CN104098588A - Tricyclic quinolone derivative, preparation method and application thereof - Google Patents

Tricyclic quinolone derivative, preparation method and application thereof Download PDF

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Publication number
CN104098588A
CN104098588A CN201310112906.8A CN201310112906A CN104098588A CN 104098588 A CN104098588 A CN 104098588A CN 201310112906 A CN201310112906 A CN 201310112906A CN 104098588 A CN104098588 A CN 104098588A
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salt
compound
formula
carbonyl
hydrate
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CN104098588B (en
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黄小光
陈矛
朱少璇
鲍颖霞
张小娜
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Baiyunshan Pharmaceutical General Factory Baiyunshan Pharmaceutical Co Ltd G
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Priority to PCT/CN2014/072773 priority patent/WO2014161412A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems

Abstract

The invention discloses a tricyclic quinolone derivative or its salt and hydrate with a novel structure and a non-basic substituent substituted C10 peripheral group. Activity determination of the compound by various strains proves that the compound has antibacterial activity on a variety of sensitive strains and resistant strains, can be used for treatment of infection diseases caused by Gram negative and positive bacteria, and is especially suitable for treatment of methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa infection.

Description

One class three ring Carbostyril derivatives and its production and use
Technical field
The present invention relates to pharmaceutical chemistry and chemotherapy field, be specifically related to class three ring quinolone compounds, its salt or their hydrates and preparation method thereof and the application in treatment bacterial infection disease medicine.
Background technology
Quinolone is the important complete synthesis microbiotic of a class, due to its good pharmacodynamics, pharmacokinetics character, and excellent anti-microbial property and less side effect and make it in clinical middle widespread use.But along with antibiotic widespread use, there is a large amount of Resistant strain, comprise that multidrug resistance bacterial strain is as methicillin resistant staphylococcus aureus (MRSA), methicillin resistant staphylococcus epidermidis (MRSE), penicillin-fast streptococcus pneumoniae (PRSP), (Mitscher, the L. A. etc. such as the faecalis of vancomycin resistance (VRE) chem. Rev. 2005, 105,559), therefore clinically in the urgent need to the effective novel antibacterial medicine for the treatment of resistant organism.
Although side effect is less in the clinical application of quinolone antibiotic, but there is the phenomenon of having withdrawn from market because having there is serious adverse drug reaction.For example, Sparfloxacin and grepafloxacin are exactly the cardiotoxicity that is called clinically " prolongation of QT gap ", cause patient heart rate uneven, and withdrawn from market (Patmore, L. etc., eur. J. Pharmacol. 2000, 406,449).2007, the Murphy of Pfizer Inc., the people's such as S. T. research finds that " prolongation of QT gap " side effect of quinolones is mainly subject to the impact of two factors, the one, quinolone parent nucleus fat-soluble, is substituent alkalescence on the nitrogen heterocyclic of C7 position in addition.Result of study shows that the parent nucleus of quinolone medicine is fat-soluble stronger, and on the nitrogen heterocyclic of C7 position, substituent alkalescence is stronger, more easily cause this side effect (Murphy, S. T. etc., bioorg. Med. Chem. Lett. 2007, 17, 2150).
Levofloxacin (Levofloxacin) is one of good carbostyril family antibacterial drugs of efficacy and saferry up to now, also be best-selling kind in antibiotics simultaneously, this medicine is to gram-positive microorganism (G (+)), Gram-negative bacteria (G (-)), anerobe, mycoplasma, chlamydozoan and mycobacterium tuberculosis all have good curative effect, at clinical middle determined curative effect, toxic side effect is very low, particularly aspect cardiac toxic (prolongation of QT gap) and phototoxicity, much lower with respect to other quinolone medicine, have good safety of medicine sexual clorminance ( mol. Pharmacol. 2001, 59:122).
In order to find good effect, do not produce the novel quinolone medicine of this class side effect, based on Murphy, S. the people's such as T. result of study, can develop safer, to there is broad spectrum antibiotic activity and good pharmacokinetic property Novel Quinolone microbiotic, thereby avoid the quinolone of some antibacterial effect excellences to occur this bad side reaction.
Summary of the invention
The object of this invention is to provide a kind of the have novel quinolone compounds of anti-microbial activity and pharmaceutically acceptable salt and hydrate thereof.
Another object of the present invention is to provide a kind of the have novel quinolone compounds of anti-microbial activity and the preparation method of acceptable salt and hydrate thereof pharmaceutically thereof.
Another object of the present invention be to provide a kind of have the novel quinolone compounds of anti-microbial activity and pharmaceutically acceptable salt and hydrate thereof in the application for the preparation for the treatment of and/or preventing in the medicine that infects the disease that causes or cause by bacterium.
General formula compound molecular structure of the present invention is as shown in following formula I:
R wherein 1for H or can be substituted containing the acyl group of C1 ~ C10;
R 2for H or can be substituted containing alkyl or the aralkyl of C1 ~ C10;
N is 1,2 or 3;
Q is 1,2 or 3.
In formula I of the present invention, the substituted radical of Carbostyril derivative C10 position can have one or more unsymmetrical carbons, and its possible optical isomer can be optically active body or racemic modification form.By standard technique of organic chemistry well known in the art, as synthesized or split to obtain corresponding optically active substance by racemic modification from chiral raw material.
