated expiration: 2028-09-17
Also published as: CN101759599A

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a tetracycline compound with an amino oxime group shown in a general formula , pharmaceutically acceptable salt thereof, an isomer thereof or a prodrug thereof: wherein R is^2a、R^2b、R^4a、R^4b、R⁵、R⁷、R⁸、R^9a、R^9bX and n are as defined in the specification; the invention also relates to a preparation method of the compounds, a pharmaceutical composition containing the compounds, and application of the compounds in preparing medicaments for treating and/or preventing tetracycline-sensitive diseases, in particular infectious diseases.

Description

Tetracycline compound with amino isonitroso

1, technical field

The invention belongs to medical technical field; Be specifically related to have tetracycline compound, its pharmacy acceptable salt, its isomer or its prodrug of amino isonitroso; The preparation method of these compounds; The pharmaceutical composition that contains these compounds, and these compounds are used for treating and/or preventing the especially purposes of the medicine of infection of tetracyclines sensitive disease in preparation.

2, background technology

1948, high-efficiency broad spectrum, have first tetracycline medication---the duomycin (chlortetraeycline) of Orally active, from streptomycete aureofacients, extract and obtain.Subsequently in a few years terramycin also from streptomycete fermentation liquid, separated with tsiklomitsin and obtained; These three kinds of microbiotic have similar antimicrobial spectrum widely; Not only to gram-positive, gram-negative bacteria has very strong anti-microbial activity, and mycoplasma, chlamydozoan and rickettsia are also had activity.Through these microbiotic are carried out Study on degradation, find that they have very similar chemical structure, being linked to each other by four loop wire shapes constitutes main body framework, and from then on " tsiklomitsin " regarded as one type of new microbiotic.Along with the TCs chemical structure is clarified gradually, many laboratories join in the semisynthetic research work of exploitation.Metacycline, Vibravenos and Minocycline HCl are some most important semi-synthetics, are called the representative of s-generation tsiklomitsin.

Tsiklomitsin has good pharmacological effect to Li Kecishi body, many gram positive organisms and gram-negative bacteria and lymphogranuloma venereum pathogenic agent, inclusion conjunctivitis pathogenic agent and psittacosis pathogenic agent; Therefore, tsiklomitsin becomes well-known " Broad spectrum antibiotics ".Yet,, directly cause appearance, even appear in extremely sensitive fungal component and the pathogenic bacterium (for example streptococcus pneumoniae and salmonella) the tetracyclines resistant organism to main and less important illness and the widely-used tsiklomitsin of disease.The increase of tetracycline resistant bacterium causes tsiklomitsin and tetracycline analogue compsn in use to reduce as first-selected microbiotic comprehensively.

Early 1990s has been researched and developed new third generation tetracycline medication, develops glycylcycline class medicine (glycyclines), represent medicine be Minocycline HCl the verivate WAY-GAR 936 (tigecylcine, GAR-936).The WAY-GAR 936 has a broad antifungal spectrum not only has the anti-microbial activity of early stage tetracyclines, and to because of the mechanism of effluxing and rrna protection mechanism the drug-fast pathogenic bacteria of tetracyclines also being had an anti-microbial activity, still active not ideal for the part gram-negative bacteria.And WAY-GAR 936 can only intravenous drip, needs medication twice in one day, and medication is inconvenient, brings misery to the patient.Its structural formula is as follows: therefore, research and develop new have good anti-microbial activity and medication easily TCs be clinical required.

3, summary of the invention

Technical scheme of the present invention is following:

The invention provides the compound shown in the general formula (I), its pharmacy acceptable salt, its isomer or its prodrug:

Wherein, R ^2aAnd R ^2bIndependently be Wasserstoffatoms, alkyl, alkenyl, alkynyl group, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, aralkyl, aryl, heterocyclic radical or heterocyclic radical alkyl respectively;

R ⁵Be Wasserstoffatoms, hydroxyl, sulfydryl, alkyl, alkenyl, alkynyl group, alkoxyl group, alkylthio, alkyl-carbonyl, alkyl carbonyl oxy, aryl carbonyl, aryl carbonyl oxygen base, alkaryl carbonyl, alkyl sulphinyl, alkyl sulphonyl, alkyl amine group, aryl, aralkyl, heterocyclic radical or heterocyclic radical alkyl;

X represents

or

R ^6aAnd R ^6bIndependently be Wasserstoffatoms respectively; Sulfydryl; Halogen; Hydroxyl; Amino; Carboxyl; Alkyl; Haloalkyl; Alkoxyl group; Halogenated alkoxy; Alkylthio; Alkyl amine group; Two (alkyl) amido; Hydroxyalkyl; Aminoalkyl group; The alkyl amine group alkyl; Carboxyalkyl; Alkyl-carbonyl; Alkyl carbonyl oxy; Alkoxy carbonyl; Alkyl sulphinyl; Alkyl sulphonyl; Sulfonic group; The alkylsulfonyl alkyl; Sulfoamido; The sulfoamido alkyl; Alkylsulfonamido; Amino-sulfonyl; The alkyl amine group alkylsulfonyl; Two (alkyl) amido alkylsulfonyl; The amino-sulfonyl alkyl; Alkylamidoalkyl; The alkyl amine group formyl radical; Two (alkyl) amido formyl radical; Formamyl; The formamyl alkyl; Aryl; Aralkyl; Aryl carbonyl; Aryl carbonyl oxygen base; Heterocyclic radical or heterocyclic radical alkyl;

R ⁷For: Wasserstoffatoms, halogen, hydroxyl, cyanic acid, nitro, carboxamido-group or-NR ^7aR ^7b,

R ^4a, R ^4b, R ^7aAnd R ^7bIndependently be Wasserstoffatoms respectively; Alkyl; Haloalkyl; Alkenyl; Alkynyl group; Alkoxyl group; Halogenated alkoxy; Alkylthio; Hydroxyalkyl; Carboxyalkyl; Aminoalkyl group; The alkyl amine group alkyl; Alkyl-carbonyl; Alkoxy carbonyl; Alkyl sulphinyl; Alkyl sulphonyl; Sulfonic group; The alkylsulfonyl alkyl; The sulfoamido alkyl; Amino-sulfonyl; The alkyl amine group alkylsulfonyl; Two (alkyl) amido alkylsulfonyl; The amino-sulfonyl alkyl; The alkyl amine group formyl radical; Two (alkyl) amido formyl radical; Formamyl; The formamyl alkyl; Aryl; Aralkyl; Aryl carbonyl; Heterocyclic radical or heterocyclic radical alkyl;

R ⁸Be Wasserstoffatoms, hydroxyl, halogen, sulfydryl, alkyl, alkenyl, alkynyl group, aryl, alkoxyl group, alkylthio, alkyl sulphinyl, alkyl sulphonyl, alkyl amine group or aralkyl;

R ^9a, R ^9bIndependently be Wasserstoffatoms, alkyl, alkenyl, alkynyl group, alkoxyl group, alkoxyalkyl, alkylthio, hydroxyalkyl, carboxyalkyl, aminoalkyl group, alkyl amine group alkyl, two (alkyl) amido alkyl, alkyl-carbonyl, alkenyl carbonyl, alkoxy carbonyl, alkylthio carbonyl, alkyl sulphinyl, alkyl sulphonyl, sulfonic group, alkylsulfonyl alkyl, sulfoamido alkyl, amino-sulfonyl, amino-sulfonyl alkyl, alkyl amine group alkylsulfonyl, two (alkyl) amido alkylsulfonyl, alkyl amine group formyl radical, two (alkyl) amido formyl radical, formamyl, formamyl alkyl, alkenyl amido formyl radical, aryl, aralkyl, aryl carbonyl, aryl acyloxy, aryl sulfonyl, aromatic yl alkyl carbonyl, arylalkyl amido carbonyl, heterocyclic radical, heterocyclic radical alkyl or bridged ring base, perhaps R respectively ^9aAnd R ^9bBe connected to form single heterocyclic radical with adjacent nitrogen-atoms,

Said R ^9aAnd R ^9bBe aryl, aralkyl, aryl carbonyl, aryl acyloxy, aryl sulfonyl, aromatic yl alkyl carbonyl, arylalkyl amido carbonyl, heterocyclic radical, heterocyclic radical alkyl, bridged ring base or R ^9aAnd R ^9bWhen being connected to form single heterocyclic radical with adjacent nitrogen-atoms; Can further be replaced by one or more substituting groups, substituting group is selected from halogen, alkyl, haloalkyl, alkoxyl group, halogenated alkoxy, hydroxyl, carboxyl, amino, hydroxyalkyl, carboxyalkyl, aminoalkyl group, sulfonic group, alkyl-carbonyl, alkoxy carbonyl, sulfoamido, sulfoamido alkyl, amino-sulfonyl, amino-sulfonyl alkyl, formamyl or formamyl alkyl;

N is 0～3 integer.

