CN100544719C - Oxazolidone-quinoline hybrid antibiotics is used for preparing the purposes of the medicine for the treatment of anthrax and other infection - Google Patents

Oxazolidone-quinoline hybrid antibiotics is used for preparing the purposes of the medicine for the treatment of anthrax and other infection Download PDF

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CN100544719C
CN100544719C CNB2004800186791A CN200480018679A CN100544719C CN 100544719 C CN100544719 C CN 100544719C CN B2004800186791 A CNB2004800186791 A CN B2004800186791A CN 200480018679 A CN200480018679 A CN 200480018679A CN 100544719 C CN100544719 C CN 100544719C
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CN1832746A (en
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克里斯蒂安·胡布施韦尔朗
让-吕克·斯派克林
达尼埃尔·K.·贝施林
汉斯·洛谢
克里斯蒂娜·施米特
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Morphochem AG fuer Kombinatorische Chemie
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Abstract

The present invention relates to the purposes that chemical compound is used for the treatment of anthrax and other infection, in described chemical compound quinolinones and oxazolidone pharmacophore by under physiological condition stable be connected base and chemical be joined together.

Description

Oxazolidone-quinoline hybrid antibiotics is used for preparing the purposes of the medicine for the treatment of anthrax and other infection
The invention describes the purposes that chemical compound is used for the treatment of anthrax and other infection, in described chemical compound quinolinones He oxazolidone (oxazolidinone) pharmacophore by under physiological condition stable be connected base and chemical be joined together.
Anthrax is by producing the acute infectious diseases that bacillus cereus anthrax bacillus (Bacillus anthracis) causes.Anthrax is the most normal to betide low the grade in the vertebrates (cattle, sheep, goat, camel, Saigae Tataricae and other plant-eating animal) wild and that raise and train, but anthrax also can occur in philtrum when the organizing of the animal of people's contact infection or infection animal.The pathogen anthrax bacillus of anthrax is big Gram-positive real estate bacillus cereus.Three virulence factors of anthrax bacillus are edema toxin, lethal toxin and k antigen.People's anthrax has three kinds of main clinical type: malignant pustule, respiratory anthrax and gastrointestinal anthrax.If do not treat, all types of anthraxs all can cause septicemia and death.Owing to think that anthrax is the lateral reactivity agent that can be used for biological warfare, anthrax has become suitable interest place recently.
The chemical compound that the invention provides formula (I) is used for the treatment of purposes or the acceptable salt of its pharmacology, solvate, hydrate or the preparation of anthrax and other infection:
Figure C20048001867900101
Wherein
A is direct key, NH, O, S, SO, SO 2, SO 2NH, PO 4,-NH-CO-NH-,-CO-NH-,-CO-,-CO-O-,-NH-CO-O-,-two or more combination in the inferior Heterocyclylalkyl of O-Z-, alkylidene, alkenylene, alkynylene, inferior assorted alkyl, arlydene, heteroarylidene, cycloalkylidene, inferior Heterocyclylalkyl, alkyl arylene or heteroaryl alkylidene or these atoms or the group;
L is selected from following group:
Figure C20048001867900111
X is CR5 or N;
Y is CR6 or N;
U is F or Cl;
Z is C 1-4Alkylidene, C 2-4Alkenylene, C 2-4Alkynylene or C 1-4Inferior assorted alkyl, wherein all groups can be by one or more hydroxyls or amino the replacement;
N is 0,1,2 or 3;
R1 is H, F, Cl, Br, I, OH, NH 2, alkyl or assorted alkyl;
R2 is H, F or Cl;
R3 is H, alkyl, thiazolinyl, alkynyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylaryl or heteroaryl alkyl, wherein all groups can by one, two or more a plurality of halogen atom such as F or Cl replace;
R4 is assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylaryl or heteroaryl alkyl;
R5 is H, F, Cl, OH, NH 2, alkyl or assorted alkyl, perhaps
If R3 is not H and R5 is not H, F, OH, NH 2Or Cl, R3 can be connected through alkylidene, alkenylene or inferior assorted alkyl with R5, perhaps can be the part of cycloalkylidene or inferior Heterocyclylalkyl;
R6 is H, F, Cl or OMe;
R8 is C 1-6Assorted alkyl or heteroaryl alkyl.
Should understand, the application's formula (I), (II) or some chemical compound (III) can have tautomeric form, it may only specifically be mentioned in the following description or describe a kind of, they can have different geometric isomer (they are represented as the cis/trans isomer usually, perhaps more generally are represented as (E) and (Z) isomer) or as the result's of one or more chiral carbon atoies different optical isomers (they are being named usually) under order or R/S system.In addition, some chemical compounds can show polymorphism.All these tautomeric forms, geometry or optical isomer (and racemate and diastereomer) and polymorphism form all comprise in the present invention.
The term alkyl refers to contain 1-10, saturated or unsaturated (being thiazolinyl and alkynyl) straight or branched alkyl of preferred 1-6 carbon atom, for example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, n-hexyl, 2,2-dimethylbutyl, n-octyl; Vinyl, acrylic (pi-allyl), isopropenyl, n-pentyl, cyclobutenyl, prenyl or own-2-thiazolinyl; Acetenyl, propinyl or butynyl.Any alkyl of this paper definition all can be by one, two or more a plurality of substituent group, for example F, Cl, Br, I, NH 2, OH, SH or NO 2Replace.
Term thiazolinyl and alkynyl refer to contain 2-10, the unsaturated straight or branched alkyl of preferred 2-6 carbon atom (has one, two or the more a plurality of pairs of keys and/or triple bond, thiazolinyl preferably has one or two two key, and alkynyl preferably has one or two triple bond), vinyl, acrylic (pi-allyl), isopropenyl, positive pentenyl, cyclobutenyl, prenyl or oneself-2-thiazolinyl for example; Acetenyl, propinyl or butynyl.Any alkenyl or alkynyl of this paper definition all can be by one, two or more a plurality of substituent group, for example F, Cl, Br, I, NH 2, OH, SH or NO 2Replace.
The assorted alkyl of term refers to the alkyl that defines herein, wherein one or more carbon atoms are substituted by oxygen, nitrogen, phosphorus or sulphur atom, for example alkoxyl such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy or tert-butoxy, alkoxyalkyl such as methoxy, ethoxyl methyl, 1-methoxy ethyl, 1-ethoxyethyl group, 2-methoxy ethyl or 2-ethoxyethyl group, alkylamino such as methylamino, ethylamino, third amino, isopropylamino, dimethylamino or lignocaine, alkylthio group such as methyl mercapto, ethylmercapto group or iprotiazem base, or cyano group.It also can refer to one of above-mentioned group that contains ketone group.The assorted alkyl of term further refers to group such as acetyl group, propiono, acetoxyl group, propionyloxy, acetylamino or the propionamido of derived from carboxylic acid or carboxylic acid amide; carboxyalkyl such as carboxymethyl, carboxyethyl or carboxylic propyl group; the carboxyalkyl ester; alkylthio group carboxylic amino; Alkoximino, alkylamino sulfo-carboxylic amino or alkoxycarbonyl amido.The assorted alkyl of this paper definition can be by one, two or more a plurality of substituent group, for example F, Cl, Br, I, NH 2, OH, SH or NO 2Replace.
The term cycloalkyl refers to have one, two or more a plurality of ring, have 3-14 carboatomic ring atom, preferred 5 or the saturated or part of 6-10 carboatomic ring atom unsaturated (have, two or the more a plurality of pairs of keys and/or triple bond) cyclic group, for example cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, tetrahydronaphthalene, cyclopentenyl or hexamethylene-2-thiazolinyl.Any cycloalkyl of this paper definition all can be by one, two or more a plurality of substituent group for example F, Cl, Br, I, OH, NH 2, SH, N 3, NO 2, alkyl such as methyl or ethyl, assorted alkyl such as methoxyl group, methylamino, dimethylamino, cyanide or wherein R7 be the group of the formula-OR7 of hydrogen, R wherein 9Be hydrogen, alkyl, cycloalkyl, aryl, aralkyl and R wherein 10Be the formula PO of hydrogen, alkyl, cycloalkyl, aryl, aralkyl 3R 9 2Or SO 3R 10Group or have at least one OH, NH 2, SO 3R 10, PO 3R 9 2Or the assorted alkyl of COOH group replaces.
The term Heterocyclylalkyl refers to the cycloalkyl that this paper defines, wherein one, two or more a plurality of carboatomic ring atom by one, two or more a plurality of oxygen, nitrogen, phosphorus or sulphur atom or S (O) 1-2Group substitutes, piperidino, morpholino or piperazinyl (piperazino) group for example, and preferred this group contains 1 or 2 nitrogen-atoms.
Term aryl refers to have 5-14 carboatomic ring atom, preferred 5 or 6-10 carboatomic ring atom have one, two or the aromatic ring yl of more a plurality of rings, for example phenyl or naphthyl.Any aryl of this paper definition all can be by one, two or more a plurality of substituent group, for example F, Cl, Br, I, OH, NH 2, SH, N 3, NO 2, alkyl such as methyl or ethyl, assorted alkyl such as methoxyl group, methylamino, dimethylamino or cyanide replace.
The term heteroaryl refers to the aryl that this paper defines, wherein one, two or more a plurality of ring carbon atom substituted by oxygen, nitrogen, boron, phosphorus or sulphur atom, for example pyridine radicals, imidazole radicals, pyrazolyl, quinolyl, isoquinolyl, pyrrole radicals, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazole base, thiadiazolyl group, indyl, indazolyl, tetrazole radical, pyrazinyl, pyrimidine radicals and pyridazinyl.
Term aryl alkyl, alkylaryl and heteroaryl alkyl, assorted alkylaryl refer to comprise at the same time or separately the group of aryl, heteroaryl and alkyl and/or assorted alkyl and/or cycloalkyl and/or Heterocyclylalkyl.
The preferred embodiment of the invention is chemical compound or the acceptable salt of its pharmacology, solvate, hydrate or the preparation of the formula (I) that is used for the treatment of anthrax, wherein
A is key, NH, O, S, SO, SO 2, SO 2NH, PO 4,-NH-CO-NH-,-CO-NH-,-CO-,-CO-O-,-two or more combination in NH-CO-O-, alkylidene, alkenylene, alkynylene, inferior assorted alkyl, arlydene, heteroarylidene, cycloalkylidene, inferior Heterocyclylalkyl, alkyl arylene or heteroaryl alkylidene or these atoms or the group; L is
Figure C20048001867900141
X is CR5 or N;
Y is CR6 or N;
U is F or Cl;
N is 0,1,2 or 3;
R1 is H, F, Cl, Br, I, OH, NH 2, alkyl or assorted alkyl;
R2 is H, F or Cl;
R3 is H, alkyl, thiazolinyl, alkynyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylaryl or heteroaryl alkyl;
R4 is assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylaryl or heteroaryl alkyl;
R5 is H, F, Cl, OH, NH 2, alkyl or assorted alkyl, perhaps
If R3 is not H and R5 is not H, F, OH, NH 2Or Cl, R3 can be connected through alkylidene, alkenylene or inferior assorted alkyl with R5, perhaps can be the part of cycloalkylidene or inferior Heterocyclylalkyl;
R6 is H, F, Cl or OMe.
Preferred and/or the advantageous embodiment of the present invention is the theme of dependent claims.
The chemical compound of preferred formula (I), wherein R1 is H or NH 2(particularly H).
The chemical compound of further preferred formula (I), wherein R2 is H or F (particularly F).
The more preferably chemical compound of formula (I), wherein R3 is ethyl, 2-propyl group, C 3-C 6Cycloalkyl, phenyl or pyridine radicals.All these groups all can be by one, two or more a plurality of fluorine atom or amino the replacement.
The more preferably chemical compound of formula (I), wherein R3 is a cyclopropyl.
The chemical compound of further preferred formula (I), wherein R3 and R5 form formula-O-CH together 2-N (Me)-or-O-CH 2-CH (Me)-bridge.Here, the preferred spatial chemistry of chiral centre is the spatial chemistry that provides the S configuration in the final chemical compound.
The further chemical compound of preferred formula (I), wherein R4 be formula-NHCOCH=CH aryl ,-O heteroaryl (being in particular-oxa--the 3-oxazolyl) ,-NHSO 2Me ,-NHCOOMe, NHCS 2Me, NHCSNH 2,-NHCSOMe or-group of NHCOMe.
The chemical compound of special preferred formula (I), wherein R4 is an acetylamino.
The further chemical compound of preferred formula (I), wherein the absolute configuration according to the C-5 of order nomenclature ， oxazolidone ring is (S).