Carbostyril derivative R in the logical formula I of formula of the present invention 1for H or can be substituted containing the acyl group of C1 ~ C10, described acyl group is selected from C1 ~ C10 alkanoyl, one or two or three halo C2 ~ C10 alkanoyls, C1 ~ C9 alkoxy carbonyl, formamyl, be selected from the aroyl of benzoyl and toluyl, be selected from aryl C1 ~ C4 alkanoyl of phenyl acetyl and phenyl propionyl, be selected from the aryloxycarbonyl of phenyloxycarbonyl, be selected from aryloxy C1 ~ C4 alkanoyl of phenoxy group ethanoyl and phenoxy group propionyl, be selected from the glyoxyl-based aryl of phenyl glyoxyl-based and be selected from benzyloxycarbonyl, styroyl oxygen base carbonyl and the optional substituted aryl C1 ~ C3 alkoxy carbonyl to nitro benzyloxycarbonyl.
In the application's context, being explained as follows in detail of the suitable example of various definition.
Except as otherwise noted, term used " rudimentary " refers to have 1 ~ 6, preferably the group of 1 ~ 4 carbon atom.
Suitable " acyl group " comprises lower alkane acyl group, such as formyl radical, ethanoyl, propionyl, caproyl, valeryl etc.; One (or two or three) halos (rudimentary) alkanoate, such as chloracetyl, trifluoroacetyl group etc.; Elementary alkoxy carbonyl, such as methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, tert-pentyloxy carbonyl, hexyloxy carbonyl etc.; Formamyl; Aroyl, such as benzoyl, toluyl etc.; Aryl (rudimentary) alkanoyl, such as phenyl acetyl, phenyl propionyl etc.], aryloxycarbonyl is [such as phenyloxycarbonyl etc.; Aryloxy (rudimentary) alkanoyl, such as phenoxy group ethanoyl, phenoxy group propionyl etc.], phenyl is glyoxyl-based; Aryl (rudimentary) alkoxy carbonyl optionally being replaced by suitable substituting group, such as benzyloxycarbonyl, styroyl oxygen base carbonyl, to nitro benzyloxycarbonyl etc.
In sum, R in logical formula I 1can be selected from that formyl radical, ethanoyl, propionyl, caproyl, valeryl, chloracetyl, trifluoroacetyl group, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, tert-pentyloxy carbonyl, hexyloxy carbonyl, formamyl, benzoyl, toluyl, phenyl acetyl, phenyl propionyl, phenyl are glyoxyl-based, benzyloxycarbonyl, styroyl oxygen base carbonyl, to nitro benzyloxycarbonyl.
Carbostyril derivative R in the logical formula I of formula of the present invention 2for H or can be substituted containing alkyl or the aralkyl of C1 ~ C10, in formula, described alkyl represents alkyl that can substituted C1 ~ C10; Described aralkyl represents can substituted arylmethyl, can substituted fragrant ethyl.
In logical formula I, suitable R 2for H or can be substituted containing alkyl or the aralkyl of C1 ~ C10, the described substituted radical that is selected from halogen atom, hydroxyl, cyano group, lower alkoxy, rudimentary alkyl-carbonyl, rudimentary alkoxy carbonyl, rudimentary alkylthio, amino, list or dibasic rudimentary alkylamino etc. that can the substituted alkyl containing C1 ~ C10 can contain; The substituted radical that maybe can contain the cyclic amino of 4 ~ 8 yuan, formamido group, rudimentary alkyl-carbonyl-amino, rudimentary alkoxycarbonyl amino, rudimentary alkyl sulfonyl amino etc. of 1 ~ 3 heterocyclic atom.
In sum, R in logical formula I 2preferred substituted radical is methyl, ethyl, propyl group, 1-methylethyl, 1-methyl-propyl, 2-methyl-propyl, 1-ethyl propyl, 2-ethyl propyl, butyl or hexyl.
Carbostyril derivative in the logical formula I of formula of the present invention, works as R 1and R 2for be H simultaneously, its chemical formula is:
In formula, n is 1,2 or 3; Q is 1,2 or 3.
Work as R 1during for H, in formula I of the present invention, the substituted radical of Carbostyril derivative C10 position can be as listed in following table 1:
The substituted radical structure list of table 1 C10 position
In the present invention, term " pharmacy acceptable salt " comprises the carboxylate salt forming with basic metal, as the salt of the mineral alkalis such as sodium, potassium, calcium, magnesium; With the carboxylate salt of organic bases formation, as meglumine, glucosamine, Trimethylamine, triethylamine, dicyclohexylamine, N, the salt of N-dibenzyl-1，2-diaminoethane, arginine, Methionin etc.; Additive salt with mineral acids such as hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid; With organic acid additive salt such as lactic acid, acetic acid, methylsulfonic acid, toxilic acid, succsinic acid, tartrate, citric acid, fumaric acid, oxalic acid, propanedioic acid, oxysuccinic acid, picric acid.
Quinolone compounds of the present invention and pharmaceutically acceptable salt and hydrate thereof, the salt that can enumerate has lactic acid salt, acetate, mesylate, maleate, succinate, tartrate, Citrate trianion, fumarate, oxalate, malonate, malate, picrate, hydrochloride, hydrobromate, nitrate, vitriol, phosphoric acid salt, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt, meglumine salt, glucosamine salt, trismethylamine salt, triethyl amine salt, dicyclohexyl amine salt, N, N-dibenzyl-1, 2-ethylenediamine salt, arginic acid salt, lysine salt.