Preferred compound is:

Wherein, R ^2aAnd R ^2bIndependently be Wasserstoffatoms respectively;

R ^4aAnd R ^4bIndependently be Wasserstoffatoms or C respectively _1-4Alkyl;

R ⁵Be Wasserstoffatoms, hydroxyl or C _1-4Alkoxyl group;

X represents

or

R ^6aAnd R ^6bIndependently be Wasserstoffatoms, hydroxyl or C respectively _1-4Alkyl;

R ⁷For-N (CH ₃) ₂,

Or

R ⁸Be Wasserstoffatoms, hydroxyl, fluorine atom, chlorine atom or methoxyl group;

R ^9a, R ^9bIndependently be respectively: Wasserstoffatoms, C _1-6Alkyl, C _2-4Alkenyl, C _2-4Alkynyl group, C _1-4Alkoxyl group, C _1-4Alkoxy C _1-4Alkyl, hydroxyl C _1-4Alkyl, carboxyl C _1-4Alkyl, amino C _1-4Alkyl, C _1-4Alkyl amine group C _1-4Alkyl, C _1-4Alkyl-carbonyl, C _1-4Alkoxy carbonyl, C _1-4Alkyl sulphinyl, C _1-4Alkyl sulphonyl, sulfonic group, alkylsulfonyl C _1-4Alkyl, sulfoamido C _1-4Alkyl, amino-sulfonyl C _1-4Alkyl, C _1-4Alkyl amine group formyl radical, two (C _1-4Alkyl) amido formyl radical, formamyl, formamyl C _1-4Alkyl, C _2-4Alkenyl amido formyl radical, phenyl, phenyl C _1-4Alkyl, phenyl C _1-4Alkyl-carbonyl, phenyl C _1-4Alkyl amine group carbonyl, 5～6 yuan of saturated or undersaturated single heterocyclic radicals, 5～6 yuan of saturated or undersaturated single heterocyclic radical C _1-4Alkyl, adamantyl or R ^9a, R ^9bConnect into 4～6 yuan of saturated or undersaturated single heterocyclic radicals with adjacent nitrogen-atoms,

Described R ^9aAnd R ^9bBe phenyl, phenyl C _1-4Alkyl, phenyl C _1-4Alkyl-carbonyl, phenyl C _1-4Alkyl amine group carbonyl, 5～6 yuan of saturated or undersaturated single heterocyclic radicals, 5～6 yuan of saturated or undersaturated single heterocyclic radical C _1-4Alkyl, adamantyl or R ^9a, R ^9bWhen connecting into 4～6 yuan of saturated or undersaturated single heterocyclic radicals with adjacent nitrogen-atoms, can further be replaced by one or more substituting groups, substituting group is selected from fluorine atom, chlorine atom, C _1-4Alkyl, fluoro C _1-4Alkyl, C _1-4Alkoxyl group, fluoro C _1-4Alkoxyl group, hydroxyl, carboxyl, amino, hydroxyl C _1-4Alkyl, carboxyl C _1-4Alkyl, amino C _1-4Alkyl, sulfonic group, C _1-4Alkoxy carbonyl, sulfoamido, amino-sulfonyl, amino-sulfonyl C _1-4Alkyl or formamyl;

N is 0 or 1.

Preferred again compound is:

Wherein, R ^2aAnd R ^2bIndependently be Wasserstoffatoms respectively;

R ^4aAnd R ^4bIndependently be Wasserstoffatoms or C respectively _1-4Alkyl;

R ⁵Be Wasserstoffatoms, hydroxyl or C _1-4Alkoxyl group;

X represents

or

R ⁷For-N (CH ₃) ₂, Or

N is 0 or 1.

Further preferred compound is:

Wherein, R ^2aAnd R ^2bIndependently be Wasserstoffatoms respectively;

R ^4aAnd R ^4bIndependently be methyl respectively;

R ⁵Be Wasserstoffatoms, hydroxyl or methoxyl group;

X representative-CH ₂-,-CH (OH)-or-CH (CH ₃)-;

R ⁷For-N (CH ₃) ₂

R ⁸Be Wasserstoffatoms;

R ^9aAnd R ^9bIndependently be respectively: Wasserstoffatoms, C _1-6Alkyl, C _1-4Alkoxyl group, C _2-4Alkenyl, C _2-4Alkynyl group, C _1-4Alkoxy C _1-4Alkyl, hydroxyl C _1-4Alkyl, carboxyl C _1-4Alkyl, amino C _1-4Alkyl, C _1-4Alkyl amine group C _1-4Alkyl, C _1-4Alkyl-carbonyl, C _1-4Alkoxy carbonyl, C _1-4Alkyl sulphonyl, sulfoamido C _1-4Alkyl, amino-sulfonyl C _1-4Alkyl, C _1-4Alkyl amine group formyl radical, two (C _1-4Alkyl) amido formyl radical, formamyl, phenyl, phenyl C _1-4Alkyl, phenyl C _1-4Alkyl-carbonyl, 5～6 yuan of saturated or undersaturated single heterocyclic radicals, 5～6 yuan of saturated or undersaturated single heterocyclic radical C _1-4Alkyl, adamantyl or R ^9a, R ^9bConnect into 4～6 yuan of saturated or undersaturated single heterocyclic radicals with adjacent nitrogen-atoms;

Described R ^9aAnd R ^9bBe phenyl, phenyl C _1-4Alkyl, phenyl C _1-4Alkyl-carbonyl, 5～6 yuan of saturated or undersaturated single heterocyclic radicals, 5～6 yuan of saturated or undersaturated single heterocyclic radical C _1-4Alkyl, adamantyl or R ^9a, R ^9bWhen connecting into 4～6 yuan of saturated or undersaturated single heterocyclic radicals with adjacent nitrogen-atoms, can further be replaced by one or more substituting groups, substituting group is selected from fluorine atom, C _1-4Alkyl, fluoro C _1-4Alkyl, C _1-4Alkoxyl group, fluoro C _1-4Alkoxyl group, hydroxyl, carboxyl, amino, hydroxyl C _1-4Alkyl, carboxyl C _1-4Alkyl, amino C _1-4Alkyl, sulfonic group, sulfoamido or amino-sulfonyl;

N is 0 or 1.

Further preferred compound is:

Wherein, R ^2aAnd R ^2bIndependently be Wasserstoffatoms respectively; R ^4aAnd R ^4bIndependently be methyl respectively;

R ⁵Be Wasserstoffatoms; X representative-CH ₂-; R ⁷For-N (CH ₃) ₂R ⁸Be Wasserstoffatoms;

R ^9aAnd R ^9bCan independently be Wasserstoffatoms, C _1-6Alkyl, C _1-4Alkoxyl group, C _1-4Alkyl amine group C _1-4Alkyl, C _1-4Alkyl-carbonyl, C _1-4Alkyl sulphonyl, sulfoamido C _1-4Alkyl, amino-sulfonyl C _1-4Alkyl, formamyl, adamantyl, C _2-4Alkenyl, C _2-4Alkynyl group, phenyl, furyl, tetrahydrofuran base, pyrryl, Pyrrolidine base, thienyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, piperidyl, pyranyl, THP trtrahydropyranyl, pyridyl, pyriconyl 、 oxazolyl 、 isoxazolyl, morpholinyl, perhaps R ^9aAnd R ^9bCoupled nitrogen-atoms forms azetidinyl, pyrryl, pyrrolidyl, imidazolyl, piperidyl, pyridyl, morpholinyl, pyriconyl, pyrazolyl, triazolyl, tetrazyl, pyrazolidyl, piperazinyl Huo oxazinyl together,

Described R ^9aAnd R ^9bDuring for phenyl, furyl, tetrahydrofuran base, pyrryl, Pyrrolidine base, thienyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, piperidyl, pyranyl, THP trtrahydropyranyl, pyridyl, pyriconyl 、 oxazolyl 、 isoxazolyl, morpholinyl, azetidinyl, pyridyl, pyriconyl, triazolyl, tetrazyl, pyrazolidyl, piperazinyl Huo oxazinyl; Can further be replaced by one or more substituting groups, said substituting group is selected from fluorine atom, C _1-4Alkyl, fluoro C _1-4Alkyl, C _1-4Alkoxyl group, fluoro C _1-4Alkoxyl group, hydroxyl, carboxyl, amino, sulfonic group, sulfoamido or amino-sulfonyl;

N is 1.

Continuing preferred compound is:

Wherein, R ^2aAnd R ^2bIndependently be Wasserstoffatoms respectively; R ^4aAnd R ^4bIndependently be methyl respectively; R ⁵Be Wasserstoffatoms; X representative-CH ₂-;

R ⁷For-N (CH ₃) ₂R ⁸Be Wasserstoffatoms;

R ^9a, R ^9bIndependently be the tertiary butyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furyl, thienyl, thiazolyl, phenyl, pyridyl, picolyl, adamantyl, perhaps R respectively ^9aAnd R ^9bThe nitrogen-atoms that is adjacent forms azetidinyl, pyrrolidyl, piperidyl 、 oxazinyl or piperazinyl,

Said R ^9aAnd R ^9bDuring for aryl, furyl, thienyl, thiazolyl, phenyl, pyridyl, picolyl, adamantyl, when azetidinyl, pyrrolidyl, piperidyl 、 oxazinyl or piperazinyl; Can further be substituted, substituting group is selected from: methyl, trifluoromethyl or trifluoromethoxy;

N is 1.

Preferred especially compound is following:

Term " alkyl " is meant saturated fat group, comprises the alkyl of straight chained alkyl (like methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl), branched-chain alkyl (like sec.-propyl, the tertiary butyl, isobutyl-etc.), naphthenic base (cycloaliphates) group (like cyclopropyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.), the substituted naphthenic base of alkyl and cycloalkyl substituted.In embodiments, straight or branched alkyl main chain can have 10 following carbon atoms, and preferred 6 following carbon atoms are (like C _1-6Straight chained alkyl, C _3-6Branched-chain alkyl), can further preferred 4 following carbon atoms; Naphthenic base can have 3-8 carbon atom, preferred 3-6 carbon atom.

Term " alkoxyl group " is meant that alkyl is connected to Sauerstoffatom with covalent linkage, comprises straight chain alkoxyl group (like methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy, heptan oxygen base, octyloxy, the ninth of the ten Heavenly Stems oxygen base, last of the ten Heavenly stems oxygen base), branched alkoxy (like isopropoxy, tert.-butoxy, isobutoxy, isopentyloxy etc.), cycloalkyloxy (like ring propoxy-, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, ring octyloxy etc.).In embodiments, straight or branched alkoxyl group main chain can have 10 following carbon atoms, and preferred 6 following carbon atoms are (like C _1-6Straight chain alkoxyl group, C _3-6Branched alkoxy), can further preferred 4 following carbon atoms; Cycloalkyloxy can have 3-8 carbon atom, preferred 3-6 carbon atom.