The more preferably chemical compound of formula (I), wherein R5 is H, F, Cl or the methoxyl group or the CF that can be replaced by one, two or three fluorine atom 3Base.
The chemical compound of further preferred formula (I), wherein X is N or CH.
The chemical compound of further preferred formula (I), wherein Y is N or CF (particularly CF).
The chemical compound of further preferred formula (I), wherein n is 0.
The chemical compound of further preferred formula (I), wherein A is a key.
The chemical compound of further preferred formula (I), wherein A is the group of following formula
Figure C20048001867900161
Wherein
Group B is NH, O, S, SO, SO 2, SO 2NH, can by one, two the alkylidene that replaces of more a plurality of fluorine atom or can by one, two or more a plurality of fluorine atom replaces and/or on the nitrogen-atoms that randomly exists by the assorted alkyl in the Asia of alkyl or acyl substituted;
Group D is the inferior Heterocyclylalkyl with randomly anellated of 1,2,3 or 4 nitrogen-atoms independently of one another, and described inferior Heterocyclylalkyl separately can by one, two or more a plurality of fluorine atom replaces and/or separately can be by alkyl or acyl substituted on one, two, three or four nitrogen-atoms;
Group E is NH, O, S, SO, SO independently of one another 2, SO 2NH, can by one, two the alkylidene that replaces of more a plurality of fluorine atom or can by one, two or more a plurality of fluorine atom replaces and/or on the nitrogen-atoms that randomly exists by the assorted alkyl in the Asia of alkyl or acyl substituted;
Group G is the inferior Heterocyclylalkyl with randomly anellated of 1,2,3 or 4 nitrogen-atoms independently of one another, and described inferior Heterocyclylalkyl separately can by one, two or more a plurality of fluorine atom replaces and/or separately can be by alkyl or acyl substituted on one, two, three or four nitrogen-atoms;
Group K is NH, O, S, SO, SO 2, SO 2NH, can by one, two the alkylidene that replaces of more a plurality of fluorine atom or can by one, two or more a plurality of fluorine atom replaces and/or on the nitrogen-atoms that randomly exists by the assorted alkyl in the Asia of alkyl or acyl substituted; And m=1,2,3 or 4.
The more preferably chemical compound of formula (I), wherein A is cycloalkylidene or the alkyl cycloalkylidene that contains 2,3 or 4 hetero atoms (preferred O, N and S), its can by one, two or more a plurality of fluorine atom replace, and nitrogen-atoms can be by alkyl or acyl substituted.
The chemical compound of further preferred formula (I); wherein A is selected from following groups; its can be further by one, two or more a plurality of fluorine atom replace, perhaps by can by one, two or the alkyl that replaces of more a plurality of fluorine atom replace, and wherein amino can be by alkyl or acyl substituted:
Figure C20048001867900171
Figure C20048001867900181
The more preferably chemical compound of formula (I), wherein A is the group of formula-V-W-, wherein V is direct key or formula NH, O, S, SO, SO 2, SO 2NH, PO 4,-NH-CO-NH-,-CO-NH-,-CO-,-CH 2-,-CO-O-,-(CH 2) 1-3-O-,-CH=CH-C (O)-or-group of NH-CO-O-, and W has the Heterocyclylalkyl of 4-7 annular atoms or has the alkyl heterocycle alkyl that contains 1-4 carbon atom in 4-7 annular atoms and the alkyl chain; All these groups all can be replaced by 1,2,3 or 4 fluorine atom, methyl or methoxy.
The chemical compound of further preferred formula (I), wherein A is the group of following formula
Figure C20048001867900182
Wherein V is formula NH, O, S, SO, SO 2, SO 2NH, PO 4,-NH-CO-NH-,-CO-NH-,-CO-,-CH 2-,-CO-O-,-(CH 2) 1-3-O-,-CH=CH-C (O)-or-group of NH-CO-O-; A is 0,1,2,3 or 4; B is 0,1,2,3 or 4; C is that 0,1,2,3 or 4 and 1,2,3 or 4 hydrogen atom can be replaced by F, methyl or methoxy.
Chemical compound more preferably described herein, wherein V is NH, O, S, SO or SO 2
Preferred especially chemical compound described herein, wherein V is O or NH, a is 0 or 1, b be 1 or 2 and c be 1 or 2.
Chemical compound more preferably described herein, wherein A is formula OCH 2The group of Het, wherein Het is the inferior Heterocyclylalkyl with optional replacement of 4,5,6 or 7 annular atomses.
Another embodiment preferred of the present invention is chemical compound or the acceptable salt of its pharmacology, solvate, hydrate or the preparation of formula (II):
Wherein
L is selected from following group:
Figure C20048001867900192
X is CR5 or N;
Y is CR6 or N;
Z is C 1-4Alkylidene, C 2-4Alkenylene, C 2-4Alkynylene or C 1-4Inferior assorted alkyl, wherein all groups can be by one or more hydroxyls or amino the replacement;
B is 1,2 or 3;
C is 1,2 or 3;
R1 is H, F, Cl, Br, I, OH, NH 2, alkyl or assorted alkyl;
R2 is H, F or Cl;
R3 is H, alkyl, thiazolinyl, alkynyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylaryl or heteroaryl alkyl, wherein all these groups all can by one, two or more a plurality of halogen atom such as F or Cl replace;
R5 is H, F, Cl, OH, NH 2, alkyl or assorted alkyl, perhaps
If R3 is not H and R5 is not H, F, OH, NH 2Or Cl, R3 can be connected through alkylidene, alkenylene or inferior assorted alkyl with R5, perhaps can be the part of cycloalkylidene or inferior Heterocyclylalkyl;
R6 is H, F, Cl or OMe;
R7 is hydrogen, formula PO 3R 9 2Or SO 3R 10Group or have at least one OH, NH 2, SO 3R 10, PO 3R 9 2Or the assorted alkyl of COOH group, wherein R 9Be hydrogen, alkyl, cycloalkyl, aryl, aralkyl, and R wherein 10Be hydrogen, alkyl, cycloalkyl, aryl, aralkyl;
R8 is C 1-6Assorted alkyl or heteroaryl alkyl.
The chemical compound of further preferred formula (II), wherein R1 is H.
The chemical compound of further preferred formula (II), wherein R2 is F or H.
The more preferably chemical compound of formula (II), wherein R3 is ethyl, 2-propyl group, C 3-C 6Cycloalkyl, phenyl or pyridine radicals.All these groups all can be by one, two or more a plurality of fluorine atom or amino the replacement.
The more preferably chemical compound of formula (II), wherein R3 is a cyclopropyl.
The chemical compound of further preferred formula (II), wherein R3 and R5 form formula-O-CH together 2-N (Me)-or-O-CH 2-CH (Me)-bridge.Here, the preferred spatial chemistry of chiral centre is the spatial chemistry that provides the S configuration in the final chemical compound.
The more preferably chemical compound of formula (II), wherein R7 is hydrogen, formula PO 3H 2, SO 3R 10, PO 3R 9 2, CH 2OPO 3H 2Or COCH 2CH 2The group of COOH, wherein R 9Be hydrogen, alkyl, cycloalkyl, aryl, aralkyl, and R wherein 10It is the ester or derivatives thereof (for example dimethylglycine (dimethyl aminoglycine)) that hydrogen, alkyl, cycloalkyl, aryl, aralkyl or connected oxygen form natural amino acid together.
The chemical compound of further preferred formula (II), wherein R8 is formula-CH 2The NHCOCH=CH aryl ,-CH 2O heteroaryl (being in particular-oxa--the 3-oxazolyl) ,-CH 2NHSO 2Me ,-CH 2NHCOOMe ,-CH 2NHCS 2Me ,-CH 2NHCSNH 2,-CH 2NHCSOMe or-CH 2The group of NHCOMe.
The chemical compound of special preferred formula (II), wherein L has following structure:
The more preferably chemical compound of formula (II), wherein R5 is H, F, Cl or the methoxyl group that can be replaced by one, two or three fluorine atom.
The chemical compound of further preferred formula (II), wherein X is N or CH.
The chemical compound of further preferred formula (II), wherein Y is CH.
The chemical compound of further preferred formula (II), wherein Z is CH 2Or CH 2CH 2
The chemical compound of special preferred formula (III)
Figure C20048001867900212
Wherein Z is-CH 2Or-CH 2-CH 2X is that CH, N or C-OMe and R3 are that cyclopropyl or X are that CR5 and R5 and R3 form formula-O-CH together 2-CH (Me)-bridge, wherein the preferred spatial chemistry of chiral centre be final chemical compound provide the spatial chemistry of S configuration and b, c and R7 with as above define identical.
The present invention also relates separately to the acceptable salt of pharmacology or the solvate and the hydrate of formula (I), (II) or chemical compound (III), and compositions and preparation.The invention describes the method for producing the useful preparation (agent) of the pharmacy contain these chemical compounds, and these chemical compounds are used for the purposes of the useful preparation of production pharmacy.
Pharmaceutical composition according to the present invention contains at least a formula (I), (II) or chemical compound (III) as activating agent, and optional carrier and/or diluent and/or auxiliary agent.Randomly, also can contain other known antibiotic according to pharmaceutical composition of the present invention.
The example of the acceptable salt of pharmacology of the chemical compound of the enough alkalescence of formula (I) and formula (II) or chemical compound (III) is the salt of the acceptable mineral acid example hydrochloric acid of physiology, hydrobromic acid, sulphuric acid and phosphoric acid; Or organic acid such as methanesulfonic acid, p-methyl benzenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic salt.In addition, the enough tart chemical compound of formula (I) can form the salt of alkali metal or alkaline-earth metal, for example sodium, potassium, lithium, calcium or magnesium salt; Ammonium salt; Or organic alkali salt, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumine, piperidines, morpholine, three-(2-hydroxyethyl) amine, lysine or arginine salt, all these salt also are the further examples of formula (II) or salt (III).Formula (I), (II) or chemical compound (III) can be by solvations, especially by hydration.Hydration can occur in the preparation process, or as the hygroscopic result of initial anhydrous formula (I), (II) or chemical compound (III) and take place.Formula (I), (II) or chemical compound (III) contain asymmetric carbon atom, and can exist with non-chiral compound, non-enantiomer mixture, enantiomeric mixture or optically pure compound.
The invention still further relates to the prodrug of forming by formula (I), (II) or chemical compound (III) and the acceptable protecting group that can under physiological condition, slough of at least a pharmacology; described protecting group is alkoxyl, aralkoxy, acyl group, acyl-oxygen methyl (as pivaloyl oxygen methyl), 2-alkyl, 2-aryl or 2-aralkoxycarbonyl-2-alkylidene ethyl or acyloxy as herein defined; as ethyoxyl, benzyloxy, acetyl group or acetoxyl group; particularly for the chemical compound of formula (I); for hydroxyl (ROH), be sulfuric ester, phosphate ester (ROPO 3Or ROCH 2OPO 3) or amino-acid ester.Preferred especially wherein R7 is the formula (II) of H or the hydroxyl prodrug of chemical compound (III).
As mentioned above, contain formula (I), (II) or chemical compound (III), their the effective preparation of treatment of solvate, salt or preparation is also included within the scope of the present invention.Generally speaking, formula (I), (II) or chemical compound (III) will give separately or with any other therapeutic agent combination by using known and acceptable pattern known in the art.The effective preparation of this treatment can give by one of following approach: oral, for example with tablet, dragee, coated tablet, pill, semi-solid agent, soft or hard capsule, for example soft hard gelatin capsule, water or oil solution, Emulsion, suspensoid or syrupy form give, parenteral, comprise intravenous, intramuscular and subcutaneous injection, for example give with injectable solution or suspension, rectum such as suppository, give by sucking or being blown into,, give with crystallite or with spray (for example liquid aerosol) for example with the powder preparation, percutaneous, for example through transdermal delivery system (TDS), as contain the plaster of active component, perhaps intranasal.For this tablet, pill, semi-solid agent, coated tablet, dragee and hard capsule, as the production of gelatine capsule, the inert inorganic or organic excipients of treatment effective product and pharmacy such as lactose, sucrose, glucose, gelatin, Fructus Hordei Germinatus, silica gel, starch or derivatives thereof, Talcum, stearic acid or its salt, exsiccant skimmed milk etc. can be mixed.For the production of soft capsule, can use excipient such as vegetable oil, oil, animal oil or artificial oil, wax, fat, polyhydric alcohol.For liquid solution agent, Emulsion or suspensoid or syrupy production, for example can use, water, alcohol, saline solution, D/W, polyhydric alcohol, glycerol, lipid, phospholipid, cyclodextrin, vegetable oil, oil, animal oil or artificial oil are as excipient.Be preferably lipid especially, more preferably phospholipid (preferred natural origin; Special preferable particle size is between 300-350nm), preferably in phosphate buffered saline (PBS) (pH=7-8, preferred 7.4).For suppository, can use, for example vegetable oil, oil, animal oil or artificial oil, wax, fat and polyhydric alcohol are as excipient.For aerosol formulation, can use the Compressed Gas that is suitable for this purpose, for example oxygen, nitrogen and carbon dioxide.The useful preparation of pharmacy can also contain and is useful on preservation, stable additive, for example salt of UV stabilizing agent, emulsifying agent, sweeting agent, aromatic, change osmotic pressure, buffer agent, coating additive and antioxidant.