In sum, the compound described in formula I of the present invention is more specifically selected from following compound:
( sthe fluoro-10-of)-9-(( s)-4-hydroxyl azepan-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID;
( sthe fluoro-10-of)-9-(( s)-4-hydroxyl azepan-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID L-arginine salt;
( sthe fluoro-10-of)-9-(( r)-4-hydroxyl azepan-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID;
( sthe fluoro-10-of)-9-(( r)-4-hydroxyl azepan-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID L-arginine salt;
( sthe fluoro-10-of)-9-(4-hydroxy piperidine-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID L-arginine salt tetrahydrate;
( sthe fluoro-10-of)-9-(4-hydroxy piperidine-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID L-arginine salt monohydrate;
( sthe fluoro-10-of)-9-(( s)-3-hydroxyl pyrroles-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID 0.75 hydrate;
( sthe fluoro-10-of)-9-(( s)-3-hydroxyl pyrroles-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID methyl esters;
( sthe fluoro-10-of)-9-(3-hydroxy azetidine-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID L-arginine salt.
The present invention also provides a kind of method of preparing formula I compound; described method comprises: the linked reaction of carrying out formula III compound and formula IV compound under the existence of acid binding agent obtains formula (V) compound; and from formula (V) compound decarboxylize blocking group (X), and/or through becoming ester or reaction to obtain formula I compound:
R wherein 1for H or can be substituted containing the acyl group of C1 ~ C10; R 2for H or can be substituted containing alkyl or the aralkyl of C1 ~ C10; N is 1,2 or 3; Q is 1,2 or 3; X is the carboxy protective group of boracic.
The method concrete steps are to exist at acid binding agent alkali; at room temperature to 200 ℃ temperature, make formula III compound and the reaction of formula IV compound; carry out preparation formula (V) compound, then remove the boron-containing group protecting group of formula (V) compound.
First, by under solvent exists and add suitable alkali, at room temperature to 200 ℃ temperature, make formula III compound and the reaction of formula IV compound, prepare intermediate formula (V) compound.
As the solvent of above-mentioned reaction, can use any solvent that reaction is had no adverse effects, preferably use pyridine, acetonitrile, dimethyl formamide, dimethyl sulfoxide (DMSO), N-Methyl pyrrolidone or hexamethylphosphoramide.
This reaction is generally carried out under acid binding agent exists.In order to improve the reaction efficiency of initiator (III), use excessive reactant (IV), for example initiator (III) is equimolar amount to 10 times molar weight relatively, preferably equimolar amount to 5 times molar weight.When using excess reactant (IV), the unreacted formula IV compound staying after reaction can reclaim and be reused for another reaction.The acid binding agent that is preferred for this reaction comprises that mineral alkali is as sodium bicarbonate and salt of wormwood etc., with following organic bases: pyridine, triethylamine, diisopropylethylamine, N, accelerine, N, N-dimethyl aminopyridine, 1,8-diazabicyclo [[5.4.0] 11 carbon-7-alkene or Isosorbide-5-Nitrae-diazabicyclo [2.2.2] octane.
Secondly, carry out the reaction of the boron-containing group protecting group of removal formula (V) compound, this reaction can, according to the relevant nature of protecting group X, be removed by hydrolysis.For example, can be in solvent having acid or alkali to process at 0 ~ 130 ℃ of temperature under existing, slough protecting group.The acid that can be used for this object comprises mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid etc.; Organic acid is as acetic acid, trifluoroacetic acid, formic acid, toluenesulphonic acids etc.; Or Lewis acid is as boron tribromide, aluminum chloride etc.For the alkali of this object, can use the oxyhydroxide of basic metal or alkaline-earth metal, as sodium hydroxide, potassium hydroxide, hydrated barta etc.; Alkaline carbonate is as sodium carbonate, salt of wormwood etc.; Alkali metal alcoholates is as sodium methylate, sodium ethylate etc.Reaction can be carried out under solvent exists, and for example, water or organic solvent are as ethanol, tetrahydrofuran (THF), dioxan, ethylene glycol, acetic acid etc., or the mixture of this organic solvent and water, and as needs, this reaction also can be carried out under existing without any solvent.
Formula III compound preparation of the present invention can be used the protection reagent react of formula II compound and boracic to obtain, as shown in following reaction scheme:
The carboxy protective group that wherein X is boracic.
Preparation method is under the existence of zinc chloride, and formula II compound, boric acid and organic acid are if acetic acid, propionic acid, trifluoroacetic acid or organic acid anhydride are as reactions such as diacetyl oxide, propionic anhydride, trifluoroacetic anhydrides.The compound of the relative formula II of amount of boric acid used is 1.1 ~ 2 molar equivalents, the boric ester derivative obtaining (III)
Specifically, the novel quinolone compounds with anti-microbial activity of the present invention be from the available raw material of commercialization ( s)-9, the fluoro-3-methyl-7-of 10-bis-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID ethyl ester (II) sets out, under zinc chloride catalysis, react with boric acid and acetic anhydride obtain two (acetyl- o) [(3 s)-9,10-bis-is fluoro-2,3-dihydro-3-methyl-7-dihydro-7 h-pyridine [1,2,3- de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylicesters- o 6, o 7] boron (III ＇) (step a); Intermediate (III ＇) reacts and obtains corresponding coupled product (V ＇) (step b) with the unhindered amina side chain (IV) (or its hydrochloride) of C10 position under organic bases exists; (4) react with aqueous acetic acid and obtain dissociating accordingly quinolone carboxylic acid (VI) (step c); Free quinolone carboxylic acid (VI) can further generate derivative (the I) (step d) such as corresponding salt or ester through modification reaction.