Term " alkylthio " is meant that alkyl is connected to sulphur atom with covalent linkage, comprises straight chain alkylthio (like methylthio group, ethylmercapto group, rosickyite base, butylthio, penta sulfenyl, own sulfenyl, heptan sulfenyl, hot sulfenyl, the ninth of the ten Heavenly Stems sulfenyl, last of the ten Heavenly stems sulfenyl), branched alkane sulfenyl (like iprotiazem base, uncle's butylthio, isobutyl sulfenyl, isoamyl sulfenyl etc.), cycloalkylthio (like ring rosickyite base, ring penta sulfenyl, hexamethylene sulfenyl, ring sulfenyl in heptan, cyclooctasulfur base etc.).In embodiments, straight or branched alkylthio main chain can have 10 following carbon atoms, and preferred 6 following carbon atoms are (like C _1-6Straight chain alkylthio, C _3-6The branched alkane sulfenyl), can further preferred 4 following carbon atoms.Cycloalkylthio can have 3-8 carbon atom, preferred 3-6 carbon atom.

Term " alkenyl " is meant that length and abovementioned alkyl are similar; But comprise the unsaturated aliphatic group of two keys at least, comprise straight alkenyl (like vinyl, propenyl, crotonyl, pentenyl, hexenyl etc.), branched alkenyl, cycloalkenyl group (like cyclopropenyl radical, cyclopentenyl, cyclohexenyl).The one or more carbon that also comprise the alkene main chain are by oxygen, nitrogen, sulphur or phosphorus atom alternate alkenyl.In embodiments, the main chain of straight or branched alkenyl can have 10 following carbon atoms, and preferred 6 following carbon atoms are (like C _2-6Straight alkenyl, C _3-6Branched alkenyl), can further preferred 4 following carbon atoms.Cycloalkenyl group can have 3-8 carbon atom, preferred 3-6 carbon atom.

Term " alkynyl group " is meant that length and abovementioned alkyl are similar, but comprises a triple-linked unsaturated aliphatic group at least.Comprise straight-chain alkynyl groups (like ethynyl, proyl, butynyl, pentynyl, hexyn etc.), side chain alkynyl group.The one or more carbon that also comprise the alkynes main chain are by oxygen, nitrogen, sulphur or phosphorus atom alternate alkynyl group.In embodiments, straight or branched alkynyl group main chain can have 10 following carbon atoms, and preferred 6 following carbon atoms are (like C _2-6Straight-chain alkynyl groups, C _3-6The side chain alkynyl group), also can preferred 4 following carbon atoms.

Term " aryl " is meant monocycle or condensed aromatic group, like phenyl, naphthyl, phenanthryl etc.

Term " heterocyclic radical " is meant and contains heteroatomic cyclic group, comprises " the saturated or unsaturated 1-4 of containing the first heteromonocyclic group of heteroatomic 4-6 " and " the saturated or unsaturated 1-4 of containing the assorted many cyclic groups of heteroatomic 8-14 unit ".Term " heteroatoms " comprises any element atom beyond carbon and the hydrogen, preferred nitrogen, oxygen, sulphur, phosphorus.

" the saturated or unsaturated 1-4 of containing the first heteromonocyclic group of heteroatomic 4-6 " comprising: contain the assorted monocycle of saturated or undersaturated 3-8 unit of 1-4 nitrogen-atoms in (1) ring, like ethylenimine, 2H-ethylenimine, diazacyclo propane, 3H-diazacyclo propylene, azetidine, 1,2-diazetidine, azete, 1,2-diazetine, pyrroles, pyrrolin, tetramethyleneimine, imidazoles, 4; 5-glyoxalidine, imidazolidine, pyrazoles, 4,5-pyrazoline, pyrazolidine, 1,2,3-triazoles, 1; 2,4-triazole, tetrazolium, pyridine, 2-pyridone, 4-pyridone, piperidines, pyridazine, pyrimidine, pyrazine, piperazine, 1,2,3-triazine, 1; 2,4-triazine, 1,3; 5-triazine, 1,2,4; 5-tetrazine, nitrogen heterocyclic heptantriene, 1,2-diazacyclo heptantriene, 1,3-diazacyclo heptantriene, 1; 4-diazacyclo heptantriene, nitrogen heterocyclic octatetraene, 1,4-dihydro-1,4-diazacyclo sarohornene etc.; (2) contain the assorted monocycle of the saturated or undersaturated 3-8 of 1-2 Sauerstoffatom or sulphur atom unit in the ring, like oxyethane, dioxirane, thiirane, trimethylene oxide, 1,2-dioxetane, Thietane, 1; 2-dithia cyclobutene, furans, THF, thiophene, 2,5-dihydro-thiophene, THTP, 1,3-dioxolane, 1; 2-dithia cyclopentenes, 1,3-dithiolane, 2H-pyrans, 2H-pyran-2-one, 3,4-dihydro 2H-pyrans, 4H-pyrans, tetrahydropyrans, 4H-pyrans-4-ketone, 1; 4-Dioxin, 1,4-dithia cyclohexadiene, 1,4-oxathiin, 1; 4-dioxane, 1; 3-dioxane, 1,3-oxathiane, oxepin, thia cycloheptatriene, 1,4-dioxane sarohornene etc.; (3) contain 1-2 Sauerstoffatom or sulphur atom and 1-3 the assorted monocycle of the saturated or undersaturated 3-8 of nitrogen-atoms unit in the ring, like oxaza Bing Wan 、 oxazole, 4,5-dihydro-oxazole 、 isoxazole, 4,5-dihydro-isoxazole, 2,3-dihydro-isoxazole, 1,2; 3-oxadiazole, 1,2,5-oxadiazole, thiazole, 4,5-thiazoline, isothiazole, 1,2,3-thiadiazoles, 1; 2,4-thiadiazoles, 1,3,4-thiadiazoles, 2H-1,2-oxazine, 4H-1,2-oxazine, 6H-1; 2-oxazine, 2H-1,3-oxazine, 4H-1,3-oxazine, 5,6-dihydro-4H-1,3-oxazine, 6H-1; 3-oxazine, 2H-1,4-oxazine, 4H-1,4-oxazine, 2H-1,3-thiazine, 4H-1,3-thiazine, 5; 6-dihydro-4H-1,3-thiazine, 6H-1,3-thiazine, 2H-1,4-thiazine, 4H-1,4-thiazine, morpholine etc.

" the saturated or unsaturated assorted many cyclic groups of the heteroatomic 8-14 of 1-4 unit that contain " comprising: contain assorted encircle of saturated or undersaturated 8-14 unit of 1-5 nitrogen-atoms in (1) ring, like indoles, isoindole, carbazole, benzoglyoxaline, indazole, benzotriazole, imidazolidine also [4 more; 5-c] pyridine, quinoline, isoquinoline 99.9,2-quinolinone, 4-quinolinone, 1-isoquinolines, acridine, phenanthridines, cinnolines, phthalazines, quinazoline, 3,4-dihydroquinazoline, quinoxaline, 1,2-dihydro-quinoxaline, 1; 8-naphthyridines, 1; 7-naphthyridines, 1,6-naphthyridines, 1,5-naphthyridines, 2; 7-naphthyridines, 2,6-naphthyridines, purine, pteridine, azophenlyene etc.; (2) first the mixing of saturated or undersaturated 8-14 of containing 1-2 Sauerstoffatom or sulphur atom in the ring encircled more, like benzo [b] furans, different benzo [b] furans, dibenzo [b] furans, benzo [b] thiophene, benzo [c] thiophene, 2H-chromogen alkene, 2H-chromogen alkene-2-ketone, 4H-chromene, 4H-chromene-4-ketone, chroman etc.; (3) first the mixing of saturated or undersaturated 8-14 of containing 1-2 Sauerstoffatom or sulphur atom and 1-3 nitrogen-atoms in the ring encircled more, like benzoxazole, benzothiazole, 4H-1, and 3-benzoxazine, azophenlyene, thiodiphenylamine, 4,6-dihydro-1H-furo [3; 4-d] imidazoles, 4,6-dihydro-1H-thieno-[3,4-d] imidazoles, 4,6-dihydro-1H-pyrrolo-[3; 4-d] imidazoles, 4,5,6,7-tetrahydrochysene-1H-benzo [d] imidazoles, 3a; 4,6,6a-tetrahydrochysene-1H-furo [3,4-d] imidazoles, 3a; 5,6,7,7a-six hydrogen-1H-benzo [d] imidazoles etc.

Term " bridged ring base " is meant that it is not the ring that connects through adjacent carbons that interannular connects; As: azabicyclic [3.1.0] hexane, two ring [3.2.1] octanes, 1; 4-diazabicylo [2.2.2] octane, 7H-7-azabicyclic [2.2.1]-2,5-heptadiene, diamantane etc.

Term " halogen " comprises fluorine, bromine, chlorine, iodine etc.

" halo " in the term " haloalkyl, halogenated alkoxy " is meant that one or more Wasserstoffatoms on the carbon atom in alkyl, the alkoxyl group is replaced by halogen atom.

Term " prodrug " is meant that those can fall " prodrug part " through chemistry or enzymically hydrolyse reaction cracking, generate the verivate that the present invention has the tetracycline compound of amino isonitroso.Term " prodrug part " comprises in vivo and can metabolism be the part of hydroxyl and advantageously keep the part of esterification in vivo.The preferred precursor drug moiety through esterase or other mechanism in vivo metabolism be hydroxyl or other useful group.The instance of prodrug part comprises and replacing and not replacement, straight or branched alkyl carboxylic acid ester moiety (like propionic ester), rudimentary chain acid ester, dialkyl-7-amino-low alkyl group acid esters (like the dimethylamino acetic ester), acylaminoalkyl acid esters (like the kharophen manthanoate), acyloxy alkyl acid esters (like pivalyl oxygen manthanoate), aryl acid esters (phenyl acid esters), aryl-alkyl acid esters (like benzoic ether), substituted (like methyl, halogen or methoxyl group substituting group) phenyl acid esters and aryl-alkyl acid esters, acyl group, alkyl acyl, dialkyl amide ethyl hydroxyl acyl group.Be preferably alkyl carboxylic acid ester, acyloxy alkyl acid esters and acyl group.