Each patient's dosage every day is about 1mg to about 4000mg, and particularly about 50mg-3g is adopted by those skilled in the art usually, it will be understood by those skilled in the art that dosage also will depend on mammiferous age, situation and the kinds of Diseases of being treated or preventing.Every day, dosage can once give, and perhaps can be divided into several times giving.Average dose can be about 50mg, 100mg, 250mg, 500mg, 1000mg and 2000mg.
What the invention still further relates to treatment mammal, Fish or birds is selected from following disease: bacterial infection and protozoan infection and with the method for bacterial infection or protozoan infection diseases associated, it comprises that giving described mammal, Fish or birds contains formula (I), (II) or chemical compound (HI) and another kind of antibiotic compositions, and wherein said chemical compound is effective for treatment in the described disease of treatment with the antibiotic amount of another kind.In further embodiment, chemical compound of the present invention can be before giving another kind of antibiotic, simultaneously or give afterwards.The antibiotic example of suitable other includes but not limited to beta-lactam, vancomycin, aminoglycoside, quinolones, chloromycetin, Tetracyclines and Macrolide.
As used herein, unless otherwise indicated, term " treatment " means reverse, alleviates, suppresses the progress of suitable disease of this term or disease or prevents its generation.As used herein, the behavior of " treatment " that has just defined above term " treatment " refers to.
As used herein, unless otherwise indicated, term or phrase " infection ", " bacterial infection ", " protozoan infection " and " with bacterial infection or protozoan infection diseases associated " comprises as described below: with streptococcus pneumoniae (Streptococcus pneumoniae), hemophilus influenza (Haemophilus influenzae), mucositis mora bacterium (Moraxella catarrhalis), staphylococcus aureus (Staphylococcus aureus), enterococcus faecalis (Enterococcusfaecalis), enterococcus faecalis (E.faecium), E. casselflavus (E casselflavus), staphylococcus epidermidis (S epidermidis), staphylococcus haemolyticus (S.haemolyticus) or Peptostreptococcus (Peptosfreptococcus spp.) infect relevant pneumonia, otitis media, rhinitis, bronchitis, tonsillitis and mastoiditis; Infect relevant pharyngitis, rheumatic fever and glomerulonephritis with micrococcus scarlatinae (Streptococcuspyogenes), C and G group B streptococcus, diphtheria corynebacterium (Corynebacferium diphtheriae) or Actinobacillus haemolyticum (Acfinobacillus haemolyticum); Infect relevant respiratory tract infection with mycoplasma pneumoniae (Mycoplasma pneumoniae), legionella pneumophilia (legionella pneumophila), streptococcus pneumoniae, hemophilus influenza or Chlamydia pneumoniae (Chlamydia pneumoniae); By staphylococcus aureus, staphylococcus haemolyticus, enterococcus faecalis, enterococcus faecalis, Enterococcus durans (E.durans), comprise that the strain that known antibacterials are tolerated such as but not limited to beta-lactam, vancomycin, aminoglycoside, quinolones, chloromycetin, Tetracyclines and Macrolide infects the blood and the tissue infection that cause and comprises endocarditis and osteomyelitis; With staphylococcus aureus, coagulase negative staphylococcus (is a staphylococcus epidermidis, staphylococcus haemolyticus etc.), micrococcus scarlatinae, streptococcus agalactiae (Streptococcus agalactiae), C-F group B streptococcus (minute-colony streptococci (minute colony streptococci)), Streptococcus viridans (viridansstreptococci), corynebacterium minutissimum (Corynebacterium minutissimum), Clostridium (Closfridium spp.) or Han Shi bartonia bodies (Bartonellahenselae) infect relevant uncomplicated skin and soft tissue infection and abscess and the elaborate heat of product; Infect relevant uncomplicated acute urinary tract infection with staphylococcus aureus, coagulase negative staphylococcus genus or enterococcus species; Urethritis and cervicitis; Infect relevant sexually transmitted disease with chlamydia trachomatis (Chlamydia trachomatis), Du Shi haemophilus (Haemophilus ducreyi), treponema pallidum (Treponema pallidurn), Ureaplasma urealyticum (Ureaplasmaurealyticum) or Diplococcus gonorrhoeae (Neiserria gonorrheae); With staphylococcus aureus (alimentary toxicosis and toxic shock syndrome) or A, the B poisoning disease relevant with the infection of C group B streptococcus; Infect relevant ulcer with helicobacter pylori (Helicobacter pylori); Infect relevant systemic febrile syndrome with Spirochaeta recurrentis (Borreliarecurrentis); Infect relevant Lyme disease with B. burgdorferi (Borreliaburgdorferi); Belong to infection relevant conjunctivitis, keratitis and dacryocystisis (decrocystitis) with chlamydia trachomatis, Diplococcus gonorrhoeae, staphylococcus aureus, streptococcus pneumoniae, micrococcus scarlatinae, hemophilus influenza or Listera; Infect the compound group of relevant dissemination Mycobacterium avium (MAC) disease with Mycobacterium avium (Mycobacterium avium) or Mycobacterium intracellulare (Mycobacteriumintracellulare); The infection that causes by mycobacterium tuberculosis (Mycobacferium tuberculosis), Mycobacterium leprae (M.leprae), mycobacterium paratuberculosis (M.paratuberculosis), mycobacterium kansasii (M.kansasii) or Mycobacterium chelonei (M.chelonei); Belong to (Campylobacter jejuni) with campylobacter jejuni and infect relevant gastroenteritis; Infect the relevant primary parasitosis of enteral with Cryptosporidium (Cryptosporidium spp.); Infect relevant odontogenic infection with Streptococcus viridans; Infect relevant persistence cough with bordetella pertussis (Bordetella pertussis), infect relevant gas gangrene with bacillus perfringens (Clostridium perfringens) or Bacteroides (Bacteroides spp.); With atherosclerosis or the cardiovascular disease relevant with helicobacter pylori or infection involving chlamydia pneumoniae.
Preferred formula (I), (II) or chemical compound (III) be used for the treatment of by gram negative bacteria such as escherichia coli (E.coli), Klebsiella pneumonia (Klebsiella pneumoniae) and other enterobacteriaceae, hemophilus influenza, mucositis mora bacterium, acinetobacter (Acinetobacter spp.), have a liking for maltose oligotrophy Zymomonas mobilis (stenothrophomonas maltophilia), Diplococcus gonorrhoeae, Neisseria meningitidis (Neisseria menigitidis), helicobacter pylori, campylobacter, Mycoplasma (Mycoplasma spp.) and legionella pneumophilia or gram positive bacteria such as bacillus cereus (Bacillus cereus), anthrax bacillus, streptococcus pneumoniae, corynebacterium (Corynebacterium spp.), the purposes of the infection of corynebacterium acnes (Propionibacteriumacne) and monocyte hyperplasia Li Site bacterium (Listeria monocytogenes) mediation.
Followingly the present invention is described in more detail with reference to embodiment.These embodiment just are intended to illustrate and should not be explained any limitation of the invention.These embodiment are according at WO03032962, WO03031443, US 60/530,822 and C.Hubschwerlen etc., Med.Chem.2003, and 11, the method described in the 2313-2319 is synthetic.
Formula (II) and chemical compound (III) can synthesize according to following reaction scheme:
Figure C20048001867900261
Figure C20048001867900271
Reaction condition:
Step 1:CH 2Cl 2, KOH (50%), 3h, room temperature; 97%.Step 2:H 2, Pt/C, 20h, room temperature; Z-Cl then, acetone, NaHCO 3, 12h, room temperature, 98%.Step 3:n-BuLi ,-60 ℃, 24h, 80%.Step 4:MsCl, triethylamine, CH 2Cl 2100%.Step 5:NaN 3, in DMF, 90 ℃, cat.Bu 4NI, 5h, 90%.Step 6:H 2, Pd (OH) 2, THF, MeOH, 24h, AcOH then, Ac 2O, room temperature, 2h, 70%.Step 7:DMF, NaH, 70 ℃, 12h, 75%.Step 8:H 2, Pd (OH) 2, MeOH, THF, 24h, room temperature, 100%.Step 9:N-methyl pyrrolidone, 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthalene alcohol-3-carboxylic acid (commercially available), TMS-Cl, H ü nig alkali or K 2CO 3, 80 ℃, 5h, 80%.
Embodiment
Embodiment 1:7-(4-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl }-piperazine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Embodiment 2:9-(4-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenyl }-piperazine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa--3a-azepine-Fei Na alkene (phenalene)-5-carboxylic acid:
Figure C20048001867900281
Embodiment 3:7-((3R, S)-3-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl amino formoxyl }-piperazine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900282
Embodiment 4:7-[(3R)-3-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl amino }-pyrrolidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-1-carboxylic acid:
Embodiment 5:7-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl }-piperazine-1-yl)-6-fluoro-1-(5-fluoro-pyridine-2-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900284
Embodiment 6:7-(4-{ (5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl }-2-fluoro-phenyl)-piperazine-1-yl)-1-(2,4-two fluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Embodiment 7:7-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl }-piperazine-1-yl)-1-cyclopropyl-8-methoxyl group-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900292
Embodiment 8:9-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenyl }-piperazine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa--3,3a-diaza-Fei Na alkene-5-carboxylic acid:
Embodiment 9:7-{ (3RS)-3-[({4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl }-ethyl-amino) methyl]-piperazine-1-yl }-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Embodiment 10:7-(4-{[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl }-piperazine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900302
Embodiment 11:7-{4-[2-(4-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl }-piperazine-1-yl)-ethyl]-piperazine-1-yl }-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900303
Embodiment 12:7-[4-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl }-piperazine-1-yl)-piperidines-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900304
Embodiment 13:7-[(3R, 4R) and (3S, 4S)-3-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl-4-aminomethyl-pyrrolidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900311
Embodiment 14:7-{4-[2-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl }-piperazine-1-yl)-2-oxo-ethyl]-piperazine-1-yl }-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinolinones-3-carboxylic acid:
Figure C20048001867900312
Embodiment 15:7-(3-{4-[5 (S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl amino }-azetidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900313
Embodiment 16:7-[(3R)-3-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl amino }-pyrrolidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900321
Embodiment 17:7-[(3R, 4S) with (3S, 4R)-3-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-the 2-fluorophenyl }-piperazine-1-carbonyl)-4-aminomethyl-pyrrolidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline carboxylic acid:
Figure C20048001867900322
Embodiment 18:7-[(3R, 4S) with (3S, 4R)-3-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl } piperazine-1-carbonyl)-4-aminomethyl-pyrrolidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900323
Embodiment 19:7-(4-{5-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-pyridine-2-yl }-1-piperazine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Embodiment 20:7-(4-{5-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-pyridine-2-yl }-piperazine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Embodiment 21:7-[(3R)-3-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl }-piperazine-1-yl)-pyrrolidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900333
Embodiment 22:1-cyclopropyl-6-fluoro-7-(4-{2-fluoro-4-[(5R)-5-(methanesulfonamido-methyl)-2-oxo-oxazolidines-3-yl]-phenyl }-piperazine-1-yl)-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900334
Embodiment 23:7-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl amino }-piperidines-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Embodiment 24:1-cyclopropyl-6-fluoro-7-(4-{2-fluoro-4-[(5S)-5-(methoxyl group thio-carbonyl-amino-methyl)-2-oxo-oxazolidines-3-yl]-phenyl }-piperazine-1-yl)-4-oxo-1,4-dihydro-[1,8]-naphthyridines-3-carboxylic acid:
Figure C20048001867900342
Embodiment 25:1-cyclopropyl-6-fluoro-7-(4-{2-fluoro-4-((5S)-5-(methyl sulfane base thio-carbonyl-amino-methyl)-2-oxo-oxazolidines-3-yl)-phenyl }-piperazine-1-yl)-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900343
Embodiment 26:1-cyclopropyl-6-fluoro-{ 4-[2-fluoro-4-{ (5S)-2-oxo-5-ghiourea group methyl-oxazolidines-3-yl }-phenyl]-piperazine-1-yl }-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900344
Embodiment 27:7-(4-{4-[5 (S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group }-piperidines-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900351
Embodiment 28:7-(4-{4-[5 (S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group }-piperidines-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900352
Embodiment 29:7-(4-{4-[5 (S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl sulfane base }-piperidines-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900353
Embodiment 30:7-(4-{4-[5 (S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenyl sulfane base }-piperidines-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Embodiment 31:7-(4-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-benzoyl }-piperazine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900362
Embodiment 32:1-cyclopropyl-6-fluoro-7-{4-[2-fluoro-4-(5-guanidine radicals methyl-2-oxo-oxazolidines-3-yl)-phenyl]-piperazine-1-yl }-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Embodiment 33:7-(4-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-benzene sulfinyl }-piperidines-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900371
Embodiment 34:7-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group }-azetidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Will be in 100mg N-{ (the 5S)-3-[4-in 2ml N-methyl-pyrrolidin-2-one (azetidine-3-oxygen base)-3-fluoro--phenyl]-2-oxo-oxazolidines-5-ylmethyl }-acetamide (MW:323.32,0.31mmol), 73mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid (MW:282.66,0.25mmol), 0.066ml trim,ethylchlorosilane (MW:108.64, d=0.859,0.51mmol) and 0.108ml triethylamine (MW:101.19, d=0.726,0.77mmol) suspension under agitation heated 7 minutes under 150 ℃ in microwave oven.Evaporation N-methyl-pyrrolidin-2-one, residue is through chromatography purification.Yield: 55mg, 30%.MS:570.5 (M+H) +, method ESI +Molecular weight=570.