The present invention also provides a kind of pharmaceutical composition, and it contains novel quinolone compounds and one or more pharmaceutical carriers and/or the thinner with anti-microbial activity of the present invention.
Said carrier refers to the pharmaceutical carrier of pharmaceutical technology routine, and tackiness agent is as derivatived cellulose, gelatin or polyvinylpyrrolidone etc.; Weighting agent is as starch etc.; Burst apart agent as calcium carbonate or sodium bicarbonate; Thinner is as water etc.; In addition, can also in composition, add other auxiliarys as flavouring agent and/or sweeting agent.
When oral, can be prepared into conventional solid preparation as tablet, pulvis or capsule etc.; While being used for injecting, can be prepared into injection liquid.
The various formulations of composition of the present invention can adopt the method for medical field routine to be prepared.The composition that compound of the present invention and above-mentioned carrier form, can put on the patient who needs this treatment by intravenous injection, subcutaneous injection or oral form.
Pharmaceutical composition exists to be applicable to medicinal dosage form.Medicinal preparation is selected from tablet, sugar coated tablet, film coated tablet, enteric coated tablet, slow releasing tablet, capsule, hard capsule, soft capsule, slow releasing capsule, oral liquid, mixture, sucks agent, granule, electuary, pill, powder, paste, sublimed preparation, suspensoid, solution, injection, powder injection, lyophilized injectable powder, suppository, ointment, plaster, creme, sprays, aerosol, drops, patch.
In the formulation of aforementioned pharmaceutical compositions, preferably injection or oral preparations.
Pharmaceutical composition of the present invention being prepared into pulvis, tablet, dispersible pulvis, when the solid of capsule, cachet, suppository and ointment or semisolid pharmaceutical formulation, can use solid carrier.Spendable solid-state carrier is preferably selected from one or more materials in thinner, seasonings, solubilizing agent, lubricant, suspension agent, tackiness agent, swelling agent etc., or can be encapsulating substance.In powderous preparations, in carrier, contain 5% or the micronize activeconstituents of 10-70%.Suitable solid carrier is selected from magnesiumcarbonate, Magnesium Stearate, talcum, sucrose, lactose, pectin, dextrin, starch, gelatin, Huang and has a liking for one or more in glue, methylcellulose gum, shuttle sodium carboxymethylcellulose pyce, lower boiling wax, theobroma oil etc.Because they are easy to administration, tablet, pulvis, cachet and capsule represent best oral solid formulation.
Liquid preparation of the present invention comprises solution, suspension and emulsion.For example, the injectable formulation of parenteral administration can be water or water---propylene glycol solution form, regulate its degree of oozing such as grade, and pH etc. make to be suitable for the physiological condition of live body.Liquid preparation also can be made into the solution form in polyoxyethylene glycol, the aqueous solution.Can be by activeconstituents is dissolved in water, then add suitable tinting material, seasonings, stablizer and thickening material, prepare oral aqueous solution.Micronized activeconstituents can be dispersed in to viscous substance as prepared and be suitable for oral aqueous suspensions in natural or synthetical glue, methylcellulose gum, glue sodium carboxymethylcellulose pyce and other known suspension agent.
For ease of administration and dosage homogeneous, it is particularly advantageous that said medicine preparation is mixed with to dosage unit form.The dosage unit form of preparation refers to be suitable for the physical sepn unit as single dose, the activeconstituents that each unit contains the predetermined amount calculating that produces desired result for the treatment of.This dosage unit form can be packaged form, as tablet, capsule be contained in tubule or bottle in pulvis, be contained in pipe or bottle in ointment, gel or creme.
Quinolone carboxylic acid derivatives provided by the invention is applied in preparation and prevents and/or treats in bacterial infection disease medicine.
In the application of above-claimed cpd, described bacterial infection disease is selected from Sepsis, warts disease, pneumonia, bronchitis, pharyngolaryngitis, endocarditis, urinary tract infections, gastrointestinal tract infection, skin infections, microbemia, pyelonephritis, urocystitis, wound infection, multiple folliculitis.
The compounds of this invention has stronger anti-microbial activity and wide antimicrobial spectrum to comprising the various pathogenic organisms of Gram-negative bacteria and gram positive bacterial strain.The compounds of this invention is as higher in the activity of levofloxacin and Ciprofloxacin to the anti-microbial activity of gram negative strain and known antimicrobial agents, and particularly, the compounds of this invention is the activity far above known antimicrobial agents to the anti-microbial activity of streptococcus aureus.