The present invention also provides the preparation method of above-claimed cpd, but is not limited only to following method, can adopt the method for describing in the following flow process and adopt technology well known in the art, synthesizes compound of the present invention, and reaction equation is following:

Reactions step:

The preparation of step 1 compd A

In reaction flask, add raw material 1, be dissolved in the vitriol oil, stir ice bath cooling down, add SODIUMNITRATE then, mixture stirs in ice bath, and reaction finishes; This mixture is dropped in the ether, separate out solid,, this solid is added in the ethanol with a small amount of ether washing after drying; Add the palladium charcoal then, stirring at room under the hydrogen pressure is filtered concentrating under reduced pressure; Residuum adds ether under vigorous stirring, filter, and drying gets compd A.

The preparation of step 2 compd B

With the compd A dihydrochloride, in the mixing solutions of N,N-DIMETHYLACETAMIDE and acetonitrile, add powdery yellow soda ash then; After mixing, slowly be added dropwise to the dichloromethane solution of raw material 2; Stirring reaction; Filter, under the vigorous stirring filtrating is dropped in the hydrochloric ether, collect gained solid and the dry compd B that gets.

The preparation of step 3 Compound C

Under room temperature, the nitrogen protection, in the exsiccant reaction flask, add compd B and N,N-DIMETHYLACETAMIDE, stirring is adding raw material 3 down, stirring reaction, and reaction is finished, and adding ethanol adds ether again, and ice bath is separated out solid under stirring, and filtration is also dry, gets Compound C.

The preparation of the compound shown in step 4 general formula (I)

In reaction flask, add Compound C and deionized water, yellow soda ash stirs and under room temperature, is added dropwise to oxammonium hydrochloride and water down; Stirring reaction, reaction is finished, and solid is separated out in cooling; Filter, solid dissolves in hot ethanol, activated carbon decolorizing; Separate out solid after cooling off placement, filter and drying, get the compound shown in the general formula (I).

R in the above reaction equation ^2a, R ^2b, R ^4a, R ^4b, R ⁵, R ⁷, R ⁸, R ^9a, R ^9b, X and n representative meaning such as preamble said.

The tetracycline compound that alkalescence of the present invention has amino isonitroso can form various salt with different nontoxic inorganic or organic acids; Described salt comprises pharmaceutically acceptable anionic salt, for example hydrochloride, hydrobromate, hydriodate, nitrate salt, vitriol, hydrosulfate, phosphoric acid salt, acid phosphate, isonicotine hydrochlorate, acetate, lactic acid salt, salicylate, Citrate trianion, acid Citrate trianion, fumarate, tartrate, pantothenate, bitartrate, ascorbate salt, SUMATRIPTAN SUCCINATE, PHENRAMINE MALEATE, gentisate, fumarate, gluconate, glucarate, saccharate, formate, benzoate, glutaminate, mesylate, esilate, benzene sulfonate, tosilate, palmitate etc.Although it must be pharmaceutically acceptable during Mammals for example that said salt gives the patient; But usually need at first from reaction mixture, to isolate the pharmaceutically unacceptable salt of tetracycline compound of the present invention in the practice; Handle the latter with alkaline reagents then and be translated into free basic cpd simply, then back one free alkali is converted into pharmaceutically-acceptable acid addition.

The tetracycline compound that acidity of the present invention has amino isonitroso can form various salt with different nontoxic inorganic or organic basess, and described salt includes but not limited to for example other alkali salt of alkali metal cation (for example potassium and sodium) and alkaline earth metal cation (for example calcium, magnesium and zinc), ammonium or water-soluble amine additive salt (for example N-NMG (meglumine) and low-grade alkane alcohol ammonium) the pharmaceutically acceptable organic amine of ethyl of salt that said pharmaceutically acceptable positively charged ion produces.This can use ordinary method and pharmaceutically acceptable positively charged ion to form as the pharmaceutically acceptable base addition salt of tart tetracycline compound of the present invention.

Tetracycline compound structure with amino isonitroso of the present invention comprises asymmetric c atom.Therefore, unless stated otherwise, otherwise the isomer (like all enantiomers and diastereomer) that is produced by said asymmetry all is included in the protection domain of the present invention.Said isomer can be through standard stripping technique and the abundant purity isomer of the synthetic acquisition of stereochemistry control.

The present invention further requires to protect the pharmaceutical composition of tetracycline compound, its pharmacy acceptable salt, its isomer or its prodrug and other active pharmaceutical ingredients with amino isonitroso, and described other active pharmaceutical ingredients comprises trimethoprim.

The present invention further requires to protect the pharmaceutical composition that comprises arbitrary compound recited above, its pharmacy acceptable salt, its isomer or its prodrug and one or more pharmaceutical carriers and/or thinner, is pharmaceutically acceptable arbitrary formulation.

Above-mentioned preparation single-dose amount contains the compound 0.002～100mg/kg weight in patients shown in the general formula (I), and preferred 0.02～50mg/kg weight in patients is for treating and/or preventing the necessary amount of a kind of tetracyclines sensitive disease or enough amounts.This dosage can change according to the bodily form and body weight, the type of disease or the concrete factors such as tetracycline derivant of the present invention like the patient.Those of ordinary skill in the art can study the significant quantity of aforementioned factor and definite The compounds of this invention and test improperly.Usually; In clinical The compounds of this invention can according to before the dosage of the clinical use of other tetracycline medication give the patient; For example can give the patient according to the dosage of the clinical use of MINOCYCLINE HCL; The dosage that requires can be suitably by giving once a day, or several times divided dose for example 2-5 dosage every day with the appropriate intervals administration or with other suitable progress administrations.

It is also understood that the conventional known precaution that consider to give tsiklomitsin usually are to guarantee its effect under regular service condition.Especially when being used for the treatment of humans and animals interior therapeutic property, the attending doctor should consider that all common-sense precaution are to avoid conventional known taboo property and toxic action.Therefore, the spinoff of usually generally acknowledging: gastrointestinal discomfort and inflammation, renal toxicity, anaphylaxis, blood picture variation and aluminium, calcium and mg ion malabsorption, should routine with due regard to.

The arbitrary compound of the present invention, its pharmacy acceptable salt, its isomer or its prodrug, can be oral or mode such as administered parenterally be applied to the patient who needs this treatment.

When being used for administered parenterally, can be made into injection.Injection means that confession that medicine is processed injects intravital solution, emulsion or suspension and confession and face with preceding preparation or be diluted to solution or the sterile preparation of the powder of suspension or strong solution, and injection can be divided into injection liquid, injectable sterile powder and concentrated solution for injection.Injection liquid means that the confession that medicine is processed is injected into sterile solution type injection liquid, emulsion-type injection liquid or the suspension type injection liquid of using in the body, can be used for intramuscularly, intravenous injection, intravenous drip etc.; Its specification has 1ml, 2ml, 5ml, 10ml, 20ml, 50ml, 100ml, 200ml, 250ml, 500ml etc., and big volume (generally the being not less than 100ml) injection liquid that wherein supplies intravenous drip to use is also claimed intravenous infusion.Injectable sterile powder means that confession that medicine is processed is faced with the suitable sterile solution of preceding usefulness and is mixed with settled solution or the evenly sterilized powder or the aseptic block of suspension; Available suitable solvent for injection preparation back injection, also available intravenous infusion preparation posterior vein instils; Sterilized powder makes with solvent crystallization, spray-drying process or freeze-drying etc.Concentrated solution for injection means that confession that medicine is processed faces the aseptic strong solution that supplies intravenous drip to use with preceding dilution.

When processing injection, can adopt the ordinary method production in the existing pharmacy field, optional use solvent or non-aqueous solvent.The most frequently used aqueous solvent is a water for injection, also available 0.9% sodium chloride solution or other suitable aqueous solution; Non-aqueous solvent commonly used is a vegetables oil, is mainly the injection VT 18, and other also have the aqueous solution of ethanol, Ucar 35, polyoxyethylene glycol etc.During the preparation injection, can not add additives, also can add suitable additives, like osmotic pressure regulator, pH value regulator, solubilizing agent, weighting agent, oxidation inhibitor, fungistat, emulsifying agent, suspending agent etc. according to the character of medicine.Osmotic pressure regulator commonly used comprises sodium-chlor, glucose, Repone K, magnesium chloride, calcium chloride, sorbyl alcohol etc., preferred sodium-chlor or glucose; PH value regulator commonly used comprises acetic acid-sodium-acetate, lactic acid, Citric Acid-Sodium Citrate, sodium hydrogencarbonate-yellow soda ash etc.; Solubilizing agent commonly used comprises Polysorbate 80, Ucar 35, Yelkin TTS, Witconol 5909 etc.; Weighting agent commonly used comprises lactose, N.F,USP MANNITOL, sorbyl alcohol, Expex etc.; Oxidation inhibitor commonly used has S-WAT, sodium sulfite anhy 96, Sodium Pyrosulfite etc.; Fungistat commonly used is phenol, cresols, trichloro-butyl alcohol etc.Injection container commonly used has glass ampoule, vial, plastic ampoule, Plastic Bottle etc.

Be used for when oral, can be made into conventional solid preparation, like tablet, capsule, pill, granule etc.; Also can be made into oral liquid, like oral solution, oral suspensions, syrup etc.Tablet means disk shape or the special-shaped flaky solid preparation that medicine and suitable auxiliary materials and mixing compacting form; With oral ordinary tablet is main, and other has lozenge, Sublingual tablet, mouth paster, chewable tablet, dispersible tablet, fuse, effervescent tablet, slow releasing tablet, controlled release tablet and enteric coated tablet etc.Capsule means medicine or is added with the auxiliary material filling in Capsules or be sealed in the solid preparation in the soft capsule material; According to its dissolving and release characteristics, can be divided into hard capsule (being commonly referred to as capsule), soft capsule (capsule and pill), slow releasing capsule, controlled release capsule and enteric coated capsule etc.Pill means medicine and suitable auxiliary material uniform mixing, and the spherical or near-spherical solid preparation so that proper method is processed comprises dripping pill, sugar-pill, piller etc.Granule means that medicine and suitable auxiliary material process the dried particles shape preparation with certain particle size, can be divided into soluble particles (being commonly referred to as particle), mix suspension grain, effervescent granule, enteric coated particles, slow-releasing granules and controlled release granule etc.Oral solution means that medicine dissolution is processed and supplies oral clarified liq preparation in suitable solvent.Oral suspensions means the insoluble solid pharmaceutical, is dispersed in the liquid medium, processes to supply oral suspension body preparation, also comprises dry suspensoid or dense suspension.Syrup means the dense aqueous sucrose solution that contains medicine.