Embodiment 35:7-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group }-pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900381
Will be in the 185mg N-{ (5S) in 2ml N-methyl-pyrrolidin-2-one-3-[-3-fluoro-4{3-(S)-(pyrrolidine-3-oxygen base) }-phenyl]-2-oxo-oxazolidines-5-ylmethyl }-acetamide (337.35,0.55mmol), 141mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid (MW:282.66,0.5mmol), 0.126ml trim,ethylchlorosilane (MW:108.64, d=0.859,1mmol) with 0.209ml triethylamine (MW:101.19, d=0.726,1.5mmol) suspension under agitation heated 7 minutes under 150 ℃ in microwave oven.Evaporation N-methyl-pyrrolidin-2-one, residue is through chromatography purification.Molecular weight=584; Yield: 140mg, 48%; MS:584.5 (M+H) +, method ESI +
Embodiment 36:7-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group }-pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Embodiment 37:7-(4-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-piperidines-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid
Embodiment 38:7-(4-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-piperidines-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900392
Embodiment 39:9-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxy group }-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa--3a-azepine-Fei Na alkene-5-carboxylic acid:
Figure C20048001867900393
Embodiment 40:9-(4-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxy group }-piperidines-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa--3a-azepine-Fei Na alkene-5-carboxylic acid:
Embodiment 41:9-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxy group }-piperidines-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa--3a-azepine-Fei Na alkene-5-carboxylic acid:
Embodiment 42:7-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group }-pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900403
Embodiment 43:9-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxy group }-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa--3a-azepine-Fei Na alkene-5-carboxylic acid:
Figure C20048001867900411
Embodiment 44:9-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxy group }-azetidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa--3a-azepine-Fei Na alkene-5-carboxylic acid:
Figure C20048001867900412
Embodiment 45:9-(4-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenyl sulfane base }-piperidines-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa--3a-azepine-Fei Na alkene-5-carboxylic acid:
Figure C20048001867900413
Embodiment 46:7-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900421
Will be in the 179mg N-{ (5S) in 2ml N-methyl-pyrrolidin-2-one-3-[3-fluoro-4-[3-(RS)-(pyrrolidine-3-ylmethoxy)]-phenyl]-2-oxo-oxazolidines-5-ylmethyl }-acetamide (MW:351.38,0.55mmol), 141mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid (MW:282.66,0.5mmol), 0.128ml trim,ethylchlorosilane (MW:108.64, d=0.859,1.0mmol) and 0.200ml triethylamine (MW:101.19, d=0.726,1.5mmol) suspension under agitation heated 7 minutes under 150 ℃ in microwave oven.Evaporation N-methyl-pyrrolidin-2-one, residue is through chromatography purification.Yield: 241mg, 81%.MS:598.5 (M+H) +, method ESI +Molecular weight=598.
Embodiment 47:9-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxymethyl }-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa--3a-azepine-Fei Na alkene-5-carboxylic acid:
Will be in the 179mg N-{ (5S) in 2ml N-methyl-pyrrolidin-2-one-3-[3-fluoro-4-[3-(RS)-(pyrrolidine-3-ylmethoxy)]-phenyl]-2-oxo-oxazolidines-5-ylmethyl }-acetamide (MW:351.38,0.55mmol), 140mg 9,10-two fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de]-1,4-benzoxazinyl-6-carboxylic acid (MW:281.21,0.5mmol), 0.128ml trim,ethylchlorosilane (MW:108.64, d=0.859,1.0mmol) and 112mg 1, (MW:112.18,1.0mmol) suspension under agitation heated 7 minutes under 150 ℃ in microwave oven 4-diazabicylo [2.2.2] octane.Evaporation N-methyl-pyrrolidin-2-one, residue is through the crystallization process purification.Yield: 161mg, 52%.MS:613.5 (M+H) +, method ESI +Molecular weight=613.
Embodiment 48:9-(4-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxymethyl }-piperidines-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa--3a-azepine-Fei Na alkene-5-carboxylic acid:
Figure C20048001867900431
Embodiment 49:7-[4-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group }-propyl group)-piperidines-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Embodiment 50:9-[4-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxy group }-propyl group)-piperidines-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa--3a-azepine-Fei Na alkene-5-carboxylic acid:
Figure C20048001867900441
Embodiment 51:7-(4-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group }-azepan-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900442
Embodiment 52:9-(4-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxy group }-azepan-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa--3a-azepine-Fei Na alkene-5-carboxylic acid:
Figure C20048001867900443
Embodiment 53:7-[4-(2-{4-[(5S)-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group }-ethyl)-piperidines-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900451
Will be in the 100mg N-{ (5S) in 2ml N-methyl-pyrrolidin-2-one-3-[3-fluoro-4-[4-(piperazine-4-base-ethyoxyl)]-phenyl]-2-oxo-oxazolidines-5-ylmethyl }-acetamide (MW:379.43,0.263mmol), 68mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid (MW:282.66,0.239mmol), 0.060ml trim,ethylchlorosilane (MW:108.64, d=0.859,0.47mmol) and 0.1ml triethylamine (MW:101.19, d=0.726,0.71mmol) suspension under agitation heated 7 minutes under 150 ℃ in microwave oven.Evaporation N-methyl-pyrrolidin-2-one, residue is through chromatography purification.Yield: 30mg, 20%.MS:626.5 (M+H) +, method ESI +Molecular weight=626.
Embodiment 54:9-[4-(2-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxy group }-ethyl)-piperidines-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa--3a-azepine-Fei Na alkene-5-carboxylic acid:
Figure C20048001867900452
Embodiment 55:7-[3 (R, S)-(2-{4-[(5S)-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group }-ethyl)-pyrrolidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Will be in the 120mg N-{ (5S) in 3ml N-methyl-pyrrolidin-2-one-3-[3-fluoro-4-[4 (R, S)-4-(piperazine-4-base-ethyoxyl)]-phenyl]-2-oxo-oxazolidines-5-ylmethyl }-acetamide (MW:365.40,0.33mmol), 85mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridines-3 carboxylic acid (MW:282.66,0.3mmol), 0.075ml trim,ethylchlorosilane (MW:108.64, d=0.859,0.6mmol) and 0.127ml triethylamine (MW:101.19, d=0.726,0.9mmol) suspension under agitation heated 7 minutes under 150 ℃ in microwave oven.Evaporate N-methyl-pyrrolidin-2-one, and residue is dissolved in the dichloromethane.Water and salt water washing organic layer are used dried over mgso, filter and evaporated filtrate.Residue is dissolved in the ethyl acetate, the gained colorless solid is filtered and drying.Yield: 159mg, 86%.Molecular weight 612.
Embodiment 56:9-[3-(2-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxy group }-ethyl)-pyrrolidine-1-yl]-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa--3a-azepine-Fei Na alkene-5-carboxylic acid:
Embodiment 57:7-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900471
Will be in the 176mg N-{ (5S) in 2ml N-methyl-pyrrolidin-2-one-3-[3-fluoro-4-[3-(RS)-(pyrrolidine-3-ylmethoxy)]-phenyl]-2-oxo-oxazolidines-5-ylmethyl }-acetamide (MW:351.38,0.5mmol), 205mg 7-chloro-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylatoboron diacetate esters (MW:409.56,0.5mmol) and 0.341ml N-ethyl diisopropylamine (MW:129.25, d=0.755,2mmol) suspension under agitation heated 7 minutes under 150 ℃ in microwave oven.Evaporation N-methyl-pyrrolidin-2-one, residue through chromatography and in ethanol crystallization come purification.Yield: 120mg, 40%.MS:597.5 (M+H) +, method ESI +Molecular weight=597.
Embodiment 58:7-[3-(2-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group }-ethyl)-pyrrolidine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900472
Embodiment 59:7-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-pyrrolidine-1-yl)-1-cyclopropyl-8-methoxyl group-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900481
Will be in the 100mg N-{ (5S) in 2ml N-methyl-pyrrolidin-2-one-3-[3-fluoro-4-[3-(RS)-(pyrrolidine-3-ylmethoxy)]-phenyl]-2-oxo-oxazolidines-5-ylmethyl }-acetamide (MW:351.38,0.284mmol), 115mg 1-cyclopropyl-7-fluoro-8-methoxyl group-4-oxo-1,4-dihydro-quinoline-3-carboxylatoboron diacetate esters (MW:405.14,0.284mmol) and 0.097ml N-ethyl diisopropylamine (MW:129.25, d=0.755,0.57mmol) suspension under agitation heated 7 minutes under 150 ℃ in microwave oven.Evaporation N-methyl-pyrrolidin-2-one, residue through chromatography and in ethanol crystallization come purification.Yield: 40mg, 23%.MS:609.5 (M+H) +, method ESI +Molecular weight=609.
Embodiment 60:7-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group }-pyrrolidine-1-yl)-6-fluoro-1-(4-hydroxyl-phenyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900482
Embodiment 61:7-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-8-methoxyl group-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Embodiment 62:7-[4-(2-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-phenyl }-2-oxo-ethyl)-piperazine-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Embodiment 63:7-(3 (S)-4-[5 (S)-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900493
Will be in the 737mg N-{ (5S) in 15ml N-methyl-pyrrolidin-2-one-3-[3-fluoro-4-[3-(S)-(pyrrolidine-3-ylmethoxy)]-phenyl]-2-oxo-oxazolidines-5-ylmethyl }-acetamide (MW:351.38,2.1mmol), 566mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridines-3 carboxylic acid (MW:282.66,2mmol), 0.505ml trim,ethylchlorosilane (MW:108.64, d=0.859,4mmol) with 0.840ml triethylamine (MW:101.19, d=0.726,6mmol) suspension under agitation heated 2 hours under 150 ℃ in microwave oven.Evaporate N-methyl-pyrrolidin-2-one, and residue is dissolved in the dichloromethane.Water and salt water washing organic layer are used dried over mgso, filter and evaporated filtrate.Residue is come purification by crystallization in ethanol and dichloromethane mixture.Yield: 972mg, 81%.MS:598.5 (M+H) +, method ESI +Molecular weight 598.
Embodiment 64:7-(3 (R)-4-[5 (S)-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Will be in the 1.228g N-{ (5S) in 30ml N-methyl-pyrrolidin-2-one-3-[3-fluoro-4-[3-(R)-(pyrrolidine-3-ylmethoxy)]-phenyl]-2-oxo-oxazolidines-5-ylmethyl }-acetamide (MW:351.38,3mmol), 1.054g 7-chloro-6-fluoro-1-cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylatoboron diacetate esters (MW:409.56,3mmol) with 2ml N-ethyl diisopropylamine (MW:129.25, d=0.755,12mmol) suspension under agitation heated 2 hours under 150 ℃ in microwave oven.Evaporate N-methyl-pyrrolidin-2-one, and residue is dissolved in the dichloromethane.With 0.1N HCl and salt water washing organic layer, use dried over mgso, filter back evaporate to dryness filtrate.Residue is dissolved in the warm ethyl acetate, leaches crystal (DC1).With solid crystallization in ethanol.Yield: 728mg, 41%.MS:597.5 (M+H) +, method ESI +Molecular weight 597.