Quinolone compounds of the present invention or its salt or hydrate also can be prepared by becoming known for preparing the method for related compound, in an embodiment, have also enumerated some representative methods, wherein, unless otherwise stated, n, q, R 1, R 2there is any implication defining for formula I quinolone derivative above, also described in an embodiment the preparation of raw material, or obtain necessary raw material by the similar approach of prior art.
Embodiment
The present invention is described by the following specific embodiments, can better understand the present invention, but scope of the present invention is not subject to the restriction of these embodiment by specific embodiment:
Embodiment 1:(S) the fluoro-10-of-9-(4-hydroxy piperidine-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1, the preparation of 4] oxazine [2,3,4-ij] QUINOLINE-6-CARBOXYLIC ACID L-arginine salt tetrahydrates (Q1)
Step (a): in dry there-necked flask, add boric acid (48.00g), diacetyl oxide (220ml) and zinc chloride (0.88g), stirring at room 30min, add afterwards ( s)-9, the fluoro-3-methyl-7-of 10-bis-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID ethyl ester (1) is (80.00g) in above-mentioned solution, 60 ℃ are reacted 16h, and concentrating under reduced pressure, slowly adds methylene dichloride (2200ml) in enriched material, use saturated NaHCO 3solution washing (2 * 1400ml), separatory, organic layer NaCl solution washing, anhydrous Na 2sO 4dry, to filter, filtrate is concentrated obtains solid, then adds anhydrous diethyl ether 900ml, stirs 30min, filters, that solid vacuum-drying obtains is two (acetyl- o) [(3 s)-9,10-bis-is fluoro-2,3-dihydro-3-methyl-7-dihydro-7 h-pyridine [1,2,3- de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylicesters- o 6, o 7] boron (2) 87.67g, productive rate 83%.
1H?NMR?(CDCl 3,?400MHz)? δ:?1.74?(d,? J?=?6.8?Hz,3H)，1.90?(s,?3H)，2.05?(s,?3H)，4.55?(dd,? J?=?12.2,?2.4?Hz,?1H)，4.62?(dd,? J?=?12.2,?2.4?Hz,?1H)，5.11-5.19?(m,?1H)，7.90?(dd,? J?=9.8,?7.3?Hz,?1H)，9.25?(s,?1H)。
Ultimate analysis (C 17h 14bF 2nO 8) measured value (calculated value, %): C49.90(49.91); H3.46(3.45); N3.41(3.42).
Step (b): in dry there-necked flask, add two (acetyl- o) [(3 s)-9,10-bis-is fluoro-2,3-dihydro-3-methyl-7-dihydro-7 h-pyridine [1,2,3- de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylicesters- o 6, o 7] boron (2) (10.00g), 4-hydroxy piperidine (4.44g) and triethylamine (2.96g), then add acetonitrile 150ml, 65 ℃ of reaction 3h, are evaporated to dryly, slowly add methylene dichloride (150ml) and water (150ml) in enriched material, separatory, organic layer NaCl solution washing, anhydrous Na 2sO 4dry, to filter, filtrate is concentrated obtains yellow solid 11.70g, and crude product productive rate 98% directly drops into step (c) reaction.
Step (c): above-mentioned steps (b) gained solid (11.70g) reacts 2h with 80 ℃ of 5% aqueous acetic acids (167ml), filters, and filter cake washes with water, vacuum-drying, recrystallization in gained solid chloroform, obtain ( sthe fluoro-10-of)-9-(4-hydroxy piperidine-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID (Q1) 6.63g, productive rate 75%.
1H?NMR?(400?MHz,?DMSO- d 6)?δ：15.21?(s,?1H),?8.94?(s,?1H),?7.56?(d,? J?=?12.3?Hz,?1H),?4.91?(q,? J?=?6.7?Hz,?1H),?4.68?(s,?1H),?4.57?(dd,? J?=?11.5,?1.7?Hz,?1H),?4.37?(dd,? J?=?11.4,?2.2?Hz,?1H),?3.73?–?3.59?(m,?1H),?3.52?–?3.36?(m,?2H),?3.23?–?3.05?(m,?2H),?1.84?(dd,? J?=?8.4,?3.9?Hz,?2H),?1.60?–?1.47?(m,?2H),?1.45?(d,? J?=?6.8?Hz,?3H).
Ultimate analysis (C 18h1 9fN 2o 5) measured value (calculated value, %): C 58.90(59.66), H 5.25(5.29), N 7.48(7.73).
Step (d): in dry there-necked flask, add ( sthe fluoro-10-of)-9-(4-hydroxy piperidine-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID (6.63g), water (34ml) and acetone (40ml), stir and start to add L-arginine (3.19g) again, 60 ℃ of reaction 1h, add gac 1g, equality of temperature stirs 30min, filters, and concentrating under reduced pressure is removed acetone, at room temperature in enriched material, slowly add Virahol (120ml), stirring at room 1 hour, filters, vacuum-drying obtain ( sthe fluoro-10-of)-9-(4-hydroxy piperidine-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID L-arginine salt tetrahydrate (Q1) 4.30g, productive rate 39%.