When processing oral prepns, can add suitable weighting agent, tackiness agent, disintegrating agent, lubricant etc.Weighting agent commonly used comprises starch, Icing Sugar, calcium phosphate, calcium sulfate two water things, dextrin, Microcrystalline Cellulose, lactose, pregelatinized Starch, N.F,USP MANNITOL etc.; Typical binders comprises Xylo-Mucine, PVP-K30, hydroxypropylcellulose, starch slurry, methylcellulose gum, TKK 021, hypromellose, gelling starch etc.; Disintegrating agent commonly used comprises dry starch, PVPP, Sodium Croscarmellose, sodium starch glycolate, low-substituted hydroxypropyl cellulose etc.; Conventional lubricants comprises Magnesium Stearate, talcum powder, sodium lauryl sulphate, micropowder silica gel etc.

Pharmaceutical composition of the present invention can also be processed external solid, semi-solid preparations such as ointment, ointment, gelifying agent, powder, rubber-emplastrum, cataplasma, patch; Liquid preparation for external application such as lotion, liniment, liniment.Ointment means that medicine and oil or water-soluble base are mixed and made into uniform semi-solid external preparation.Ointment means medicine dissolution or is scattered in and forms uniform semi-solid external preparation in the emulsion-type matrix.Gelifying agent means that medicine and the auxiliary material that can form gel process the glop or the semi-solid preparation of homogeneous, suspendible or emulsion-type.Powder mean medicine or with suitable auxiliary material through the dry powdered preparation of pulverizing, uniform mixing is processed, be divided into oral powder and powder is used in the part.Rubber-emplastrum is coated the emplastrum of processing on the back lining materials after being meant matrix mixings such as medicine and rubber.Cataplasma is coated the emplastrum of processing on the back lining materials after being meant medicine and hydrophilic matrix mixing.Patch means Pasting on skin, and medicine can produce a kind of laminar preparation of general or local action; Said preparation has back sheet, drug depot, the tamanori layer of (or nothing) release-controlled film arranged and faces the resist of removing with preceding need; Can be used for the intact skin surface, also can be used for having illness or incomplete skin surface.Lotion means solution, emulsion, the suspension of drug, supplies to clean or smear the preparation that no damaged skin is used.Liniment means solution, emulsion or the suspension that medicine is processed with ethanol, oil or The suitable solvent, supplies no damaged skin to rub the liquid preparation of wiping usefulness.Paint means water-based or oily solution, emulsion, the suspension of drug, supplies to face with the preceding liquid preparation of getting or be applied to skin or oral cavity and throat's mucous membrane that dips in gauze or cotton.Liniment means medicine dissolution in containing the film forming material organic solvent, is coated with to put film forming liquid preparation for external application behind the affected part on the skin.

When pharmaceutical composition of the present invention was processed external solid, semi-solid preparation, the greasing base that ointment is commonly used had: Vaseline, paraffin, Liquid Paraffin, silicone oil, beeswax, Triple Pressed Stearic Acid etc.; Water-soluble base has polyoxyethylene glycol; Emulsion-type matrix is commonly used has soda soap, trolamine soap class, fatty alcohol sulphuric acid (ester) sodium class, gather mountain plough ester, yolk, direactive glyceride, Fatty Alcohol(C12-C14 and C12-C18) etc.; Can add wetting Agent for Printing Inks, sanitas, oxidation inhibitor or transdermal enhancer in case of necessity.The water-soluble base of gelifying agent generally has formations such as water, glycerine or Ucar 35 and derivatived cellulose, carbomer and alginates, tragakanta, gelatin, starch; Oil-base gel matrix has Liquid Paraffin and T 46155 or wax and colloid silicon or aluminium soap, zinc soap to constitute; Can add wetting Agent for Printing Inks, sanitas, oxidation inhibitor or transdermal enhancer in case of necessity.Rubber-emplastrum matrix commonly used has rubber, thermoplastic rubber, rosin, rosin derivative, Vaseline, yolk and zinc oxide etc.The matrix that cataplasma is commonly used has ZX-I, Xylo-Mucine, gelatin, glycerine and micropowder silica gel etc.Patch matrix commonly used has ethene-acetate ethylene copolymer, Zylox and polyoxyethylene glycol etc.Emplastrum (rubber-emplastrum, cataplasma, patch) back lining materials commonly used has cotton, non-woven fabrics, paper etc.; Lid lining material commonly used has separate paper, plastics film, aluminium foil-polyethylene composite film, stearic gauze etc.Liquid preparation for external application such as lotion, liniment, liniment, solvent commonly used has water, ethanol, glycerine, vegetables oil, Liquid Paraffin etc.; Film forming material commonly used has Z 150PH, Vinylpyrrolidone polymer, crylic acid resin etc.; Softening agent has glycerine, Ucar 35, Witcizer 300 etc.; It is suitable to skin or the non-stimulated additives of mucous membrane to add in case of necessity.

The invention still further relates to tetracycline compound and treat and/or prevent the application in the tetracyclines sensitive diseases medicine in preparation with amino isonitroso.The tetracyclines sensitive disease comprises infection (comprising that other tetracycline compound resistance infects), cancer, mellitus and has been found that tetracycline compound is to other effective other disease.

Tetracycline compound has a broad antifungal spectrum with amino isonitroso of the present invention; Anti-microbial activity is high, common comprises that gram-negative or positive bacteria such as MSSA (MSSA), methicillin-resistant staphylococcus aureus (MRSA), enterococcus faecalis, faecium, intestinal bacteria, hemophilus influenzae etc. all show outstanding anti-microbial activity to most of.Described " tetracyclines sensitive disease " comprises and gives the disease that tetracycline compound that the present invention has amino isonitroso can treat, prevents or improve.

The tetracycline compound that the present invention has amino isonitroso also can be used for preparing the medicine of the tetracyclines susceptibility infection of treating other; Other tetracyclines susceptibility infects and comprises rickettsial infection, and lymphogranuloma venereum, inclusion conjunctivitis and psittacosis pathogenic infection etc.

Described tetracycline compound comprises many compounds with tsiklomitsin ring structure; The instance of tetracycline compound comprises: duomycin, terramycin, Demethylchlortetracycline, metacycline, Sancycline, Rolitetracycline, guamecycline, Minocycline HCl, Vibravenos, chelocardin, and in other verivate and analogue that contains similar Fourth Ring structure is also included within.

Below further set forth the beneficial effect with tetracycline compound of amino isonitroso of the present invention through in-vitro antibacterial experiment, but should this be interpreted as that the tetracycline compound with amino isonitroso of the present invention only has following beneficial effect.

The antibacterial activity in vitro of experimental example The compounds of this invention

Supply the examination bacterial classification: following bacterial strain is all bought in public institution

Clinical isolates strain: gram positive organism: MSSA (MSSA), methicillin-resistant staphylococcus aureus (MRSA), enterococcus faecalis, faecium; Gram-negative bacteria: intestinal bacteria, hemophilus influenzae.

Trial-product: compound 1～20, its chemical name and structural formula are seen the preparation embodiment of each compound.WAY-GAR 936: commercial; Linwzolid: commercial.

Experimental technique: agar dilution, with reference to " pharmacological testing methodology " P1659-1660, People's Health Publisher, chief editor: Xu Shuyun etc., release: the 1st edition the 3rd edition the 5th printing January in 2002 in August nineteen eighty-two.

Table 1 The compounds of this invention is to the anti-microbial activity of clinical isolates

Wherein "-" expression does not have to measure the anti-microbial activity to this bacterial strain

Experimental result and conclusion:

Visible by table 1 experimental result; The compounds of this invention all has excellent antibiotic active to clinical above gram-positive and negative representative strain; Overwhelming majority compounds are stronger or quite than the anti-microbial activity of WAY-GAR 936, and the anti-microbial activity of clinical isolating gram positive organism is better than linwzolid.

Above-mentioned experimental result shows that The compounds of this invention is compared with immediate prior art, and effect is more excellent, has has a broad antifungal spectrum, advantage that anti-microbial activity is high, for having the new compound of good clinical application potential.

4, embodiment

Below, foregoing of the present invention is done further to specify through the embodiment of embodiment form.But should this scope that is interpreted as the above-mentioned theme of the present invention only not limited to following examples.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.The auxiliary material of each formulation can be replaced with acceptable accessories in following examples, perhaps reduces, increases.

Embodiment 1 [S-(4 α, 12a α)]-9-[2-(tertiary butyl amido)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-eight Hydrogen-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 1)

Step 1 [S-(4 α, 12a α)]-9-amino-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide dihydrochloride

In reaction flask, throw 5.3g (0.01mol) [S-(4 α, 12a α)]-9-amino-4, two (dimethylin)-1,4 of 7-, 4a; 5,5a, 6,11,12a-octahydro-3; 10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide dihydrochloride; Be dissolved in the vitriol oil of 70ml, stir ice bath cooling down, add 1.3g SODIUMNITRATE then, mixture stirs 1h in ice bath.Reaction is finished, and this mixture is dropped in the 800ml ether, separates out solid, with a small amount of ether washing after drying.This solid is added in the 20ml ethanol, add the palladium charcoal of 0.4g10% then, stirring at room 1h under the 2MPa hydrogen pressure.Filter, concentrating under reduced pressure, residuum add the 200ml ether under vigorous stirring.Filter, drying gets solid chemical compound 4.5g, yield: 82.5%.