Embodiment 65:7-[4-(2-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group }-ethylidene)-piperidines-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Embodiment 66:7-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-azetidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900512
Will be in 179mg N-{ (the 5S)-3-[4-in 2ml N-methyl-pyrrolidin-2-one (azetidine-3-ylmethoxy)-3-fluoro--phenyl]-2-oxo-oxazolidines-5-ylmethyl }-acetamide (MW:337.35,0.31mmol), 100mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid (MW:282.66,0.25mmol), 0.134ml trim,ethylchlorosilane (MW:108.64, d=0.859,1.059mmol) and 0.197ml triethylamine (MW:101.19, d=0.726,1.41mmol) suspension under agitation heated 7 minutes under 150 ℃ in microwave oven.Evaporation N-methyl-pyrrolidin-2-one, residue is through chromatography purification.Yield: 82mg, 40%.MS:583.5 (M+H) +, method ESI +Molecular weight=584.
Embodiment 67:7-(2-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-1-oxa--6-azepine-spiral shell [2.5] suffering-6-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900521
Embodiment 68:7-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group }-4-methoxyl group-pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]-naphthyridines-3-carboxylic acid:
Figure C20048001867900522
Embodiment 69:7-(3 (R)-4-[5 (S)-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900523
Will be in the 150mg N-{ (5S) in 2ml N-methyl-pyrrolidin-2-one-3-[3-fluoro-4-[3-(R)-(pyrrolidine-3-ylmethoxy)]-phenyl]-2-oxo-oxazolidines-5-ylmethyl }-acetamide (MW:351.38,0.42mmol), 100mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridines-3-carboxylic acid (MW:282.66,0.35mmol), 0.147ml trim,ethylchlorosilane (MW:108.64, d=0.859,1.16mmol) and 0.216ml triethylamine (MW:101.19, d=0.726,1.54mmol) suspension under agitation heated 7 minutes under 150 ℃ in microwave oven.Evaporation N-methyl-pyrrolidin-2-one, residue is through chromatography purification.Yield: 150mg, 60%.MS:598.5 (M+H) +, method ESI +Molecular weight 598.
Embodiment 70:7-[4-(2-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group }-ethyl)-piperidines-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900531
Embodiment 71:7-(3-{4-[5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group }-piperidines-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900532
Will be in the 100mg N-{ (5S) in 2ml N-methyl-pyrrolidin-2-one-3-[3-fluoro-4-{3-(RS)-piperidines-3-oxygen base }-phenyl]-2-oxo-oxazolidines-5-ylmethyl } acetamide (MW:351.38,0.28mmol), 67mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridines-3 carboxylic acid (MW:282.66,0.23mmol), 0.060ml trim,ethylchlorosilane (MW:108.64, d=0.859,0.47mmol) and 0.10ml triethylamine (MW:101.19, d=0.726,0.71mmol) suspension under agitation heated 7 minutes under 150 ℃ in microwave oven.Evaporation N-methyl-pyrrolidin-2-one, residue is through chromatography purification.Yield: 60mg, 42%.MS:598.5 (M+H) +, method ESI +
Embodiment 72:7-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-hydroxy-piperdine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900541
Step 1:(4-benzyloxy-3-fluoro-phenyl)-benzyq carbamate:
Stir under room temperature and the normal pressure 34.9g 1-benzyloxy-2-fluoro-4-nitro-benzene (WO 03064413) in the 350ml ethyl acetate (MW:247.28,141mmol) and 340mg 5% carried by active carbon platinum solution.Use the HPLC monitoring reaction, afterreaction finished in 20 hours.Use the glass fiber filter paper filtering catalyst, and decompression is evaporated to filtrate down dried.The oily residue is dissolved in the 500ml acetone, and (MW:84.01 208mmol) handles with 250ml saturated sodium bicarbonate solution and 17.5g sodium bicarbonate.Mixture is cooled to 5 ℃, and (MW:170.59 152mmol) handles to splash into the 26.08g benzyl chloroformate.At room temperature stirred 2 hours, and with TLC (hexane/ethyl acetate 3: 1) monitoring reaction.Evaporation acetone with 500ml water dilution residue, and leaches solid.With 500ml water washing crystal, and dry.Yield: 48.05g, 95.8%.MS：352.5(M+H) +，350.8，(M-H) -。Method ESI +, ESI -
Step 2:(5R)-3-(4-benzyloxy-3-fluoro-phenyl)-5-methylol-oxazolidines-2-ketone:
Will (MW:351.38, agitating solution 50mmol) be cooled to-78 ℃ with dry ice/acetone batch in the 17.5g in the 30ml anhydrous tetrahydro furan (4-benzyloxy-3-fluoro-phenyl)-benzyq carbamate.Splash into 22.8ml 2.3M n-BuLi (52.5mmol) solution in normal hexane, and reactant mixture was stirred 15 minutes down at-78 ℃.(MW:144.17 60mmol), makes reactant be warmed to room temperature to add 7.92g R (-)-glycidyl butyrate.Use the HPLC monitoring reaction, use the saturated ammonium chloride solution cessation reaction, and dilute with the 100ml ethyl acetate.With 200ml water and 200ml salt water washing organic layer.Use the dried over mgso organic layer, filter, and evaporated filtrate under the decompression.With residue crystallization in 200ml 1/1-ethyl acetate/hexane mixture.Collect solid, recrystallization in 150ml 9/1 ethyl acetate/dichloromethane mixture.Collect clear crystal and dry.Yield: 10.4g, 65.5%.MS：318.1(M+H) +。Method ESI +
Step 3:(5S)-5-azido-methyl-3-(4-benzyloxy-3-fluoro-phenyl)-oxazolidines-2-ketone:
Stirring and the 10 ℃ of following 4.32g of using mesyl chloride (MW:114.55,37.82mmol) handle 10g (5R)-3-(4-benzyloxy-3-fluoro-the phenyl)-5-methylol-oxazolidines-2-ketone (MW:317.32 in the 300ml dichloromethane, 31.51mmol) and 4.78g triethylamine (MW:101.19,47.26mmol) solution.Reactant was at room temperature stirred 1 hour, with TLC (ethyl acetate: monitoring reaction hexane 1: 1).With 100ml water cessation reaction, and with 100ml salt water washing organic layer.Use the dried over mgso organic layer, filter, decompression is evaporated filtrate down.Residue is dissolved in the 100ml dimethyl formamide, add the 5.12g Hydrazoic acid,sodium salt (MW:65.01,78.7mmol) and the tetrabutylammonium iodide of catalytic amount.Suspension stirring under 90 ℃ is spent the night.Use the HPLC monitoring reaction.Decompression is the evaporation dimethyl formamide down, and residue is dissolved in the 200ml dichloromethane, uses 100ml water and 100ml salt water washing organic layer successively.Use the dried over mgso dichloromethane solution, filter, decompression is evaporated filtrate down.With residue in 150ml 1/1 ethyl acetate: crystallization in the mixture of hexane.Collect crystal and obtain pale solid.Yield: 10.4g, 97%.MS：343.1(M+H) +-。Method: ESI +
Step 4:N-[(5S)-{ 3-(3-fluoro-4-hydroxyl-phenyl) }-2-oxo-oxazolidines-5-ylmethyl]-acetamide:
Will be in 1: 1 methanol of 400ml under room temperature and hydrogen: the 10.4g in the ethyl acetate mixture (5S)-5-azido-methyl-3-(4-benzyloxy-3-fluorophenyl) oxazolidine-2-ketone (and MW:342.33,30.38mmol) and 1.5g 10% activated carbon-carried palladium suspension stirred two.Use the glass fiber filter paper filtration catalizer, decompression is evaporated filtrate down.Residue is dissolved in the 100ml acetic acid, and (MW:102.09 36.45mmol) handles with the 3.72g acetic anhydride.Decompression is evaporating solvent down, with residue 1: 1 ethyl acetate: crystallization in the mixture of hexane obtains pale solid.Yield: 6.76g, 83%.MS：269.4(M+H) +，267.3，(M-H) -。Method ESI +, ESI -
Step 5:4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-hydroxy-piperdine-1-benzyl carboxylate
Down will be at 100 ℃ in the 22.72g 1-oxa-in the 150ml dimethyl formamide-6-azepine-spiral shell [2.5] octane-6-benzyl carboxylate (WO 9803507) (MW:247.29,92mmol), 21.45g N-[(5S)-{ 3-(3-fluoro-4-hydroxyl-phenyl) }-2-oxo-oxazolidines-5-ylmethyl]-acetamide (MW:268.246,80mmol) (MW:138.20,120mmol) suspension stirred 7 hours with the 16.58g potassium carbonate.With TLC (methylene chloride 9: 1) monitoring reaction.Decompression is the evaporation dimethyl formamide down, and residue is dissolved in 9: 1 methylene chloride/methanol mixture of 600ml.With 400ml water and 400ml salt water washing organic layer.Use the dried over mgso organic layer, filter, with 250ml ethyl acetate dilution filtrate.Decompression enriched mixture to final volume down is 400ml.Slurry at room temperature stirred spend the night.Leach crystal, successively with 150ml ethyl acetate and the washing of 100ml pentane.Yield: 31.65g, 76.7%.MS:516.8 (M+H) +, method ESI +
Step 6:N-[{ (5S)-3[3-fluoro-4-(4-hydroxy-piperdine-4-base-methoxyl group)-phenyl]-2-oxo-oxazolidines-5-ylmethyl }]-acetamide:
Will be under hydrogen in the 31g4-{4-[(5S in 310ml methanol and the 150ml ethyl acetate)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluorophenoxy methyl-4-hydroxy-piperdine-1-benzyl carboxylate (MW:515.54,60.13mmol) and 2.5g 10% activated carbon-carried palladium suspension stirred 4 hours.With TLC (ethyl acetate) monitoring reaction.With 300ml methanol diluting reaction slurry, be warmed to 40 ℃, use the glass fiber filter paper filtration catalizer.Filtrate is concentrated into 150ml, and with the dilution of 300ml ethyl acetate, reconcentration is to 200ml.Add the 200ml ether, under agitation suspension is cooled to 0 ℃.Collect solid, drying.Yield: 21.6g, 94.3%.MS:382.6 (M+H) +, method ESI +
Step 7:7-(4-{[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-hydroxy-piperdine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Under agitation will be in the 71mg 7-chloro-1-cyclopropyl-6-fluoro-1 in 1ml N-methyl-pyrrolidin-2-one, 4-dihydro-4-oxo-[1,8] naphthyridines-3-carboxylic acid (MW:282.66,0.25mmol), 95mg N-[{ (5S)-3[3-fluoro-4-(4-hydroxy-piperdine-4-ylmethoxy)-phenyl]-2-oxo-oxazolidines-5-ylmethyl]-acetamide (MW:381.40,0.25mmol), 102mg triethylamine (MW:101.19,1.0mmol) and the 81mg trim,ethylchlorosilane (MW:108.64,0.75mmol) suspension is 80 ℃ of down heating 5 hours.With TLC (dichloromethane: monitoring reaction methanol 9: 1).Evaporation N-methyl-pyrrolidin-2-one is dissolved in 9: 1 dichloromethane of 20ml with residue: in the carbinol mixture, use 10ml 0.1N aqueous hydrochloric acid solution and 20ml salt water washing gained solution successively.Use the dried over mgso organic layer, filter and evaporated filtrate.Residue is dissolved in 9: 1 dichloromethane of 10ml: in the carbinol mixture, with the dilution of 20ml ethyl acetate.The solid of collecting precipitation obtains pale solid.Decompression mother liquid evaporation down obtains second batch of product.Yield: 100mg, 64%.MS：628.8(M+H) +，626.8(M-H) -。Method ESI +, ESI -
Embodiment 73:7-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-phosphonato-piperidines-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900571
Step 1:7-[4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxymethyl }-4-(two-benzyloxy-phosphorus acyloxy)-piperidines-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