1H?NMR?(400?MHz,DMSO- d 6?)?δ:?8.79?(s,?1H),?7.95?(s,?4H),?7.52?(d,? J?=?12.5?Hz,?1H),?7.16?(s,?2H),?4.87?–?4.77?(m,?1H),?4.54?(dd,? J?=?11.4,?1.7?Hz,?1H),?4.34?(dd,? J?=?11.3,?2.2?Hz,?1H),?3.65?(ddd,? J?=?12.8,?8.6,?3.8?Hz,?1H),?3.44?–?3.34?(m,?3H),?3.18?–?2.94?(m,?6H),?1.83?(dd,? J?=?7.9,?3.7?Hz,?2H),?1.63?–?1.45?(m,?6H),?1.43?(d,? J?=?6.7?Hz,?3H).
Ultimate analysis (C 24h 41fN 6o 11) measured value (calculated value, %): C 47.51(47.36), H 6.88(6.79), N 14.00(13.81).
Karl Fischer method is measured water content: 11.80%.
Embodiment 2:(S) the fluoro-10-of-9-((S)-3-hydroxyl pyrroles-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1, the preparation of 4] oxazine [2,3,4-ij] QUINOLINE-6-CARBOXYLIC ACID 0.75 hydrates (Q2)
Step (a) is with embodiment 1 step (a).
Step (b): in dry there-necked flask, add two (acetyl- o) [(3 s)-9,10-bis-is fluoro-2,3-dihydro-3-methyl-7-dihydro-7 h-pyridine [1,2,3- de] [Isosorbide-5-Nitrae] benzoxazine-6-carboxylicesters- o 6, o 7] boron (2) (8.00g), ( s)-3-hydroxyl pyrroles's hydrochloride (3.63g) and triethylamine (5.94g), then add acetonitrile 120ml, 75 ℃ of reaction 3h, be evaporated to dryly, in enriched material, slowly add methylene dichloride (150ml) and water (150ml), separatory, organic layer NaCl solution washing, anhydrous Na 2sO 4dry, to filter, filtrate is concentrated obtains yellow solid 9.29g, and crude product quantitative yield directly drops into step (c) reaction.
Step (c): above-mentioned steps (b) gained solid (9.29g) reacts 6h with 80 ℃ of 5% aqueous acetic acids (133ml), filters, and filter cake washes with water, vacuum-drying, gained solid recrystallization in chloroform, obtain ( sthe fluoro-10-of)-9-(( s)-3-hydroxyl pyrroles-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID 5.70g, productive rate 84%.
1H?NMR?(400?MHz,?DMSO- d 6)?δ:?14.33?(s,?1H),?8.85?(s,?1H),?7.51?(d,? J?=?14.3?Hz,?1H),?4.92?(s,?1H),?4.86?(dd,? J?=?13.2,?6.5?Hz,?1H),?4.51?(dd,? J?=?11.3,?1.3?Hz,?1H),?4.34?(s,?1H),?4.26?(dd,? J?=?11.3,?1.8?Hz,?1H),?4.05?–?3.82?(m,?2H),?3.62?(dd,? J?=?9.4,?7.8?Hz,?1H),?3.40?(d,? J?=?10.7?Hz,?1H),?1.99?–?1.86?(m,?1H),?1.86?–?1.72?(m,?1H),?1.45?(d,? J?=?6.7?Hz,?3H)。
Ultimate analysis (C 17h 17fN 2o 5) measured value (calculated value, %): C 58.64(58.62), H 4.94(4.92), N 7.99(8.04).
Step (d): in dry there-necked flask, add ( sthe fluoro-10-of)-9-(( s)-3-hydroxyl pyrroles-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID (8.00g) and ethanol (470ml), post-heating to the 100 ℃ dissolving that stirs, adds gac 1g, and equality of temperature stirs 30min, filter, filtrate is cooled to room temperature, more slowly adds water (470ml), is cooled to afterwards 0 ℃ and stirs 2.5h, filter, filter cake washing with alcohol, 45 ℃ of vacuum-dryings, obtain ( sthe fluoro-10-of)-9-(( s)-3-hydroxyl pyrroles-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID 0.75 hydrate (Q2) 4.06g, yield 49%.
1H?NMR?(400?MHz,?DMSO- d 6?)?δ:?14.76?(s,?1H),?8.84?(s,?1H),?7.48?(d,? J?=?14.3?Hz,?1H),?4.93?(s,?1H),?4.86?(d,? J?=?6.2?Hz,?1H),?4.52?(d,? J?=?11.2?Hz,?1H),?4.34?(s,?1H),?4.26?(d,? J?=?11.0?Hz,?1H),?4.08?–?3.85?(m,?2H),?3.62?(s,?1H),?3.40?(d,? J?=?10.7?Hz,?1H),?2.05?–?1.87?(m,?1H),?1.86?–?1.72?(m,?1H),?1.46?(d,? J?=?6.5?Hz,?3H)。
Ultimate analysis (C 17h 18.5fN 2o 5.75) measured value (calculated value, %): C 57.24(56. 43), H 4.86(5.15), N 7.12(7.74).
Karl Fischer method is measured water content: 3.71%.
Embodiment 3:( sthe fluoro-10-of)-9-(( s)-3-hydroxyl pyrroles-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] preparation of QUINOLINE-6-CARBOXYLIC ACID methyl esters (Q3)
Step (a) and (b) and (c) with embodiment 2 step (a) and (b) and (c).