Step 2 [S-(4 α, 12a α)]-9-[(chloracetyl) amino]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide

Under 0 ℃ that 5.5g (10mmol) [S-(4 α, 12a α)]-9-is amino-4, two (dimethylin)-1,4 of 7-, 4a; 5,5a, 6,11,12a-octahydro-3; 10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide dihydrochloride is in the mixing solutions of N,N-DIMETHYLACETAMIDE 60ml and 10ml acetonitrile; Add 6.4g powdery yellow soda ash then, after mixing, slowly be added dropwise to 1.4g chloroacetyl chloride/10ml dichloromethane solution, stirring reaction 120min; Filter, under the vigorous stirring filtrating is dropped to 200ml and contain in the ether of 5ml1M hydrochloric acid, collect gained solid and the dry 4.8g of getting, yield: 87.4%.

Step 3 [S-(4 α, 12a α)]-9-[2-(tertiary butyl amido)-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide

Under room temperature, the nitrogen protection, in the exsiccant reaction flask, add [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1,4 of 7-; 4a, 5,5a, 6; 11,12a-octahydro-3,10,12; 12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol) and N,N-DIMETHYLACETAMIDE 50ml stirs adding 1.1g (15mmol) tert-butylamine down, stirring reaction 2h.Reaction is finished, and adds the ethanol of 50ml, adds the ether of 100ml again, and ice bath stirs down and separates out solid, filters and dry, gets product 2.2g, yield: 76.8%.

Step 4, in reaction flask, add [S-(4 α, 12a α)]-9-[2-(tertiary butyl amido)-acetamido]-4, two (dimethylin)-1,4 of 7-; 4a, 5,5a, 6,11; 12a-octahydro-3,10,12,12a-tetrahydroxy-1; 11-dioxo-2-tetracene methane amide 5.9g (10mmol) and deionized water 40ml, yellow soda ash 1g (12mmol) stirs down and under room temperature, is added dropwise to oxammonium hydrochloride 0.8g (11mmol) and water 20ml, in 50 ℃ of stirring reaction 24h.Reaction is finished, and reduces to about 10 ℃, separates out solid.Filter, solid dissolves in hot ethanol, activated carbon decolorizing, cooling is separated out solid after placing, filter and dry, target compound 3.2g, yield: 53.2%.

Molecular formula: C ₂₉H ₄₀N ₆O ₈Molecular weight: 600.66 mass spectrums (m/e): 601 (M+1)

Ultimate analysis: theoretical value: C, 57.99%; H, 6.71%; N, 13.99%

Measured value: C, 57.89%; H, 6.62%; N, 13.90%

Embodiment 2 [S-(4 α, 12a α)]-9-[2-(N, TMSDMA N dimethylamine base)-1-hydroxyl imido grpup-ethylamino-]-4, the two (n n dimetylaniline of 7- Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 2)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 0.7g (15mmol) dimethyl amine.Get [S-(4 α, 12a α)]-9-[2-(N, TMSDMA N dimethylamine base)-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.2g, yield: 78.5%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(N, TMSDMA N dimethylamine base)-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 5.6g (10mmol), oxammonium hydrochloride 0.8g (11mmol).Get target compound 2.9g, yield: 51.2%.

Molecular formula: C ₂₇H ₃₆N ₆O ₈Molecular weight: 572.61 mass spectrums (m/e): 573 (M+1)

Ultimate analysis: theoretical value: C, 56.63%; H, 6.34%; N, 14.68%

Measured value: C, 56.54%; H, 6.43%; N, 14.59%

Embodiment 3 [S-(4 α, 12a α)]-9-[2-(N, TMSDEA N diethylamine base)-1-hydroxyl imido grpup-ethylamino-]-4, the two (n n dimetylaniline of 7- Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 3)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 1.1g (15mmol) diethylamine.Get [S-(4 α, 12a α)]-9-[2-(N, TMSDEA N diethylamine base)-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a; 5,5a, 6,11,12a-octahydro-3; 10,12,12a-tetrahydroxy-1, the preparation 2.3g of 11-dioxo-2-tetracene methane amide, yield: 79.3%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(N, TMSDEA N diethylamine base)-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 5.9g (10mmol), oxammonium hydrochloride 0.8g (11mmo1).Get target compound 3.3g, yield: 54.9%.

Ultimate analysis: theoretical value: C, 57.99%; H, 6.71%; N, 13.99%

Measured value: C, 57.89%; H, 6.80%; N, 13.89%

Embodiment 4 [S-(4 α, 12a α)]-9-[2-(cyclopropyl amido)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a- Octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 4)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 0.9g (15mmol) cyclopropylamine.Get [S-(4 α, 12a α)]-9-[2-(cyclopropyl amido)-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.0g, yield: 71.2%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(cyclopropyl amido)-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 5.7g (10mmol), oxammonium hydrochloride 0.8g (11mmol).Get target compound 2.8g, yield: 48.4%.

Molecular formula: C ₂₈H ₃₆N ₆O ₈Molecular weight: 584.62 mass spectrums (m/e): 585 (M+1)

Ultimate analysis: theoretical value: C, 57.52%; H, 6.21%; N, 14.38%

Measured value: C, 57.43%; H, 6.30%; N, 14.30%

Embodiment 5 [S-(4 α, 12a α)]-9-[2-(cyclobutyl amido)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a- Octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 5)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 1.1g (15mmol) encircles butylamine.Get [S-(4 α, 12a α)]-9-[2-(cyclobutyl amido)-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.1g, yield: 73.1%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(cyclobutyl amido)-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 5.8g (10mmol), oxammonium hydrochloride 0.8g (11mmol).Get target compound 3.1g, yield: 52.6%.

Molecular formula: C ₂₉H ₃₈N ₆O ₈Molecular weight: 598.65 mass spectrums (m/e): 599 (M+1)

Ultimate analysis: theoretical value: C, 58.18%; H, 6.40%; N, 14.04%

Measured value: C, 58.08%; H, 6.50%; N, 13.98%

Embodiment 6 [S-(4 α, 12a α)]-9-[2-(cyclopentyl amido)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a- Octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 6)

Step 1,2 is with embodiment 1.

Step 3 in 3 preparing method's reference implementations example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 1.3g (15mmol) cyclopentyl amine.Get [S-(4 α, 12a α)]-9-[2-(cyclopentyl amido)-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.3g, yield: 75.8%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(cyclopentyl amido)-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.0g (10mmol), oxammonium hydrochloride 0.8g (11mmol).Get target compound 3.1g, yield: 50.6%.

Molecular formula: C ₃₀H ₄₀N ₆O ₈Molecular weight: 612.67 mass spectrums (m/e): 613 (M+1)

Ultimate analysis: theoretical value: C, 58.81%; H, 6.58%; N, 13.72%

Measured value: C, 58.73%; H, 6.65%; N, 13.63%

Embodiment 7 [S-(4 α, 12a α)]-9-[2-(cyclohexyl amido)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a- Octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 7)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 1.5g (15mmol) cyclo-hexylamine.Get [S-(4 α, 12a α)]-9-[2-(cyclohexyl amido)-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.4g, yield: 77.4%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(cyclohexyl amido)-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.1g (10mmo1), oxammonium hydrochloride 0.8g (11mmol).Get target compound 3.6g, yield: 57.4%.

Molecular formula: C ₃₁H ₄₂N ₆O ₈Molecular weight: 626.70 mass spectrums (m/e): 613 (M+1)

Ultimate analysis: theoretical value: C, 59.41%; H, 6.75%; N, 13.41%

Measured value: C, 59.32%; H, 6.83%; N, 13.30%

Embodiment 8 [S-(4 α, 12a α)]-9-[2-(furans-2-yl) amido-1-hydroxyl imido grpup-ethylamino-]-4, the two (n n dimetylaniline of 7- Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 8)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 1.2g (15mmol) 2-amino-furans.Get [S-(4 α, 12a α)]-9-[2-(furans-2-yl) amido-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.2g, yield: 73.7%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(furans-2-yl) amido-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.0g (10mmol), oxammonium hydrochloride 0.8g (11mmol).Get target compound 3.7g, yield: 60.6%.

Molecular formula: C ₂₉H ₃₄N ₆O ₉Molecular weight: 610.62 mass spectrums (m/e): 613 (M+1)

Ultimate analysis: theoretical value: C, 57.04%; H, 5.61%; N, 13.76%

Measured value: C, 56.96%; H, 5.72%; N, 13.66%

Embodiment 9 [S-(4 α, 12a α)]-9-[2-(thiophene-2-yl) amido-1-hydroxyl imido grpup-ethylamino-]-4, the two (n n dimetylaniline of 7- Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 9)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 1.5g (15mmol) 2-amino-thiophene.Get [S-(4 α, 12a α)]-9-[2-(thiophene-2-yl) amido-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.1g, yield: 70.2%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(thiophene-2-yl) amido-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.1g (10mmol), oxammonium hydrochloride 0.8g (11mmol).Get target compound 3.1g, yield: 50.1%.

Molecular formula: C ₂₉H ₃₄N ₆O ₈S molecular weight: 626.68 mass spectrums (m/e): 627 (M+1)

Ultimate analysis: theoretical value: C, 55.58%; H, 5.47%; N, 13.41%; S, 5.12%

Measured value: C, 55.49%; H, 5.55%; N, 13.30%; S, 5.10%

Embodiment 10 [S-(4 α, 12a α)]-9-[2-(thiazol-2-yl) amido-1-hydroxyl imido grpup-ethylamino-]-4, the two (n n dimetylaniline of 7- Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo 2-tetracene methane amide (compound 10)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 1.5g (15mmol) 2-amino-thiazolyl-.Get [S-(4 α, 12a α)]-9-[2-(thiazol-2-yl) amido-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.3g, yield: 75.2%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(thiazol-2-yl) amido-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.1g (10mmol), oxammonium hydrochloride 0.8g (11mmol).Get target compound 3.0g, yield: 47.8%.