With 138mg dibenzyl N, N-diisopropylaminoethyl phosphite ester (phosphoramidite) (MW:345.42,0.4mmol) handle 125mg7-(4-{[(5S)-5-(acetylaminohydroxyphenylarsonic acid the methyl)-2-oxo-oxazolidines-3-yl in the 1ml dichloromethane]-2-fluoro-phenoxymethyl }-4-hydroxy-piperdine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid (MW:627.60,0.2mmol) and 42mg tetrazolium (MW:70.05,0.6mmol) suspension.The original suspension clarification that slowly becomes.Solution was at room temperature stirred 2 hours, and monitor with TLC (methylene chloride 9: 1).Reactant mixture is cooled to 0 ℃, is used for the 0.6ml 0.5M metachloroperbenzoic acid solution-treated of dichloromethane.Mixture was at room temperature stirred 2 hours, with the dilution of 20ml dichloromethane.Organic layer is used 20ml saturated sodium bicarbonate aqueous solution and the water washing of 20ml salt successively, uses dried over mgso.Slurry is filtered, and decompression is evaporated filtrate down.Residue as eluent, obtains pale solid with 9/1 methylene chloride/methanol mixture through the silica gel chromatography purification.Yield: 158mg, 89%.MS：889.3(M+H) +，887.0(M-H) -。Method ESI +, ESI -
Step 2:7-(4-{4-[(5S)-(5-acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-phosphonato-piperidines-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Will be under room temperature and the hydrogen in the 158mg 7-[4-{4-[(5S in 20ml 6/3/1 methylene chloride/aqueous mixtures)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxymethyl }-4-(two-benzyloxy-phosphorus acyloxy)-piperidines-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] (MW:887.84 0.177mmol) stirred 3 hours with 20mg 20% carried by active carbon leptynol naphthyridines-3-carboxylic acid.Use the glass fiber filter paper filtration catalizer.Decompression is evaporating solvent down, and residue is dissolved in the 10ml methanol.Dilute this solution with 20ml water, the adularescent solid is separated out simultaneously.Collect solid, drying.Yield: 85mg, 68%.MS：709.0(M+H) +，706.5(M-H) -。Method ESI +, ESI -
Embodiment 74:7-[4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-(2,6-diaminourea-hexylyloxy)-piperidines-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900591
Step 1:4-{4-[(5S)-(5-acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-hydroxy-piperdine-1-carboxylic acid tert-butyl ester:
Similar to embodiment 72 steps 5, by making 3.83g 1-oxa--6-azepine-spiral shell [2.5] octane-6-carboxylic acid tert-butyl ester (the WO 0204462) (MW:213.28 in the 30ml dimethyl formamide, 18mmol), 4.02g N-[(5S)-{ 3-(3-fluoro-4-hydroxyl-phenyl) }-2-oxo-oxazolidines-5-ylmethyl]-acetamide (MW:268.246,15mmol) with 3.1g potassium carbonate (MW:138.20,22.5mmol) reaction.Yield: 4.89g, 67%.MS:482.6 (M+H) +, method ESI +
Step 2:4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-(2,6-two-benzyloxycarbonyl amino-hexylyloxy)-piperidines-1-carboxylic acid tert-butyl ester:
Use 115mg N-(3-dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride (MW:191.70 in room temperature with under stirring, 0.6mmol) handle 96mg4-{4-[5-(5S)-(acetylaminohydroxyphenylarsonic acid the methyl)-2-oxo-oxazolidines-3-yl in the 2ml dichloromethane]-2-fluoro-phenoxymethyl }-4-hydroxy-piperdine-1-carboxylic acid tert-butyl ester (MW:481.52,0.2mmol), 195mg Z-Lys (Z)-OH (MW:414.46,0.4mmol) and 49mg 4-dimethylamino naphthyridine (MW:122.17,0.4mmol) suspension.The reactant mixture stirring is spent the night.With 20ml ethyl acetate diluted mixture thing, organic layer is used 10ml 1N aqueous hydrochloric acid solution, 20ml water and the water washing of 20ml salt successively.Use the dried over mgso organic layer, filter, evaporated filtrate is to doing.Residue as eluent, obtains colourless thickness grease with 9/1 methylene chloride/methanol mixture through the silica gel chromatography purification.Yield: 150mg, 88%.MS:878.8 (M+H) +, method ESI +
Step 3:2,6-two-benzyloxycarbonyl amino-caproic acid 4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-the piperidin-4-yl ester hydrochloride:
With 200mg 4-{4-[5-(5S)-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-(2,6-two-benzyloxycarbonyl amino-hexylyloxy)-(MW:977.97 0.22mmol) is dissolved in the 4ml 1.25M anhydrous hydrochloric acid in methanol piperidines-1-carboxylic acid tert-butyl ester.Reactant was stirred 2 hours down at 40 ℃, and decompression is distilled down to remove and is desolvated, and obtains pale solid.Yield: 178mg, quantitatively.MS:778.8 (M+H) +, method ESI +
Step 4:7-[4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-(2,6-two-benzyloxycarbonyl amino-hexylyloxy)-piperidines-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Similar to embodiment 72 steps 7, be used in the 62mg 7-chloro-1-cyclopropyl-6-fluoro-1 in 1ml N-methyl-pyrrolidin-2-one, 4-dihydro-4-oxo-[1,8] naphthyridines-3-carboxylic acid (MW:282.66,0.25mmol), 178mg 2,6-two-benzyloxycarbonyl amino-caproic acid 4-{4-[5-(5S)-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-piperidin-4-yl ester hydrochloride (MW:814.31,0.22mmol), 90mg triethylamine (MW:101.19,0.88mmol) and the 48mg trim,ethylchlorosilane (MW:108.64,0.44mmol).Yield: 94mg, 42%.MS:1025.3 (M+H) +, method ESI +
Step 5:7-[4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-(2,6-diaminourea-hexylyloxy)-piperidines-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Will be under room temperature and the hydrogen in the 94mg 7-[4-{4-[(5S in 20ml 6/3/1 methylene chloride/aqueous mixtures)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-(2,6-two-benzyloxycarbonyl amino-hexylyloxy)-piperidines-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] (MW:1024.05 0.091mmol) stirred 4 hours with 20mg 20% carried by active carbon leptynol naphthyridines-3-carboxylic acid.With glass fiber filter paper elimination catalyst.Decompression is evaporating solvent down, and residue is dissolved in the 10ml methanol.Solution is diluted with 20ml water, and the adularescent solid is separated out simultaneously.Collect solid, drying.Yield: 29mg, 43%.MS:757.0 (M+H) +, 755.2, method ESI +, ESI -
Embodiment 75: mono succinate [4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-1-(6-carboxyl-8-cyclopropyl-3-fluoro-5-oxo-5,8-dihydro-[1,8] naphthyridines-2-yl)-piperidin-4-yl] ester:
Figure C20048001867900611
Step 1: succinic acid 4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-1-tertbutyloxycarbonyl-piperidin-4-yl ester benzyl ester:
Similar to embodiment 74 steps 2, use 1.3g N-(3-dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride (MW:191.70 in room temperature with under stirring, 6.8mmol) handle the 825mg 4-{4-[(5S in the 10ml dichloromethane)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxy group-methyl }-4-hydroxy-piperdine-1-carboxylic acid tert-butyl ester (MW:481.52,1.71mmol), 1.07g mono succinate benzyl ester (MW:208.21,5.14mmol) and 0.63g 4-dimethylamino naphthyridine (MW:122.17,5.1mmol).Yield: 820mg, 70%.MS:673.3 (M+H) +, method ESI +
Step 2: succinic acid 4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-piperidin-4-yl ester benzyl ester:
With 820mg succinic acid 4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-the 1-tertbutyloxycarbonyl-(MW:671.72 1.23mmol) is dissolved in the 4ml trifluoroacetic acid piperidin-4-yl ester benzyl ester.Reactant mixture was at room temperature stirred 1 hour.Evaporating solvent is dissolved in residue in 30ml 9/1 methylene chloride/methanol mixture, and organic layer is used 30ml saturated sodium bicarbonate aqueous solution and the water washing of 30ml salt successively.Use the dried over mgso organic layer, filter, decompression is evaporated filtrate down.Residue is through the silica gel chromatography purification, with containing 95/5 methylene chloride/methanol mixture of 2% triethylamine as eluent.Yield: 420mg, 60%.MS:572.7 (M+H) +, method ESI +
Step 3: succinic acid 4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-1-(6-carboxyl-8-cyclopropyl-3-fluoro-5-oxo-5,8-dihydro-[1,8] naphthyridines-2-yl)-piperidin-4-yl ester benzyl ester:
Similar to embodiment 72 steps 7, be used in the 113mg 7-chloro-1-cyclopropyl-6-fluoro-1 in 2ml N-methyl-pyrrolidin-2-one, 4-dihydro-4-oxo-[1,8] naphthyridines-3-carboxylic acid (MW:282.66,0.4mmol), 230mg succinic acid 4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl-piperidin-4-yl ester benzyl ester (MW:571.60,0.4mmol), 161mg triethylamine (MW:101.19,1.6mmol) and the 87mg trim,ethylchlorosilane (MW:108.64,0.8mmol).Yield: 25mg, 7.6%.MS:819 (M+H) +, 817.8, method ESI +, ESI -
Step 4: mono succinate [4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-1-(6-carboxyl-8-cyclopropyl-3-fluoro-5-oxo-5,8-dihydro-[1,8] naphthyridines-2-yl)-piperidin-4-yl] ester:
Similar to embodiment 74 steps 5, be used in the 22mg succinic acid 4-{4-[(5S in 20ml 1/1 oxolane/carbinol mixture)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-1-(6-carboxyl-8-cyclopropyl-3-fluoro-5-oxo-5,8-dihydro-[1,8] naphthyridines-2-yl)-(MW:817.80 is 0.026mmol) with 2mg 20% carried by active carbon palladium dydroxide for piperidin-4-yl ester benzyl ester.Yield: 16mg, 81%.MS:729 (M+H) +, 727 (M+H) -, method ESI +, ESI -
Embodiment 76:7-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-hydroxy-piperdine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
With 67.81g 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid boron diacetate esters complex (boron diacetate complex) (MW:410.57 0.165mol) handles 60g N-[{ (5S)-3[3-fluoro-4-(4-hydroxy-piperdine-4-ylmethoxy)-phenyl in 300ml N-methyl-pyrrolidin-2-one]-2-oxo-oxazolidines-5-ylmethyl }]-acetamide (C 18H 24FN 3O 5, MW:381.40,0.157mol) and 26.87ml ethyl diisopropylamine (MW:129.25,0.157mol) solution, and mixture stirred 5 hours down at 80 ℃.Decompression is evaporation N-methyl-pyrrolidin-2-one down, and residue is dissolved in the 300ml methanol.In this solution, blast anhydrous hydrogen chloride under 10 ℃, continuing 30 minutes.This solution is at room temperature stirred, have yellow solid to separate out simultaneously.With of the conversion of HPLC monitoring boron compound to free acid.With 300ml ethyl acetate diluted mixture thing.Cross filter solid, with 100ml 8/2 ethyl acetate/methanol and the washing of 100ml ethyl acetate.The yellow solid drying is obtained the 86.4g yellow solid.Under 40 ℃, this solid is dissolved in the 200ml dimethyl sulfoxine, under agitation this yellow solution is added in the 1000ml water.Collect yellow solid, wash drying with water.Yield: 73g, 74.5%.MS:627.8 (M+H) +, 625.8 (M+H) -, method ESI +, ESI -
Embodiment 77:7-[4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxymethyl }-4-(two-benzyloxy-phosphorus acyloxy)-piperidines-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900641
The 31.8g dibenzyl diisopropylaminoethyl phosphite ester (MW:345.42 that under room temperature and stirring, is used for the 20ml dichloromethane, 92.15mmol) 35g 7-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid the methyl)-2-oxo-oxazolidines-3-yl of solution-treated in the 700ml dichloromethane]-2-fluoro-phenoxymethyl }-4-hydroxy-piperdine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (MW:626.61,55.85mmol) and 6.45g tetrazolium (MW:70.05,92.15mmol) suspension.With TLC (methylene chloride 9: 1) monitoring reaction.Reactant was stirred 1 hour, and use 200ml 1N aqueous hydrochloric acid solution and 100ml saturated sodium bicarbonate solution purging compound down at 0 ℃.Water layer reuse 200ml washed with dichloromethane.Merge organic layer, be concentrated into 500ml, (MW:90.12,95mmol) aqueous solution is handled at room temperature to use 13.2ml 70% t-butyl hydroperoxide.Reactant was stirred 30 minutes, with the dilution of 500ml dichloromethane, organic layer 200ml 1N aqueous hydrochloric acid solution and the water washing of 300ml salt.The organic layer dried over mgso is filtered, and decompression is evaporated filtrate down.Residue is dissolved in the 400ml dichloromethane, with the dilution of 400ml normal hexane.Mixture being concentrated (300mbar bathes 40 ℃ of temperature) to volume is 400ml.Thickness grease is decanted and be dissolved in the 400ml backflow methanol.To be concentrated into 300ml under this solution decompression, at room temperature stir and spend the night.Slurry is cooled to 0 ℃, collects solid.Yield: 27.60g, 55.6%.MS:888.3 (M+H) +, 885.8 (M+H) -, method ESI +, ESI -