Step (d): in dry there-necked flask room temperature add ( sthe fluoro-10-of)-9-(( s)-3-hydroxyl pyrroles-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID (8.00g), K 2cO 3(6.36g) and DMF(46ml), after stirring, add CH 3i(4.90g), reheat to 50 ℃ of reaction 8h, be cooled to room temperature, add ethyl acetate (100ml) and water (50ml), separatory, ethyl acetate for water (100ml) extraction, separatory, merges organic phase, organic phase water (200ml) washing, saturated aqueous common salt (200ml) washing, Na 2sO 4dry, to filter, filtrate concentrates to obtain crude product, and crude product recrystallization in ethanol obtains 6.52g product (Q3), yield 78%.
1H?NMR?(400?MHz,?DMSO- d 6?)?δ:?8.84?(s,?1H),?7.48?(d,? J?=?14.3?Hz,?1H),?4.93?(s,?1H),?4.86?(d,? J?=?6.2?Hz,?1H),?4.52?(d,? J?=?11.2?Hz,?1H),?4.34?(s,?1H),?4.26?(d,? J?=?11.0?Hz,?1H),?4.08?–?3.85?(m,?2H),?3.77?(s,?3H)，3.62?(s,?1H),?3.40?(d,? J?=?10.7?Hz,?1H),?2.05?–?1.87?(m,?1H),?1.86?–?1.72?(m,?1H),?1.46?(d,? J?=?6.5?Hz,?3H)。
Ultimate analysis (C 18h 19fN 2o 5) measured value (calculated value, %): C 59.62(59.66), H 5.20(5.29), N 7.79(7.73).
Embodiment 4: antibacterial activity in vitro determination experiment
1. experiment material and instrument
1.1 a) gram-positive microorganisms: streptococcus aureus CMCC26112, the streptococcus aureus of clinical separated methicillin-sensitivity (MSSA); The streptococcus aureus of clinical separated methicillin resistance (MRSA); Methicillin resistance staphylococcus epidermidis (MRSE).B) Gram-negative bacteria: intestinal bacteria CMCC44113; Pseudomonas aeruginosa CMCC10211.
1.2 substratum: M-H (Muller-Hinton) susceptibility nutrient agar (the wherein M-H substratum of 5% defiber sheep blood for streptococcus pneumoniae and enterococcus faecalis) and M-H meat soup dehydrated medium (French Biomerieux SA).
1.3 testing compounds: the compound of preparing according to embodiment 1 to embodiment 3: Q1, Q2, Q3.
1.4 positive control medicines: ciprofloxacin HCl, levofloxacin hydrochloride, vancomycin hydrochloride (Nat'l Pharmaceutical & Biological Products Control Institute).
1.5 test apparatuses: ES02 type multiple spot inoculation instrument (Japan); QMI300SVBA type CO2gas incubator (U.S.); DESICHEKIDK214408 type is than turbid instrument.
2. test method
Measure MICs of antibiotic is measured: the agar doubling dilution that (Minimal Inhibitory Concentration MIC) adopts U.S. CLSI (standard committee of American National clinical labororatory) to recommend, with 0.9% sodium chloride solution, testing drug is dissolved, after two-fold dilution, it is 128～0.016 μ gL that liquid and M-H substratum are mixed into concentration in proportion -1a series of pastilles dull and stereotyped.From hatching the agar plate of 18～24h, choose 3～5 bacterium colonies, with 0.9% sodium chloride solution dilution, put bacterium and regulate bacterial concentration Wei0.5 Maxwell unit (1 * 10 than turbid instrument 8～2 * 10 8cFU/ml), redilution is 10 times (10 7), with the dibbling of multiple spot inoculation instrument, bacterial load is 10 4cFU/ point.Hatch 18～24h for 35 ℃; Every batch of test compares with respective standard bacterial strain.Judging criterion by version CLSI in 2009, judges drug susceptibility.
3. experimental result
The antibacterial activity in vitro of table 2 the compounds of this invention and positive control (MIC, μ g/mL)
As seen from Table 2: in the antibacterial activity in vitro test of selected 27 kinds of bacterial strains, testing compound Q1 and Q2 show stronger activity, especially to Resistant strain, show the activity stronger than positive control drug.Particularly 1 pair of gram-positive microorganism of compound Q (G (+)) and Gram-negative bacteria (G (-)) show the anti-microbial activity compared with balance, it is the more than 8 times of levofloxacin hydrochloride to streptococcus aureus CMCC26112 anti-microbial activity, is the more than 32 times of Ciprofloxacin activity; Particularly to MRSA activity be levofloxacin hydrochloride and Ciprofloxacin 2000 times or more than.In Gram-negative bacteria, this compound is the more than 2 times of levofloxacin hydrochloride activity to intestinal bacteria CMCC44113 activity, is the more than 8 times of ciprofloxacin HCl activity; To Pseudomonas aeruginosa CMCC10211 activity, be the more than 8 times of levofloxacin hydrochloride activity, be worth further research and development.
Above-described embodiment is preferably embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification made under spirit of the present invention and principle, substitutes, combination, simplify; all should be equivalent replacement mode, within being included in protection scope of the present invention.

Claims (12)

1. the following quinolone compounds of a class general formula, its pharmaceutically acceptable salt or their hydrate:
R wherein 1for H or can be substituted containing the acyl group of C1 ~ C10;
R 2for H or can be substituted containing alkyl or the aralkyl of C1 ~ C10;
N is 1,2 or 3;
Q is 1,2 or 3.