Molecular formula: C ₂₈H ₃₃N ₇O ₈S molecular weight: 627.67 mass spectrums (m/e): 628 (M+1)

Ultimate analysis: theoretical value: C, 53.58%; H, 5.30%; N, 15.62%; S, 5.11%

Measured value: C, 53.49%; H, 5.40%; N, 15.53%; S, 5.10%

Embodiment 11 [S-(4 α, 12a α)]-9-[2-(4-trifluoromethyl-benzene-1-yl) amido-1-hydroxyl imido grpup-ethylamino-]-4, the two (n n dimetylaniline of 7- Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 11)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1,4 of 7-, 4a; 5,5a, 6,11,12a-octahydro-3; 10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 2.4g

(15mmol) 4-trifluoromethyl-aniline.Get [S-(4 α, 12a α)]-9-[2-(4-trifluoromethyl-benzene-1-yl) amido-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a; 5,5a, 6,11,12a-octahydro-3; 10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.6g, yield: 77.0%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(4-trifluoromethyl-benzene-1-yl) amido-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.7g (10mmol), oxammonium hydrochloride 0.8g (11mmol).Get target compound 3.5g, yield: 51.0%.

Molecular formula: C ₃₂H ₃₅F ₃N ₆O ₈Molecular weight: 688.65 mass spectrums (m/e): 689 (M+1)

Ultimate analysis: theoretical value: C, 55.81%; H, 5.12%; N, 12.20%; F8.28%

Measured value: C, 55.73%; H, 5.23%; N, 12.12%; F, 8.19%

Embodiment 12 [S-(4 α, 12a α)]-9-[2-(4-trifluoromethoxy-benzene-1-yl) amido-1-hydroxyl imido grpup-ethylamino-]-4, the two (n n dimetylaniline of 7- Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 12).

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 2.7g (15mmol) 4-trifluoromethoxy-aniline.Get [S-(4 α, 12a α)]-9-[2-(4-trifluoromethoxy-benzene-1-yl) amido-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a; 5,5a, 6,11,12a-octahydro-3; 10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g, yield: 78.1%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(4-trifluoromethoxy-benzene-1-yl) amido-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.9g (10mmol), oxammonium hydrochloride 0.8g (11mmol).Get target compound 3.9g, yield: 55.3%.

Molecular formula: C ₃₂H ₃₅F ₃N ₆O ₉Molecular weight: 704.65 mass spectrums (m/e): 705 (M+1)

Ultimate analysis: theoretical value: C, 54.54%; H, 5.01%; N, 11.93%; F8.09%

Measured value: C, 54.45%; H, 5.12%; N, 11.86%; F, 8.00%

Embodiment 13 [S-(4 α, 12a α)]-9-[2-(pyridin-3-yl) amido-1-hydroxyl imido grpup-ethylamino-]-4, the two (n n dimetylaniline of 7- Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 13)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 1.4g (15mmol) 3-amino-pyridine.Get [S-(4 α, 12a α)]-9-[2-(pyridin-3-yl) amido-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.3g, yield: 75.5%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(pyridin-3-yl) amido-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.1g (10mmo1), oxammonium hydrochloride 0.8g (11mmo1).Get target compound 3.1g, yield: 49.8%.

Molecular formula: C ₃₀H ₃₅N ₇O ₈Molecular weight: 621.64 mass spectrums (m/e): 622 (M+1)

Ultimate analysis: theoretical value: C, 57.96%; H, 5.67%; N, 15.77%

Measured value: C, 57.88%; H, 5.75%; N, 15.68%

Embodiment 14 [S-(4 α, 12a α)]-9-[2-[(pyridin-3-yl) methyl] amido-1-hydroxyl imido grpup-ethylamino-]-4, the two (n n dimetylaniline of 7- Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 14)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 1.6g (15mmol) 3-pyridyl-methanamine.Get [S-(4 α, 12a α)]-9-[2-[(pyridin-3-yl) methyl] amido-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a; 5,5a, 6,11,12a-octahydro-3; 10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.4g, yield: 78.1%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-[(pyridin-3-yl) methyl] amido-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.2g (10mmol), oxammonium hydrochloride 0.8g (11mmol).Get target compound 3.5g, yield: 54.6%.

Molecular formula: C ₃₁H ₃₇N ₇O ₈Molecular weight: 635.67 mass spectrums (m/e): 636 (M+1)

Ultimate analysis: theoretical value: C, 58.57%; H, 5.87%; N, 15.42%

Measured value: C, 58.49%; H, 5.96%; N, 15.35%

Embodiment 15 [S-(4 α, 12a α)]-9-[2-(azetidine-1-yl)-1-hydroxyl imido grpup-ethylamino-]-4, the two (n n dimetylaniline of 7- Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 15)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 0.9g (15mmol) azetidine hydrochloride.Get [S-(4 α, 12a α)]-9-[2-(azetidine-1-yl)-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.1g, yield: 74.5%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(azetidine-1-yl)-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 5.7g (10mmol), oxammonium hydrochloride 0.8g (11mmol).Get target compound 2.6g, yield: 44.6%.

Ultimate analysis: theoretical value: C, 57.52%; H, 6.21%; N, 14.38%

Measured value: C, 57.43%; H, 6.32%; N, 14.29%

Embodiment 16 [S-(4 α, 12a α)]-9-[2-(tetramethyleneimine-1-yl)-1-hydroxyl imido grpup-ethylamino-]-4, the two (n n dimetylaniline of 7- Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene first (compound 16)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 1.1g (15mmol) tetramethyleneimine.Get [S-(4 α, 12a α)]-9-[2-(tetramethyleneimine-1-yl)-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.3g, yield: 78.3%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(tetramethyleneimine-1-yl)-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 5.8g (10mmol), oxammonium hydrochloride 0.8g (11mmol).Get target compound 3.1g, yield: 51.9%.

Ultimate analysis: theoretical value: C, 58.18%; H, 6.40%; N, 14.04%

Measured value: C, 58.09%; H, 6.45%; N, 13.98%

Embodiment 17 [S-(4 α, 12a α)]-9-[2-(piperidines-1-yl)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-eight Hydrogen-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 17)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 1.3g (15mmol) piperidines.Get [S-(4 α, 12a α)]-9-[2-(piperidines-1-yl)-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.4g, yield: 79.1%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(piperidines-1-yl)-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.0g (10mmol), oxammonium hydrochloride 0.8g (11mmol).Get target compound 3.6g, yield: 58.8%.

Ultimate analysis: theoretical value: C, 58.81%; H, 6.58%; N, 13.72%

Measured value: C, 58.76%; H, 6.65%; N, 13.65%

Embodiment 18 [, S-(4 α, 12a α)]-9-[2-(4-methyl-piperazine-1-yl)-1-hydroxyl imido grpup-ethylamino-]-4, the two (n n dimetylaniline of 7- Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 18)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 1.5g (15mmol) N methyl piperazine.Get [S-(4 α, 12a α)]-9-[2-(4-methyl-piperazine-1-yl)-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.4g, yield: 77.9%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(4-methyl-piperazine-1-yl)-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.1g (10mmol), oxammonium hydrochloride 0.8g (11mmol).Get target compound 3.3g, yield: 52.4%.

Molecular formula: C ₃₀H ₄₁N ₇O ₈Molecular weight: 627.69 mass spectrums (m/e): 628 (M+1)

Ultimate analysis: theoretical value: C, 57.40%; H, 6.58%; N, 15.62%

Measured value: C, 57.32%; H, 6.65%; N, 15.53%

Embodiment 19 [S-(4 α, 12a α)]-9-[2-(3,4,5,6-tetrahydrochysene-2H-1,2-oxazine-2-yl)-1-hydroxyl imido grpup-ethylamino-]-4, the two (n n dimetylaniline of 7- Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 19)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1,4 of 7-; 4a, 5,5a, 6,11; 12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol); 1.3g (15mmol) 3,4,5,6-tetrahydrochysene-2H-1,2-oxazine.Get [S-(4 α, 12a α)]-9-[2-(3,4,5,6-tetrahydrochysene-2H-1,2-oxazine-2-yl)-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a, 6,11; 12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.2g, yield: 72.6%.

4, step 4 in preparing method's reference implementation example 1, [S-(4 α, 12a α)]-[2-(3,4,5 for 9-in throwing; 6-tetrahydrochysene-2H-1,2-oxazine-2-yl)-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a; 5,5a, 6,11,12a-octahydro-3; 10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.0g (10mmol), oxammonium hydrochloride 0.8g (11mmol).Get target compound 3.0g, yield: 49.3%.

Molecular formula: C ₂₉H ₃₈N ₆O ₉Molecular weight: 614.65 mass spectrums (m/e): 615 (M+1)

Ultimate analysis: theoretical value: C, 56.67%; H, 6.23%; N, 13.67%

Measured value: C, 56.58%; H, 6.30%; N, 13.70%

Embodiment 20 [S-(4 α, 12a α)]-9-[2-(diamantane-1-yl) amido-1-hydroxyl imido grpup-ethylamino-]-4, the two (n n dimetylaniline of 7- Base)-1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1, the preparation of 11-dioxo-2-tetracene methane amide (compound 20)

Step 1,2 is with embodiment 1.

3, step 3 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[(2-chloracetyl) amido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.7g (5mmol), 2.3g (15mmol) 1-amantadine.Get [S-(4 α, 12a α)]-9-[2-(diamantane-1-yl) amido-acetamido]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 2.1g, yield: 63.1%.

4, step 4 in preparing method's reference implementation example 1 is thrown [S-(4 α, 12a α)]-9-[2-(diamantane-1-yl) amido-acetamido]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a; 6,11,12a-octahydro-3,10; 12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide 6.6g (10mmo1), oxammonium hydrochloride 0.8g (11mmol).Get target compound 2.9g, yield: 43.1%.