Embodiment 78:7-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-phosphonato-piperidines-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
With 27g 7-[4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxymethyl }-4-(two-benzyloxy-phosphorus acyloxy)-piperidines-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (MW:886.85,30.44mmol) be suspended in the 600ml acetonitrile, the 53ml 33% anhydrous hydrobromic acid solution that is used for acetic acid is handled.With this yellow suspension with 150ml acetic acid dilution and be heated to 45 ℃.Use the HPLC/MS monitoring reaction, afterreaction finished in 3 hours.This thickness suspension is under agitation added in the 1.5L water.Collect the canescence crystal, with 300ml water, 150ml ethanol and the washing of 150ml ether.Solid suspension in 1.3L water, is handled with 35ml (35mmol) 1M sodium hydrate aqueous solution.After the solid dissolving, brown yellow solution is also filtered with the 15g charcoal treatment.With three batches of 200ml 95/5 methylene chloride/methanol mixture extraction filtrates.Water layer makes the product crystallization with 40ml1M HCl solution-treated by stirring.Collect solid, drying.Yield: 17.3g, 80.4%.MS:609.7 (M+H) +, 607.8 (M+H) -, method ESI +, ESI -
Embodiment 79:7-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-hydroxy-piperdine-1-yl)-1-cyclopropyl-6-fluoro-8-methoxyl group-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900661
Similar to embodiment 76, be used in 114mgN-[{ (5S)-3[3-fluoro-4-(4-hydroxy-piperdine-4-the ylmethoxy)-phenyl in 1ml N-methyl-pyrrolidin-2-one]-2-oxo-oxazolidines-5-base-methyl }]-acetamide (MW:381.40,0.3mmol), 127mg 1-cyclopropyl-6,7-two fluoro-1,4-dihydro-8-methoxyl group-4-oxo-3-quinoline carboxylic acid diacetyl borate (Sakurai, Nobuhiro; Sano, Mitsuharu; Hirayama, Fumihiro; Kuroda, Tsuyoshi; Uemori, Satoru; Bioorg.Med.Chem.Lett.; 8; 16; 1998; 2185-2190) (MW:423.137,0.3mmol) and the 38mg ethyl diisopropylamine (MW:129.25,0.3mmol).Yield: 137mg, 69.5%.MS:658.2 (M+H) +, 655.8 (M+H) -, method ESI +, ESI -
Embodiment 80:7-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-hydroxy-piperdine-1-yl)-1-cyclopropyl-8-methoxyl group-4-oxo-1,4-dihydro-quinoline-3 carboxylic acid
Figure C20048001867900662
Similar to embodiment 76, be used in 114mgN-[{ (5S)-3[3-fluoro-4-(4-hydroxy-piperdine-4-the ylmethoxy)-phenyl in 2ml N-methyl-pyrrolidin-2-one]-2-oxo-oxazolidines-5-base-methyl }]-acetamide (MW:381.40,0.3mmol), 121mg 1-cyclopropyl-8-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylatoboron diacetate esters (WO 03032962) (MW:405.15,0.3mmol) and the 77mg ethyl diisopropylamine (MW:129.25,0.6mmol).Yield: 117mg, 61.2%.MS:639.8 (M+H) +, 637.5 (M+H) -, method ESI +, ESI -
Embodiment 81:9-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxymethyl }-4-hydroxy-piperdine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa--3a-azepine-Fei Na alkene-5-carboxylic acid:
Figure C20048001867900671
Down will be at 80 ℃ in the 140mg 9 in 1ml N-methyl-pyrrolidin-2-one, 10-two fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de]-1,4-benzoxazinyl-6-carboxylic acid (MW:281.22,0.5mmol), 191mg N-[{ (5S)-3[3-fluoro-4-(4-hydroxy-piperdine-4-ylmethoxy)-phenyl]-2-oxo-oxazolidines-5-base-methyl]-acetamide (MW:381.40,0.5mmol) and the 129mg ethyl diisopropylamine (MW:129.25,1mmol) solution stirring is 24 hours.Decompression is evaporating solvent down.Residue is dissolved in the methanol, and the 10ml 1.2M solution of anhydrous hydrochloric acid that is used for methanol is handled.Evaporation methanol is dissolved in residue in the ethyl acetate.Collect solid, crystallization is twice in dichloromethane/alcohol mixture.Yield: 88mg, 27%.MS:643.7 (M+H) +, 641.5 (M+H) -, method ESI +, ESI -
Embodiment 82:7-(3-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-3-hydroxyl-pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900681
Step 1:1-oxa--5-azepine-spiral shell [2.4] heptane-5-benzyl carboxylate:
With the 2.16g sodium bicarbonate (MW:84.01,26.28mmol) and 2.47g 80% metachloroperbenzoic acid (MW:172.57 11.48mmol) handles 3-methylene-pyrrolidine-1-benzyl carboxylate (WO 9624593) solution in the 5ml dichloromethane.Reactant mixture was at room temperature stirred 3 hours.With 20ml saturated sodium bisulfite solution and 45ml dichloromethane diluted reaction mixture.Organic layer is used 30ml saturated sodium bicarbonate aqueous solution and salt water washing successively.Use the dried over mgso organic layer.Residue obtains pale solid through silica gel chromatography (1/1 ethyl acetate/normal hexane) purification.Yield: 440mg, 57%.MS:234.1 (M+H) +, method ESI +
Step 2:3-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-3-hydroxyl-pyrrolidine-1-benzyl carboxylate:
Handle 420mgN-[(5S in the 2ml dimethyl formamide with the 83mg sodium hydride)-{ 3-(3-fluoro-4-hydroxyl-phenyl) }-2-oxo-oxazolidines-5-ylmethyl]-acetamide (MW:268.246,1.56mmol) solution.At room temperature this suspension was stirred 1 hour.(MW:233.26,1.88mmol) solution stir mixture 3 hours down at 70 ℃ to be incorporated in 440mg 1-oxa--5-azepine-spiral shell [2.4] heptane-5-benzyl carboxylate among the 1ml DMF.Decompression is the evaporation dimethyl formamide down, and residue obtains pale powder through silica gel chromatography (95/5 methylene chloride/methanol mixture that contains 1% ammonia) purification.Yield: 630mg, 80%.MS:502.5 (M+H) +, method ESI +
Step 3:N-{ (5S)-3-[3-fluoro-4-(3-hydroxyl-pyrrolidine-3-base-methoxyl group)-phenyl]-2-oxo-oxazolidines-5-ylmethyl }-acetamide:
Will be under hydrogen in the 660mg3-{4-[(5S in the 20ml 1/1 ethyl acetate/methanol mixture)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl-3-hydroxyl-pyrrolidine-1-benzyl carboxylate (MW:501.51,1.31mmol) and 20mg 10% activated carbon-carried palladium suspension stirred 12 hours.Use the glass fiber filter paper filtering catalyst, decompression is evaporated filtrate down, obtains colorless oil.Yield: 400mg, 83.2%.MS:368.4 (M+H) +, method ESI +
Step 4:7-(3-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-3-hydroxyl-pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Similar to embodiment 72 steps 7, be used in the 39mg 7-chloro-1-cyclopropyl-6-fluoro-1 in 2ml N-methyl-pyrrolidin-2-one, 4-dihydro-4-oxo-[1,8] naphthyridines-3-carboxylic acid (MW:282.66,0.24mmol), 99mg N-{ (5S)-3-[3-fluoro-4-(3-hydroxyl-pyrrolidine-3-ylmethoxy)-phenyl]-2-oxo-oxazolidines-5-ylmethyl-acetamide (MW:367.38,0.24mmol), 101mg triethylamine (MW:101.19,1.0mmol) and the 80mg trim,ethylchlorosilane (MW:108.64,0.75mmol).Yield: 70mg, 46%.MS:614.7 (M+H) +, 612.7 (M+H) -, method ESI +, ESI -
Embodiment 83:7-(3-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-3-hydroxyl-pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900691
Similar to embodiment 76, be used in 106mgN-{ (5S)-3-[3-fluoro-4-(3-hydroxyl pyrrolidine-3-the ylmethoxy)-phenyl in 2ml N-methyl-pyrrolidin-2-one]-2-oxo-oxazolidines-5-base-methyl }-acetamide (MW:367.38,0.29mmol), 119mg (7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid boron diacetate esters complex (MW:410.57,0.29mmol) and the 75mg ethyl diisopropylamine (MW:129.25,0.58mmol).Yield: 19mg, 11%.MS:613.5 (M+H) +, 611.5 (M+H) -, method ESI +, ESI -
Embodiment 84:7-(3-14-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-3-hydroxyl-pyrrolidine-1-yl)-1-cyclopropyl-6-fluoro-8-methoxyl group-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900701
Similar to embodiment 76; be used in 143mgN-{ (5S)-3-[3-fluoro-4-(3-hydroxyl-pyrrolidine-3-the ylmethoxy)-phenyl in 2ml N-methyl-pyrrolidin-2-one]-2-oxo-oxazolidines-5-base-methyl }-acetamide (MW:367.38; 0.39mmol), 165mg 1-cyclopropyl-6; 7-two fluoro-1; 4-dihydro-8-methoxyl group-4-oxo-3-quinoline-carboxylic acid diacetyl borate (MW:423.137; 0.39mmol) and the 100mg ethyl diisopropylamine (MW:129.25,0.78mmol).Yield: 143mg, 57%.MS:643.7 (M+H) +, 641.7 (M+H) -, method ESI +, ESI -
Embodiment 85:7-(3-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-3-hydroxyl-pyrrolidine-1-yl)-1-cyclopropyl-8-methoxyl group-4-oxo-1,4-dihydro-quinoline-3 carboxylic acid:
Figure C20048001867900711
Similar to embodiment 76, be used in 48mgN-{ (5S)-3-[3-fluoro-4-(3-hydroxyl-pyrrolidine-3-the ylmethoxy)-phenyl in the 1ml N-methylpyrrolidin-2-ketone]-2-oxo-oxazolidines-5-base-methyl }-acetamide (MW:367.38,0.13mmol), 53mg 1-cyclopropyl-8-methoxyl group-4-oxo-1,4-dihydroquinoline-3-carboxylatoboron diacetate esters (MW:405.15,0.13mmol) and the 33mg ethyl diisopropylamine (MW:129.25,0.26mmol).Yield: 41mg, 50%.MS:625.8 (M+H) +, 623.8 (M+H) -, method ESI +, ESI -
Embodiment 86:9-(3-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidine-3-yl]-2-fluoro-phenoxymethyl }-3-hydroxyl-pyrrolidine-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa--3a-azepine-Fei Na alkene-5-carboxylic acid:
Similar to embodiment 81, be used in the 110mg9 in 2ml N-methyl-pyrrolidin-2-one, 10-two fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de]-1,4-benzoxazinyl-6-carboxylic acid (MW:281.22,0.39mmol), 143mg N-{ (5S)-3-[3-fluoro-4-(3-hydroxyl-pyrrolidine-3-ylmethoxy)-phenyl]-2-oxo-oxazolidines-5-ylmethyl-acetamide (MW:367.38,0.39mmol) and the 100mg ethyl diisopropylamine (MW:129.25,0.78mmol).Yield: 103mg, 42%.MS：629.8(M+H) +。Method ESI +
Embodiment 87:7-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-hydroxyl-azepan-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Figure C20048001867900721
Step 1:4-methylene-azepan-1-carboxylic acid tert-butyl ester:
Handle 1g first base three phenyl phosphonium bromide (MW:357.22,2.79mmol) solution in the 20ml oxolane at the 1.22ml 2.3M n-butyllithium solution that is used for normal hexane (2.8mmol) under-78 ℃.Under-78 ℃, reactant mixture was stirred 10 minutes, stirred 1 hour down at 0 ℃ then.Yellow suspension is cooled to-78 ℃, and is used for 595mg 4-oxo-azepan-1-carboxylic acid tert-butyl ester (WO 2000044376) (MW:213.279,2.78mmol) solution-treated of 10ml oxolane.Reactant mixture was at room temperature stirred 1.5 hours.Make the reactant mixture cessation reaction with the 30ml saturated aqueous ammonium chloride, with the dilution of 30ml ethyl acetate.Organic layer is used 30ml water and the water washing of 30ml salt successively, with dried over mgso and filtration.Decompression is evaporated filtrate down, and residue is through silica gel chromatography (cyclohexane extraction: ethyl acetate 1: 1) purification.Yield: 487mg, 83%.NMR (CDCl 3): 1.35ppm (s, 9H, the tert-butyl group); 1.6ppm (m, 2H ,-CH 2-), 2.14ppm (m, 2H), 2.33ppm (m, 2H); 3.29ppm (m, 4H, N-CH 2); 4.67ppm (m, 2H, vinyl-CH 2).