2. quinlone compound as claimed in claim 1, its pharmaceutically acceptable salt or their hydrate, R in described logical formula I 1be selected from that formyl radical, ethanoyl, propionyl, caproyl, valeryl, chloracetyl, trifluoroacetyl group, methoxycarbonyl, ethoxy carbonyl, tert-butoxycarbonyl, tert-pentyloxy carbonyl, hexyloxy carbonyl, formamyl, benzoyl, toluyl, phenyl acetyl, phenyl propionyl, phenyl are glyoxyl-based, benzyloxycarbonyl, styroyl oxygen base carbonyl, to nitro benzyloxycarbonyl.
3. quinlone compound as claimed in claim 1, its pharmaceutically acceptable salt or their hydrate, R in described logical formula I 2be selected from methyl, ethyl, propyl group, 1-methylethyl, 1-methyl-propyl, 2-methyl-propyl, 1-ethyl propyl, 2-ethyl propyl, butyl or hexyl.
4. quinlone compound as claimed in claim 1, its pharmaceutically acceptable salt or their hydrate, R in described logical formula I 1for H; R 2for H.
5. quinolone compounds as claimed in claim 1, it is acceptable salt or their hydrate pharmaceutically, described salt is selected from lactic acid salt, acetate, mesylate, maleate, succinate, tartrate, Citrate trianion, fumarate, oxalate, malonate, malate, picrate, hydrochloride, hydrobromate, nitrate, vitriol, phosphoric acid salt, sodium salt, sylvite, calcium salt, magnesium salts, zinc salt, meglumine salt, glucosamine salt, trismethylamine salt, triethyl amine salt, dicyclohexyl amine salt, N, N-dibenzyl-1, 2-ethylenediamine salt, arginic acid salt, lysine salt.
6. quinlone compound as claimed in claim 1, its pharmaceutically acceptable salt or their hydrate, it is selected from: the fluoro-10-of (S)-9-(4-hydroxy piperidine-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazines [2,3,4-ij] QUINOLINE-6-CARBOXYLIC ACID L-arginine salt tetrahydrate.
7. quinlone compound as claimed in claim 1, its pharmaceutically acceptable salt or their hydrate, it is selected from: ( sthe fluoro-10-of)-9-(( s)-3-hydroxyl pyrroles-1-yl)-3-methyl-7-carbonyl-3,7-dihydro-2H-[1,4] oxazine [2,3,4- ij] QUINOLINE-6-CARBOXYLIC ACID 0.75 hydrate.
8. the method for a preparationⅠcompound; described method comprises: the linked reaction of carrying out formula III compound and formula IV compound under the existence of acid binding agent obtains formula V compound; and from formula V compound decarboxylize blocking group X, and/or through becoming ester reaction to obtain formula I compound:
R wherein 1for H or can be substituted containing the acyl group of C1 ~ C10; R 2for H or can be substituted containing alkyl or the aralkyl of C1 ~ C10; N is 1,2 or 3; Q is 1,2 or 3; X is the carboxy protective group of boracic.
9. pharmaceutical composition, contains any one compound and one or more pharmaceutical carriers and/or the thinner in claim 1 ~ 7.
10. pharmaceutical composition as claimed in claim 9, it is injection or oral preparations.
11. prevent and/or treat the application in bacterial infection disease medicine in preparation as any one the compound in claim 1 ~ 7.
The application of 12. compounds as claimed in claim 11, described bacterial infection disease comprises Sepsis, warts disease, pneumonia, bronchitis, pharyngolaryngitis, endocarditis, urinary tract infections, gastrointestinal tract infection, skin infections, microbemia, pyelonephritis, urocystitis, wound infection, multiple folliculitis.
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CN104817572A (en) * 2015-04-24 2015-08-05 河南大学 Chiral aminomethyl aminomethyl triazole substituted tricyclic fluoroquinolone carboxylic acid derivative and preparation method and applications thereof
CN104910177A (en) * 2015-04-24 2015-09-16 河南大学 Aminomethyl triazole-substituted tricyclic fluoroquinolone carboxylic acid derivative and preparation method and application thereof
CN107586302A (en) * 2017-11-03 2018-01-16 梯尔希（南京）药物研发有限公司 A kind of Ofloxacin impurity D preparation method

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CN104817572A (en) * 2015-04-24 2015-08-05 河南大学 Chiral aminomethyl aminomethyl triazole substituted tricyclic fluoroquinolone carboxylic acid derivative and preparation method and applications thereof
CN104910177A (en) * 2015-04-24 2015-09-16 河南大学 Aminomethyl triazole-substituted tricyclic fluoroquinolone carboxylic acid derivative and preparation method and application thereof
CN104817572B (en) * 2015-04-24 2017-02-01 河南大学 Chiral aminomethyl aminomethyl triazole substituted tricyclic fluoroquinolone carboxylic acid derivative and preparation method and applications thereof
CN104910177B (en) * 2015-04-24 2017-02-22 河南大学 Aminomethyl triazole-substituted tricyclic fluoroquinolone carboxylic acid derivative and preparation method and application thereof
CN107586302A (en) * 2017-11-03 2018-01-16 梯尔希（南京）药物研发有限公司 A kind of Ofloxacin impurity D preparation method

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