Molecular formula: C ₃₅H ₄₆N ₆O ₈Molecular weight: 678.78 mass spectrums (m/e): 679 (M+1)

Ultimate analysis: theoretical value: C, 61.93%; H, 6.83%; N, 12.38%

Measured value: C, 61.86%; H, 6.90%; N, 12.35%

With reference to above-mentioned preparation method, also prepared following compound

The preparation of FORMULATION EXAMPLE 1 The compounds of this invention freeze-dried powder

1, prescription:

Prescription 1

Prescription 2

2, preparation technology: take by weighing raw material and auxiliary material according to prescription, N.F,USP MANNITOL is added about 80% water for injection stirring and dissolving (Expex boils dissolving to be put cold), add the raw material stirring dissolving again; Regulate the appropriate pH value, benefit adds to the full amount of water for injection, and adds dosing amount 0.05% needle-use activated carbon absorption 15 minutes; Filtering decarbonization, smart filter, work in-process chemical examination; Can, lid is rolled in freeze-drying, tamponade.Step of freeze drying is :-40 ℃ of pre-freezes 3 hours, with on average per hour 1 ℃ heat up, be warming up to 2 ℃ and carry out low-temperature vacuum drying, the 30 ℃ of high-temperature vacuum dryings that are rapidly heated, vacuum degree control is below the 0.1mm mercury column.

The preparation of FORMULATION EXAMPLE 2 The compounds of this invention aseptic powder injections

1, prescription:

Prescription 1

Prescription 2

2, preparation technology: will prepare used antibiotic glass bottle, plug etc. and carry out aseptically process; Take by weighing raw material and auxiliary material by prescription, pulverize mixing, place the portioning machine packing, the detection at any time loading amount; Jump a queue, gland, finished product is examined entirely, the packing warehouse-in.

The preparation of FORMULATION EXAMPLE 3 The compounds of this invention tablets

1, prescription:

Prescription 1

Prescription 2

2, preparation technology: take by weighing raw material and auxiliary material according to prescription, raw material pulverizing is crossed 100 mesh sieves, all the other auxiliary materials are crossed 100 mesh sieves respectively; Raw material, starch, hydroxypropylcellulose and Microcrystalline Cellulose are mixed, add mixer-granulator, 50% aqueous ethanolic solution (or 2%PVP-K30 aqueous solution) that adds 1%HPMC is an amount of, stirs 15 minutes, processes particle; Particle is dried being lower than under 50 ℃ the condition; Dry good particle adds micropowder silica gel and Magnesium Stearate, and whole grain mixes; Sampling, the work in-process chemical examination; According to the definite sheet weight sheet of chemical examination; Finished product is examined entirely, the packing warehouse-in.

The preparation of FORMULATION EXAMPLE 4 The compounds of this invention ointment

1, prescription:

Prescription 1:

Prescription 2:

2, preparation technology: card taking POP 940 adds an amount of water and is dipped into dissolving fully, adds ethyl p-hydroxybenzoate (using dissolve with ethanol), adds glycerine, tween 80 again; Stirring and evenly mixing; Add raw material stirring mixing or dissolving, add the trolamine neutralization at last, the ointment of water-soluble base.

Those skilled in the art will know or only use routine test just can confirm many embodiments that are equal to of concrete grammar described herein.The embodiment that is equal to is like this considered within the scope of the present invention, and is included in claims scope.

Claims

1. the compound shown in the general formula (I) or its pharmacy acceptable salt:

Wherein, R ^2aAnd R ^2bIndependently be Wasserstoffatoms respectively;

R ^4aAnd R ^4bIndependently be methyl respectively;

R ⁵Be Wasserstoffatoms;

X representative-CH ₂-;

R ⁷For-N (CH ₃) ₂

R ⁸Be Wasserstoffatoms;

R ^9aAnd R ^9bIndependently be Wasserstoffatoms, C respectively _1-6Straight or branched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 5～6 yuan of saturated or undersaturated single heterocyclic radicals, 5～6 yuan of saturated or undersaturated single heterocyclic radical C _1-4Straight or branched alkyl, adamantyl, perhaps R ^9aAnd R ^9bCoupled nitrogen-atoms forms 4～6 yuan of saturated or undersaturated single heterocyclic radicals together;

Described R ^9aAnd R ^9bBe phenyl, 5～6 yuan of saturated or undersaturated single heterocyclic radicals, 5～6 yuan of saturated or undersaturated single heterocyclic radical C _1-4Straight or branched alkyl, adamantyl, perhaps R ^9aAnd R ^9bWhen coupled nitrogen-atoms forms 4～6 yuan of saturated or undersaturated single heterocyclic radicals together, can further be replaced by one or more substituting groups, said substituting group is selected from C _1-4Straight or branched alkyl, fluoro C _1-4Straight or branched alkyl, C _1-4Straight or branched alkoxyl group or fluoro C _1-4The straight or branched alkoxyl group;

N is 1.

2. compound as claimed in claim 1 or its pharmacy acceptable salt:

Wherein, R ^2aAnd R ^2bIndependently be Wasserstoffatoms respectively;

R ^4aAnd R ^4bIndependently be methyl respectively;

R ⁵Be Wasserstoffatoms;

X representative-CH ₂-;

R ⁷For-N (CH ₃) ₂

R ⁸Be Wasserstoffatoms;

R ^9aAnd R ^9bIndependently be Wasserstoffatoms, C respectively _1-6Straight or branched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, furyl, tetrahydrofuran base, pyrryl, Pyrrolidine base, thienyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, piperidyl, pyranyl, THP trtrahydropyranyl, pyridyl, pyriconyl 、 oxazolyl 、 isoxazolyl, morpholinyl, adamantyl, perhaps R ^9aAnd R ^9bCoupled nitrogen-atoms forms azetidinyl, pyrryl, pyrrolidyl, imidazolyl, piperidyl, morpholinyl, pyriconyl, pyrazolyl, triazolyl, tetrazyl, pyrazolidyl, piperazinyl Huo oxazinyl together,

Described R ^9aAnd R ^9bBe phenyl, furyl, tetrahydrofuran base, pyrryl, Pyrrolidine base, thienyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, piperidyl, pyranyl, THP trtrahydropyranyl, pyridyl, pyriconyl 、 oxazolyl 、 isoxazolyl, morpholinyl, adamantyl, perhaps R ^9aAnd R ^9bWhen coupled nitrogen-atoms forms azetidinyl, pyrryl, pyrrolidyl, imidazolyl, piperidyl, morpholinyl, pyriconyl, pyrazolyl, triazolyl, tetrazyl, pyrazolidyl, piperazinyl Huo oxazinyl together; Can further be replaced by one or more substituting groups, said substituting group is selected from C _1-4Straight or branched alkyl, fluoro C _1-4Straight or branched alkyl, C _1-4Straight or branched alkoxyl group or fluoro C _1-4The straight or branched alkoxyl group;

N is 1.

3. want 2 described compounds or its pharmacy acceptable salt like right:

R ^9aAnd R ^9bIndependently be the tertiary butyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, furyl, thienyl, thiazolyl, phenyl, pyridyl, adamantyl, perhaps R respectively ^9aAnd R ^9bCoupled nitrogen-atoms forms azetidinyl, pyrrolidyl, piperidyl 、 oxazinyl or piperazinyl together,

Described R ^9aAnd R ^9bBe furyl, thienyl, thiazolyl, phenyl, pyridyl, adamantyl, perhaps R ^9aAnd R ^9bWhen coupled nitrogen-atoms forms azetidinyl, pyrrolidyl, piperidyl 、 oxazinyl or piperazinyl together, can further be replaced by one or more substituting groups, said substituting group is selected from methyl, trifluoromethyl or trifluoromethoxy;

N is 1.

4. the compound that is described below or its pharmacy acceptable salt, said compound is selected from:

[S-(4 α, 12a α)]-9-[2-(tertiary butyl amido)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,

[S-(4 α, 12a α)]-9-[2-(N, TMSDMA N dimethylamine base)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,

[S-(4 α, 12a α)]-9-[2-(N, TMSDEA N diethylamine base)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,

[S-(4 α, 12a α)]-9-[2-(cyclopropyl amido)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,

[S-(4 α, 12a α)]-9-[2-(cyclobutyl amido)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,

[S-(4 α, 12a α)]-9-[2-(cyclopentyl amido)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,

[S-(4 α, 12a α)]-9-[2-(cyclohexyl amido)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,

[S-(4 α, 12a α)]-9-[2-(furans-2-yl) amido-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,

[S-(4 α, 12a α)]-9-[2-(thiophene-2-yl) amido-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6; 11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide, [S-(4 α; 12a α)]-and 9-[2-(thiazol-2-yl) amido-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6; 11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide

[S-(4 α, 12a α)]-9-[2-(4-trifluoromethyl-benzene-1-yl) amido-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,

[S-(4 α, 12a α)]-9-[2-(4-trifluoromethoxy-benzene-1-yl) amido-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,

[S-(4 α, 12a α)]-9-[2-(pyridin-3-yl) amido-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,

[S-(4 α, 12a α)]-9-[2-[(pyridin-3-yl) methyl] amido-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,

[S-(4 α, 12a α)]-9-[2-(azetidine-1-yl)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,

[S-(4 α, 12a α)]-9-[2-(tetramethyleneimine-1-yl)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,

[S-(4 α, 12a α)]-9-[2-(piperidines-1-yl)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,

[S-(4 α, 12a α)]-9-[2-(4-methyl-piperazine-1-yl)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide,

[S-(4 α, 12a α)]-9-[2-(3,4,5,6-tetrahydrochysene-2H-1,2-oxazine-2-yl)-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1 of 7-; 4,4a, 5,5a, 6,11; 12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide and

[S-(4 α, 12a α)]-9-[2-(diamantane-1-yl) amido-1-hydroxyl imido grpup-ethylamino-]-4, two (dimethylin)-1,4 of 7-, 4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-tetracene methane amide.

5. the pharmaceutical composition that comprises each described compound of claim 1～4 or its pharmacy acceptable salt and other active pharmaceutical ingredients.

6. the pharmaceutical composition of forming like each described compound of claim 1～4 or its pharmacy acceptable salt and one or more pharmaceutical carriers and/or thinner is pharmaceutically acceptable arbitrary formulation.

7. treat and/or prevent the application in the tetracyclines sensitive diseases medicine like each described compound of claim 1～4 or its pharmacy acceptable salt in preparation.