Step 2:1-oxa--6-azepine-spiral shell [2.6] nonane-6-carboxylic acid tert-butyl ester:
Similar to embodiment 82 steps 1, be used in the 4-methylene-azepan-1-carboxylic acid tert-butyl ester (MW:211.307 in the 5ml dichloromethane, 1.73mmol), (MW 172.57,6.05mmol) for 1.16g sodium bicarbonate (MW:84.0113.8mmol) and 1.36g 80% metachloroperbenzoic acid.Yield: 250mg, 63%.MS:228.8 (M+H) +, 127.8 (M-(CH 3) 3COCO), method ESI +
Step 3:4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-hydroxyl-azepan-1-carboxylic acid tert-butyl ester:
Similar to embodiment 72 steps 5, be used in 247mg 1-oxa--6-azepine-spiral shell [2.6] nonane-6-carboxylic acid tert-butyl ester (MW:227.31 in the 150ml dimethyl formamide, 1.08mmol), 296mg N-[(5S)-{ 3-(3-fluoro-4-hydroxyl-phenyl) }-2-oxo-oxazolidines-5-ylmethyl]-acetamide (MW:268.246,80mmol) and the 228mg potassium carbonate (MW:138.20,1.65mmol).Yield: 334mg, 62%.MS:496.8 (M+H) +, 440.8 (M-C (CH 3) 3+ H) +, method ESI +
Step 4:N-{ (5S)-3-[3-fluoro-4-(4-hydroxyl-azepan-4-ylmethoxy)-phenyl]-2-oxo-oxazolidines-5-ylmethyl }-acetamide:
At 35 ℃ of 334mg4-{4-[(5S that will be down in the 3ml 1.25M solution of anhydrous hydrochloric acid in the methanol)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-(MW:495.55,0.674mmol) solution stirring is four hours for 4-hydroxyl-azepan-1-carboxylic acid tert-butyl ester.Decompression is evaporating solvent down.Residue is dissolved in the 4ml water, and water layer is neutralized to pH 7 with saturated sodium bicarbonate solution.Evaporation water is dissolved in residue in 30ml 9/1 methylene chloride/methanol mixture.Filter not dissolved salt, filtrate is evaporated to dried, obtain pale solid.Yield: 266mg, quantitatively, MS:395.8 (M+H) +, 440.6 (M+HCOO -), method ESI +, ESI -
Step 5:7-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-hydroxyl--azepan-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid:
Similar to embodiment 76, be used in 150mgN-{ (5S)-3-[3-fluoro-4-(4-hydroxyl-azepan-4-the ylmethoxy)-phenyl in 2ml N-methyl-pyrrolidin-2-one]-2-oxo-oxazolidines-5-base-methyl }-acetamide (MW:395.43) and 98mg ethyl diisopropylamine (MW:129.25,0.758mmol), 163mg (7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid boron diacetate esters complex (MW:410.57,0.397mmol).Yield: 70mg, 28.8%.MS:641.7 (M+H) +, method ESI +
Embodiment 88:7-(4-{4-[(5S)-5-(acetylaminohydroxyphenylarsonic acid methyl)-2-oxo-oxazolidines-3-yl]-2-fluoro-phenoxymethyl }-4-hydroxyl-azepan-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridines-3-carboxylic acid:
Figure C20048001867900741
Similar to embodiment 72 steps 7, be used in the 98mg 7-chloro-1-cyclopropyl-6-fluoro-1 in the 1ml N-methylpyrrolidin-2-ketone, 4-dihydro-4-oxo-[1,8] naphthyridines-3-carboxylic acid (MW:282.66,0.348mmol), 138mg N-{ (5S)-3-[3-fluoro-4-(4-hydroxyl-azepan-4-ylmethoxy)-phenyl]-2-oxo-oxazolidines-5-ylmethyl-acetamide (MW:395.43,0.348mmol), 140mg triethylamine (MW:101.19,1.39mmol) and the 113mg trim,ethylchlorosilane (MW:108.64,1.04mmol).Yield: 150mg, 77%.MS:642.7 (M+H) +, 640.7 (M+H) -, method ESI +, ESI -
The chemical compound of being tested is lower than 0.03 μ g/ml at the MIC of the several bacterial strains of anthrax bacillus.

Claims (25)

1. the chemical compound of formula (I) or the acceptable salt of its pharmacology, solvate, hydrate or preparation are used for the treatment of purposes in the medicine of anthrax in production:
Figure C2004800186790002C1
Wherein
A is key, NH, O, S, SO, SO 2, SO 2NH, PO 4,-NH-CO-NH-,-CO-NH-,-CO-,-CO-O-,-NH-CO-O-,-two or more combination in the inferior Heterocyclylalkyl of O-Z-, alkylidene, alkenylene, alkynylene, inferior assorted alkyl, arlydene, heteroarylidene, cycloalkylidene, inferior Heterocyclylalkyl, alkyl arylene or heteroaryl alkylidene or these atoms or the group;
L is selected from following group:
Figure C2004800186790002C2
X is CR5 or N;
Y is CR6 or N;
U is F or Cl;
Z is C 1-4Alkylidene, C 2-4Alkenylene, C 2-4Alkynylene or C 1-4Inferior assorted alkyl, wherein all groups can be by one or more hydroxyls or amino the replacement;
N is 0,1,2 or 3;
R1 is H, F, Cl, Br, I, OH, NH 2, alkyl or assorted alkyl;
R2 is H, F or Cl;
R3 is H, alkyl, thiazolinyl, alkynyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylaryl or heteroaryl alkyl, wherein all these groups all can by one, two or more a plurality of halogen atom such as F or Cl replace;
R4 is assorted alkyl, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, alkylaryl or heteroaryl alkyl;
R5 is H, F, Cl, OH, NH 2, alkyl or assorted alkyl, perhaps
If R3 is not H and R5 is not H, F, OH, NH 2Or Cl, R3 can be connected through alkylidene, alkenylene or inferior assorted alkyl with R5, perhaps can be the part of cycloalkylidene or inferior Heterocyclylalkyl;
R6 is H, F, Cl or OMe;
R8 is C 1-6Assorted alkyl or heteroaryl alkyl.
2. according to the purposes of claim 1, wherein R1 is H.
3. according to the purposes of claim 1 or 2, wherein R2 is F or H.
4. according to each purposes of aforementioned claim, wherein R3 is ethyl, 2-propyl group, C 3-C 6Cycloalkyl, phenyl or pyridine radicals, wherein all these groups all can be by one, two or more a plurality of fluorine atom or amino the replacement.
5. according to each purposes of aforementioned claim, wherein R3 is a cyclopropyl.
6. according to each purposes of aforementioned claim, wherein R3 and R5 form formula-O-CH together 2-N (Me)-or-O-CH 2-CH (Me)-group.
7. according to each purposes of aforementioned claim, wherein R4 is an acetylamino.
8. according to each purposes of aforementioned claim, wherein the absolute configuration according to the C-5 of order nomenclature ， oxazolidone ring is (S).
9. according to each purposes of aforementioned claim, wherein X is N or CH.
10. according to each purposes of aforementioned claim, wherein Y is CF or CH.
11. according to each purposes of aforementioned claim, wherein n is 0.
12. according to each the purposes of claim 1-11, wherein A is the group of following formula
Figure C2004800186790004C1
Wherein
Group B is can be by one, two or more a plurality of fluorine atom alkylidene, O, S, SO, the SO that replace 2, SO 2NH base or can by one, two or more a plurality of fluorine atom replaces and/or on the nitrogen-atoms that randomly exists by the assorted alkyl in the Asia of alkyl or acyl substituted;
Group D is the inferior Heterocyclylalkyl with randomly anellated of 1,2,3 or 4 nitrogen-atoms independently of one another, and described inferior Heterocyclylalkyl separately can by one, two or more a plurality of fluorine atom replaces and/or separately can be by alkyl or acyl substituted on one, two, three or four nitrogen-atoms;
Group E is can be by one, two or more a plurality of fluorine atom alkylidene, O, S, SO, the SO that replace independently of one another 2, SO 2NH base or can by one, two or more a plurality of fluorine atom replaces and/or on the nitrogen-atoms that randomly exists by the assorted alkyl in the Asia of alkyl or acyl substituted;
Group G is the inferior Heterocyclylalkyl with randomly anellated of 1,2,3 or 4 nitrogen-atoms independently of one another, and described inferior Heterocyclylalkyl separately can by one, two or more a plurality of fluorine atom replaces and/or separately can be by alkyl or acyl substituted on one, two, three or four nitrogen-atoms;
Group K is can be by one, two or more a plurality of fluorine atom alkylidene, O, S, SO, the SO that replace 2, SO 2NH base or can by one, two or more a plurality of fluorine atom replaces and/or on the nitrogen-atoms that randomly exists by the assorted alkyl in the Asia of alkyl or acyl substituted; And m=1,2,3 or 4.
13. according to each the purposes of claim 1-11, wherein A is the group of formula-V-W-, wherein V is direct key or formula NH, O, S, SO, SO 2, SO 2NH, PO 4,-NH-CO-NH-,-CO-NH-,-CO-,-CH 2-,-CO-O-,-(CH 2) 1-3-O-,-CH=CH-C (O)-or-group of NH-CO-O-, and W has the Heterocyclylalkyl of 4-7 annular atoms or has the alkyl heterocycle alkyl that 1-4 carbon atom arranged in 4-7 annular atoms and the alkyl chain; All these groups all can be replaced by 1,2,3 or 4 fluorine atom, methyl or methoxy.
14. according to each the purposes of claim 1-11, wherein A is the group of following formula
Figure C2004800186790005C1
Wherein
V is formula NH, O, S, SO, SO 2, SO 2NH, PO 4,-NH-CO-NH-,-CO-NH-,-CO-,-CH 2-,-CO-O-,-(CH 2) 1-3-O-,-CH=CH-C (O)-or-group of NH-CO-O-; A is 0,1,2,3 or 4; B is 0,1,2,3 or 4; C is that 0,1,2,3 or 4 and 1,2,3 or 4 hydrogen atom can be replaced by F, methyl or methoxy.
15. according to the purposes of claim 13 or 14, wherein V is NH, O, S, SO or SO 2
16. according to the purposes of claim 13 or 14, wherein V is O or NH; A is 0 or 1; B is 1 or 2 and c is 1 or 2.
17. each purposes according to claim 1-11; wherein A is selected from following groups; its can by one, two or more a plurality of fluorine atom replace, perhaps can be replaced, and wherein amino can be by alkyl or acyl substituted by the alkyl that one or more fluorine atoms replace:
Figure C2004800186790006C1
Figure C2004800186790007C1
18. according to each the purposes of claim 1-6 and 8-10, the chemical compound of wherein said formula (I) is represented by formula (II):
Wherein
L is selected from following group:
Figure C2004800186790008C2
B is 1,2 or 3;
C is 1,2 or 3;
R7 is hydrogen, formula PO 3R 9 2Or SO 3R 10Group or have at least one OH, NH 2, SO 3R 10, PO 3R 9 2Or the assorted alkyl of COOH group, wherein R 9Be hydrogen, alkyl, cycloalkyl, aryl, aralkyl, and R wherein 10Be hydrogen, alkyl, cycloalkyl, aryl, aralkyl;
Possible being connected as defined above between X, Y, Z, R1, R2, R3, R5, R6, R8 and R3 and the R5.
19. according to the purposes of claim 18, wherein R7 is hydrogen or formula SO 3H, PO 3H 2, PO 3(CH 2C 6H 5) 2, CH 2OPO 3H or COCH 2CH 2The group of COOH, perhaps connected oxygen forms the ester or derivatives thereof of natural amino acid together.
20. according to the purposes of claim 18 or 19, wherein R8 is formula-CH 2The NHCOCH=CH aryl ,-CH 2The O heteroaryl ,-CH 2NHSO 2Me ,-CH 2NHCOOMe ,-CH 2NHCS 2Me ,-CH 2NHCSNH 2,-CH 2NHCSOMe or-CH 2The group of NHCOMe.
21. according to each the purposes of claim 18-20, wherein L is the group of following formula:
Figure C2004800186790009C1
22. according to each the purposes of claim 18-21, wherein R5 is H, F, Cl or the methoxyl group that can be replaced by one, two or three fluorine atom.
23. according to each the purposes of claim 18-22, wherein Z is CH 2Or CH 2CH 2
24. the pharmaceutical composition that contains the chemical compound that defines in each of aforementioned claim and optional carrier and/or auxiliary agent and/or diluent is used for the treatment of purposes in the medicine of anthrax in production.
25. prodrug is used for the treatment of purposes in the medicine of anthrax in production, the protecting group that described prodrug is sloughed under physiological condition by chemical compound that defines in each of aforementioned claim and the acceptable meeting of at least a pharmacology is formed.
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